Development and biological evaluation of protective effect of kidney targeted N-acetylated chitosan nanoparticles containing thymoquinone for the treatment of DNA damage in cyclophosphamide-induced haemorrhagic cystitis.

Thymoquinone (TQ), the most prominent constituent of Nigella sativa seeds, essential oil, is reported to possess an organ protective effect via Nrf2 expression and activation of Phase-II antioxidant enzymes. Haemorrhagic cystitis is the sudden onset of haematuria combined with bladder pain and irritable bladder symptoms are the known toxic effects of cyclophosphamide (CYP) chemotherapy. The objective of the present study was to investigate and compare the protective effect of thymoquinone (TQ) and thymoquinone nanoparticles (TQ-NP) in the kidney against CYP-induced haemorrhagic cystitis. Primarily, TQ-NP was fabricated by synthesis of N-acetylated chitosan and nanoparticle preparation by the ionic gelation technique. They were characterized by particle size, polydispersive index (PDI), zeta potential, entrapment efficiency (EE), SEM, and dynamic scattering calorimetry (DSC). Moreover, fluorescein isothiocyanate (FITC) labeled NPs were prepared for biodistribution studies. The protective mechanisms of TQ-NP included its anti-inflammatory activity, inhibitory effects on cytokine levels, and protection against the DNA damage in the bladder epithelium. The cystitis was induced in rats by orally administering 200 mg/kg of CYP. The dose-dependent protective effect of the TQ-NP was determined by intravenously administering 1, 2, and 5 mg/kg of the TQ-NP to CYP-treated rats. The present study revealed that the TQ-NP prepared by ionic gelation method provides kidney targeted delivery of TQ as compared to TQ solution. The mean particle size, PDI, and %EE of TQ-NP were 272.6 nm, 0.216, 70.81 ± 0.12% respectively. The zeta potential of thymoquinone-loaded nanoparticles was found to be -20.7 mV and - 22.6 mV respectively before and after lyophilization. SEM study also confirmed the small size and spherical shape. Pharmacokinetic studies revealed the improvement in half-life and prolonged action of the TQ-NP as compared to the TQ solution. Also, TQ-NP administration showed more protection against the characteristic histological alterations in the bladder in comparison to TQ solution. The present study indicates that TQ-NP exerts potent anti-oxidant, DNA protective and cytokine inhibitory activity at considerably lower concentrations as compared to plain TQ solution. The nano formulation of TQ using N-acetylated chitosan provides effective kidney targeted delivery of TQ, which in turn improves its retention and protective efficacy against CYP-induced haemorrhagic cystitis.

Plant-derived natural therapeutics targeting cannabinoid receptors in metabolic syndrome and its complications: A review.

The endocannabinoid system (ECS) is natural physiological system in the humans. The presence of the ECS system involves different roles in body. The endocannabinoid system involves regulation of most of the centers, which regulates the hunger and leads to changes in the weight. In the present article, we reviewed the role of natural cannabinoid compounds in metabolic disorders and related complications. We studied variety of a plant-derived cannabinoids in treating the metabolic syndrome including stoutness, fatty acid liver diseases, insulin obstruction, dementia, hypertension, lipid abnormalities, non-alcoholic steatohepatitis, endothelial damage, and polycystic ovarian syndrome and so on. The activation of cannabinoid receptors demonstrates a significant number of beneficial approaches concerning metabolic syndrome and reduces the pro-inflammatory cytokines on account of aggravation, decreased oxidative stress and uneasiness, diminishes liver fibrosis, with reduces adiponectin. Pre-clinical investigations of plant-derived cannabinoids resulted in promising outcomes. The different distinctive plant-derived cannabinoids were discovered like cannabidiol (CBD), cannabinol (CBN), cannabichromene (CBC), and cannabidiol (CBG). It has been observed that endogenous cannabinoids and plant-derived cannabinoids have an advantageous impact on limiting the metabolic disorder arising due to lifestyle changes.

Animal Models of Inflammation for Screening of Anti-inflammatory Drugs: Implications for the Discovery and Development of Phytopharmaceuticals.

Inflammation is one of the common events in the majority of acute as well as chronic debilitating diseases and represent a chief cause of morbidity in today's era of modern lifestyle. If unchecked, inflammation leads to development of rheumatoid arthritis, diabetes, cancer, Alzheimer's disease, and atherosclerosis along with pulmonary, autoimmune and cardiovascular diseases. Inflammation involves a complex network of many mediators, a variety of cells, and execution of multiple pathways. Current therapy for inflammatory diseases is limited to the steroidal and non-steroidal anti-inflammatory agents. The chronic use of these drugs is reported to cause severe adverse effects like gastrointestinal, cardiovascular, and renal abnormalities. There is a massive need to explore new anti-inflammatory agents with selective action and lesser toxicity. Plants and isolated phytoconstituents are promising and interesting sources of new anti-inflammatories. However, drug development from natural sources has been linked with hurdles like the complex nature of extracts, difficulties in isolation of pure phytoconstituents, and the yield of isolated compounds in minute quantities that is insufficient for subsequent lead development. Although various in-vivo and in-vitro models for anti-inflammatory drug development are available, judicious selection of appropriate animal models is a vital step in the early phase of drug development. Systematic evaluation of phytoconstituents can facilitate the identification and development of potential anti-inflammatory leads from natural sources. The present review describes various techniques of anti-inflammatory drug screening with its advantages and limitations, elaboration on biological targets of phytoconstituents in inflammation and biomarkers for the prediction of adverse effects of anti-inflammatory drugs. The systematic approach proposed through present article for anti-inflammatory drug screening can rationalize the identification of novel phytoconstituents at the initial stage of drug screening programs.

D-pinitol attenuates cisplatin-induced nephrotoxicity in rats: Impact on pro-inflammatory cytokines.

Cisplatin has been widely used as a first-line agent against various forms of solid cancers. However, nephrotoxicity is the major limiting factor for its clinical use. Several clinical and pre-clinical studies have suggested different strategies for the reduction of cisplatin-induced nephrotoxicity. The present study was conducted to investigate the efficacy of D-Pinitol, against cisplatin-induced nephrotoxicity in Swiss albino mice. A single intraperitoneal injection of cisplatin (20 mg/kg) was used to induce nephrotoxicity in mice. Administration of cisplatin in mice is linked with elevated oxidative stress, imbalanced biochemical parameters, apoptosis and stimulation of mitogen-activated protein kinase (MAPK) pathway. D-Pinitol is a member of the flavonoid family and a chief constituent of Sutherlandia fruitesecnce. It was administered with saline water (10, 20, 40 mg/kg, p.o.) for seven consecutive days after a single dose of cisplatin. At the end of experiment, animals were sacrificed and biochemical parameters in serum and urine were recorded. Kidneys were isolated for the estimation of tumor necrosis factor-alpha, interleukin-1ß, interlukin-6 levels and histopathological evaluations. It was noted that D-Pinitol significantly ameliorated biochemical levels of serum and urinary creatinine and blood urea nitrogen. Tissue homogenate levels of TNF-α, IL-6, IL-1ß and the renal expression of tissue nitrites were also significantly decreased in D-Pinitol treated mice. These results were supplemented by histopathological findings. This study highlights the potential role of D-Pinitol against cisplatin-induced toxicity, exhibited through favorable alterations in biochemical and histological changes as well as reduction in oxidative stress and cytokine levels.

Anti-inflammatory activity of bartogenic acid containing fraction of fruits of Barringtonia racemosa Roxb. in acute and chronic animal models of inflammation.

The fruits of Barringtonia racemosa are traditionally used in Indian medicine for the treatment of pain and inflammatory conditions. In this study, a fraction of ethyl acetate extract of fruits of B. racemosa (BREAF) was investigated for anti-inflammatory activity in experimental models of acute and chronic inflammation. Activity against acute inflammation was evaluated in inflammogens induced rat paw edema models. Whereas, effect in chronic inflammation was evaluated in cotton pellet granuloma and oxazolone induced delayed type hypersensitivity (DTH) model in mice. The BREAF exhibited dose dependent anti-inflammatory activity in both acute and chronic models at oral doses of 5, 10 and 20 mg/kg. BREAF inhibited both phases of carrageenan induced rat paw inflammation. The reduction in paw inflammation by BREAF was also evident in histamine and serotonin induced inflammation in rats. Effect of BREAF on DTH indicates inhibition of immune mediated inflammation. The reduction in cotton pellet granuloma by BREAF treatment shows inhibition of proliferative changes associated with chronic inflammation. Analysis of BREAF after chromatographic separations showed presence of bartogenic acid as a major constituent. Hence, it is proposed that anti-inflammatory effects of BREAF can be partially attributed to its bartogenic acid content. The minute doses at which this fraction shows anti-inflammatory effects emphasizes the need for further investigations on its efficacy in the immuno-inflammatory conditions.