Ji Xiao

Remimazolam (RMZ) is an ultra‑short‑acting sedative anesthetic that provides protection against cerebral and hepatic ischemia/reperfusion injury. However, its potential cardioprotective effect in myocardial ischemia reperfusion injury (MIRI) remains to be fully elucidated. The present study investigated the hypothesis that RMZ can mitigate MIRI, clarifying its underlying mechanisms. Using a mouse MIRI model, the effects of RMZ on cardiac function, cell death, lipid peroxidation, Fe²⁺ accumulation and ferroptosis‑related markers were assessed, together with transmission electron microscopy (TEM) imaging. Transcriptomic analysis identified ferroptosis signatures in cardiomyocytes (CMs). Ferrostatin‑1 (Fer‑1) served as a positive control to validate the anti‑ferroptotic effects of RMZ. Additional mechanistic studies were conducted with H9C2 cells subjected to oxygen‑glucose deprivation/reoxygenation (OGD/R) to evaluate cell death, lipid peroxidation, Fe²⁺ accumulation, TEM and the signaling pathways involved. In the MIRI model, mice treated with RMZ exhibited greater resistance to MIRI, as evidenced by improved cardiac function, reduced myocardial injury markers and decreased TUNEL‑positive CMs. Transcriptomic analysis indicated the activation of ferroptosis following MIRI. Furthermore, RMZ and Fer‑1 inhibited Fe²⁺ accumulation, restored glutathione (GSH) levels, enhanced glutathione peroxidase 4 (GPX4) expression and alleviated mitochondrial ferroptosis damage. In the OGD/R model using H9C2 cells, RMZ normalized Fe²⁺, GSH and GSH/oxidized GSH levels, decreased peroxidase activity and reduced OGD/R‑induced ferroptosis, which was associated with the restoration of the protein kinase B (AKT)/solute carrier family 7 member 11 (SLC7A11)/glutathione peroxidase 4 (GPX4) axis. These findings demonstrated that RMZ protects against MIRI by inhibiting ferroptosis that involves the activation of the AKT/SLC7A11/GPX4 signaling cascade, highlighting its therapeutic potential for improving cardiac outcomes following reperfusion injury.

Background: Sepsis‐induced acute lung injury (SI‐ALI) represents a life‐threatening condition driven by dysregulated immune responses and redox imbalance. Demethoxycurcumin (DMC), a bioactive analog of curcumin, exhibits marked anti‐inflammatory and free radical‐scavenging capacities. Despite its potential, the precise molecular pathways through which DMC mitigates SI‐ALI pathogenesis have yet to be fully elucidated. Methods: SI‐ALI was induced in mice through lipopolysaccharide (LPS) administration. Lung injury was assessed by histopathological analysis and measurement of wet‐to‐dry (W/D) weight ratios. Oxidative stress markers were quantified using ELISA, and inflammatory cytokine mRNA levels were analyzed by RT‐PCR. Ferroptosis‐related proteins and Nrf2 pathway activation were evaluated through Western blotting and immunofluorescence. Mitochondrial ultrastructure was examined via transmission electron microscopy (TEM). The involvement of the Nrf2 pathway was further confirmed by using the Nrf2 inhibitor ML385. Results: DMC treatment significantly alleviated lung injury in a dose‐dependent manner, improving histopathology and reducing W/D weight ratios. It attenuated inflammation by suppressing IL‐6, TNF‐α, and IL‐1β expression and restored oxidative balance by enhancing glutathione (GSH) levels while decreasing malondialdehyde (MDA). Moreover, DMC upregulated glutathione peroxidase 4 (GPX4) and SLC7A11, downregulated cyclooxygenase‐2 (COX2) and ACSL4, reduced nonheme iron and 4‐hydroxynonenal (4‐HNE) production, and improved mitochondrial morphology, collectively demonstrating its inhibitory effects on ferroptosis. Nrf2 inhibition partially reversed these protective effects, underscoring the central role of the Nrf2 pathway in DMC’s mechanism of action. Conclusion: DMC ameliorates SI‐ALI by mitigating inflammation and ferroptosis through Nrf2 pathway activation, suggesting a potential therapeutic strategy for SI‐ALI treatment.

Objectives: Hippocampal neurogenesis is closely related to learning and memory, and hippocampal neurogenesis disorders are involved in the development of many neurodegenerative diseases. Mineralocorticoid receptor (MR) plays a vital role in regulating stress response, neuroendocrine and cognitive functions, and is involved in regulating the integrity and stability of neural networks. However, the potential role of MR in the pathogenesis of postoperative cognitive dysfunction (POCD) is unclear. Therefore, this study evaluated the effect and mechanism of MR activation on postoperative hippocampal neurogenesis and cognitive function in aged mice. Methods: 18-month-old male Kunming mice were randomly divided into Control group (C group), Surgery group (S group), Surgery+ Aldosterone group (S+Aldo group), Surgery + Wortmannin group (S+Wort group), Surgery + Aldosterone + Wortmannin group (S+Aldo+Wort group). Laparotomy was used to establish an animal model of postoperative cognitive dysfunction. After surgery, mice were intraperitoneally injected with aldosterone (100 ug/kg,150 ug/kg,200 ug/kg) and / or wortmannin (1 mg/kg); One day before the sacrifice, mice were injected intraperitoneally with BrdU (100 mg / kg / time, 3 times in total). Mice were subjected to Morris water maze and field tests at 1, 3, 7, and 14 days after surgery. Immunofluorescence was used to detect the number of BrdU +, Nestin +, BrdU/Nestin + positive cells in the hippocampal dentate gyrus of mice at 1, 3, 7 and 14 days after surgery. Western-blot was used to detect PI3K/Akt/GSK-3β signaling pathway related proteins Akt, p-Akt, GSK-3β, P-GSK-3β expression. Results: Stress impairs the performance of aged mice in water maze and open field tests, reduces the number of BrdU/Nestin+ cells in the hippocampal dentate gyrus, and inhibits the phosphorylation of Akt and GSK-3β proteins in the hippocampus. Aldosterone treatment promotes P-Akt, P-GSK-3β protein expression and hippocampal neural stem cell proliferation, and improves postoperative cognitive dysfunction. However, wortmannin treatment significantly reversed these effects of aldosterone. Conclusions: The mineralocorticoid receptor agonist aldosterone promotes the proliferation of hippocampal neural stem cells and improves cognitive dysfunction in aged mice after surgery, and the mechanism may be related to activation of PI3K/Akt/GSK-3β signaling.

Background: Ferroptosis is unique among different types of regulated cell death and closely related to organ injury. Whether ferroptosis occurs in sepsis-associated acute kidney injury (SA-AKI) is not clear. Nuclear factor-erythroid-2-related factor 2 (Nrf2) is crucial to the regulation of ferroptosis. We and others have shown that Maresin conjugates in tissue regeneration 1 (MCTR1) or other members of specialized pro-resolving mediators (SPMs) can actively regulate inflammation resolution and protect organs against injury in inflammatory diseases by activating the Nrf2 signaling. The aim of this study was to determine whether ferroptosis occurs in SA-AKI. Furthermore, we investigated the potential role and mechanism of MCTR1 in the regulation of ferroptosis in SA-AKI, which mainly focus on the Nrf2 signaling.Results: We demonstrated for the first time that ferroptosis is present in SA-AKI. Moreover, MCTR1 effectively suppressed ferroptosis in SA-AKI. Meanwhile, MCTR1 upregulated the expression of Nrf2 in the kidney of septic mice. Nrf2 inhibitor ML-385 reversed MCTR1-regulated ferroptosis and AKI, implying that Nrf2 is involved in the inhibitory effects of MCTR1 on ferroptosis in SA-AKI. Further, MCTR1 inhibited ferroptosis and elevated the expression of Nrf2 in LPS-induced HK-2 cells. However, Nrf2 siRNA offset the effect of MCTR1 on ferroptosis. Finally, we observed that MCTR1 ameliorates multi-organ injury and improves survival in animal models of sepsis.Conclusions: These data demonstrate that MCTR1 suppresses ferroptosis in SA-AKI through the Nrf2 signaling. Our study enriches the pathophysiological mechanism of SA-AKI and provides new therapeutic ideas and potential intervention targets for SA-AKI.

The liver X receptors (LXRs) are members of the nuclear receptor superfamily. The activated LXRs have a variety of biological functions, for instance they can not only regulate the metabolism of cholesterol, fatty acids and glucose, but also play an important role in immune inflammatory response. Massive studies have shown that LXRs are involved in the occurrence and progress of inflammatory-related diseases, and can inhibit the inflammation of some inflammatory-related diseases in the nervous system, the respiratory system, and the cardiovascular system. In this review, we summarized the recent progress regarding LXRs in inflammatory-related diseases, including the structure, function and anti-inflammatory mechanism of LXRs, in order to provide new methods for preventing and treating inflammatory-related diseases.

Advanced oxidation protein products (AOPPs) are novel biomarkers of oxidative damage to proteins and a novel class of inflammatory mediators. AOPPs can promote oxidative stress (OS) and inflammation and thus participate in many pathophysiological disease processes. Atherosclerosis is a chronic inflammatory disease of blood vessels that is characterized by low-density lipoprotein infiltration into the endothelial intima and the formation of atherosclerotic plaques. Inflammation and OS are established risk factors for the formation of atherosclerosis. Accumulated studies show that AOPPs can accelerate the progression of atherosclerosis through OS and inflammation. Additionally, AOPPs can accelerate the formation of atherosclerotic plaques by inhibiting high-density lipoprotein receptor scavenger receptor class B type I-mediated high-density lipoprotein cholesterol reverse transport, leading to metabolic disturbances. Some studies have suggested that plasma AOPPs levels are independently positively correlated with blood pressure and are also independent risk factors for cardiovascular disease. AOPPs can trigger oxidative bursts of neutrophils, monocytes and phagocytic cells, increase the generation of reactive oxygen species and promote the secretion of cytokines to accelerate endothelial cell injury. Detecting the levels and inhibiting the formation of AOPPs may provide a novel approach to monitor the progress and improve the prognosis of atherosclerosis.

P38 MAPK (mitogen-activated protein kinase) is a critical regulator in lung inflammation. It can be inactivated by DUSP1 (dual-specificity phosphatase 1) which was identified as a putative target of miR-429. miR-429 mimics directly targeted to the 3′-UTR of the gene encoding DUSP1 may result in the translational attenuation of DUSP1. Moreover, the phosphorylation of p38 MAPK was prolonged after miR-429 mimic treatment. Additionally, miR-429 expression was sensitive to LPS (lipopolysaccharide) stimulation and the miR-429 mimics increased the production of pro-inflammatory cytokines. However, anti-miR-429 reduced the LPS-induced production of pro-inflammatory cytokines. These results provide direct evidence that miR-429 is involved in the LPS-induced inflammatory response. In parallel with miR-429, miR-200b and miR-200c, but not miR-200a or miR-141, shared similar effects. In vivo, LPS induced the expression of miR-429, miR-200b and miR-200c in lung. At the same time, inhibiting these miRNAs by anti-miRNAs attenuated the LPS-induced pulmonary inflammatory response and injury. These findings reveal that miR-429 possesses pro-inflammatory activities and may be a potential therapy target for LPS-induced lung injury.