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Episode 122 – Herbal Lore

Steve’s Top 5 Herbs! 

Harpagophytum procumbens (Devil’s Claw)

Among its abundant metabolites, Harpagoside has been substantiated as an anti-inflammatory component. Root’s extract of Devil’s claw has been claimed to possess inhibition potential of NO, inflammatory cytokines (IL-6, IL-1?, and TNF-?), and PGE2, as well as prevention of arachidonic acid metabolism and eicosanoid biosynthesis, leading to COX-2 inhibition and reducing inflammation. Over an RCT, the effectiveness of Devil’s claw in osteoarthritis remission has been assessed. At the end of treatment period, anti-inflammatory effects of H. procumbens have been observed.[1]

Ginger

Oral administration of Z. officinale extract has shown different and inconsistent effects, depending on the quantity of consumption. Although administration of squeezed ginger extract to mice one time or twice has elevated the tumor necrosis factor-? (TNF-?) in peritoneal cells, long-term consumption of the extract has increased the serum corticosterone level and has reduced proinflammatory markers. Z. officinale was also tested in type 2 diabetic patients with low-grade inflammation; after 2 months of treatment, serum level of TNF-? and high-sensitivity C-reactive protein (hs-CRP) were decreased definitely. In patients with osteoarthritis, ginger had not only efficacy in pain improvement identical to Diclofenac 100 mg but also no side effects. Ginger extract has been compared to Ibuprofen and Indomethacin in OA patients; the results have exerted improving function of Ibuprofen, Indomethacin, and ginger extract equally in pain score. Ginger powder has had ameliorative effect in musculoskeletal and rheumatism patients through inhibiting cyclooxygenase and lipoxygenase pathway in synovial fluid.[2]

The picture below shows the biochemistry associated with inflammation.

 

Ginger helps with metabolic syndrome

In recent years, metabolic syndromes (MetSs), including diabetes mellitus, dyslipidemia, and cardiovascular diseases, have become a common health problem in both developed and developing countries. Accumulating data have suggested that traditional herbs might be able to provide a wide range of remedies in prevention and treatment of MetSs. Ginger (Zingiber officinale Roscoe, Zingiberaceae) has been documented to ameliorate hyperlipidemia, hyperglycemia, oxidative stress, and inflammation. These beneficial effects are mediated by transcription factors, such as peroxisome proliferator-activated receptors, adenosine monophosphate-activated protein kinase, and nuclear factor κB.[3]

Thyme

A recent study compared the antibacterial effects of several essential oils (EOs) alone and in combination against different Gram-positive and Gram-negative bacteria associated with food products. Parsley, lovage, basil, and thyme EOs, as well as their mixtures (1:1, v/v), were tested against Bacillus cereus, Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, and Salmonella typhimurium. The inhibitory effects ranged from strong (thyme EO against E. coli) to no inhibition (parsley EO against P. aeruginosa). Thyme EO exhibited strong (against E. coli), moderate (against S. typhimurium and B. cereus), or mild inhibitory effects (against P. aeruginosa and S. aureus), and basil EO showed mild (against E. coli and B. cereus) or no inhibitory effects (against S. typhimurium, P. aeruginosa, and S. aureus). Parsley and lovage EOs revealed no inhibitory effects against all tested strains. Combinations of lovage/thyme and basil/thyme EOs displayed antagonistic effects against all bacteria, parsley/thyme EOs against B. cereus, S. aureus, P. aeruginosa, and E. coli, and lovage/basil EOs against B. cereus and E. coli. Combinations of parsley/lovage and parsley/basil EOs exhibited indifferent effects against all bacteria. The combination of lovage/basil EO showed indifferent effect against S. aureus, P. aeruginosa, and S. typhimurium, and the combination parsley/thyme EO against S. typhimurium. Thyme EO has the highest percentage yield and antibacterial potential from all tested formulations; its combination with parsley, lovage, and basil EOs determines a reduction of its antibacterial activity. Hence, it is recommended to be used alone as the antibacterial agent.[4]

Comparison of Antimicrobial Activities of Thyme and Other Spices

Al-Turki et al. reported the antibacterial activities of thyme, peppermint, sage, black pepper and garlic hydrosols against B. subtilis and S. enteritidis, using the agar disk diffusion method. Thyme hydrosol demonstrated more significant inhibitory effects on B. subtilis and S. enteritidis than sage, peppermint, and black pepper hydrosols, with the mean DIZs 20 mm for B. subtilis and 15 mm for S. enteritidis. According to a recent study, the antimicrobial effects of the six plant hydrosols on S. aureus, E. coli, S. typhimurium, P. aerugenosa, and C. albicans were tested by determining the microbial growth zones on hydrosol agar plates and control agar plates. The results showed that at 15% thyme hydrosol completely inhibited E. coli and S. typhimurium, but C. albicans was inactive to the tested hydrosols. Researches assessed the antimicrobial activities of five plant EOs against psychrotrophic microorganisms (P. fluorescens, Pseudomonas putida (P. putida), P. fragi, B. thermosphacta, and C. albicans) isolated from spoiled chilled meat products and some reference strains (P. fluorescens ATCC 17397, P. putida NBIMCC (National Bank for Industrial Microorganisms and Cell Cultures) 561, P. aeruginosa ATCC 9027, and C. albicans ATCC 10231) using the method of disc diffusion and serial broth dilution. The results indicated that the antimicrobial effects of the EOs were equal at 37 °C and 4 °C. Thyme EO exhibited the highest antimicrobial activities with the MICs ranging from 0.05% to 0.8% w/v. Another study observed the anti-Vibrio alginolyticus (V. alginolyticus) activities of five aromatic plant EOs using agar well diffusion test, and the MICs and MBCs were examined using the broth microdilution susceptibility method.

Thyme EO was proved to be the most efficient against 13 V. alginolyticus strains compared with 4 other EOs, with the MICs ranges of 0.078–0.31 mg/mL and MBCs ranges of 0.31–1.25 mg/mL. Also, another study assessed the growth inhibition of some indicators of spoilage bacteria strains (L. innocua, S. marcescens, and P. fluorescens) and the concentration effects of five spice EOs using the agar disc diffusion method. Only the EO of thyme showed inhibitive effects on all tested bacteria at all added doses (100%, 50%, 25%, 12.5%, and 5%). Researches evaluated the antibacterial activities of EOs from thyme, Thymus kotschyanus, Ziziphora tenuior, and Ziziphora clinopodioides, against two Gram-positive bacteria (B. cereus and L. monocytogenes) and two Gram-negative bacteria (S. typhimurium and E. coli), using the agar disc diffusion and micro-well dilution assay. The EO of thyme showed the highest antibacterial activities, with the widest inhibition zones and the lowest MICs (0.312–1.25 μL/mL), and B. cereus was the most sensitive bacterium tested. Earlier research investigated the antibacterial effects of several EOs on 18 pathogenic bacteria and 15 spoilage bacteria by agar disc diffusion test. The results showed that thyme-1 (T. vulgaris) EO and thyme-2 (T. vulgaris ct linalool) EO exerted the highest antibacterial activities against 18 pathogenic bacteria strains compared with other spices, except for P. aeruginosa. Thyme-1 EO also demonstrated the best antibacterial effects on spoilage bacteria. In addition, the antimicrobial effects of 17 spices and herbs against Shigella strains were tested in another study. The MICs were determined by the agar dilution method with dried ground spices and herbs added to the broth and agar, and the results showed that MICs of thyme were 0.5–1% w/v for the Shigella strains. The study also used various combinations of temperatures (12, 22, and 37 °C), pH values (5.0, 5.5, and 6.0), and NaCl concentrations (1%, 2%, 3%, and 4% w/v), and the inclusion or exclusion of thyme or basil at 1% w/v in a Mueller–Hinton agar model system to test the inhibitory effects of thyme and basil. In the presence of thyme, Shigella flexneri (S. flexneri) did not develop Colony-Forming Units (CFU) during the seven-day incubation period for 16 of the 18 tested combinations.

Some studies compared the antimicrobial activities of different extracts of thyme. One study evaluated and compared the antimicrobial activities of the infusion, decoction, and hydroalcoholic extracts prepared from thyme against S. aureus, S. epidermidis, E. coli, Klebsiella spp., P. aeruginosa, Enterobacter aerogenes (E. aerogenes), Proteus vulgaris (P. vulgaris), and Enterobacter sakazakii (E. sakazakii) using the disc diffusion halo test. For Gram-positive species, thyme extracts only presented activity against S. epidermidis, and hydroalcoholic extract showed a lower antibacterial activity than decoction and infusion extracts, which showed the similar activities. For Gram-negative species, thyme extracts showed antimicrobial activities in the order of E. coli > P. vulgaris, P. aeruginosa > E. aerogenes = E. sakazakii; decoction and hydroalcoholic extracts had similar effects against the bacteria except P. aeruginosa, while the lowest activity was observed in infusion extracts. Moreover, the antifungal effects of thyme EO, hydrosol and propolis extracts on natural mycobiota on the surface of sucuk were evaluated in a study. The results showed that potassium sorbate (15% w/v, in water), thyme EO (10 mg/mL, in dimethyl sulfoxide), and propolis extract (50 mg/mL, in dimethyl sulfoxide) reduced by 4.88, 2.45, and 2.05 log CFU/g in yeast-mold counting compared with sterile water, respectively.

In another study, researches analyzed the polyphenolic fractions and oil fractions of oilseeds from 4 spices, including thyme, for their antimicrobial activities against 35 bacterial strains. The results showed that oil fractions of all spice oilseeds were more active than their polyphenolic fractions, and thyme oil fraction had the highest antibacterial activities compared with other spice oilseeds. Scientists also studied the growth of Candida lusitaniae (C. lusitaniae) on different concentrations of nisin (0.1–3 mmol/L), thymol (0.02–1.5 mmol/L), carvacrol (0.02–1 mmol/L), or cymene (0.02–3 mmol/L) in broths (pH = 5, 25 °C), and also evaluated the inhibitory activity of thymol against C. lusitaniae in tomato juice. Thymol, carvacrol, and cymene totally inhibited the yeast growth for more than 21 days at 25 °C when the concentrations were higher than 1 mmol/L. Compared with the control without thymol, the activity of thymol against C. lusitaniae in tomato juice was significant.

In conclusion, the results obtained from a number of investigations with good quality indicated that thyme possessed effective antimicrobial activities against several pathogenic and spoilage bacteria and fungi, like S. aureus and E. coli, with low MICs (≤1100 μL/mL). As thyme is a safe herb to consume in therapeutic amounts, thyme can also work as an anti-microbial agent in the body.[5]

Yerba mate – Xenohormetins

“Let food be thy medicine and medicine be thy food” quoted by Hippocrates, and its more modern analog “an apple a day keeps the doctor away” both reflect the implicitness of food on health. Plants that traditionally served as food, fuel, water and fiber, are now being engineered as a source of natural bioactive compounds with particular attention focused on nutraceutical products and functional foods. This has in turn given rise to the concept of xenohormesis, or molecular networking between species, which tries to explain the multiple positive effects of plant-derived polyphenols on human health. This consists in the idea that our body reacts to the signals that plants generate in periods of stress. In this sense, these biochemical signals, called xenohormetins, fulfill important metabolic and defensive functions in plants, such as protection against UV radiation and pathogen infection, nodulation, hormone transportation, as well as several other functions such as defence against herbivorism or pollination. The induction of protective secondary metabolites, especially phenolics, allows plants to withstand the effect of environmental stressors, as a self-defense  mechanism against external conditions. Thus, this complex mechanism to protect themselves and improved throughout evolution can be in part extrapolated to humans through plant food consumption challenging their own genetic inheritance by modifying innate responses.[6]

A recent study evaluated whether long-term supplementation with dietary yerba mate has beneficial effects on adiposity and its related metabolic dysfunctions in diet-induced obese mice. C57BL/6J mice were randomly divided into two groups and fed their respective experimental diets for 16 weeks as follows:

(1) control group fed with high-fat diet (HFD) and

(2) mate group fed with HFD plus yerba mate.

Dietary yerba mate increased energy expenditure and thermogenic gene mRNA expression in white adipose tissue (WAT) and decreased fatty acid synthase (FAS) mRNA expression in WAT, which may be linked to observed decreases in body weight, WAT weight, epididymal adipocyte size, and plasma leptin level. Yerba mate also decreased levels of plasma lipids (free fatty acids, triglycerides, and total cholesterol) and liver aminotransferase enzymes, as well as the accumulation of hepatic lipid droplets and lipid content by inhibiting the activities of hepatic lipogenic enzymes, such as FAS and phosphatidate phosphohydrolase, and increasing fecal lipid excretion. Moreover, yerba mate decreased the levels of plasma insulin as well as the homeostasis model assessment of insulin resistance, and improved glucose tolerance. Circulating levels of gastric inhibitory polypeptide and resistin were also decreased in the mate group. The researches found that long-term supplementation of dietary yerba mate may be beneficial for improving diet-induced adiposity, insulin resistance, dyslipidemia, and hepatic steatosis.[7]

Yerba Maté (YM), has become a popular herb ingested for enhancing metabolic health and weight-loss outcomes. Until now, no studies have tested the combined metabolic, satiety, and psychomotor effects of YM during exercise. We tested whether YM ingestion affects fatty acid oxidation (FAO), profile of mood state score (POMS), and subjective appetite scale (VAS), during prolonged moderate exercise. Twelve healthy active females were randomized to ingest either 2 g of YM or placebo (PLC) in a repeated-measures design. Participants rested for 120 min before performing a 30-min cycling exercise corresponding to individuals’ crossover point intensity (COP). FAO, determined using indirect calorimetry, was significantly higher during the 30-min exercise in YM vs. PLC (0.21 ± 0.07 vs. 0.17 ± 0.06 g/min, p < 0.05). VAS scores for hunger, prospective eating, and desire to eat were all reduced (p < 0.05). Whereas, POMS measures of focus, energy, and concentration were all increased (p < 0.05). There was no significant time-effect for any of the measured variables, nor was there any interaction effects between YM treatment and time. Combining YM intake with prolonged exercise at targeted “fat-loss”‘ intensities augments FAO and improves measures of satiety and mood state. Such positive combined metabolic, satiety, and psychomotor effects may provide an important role for designing future fat and weight-loss lifestyle interventions.[8]

Hibiscus Sabdariffa

The antioxidant capabilities of plant polyphenols have been well established by many in vitro and in vivo studies, demonstrating a clear correlation with health. To this end, botanical polyphenols could be used as possible therapeutic sources to treat obesity. Oxidative stress is implicated in the development of many chronic conditions, including obesity. This is due to an imbalance between excess reactive oxygen species (ROS) and the inability of the intracellular defence system to efficiently eliminate these oxidative agents. This dysregulation leads to the oxidation and damage of macromolecules such as carbohydrates, lipids, proteins and nucleic acids, which finally cause organelle and cell dysfunction and contributes to the progression of the pathology.

ROS are a set of unstable molecules and free radicals derived from molecular oxygen (O2) and are mainly generated in the oxidative respiratory chain of the mitochondria. Superoxide anion (O2) is generally the precursor of the majority of the ROS produced, and can lead to the formation of hydrogen peroxide (H2O2), and consequently hydroxyl radical (OH) by Fenton’s reaction.

Oxidative damage is generally prevented through the release of intercellular and intracellular antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GR), which act as scavengers for the different ROS. Additionally, O2 – and H2O2 can also be generated by NADPH oxidase, a membrane-bound enzymatic complex, which plays an important role in cellular proliferation, serotonin biosynthesis, endothelial signalling, regulation of renal functions, and the immune response against microorganisms, although its overexpression is associated with various neurological diseases and cancers.

HSp (Hibiscus sabdariffa polyphenols) illustrated above blocks O2- and H2O2 pro-oxidants, as well as regenerating glutathione.

A correlation exists between obesity and as a chronic inflammatory process has been detected in the adipose tissue of obese experimental animal models as well as in humans, along with an increased NADPH oxidase expression and decrease in antioxidant enzymes. Other studies have reported that high levels of fatty acids and glucose increase intracellular ROS generation in adipocyte cell cultures. According to these reports, adipocytes in obese individuals undergo hypertrophy as a result of an excess caloric intake and a low metabolic rate. Consequently, the increased expression of NADPH oxidase, exacerbated fatty acid oxidation in the mitochondria, and decreased expression of SOD, CAT and GPx lead to an excessive production of ROS. ROS also function as mediators for the activation of nuclear factor-kB (NF-kB) and mitogen-activated protein kinase (MAPK), contributing to the dysregulation of the expression of inflammatory adipokines and a low-grade but chronic state of inflammation.[9]

Effects of HSp polyphenols on inflammation-related and MAPK pathways.

Various studies have indicated a possible role for HS polyphenols ROS in obesity-related disorders. For extracts have shown a higher capability to scavenge peroxyl radicals in water environments than in lipophilic systems, as well as a stronger metal-reducing effect than olive leaf. The antioxidant properties of HS polyphenols have also been measured in the plasma of rats after an acute ingestion of a polyphenol-enriched HS extract. In a later study, a correlation between the presence of phenolic acids in plasma at shorter times and its antioxidant effect through ferric ion reduction and superoxide scavenging was reported. Furthermore, the presence of flavonol glucuronides (quercetin and kaempferol) in plasma samples at longer times correlated with an inhibitory effect on lipid peroxidation. Furthermore, a polyphenol-enriched HS extract exerted a higher effect on inhibiting intracellular ROS formation than an aqueous HS extract in a culture of hypertrophied adipocytes [20]. All these data suggest that finding a suitable combination of bioactive HS polyphenols could represent an opportunity to ameliorate obesity-associated oxidative stress.[10]

HS and Fat Loss

HS polyphenols have been proven to regulate AMPK as well as several transcription factors related to lipid and glucose homeostasis, such as PPARs and SREBP-1c in hyperlipidemic mice model. Growing evidence indicates that these transcription factors are critical regulators of hepatic lipid metabolism, stimulating the expression of several enzymes implicated in liver fatty-acid synthesis, glucose transport and gluconeogenesis [23]. Consistent with this hypothesis, a recently discovered low molecular weight compound acting as an adiponectin receptor (AdipoR) agonist, AdipoRon, has been proposed as a possible molecular tool to improve insulin resistance, by mediating the activation of AMPK and PPAR-pathways, mimicking the effect of adiponectin. Thiazolidinediones are oral medications for type 2 diabetes that function as synthetic ligands and potent agonists of PPAR-g, being highly effective in reducing glucose levels and improving insulin sensitivity. However, the administration of thiazolidineones is associated with the occurrence of severe side effects such as fluid retention, weight gain, cardiac hypertrophy, bone fractures and hepatotoxicity.

The use of polyphenols as mild PPAR- agonists based on selective cofactor-receptor interactions, while avoiding the side effects observed in synthetic agonists, has been postulated as an opportunity for the management of obesity. In fact, some polyphenols such as resveratrol or scutellarin have shown experimentally the capability to modulate PPAR. Moreover, extensive effort has been recently made on the design of alternative synthetic PPAR modulators, such as metaglidasen, that are devoid of the typical side effects observed with thiazolidinedione anti-diabetic agents.

The ability of HS polyphenolic extracts to activate AMPK has also been associated with the activation of PPAR, which triggers FASN inhibition, stimulating fatty acid oxidation and antioxidant enzyme expression, thereby reducing lipid content and oxidative stress, which enhance mitochondrial metabolism and lipid management. HS polyphenols has also been correlated with a significant increase in serum adiponectin and decrease in serum leptin, which can revert overweight-induced metabolic alterations.[11]

Matt’s Top 5 Herbs! 

Coriandrum Sativum

Coriandrum sativum L. is a member of the Apiaceae family native to the Mediterranean region. The leaf of C. sativum L. is called Chinese parsley “phakchi” and is mainly eaten as a raw herb. On the other hand, the seed of C. sativum L. is generally used as a spice and crude plant drug. Because the seed is rich in essential oils that give off a characteristic aroma like citrus, their essential oils are used in aromatic oil therapy. Various health functions of C. sativum L. have been reported, including analgesic,  detoxificating, antibacterial, antioxidant, anticancer, and antiinflammatory activities. However, most of the studies on the health functions of C. sativum L. have focused on the effects of essential oils from the leaves and seeds. For example, linalool, which is the main component in C. sativum L., has been reported to induce cell cycle arrest and apoptosis in leukemia cells and cervical cancer cells through cyclin-dependent kinases inhibitors.

Coriandrum sativum stimulates NO production and phagocytosis activity in the immune cells  Macrophages also produce NO, which has antitumor and antibacterial activities. NO is synthesized from L-arginine by an enzyme called iNOS. Hence, the effect of Coriandrum sativum on NO production and iNOS gene expression in immune cells was examined. Immune cells were treated with Coriandrum sativum for 24 h and used for the assays. Coriandrum sativum significantly enhanced NO production in immunecells in a dose-dependent manner. In addition, Coriandrum sativum also significantly enhanced the expression levels of the iNOS gene in immune cells, suggesting that Coriandrum sativum stimulates NO production by enhancing iNOS gene expression.

The effect of Coriandrum sativum on phagocytosis activity was evaluated. Phagocytosis is another key role of macrophages, eventually leading to activation of the adaptive immune system. Immune cells were treated with 500 µg mL−1  of Coriandrum sativum for 6 h, and Zymosan A-mediated phagocytosis activity was measured using a flow cytometer. Coriandrum sativum significantly helped the phagocytosis activity of immunecells compared with control (p <0.01). The phagocytosis rate of the Coriandrum sativum-treated cells was 41.8%, whereas that of the control cells was 29.9%. Our findings suggest that Coriandrum sativum stimulates cytokine production, NO production, and the phagocytosis activity of macrophages, thereby contributing to the enhancement of host defense against pathogens.[1]

The researchers concluded by saying that C. sativum had an immunostimulatory effect on cell lines and mice, suggesting that C. sativum could stimulate macrophage activity in humans. The daily ingestion of C. sativum L. seeds may contribute to activating host defense against pathogens by stimulating both innate and adaptive immunities due to macrophage activation.[2]

Gut Parasites

Phytotherapy can be an alternative for the control of gastrointestinal parasites in human and animals. Coriander (Coriandrum sativum L.) is a medicinal plant which grown as a spice crop all over the world. The seeds of this plant have been used to treat parasitic disease, indigestion, diabetes, rheumatism and pain in the joints. A study was carried out to compare the efficacy of Niclosamid and alcoholic seed extract of C. sativum on Hymenolepis nana infection, in vivo and vitro. For in vivo study, Balb/c mice were used, to compare the efficacy of 50 mg/kg body weight (B.W) of Niclosamid with different doses of alcoholic extracts of C. sativum (250, 500, and 750 mg/kg B.W). It was found that the efficacy of Niclosamid had reached 100 % after 11 days post treatment, while the efficacy of 500 and 750 mg/kg B.W of C. sativum reached to 100 % after 15 days after treatment. It was found in that the addition of 1000 mg/ml of Niclosamid had paralyzed and killed worms within 5 min, while C. sativum killed them within 30 min. Our results showed that extract of C. sativum has good effect against H. nana and could be use in traditional medicine for treatment of parasitic disease without notable side effects.[3]

Rosemary

In a recent study, three phenolic extracts were examined, without volatile fraction, against common food pathogens. The samples, all suitable for food application, were from the leaves of Rosmarinus officinalis L., Vitis vinifera L., and the root of Polygonum cuspidatum L. The microorganisms tested were Escherichia coli O157:H7, Salmonella Enteritidis, Salmonella Typhi, Yersinia enterocolitica and Listeria monocytogenes, well-known as important food pathogens.

The results demonstrated a microbicidal activity of all the tested compounds at different concentrations; the rosemary extract showed greater efficacy than the other compounds against the tested microorganisms. In particular, the best results were obtained with rosemary extract against E. coli O157:H7 and L. monocytogenes with values of 200 and 270 μg/mL, respectively.

The scientists found that rosemary extract, often present as a natural antioxidant in food, can also be proposed as a natural disinfectant in the food field.[4]

Gentamicin (GM)-induced hepatotoxicity

Rosemary (Rosmarinus officinalis; RM) and thyme ( Thymus vulgaris; TV) are used as natural remedies for all sorts of things throughout the world. Scientists designed a study to investigate the preventive effect of aqueous extracts of RM or TV on the gentamicin (GM)-induced hepatotoxicity and abnormalities of lipid profile in rats.

Both plant extracts exhibited an in vitro antioxidant activity as determined by the 1,1-diphenyl-2-picrylhydrazyl assay. Radical scavenging activity for TV extract was 48.7% and for RM extract was 25.6%. Polyphenolic determination by high-performance liquid chromatography for both extracts revealed that catechin, coumarin, cinnamic acid and rutin were detected in both extracts. RM extract had higher values than TV extract in all except rutin. Ferulic acid and quercetin were also detected in TV extract and sinapic acid and oleuropein were detected in RM extract.

In rats given GM intraperitoneally for 10 days and coadministered either RM extract or TV extract orally, both aqueous extracts demonstrated similar hepatoprotective effects manifested by approximate normalization of plasma liver enzymes (AST and ALT), bilirubin level and total protein concentration compared with the group given GM only. Abnormal lipid parameters and raised hydrogen peroxide levels were ameliorated by both extracts.

Pancreatic lipase activity was markedly reduced by RM extract, which is one way it aids in weight loss. Also, the atherogenic index value was significantly reduced by both extracts as compared to that of GM group. DNA fragmentation analysis confirmed tissue damage by GM and its amelioration by the extracts.

The scientists found that RM and TV extracts could be helpful in ameliorating some aspects of gentamicin toxicity.[5]

Rosemary helps your heart after a heart attack

Myocardial infarction (MI) is one of the leading causes of morbidity and mortality worldwide. Dietary intervention on adverse cardiac remodelling after MI has significant clinical relevance. Rosemary leaves are a natural product with antioxidant/anti-inflammatory properties, and it may have a beneficial effect on a heart post heart attack.

To determine the effect of the dietary supplementation of rosemary leaves on cardiac remodeling after MI, male Wistar rats were divided into 6 groups after sham procedure or experimental induced MI: 1) Sham group fed standard chow (SR0, n = 23); 2) Sham group fed standard chow supplemented with 0.02% rosemary (R002) (SR002, n = 23); 3) Sham group fed standard chow supplemented with 0.2% rosemary (R02) (SR02, n = 22); 4) group submitted to MI and fed standard chow (IR0, n = 13); 5) group submitted to MI and fed standard chow supplemented with R002 (IR002, n = 8); and 6) group submitted to MI and fed standard chow supplemented with R02 (IR02, n = 9).

After 3 months of the treatment, systolic pressure evaluation, echocardiography and euthanasia were performed. Left ventricular samples were evaluated for: fibrosis, cytokine levels, apoptosis, energy metabolism enzymes, and oxidative stress.

Rosemary dietary supplementation attenuated cardiac remodelling by improving energy metabolism and decreasing oxidative stress. Rosemary supplementation of 0.02% improved diastolic function and reduced hypertrophy after MI. Regarding rosemary dose, 0.02% and 0.2% for rats are equivalent to 11 mg and 110 mg for humans, respectively.

The researchers found that rosemary may help post heart attack victims improve their heart function.

Schizandra

Schisandra chinensis is a plant species well-known in Traditional Chinese Medicine (TCM) and also in modern Chinese medicine. The first description of S. chinensis species can be found in a 1596 work on ancient Chinese medicine written by Li Shih-Chen —“Peˆn T’shao Kang Mu”. The fruit of the Chinese magnolia vine was used in the treatment of diseases of the gastrointestinal tract, respiratory failure,  cardiovascular diseases, in the states of body fatigue and weakness, excessive sweating and insomnia.

The material is also known from the traditional Russian medicine, in which it was described as a tonic, reducing hunger, fatigue, delaying the aging process, increasing vitality, and improving mental health.

The Health Benefits of Schizandra

Dibenzocyclooctadiene lignans (found in Schizandra) are a large group of chemical compounds with different modes of action. It is, however, possible, to identify the main directions of their biological activity, namely: blocking of calcium channels (Ca2+), reducing the level of: serum glutamic pyruvic transaminase (SGPT), liver glutamic-pyruvic transaminase (LGPT), alanine aminotransferase (ALT), aspartate aminotransferase (AST), inhibition of cyclooxygenase 1 and 2 (COX 1 and 2), inhibition of the production of nitric oxide (NO), inhibition of gene expression of proinflammatory cytokines, and inactivation of cytochrome P450.

In recent years, other valuable biological properties have been demonstrated for some dibenzocyclooctadiene lignans, such as: inhibition of platelet aggregation, the action of inhibiting the proliferation of human immunodeficiency virus (HIV) and adjuvant action in cancer treatment by: inhibiting early oncogenic activation of the Epstein-Barr virus (EBV-EA), reversing multidrug resistance dependent on P-glycoprotein (Pgp-MDR) in tumor cells, and sensitization of liver cancer cells to the effects of doxorubicin.

Hepatoprotective activity

Hepatoprotective activity is the best-known profile of action of S. chinensis fruit extracts and of individual dibenzocyclooctadiene lignans. The available literature contains many reports on scientific studies that confirm these properties of the fruit extracts. The most recent ones concern detailed studies on the mode of action of individual lignans. For example, the mechanism of action of gomisin A has been studied. It has been shown that it increases the microsomal activity of: cytochrome B5, P450, NADPH cytochrome C reductase, N-demethylase aminophenazone, 7-ethoxycoumarin O-deethylase, and reduces the activity of 3,4-dibenzopyrene hydroxylase. It also accelerates the proliferation of hepatocytes, the endoplasmic reticulum, and the hepatic flow.

On the other hand, it has been demonstrated that the mechanism of the hepatoprotective action of  schisandrin is based on increasing the concentration of mitochondrial glutathione. It has also been shown that γ-schisandrin raises the concentration of vitamin C in the liver in test animals, which may also have an impact on its protective effect on hepatocytes and oxidation of lipids. Moreover, schisandrin B has been shown to protect against oxidative damage to liver tissues, too.

A recently conducted study on hepatoprotective effects of six schisandra lignans: gomisin A, schisandrin, deoxyschisandrin, schisandrin B, schisandrin C, and schisantherin A, on acetaminophen-induced liver injury has found that these effects are partially associated with the inhibition of cytochrome-mediated bioactivation. The results of morphological and biochemical assessment of this study demonstrated the protective effects of all the tested lignans against acetaminophen-induced liver injury.

Among the investigated oxidative damage in liver, heart and exerted the strongest hepatoprotective effects.

Anti-inflammatory activity

The mechanism of anti-inflammatory action of schisandra lignans has been elucidated. It is based on the inhibition of the action of nitric oxide (NO) and the production of prostaglandins by stimulating the release of cyclooxygenase 2 (COX2) and inhibition of the expression of nitric oxide synthase (NOS).

Antioxidative and detoxification activities

Studies on the antioxidative and detoxification mechanisms of action of dibenzocyclooctadiene lignans have shown that they inhibit microsomal lipid peroxidation, reduce the concentration of superoxide radicals, inhibit microsomal NADPH oxidation in hepatocytes and reduce the release of alanine aminotransferase (ALT) and lactate dehydrogenase, which increases membrane integrity and viability of hepatocytes.

Moreover, the mechanism of protective, antioxidant and detoxifying action of lignans on hepatocytes is based on the increase in hepatic glutathione levels, and the activity of glutathione reductase and glutathione S-transferase. The latest studies have shown that schisandrin B attenuates doxorubicin induced cardiac dysfunction via antioxidative and anti-inflammatory effects. Schisandrin B has been shown to protect against oxidative damage in liver, heart and brain tissues in rodents.

Anticancer activity

Anticancer activity of schisandra lignans has been studied in recent years. Researchers have been identifying the compounds responsible for this activity and studying its mechanisms. They have shown that gomisin A acts by inhibiting the production of the placental form of glutathione S-transferase (tumor marker) in hepatocytes and by increasing the excretion of the carcinogen; it also influences cytokinesis and reduces the number of focal neoplastic lesions in the liver. Other studies on gomisin A have shown anticancer activity on the colon carcinoma. It displayed apoptotic activity through caspase-7 cleavage in colon carcinoma HCT-116 cells.

A recent investigation concerned the effects of gomisin A on cancer cell proliferation and cell cycle arrest in HeLa cells. Gomisin A significantly inhibited cell proliferation, especially in the presence of tumour necrosis factor-α (TNF-α).

In vitro studies on human leukemia cells—U973, it has been shown that another schisandra lignan—gomisin N, induces their apoptosis. The same mechanism of action of gomisin N has also been confirmed for hepatoma cells.

Apart from gomisin N, studies of the mechanism of anticancer action against two human tumor cell lines (adenocarcinoma cells—2008 and colon adenocarcinoma cells—LoVo) also included deoxyschisandrin. Both these lignans inhibited cell growth in a dosedependent manner on both cell lines, but by inducing different types of cell death. In particular, deoxyschisandrin caused apoptosis in colon adenocarcinoma cells (LoVo) but not in ovarian adenocarcinoma cells (2008), while gomisin N induced apoptosis on both the cell lines used.

As it turns out, the responsibility for the antitumor activity of the extracts from the fruits of S. chinensis is carried not only by dibenzocyclooctadiene lignans, but also by their polysaccharide fraction. A recent study confirmed the antitumor and immunomodulatory activities of water-soluble low-molecular-weight polysaccharide from S. chinensis.[6]

Immunostimulant activity

Research conducted in recent years has focused on studying the biological activity of the polysaccharide fraction from extracts of the fruits of S. chinensis. The immunostimulatory, immunomodulatory and antitumor action of water-soluble low-molecular-weight polysaccharide from S. chinensis has been proved. The polysaccharide fraction exhibited immunomodulating properties, such as improving the weight of immune organs, enhancing the phagocytic activity of peritoneal macrophages, promoting hemolysin formation, and increasing lymphocyte transformation.

Influence on the central nervous system, adaptogenic and ergogenic activities

The dibenzocyclooctadiene lignans contained in the extract from the fruits of S. chinensis represent a group of natural chemical structures, which are now considered protectants against neuronal cell death and cognitive impairment in neurological disorders.

In addition, the activity of polysaccharides contained in the fruits of S. chinensis is also studied in this respect. It has been shown that they, too, play an important role by raising the level of neurotransmitters in the central nervous system.

Extracts from the fruits of S. chinensis are used in neurasthenia and states of exhaustion; they improve the ability to learn and memorize, indirectly increase alertness, improve concentration and mental performance. They are used as adjuvant substances in the treatment of Alzheimer’s, Parkinson’s, and Meniere’s diseases, and ADHD (attention deficit hyperactivity disorder). The fruit extracts exhibit antidepressant activity without inducing drowsiness.

The fruits of S. chinensis have been recorded in some East Asian pharmacopoeias as an effective somnificant for the treatment of insomnia. However, the mechanism of the sedative and hypnotic effects of this plant raw material is still unclear. It has been shown that schisandrin—the dominant compound in S. chinensis fruit extract, produces beneficial sedative and hypnotic bioactivity, which might be mediated by the modification of the serotonergic system.

Moreover, adaptogenic and ergogenic properties of extracts from S. chinensis fruits were already well known from the traditional use of this plant. For this reason, S. chinensis, besides such plant species as Eleutherococcus senticosus, Panax ginseng, Panax quinquefolius or Rhodiola rosea, is classified as one of the worldwide known adaptogenic raw material.[7]

Influence on the respiratory system

The most recent studies of the pharmacological properties of S. chinensis fruit extracts have reported a beneficial role in the treatment of some respiratory system disorders. Data from 2014 suggest that S. chinensis fruit extracts have possible application as an antiasthmatic drug because they lower airway hyperresponsiveness, immunoglobuline E level, and immune cell infiltration in mice with asthma. The results also suggest that the fruit extracts could be used as a complementary or alternative medicine to glucocorticoids.

It has also been shown that extracts from the fruits of S. chinensis reduce cough frequency and pulmonary inflammation in cough hypersensitivity induced in guinea pigs by exposure to cigarette smoke. Lignans were indicated as the compounds likely to be responsible for this effect.[8]

Influence on the cardiovascular system

Recently, S. chinensis fruit extracts and the dibenzocyclooctadiene lignans contained in them have gained attention for their potential role in the treatment of cardiovascular diseases, such as hypertension and myocardial infarction, which corroborates the observed effects of this species in traditional settings. Scientific investigations of the molecular mechanisms behind the observed phenomena have revealed that S. chinensis fruit extracts and its lignans exert cardiovascular protective activity by controlling multiple signalling pathways involved in various biological processes, such as vascular contractility, fibrosis, inflammation, oxidative stress, and apoptosis.

Anti-obesity activities

  1. chinensis fruit extract has been evaluated for inhibition effects on adipocyte differentiation in 3T3- L1 cells and anti-obesity properties in induced obese rats. S. chinensis fruit extracts inhibited preadipocyte differentiation and adipogenesis in cultured cells, leading to decreased body weight and fat tissue mass in high-fat diet obese rats.

Antiviral activity

The latest research has dealt with antiviral activity of dibenzocyclooctadiene lignans. Assays have shown that schisandrin B and deoxyschisandrin selectively inhibited the HIV-1 reverse transcriptase-associated DNA polymerase activity. Schisandrin B was able to impair the early phases of HIV-1 replication in cellbased assays. In addition, schisandrin B was also able to impair HIV-1 reverse transcriptase drug resistant mutants and the early phases of viral replication.

Schisandra lignans are also active against plant viruses. It has been demonstrated that the natural product—schisanthenol and its synthetic derivatives, were active against tobacco mosaic virus.[9]

Antibacterial activity

The essential oil, and also an extract from schisandra berry showed antibacterial effects against Gram positive (Staphylococcus epidermidis, Staphylococcus aureus, Bacillus subtilis) and Gram negative  Chlamydia pneumoniae, C. trachomatis, Escherichia coli, Pseudomonas aeruginosa, Proteus vulgaris) bacteria.[10]

Withania

Withania may benefit cancer sufferers

Mounting evidence from cell culture and animal studies suggest that WS possesses antitumorigenic properties. In 1967, it was first demonstrated experimentally that the root extract resulted in lowered cancer incidence in vivo. Ever since, research interest in WS as an anti-tumorigenic agent has grown. This is apparent from the increase in the number of publications citing Withaferin A (WA; a withanolide from the WS plant) over the past decade from less than 5 in 2002 to more than 50 in 2015. Researchers are just starting to scratch the surface of molecular pathways modulated by WS and its withanolides in order to counter the carcinogenic process. Not only has WS and its withanolides been shown to have therapeutic potential against cancer, some of them have also been shown to possess cancer preventive properties.[11]

The cancer fighting properties have been seen not only with root extracts, but also with leaf extracts which is a relatively underused part of the Ashwagandha plant. In addition to directly protecting against carcinogenesis, WS and especially WA has been shown to be hepatoprotective. From the perspective of Ayurvedic medicine, there are several important implications of Ashwagandha for the treatment and prevention of cancer.

As mentioned previously, the role of Ashwagandha in regeneration and rejuvenation can potentially be pivotal to improve longevity and quality of human life. Thus, this idea of overall health promotion may lead towards prevention of chronic disease like cancer. However, the dosage of Ashwagandha administered as treatment for cancer is presumably quite different to what is given as a general  supplement that promotes good health. Careful research needs to be conducted to determine these parameters so that the factors pertaining to the use of Ashwagandha as a chemopreventive agent can be accurately established.[12]

Cancer pathways modulated by Withania somnifera (WS) and its withanolides (WA)

Cell survival/ apoptosis

Most discussions on anti-tumorigenic properties of WS pertain to its ability to activate apoptotic pathways in cancer cells. Even within the realm of cancer chemoprevention, cell survival and the activation of pro-apoptotic pathways holds important implications where successful reversal of the carcinogenesis process essentially requires the early clearance or destruction of impaired cells. Several currently known chemopreventive agents such as the isothiocyanate, sulforaphane [49] and the triterpenoid, CDDO-Im exhibit this property.

A plethora of in vitro evidence exists about the induction of apoptosis by WS, WA as well as other withanolides. Some of the earliest hints of tumor suppression by WS came from a study that evaluated the potential of leaf extract to inhibit tumor formation in nude mice subcutaneously injected with fibrosarcoma HT1080 cells. It was observed that treating mice with the leaf extract (0.3 mL of 24 µg/mL extract in cell growth medium, s.c.) resulted in reduced tumor size and was in part mediated via upregulation of p53.

Interestingly, the authors of the paper used NMR to identify the component responsible for this action to be withanone. Induction of apoptosis by WA has been noted in some in vivo models where treatment with 4 mg/kg WA, i.p. 5 times for 2 weeks markedly reduced MDA-MB-231 tumor weights in nude mice as well as increased apoptosis compared to tumors in control mice. While the exact mechanisms for induction of apoptosis by WS and its withanolides are yet to be established, data from several publications suggest that enhanced expression of proapoptotic genes as well as the suppression of proliferative pathways are possible targets. In a study conducted on a xenograft mouse model of cervical cancer, it was shown that 8 mg/kg WA, i.p. treatment for 6 weeks resulted in 70% reduction in tumor volume compared to controls as well as heightened expression of p53 and lowered expression of pro-caspase 3/Bcl2.[13]

The ability of WA to downregulate oncogenic proteins that have anti-apoptotic function such as Bcl2 has been reported by others as well. Whether this phenomena occurs in vivo within the tumor micro-environment to the extent that WA can selectively slow the growth of tumor cells via the aforementioned mechanisms while stabilizing the apoptotic function of normal cells has not been clearly determined. Ultimately, to utilize WS as a chemopreventive agent, the pharmacological conditions under which normal cells will survive while pre-cancerous/ cancerous cells will undergo death need to be assessed.

Selective killing of cancer cells by WA is an idea that has been put forward by many. By comparing cell lines that are cancerous and non-cancerous, WA has been shown to be cytotoxic to only  cancerous cell lines [60]. A point to note is that, these cell lines have inherent differences that can result in differential drug uptake, retention and toxicity. Therefore, mechanistic explorations of how tumor cells vs. non-tumor cells respond to WS and its withanolides require further investigation.[14]

Angiogenesis

It is widely accepted that angiogenesis is a vital process exploited by tumors to facilitate their own growth. In addition to tumor masses, early stage carcinogenic events may also utilize angiogenesis suggesting that it could be attenuated in a cancer preventive context. Angiogenesis has been categorized as a marker of cancer progression given the differences that occur in new blood vessel formation during early and late stages of carcinogenesis.

The role of WS and its withanolides on angiogenesis has been studied. The first report related to anti-angiogenic effect was published in 2004, where WA was shown to be a potent inhibitor of angiogenesis both in vitro and in vivo. In another study, WS was shown to inhibit angiogenesis in a VEGF-induced neovascularization model in vivo. A recent study along with molecular docking analyses corroborated the mechanism of this finding by showing that WA may directly bind to VEGF and thereby hamper angiogenesis. Further in vitro and in vivo experimentation is required to validate the physiological relevance of this finding.[15]

Stress response

In recent years, the role of stress response pathways in cancer chemoprevention has been closely evaluated. WS and some of its withanolides have been shown to be mediators of the heat shock response. The heat shock response is essential to cellular homeostasis given its function in facilitating the degradation of misfolded proteins. Transcriptional regulation of multiple classes of genes by Heat shock transcription factor 1 (HSF1) is considered to be an important regulatory step of this mechanism. WA has been shown to bind HSP90 to inhibit its chaperone activity through an ATP-dependent mechanism in pancreatic cancer cells.

This has been proposed to be one of the mechanisms by which WA exerts its antitumorigenic activity. A multiple compound screening study that utilized heat shock response induction as an endpoint identified WA as one of the potent mediators of the heat shock response wherein 1–4 µM WA was shown to be thiol-reactive and also shown to induce protein expression of HSP72 and 27. In a subsequent analysis, researches demonstrated that modulation of heat shock inducing activity of WA is feasible by structural modifications. It is important to point out that the effect of leaf or root extracts of WS on heat shock response has not been determined.[16]

In addition to the heat shock response, several other stress response pathways have also been shown to be affected by WS and some of its withanolides. Several reports note that WA is a strong inducer of oxidative stress, mediated primarily via the generation of reactive oxygen species. Interestingly, a report by researches suggested that WS extract did not provide any protection against oxidative damage caused by high glucose and hydrogen peroxide in human cancer cells, possibly suggesting that the pro-oxidant characteristics of WA would not render useful in protecting against oxidative damage.

The exact percentages of withanolides in this leaf extract were not revealed, making it difficult to understand the exact mechanism underlying the observation. Furthermore, whether oxidative stress induction by WA is a very early molecular event that facilitates downstream cytoprotective pathways in order to ultimately guard cells and organisms is also currently unknown. WS and its withanolides have also been shown to up regulate the expression of several phase II enzymes suggesting that other cytoprotective pathways, such as Nrf2 directly or indirectly, may be mediated by the action of withanolides.[17]

Inflammation and immune regulation

Researchers are on the brink of identifying the pivotal roles played by inflammation and immune function in cancer. Reducing chronic inflammation to prevent certain types of cancers (e.g., hepatitis  virus-induced inflammation and liver cancer) as well as utilizing immunotherapy as a successful treatment strategy for cancer are two key widely sought after areas of current cancer research. It is indeed desirable that some future chemopreventive drugs possess anti-inflammatory properties and also exhibit the ability to induce a robust immune response against early stage malignancies. Whether certain compounds that activate the immune system could potentially be utilized to prevent cancer has not been studied in detail, perhaps due to the fact that hyperactivation of the immune system could lead to several undesired challenges. Nevertheless, controlled activation of the immune system by WS is well-documented. In fact, two human studies with WS have looked at immunological end points. These studies suggest that the mechanism of action is driven by lymphocyte and NK cell activation.

Anti-inflammatory properties of WA are attributable to directly targeting cysteine 179 of IKK-β leading to the inhibition of NF-kB activity. WA has also shown COX-2 inhibitory activity in some experimental models. The anti-inflammatory and immune effects of WS and withanolides warrants further investigation, especially given the role of Ashwagandha as an adaptogen in traditional medicine.[18]

Ganoderma lucidium (Reishi)

An effective anti-inflammatory drug should be able to inhibit the development of chronic inflammation without interfering in normal homeostasis. A number of herbal drugs have been identified in the past that can target inflammatory cytokines. Among these, Ganoderma lucidum: a powerful medicinal mushroom has been found to possess immune-modulating and immune-potentiating capabilities and has been characterized as a wonder herb.[19]

Autoimmunity – Crohn’s Disease – Th1 Dominant Condition

Crohn’s disease (CD), an inflammatory bowel disease (IBD), is an immune-mediated disorder characterized by relapsing and remitting inflammation of the gastrointestinal tract. The exact etiology of Crohn’s disease is unknown, but both genetic and environmental causes have been implicated.  Crohn’s disease affects 1.4 million Americans, of which 140,000 are under the age of 18. Approximately 25% of all new cases in the population are under 20 years of age, and roughly 30,000 new patients are diagnosed annually.

CD is considered to be a result of a multifactorial interplay that is driven by innate and adaptive immune responses. Studies in mice and humans implicate dysregulation of intestinal CD4+ T cell subgroups leading to an abnormal immune response to bacterial antigens in a genetically predisposed individual. Th1/Th17 cells lead to increased production of effector T cell responses and an imbalance with regulatory T cells. CD pathogenesis includes upregulation of multiple cytokines including: TNF-a, IFN-γ, IL-1, IL-2, IL-6, IL-12, and IL-17.

Current therapies work by either broadly suppressing the immune system or by suppressing specific aspects of the inflammatory pathway. Despite the predominance of numerous inflammatory cytokines (TNF-a, IFN-γ, IL-17) involved in the pathogenesis of CD, the only cytokine-directed monoclonal antibodies that have shown efficacy in the treatment of CD are those targeted against TNF-a.

Treatments for CD, including corticosteroids, immunomodulators and biologics, are each associated with significant toxicities. Corticosteroids may cause suppression of the hypothalamic-pituitary adrenal axis, bone demineralization and growth suppression. Immunomodulators also have potential adverse effects including myelosuppression, hepatitis and increased risk of malignancies. Patients treated with anti-TNF-a therapy may develop antigenicity, loss of response, and toxicities such as infection, lupus-like syndrome and malignancy.

Treatment with biologic agents is also expensive. Additionally, treatment failure is common, with up to 18% of children requiring surgery within 5 years of disease onset. Therefore, alternative less toxic, orally administered interventions are being sought.

A formula of Ganoderma lucidium (FAHF-2) effects on CD were examined in a recent study which demonstrated that FAHF-2 reduced production of TNF-a, IFN-γ and other inflammatory cytokines by PBMCs and inflamed colonic biopsies from CD subjects. FAHF-2 was also effective in treating colitis in a murine model. This established the potential of FAHF-2 as a novel treatment for CD.

Clinical trials of FAHF-2 in patients with food allergies showed that it was safe, well tolerated and had multiple immunomodulatory effects.

Ganoderma lucidum (G. lucidum) is a major constituent in FAHF-2 and t is also a major constituent in other traditional Chinese medicine formulas such as anti-asthma herbal medicines intervention (ASHMI or ASHMI™). ASHMI was recently shown to be effective in a neutrophil predominant, steroid resistant asthma model. The therapeutic effect was associated with significant suppression of pro-allergic Th2 cytokines and pro-inflammatory cytokines TNF-a and IL-17.

Ganoderic acid C1 (GAC1) is a triterpenoid isolated from G. lucidum. A number of previous studies reported that polysaccharides from G. lucidum modulated cytokines. In unpublished work, it was  found that the triterpenoid fraction of G.lucidum was more potent than the polysaccharide fractions in suppression of TNF-a. GAC1 was the most potent triterpenoid. GAC1 inhibited TNF-a production by a murine macrophage cell line via down-regulation of the NF-κB signaling pathway, a key feature of both neutrophil predominant asthma and CD.

In a recent study, it was demonstrated for the first time that GAC1 exhibited inhibitory effects on TNF-a and other inflammatory cytokines including IFN-γ and IL-17 by PBMCs and inflamed intestinal biopsy tissue from CD subjects. GAC1 did not show signs of cytotoxicity in vitro.[20]

Monoclonal antibodies against TNF-a have revolutionized the treatment of CD and therefore our initial focus of investigation was on suppressing TNF-a production. CD14+ macrophages, adipocytes, fibroblast and T cells produce increased amounts of TNF-a, which perpetuates inflammation in CD. TNF-a levels are elevated in the serum and inflamed mucosa in patients with CD. Serum levels of TNF-a have been shown to correlate with clinical and laboratory indices of intestinal disease activity.

TNF-a is also secreted by LPMCs from CD patients. TNF-a effects include hypervasculization, angiogenesis, and increased pro-inflammatory cytokine production by macrophages and T-cells. Moreover, it causes mucosal barrier alterations, cell death of intestinal epithelial cells, tissue destruction, suppression of regulatory macrophages and activation of NF-κB. Since GAC1 significantly inhibited TNF-a production by both PBMCs and inflamed mucosa from CD, it is likely to be beneficial in combating inflammation in CD.

Unlike monoclonal antibodies against TNF-a, GAC1 is able to abrogate secretion of multiple inflammatory cytokines implicated in the pathogenesis of CD. CD is driven by a Th-1/Th-17 profile leading to increased secretion of IFN-γ and IL-17. IFN-γ is a proinflammatory cytokine that activates macrophages, augments antigen processing, alters tight junction activity and induces the death of epithelial cells. IL-17, part of the Th-17 response, mediates pro-inflammatory functions such as the recruitment of neutrophils and the secretion of matrix metalloproteinases.

It has been linked to degradation of tissue during inflammatory responses. IL-17 may also have a protective role within the intestine that has yet to be fully elucidated. Increased IL-1, IL-17A/F, IFN-γ and IL-6 are found in inflamed mucosa of CD. Interestingly, monoclonal antibodies targeted against IFN-γ (fontolizumab) and IL-17A (secukinumab) were not effective.

This suggests that a multi-pronged approach that suppresses multiple cytokines may be necessary. GAC1 inhibits IFN-γ and IL17A production in addition to TNF-a, and therefore may be efficacious in attenuating the inflammation that occurs in CD. NF-κB is known to play a central role in immune and inflammatory responses and is involved in transcriptional regulation of many cytokine genes, including TNF-a.

Inflammatory cytokines and intestinal microorganisms activate the NF-κB transcription factor process by inducing the phosphorylation and consequent degradation of IκB by its kinase. This allows NF-κB translocation into the cell nucleus to activate gene expression for relevant inflammatory proteins. The activated form of this transcription factor has been detected in mononuclear and epithelial cells of the inflamed colon.

Recent studies have shown that NF-κB may be a good target for CD therapy. GAC1 inhibited IκB activation both in PBMCs and mucosa, suggesting that it may work to decrease mucosal inflammation by down-regulation of the NF-κB signaling pathway. GAC1, alone or perhaps together with other compounds in has potential to be developed as a therapy for CD and other inflammatory conditions. Scientists have previously demonstrated that FAHF-2, the formulation containing GAC1, has anti-inflammatory effects both in human samples from CD and in a murine model of colitis.

Although allergic and non-allergic immune disorders are different clinical entities, neutrophil-predominant steroid-resistant asthma, food allergy and CD share some similar innate and adaptive immunological pathways. The common abnormalities include: increased TNF-a and activation of the NF-κB signaling pathway. We have shown that G. lucidum, a key herbal constituent in FAHF-2 and ASHMI, has anti-inflammatory effects on cytokines involved in both allergic and non-allergic disorders.

In conclusion, this study establishes a framework for refining an herbal therapy into its active components to ease use in clinical studies in inflammatory bowel disease patients. GAC1 has beneficial anti-inflammatory effects on cytokine production by PBMCs and colonic mucosa from CD subjects, showing promise for further development as a treatment for CD.[21]

Asthma – Th2 Dominant Condition

Allergic asthma is a common childhood disease that often persists into adulthood. The prevalence of childhood allergic diseases has increased dramatically in recent decades in many parts of the world, and children who mount an immune response to inhalant allergens have an increased risk of developing asthma. This immune response includes both IgE antibodies and type 2 helper T (Th2) cells, which are thought to contribute to inflammation in the respiratory tract. Moreover, sensitization to indoor allergens (dust mites, cats, and dogs) is strongly associated with asthma. The allergic disorders and diseases are characterized by predominant Th2 cytokine (IL-4, IL-5, and IL-13) production.

Ganoderma lucidum, a medicinal mushroom, is among the most popular herbal medicines in East Asia. G. lucidum has been reported to be effective in modulating immune functions, inhibiting tumor growth, and in the treatment of chronic hepatopathy, hypertension, neoplasia, and hyperglycemia. G. lucidum has also been used to prevent and treat atopic diseases in several mouse and human models. The main functional components of G. lucidum include polysaccharides, proteins, peptides, amino acids, and triterpenes. Polysaccharides are well known for their immunomodulatory and anti-tumor functions by reportedly enhancing the cytotoxic activity of natural killer cells and increasing tumor necrosis factor-a and interferon-g release from macrophages and lymphocytes, respectively.

The polysaccharide component from G. lucidum (PS-G) has also been reported to elicit anti-apoptotic effects on neutrophils, which primarily depend on the activation of Akt-regulated signaling pathways. We previously demonstrated that PS-G can rapidly and effectively promote the activation and maturation of immature healthy human dendritic cells (DCs), and promote T helper 1 immune responses in mice, thereby suggesting that PS-G may possess a potential capacity for regulating immune responses.[22]

Dendritic cells are powerful antigen-presenting cells, the primary function which is to capture, process, and present antigens to naïve T cells. Immature DCs reside in non-lymphoid tissues where DCs can capture and process antigens. Fully-mature DCs have a high surface expression of major histocompatibility complex (MHC) class II and co-stimulatory molecules (CD80 and CD86), but a decreased capacity to internalize antigens. The induction of DC maturation is critical for the induction of Ag-specific T lymphocyte responses and may be essential for the development of human (Censored) relying on T cell immunity. IL-12 production is also an important marker for DC maturation and can be used to select Th1-inducing adjuvants. IL-10, a cytokine that inhibits inflammatory and cell-mediated immune responses, has enormous potential for treating inflammatory and autoimmune disorders.

IL-23, which is mainly produced by macrophages and DCs, was recently identified as a cytokine that induces IL-17 expression. IL-17 production is enhanced in acute atopic dermatitis lesions and allergic contact dermatitis. The results showed that PS-G increased the expression of CD80, CD86, CD83, and HLA-DR molecules on the cell membranes of Der p 1-pulsed MD-DCs. Even though the maturation markers of MD-DCs from children with allergic asthma treated with PS-G alone increased, the effect was as clear as the effect in MD-DCs treated with LPS alone. Taken together, PS-G or LPS alone induces the maturation of MD-DCs from allergic asthma patients, and LPS- and PS-G-treated MD-DCs showed decreased antigen processing compared to control MDDCs and MD-DCs treated with Der p 1 alone.

We also evaluated the production of cytokines (IL-12 p40, IL-12 p70, IL-6, IL-23, and IL-10) in MD-DCs from allergic asthma children, and found that PS-G alone stimulated Der p 1-pulsed DCs to secrete IL-12 p40, IL-12 p70, IL6, IL23, and IL-10. The different responses of PS-G on DCs from healthy and allergic donors are particularly noteworthy. PS-G induced a large amount of IL-12 p40 from healthy compared to atopic donors. IL-12 is a heterodimeric cytokine produced by activated macrophages, neutrophils, and dendritic cells. Endogenous IL-12p40 selectively inhibits AHR and airway remodeling in an asthma model with prolonged antigen exposure.[23]

IL-12B is located in this genomic region and encodes IL-12p40; however, the allelic effects of this polymorphism on asthma susceptibility and asthma-related phenotypes has been shown. The first report suggested that the heterozygous genotype was more frequently detected in children with severe asthma. The genetic variation in the promoter of IL-12B displays functional activity and cytokine production capacity.

We also showed that the amount of IL-23 produced by PS-G on DCs from healthy donors was higher than allergic donors.  The p40 subunit of IL-12 is shared by IL-23, a cytokine with actions similar to, but distinct from IL-12. A protective role for the Th1 response generated by IL-12/IL-23 has been suggested based on infectious diseases in children with genetic defects of the IL-12/23 – IFN-g circuit.

PS-G-induced IL-12 p40 and IL-12 p70 secretion, and shifted the immune balance towards Th1. The data presented in a recent study also shows that PS-G induces IL-10 secretion. This spells great news for asthmatics.

Recent observations indicate that DCs play important roles in activating regulatory T (Treg) cells, including induction of CD4+ T cells into Foxp3+ Treg cells in vitro, IL-10-producing CD4+ Treg cells, and regulating the balance of Th1/Th2 immunity. Cytokines are involved in orchestrating the initiation and maintenance of allergic inflammatory responses.

Th2 cytokines, such as IL-4, IL-5, and IL-13, are involved in the development and maintenance of the allergic immune response. The Th1 cytokine, IFN-g, is known to down-regulate Th2 responses by antagonizing IL-4. The selective production of IFN-g is tightly regulated and is highly dependent on the reactivity of DCs to the environment, which in turn contributes to the T-cell polarization process. PS-G increases IL-6 and IL-23 production in DCs, although IL-6 and IL-23 appear to play a role in the induction of IL-17 by human CD4+ T cells, IL-1b, and TGF-b, in combination with other factors, which are essential in the induction of IL-17 production. Thus, the production of IL-17A by the stimulation of naïve T cells with DCs pulsed with PS-G, was not significantly changed in this study.[24]

Th17 cytokines have been shown to have an association with allergic disease. Th17 cells are highly involved in the development and maintenance of psoriasis, and a possible role for IL-17, IL-22, and Th17 cells in atopic dermatitis or allergic contact dermatitis is emerging. Nickel-specific Th0, Th1, or Th2 clones from allergic contact dermatitis patients have been shown to produce IL-17. Elevated IL-17 concentrations have also been found in lung and blood of allergic asthma patients and has been linked to the severity of asthma. Whether or not a specific role exists for Th17 cells in asthma, however, is controversial.

This is the first study to demonstrate that PS-G induces the production of Th1 cytokines produced by naïve human T cells through a direct effect on DCs in a model of children with allergic asthma. These results extend to previous findings that PS-G can induce gene expression changes in human DCs, and specifically promote Th1 cytokine release in BALB/c mice. Other studies have reported on the immunomodulatory and adjuvant activities of PS-G in mice. The cytokine environment encountered by a naïve CD4+ T cell plays a prominent role in determining whether or not naïve CD4+ T cells develop into Th1 or Th2 cells. Thus, the same naïve CD4+ T cells can give rise to Th1 or Th2 cells under the influence of environmental (e.g., cytokine) and genetic factors.

IFN-g production is related to an increase in IL-12 p40 and IL-12 p70 production observed when MDDCs from children with allergic asthma are pulsed by Der p 1 in the presence of PS-G. Taken together, the research suggest DCs may be the key cell type in children with allergic asthma.

IL-12 also has an important function in promoting Th1 immune responses and limiting the establishment and maintenance of Th2-type responses, mainly by enhancing IFN-g production and by providing an effective deviation signal during the early differentiation of Th0 cells. Thus, IL-12 p40 and IL-12 p70 production by PS-G may contribute to switching the balance from an established Th2 response to a more pronounced Th1 response.

Attempts to evaluate the effect of PS-G on specific T-cell proliferation in allergic asthmatic children has led to an apparent dichotomy for naïve T cells. Whereas naïve T cells exhibit a weak proliferative response to Der p 1-pulsed DCs, increased T cell proliferation is observed with PS-G-treated MD-DCs. T-cell proliferation requires at least two signals, one through contact of antigen MHC with T cell receptors and the other through an interaction between co-stimulatory molecules.

Thus, the varying degrees of DC maturation may explain the differences observed in T-cell proliferation. Similarly, lactic acid bacteria have been shown to have roles in modulating DC maturation from allergic patients. Indeed, in response to Der p 1, DCs express quite low levels of co-stimulatory molecules compared to PS-Gpulsed DCs, which express intense up-regulation of the surface markers (i.e., CD80, CD83, CD86, and HLADR).

There is an apparent relationship between the emergence of the PS-G-dependent T cell population and the increase in IFN-g production.

Thus, the research suggest that PS-G may switch the established Th2 response in allergic patients towards a long-lasting Th1 response, and may therefore represent a new therapeutic strategy for the treatment of children with allergic asthma. Below are graphs showing the beneficial changes in cytokines associated with Ganoderma use in asthmatics[25]:

[1] J Sci Food Agric. 2017 Apr 2. Immunostimulatory effect of aqueous extract of Coriandrum sativum L. seed on macrophages. Ishida M1, Nishi K1,2, Kunihiro N1, Onda H3, Nishimoto S4, Sugahara T.

[2] J Sci Food Agric. 2017 Apr 2. Immunostimulatory effect of aqueous extract of Coriandrum sativum L. seed on macrophages. Ishida M1, Nishi K1,2, Kunihiro N1, Onda H3, Nishimoto S4, Sugahara T.

[3] J Parasit Dis. 2016 Dec;40(4):1307-1310. In vitro and in vivo anthelmintic activity of seed extract of Coriandrum sativum compared to Niclosamid against Hymenolepis nana infection. Hosseinzadeh S1, Ghalesefidi MJ2, Azami M3, Mohaghegh MA4, Hejazi SH5, Ghomashlooyan M4.

[4] Nat Prod Res. 2017 Sep 15:1-7. The antimicrobial effects of three phenolic extracts from Rosmarinus officinalis L., Vitis vinifera L. and Polygonum cuspidatum L. on food pathogens. Santomauro F1, Sacco C1, Donato R1, Bellumori M2, Innocenti M2, Mulinacci N2.

[5] Hum Exp Toxicol. 2017 Jan 1:960327117710534. Hypolipidemic and hepatoprotective activities of rosemary and thyme in gentamicin-treated rats. Hegazy AM1, Abdel-Azeem AS1, Zeidan HM2, Ibrahim KS3, Sayed EE1.

[6] Phytochem Rev. 2017;16(2):195-218. Current knowledge of Schisandra chinensis (Turcz.) Baill. (Chinese magnolia vine) as a medicinal plant species: a review on the bioactive components, pharmacological properties, analytical and biotechnological studies. Szopa A1, Ekiert R2, Ekiert H1.

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[8] Phytochem Rev. 2017;16(2):195-218. Current knowledge of Schisandra chinensis (Turcz.) Baill. (Chinese magnolia vine) as a medicinal plant species: a review on the bioactive components, pharmacological properties, analytical and biotechnological studies. Szopa A1, Ekiert R2, Ekiert H1.

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[1] Review of Anti-Inflammatory Herbal Medicines. Mona Ghasemian,1 Sina Owlia,2 and Mohammad Bagher Owlia Advances in Pharmacological Sciences Volume 2016, Article ID 9130979, 11 pages

[2] Review of Anti-Inflammatory Herbal Medicines. Mona Ghasemian,1 Sina Owlia,2 and Mohammad Bagher Owlia Advances in Pharmacological Sciences Volume 2016, Article ID 9130979, 11 pages

[3] Ann N Y Acad Sci. 2017 Jun;1398(1):83-98. Beneficial effects of ginger Zingiber officinale Roscoe on obesity and metabolic syndrome: a review. Wang J1,2, Ke W1, Bao R1, Hu X1,2, Chen F1.

[4] J Food Drug Anal. 2017 Apr;25(2):403-408. Antibacterial activity and interactions of plant essential oil combinations against Gram-positive and Gram-negative bacteria. Semeniuc CA1, Pop CR1, Rotar AM2.

[5] Int J Mol Sci. 2017 Jun; 18(6): 1283. Antibacterial and Antifungal Activities of Spices Qing Liu,1 Xiao Meng,1 Ya Li,1 Cai-Ning Zhao,1 Guo-Yi Tang,1 and Hua-Bin Li1,2,*

[6] Multi-Targeted Molecular Effects of Hibiscus sabdariffa Polyphenols: An Opportunity for a Global Approach to Obesity. Herranz-López M, Olivares-Vicente M, Encinar JA, Barrajón-Catalán E, Segura-Carretero A, Joven J, Micol V. Nutrients. 2017 Aug 20;9(8).

[7] J Med Food. 2017 Sep 5. Long-Term Dietary Supplementation with Yerba Mate Ameliorates Diet-Induced Obesity and Metabolic Disorders in Mice by Regulating Energy Expenditure and Lipid Metabolism. Choi MS1, Park HJ1, Kim SR2, Kim DY3, Jung UJ3.

[8] Nutrients. 2017 Aug 15;9(8). Yerba Maté (Ilex paraguariensis) Metabolic, Satiety, and Mood State Effects at Rest and during Prolonged Exercise. Alkhatib A1, Atcheson R2.

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