In silico investigation of nonsynonymous single nucleotide polymorphisms in BCL2 apoptosis regulator gene to design novel protein-based drugs against cancer.

BCL2 apoptosis regulator gene encodes Bcl-2 pro-survival protein, which plays an important role to evade apoptosis in various cancers. Moreover, single nucleotide polymorphisms (SNPs) in the BCL2 gene can be nonsynonymous (nsSNPs), which might affect the protein stability and probably its function. Therefore, we implement cutting-edge computational techniques based on the Spherical Polar Fourier and Monte-Carlo algorithms to investigate the impact of these SNPs on the B cell lymphoma-2 (Bcl-2) stability and therapeutic potential of protein-based molecules to inhibit this protein. As a result, we identified two nsSNPs (Q118R and R129C) to be deleterious and highly conserved, having a negative effect on protein stability. Additionally, molecular docking and molecular dynamics simulations confirmed the decreased binding affinity of mutated Bcl-2 variants to bind three-helix bundle protein inhibitor as these mutations occurred in the protein-protein binding site. Overall, this computational approach investigating nsSNPs provides a useful basis for designing novel molecules to inhibit Bcl-2 pro-survival pathway in malignant cells.

Calcineurin and mTOR inhibitors in kidney transplantation: integrative metamodeling on transplant survival and kidney function.

In our study, we examined the efficacy of mTOR (mammalian target of rapamycin) inhibitors, specifically rapamycin (Rap), compared to calcineurin inhibitors (CNIs) in kidney transplantation. By conducting a comprehensive search across reputable databases (EMBASE, Scopus, PubMed, Cochrane, and Crossref), we gathered data for a six-month post-transplantation period. Our analysis revealed that mTOR inhibitor administration resulted in improved glomerular filtration rate (GFR) and serum creatinine levels. However, it is important to note that the mTOR inhibitor group had a higher incidence of acute rejection after biopsy. Through molecular modeling, we observed that Rap exhibited a superior binding affinity for mTOR compared to CNIs' binding to calcineurin, probably contributing to the transplant rejection. Our meta-analysis supports the cautious use of an optimal mTOR inhibitor in conjunction with careful consideration of clinical features when minimizing CNIs early in the transplantation process. This is because mTOR inhibitors have complementary mechanisms of action, a low nephrotoxicity profile, and favorable outcomes in serum creatinine and GFR, which contribute to improved transplant survival.

Deciphering Molecular Mechanisms of Carbon TetrachlorideInduced Hepatotoxicity (Fibrosis): A Brief Systematic Review.

The liver plays a critical role in metabolic processes, making it vulnerable to injury. Researchers often study carbon tetrachloride (CCl4)-induced hepatotoxicity in model organisms because it closely resembles human liver damage. This toxicity occurs due to the activation of various cytochromes, including CYP2E1, CYP2B1, CYP2B2, and possibly CYP3A, which produce the trichloromethyl radical (CCl3*). CCl3* can attach to biological molecules such as lipids, proteins, and nucleic acids, impairing lipid metabolism and leading to fatty degeneration. It can also combine with DNA to initiate hepatic carcinogenesis. When exposed to oxygen, CCl3* generates more reactive CCl3OO*, which leads to lipid peroxidation and membrane damage. At the molecular level, CCl4 induces the release of several inflammatory cytokines, including TNF-α and NO, which can either help or harm hepatotoxicity through cellular apoptosis. TGF-ß contributes to fibrogenesis, while IL-6 and IL-10 aid in recovery by minimizing anti-apoptotic activity and directing cells toward regeneration. To prevent liver damage, different interventions can be employed, such as antioxidants, mitogenic agents, and the maintenance of calcium sequestration. Drugs that prevent CCl4- induced cytotoxicity and proliferation or enhance CYP450 activity may offer a protective response against hepatic carcinoma.

The Role of Vitamins in DNA Methylation as Dietary Supplements or Neutraceuticals: A Systematic Review.

Epigenetic modifications play a vital role in gene regulation associated with different pathologies. Various nutrients in our diet, such as vitamins can modulate these epigenetic mechanism. They also can regulatenderlying pathophysiological factors and processes that directly or indirectly. Most importantly, A, B, C, and D vitamins have recently been shown to be involved in this type of regulation together with vitamins E and K. Despite their effect on the DNA methylation process, an in-depth understanding of vitamin-mediated epigenetic alterations have yet to be investigated. Moreover, the role of vitamins in DNA methylation as nutraceuticals might be important to use for targeted therapy of various human diseases. Overall, this review provides a brief survey of the role of vitamins as epigenetic modulators or nutraceuticals, emphasizing their potential in epigenetic therapy.

In-silico analysis of non-synonymous single nucleotide polymorphisms in human ß-defensin type 1 gene reveals their impact on protein-ligand binding sites.

Single nucleotide polymorphism (SNPs) is an important genetic biomarker to assess protein function and its possible contribution to genetic diseases, such as the ß- defensin 1 gene (DEFB1)-associated non-synonymous SNPs (nsSNPs). Defensins are antimicrobial and immunomodulatory peptides, acting as part of innate immunity, and killing bacteria by interacting phosphatidylinositol 4,5-bisphosphate (PIP2). Therefore, we apply cutting-edge computational algorithms to identify detrimental SNPs in the DEFB1 gene that potentially impact PIP2 binding sites. Furthermore, 4 most important nsSNPs in the DEFB1 gene were discovered (C67S, T58S, G62W, and Y35C) and only two of them were found to be linked to the PIP2 binding site-forming residues (Thr58 and Tyr35). Additional molecular docking and molecular dynamics simulations confirmed the decreased binding affinity of DEFB1 to bacterial PIP2 due to these mutations. Overall, this computational study analyzing nsSNPs in DEFB1 provides more understanding of how these missense mutations could impair or change protein functions by altering the PIP2 binding site.

The Role of Clusterin Transporter in the Pathogenesis of Alzheimer's Disease at the Blood-Brain Barrier Interface: A Systematic Review.

Alzheimer's disease (AD) is considered a chronic and debilitating neurological illness that is increasingly impacting older-age populations. Some proteins, including clusterin (CLU or apolipoprotein J) transporter, can be linked to AD, causing oxidative stress. Therefore, its activity can affect various functions involving complement system inactivation, lipid transport, chaperone activity, neuronal transmission, and cellular survival pathways. This transporter is known to bind to the amyloid beta (Aß) peptide, which is the major pathogenic factor of AD. On the other hand, this transporter is also active at the blood-brain barrier (BBB), a barrier that prevents harmful substances from entering and exiting the brain. Therefore, in this review, we discuss and emphasize the role of the CLU transporter and CLU-linked molecular mechanisms at the BBB interface in the pathogenesis of AD.

In Silico Drug Screening Analysis against the Overexpression of PGAM1 Gene in Different Cancer Treatments.

Phosphoglycerate mutase 1 (PGAM1) is considered as a novel target for multiple types of cancer drugs for the upregulation in tumor, cell prefoliation, and cell migration. During aerobic glycolysis, PGAM1 plays a critical role in cancer cell metabolism by catalyzing the conversion of 3-phosphoglycerate (3PG) to 2-phosphoglycerate (2PG). In this computational-based study, the molecular docking approach was used with the best binding active sites of PGAM1 to screen 5,000 Chinese medicinal phytochemical library. The docking results were three ligands with docking score, RMSD-refine, and residues. Docking scores were -16.57, -15.22, and -15.74. RMSD values were 0.87, 2.40, and 0.98, and binding site residues were Arg 191, Arg 191, Arg 116, Arg 90, Arg 10, and Tyr 92. The best compounds were subjected to ADMETsar, ProTox-2 server, and Molinspiration analysis to evaluate the toxicological and drug likeliness potential of such selected compounds. The UCSF-Chimera tool was used to visualize the results, which shows that the three medicinal compounds named N-Nitrosohexamethyleneimine, Subtrifloralactone-K, and Kanzonol-N in chain-A were successfully binding with the active pockets of PGAM1. The study might facilitate identifying the hit molecules that could be beneficial in the development of antidrugs against various types of cancer treatment. These hit phytochemicals could be beneficial for further investigation of a novel target for cancer.

Reverse vaccinology assisted designing of multiepitope-based subunit vaccine against SARS-CoV-2.

BACKGROUND: Coronavirus disease 2019 (COVID-19) linked with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cause severe illness and life-threatening pneumonia in humans. The current COVID-19 pandemic demands an effective vaccine to acquire protection against the infection. Therefore, the present study was aimed to design a multiepitope-based subunit vaccine (MESV) against COVID-19. METHODS: Structural proteins (Surface glycoprotein, Envelope protein, and Membrane glycoprotein) of SARS-CoV-2 are responsible for its prime functions. Sequences of proteins were downloaded from GenBank and several immunoinformatics coupled with computational approaches were employed to forecast B- and T- cell epitopes from the SARS-CoV-2 highly antigenic structural proteins to design an effective MESV. RESULTS: Predicted epitopes suggested high antigenicity, conserveness, substantial interactions with the human leukocyte antigen (HLA) binding alleles, and collective global population coverage of 88.40%. Taken together, 276 amino acids long MESV was designed by connecting 3 cytotoxic T lymphocytes (CTL), 6 helper T lymphocyte (HTL) and 4 B-cell epitopes with suitable adjuvant and linkers. The MESV construct was non-allergenic, stable, and highly antigenic. Molecular docking showed a stable and high binding affinity of MESV with human pathogenic toll-like receptors-3 (TLR3). Furthermore, in silico immune simulation revealed significant immunogenic response of MESV. Finally, MEV codons were optimized for its in silico cloning into the Escherichia coli K-12 system, to ensure its increased expression. CONCLUSION: The MESV developed in this study is capable of generating immune response against COVID-19. Therefore, if designed MESV further investigated experimentally, it would be an effective vaccine candidate against SARS-CoV-2 to control and prevent COVID-19.