Integrated gene expression profiling and functional enrichment analyses to discover biomarkers and pathways associated with Guillain-Barré syndrome and autism spectrum disorder to identify new therapeutic targets.

Guillain-Barré syndrome (GBS) is one of the most prominent and acute immune-mediated peripheral neuropathy, while autism spectrum disorders (ASD) are a group of heterogeneous neurodevelopmental disorders. The complete mechanism regarding the neuropathophysiology of these disorders is still ambiguous. Even after recent breakthroughs in molecular biology, the link between GBS and ASD remains a mystery. Therefore, we have implemented well-established bioinformatic techniques to identify potential biomarkers and drug candidates for GBS and ASD. 17 common differentially expressed genes (DEGs) were identified for these two disorders, which later guided the rest of the research. Common genes identified the protein-protein interaction (PPI) network and pathways associated with both disorders. Based on the PPI network, the constructed hub gene and module analysis network determined two common DEGs, namely CXCL9 and CXCL10, which are vital in predicting the top drug candidates. Furthermore, coregulatory networks of TF-gene and TF-miRNA were built to detect the regulatory biomolecules. Among drug candidates, imatinib had the highest docking and MM-GBSA score with the well-known chemokine receptor CXCR3 and remained stable during the 100 ns molecular dynamics simulation validated by the principal component analysis and the dynamic cross-correlation map. This study predicted the gene-based disease network for GBS and ASD and suggested prospective drug candidates. However, more in-depth research is required for clinical validation.Communicated by Ramaswamy H. Sarma.

17 common differentially expressed genes (DEGs) were identified from 693 DEGs of the GBS dataset (GSE72748) and 365 DEGs of the ASD dataset (GSE113834), which is the preliminary part of this investigation.From the PPI network analysis, a total of 10 hub genes were identified and two common DEGs named CXCL9 and CXCL10 were found in both the hub gene and essential module analysis.The identified leading pathways and GO pathways, TF-gene interaction, and TF-miRNAs network has made the process more relevant and appropriate for suggesting probable drug candidates.Among the drug candidates, imatinib was suggested as the main drug candidate due to its interaction with the hub gene CXCL9 and CXCL10 and lower p value than the other candidates. It showed the highest binding affinity score and remained stable with the CXCR3 chemokine receptor.

Targeting Estrogen Signaling in the Radiation-induced Neurodegeneration: A Possible Role of Phytoestrogens.

Radiation for medical use is a well-established therapeutic method with an excellent prognosis rate for various cancer treatments. Unfortunately, a high dose of radiation therapy comes with its own share of side effects, causing radiation-induced non-specific cellular toxicity; consequently, a large percentage of treated patients suffer from chronic effects during the treatment and even after the post-treatment. Accumulating data evidenced that radiation exposure to the brain can alter the diverse cognitive-related signaling and cause progressive neurodegeneration in patients because of elevated oxidative stress, neuroinflammation, and loss of neurogenesis. Epidemiological studies suggested the beneficial effect of hormonal therapy using estrogen in slowing down the progression of various neuropathologies. Despite its primary function as a sex hormone, estrogen is also renowned for its neuroprotective activity and could manage radiation-induced side effects as it regulates many hallmarks of neurodegenerations. Thus, treatment with estrogen and estrogen-like molecules or modulators, including phytoestrogens, might be a potential approach capable of neuroprotection in radiation-induced brain degeneration. This review summarized the molecular mechanisms of radiation effects and estrogen signaling in the manifestation of neurodegeneration and highlighted the current evidence on the phytoestrogen mediated protective effect against radiationinduced brain injury. This existing knowledge points towards a new area to expand to identify the possible alternative therapy that can be taken with radiation therapy as adjuvants to improve patients' quality of life with compromised cognitive function.

In silico design of epitope-based peptide vaccine against non-typhoidal Salmonella through immunoinformatic approaches.

Non-typhoidal Salmonella (NTS) is one of the leading bacterial causes of many invasive human infections with a high antibiotic resistance profile. With this concern, the current study aimed to design an effective epitope-based peptide vaccine against NTS species as a successive and substitutive protective measure of invasive NTS disease. To design rationally, the current study considered a comprehensive in silico workflow combination of both immunoinformatics and molecular modeling approaches, including molecular docking and molecular dynamics (MD) simulation. We identified the two most promising T cell epitopes KVLYGIFAI and YGIFAITAL, and three B cell epitopes AAPVQVGEAAGS, TGGGDGSNT, and TGGGDGSNTGTTTT, in the outer membrane of NTS. Using these epitopes, a multiepitope vaccine was subsequently constructed along with appropriate adjuvant and linkers, which showed a good binding affinity and stability with toll-like receptor 2 (TLR2) in both molecular docking and MD simulation. Furthermore, in silico immune simulation described a strong immune response with a high number of antibodies, interferon-γ, and activated B and T cells. This study collectively suggests that predicted vaccine constructs could be considered potential vaccine candidates against common NTS species.Communicated by Ramaswamy H. Sarma.

Molecular Docking and Dynamics Simulation of Natural Compounds from Betel Leaves (Piper betle L.) for Investigating the Potential Inhibition of Alpha-Amylase and Alpha-Glucosidase of Type 2 Diabetes.

Piper betle L. is widely distributed and commonly used medicinally important herb. It can also be used as a medication for type 2 diabetes patients. In this study, compounds of P. betle were screened to investigate the inhibitory action of alpha-amylase and alpha-glucosidase against type 2 diabetes through molecular docking, molecular dynamics simulation, and ADMET (absorption, distribution, metabolism, excretion, and toxicity) analysis. The molecule apigenin-7-O-glucoside showed the highest binding affinity among 123 (one hundred twenty-three) tested compounds. This compound simultaneously bound with the two-target proteins alpha-amylase and alpha-glucosidase, with high molecular mechanics-generalized born surface area (MM/GBSA) values (ΔG Bind = -45.02 kcal mol-1 for alpha-amylase and -38.288 for alpha-glucosidase) compared with control inhibitor acarbose, which had binding affinities of -36.796 kcal mol-1 for alpha-amylase and -29.622 kcal mol-1 for alpha-glucosidase. The apigenin-7-O-glucoside was revealed to be the most stable molecule with the highest binding free energy through molecular dynamics simulation, indicating that it could compete with the inhibitors' native ligand. Based on ADMET analysis, this phytochemical exhibited a wide range of physicochemical, pharmacokinetic, and drug-like qualities and had no significant side effects, making them prospective drug candidates for type 2 diabetes. Additional in vitro, in vivo, and clinical investigations are needed to determine the precise efficacy of drugs.

Chemotherapeutic Activities of Dietary Phytoestrogens against Prostate Cancer: From Observational to Clinical Studies.

Prostate cancer remains one of the most frequent and deadliest malignancies in males, where the rate of disease progression is closely associated with the type of dietary intake, specifically a Western-style diet. Indeed intake of the Asian diet, which contains abundant phytoestrogens, is inversely correlated with a higher risk of prostate cancer, suggesting a chemoprotective effect of phytoestrogen against cancer progression. Although the role of phytoestrogens in cancer treatment has been well documented, their impact on prostate cancer is not well understood. Therefore, the present review discusses the possible chemopreventive effect of phytoestrogens, emphasizing their efficacy at the different stages of carcinogenesis. Furthermore, phytoestrogens provide a cytoprotective effect in conventional chemotherapy and enhance chemosensitivity to tumor cells, which have also been discussed. This compilation provides a solid basis for future research on phytoestrogens as a promising avenue for anticancer drug development and also recommends these beneficiary compounds in the daily diet to manage and prevent prostate cancer.

Chemotherapeutic potential of hesperetin for cancer treatment, with mechanistic insights: A comprehensive review.

BACKGROUND: Cancer has become a significant concern in the medical sector with increasing disease complexity. Although some available conventional treatments are still a blessing for cancer patients, short-and long-term adverse effects and poor efficiency make it more difficult to treat cancer patients, demonstrating the need for new potent and selective anticancer drugs. In search of potent anticancer agents, naturally occurring compounds have always been admired due to their structural diversity, where Hesperetin (HSP) may be one of the potent candidates. PURPOSE: We aimed to summarize all sources, pharmacological properties, anticancer activities of HSP against numerous cancers types through targeting multiple pathological processes, mechanism of HSP on sensitizing the current anti-cancer agents and other phytochemicals, overcoming resistance pattern and determining absorption, distribution, metabolism, excretion, and toxicity (ADME/Tox). METHODS: Information was retrieved from PubMed, Science Direct, and Google Scholar based on some key points like Hesperetin, cancer name, anticancer resistance, nanoformulation, and ADME/Tox was determined by in silico approaches. RESULT: HSP is a phytoestrogen present in citrus fruits in a high concentration (several hundred mg/kg) and exhibited anti-cancer activities through interfering at several pathways. HSP can suppress tumor formation by targeting several cellular proteins such as cell cycle regulatory, apoptosis, metastatic, tyrosine kinase, growth factor receptor, estrogen metabolism, and antioxidant-related protein.HSP has shown remarkable synergistic properties in combination therapy and has been reported to overcome multidrug cancer resistance drugs, leading to an improved defensive mechanism. These anticancer activities of HSP may be due to proper structural chemistry. CONCLUSION: Overall, HSP showed potential anticancer activities against all cancer and possess better pharmacokinetic properties. So this phytochemical alone or combination with other agents can be an effective alternative drug for cancer treatment.

Computational Insights into the Deleterious Impacts of Missense Variants on N-Acetyl-d-glucosamine Kinase Structure and Function.

An enzyme of the mammalian amino-sugar metabolism pathway, N-acetylglucosamine kinase (NAGK), that synthesizes N-acetylglucosamine (GlcNAc)-6-phosphate, is reported to promote dynein functions during mitosis, axonal and dendritic growth, cell migration, and selective autophagy, which all are unrelated to its enzyme activity. As non-enzymatic structural functions can be altered by genetic variation, we made an effort in this study aimed at deciphering the pathological effect of nonsynonymous single-nucleotide polymorphisms (nsSNPs) in NAGK gene. An integrated computational approach, including molecular dynamics (MD) simulation and protein-protein docking simulation, was used to identify the damaging nsSNPs and their detailed structural and functional consequences. The analysis revealed the four most damaging variants (G11R, G32R, G120E, and A156D), which are highly conserved and functional, positioned in both small (G11R and G32R) and large (G120E and A156D) domains of NAGK. G11R is located in the ATP binding region, while variants present in the large domain (G120E and A156D) were found to induce substantial alterations in the structural organizations of both domains, including the ATP and substrate binding sites. Furthermore, all variants were found to reduce binding energy between NAGK and dynein subunit DYNLRB1, as revealed by protein-protein docking and MM-GBSA binding energy calculation supporting their deleteriousness on non-canonical function. We hope these findings will direct future studies to gain more insight into the role of these variants in the loss of NAGK function and their role in neurodevelopmental disorders.

Microbial Quality Assessment and Efficacy of Low-Cost Disinfectants on Fresh Fruits and Vegetables Collected from Urban Areas of Dhaka, Bangladesh.

This study aimed to examine the total viable bacteria (TVBC); total coliform (TCC); fecal coliform (TFC); pathogenic Pseudomonas spp., Staphylococcus aureus, and total fungi (TF); and the effect of different low-cost disinfectants (sterile water, salt water, blanched, and vinegar) in decontamination of 12 types of fruit and 10 types of vegetables. In fruit samples, the lowest TVBC was enumerated at 3.18 ± 0.27 log CFU/g in Indian gooseberry and the highest at 6.47 ± 0.68 log CFU/g in guava. Staphylococci (2.04 ± 0.53-5.10 ± 0.02 log CFU/g), Pseudomonas (1.88 ± 0.03-5.38 ± 0.08 log CFU/g), and total fungi (2.60 ± 0.18-7.50 ± 0.15 log CFU/g) were found in all fruit samples; however, no Salmonella was detected in fruit samples. Similarly, the lowest TVBC recorded 5.67± 0.49 log CFU/g in cucumber and the highest 7.37 ± 0.06 log CFU/g in yard long bean. The Staphylococci (3.48 ± 0.13-4.81 ± 0.16 log CFU/g), Pseudomonas (3.57± 0.21- 4.75 ± 0.23 log CFU/g), TCC (1.85 ± 1.11-56.50 ± 37.14 MPN/g), TFC (1.76 ± 0.87- 3.78 ± 3.76 MPN/g), and TF (3.79 ± 0.18-4.40 ± 0.38 log CFU/g) were recorded in all vegetables samples, but no Salmonella was detected in yard long bean, pointed gourd, carrot, tomato, cucumber, or brinjal. However, vinegar showed the highest microbial load reduction of selected fruit and vegetables among the different treatments. With vinegar treatment, the highest reduction of TVBC (1.61-log) and TF (2.54-log) was observed for fruits, and TVBC (2.31-log) and TF (2.41-log) for vegetables. All the disinfectant treatments resulted in significant (p < 0.01) bacterial load reduction compared to control for the studied fruits and vegetable samples.

Potential roles of natural products in the targeting of proteinopathic neurodegenerative diseases.

Defective proteostasis is associated with the gradual accumulations of misfolded proteins and is a hallmark of many age-associated neurodegenerative diseases. In the aged brain, maintenance of the proteostasis network presents a substantial challenge, and its loss contributes to the onset and progression of neurological diseases associated with cognitive decline due to the generation of toxic protein aggregates, a process termed 'proteinopathy'. Emerging evidence suggests that reversing proteinopathies by boosting proteostasis might provide an effective means of preventing neurodegeneration. From this perspective, phytochemicals may play significant roles as potent modulators of the proteostasis network, as previous reports have suggested they can interact with various network components to modify pathologies and confer neuroprotection. This review focuses on some potent phytochemicals that directly or indirectly modulate the proteostasis network and on their possible molecular targets. In addition, we propose strategies for the natural product-based modulation of proteostasis machinery that target proteinopathies.

Emerging potential of cannabidiol in reversing proteinopathies.

The aberrant accumulation of disease-specific protein aggregates accompanying cognitive decline is a pathological hallmark of age-associated neurological disorders, also termed as proteinopathies, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and multiple sclerosis. Along with oxidative stress and neuroinflammation, disruption in protein homeostasis (proteostasis), a network that constitutes protein surveillance system, plays a pivotal role in the pathobiology of these dementia disorders. Cannabidiol (CBD), a non-psychotropic phytocannabinoid of Cannabis sativa, is known for its pleiotropic neuropharmacological effects on the central nervous system, including the ability to abate oxidative stress, neuroinflammation, and protein misfolding. Over the past years, compelling evidence has documented disease-modifying role of CBD in various preclinical and clinical models of neurological disorders, suggesting the potential therapeutic implications of CBD in these disorders. Because of its putative role in the proteostasis network in particular, CBD could be a potent modulator for reversing not only age-associated neurodegeneration but also other protein misfolding disorders. However, the current understanding is insufficient to underpin this proposition. In this review, we discuss the potentiality of CBD as a pharmacological modulator of the proteostasis network, highlighting its neuroprotective and aggregates clearing roles in the neurodegenerative disorders. We anticipate that the current effort will advance our knowledge on the implication of CBD in proteostasis network, opening up a new therapeutic window for aging proteinopathies.

Phytosterols: Targeting Neuroinflammation in Neurodegeneration.

Plant-derived sterols, phytosterols, are well known for their cholesterol-lowering activity in serum and their anti-inflammatory activities. Recently, phytosterols have received considerable attention due to their beneficial effects on various non-communicable diseases, and recommended use as daily dietary components. The signaling pathways mediated in the brain by phytosterols have been evaluated, but little is known about their effects on neuroinflammation, and no clinical studies have been undertaken on phytosterols of interest. In this review, we discuss the beneficial roles of phytosterols, including their attenuating effects on inflammation, blood cholesterol levels, and hallmarks of the disease, and their regulatory effects on neuroinflammatory disease pathways. Despite recent advancements made in phytosterol pharmacology, some critical questions remain unanswered. Therefore, we have tried to highlight the potential of phytosterols as viable therapeutics against neuroinflammation and to direct future research with respect to clinical applications.

Molecular simulation studies to reveal the binding mechanisms of shikonin derivatives inhibiting VEGFR-2 kinase.

Traditional vascular endothelial growth factor receptor 2 (VEGFR-2) inhibitors can manage angiogenesis; however, severe toxicity and resistance limit their long-term applications in clinical therapy. Shikonin (SHK) and its derivatives could be promising to inhibit the VEGFR-2 mediated angiogenesis, as they are reported to bind in the catalytic kinase domain with low affinity. However, the detailed molecular insights and binding dynamics of these natural inhibitors are unknown, which is crucial for potential SHK based lead design. Therefore, the present study employed molecular modeling and simulations techniques to get insight into the binding behaviors of SHK and its two derivates, ß-hydroxyisovalerylshikonin (ß-HIVS) and acetylshikonin (ACS). Here the intermolecular interactions between protein and ligands were studied by induced fit docking approach, which were further evaluated by treating QM/MM (quantum mechanics/molecular mechanics) and molecular dynamics (MD) simulation. The result showed that the naphthazarin ring of the SHK derivates is vital for strong binding to the catalytic domain; however, the binding stability can be modulated by the side chain modification. Because of having electrostatic potential, this ring makes essential interactions with the DFG (Asp1046 and Phe1047) motif and also allows interacting with the allosteric binding site. Taken together, the studies will advance our knowledge and scope for the development of new selective VEGFR-2 inhibitors based on SHK and its analogs.

Computational SNP Analysis and Molecular Simulation Revealed the Most Deleterious Missense Variants in the NBD1 Domain of Human ABCA1 Transporter.

The ATP-binding cassette transporter A1 (ABCA1) is a membrane-bound exporter protein involved in regulating serum HDL level by exporting cholesterol and phospholipids to load up in lipid-poor ApoA-I and ApoE, which allows the formation of nascent HDL. Mutations in the ABCA1 gene, when presents in both alleles, disrupt the canonical function of ABCA1, which associates with many disorders related to lipid transport. Although many studies have reported the phenotypic effects of a large number of ABCA1 variants, the pathological effect of non-synonymous polymorphisms (nsSNPs) in ABCA1 remains elusive. Therefore, aiming at exploring the structural and functional consequences of nsSNPs in ABCA1, in this study, we employed an integrated computational approach consisting of nine well-known in silico tools to identify damaging SNPs and molecular dynamics (MD) simulation to get insights into the magnitudes of the damaging effects. In silico tools revealed four nsSNPs as being most deleterious, where the two SNPs (G1050V and S1067C) are identified as the highly conserved and functional disrupting mutations located in the NBD1 domain. MD simulation suggested that both SNPs, G1050V and S1067C, changed the overall structural flexibility and dynamics of NBD1, and induced substantial alteration in the structural organization of ATP binding site. Taken together, these findings direct future studies to get more insights into the role of these variants in the loss of the ABCA1 function.

Structural and Dynamic Characterizations Highlight the Deleterious Role of SULT1A1 R213H Polymorphism in Substrate Binding.

Sulfotransferase 1A1 (SULT1A1) is responsible for catalyzing various types of endogenous and exogenous compounds. Accumulating data indicates that the polymorphism rs9282861 (R213H) is responsible for inefficient enzymatic activity and associated with cancer progression. To characterize the detailed functional consequences of this mutation behind the loss-of-function of SULT1A1, the present study deployed molecular dynamics simulation to get insights into changes in the conformation and binding energy. The dynamics scenario of SULT1A1 in both wild and mutated types as well as with and without ligand showed that R213H induced local conformational changes, especially in the substrate-binding loop rather than impairing overall stability of the protein structure. The higher conformational changes were observed in the loop3 (residues, 235-263), turning loop conformation to A-helix and B-bridge, which ultimately disrupted the plasticity of the active site. This alteration reduced the binding site volume and hydrophobicity to decrease the binding affinity of the enzyme to substrates, which was highlighted by the MM-PBSA binding energy analysis. These findings highlight the key insights of structural consequences caused by R213H mutation, which would enrich the understanding regarding the role of SULT1A1 mutation in cancer development and also xenobiotics management to individuals in the different treatment stages.