Withania somnifera extracts induced attenuation of HIV-1: a mechanistic approach to restrict viral infection.

BACKGROUND: Several anti-retroviral drugs are available against Human immunodeficiency virus type-1, but have multiple adverse side effects. Hence, there is an incessant compulsion for effectual anti-retroviral agents with minimal or no intricacy. Traditionally, natural products have been the most successful source for the development of new medications. Withania somnifera, also known as Ashwagandha, is the utmost treasured medicinal plant used in Ayurveda, which holds the potential to give adaptogenic, immunomodulatory, and antiviral effects. However, its effect on HIV-1 replication at the cellular level has never been explored. Herein, we focused on the anti-HIV-1 activity and the probable mechanism of action of hydroalcoholic and aqueous extracts of Withania somnifera roots and its phytomolecules. METHODS: The cytotoxicity of the extracts was determined through MTT assay, while the in vitro anti-HIV-1 activity was assessed in TZM-bl cells against the HIV-1 strains of X4 and R5 subtypes. Results were confirmed in peripheral blood mononuclear cells, using the HIV-1 p24 antigen assay. Additionally, the mechanism of action was determined through the Time of Addition assay, which was further validated through the series of enzymatic assays, i.e. HIV-1 Integrase, Reverse transcriptase, and Protease assays. To explore the role of the identified active metabolites of Withania somnifera in antiretroviral activity, molecular docking analyses were performed against these key HIV-1 replication enzymes. RESULTS: The hydroalcoholic and aqueous extracts of Withania somnifera roots were found to be safer at the sub-cytotoxic concentrations and exhibited their ability to inhibit replication of two primary isolates of HIV-1 through cell-associated and cell-free assays, in dose-dependent kinetics. Several active phytomolecules found in Withania somnifera successfully established hydrogens bonds in the active binding pocket site residues responsible for the catalytic activity of HIV replication and therefore, signifying their role in the attenuation of HIV-1 infection as implied through the in silico molecular docking studies. CONCLUSIONS: Our research identified both the hydroalcoholic and aqueous extracts of Withania somnifera roots as potent inhibitors of HIV-1 infection. The in silico analyses also indicated the key components of Withania somnifera with the highest binding affinity against the HIV-1 Integrase by 12-Deoxywithastramonolide and 27-Hydroxywithanone, HIV-1 Protease by Ashwagandhanolide and Withacoagin, and HIV-1 Reverse transcriptase by Ashwagandhanolide and Withanolide B, thereby showing possible mechanisms of HIV-1 extenuation. Overall, this study classified the role of Withania somnifera extracts and their active compounds as potential agents against HIV-1 infection.

In vitro effect of Withania somnifera, AYUSH-64, and remdesivir on the activity of CYP-450 enzymes: Implications for possible herb-drug interactions in the management of COVID-19.

Ayurvedic medicines Withania somnifera Dunal (ashwagandha) and AYUSH-64 have been used for the prevention and management of COVID-19 in India. The present study explores the effect of Ashwagandha and AYUSH-64 on important human CYP enzymes (CYP3A4, CYP2C8, and CYP2D6) to assess their interaction with remdesivir, a drug used for COVID-19 management during the second wave. The study also implies possible herb-drug interactions as ashwagandha and AYUSH-64 are being used for managing various pathological conditions. Aqueous extracts of ashwagandha and AYUSH-64 were characterized using LC-MS/MS. A total of 11 and 24 phytoconstituents were identified putatively from ashwagandha and AYUSH-64 extracts, respectively. In addition, in silico studies revealed good ADME properties of most of the phytoconstituents of these herbal drugs and suggested that some of these might possess CYP-450 inhibitory activity. In vitro CYP-450 studies with human liver microsomes showed moderate inhibition of CYP3A4, 2C8, and 2D6 by remdesivir, while ashwagandha had no inhibitory effect alone or in combination with remdesivir. AYUSH-64 also exhibited a similar trend; however, a moderate inhibitory effect on CYP2C8 was noticed. Thus, ashwagandha seems to be safe to co-administer with the substrates of CYP3A4, CYP2C8, and CYP2D6. However, caution is warranted in prescribing AYUSH-64 along with CYP2C8 substrate drugs. Furthermore, preclinical and clinical PK studies would be helpful for their effective and safer use in the management of various ailments along with other drugs.

Corrigendum: Randomized, Double Blind, Placebo Controlled, Clinical Trial to Study Ashwagandha Administration in Participants Vaccinated Against COVID-19 on Safety, Immunogenicity, and Protection With COVID-19 Vaccine-A Study Protocol.

[This corrects the article DOI: 10.3389/fmed.2022.761655.].

Randomized, Double Blind, Placebo Controlled, Clinical Trial to Study Ashwagandha Administration in Participants Vaccinated Against COVID-19 on Safety, Immunogenicity, and Protection With COVID-19 Vaccine-A Study Protocol.

INTRODUCTION: Vaccines have emerged as the most effective tool in the fight against COVID-19. Governments all over the world have rolled out the COVID-19 vaccine program for their populations. Oxford-AstraZeneca COVID-19 vaccine (COVISHIELD™) is widely used in India. A large number of Indian people have been consuming various traditional medicines in the hope of better protection against COVID-19 infection. Several studies have reported immunological benefits of Withania somnifera (Ashwagandha) and its potential as a vaccine adjuvant. We propose to study the safety, immunogenicity and clinical protection offered by a 6-month regimen of Ashwagandha in participants who volunteer to be vaccinated against COVID-19 (COVISHIELDTM) in the ongoing national program of vaccination. METHODS AND ANALYSIS: We designed a prospective, randomized, double-blind, parallel-group, placebo-controlled, two-arm, exploratory study on healthy volunteers receiving the COVISHIELDTM vaccine. The administration of Ashwagandha will begin within 7 days of the first or second dose of COVISHIELDTM. Primary outcome measure is immunogenicity as measured by SARS-CoV-2 spike (S1) and RBD-specific IgG antibody titres. Secondary outcome measures are safety, protective immune response and quality of life measures. All adverse events will be monitored at each time throughout the study. Participants will be tracked on a daily basis with a user-friendly mobile phone application. Following power calculation 600 participants will be recruited per arm to demonstrate superiority by a margin of 7% with 80% power. Study duration is 28 weeks with interim analysis at the end of 12 weeks. ETHICS AND DISSEMINATION: Ethics approval was obtained through the Central and Institutional Ethics Committees. Participant recruitment commenced in December 2021. Results will be presented in conferences and published in preprints followed by peer-reviewed medical journals. CLINICAL TRIAL REGISTRATION: [www.ClinicalTrials.gov], identifier [CTRI/2021/06/034496].

Exploring AyuGenomics approach for understanding COVID-19 predisposition and progression.

Recent reports on COVID-19 suggest that, the susceptibility to COVID-19 infection and its progression have a genetic predisposition. Majorly associated genetic variants are found in human leukocyte antigen (HLA), angiotensin convertase enzyme (ACE; rs1799752: ACE2; rs73635825), and transmembrane protease serine 2 (TMPRSS-2; rs12329760) genes. Identifying highly prone population having these variants is imperative for determining COVID-19 therapeutic strategies. Ayurveda (Indian traditional system of medicine) concept of Prakriti holds potential to predict genomic and phenotypic variations. Reported work on Prakriti correlates HLA-DR alleles with three broad phenotypes (Tridosha) described in Ayurveda (AyuGenomics). This is suggestive of differences in immune responses in individuals with specific constitutions. Therefore, the reported studies provide clues for clinically relevant hypotheses to be tested in systematic studies. The proposed approach of Ayurveda-based phenotype screening may offer a way ahead to design customized strategies for management of COVID-19 based on differences in Prakriti, immune response, and drug response. However, this needs clinical evaluation of the relation between Prakriti and genetic or phenotypic variants in COVID-19 prone and resistant populations.

Ayurveda botanicals in COVID-19 management: An in silico multi-target approach.

The Coronavirus disease (COVID-19) caused by the virus SARS-CoV-2 has become a global pandemic in a very short time span. Currently, there is no specific treatment or vaccine to counter this highly contagious disease. There is an urgent need to find a specific cure for the disease and global efforts are directed at developing SARS-CoV-2 specific antivirals and immunomodulators. Ayurvedic Rasayana therapy has been traditionally used in India for its immunomodulatory and adaptogenic effects, and more recently has been included as therapeutic adjuvant for several maladies. Amongst several others, Withania somnifera (Ashwagandha), Tinospora cordifolia (Guduchi) and Asparagus racemosus (Shatavari) play an important role in Rasayana therapy. The objective of this study was to explore the immunomodulatory and anti SARS-CoV2 potential of phytoconstituents from Ashwagandha, Guduchi and Shatavari using network pharmacology and docking. The plant extracts were prepared as per ayurvedic procedures and a total of 31 phytoconstituents were identified using UHPLC-PDA and mass spectrometry studies. To assess the immunomodulatory potential of these phytoconstituents an in-silico network pharmacology model was constructed. The model predicts that the phytoconstituents possess the potential to modulate several targets in immune pathways potentially providing a protective role. To explore if these phytoconstituents also possess antiviral activity, docking was performed with the Spike protein, Main Protease and RNA dependent RNA polymerase of the virus. Interestingly, several phytoconstituents are predicted to possess good affinity for the three targets, suggesting their application for the termination of viral life cycle. Further, predictive tools indicate that there would not be adverse herb-drug pharmacokinetic-pharmacodynamic interactions with concomitantly administered drug therapy. We thus make a compelling case to evaluate the potential of these Rasayana botanicals as therapeutic adjuvants in the management of COVID-19 following rigorous experimental validation.

Withania somnifera (L.) Dunal: Opportunity for Clinical Repurposing in COVID-19 Management.

As the COVID-19 pandemic is progressing, the therapeutic gaps in conventional management have highlighted the need for the integration of traditional knowledge systems with modern medicine. Ayurvedic medicines, especially Ashwagandha (Withania somnifera (L.) Dunal, WS), may be beneficial in the management of COVID-19. WS is a widely prescribed Ayurvedic botanical known as an immunomodulatory, antiviral, anti-inflammatory, and adaptogenic agent. The chemical profile and pharmacological activities of WS have been extensively reported. Several clinical studies have reported its safety for use in humans. This review presents a research synthesis of in silico, in vitro, in vivo, and clinical studies on Withania somnifera (L.) Dunal (WS) and discusses its potential for prophylaxis and management of COVID-19. We have collated the data from studies on WS that focused on viral infections (HIV, HSV, H1N1 influenza, etc.) and noncommunicable diseases (hypertension, diabetes, cancer, etc.). The experimental literature indicates that WS has the potential for 1) maintaining immune homeostasis, 2) regulating inflammation, 3) suppressing pro-inflammatory cytokines, 4) organ protection (nervous system, heart, lung, liver, and kidney), and 5) anti-stress, antihypertensive, and antidiabetic activities. Using these trends, the review presents a triangulation of Ayurveda wisdom, pharmacological properties, and COVID-19 pathophysiology ranging from viral entry to end-stage acute respiratory distress syndrome (ARDS). The review proposes WS as a potential therapeutic adjuvant for various stages of COVID-19 management. WS may also have beneficial effects on comorbidities associated with the COVID-19. However, systematic studies are needed to realize the potential of WS for improving clinical outcome of patients with COVID-19.

Management of Type 2 Diabetes: Current Strategies, Unfocussed Aspects, Challenges, and Alternatives.

Type 2 diabetes mellitus (T2DM) accounts for >90% of the cases of diabetes in adults. Resistance to insulin action is the major cause that leads to chronic hyperglycemia in diabetic patients. T2DM is the consequence of activation of multiple pathways and factors involved in insulin resistance and ß-cell dysfunction. Also, the etiology of T2DM involves the complex interplay between genetics and environmental factors. This interplay can be governed efficiently by lifestyle modifications to achieve better management of diabetes. The present review aims at discussing the major factors involved in the development of T2DM that remain unfocussed during the anti-diabetic therapy. The review also focuses on lifestyle modifications that are warranted for the successful management of T2DM. In addition, it attempts to explain flaws in current strategies to combat diabetes. The employability of phytoconstituents as multitargeting molecules and their potential use as effective therapeutic adjuvants to first line hypoglycemic agents to prevent side effects caused by the synthetic drugs are also discussed.

Withania somnifera (L.) Dunal: A potential therapeutic adjuvant in cancer.

ETHNOPHARMACOLOGICAL RELEVANCE: Withania somnifera (L.) Dunal (WS) is one of the moststudied Rasayana botanicals used in Ayurveda practice for its immunomodulatory, anti-aging, adaptogenic, and rejuvenating effects. The botanical is being used for various clinical indications, including cancer. Several studies exploring molecular mechanisms of WS suggest its possible role in improving clinical outcomes in cancer management. Therefore, research on WS may offer new insights in rational development of therapeutic adjuvants for cancer. AIM OF THIS REVIEW: The review aims at providing a detailed analysis of in silico, in vitro, in vivo, and clinical studies related to WS and cancer. It suggests possible role of WS in regulating molecular mechanisms associated with carcinogenesis. The review discusses potential of WS in cancer management in terms of cancer prevention, anti-cancer activity, and enhancing efficacy of cancer therapeutics. MATERIAL AND METHODS: The present narrative review offers a critical analysis of published literature on WS studies in cancer. The reported studies were analysed in the context of pathophysiology of cancer, commonly referred as 'cancer hallmarks'. The review attempts to bridge Ayurveda knowledge with biological insights into molecular mechanisms of cancer. RESULTS: Critical analysisof the published literature suggests an anti-cancer potential of WS with a key role in cancer prevention. The possible mechanisms for these effects are associated with the modulation of apoptotic, proliferative, and metastatic markers in cancer. WS can attenuate inflammatory responses and enzymes involved in invasion and metastatic progression of cancer.The properties of WS are likely to be mediated through withanolides, which may activate tumor suppressor proteins to restrict proliferation of cancer cells. Withanolides also regulate the genomic instability, and energy metabolism of cancer cells. The reported studies indicate the need for deeper understanding of molecular mechanisms of WS in inhibiting angiogenesis and promoting immunosurveillance. Additionally, WS can augment efficacy and safety of cancer therapeutics. CONCLUSION: The experimentally-supported evidence of immunomodulatory, anti-cancer, adaptogenic, and regenerative attributes of WS suggest its therapeutic adjuvant potential in cancer management. The adjuvant properties of withanolides can modulate multidrug resistance and reverse chemotherapy-induced myelosuppression. These mechanisms need to be further explored in systematically designed translational and clinical studies that will pave the way for integration of WS as a therapeutic adjuvant in cancer management.

Understanding the relevance of herb-drug interaction studies with special focus on interplays: a prerequisite for integrative medicine.

Integrative medicine refers to the blending of conventional and evidence-based complementary medicines and therapies with the aim of using the most appropriate of either or both modalities for ultimate patient benefits. One of the major hurdles for the same is the chances of potential herb-drug interactions (HDIs). These HDIs could be beneficial or harmful, or even fatal; therefore, a thorough understanding of the eventualities of HDIs is essential so that a successful integration of the modern and complementary alternative systems of medicine could be achieved. Here, we summarize all the important points related to HDIs, including types, tools/methods for study, and prediction of the HDIs, along with a special focus on interplays between drug metabolizing enzymes and transporters. In addition, this article covers future perspective, with a focus on background endogenous players of interplays and approaches to predict the drug-disease-herb interactions so as to fetch the desired effects of these interactions.

Targeting receptors of advanced glycation end products (RAGE): Preventing diabetes induced cancer and diabetic complications.

Cancer and diabetes are the two major disorders that affect a large proportion of the world's population. Results from multiple epidemiological studies have concluded that diabetes and cancer are linked, and diabetic patients live at much higher risks of developing cancer and diabetic complications at the later phase of disease. Inflammation is the central pathway that mediates both diabetic complications as well as cancer. Receptor of advanced glycation end products (RAGE) is a non-specific multi-ligand pattern recognition receptor that induces the inflammatory responses by binding with multiple ligands. RAGE and its ligands are upregulated in diabetes, inflammation and cancer. Advanced glycation end products (AGEs), high mobility group box protein-1 (HMGB1) and S100 proteins are the major RAGE ligands that contribute to these consequences and an increased release of RAGE ligands during diabetic conditions can be a possible mechanism leading to diabetic complications and cancer. Moreover, further release of RAGE ligands from cancer cells can be a possible mechanism behind the worsening of diabetic complications in diabetic cancer patients. Inhibition of RAGE signaling can prevent diabetic complications and cancer in diabetic patients and can be helpful in the management of worsening diabetic complications and cancer in diabetic cancer patients. Curcumin, Quercetin and Withaferin A are known to inhibit multiple molecular pathways that are involved in RAGE signaling. The combined effects of these molecules can be explored to achieve the complete inhibition of RAGE signaling in diabetic patients.

Antidiabetic properties of aqueous and methanol extracts from the trunk bark of Ceiba pentandra in type 2 diabetic rat.

The type 2 diabetes is one of the major global health issues that affects millions of people. This study evaluated the antidiabetic activity of aqueous extracts (AECP) and methanol extracts (MECP) from Ceiba pentandra trunk bark on an experimental model of type 2 diabetes (T2D). This model was induced in rats by the combination of a high-fat diet (HFD) and a single dose of streptozotocin (40 mg/kg, intraperitoneal) at the seventh day of experimentation. Diabetes was confirmed on day 10 by fasting blood glucose more than or equal to 200 mg/dL. Diabetic animals still under HFD were treated orally and twice daily, with MECP and AECP (75 and 150 mg/kg) or metformin (40 mg/kg) for 14 days. During the experiment, blood glucose and animal weights were determined. Oral glucose tolerance test was performed on day 15, followed by animals sacrifice for blood, liver, and pancreas collection. Total cholesterol and triglyceride levels were evaluated in plasma, whereas malondialdehyde (MDA), glutathione (GSH), superoxide dismutase, and catalase were quantified in tissue homogenates. AECP and MECP significantly reduced the hyperglycemia by up to 62% and significantly improved the oral glucose tolerance test. The impaired levels of cholesterol and triglycerides registered in diabetic control were significantly reversed by both extracts at all the doses used. Alterations in diabetic pancreas weight, GSH, and MDA were also significantly reversed by plant extracts. AECP and MECP possess type 2 antidiabetic effects that could result from their ability to improve the peripheral use of glucose, lipid metabolism or from their capacity to reduce oxidative stress. These finding provide a new avenue for better control and management of early or advanced T2D.

In vitro and in vivo anticancer efficacy potential of Quercetin loaded polymeric nanoparticles.

Quercetin (QCT) is a flavonoid, abundantly present in plants and has gained considerable interest for its antioxidant property and chemo preventive activity. Bioavailability of QCT is very low due to its poor aqueous solubility and instability. Researchers are working on the application of nanotechnology to target chemotherapeutic drugs to the tumour site. The aim of the present study was to develop quercetin loaded chitosan nanoparticles (QCT-CS NPs) with enhanced encapsulation efficiency and sustained release property. We prepared biocompatible NPs with small size (<200 nm) and encapsulation efficiency of 79.78%. In vitro drug release study exhibited a cumulative amount of 67.28% release of QCT over a period of 12 h. at pH 7.4. In vitro cytotoxicity assay showed significantly reduced IC50 value of QCT-CS NPs as compared to free QCT (p < 0.05). Intra venous treatment of QCT-CS NPs in tumour xenograft mice with A549 and MDA MB 468 cells exerted significant reduction of tumour volume in comparison to disease control groups (p < 0.05). Serum anti oxidant enzyme superoxide dismutase (SOD) level markedly increased in QCT-CS NPs treated tumour bearing mice than free QCT treated group. In summary, the recent investigations reported successful encapsulation of QCT in chitosan (CS) NPs to target the tumour microenvironment and exhibited enhanced efficacy of QCT-CS NPs in cancer therapy.

Potential synergistic effects of quercetin with other phytoconstituents of Costus pictus (insulin plant) extract in the control of hyperglycemia and prevention of NSAID-induced gastroenteropathy in diabetic rats.

There is a need of multifactorial management to treat T2DM. Till date, no clinically simulated animal model and therapy for NSAID-induced gastroenteropathic damage (NSAID-iGD) in T2DM patients. T2DM was developed using high-fat diet plus multiple low doses of streptozotocin (30 mg/kg, IP). Rats treated with ethanolic extract of Insulin plant (EIP; 125, 250 and 500 mg/kg, PO; b.i.d.)/Quercetin (QCT; 50 mg/kg)/vehicle for total 10 days. Diclofenac sodium (DCF; 7.5 mg/kg, PO, b.i.d.) administered for final five days of EIP/vehicle administration. Rats fasted after last dose on the 9th day; water was provided ad libitum. 12 h after the last dose on 10th day, GI tracts assessed for haemorrhagic damage, XO activity, LPO, intestinal permeability, luminal pH alterations along with haematological, biochemical and histological parameters. The evidence suggested that DCF administration caused significant gastroenteropathic damage. In presence of T2DM, NSAID-iGD significantly exacerbated. Whereas, QCT/EIP treatment significantly attenuated T2DM dependent exacerbation of NSAID-iGD, and also efficiently managed T2DM in a dose-dependent manner. Low amount of QCT in EIP(190.96 ±â€¯7.5 ng/mg) than its effective dose(50 mg/kg) indicates that EIP's other phytoconstituents (e.g. Kaempferol, Ascorbic acid, Lupeol, Diosgenin, ß-sitosterol, Stigmasterol, ß-amyrin, etc.) giving synergistic actions. Costus pictus/QCT has potential to be promising candidate to treat patient with T2DM and NSAID-gastroenteropathy in T2DM.

Curcumin, a component of turmeric, efficiently prevents diclofenac sodium-induced gastroenteropathic damage in rats: A step towards translational medicine.

There is a need to find/discover novel leads to treat complex and/or multi-factorial disease(s). Curcumin (CUR) is one of the promising lead molecules which need its further evaluation against NSAID-induced gastroenteropathy. Hence, the aim of the present study was to explore the pharmaco-mechanistic efficacy of CUR against NSAID-induced gastroenteropathy. Rats were treated twice daily with CUR (25, 50 and 100 mg kg-1 peroral) or vehicle for 10 days. In some experiments, diclofenac sodium (DIC; 9 mg kg-1) was administered orally twice daily for the final 5 days of CUR/vehicle administration. After the last dose on 9th day, rats were fasted. 12 h after the last dose on 10th day, rats were euthanized and their GI tracts were assessed for haemorrhagic lesions, lipid peroxidation, intestinal permeability and GI luminal pH alterations along with haemato-biochemical estimations. The macroscopic, biochemical, haematological and histological evidences suggested that co-administration of CUR resulted in dose dependent attenuation of the NSAID-induced gastroenteropathic damage and the mechanisms may be related to its ability to prevent the NSAID-induced alterations in the GI luminal pH, lipid peroxidation/oxidative stress, GI blood loss and intestinal permeability alteration. Based on these pharmaco-mechanistic results we propose it as a promising lead to treat NSAID-gastroenteropahty.

Overcoming the exacerbating effects of ranitidine on NSAID-induced small intestinal toxicity with quercetin: Providing a complete GI solution.

There is a need to find/discover novel leads to treat complex and/or multi-factorial-pathogenic disease(s) like Nonsteroidal anti-inflammatory drugs (NSAID)-induced gastroenteropathy or gastrointestinal (GI) toxicity as it has emerged as an important medical and socioeconomic problem. There is no approved therapeutic strategy to prevent NSAID-induced enteropathic damage and highly effective gastro-protective drugs such as ranitidine hydrochloride (RAN) exacerbate it. In this purview, the multi target drug discovery approach (MTDD), combination approach and hit to lead strategies based on the foundation of ethnopharmacology and/or reverse pharmacology holds strong potential. Hence, the primary objectives of the current study were to explore the mechanism behind the preventative/curative effects of quercetin (QCT) on RAN exacerbated diclofenac sodium (DIC)-induced enteropathic damage and to assess the effects of co-administration of QCT and RAN on DIC-induced gastropathic damage in rats. Rats were treated twice daily with QCT (35, 50 and 100 mg kg-1 PO) and/or RAN (15 mg kg-1 PO) or vehicle for a total of 10 days. In some experiments, DIC (9 mg kg-1) was administered orally twice daily for the final 5 days of RAN/QCT + RAN/vehicle administration. Rats in all the groups were fasted after the last dose on 9th day (free access to water). 12 h after the last dose on 10th day, rats were euthanized and their GI tracts were assessed for haemorrhagic damage, alteration in xanthine oxidase (XO) activity, lipid peroxidation, intestinal permeability and GI luminal pH alterations along with haematological and biochemical estimations. The macroscopic, haematological, biochemical and histological evidences suggested that, though, RAN prevented the DIC-induced gastric injury, it exacerbated enteropathic damage. However, QCT not only significantly attenuated the RAN-induced exacerbation of enteropathic damage caused by DIC at the doses of 50 and 100 mg kg-1, but, this combination provided complete GI safety against the toxic effects of DIC too. The mechanisms behind the gastro-enteroprotective ability of QCT may be related to its ability to inhibit XO activity thus, preventing enhanced oxidative stress on GI tissues, prevent lipid peroxidation, IP alteration and alteration in GI luminal pH. The preventative effects of QCT on NSAID-induced gastroenteropathy were ably supported by the QCT induced prevention of GI blood loss and serum protein loss. These pharmaco-mechanistic results of QCT are aligning to combination based MTDD approach and hence we propose it as a promising lead to treat NSAID-gastroenteropahty and related complications.

Co-administration of quercetin with pantoprazole sodium prevents NSAID-induced severe gastroenteropathic damage efficiently: Evidence from a preclinical study in rats.

Management of Nonsteroidal anti-inflammatory drug (NSAID)-induced gastroenteropathy has emerged as a major medical and socioeconomic problem mainly because the highly efficacious gastroprotective drugs i.e. proton pump inhibitors (PPIs) like pantoprazole sodium (PTZ), worsen the NSAID-induced enteropathic damage and lack of approved therapeutic strategies/interventions to prevent this damage. Hence, the primary objective of the current study was to assess whether we can protect the GI mucosa against gastroenteropathic damage caused by diclofenac sodium (DIC) in rats by co-administration of PTZ and quercetin (QCT). Rats were treated twice daily with QCT (35, 50 and 100mgkg-1 peroral) and/or PTZ (4mgkg-1) or vehicle for a total of 10 days. In some experiments, DIC (9mgkg-1) was administered orally twice daily for the final 5days of PTZ/QCT+PTZ/vehicle administration. Rats in all the groups were fasted after the last dose on 9th day, but, water was provided ad libitum. 12h after the last dose on 10th day, rats were euthanized and their GI tracts were assessed for haemorrhagic damage, lipid peroxidation, intestinal permeability and GI luminal pH alterations along with haematological and biochemical estimations. The experimental evidences suggested that co-administration of QCT with PTZ significantly attenuated the exacerbation of NSAID-induced enteropathic damage in a dose dependent manner. The combination of PTZ 4mgkg-1 and QCT at the doses of 50 or 100mgkg-1 was found to effective in preventing the DIC-induced gastroenteropathy. The present report focuses on the gastroenteroprotective ability of QCT and the mechanisms may be related to its ability to prevent GI blood loss, the lipid peroxidation, intestinal permeability alteration and alteration in GI luminal pH.

Clinical importance of nonsteroidal anti-inflammatory drug enteropathy: the relevance of tumor necrosis factor as a promising target.

The pathogenesis of nonsteroidal anti-inflammatory drug (NSAID) enteropathy is still unclear, and consequently, there is no approved therapeutic strategy for ameliorating such damage. On the other hand, molecular treatment strategies targeting tumor necrosis factor (TNF) exerts beneficial effects on NSAID-induced intestinal lesions in rodents and rheumatoid arthritis patients. Thus, TNF appears to be a potential therapeutic target for both the prevention and treatment of NSAID enteropathy. However, the causative relationship between TNF and NSAID enteropathy is largely unknown. Currently approved anti-TNF agents are highly expensive and exhibit numerous side effects. Hence, in this review, the pivotal role of TNF in NSAID enteropathy has been summarized and plant-derived polyphenols have been suggested as useful alternative anti-TNF agents because of their ability to suppress TNF activated inflammatory pathways both in vitro and in vivo.

A novel model for NSAID induced gastroenteropathy in rats.

INTRODUCTION: Progress in management of Nonsteroidal anti-inflammatory drug (NSAID) induced gastrointestinal toxicity requires the availability of appropriate experimental animal models that are as close to humans as feasible. Our objective was to develop a rat model for NSAID-induced gastroenteropathy and also to simulate the common clinical scenario of co-administration of NSAID and proton pump inhibitor (PPI) to explore if PPI contribute to exacerbation of NSAID-enteropathy. METHODS: Rats were treated twice daily with pantoprazole sodium (PTZ; 10mg/kg peroral) or vehicle for a total of 10days. In some experiments, Diclofenac sodium (DCF; 9mg/kg) or vehicle was administered orally twice daily for the final 5days of PTZ/vehicle administration. After the last dose on 9th day, rats in all the groups were fasted but water was provided ad libitum. 12h after the last dose on 10th day, rats in all the groups were euthanized and their gastrointestinal tracts were assessed for haemorrhagic lesions, lipid peroxidation, intestinal permeability and gastrointestinal luminal pH alterations. Changes in haemoglobin, haematocrit and serum levels of albumin, total protein, ALT and bilirubin were calculated. RESULTS: The macroscopic and histological evidence suggested that administration of DCF resulted in significant gastroenteropathic damage and co-administration of PTZ resulted in significant exacerbation of NSAID enteropathy, while attenuation of NSAID induced gastropathy was observed. Our results were further supported by the significant decrease in haemoglobin and haematocrit levels and serum levels of albumin and total proteins, an increase in oxidative stress and intestinal permeability with the use of DCF either alone or in combination with PTZ. CONCLUSIONS: This model was developed to simulate the human clinical situation during NSAID therapy and indeed the present DCF regimen caused both gastric and small bowel alterations, such as multiple erosive lesions, together with a decrease in haemoglobin, haematocrit, serum albumin, serum total protein levels and IP alteration, known to occur in patients receiving NSAIDs. Additionally, this paper provides yet another evidence for PPI induced exacerbation of NSAID enteropathy.