Virus-associated neuroendocrine cancers: Pathogenesis and current therapeutics.

Neuroendocrine neoplasms (NENs) comprise malignancies involving neuroendocrine cells that often lead to fatal pathological conditions. Despite escalating global incidences, NENs still have poor prognoses. Interestingly, research indicates an intricate association of tumor viruses with NENs. However, there is a dearth of comprehension of the complete scenario of NEN pathophysiology and its precise connections with the tumor viruses. Interestingly, several cutting-edge experiments became helpful for further screening of NET for the presence of polyomavirus, Human papillomavirus (HPV), Kaposi sarcoma-associated herpesvirus (KSHV), Epstein Barr virus (EBV), etc. Current research on the neuroendocrine tumor (NET) pathogenesis provides new information concerning their molecular mechanisms and therapeutic interventions. Of note, scientists observed that metastatic neuroendocrine tumors still have a poor prognosis with a palliative situation. Different oncolytic vector has already demonstrated excellent efficacies in clinical studies. Therefore, oncolytic virotherapy or virus-based immunotherapy could be an emerging and novel therapeutic intervention. In-depth understanding of all such various aspects will aid in managing, developing early detection assays, and establishing targeted therapeutic interventions for NENs concerning tumor viruses. Hence, this review takes a novel approach to discuss the dual role of tumor viruses in association with NENs' pathophysiology as well as its potential therapeutic interventions.

Expression Profile, Molecular Association, and Clinical Significance of POLD4 in Glioblastoma.

The POLD4 gene encodes a subunit (δ4) of DNA polymerase delta, which is a key enzyme involved in DNA replication and repair. Recent studies have suggested that POLD4 plays a crucial role in developing certain cancers. However, there is a lack of knowledge regarding the role of POLD4 in the context of glioblastoma (GBM). Therefore, in this study we have used various cancer bioinformatics tools to explore the role of POLD4 in glioblastoma. Data from various sources were accessed to analyze POLD4 gene expression and estimate tumor-infiltrating immune cells in glioblastoma. Methylation data were retrieved using the MEXPRESS web browser and analyzed. UALCAN webserver was used to analyze the protein expression of POLD4. Gene correlation and pathway enrichment analysis were performed using cBioPortal and GSEA software, respectively. Afterward, survival analysis was performed. POLD4 was significantly upregulated in glioblastoma at both gene and protein levels in GBM, and ROC curve analysis revealed it as a potential biomarker in glioblastoma. GSEA analysis of TCGA-GBM pan-cancer study exhibited that POLD4 expression was associated with critical pathways, such as interferon-gamma response, G2M checkpoint, inflammatory response, E2F targets, EMT transition, and KRAS signaling pathways. Furthermore, POLD4 expression was positively correlated with DNA methylation at 3 CpG sites, including Cg16509978, with a Pearson correlation coefficient value of 0.398 (p-value ≤ 0.01), while the promoter region had a positive correlation but was not significant. In addition, POLD4 is significantly linked with poor OS, PFS, and DFS. We also found association of POLD4 expression with altered immune cell infiltration. In conclusion, POLD4 is significantly upregulated in glioblastoma and may be used as a potential diagnostic or prognostic biomarker for GBM patients. However, to establish the same a large cohort study is needed. Using TCGA data and various cancer bioinformatics tools mentioned above we observed very high level of gene and protein expression of POLD4 in glioblastoma patients. The expression of POLD4 was significantly correlated with inflammatory and oncogenic pathways and it also has a significant correlation with adverse outcome in patients with glioblastoma.

Non-coding RNA in idiopathic interstitial pneumonia and Covid-19 pulmonary fibrosis.

Pulmonary fibrosis is the key feature of majority of idiopathic interstitial pneumonias (IIPs) as well as many patients with post-COVID-19. The pathogenesis of pulmonary fibrosis is a complex molecular process that involves myriad of cells, proteins, genes, and regulatory elements. The non-coding RNA mainly miRNA, circRNA, and lncRNA are among the key regulators of many protein coding genes and pathways that are involved in pulmonary fibrosis. Identification and molecular mechanisms, by which these non-coding RNA molecules work, are crucial to understand the molecular basis of the disease. Additionally, elucidation of molecular mechanism could also help in deciphering a potential diagnostic/prognostic marker as well as therapeutic targets for IIPs and post-COVID-19 pulmonary fibrosis. In this review, we have provided the latest findings and discussed the role of these regulatory elements in the pathogenesis of pulmonary fibrosis associated with Idiopathic Interstitial Pneumonia and Covid-19.

Novel Imidazole Phenoxyacetic Acids as Inhibitors of USP30 for Neuroprotection Implication via the Ubiquitin-Rho-110 Fluorometric Assay: Design, Synthesis, and In Silico and Biochemical Assays.

USP30, a deubiquitinating enzyme family, forfeits the ubiquitination of E3 ligase and Parkin on the surface of mitochondria. Inhibition of USP30 results in mitophagy and cellular clearance. Herein, by understanding structural requirements, we discovered potential USP30 inhibitors from an imidazole series of ligands via a validated ubiquitin-rhodamine-110 fluorometric assay. A novel catalytic use of the Zn(l-proline)2 complex for the synthesis of tetrasubstituted imidazoles was identified. Among all compounds investigated, 3g and 3f inhibited USP30 at IC50 of 5.12 and 8.43 µM, respectively. The binding mode of compounds at the USP30 binding site was understood by a docking study and interactions with the key amino acids were identified. Compound 3g proved its neuroprotective efficacy by inhibiting apoptosis on SH-SY5Y neuroblastoma cells against dynorphin A (10 µM) treatment. Hence, the present study provides a new protocol to design and develop ligands against USP30, thereby offering a therapeutic strategy under conditions like kidney damage and neurodegenerative disorders including Parkinson's disease.

Healthy Gut, Healthy Brain: The Gut Microbiome in Neurodegenerative Disorders.

BACKGROUND: The central nervous system (CNS) known to regulate the physiological conditions of human body, also itself gets dynamically regulated by both the physiological as well as pathological conditions of the body. These conditions get changed quite often, and often involve changes introduced into the gut microbiota which, as studies are revealing, directly modulate the CNS via a crosstalk. This cross-talk between the gut microbiota and CNS, i.e., the gut-brain axis (GBA), plays a major role in the pathogenesis of many neurodegenerative disorders such as Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS) and Huntington's disease (HD). OBJECTIVE: We aim to discuss how gut microbiota, through GBA, regulate neurodegenerative disorders such as PD, AD, ALS, MS and HD. METHODS: In this review, we have discussed the present understanding of the role played by the gut microbiota in neurodegenerative disorders and emphasized the probable therapeutic approaches being explored to treat them. RESULTS: In the first part, we introduce the GBA and its relevance, followed by the changes occurring in the GBA during neurodegenerative disorders and then further discuss its role in the pathogenesis of these diseases. Finally, we discuss its applications in possible therapeutics of these diseases and the current research improvements being made to better investigate this interaction. CONCLUSION: We concluded that alterations in the intestinal microbiota modulate various activities that could potentially lead to CNS disorders through interactions via the GBA.

Recalibrating the Existence of New Neurons in Adult Brain.

New neurons were shown to born throughout adulthood, a process known as neurogenesis. Last year, the human hippocampal neurogenesis field was flipped on its head by a paper in Nature from Sorrells et al. questioning the presence of human hippocampal neurogenesis during adulthood ( Sorrells, S.F. et al.  2018 Nature , 555 , 377 - 381 ). Now, a new study by Moreno-Jiménez et al. reported that human brain can make new neurons well beyond middle age until the tenth decade of their life, and earlier studies have failed to find the neurogenesis due to its flawed methods. This paper also finds that production of new neurons drastically drops in patients suffering from Alzheimer's disease. Here, we discuss key findings of this paper, emphasizing how improved protocols and tissue preservation lead to visualization of adult neurogenesis and further highlighting in what way this drop of neurogenesis in Alzheimer's disease brain could possibly open new roads to therapy.

Efficacy and dermal toxicity analysis of Sildenafil citrate based topical hydrogel formulation against traumatic wounds.

Sildenafil Citrate (SC) is a US FDA approved drug, have been used to treat wounds due to their nitric oxide (NO) stimulating activity in the tissue. But, there are only a few studies about the topical effect of this drug on the healing of traumatic wounds. The purpose of the study is to develop topical SC hydrogel (SCH) and to investigate its dermal toxicity and wound healing efficacy in Sprague dawley rats. In the present study, hydrogel containing SC showed no change and stable with respect to pH, homogeneity, spreadability and effiecient encapsulation. SEM analysis represents the uniform texture of the SCH. Acute dermal toxicity of the SCH exhibited that the formulations are devoid of any toxic effects and safe to be used. Percentage of wound contraction, re-epithelization, tensile strength and biochemical parameters such as hydroxyproline, collagen, total protein and NO content at dermal level prove the wound healing efficacy of prepared SCH. In addition, histopathology confirmed that the SCH promoted re-epithelization, collagen synthesis, deposition and regeneration of skin appendages. Results demonstrated that SCH has no dermal toxicity and promoted wound healing. Thus, prepared SCH shows promising skin wound healing property against traumatic wounds.