Mir Shoebulla Adil

The role of claudin-17 (Cldn17), a tight-junction protein, in vascular permeability remains unclear. We investigated the impact of Cldn17 suppression on vascular permeability. The Miles assay demonstrated significantly increased vascular permeability in the lungs and skin of Cldn17^−/− mice, as evidenced by elevated Evan’s blue dye extravasation. The Matrigel plug assay demonstrated increased hemoglobin extravasation. Histopathological analysis revealed alveolar flooding, inflammatory cell infiltration, and lung injury in Cldn17^−/− lungs. Wet/dry lung weight ratios indicated pulmonary edema, supporting the role of Cldn17 in pulmonary fluid balance, which was exacerbated with lipopolysaccharide administration. Ribosomal nucleic acid sequencing identified distinct transcriptional changes, with the principal component analysis showing clear clustering. Differential gene expression analysis highlighted significant alterations in inflammatory and metabolic pathways. Gene ontology and pathway enrichment analyses revealed the upregulation of immune-related processes, including leukocyte adhesion, interferon–gamma response, and neutrophil degranulation, alongside metabolic dysregulation affecting lipid transport and cytoskeletal organization. Reactome pathway analysis implicated Cldn17 in antigen presentation, interleukin-17 signaling, and inflammatory responses. These findings establish Cldn17 as a critical regulator of vascular permeability and immune homeostasis. Its deficiency drives vascular leakage, exacerbates lung injury, and alters immune signaling pathways, underscoring its potential as a therapeutic target for inflammatory lung diseases.

Pulmonary arterial hypertension (PAH) is a progressive disease in which pulmonary arterial (PA) endothelial cell (EC) dysfunction is associated with unrepaired DNA damage. BMPR2 is the most common genetic cause of PAH. We report that human PAEC with reduced BMPR2 have persistent DNA damage in room air after hypoxia (reoxygenation), as do mice with EC-specific deletion of Bmpr2 (EC-Bmpr2^-/-) and persistent pulmonary hypertension. Similar findings are observed in PAEC with loss of the DNA damage sensor ATM, and in mice with Atm deleted in EC (EC-Atm^-/-). Gene expression analysis of EC-Atm^-/- and EC-Bmpr2^-/- lung EC reveals reduced Foxf1, a transcription factor with selectivity for lung EC. Reducing FOXF1 in control PAEC induces DNA damage and impaired angiogenesis whereas transfection of FOXF1 in PAH PAEC repairs DNA damage and restores angiogenesis. Lung EC targeted delivery of Foxf1 to reoxygenated EC-Bmpr2^-/- mice repairs DNA damage, induces angiogenesis and reverses pulmonary hypertension.

Despite the availability of effective antifungal therapy, cryptococcal meningoencephalitis (CM) remains associated with elevated mortality. The spectrum of symptoms associated with the central nervous system (CNS) cryptococcosis is directly caused by the high fungal burden in the subarachnoid space and the peri-endothelial space of the CNS vasculature, which results in intracranial hypertension (ICH). Management of intracranial pressure (ICP) through aggressive drainage of cerebrospinal fluid by lumbar puncture is associated with increased survival. Unfortunately, these procedures are invasive and require specialized skills and supplies that are not readily available in resource-limited settings that carry the highest burden of CM. The institution of pharmacologic therapies to reduce the production or increase the resorption of cerebrospinal fluid would likely improve clinical outcomes associated with ICH in patients with CM. Here, we discuss the potential role of multiple pharmacologic drug classes such as diuretics, corticosteroids, and antiepileptic agents used to decrease ICP in various neurological conditions as potential future therapies for CM.

The multi-gene claudin (CLDN) family of tight junction proteins have isoform-specific roles in blood–tissue barrier regulation. CLDN17, a putative anion pore-forming CLDN based on its structural characterization, is assumed to regulate anion balance across the blood-tissue barriers. However, our knowledge about CLDN17 in physiology and pathology is limited. The current study investigated how Cldn17 deficiency in mice affects blood electrolytes and kidney structure. Cldn17^−/− mice revealed no breeding abnormalities, but the newborn pups exhibited delayed growth. Adult Cldn17^−/− mice displayed electrolyte imbalance, oxidative stress, and injury to the kidneys. Ingenuity pathway analysis followed by RNA-sequencing revealed hyperactivation of signaling pathways and downregulation of SOD1 expression in kidneys associated with inflammation and reactive oxygen species generation, demonstrating the importance of Cldn17 in the maintenance of electrolytes and reactive oxygen species across the blood-tissue barrier.

Akt1 suppression in advanced cancers has been indicated to promote metastasis. Our understanding of how Akt1 orchestrates this is incomplete. Using the NanoString^®-based miRNA and mRNA profiling of PC3 and DU145 cells, and subsequent data analysis using the DIANA-mirPath, dbEMT, nCounter, and Ingenuity^® databases, we identified the miRNAs and associated genes responsible for Akt1-mediated prostate cancer (PCa) epithelial-to-mesenchymal transition (EMT). Akt1 loss in PC3 and DU145 cells primarily induced changes in the miRNAs and mRNAs regulating EMT genes. These include increased miR-199a-5p and decreased let-7a-5p expression associated with increased TGFβ-R1 expression. Treatment with locked nucleic acid (LNA) miR-199a-5p inhibitor and/or let-7a-5p mimic induced expression changes in EMT genes correlating to their anticipated effects on PC3 and DU145 cell motility, invasion, and TGFβ-R1 expression. A correlation between increased miR-199a-5p and TGFβ-R1 expression with reduced let-7a-5p was also observed in high Gleason score PCa patients in the cBioportal database analysis. Collectively, our studies show the effect of Akt1 suppression in advanced PCa on EMT modulating miRNA and mRNA expression changes and highlight the potential benefits of miR-199a-5p and let-7a-5p in therapy and/or early screening of mPCa.

Visual dysfunction resulting from optic neuritis (ON) is one of the most common clinical manifestations of multiple sclerosis (MS), characterized by loss of retinal ganglion cells, thinning of the nerve fiber layer, and inflammation to the optic nerve. Current treatments available for ON or MS are only partially effective, specifically target the inflammatory phase, and have limited effects on long-term disability. Fingolimod (FTY) is an FDA-approved immunomodulatory agent for MS therapy. The objective of the current study was to evaluate the neuroprotective properties of FTY in the cellular model of ON-associated neuronal damage. R28 retinal neuronal cell damage was induced through treatment with tumor necrosis factor-α (TNFα). In our cell viability analysis, FTY treatment showed significantly reduced TNFα-induced neuronal death. Treatment with FTY attenuated the TNFα-induced changes in cell survival and cell stress signaling molecules. Furthermore, immunofluorescence studies performed using various markers indicated that FTY treatment protects the R28 cells against the TNFα-induced neurodegenerative changes by suppressing reactive oxygen species generation and promoting the expression of neuronal markers. In conclusion, our study suggests neuroprotective effects of FTY in an in vitro model of optic neuritis.

BACKGROUND: Medication errors may account up to one-third of all medical errors in hospitals, thereby leading to adverse outcomes such as higher mortality rate and longer hospital stay. OBJECTIVES: The primary objective of the study was to determine

A cluster of pneumonia cases of unknown etiology associated with pyrexia and acute respiratory distress was identified in Southern China. Links between the previous severe acute respiratory syndrome (SARS) cases and the region’s seafood market were noted with the possibility of a new zoonosis and SARS-CoV-2 was identified as the responsible agent. Currently, there are no effective prophylactic or therapeutic options to deal with coronavirus disease-19 (COVID-19) or any other human coronavirus (HCoV) infections. Convalescent plasma (CP) therapy is a classic adaptive immunotherapy which has been in use for more a century to prevent and treat infections including SARS, Middle East respiratory syndrome (MERS), and H1N1 pandemic. Moreover, the World Health Organization regarded CP transfusion as the most promising therapy to treat MERS-CoV. This review was undertaken to demonstrate the potential of CP in the treatment of the pandemic COVID-19 disease. A total of eight studies conducted on CP therapy in patients with COVID-19 were reviewed wherein 25,028 patients above 18 years of age were involved. The vast majority of patients reported favorable outcomes when treated with CP with <1% serious adverse events. Despite its promising beneficial effects in patients severely ill with COVID-19, CP therapy requires further evaluation in randomized clinical trials (RCTs) as a lack of satisfactory efficacy data from this area certainly enhances the hesitancy with regard to employing this treatment. In the present circumstances of unsatisfactory pharmacological therapy and the urgent need for a successful curative remedy, considering the use of CP therapy is reasonable provided RCTs confirm its safety, efficacy, and tolerability.