Background: Non-alcoholic fatty liver disease (NAFLD) represents the most common form of chronic liver disease that urgently needs effective therapy. Rosavin, a major constituent of the Rhodiola Rosea plant of the family Crassulaceae, is believed to exhibit multiple pharmacological effects on diverse diseases. However, its effect on non-alcoholic steatohepatitis (NASH), the progressive form of NAFLD, and the underlying mechanisms are not fully illustrated. Aim: Investigate the pharmacological activity and potential mechanism of rosavin treatment on NASH management via targeting hepatic cell death-related (HSPD1/TNF/MMP14/ITGB1) mRNAs and their upstream noncoding RNA regulators (miRNA-6881-5P and lnc-SPARCL1-1:2) in NASH rats. Results: High sucrose high fat (HSHF) diet-induced NASH rats were treated with different concentrations of rosavin (10, 20, and 30 mg/kg/day) for the last four weeks of dietary manipulation. The data revealed that rosavin had the ability to modulate the expression of the hepatic cell death-related RNA panel through the upregulation of both (HSPD1/TNF/MMP14/ITGB1) mRNAs and their epigenetic regulators (miRNA-6881-5P and lnc-SPARCL1-1:2). Moreover, rosavin ameliorated the deterioration in both liver functions and lipid profile, and thereby improved the hepatic inflammation, fibrosis, and apoptosis, as evidenced by the decreased protein levels of IL6, TNF-α, and caspase-3 in liver sections of treated animals compared to the untreated NASH rats. Conclusion: Rosavin has demonstrated a potential ability to attenuate disease progression and inhibit hepatic cell death in the NASH animal model. The produced effect was correlated with upregulation of the hepatic cell death-related (HSPD1, TNF, MMP14, and ITGB1) mRNAs—(miRNA-6881-5P—(lnc-SPARCL1-1:2) RNA panel.

Myocardial ischemia‑reperfusion injury (MI/R) is considered a main risk factor for global cardiac mortality and morbidity, for which no effective treatment exists. Both inflammation and epigenetic regulation play a pivotal role in the early stage of MI/R. The present study aimed at investigating the prospective anti-inflammatory role of trans-anethole (TNA) in targeting MI/R and its related mechanism in upregulating the expression of the inflammatory and cardiac-related gene (VAV3), and its epigenetic regulators (lncRNA-JRKL-AS1 and miR-1298) that were retrieved from in-silico data analysis in an ischemia/reperfusion (I/R) rat model. TNA was administered in 3 doses (50, 100, and 200 mg/kg), 15 min prior to coronary ligation in male Wistar rats. The left ventricular end-diastolic pressure and dP/dtmax were assessed. Histopathological, biochemical, and molecular analyses were performed to assess the effects of TNA pre-treatment on the I/R rats model. TNA alleviated the I/R-induced cardiac injury pathologically and improved the cardiac function tests and enzymes. At the molecular level, TNA upregulated the expression level of the retrieved RNA-based panel (VAV3 mRNA/miR-1298/lncRNA JRKL-AS1). At the protein level, TNA decreased the cardiac content of the pro-inflammatory cytokine TNF-α. TNA has demonstrated a potential ability to alleviate the cardiac injury and attenuate the inflammatory response following ischemia-reperfusion in the rat model through modulation of the expression of RNA panel (VAV3 mRNA/miR-1298/lncRNA JRKL-AS1) and TNF- α protein.

Background: NAFLD and NASH are emerging as primary causes of chronic liver disease, indicating a need for an effective treatment. Mutaflor® probiotic, a microbial treatment of interest, was effective in sustaining remission in ulcerative colitis patients. Objective: To construct a genetic-epigenetic network linked to HSC signaling as a modulator of NAFLD/NASH pathogenesis, then assess the effects of Mutaflor^® on this network. Methods: First, in silico analysis was used to construct a genetic-epigenetic network linked to HSC signaling. Second, an investigation using rats, including HFHSD induced NASH and Mutaflor^® treated animals, was designed. Experimental procedures included biochemical and histopathologic analysis of rat blood and liver samples. At the molecular level, the expression of genetic (FOXA2, TEAD2, and LATS2 mRNAs) and epigenetic (miR-650, RPARP AS-1 LncRNA) network was measured by real-time PCR. PCR results were validated with immunohistochemistry (α-SMA and LATS2). Target effector proteins, IL-6 and TGF-β, were estimated by ELISA. Results: Mutaflor^® administration minimized biochemical and histopathologic alterations caused by NAFLD/NASH. HSC activation and expression of profibrogenic IL-6 and TGF-β effector proteins were reduced via inhibition of hedgehog and hippo pathways. Pathways may have been inhibited through upregulation of RPARP AS-1 LncRNA which in turn downregulated the expression of miR-650, FOXA2 mRNA and TEAD2 mRNA and upregulated LATS2 mRNA expression. Conclusion: Mutaflor^® may slow the progression of NAFLD/NASH by modulating a genetic-epigenetic network linked to HSC signaling. The probiotic may be a useful modality for the prevention and treatment of NAFLD/NASH.

Introduction: Chemotherapy-induced cognitive impairment, commonly referred to as “chemobrain”, represents a frequent and distressing complication of cancer therapy. Doxorubicin (DOX), a widely used chemotherapeutic agent, contributes to these deficits partly through mechanisms involving oxidative stress, inflammatory cascades, and disruption of glutamate homeostasis, but unfortunately, the precise role of altered glutamate transport and neurotrophic signaling remains poorly addressed. Lurasidone (LURA), an atypical antipsychotic, exhibits potent 5-HT7 receptor antagonism and pro-cognitive properties, making it a strong candidate to counteract these deficits. However, its potential to rescue glutamate homeostasis and neuroplasticity pathways in chemobrain has not been explored. This study investigated whether LURA could counteract DOX-induced chemobrain by restoring CREB/BDNF/Glt-1 signaling and re-establishing glutamate homeostasis in the hippocampus and prefrontal cortex. Methods: Forty-eight male Wistar rats were assigned to control, LURA, DOX, or DOX/LURA groups. Behavioral performance was assessed using the open field, novel object recognition, and Morris water maze tests. Hippocampal and prefrontal tissues were evaluated for protein expression of the CREB/BDNF/Glt-1 pathway, glutamate and GABA levels, oxidative stress indices, and histopathological and immunohistochemical markers of neurodegeneration, apoptosis, and astrocytic activation. Results: DOX administration resulted in pronounced cognitive decline, oxidative stress, neuroinflammation, neuronal loss, and substantial downregulation of CREB/BDNF/Glt-1 signaling, accompanied by elevated glutamate and reduced GABA levels. LURA co-treatment markedly improved behavioral outcomes, reinstated CREB/BDNF/Glt-1 expression, ameliorated glutamate/GABA balance, and reduced neurodegeneration, caspase-3 activation, and astrocytic reactivity. Discussion: This study provides the first evidence that lurasidone mitigates doxorubicin-induced chemobrain. This neuroprotective effect is associated with the restoration of glutamate homeostasis and the upregulation of hippocampal and prefrontal CREB/BDNF/Glt-1 signaling, highlighting lurasidone as a promising therapeutic option for chemotherapy-induced cognitive impairment.

Background: Disrupted iron homeostasis is increasingly perceived as a key driver of major depressive disorder pathogenesis; hence, targeting ferroptotic cascades may reveal novel therapeutic targets. This study evaluated the neuroprotective potential of the oral iron chelator deferasirox (DEF) against chronic unpredictable mild stress (CUMS)-induced depressive-like behaviors and cognitive deficits in Wistar rats. Methods: We specifically explored whether DEF could provide neuroprotection by targeting ferroptotic and oxidative stress pathways. Male Wistar rats were exposed to a 6-week CUMS protocol and treated with DEF (10, 20, or 40 mg/kg). Results: CUMS-exposed rats exhibited significant anhedonia, behavioral despair, and impaired spatial and recognition memory. Further analyses revealed a reduction in colonic and choroid plexus occludin, reflecting compromised structural integrity of both the intestinal and blood-CSF barriers, accompanied by enhanced hippocampal iron accumulation with increased Acyl-CoA synthetase long-chain family member 4 (ACSL4), Acyl-CoA synthetase family member 2 (ACSF2), and citrate synthase expression, alongside exaggerated oxidative stress and deficient neuroprotective mediators, specifically BDNF and synaptophysin, and increased neurofibrillary tangle (NFT) deposition, collectively exacerbating neurodegenerative pathology. DEF treatment ameliorated most of these effects, significantly reducing iron deposition, attenuating ferroptosis-related signaling, reducing oxidative stress, diminishing the ongoing neurodegeneration, and replenishing the depleted pool of BDNF and synaptophysin, which was accompanied by a reduction in depressive-like symptoms and improved cognitive functions. Conclusions: These findings support a link between ferroptosis-related signaling and depression-like phenotypes, reinforcing the concept of a metal-driven component in depression pathophysiology and offering a mechanistic rationale for further exploring targeting ferroptotic pathways and central iron regulation as potential targeted strategies in depression management.