Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been shown to be renoprotective in ischemia-reperfusion (I/R) injury, with several proposed mechanisms, though additional mechanisms likely exist. This study investigated the impact of luseogliflozin on kidney fibrosis at 48 h and 1 week post I/R injury in C57BL/6 mice. Luseogliflozin attenuated kidney dysfunction and the acute tubular necrosis score on day 2 post I/R injury, and subsequent fibrosis at 1 week, as determined by Sirius red staining. Metabolomics enrichment analysis of I/R-injured kidneys revealed suppression of the glycolytic system and activation of mitochondrial function under treatment with luseogliflozin. Western blotting showed increased nutrient deprivation signaling with elevated phosphorylated AMP-activated protein kinase and Sirtuin-3 in luseogliflozin-treated kidneys. Luseogliflozin-treated kidneys displayed increased protein levels of carnitine palmitoyl transferase 1α and decreased triglyceride deposition, as determined by oil red O staining, suggesting activated fatty acid oxidation. Luseogliflozin prevented the I/R injury-induced reduction in nuclear factor erythroid 2-related factor 2 activity. Western blotting revealed increased glutathione peroxidase 4 and decreased transferrin receptor protein 1 expression. Immunostaining showed reduced 4-hydroxynonenal and malondialdehyde levels, especially in renal tubules, indicating suppressed ferroptosis. Luseogliflozin may protect the kidney from I/R injury by inhibiting ferroptosis through oxidative stress reduction.

BACKGROUND: Despite advancements in reconstructive procedures, ischemia-reperfusion (I/R) injury remains a significant challenge in reconstructive surgery, with mitochondrial dysfunction playing a pivotal role. Mitochondrial transplantation has emerged as a promising therapeutic strategy to address this issue. This study aims to evaluate the impact of umbilical cord mesenchymal stem cell-derived mitochondrial transplantation on skin flap I/R models in rats.
METHODS: Twenty male rats underwent I/R injury on skin flaps, with or without mitochondrial transplantation administered via intravenous or subcutaneous routes. Analysis encompassed histopathology, inflammatory, apoptotic, oxidative stress, and hypoxia markers.
RESULTS: Results revealed a reduction in inflammation, apoptosis, oxidative stress, and hypoxia in the transplantation group compared to controls.
CONCLUSIONS: The findings suggest that umbilical cord mesenchymal stem cell-derived mitochondrial transplantation shows promise in enhancing flap viability and attenuating I/R injury, offering valuable insights for improved outcomes in reconstructive surgery. However, further exploration in larger animal models and refinement of delivery methods and dosage are warranted to fully elucidate its clinical translatability.

Kidney diseases pose a global healthcare burden, with millions requiring renal replacement therapy. Ischemia/reperfusion injury (IRI) is a common pathology of acute kidney injury, causing hypoxia and subsequent inflammation-induced kidney damage. Accurate detection of acute kidney injury due to IRI is crucial for timely intervention. We used longitudinal, multi-parametric magnetic resonance imaging (MRI) employing arterial spin labelling (ASL), diffusion weighted imaging (DWI), and dynamic contrast enhanced (DCE)-MRI to assess IRI induced changes in both the injured and healthy contralateral kidney, in a unilateral IRI mouse model (n = 9). Multi-parametric MRI demonstrated significant differences in kidney volume (p = 0.001), blood flow (p = 0.002), filtration coefficient (p = 0.038), glomerular filtration rate (p = 0.005) and apparent diffusion coefficient (p = 0.048) between the injured kidney and contralateral kidney on day 1 post-IRI surgery. Identification of the injured kidney using principal component analysis including most of the imaging parameters demonstrated an area under the curve (AUC) of 0.97. These results point to the utility of multi-parametric MRI in early detection of IRI-induced kidney damage suggesting that the combination of various MRI parameters may be suitable for monitoring the extent of injury in this model.

BACKGROUND: Ischemia reperfusion (IR) causes impaired myocardial function, and autophagy activation ameliorates myocardial IR injury. Isoliquiritigenin (ISO) has been found to protect myocardial tissues via AMPK, with exerting anti-tumor property through autophagy activation. This study aims to investigate ISO capacity to attenuate myocardial IR through autophagy activation mediated by AMPK/mTOR/ULK1 signaling.
METHODS: ISO effects were explored by SD rats and H9c2 cells. IR rats and IR-induced H9c2 cell models were established by ligating left anterior descending (LAD) coronary artery and hypoxia/re-oxygenation, respectively, followed by low, medium and high dosages of ISO intervention (Rats: 10, 20, and 40 mg/kg; H9c2 cells: 1, 10, and 100 μmol/L). Myocardial tissue injury in rats was assessed by myocardial function-related index, HE staining, Masson trichrome staining, TTC staining, and ELISA. Autophagy of H9c2 cells was detected by transmission electron microscopy (TEM) and immunofluorescence. Autophagy-related and AMPK/mTOR/ULK1 pathway-related protein expressions were detected with western blot.
RESULTS: ISO treatment caused myocardial function improvement, and inhibition of myocardial inflammatory infiltration, fibrosis, infarct area, oxidative stress, CK-MB, cTnI, and cTnT expression in IR rats. In IR-modeled H9c2 cells, ISO treatment lowered apoptosis rate and activated autophagy and LC3 fluorescence expression. In vivo and in vitro, ISO intervention exhibited enhanced Beclin1, LC3II/LC3I, and p-AMPK/AMPK levels, whereas inhibited P62, p-mTOR/mTOR and p-ULK1(S757)/ULK1 protein expression, activating autophagy and protecting myocardial tissues from IR injury.
CONCLUSIONS: ISO treatment may induce autophagy by regulating AMPK/mTOR/ULK1 signaling, thereby improving myocardial IR injury, as a potential candidate for treatment of myocardial IR injury.

Liver transplantation has evolved into a mature clinical field but scarcity of usable organs poses a unique challenge. Expanding the donor pool requires novel approaches for protecting hepatic physiology and cellular homeostasis. Here we define hepatocellular injury during transplantation, with an emphasis on modifiable cell death pathways as future therapeutics.

Chronic kidney disease (CKD) has emerged as a significant global public health concern. Recent epidemiological studies have highlighted the link between exposure to fine particulate matter (PM2.5) and a decline in renal function. PM2.5 exerts harmful effects on various organs through oxidative stress and inflammation. Acute kidney injury (AKI) resulting from ischaemia-reperfusion injury (IRI) involves biological processes similar to those involved in PM2.5 toxicity and is a known risk factor for CKD. The objective of this study was to investigate the impact of PM2.5 exposure on IRI-induced AKI. Through a unique environmentally controlled setup, mice were exposed to urban PM2.5 or filtered air for 12 weeks before IRI followed by euthanasia 48 h after surgery. Animals exposed to PM2.5 and IRI exhibited reduced glomerular filtration, impaired urine concentration ability, and significant tubular damage. Further, PM2.5 aggravated local innate immune responses and mitochondrial dysfunction, as well as enhancing cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway activation. This increased renal senescence and suppressed the anti-ageing protein klotho, leading to early fibrotic changes. In vitro studies using proximal tubular epithelial cells exposed to PM2.5 and hypoxia/reoxygenation revealed heightened activation of the STING pathway triggered by cytoplasmic mitochondrial DNA, resulting in increased tubular damage and a pro-inflammatory phenotype. In summary, our findings imply a role for PM2.5 in sensitising proximal tubular epithelial cells to IRI-induced damage, suggesting a plausible association between PM2.5 exposure and heightened susceptibility to CKD in individuals experiencing AKI. Strategies aimed at reducing PM2.5 concentrations and implementing preventive measures may improve outcomes for AKI patients and mitigate the progression from AKI to CKD. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Myocardial ischemia-reperfusion injury (MIRI) is a common clinic scenario that occurs in the context of reperfusion therapy for acute myocardial infarction. It has been shown that cocaine and amphetamine-regulated transcript (CART) can ameliorate cerebral ischemia-reperfusion (I/R) injury, but the effect of CART on MIRI has not been studied yet. Here, we revealed that CART protected the heart during I/R process by inhibiting apoptosis and excessive autophagy, indicating that CART would be a potential drug candidate for the treatment of MIRI. Further analysis showed that CART upregulated the activation of phospho-AKT, leading to downregulation of lactate dehydrogenase (LDH) release, apoptosis, oxidative stress and excessive autophagy after I/R, which was inhibited by PI3K inhibitor, LY294002. Collectively, CART attenuated MIRI through inhibition of cardiomyocytes apoptosis and excessive autophagy, and the protective effect was dependent on PI3K/AKT signalling pathway.

Background: The effects of sodium-glucose cotransporter-2 (SGLT-2) inhibitors on ischemia reperfusion injury (IRI) is a novel concept and only limited number of animals studies have yet been investigated. We aimed to perform a systematic review of literature to explore the clinical studies which investigated the effects of SGLT-2 inhibitors on myocardial IRI setting.Methods: We searched MEDLINE, Embase, and Cochrane Library from inception until December 7th, 2023. ClinicalTrials.gov was also explored for ongoing studies. Two authors independently conducted the literature search, examined the studies, and evaluated the eligibility criteria. Any disagreements or uncertainties were resolved by the corresponding author. The search strategy followed the PICO process (Population, Intervention, Comparison, and Outcome) and Emtree was used to select relevant keywords.Results: Of 220 articles identified from the literature research, five articles were included in the study, of which three studies lately were retracted. The remaining studies included 1229 participants, with 209 receiving SGLT-2 inhibitors and 1090 not receiving them. All of the participants were diabetic patients admitted with acute myocardial infarction (AMI), undergoing percutaneous coronary intervention (PCI). The results demonstrated that the use of SGLT-2 inhibitors is associated with lower troponin levels, and higher rates of ST resolution. The results of the studies also showed smaller infarct sizes, lower inflammatory biomarkers and improved left ventricular function at discharge among SGLT-2 inhibitor users.Conclusion: In line with in vivo and ex vivo findings, the results of this systematic review supported benefits of SGLT-2 inhibitors in IRI through reducing infarct size and inflammatory biomarkers. However, further clinical trials are warranted to provide robust evidence.

Ischemia-reperfusion injury (IRI) is a complex phenomenon. Although researchers have long been aware of IRI, its complex signaling events and potential therapeutic targets are still an active research area. The role of reactive oxygen species in IRI has garnered great interest among scientists. Recent studies have found that reactive oxygen species produced by IRI can activate redox-sensitive transient receptor potential channels (redox TRPs). The discovery of redox TRPs provides a new perspective for understanding the mechanism of IRI.

BACKGROUND: Renal ischemia reperfusion injury is a major cause of perioperative acute kidney injury. Alpha-1-antitrypsin (AAT), a protease inhibitor, might improve outcomes by reducing inflammation and apoptosis. We investigated the effects of a single intravenous dose of AAT immediately before ischemia in a rat bilateral renal clamping model.
METHODS: Both renal pedicles of male Sprague-Dawley rats were clamped (45 min). Plasma and renal tissue were collected at 3 h, 24 h, and 7 d. Intravenous AAT (60 mg/kg) was administered 5 min before clamping. Controls received saline. Shams underwent surgery without clamping or injection. Kidney function was assessed by plasma creatinine; injury by aspartate aminotransferase, heart-type-fatty-acid-binding-protein, and histopathology. Renal gene expression of tumor necrosis factor α, interleukin (IL)-6, heat shock protein 70, Chemokine (C-X-C motif) ligand 2, cyclo-oxygenase 2, endothelin-1, IL-10, heme oxygenase 1, B-cell lymphoma 2, and bcl-2-like protein 4 were determined by quantitative reverse transcriptase polymerase chain reaction.
RESULTS: None of the 3 h and 24 h end points were different between Control and AAT. In Sham, survival was 100% (6/6), 33% in Control (2/6), and 83% (5/6) in AAT (overall log-rank 0.03). At 7 d, plasma creatinine was lower with higher glomerular filtration rate in surviving AAT treated animals compared to Control (P < 0.001, P 0.03, respectively). These also had lower tumor necrosis factor α and IL-6 gene expression (P 0.001, P < 0.001, respectively).
CONCLUSIONS: These data suggest that a single intravenous dose of AAT immediately before ischemia might affect proinflammatory gene expression, glomerular filtration rate and animal survival at 1 wk after reperfusion despite an absence of improvement in early renal function and injury. These findings deserve further investigating in sufficiently powered studies including both sexes.