👤 Kareem Abdou

Huntington’s disease (HD) pathogenesis involves diverse cellular mechanisms, yet the contributions of pyroptosis and ferroptosis remain elusive. Roflumilast, a phosphodiesterase-4 (PDE-4) inhibitor, has shown neuroprotective effects, but its precise mechanisms are yet to be elucidated. We evaluated the potential neuroprotective and therapeutic effects of roflumilast in 3-nitropropionic acid (3-NP)-induced HD-like neurodegeneration, focusing on pyroptotic and ferroptotic cell death signaling. Adult male Wistar rats were assigned to five groups: normal control (saline + 0.5% carboxymethyl cellulose), roflumilast-control (1 mg/kg/day, p.o. for 21 days), 3-NP (20 mg/kg/day, i.p. for seven days), roflumilast-prophylactic (1 mg/kg/day, p.o. for 21 days prior to 3-NP), and roflumilast-treatment (1 mg/kg/day, p.o. for 21 days post-3-NP). Behavioral outcomes of the open-field, rotarod, and grip strength tests were assessed. Striatal PDE-4, total and p-CREB, BDNF, interleukin-1β, and markers of pyroptosis (NLRP3, caspase-1, and gasdermin D) and ferroptosis (iron, GPx4, GSH, and malondialdehyde) were measured alongside histopathological alterations and GFAP and Iba-1 immunohistochemical staining. Bioinformatics was used to visualize the target genes’ protein-protein interaction network. Behavioral assessments revealed impaired locomotion, motor coordination, and muscle strength in the 3-NP-injected rats. Biochemical analysis showed increased striatal PDE-4 expression and decreased p-CREB/BDNF axis alongside NLRP3 inflammasome/caspase-1/gasdermin D activation and elevated interleukin-1β. In parallel, ferroptosis was evidenced by increased striatal iron and malondialdehyde levels, along with reduced GPx4 and GSH. Histopathological examination revealed pronounced striatal neurodegeneration, accompanied by enhanced GFAP and Iba-1 immunostaining, indicating astrogliosis and microglial activation. Roflumilast, administered prophylactically or therapeutically, significantly improved functional and behavioral abnormalities while ameliorating biochemical, histopathological, and immunohistochemical derangements induced by 3-NP. The therapeutic regimen exhibited superior efficacy relative to prophylaxis. Conclusively, roflumilast exerts therapeutic and neuroprotective effects in HD-like neurodegeneration by mitigating pyroptosis and ferroptosis, attenuating astrogliosis, microglial activation, and neuroinflammation, and restoring synaptic plasticity. A graphical abstract illustrating the proposed mechanistic pathway underlying the neuroprotection of the PDE-4 inhibitor roflumilast through reducing striatal pyroptosis, ferroptosis, microglial and astrocyte activation, and neuroinflammation, while restoring synaptic plasticity in experimental Huntington’s disease-like neurodegeneration induced by 3-NP. [Image: see text] Show less

Hepatitis C virus (HCV) is considered a major global public health problem. Recently, there are great advances in HCV therapy, but there are some limitations that are creating an urgent need for assessment of some cytokines that have a potent antiviral effect in the immune system and anti-inflammatory effects to provide a potential novel immunotherapeutic target in HCV infection. This study was directed to assess the serum levels and gene expression levels of Galectin-4 (LEG4), Interleukin-27 (IL-27), and Complement-7 (C-7) and their correlation with the viral load in HCV infection. There were significant elevations in the mean levels of gene expression and serum levels of all studied parameters LEG4, IL-27, and C-7 in the HCV group compared to the control group. Significant negative correlations between the viral load and each of the serum proteins and gene expressions of both LEG4 and IL-27 in HCV patients were found. The gene expression levels of LEG4, IL-27, and C-7 were positively correlated with their corresponding serum proteins in HCV patients. LEG4 and IL-27 showed significant negative correlations with the viral load, which could be an immune response to the control of the extent of hepatic inflammation, thus creating a potential novel immunotherapeutic approach in HCV infection for further studies or therapeutic clinical trials. Show less

Metabolic syndrome (MetS) is an aberration associated with increased risk for cancer and inflammation. Adiponectin, an adipocyte-produced abundant protein hormone, has countering effect on the diabetogenic and atherogenic components of MetS. Plasma levels of adiponectin are negatively correlated with onset of cancer and cancer patient mortality. We previously performed microsatellite linkage analyses using adiponectin as a surrogate marker and revealed two QTLs on chr5 (5p14) and chr14 (14q13). Using individuals from 85 extended families that contributed to the linkage and who were measured for 42 clinical and biologic MetS phenotypes, we tested QTL-based SNP associations, peripheral white blood cell (PWBC) gene expression, and the effects of cis-acting SNPs on gene expression to discover genomic elements that could affect the pathophysiology and complications of MetS. Adiponectin levels were found to be highly intercorrelated phenotypically with the majority of MetS traits. QTL-specific haplotype-tagging SNPs associated with MetS phenotypes were annotated to 14 genes whose function could influence MetS biology as well as oncogenesis or inflammation. These were mechanistically categorized into four groups: cell-cell adhesion and mobility, signal transduction, transcription and protein sorting. Four genes were highly prioritized: cadherin 18 (CDH18), myosin X (MYO10), anchor protein 6 of AMPK (AKAP6), and neuronal PAS domain protein 3 (NPAS3). PWBC expression was detectable only for the following genes with multi-organ or with multi-function properties: NPAS3, MARCH6, MYO10 and FBXL7. Strong evidence of cis-effects on the expression of MYO10 in PWBC was found with SNPs clustered near the gene's transcription start site. MYO10 expression in PWBC was marginally correlated with body composition (p = 0.065) and adipokine levels in the periphery (p = 0.064). Variants of genes AKAP6, NPAS3, MARCH6 and FBXL7 have been previously reported to be associated with insulin resistance, inflammatory markers or adiposity studies using genome-wide approaches whereas associations of CDH18 and MYO10 with MetS traits have not been reported before. Adiponectin QTLs-based SNP association and mRNA expression identified genes that could mediate the association between MetS and cancer or inflammation. Show less