Hajir A. Al Saihati

Severe COVID-19 is marked by a dysregulated inflammatory response, known as a cytokine storm, resulting in acute respiratory distress syndrome (ARDS) and multiple organ failure. Mesenchymal stem cell-derived exosomes (MSC-Exos) have demonstrated potential as immunomodulatory agents. This work investigates the possibility of MSC-Exos to mitigate excessive inflammation in COVID-19 by targeting the mitogen-activated protein kinase (MAPK) signalling pathway. We integrated molecular docking analysis between TGF-β and Annexin A1 as exosomal proteins and key component proteins of the MAPK pathway (p38, ERK1/2, JNK1). The in-silico results were then validated in vivo using a Syrian hamster model of SARS-CoV-2 infection. Quantitative PCR (qPCR), western blotting, and histological examination were employed to evaluate the effects of MSC-Exos therapy on MAPK pathway activation, cytokine production, and lung tissue pathology. The in-silico study revealed extensive hydrogen bonding and hydrophobic interactions at the protein–protein interfaces between exosomal proteins and MAPK components. These interactions suggest that exosomal proteins may modulate MAPK signaling pathways. In vivo, MSC-Exos administration led to marked downregulation of pivotal genes in the MAPK signaling pathway (MEKK1, MEKK2, MEKK3), diminished phosphorylation of JNK1, p38, and ERK1/2, and lowered production of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α). Histopathological examination demonstrated ameliorated lung tissue structure, characterized by diminished alveolar wall thickness and decreased immune cell infiltration. MSC-Exos elicit immunomodulatory effects in SARS-CoV-2-Infected hamsters, partially by directly targeting and blocking the MAPK signaling pathway. These findings offer a compelling justification for the clinical assessment of MSC-Exos as a therapeutic approach to alleviate the cytokine storm and enhance outcomes in severe COVID-19 by targeting the ACE2-Independent pathway. The online version contains supplementary material available at 10.1186/s13287-026-04980-z.

Emerging evidence suggests that chronic use of gastric acid‐suppressing medications may contribute to neurocognitive decline, yet the underlying mechanisms remain poorly defined. Proton pump inhibitors like omeprazole and histamine‐2 receptor antagonists such as ranitidine are widely prescribed for gastrointestinal disorders, but their long‐term impact on brain function. Forty‐eight male Wistar rats were assigned to six groups receiving either control diet, B ₁₂ alone, omeprazole, ranitidine, or co‐treatment with B ₁₂ for 90 days. Behavioral and cognitive assessments revealed early deficits in the drug‐only‐treated groups (omeprazole and ranitidine). Notably, B ₁₂ ameliorated omeprazole‐induced impairments but failed to reverse ranitidine‐associated deficits, suggesting divergent neurotoxic pathways. Biochemical profiling included serum B ₁₂ , homocysteine, cortisol, glucose, insulin, liver enzymes, and neurotransmitter. To complement these in vivo findings, an in silico approach was employed to explore molecular interactions of omeprazole and ranitidine with proteins critical for vitamin B ₁₂ transport (CBLIF and TCN2) and cholinergic neurotransmission (CHRNA7). Together, these in vivo and in silico results suggest that omeprazole‐induced cognitive decline may involve B ₁₂ depletion and other mechanisms, whereas ranitidine likely acts via alternative pathways. This study provides novel mechanistic insights into differential cognitive risks associated with chronic acid‐suppressing therapy, with implications for long‐term management in populations vulnerable to neurodegeneration.

Triclosan (TCS) is a widely used antimicrobial agent raising concern about its potential toxicity and adverse effects on fertility. This study investigated the protective efficacy of clomiphene citrate, conventional selenium, nanoselenium and Tribulus terrestris extract (TTE) against TCS‐induced toxicity in male rats. Six experimental groups were established: control, TCS‐exposed and TCS co‐treated with each therapeutic agent. Semen quality; testicular and hepatic biochemical, oxidative and mitochondrial markers; hormone profiles; neurotransmitters; and histopathology were assessed. Specific reproductive (SOX9, inhibin B) and hepatic (Nrf2, NF‐κB) markers were quantified to evaluate spermatogenesis, oxidative stress and inflammatory responses. In silico analyses, including molecular docking and molecular dynamics simulations, examined the interactions of TCS with CYP17A1 and GPX4 to elucidate potential mechanisms of enzyme inhibition. The results demonstrated that TCS exposure impaired reproductive and hepatic function, disrupted hormonal balance, induced oxidative stress and tissue damage. Treatments with selenium (conventional and nanoforms) and TTE significantly mitigated these alterations, restoring biochemical and hormonal parameters and improving tissue architecture. Among these, nanoselenium and TTE showed the most pronounced protective effects, emphasizing their comparative efficacy in counteracting TCS‐induced toxicity. The findings highlight the potential of nanoselenium and TTE as promising protective agents against TCS‐related reproductive and hepatic damage.

Alzheimer's (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and neurochemical imbalances. The present study aims to ensure the correct dosage of scopolamine (SC) for inducing AD using Quality by Design to optimize the predictive biomarker acetylcholine esterase. Further, neuroprotective effects will be assessed with variable doses of bee venom (BV) by analyzing its effect on cognitive function, neurochemical markers, and oxidative stress. The goal of this study is to improve models of AD and learn more about how BV can protect neurons in a dose-dependent way during treatment. Methods: The rats were randomly divided into six groups (n = 6): Control, SC -induced AD, SC + Memantine (1 mg/kg bwt p.o.), and three BV doses (5, 10, 15 µl/kg, i.p, every other day) to study dose-dependent effects combined with SC. Memantine and BV were given to the animals two months before they developed AD, which happened on its own 14 days after treatment. After four days of behavioral assessment using the Morris Water Maze to evaluate cognitive function, the animals were humanely sacrificed. Blood and brain samples were collected for the measurement of serum liver and kidney function markers, oxidative and nitrosative stress parameters, cellular energy metabolites, amino acid profiles, neurotransmitters, and inflammatory markers in brain tissue. Results and Conclusion: The most remarkable neuroprotective effect was found in the group treated with BV medium and high dose showed a plateau, beyond which no more improvement was shown. These findings point toward a promising therapeutic approach for BV in the cognitive decline of AD.

The JAK/STAT signaling pathway plays a crucial role in the release of interferons (IFNs) and the proinflammatory response during SARS-CoV-2 infection, contributing to the cytokine storm characteristic of severe COVID-19 cases. STAT3, a key protein in this pathway, has been implicated in promoting inflammation, making its inhibition a potential therapeutic strategy to mitigate disease severity. Mesenchymal Stem Cell-derived Extracellular Vesicles (MSC-EVs), enriched with immunomodulatory and antiviral miRNAs, offer a promising therapeutic approach by modulating gene expression and regulating inflammatory responses. This study investigates the ability of Lyophilized MSC-EVs to inhibit the JAK/STAT pathway, highlighting their potential application in COVID-19 management. Male Syrian hamsters were used as an experimental model, housed under controlled laboratory conditions. SARS-CoV-2 (hCoV-19/Egypt/NRC-03/2020) was propagated in Vero E6 cells, and viral titers were determined using plaque assays. Hamsters were intranasally challenged with the virus and treated intraperitoneally with 0.5 mL of lyophilized human Wharton’s jelly-derived MSC-extracellular vesicles (MSC-EVs). Histopathological evaluations were performed on lung tissues using H&E, Masson’s trichrome, and immunohistochemical staining. Morphometric analyses were conducted to assess lung injury and fibrosis. Western blotting was employed to evaluate protein expression. All procedures adhered to ethical and biosafety guidelines. The administration of MSC-EVs significantly upregulated the expression levels of miRNA-146a, miRNA-124, miRNA-155, miRNA-29b, miRNA-7, miRNA-145 and miRNA-18a compared to their levels in the COVID-19 group, suggesting a targeted release of miRNA-cargo from the MSC-EVs into the lung tissue of the animals. MSC-EVs impaired the activation of the STAT3/STAT1 signaling pathway and reduced the cytokine storm and coagulopathy associated with COVID-19. These findings suggest that MSC-EVs have the potential to effectively mitigate the pathogenesis of COVID-19 by targeting the JAK/STAT signaling pathway. Further research is needed to fully understand the mechanisms underlying the therapeutic effects of MSC-EVs and their clinical application in combating the COVID-19 pandemic.

Coronavirus disease 2019 (COVID-19) has created a global pandemic with significant morbidity and mortality. SARS-CoV-2 primarily infects the lungs and is associated with various organ complications. Therapeutic approaches to combat COVID-19, including convalescent plasma and vaccination, have been developed. However, the high mutation rate of SARS-CoV-2 and its ability to inhibit host T-cell activity pose challenges for effective treatment. Mesenchymal stem cells (MSCs) and their extracellular vesicles (MSCs–EVs) have shown promise in COVID-19 therapy because of their immunomodulatory and regenerative properties. MicroRNAs (miRNAs) play crucial regulatory roles in various biological processes and can be manipulated for therapeutic purposes. We aimed to investigate the role of lyophilized MSC–EVs and their microRNAs in targeting the receptors involved in SARS-CoV-2 entry into host cells as a strategy to limit infection. In silico microRNA prediction, structural predictions of the microRNA–mRNA duplex, and molecular docking with the Argonaut protein were performed. Male Syrian hamsters infected with SARS-CoV-2 were treated with human Wharton’s jelly-derived Mesenchymal Stem cell-derived lyophilized exosomes (Bioluga Company)via intraperitoneal injection, and viral shedding was assessed. The potential therapeutic effects of MSCs–EVs were measured via histopathology of lung tissues and PCR for microRNAs. The results revealed strong binding potential between miRNA‒mRNA duplexes and the AGO protein via molecular docking. MSCs–EVs reduced inflammation markers and normalized blood indices via the suppression of viral entry by regulating ACE2 and TMPRSS2 expression. MSCs–EVs alleviated histopathological aberrations. They improved lung histology and reduced collagen fiber deposition in infected lungs. We demonstrated that MSCs–EVs are a potential therapeutic option for treating COVID-19 by preventing viral entry into host cells.