Role of auto-antibodies in the mechanisms of dengue pathogenesis and its progression: a comprehensive review.

A complex interaction among virulence factors, host-genes and host immune system is considered to be responsible for dengue virus (DENV) infection and disease progression. Generation of auto-antibodies during DENV infection is a major phenomenon that plays a role in the pathophysiology of dengue hemorrhagic fever and dengue shock syndrome. Hemostasis, thrombocytopenia, hepatic endothelial dysfunction, and autoimmune blistering skin disease (pemphigus) are different clinical manifestations of dengue pathogenesis; produced due to the molecular mimicry of DENV proteins with self-antigens like coagulation factors, platelets and endothelial cell proteins. This review elaborately describes the current advancements in auto-antibody-mediated immunopathogenesis which inhibits coagulation cascade and promotes hyperfibrinolysis. Auto-antibodies like anti-endothelial cell antibodies-mediated hepatic inflammation during severe DENV infection have also been discussed. Overall, this comprehensive review provides insight to target auto-antibodies that may act as potential biomarkers for disease severity, and a ground for the development of therapeutic strategy against DENV.

Ultradiluted SARS-CoV-2 Spike Protein mitigates hyperinflammation in lung via ferritin and MMP-9 regulation in BALB/c mice.

AIM: This study investigated the prophylactic and therapeutic role of ultradiluted preparation of the Delta variant of SARS-CoV-2 recombinant spike (S) protein during S antigen-induced inflammatory process of disease progression along with the probable mechanism of action. MAIN METHODS: Ultradiluted S protein (UDSP) was prepared and administered orally to adult BALB/c mice before and after administration of S antigen intranasally. After an observation period of 72 h, animals were sacrificed and expression level of ferritin was assayed through ELISA. The genetic expressions of cytokines, IL-6, IL-10, IL-1ß, TNFα, IL-17, MMP-9, TIMP-1, ferritin light and heavy chains, and mitochondrial ferritin from lung tissues were investigated through RT-PCR. Formalin-fixed lung tissue sections were stained with hematoxylin and eosin to observe the degree of pathological changes. The activity of MMP-9 in lung tissues was investigated through gelatin zymography and immunofluorescence of MMP-9 in lung tissue sections was performed to revalidate the finding from gelatin zymography. Systems biology approach was used to elucidate a probable pathway where UDSP attenuated the inflammation through the regulation of pro- and anti-inflammatory cytokines. KEY FINDINGS: UDSP attenuated the S antigen-induced hyperinflammation in the lung by regulating pro- and anti-inflammatory cytokines, calming cytokine storm, reducing ferritin level both in transcriptional and translational levels, and restoring critical ratio of MMP-9: TIMP-1. SIGNIFICANCE: Our findings suggest a probable pathway by which UDSP might have attenuated inflammation through the regulation of cytokines, receptors, and other molecules. This proclaims UDSP as a promising antiviral agent in the treatment of COVID-19-induced immunopathogenesis.

3D structure prediction of VAPC1 and identification of dual natural inhibitors for VPAC1 and EGFR.

Vasoactive intestinal polypeptide receptor 1 (VPAC1) and epidermal growth factor receptor (EGFR) are associated with signal transduction pathways relevant to neuroblastoma, cancer of breast, prostate and lungs. In order to identify appropriate ligand analogues for simultaneous inhibition of EGFR and VPAC1, in-silico homology modelling of VPAC1 and its characterization by molecular interaction studies have been undertaken. Homology modelling was performed with the Swiss Model and validation of the predicted 3D structure was carried out using PROCHECK and RAMPAGE. Ramachandran's plot of the predicted structure from this two software revealed that 92% and 94% of the residues were in the most favoured region, respectively. Compounds screened from Naturally Occurring Plant-based Anti-Cancerous Compound-Activity-Target (NPACT) database having strong interactions with EGFR were further checked for ADMET properties. Molecular interaction studies revealed four compounds namely Fisetin, Genistein, Tectorigenin, and Tephrosin docked with VPAC1 having respective binding energies of -7.1, -6.98, -6.9 and - 6.61 kcal/mol. Fisetin and Genistein with a rotatable bond and lower molecular weight increased their drug-likeness than the others. Therefore, simultaneous inhibition of VPAC1 and EGFR, in turn, might inhibit the progression of breast carcinoma. The results obtained were further substantiated by comparing them with positive and negative controls. Quercetin was used as positive control, and strong binding energy of -7.54 kcal/mol with EGFR is in accordance with experimental evidence. 3-O-cis-p coumaroyl alphitolic acid was used as negative control, where docking was not possible in absence of binding with either EGFR or VIPR1.