Expanded profiling of Remdesivir as a broad-spectrum antiviral and low potential for interaction with other medications in vitro.

Remdesivir (GS-5734; VEKLURY) is a single diastereomer monophosphoramidate prodrug of an adenosine analog (GS-441524). Remdesivir is taken up by target cells and metabolized in multiple steps to form the active nucleoside triphosphate (GS-443902), which acts as a potent inhibitor of viral RNA-dependent RNA polymerases. Remdesivir and GS-441524 have antiviral activity against multiple RNA viruses. Here, we expand the evaluation of remdesivir's antiviral activity to members of the families Flaviviridae, Picornaviridae, Filoviridae, Orthomyxoviridae, and Hepadnaviridae. Using cell-based assays, we show that remdesivir can inhibit infection of flaviviruses (such as dengue 1-4, West Nile, yellow fever, Zika viruses), picornaviruses (such as enterovirus and rhinovirus), and filoviruses (such as various Ebola, Marburg, and Sudan virus isolates, including novel geographic isolates), but is ineffective or is significantly less effective against orthomyxoviruses (influenza A and B viruses), or hepadnaviruses B, D, and E. In addition, remdesivir shows no antagonistic effect when combined with favipiravir, another broadly acting antiviral nucleoside analog, and has minimal interaction with a panel of concomitant medications. Our data further support remdesivir as a broad-spectrum antiviral agent that has the potential to address multiple unmet medical needs, including those related to antiviral pandemic preparedness.

Correlation of various serum biomarkers with the severity of diabetic retinopathy.

Hyperglycemia induced inflammation and angiogenic factors are implicated as a contributor to the onset and progression of diabetic retinopathy (DR) in type 2 diabetes mellitus patients (T2DM). Tumor necrosis factor (TNF-alpha) and C-reactive protein (CRP) are inflammatory cytokines which induce retinal VEGF and are involved in the progression of proliferative diabetic retinopathy (PDR). Therefore the aim of the present study is to investigate the relationship between diabetic retinopathy and systemic inflammation in patients with type 2 diabetes mellitus. MATERIALS AND METHODS: Patients with T2DM, with or without diabetic retinopathy were included in the study. Serum inflammatory cytokines, vascular growth factor were studied in different stages of DR. RESULTS: Patients with T2DM with and without diabetic retinopathy were compared. Patients with diabetic retinopathy had increased serum levels of inflammatory cytokines CRP, TNF-alpha, as well as VEGF compared to serum levels of diabetic patients without retinopathy. CONCLUSION: T2DM patients with retinopathy have higher levels of circulating inflammatory cytokines and VEGF compared to patients without retinopathy. These proinflammatory cytokines and angiogenic factors are involved in the progression of DR and proliferative diabetic retinopathy. The results showed the importance of inflammation and vascular endothelial growth factor in the progression of NPDR and PDR.

Protective effect of alpha glucosyl hesperidin (G-hesperidin) on chronic vanadium induced testicular toxicity and sperm nuclear DNA damage in male Sprague Dawley rats.

The study was conducted to evaluate the vanadium-induced testicular toxicity and its effect on sperm parameters, sperm nuclear DNA damage and histological alterations in Sprague Dawley rats and to assess the protective effect of G-hesperidin against this damage. Treatment of rats with vanadium at a dose of 1 mg kg bw(-1) for 90 days resulted in significant reduction in serum testosterone levels, sperm count and motility. Further, a parallel increase in abnormal sperm morphology and adverse histopathological changes in testis was also associated with vanadium administration when compared to normal control. Moreover, sperm chromatin dispersion assay revealed that vanadium induces sperm nuclear DNA fragmentation. A marked increase in testicular malondialdehyde levels and decreased activity of antioxidant enzymes such as superoxide dismutase and catalase indicates vanadium-induced oxidative stress. Co-administration of G-hesperidin at a dose of 25 and 50 mg kg bw(-1) significantly attenuated the sperm parameters and histological changes by restoring the antioxidant levels in rat testis. These results suggested that vanadium exposure caused reduced bioavailability of androgens to the tissue and increased free radical formation, thereby causing structural and functional changes in spermatozoa. G-hesperidin exhibited antioxidant effect by protecting the rat testis against vanadium-induced oxidative damage, further ensures antioxidant potential of bioflavonoids.

Partial role of multiple pathways in infarct size limiting effect of quercetin and rutin against cerebral ischemia-reperfusion injury in rats.

BACKGROUND: Reperfusion therapy used in the treatment of cerebral ischemia often causes reperfusion neurological injury. Multiple pathological processes are involved in this injury including oxidative stress and components of the inflammatory response appear to play key roles in these deleterious effects. Thus new therapeutic strategies aimed at neutralization of OS-induced neurotoxicity support the application of natural antioxidant bioflavonoids. Both experimental and epidemiological evidence demonstrate that bioflavonoid such as quercetin and rutin are neuroprotective in models of cerebral ischemia reperfusion injury. However, recent studies indicate that the radical scavenger property of quercetin and rutin is unlikely to be the only reason for their cerebroprotective actions and in fact, a wide spectrum of cellular signaling events may well account for their biological actions. AIM: In this study we attempted to establish the various mechanisms involved in the cerebroprotective activity of quercetin and rutin. METHODS: Adult Sprague Dawely rats were anesthetized with thiopentone and subjected to global cerebral ischemia by occlusion of bicommon carotid arteries. Infarct size (TTC staining), SOD, MDA, CAT and MPO levels was assessed 4 h after the onset of ischemia. RESULTS: Quercetin (50 mg/kg) and rutin (10 mg/kg) administered 10 min before reperfusion resulted in significant reduction of infarct size, MDA, and MPO levels and significant increase in SOD and CAT levels. Administration of L-NAME prior to administration of quercetin and rutin, significantly reduced the cerebroprotection offered by quercetin and rutin. CONCLUSIONS: Possible partial role of antioxidant, anti-inflammatory and involvement of NO in the beneficial effects of bioflavonoids quercetin and rutin against cerebral ischemia reperfusion injury was observed.

Immunostimulant, cerebroprotective & nootropic activities of Andrographis paniculata leaves extract in normal & type 2 diabetic rats.

BACKGROUND & OBJECTIVES: A large number of plants have been recognized to be effective in the treatment of diabetes mellitus. Persistent hyperglycaemia is associated with decreased function of immune system and cerebral ischaemia mainly due to increased oxidative stress and inflammatory response. Andrographis paniculata is a medicinal plant widely used in folk medicine for various purposes. In this study the effect of chronic administration (7 days) of methanolic extract of A. paniculata leaves was studied in rats with experimentally induced diabetes, nootropic and immunostimulant activities were evaluated. The effect of acute administration of methanolic extract of A. paniculata leaves was also studied for cerebroprotective activity. METHODS: Type 2 diabetes was induced in rats by streptozotocin (STZ) (65 mg/kg) + nicotinamide (150 mg/kg). Various biochemical parameters were estimated using standard methods. RESULTS: A significant (P<0.05) increase in cognitive function was observed in both normal and type 2 diabetic rats. Nootropic activity in terms of per cent reduction in latency period was more in type 2 diabetic rats. A significant increase in blood lymphocyte count, splenic lymphocyte count and peritoneal macrophage count was observed in both normal and type 2 diabetic rats. Immunostimulant activity was observed more in type 2 diabetic rats. The per cent decrease in cerebral infarction was more in type 2 diabetic rats when compared to normal rats. The per cent increase in superoxide dismutase (SOD) levels was more in type 2 diabetic rats. INTERPRETATION & CONCLUSIONS: The antioxidant activity of the methanolic extract of A. paniculata leaves was evident by decreased tissue malondialdehyde (MDA) levels and increased SOD levels. These properties may be responsible for the observed cerebroprotective activity. The methanolic leaf extract of A. paniculata showed significant immunostimulant, cerebroprotective and nootropic activities in normal and type 2 diabetic rats.

Preparation and characterization of quercetin and rutin cyclodextrin inclusion complexes.

The objective of the present study is to prepare and characterize cyclodextrin inclusion complexes of quercetin and rutin to improve their aqueous solubility and dissolution properties. Inclusion complexes of quercetin and rutin with beta-cyclodextrin (beta-CD) and hydroxyl propyl-beta-cyclodextrin (HP-beta-CD) were prepared by kneading and coevaporation methods. Characterization of inclusion complexes was done by phase solubility analysis and was supported by X-ray powder diffractometry (XRD), differential scanning calorimetry (DSC), and Fourier-transform infra red spectroscopy (FT-IR) analysis. Inclusion complexes exhibited higher rates of dissolution than the corresponding physical mixtures and pure drug. Higher dissolution rates were observed with HP-beta-CD kneaded complexes in comparison to the products with beta-CD.

Evaluation of hypoglycemic and antihyperglycemic effects of Datura metel (Linn.) seeds in normal and alloxan-induced diabetic rats.

The seed powder of Datura metel was tested for its hypoglycemic activity in normal and alloxan-induced diabetic rats. Graded doses (25, 50 and 75 mg/kg, p.o.) of the seed powder when given to both normal and diabetic rats produced significant reduction in blood glucose at the 8 h. The effect was found to be dose dependent with all treatments at the doses administered.

Antidiabetic activity of a polyherbal preparation (tincture of panchparna) in normal and diabetic rats.

The present work was executed to evaluate the anti-diabetic potency of a polyherbal formulation, and its influence on derangement in the metabolism of glucose and cholesterol and changes in sodium levels in serum and urine in normal and alloxan induced diabetic rats. Serum glucose and serum cholesterol levels were found to be increased in diabetic animals. Serum sodium and urinary sodium, hepatic glycogen levels are found to be decreased in diabetic state. Treatment with the polyherbal formulation (1.0 ml/kg body wt) for 30 days in diabetic animals has shown decrease in serum glucose and serum cholesterol levels in comparison to control animals, whereas in normal treated animals, the formulation does not effect the serum glucose and serum cholesterol levels. Serum sodium and urinary sodium levels were increased in both diabetic treated and the control animals. Hepatic glycogen levels were increased in diabetic treated animals, but there was no change in the control treated animals.