Pulmonary fibrosis (PF) is a life-threatening disorder that severely disrupts normal lung architecture and function, resulting in severe respiratory failure and death. It has no definite treatment. Empagliflozin (EMPA), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, has protective potential in PF. However, the mechanisms underlying these effects require further elucidation. Therefore, this study aimed to evaluate the ameliorative effect of EMPA against bleomycin (BLM)-induced PF and the potential mechanisms. Twenty-four male Wister rats were randomly divided into four groups: control, BLM treated, EMPA treated, and EMPA+BLM treated. EMPA significantly improved the histopathological injuries illustrated by both hematoxylin and eosin and Masson’s trichrome-stained lung tissue sections, as confirmed by electron microscopic examination. It significantly reduced the lung index, hydroxyproline content, and transforming growth factor β1 levels in the BLM rat model. It had an anti-inflammatory effect, as evidenced by a decrease in the inflammatory cytokines’ tumor necrosis factor alpha and high mobility group box 1, inflammatory cell infiltration into the bronchoalveolar lavage fluid, and the CD68 immunoreaction. Furthermore, EMPA mitigated oxidative stress, DNA fragmentation, ferroptosis, and endoplasmic reticulum stress, as evidenced by the up-regulation of nuclear factor erythroid 2-related factor expression, heme oxygenase-1 activity, glutathione peroxidase 4 levels, and a decrease in C/EBP homologous protein levels. This protective potential could be explained on the basis of autophagy induction via up-regulating lung sestrin2 expression and the LC3 II immunoreaction observed in this study. Our findings indicated that EMPA protected against BLM-induced PF-associated cellular stress by enhancing autophagy and modulating sestrin2/adenosine monophosphate-activated protein kinase/nuclear factor erythroid 2-related factor 2/heme oxygenase 1 signaling.

Doxorubicin (DOX) is an anticancer antibiotic which has various effects in human cancers. It is one of the commonly known causes of drug-induced nephrotoxicity, which results in acute renal injury. Adrenomedullin (ADM), a vasodilator peptide, is widely distributed in many tissues and has potent protective effects. Therefore, the current study aimed to examine the protective potential mechanisms of ADM against DOX-induced nephrotoxicity. A total of 28 male Wistar rats were randomized into four groups: control group, doxorubicin group (15 mg/kg single intraperitoneal injection of DOX), adrenomedullin + doxorubicin group (12 μg/kg/day intraperitoneal injection of ADM) 3 days prior to DOX injection and continuing for 14 days after the model was established, and adrenomedullin group. Kidney function biomarkers, oxidative stress markers, and inflammatory mediators (TNF-α, NLRP3, IL-1β, and IL-18) were assessed. The expressions of gasdermin D and ASC were assessed by real-time PCR. Furthermore, the abundances of caspase-1 (p20), Bcl-2, and Bax immunoreactivity were evaluated. ADM administration improved the biochemical parameters of DOX-induced nephrotoxicity, significantly reduced oxidative damage markers and inflammatory mediators, and suppressed both apoptosis and pyroptosis. These results were confirmed by the histopathological findings and revealed that ADM’s antioxidant, anti-inflammatory, anti-apoptotic, and anti-pyroptotic properties may have prospective applications in the amelioration of DOX-induced nephrotoxicity.

Stroke represents a worldwide major cause of death and long-term adult disability. Various human diseases pathogenesis, including stroke, are associated with dysregulation of long noncoding RNA (LncRNA) and microRNA (miR). However, their potential role is yet to be elucidated. This work aimed to assess the role of LncRNA X-inactive specific transcript (XIST), miR-340-5p, and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase (PFKFB)3 as peripheral blood biomarkers for acute cerebrovascular stroke diagnosis and severity prediction. This cross-sectional study included 120 participants divided into 3 groups; healthy controls, acute ischemic stroke patients, and acute hemorrhagic stroke patients. XIST, miR-340-5p, and PFKFB3 expression were assessed by RT-qPCR, whereas PFKFB3, hypoxia inducible factor 1-alpha (HIF-1α) and vascular endothelial growth factor (VEGF) serum proteins were measured by ELISA. Compared to healthy control, XIST and PFKFB3 mRNA expression were significantly upregulated in stroke patients, with the highest levels in hemorrhagic type, while miR-340-5p expression was significantly downregulated and its lowest level was in hemorrhagic stroke. Serum PFKFB3, HIF-1α, and VEGF levels were significantly elevated in stroke patients with the highest levels in hemorrhagic stroke. These biomarkers correlated with National Institute of Health Stroke Scale (NIHSS). Regression analysis using NIHSS as dependent variable confirmed that PFKFB3 mRNA relative expression was the independent predictor (β = 0.7, P = .003). Receiver operating characteristic analyses revealed that XIST, miR-340-5p, and PFKFB3 mRNA relative expression levels were useful biomarkers discriminating ischemic from hemorrhagic stroke (AUC were 0.99, 0.979, and 0.980, respectively). XIST, miR-340-5p, and PFKFB3 might be involved in acute cerebrovascular stroke pathogenesis and progression providing opportunities for early detection and assessing the severity.