Extent of Virulence and Antibiotic Resistance Genes in Helicobacter pylori and Campylobacteria.

Helicobacter pylori, a member of the clade campylobacteria, is the leading cause of chronic gastritis and gastric cancer. Virulence and antibiotic resistance of H. pylori are of great concern to public health. However, the relationship between virulence and antibiotic resistance genes in H. pylori in relation to other campylobacteria remains unclear. Using the virulence and comprehensive antibiotic resistance databases, we explored all available 354 complete genomes of H. pylori and compared it with 90 species of campylobacteria for virulence and antibiotic resistance genes/proteins. On average, H. pylori had 129 virulence genes, highest among Helicobacter spp. and 71 antibiotic resistance genes, one of the lowest among campylobacteria. Just 2.6% of virulence genes were shared by all campylobacterial members, whereas 9.4% were unique to H. pylori. The cytotoxin-associated genes (cags) seemed to be exclusive to H. pylori. Majority of the isolates from Asia and South America were cag2-negative and many antibiotic resistance genes showed isolate-specific patterns of occurrence. Just 15 (8.8%) antibiotic resistance genes, but 103 (66%) virulence genes including 25 cags were proteomically identified in H. pylori. Arcobacterial members showed large variation in the number of antibiotic resistance genes and there was a positive relation with the genome size. Large repository of antibiotic resistance genes in campylobacteria and a unique set of virulence genes might have important implications in shaping the course of virulence and antibiotic resistance in H. pylori.

Prevalence and heterogeneity of antibiotic resistance genes in Orientia tsutsugamushi and other rickettsial genomes.

Despite a million infections every year and an estimated one billion people at risk, scrub typhus is regarded as a neglected tropical disease. The causative bacterium Orientia tsutsugamushi, a member of rickettsiae, seems to be intrinsically resistant to several classes of antibiotics. The emergence of antibiotic-resistant scrub typhus is likely to become a global public health concern. Yet, it is unknown as to how common antibiotic resistance genes are in O. tsutsugamushi, and how variable these loci are among the genomes of rickettsiae. By using the comprehensive antibiotic resistance database, we explored 79 complete genomes from 24 species of rickettsiae for antibiotic resistance loci. There were 244 unique antibiotic resistance genes in rickettsiae. Both the total and unique antibiotic resistance genes in O. tsutsugamushi were significantly less compared to other members of rickettsiae. However, antibiotic resistance genes in O. tsutsugamushi genomes were more unique and highly variable. Many genes such as resistant variants of evgS, and vanS A/G were present in numerous copies. These results will have important implications in the context of antibiotic-resistant scrub typhus.

Molecular detection of monkeypox and related viruses: challenges and opportunities.

The recent widespread emergence of monkeypox (mpox), a rare and endemic zoonotic disease by monkeypox virus (MPXV), has made global headlines. While transmissibility (R0 ≈ 0.58) and fatality rate (0-3%) are low, as it causes prolonged morbidity, the World Health Organization has declared monkeypox as a public health emergency of international concern. Thus, effective containment and disease management require quick and efficient detection of MPXV. In this bioinformatic overview, we summarize the numerous molecular tests available for MPXV, and discuss the diversity of genes and primers used in the polymerase chain reaction-based detection. Over 90 primer/probe sets are used for the detection of poxviruses. While hemagglutinin and A-type inclusion protein are the most common target genes, tumor necrosis factor receptor and complement binding protein genes are frequently used for distinguishing Clade I and Clade II of MPXV. Problems and possibilities in the detection of MPXV have been discussed.

FBXL20 promotes breast cancer malignancy by inhibiting apoptosis through degradation of PUMA and BAX.

Apoptosis is a programmed cell death that efficiently removes damaged cells to maintain tissue homeostasis. Defect in apoptotic machinery can lead to tumor development, progression, and resistance to chemotherapy. PUMA (p53 upregulated modulator of apoptosis) and BAX (BCL2-associated X protein) are among the most well-known inducers of apoptosis. It has been reported that expression levels of BAX and PUMA are controlled at the posttranslational level by phosphorylation. However, the posttranslational regulation of these proapoptotic proteins remains largely unexplored. In this study, using biochemical, molecular biology, flow cytometric, and immunohistochemistry techniques, we show that PUMA and BAX are the direct target of the F-box protein FBXL20, which restricts their cellular levels. FBXL20 directs the proteasomal degradation of PUMA and BAX in a protein kinase AKT1-dependent manner to promote cancer cell proliferation and tumor growth. Interestingly, inactivation of AKT1 results in activation of another protein kinase GSK3α/ß, which facilitates the proteasomal degradation of FBXL20 by another F-box protein, FBXO31. Thus, a switch between two signaling kinases AKT1 and GSK3α/ß modulates the functional activity of these proapoptotic regulators, thereby determining cell survival or death. RNAi-mediated ablation of FBXL20 results in increased levels of PUMA as well as BAX, which further enhances the sensitivity of cancer cells to chemotherapeutic drugs. We showed that high level expression of FBXL20 in cancer cells reduces therapeutic drug-induced apoptosis and promotes chemoresistance. Overall, this study highlights the importance of targeting FBXL20 in cancers in conjunction with chemotherapy and may represent a promising anticancer strategy to overcome chemoresistance.

Feedback-regulated transcriptional repression of FBXO31 by c-Myc triggers ovarian cancer tumorigenesis.

FBXO31, a member of F-box protein family, has been shown to play an important role in preventing tumorigenesis by preserving genomic stability during cell proliferation as well as upon genotoxic stress. Inactivation of FBXO31 due to loss of heterozygosity is associated with various cancers, including ovarian cancer, one of the deadliest forms of gynecological cancers. However, the role and regulation of FBXO31 in ovarian cancer remained elusive. Here, using biochemical and molecular biology techniques, we show that c-Myc suppresses the mRNA levels of FBXO31 in ovarian cancer. Chromatin immunoprecipitation experiment showed that c-Myc is recruited to the promoter region of FBXO31 and prevents FBXO31 mRNA synthesis. In contrast, FBXO31 maintains the c-Myc expression at an optimum through proteasome pathway. FBXO31 interacts with and facilitates the polyubiquitination of c-Myc through the SCF complex and thereby inhibits ovarian cancer growth both in vitro and in vivo. Moreover, FBXO31-mediated proteasomal degradation of c-Myc is unique. Unlike other negative regulators, FBXO31 recognizes c-Myc in phosphorylation independent manner to direct its degradation. Further, expression levels analysis revealed that c-Myc and FBXO31 share a converse correlation of expression in ovarian cancer cell lines and patient samples. We observed an increase in the expression levels of c-Myc with a concomitant decrease in the levels of FBXO31 in higher grades of ovarian cancer patient samples. In conclusion, our study demonstrated that oncogene c-Myc impairs the tumor-suppressive functions of FBXO31 to promote ovarian cancer progression, and therefore c-Myc-FBXO31 axis can be explored to develop better cancer therapy.

Functional analysis of Escherichia coli K12 toxin-antitoxin systems as novel drug targets using a network biology approach.

Bacterial resistance to various drugs and antibiotics has become a significant issue in the fight against infectious diseases. Due to the presence of diverse toxin-antitoxin (TA) systems, bacteria undergo adaptive metabolic alterations and can tolerate the effects of drugs and antibiotics. Bacterial TA systems are unique and can be therapeutic targets for developing new antimicrobial agents, owing to their ability to influence bacterial fate. With this background, our study aims to identify novel drug targets against Escherichia coli K12 MG1655 antitoxin using homology modelling approach. In this study, the protein-protein interaction network of 87 E. coli K12 MG1655 TA systems identified through literature mining was screened for the identification of hub proteins. The model evaluation, assessment, and homology modelling of the hub proteins were evaluated. Furthermore, computer-aided mathematical models of selected phytochemicals have been tested against the identified hub proteins. The TA system was functionally enriched in regulation of cell growth, negative regulation of cell growth, regulation of mRNA stability, mRNA catabolic process and RNA phosphodiester bond hydrolysis. RelE, RelB, MazE, MazF, MqsR, MqsA, and YoeB were identified as hub proteins. The robustness and superior quality of the RelB and MazE modelled structure were discovered by model evaluation, quality assessment criteria, and homology modelling of hub proteins. Clorobiocin was found to be a strong inhibitor by docking these modelled structures. Clorobiocin could be utilized as an antibacterial agent against multidrug resistant E. coli which may inactivate antitoxins and cause programmed cell death.

2,5-Bis(2,2,2-trifluoroethoxy)phenyl-tethered 1,3,4-Oxadiazoles Derivatives: Synthesis, In Silico Studies, and Biological Assessment as Potential Candidates for Anti-Cancer and Anti-Diabetic Agent.

In the present work, a series of new 1-{5-[2,5-bis(2,2,2-trifluoroethoxy)phenyl]-1,3,4-oxadiazol-3-acetyl-2-aryl-2H/methyl derivatives were synthesized through a multistep reaction sequence. The compounds were synthesized by the condensation of various aldehydes and acetophenones with the laboratory-synthesized acid hydrazide, which afforded the Schiff's bases. Cyclization of the Schiff bases yielded 1,3,4-oxadiazole derivatives. By spectral analysis, the structures of the newly synthesized compounds were elucidated, and further, their anti-cancer and anti-diabetic properties were investigated. To examine the dynamic behavior of the candidates at the binding site of the protein, molecular docking experiments on the synthesized compounds were performed, followed by a molecular dynamic simulation. ADMET (chemical absorption, distribution, metabolism, excretion, and toxicity) prediction revealed that most of the synthesized compounds follow Lipinski's rule of 5. The results were further correlated with biological studies. Using a cytotoxic assay, the newly synthesized 1,3,4-Oxadiazoles were screened for their in vitro cytotoxic efficacy against the LN229 Glioblastoma cell line. From the cytotoxic assay, the compounds 5b, 5d, and 5m were taken for colony formation assay and tunnel assay have shown significant cell apoptosis by damaging the DNA of cancer cells. The in vivo studies using a genetically modified diabetic model, Drosophila melanogaster, indicated that compounds 5d and 5f have better anti-diabetic activity among the different synthesized compounds. These compounds lowered the glucose levels significantly in the tested model.

Placental Expression and Relative Role of Anti-inflammatory Annexin A1 and Animal Lectin Galectin-3 in the Pathogenesis of Preeclampsia.

Preeclampsia (PE) remains the major cause for maternal and foetal mortality and morbidity all over the world. Preeclampsia is associated with maternal, placental aggravated inflammatory response and generalized endothelial damage. AnnexinA1 (AnxA1) is glucocorticoid regulated protein regulates a wide range of cellular and molecular steps of the inflammatory response and is implicated in resolution of inflammation. Galectin-3 (Gal-3), ß-galcotoside-binding lectin participates in many functions, both intra- and extracellularly. Recently it has been shown that galectin-3 modulates the inflammation. Role of AnxA1 and Galectin-3 is poorly studied in context with human reproductive disease like Preeclampsia. Therefore, the present study examined the expression of AnxA1 and Gal-3 which are involved in modulation of inflammation and their association in the placental bed of pregnancy with and without PE. The study group consisted of placental bed biopsy tissues obtained from pregnancies with PE (n = 30) and without (n = 30) PE. The expression of AnxA1 and Gal-3 in the placental bed tissues was evaluated quantitatively using Immunohisto-chemistry (IHC), western blot and mRNA expression analysis by quantitative RT-PCR. Our IHC, western blot and RT PCR analyses showed the increase in the expression of AnxA1 and Gal-3 in PE group compared with the normotensive control group (P < 0.001). The increased expression of AnxA1 and Gal-3 in placental bed may be associated with a systemic inflammatory response in PE, suggesting role of AnxA1 and Gal-3 in PE pathogenesis.

Network topology analysis of essential genes interactome of Helicobacter pylori to explore novel therapeutic targets.

The Helicobacter pylori chronic colonization produces a wide range of gastric diseases in the gastric mucosa by abetting inflammation. Amidst coevolution and reorganization of its metabolism with humans, it has become difficult still imperative to understand and prevent its growth. This study focus to explore functional insights into identification of hub proteins/genes by aggregating the behavior of genes connected in a protein-protein interaction (PPI) network. We have constructed a PPI network of 123 essential genes along with 1213 interactions in H. pylori 26695. The degree and other centrality measures analysis assist in identifying the important hub nodes, which are top-ranked proteins. A total of nine proteins (recA, guaA, dnaK, rpsB, rplQ, rpmA, rpmC, rpmF, and rpsE) were obtained with high degree (k), betweenness centrality (BC) value. Gene ontology analysis reveals 8, 5 and 3 GO terms correspond to biological processes, cellular components and molecular function respectively. Gene complexes of hypothetical proteins (HPs) were related to aminoacyl-tRNA biosynthesis, biosynthesis of secondary metabolites, bacterial secretion system and protein export. The MCODE analysis revealed that protein from module M1, M3 and M6 include the proteins which have highest degree and BC values. It is noteworthy to mention that the bifunctional GMP synthase/glutamine amidotransferase protein (guaA), molecular chaperon (dnaK), recombinase A (recA) constitute as hub proteins. As a result, these genes are considered as network hub nodes that might be used as therapeutic targets. Our analysis affords a detailed understanding of the molecular process and pathways regulated by the essential genes in H. pylori 26695.

Genome-scale protein interaction network construction and topology analysis of functional hypothetical proteins in Helicobacter pylori divulges novel therapeutic targets.

The emergence and spread of multi-drug resistance among Helicobacter pylori (H. pylori) strain raise more stakes for genetic research for discovering new drugs. The quantity of uncharacterized hypothetical proteins in the genome may provide an opportunity to explore their property and promulgation could act as a platform for designing the drugs, making them an intriguing genetic target. In this context, the present study aims to identify the key hypothetical proteins (HPs) and their biological regulatory processes in H. pylori. This investigation could provide a foundation to establish the molecular connectivity among the pathways using topological analysis of the protein interaction networks (PINs). The giant network derived from the extended network has 374 nodes connected via 925 edges. A total of 43 proteins with high betweenness centrality (BC), 54 proteins with a large degree, and 23 proteins with high BC and large degrees have been identified. HP 1479, HP 0056, HP 1481, HP 1021, HP 0043, HP 1019, gmd, flgA, HP 0472, HP 1486, HP 1478, and HP 1473 are categorized as hub nodes because they have a higher number of direct connections and are potentially more important in understanding HP's molecular interactions. The pathway enrichment analysis of the network clusters revealed significant involvement of HPs in pathways such as flagellar assembly, bacterial chemotaxis and lipopolysaccharide biosynthesis. This comprehensive computational study revealed HP's functional role and its druggability characteristics, which could be useful in the development of drugs to combat H. pylori infections.

Molecular Insights on the Possible Role of Annexin A2 in COVID-19 Pathogenesis and Post-Infection Complications.

Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) has infected >235 million people and killed over 4.8 million individuals worldwide. Although vaccines have been developed for prophylactic management, there are no clinically proven antivirals to treat the viral infection. Continuous efforts are being made all over the world to develop effective drugs but these are being delayed by periodic outbreak of mutated SARS-CoV-2 and a lack of knowledge of molecular mechanisms underlying viral pathogenesis and post-infection complications. In this regard, the involvement of Annexin A2 (AnxA2), a lipid-raft related phospholipid-binding protein, in SARS-CoV-2 attachment, internalization, and replication has been discussed. In addition to the evidence from published literature, we have performed in silico docking of viral spike glycoprotein and RNA-dependent RNA polymerase with human AnxA2 to find the molecular interactions. Overall, this review provides the molecular insights into a potential role of AnxA2 in the SARS-CoV-2 pathogenesis and post-infection complications, especially thrombosis, cytokine storm, and insulin resistance.

Reciprocal regulation of pro-inflammatory Annexin A2 and anti-inflammatory Annexin A1 in the pathogenesis of rheumatoid arthritis.

Annexin A2 has been implicated in several immune modulated diseases including Rheumatoid arthritis (RA) pannus formation. The most relied treatment option for RA pathogenesis is glucocorticoids. Glucocorticoids regulate the synthesis, phosphorylation and cellular deposition of Annexin A1. This annexin mediates the anti-inflammatory actions of glucocorticoids. These two first characterized members of annexin superfamily proteins acts reciprocally, one as an anti-inflammatory and the other proinflammatory in nature. The possibility of these molecules as soluble biomarkers and as an upstream regulator of major cytokine devastation at RA microenvironment has not been previously explored. Current study elucidates the reciprocal regulation of these two annexins in RA pathogenesis. These Annexin A2/A1 and downstream cytokines in RA serum were analysed by ELISA. Western blot, Immunocytochemistry, immunoprecipitation and Immunohistochemistry were adapted to analyse these molecules in tissue and synovial fibroblasts and also in different experimental conditions. Significant increase in the level of Annexin A2 was noticed in naïve RA patients compared to controls (14.582 ± 1.766 ng/ml vs. 7.37 ± 1.450 ng/ml; p ≤ 0.001). In remission cases significant low levels was detected. On the contrary, significant decrease in the level of Annexin A1 was noticed in naïve RA patients compared to healthy controls (12.322 ± 2.91 vs. 16.998 ± 4.298 ng/ml; p ≤ 0.001), wherein remission cases serum Annexin A1 was significantly high. The knockdown of proinflammatory Annexin A2 by siRNA/antibody treatment could mimic the glucocorticoid treatment as which induced cellular Annexin A1 and membrane translocation resulting in the terminal action. Current data elucidating the regulatory interplay between Annexin A2 and Annexin A1 in RA pathogenesis.

Cell surface interaction of annexin A2 and galectin-3 modulates epidermal growth factor receptor signaling in Her-2 negative breast cancer cells.

Overexpression and activation of tyrosine kinase receptors like EGFR and Src regulate the progression and metastasis of Her-2 negative breast cancer. Recently we have reported the role of cell membrane interaction of phospholipid-binding protein annexin A2 (AnxA2) and EGFR in regulating cellular signaling in the activation of angiogenesis, matrix degradation, invasion, and cancer metastasis. Beta-galactoside-specific animal lectin galectin-3 is an apoptosis inhibitor, and cell surface-associated extracellular galectin-3 also has a role in cell migration, cancer progression, and metastasis. Similar expression pattern and membrane co-localization of these two proteins made us to hypothesize in the current study that galectin-3 and AnxA2 interaction is critical for Her-2 negative breast cancer progression. By various experimental analyses, we confirm that glycosylated AnxA2 at the membrane surface interacts with galectin-3. N-linked glycosylation inhibitor tunicamycin treatment convincingly blocked AnxA2 membrane translocation and its association with galectin-3. To analyze whether this interaction has any functional relevance, we tried to dissociate this interaction with purified plant lectin from chickpea (Cicer arietinum agglutinin). This highly specific 30 kDa plant lectin could dissociate AnxA2 from endogenous lectin galectin-3 interaction at the cell surface. This dissociation could down-regulate Bcl-2 family proteins, cell proliferation, and migration simultaneously triggering cell apoptosis. Targeting this interaction of membrane surface glycoprotein and its animal lectin in Her-2 negative breast cancer may be of therapeutic value.

MIEN1, a novel interactor of Annexin A2, promotes tumor cell migration by enhancing AnxA2 cell surface expression.

BACKGROUND: Migration and invasion enhancer 1 (MIEN1) is a novel gene found to be abundantly expressed in breast tumor tissues and functions as a critical regulator of tumor cell migration and invasion to promote systemic metastases. Previous studies have identified post-translational modifications by isoprenylation at the C-terminal tail of MIEN1 to favor its translocation to the inner leaflet of plasma membrane and its function as a membrane-bound adapter molecule. However, the exact molecular events at the membrane interface activating the MIEN1-driven tumor cell motility are vaguely understood. METHODS: MIEN1 was first studied using in-silico analysis on available RNA sequencing data of human breast tissues and its expression was ascertained in breast cells. We performed several assays including co-immunoprecipitation, wound healing, western blotting and immunofluorescence to decipher the molecular events involved in MIEN1-mediated tumor cell migration. RESULTS: Clinically, MIEN1 is predominantly overexpressed in Her-2 and luminal B subtypes of breast tumors, and its increased expression correlates with poor disease free survival. Molecular studies identified a phosphorylation-dependent activation signal in the immunoreceptor tyrosine based activation motif (ITAM) of MIEN1 and the phosphorylation-deficient MIEN1-mutants (Y39F/50 F) to regulate filopodia generation, migration and invasion. We found that ITAM-phosphorylation of MIEN1 is significantly impaired in isoprenylation-deficient MIEN1 mutants indicating that prenylation of MIEN1 and membrane association is required for cross-phosphorylation of tyrosine residues. Furthermore, we identified MIEN1 as a novel interactor of Annexin A2 (AnxA2), a Ca(2+) -dependent phospholipid binding protein, which serves as an extracellular proteolytic center regulating plasmin generation. Fluorescence resonance energy transfer (FRET) confirmed that MIEN1 physically interacts with AnxA2 and functional studies revealed that they mutually cooperate to accentuate tumor cell motility. Interestingly, our study identified that ectopic overexpression of MIEN1 significantly enhances Tyr23-phosphorylation on AnxA2, thereby stimulating cell surface translocation of AnxA2 and catalyzing the activation of its proteolytic activity. CONCLUSION: Our data show that the presence and interaction of both MIEN1 and AnxA2 in breast tumors are crucial drivers of cell motility. Our study has now deciphered a novel regulatory network governing the vicious process of breast tumor cell invasion-metastasis, and findings suggest MIEN1-AnxA2 as prospective targets to counter the deadly disease.

Integrated molecular-network analysis reveals infertility-associated key genes and transcription factors in the non-obstructive azoospermia.

BACKGROUND: Male infertility is a multifactorial reproductive health problem with complex causes. Non-obstructive azoospermia (NOA) is characterized by failure of spermatogenesis, leading to the absence of spermatozoa in ejaculates. The molecular mechanism underlying the NOA is still not well understood. OBJECTIVES: This study aims to identify the key genes involved in male infertility that could be a potential biomarker in the diagnosis and prognosis of azoospermia. STUDY DESIGN: The microarray expression profiles dataset GSE45885 and GSE45887 were downloaded from the NCBI's Gene Expression Omnibus (GEO) database and analyzed for male infertility-associated differentially expressed genes (DEGs) using the GEO2R tool. The common DEGs between the two datasets were combined and their protein-protein interaction (PPI) network was constructed using Cytoscape to reveal the hub genes by topology and module analysis. In addition, transcription factors (TFs) and protein kinases regulating the hub genes were identified using the X2K tool. Then, the expression of the hub genes was validated by analyzing the GSE190752 microarray dataset. Further, the PPI network was screened for biological roles and enriched pathways using DAVID software. RESULTS: About 256 DEGs associated with NOA were identified and constructed the PPI network to find the infertility-associated proteins. The biological processes linked with these proteins were spermatogenesis, cell differentiation, flagellated sperm motility, and spermatid development. The topology and module analysis of the infertility-associated protein network identified the hub genes TEX38, FAM71F, PRR30, FAM166A, LYZL6, TPPP2, ARMC12, SPACA4, and FAM205A, which were found to be upregulated in the non-obstructive azoospermia. In addition, a total of 23 transcription factors and 3 protein kinases that are regulating these key hub genes were identified. Further these hub genes expression was validated using the microarray data and found that their expression was increased in the testicular biopsies obtained from NOA subjects, compared to healthy individuals. CONCLUSION: The identified key genes and its associated transcription factors are known to regulate the infertility-related processes in the non-obstructive azoospermia. Also, the clinical sample-based microarray data validation for the expression of these key hub genes indicates their potentiality to develop them as diagnostic or prognostic biomarkers for NOA.

Tissue plasminogen activator receptor ANXA2 and its complementary regulator anti-inflammatory ANXA1 as prognostic indicators of inflammatory response in COVID-19 pathogenesis.

COVID-19 patients demonstrating hyperactive immunologic response appear to have a severe illness with a poor prognosis. This study hypothesizes that the pro-inflammatory Annexin A2 (ANXA2) has role in COVID-19 pathogenesis. In thisobservational study, serum levels of ANXA2 along with interleukin 1 beta (IL1ß), IL6, tumour necrosis factor-alpha (TNFα), and anti-inflammatory ANXA1 were determined by sandwich ELISA in 20 each control, mild, moderate, and severe COVID-19 subjects.The ANXA2 levels (130 ng/mL, p < 0.001) were significantly elevated in severe COVID-19 subjects, compared to mild, moderate and controls. Similarly, all the other pro-inflammatory biomarkers levels were also significantly correlated with disease severity (p < 0.0001). However, ANXA1 showed significantly negative correlation with disease severity (p < 0.0001). Furthermore, the pro-inflammatory ANXA2 showed utility in mortality prediction with 86% sensitivity and specificity, and 57% positive predictive value at a serum threshold of 94 ng/mL. Overall,ANXA2 and ANXA1 along with IL1ß, IL6, TNFα, would be beneficial biomarkers in assessing the COVID-19 severity and mortality prediction.

Efficacy of HDAC inhibitors and epigenetic modulation in the amelioration of synovial inflammation, cellular invasion, and bone erosion in rheumatoid arthritis pathogenesis.

Rheumatoid arthritis (RA), an auto-immune disorder affected 1 % of the population around the globe. The pathophysiology of RA is highly concerted process including synovial hyperplasia, pannus formation, bone erosion, synovial cell infiltration in joints, and cartilage destruction. However, recent reports suggest that epigenetics play a pivotal role in the formation and organization of immune response in RA. Particularly, altered DNA methylation and impaired microRNA (miRNA) were detected in several immune cells of RA patients, such as T regulatory cells, fibroblast-like synoviocytes, and blood mononuclear cells. All these processes can be reversed by regulating the ubiquitous or tissue-based expression of histone deacetylases (HDACs) to counteract and terminate them. Hence, HDAC inhibitors (HDACi) could serve as highly potent anti-inflammatory regulators in the uniform amelioration of inflammation. Therefore, this review encompasses the information mainly focussing on the epigenetic modulation in RA pathogenesis and the efficacy of HDACi as an alternative therapeutic option for RA treatment. Overall, these studies have reported the targeting of HDAC1, 2 & 6 molecules would attenuate synoviocyte inflammation, cellular invasion, and bone erosion. Further, the inhibitors such as trichostatin A, suberoyl bis-hydroxamic acid, suberoyl anilide hydroxamic acid, and other compounds are found to attenuate synovial inflammatory immune response, clinical arthritis score, paw swelling, bone erosion, and cartilage destruction. Insight to view this, more clinical studies are required to determine the efficacy of HDACi in RA treatment and to unravel the underlying molecular mechanisms.

Implicative role of epidermal growth factor receptor and its associated signaling partners in the pathogenesis of Alzheimer's disease.

Epidermal growth factor receptor (EGFR) plays a pivotal role in early brain development, although its expression pattern declines in accordance with the maturation of the active nervous system. However, recurrence of EGFR expression in brain cells takes place during neural functioning decline and brain atrophy in order to maintain the homeostatic neuronal pool. As a consequence, neurotoxic lesions such as amyloid beta fragment (Aß1-42) formed during the alternative splicing of amyloid precursor protein in Alzheimer's disease (AD) elevate the expression of EGFR. This inappropriate peptide deposition on EGFR results in the sustained phosphorylation of the downstream signaling axis, leading to extensive Aß1-42 production and tau phosphorylation as subsequent pathogenesis. Recent reports convey that the pathophysiology of AD is correlated with EGFR and its associated membrane receptor complex molecules. One such family of molecules is the annexin superfamily, which has synergistic relationships with EGFR and is known for membrane-bound signaling that contributes to a variety of inflammatory responses. Besides, Galectin-3, tissue-type activated plasminogen activator, and many more, which lineate the secretion of pro-inflammatory cytokines (TNF-α, IL-1ß, IL-6, and IL-18) result in severe neuronal loss. Altogether, we emphasized the perspectives of cellular senescence up-regulated by EGFR and its associated membrane receptor molecules in the pathogenesis of AD as a target for a therapeutical alternative to intervene in AD.

Systems Pharmacology and Pharmacokinetics Strategy to Decode Bioactive Ingredients and Molecular Mechanisms from Zingiber officinale as Phyto-therapeutics against Neurological Diseases.

BACKGROUND: The bioactive constituents from Zingiber officinale (Z. officinale) have shown a positive effect on neurodegenerative diseases like Alzheimer's disease (AD), which manifests as progressive memory loss and cognitive impairment. OBJECTIVE: This study investigates the binding ability and the pharmaco-therapeutic potential of Z. officinale with AD disease targets by molecular docking and molecular dynamic (MD) simulation approaches. METHODS: By coupling enormous available phytochemical data and advanced computational technologies, the possible molecular mechanism of action of these bioactive compounds was deciphered by evaluating phytochemicals, target fishing, and network biological analysis. RESULTS: As a result, 175 bioactive compounds and 264 human target proteins were identified. The gene ontology and Kyoto Encyclopaedia of Genes and Genomes pathway enrichment analysis and molecular docking were used to predict the basis of vital bioactive compounds and biomolecular mechanisms involved in the treatment of AD. Amongst selected bioactive compounds, 10- Gingerdione and 1-dehydro-[8]-gingerdione exhibited significant anti-neurological properties against AD targeting amyloid precursor protein with docking energy of -6.0 and -5.6, respectively. CONCLUSION: This study suggests that 10-Gingerdione and 1-dehydro-[8]-gingerdione strongly modulates the anti-neurological activity and are associated with pathological features like amyloid-ß plaques and hyperphosphorylated tau protein are found to be critically regulated by these two target proteins. This comprehensive analysis provides a clue for further investigation of these natural compounds' inhibitory activity in drug discovery for AD treatment.