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Glial activation and neuroinflammation play significant roles in apoptosis as well as in the development of cognitive and memory deficits. Neuroinflammation is also a critical feature in the pathogenesis of neurodegenerative disorders such as Alzheimer and Parkinson’s diseases. Previously, hesperetin has been shown to be an effective antioxidant and anti-inflammatory agent. In the present study, in vivo and in vitro analyses were performed to evaluate the neuroprotective effects of hesperetin in lipopolysaccharide (LPS)-induced neuroinflammation, oxidative stress, neuronal apoptosis and memory impairments. Based on our findings, LPS treatment resulted in microglial activation and astrocytosis and elevated the expression of inflammatory mediators such as phosphorylated-Nuclear factor-κB (p-NF-κB), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) in the cortical and hippocampal regions and in BV2 cells. However, hesperetin cotreatment markedly reduced the expression of inflammatory cytokines by ameliorating Toll-like receptor-4 (TLR4)-mediated ionized calcium-binding adapter molecule 1/glial fibrillary acidic protein (Iba-1/GFAP) expression. Similarly, hesperetin attenuated LPS-induced generation of reactive oxygen species/lipid per oxidation (ROS/LPO) and improved the antioxidant protein level such as nuclear factor erythroid 2-related factor 2 (Nrf2) and Haem-oxygenase (HO-1) in the mouse brain. Additionally, hesperetin ameliorated cytotoxicity and ROS/LPO induced by LPS in HT-22 cells. Moreover, hesperetin rescued LPS-induced neuronal apoptosis by reducing the expression of phosphorylated-c-Jun N-terminal kinases (p-JNK), B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax), and Caspase-3 protein and promoting the Bcl-2 protein level. Furthermore, hesperetin enhanced synaptic integrity, cognition, and memory processes by enhancing the phosphorylated-cAMP response element binding protein (p-CREB), postsynaptic density protein-95 (PSD-95), and Syntaxin. Overall, our preclinical study suggests that hesperetin conferred neuroprotection by regulating the TLR4/NF-κB signaling pathway against the detrimental effects of LPS.

Loss of muscle mass and strength with aging, termed sarcopenia is accelerated in several comorbidities including chronic heart failure (CHF) and chronic obstructive pulmonary diseases (COPD). However, the effective circulating biomarkers to accurately diagnose and assess sarcopenia are not known. We recruited male healthy controls and patients with CHF and COPD (n = 81–87/group), aged 55–74 years. Sarcopenia was clinically identified based on hand-grip strength, appendicular skeletal muscle index and physical capacity as recommended by the European working group for sarcopenia. The serum levels of amino-terminal pro-peptide of type-III procollagen, c-terminal agrin fragment-22, osteonectin, irisin, fatty acid-binding protein-3 and macrophage migration inhibitory factor were significantly different between healthy controls and patients with CHF and COPD. Risk scores for individual biomarkers were calculated by logistic regressions and combined into a cumulative risk score. The median cutoff value of 3.86 was used to divide subjects into high- and low-risk groups for sarcopenia with the area under the curve of 0.793 (95% CI = 0.738–0.845, p  < 0.001). A significantly higher incidence of clinical sarcopenia was found in high-risk group. Taken together, the battery of biomarkers can be an effective tool in the early diagnosis and assessment of sarcopenia.

Cognitive decline and memory impairment induced by oxidative brain damage are the critical pathological hallmarks of Alzheimer’s disease (AD). Based on the potential neuroprotective effects of melatonin, we here explored the possible underlying mechanisms of the protective effect of melatonin against scopolamine-induced oxidative stress-mediated c-Jun N-terminal kinase (JNK) activation, which ultimately results in synaptic dysfunction, neuroinflammation, and neurodegeneration. According to our findings, scopolamine administration resulted in LPO and ROS generation and decreased the protein levels of antioxidant proteins such as Nrf2 and HO-1; however, melatonin co-treatment mitigated the generation of oxidant factors while improving antioxidant protein levels. Similarly, melatonin ameliorated oxidative stress-mediated JNK activation, enhanced Akt/ERK/CREB signaling, promoted cell survival and proliferation, and promoted memory processes. Immunofluorescence and western blot analysis indicated that melatonin reduced activated gliosis via attenuation of Iba-1 and GFAP. We also found that scopolamine promoted neuronal loss by inducing Bax, Pro-Caspase-3, and Caspase-3 and reducing the levels of the antiapoptotic protein Bcl-2. In contrast, melatonin significantly decreased the levels of apoptotic markers and increased neuronal survival. We further found that scopolamine disrupted synaptic integrity and, conversely, that melatonin enhanced synaptic integrity as indicated by Syntaxin, PSD-95, and SNAP-23 expression levels. Furthermore, melatonin ameliorated scopolamine-induced impairments in spatial learning behavior and memory formation. On the whole, our findings revealed that melatonin attenuated scopolamine-induced synaptic dysfunction and memory impairments by ameliorating oxidative brain damage, stress kinase expression, neuroinflammation, and neurodegeneration. Graphical Abstract The proposed schematic diagram showing the neuroprotective effect of melatonin against scopolamine-induced oxidative stress-mediated synaptic dysfunction, memory impairment neuroinflammation and neurodegeneration.

Humans have witnessed three deadly pandemics so far in the twenty-first century which are associated with novel coronaviruses: SARS, Middle East respiratory syndrome (MERS), and COVID-19. All of these viruses, which are responsible for causing acute respiratory tract infections (ARTIs), are highly contagious in nature and/or have caused high mortalities. The recently emerged COVID-19 disease is a highly transmittable viral infection caused by another zoonotic novel coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Similar to the other two coronaviruses such as SARS-CoV-1 and MERS-CoV, SARS-CoV-2 is also likely to have originated from bats, which have been serving as established reservoirs for various pathogenic coronaviruses. Although, it is still unknown how SARS-CoV-2 is transmitted from bats to humans, the rapid human-to-human transmission has been confirmed widely. The disease first appeared in Wuhan, China, in December 2019 and quickly spread across the globe, infected 48,539,872 people, and caused 1,232,791 deaths in 215 countries, and the infection is still spreading at the time of manuscript preparation. So far, there is no definite line of treatment which has been approved or vaccine which is available. However, different types of potential vaccines and therapeutics have been evaluated and/or are under clinical trials against COVID-19. In this review, we summarize different types of acute respiratory diseases and briefly discuss earlier outbreaks of coronaviruses and compare their occurrence and pathogenicity with the current COVID-19 pandemic. Various epidemiological aspects of COVID-19 such as mode of spread, death rate, doubling time, etc., have been discussed in detail. Apart from this, different technical issues related to the COVID-19 pandemic including use of masks and other socio-economic problems associated with the pandemic have also been summarized. Additionally, we have reviewed various aspects of patient management strategies including mechanism of action, available diagnostic tools, etc., and also discussed different strategies for the development of effective vaccines and therapeutic combinations to deal with this viral outbreak. Overall, by the inclusion of various references, this review covers, in detail, the most important aspects of the COVID-19 pandemic.

Heart disease is a fatal human disease, rapidly increases globally in both developed and undeveloped countries and consequently, causes death. Normally, in this disease, the heart fails to supply a sufficient amount of blood to other parts of the body in order to accomplish their normal functionalities. Early and on-time diagnosing of this problem is very essential for preventing patients from more damage and saving their lives. Among the conventional invasive-based techniques, angiography is considered to be the most well-known technique for diagnosing heart problems but it has some limitations. On the other hand, the non-invasive based methods, like intelligent learning-based computational techniques are found more upright and effectual for the heart disease diagnosis. Here, an intelligent computational predictive system is introduced for the identification and diagnosis of cardiac disease. In this study, various machine learning classification algorithms are investigated. In order to remove irrelevant and noisy data from extracted feature space, four distinct feature selection algorithms are applied and the results of each feature selection algorithm along with classifiers are analyzed. Several performance metrics namely: accuracy, sensitivity, specificity, AUC, F1-score, MCC, and ROC curve are used to observe the effectiveness and strength of the developed model. The classification rates of the developed system are examined on both full and optimal feature spaces, consequently, the performance of the developed model is boosted in case of high variated optimal feature space. In addition, P-value and Chi-square are also computed for the ET classifier along with each feature selection technique. It is anticipated that the proposed system will be useful and helpful for the physician to diagnose heart disease accurately and effectively.

The recent pandemic of coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 has raised global health concerns. The viral 3-chymotrypsin-like cysteine protease (3CLpro) enzyme controls coronavirus replication and is essential for its life cycle. 3CLpro is a proven drug discovery target in the case of severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). Recent studies revealed that the genome sequence of SARS-CoV-2 is very similar to that of SARS-CoV. Therefore, herein, we analysed the 3CLpro sequence, constructed its 3D homology model, and screened it against a medicinal plant library containing 32,297 potential anti-viral phytochemicals/traditional Chinese medicinal compounds. Our analyses revealed that the top nine hits might serve as potential anti- SARS-CoV-2 lead molecules for further optimisation and drug development process to combat COVID-19. [Display omitted] •SARS-CoV-2 3CLpro is conserved, share 99.02% sequence identity with SARS-CoV 3CLpro and together with 12 point-mutations.•Mutations disrupt important hydrogen bonds and alter the receptor binding site of SARS-CoV-2 3CLpro.•Medicinal plants phytochemicals were proved potential anti-COVID-19 druggable candidates.

Hesperetin is a bioactive flavonoid in the body, produced from hesperidin. No comprehensive studies have shown its protective effects in neurodegenerative disorders. Here, we hypothesized that hesperetin may protect the mice brain against Aβ-induced neurodegeneration. Twenty-four hours after intracerebroventricular injection of Aβ1-42, the treated group was injected hesperetin. For in vitro experiments, HT22 and BV-2 cells were used. Immunoblot, immunofluorescence, and behavioral analyses were used to evaluate the different parameters. Our results indicated that hesperetin significantly attenuated oxidative stress, as assessed by the expression of Nrf2/HO-1 and LPO and ROS assays, in the hippocampus, cortex, and in vitro HT22 cells. Similarly, activated glial cells were regulated by hesperetin, as assessed by the expression of GFAP and Iba-1. Moreover, the expression of TLR4, p-NF-κB, and downstream targets was analyzed; the results showed that hesperetin reinstated the expression of these markers. The effects of hesperetin were further confirmed by using specific TLR4 and p-NF-κB inhibitors in BV-2 cells. Next, we evaluated Aβ pathology in the cortex, hippocampus, and HT22 cells, showing that hesperetin significantly reduced the Aβ pathology. Furthermore, the antiapoptotic effects of hesperetin were assessed, which showed strong antiapoptotic effects. Overall, the neuroprotective effect of hesperetin was found to be a multipotent effect, involving the inhibition of oxidative stress, neuroinflammation, apoptotic cell death, and cognitive consolidation. Given antioxidant, anti-inflammatory, and antiapoptotic potentials against Aβ-induced neurodegeneration and memory impairment, hesperetin may be a promising therapeutic agent for Alzheimer’s disease–like neurological disorders.

Natural products have played a critical role in medicine due to their ability to bind and modulate cellular targets involved in disease. Medicinal plants hold a variety of bioactive scaffolds for the treatment of multiple disorders. The less adverse effects, affordability, and easy accessibility highlight their potential in traditional remedies. Identifying pharmacological targets from active ingredients of medicinal plants has become a hot topic for biomedical research to generate innovative therapies. By developing an unprecedented opportunity for the systematic investigation of traditional medicines, network pharmacology is evolving as a systematic paradigm and becoming a frontier research field of drug discovery and development. The advancement of network pharmacology has opened up new avenues for understanding the complex bioactive components found in various medicinal plants. This study is attributed to a comprehensive summary of network pharmacology based on current research, highlighting various active ingredients, related techniques/tools/databases, and drug discovery and development applications. Moreover, this study would serve as a protocol for discovering novel compounds to explore the full range of biological potential of traditionally used plants. We have attempted to cover this vast topic in the review form. We hope it will serve as a significant pioneer for researchers working with medicinal plants by employing network pharmacology approaches.

Background Middle East Respiratory Syndrome Coronavirus (MERS-COV) is the main cause of lung and kidney infections in developing countries such as Saudi Arabia and South Korea. This infectious single-stranded, positive (+) sense RNA virus enters the host by binding to dipeptidyl-peptide receptors. Since no vaccine is yet available for MERS-COV, rapid case identification, isolation, and infection prevention strategies must be used to combat the spreading of MERS-COV infection. Additionally, there is a desperate need for vaccines and antiviral strategies. Methods The present study used immuno-informatics and computational approaches to identify conserved B- and T cell epitopes for the MERS-COV spike (S) protein that may perform a significant role in eliciting the resistance response to MERS-COV infection. Results Many conserved cytotoxic T-lymphocyte epitopes and discontinuous and linear B-cell epitopes were predicted for the MERS-COV S protein, and their antigenicity and interactions with the human leukocyte antigen (HLA) B7 allele were estimated. Among B-cell epitopes, QLQMGFGITVQYGT displayed the highest antigenicity-score, and was immensely immunogenic. Among T-cell epitopes, MHC class-I peptide YKLQPLTFL and MHC class-II peptide YCILEPRSG were identified as highly antigenic. Furthermore, docking analyses revealed that the predicted peptides engaged in strong bonding with the HLA-B7 allele. Conclusion The present study identified several MERS-COV S protein epitopes that are conserved among various isolates from different countries. The putative antigenic epitopes may prove effective as novel vaccines for eradication and combating of MERS-COV infection.

Plants have developed sophisticated and complex epigenetic regulation-based mechanisms to maintain stable growth and development under diverse environmental conditions. Histone deacetylases (HDACs) are important epigenetic regulators in eukaryotes that are involved in the deacetylation of lysine residues of histone H3 and H4 proteins. Plants have developed a unique HDAC family, HD2, in addition to the RPD3 and Sir2 families, which are also present in other eukaryotes. HD2s are well conserved plant-specific HDACs, which were first identified as nucleolar phosphoproteins in maize. The HD2 family plays important roles not only in fundamental developmental processes, including seed germination, root and leaf development, floral transition, and seed development but also in regulating plant responses to biotic and abiotic stresses. Some of the HD2 members coordinate with each other to function. The HD2 family proteins also show functional association with RPD3-type HDACs and other transcription factors as a part of repression complexes in gene regulatory networks involved in environmental stress responses. This review aims to analyse and summarise recent research progress in the HD2 family, and to describe their role in plant growth and development and in response to different environmental stresses.