Multidrug resistance (MDR) is regarded as one of the bottlenecks of successful clinical treatment for numerous chemotherapeutic agents. Multiple key regulators are alleged to be responsible for MDR and making the treatment regimens ineffective. In this review, we discuss MDR in relation to P-glycoprotein (P-gp) and its down-regulation by natural bioactive molecules. P-gp, a unique ATP-dependent membrane transport protein, is one of those key regulators which are present in the lining of the colon, endothelial cells of the blood brain barrier (BBB), bile duct, adrenal gland, kidney tubules, small intestine, pancreatic ducts and in many other tissues like heart, lungs, spleen, skeletal muscles, etc. Due to its diverse tissue distribution, P-gp is a novel protective barrier to stop the intake of xenobiotics into the human body. Over-expression of P-gp leads to decreased intracellular accretion of many chemotherapeutic agents thus assisting in the development of MDR. Eventually, the effectiveness of these drugs is decreased. P-gp inhibitors act by altering intracellular ATP levels which are the source of energy and/or by affecting membrane contours to increase permeability. However, the use of synthetic inhibitors is known to cause serious toxicities. For this reason, the search for more potent and less toxic P-gp inhibitors of natural origin is underway. The present review aims to recapitulate the research findings on bioactive constituents of natural origin with P-gp inhibition characteristics. Natural bioactive constituents with P-gp modulating effects offer great potential for semi-synthetic modification to produce new scaffolds which could serve as valuable investigative tools to recognize the function of complex ABC transporters apart from evading the systemic toxicities shown by synthetic counterparts. Despite the many published scientific findings encompassing P-gp inhibitors, however, this article stand alones because it provides a vivid picture to the readers pertaining to Pgp inhibitors obtained from natural sources coupled with their mode of action and structures. It provides first-hand information to the scientists working in the field of drug discovery to further synthesise and discover new P-gp inhibitors with less toxicity and more efficacies.

Medicinal plants, vegetables and fruits are the sources of huge number of bioactive lead/scaffolds with therapeutic and nutraceutical importance. Bioautography is a means of target-directed isolation of active molecules on chromatogram. Organic solvents employed in chromatographic separation process can be completely removed before biological detection because these solvents cause inactivation of enzymes and/or death of living organisms. They offer a rapid and easy identification of bioactive lead/scaffolds in complex matrices of plant extracts. Bioautography is a technique to isolate hit(s)/lead(s) by employing a suitable chromatographic process followed by a biological detection system. This review critically describes the methodologies to identify antimicrobial, antioxidant, enzyme inhibitor lead/scaffolds by employing bioautography. A significant number of examples have been incorporated to authenticate the methodologies.

Abroma augusta L. (Malvaceae) leaf is traditionally used to treat diabetes in India and Southern Asia. Therefore, current study was performed to evaluate the protective effect of defatted methanol extract of A. augusta leaves (AA) against type 2 diabetes mellitus (T2DM) and its associated nephropathy and cardiomyopathy in experimental rats. Antidiabetic activity of AA extracts (100 and 200 mg/kg, p.o.) was measured in streptozotocin-nicotinamide induced type 2 diabetic (T2D) rat. Fasting blood glucose level (at specific interval) and serum biochemical markers (after sacrifice) were measured. Redox status, transcription levels of signal proteins (NF-κB and PKCs), mitochondria dependent apoptotic pathway (Bad, Bcl-2, caspase cascade) and histological studies were performed in kidneys and hearts of controls and AA treated diabetic rats. Phytochemical screening of extracts revealed the presence of taraxerol, flavonoids and phenolic compounds in the AA. T2D rats showed significantly (p < 0.01) elevated fasting blood glucose level. Alteration in serum lipid profile and release of membrane bound enzymes like lactate dehydrogenase and creatine kinase, which ensured the participation of hyperlipidemia and cell membrane disintegration in diabetic pathophysiology. T2DM caused alteration in the serum biochemical markers related to diabetic complications. T2DM altered the redox status, decreased the intracellular NAD and ATP concentrations in renal and myocardial tissues of experimental rats. Investigating the molecular mechanism, activation PKC isoforms was observed in the selected tissues. T2D rats also exhibited an up-regulation of NF-κB and increase in the concentrations of pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α) in the renal and cardiac tissues. The activation of mitochondria dependent apoptotic pathway was observed in renal and myocardial tissues of the T2D rats. However, Oral administration of AA at the doses of 100 and 200 mg/kg body weight per day could reduce hyperglycemia, hyperlipidemia, membrane disintegration, oxidative stress, vascular inflammation and prevented the activation of oxidative stress induced signaling cascades leading to cell death. Histological studies also supported the protective characteristics of AA. Results suggest that AA could offer prophylactic role against T2DM and its associated reno- and cardio- toxicity.

The present investigation was executed to reveal the protective mechanism of rosmarinic acid (RA) against cadmium (Cd)-induced nephrotoxicity. RA exhibited a concentration-dependent anti-apoptotic effect against CdCl₂ in isolated mouse proximal tubular epithelial cells. Cd treatment significantly (p < 0.01) imparted oxidative stress to the renal cells via excessive ROS production, triggering NO level, NADPH oxidase activation, and impairment of cellular redox defense system. Cd-mediated oxidative stress significantly (p < 0.01) endorsed apoptosis to the murine kidney cells by triggering NF-κB/PKC-δ/TNFR2 activation. In addition, CdCl₂ induced renal fibrosis by triggering TGF-β1/SMAD3/α-SMA/collagen signaling within renal cells. On the other hand, RA significantly (p < 0.05–0.01) attenuated Cd-provoked oxidative stress and associated pathological signal transduction in murine renal cells. RA treatment also could significantly (p < 0.05–0.01) reciprocate Cd-mediated pathological changes in blood and urine parameters in mice. In addition, histological data supported the pharmacological findings. In silico chemometric analyses predicted the possible interactions between RA and different signal proteins and anticipated drug-likeness characteristics of RA. Hence, RA can potentially be applied as a therapeutic agent to treat Cd-mediated nephrotoxicity in future.