Neuroprotective effect of taxifolin against aluminum chloride-induced dementia and pathological alterations in the brain of rats: possible involvement of toll-like receptor 4.

Aluminum (Al) overexposure damages various organ systems, especially the nervous system. Regularly administered aluminum chloride (AlCl3) to rats causes dementia and pathophysiological alterations linked to Alzheimer's disease (AD). Taxifolin's neuroprotective effects against AlCl3-induced neurotoxicity in vitro and in vivo studies were studied. Taxifolin (0.1, 0.3, 1, 3, and 10 µM) was tested against AlCl3 (5 mM)-induced neurotoxicity in C6 and SH-SY5Y cells using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays. Additionally, neural morphology was examined by confocal microscopy. Additionally, taxifolin's mode of binding with the co-receptor of toll-like receptor 4 (TLR4), human myeloid differentiation-2 (hMD-2) was investigated. AlCl3 (25 mg/kg/d, i.p.) was administered to rats for 14 d, and from the eighth day, taxifolin (1, 2, and 5 mg/kg/d, i.p.) was given along with AlCl3. This study assessed memory impairment using the Morris water maze, plus maze, and pole tests. This study also performed measurement of oxidant (malondialdehyde [MDA] and nitrite), antioxidant (reduced glutathione), and inflammatory (myeloperoxidase [MPO] activity, TLR4 expression) parameters in rats' brain in addition to histopathology. The docking score for taxifolin with hMD-2 was found to be -4.38 kcal/mol. Taxifolin treatment reduced the neurotoxicity brought on by AlCl3 in both C6 and SH-SY5Y cells. Treatment with 10 µM taxifolin restored AlCl3-induced altered cell morphology. AlCl3 administration caused memory loss, oxidative stress, inflammation (increased MPO activity and TLR4 expression), and brain atrophy. Taxifolin treatment significantly improved the AlCl3-induced memory impairment. Taxifolin treatment also mitigated the histopathological and neurochemical consequences of repeated AlCl3 administration in rats. Thus, taxifolin may protect the brain against AD.

Recent Advances in Therapeutic Approaches Against Ebola Virus Infection.

BACKGROUND: Ebola virus (EBOV) is a genus of negative-strand RNA viruses belonging to the family Filoviradae that was first described in 1976 in the present-day Democratic Republic of the Congo. It has intermittently affected substantial human populations in West Africa and presents itself as a global health menace due to the high mortality rate of patients, high transmission rate, difficult patient management, and the emergence of complicated autoimmune disease-like conditions post-infection. OBJECTIVE: EBOV or other EBOV-like species as a biochemical weapon pose a significant risk; hence, the need to develop both prophylactic and therapeutic medications to combat the virus is unquestionable. METHODS: In this review work, we have compiled the literature pertaining to transmission, pathogenesis, immune response, and diagnosis of EBOV infection. We included detailed structural details of EBOV along with all the available therapeutics against EBOV disease. We have also highlighted current developments and recent advances in therapeutic approaches against Ebola virus disease (EVD). DISCUSSION: The development of preventive vaccines against the virus is proving to be a successful effort as of now; however, problems concerning logistics, product stability, multi- dosing, and patient tracking are prominent in West Africa. Monoclonal antibodies that target EBOV proteins have also been developed and approved in the clinic; however, no small drug molecules that target these viral proteins have cleared clinical trials. An understanding of clinically approved vaccines and their shortcomings also serves an important purpose for researchers in vaccine design in choosing the right vector, antigen, and particular physicochemical properties that are critical for the vaccine's success against the virus across the world. CONCLUSION: Our work brings together a comprehensive review of all available prophylactic and therapeutic medications developed and under development against the EBOV, which will serve as a guide for researchers in pursuing the most promising drug discovery strategies against the EBOV and also explore novel mechanisms of fighting against EBOV infection.

Effects of eugenol on the behavioral and pathological progression in the MPTP-induced Parkinson's disease mouse model.

Parkinson's disease (PD) is the world's second most common neurological disorder. Oxidative stress and neuroinflammation play a crucial role in the pathogenesis of PD. Eugenol is a phytochemical with potent antioxidant and anti-inflammatory activity. The present investigation is aimed to study the effect of eugenol in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced mouse model of PD and its relationship to antioxidant effect. The effects of seven days of oral pre-treatment and post-treatment with three doses of eugenol (25, 50 and 100 mg/kg/day) were investigated against the MPTP-induced PD mouse model. In addition to the assessment of behavioural parameters using various tests (actophotometer, beam walking test, catalepsy, rearing, rotarod), biochemical parameters including lipid peroxidation and reduced glutathione levels in brain tissues, were also estimated in this study. The binding mode of eugenol in the human myeloid differentiation factor-2 (hMD-2) was also studied. Results showed that MPTP administration in mice resulted in the development of motor dysfunction (impaired motor coordination and hypo locomotion) similar to that of PD in different behavioural studies. Pre-treatment with eugenol reversed motor dysfunction caused by MPTP administration while post-treatment with eugenol at a high dose aggravated the symptoms of akinesia associated with MPTP administration. MPTP resulted in increased lipid peroxidation while decreased reduced glutathione levels in the brains of mice. MPTP-induced increased lipid peroxidation and attenuated levels of reduced glutathione were found to be alleviated with eugenol pre-treatment while augmented with eugenol post-treatment. Eugenol showed a binding affinity of -6.897 kcal/mol against the MD2 coreceptor of toll-like receptor-4 (TLR4). Biochemical, as well as neurobehavioral studies, showed that eugenol is having a protective effect, but does not have a curative effect on PD.

Neuroprotective Effects of Ethyl Pyruvate against Aluminum Chloride-Induced Alzheimer's Disease in Rats via Inhibiting Toll-Like Receptor 4.

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by the formation of insoluble deposits of ß-amyloid (Aß) plaques within the parenchyma of the brain. The present study aimed to investigate the neuroprotective role of ethyl pyruvate against in vitro and in vivo model of aluminum chloride (AlCl3)-induced AD. Effect of ethyl pyruvate (5, 10, 20, 40 mM) against AlCl3 (1250 µM)-induced neurotoxicity in primary neuron-glial mixed cell culture was evaluated using cell viability assays (MTT assay as well as calcein-AM/propidium iodide fluorescent dyes). In vivo model, AlCl3 (50 mg/kg) were given through intraperitoneal route (i.p.) once daily for 4 weeks in rats and after 2 weeks, ethyl pyruvate (50, 100, 200 mg/kg/day) was co-administered with AlCl3 once daily via the oral route. The present study, in addition to perform histopathology of the brain, also estimated oxidant and antioxidant parameters as well as memory impairment using pole test, plus maze, and Morris water maze test. The binding mode of ethyl pyruvate in the hMD-2 was also studied. Results of in vitro studies showed that the AlCl3 administration resulted in neuronal cell death. AlCl3 administration in rats resulted in memory loss, oxidative stress (increased lipid peroxide and nitric oxide), impairment of antioxidant mechanisms (superoxide dismutase, catalase, and reduced glutathione), and deposition of amyloid plaques in cerebral cortex region of the brain. AlCl3 also resulted in the overexpression of the TLR4 receptors in the brain tissues. Administration of ethyl pyruvate ameliorated the AlCl3-induced neurotoxicity in neuron-glial mixed cell culture as well as histopathological, neurochemical, and behavioral consequences of chronic administration of AlCl3 in the rat. Ethyl pyruvate showed a docking score of 4.048. Thus, ethyl pyruvate is effective against in vitro and in vivo models of AlCl3-induced AD.

Therapeutic potential of snake venom in cancer therapy: current perspectives.

Many active secretions produced by animals have been employed in the development of new drugs to treat diseases such as hypertension and cancer. Snake venom toxins contributed significantly to the treatment of many medical conditions. There are many published studies describing and elucidating the anti-cancer potential of snake venom. Cancer therapy is one of the main areas for the use of protein peptides and enzymes originating from animals of different species. Some of these proteins or peptides and enzymes from snake venom when isolated and evaluated may bind specifically to cancer cell membranes, affecting the migration and proliferation of these cells. Some of substances found in the snake venom present a great potential as anti-tumor agent. In this review, we presented the main results of recent years of research involving the active compounds of snake venom that have anticancer activity.

2D and 3D-QSAR study on 4-anilinoquinozaline derivatives as potent apoptosis inducer and efficacious anticancer agent.

BACKGROUND: Apoptosis is known as programmed cell death that plays an important role in tumor biology. METHODS: In this study, apoptosis-inducing activity is predicted by using a QSAR modeling approach for a series of 4-anilinoquinozaline derivatives. 2D-QSAR model for the prediction of apoptosis-inducing activity was obtained by applying multiple linear regression giving r2 = 0.8225 and q2 = 0.7626, principal component regression giving r2 = 0.7539 and q2 = 0.6669 and partial least squares giving r2 = 0.8237 and q2 = 0.6224. RESULTS: QSAR study revealed that alignment-independent descriptors and distance-based topology index are the most important descriptors in predicting apoptosis-inducing activity. 3D-QSAR study was performed using k-nearest neighbor molecular field analysis (kNN-MFA) approach for both electrostatic and steric fields. Three different kNN-MFA 3D-QSAR methods (SW-FB, SA, and GA) were used for the development of models and tested successfully for internal (q2 > 0.62) and external (predictive r2 > 0.52) validation criteria. Thus, 3D-QSAR models showed that electrostatic effects dominantly determine the binding affinities. CONCLUSIONS: The QSAR models developed in this study would be useful for the development of new apoptosis inducer as anticancer agents.