There is a widespread repeated exposure of the population to the pesticides and heavy metals of occupational and environmental origin. Such population is forced to undergo continuous stress imposed by combined exposure of the heavy metals and different classes of the pesticides used in agricultural as well as health practices. The existing reports from several workers have indicated that heavy metals and pesticides in combination may lead more severe impact on the human health when compared to their individual effects. Such a combination of pesticides and heavy metals may also change or influence the detection of exposure. Several studies in past have shown the synergistic toxic effects of heavy metals and pesticides. Such evaluations have revealed the synergistic interactions of various heavy metals and pesticides in animals as well as humans. The aim of the present article is to provide a synthesis of existing knowledge on the synergistic effects of heavy metal and pesticides in living systems. The information included in this article may be useful for different environment protection agencies and policy makers to consider the combined effects of heavy metals and pesticides on humans while designing strategies toward environmental protection and safety regulations about human health.

The effects of lead exposure on mammals are reported to be devastating. Lead is present in all the abiotic environmental components such as brass, dust, plumbing fixtures, soil, water, and lead mixed imported products. Its continuous use for several industrial and domestic purposes has caused a rise in its levels, thereby posing serious threats to human health. The mechanisms involved in lead-induced toxicity primarily include free-radical-mediated generation of oxidative stress which directly imbalances the prooxidants and the antioxidants in body. The toxicity of lead involves damage primarily to major biomolecules (lipid, protein, and nucleic acids) and liver (hepatotoxicity), nervous system (neurotoxicity), kidney (nephrotoxicity) and DNA (genotoxicity), present in animals and humans. The activation of c-Jun NH2-terminal kinase, phosphoinositide 3-kinase, or Akt and p38 mitogen activated protein kinase signaling pathways are important for lead cytotoxicity. Lead increased apoptosis through signaling cascade and associated factors and significantly impairs cell differentiation and maturation. In addition, lead has great impact on metabolic pathways such as heme synthesis, thereby leading to the onset of anemia in lead exposed people. This review encompasses an updated account of varied aspects of lead-induced oxidative stress and the biomolecular consequences such as perturbations in physiological processes, apoptosis, carcinogenesis, hormonal imbalance, loss of vision, and reduced fertility and their possible remediation through synthetic (chelators) and natural compounds (plant-based principles). This paper is primarily concerned with the biomedical implications of lead-induced generation of free radical and the toxicity management in the mammalian system.

Coumarins, identified as plant secondary metabolites possess diverse biological activities including anti-angiogenic properties. Daphnetin (DAP), a plant derived dihydroxylated derivative of coumarin has shown significant pharmacological properties such as anticancer, anti-arthritic and anti-inflammatory. The present study was performed to investigate the anti-angiogenic potential of DAP, focusing on the mechanism of action. The in vivo anti-angiogenic potential of DAP was evaluated by vascular endothelial growth factor (VEGF)-induced rat aortic ring (RAR) assay and chick chorioallantoic membrane (CAM) assay. For in vitro evaluation, wounding migration, transwell invasion, tube formation and apoptosis assays were performed on VEGF (8 ng/mL)-induced human umbilical vein endothelial cells (HUVECs). The cellular mechanism of DAP was examined on TNFα (10 ng/mL) and VEGF-induced HUVECs by extracting the mRNA and protein levels using RT-qPCR and western blotting. Our data demonstrated that DAP inhibited the in vivo angiogenesis in the RAR and CAM assay. DAP also inhibited the different steps of angiogenesis, such as migration, invasion, and tube formation in HUVECs. DAP inhibited nuclear factor-κB signalling together including TNF-α induced IκBα degradation; phosphorylation of IκB kinase (IKKα/β) and translocation of the NF-κB-p65 protein. Furthermore, western blotting revealed that DAP significantly down-regulated the VEGF-induced signalling such as c-Src, FAK, ERK1/2 and the related phosphorylation of protein kinase B (Akt) and VEGFR2 expressions. DAP reduced the elevated mRNA expression of iNOS, MMP2 and also, induced apoptosis in VEGF-stimulated HUVECs by the caspase-3 dependent pathway. Taken together, this study reveals that DAP may have novel prospective as a new multi-targeted medication for the anti-angiogenesis and cancer therapy.

Background: Cyclophosphamide (CPA) is the most widely prescribed cancer chemotherapeutic agent which shows serious neurotoxic side effect. Generation of reactive oxygen species at the cellular level is the basic mechanism of cyclophosphamide induced neurotoxicity. Edaravone is the synthetic drug used for brain stroke and has potent antioxidant property. Objective: This study aimed to investigate the effect of edaravone on neurobehavioral and neuropathological alteration induced by cyclophosphamide in male rats. Methods: Twenty eight Sprague-Dawley rats were equally divided into four groups of seven rats in each. The control group received saline, and other groups were given CPA intraperitoneally (100 mg/kg), CPA (100 mg/kg) intraperitoneally + Edaravone (10 mg/kg) orally, or Edaravone (10 mg/kg) orally for one month. Results: Our data showed that CPA significantly elevated brain AChE activity in the hippocampal region. A decrease in the total antioxidant capacity and a reduction in the CAT, SOD, and GPX activity occurred in the brains of the rats exposed to CPA. CPA-treated rats showed a significant impairment in long-termmemory and motor coordination. These results were supported by histopathological observations of the brain. Results revealed that administration of edaravone reversed AChE activity alternation and ameliorated behavioral and histopathological changes induced by CPA. Conclusion: This study suggests that co-administration of edaravone with cyclophosphamide may be a useful intriguing therapeutic approach to overcome cyclophosphamide induced neurotoxicity.

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