Polyphenol-based targeted therapy for oral submucous fibrosis.

Oral submucous fibrosis (OSF) is a chronic, progressive, and precancerous condition mainly caused by chewing areca nut. Currently, OSF therapy includes intralesional injection of corticosteroids with limited therapeutic success in disease management. Therefore, a combined approach of in silico, in vitro and in vivo drug development can be helpful. Polyphenols are relatively safer than other synthetic counterparts. We used selected polyphenols to shortlist the most suitable compound by in silico tools. Based on the in silico results, epigallocatechin-3-gallate (EGCG), quercetin (QUR), resveratrol, and curcumin had higher affinity and stability with the selected protein targets, transforming growth factor beta-1 (TGF-ß1), and lysyl oxidase (LOX). The efficacy of selected polyphenols was studied in primary buccal mucosal fibroblasts followed by in vivo areca nut extract induced rat OSF model. In in vitro studies, the induced fibroblast cells were treated with EGCG and QUR. EGCG was safer at higher concentrations and more efficient in reducing TGF-ß1, collagen type-1A2 and type-3A1 mRNA expression than QUR. In vivo studies confirmed that the EGCG hydrogel was efficient in improving the disease conditions compared to the standard treatment betamethasone injection with significant reduction in TGF-ß1 and collagen concentrations with increase in mouth opening. EGCG can be considered as a potential, safer and efficient phytomolecule for OSF therapy and its mucoadhesive topical formulation help in the improvement of patient compliance without any side effects. Highlights Potential polyphenols were shortlisted to treat oral submucous fibrosis (OSF) using in silico tools Epigallocatechin 3-gallate (EGCG) significantly reduced TGF-ß1 and collagen both in vitro and in vivo EGCG hydrogel enhanced antioxidant defense, modulated inflammation by reducing TGF-ß1 and improved mouth opening in OSF rat model.

Prophylactic effect of Trigonella foenum-graecum L. seed extract on inflammatory markers and histopathological changes in high-fat-fed ovariectomized rats.

Background and aim: Trigonella foenum-graecum L. seeds (TFG) are used as spices in Indian cuisine. In Indian traditional medicine, TFG is used to treat diabetes, dyslipidemia, obesity, arthritis, cancer, digestive disorders, and postmenopausal conditions. Pathophysiology of postmenopausal diseases involves low-grade systemic inflammation. The purpose of this study is to investigate the prophylactic effect of petroleum ether fraction of TFG-extract (PE-TFG) on inflammatory markers, and histopathological changes in ovariectomized rats (OVX-rats) fed with a high-fat diet (HFD). Experimental procedure: OVX female Sprague Dawley rats were used for the study. Three weeks after ovariectomy, rats were randomized in different groups and administered PE-TFG, atorvastatin, diosgenin, 17ß-estradiol for 12 weeks along with HFD. The sham-operated rats (S.OVX) were fed with a standard pellet diet. At the end of 12-weeks, rats were sacrificed, and blood samples were used to estimate lipid profile, glucose, hepatic markers, TNF-α, and leptin. Liver, kidney, and common carotid artery were isolated for testing oxidative stress markers, mRNA expression of adiponectin, PPAR-γ, and histopathological changes. Results: Administration of PE-TFG significantly decreased (P < 0.05) total cholesterol, LDL, hepatic markers, leptin, TNF-α and improved mRNA expression of adiponectin and PPAR-γ in HFD-fed OVX-rats. Further, micro and macro hepatic steatosis, inflammation, glomerular hypertrophy, degenerated tubules in kidney, increased tunica intima, and media thickness of common carotid artery and the pathological changes were not significant upon PE-TFG administration compared to S.OVX-rats. Conclusion: PE-TFG protects cellular inflammation and metabolic alternations in HFD-fed OVX-rats and thus can be explored further in postmenopausal diseases as a prophylactic agent.

Effect of Moringa oleifera leaf extract on exercise and dexamethasone-induced functional impairment in skeletal muscles.

BACKGROUND: Chronic administration of steroids like dexamethasone produces symptoms including weight loss and skeletal muscle dysfunction. Similar events are reported in chronic or high-intensity exercises, that can lead to fatigue and muscle damage. OBJECTIVE: In the present study, the effect of Moringa oleifera leaf extract was evaluated against dexamethasone (Dex) and exercise (Exe)-induced muscle changes in rats. MATERIALS AND METHODS: Six groups each containing 6 rats, namely normal, Dex control, Exe Control, Dex + M. oleifera leaf extract (300mg/kgp.o.), Dex + Exe, Dex + Exe + M. oleifera leaf extract were assessed in the study. Dex was administered at 0.6 mg/kg i.p. daily for 7 days. Exercise was given for a total of 10 days after 30 minutes of dosing using treadmill equipment for 900 seconds at speed 18 m/min. Animals were assessed for variation in body weight, muscular endurance using treadmill, locomotor activity using actophotometer, motor coordination using rotarod on day zero, and day seven. Hemidiaphragm of rats were isolated and used for evaluation of the glucose uptake. Gastrocnemius muscle was isolated and subjected to hematoxylin and eosin staining. RESULTS: Dex and Exe control animals showed a significant decrease in skeletal muscle activity when compared to normal control animals in the actophotometer test. Improvement in endurance were seen in Dex + M. oleifera leaf extract, and Dex + exercise + M. oleifera leaf extract groups compared to Dex control group. Improvement in locomotor activity was seen in Dex group subjected to exercise and was significant when treated with M. oleifera leaf extract. Histology reports were in accordance with the functional parameters. CONCLUSION: M. oleifera leaf extract supplemented with exercise showed a reversal in the dexamethasone-induced functional impairment in skeletal muscles.

Modulation of inflammatory markers by petroleum ether fraction of Trigonella foenum-graecum L. seed extract in ovariectomized rats.

This study evaluates the modulation of inflammatory markers by petroleum ether fraction of Trigonella foenum-graecum L. (PE-TFG) seed extract in ovariectomized rats. The HPTLC method was used for standardization and to quantify the diosgenin in PE-TFG. For testing PE-TFG in rats, the total duration of treatment was 12-weeks, and the rats were sacrificed on week 12. The tissue samples such as blood, liver, heart, and aorta were isolated for testing inflammatory markers such as adiponectin, leptin, PPAR-γ, TNF-α, lipid profile, hepatic markers, antioxidants, and oxidative stress markers. The PE-TFG treatment decreased the elevation of total cholesterol, triglyceride, AST, and ALT. Upon PE-TFG treatment, there was a significant increase in adiponectin and PPAR-γ mRNA expression. Leptin and TNF-α were normal after treatment with PE-TFG seed extract. Further, micro-steatosis of hepatocytes marked glomerular hypertrophy in the kidney and increased thickness of tunica intima and media of common carotid artery was reversed after treatment with PE-TFG. PRACTICAL APPLICATIONS: Trigonella foenum-graecum L. is a curative plant used to treat inflammatory conditions like diabetes, obesity, dyslipidemia, arthritis, cancer, and digestive disorders. In our study, PE-TFG supplementation has a protective effect on OVX-induced inflammation, oxidative stress, mRNA expression of adiponectin and PPAR-γ, hepatic steatosis, and decreased thickness of tunica intima and media of common carotid artery.

Biological activity of a small molecule indole analog, 1-[(1H-indol-3-yl)methylene]-2-phenylhydrazine (HMPH), in chronic inflammation.

A synthetic small molecule, 1-[(1H-indol-3-yl)methylene]-2-phenylhydrazine (HMPH) was conveniently synthesised by a one-step reaction, purified and characterised by chromatographic and spectroscopic methods. HMPH scavenged free radicals and inhibited lipopolysaccharide (LPS)-induced ROS generation and NO release in RAW-264.7 cells without signs of any detectable cytotoxicity. HMPH inhibited lipid peroxidation (LPO) with IC50 of 135 ± 9 as against 58 ± 8 µM for α-tocopherol. Further, HMPH (>50 µM) significantly reduced the LPS-induced TNF-α release in mouse peritoneal macrophages and in human peripheral blood mononuclear cells (PBMCs). HMPH did not show any visible signs of toxicity in rats up to 400 mg/kg/intraperitoneal and 2000 mg/kg/oral. HMPH at 25 and 50 mg/kg attenuated neutrophil infiltration in air-pouch lavage and bronchoalveolar lavage (BAL) in rat models. HMPH also reduced myeloperoxidase (MPO), nitrite and TNF-α in air-pouch lavage in addition to MPO in plasma. HMPH reduced acute paw-inflammation in carrageenan-induced paw-edema. HMPH consistently decreased both ipsilateral and contralateral paw inflammation, minimised the clinical scores of arthritis, prevented body weight (B.wt.) loss, attenuated serum C-reactive protein (C-RP) and rheumatoid factors (RF) in rat model of adjuvant-induced arthritis. Histopathology and radio-graphical reports show that HMPH reduced bone erosion in both ipsilateral and contralateral paw joints. Failure to inhibit COX suggests that effectiveness of HMPH in both acute and chronic inflammation is mediated by a multimodal mechanism involving modulation of immunity, attenuating TNF-α, protecting bone attrition and reducing oxidative stress.

Radioprotective effect of Ocimum sanctum and amifostine on the salivary gland of rats after therapeutic radioiodine exposure.

The current study investigated the radioprotective effect of Ocimum sanctum on the salivary gland of rats administered radioiodine ((131)I) and compared its efficacy with a known radioprotectant, amifostine. The experimental rats were divided in four groups and sacrificed in three different batches at 1, 3, and 6 months of time interval after 18.5 MBq/100g (i.p.) (131)I exposure. Six months duration batch received (131)I exposure twice with the gap of 3 months. Two groups of experimental rats were presupplemented with O. sanctum (40 mg/kg for 5 days, orally) and amifostine (200 mg/kg, s.c) before (131)I exposure separately. Increased Technetium-99m-pertechnetate ((99m)TcO(4)(-)) uptake at 30 minutes post injection in salivary glands of only (131)I exposed rats may imply delay in clearance at 6 months of exposure in comparison to their counterparts sacrificed at 1 month. Parotid gland histology showed atrophy with lipomatosis in only (131)I exposed rats at 3 and 6 months of duration. O. sanctum and amifostine presupplemented and subsequently exposed to (131)I rats at 3 and 6 months duration exhibited comparable histopathology with controls. Our study indicates possible radioprotective effect of O. sanctum and amifostine against high-dose (131)I exposure.

Chronotherapeutic drug delivery for early morning surge in blood pressure: a programmable delivery system.

The purpose of the study was to develop pulsatile capsule dosage form of valsartan for controlled delivery. In the majority of individuals blood pressure rises in the early morning hours, which lead to serious cardiovascular complications. Formulations with constant/programmable delivery rates make it possible to deliver drug at definite time or controlled rate in chronopharmacokinetic studies. The prepared system contained swellable polymer (l-hydroxypropyl cellulose (L-HPC), xanthan gum, polyethylene oxide or sodium alginate) together with drug tablet and erodible tablet (L-HPC or guar gum) in a pre-coated capsule. Various formulation factors were investigated through series of tests, in vitro dissolution and ex vivo continuous dissolution-absorption studies. We found that the type, amount of polymers and erodible tablet influenced the drug release. The formulation containing 200 mg sodium alginate and erodible tablet (150 mg) containing 50% guar gum and 46% lactose showed 5-6 h lag time and 10+/-2.1% drug release in initial 6 h following rapid release (99+/-1.7% release in 12 h) of drug was observed. The continuous dissolution-absorption study conducted using everted rat intestinal segment indicated delay in absorption of drug. Thus this approach can provide a useful means for timed release of valsartan and may be helpful for patients with morning surge.