Inhibition of Chikungunya Virus Infection by 4-Hydroxy-1-Methyl-3-(3-morpholinopropanoyl)quinoline-2(1H)-one (QVIR) Targeting nsP2 and E2 Proteins.

The re-emergence of Chikungunya virus (CHIKV) infection in humans with no approved antiviral therapies or vaccines is one of the major problems with global significance. In the present investigation, we screened 80 in-house quinoline derivatives for their anti-CHIKV activity by computational techniques and found 4-hydroxy-1-methyl-3-(3-morpholinopropanoyl)quinoline-2(1H)-one (QVIR) to have potential binding affinities with CHIKV nsP2 and E2 glycoproteins. QVIR was evaluated in vitro for its anti-CHIKV potential. QVIR showed strong inhibition of CHIKV infection with an EC50 (50% effective concentration) value of 2.2 ± 0.49 µM without significant cytotoxicity (CC50 > 200 µM) and was chosen for further elucidation of its antiviral mechanism. The infectious viral particle formation was abolished by approximately 72% at a QVIR concentration of 20 µM during infection in the BHK-21 cell line, and the CHIKV RNA synthesis was diminished by 84% for nsP2 as well as 74% for E2, whereas the levels of viral proteins were decreased by 69.9% for nsP2 and 53.9% for E2. Flow cytometry analysis confirmed a huge decline in the expression of viral nsP2 and E2 proteins by 71.84 and 67.7%, respectively. Time of addition experiments indicated that QVIR inhibited viral infection at early and late stages of viral replication cycle, and the optimal inhibition was observed at 16 h post infection. The present study advocates for the first time that QVIR acts as a substantial and potent inhibitor against CHIKV and might be as an auspicious novel drug candidate for the development of therapeutic agents against CHIKV infections.

Functional Neuroproteomics: An Imperative Approach for Unravelling Protein Implicated Complexities of Brain.

A proteome is defined as a comprehensive protein set either of an organ or an organism at a given time and under specific physiological conditions. Accordingly, the study of the nervous system's proteomes is called neuroproteomics. In the neuroproteomics process, various pieces of the nervous system are "fragmented" to understand the dynamics of each given sub-proteome in a much better way. Functional proteomics addresses the organisation of proteins into complexes and the formation of organelles from these multiprotein complexes that control various physiological processes. Current functional studies of neuroproteomics mainly talk about the synapse structure and its organisation, the major building site of the neuronal communication channel. The proteomes of synaptic vesicle, presynaptic terminal, and postsynaptic density, have been examined by various proteomics techniques. The objectives of functional neuroproteomics are: to solve the proteome of single neurons or astrocytes grown in cell cultures or from the primary brain cells isolated from tissues under various conditions, to identify the set of proteins that characterize specific pathogenesis, or to determine the group of proteins making up postsynaptic or presynaptic densities. It is usual to solve a particular sub-proteome like the heat-shock response proteome or the proteome responding to inflammation. Post-translational protein modifications alter their functions and interactions. The techniques to detect synapse phosphoproteome are available. However, techniques for the analysis of ubiquitination and sumoylation are under development.

Box-Behnken supported development and validation of robust HPTLC method: an application in estimation of punarnavine in leaf, stem, and their callus of Boerhavia diffusa Linn.

Boerhavia diffusa (BD) Linn. (Nyctaginaceae) is one of the most commonly used herbs in the Indian traditional system of medicine for the urinary disorders. The aim of the current investigation was to carry out initiation, development, and maintenance of BD callus cultures and quantitative estimation of punarnavine in plant and callus extracts. Leaves and stem of BD were used as explant for the tissue culture studies using Murashige and Skoog (MS) basal medium. MS Media comprising 2,4-Dichlorophenoxy acetic acid (2,4-D) (1 ppm) and 2,4-D (1 ppm) + Indole-3-acetic acid (IAA) (1.0 ppm) were found to yield friable callus from leaf explant; similarly, 2,4-D (0.3 ppm) + IAA (0.75 ppm) + Kinetin (0.3 ppm) and 2,4-D (0.5 ppm) + Naphthalene acetic acid (NAA) (1.5 ppm) + Kinetin (0.3 ppm) were found to yield friable callus from the stem explant. High-performance thin-layer chromatography method was been developed for the quantitative estimation of punarnavine (R f = 0.73) using mobile phase containing toluene: ethyl acetate: formic acid in the ratio (7.0:2.5:0.7, v/v/v) at 262 nm. The validated method was found linear (r 2 = 0.9971) in a wide range (100-1000 ng spot-1), precise, accurate, and robust. The values of limit of detection, LOD = 30.3 ng spot-1, and limit of quantification, LOQ = 100.0 ng spot-1. The robustness of the method was proved by applying the Box-Behnken design (BBD). The developed method found appropriate for the quality control of medicinal plants containing punarnavine as a constituent.

Deciphering the Role of WNT Signaling in Metabolic Syndrome-Linked Alzheimer's Disease.

It has been well established in recent research that there is a strong correlation between metabolic syndrome (MetS) and Alzheimer's disease (AD). However, the knowledge of exact mechanistic behind this association remains elusive. It has been reported in recent studies that inflammation and hypercoagulation are pivotal to the pathophysiology of MetS-induced AD. It is rather captivating that aberrant Wnt signaling pathway has been found to be implicated in each of the four conditions, i.e., inflammation, hypercoagulation, MetS, and AD. Deregulation of Wnt signaling has been affiliated with numerous brain pathologies, including Alzheimer's disease and insulin resistance. In recent past, it has been proposed that the Wnt pathway can act as a central integrator of metabolic signals from peripheral organs to the brain, which would constitute a unique character for Wnt signaling in glucose metabolism. The review educates in what way distinct components of Wnt signaling impact effector mediators of inflammation, hypercoagulation, which in turn decelerate the progression of AD in MetS. Furthermore, components of Wnt signaling, namely, Wnt3a and GSK-3ß, interlink MetS and AD. The review opines a contemporary hypothesis that Wnt signaling is implicated in the pathogenesis of MetS-induced AD via impacting inflammation and coagulation. Hence, targeting Wnt signaling could be a novel approach to halt the progression of MetS-linked AD.

Upcoming diagnostic biomarkers with promising prospects in neurological disorders.

An exponential increase in the prevalence of neurological disorders requires substantial steps to be taken for their prevention and treatment. Neurodiagnostic biomarkers are gaining momentum presently in order to enhance the diagnostic accuracy of neurodegenerative disorders, to precisely assess their advancement and to monitor the efficiency of therapeutic interventions. Therefore, the primary focus of the present review is the recent development in this field of neurodiagnostic biomarkers, and the current state of biomarker exploration in the context of various neurodegenerative diseases. This review encompasses an updated and detailed account of specific (ß-Amyloid, Tau and Phospho-tau 181, Tar-DNA binding protein-43, Progranulin, a-synuclein, Clusterin, etc) and non-specific (genetic, synaptic, inflammatory and coagulation) neurodiagnostic biomarkers and the recent advances in this growing field. This comprehensive review also suggests the utilization of neurodiagnostic markers in network approaches and personalized medication that will eventually improvise the existing diagnostic and therapeutic complexities of neurodiagnostic biomarkers.

Targeting malaria and leishmaniasis: Synthesis and pharmacological evaluation of novel pyrazole-1,3,4-oxadiazole hybrids. Part II.

In continuance with earlier reported work, an extension has been carried out by the same research group. Mulling over the ongoing condition of resistance to existing antimalarial agents, we had reported synthesis and antimalarial activity of certain pyrazole-1,3,4-oxadiazole hybrid compounds. Bearing previous results in mind, our research group ideated to design and synthesize some more derivatives with varied substitutions of acetophenone and hydrazide. Following this, derivatives 5a-r were synthesized and tested for antimalarial efficacy by schizont maturation inhibition assay. Further, depending on the literature support and results of our previous series, certain potent compounds (5f, 5n and 5r) were subjected to Falcipain-2 inhibitory assay. Results obtained for these particular compounds further strengthened our hypothesis. Here, in this series, compound 5f having unsubstituted acetophenone part and a furan moiety linked to oxadiazole ring emerged as the most potent compound and results were found to be comparable to that of the most potent compound (indole bearing) of previous series. Additionally, depending on the available literature, compounds (5a-r) were tested for their antileishmanial potential. Compounds 5a, 5c and 5r demonstrated dose-dependent killing of the promastigotes. Their IC50 values were found to be 33.3 ±â€¯1.68, 40.1 ±â€¯1.0 and 19.0 ±â€¯1.47 µg/mL respectively. These compounds (5a, 5c and 5r) also had effects on amastigote infectivity with IC50 of 44.2 ±â€¯2.72, 66.8 ±â€¯2.05 and 73.1 ±â€¯1.69 µg/mL respectively. Further target validation was done using molecular docking studies. Acute oral toxicity studies for most active compounds were also performed.

Exploring the multifaceted neuroprotective actions of Emblica officinalis (Amla): a review.

Today, neurological disorders such as epilepsy, depression, tardive dyskinesia, and stress, and neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, dementia, and Huntington's disease affect millions of people all over the world. Existing pharmacological interventions do not meet the desired therapeutic benefits for a significant number of patients, and hence, numerous research studies are in progress to find novel therapies for these disorders. Herbal drugs, which have been used in traditional medicine for centuries, are also being explored and scientifically evaluated for the treatment of these neurological disorders. While substantial evidence exists for the antioxidant, anti-inflammatory, anti-hyperlipidemic, and anti-hyperglycemic effects of Emblica officinalis, in vivo and in vitro studies, have also revealed its beneficial therapeutic activities in numerous neurological disorders. These diverse neuroprotective pharmacodynamic actions of E. officinalis corroborated by accumulating evidence in pre-clinical research studies deserve the attention of the scientific community to develop viable pharmacotherapeutic strategies. The present review elaborates upon the latest scientific evidence pertaining to the pharmacological effects of E. officinalis in numerous neurological and neurodegenerative disorders and also gives way for future research in this area.

Unfolding the pleiotropic facades of rosuvastatin in therapeutic intervention of myriads of neurodegenerative disorders.

Rosuvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme (HMG-CoA) reductase inhibitor, and one of the most popular antihyperlipidemic medications have been found to possess pharmacodynamic activities much different from its usual indication. Recent research studies have revealed the efficacy of rosuvastatin in attenuating neuroinflammation, reducing the progression of Alzheimer's disease, providing protection against cerebral ischaemia and spinal cord injury as well as ameliorating epilepsy. Mechanisms behind the neuroprotective potential of rosuvastatin can be attributed to its pleiotropic effects, independent of its ability to inhibit HMG-CoA reductase. These processes include modulation of several cellular pathways, isoprenylation, effects on oxidative stress, nitrosative levels, inflammation, and immune response. This review aims to assimilate and summarize recent findings on the pharmacological actions of rosuvastatin in attenuating neurological disorders in order to guide future research in this space.

Rosuvastatin alleviates high-salt and cholesterol diet-induced cognitive impairment in rats via Nrf2-ARE pathway.

OBJECTIVE: The objectives of our study were to investigate the possible effect of rosuvastatin in ameliorating high salt and cholesterol diet (HSCD)-induced cognitive impairment and to also investigate its possible action via the Nrf2-ARE pathway. METHODS: In silico studies were performed to check the theoretical binding of rosuvastatin to the Nrf2 target. HSCD was used to induce cognitive impairment in rats and neurobehavioral studies were performed to evaluate the efficacy of rosuvastatin in enhancing cognition. Biochemical analyses were used to estimate changes in oxidative markers. Western blot and immunohistochemical analyses were done to check Nrf2 translocation. TUNEL and caspase 3 tests were performed to evaluate reversal of apoptosis by rosuvastatin. RESULTS: Rosuvastatin showed good theoretical affinity to Nrf2, significantly reversed changes in oxidative biomarkers which were induced by HSCD, and also improved the performance of rats in the neurobehavioral test. A rise in nuclear translocation of Nrf2 was revealed through immunohistochemical analysis and western blot. TUNEL staining and caspase 3 activity showed attenuation of apoptosis. DISCUSSION: We have investigated a novel mechanism of action for rosuvastatin (via the Nrf2-ARE pathway) and demonstrated that it has the potential to be used in the treatment of cognitive impairment.

Exploring novel pharmacotherapeutic applications and repurposing potential of sodium glucose CoTransporter 2 inhibitors.

Sodium glucose cotransporter 2 (SGLT2) inhibitors are a relatively new class of anti-hyperglycaemic drugs with a distinctive mechanism of action focusing on renal absorption of glucose. Apart from its anti-hyperglycaemic effects, a multitude of research studies on this class have revealed that these drugs have far more versatile and comprehensive pharmacological effects than previously believed. Approximately 30% of FDA approved drugs are repurposed and used for indications other than those for which they were initially intended. Repurposing already approved drugs leads to significant reduction in pre-clinical and clinical R&D costs as well as minimizing the burden with respect to obtaining regulatory approval. SGLT2 inhibitors have been found to exhibit cardioprotective, renoprotective, anti-hyperlipidaemic, anti-atherosclerotic, anti-obesity, anti-neoplastic, hepatoprotective, and renoprotective effects in in vitro, pre-clinical, and clinical studies. The pleiotropic effects of this class have been attributed to a variety of its pharmacodynamic actions such as natriuresis, haemoconcentration, deactivation of RAAS, ketone body formation, alterations in energy homeostasis, glycosuria, lipolysis, anti-inflammatory, and anti-oxidative actions. These favourable observations encourage further research on this multifaceted class in order to effectively explore and harness its full potential and consequently lead to clinical outcomes.

Tannins Enriched Fraction of Emblica officinalis Fruits Alleviates High-Salt and Cholesterol Diet-Induced Cognitive Impairment in Rats via Nrf2-ARE Pathway.

Modern diets containing high quantities of salt and cholesterol have exhibited to cause a considerable effect on our health. Such diets, when consumed in the long term, have also shown to be a precursor to several disorders such as the metabolic disorder and consequently, various other diseases, including cognitive deficits. In the present study, we used a high salt and cholesterol diet (HSCD) to induce cognitive impairment in rats and also investigated the pharmacological action of tannins enriched fractions of Emblica officinalis (EOT) - a fruit that has been traditionally used for the treatment of numerous disorders for centuries. Significant alterations in MDA, GSH, TBARS, GPx, mitochondrial ATP, and mitochondrial membrane potential levels were observed in rats fed HSCD, which indicated presence of oxidative stress. Moreover, classic signs of cognitive impairment and deficits in spatial learning and memory were observed in the neurobehavioral tests. E. officinalis tannins exhibited good affinity to Nrf2 receptors in in silico studies, significantly reversed the changes in the aforementioned biomarkers of oxidative stress which were altered in the model group, as well as improved the performance of rats in Morris water maze task. Our results also reflected that EOT supplementation significantly increased the expression of Nrf2 in the CA1 region of hippocampus and cortex. Additionally, TUNEL assay indicated that EOT supplementation led to reversal of DNA fragmentation and apoptosis caused by HSCD. Immunohistochemical analysis and western blot further revealed a surge in the nuclear location of Nrf2. Through our study, we have demonstrated that cognitive impairment can be caused in rats via HSCD as a result of the oxidative stress induced by the same. Additionally, we have investigated a novel mechanism of action for EOT (which strongly suggests to be via the Nrf2-ARE pathway) and demonstrated that it has the potential to be used in the treatment of cognitive impairment.

High-salt- and cholesterol diet-associated cognitive impairment attenuated by tannins-enriched fraction of Emblica officinalis via inhibiting NF-kB pathway.

Metabolic disorders are closely associated with dietary habits and seem to be related to neuroinflammation and neurodegenerative disease in humans. Emblica officinalis (EOT) fruits not only have good nutritional value but also have excellent therapeutic potential. We used a tannins-enriched fraction of EOT fruit with the expectation of controlling diet-induced neuroinflammation and cognitive impairment in rats. A high-salt and cholesterol diet (HSCD) was used to induce neuroinflammation and cognitive impairment in rats. The diet of the rats was then supplemented with EOT (100 and 200 mg/kg b.w.) for 7 weeks. In order to evaluate the neuroprotective effects of EOT; in silico study, neurobehavioral tests, biochemical analyses, and immunohistochemical studies were performed. In silico study of p50 (NF-κB1) receptors with emblicanin (the main constituent of EOT) suggests that EOT has binds to NF-κB. EOT treatment reversed the HSCD-induced behavioral and memory disturbances in a step-down-type passive avoidance test. EOT treatment also inhibited HSCD-induced NF-κB upstream signaling, including the release of Th1, such as TNF-α, and downstream signaling Th2, such as IL-10, by flow cytometer. In addition, EOT treatment attentuated the HSCD-induced increase in the level of cognitive impairment markers, such as amyloid ß. Furthermore, immunohistochemical results demonstrated that EOT modulated neuronal cell death by inhibiting the overexpression of NF-kB in brain. This study confirms that EOT may be a promising therapy in ameliorating the neurotoxicity of HSCD; however further studies are warranted to elucidate the exact mechanism of action of EOT.

Rosuvastatin Attenuates High-Salt and Cholesterol Diet Induced Neuroinflammation and Cognitive Impairment via Preventing Nuclear Factor KappaB Pathway.

Recent attention is focused on the impact of diet on health and mental well-being. High-salt and cholesterol diet (HSCD) is known to be associated with neuroinflammation which is the predominant factor for neurodegenerative disease like Alzheimer disease (AD). In the present study, we examined the neuroprotective potential of rosuvastatin, an HMG-CoA reductase inhibitor against HSCD induced neuroinflammation and cognitive impairment. Our results demonstrated that HSCD-induced cognitive impairment as determined by Morris water maze (MWM) task. HSCD also activated nuclear factor kappaB (NF-kB) signaling pathway. The cytokine response was measured using a cytometric bead-based assay quantified by flow cytometry. Treatment with rosuvastatin decreased the production of nitric oxide (NO), tumor necrosis factor alpha (TNF-α) and increased interleukin-10 (IL-10) in a dose-dependent manner. Our results also demonstrated that the rosuvastatin modulates neuronal cell death by inhibiting the overexpression of NF-kB in the CA1 region of hippocampus. In addition, molecular docking study of rosuvastatin indicated high affinity and tighter binding capacity for the active site of the NF-kB. These results suggest that HSCD-triggered inflammatory response and cognitive impairment may be associated with NF-κB signaling pathway. Therefore, treatment with rosuvastatin could be a potential new therapeutic strategy for sporadic dementia of AD.