Single and repeated dose (28 days) intravenous toxicity assessment of bartogenic acid (an active pentacyclic triterpenoid) isolated from Barringtonia racemosa (L.) fruits in mice.

Bartogenic acid (BA), an active pentacyclic triterpenoid, has been reported for anti-diabetic, anti-inflammatory, anti-arthritic, anti-cancer, and anti-tumor activity. However, toxicity profiling of BA has not been reported till date. Hence, this study is designed to evaluate the single dose (12.5, 25, 50 and 100 mg/kg) and repeated dose (1.5, 6, and 24 mg/kg) intravenous toxicity of BA in BALB/c mice. Control group received vehicle. In single dose toxicity study, two mortalities were observed at 100 mg/kg of BA whereas lower doses were well tolerated. In repeated dose toxicity study, no mortality was observed. 1.5 mg/kg of BA was well tolerated in mice of both sexes. At 6 mg/kg of BA, female mice showed significant reduction in the body weight as compared to the control group however no significant change was observed in male mice. 24 mg/kg of BA showed significant reduction in the body weight in mice of both sexes. Further, these mice showed significant change in the relative organ weight. However, no toxicologically relevant changes were observed in hematology, biochemistry, and histopathology. Based on the findings, No-Observed-Adverse-Effect-Level (NOAEL) for BA were found to be<24 mg/kg for male mice and<6 mg/kg for female mice.

Tumor-suppressing effect of bartogenic acid in ovarian (SKOV-3) xenograft mouse model.

Bartogenic acid (BA), a natural pentacyclic triterpenoid, proved to have chemomodulatory, anticancer, antidiabetic, anti-arthritic, and anti-inflammatory activity. Based on structure-activity relationship (SAR) approaches, BA has close structural resemblance to oleanolic acid and ursolic acid. These two pentacyclic triterpenoids are well accepted with respect to their therapeutic value in various ailments including anti-cancer activity. The aim of this study is to evaluate the efficacy of BA as a possible antitumor agent, along with its safety in SKOV-3 ovarian cancer. In vitro cytotoxicity of BA and paclitaxel on human ovarian cancer cells (SKOV-3) was assessed using MTT assay. Antitumor potential of BA alone, standard anticancer drug (paclitaxel) alone, and BA in combination with paclitaxel were evaluated in SKOV-3 xenografted SCID mice. Immunohistochemical analysis of NF-κB was performed and analyzed in SKOV-3 tumors. BA alone and BA in combination with paclitaxel significantly inhibited the tumor growth. IC50 of BA was found to be 15.72 µM. Similarly, paclitaxel showed significant antitumor effect with IC50 of 3.234 µM. Treatments of paclitaxel, BA, and combination of BA with paclitaxel were well tolerated during treatment period. Immunohistochemical analysis of NF-κB in SKOV-3 tumors treated with BA in combination with paclitaxel revealed antitumor effect in terms of inhibition of NF-κB. Our results suggested that BA exhibits promising antitumor effect in the restriction of SKOV-3 cells and tumors with considerable safety.

Effect of pantoprazole on I-R-induced myocardial injury in diabetic rats targeting inflammatory cytokine release and oxidative stress.

OBJECTIVES: To evaluate the pleiotropic potential and underlying mechanism of pantoprazole (PPZ) (common Proton Pump Inhibitors, PPIs) in type 2 diabetes mellitus (T2DM) -associated ischemia/reperfusion (I-R)-induced myocardial infarction which is still uncharted. Whereas some other PPIs have demonstrated their anti-diabetic, antioxidant, and anti-inflammatory potential. MATERIALS AND METHODS: We evaluated the potential of coinciding treatment of PPZ (4 mg/kg/po/day for 8 weeks) in Wistar albino rats against STZ (50 mg/kg/IP) induced T2DM model and I-R provoked cardiac infarction model in diabetic and non-diabetic condition. RESULTS: PPZ significantly inhibited the perturbed deviations in blood glucose concentration, HbA1c, C-peptide, plasma insulin, and ameliorated the lipid profile (dyslipidemia). PPZ protected myocardial tissue against lipid peroxidation by restoring the levels of serum TBARS and reduced NBT. The significant protective effects of PPZ were evident by ameliorating CKMB, LDH, cTnI, and myocardial oxidative stress in PPZ treated animals. Additionally, PPZ prominently reduced various proinflammatory cytokines release including TGF-ß1, TNF-α, and IL-6. PPZ upsurges the bioavailability of nitrite/nitrate concentration which may pacify the impact of myocardial infarction in diabetic I-R injury. CONCLUSION: The consequences indicate that PPZ possesses a potent protective effect against diabetic I-R-induced myocardial infarction via suppressing oxidative stress, inflammation, and dyslipidemia-associated tissue damage.

Acceleration of Wound Healing in Diabetic Rats through Poly Dimethylaminoethyl Acrylate-Hyaluronic Acid Polymeric Hydrogel Impregnated with a Didymocarpus pedicellatus Plant Extract.

Wound is the major health problem associated with skin damages and arises because of various types of topical injuries. Furthermore, wounds in patients with diabetes take a relatively long time to heal. Currently, herbal medicines have been extensively used for wound care and management. Here, we engineered polymeric hybrid hydrogel of dimethylaminoethyl acrylate and hyaluronic acid (pDMAEMA-HA), which was impregnated with a herbal extract of Didymocarpus pedicellatus. The developed polymeric hybrid hydrogel system can be used for effective therapy of incurable wounds. Therefore, the development of D. pedicellatus-impregnated pDMAEMA-HA (pDPi-DMAEMA-HA) hybrid hydrogel was accomplished by the synthesis of pDMAEMA-HA hydrogel via the optimization of various reaction parameters followed by impregnation of herbal drugs D. pedicellatus. The developed hydrogel composite was well characterized via various techniques, and swelling kinetics was performed to analyze the water uptake property. The swelling ratio was found to be 1600% in both types of hydrogels. To evaluate the wound healing of these polymeric hydrogels, the Wistar rats full-thickness excision wound model was utilized. The healing strength of hydrogels was determined using measurement of wound contraction and histopathological study. The results of wound healing by these polymeric hydrogels revealed that animals treated with the pDPi-DMAEMA-HA hybrid hydrogel group were found to have a higher level of wound closure as compared to marketed formulation as well as polymeric hybrid hydrogel. The histopathologic examinations implied that pDPi-DMAEMA-HA hybrid hydrogel and polymeric hybrid hydrogel-treated groups exhibited enhanced cutaneous wound repair as well as high level of cellular repair and maintenance compared to the standard group because of hyaluronic acid roles in various stages of wound repair.

Dose and time-dependent toxicological impact of pantoprazole on vascular endothelium and renal tissue.

Proton pump inhibitors (PPIs) have wide pleiotropic action in addition to their therapeutic potential in gastroesophageal reflux diseases. Conversely, recent reports revealed a significant incidence of toxic events of PPIs including nephritis, osteoporosis, and cardiac damage. Thus, the study was designed to reconcile the deceptive contraindications. The present investigation targeted to reveal the toxic impact of sub-acute and sub-chronic administration of pantoprazole (PPZ) with different concentrations (low dose 4 mg/kg, medium-dose 8 mg/kg and high dose 16 mg/kg once a day) on normal vascular endothelium and renal tissue of rats. Vascular endothelial dysfunction (VED) was estimated by the contractility of an isolated aortic ring, nitrite/nitrate concentration, oxidative stress, and integrity of the endothelium layer. Moreover, the renal abnormalities were further confirmed by an increased level of serum creatinine, blood urea nitrogen (BUN), the incidence of microproteinuria, and structural alteration. Sub-acute administration of PPZ treatment did not produce any toxicological impact on endothelium and renal tissue. Whereas, sub-chronic administration of PPZ treatment causes moderate VED and renal dysfunction in a dose-dependent manner. Sub-chronic treatment of PPZ also influences the mitigation of NO and elevation of oxidative stress. Collecting all the evidence, it concludes that decreased nitric oxide availability and increased levels of oxidative stress may be a possible underlying mechanism of causing VED and renal abnormalities from high-dose PPZ treatment.

Pharmacognostic and pharmacological evaluation of Eulaliopsis binata plant extracts by measuring in vitro/in vivo safety profile and anti-microbial potential.

The present investigation emphasizes the pharmacognostic and phytochemical screening of Eulaliopsis binata and further evaluates the extracts of this plant for toxicological profile and anti-bacterial potential based on in vivo/in vitro assays. Microscopy, powder characteristics of the leaf material, and physicochemical and phytochemical screening were assessed for pharmacognostic evaluation. Dry leaves of Eulaliopsis binata were extracted using different solvents (methanol, ethyl acetate, and hexane), and the extracts obtained were further investigated for in vitro/in vivo toxicological study. Moreover, acute toxicity was assessed by evaluating the anti-oxidant defense system and anatomical damage in vital organs. In addition, anti-bacterial activity of all the extracts was assessed by the Kirby-Bauer method. Physicochemical and microscopic observations showed the unique identification mark for leaf powder and leaf transverse section. Phytochemical investigation evidenced the presence of flavonoids and phenolic contents in the methanolic extract. All extracts were found to be hemocompatible and exhibited no induction of behavioral alteration and no alteration in the anti-oxidant potential and anatomical structure of the vital organs. On the other hand, the methanolic extract showed a significant upsurge in the reduced glutathione level, whereas all extracts showed significant anti-bacterial potential in a dose-dependent manner. Eulaliopsis binata has inimitable pharmacognostical characteristics, good safety profile and significant anti-oxidant and anti-bacterial potential that show immense possibility for its further investigation for pharmacological use.

Combined and individual strategy of exercise generated preconditioning and low dose copper nanoparticles serve as superlative approach to ameliorate ISO-induced myocardial infarction in rats.

BACKGROUND: Myocardial infarction (MI) is a solitary fatal condition with towering prevalence of mortality worldwide. Our previous study reports that low-dose copper nanoparticles (CuNP) can halt the progression of diabetes-induced cardiotoxicity as copper has anti-inflammatory, anti-proliferative and anti-oxidant potential. In addition, exercise training has also been considered a hallmark for cardiac health. METHOD: Cardioprotective potential of CuNP (1mg/kg/day, po, 4 weeks) and exercise (swimming, 90min, 5days/4 weeks) either alone or in combination was estimated by measuring the surge in serum nitrite/nitrate concentration and reduction in creatine kinase MB (CKMB), lactate dehydrogenase (LDH), cardiac troponin I (cTnI), lipid profile, oxidative stress, structural abnormalities against isproterenol (ISO)-induced MI. RESULTS: ISO significantly increased CKMB, LDH, cTnI, lipid alteration, oxidative stress, structural abnormalities and decrease nitrite/nitrate concentration in serum. Quantitative estimation of total and phosphorylated Akt(SER-473)/GSK-3b(SER-9) indicated the significant reduction in pAkt and pGSK-3b in ISO treated animal. Individual and combined treatment of CuNP and exercise significantly reduce ISO -induced CKMB, cTnI, LDH, and improve nitrite/nitrate concentration and lipid profile. Attenuation of myocardial oxidative stress and serum TBARS revealed the associated preconditioning effect of exercise and CuNP against oxidative stress. Exercise and CuNP also showed the protective potential against structural abnormalities. However, the cardioprotective effect of individual and combined strategy of exercise and CuNP was vanished by wortmannin and also avoid the downregulation of pGSK-3b. CONCLUSION: Low-dose CuNP and exercise training significantly prevents ISO-induced MI through preconditioning and GSK-3b inhibition. Ability to upsurge the NO level, lipid profile and reduced oxidative stress improve the potency of combined strategy.

Exercise preconditioning and low dose copper nanoparticles exhibits cardioprotection through targeting GSK-3ß phosphorylation in ischemia/reperfusion induced myocardial infarction.

BACKGROUND: Drinking water from copper vessels and aerobic exercise have been the known facts for cardioprotection. Our previous report explored the significant cardioprotective potential of copper and exercise training by increasing phosphorylation of GSK-3ß and anti-oxidant potential. OBJECTIVE: Present study focuses the therapeutic potential of CuNP and exercise training through their molecular interaction with GSK-3ß, inflammatory cytokinin, oxidative stress and necrosis. METHODS: The Myocardial damage was assessed by estimating the serum nitrite/nitrate concentration, increased CKMB, LDH, cTnI level, oxidative stress, inflammatory cytokinin and structural abnormalities in I/R insulted rats. Expression of Akt/pAkt and GSK-3ß/pGSK-3ß was measured by western blotting. RESULT: Treatment with CuNP (1 mg/kg/day, p.o., 4 weeks) and exercise training (swimming, 90 min/4 weeks) either alone or in combination markedly reduced I/R induced myocardial damage by attenuating biochemical and structural alteration. A significant reduction in oxidative stress and inflammatory mediators were observed in CuNP and exercise training treatment against I/R insulted rats. Moreover, improved serum NO bioavailability was observed in CuNP and exercise treated rats. Wortmannin associated blockage of cardioprotection induced by CuNP and exercise training and up-regulation of pAkt and pGSK-3ß in I/R insulted heart confirmed the GSK-3ß phosphorylation potential of CuNP and exercise training and -associated cardioprotection. CONCLUSION: Treatment with CuNP and exercise training either alone or in combination favourably phosphorylate GSK-3ß kinase pathways and further diminish oxidative stress, inflammatory cytokines, apoptosis and increase serum bioavailability of NO in the I/R insulted rats which tends to protect myocardial damage.

Pulmonary hypertension: Molecular aspects of current therapeutic intervention and future direction.

Pulmonary hypertension (PH) is a life-threatening lung disorder with towering prevalence and risk for future has been gradually rising worldwide. Even, no specific medications are available for pulmonary hypertension; various classes of treatment based upon the origin and magnitude of hypertension are still used for the treatment of PH. Consideration of molecular or signaling modulation is the imperative approach that can offer a new notion for prevalent pharmacotherapeutic agents. Instead of concurrent targets, including endothelin receptor antagonists (ETA/ETB), phosphodiesterase 5 inhibitor (PDF-5), calcium channel blockers, anticoagulants, diuretics, and long acting prostacyclin analog, recent scientific reports revealed the numerous potential alternative therapeutic approaches that can significantly target the pathological signaling alteration associated with PH. Understanding precise molecular cascade involved in PH can be useful for designing preclinical animal experiments and human clinical trials to evaluate target specific novel therapeutic interventions for the treatment of PH. In this review, we discussed the possible molecular signaling involved in the pathogenesis of PH and detailed account of the current status of medications employed for the treatment of PH. Moreover, the newly identified potential target sites and alternative approaches for treating the PH have been discussed.

Electrochemically synthesized highly crystalline nitrogen doped graphene nanosheets with exceptional biocompatibility.

This work reports first electrochemical preparation of exceptionally biocompatible, highly crystalline, and well exfoliated nitrogen doped graphene nanosheets (eNGS) from carbon nanosheets for the development of mighty platforms in the field of modern biosensing and other biological applications for human welfare. eNGS displayed exceptional biocompatibility. Administration of the as-synthesized eNGS to rat models did not lead to any significant deviation or inimical consequences in its functional observation battery (FOB) tests, GSH levels or the histology of the vital organs of the rat models. The pictomicrographs of myocytes nuclei and myofibrillar for heart, hippocampus (CA1) section for brain, central vein, and hepatocytes for liver and parenchyma, tubules and glomeruli for kidney also remained unaffected. Moreover, the resultant nanoelectrocatalyst displayed enhanced electrochemical performance towards real-time sensing of dopamine (DA) from human urine sample in the presence of interferences, such as ascorbic acid (AA) and uric acid (UA).

Therapeutic Implications of Superoxide Dismutase And Its Importance in Kinase Drug Discovery.

In recent years, several scientific investigations have reported the therapeutic implications of superoxide dismutase (SOD) against oxidative stress and -induced pathology in clinical and preclinical trials. Indeed, various kinase, molecular signaling and physiological process has altered by reactive oxygen species. In spite of the abundant available literature reports, patents, clinical trials and commercialized products, the therapeutic application of SOD as a potential drug still remains unclear. Owing to the technical challenges associated with the utilization of SOD as a drug, we revisited the structural arrangement and cellular signaling, significant association with kinase, exploring the new target sites and introducing new formulation strategies such as gene modulation, nano-formulations and click chemistry is a prerequisite. In-addition to gene modulation strategies, encapsulated formulation within a nano-carrier for producing promising SOD therapeutic effects, application of click chemistry including bioconjugation and cyclo-addition are the most prominent methods to produce highly efficient SOD formulations. Thus, the present review enlightens the foremost technique which may have better interaction with kinase and other cellular signaling for regulating the physiological process.

Effect of L-pGlu-(1-benzyl)-l-His-l-Pro-NH2 against in-vitro and in-vivo models of cerebral ischemia and associated neurological disorders.

Central nervous system plays a vital role in regulation of most of biological functions which are abnormally affected in various disorders including cerebral ischemia, Alzheimer's and Parkinson's (AD and PD) worldwide. Cerebral stroke is an extremely fatal and one of the least comprehensible neurological disorders due to limited availability of prospective clinical approaches and therapeutics. Since, some endogenous peptides like thyrotropin-releasing hormone have shown substantial neuroprotective potential, hence present study evaluates the newer thyrotropin-releasing hormone (TRH) analogue L-pGlu-(1-benzyl)-l-His-l-Pro-NH2 for its neuroprotective effects against oxygen glucose deprivation (OGD), glutamate and H2O2 induced injury in pheochromocytoma cell lines (PC-12 cells) and in-vivo ischemic injury in mice. Additionally, the treatment was further analyzed with respect to models of AD and PD in mice. Cerebral ischemia was induced by clamping both bilateral common carotid arteries for ten minutes. Treatment was administered to the mice five minute after restoration of blood supply to brain. Consequential changes in neurobehavioural, biochemical and histological parameters were assessed after a week. L-pGlu-(1-benzyl)-l-His-l-Pro-NH2 showed significant reduction in glutamate, H2O2 and OGD -induced cell death in concentration and time dependent manner. Moreover, L-pGlu-(1-benzyl)-l-His-l-Pro-NH2 resulted in a substantial reduction in CA1 (Cornus Ammonis 1) hippocampal neuronal cell death, inflammatory cytokines, TNF-α, IL-6 and oxidative stress in hippocampus. In addition, L-pGlu-(1-benzyl)-l-His-l-Pro-NH2 was found to be protective in two acute models of AD and PD as well these findings demonstrate the neuroprotective potential of L-pGlu-(1-benzyl)-l-His-l-Pro-NH2 in cerebral ischemia and other diseases, which may be mediated through reduction of excitotoxicity, oxidative stress and inflammation.

Albiglutide: Is a better hope against diabetes mellitus?

Type-2 diabetes mellitus (T2DM) is the chronic metabolic disorder which provokes several pitfall signalling. Though, a series of anti-diabetic drugs are available in the market but T2DM is still a huge burden on the developed and developing countries. Numerous studies and survey predict the associated baleful circumstances in near future due to incessant increase in this insidious disorder. The novelty of recent explored anti-diabetic drugs including glitazone, glitazaar and gliflozines seems to be vanished due to their associated toxic side effects. Brown and Dryburgh (1970) isolated an intestinal amino acid known as gastric inhibitory peptide (GIP) which had insulinotropic activity. Subsequently in 1985, another incretin glucagon likes peptide 1 (GLP-1) having potent insulinotropic properties was discovered by Schmidt and his co-workers. On the basis of results' obtained by Phase III Harmony program FDA approved (14 April, 2014) new GLP-1 agonist 'Albiglutide (ALB)', in addition to exiting components Exenatide (Eli Lilly, 2005) and Liraglutide (Novo Nordisk, 2010). ALB stimulates the release of protein kinase A (PKA) via different mechanisms which ultimately leads to increase in intracellular Ca(2+) levels. This increased intracellular Ca(2+) releases insulin vesicle from ß-cells. In-addition, ALB being resistant to degradation by dipeptidyl peptidase-4 (DPP-4) and has longer half life. DPP-4 can significantly degrade the level of GLP-1 agonist by hydrolysis. In spite of potent anti-hypergycemic activity, ALB has pleiotropic action of improving cardiovascular physiology. In light of these viewpoints we reveal the individual pharmacological profile of ALB and the critical analyse about its future perspective in present review.

Hydrothermally functionalized biocompatible nitrogen doped graphene nanosheet based biomimetic platforms for nitric oxide detection.

Hydrothermal synthesis of nanocomposites is of significant importance, as it affords facile, biocompatible, nontoxic, and economic fabrication. Herein, we report a hitherto unexplored cytocompatible and reusable biomimetic electrochemical sensor based on pyridyl porphyrin functionalized nitrogen doped graphene nanosheets. The porphyrin functionalized nitrogen doped graphene nanosheets (PFNGS) were prepared by a low temperature hydrothermal method via non-covalent strategies with a minimal impact on their physicochemical properties. Owing to their exceptional attributes like operational ease, low cost, portability, and sensitivity, the as-synthesized PFNGS, formed by π-π interactions, were employed for sensing nitric oxide (NO), which is a key regulator of diverse biological processes. Compared to porphyrin and nitrogen doped graphene nanosheets alone, PFNGS exhibited exceptional sensitivity (3.6191 µA µM-1) and remarkable electrocatalytic properties (0.61 V). This clearly outperforms the previously reported modified electrode materials for the electrochemical detection of NO. Cyclic voltammetry (CV) data also suggested that the PFNGS modified electrode possessed an increased reactive surface area, which results in an increase in the number of reactive sites and low charge transfer resistance. These results also demonstrated that the PFNGS modified electrode showed high stability and reproducibility, the limit of detection (LOD) (S/N = 3) of which was estimated to be 1 nM. Our PFNGS were found to be highly biocompatible and could also detect NO released from macrophage cells. This blend of biocompatibility, electrode stability, electrocatalytic activity along with enhanced sensitivity and selectivity makes PFNGS a powerful and reliable nanomaterial for various biomedical applications in complex biological systems.

Pharmacoresistant Epilepsy: A Current Update on Non-Conventional Pharmacological and Non-Pharmacological Interventions.

Uncontrolled seizure or epilepsy is intricately related with an increase risk of pharmacoresistant epilepsy. The failure to achieve seizure control with the first or second drug trial of an anticonvulsant medication given at the appropriate daily dosage is termed as pharmacoresistance, despite the fact that these drugs possess different modes of action. It is one of the devastating neurological disorders act as major culprit of mortality in developed as well as developing countries with towering prevalence. Indeed, the presence of several anti-epileptic drug including carbamazepine, phenytoin, valproate, gabapentin etc. But no promising therapeutic remedies available to manage pharmacoresistance in the present clinical scenario. Hence, utility of alternative strategies in management of resistance epilepsy is increased which further possible by continuing developing of promising therapeutic interventions to manage this insidious condition adequately. Strategies include add on therapy with adenosine, verapamil etc or ketogenic diet, vagus nerve stimulation, focal cooling or standard drugs in combinations have shown some promising results. In this review we will shed light on the current pharmacological and non pharmacological mediator with their potential pleiotropic action on pharmacoresistant epilepsy.

Evaluation of terfenadine and ketoconazole-induced QT prolongation in conscious telemetered guinea pigs.

Terfenadine and ketoconazole are the most widely used positive reference agents in non-clinical cardiac repolarization safety studies. The aim of the present study was to evaluate the effects of terfenadine, ketoconazole and their combination on QT prolongation using conscious guinea pigs. Conscious telemetered guinea pigs were orally administered terfenadine (50 mg/kg), ketoconazole (200 mg/kg) or a combination of the two, and effects on QT were recorded using a telemetry system. The QT correction was carried out with Bazett's formula to eliminate confounding effect of HR. Neither terfenadine nor ketoconazole produced any effect on the RR and QT intervals, QRS complex or heart rate (HR). However, a combination of terfenadine and ketoconazole significantly prolonged the RR and QT intervals and decreased HR in a time-dependent manner. This study demonstrated that the combination of terfenadine and ketoconazole produces QT prolongation in conscious telemetered guinea pigs.