Abstract
This study explores the effects of the Mediterranean diet, herbal remedies, and their phytochemicals on various gastrointestinal conditions and reviews the global use of medicinal plants for common digestive problems. The review highlights key plants and their mechanisms of action and summarizes the latest findings on how plant-based products influence the digestive system and how they work. We searched various sources of literature and databases, including Google Scholar, PubMed, Science Direct, and MedlinePlus. Our focus was on gathering relevant papers published between 2013 and August 2023. Certain plants exhibit potential in preventing or treating digestive diseases and cancers. Notable examples include Curcuma longa, Zingiber officinale, Aloe vera, Calendula officinalis, Lavandula angustifolia, Thymus vulgaris, Rosmarinus officinalis, Ginkgo biloba, Cynodon dactylon, and Vaccinium myrtillus. The phytochemical analysis of the plants showed that compounds such as quercetin, anthocyanins, curcumin, phenolics, isoflavones glycosides, flavonoids, and saponins constitute the main active substances within these plants. These natural remedies have the potential to enhance the digestive system and alleviate pain and discomfort in patients. However, further research is imperative to comprehensively evaluate the benefits and safety of herbal medicines to use their active ingredients for the development of natural and effective drugs.
1 Introduction
Globally, digestive disorders are widespread, often frustrating, and occasionally life threatening. In 2019, digestive disorders accounted for 2276.27 million predicted prevalent cases, 2.56 million fatalities, and 88.99 million disability-adjusted life-years worldwide [1]. Some digestive disorders and ailments are acute, lasting only a short period, while others are chronic, persisting over the long term. Common symptoms of digestive disorders, including bleeding, bloating, constipation, diarrhea, heartburn, incontinence, abdominal discomfort, swallowing, weight gain or loss, nausea, and vomiting [2]. Regrettably, most people suffer from gut and digestive system issues virtually from birth. Common digestive disorders include gastroesophageal reflux disease (GERD), irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), colorectal cancer (CRC), peptic ulcer disease (PUD), as well as lactose intolerance, hiatal hernia, liver disease (LD), pancreatitis, heartburn, and cancer (Figure 1) [3]. While conventional medications are commonly used to treat digestive disorders, they come with inherent risks. These drugs often yield adverse effects such as nausea, vomiting, and diarrhea. Moreover, certain oral medications may negatively impact the digestive tract, leading to esophageal strictures, ulcers, bleeding, and constriction. When multiple medications are administered concurrently, the potential for interactions increases significantly. These interactions can lead to adverse effects, including food allergies, sensitivities, and exacerbation of existing conditions such as diabetes, renal illness, or LD [4,5]. Alternative medicine offers a wealth of treatment possibilities. Natural substances and their structural analogs have significantly influenced pharmacotherapy in the past. The quest for scaffolds exhibiting a wide range of bioactivities and substantial structural diversity remains feasible through the use of natural products. These scaffolds can be either directly produced or serve as building blocks for the development of novel drugs. However, natural products face persistent challenges due to high attrition rates in medication research. Factors such as sustainable supply, accessibility, and intellectual property restrictions add complexity to their utilization. Fortunately, recent scientific and technological advancements are addressing these concerns and opening up new opportunities [6].
Common digestive disorders. CD: Crohn’s disease; UC: ulcerative colitis; IBS: irritable bowel syndrome; GERD: gastroesophageal reflux disease; PUD: peptic ulcer disease.
The Mediterranean flora includes numerous aromatic and diverse medicinal plants that have long been an integral part of local culture, representing a wide range of ecological contexts [7,8]. Among the plants that are traditionally used in the Mediterranean Basin, species from the Lamiaceae, Asteraceae, and Apiaceae families are the most prevalent. Notably, some of these plants have already been examined for their pharmacological properties, including sage, rosemary, thyme, oregano, lavender, and other Lamiaceae species [9]. Natural bioactive compounds have been used for food and medicine purposes since prehistoric times. People have employed plants in traditional recipes to improve nutrition and overall health. Interestingly, many contemporary medications are rooted in the traditional knowledge of plant-based medicinal potential. The overwhelming majority of the population (approximately 80%, particularly in developing countries) continues to rely on plant-based traditional medicines for basic health care needs [10]. These digestive plant preparations operate through various mechanisms, including healing the intestine lining, activating the mechanical and chemical digestion, as well as promoting smooth bowel movements, enhancing bowel frequency, detoxifying and eliminating toxins, and soothing upset stomach. Furthermore, they play a role in reducing gas, bloating, and other digestive problems. Medicinal plants likely represent the earliest form of medication, having been utilized by diverse societies throughout history. They have been utilized by many societies throughout history and continue to be an important element of our current technological advanced society. Plant-derived pharmaceuticals or natural compounds and their derivatives account for over than half of all clinically used medications [11].
Medicinal plants and phytomedicines offer several benefits, including their natural origin, minimal side effects, and avoidance of dissatisfaction associated with conventional medication [12]. A recent study provides compelling evidence that various functional food types such as probiotics, prebiotics, and herbs may have a favorable impact on the digestive tract [13]. Probiotics are likely to be beneficial in the prevention of IBD, whereas prebiotics include fibers that may inhibit the development of IBD [14,15,16]. Triangles, elm, and pie plant are herbs that may be associated with alleviating symptoms of IBDs. Mastic, herbal origin, may help manage heartburn, which is a common symptom of GERD [17]. Blueberries have been shown to lessen diarrhea, a frequent sign of gastrointestinal illnesses [18]. A double-blind experiment revealed that Aloe vera alleviated symptoms of persistent constipation [19]. In addition, A. vera syrup showed promise in managing GERD in a preliminary randomized positive-controlled experiment [20]. The bioactive components of Mediterranean diet (MD) known for their health benefits found to reduce chronic inflammation by influencing C-reactive protein, interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) [21]. Recent analysis suggests that inflammation-induced platelet-activating factor plays a pivotal role in initiating cardiovascular diseases (CVD) rather than a mere rise in blood cholesterol levels [22]. Given the link between diet and gastrointestinal health, further research is needed to explore the potential impact of specific functional foods and bioactive substances synergistically present in the MD [23]. More clinical and epidemiological studies are essential to unravel the intricate role of nutrition and bioactive chemicals in gastrointestinal illnesses to promote the consumption of functional foods [23].
The purpose of the current review is to explore the diverse mechanisms of action associated with herbal-based medicine and the MD, along with their active components, specifically concerning the digestive system. In addition, we highlight their potential advantages for human health, particularly in the prevention and treatment of digestive disorders such as GERD, IBS, IBD, CRC, and PUD. Our focus lies on identifying the most prevalent and effective active compounds and compiling a list of important medicinal herbs.
2 MD
The traditional MD emerged in the nations of the Mediterranean Basin, where a warm and pleasant environment supports the cultivation of a wide variety of fruits and vegetables all year. Consequently, the MD is characterized by an abundance of these fruits and vegetables, along with the prominent use of extra virgin olive oil as the primary source of fat. Legumes, whole grains, nuts, seeds, and fragrant herbs also play a vital role in this dietary pattern [24,25]. Today, the phrase “MD” broadly refers to the typical eating practices of nations bordering the Mediterranean Sea. However, it is essential to recognize that historically, the Greek term “diaita” referred to more than just daily dietary habits. It encompassed a complete way of life, aligning with modern concepts of lifestyle and well-being [26]. Recent studies demonstrate that these components may have health advantages such as protection against and prevention of significant health issues such as diabetes, CVD, skin disease, digestive disease, and aging [10,27]. Active substances derived from MD such as polyphenols, omega-3 fatty acids, carotenoids, vitamins, folate, magnesium, aromatic compounds (e.g., rosmarinic acid), and curcumin are proven for their protective as well as therapeutic effects on the aforementioned disorders (Table 1). Interestingly, plants synthesize an estimated 100,000 of these organic compounds, yet only 10% of them have been identified. These metabolites fall into three categories: terpenes, phenolics, and alkaloids (nitrogen-containing chemicals), each with therapeutic effects. Flavonoids, found in blueberries, strawberries, grapes, melons, citrus fruits, apricots, onions, cabbage, fennel, tomatoes, lettuce, broccoli, spinach, and other foods, as well as frequent yogurt eating appear to reduce the probability of developing several tumors [24,25]. The active compounds found in medicinal and aromatic plants vary greatly based on the portion of the plant (inflorescence, bracts, leaves, stems), the developmental stage, the season, the time of day, and the environmental factors that influenced the cultivation or natural growth of an aromatic-medicinal plant [28,29].
Active compounds from MD with their target mechanisms in various diseases
| Active compound | Plant source | Disease | Target | References |
|---|---|---|---|---|
| Polyphenols | Olive oil, fruits, vegetables, nuts, legumes, cereals | Obesity, diabetes, CVD, cancer, neurodegenerative disease, digestive diseases, skin diseases | Antioxidant, anti-inflammatory, anti-diabetic, anti-atherogenic, anti-cancer, neuroprotective, gastroprotective, dermatoprotective | [30,31] |
| Omega-3 fatty acids | Fish, nuts, seeds | Obesity, diabetes, CVD, cancer, neurodegenerative disease, digestive diseases, skin diseases | Anti-inflammatory, anti-diabetic, anti-atherogenic, anti-cancer, neuroprotective, gastroprotective, dermatoprotective | [30] |
| Fiber | Fruits, vegetables, nuts, legumes, cereals | Obesity, diabetes, CVD, cancer, digestive diseases | Prebiotic, satiating, anti-diabetic, anti-atherogenic, anti-cancer, gastroprotective | [32] |
| Carotenoids | Fruits, vegetables | Obesity, diabetes, CVD, cancer, skin diseases | Antioxidant, anti-inflammatory, anti-diabetic, anti-atherogenic, anti-cancer, dermatoprotective | [33] |
| Vitamin C | Fruits, vegetables | Obesity, diabetes, CVD, cancer, skin diseases | Antioxidant6, anti-inflammatory, anti-diabetic, anti-atherogenic, anti-cancer, dermatoprotective5 | [32,33] |
| Vitamin E | Olive oil, nuts, seeds | Obesity, diabetes, CVD, cancer, skin diseases | Antioxidant, anti-inflammatory, anti-diabetic, anti-atherogenic, anti-cancer, dermatoprotective | [32,33] |
| Folate | Fruits, vegetables | CVD | Anti-atherogenic | [32,33] |
| Magnesium | Nuts, seeds | CVD | Anti-hypertensive | [33,34] |
| Aromatic compounds | Rosemary | Obesity, cancer, skin diseases | Anti-obesity, anti-cancer, antimicrobial | [35] |
| Curcumin | Turmeric | Obesity, diabetes, CVD, cancer, neurodegenerative disease | Antioxidant, anti-inflammatory, anti-diabetic, anti-atherogenic, anti-cancer, neuroprotective | [35] |
It is challenging to trace the origins of Mediterranean cuisine, although it most likely evolved alongside cultures inhabiting the Mediterranean Basin since the birth of civilization. Over time, this culinary tradition absorbed influences from various invaders while preserving many local customs. The Fertile Crescent, the Near East geographical region, lies between the eastern tip of the Mediterranean Sea and the Persian Gulf, and it encompasses areas such as Mesopotamia, Canaan, and some argue, Northern Egypt. These regions may well had contributed to the rich tapestry of Mediterranean cuisine [36].
3 Digestive diseases
According to a recent survey published involving 73,000 adults across 33 countries on six continents, more than 40% of the global population experiences functional gastrointestinal disorders (FGIDs). Among these individuals, 49.5% of females and 36.6% of males meet eligibility for at least one of the FGIDs [37]. Digestive disorders influence approximately 40 million people in the United States leading to millions of clinical visits annually. The associated costs reached a staggering $119.6 billion in the year 2018 [38,39]. Furthermore, the burden of digestive disorders is elevating in developing countries [39]. These common digestive diseases that affect millions of people worldwide significantly affect the quality of life and contribute to morbidity and mortality. Accurate diagnosis and appropriate management, both pharmacological and nonpharmacological, are of utmost importance. Some of the main digestive diseases, their impact on work activities, and why they are important are addressed here.
3.1 GERD
GERD is a digestive disease characterized by the backflow of stomach acid or bile into the esophagus, leading to irritation and inflammation of its lining. The disrupting mechanism in the lower esophageal sphincter ordinarily prevents stomach contents from refluxing. Common symptoms of GERD include heartburn, chest discomfort, regurgitation, and trouble swallowing. GERD is a prevalent condition that affects people of all ages and genders, with global rates ranging from 8 to 33% [40]. GERD is mainly associated with proton pump inhibitor (PPIs) management [41]. PPI medications are often prescribed as an initial empirical diagnostic strategy for patients with typical GERD symptoms (such as heartburn and regurgitation) and atypical symptoms (such as noncardiac chest pain, chronic cough, hoarseness, throat clearing, and wheezing) [42,43]. Functional esophageal problems are mainly treated with neuromodulators, which alter the neuronal activity without acting as neurotransmitters. Various notable neuromodulators explored for managing functional esophageal issues, particularly noncardiac chest discomfort, such as tricyclic antidepressants, trazodone, selective serotonin reuptake inhibitors, and serotonin norepinephrine, reuptake inhibitors [44]. In addition, many Mediterranean plants, such as Artemisia absinthium, Humulus lupulus, Matricaria recutita, Foeniculum vulgare, and Thymus vulgaris, are well-known for their effects on GERD therapies. These plants contain active constituents that contribute to their therapeutic properties are listed in Table 2.
Mediterranean plants and their active compounds used to treat specific digestive diseases, with their mechanisms of action
| Plant | Active compound | Digestive disease | Mechanism of action | Reference |
|---|---|---|---|---|
| Artemisia absinthium (Wormwood) | Sesquiterpene lactones, flavonoids, phenolic acids | GERD, PUD | Antacid, anti-inflammatory, antibacterial, antispasmodic, cytoprotective | [45] |
| Humulus lupulus (Hops) | Alpha and beta acids, flavonoids, prenylated chalcones | GERD, PUD, IBS | Antacid, anti-inflammatory, antibacterial, antispasmodic, anxiolytic | [46] |
| Ginkgo biloba (Ginkgo) | Flavonoids, terpenoids | IBS, IBD, CRC | Anti-inflammatory, antioxidant, immunomodulatory, anticancer | [47] |
| Panax spp. (Ginseng) | Ginsenosides, polysaccharides, phenolic compounds | IBS, IBD, CRC, LD | Anti-inflammatory, antioxidant, immunomodulatory, anticancer, hepatoprotective | [48] |
| Ganoderma lucidum (Reishi mushroom) | Triterpenoids, polysaccharides, phenolic compounds | IBS, IBD, CRC, LD | Anti-inflammatory, antioxidant, immunomodulatory, anticancer, hepatoprotective | [49] |
| Gynostemma pentaphyllum (Jiaogulan) | Gypenosides, flavonoids, saponins | IBS, IBD, CRC, LD | Anti-inflammatory, antioxidant, immunomodulatory, anticancer, hepatoprotective | [46] |
| Matricaria recutita (Chamomile) | Flavonoids, terpenoids, coumarins, phenolic acids | GERD, PUD, IBS, IBD | Antacid, anti-inflammatory, antibacterial, antispasmodic, sedative | [50] |
| Foeniculum vulgare (Fennel) | Monoterpenes, phenylpropanoids, flavonoids, coumarins | GERD, PUD, IBS, IBD | Antacid, anti-inflammatory, antibacterial, antispasmodic, carminative | [51] |
| Thymus vulgaris (Thyme) | Phenolic monoterpenes, flavonoids, phenolic acids | GERD, PUD, IBS, IBD | Antacid, anti-inflammatory, antibacterial, antispasmodic, antioxidant | [52] |
| Rosmarinus officinalis (Rosemary) | Phenolic diterpenes, flavonoids, phenolic acids | GERD, PUD, IBS, IBD, CRC | Antacid, anti-inflammatory, antibacterial, antispasmodic, antioxidant, anticancer | [51] |
| Salvia officinalis (Sage) | Phenolic diterpenes, flavonoids, phenolic acids | GERD, PUD, IBS, IBD, CRC | Antacid, anti-inflammatory, antibacterial, antispasmodic, antioxidant, anticancer | [53] |
| Origanum vulgare (Oregano) | Phenolic monoterpenes, flavonoids, phenolic acids | GERD, PUD, IBS, IBD, CRC | Antacid, anti-inflammatory, antibacterial, antispasmodic, antioxidant, anticancer | [54] |
| Cynodon dactylon (Bermuda grass) | Flavonoids, phenolic acids, triterpenoids, steroids | PUD, IBD, CRC | Anti-ulcer, anti-inflammatory, antioxidant, anticancer | [55] |
| Borago officinalis (Borage) | Gamma-linolenic acid, rosmarinic acid, flavonoids | GERD, PUD, IBS, IBD | Antacid, anti-inflammatory, antibacterial, antispasmodic | [56] |
| Lavandula angustifolia (Lavender) | Linalool, linalyl acetate, terpenoids, flavonoids | GERD, PUD, IBS, IBD | Antacid, anti-inflammatory, antibacterial, antispasmodic, sedative | [50] |
| Mentha piperita (Peppermint) | Menthol, menthone, flavonoids, phenolic acids | GERD, PUD, IBS, IBD | Antacid, anti-inflammatory, antibacterial, antispasmodic, carminative | [56] |
| Calendula officinalis (Marigold) | Flavonoids, triterpenoids, carotenoids, phenolic acids | PUD, IBD, CRC | Anti-ulcer, anti-inflammatory, antioxidant, anticancer | [57] |
| Aloe vera (Aloe) | Anthraquinones, polysaccharides, phenolic compounds | PUD, IBD, CRC | Anti-ulcer, anti-inflammatory, immunomodulatory, anticancer | [58] |
| Curcuma longa (Turmeric) | Curcumin, curcuminoids, turmerones | PUD, IBD, CRC, LD | Anti-ulcer, anti-inflammatory, antioxidant, immunomodulatory, anticancer, hepatoprotective | [59] |
| Zingiber officinale (Ginger) | Gingerols, shogaols, zingerone | PUD, IBD, CRC, LD | Anti-ulcer, anti-inflammatory, antioxidant, immunomodulatory, anticancer, hepatoprotective | [60] |
| Daucus carota (Carrot) | Carotenoids, flavonoids, phenolic acids, polyacetylenes | GERD, PUD, IBS, IBD, CRC | Antacid, anti-inflammatory, antioxidant, anticancer, prebiotic | [61] |
| Nerium oleander (Oleander) | Cardiac glycosides, flavonoids, phenolic acids | PUD, IBD | Anti-ulcer, anti-inflammatory, immunomodulatory, cytoprotective | [45] |
| Amaranthus viridis (Amaranth) | Betalains, flavonoids, phenolic acids, saponins | PUD, IBD, CRC | Anti-ulcer, anti-inflammatory, antioxidant, anticancer, prebiotic | [62] |
| Vaccinium myrtillus (Bilberry) | Anthocyanins, flavonoids, phenolic acids | GERD, PUD, IBS, IBD, CRC | Antacid, anti-inflammatory, antioxidant, anticancer, anti-diarrheal | [47] |
| Taraxacum officinale (Dandelion) | Sesquiterpene lactones, flavonoids, phenolic acids, coumarins | GERD, PUD, IBS, IBD, LD | Antacid, anti-inflammatory, antibacterial, antispasmodic, hepatoprotective | [63] |
| Punica granatum (Pomegranate) | Anthocyanins, flavonoids, tannins, organic acids, and xanthonoids | CRC, UC, IBS, BUD, IBD | Anti-ulcer, anti-inflammatory, antioxidant, anticancer, Anxiolytics | [46] |
GERD: gastroesophageal reflux disease; PUD: peptic ulcer disease; IBS: irritable bowel syndrome; IBD: inflammatory bowel disease; CRC: colorectal cancer; UC: ulcerative colitis.
3.2 PUD
PUD arises from acid peptic damage to the gastrointestinal tract, leading to the loss of the protective mucosal barrier. While peptic ulcers most commonly occur in the stomach or proximal duodenum, they can also be found in the esophagus or Meckel’s diverticulum [64]. The primary cause of PUD includes Helicobacter pylori infection and nonsteroidal anti-inflammatory medications (NSAIDs) [65]. The lifetime prevalence of PUD in the general population is estimated to be around 51%, with an annual incidence of 01–03% [64,65,66,67]. Due to the increasing frequency of antibiotic resistance, effective treatment of H. pylori infection has become an international concern [65]. The typical first-line therapy of PUD involved PPIs along with antibiotics, such as clarithromycin plus amoxicillin or metronidazole. However, the efficacy of this regimen in eradicating H. pylori has declined from over 90% two decades ago to less than 70% currently in many countries due to antibiotic resistance [65]. Table 2 highlights examples of Mediterranean plants, such as T. vulgaris, Rosmarinus officinalis, Salvia officinalis, Origanum vulgare, and Mentha piperita. These botanicals are well known for their therapeutic effects in managing PUD.
3.3 IBD
IBD is a chronic and recurrent gastrointestinal condition. The immune regulatory system, responsible for maintaining a delicate balance between tolerance and reactivity to gut microorganisms, becomes compromised in IBD. Common symptoms of IBD include diarrhea, stomach discomfort, weight loss, and fever. In addition, IBD can lead to severe physical and mental distress, significantly impacting both individuals and society, resulting in substantial health-care expenses [68]. The global prevalence of IBDs, including Crohn’s disease (CD) and UC, is increasing, notably in the Mediterranean area [69]. Approximately 2 million Europeans and 15 million North Americans are affected by IBD, with medical costs constituting a significant portion of health-care expenditures. Recent large-scale genome-wide association studies have identified more than 200 genetic loci linked to IBD, some of which are shared with other chronic autoimmune illnesses [70]. Clinically, anti-inflammatory agents (such as aminosalicylates and corticosteroids), immunosuppressants (such as azathioprine and methotrexate), and biologics (such as anti-TNF antibodies and anti-integrin antibodies) are the most commonly used drugs to treat IBD [68]. Many Mediterranean plants, including as Curcuma longa, Zingiber officinale, Daucus carota, Amaranthus viridis, and Vaccinium myrtillus, have prospective effects on IBD therapies. These plants contain active constituents that contribute to their therapeutic properties are listed in Table 2.
3.4 CRC
CRC remains a significant global health concern, with over 1.85 million cases and 850,000 deaths reported annually. As the third most common cause of cancer-related mortality worldwide, CRC poses substantial challenges for patients and healthcare systems. Notably, 25% of individuals initially diagnosed with localized disease will eventually develop metastases, while 20% of newly diagnosed CRC patients already present with metastatic disease. For patients with metastatic CRC that is not curable, treatment options primarily include cytotoxic chemotherapy and biologic therapy. The latter includes immunotherapy and antibodies treating cellular growth factors. Although extended lifespans remain relatively rare, there is a growing expectation of increased longevity. Genomic profiling makes it possible to select therapies, maximizing benefits for a broader population while minimizing exposure to the adverse effects of ineffective medications [71]. Despite advances in our understanding of CRC etiology, precursor lesions, and risk factors, a clear explanation for the recent rise in cancer cases among young people remains elusive. [72]. Further research is essential to unravel the underlying mechanisms driving this concerning trend. Table 2 includes examples of Mediterranean plants, such as A. vera, Calendula officinalis, Gynostemma pentaphyllum, Ganoderma lucidum, and Cynodon dactylon, as well as their active constituents that may have effects on CRC medication.
3.5 IBS
IBS is characterized by the abdominal discomfort during defecation or a change in bowel behavior [73]. Common symptoms include abdominal discomfort, bowel difficulty, and bloating, as well as the elimination of potentially dangerous symptoms such as unexpected weight loss, rectal bleeding, or a recent change in bowel function. Studies from Southeast Asia and the Middle East report a prevalence of 7.0%, that from North America, Europe, and Australasia report a prevalence of 11.8–14.0%, and that from South Europe, Africa, and South America report a prevalence of 15.0–21.0%. [74]. A meta-analysis of 56 global studies revealed that the prevalence of IBS tends to be slightly but considerably greater in women compared to men [75]. In general, IBS has a significant impact on the individual, affecting their quality of life and imposing significant societal and economic burdens [76]. Many Mediterranean plants such as H. lupulus, Panax spp., Borago officinalis, Lavandula angustifolia, and Taraxacum officinale are well known for their effects on IBS therapies. These plants contain active constituents that contribute to their therapeutic properties are listed in Table 2.
3.6 Liver digestive associated diseases
The liver, a vital organ, performs multiple essential functions such as blood filtration, bile production, nutrition metabolization, and blood volume regulation. However, the liver is susceptible to various disorders that impair its function and give rise to digestive complications. Liver malfunction inhibits normal nutrient digestion and absorption, potentially leading to gastrointestinal inflammation and bleeding. Some treatments of gastrointestinal LDs include medications (e.g., antibiotics, steroids, immunosuppressants, antivirals, chelating agents, anticancer drugs, and lifestyle modifications such as avoiding alcohol, losing weight, eating a healthy diet) [77,78,79]. Globally, LDs claim the lives of over 2 million people annually, and among these fatalities, cirrhosis accounts for approximately 1.16 million deaths. Alcohol and nonalcoholic fatty liver disease (NAFLD) are currently the main causes of cirrhosis in Western developed nations [80]. Liver damage is often associated with oxidative damage, an increase in tissue lipid peroxidation, aspartate aminotransferase (AST), alanine transaminase (ALT), alkaline phosphatase, total bilirubin, total protein, and cell necrosis [81,82]. Hepatic disease treatment is significantly affected by conventional therapies derived from natural sources. Active chemicals found in Mediterranean medicinal plants (Table 3) are utilized to treat digestive problems related to the liver. One such compound is silymarin, known for its antioxidant properties and its impact on enzyme systems involved in fibrosis and cirrhosis. Clinical trials have demonstrated that silymarin treatment significantly reduces liver-related mortality in patients with cirrhosis [83].
Common LDs. The main Mediterranean plants’ active compounds used to treat LDs and their target mechanism of action
| LD | Cause | Active compound | Plant source | Mechanism of action | References |
|---|---|---|---|---|---|
| Alcohol-related liver disease | Excessive alcohol consumption | Silymarin | Milk thistle (Silybum marianum) | Antioxidant, anti-inflammatory, antifibrotic and anti-apoptotic effects | [84] |
| Fatty liver disease | Excess fat accumulation | Curcumin | Turmeric (Curcuma longa) | Modulation of lipid metabolism, inflammation, oxidative stress, and insulin resistance | [85] |
| Hemochromatosis | Genetic, absorption too much iron | Phyllanthin | Bhumyamalaki (Phyllanthus amarus) | Chelation of iron and inhibition of iron absorption | [86] |
| Wilson disease | Genetic, preventing removal excess copper | Tetrathiomolybdate | Brassica spp. | Reduction of copper levels and inhibition of copper-dependent enzymes | [87] |
| Liver cancer | chronic viral infections, cirrhosis, exposure to toxins, and genetic factors | Betulinic acid | White birch (Betula alba) | Induction of apoptosis, inhibition of angiogenesis, and modulation of signaling pathways | [88] |
| Autoimmune hepatitis | Autoimmunity, attacks the liver cells | Glycyrrhizin | Licorice (Glycyrrhiza glabra) | Suppression of immune response, reduction of inflammation, and protection of hepatocytes | [89] |
| Primary sclerosing cholangitis | Bile ducts become inflamed and scarred | Silymarin | Milk thistle (Silybum marianum) | Antioxidant, anti-inflammatory, antifibrotic, and anti-apoptotic effects1, reduced hepatic TIMP-1/2 | [90] |
| Primary biliary cholangitis | Autoimmunity, attacks the small bile ducts | Oleanolic acid | Olive (Olea europaea) | Anti-inflammatory, immunomodulatory, and hepatoprotective effects | [91] |
Recent research has highlighted the potential of several natural compounds in mitigating liver damage. Among these compounds, resveratrol, glycyrrhetinic acid, phytolanthin, curcumin, and silymarin have demonstrated to possess both anti-inflammatory and antioxidant activities in animal models of LDs. These compounds show promise in reducing liver damage. Milk thistle silymarin, in particular, enhances hepatic glutathione and may contribute to the antioxidant defense of the liver [92,93]. In a randomized study involving 97 patients with histologically diagnosed mild, acute, and subacute LD caused by alcohol abuse, silymarin treatment for 4 our weeks resulted in a significantly greater improvement in liver function. This improvement was evidenced by a decrease in ALT and AST levels, compared with placebo [94]. Moreover, a double-blind controlled trial [94] demonstrated the efficacy of silymarin therapy in reducing elevated liver enzymes in patients with ALD, cirrhosis, and NAFLD. Silymarin has been significantly improved liver aminotransferases in patients with NAFLD without causing any particular negative effects, as shown in a randomized, double-blind, placebo-controlled trial [95]. Due to its anti-inflammatory properties, silymarin was found to downregulate the expression of NF-κB, IL-6, MMP-2, MMP-13, transforming growth factor beta-1, tumor-suppressor Krueppel-like factor, collagen α1 expression, and platelet-derived growth factor signaling in an alcoholic fatty liver model in rats [96,97].
Recent research has explored the therapeutic potential of curcumin in improving NAFLD, and it reduces the production of triglycerides (TG) [98] by inhibiting HMG-COA reductase [99]. In mice models, curcumin effectively reduces hepatic steatosis and lowers elevated hepatic TG [100]. When curcumin was supplemented to adult patients with metabolic syndrome, their body mass index values as well as their serum glucose levels, glycated hemoglobin, AST, ALT, TG, and total cholesterol were all below those of the placebo group [101]. Patients with NAFLD who received daily low-dose phospholipid curcumin supplementation for two months show a substantial decrease in their hepatic steatosis and enzyme levels when compared to placebo [102]. In addition, glycyrrhetinic acid showed to promote the growth of liver cells by binding to the epithelial growth factor receptor, enhancing the hepatic antioxidant defense, acting as an anti-inflammatory agent (Table 3), and activating the extracellular signal-regulated kinases (ERK2) pathway, along with stimulating DNA synthesis in liver cells [103,104]. 18β-glycyrrhetinic acid further reduces oxidative stress and the expression of inflammatory markers by downregulating of NF-κB and upregulating nuclear factor erythroid 2–related factor 2 (Nrf2) target genes. These effects were observed in both in vitro cel models and in vivo animal models with hepatic injury [105,106]. Furthermore, ethanolic extracts of Phyllanthus amarus exhibits strong hepatoprotective properties in both in vitro and in vivo settings. Recent studies have shed light on the potential benefits of Phyllanthus extract in the treatment of both acute and chronic hepatitis in children [38]. In addition, phytolanthin, a compound found in Phyllanthus, has demonstrated protective effects on rat livers exposed to galactosamine and carbon tetrachloride-induced cytotoxicity [107]. Another intriguing compound, resveratrol, plays a crucial role in safeguarding the liver following hepatocyte injury by modulating the expression of the nuclear transcription factors Nrf2 and NF-κB and downregulating the expression of HO-1 and iONS genes. Resveratrol effectively protects the liver following hepatocyte injury by reducing oxidative stress [108]. Furthermore, the Mediterranean foods, particularly plants, are thought to be rich in various kinds of chemical compounds that deserve clinical investigation to figure out their importance in treating digestive system-related liver illnesses.
4 MD importance in digestive diseases
Functional foods, enriched with specific minerals, vitamins, fatty acids, and dietary fibers, contain biologically active substances. These include phytochemicals, antioxidants, and probiotics, which have the potential to improve health and reduce disease risk [109,110,111]. Polyunsaturated fatty acids (found in olive oil and nuts) and antioxidative bioactive substances such as flavonoids, phytosterols, terpenes, and polyphenols exhibit anti-atherogenic and anti-inflammatory functions. Similarly, a perfect balance of micronutrients, including vitamins and minerals, which are rich in this diet, aids in the prevention of malnutrition and immunodeficiencies [112]. Concerning digestive disorders, high intakes of mono- and disaccharides, along with total lipids, for example, continuously increase the risk of developing IBD. Higher vegetable consumption may lower the incidence of UC, whereas higher fruit and/or dietary fiber consumption may offer protection against CD. Probiotics and prebiotics may influence gut microbiota and lessen the chance of IBD relapse. Previous studies have linked depression and emotional stress with the appearance of FGIDs such as functional dyspepsia and IBS [113,114]. Dietary patterns and the overall diet may be more relevant in illness risk than particular meals or nutrients [115]. Malnutrition impairs the clinical course of underlying disorders and is linked to poor clinical outcomes. Dietary control of gastrointestinal illness pathophysiology by manipulation of intestinal permeability and inflammation [116,117]. The individuals living in the Mediterranean Basin had underneath death rate with the prevalence of cardiovascular and cancer disorders than other populations, according to Ancel Benjamin. MD is marked by an excessive amount of grains, vegetables, fruit, olive oil, and tiny amounts of dairy products, pastry, sweets, and meat-based foods all simultaneously [118,119].
5 Mechanism of action of Mediterranean plants active compounds used to treat specific digestive diseases
There is still much to learn about the exact mechanism of action by which the active chemicals in medicinal plants and MDs accomplish their therapeutic effects. Figure 2 shows the potential target mechanisms by which gastrointestinal tract diseases can be managed through medicinal herbs and their active phytocompounds.
Mediterranean active compounds target mechanisms.
5.1 Antacidity
The release of gastric acid by parietal cells in the stomach plays a crucial role in regulating the acidity of the digestive tract. However, an overabundance of acid, on the other hand, can cause a variety of digestive illnesses such as GERD, PUD, and nonulcer dyspepsia. Notably, peptic ulcers can result in severe complications such as excessive bleeding due to erosion of blood vessels [120]. To avoid excessive acid production, H2 antagonists, such as ranitidine, bind to H2 receptors, thereby inhibiting histamine binding and reducing acid output [121]. In addition, the hydrogen potassium ATPase enzyme, which is responsible for the final step of acid secretion into the stomach, is inhibited by PPI. Remarkably, PPI are prodrugs become active only after cleaving in the acidic secretory canaliculi of parietal cells by an acid. In the liver, P450 enzymes break down PPIs, with cytochrome P450 2C19 being the most common P450 enzyme involved in the breakdown of the different PPIs, albeit the specific P450 enzymes involved, although specific P450 enzymes may vary slightly [122,123]. Beyond conventional pharmaceutical approaches, antacid effects have been observed in phytochemicals. Flavonoids, alkaloids, tannins, and saponins are some phytochemicals that have been studied for their antacid characteristics. Notably, Mediterranean medicinal herbs such as A. absinthium and H. lupulus are two major Mediterranean medicinal herbs have been used as antacids [45,46,118,121]. However, while certain medicinal herbs have been demonstrated to have antacid characteristics, they should not replace standard medical therapy [124]. Table 2 provides an overview of 14 Mediterranean plants and their active constituents, which are well known for their antacid effects.
5.2 Anti-inflammation
Inflammation is the body’s complicated biological respond to various stimuli such as germs, damaged cells, or irritants [125]. In the context of health, understanding inflammation and its modulation is crucial. Mediterranean medicinal plants rich in phytocompounds such as curcumin, resveratrol, anthocyanins, quercetin, and gingerol (Table 2) play a crucial role in reducing toll-like receptor (TLR) 4 receptor expression along with NF-κB transcription factor operation, hence minimizing the synthesis of downstream pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1, as well as free radicals such as nitric oxide and reactive species (ROS). Furthermore, these phytochemicals stimulate the Nrf-2 signaling pathway, which falls oxidative stress [126]. Some plant chemicals can reduce inflammation by affecting miRNAs and genes that control it. For example, miR-155 and miR-21 are two miRNAs that increase inflammation by activating NF-κB and its target genes such as TNF-α, IL-6, and mitogen-activated proteins (MAPKs). Many plant chemicals mentioned earlier (Figure 3) can lower the levels of these miRNAs and reduce inflammation [125,127]. These plant chemicals can also change the activity of enzymes that modify the DNA and histones, such as histrone acetyl transferases and HDACs, and affect the expression of inflammatory genes [125]. Inflammation within the digestive system can cause problems like IBD, IBS, and GERD [125]. Following MD, which is rich in plant chemicals, can improve the symptoms and markers of inflammation in children and teens with mild to moderate IBD. After 12 weeks of therapy, the majority of the participants in a clinical investigation achieved recovery. Participants who followed the MD protocol had a substantial decrease in both clinical ratings (PCDAI and PUCAI) and most inflammatory markers (CRP, calprotectin, TNF-α, IL17, IL12, and IL13) when compared to those in the control group, with faster recovery in both PCDAI and CRP [128]. Mediterranean medicinal plants offer a natural arsenal against inflammation, providing valuable insights for therapeutic strategies.
Major phytochemicals of Mediterranean medicinal plants and their antidigestive mechanisms. TLR: Toll-like receptor; NF-Kb: nuclear factor kappa B; COX: cyclooxygenase; iNOS: nitric oxide synthases; ERK2: extracellular signal-regulated kinases; MAPK: mitogen-activated protein; TNF-α: tumor necrosis factor alpha; IL: interleukin; Nrf2: nuclear factor erythroid 2–related factor 2; mIR: microRNA; AP-1: activator protein 1; PI3K: phosphoinositide 3-kinases; AKT: Protein kinase B; JNK: Jun N-terminal kinase; TRIF: TIR-domain-containing adapter-inducing interferon-β; HMGB1: high mobility group box 1; LOX: lysyl oxidase; MYD: myeloid differentiation primary response.
5.2.1 Quercetin
Quercetin is a flavonoid abundant in various dietary sources, including citrus fruits, apples, onions, red grapes, and tea [125]. This phenolic molecule exhibits a remarkable array of health-promoting issues and serves as anti-inflammatory, antioxidant, chemopreventive, and neuroprotective [129]. In macrophages and human PBMCs, quercetin decreases the production of TLR4 and hinders NF-κB trafficking to the nucleus, which alleviates the inflammatory response [125]. It also suppresses cyclooxygenase (COX)-2 and nitric oxide synthases (iNOS) gene expression in vitro and greatly lowers the generation of proinflammatory cytokines in LPS-activated macrophages via the MAP kinases and NF-κB pathway [130]. In LPS-treated RAW 264.7 macrophages, quercetin inhibits NF-κB activation via regulating the NF-κB/IB complex and reduces phosphorylated ERK kinase and p38 MAP kinase [130]. It has been observed that quercetin and its metabolite can also suppress the NF-κB pathway indirectly by activating the Nrf2 signaling cascade [131]. Furthermore, quercetin has been demonstrated to upregulate miR-146a, which is followed by a reduction in NF-κB, TNF-α, IL-6, and IL-17 levels. The quercetin content of Mediterranean plants may have cytoprotective properties in digestive diseases such as IBD, IBS, and GERD [125].
5.2.2 Curcumin
Curcumin, a polyphenol derived from the ginger plant C. longa [132,133] plays a pivotal role in managing various inflammatory conditions, including rheumatoid arthritis, IBD, nephropathies, and certain malignancies [125]. Curcumin has a strong anti-inflammatory effect, which is attributed to its regulation of the TLR4 and MyD88 pathways in macrophages, and it effectively prevents NF-κB activation [134,135]. In addition, curcumin suppresses MAPK and AP-1 transcription factor activation along with inhibiting IB-phosphorylation and degradation [136,137]. These antagonistic effects on TLR4 signaling pathways and downstream mediators are followed by suppression of proinflammatory cytokines such as TNF-α, IL-1, and IL-6 [125]. A research indicates that curcumin pretreatment protects against T cell-mediated hepatitis in mice. The strong impact of curcumin may be attributed in part to decreasing the expression levels of TLR2, TLR4, and TLR9 in the liver [138]. Moreover, curcumin was found to downregulated miR-155 levels in vivo and in vitro following LPS stimulation via depleting the phosphoinositide 3-kinase PI3K/AKT pathway [139]. Regular consumption of curcumin reduces the expression of miR-21 and miR-155 in clinical investigations. Consequently, this was followed by a reduction of the proliferative kinases AKT and JNK, as well as the transcription factor AP-1, which reduced inflammation by decreasing NF-κB activation, TNF-α, and IL-6 production [140,141]. Curcumin is typically taken three times per day at doses ranging between 400 and 600 mg. Remarkably, it exhibits no adverse effects on the kidney or liver when taken up to 12 g/day [142,143]. However, extremely high dosages may lead to stomach distress and gastric ulcers [144]. Hence, curcumin, which is a key ingredient in Mediterranean traditional medicine, may be a safer compared with NSAIDs for inflammation. A study indicates that curcumin can decrease the development of TLR2, TLR4, and HMGB1 in rats suffering from fibrogenesis expression of ligand molecules, suggesting that curcumin’s hepatoprotective mechanism may be attributed to its antioxidant activity [145,146]. In addition, curcumin may lower other ROS-producing enzymes such as iNOS, the COX system, and arachidonate 5-lipoxygenase, as well as reducing the action of numerous pyoderma gangrenosums [144].
5.2.3 Anthocyanins
Anthocyanins, flavonoids present in many fruits and vegetables, particularly in the Mediterranean area, represent a part of the traditional diet [147]. They may aid in the prevention or treatment of digestive illnesses such as IBD, UC, CD, and CRC. Anthocyanin has recently been shown to be beneficial in the treatment of fatty liver and inflammation (125). Anthocyanins, in particular, reduce proinflammatory mediators like as iNOS and TNF-α by lowering TLR4 expression and inactivating NF-κB [148]. They also help to protect against oxidative stress by stimulating the Nrf2/HO-1 signaling pathway [149]. Anthocyanins have been shown to inhibit proinflammatory TNF-α signaling and gene expression in murine livers [150]. A clinical investigation, including individuals with UC for example, found that supplementation with anthocyanin-rich bilberry extract improved patients’ activity and quality of life. A recent study shed the light on the health-promoting effects of anthocyanins derived from purple sweet potato extracts. It decreased colonic inflammation and inhibited the development of carcinogenesis in a rat model of colitis-associated CRC. Furthermore, a meta-analysis of epidemiological data supports the potential benefits of anthocyanin consumption. Increased intake of anthocyanin was associated with a decreased risk of CRC [147,151].
5.3 Antibacterial
Bacterial infections of the gastrointestinal system are most commonly caused by bacteria or bacterial toxins of contaminated food or drink. Dental caries, periodontal disease, shigellosis, salmonellosis, and typhoid fever exemplify bacterial disorders of the digestive system [152,153,154]. However, plants such as A. absinthium, H. lupulus, F. vulgare, T. vulgaris, T. officinale, and their derived metabolites of different Mediterranean habit (Table 2) inhibit damaging factors of pathogenic microorganisms. There have been reports of phytochemical components that provide a fascinating defense mechanism against predation by a variety of Gram-positive and Gram-negative bacteria, along with antibiotic-resistant bacteria. These constituents include tannins, flavonoids, alkaloids, glycosides, cyanogenetic glycosides, reducing sugar, and several other aromatic compounds [155,156]. Reports suggest that flavonoids and polyphenolic chemicals may have antibacterial activity because of their capacity to bind to bacterial cell walls and impede microbial development [157]. In addition, antivirulence phytochemical research has mostly focused on in vitro quorum quenching with their antibiofilm characteristics. Notably, myristic acid, which reduces virulence in vitro, paradoxically acts as a signal molecule that increases Pseudomonas aeruginosa pathogenicity in a dermonecrotic animal model. Moreover, certain mouse models have revealed that type three secretion systems play a pivotal role as virulence determinants [158]. Anthocyanins, abundant in various foods, may help the digestive tract by reducing oxidative stress, alleviating inflammation, and modulating gut flora [159].
5.4 Antispasmodic
Medicines with antispasmodic properties are frequently used to lessen excessive smooth muscle contractility, which often leads to stomach pain and cramping associated with various gastrointestinal, biliary, or genitourinary tract conditions [160]. A significant portion of the population experience conditions such as IBS, biliary colic brought on by gallstones, gastritis, colitis, pancreatitis, or dysmenorrhea, all of which commonly require antispasmodic medication to reduce symptoms [161,162,163,164]. Antispasmodic drugs are also employed to alleviate the pain during medical procedures such as colonoscopy [165]. Multiple Mediterranean medicinal herbs, including Zanthoxylum armatum, Matricaria chamomilla, F. vulgare, Pycnocycla spinosa, Atropa belladonna, L. angustifolia, Mentha pulegium, Glycyrrhiza ularensis, Anethum graveolens, and Origanum majorana contribute to symptom relief through their antispasmodic properties [161]. Phytochemicals have been demonstrated to have antispasmodic characteristics, particularly secondary metabolites such as terpenes, phenolics, and alkaloids, are responsible for these plants’ pharmacological actions [162].
5.5 Cytoprotective
The capacity of cells to endure damaging stimuli while maintaining structural and functional integrity is referred to cytoprotecting. Cytoprotective drugs prevent or minimize damage to the gastrointestinal mucosa caused by different variables such as acid, pepsin, and H. pylori in the setting of digestive illnesses [166]. Various Mediterranean medicinal herbs, including Olea europaea, Rosmarinus officinalis, T. vulgaris, O. vulgare, and Salvia officinalis, have cytoprotective action [167]. Phytochemicals including curcumin, resveratrol, quercetin, and gingerol that target TLR4/NF-κB-mediated inflammatory mechanisms have cytoprotective activities [167].
5.6 Anxiolytics
Anxiolytics, a class of medications, exert their effects by targeting the gamma-aminobutyric acid (GABA) receptor. This receptor regulates chloride ion entry into neurons, leading to neuronal hyperpolarization [168]. However, the precise mechanism of action of anxiolytics is yet unknown [169]. Several medicinal herbs have been explored for their anxiolytic properties including pomegranate, lavender, hops, maypop, lemon balm, valerian, and peppermint [170]. Pomegranate contains various phytochemicals, such as anthocyanins, flavonoids, tannins, organic acids, and xanthonoids, and have demonstrated anxiolytic properties [171]. Phytochemicals in pomegranate likely exert their effects through multiple ways, including inhibition of GABAergic receptors, modulation of N-methyl-D-aspartate and CaMKII/CREB pathways, reduction of oxidative stress via TLR4 and iNOS inhibition, control of cytokines and NF-kB generation, and activation of Nrf2 and AMPK. While anxiolytics offer relief, they may come with undesirable side effects, including addiction, depression, suicidal tendencies, seizures, sexual dysfunction, and headaches [172]. Exploring the anxiolytic potential of medicinal herbs provides valuable insights for managing anxiety while minimizing adverse effects associated with conventional medications.
5.7 Antioxidant
Antioxidants are molecules that have the potential to neutralize free radicals and prevent them from causing cell injury. In digestive diseases, oxidative stress can trigger inflammation and mucosal damage [173]. According to scientific studies, antioxidant properties are the key mechanism for phytochemicals to alleviate various disease pathways by increasing the antioxidant defense mechanisms of cells, scavenging free radicals, decreasing lipid peroxidation, boosting anti-inflammatory potential, and further protecting hepatic cell damage [84]. Terpenoids (such as monoterpenes and carotenoids) and polyphenols (such as quercetin and other flavonoids) are significant phytochemicals having antioxidant properties. In this context, lavender, hops, maypop, lemon balm, valerian, and peppermint are among the therapeutic herbs used to treat antioxidant-related illnesses [174]. In addition, bioactive phytochemicals from Hypericum species exhibit both anti-inflammatory and antioxidant properties [175]. Numerous antioxidant compounds have been found to be abundant in Rosmarinus officinalis, Z. officinale, F. vulgare, C. longa, and fragrans. Because these foods are antioxidant rich, regular consumption of these foods offers additional health benefits [176]. Quercetin is a strong antioxidant that suppresses the generation of lipid peroxides and lysosomal enzymes like the acid phosphatase and cathepsin D [177,178]. On the other hand, curcumin reduces oxidative damage during inflammation by stimulating the Nrf2-Keap1 pathway and enhancing antioxidant enzyme efficiency [179].
5.8 Immunomodulatory
Immunomodulators are chemicals that alter or control the immune system to improve the body’s response to a medical condition and diseases. Immunomodulators can help regulate symptoms and preserve immune system homeostasis in the context of digestive diseases [180]. Several Mediterranean medicinal herbs, including Echinacea purpurea, Panax ginseng, C. longa, and Allium sativum, are used to treat immunomodulatory-related disorders [181]. Medicinal plants and isolated compounds with immunomodulatory properties are prospective treatments for digestive diseases and viral infections such as COVID-19. Polysaccharides, terpenoids, flavonoids, alkaloids, glycosides, and lactones are plant phytochemicals that play a crucial role in immunomodulation [182].
5.9 Anticancer
The intricacies of cancer pathobiology are strongly linked to the primary challenges in developing target-specific anticancer medications. Autophagy, alongside apoptosis, plays a critical role in cellular mechanisms related to cancer genesis and treatment. However, due to the abnormalities in signaling pathways, notably apoptosis, many tumor types developed resistance against treatment. Autophagy might be investigated as another cell fate mechanism for the exploration of target-specific antitumor medicines [183]. Growing evidence suggests that phytochemicals, which alter various signaling targets, including both autophagy and apoptosis, exhibit anticancer outcome [184]. Phytocompounds anticancer actions were shown to be selective and specific to cancer cells, involving the control of autophagy and apoptosis [183]. Numerous studies have documented the protective effects of curcumin against UC, CD, pancreatic, and colorectal malignancies [185]. In addition, researchers have explored phytochemicals derived from Mediterranean plants across a range of cancer cell lines to uncover their critical biological pathways in cancer genesis and control (Table 4) [183].
Phytochemical compounds from Mediterranean plants and their in vitro biological regulatory pathways in the genesis and control of cancer
| Active compound | Cell line | Biological pathway |
|---|---|---|
| Resveratol | Human colon carcinoma | Activate apoptosis-3 and 8/FADD |
| Eriocalyxin | Human pancreatic cancer | Activate caspase 8 and 9 inhibit caspases 3 and 7 |
| Apigenin | CRD | Activate NAG-1, p53, cleave caspase 3 |
| Allicin | Human gastric cancer | Inhibit p38 expression and cleave caspase 3 |
| Evodiamine | Human gastric cancer | Activate beclin-2, Bax, downregulate Bcl-2 |
| Gingerol | Human colon cancer | Inhibit JNK, ERK1-2, P38 MAPK |
| Toxicarioside O | CRD | Inhibit Akt/Mtor |
| Oleanolic acid | Human pancreatic | Modulate JNK, mTOR pathway |
| Oridonin | Human hepatocellular carcinoma | Activation caspase-3 downregulate Bcl-2 and upregulate Bax |
| Thymoquinone | Oral cancer | Increase expression of LC3-II, Bax expression |
| Tetrandrine | Hepatocellular carcinoma | inhibit Wnt/Beta-catenin |
| Quinacrine | Human colon cancer | Activation p53, p21, inhibit topoisomerase |
| Chloroquine | Pancreatic cancer | Decrease the level of O2 |
| Isorhamnetin | Colon cancer | Increase ROS |
| Benzylisothiocyanates | Pancreatic cancer | Decrease phosphorylation of PI3K/Akt/FOXO1/PDK1/mTOR/FOXO3a |
| Kaempferol | CRD | Generates ROS and p53 signal |
| Triptolide | Human pancreatic | Inhibit Akt-mTOR-p70S6K |
NAG-1: nonsteroidal anti-inflammatory drug-activated gene 1; Bax: Bcl-2-associated X protein; JNK: Jun N-terminal kinase; ERK2: extracellular signal-regulated kinases; MAPK: mitogen-activated protein; AKT: protein kinase B; mTOR: mammalian target of rapamycin; JNK: Jun N-terminal kinase; LC3-II: phosphatidylethanolamine conjugate II; ROS: reactive species; PI3K: phosphoinositide 3-kinases; PI3K/Akt/FOXO1/PDK1/mTOR/FOXO3a; signaling pathway, p70S6K: p70 ribosomal S6 kinase.
5.10 Hepatoprotective
Based on experimental validation, natural bioactive substances derived from plants are promising options for predicting and alleviating hepatotoxic effects and chronic problems [84]. Several in silico investigations and molecular networking substances have also highlighted active phytochemicals derived from natural sources as potential hepatoprotective agents [84]. Plant products contain a range of phytochemicals that exhibit the hepatoprotective effect against CCl4-induced toxicity by downregulating liver marker enzymes and activating the antioxidative capability of the liver cells, resulting in liver repair [88]. Despite the fact that these drugs show significant hepatoprotective benefits in animal and cell culture models, a lack of clinical research continues to be a barrier to their official recognition. Therefore, controlled clinical studies are required to establish the therapeutic effectiveness of possibly hepatoprotective substances. Understanding the fundamentals of phytochemical hepatoprotective action might guide future medication development and aid in the prevention of clinical trial failure. Furthermore, the development of innovative delivery methods that improve the bioavailability of weakly water-soluble drugs may improve the findings that have previously been obtained. Most significantly, published data indicate that phytochemicals modulate distinct signaling pathways to varying degrees, highlighting the necessity for the use of mixtures of numerous hepatoprotective substances in both experimental research and clinical trials [186]. Many plants, such as the roots of T. officinale and the leaves of Mentha longifolia, are utilized in various herbal formulations as hepatoprotectives. It has been discovered that curcumin prevents the hepatitis C virus from entering by changing the fluidity of the membrane and the way the virus binds and fuses [185]. In addition, total saponins from Panax notoginseng have been shown to have a promising effect on fatty LD [187]. Dietary polyphenols and their metabolites have been also found to be crucial for preserving the microbial balance and overall health of the gut [185].
6 Challenges of MD for health and well-being
The MD has been demonstrated to be an appropriate dietary regimen that may lower the risk of noncommunicable diseases [188]. Promoting the MD as a healthy dietary pattern, on the other hand, offers obstacles that require the involvement of all levels of society [188]. One difficulty is the lack of a uniform definition and scoring system for the MD [189]. Another problem is the effect of nutritional transition, which encourages the move of traditional foods to Westernized diets, complicating adherence to the MD [189]. Despite its growing global appeal, adherence to the MD model is declining due to a variety of variables such as lifestyle changes, food globalization, economic, and sociocultural considerations [190]. These alterations endanger the maintenance and transfer of the Mediterranean food legacy to future generations [190]. Interestingly, middle-aged and older Hispanic or Latino people who adhere to the MD experience improved cognitive function and reduced 7-year learning and memory loss. MD that is culturally adjusted may minimize the risk of cognitive decline and Alzheimer’s disease [191]. More cross-disciplinary research on the environmental, economic, sociocultural, and sustainability components of the MD is expected to be extremely important [190]. MD containing plenty of plant foods with limited processing has been associated with increased life expectancy and a decreased risk of developing a number of chronic diseases [192]. Moreover, a Mediterranean-style diet may reduce the prevalence of gestational diabetes mellitus in pregnant women with metabolic risk factors [193]. A Mediterranean-style diet has also been shown to reduce the likelihood of GERD symptoms [194]. Unfortunately, as life and the drug industry have advanced, this knowledge has become steadily less communicated and is on the verge of extinction, necessitating the need to preserve and integrate traditional medicine into the current health system through ethnobotany and ethnopharmacology [195]. As the diet is contributing mainly in obesity, it raised the risk of a variety of benign digestive disorders. Obesity-induced mechanical and humoral variables are implicated in the development of esophageal illnesses, whereas obesity-induced proinflammatory and inflammatory cytokines appear to be involved in the pathophysiology of other digestive disorders. Furthermore, excess weight and obesity increase free fatty acid, TNF-α, and resistin levels while decreasing adiponectin. This causes insulin resistance and changes in the IGF-1 pathway, as well as inhibiting apoptosis and increasing cell proliferation on target cells. Obesity elevates free fatty acids and modifies adipocytokines. This metabolic change results in metabolic syndrome, which includes insulin resistance, dyslipidemia, and hypertension. In addition, metabolic changes and metabolic syndrome have a role in both benign and malignant digestive disorders. Obesity’s mechanical impact may lead to esophageal disease and other digestive disorders [196].
7 Conclusion
Disorders affecting the digestive system have a substantial impact on global health, resulting in elevated rates of illness and mortality. These challenges are particularly pronounced in rural areas where knowledge about sanitation and disease prevention is limited. In less developed countries, plant-based therapies frequently serve as the primary approach for preventing and treating gastrointestinal diseases. Numerous studies have validated the traditional use of these therapies by investigating their pharmacological effects on various diets and plants. These effects include reducing gas, relieving spasms, slowing intestinal transit, influencing gut motility, stimulating absorption, or decreasing electrolyte secretion. The MD, renowned for its rich variety of plant-based foods, is acknowledged as a dietary pattern that promotes overall health and well-being. This diet incorporates foods high in polyphenols, such as olive oil, walnuts, vegetables, fruits, legumes, wild edible plants, and whole grains, all of which are known to provide digestive benefits. Phytochemicals derived from plants and diet, particularly polyphenols, can function independently or synergistically to mitigate digestive system complications. Present scientific assessments of plant-based products primarily aim to validate and identify active components in extracts and other preparations. However, certain herbal preparations or active ingredients can cause severe side effects under specific conditions. As a result, it is crucial to establish a scientific foundation for their activity and to better evaluate the quality, effectiveness, and safety of traditionally used diets and medicinal plant-based preparations. Well-designed clinical trials are required to verify herbal medicines and offer the proof that’s needed to justify their efficacy. The safety and tolerability of traditional and herbal medications used to treat problems of the digestive system have not been well studied in clinical trials, but those that have been performed have generally shown minimal adverse effects. To create alternative treatments for digestive disorders, more research on traditional plant-based remedies is necessary given the promising results of previous studies.
Acknowledgments
Author thanks Professor Bashar Saad work at Arab American University-Palestine and Al-Qasemi Academic College-Baqa Algharbiya for his expertise and support.
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Funding information: Author states no funding involved.
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Author contributions: A.K. performed the study conception and design, data collection and analysis, wrote the review paper, read and approved the final manuscript and agreed to be accountable for all aspects of the work. A.K. is the corresponding author and responsible for correctness reviewing data.
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Conflict of interest: Author states no conflict of interest.
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Data availability statement: The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
References
[1] Wang Y, Huang Y, Chase RC, Li T, Ramai D, Li S, et al. Global burden of digestive diseases: A systematic analysis of the global burden of diseases study, 1990-2019. Gastroenterology. 2023 Jun;165(3):773–83.10.1053/j.gastro.2023.05.050Search in Google Scholar PubMed
[2] Cao X, Zolnikova O, Maslennikov R, Reshetova M, Poluektova E, Bogacheva A, et al. Low short-chain-fatty-acid-producing activity of the gut microbiota is associated with hypercholesterolemia and liver fibrosis in patients with metabolic-associated (Non-Alcoholic) fatty liver disease. Gastrointest Disord. 2023 Oct 30;5(4):464–73.10.3390/gidisord5040038Search in Google Scholar
[3] Kliegman RM, Toth H, Bordini BJ, Basel D, editors. Nelson pediatric symptom-based diagnosis. Nelson: Elsevier Health Sciences; 2022 Jan.Search in Google Scholar
[4] Hazel K, O’Connor A. Emerging treatments for inflammatory bowel disease. Ther Adv Chronic Dis. 2020 Feb;11:2040622319899297.10.1177/2040622319899297Search in Google Scholar PubMed PubMed Central
[5] Cai Z, Wang S, Li J. Treatment of inflammatory bowel disease: a comprehensive review. Front Med. 2021 Dec;8:765474.10.3389/fmed.2021.765474Search in Google Scholar PubMed PubMed Central
[6] Atanasov AG, Zotchev SB, Dirsch VM, Supuran CT. International natural product sciences taskforce. Nat Rev Drug Discov. 2021;20:200–16. 10.1038/s41573-020-00114-z Search in Google Scholar PubMed PubMed Central
[7] Cuvelier ME. Antioxidative activity and phenolic composition of pilot-plant and commercial extracts of sage and rosemary. JAOCS. 2002;162:981–7.Search in Google Scholar
[8] El-Darier SM, El-Mogaspi FM. Ethnobotany and relative importance of some endemic plant species at El-Jabal El-Akhdar Region (Libya). World J Agric Sci. 2009;5(3):353–60.Search in Google Scholar
[9] Ezzoubi Y, Bousta D, Farah A. A Phytopharmacological review of a Mediterranean plant: Lavandula stoechas L. Clin Phytoscience. 2020 Dec;6:1–9.10.1186/s40816-019-0142-ySearch in Google Scholar
[10] Grigoriadou K, Krigas N, Lazari D, Maloupa E. Sustainable use of mediterranean medicinal-aromatic plants. In Feed additives. Cambridge, Massachusetts: Academic Press; 2020. p. 57–74.10.1016/B978-0-12-814700-9.00004-2Search in Google Scholar
[11] Cheema HS, Prakash O, Pal A, Khan F, Bawankule DU, Darokar MP. Glabridin induces oxidative stress mediated apoptosis like cell death of malaria parasite Plasmodium falciparum. Parasitol Int. 2014 Apr;63(2):349–58.10.1016/j.parint.2013.12.005Search in Google Scholar PubMed
[12] Kmail A, Mansour B, Hanaisheh R, Omar G, Jaradat N, Said O, et al. Modulatory effects of leave and fruit extracts of ficus sycomorus on cytostatic and inflammatory mediators in monocultures and Co-cultures of human Keratinocyte (HaCat) and human Monocyte (THP-1) cell lines. EJMP. 2022;33(9):1–14.10.9734/ejmp/2022/v33i930486Search in Google Scholar
[13] Granato D, Barba FJ, Bursać Kovačević D, Lorenzo JM, Cruz AG, Putnik P. Functional foods: Product development, technological trends, efficacy testing, and safety. Annu Rev Food Sci Technol. 2020 Mar;11:93–118.10.1146/annurev-food-032519-051708Search in Google Scholar PubMed
[14] Jakubczyk D, Leszczyńska K, Górska S. The effectiveness of probiotics in the treatment of inflammatory bowel disease (IBD) – a critical review. Nutrients. 2020 Jul;12(7):1973.10.3390/nu12071973Search in Google Scholar PubMed PubMed Central
[15] Mack DR. Probiotics in inflammatory bowel diseases and associated conditions. Nutrients. 2011 Feb;3(2):245–64.10.3390/nu3020245Search in Google Scholar PubMed PubMed Central
[16] Brownawell AM, Caers W, Gibson GR, Kendall CW, Lewis KD, Ringel Y, et al. Prebiotics and the health benefits of fiber: current regulatory status, future research, and goals. J Nutr. 2012 May;142(5):962–74.10.3945/jn.112.158147Search in Google Scholar PubMed
[17] Carreras-Torres R, Ibanez-Sanz G, Obon-Santacana M, Duell EJ, Moreno V. Identifying environmental risk factors for inflammatory bowel diseases: a Mendelian randomization study. Sci Rep. 2020;10(1):19273.10.1038/s41598-020-76361-2Search in Google Scholar PubMed PubMed Central
[18] Blanton C, He Z, Gottschall-Pass KT, Sweeney MI. Probiotics blunt the anti-hypertensive effect of blueberry feeding in hypertensive rats without altering hippuric acid production. PLoS One. 2015 Nov;10(11):e0142036.10.1371/journal.pone.0142036Search in Google Scholar PubMed PubMed Central
[19] Odes HS, Madar Z. A double-blind trial of a celandin, aloevera and psyllium laxative preparation in adult patients with constipation. Digestion. 1991 Feb;49(2):65–71.10.1159/000200705Search in Google Scholar PubMed
[20] Panahi Y, Khedmat H, Valizadegan G, Mohtashami R, Sahebkar A. Efficacy and safety of Aloe vera syrup for the treatment of gastroesophageal reflux disease: a pilot randomized positive-controlled trial. J Tradit Chin Med. 2015 Dec;35(6):632–6.10.1016/S0254-6272(15)30151-5Search in Google Scholar
[21] Menzel J, Jabakhanji A, Biemann R, Mai K, Abraham K, Weikert C. Systematic review and meta-analysis of the associations of vegan and vegetarian diets with inflammatory biomarkers. Sci Rep. 2020 Dec;10(1):21736.10.1038/s41598-020-78426-8Search in Google Scholar PubMed PubMed Central
[22] Tsoupras A, Lordan R, Zabetakis I. Inflammation, not cholesterol, is a cause of chronic disease. Nutrients. 2018 May;10(5):604.10.3390/nu10050604Search in Google Scholar PubMed PubMed Central
[23] Elmaliklis IN, Liveri A, Ntelis B, Paraskeva K, Goulis I, Koutelidakis AE. Increased functional foods’ consumption and Mediterranean diet adherence may have a protective effect in the appearance of gastrointestinal diseases: a case–control study. Medicines. 2019 Apr;6(2):50.10.3390/medicines6020050Search in Google Scholar PubMed PubMed Central
[24] Park JY, Nicolas G, Freisling H, Biessy C, Scalbert A, Romieu I, et al. Comparison of standardised dietary folate intake across ten countries participating in the European Prospective Investigation into Cancer and Nutrition. Br J Nutr. 2012 Aug;108(3):552–69.10.1017/S0007114511005733Search in Google Scholar PubMed
[25] Merra G, Noce A, Marrone G, Cintoni M, Tarsitano MG, Capacci A, et al. Influence of mediterranean diet on human gut microbiota. Kompass Nutr Dietetics. 2022 Apr;2(1):19–25.10.1159/000523727Search in Google Scholar
[26] Hidalgo-Mora JJ, García-Vigara A, Sánchez-Sánchez ML, García-Pérez MÁ, Tarín J, Cano A. The Mediterranean diet: A historical perspective on food for health. Maturitas. 2020 Feb;132:65–9.10.1016/j.maturitas.2019.12.002Search in Google Scholar PubMed
[27] Saad B, Dakwar S, Said O, Abu-Hijleh G, Battah FA, Kmeel A, et al. Evaluation of medicinal plant hepatotoxicity in co-cultures of hepatocytes and monocytes. Evidence-Based Complementary Altern Med. 2006 Mar;3:93–8.10.1093/ecam/nel002Search in Google Scholar PubMed PubMed Central
[28] Kokkini S, Karousou R, Dardioti A, Krigas N, Lanaras T. Autumn essential oils of Greek oregano. Phytochemistry. 1997 Mar;44(5):883–6.10.1016/S0031-9422(96)00576-6Search in Google Scholar
[29] Lis A, Kowal M, Kończak J. Chemical Composition Variability of the Herb Essential Oil in the Ontogenesis of Artemisia campestris subsp. campestris. Nat Product Commun. 2015 Oct;10(10):1934578X1501001032.10.1177/1934578X1501001032Search in Google Scholar
[30] Saad B. A review of the anti-obesity effects of wild edible plants in the mediterranean diet and their active compounds: from traditional uses to action mechanisms and therapeutic targets. Int J Mol Sci. 2023 Aug;24(16):12641.10.3390/ijms241612641Search in Google Scholar PubMed PubMed Central
[31] Sitarek P, Merecz-Sadowska A, Kowalczyk T, Wieczfinska J, Zajdel R, Śliwiński T. Potential synergistic action of bioactive compounds from plant extracts against skin infecting microorganisms. Int J Mol Sci. 2020 Jul;21(14):5105.10.3390/ijms21145105Search in Google Scholar PubMed PubMed Central
[32] Goh BH, Mocan A, Xiao J, Mah SH, Yap WH. Targeting human inflammatory skin diseases with natural products: exploring potential mechanisms and regulatory pathways. Front Pharmacology. 2021 Nov;12:791151.10.3389/fphar.2021.791151Search in Google Scholar PubMed PubMed Central
[33] Delgado A, Gonçalves S, Romano A. Mediterranean diet: the role of phenolic compounds from aromatic plant foods. Foods. 2023 Feb;12(4):840.10.3390/foods12040840Search in Google Scholar PubMed PubMed Central
[34] Arnesen EK, Thorisdottir B, Bärebring L, Söderlund F, Nwaru BI, Spielau U, et al. Nuts and seeds consumption and risk of cardiovascular disease, type 2 diabetes and their risk factors: a systematic review and meta-analysis. Food Nutr Res. 2023;67:1–33.10.29219/fnr.v67.8961Search in Google Scholar PubMed PubMed Central
[35] Detopoulou P, Demopoulos CA, Antonopoulou S. Micronutrients, phytochemicals and mediterranean diet: A potential protective role against COVID-19 through modulation of PAF actions and metabolism. Nutrients. 2021 Jan;13(2):462.10.3390/nu13020462Search in Google Scholar PubMed PubMed Central
[36] Arnoni Y, Berry EM. On the origins and evolution of the Mediterranean diet. In The Mediterranean Diet. London: Academic Press; 2015 Jan. p. 3–11.10.1016/B978-0-12-407849-9.00001-4Search in Google Scholar
[37] Sperber AD, Bangdiwala SI, Drossman DA, Ghoshal UC, Simren M, Tack J, et al. Worldwide prevalence and burden of functional gastrointestinal disorders, results of Rome Foundation Global Study. Gastroenterology. 2021 Jan;160(1):99–114.10.1053/j.gastro.2020.04.014Search in Google Scholar PubMed
[38] Peery AF, Crockett SD, Murphy CC, Jensen ET, Kim HP, Egberg MD, et al. Burden and cost of gastrointestinal, liver, and pancreatic diseases in the United States: update 2021. Gastroenterology. 2022 Feb;162(2):621–44.10.1053/j.gastro.2021.10.017Search in Google Scholar PubMed PubMed Central
[39] Sepanlou SG, Malekzadeh F, Delavari F, Naghavi M, Forouzanfar MH, Moradi-Lakeh M, et al. Burden of gastrointestinal and liver diseases in Middle East and North Africa: results of global burden of diseases study from 1990 to 2010. Middle East J Digestive Dis. 2015 Oct;7(4):201.Search in Google Scholar
[40] Baklola M, Terra M, Badr A, Fahmy FM, Elshabrawy E, Hawas Y, et al. Prevalence of gastro-oesophageal reflux disease, and its associated risk factors among medical students: a nation-based cross-sectional study. BMC Gastroenterol. 2023 Aug;23(1):269.10.1186/s12876-023-02899-wSearch in Google Scholar PubMed PubMed Central
[41] Shaheen NJ, Hansen RA, Morgan DR, Gangarosa LM, Ringel Y, Thiny MT, et al. The burden of gastrointestinal and liver diseases, 2006. J Am Coll Gastroenterol ACG. 2006 Sep;101(9):2128–38.10.1111/j.1572-0241.2006.00723.xSearch in Google Scholar PubMed
[42] Fass R, Ofman JJ, Gralnek IM, Johnson C, Camargo E, Sampliner RE, et al. Clinical and economic assessment of the omeprazole test in patients with symptoms suggestive of gastroesophageal reflux disease. Arch Intern Med. 1999 Oct;159(18):2161–8.10.1001/archinte.159.18.2161Search in Google Scholar PubMed
[43] Fass O, Sampliner C, Wendel F. The omeprazole test is as sensitive as 24‐h oesophageal pH monitoring in diagnosing gastro‐oesophageal reflux disease in symptomatic patients with erosive oesophagitis. Aliment Pharmacol Ther. 2000 Apr;14(4):389–96.10.1046/j.1365-2036.2000.00733.xSearch in Google Scholar PubMed
[44] Roark R, Sydor M, Chatila AT, Umar S, De La Guerra R, Bilal M, et al. Management of gastroesophageal reflux disease. Disease-a-Month. 2020 Jan;66(1):100849.10.1016/j.disamonth.2019.02.002Search in Google Scholar PubMed
[45] Mintah SO, Asafo-Agyei T, Archer MA, Junior PA, Boamah D, Kumadoh D, et al. Medicinal plants for treatment of prevalent diseases. Pharmacogn-Med Plants. 2019. p. 1–9. 10.5772/intechopen.82049.Search in Google Scholar
[46] Tran N, Pham B, Le L. Bioactive compounds in anti-diabetic plants: From herbal medicine to modern drug discovery. Biology. 2020 Aug;9(9):252.10.3390/biology9090252Search in Google Scholar PubMed PubMed Central
[47] Cordero CS, Meve U, Alejandro GJ. Ethnobotanical documentation of medicinal plants used by the indigenous panay bukidnon in lambunao, iloilo, Philippines. Front Pharmacol. 2022 Jan;12:790567.10.3389/fphar.2021.790567Search in Google Scholar PubMed PubMed Central
[48] Kang Z, Zhonga Y, Wu T, Huang J, Zhao H, Liu D. Ginsenoside from ginseng: a promising treatment for inflammatory bowel disease. Pharmacol Rep. 2021 Jun;73:700–11.10.1007/s43440-020-00213-zSearch in Google Scholar PubMed PubMed Central
[49] Shaito A, Thuan DT, Phu HT, Nguyen TH, Hasan H, Halabi S, et al. Herbal medicine for cardiovascular diseases: efficacy, mechanisms, and safety. Front Pharmacol. 2020 Apr;11:422.10.3389/fphar.2020.00422Search in Google Scholar PubMed PubMed Central
[50] Batiha GE, Teibo JO, Wasef L, Shaheen HM, Akomolafe AP, Teibo TK, et al. A review of the bioactive components and pharmacological properties of Lavandula species. Naunyn-schmiedeberg’s Arch Pharmacol. 2023 May;396(5):877–900.10.1007/s00210-023-02392-xSearch in Google Scholar PubMed PubMed Central
[51] Mangisa M, Kemboi D, Fouche G, Nthambeleni R, Langat MK, Tarirai C, et al. Ethnomedicinal Uses, phytochemistry and pharmacological properties of Suregada genus: a review. Pharmaceuticals. 2023 Sep;16(10):1390.10.3390/ph16101390Search in Google Scholar PubMed PubMed Central
[52] Vivanco PG, Taboada P, Coelho A. The Southern European atlantic diet and its supplements: The chemical bases of its anticancer properties. Nutrients. 2023 Oct;15(19):4274.10.3390/nu15194274Search in Google Scholar PubMed PubMed Central
[53] Pavić V, Jakovljević M, Molnar M, Jokić S. Extraction of carnosic acid and carnosol from sage (Salvia officinalis L.) leaves by supercritical fluid extraction and their antioxidant and antibacterial activity. Plants. 2019 Jan;8(1):16.10.3390/plants8010016Search in Google Scholar PubMed PubMed Central
[54] Gutiérrez-Grijalva EP, Picos-Salas MA, Leyva-López N, Criollo-Mendoza MS, Vazquez-Olivo G, Heredia JB. Flavonoids and phenolic acids from oregano: Occurrence, biological activity and health benefits. Plants. 2017 Dec;7(1):2.10.3390/plants7010002Search in Google Scholar PubMed PubMed Central
[55] Al-Snafi AE. Chemical constituents and pharmacological effects of Cynodon dactylon-A review. IOSR J Pharm. 2016;6(7):17–31.10.9790/3013-06721731Search in Google Scholar
[56] Monari S, Ferri M, Salinitro M, Tassoni A. New insights on primary and secondary metabolite contents of seven italian wild food plants with medicinal applications: A comparative study. Plants. 2023 Sep;12(18):3180.10.3390/plants12183180Search in Google Scholar PubMed PubMed Central
[57] Dereli FT, Ilhan M, Belwal T, editors. Novel drug targets with traditional herbal medicines: Scientific and clinical evidence. Cham: Springer International Publishing; 2022. p. 495–512.Search in Google Scholar
[58] Hęś M, Dziedzic K, Górecka D, Jędrusek-Golińska A, Gujska E. Aloe vera (L.) Webb.: natural sources of antioxidants–a review. Plant Foods for Human Nutrition. Dordrecht, Netherlands. Vol. 74; 2019 Sep. p. 255–6510.1007/s11130-019-00747-5Search in Google Scholar PubMed PubMed Central
[59] Fuloria S, Mehta J, Chandel A, Sekar M, Rani NN, Begum MY, et al. A comprehensive review on the therapeutic potential of Curcuma longa Linn. in relation to its major active constituent curcumin. Front Pharmacol. 2022 Mar;13:820806.10.3389/fphar.2022.820806Search in Google Scholar PubMed PubMed Central
[60] Semwal RB, Semwal DK, Combrinck S, Viljoen AM. Gingerols and shogaols: Important nutraceutical principles from ginger. Phytochemistry. 2015 Sep;117:554–68.10.1016/j.phytochem.2015.07.012Search in Google Scholar PubMed
[61] Chaachouay N, Belhaj S, El Khomsi M, Benkhnigue O, Zidane L. Herbal remedies used to treat digestive system ailments by indigenous communities in the Rif region of northern Morocco. Vegetos. 2024 Feb;37(1):379–96.10.1007/s42535-023-00606-4Search in Google Scholar
[62] Aziz MA, Adnan M, Khan AH, Shahat AA, Al-Said MS, Ullah R. Traditional uses of medicinal plants practiced by the indigenous communities at Mohmand Agency, FATA, Pakistan. J Ethnobiol Ethnomed. 2018 Dec;14:1–6.10.1186/s13002-017-0204-5Search in Google Scholar PubMed PubMed Central
[63] Martinez-Aledo N, Navas-Carrillo D, Orenes-Pinero E. Medicinal plants: active compounds, properties and antiproliferative effects in colorectal cancer. Phytochem Rev. 2020 Feb;19:123–37.10.1007/s11101-020-09660-1Search in Google Scholar
[64] Del Valle J. Peptic ulcer disease and related disorders. Harrisons Princ Intern Med. 2005;16(2):1746.Search in Google Scholar
[65] Lanas A, Chan FK. Peptic ulcer disease. Lancet. 2017 Aug;390(10094):613–24.10.1016/S0140-6736(16)32404-7Search in Google Scholar PubMed
[66] Rosenstock SJ, Jørgensen T. Prevalence and incidence of peptic ulcer disease in a Danish County--a prospective cohort study. Gut. 1995 Jun;36(6):819–24.10.1136/gut.36.6.819Search in Google Scholar PubMed PubMed Central
[67] Kurata JH, Nogawa AN, Abbey DE, Petersen F. A prospective study of risk for peptic ulcer disease in Seventh-Day Adventists. Gastroenterology. 1992 Mar;102(3):902–9.10.1016/0016-5085(92)90176-YSearch in Google Scholar PubMed
[68] McQuaid KR. Drugs used in the treatment of gastrointestinal diseases (Ch. 62). In: Katzung BG, Trevor AJ, editors. Basic and Clinical Pharmacology. 15th edn. San Francisco: McGraw-Hill/Medical; 2020.Search in Google Scholar
[69] Alatab S, Sepanlou SG, Ikuta K, Vahedi H, Bisignano C, Safiri S, et al. The global, regional, and national burden of inflammatory bowel disease in 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Gastroenterol Hepatol. 2020 Jan;5(1):17–30.Search in Google Scholar
[70] Benchimol EI, Mack DR, Guttmann A, Nguyen GC, To T, Mojaverian N, et al. Inflammatory bowel disease in immigrants to Canada and their children: a population-based cohort study. Off J Am Coll Gastroenterol ACG. 2015 Apr;110(4):553–63.10.1038/ajg.2015.52Search in Google Scholar PubMed
[71] Biller LH, Schrag D. Diagnosis and treatment of metastatic colorectal cancer: a review. Jama. 2021 Feb;325(7):669–85.10.1001/jama.2021.0106Search in Google Scholar PubMed
[72] Kanth P, Inadomi JM. Screening and prevention of colorectal cancer. Bmj. 2021 Sep;374:n1855.10.1136/bmj.n1855Search in Google Scholar PubMed
[73] Singh P, Tuck C, Gibson PR, Chey WD. The role of food in the treatment of bowel disorders: focus on irritable bowel syndrome and functional constipation. Am J Gastroenterology. 2022 Jun;117(6):947.10.14309/ajg.0000000000001767Search in Google Scholar PubMed PubMed Central
[74] Lovell RM, Ford AC. Global prevalence of and risk factors for irritable bowel syndrome: a meta-analysis. Clin Gastroenterol Hepatol. 2012 Jul;10(7):712–21.10.1016/j.cgh.2012.02.029Search in Google Scholar PubMed
[75] Lovell RM, Ford AC. Effect of gender on prevalence of irritable bowel syndrome in the community: systematic review and meta-analysis. Off J Am Coll Gastroenterol ACG. 2012 Jul;107(7):991–1000.10.1038/ajg.2012.131Search in Google Scholar PubMed
[76] Canavan C, West J, Card T. The economic impact of the irritable bowel syndrome. Aliment Pharmacol Ther. 2014 Nov;40(9):1023–34.10.1111/apt.12938Search in Google Scholar PubMed
[77] Bond A, Huijbers A, Pironi L, Schneider SM, Wanten G, Lal S. Diagnosis and management of intestinal failure‐associated liver disease in adults. Aliment Pharmacol Ther. 2019 Sep;50(6):640–53.10.1111/apt.15432Search in Google Scholar PubMed
[78] Cui Y, Wang Q, Chang R, Zhou X, Xu C. Intestinal barrier function–non-alcoholic fatty liver disease interactions and possible role of gut microbiota. J Agric Food Chem. 2019 Feb;67(10):2754–62.10.1021/acs.jafc.9b00080Search in Google Scholar PubMed
[79] Trefts E, Gannon M, Wasserman DH. The liver. Curr Biol. 2017;27(21):R1147–51.10.1016/j.cub.2017.09.019Search in Google Scholar PubMed PubMed Central
[80] Asrani SK, Devarbhavi H, Eaton J, Kamath PS. Burden of liver diseases in the world. J Hepatology. 2019 Jan;70(1):151–71.10.1016/j.jhep.2018.09.014Search in Google Scholar PubMed
[81] Ding L, Li J, Song B, Xiao X, Huang W, Zhang B, et al. Andrographolide prevents high-fat diet–induced obesity in C57BL/6 mice by suppressing the sterol regulatory element-binding protein pathway. J Pharmacol Exp Therapeutics. 2014 Nov;351(2):474–83.10.1124/jpet.114.217968Search in Google Scholar PubMed
[82] Marjani M, Baghaei P, Dizaji MK, Bayani PG, Fahimi F, Tabarsi P, et al. Evaluation of hepatoprotective effect of silymarin among under treatment tuberculosis patients: a randomized clinical trial. Iran J Pharm Res: IJPR. 2016;15(1):247.Search in Google Scholar
[83] Saller R, Meier R, Brignoli R. The use of silymarin in the treatment of liver diseases. Drugs. 2001 Dec;61:2035–63.10.2165/00003495-200161140-00003Search in Google Scholar PubMed
[84] Pandey B, Baral R, Kaundinnyayana A, Panta S. Promising hepatoprotective agents from the natural sources: a study of scientific evidence. Egypt Liver J. 2023 Mar;13(1):14.10.1186/s43066-023-00248-wSearch in Google Scholar
[85] Arman M, Chowdhury KA, Bari MS, Khan MF, Huq MM, Haque MA, et al. Hepatoprotective potential of selected medicinally important herbs: evidence from ethnomedicinal, toxicological and pharmacological evaluations. Phytochem Rev. 2022 Dec;21(6):1863–86.10.1007/s11101-022-09812-5Search in Google Scholar
[86] Ugwu CE, Suru SM. Medicinal plants with hepatoprotective potentials against carbon tetrachloride-induced toxicity: a review. Egypt Liver J. 2021 Dec;11(1):1–26.10.1186/s43066-021-00161-0Search in Google Scholar
[87] Son CG, Wei Z, Raghavendran HB, Wang JH, Janda E. Medicinal herbs and their active compounds for fatty liver diseases. Evidence-Based Complementary Altern Med. 2017 Jan;2017:3612478.10.1155/2017/3612478Search in Google Scholar PubMed PubMed Central
[88] Fulda S. Betulinic acid for cancer treatment and prevention. Int J Mol Sci. 2008 Jun;9(6):1096–107.10.3390/ijms9061096Search in Google Scholar PubMed PubMed Central
[89] Gong JY, Ren H, Peng SY, Xing K, Fan L, Liu MZ, et al. Comparative effectiveness of glycyrrhizic acid preparations aimed at preventing and treating anti-tuberculosis drug-induced liver injury: a network meta-analysis of 97 randomized controlled trials. Phytomedicine. 2022 Apr;98:153942.10.1016/j.phymed.2022.153942Search in Google Scholar PubMed
[90] Kara E, Coşkun T, Kaya Y, Yumuş O, Vatansever S, Var A. Effects of silymarin and pentoxifylline on matrix metalloproteinase-1 and-2 expression and apoptosis in experimental hepatic fibrosis. Curr Ther Res. 2008 Dec;69(6):488–502.10.1016/j.curtheres.2008.12.003Search in Google Scholar PubMed PubMed Central
[91] Sen A. Prophylactic and therapeutic roles of oleanolic acid and its derivatives in several diseases. World J Clin Cases. 2020 May;8(10):1767.10.12998/wjcc.v8.i10.1767Search in Google Scholar PubMed PubMed Central
[92] Kataria R, Pickett-Blakely O. The Mediterranean Diet in Gastrointestinal and liver diseases. Curr Treat Options Gastroenterol. 2020 Dec;18:718–28.10.1007/s11938-020-00318-7Search in Google Scholar
[93] Yao Y, Habib M, Bajwa HF, Qureshi A, Fareed R, Altaf R, et al. Herbal therapies in gastrointestinal and hepatic disorders: An evidence-based clinical review. Front Pharmacol. 2022 Oct;13:3980.10.3389/fphar.2022.962095Search in Google Scholar PubMed PubMed Central
[94] Salmi HA, Sarna S. Effect of silymarin on chemical, functional, and morphological alterations of the liver: a double-blind controlled study. Scand J Gastroenterol. 1982 Jun;17(4):517–21.10.3109/00365528209182242Search in Google Scholar PubMed
[95] Anushiravani A, Haddadi N, Pourfarmanbar M, Mohammadkarimi V. Treatment options for nonalcoholic fatty liver disease: a double-blinded randomized placebo-controlled trial. Eur J Gastroenterol Hepatol. 2019 May;31(5):613–7.10.1097/MEG.0000000000001369Search in Google Scholar PubMed
[96] Clichici S, Olteanu D, Nagy AL, Oros A, Filip A, Mircea PA. Silymarin inhibits the progression of fibrosis in the early stages of liver injury in CCl4-treated rats. J Med Food. 2015 Mar;18(3):290–8.10.1089/jmf.2013.0179Search in Google Scholar PubMed
[97] Zhang P, Ma D, Wang Y, Zhang M, Qiang X, Liao M, et al. Berberine protects liver from ethanol-induced oxidative stress and steatosis in mice. Food Chem Toxicol. 2014 Dec;74:225–32.10.1016/j.fct.2014.10.005Search in Google Scholar PubMed
[98] Simental-Mendía LE, Pirro M, Gotto AM Jr, Banach M, Atkin SL, Majeed M, et al. Lipid-modifying activity of curcuminoids: A systematic review and meta-analysis of randomized controlled trials. Crit Rev Food Sci Nutr. 2019 Apr;59(7):1178–87.10.1080/10408398.2017.1396201Search in Google Scholar PubMed
[99] Zendedel E, Butler AE, Atkin SL, Sahebkar A. Impact of curcumin on sirtuins: A review. J Cell Biochem. 2018 Dec;119(12):10291–300.10.1002/jcb.27371Search in Google Scholar PubMed
[100] Lee ES, Kwon MH, Kim HM, Woo HB, Ahn CM, Chung CH. Curcumin analog CUR5–8 ameliorates nonalcoholic fatty liver disease in mice with high-fat diet-induced obesity. Metabolism. 2020 Feb;103:154015.10.1016/j.metabol.2019.154015Search in Google Scholar PubMed
[101] Rahmani S, Asgary S, Askari G, Keshvari M, Hatamipour M, Feizi A, et al. Treatment of non‐alcoholic fatty liver disease with curcumin: A randomized placebo‐controlled trial. Phytother Res. 2016 Sep;30(9):1540–8.10.1002/ptr.5659Search in Google Scholar PubMed
[102] Mirhafez SR, Azimi-Nezhad M, Dehabeh M, Hariri M, Naderan RD, Movahedi A, et al. The effect of curcumin phytosome on the treatment of patients with non-alcoholic fatty liver disease: a double-blind, randomized, placebo-controlled trial. In: Pharmacological properties of plant-derived natural products and implications for human health. Vol. 1308; 2021. p. 25–35.10.1007/978-3-030-64872-5_3Search in Google Scholar PubMed
[103] Chen G, Bei B, Feng Y, Li X, Jiang Z, Si JY, et al. Glycyrrhetinic acid maintains intestinal homeostasis via HuR. Front Pharmacology. 2019 May;10:535.10.3389/fphar.2019.00535Search in Google Scholar PubMed PubMed Central
[104] Kim M, Yang SG, Kim JM, Lee JW, Kim YS, Lee JI. Silymarin suppresses hepatic stellate cell activation in a dietary rat model of non-alcoholic steatohepatitis: Analysis of isolated hepatic stellate cells. Int J Mol Med. 2012 Sep;30(3):473–9.10.3892/ijmm.2012.1029Search in Google Scholar PubMed PubMed Central
[105] Harish R, Shivanandappa T. Antioxidant activity and hepatoprotective potential of Phyllanthus niruri. Food Chem. 2006 Mar;95(2):180–5.10.1016/j.foodchem.2004.11.049Search in Google Scholar
[106] Lin CM, Lee JF, Chiang LL, Chen CF, Wang D, Su CL. The protective effect of curcumin on ischemia-reperfusion–induced liver injury. In Transplantation proceedings. Vol. 44. Issue 4. USA: Elsevier; 2012 May. p. 974–7.10.1016/j.transproceed.2012.01.081Search in Google Scholar PubMed
[107] Antunes C, Arbo MD, Konrath EL. Hepatoprotective native plants documented in Brazilian traditional medicine literature: Current knowledge and prospects. Chem & Biodivers. 2022 Jun;19(6):e202100933.10.1002/cbdv.202100933Search in Google Scholar PubMed
[108] Ahmad A, Ahmad R. Resveratrol mitigate structural changes and hepatic stellate cell activation in N′-nitrosodimethylamine-induced liver fibrosis via restraining oxidative damage. Chem-Biol Interact. 2014 Sep;221:1–2.10.1016/j.cbi.2014.07.007Search in Google Scholar PubMed
[109] Koutelidakis A, Dimou C. The effects of functional food and bioactive compounds on biomarkers of cardiovascular diseases. In: Martirosyan D, editor. Functional foods in health and disease; USA. 1st edn. 2016. p. 89–117.Search in Google Scholar
[110] Kwak NS, Jukes DJ. Functional foods. Part 2: the impact on current regulatory terminology. Food Control. 2001 Mar;12(2):109–17.10.1016/S0956-7135(00)00029-3Search in Google Scholar
[111] Trichopoulou A, Bamia C, Trichopoulos D. Anatomy of health effects of Mediterranean diet: Greek EPIC prospective cohort study. Bmj. 2009 Jun;338:b2337.10.1136/bmj.b2337Search in Google Scholar PubMed PubMed Central
[112] García-Montero C, Fraile-Martinez O, Gomez-Lahoz AM, Pekarek L, Castellanos AJ, et al. Nutritional components in Western diet versus Mediterranean diet at the gut microbiota–immune system interplay. Implications for health and disease. Nutrients. 2021 Feb;13(2):699.10.3390/nu13020699Search in Google Scholar PubMed PubMed Central
[113] Vanuytsel T, Van Wanrooy S, Vanheel H, Vanormelingen C, Verschueren S, Houben E, et al. Psychological stress and corticotropin-releasing hormone increase intestinal permeability in humans by a mast cell-dependent mechanism. Gut. 2014 Aug;63(8):1293–9.10.1136/gutjnl-2013-305690Search in Google Scholar PubMed
[114] De la Roca-Chiapas JM, Solís-Ortiz S, Fajardo-Araujo M, Sosa M, Córdova-Fraga T, Rosa-Zarate A. Stress profile, coping style, anxiety, depression, and gastric emptying as predictors of functional dyspepsia: a case-control study. J Psychosom Res. 2010 Jan;68(1):73–81.10.1016/j.jpsychores.2009.05.013Search in Google Scholar PubMed
[115] Gentschew L, Ferguson LR. Role of nutrition and microbiota in susceptibility to inflammatory bowel diseases. Mol Nutr Food Res. 2012 Apr;56(4):524–35.10.1002/mnfr.201100630Search in Google Scholar PubMed
[116] Valdes AM, Walter J, Segal E, Spector TD. Role of the gut microbiota in nutrition and health. Bmj. 2018 Jun;361.10.1136/bmj.k2179Search in Google Scholar PubMed PubMed Central
[117] Santonicola A, Gagliardi M, Guarino MP, Siniscalchi M, Ciacci C, Iovino P. Eating disorders and gastrointestinal diseases. Nutrients. 2019 Dec;11(12):3038.10.3390/nu11123038Search in Google Scholar PubMed PubMed Central
[118] De Luca I, Di Cristo F, Valentino A, Peluso G, Di Salle A, Calarco A. Food-derived bioactive molecules from mediterranean diet: nanotechnological approaches and waste valorization as strategies to improve human wellness. Polymers. 2022 Apr;14(9):1726.10.3390/polym14091726Search in Google Scholar PubMed PubMed Central
[119] Menotti A, Puddu PE, Catasta G. Dietary habits, cardiovascular and other causes of death in a practically extinct cohort of middle-aged men followed-up for 61 years. Nutr Metab Cardiovasc Dis. 2022 Aug;32(8):1819–29.10.1016/j.numecd.2022.04.010Search in Google Scholar PubMed
[120] Jenkins D, Modolell I. Proton pump inhibitors. BMJ. 2023 Nov;383:e070752.10.1136/bmj-2022-070752Search in Google Scholar PubMed
[121] Voropaiev M, Nock D. Onset of acid-neutralizing action of a calcium/magnesium carbonate-based antacid using an artificial stomach model: an in vitro evaluation. BMC Gastroenterol. 2021 Dec;21(1):1–6.10.1186/s12876-021-01687-8Search in Google Scholar PubMed PubMed Central
[122] El Rouby N, Lima JJ, Johnson JA. Proton pump inhibitors: from CYP2C19 pharmacogenetics to precision medicine. Expert Opin Drug Metab Toxicol. 2018 Apr;14(4):447–60.10.1080/17425255.2018.1461835Search in Google Scholar PubMed PubMed Central
[123] Modak AS, Klyarytska I, Kriviy V, Tsapyak T, Rabotyagova Y. The effect of proton pump inhibitors on the CYP2C19 enzyme activity evaluated by the pantoprazole-13C breath test in GERD patients: clinical relevance for personalized medicine. J Breath Res. 2016 Dec;10(4):046017.10.1088/1752-7163/10/4/046017Search in Google Scholar PubMed
[124] Arya AK, Durgapal M, Bachheti A, Joshi KK, Gonfa YH, Bachheti RK, et al. Ethnomedicinal use, phytochemistry, and other potential application of aquatic and semiaquatic medicinal plants. Evidence-Based Complementary Altern Med. 2022 Aug;2022:4931556.10.1155/2022/4931556Search in Google Scholar PubMed PubMed Central
[125] Saleh HA, Yousef MH, Abdelnaser A. The anti-inflammatory properties of phytochemicals and their effects on epigenetic mechanisms involved in TLR4/NF-κB-mediated inflammation. Front Immunol. 2021 Mar;12:606069.10.3389/fimmu.2021.606069Search in Google Scholar PubMed PubMed Central
[126] Yu C, Wang D, Yang Z, Wang T. Pharmacological effects of polyphenol phytochemicals on the intestinal inflammation via targeting TLR4/NF-κB signaling pathway. Int J Mol Sci. 2022 Jun;23(13):6939.10.3390/ijms23136939Search in Google Scholar PubMed PubMed Central
[127] Lillehoj H, Liu Y, Calsamiglia S, Fernandez-Miyakawa ME, Chi F, Cravens RL, et al. Phytochemicals as antibiotic alternatives to promote growth and enhance host health. Vet Res. 2018 Dec;49(1):1–8.10.1186/s13567-018-0562-6Search in Google Scholar PubMed PubMed Central
[128] El Amrousy D, Elashry H, Salamah A, Maher S, Abd-Elsalam SM, Hasan S. Adherence to the mediterranean diet improved clinical scores and inflammatory markers in children with active inflammatory bowel disease: A randomized trial. J Inflamm Res. 2022 Mar;2022:2075–86.10.2147/JIR.S349502Search in Google Scholar PubMed PubMed Central
[129] Fürst R, Zündorf I. Plant-derived anti-inflammatory compounds: hopes and disappointments regarding the translation of preclinical knowledge into clinical progress. Mediators Inflamm. 2014 Oct;2014:146832.10.1155/2014/146832Search in Google Scholar PubMed PubMed Central
[130] Cho SY, Park SJ, Kwon MJ, Jeong TS, Bok SH, Choi WY, et al. Quercetin suppresses proinflammatory cytokines production through MAP kinases and NF-κB pathway in lipopolysaccharide-stimulated macrophage. Mol Cell Biochem. 2003 Jan;243:153–60.10.1023/A:1021624520740Search in Google Scholar
[131] Shao D, Lian Z, Di Y, Zhang L, Rajoka MS, Zhang Y, et al. Dietary compounds have potential in controlling atherosclerosis by modulating macrophage cholesterol metabolism and inflammation via miRNA. npj Science of Food. 2018 Jul;2(1):13.10.1038/s41538-018-0022-8Search in Google Scholar PubMed PubMed Central
[132] Aggarwal BB, Kumar A, Bharti AC. Anticancer potential of curcumin: preclinical and clinical studies. Anticancer Res. 2003 Jan;23(1/A):363–98.Search in Google Scholar
[133] Menon VP, Sudheer AR. Antioxidant and anti-inflammatory properties of curcumin. In: The molecular targets and therapeutic uses of Curcumin in health and disease. Vol. 595; 2007 Jan; p. 105–25.10.1007/978-0-387-46401-5_3Search in Google Scholar PubMed
[134] Lubbad A, Oriowo MA, Khan I. Curcumin attenuates inflammation through inhibition of TLR-4 receptor in experimental colitis. Mol Cell Biochem. 2009 Feb;322:127–35.10.1007/s11010-008-9949-4Search in Google Scholar PubMed
[135] Guimarães MR, Leite FR, Spolidorio LC, Kirkwood KL, Rossa C Jr. Curcumin abrogates LPS-induced pro-inflammatory cytokines in RAW 264.7 macrophages. Evidence for novel mechanisms involving SOCS-1,-3 and p38 MAPK. Arch Oral Biol. 2013 Oct;58(10):1309–17.10.1016/j.archoralbio.2013.07.005Search in Google Scholar PubMed PubMed Central
[136] Sandner G, König A, Wallner M, Weghuber J. Functional foods-dietary or herbal products on obesity: Application of selected bioactive compounds to target lipid metabolism. Curr Opin Food Sci. 2020 Aug;34:9–20.10.1016/j.cofs.2020.09.011Search in Google Scholar
[137] Hatcher H, Planalp R, Cho J, Torti FM, Torti SV. Curcumin: from ancient medicine to current clinical trials. Cell Mol Life Sci. 2008 Jun;65:1631–52.10.1007/s00018-008-7452-4Search in Google Scholar PubMed PubMed Central
[138] Tu CT, Han B, Yao QY, Zhang YA, Liu HC, Zhang SC. Curcumin attenuates Concanavalin A-induced liver injury in mice by inhibition of Toll-like receptor (TLR) 2, TLR4 and TLR9 expression. Int Immunopharmacol. 2012 Jan;12(1):151–7.10.1016/j.intimp.2011.11.005Search in Google Scholar PubMed
[139] Ma F, Liu F, Ding L, You M, Yue H, Zhou Y, et al. Anti-inflammatory effects of curcumin are associated with down regulating microRNA-155 in LPS-treated macrophages and mice. Pharm Biol. 2017 Jan;55(1):1263–73.10.1080/13880209.2017.1297838Search in Google Scholar PubMed PubMed Central
[140] Reuter S, Gupta SC, Park B, Goel A, Aggarwal BB. Epigenetic changes induced by curcumin and other natural compounds. Genes Nutr. 2011 May;6:93–108.10.1007/s12263-011-0222-1Search in Google Scholar PubMed PubMed Central
[141] Esatbeyoglu T, Huebbe P, Ernst IM, Chin D, Wagner AE, Rimbach G. Curcumin—from molecule to biological function. Angew Chem Int Ed. 2012 May;51(22):5308–32.10.1002/anie.201107724Search in Google Scholar PubMed
[142] Lichtenstein GR, Hanauer SB, Sandborn WJ. Emerging treatment options in mild to moderate ulcerative colitis. Gastroenterol Hepatol. 2015 Mar;11(3 Suppl 1):1.Search in Google Scholar
[143] Rahmani AH, Alsahli MA, Aly SM, Khan MA, Aldebasi YH. Role of curcumin in disease prevention and treatment. Adv Biomed Res. 2018;7:38.10.4103/abr.abr_147_16Search in Google Scholar PubMed PubMed Central
[144] Ferraz CR, Carvalho TT, Manchope MF, Artero NA, Rasquel-Oliveira FS, Fattori V, et al. Therapeutic potential of flavonoids in pain and inflammation: mechanisms of action, pre-clinical and clinical data, and pharmaceutical development. Molecules. 2020 Feb;25(3):762.10.3390/molecules25030762Search in Google Scholar PubMed PubMed Central
[145] Trinchet JC, Coste T, Levy VG, Vivet F, Duchatelle V, Legendre C. Traitement de l’hépatite alcoolique par la silymarine. Une étude comparative en double insu chez 116 malades. Gastroentérologie Clin et Biologique. 1989;13(2):120–4.Search in Google Scholar
[146] Saad B, Ghareeb B, Kmail A. Metabolic and epigenetics action mechanisms of antiobesity medicinal plants and phytochemicals. Evidence-based Complementary Altern Med. 2021 Jun;2021:1–9.10.1155/2021/9995903Search in Google Scholar PubMed PubMed Central
[147] Mannino G, Gentile C, Ertani A, Serio G, Bertea CM. Anthocyanins: Biosynthesis, distribution, ecological role, and use of biostimulants to increase their content in plant foods – A review. Agriculture. 2021 Mar;11(3):212.10.3390/agriculture11030212Search in Google Scholar
[148] Cui HX, Chen JH, Li JW, Cheng FR, Yuan K. Protection of anthocyanin from Myrica rubra against cerebral ischemia-reperfusion injury via modulation of the TLR4/NF-κB and NLRP3 pathways. Molecules. 2018 Jul;23(7):1788.10.3390/molecules23071788Search in Google Scholar PubMed PubMed Central
[149] Aboonabi A, Singh I. Chemopreventive role of anthocyanins in atherosclerosis via activation of Nrf2–ARE as an indicator and modulator of redox. Biomed Pharmacother. 2015 May;72:30–6.10.1016/j.biopha.2015.03.008Search in Google Scholar PubMed
[150] Wei J, Zhang G, Zhang X, Xu D, Gao J, Fan J. Anthocyanins delay ageing-related degenerative changes in the liver. Plant Foods Hum Nutr. 2017 Dec;72:425–31.10.1007/s11130-017-0644-zSearch in Google Scholar PubMed
[151] Cappellini F, Marinelli A, Toccaceli M, Tonelli C, Petroni K. Anthocyanins: from mechanisms of regulation in plants to health benefits in foods. Front Plant Sci. 2021 Oct;12:748049.10.3389/fpls.2021.748049Search in Google Scholar PubMed PubMed Central
[152] Lauwers GY, Langner C. Inflammatory and infectious pathology of the gastrointestinal tract: an introduction. Virchows Arch. 2018 Jan;472:1–2.10.1007/s00428-017-2284-ySearch in Google Scholar PubMed
[153] Khare T, Anand U, Dey A, Assaraf YG, Chen ZS, Liu Z, et al. Exploring phytochemicals for combating antibiotic resistance in microbial pathogens. Front Pharmacology. 2021 Jul;12:720726.10.3389/fphar.2021.720726Search in Google Scholar PubMed PubMed Central
[154] Tiku AR. Antimicrobial compounds (phytoanticipins and phytoalexins) and their role in plant defense. Co-Evolution Secondary Metabolites; 2020. p. 845–68.10.1007/978-3-319-96397-6_63Search in Google Scholar
[155] Biharee A, Sharma A, Kumar A, Jaitak V. Antimicrobial flavonoids as a potential substitute for overcoming antimicrobial resistance. Fitoterapia. 2020 Oct;146:104720.10.1016/j.fitote.2020.104720Search in Google Scholar PubMed
[156] Rahman SA, Abd-Ellatif SA, Deraz SF, Khalil AA. Antibacterial activity of some wild medicinal plants collected from western Mediterranean coast, Egypt: Natural alternatives for infectious disease treatment. Afr J Biotechnol. 2011;10(52):10733–43.10.5897/AJB11.007Search in Google Scholar
[157] Sivapriya M, Dinesha R, Harsha R, Gowda SS, Srinivas L. Antibacterial activity of different extracts of Sundakai (Solanum torvum) fruit coat. Int J Biol Chem. 2011;5(1):61–7.10.3923/ijbc.2011.61.67Search in Google Scholar
[158] Díaz-Nuñez JL, García-Contreras R, Castillo-Juárez I. The new antibacterial properties of the plants: Quo vadis studies of anti-virulence phytochemicals? Front Microbiol. 2021 May;12:667126.10.3389/fmicb.2021.667126Search in Google Scholar PubMed PubMed Central
[159] Mattioli R, Francioso A, Mosca L, Silva P. Anthocyanins: A comprehensive review of their chemical properties and health effects on cardiovascular and neurodegenerative diseases. Molecules. 2020 Aug;25(17):3809.10.3390/molecules25173809Search in Google Scholar PubMed PubMed Central
[160] Williams M, McCarthy D, Foster A, Yednock SF, Rydel R, Messersmith E, et al. Comprehensive medicinal chemistry II Volume 6: Therapeutic Areas I: Central nervous system, pain, metabolic syndrome, urology, gastrointestinal and cardiovascular. Amsterdam, Netherlands: Elsevier; 2007.Search in Google Scholar
[161] Rauf A, Akram M, Semwal P, Mujawah AA, Muhammad N, Riaz Z, et al. Antispasmodic potential of medicinal plants: a comprehensive review. Oxid Med Cell Longev. 2021 Nov;2021:4889719.10.1155/2021/4889719Search in Google Scholar PubMed PubMed Central
[162] Dereli FT. Plant-based bioactive components: Phytochemicals: A review. Bioactive components: A sustainable system for good health and well-being. Singapore: Springer; 2022 Dec. p. 27–33.10.1007/978-981-19-2366-1_2Search in Google Scholar
[163] Annaházi A, Róka R, Rosztóczy A, Wittmann T. Role of antispasmodics in the treatment of irritable bowel syndrome. World J Gastroenterol: WJG. 2014 May;20(20):6031.10.3748/wjg.v20.i20.6031Search in Google Scholar PubMed PubMed Central
[164] Baiu I, Hawn MT. Gallstones and biliary colic. JAMA. 2018 Oct;320(15):1612.10.1001/jama.2018.11868Search in Google Scholar PubMed
[165] Sanagapalli S, Agnihotri K, Leong R, Corte CJ. Antispasmodic drugs in colonoscopy: a review of their pharmacology, safety and efficacy in improving polyp detection and related outcomes. Ther Adv Gastroenterol. 2017 Jan;10(1):101–13.10.1177/1756283X16670076Search in Google Scholar PubMed PubMed Central
[166] Shi X, Chen Z, Yang Y, Yan S. Bile reflux gastritis: insights into pathogenesis, relevant factors, carcinomatous risk, diagnosis, and management. Gastroenterol Res Pract. 2022;2022:2642551.10.1155/2022/2642551Search in Google Scholar PubMed PubMed Central
[167] Siddiqui AJ, Jahan S, Singh R, Saxena J, Ashraf SA, Khan A, et al. Plants in anticancer drug discovery: from molecular mechanism to chemoprevention. BioMed Res Int. 2022 Mar;2022:5425485.10.1155/2022/5425485Search in Google Scholar PubMed PubMed Central
[168] Skolnick P, Paul SM. Benzodiazepines and nonbenzodiazepines. In Receptor binding in drug research. Boca Raton, Florida, USA: CRC Press; 2020 Aug. p. 53–75Search in Google Scholar
[169] Bourin M. Mechanisms of action of anxiolytics. Psychiatry neurosci update: Epistemology clin psychiatry–Vol IV. Vol. 4; 2021. p. 195–211.10.1007/978-3-030-61721-9_18Search in Google Scholar
[170] Kenda M, Kočevar Glavač N, Nagy M, Sollner Dolenc M. Medicinal plants used for anxiety, depression, or stress treatment: An update. Molecules. 2022 Sep;27(18):6021.10.3390/molecules27186021Search in Google Scholar PubMed PubMed Central
[171] Nallusamy S, Mannu J, Ravikumar C, Angamuthu K, Nathan B, Nachimuthu K, et al. Exploring phytochemicals of traditional medicinal plants exhibiting inhibitory activity against main protease, spike glycoprotein, RNA-dependent RNA polymerase and non-structural proteins of SARS-CoV-2 through virtual screening. Front Pharmacol. 2021 Jul;12:667704.10.3389/fphar.2021.667704Search in Google Scholar PubMed PubMed Central
[172] Flores-Bazán T, Betanzos-Cabrera G, Guerrero-Solano JA, Negrete-Díaz JV, German-Ponciano LJ, Olivo-Ramírez D. Pomegranate (Punica granatum L.) and its phytochemicals as anxiolytic; an underreported effect with therapeutic potential: a systematic review. Brain Res. 2023 Aug;1820:148554.10.1016/j.brainres.2023.148554Search in Google Scholar PubMed
[173] Ali MY, Sina AA, Khandker SS, Neesa L, Tanvir EM, Kabir A, et al. Nutritional composition and bioactive compounds in tomatoes and their impact on human health and disease: A review. Foods. 2020 Dec;10(1):45.10.3390/foods10010045Search in Google Scholar PubMed PubMed Central
[174] Gutiérrez-del-Río I, López-Ibáñez S, Magadán-Corpas P, Fernández-Calleja L, Pérez-Valero Á, Tuñón-Granda M, et al. Terpenoids and polyphenols as natural antioxidant agents in food preservation. Antioxidants. 2021 Aug 8;10(8):1264.10.3390/antiox10081264Search in Google Scholar PubMed PubMed Central
[175] Kmail A. Protective Role of Hypericum perforatum L. and Hypericum triquetrifolium Turra against Inflammatory Diseases: Evidence from in vitro and in vivo studies. Eur J Med Plants. 2022 Dec;33(12):34–47.10.9734/ejmp/2022/v33i121112Search in Google Scholar
[176] Sen S, Chakraborty R. Food in health preservation and promotion: A special focus on the interplay between oxidative stress and pro-oxidant/antioxidant. Explor Nutr Health Benefits Funct Foods. Boston, USA: IGI Global; 2017. p. 265–300.10.4018/978-1-5225-0591-4.ch013Search in Google Scholar
[177] Nunes CD, Barreto Arantes M, Menezes de Faria Pereira S, Leandro da Cruz L, de Souza Passos M, Pereira de Moraes, et al. Plants as sources of anti-inflammatory agents. Molecules. 2020 Aug;25(16):3726.10.3390/molecules25163726Search in Google Scholar PubMed PubMed Central
[178] Ibrahim R, Barron D. Phenylpropanoids. In Methods in plant biochemistry. Vol. 1. Springer, Boston, MA: Academic Press; 1989 Jan. p. 75–111.10.1016/B978-0-12-461011-8.50009-3Search in Google Scholar
[179] Lin X, Bai D, Wei Z, Zhang Y, Huang Y, Deng H, et al. Curcumin attenuates oxidative stress in RAW264. 7 cells by increasing the activity of antioxidant enzymes and activating the Nrf2-Keap1 pathway. PLoS One. 2019 May;14(5):e0216711.10.1371/journal.pone.0216711Search in Google Scholar PubMed PubMed Central
[180] Zebeaman M, Tadesse MG, Bachheti RK, Bachheti A, Gebeyhu R, Chaubey KK. Plants and plant-derived molecules as natural immunomodulators. Bio Med Res Int. 2023 Jun;2023:7711297.10.1155/2023/7711297Search in Google Scholar PubMed PubMed Central
[181] Di Sotto A, Vitalone A, Di Giacomo S. Plant-derived nutraceuticals and immune system modulation: an evidence-based overview. Vaccines. 2020 Aug;8(3):468.10.3390/vaccines8030468Search in Google Scholar PubMed PubMed Central
[182] Alhazmi HA, Najmi A, Javed SA, Sultana S, Al Bratty M, Makeen HA, et al. Medicinal plants and isolated molecules demonstrating immunomodulation activity as potential alternative therapies for viral diseases including COVID-19. Front Immunol. 2021 May;12:637553.10.3389/fimmu.2021.637553Search in Google Scholar PubMed PubMed Central
[183] Rahman MA, Hannan MA, Dash R, Rahman MH, Islam R, Uddin MJ, et al. Phytochemicals as a complement to cancer chemotherapy: Pharmacological modulation of the autophagy-apoptosis pathway. Front Pharmacol. 2021 May;12:639628.10.3389/fphar.2021.639628Search in Google Scholar PubMed PubMed Central
[184] Ferdous UT, Yusof ZN. Medicinal prospects of antioxidants from algal sources in cancer therapy. Front Pharmacol. 2021 Mar;12:593116.10.3389/fphar.2021.593116Search in Google Scholar PubMed PubMed Central
[185] Sen S, Chakraborty R. Herbs gastrointestinal protection, and oxidative stress. In Gastrointestinal Tissue. Cambridge, Massachusetts: Academic Press; 2017 Jan. p. 259–74.10.1016/B978-0-12-805377-5.00019-9Search in Google Scholar
[186] Domitrović R, Potočnjak I. A comprehensive overview of hepatoprotective natural compounds: mechanism of action and clinical perspectives. Arch Toxicol. 2016 Jan;90:39–79.10.1007/s00204-015-1580-zSearch in Google Scholar PubMed
[187] Garcia-Cortes M, Robles-Diaz M, Stephens C, Ortega-Alonso A, Lucena MI, Andrade RJ. Drug induced liver injury: an update. Arch Toxicol. 2020 Oct;94:3381–407.10.1007/s00204-020-02885-1Search in Google Scholar PubMed
[188] Martinez-Lacoba R, Pardo-Garcia I, Amo-Saus E, Escribano-Sotos F. Mediterranean diet and health outcomes: A systematic meta-review. Eur J Public Health. 2018 Oct;28(5):955–61.10.1093/eurpub/cky113Search in Google Scholar PubMed
[189] AlAufi NS, Chan YM, Waly MI, Chin YS, Mohd Yusof BN, Ahmad N. Application of mediterranean diet in cardiovascular diseases and type 2 diabetes mellitus: Motivations and challenges. Nutrients. 2022 Jul;14(13):2777.10.3390/nu14132777Search in Google Scholar PubMed PubMed Central
[190] Guasch‐Ferré M, Willett WC. The Mediterranean diet and health: A comprehensive overview. J Intern Med. 2021 Sep;290(3):549–66.10.1111/joim.13333Search in Google Scholar PubMed
[191] Moustafa B, Trifan G, Isasi CR, Lipton RB, Sotres-Alvarez D, Cai J, et al. Association of Mediterranean diet with cognitive decline among diverse hispanic or latino adults from the Hispanic Community Health Study/Study of Latinos. JAMA Netw Open. 2022 Jul;5(7):e2221982.10.1001/jamanetworkopen.2022.21982Search in Google Scholar PubMed PubMed Central
[192] Tosti V, Bertozzi B, Fontana L. Health benefits of the Mediterranean diet: metabolic and molecular mechanisms. J Gerontology: Ser A. 2018 Mar;73(3):318–26.10.1093/gerona/glx227Search in Google Scholar PubMed PubMed Central
[193] H. Al Wattar B, Dodds J, Placzek A, Beresford L, Spyreli E, Moore A, et al. Mediterranean-style diet in pregnant women with metabolic risk factors (ESTEEM): A pragmatic multicentre randomised trial. PLoS Med. 2019 Jul;16(7):e1002857.10.1371/journal.pmed.1002857Search in Google Scholar PubMed PubMed Central
[194] Mone I, Kraja B, Bregu A, Duraj V, Sadiku E, Hyska J, et al. Adherence to a predominantly Mediterranean diet decreases the risk of gastroesophageal reflux disease: a cross-sectional study in a South Eastern European population. Dis Esophagus. 2016 Oct;29(7):794–800.10.1111/dote.12384Search in Google Scholar PubMed
[195] Senouci F, Ababou A, Chouieb M. Ethnobotanical survey of the medicinal plants used in the Southern Mediterranean. Case study: the region of Bissa (Northeastern Dahra Mountains, Algeria). Pharmacogn J. 2019;11(4):647–59.10.5530/pj.2019.11.103Search in Google Scholar
[196] Aron-Wisnewsky J, Warmbrunn MV, Nieuwdorp M, Clément K. Metabolism and metabolic disorders and the microbiome: the intestinal microbiota associated with obesity, lipid metabolism, and metabolic health – pathophysiology and therapeutic strategies. Gastroenterology. 2021 Jan;160(2):573–99.10.1053/j.gastro.2020.10.057Search in Google Scholar PubMed
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