Effect of polyphenols against complications of COVID-19: current evidence and potential efficacy.

The COVID-19 pandemic that started in 2019 and resulted in significant morbidity and mortality continues to be a significant global health challenge, characterized by inflammation, oxidative stress, and immune system dysfunction.. Developing therapies for preventing or treating COVID-19 remains an important goal for pharmacology and drug development research. Polyphenols are effective against various viral infections and can be extracted and isolated from plants without losing their therapeutic potential. Researchers have developed methods for separating and isolating polyphenols from complex matrices. Polyphenols are effective in treating common viral infections, including COVID-19, and can also boost immunity. Polyphenolic-based antiviral medications can mitigate SARS-CoV-2 enzymes vital to virus replication and infection. Individual polyphenolic triterpenoids, flavonoids, anthraquinonoids, and tannins may also inhibit the SARS-CoV-2 protease. Polyphenol pharmacophore structures identified to date can explain their action and lead to the design of novel anti-COVID-19 compounds. Polyphenol-containing mixtures offer the advantages of a well-recognized safety profile with few known severe side effects. However, studies to date are limited, and further animal studies and randomized controlled trials are needed in future studies. The purpose of this study was to review and present the latest findings on the therapeutic impact of plant-derived polyphenols on COVID-19 infection and its complications. Exploring alternative approaches to traditional therapies could aid in developing novel drugs and remedies against coronavirus infection.

The effect of oral supplementation of Paricalcitol on C-reactive protein levels in chronic kidney disease patients: GRADE-assessed systematic review and dose-response meta-analysis of data from randomized controlled trials.

BACKGROUND: Previous studies investigating the effect of oral supplementation of paricalcitol on reactive protein levels in chronic kidney disease (CKD) patients reported inconsistent findings. In this systematic review and meta-analysis, we have analyzed and interpreted the results obtained from previous randomized clinical trials on the effect of paricalcitol on C-reactive protein in CKD patients in the literature. METHODS: MEDLINE, SciVerse Scopus, and Clarivate Analytics Web of Science databases were searched until January 2023 and related articles were obtained through a careful screening process allowing extraction of required data from selected articles. The effect size was calculated using a random effect model and weighted mean differences (WMD) and 95% confidence intervals (CI). Heterogeneity among studies was evaluated using Cochran's Q test and I2. RESULTS: Amongst the 182 articles obtained from the initial search, 4 studies (6 arms) were finally included in the meta-analysis. Pooled analysis shows that C-reactive protein levels significantly decrease after oral supplementation with paricalcitol (WMD: -2.55 mg/L, 95% CI (-4.99 to -0.11; P = 0.04). The studies used in this meta-analysis showed significant heterogeneity (I2 = 66.3% and P = 0.01). CONCLUSION: Oral paricalcitol supplementation in CKD patients can significantly reduce C-reactive protein levels, which may prevent CKD progression.

Curcumin Nanofibers: A Novel Approach to Enhance the Anticancer Potential and Bioavailability of Curcuminoids.

Development of novel treatment methods for cancer is needed given the limitations of current treatment methods, including side effects and chemotherapeutic resistance, which may provide new hope to cancer patients. Cancer is the second leading cause of global mortality. Curcumin, the active ingredient of turmeric, has been used since ancient times for various therapeutic purposes. Several studies have identified its activity against cancer. Despite the established anticancer activity of curcumin, its low aqueous solubility and bioavailability are barriers to its effectiveness. In an attempt to solve this problem, many studies have formulated curcumin nanofiber preparations using a variety of methods. Electrospinning is a simple and affordable method for the production of nanofibers. Studies have shown increased curcumin bioavailability in nanofibers resulting from their high surface/volume ratio and porosity. We have undertaken a detailed review of studies on the anticancer effects of curcumin nanofibers. Curcumin acts by inhibiting various biological cancer pathways, including NF-κB, mTOR, complex I, cytokines, expression of p-p65, Ki67, and angiogenesis-associated genes. It also induces apoptosis through activation of caspase pathways and ROS production in cancer cells. Curcumin-loaded PLA50/PVP50/Cur15 nanofibers were investigated in breast cancer, one of the most studied cancers, and was shown to have significant effects on the widely used HeLa-cell line. Most of the studies undertaken have been performed in cell lines in vitro, while relatively few animal studies have been reported. More preclinical and clinical studies are needed to evaluate the anticancer activity of curcumin nanofibers. Amongst studies undertaken, a variety of curcumin nanofibers of various formulations have been shown to suppress a variety of cancer types. Overall, curcumin nanofibers have been found to be more efficient than free curcumin. Thus, curcumin nanofibers have been observed to improvise cancer treatment, offering great potential for effective cancer management. Further studies, both in vitro and in vivo, involving curcumin nanofibers have the potential to benefit cancer management.

Impact of Phytochemicals on PPAR Receptors: Implications for Disease Treatments.

Peroxisome proliferator-activated receptors (PPARs) are members of the ligand-dependent nuclear receptor family. PPARs have attracted wide attention as pharmacologic mediators to manage multiple diseases and their underlying signaling targets. They mediate a broad range of specific biological activities and multiple organ toxicity, including cellular differentiation, metabolic syndrome, cancer, atherosclerosis, neurodegeneration, cardiovascular diseases, and inflammation related to their up/downstream signaling pathways. Consequently, several types of selective PPAR ligands, such as fibrates and thiazolidinediones (TZDs), have been approved as their pharmacological agonists. Despite these advances, the use of PPAR agonists is known to cause adverse effects in various systems. Conversely, some naturally occurring PPAR agonists, including polyunsaturated fatty acids and natural endogenous PPAR agonists curcumin and resveratrol, have been introduced as safe agonists as a result of their clinical evidence or preclinical experiments. This review focuses on research on plant-derived active ingredients (natural phytochemicals) as potential safe and promising PPAR agonists. Moreover, it provides a comprehensive review and critique of the role of phytochemicals in PPARs-related diseases and provides an understanding of phytochemical-mediated PPAR-dependent and -independent cascades. The findings of this research will help to define the functions of phytochemicals as potent PPAR pharmacological agonists in underlying disease mechanisms and their related complications.

Ginger and its constituents: Role in treatment of inflammatory bowel disease.

Inflammatory bowel diseases (IBD), with obscure etiology, are rising and are of worldwide concern. Of the various components of IBD pathogenesis and progression, irritation appears to play a major part. Investigations on the molecular and cellular pathways that activate the IBD provide the focus for the development of useful therapies. Ginger (the rhizome of Zingiber officinale) has a broad spectrum of clinical applications due to its anti-inflammatory and anti-oxidative functions. Inflammation and oxidative stress are the key pathogenic factors in many diseases, including IBD. The most established components of ginger are phenolic compounds called gingerols. A wide range of pharmacological activities of the potential therapeutic benefit of Z. officinale have been detailed. In this regard, the anti-inflammatory activity of ginger has been documented by many researchers. It was shown that ginger is a potent inhibitor of the nuclear factor kappa B (NF-κB), signal transducer of activators of transcription (STATs), Nod-like receptor family proteins (NLRPs), toll-like receptors (TLRs), mitogen-activated protein kinase (MAPKs), and mTOR (mTOR) pathways, as well as inhibiting various pro-inflammatory cytokines. In the present report, the potential application of ginger in the management of IBD is reviewed in detail, with an emphasis on the relevant properties of ginger and its bioactive components. The significance of the functions, side effects, and delivery of ginger to the digestive system for particular application in IBD are also considered.

Harnessing Therapeutic Potentials of Statins Using Nanofibrous Carriers.

Statins are a wide category of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor drugs extensively prescribed for hypercholesterolemia. In fact, many studies showed beneficial effects of these agents on a variety of related illnesses, which include increased atherosclerotic plaque stability, decreased proliferation of vascular smooth muscle, platelet aggregation, the dampening of vascular inflammation, and also anabolic effects on bone tissue. Therefore, these drugs are considered as pleiotropic agents having different clinical applications other than those for which they were initially developed. Controlled drug delivery is an efficient way of delivery in tissue engineering. Amongst different controlled release formulations, nanofibers are a novel, alternative, widely used agent because of their unique properties. These include their sustained release of drug, a high drug-loading capacity, flexible shapes with a high surface-to-volume ratio, and superior porosity. Electrospinning is an economic and a simple method employed to produce nanofibers. In this report, studies related to statin nanofiber applications have been reviewed and their results have been summarized. Four different applications of statin nanofibers have been reported, including bone generation, endothelial stenosis and thrombosis, peripheral nerve injury, and anti-inflammatory action. Studies carried out both in vitro and in vivo showed effectiveness of statins in bone healing, aneurysm, and the healing of sciatic nerve injury. In addition, statins showed apoptosis effects and anti-inflammatory effects, with dose-dependent reduction of IL-6 and dose-independent reduction of TNF-α. Despite these promising results, validation via clinical trials is yet to be performed. The scope of statins in their pleiotropic range of actions is still not completely explored, and studies are still needed to enlighten different useful aspects of such drugs.

Impact of Curcumin on Microsomal Enzyme Activities: Drug Interaction and Chemopreventive Studies.

Curcumin, a yellow pigment in Asian spice, is a natural polyphenol component of Curcuma longa rhizome. Curcuminoid components include curcumin, demethoxycurcumin (DMC), and bisdemethoxycurcumin (BDMC). Previous studies established curcumin as a safe agent based on preclinical and clinical evaluations and curcuminoids have been approved by the US Food and Drug Administration (FDA) as "Generally Recognized as Safe" (GRAS). The present review collects and summarizes clinical and preclinical studies of curcumin interactions, with an emphasis on the effect of curcumin and curcumin analogs on the mRNA and protein levels of microsomal CYP450 enzymes (phase I metabolism) and their interactions with toxicants, drugs and drug probes. The literature search was conducted using keywords in various scientific databases, including Web of Science, Scopus, PubMed, and Google Scholar. Studies concerning the impact of curcumin and curcumin analogs on microsomal enzyme activity are reviewed and include oral, topical, and systemic treatment in humans and experimental animals, as well as studies from in vitro research. When taken together, the data identified some inconsistent results between various studies. The findings showed significant inhibition of CYP450 enzymes by curcumin and its analogs. However, such effects are often differed when curcumin and curcumin analogs were coadministered with toxicant and other drugs and drug probes. We conclude from this review that herb-drug interactions should be considered when curcumin and curcumin analogs are consumed.

Resveratrol: Mechanistic and therapeutic perspectives in pulmonary arterial hypertension.

Resveratrol, trans 3,5,4'-trihydroxystilbene, is a stilbenoid polyphenol with a wide range of properties including antioxidant, neuroprotective, cardioprotective, anti-inflammatory and anticancer activities. It is found in the skins of grape (50-100 µg/mL), red wine, peanuts, bilberries, blueberries and cranberries. The most important effects of resveratrol have been found in cardiovascular disease, with pulmonary arterial hypertension (PAH) being a major severe and progressive component. Many factors are involved in the pathogenesis of PAH, including enzymes, transcription factors, proteins, chemokines, cytokines, hypoxia, oxidative stress and others. Resveratrol treats PAH through its actions on various signaling pathways. These signaling pathways are mainly suppressed SphK1-mediated NF-κB activation, BMP/SMAD signaling pathway, miR-638 and NR4A3/cyclin D1 pathway, SIRT1 pathway, Nrf-2, HIF-1 α expression, MAPK/ERK1 and PI3K/AKT pathways, and RhoA-ROCK signaling pathway. Resveratrol efficiently inhibits the proliferation of pulmonary arterial smooth muscle cells and right ventricular remodeling, which are underlying processes leading to enhanced PAH. While supportive evidence from randomized controlled trials is yet to be available, current in vitro and in vivo studies seem to be convincing and suggest a therapeutic promise for the use of resveratrol in PAH.

Interactions between antidiabetic drugs and herbs: an overview of mechanisms of action and clinical implications.

Diabetes is a complex condition with a variety of causes and pathophysiologies. The current single target approach has not provided ideal clinical outcomes for the treatment of the disease and its complications. Herbal medicine has been used for the management of various diseases such as diabetes over centuries. Many diabetic patients are known to use herbal medicines with antidiabetic properties in addition to their mainstream treatments, which may present both a benefit as well as potential risk to effective management of their disease. In this review we evaluate the clinical and experimental literature on herb-drug interactions in the treatment of diabetes. Pharmacokinetic and pharmacodynamic interactions between drugs and herbs are discussed, and some commonly used herbs which can interact with antidiabetic drugs summarised. Herb-drug interactions can be a double-edged sword presenting both risks (adverse drug events) and benefits (through enhancement). There is a general lack of data on herb-drug interactions. As such, more rigorous scientific research is urgently needed to guide clinical practice as well as to safeguard the wellbeing of diabetes patients.

An ethnopharmacological approach to the preliminary screening of native Australian herbal medicines for anticancer activity.

BACKGROUND: Five plants used traditionally by Australian Aboriginals and two edible native Australian fruits have been investigated for anticancer activity. The aim was to identify native Australian herbal medicines which displayed anticancer activity, with cytotoxicity to cancer cells but sparing or even proliferating normal immunological cells, and subsequently provide potentially new anticancer drug leads. METHODS: Extracts and derived fractions were assayed for cell viability against a multiple myeloma cell line, RPMI-8226, in comparison to the peripheral blood mononuclear cells (PBMC) representing normal human immunological cells. RESULTS: None of the crude extracts exhibited the desirable differential activity; however, following further fractionation of the Eremophila duttonii F. Muell. (Myoporaceae) extract, one fraction (termed F01) exhibited a greater cytotoxicity to the cancer cell line than to the normal cells. CONCLUSIONS: One fraction may potentially contain valuable compounds which may be useful for further investigation. This may focus on the identification of the bioavailable purified compounds present within these fractions or by detailed delineation of the related mechanisms of action.

Management of cardiorenal metabolic syndrome in diabetes mellitus: a phytotherapeutic perspective.

Cardiorenal syndrome (CRS) is a complex disease in which the heart and kidney are simultaneously affected and their deleterious declining functions are reinforced in a feedback cycle, with an accelerated progression. Although the coexistence of kidney and heart failure in the same individual carries an extremely bad prognosis, the exact cause of deterioration and the pathophysiological mechanisms underlying the initiation and maintenance of the interaction are complex, multifactorial in nature, and poorly understood. Current therapy includes diuretics, natriuretic hormones, aquaretics (arginine vasopressin antagonists), vasodilators, and inotropes. However, large numbers of patients still develop intractable disease. Moreover, the development of resistance to many standard therapies, such as diuretics and inotropes, has led to an increasing movement toward utilization and development of novel therapies. Herbal and traditional natural medicines may complement or provide an alternative to prevent or delay the progression of CRS. This review provides an analysis of the possible mechanisms and the therapeutic potential of phytotherapeutic medicines for the amelioration of the progression of CRS.

Preventative effect of Zingiber officinale on insulin resistance in a high-fat high-carbohydrate diet-fed rat model and its mechanism of action.

Insulin resistance is a core component of metabolic syndrome and usually precedes the development of type 2 diabetes mellitus. We have examined the preventative effect of an ethanol extract of ginger (Zingiber officinale, Zingiberaceae) on insulin resistance in a high-fat high-carbohydrate (HFHC) diet-fed rat model of metabolic syndrome. The HFHC control rats displayed severe insulin resistance, whilst rats treated with ginger extract (200 mg/kg) during HFHC diet feeding showed a significant improvement of insulin sensitivity using the homeostatic model assessment of insulin resistance (HOMA-IR) after 10 weeks (p < 0.01). An in vitro mechanistic study showed that (S)-[6]-gingerol, the major pungent phenolic principle in ginger, dose-dependently (from 50 to 150 µM) increased AMPK α-subunit phosphorylation in L6 skeletal muscle cells. This was accompanied by a time-dependent marked increment of PGC-1α mRNA expression and mitochondrial content in L6 skeletal muscle cells. These results suggest that the protection from HFHC diet-induced insulin resistance by ginger is likely associated with the increased capacity of energy metabolism by its major active component (S)-[6]-gingerol.

Compound K modulates fatty acid-induced lipid droplet formation and expression of proteins involved in lipid metabolism in hepatocytes.

BACKGROUND & AIMS: A key factor in the development of type 2 diabetes and non-alcoholic fatty liver disease (NAFLD) is hepatic steatosis. Incubation of human hepatic cells with free fatty acids (FFAs) causes accumulation of neutral lipids in lipid droplets (LDs) and serves as a model for hepatic steatosis. Ginsenosides, active constituents of ginsengs, have demonstrated beneficial effects in various pharmacological areas, including diabetes, however their effect on lipid accumulation in hepatocytes remains unclear. Here, we examine the effect of compound K (ComK), an active metabolite of ginsenosides, on the regulation of LD formation and on the expression of proteins involved in lipid homeostasis in hepatocytes. METHODS: HuH7 cells were pretreated with ComK, followed by lipid loading with FFA. LDs were visualized using Oil Red O staining and immunohistochemistry for the LD-related protein PLIN2. Triglyceride levels were determined in isolated LDs. The expression of proteins involved in lipid homeostasis was examined by Western blotting. RESULTS: Treatment with ComK significantly decreased LD formation in FFA-loaded HuH7 cells and increased phosphorylation levels of AMPK, and its substrate ACC. ComK also increased protein expression of peroxisome proliferator-activated receptor-α (PPAR-α) and acyl-CoA oxidase (ACOX1) together with elevated activity of a PPAR-α response element reporter construct. These effects were inhibited by the PPAR-α antagonist MK886. CONCLUSIONS: ComK reduced LD formation and TG accumulation in FFA-loaded hepatocytes, in part by up-regulating AMPK activity and PPAR-α related pathways. These results suggest that ComK may have efficacy for the treatment of hepatic steatosis and associated diseases.

Identification of a Calcium Signalling Pathway of S-[6]-Gingerol in HuH-7 Cells.

Calcium signals in hepatocytes control cell growth, proliferation, and death. Members of the transient receptor potential (TRP) cation channel superfamily are candidate calcium influx channels. NF κ B activation strictly depends on calcium influx and often induces antiapoptotic genes favouring cell survival. Previously, we reported that S-[6]-gingerol is an efficacious agonist of the transient receptor potential cation channel subfamily V member 1 (TRPV1) in neurones. In this study, we tested the effect of S-[6]-gingerol on HuH-7 cells using the Fluo-4 calcium assay, RT-qPCR, transient cell transfection, and luciferase measurements. We found that S-[6]-gingerol induced a transient rise in [Ca(2+)] i in HuH-7 cells. The increase in [Ca(2+)] i induced by S-[6]-gingerol was abolished by preincubation with EGTA and was also inhibited by the TRPV1 channel antagonist capsazepine. Expression of TRPV1 in HuH-7 cells was confirmed by mRNA analysis as well as a test for increase of [Ca(2+)] i by TRPV1 agonist capsaicin and its inhibition by capsazepine. We found that S-[6]-gingerol induced rapid NF κ B activation through TRPV1 in HuH-7 cells. Furthermore, S-[6]-gingerol-induced NF κ B activation was dependent on the calcium gradient and TRPV1. The rapid NF κ B activation by S-[6]-gingerol was associated with an increase in mRNA levels of NF κ B-target genes: cIAP-2, XIAP, and Bcl-2 that encode antiapoptotic proteins.

Proceedings of conference on Mechanism-Based Development of Natural Products for Human Health.

Mechanism-Based Development of Natural Products in Human Health.

(S)-[6]-Gingerol enhances glucose uptake in L6 myotubes by activation of AMPK in response to [Ca2+]i.

PURPOSE: The aim of this study was to investigate the mechanism of (S)-[6]-gingerol in promoting glucose uptake in L6 skeletal muscle cells. METHODS: The effect of (S)-[6]-gingerol on glucose uptake in L6 myotubes was examined using 2-[1,2-3H]-deoxy-D-glucose. Intracellular Ca2+ concentration was measured using Fluo-4. Phosphorylation of AMPKα was determined by Western blotting analysis. RESULTS: (S)-[6]-Gingerol time-dependently enhanced glucose uptake in L6 myotubes. (S)-[6]-Gingerol elevated intracellular Ca2+ concentration and subsequently induced a dose- and time-dependent enhancement of threonine172 phosphorylated AMPKα in L6 myotubes via modulation by Ca2+/calmodulin-dependent protein kinase kinase. CONCLUSION: The results indicated that (S)-[6]-gingerol increased glucose uptake in L6 skeletal muscle cells by activating AMPK. (S)-[6]-gingerol, a major component of Zingiber officinale, may have potential for development as an antidiabetic agent.

Light-to-moderate ethanol feeding augments AMPK-α phosphorylation and attenuates SREBP-1 expression in the liver of rats.

PURPOSE: Fatty liver disease, a hepatic manifestation of metabolic syndrome, is one of the major causes of chronic liver diseases. Epidemiological studies suggest that regular light-to-moderate ethanol consumption lowers the risk of developing metabolic disorders including dislipidemia, insulin resistance, type 2 diabetes and fatty liver disease. However, the mechanism(s) of the protective effect of light-to-moderate ethanol consumption on the liver remains unknown. METHODS: In the present study, we investigated the effects of light (6%, 0.94 g/kg/day) and moderate (12%, 1.88 g/kg/day) ethanol feeding in rats for 3 weeks on the circulating and hepatic biochemical profiles and on the hepatic protein expression and phosphorylation status of adenosine monophosphate-activated protein kinase-α (AMPK-α) and other down-stream targets of this enzyme including sterol regulatory element-binding protein-1 (SREBP-1), SREBP cleavage-activating protein (SCAP) and 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoA reductase). RESULTS: Despite no significant difference in food-intake among the groups, light ethanol treatment significantly increased the body weight compared to control rats. Serum glucose, insulin, total cholesterol, triglycerides, phospholipids and hepatic cholesterol and triglycerides were not significantly different among the groups. However, serum free fatty acids were significantly reduced with light ethanol treatment. Both light and moderate ethanol treatment significantly increased the hepatic levels of phosphorylated AMPK-α protein and this was associated with significant reduction of SREBP-1 protein expression, suggesting an enhanced fatty acid oxidation. In addition, light ethanol treatment significantly decreased the SCAP protein expression in the liver. However, liver HMG-CoA protein expression was not significantly different with ethanol consumption. CONCLUSION: Chronic light-to-moderate ethanol consumption increased AMPK activation which was associated with decreased expression of SREBP-1 and SCAP in the liver. Thus, our studies provide mechanistic evidence for the earlier epidemiological studies that indicate light-to-moderate ethanol intake lowers the risk of development of fatty liver disease and other metabolic disorders. Our studies demonstrate that the protective effects of light-to-moderate ethanol arise at least in part by increased phosphorylation of AMPK-α and decreased SREBP-1 expression in the liver. Further studies are warranted to determine the effects of light-to-moderate ethanol on intracellular up-stream and down-stream targets of AMPK and also on the implications of light-to-moderate ethanol in protecting non-alcoholic fatty liver disease.

Attenuation of Proinflammatory Responses by S-[6]-Gingerol via Inhibition of ROS/NF-Kappa B/COX2 Activation in HuH7 Cells.

Introduction. Hepatic inflammation underlies the pathogenesis of chronic diseases such as insulin resistance and type 2 diabetes mellitus. S-[6]-Gingerol has been shown to have anti-inflammatory properties. Important inflammatory mediators of interleukins include nuclear factor κ B (NF κ B) and cyclooxygenase 2 (COX2). We now explore the mechanism of anti-inflammatory effects of S-[6]-gingerol in liver cells. Methods. HuH7 cells were stimulated with IL1ß to establish an in vitro hepatic inflammatory model. Results. S-[6]-Gingerol attenuated IL1ß-induced inflammation and oxidative stress in HuH7 cells, as evidenced by decreasing mRNA levels of inflammatory factor IL6, IL8, and SAA1, suppression of ROS generation, and increasing mRNA levels of DHCR24. In addition, S-[6]-gingerol reduced IL1ß-induced COX2 upregulation as well as NF κ B activity. Similar to the protective effects of S-[6]-gingerol, both NS-398 (a selective COX2 inhibitor) and PDTC (a selective NF κ B inhibitor) suppressed mRNA levels of IL6, IL8, and SAA1. Importantly, PDTC attenuated IL1ß-induced overexpression of COX2. Of particular note, the protective effect of S-[6]-gingerol against the IL1ß-induced inflammatory response was similar to that of BHT, an ROS scavenger. Conclusions. The findings of this study demonstrate that S-[6]-gingerol protects HuH7 cells against IL1ß-induced inflammatory insults through inhibition of the ROS/NF κ B/COX2 pathway.