👤 Dalia Salah

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

Brain aging is a multifactorial process associated with oxidative stress, chronic neuroinflammation, and synaptic dysfunction, ultimately leading to cognitive decline and increased susceptibility to neurodegenerative disorders. Epigallocatechin gallate (EGCG) is a potent antioxidant and anti-inflammatory agent, but its therapeutic potential is limited by poor stability and bioavailability. In this study, a dual nano delivery system was developed by loading chitosan-EGCG nanoparticles into mesenchymal stem cell-derived exosomes (Ex-Chit-EGCG NPs) and evaluated for neuroprotective efficacy in a D-galactose-induced brain aging model. Intranasal administration of Ex-Chit-EGCG NPs significantly improved cognitive and locomotor performance compared with exosomes alone, as evidenced by enhanced outcomes in Y-maze and open field tests. Biochemical analyses revealed that Ex-Chit-EGCG NPs effectively reduced lipid peroxidation, restored glutathione levels, and reactivated the LKB1/AMPK/SIRT1 signaling pathway. Molecular investigations demonstrated upregulation of Nrf2, BDNF, and SIRT1 together with suppression of NF-κB and Iba-1 expression, indicating attenuation of oxidative and inflammatory responses. Histopathological and immunohistochemical evaluations confirmed these findings, showing preservation of cortical and brain stem architecture with marked reductions in neuronal necrosis, gliosis, BAX, GFAP, and NLRP3 expression. Collectively, the results demonstrate that Ex-Chit-EGCG NPs exert superior neuroprotective effects compared with exosomes alone, highlighting the therapeutic advantage of combining EGCG with chitosan nanocarriers and exosomal delivery. This dual nanotherapeutic strategy offers a promising and non-invasive approach for mitigating brain aging and holds potential for translation into therapies targeting age-related neurodegenerative disorders. Show less

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by progressive cognitive impairment and the accumulation of amyloid-β (Aβ) peptides. In this study, a novel series of triazole and phosphazine derivatives were synthesized and evaluated for neuroprotective activity in an aluminum chloride (AlCl Show less

Hepatitis C virus (HCV) infection is a significant global health concern, as both acute and chronic hepatitis caused by HCV can lead to liver cancer and long-term liver damage. Thymoquinone (TQ), the active compound found in the remarkable herb Nigella sativa, has various anti-inflammatory and antiproliferative effects. In this study, we investigated the effect of TQ on the interferon-alpha (IFN-α) pathway and its ability to prevent HCV replication in the HepG2 cell line. Our findings showed no significant alterations in cell viability or lactate dehydrogenase (LDH) production in TQ-treated cells, while significant alteration in both factors was detected in cells treated with Sovaldi, the most commonly used drug for treatment of HCV infection. Interestingly, the level of the HCV NS5A protein was significantly reduced in infected cells treated with either TQ or Sovaldi in a dose-dependent manner. The expression of phosphorylated Raf-1 (phospho-Raf-1) and phospho-Mek-1 in infected cells was inhibited by TQ treatment, and the potential interaction between TQ and Ref-1 was confirmed by a molecular docking simulation. Unlike autophagy-related 12 (Atg12), the expression of LC3B in infected cells was also inhibited in a dose-dependent manner by TQ treatment. Conversely, the levels of interleukin-27 (IL-27) and interferon-alpha (IFN-α) in infected cells were significantly increased in a time- and dose-dependent manner by TQ treatment. These data suggest that TQ exerts antiviral effects in HepG2 cells by disrupting HCV replication through targeting of the Raf-1 signaling pathway and promoting the overproduction of IL-27 and IFN-α in infected cells. Show less

End-stage kidney disease (ESRD) patients on dialysis face pronounced cardiovascular and metabolic risks due to disruptions in lipoprotein(a), phosphorus, potassium, uric acid, and lipid balance. Current therapeutic options offer limited capacity to address these multifaceted abnormalities. Niacin is unique in this regard, as it not only lowers lipoprotein(a) but also influences phosphorus and uric acid metabolism. This study evaluates the efficacy of niacin therapy in improving these biochemical markers, thereby addressing an important therapeutic gap in this vulnerable population. In a randomized, controlled trial, 50 hemodialysis patients were divided into two groups of twenty-five each. The control group continued standard care, while the niacin group received 500 mg/day niacin alongside standard therapy. Patients were followed for 3 months. Systolic and diastolic blood pressure were stabilized by niacin administration, in contrast to the control group, where both parameters rose significantly. Phosphorus decreased significantly in the niacin group (5.59 to 4.85 mg/dL, Niacin (500 mg/day) offers significant cardiovascular and metabolic benefits for hemodialysis patients, supporting its role as an adjunctive therapy in managing ESRD-associated risks. https://clinicaltrials.gov/, NCT06406140. Show less

Hepatocellular carcinoma (HCC) is the most common primary liver cancer. Chronic hepatitis and liver cirrhosis lead to accumulation of genetic alterations driving HCC pathogenesis. This study is designed to explore genomic landscape of HCC in Egyptian patients by whole exome sequencing. Whole exome sequencing using Ion Torrent was done on 13 HCC patients, who underwent surgical intervention (7 patients underwent living donor liver transplantation (LDLT) and 6 patients had surgical resection}. Mutational signature was mostly S1, S5, S6, and S12 in HCC. Analysis of highly mutated genes in both HCC and Non-HCC revealed the presence of highly mutated genes in HCC (AHNAK2, MUC6, MUC16, TTN, ZNF17, FLG, MUC12, OBSCN, PDE4DIP, MUC5b, and HYDIN). Among the 26 significantly mutated HCC genes-identified across 10 genome sequencing studies-in addition to TCGA, APOB and RP1L1 showed the highest number of mutations in both HCC and Non-HCC tissues. Tier 1, Tier 2 variants in TCGA SMGs in HCC and Non-HCC (TP53, PIK3CA, CDKN2A, and BAP1). Cancer Genome Landscape analysis revealed Tier 1 and Tier 2 variants in HCC (MSH2) and in Non-HCC (KMT2D and ATM). For KEGG analysis, the significantly annotated clusters in HCC were Notch signaling, Wnt signaling, PI3K-AKT pathway, Hippo signaling, Apelin signaling, Hedgehog (Hh) signaling, and MAPK signaling, in addition to ECM-receptor interaction, focal adhesion, and calcium signaling. Tier 1 and Tier 2 variants KIT, KMT2D, NOTCH1, KMT2C, PIK3CA, KIT, SMARCA4, ATM, PTEN, MSH2, and PTCH1 were low frequency variants in both HCC and Non-HCC. Our results are in accordance with previous studies in HCC regarding highly mutated genes, TCGA and specifically enriched pathways in HCC. Analysis for clinical interpretation of variants revealed the presence of Tier 1 and Tier 2 variants that represent potential clinically actionable targets. The use of sequencing techniques to detect structural variants and novel techniques as single cell sequencing together with multiomics transcriptomics, metagenomics will integrate the molecular pathogenesis of HCC in Egyptian patients. Show less

Cardiovascular disease (CVD) is one of the major causes of human death. Preliminary evidence indicates that the inhibition treatment of Cholesteryl Ester Transfer Protein (CETP) causes the most pronounced increase in HDL cholesterol reported so far. Merck has disclosed certain (4 Show less