Vikas Kumar

Novel glycoside from Wedelia calendulacea inhibits diethyl nitrosamine-induced renal cancer via downregulating the COX-2 and PEG2 through nuclear factor-κB pathway

A new compound derivative of glycoside 19-α-hydroxy-ursolic acid glucoside (19-α-hydroxyurs-12(13)-ene-28-oic acid-3-O-β-d-glucopyranoside (HEG) was isolated from whole plant of Wedelia calendulacea (Compositae). The structure was elucidated and established by standard spectroscopy approaches. Diethylnitrosamine (DEN) (200xa0mg/kg) and ferric nitrilotriacetate (Fe-NTA) (9xa0mg/kg) were used for induction of renal cell carcinoma (RCC) in the rats. The rats were further divided into different groups and were treated with HEG doses for 22xa0weeks. Anti-cancer effect in RCC by HEG was dose dependent to restrict the macroscopical changes as compared to DENxa0+xa0Fe-NTA-control animals. Significant alteration in biochemical parameters and dose-dependent alleviation in Phase I and Phase II antioxidant enzymes were responsible for its chemo-protective nature. HEG in dose-dependent manner was significant to alter the elevated levels of pro-inflammatory cytokines and inflammatory mediators during RCC. The histopathological changes were observed in the HEG pre-treated group, which was proof for its safety concern as far as its toxicity is concerned. The isolated compound HEG can impart momentous chemo-protection against experimental RCC by suppressing the cyclooxygenase (COX-2) and prostaglandin E2 (PGE2) expression via nuclear factor-kappa B (NF-κB) pathway.

Attenuation of neurobehavioral and neurochemical abnormalities in animal model of cognitive deficits of Alzheimer’s disease by fermented soybean nanonutraceutical

The present study was performed to evaluate the efficacy of nanonutraceuticals (NN) for attenuation of neurobehavioral and neurochemical abnormalities in Alzheimer’s disease. Solid-state fermentation of soybean with Bacillus subtilis was performed to produce different metabolites (nattokinase, daidzin, genistin and glycitin and menaquinone-7). Intoxication of rats with colchicine caused impairment in learning and memory which was demonstrated in neurobehavioral paradigms (Morris water maze and passive avoidance) linked with decreased activity of acetylcholinesterase (AChE). NN treatment led to a significant increase in TLT in the retention trials as compared to acquisition trial TLT suggesting an improved learning and memory in rats. Further, treatment of NN caused an increase in the activity of AChE (42%), accompanied with a reduced activity of glutathione (42%), superoxide dismutase (43%) and catalase (41%). It also decreased the level of lipid peroxidation (28%) and protein carbonyl contents (30%) in hippocampus as compared to those treated with colchicine alone, suggesting a possible neuroprotective efficacy of NN. Interestingly, in silico studies also demonstrated an effective amyloid-β and BACE-1 inhibition activity. These findings clearly indicated that NN reversed colchicine-induced behavioral and neurochemical alterations through potent antioxidant activity and could possibly impart beneficial effects in cognitive defects associated with Alzheimer’s disease.

Umbelliferon-α-d-glucopyranosyl-(2I → 1II)-α-Dglucopyranoside ameliorates Diethylnitrosamine induced precancerous lesion development in liver via regulation of inflammation, hyperproliferation and antioxidant at pre-clinical stage

It is well documented that anomalous production of inflammatory proteins linked with most of the toxic expression and genesis of diverse chronic disease including cancer. Diethylnitrosamine (DEN) a well-known hepatotoxin and hepatocarcinogen, can induce oxidative stress and inflammatory reaction in it. Umbelliferone, secondary metabolites, is present in different plants and widely consumed by humans as medicine and food supplements. The aim of the current study was to scrutinize the chemoprotective potential of umbelliferon-α-d-glucopyranosyl-(2I→1II)-α-d-glucopyranoside (UFD) against DEN-induced hepatocellular carcinoma (HCC) in experimental rats. Single intraperitoneal injection of DEN (200mg/kg) was used for induction of HCC in rats and rats were grouped and orally treated with UFD (5, 10 and 20mg/kg) dose for 22 weeks. Parameters under investigation included hepatic, non-hepatic enzymes, oxidative stress, pro-inflammatory cytokines, COX-2 and NF-κB level along with histopathological examination in HCC rats. UFD exerted protective effect via reduction of oxidative stress, liver and non-liver parameters in a dose-dependent manner. It also reduced the expression of TNF-α, IL-1β, IL-6 and COX-2 in diseased rats. Our result revealed the essential repression of the inflammation cascade through modulation of nuclear factor-kappa B (NF-κB) signaling pathway.

Amelioration of diethylnitrosamine (DEN)-induced hepatocellular carcinogenesis in animal models via knockdown oxidative stress and proinflammatory markers by Madhuca longifolia embedded silver nanoparticles

In hepatocellular carcinoma (HCC), primary liver cancer is primarily responsible for inflammation-related cancer as more than 90% of HCCs emerge with regard to hepatic damage and inflammation. Tenacious inflammation is known to advance and intensify liver tumours. Nanomaterials, for example, silver nanoparticles synthesized from plant-derived materials have shown great outcomes in reducing the pre-cancerous nodules and have anticancer properties. The aim of the present investigation was to biosynthesize, characterize and evaluate the anticancer activity of nanoparticles-embedded Madhuca longifolia extract (MLAgNPs) on an experimental model of hepatic cancer in rats. M. longifolia contains a high amount of flavonoids and other phenolic derivative. The silver nanoparticles synthesized by M. longifolia were characterized by various instruments, including UV-Vis spectrophotometry, X-ray beam diffraction, field-emission scanning electron microscopy with energy dispersive X-ray analysis, transmission electron microscopy and Fourier transform infrared spectroscopy. Liver cancer was induced to 36 Wistar rats by a single dose of diethylnitrosamine (DEN) (200 mg kg−1 BW). Hepatic cancer by MLAgNPs dose-dependently limited macroscopical variation compared with the DEN-induced hepatic cancer groups. The serum and liver were taken to measure the antioxidant parameters, proinflammatory cytokines and for a histopathological study. Serum hepatic and serum non-hepatic along with inflammatory cytokines were also assessed. Reduction in the levels of proinflammatory cytokines, namely tumour necrosis factor-α, interleukin-6, interleukin-1β, nuclear factor kappa beta (NF-κB), and improved membrane-bound enzyme activity were also detected. It was found that minor morphological anomalies were identified in the histopathology analysis in the MLAgNPs-treated groups. It could be concluded that silver nanoparticles introduce an extraordinary potential for use as adjuvants in hepatic cancer treatment because of their antioxidant abilities and ability to diminish inflammation in liver tissue by attenuating the NF-κB pathway.

Implication of nano-antioxidant therapy for treatment of hepatocellular carcinoma using PLGA nanoparticles of rutin

AIMnThe present work describes the development of poly(lactic co-glycolic acid) (PLGA) nanoparticles (NPs) of rutin (RT) for the treatment of hepatocellular carcinoma in rats.nnnMATERIALS & METHODSnRT-loaded PLGA NPs (RT-PLGA-NPs) were prepared by double emulsion evaporation method. Further these are optimized by Box-Behnken design. PLGA NPs were evaluated for size, polydispersity index, drug-loading capacity, entrapment, gastric stability, inxa0vitro drug release, inxa0vivo preclinical studies and biochemical studies.nnnRESULTSnPreclinical evaluation of RT-PLGA-NPs for anticancer activity through oral route exhibited significant improvement in hepatic, hematologic and renal biochemical parameters. Highly superior activity was observed in regulating oxidative stress and inflammatory markers, antioxidant enzymes, cytokines and inflammatory mediators and their role on plasma membrane ATPases responsible for destruction in liver tissues.nnnCONCLUSIONnHistopathological evaluation indicated reduced incidence of hepatic nodules, necrosis formation, infiltration of inflammatory cells, blood vessel inflammation and cell swelling with RT-PLGA-NP treatment along with considerable downregulation in the levels of proinflammatory cytokines.

Commentary: L-3-n-butylphthalide Rescues Hippocampal Synaptic Failure and Attenuates Neuropathology in Aged APP/PS1 Mouse Model of Alzheimer's Disease

Mouse Model of Alzheimers Disease. According to World Health Organization estimation about 18 million people worldwide are suffering from Alzheimers disease (AD) and figures would shoot up to 34 million by 2025 in aging population. The onset and propagation of AD is unrelenting from cellular to molecular levels, governed by multitude of factors leading to a continual decrease in cognitive abilities (Felsenstein et al., 2014). Recent advances in understanding the genetic factors that predispose to AD, as well as in biomarker development have brought with them the promise of earlier and more reliable diagnosis of this disease. However, treatment regime and strategies available, approved by US-FDA are limited by their scope to alter pharmacological targets that can provide symptomatic relief to the patient (Lannfelt et al., 2014). The present stock of drugs for AD consists of donepezil, galantamine, rivastigmine, and memantine. The primary mechanism of action for these drugs is to decrease the acetyl cholinesterase (AChE) levels thus altering acetylcholine level, while memantine is a low-affinity voltage-dependent uncompetitive antagonist at glutamatergic N-methyl d-aspartate receptor (NMDA) thereby blocking the activity of the neurotransmitter glutamate. All the existing treatments for AD are only symptomatic but non curative (Lannfelt et al., 2014). Under these circumstances a drug molecule with multiple pharmacological properties with intent to modify as well as reduce the risk factors contributing toward disease burden will be highly appreciated. Drugs that are aimed at disrupting AD disease progression by inhibition/degradation of the protein mis-folding of β-amyloid (Aβ) into neurotoxic oligomeric aggregates has been encouraged for AD (Scheff et al., 2007). With the advent of new diagnostic tools various pathological conditions have been identified at different stages of AD. Accumulation of amyloid beta (Aβ) to form clumps known as neuritic or senile plaques is considered as hallmark of AD. The buildup of these plaques seems to be a crucial as they lead to oxidative stress coupled with mitochondrial dysfunction and barrage of inflammatory cascade causing neuronal cell death. Studies carried by Zhang et al. (2016) on L-3-n-butylphthalide

Quinazoline clubbed 1,3,5-triazine derivatives as VEGFR2 kinase inhibitors: design, synthesis, docking, in vitro cytotoxicity and in ovo antiangiogenic activity

A series of quinazoline clubbed 1,3,5-triazine derivatives (QCT) were synthesized and evaluated for their in vitro anticancer activity against HeLa (human cervical cancer), MCF-7 (human breast cancer cell), HL-60 (human promyelocytic leukemia cell), HepG2 (human Hepatocellular carcinoma cell), and one normal cell line HFF (human foreskin fibroblasts). In vitro assay result encouraged to further move towards in ovo anticancer evaluation using chick embryo. The series of QCT derivatives showed higher anticancer and antiangiogenic activity against HeLa and MCF-7 cell lines. In the series, synthetic molecule 8d, 8l, and 8m displayed significant activity. Further, these results substantiated by docking study on VGFR2. SAR study concluded that the potency of drugs depends on the nature of aliphatic substitution and the heterocyclic ring system.Graphical Abstract

Amelioration of neurodegeneration and cognitive impairment by Lemon oil in experimental model of Stressed mice

Citrous lemon (Rutaceae) an Indian folk medicine has been used for the treatment of various pathological diseases viz., diabetes, cardiovascular, inflammation, hepatobiliary dysfunction and neurodegenerative disorder. Can lemon oil altered the memory of unstressed and stressed mice, a basic question for which the present work was put on trial. The present investigation was intended to assess the impact of Lemon oil on memory of unstressed and Stressed Swiss young Albino mice. Lemon oil (50 and 100u202fmg/kg o.r.) and donepezil (10u202fmg/kg) were guided for three weeks to different groups of stressed and unstressed mice. The nootropic movement was assessed utilizing elevated plus maze and Hebbs Williams Maze. Cerebrum acetylcholinesterase (AChE), plasmacorticosterone, decreased glutathione, lipid per oxidation alongside superoxide dismutase and catalase was surveyed as marker for disease. Histopathology was performed for estimation of drug effects. Acute immobilized stress was induce, lemon oil (100u202fmg/kg) and donepezil together indicated memory enhancing movement both in stressed and unstressed mice. Lemon oil significantly (pu202f<u202f0.001) altered and lowered brain AChE activity both in stressed and unstressed mice. Scopolamine induced amnesia was also significantly altered and reversed both in stressed and unstressed mice by lemon oil at a dose of 50 and 100u202fmg/kg. Lemon oil (50 and 100u202fmg/kg) was further able to control the corticosterone level in plasma for stressed mice. Lemon oil significantly (pu202f<u202f0.001) elevated the level of catalase, superoxide dismutase and reduced glutathione levels both in stressed and unstressed animals with respect to controlled group along with TBARS both in stressed and unstressed compared with control group. Hence it can be concluded that memory enhancing activity might be related to reduction in AChE and TBARS activity and by elevated GSH, SOD and catalase through decrease in raised plasma corticosterone levels.

Preclinical renal chemo-protective potential of Prunus amygdalus Batsch seed coat via alteration of multiple molecular pathways

Abstract Prunus amygdalus Batsch (almond) is a classical nutritive traditional Indian medicine. Along with nutritive with anti-oxidant properties, it is, clinically, used in the treatment of various diseases with underlying anti-oxidant mechanism. This study is an effort to scrutinise the renal protective effect of P. amygdalus Batsch or green almond (GA) seed coat extract and its underlying mechanism in animal model of Ferric nitrilotriacetate (Fe-NTA) induced renal cell carcinoma (RCC). RCC was induced in Swiss Albino Wistar rats by intraperitoneal injection of Fe-NTA. The rats were then treated with ethanolic extract of GA (25, 50 and 100u2009mg/kg per oral) for 22 weeks. Efficacy of GA administration was evaluated by change in biochemical, renal, macroscopical and histopathological parameters and alterations. Additionally, interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and inflammatory mediator including prostaglandin E2 (PGE2), nuclear factor-kappa B (NF-κB) were also observed to explore the possible mechanisms. The oral administration of GA significantly (pu2009<u2009.001) altered the Fe-NTA induced RCC in rats by inhibition of renal nodules, decolourisation of tissues, tumour promoter marker including thymidine 3[H] incorporation, ornithine decarboxylase, renal parameters and anti-oxidant parameters in serum. Additionally, GA treatment significantly (pu2009<u2009.001) down-regulated the IL-6, IL-1β, TNF-α, inflammatory mediators PGE2 and NF-κB in a dose-dependent manner. Histopathology observation supported the renal protective effect of GA by alteration in necrosis, size of Bowman capsules and inflammatory cells. Hence, it can be concluded that GA possesses observable chemo-protective action and effect on Fe-NTA induced RCC via dual inhibition mechanism one by inhibiting free radical generation and second by inhibiting inflammation.

Therapeutic role of calcium and vitamin K3 in chemically induced hepatocarcinogenesis – new tools for cancer treatment

Abstract HCC has been reported to be immensely occurring carcinoma worldwide. Recent days the mortality occurred due to liver cancer has also been found to be increased at an alarming speed affecting mostly the young patients. The aim of the current study was to decipher the role of calcium and vitamin K3 in the treatment of chemically induced hepatocarcinogenesis in the male Wistar rats. Liver cancer was induced via a subnecrogenic dose of 160u2009mg/kg body weight, diethylnitrosamine (DENA) when associated with fasting/refeeding in male Wistar rats. It elevated the serum glutamate oxaloacetate (SGOT), serum glutamate pyruvate transaminase (SGPT), alkaline phosphatase (ALP), bilirubin, total cholesterol (CH), triglycerides (TG), alfa-fetoprotein (AFP) and reduced high-density lipoprotein (HDL). Histopathological examination of liver tissue showed marked carcinogenicity of the chemical carcinogen. Food, water intake and animal weights were also assessed, respectively. The animals exposed to DENA showed a significant decrease in the body weight. The elevated levels of serum SGOT, SGPT, ALP, AFP, TC and TG were restored by administration of calcium and Vit K (ad libitum) combination at higher dose than the normal dietary requirement (3u2009mg/kg) daily for 12u2009weeks p.o. Physiological and biochemical analysis showed the beneficial effects of calcium and vitamin K3 combination in the animals exposed to DENA. The results deciphered the beneficial effects of calcium and vitamin K3 in combination.