The ischemia-reperfusion process of a donor heart during heart transplantation leads to severe mitochondrial dysfunction, which may be the main cause of donor heart dysfunction after heart transplantation. Pyruvate carboxylase (PC), an enzyme found in mitochondria, is said to play a role in the control of oxidative stress and the function of mitochondria. This research examined the function of PC and discovered the signaling pathways controlled by PC in myocardial IRI. We induced IRI using a murine heterotopic heart transplantation model in vivo and a hypoxia-reoxygenation cell model in vitro and evaluated inflammatory responses, oxidative stress levels, mitochondrial function, and cardiomyocyte apoptosis. In both in vivo and in vitro settings, we observed a significant decrease in PC expression during myocardial IRI. PC knockdown aggravated IRI by increasing MDA content, LDH activity, TUNEL-positive cells, serum cTnI level, Bax protein expression, and the level of inflammatory cytokines and decreasing SOD activity, GPX activity, and Bcl-2 protein expression. PC overexpression yielded the opposite findings. Additional research indicated that reducing PC levels could block the Wnt/β-catenin pathway and glutamine metabolism by hindering the movement of β-catenin to the nucleus and reducing the activity of complex I and complex II, as well as ATP levels, while elevating the ratios of NADP+/NADPH and GSSG/GSH. Overall, the findings indicated that PC therapy can shield the heart from IRI during heart transplantation by regulating glutamine metabolism through the Wnt/β-catenin pathway.

The innate immune system is the body\'s natural defense system, which recognizes a wide range of microbial molecules (such as bacterial DNA and RNA) and abnormal molecules within cells (such as misplaced DNA, self-antigens) to play its role. DNA released into the cytoplasm activates the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway to initiate an immune response. Ischemia-reperfusion injury (IRI) after acute myocardial infarction refers to the phenomenon where myocardial tissue suffers further damage upon the restoration of blood flow. This issue is a significant clinical problem in the treatment of myocardial infarction, as it can diminish the effectiveness of reperfusion therapy and lead to further deterioration of cardiac function. Studies have found that the cGAS-STING signaling pathway is closely related to this phenomenon. Therefore, this review aims to describe the role of the cGAS-STING signaling pathway in ischemia-reperfusion injury after myocardial infarction and summarize the current development status of cGAS-STING pathway inhibitors and the application of nanomaterials to further elucidate the potential of this pathway as a therapeutic target.

BACKGROUND: Abdominal aortic aneurysms and peripheral artery disease pose significant health risks, ranking third after heart attacks and cerebral strokes. Surgical interventions often involve temporary aortic clamping, leading to ischemia-reperfusion injury and tissue damage. Colchicine and mesenchymal stem cells have shown promise, individually, in mitigating ischemia-reperfusion injury, but their combined effects remain understudied.
METHODS: This study utilized 42 male Wistar rats, divided into six groups: Control, Sham, Ischemia-Reperfusion, Colchicine, Mesenchymal stem cell, and Mix (colchicine and mesenchymal stem cell). The ischemia-reperfusion model involved clamping the abdominal aorta for 60 min, followed by 120 min of reperfusion. Colchicine and mesenchymal stem cell treatments were administered as pre- and post-ischemia interventions, respectively. Mesenchymal stem cells were cultured, characterized by flow cytometry, and verified for specific surface antigens. Blood and tissue samples were analyzed for oxidative stress markers, nitric oxide metabolites, and apoptosis using TUNEL.
RESULTS: There were significant differences between the groups in terms of the serum total antioxidant capacity (p < 0.001) and inflammation markers (ischemia-modified albumin, p = 0.020). The combined therapy group (Mix) exhibited the lowest inflammation levels. Arginine levels also showed significant variation (p = 0.028), confirming the ischemia-reperfusion injury model. In muscle tissues, the total antioxidant capacity (p = 0.022), symmetric dimethylarginine, and citrulline levels (p < 0.05) indicated nitric oxide metabolism. Apoptosis was notably high in the ischemia-reperfusion injury group as anticipated. It appeared to be reduced by colchicine, mesenchymal stem cells, and their combination, with the most significant decrease observed in the Mix group (p < 0.001).
CONCLUSIONS: This study highlights the potential of using combined colchicine and mesenchymal stem cell therapy to reduce muscle damage caused by ischemia-reperfusion injury. Further research is needed to understand the underlying mechanisms and confirm the clinical significance of this approach in treating extremity ischemia-reperfusion injuries.

MicroRNAs (miRNAs) are the short endogenous non-coding RNAs that regulate the expression of the target gene at posttranscriptional level through degrading or inhibiting the specific target messenger RNAs (mRNAs). MiRNAs regulate the expression of approximately one-third of protein coding genes, and in most cases inhibit gene expression. MiRNAs have been reported to regulate various biological processes, such as cell proliferation, apoptosis and differentiation. Therefore, miRNAs participate in multiple diseases, including ischemia-reperfusion (I/R) injury. Hydrogen sulfide (H2S) was once considered as a colorless, toxic and harmful gas with foul smelling. However, in recent years, it has been discovered that it is the third gas signaling molecule after carbon monoxide (CO) and nitric oxide (NO), with multiple important biological functions. Increasing evidence indicates that H2S plays a vital role in I/R injury through regulating miRNA, however, the mechanism has not been fully understood. In this review, we summarized the current knowledge about the role of H2S in I/R injury by regulating miRNAs, and analyzed its mechanism in detail.

UNASSIGNED: Cardiac surgery-associated acute kidney injury (CSA-AKI) is a serious complication in patients undergoing cardiac surgery with extracorporeal circulation (ECC) that increases postoperative complications and mortality. CSA-AKI develops due to a combination of patient- and surgery-related risk factors that enhance renal ischemia-reperfusion injury. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) such as empagliflozin reduce renal glucose reabsorption, improving tubulo-glomerular feedback, reducing inflammation and decreasing intraglomerular pressure. Preclinical studies have observed that SGLT2i may provide significant protection against renal ischemia-reperfusion injury due to their effects on inadequate mitochondrial function, reactive oxygen species activity or renal peritubular capillary congestion, all hallmarks of CSA-AKI. The VERTIGO (EValuating the Effect of periopeRaTIve empaGliflOzin) trial is a Phase 3, investigator-initiated, randomized, double-blind, placebo-controlled, multicenter study that aims to explore whether empagliflozin can reduce the incidence of adverse renal outcomes in cardiac surgery patients.
UNASSIGNED: The VERTIGO study (EudraCT: 2021-004938-11) will enroll 608 patients that require elective cardiac surgery with ECC. Patients will be randomly assigned in a 1:1 ratio to receive either empagliflozin 10 mg orally daily or placebo. Study treatment will start 5 days before surgery and will continue during the first 7 days postoperatively. All participants will receive standard care according to local practice guidelines. The primary endpoint of the study will be the proportion of patients that develop major adverse kidney events during the first 90 days after surgery, defined as ≥25% renal function decline, renal replacement therapy initiation or death. Secondary, tertiary and safety endpoints will include rates of AKI during index hospitalization, postoperative complications and observed adverse events.
UNASSIGNED: The VERTIGO trial will describe the efficacy and safety of empagliflozin in preventing CSA-AKI. Patient recruitment is expected to start in May 2024.

β3-Adrenergic receptor (β3AR) agonists have been shown to protect against ischemia-reperfusion injury (IRI). Since β3ARs are present both in cardiomyocytes and in endothelial cells, the cellular compartment responsible for this protection has remained unknown. Using transgenic mice constitutively expressing the human β3AR (hβ3AR) in cardiomyocytes or in the endothelium on a genetic background of null endogenous β3AR expression, we show that only cardiomyocyte expression protects against IRI (45 min ischemia followed by reperfusion over 24 h). Infarct size was also limited after ischemia-reperfusion in mice with cardiomyocyte hβ3AR overexpression on top of endogenous β3AR expression. hβ3AR overexpression in these mice reduced IRI-induced cardiac fibrosis and improved long-term left ventricular systolic function. Cardiomyocyte-specific β3AR overexpression resulted in a baseline remodeling of the mitochondrial network, characterized by upregulated mitochondrial biogenesis and a downregulation of mitochondrial quality control (mitophagy), resulting in elevated numbers of small mitochondria with a depressed capacity for the generation of reactive oxygen species but improved capacity for ATP generation. These processes precondition cardiomyocyte mitochondria to be more resistant to IRI. Upon reperfusion, hearts with hβ3AR overexpression display a restoration in the mitochondrial quality control and a rapid activation of antioxidant responses. Strong protection against IRI was also observed in mice infected with an adeno-associated virus (AAV) encoding hβ3AR under a cardiomyocyte-specific promoter. These results confirm the translational potential of increased cardiomyocyte β3AR expression, achieved either naturally through exercise or artificially through gene therapy approaches, to precondition the cardiomyocyte mitochondrial network to withstand future insults.

UNASSIGNED: Microcirculatory perfusion disorder and inflammatory response are critical links in acute kidney injury (AKI). We aim to construct anti-vascular cell adhesion molecule-1(VCAM-1) targeted microbubbles (TM) to monitor renal microcirculatory perfusion and inflammatory response.
UNASSIGNED: TM carrying VCAM-1 polypeptide was constructed by biological coupling. The binding ability of TM to human umbilical vein endothelial cells (HUVECs) was detected. Bilateral renal ischemia-reperfusion injury (IRI) models of mice were established to evaluate microcirculatory perfusion and inflammatory response using TM. Thirty-six mice were randomly divided into six groups according to the different reperfusion time (0.5, 2, 6, 12, and 24 h) and sham-operated group (Sham group). The correlation of TM imaging with serum and histopathological biomarkers was investigated.
UNASSIGNED: TM has advantages such as uniform distribution, regular shape, high stability, and good biosafety. TM could bind specifically to VCAM-1 molecule expressed by tumor necrosis factor-alpha (TNF-α)-treated HUVECs. In the renal IRI-AKI model, the area under the curve (AUC) of TM significantly decreased both in the renal cortical and medullary after 2 h of reperfusion compared with the Sham group (p < 0.05). Normalized intensity difference (NID) of TM at different reperfusion time was all higher than that of blank microbubbles (BM) and the Sham group (p < 0.05). Ultrasound molecular imaging of TM could detect AKI early before commonly used renal function markers, histopathological biomarkers, and BM imaging. AUC of TM was negatively correlated with serum creatinine (Scr), blood urea nitrogen (BUN), and Cystatin C (Cys-C) levels, and NID of TM was linearly correlated with VCAM-1, TNF-α, and interleukin-6 (IL-6) expression (p < 0.05).
UNASSIGNED: Ultrasound molecular imaging based on TM carrying VCAM-1 polypeptide can accurately evaluate the changes in renal microcirculatory perfusion and inflammatory response, which might be a promising modality for early diagnosis of AKI.

UNASSIGNED: Patients with cirrhosis undergoing liver transplantation frequently exhibit systemic inflammation, coagulation derangements, and edema, indicating endothelial dysfunction. This syndrome may worsen after ischemia-reperfusion injury of the liver graft, coincident with organ dysfunction that worsens patient outcomes. Little is known about changes in endothelial permeability during liver transplantation. We hypothesized that sera from these patients would increase permeability in cultured human endothelial cells ex vivo.
UNASSIGNED: Adults with cirrhosis presenting for liver transplantation provided consent for blood collection during surgery. Sera were prepared at five time points spanning the entire operation. The barrier function of human pulmonary microvascular endothelial cells in culture was assessed by transendothelial resistance measured using the ECIS ZΘ system. Confluent cells from two different endothelial cell donors were stimulated with human serum from liver transplant patients. Pooled serum from healthy men and purified inflammatory agonists served as controls. The permeability response to serum was quantified as the area under the normalized resistance curve. Responses were compared between time points and analyzed for associations with clinical characteristics of liver transplant patients and their grafts.
UNASSIGNED: Liver transplant sera from all time points during surgery-induced permeability in both endothelial cell lines. The magnitude of permeability change was heterogeneous between patients, and there were differences in the effects of sera on the two endothelial cell lines. In one of the cell lines, the severity of liver disease was associated with greater permeability at the start of surgery. In the same cell line, serum collected 15 min after liver reperfusion induced significantly more permeability as compared to that collected at the start of surgery. Early postreperfusion sera from patients undergoing living donor transplants induced more permeability than sera from deceased donor transplants. Sera from two exemplary cases of patients on preoperative dialysis, and one patient with an unexpectedly long warm ischemia time of the liver graft, induced exaggerated and prolonged endothelial permeability.
UNASSIGNED: Serum from patients with cirrhosis undergoing liver transplantation induces permeability of cultured human pulmonary microvascular endothelial cells. Increased endothelial permeability during liver transplantation may contribute to organ injury and present a target for future therapeutics.

Hemorrhagic shock (HS), a leading cause of preventable death, is characterized by severe blood loss and inadequate tissue perfusion. Reoxygenation of ischemic tissues exacerbates organ damage through ischemia-reperfusion injury. SUMOylation has been shown to protect neurons after stroke and is upregulated in response to cellular stress. However, the role of SUMOylation in organ protection after HS is unknown. This study aimed to investigate SUMOylation-mediated organ protection following HS. Male Wistar rats were subjected to HS (blood pressure of 40 ± 2 mmHg, for 90 min) followed by reperfusion. Blood, kidney, and liver samples were collected at various time points after reperfusion to assess organ damage and investigate the profile of SUMO1 and SUMO2/3 conjugation. In addition, human kidney cells (HK-2), treated with the SUMOylation inhibitor TAK-981 or overexpressing SUMO proteins, were subjected to oxygen and glucose deprivation to investigate the role of SUMOylation in hypoxia/reoxygenation injury. The animals presented progressive multiorgan dysfunction, except for the renal system, which showed improvement over time. Compared to the liver, the kidneys displayed distinct patterns in terms of oxidative stress, apoptosis activation, and tissue damage. The global level of SUMO2/3 in renal tissue was also distinct, suggesting a differential role. Pharmacological inhibition of SUMOylation reduced cell viability after hypoxia-reoxygenation damage, while overexpression of SUMO1 or SUMO2 protected the cells. These findings suggest that SUMOylation might play a critical role in cellular protection during ischemia-reperfusion injury in the kidneys, a role not observed in the liver. This difference potentially explains the renal resilience observed in HS animals when compared to other systems.

Numerous natural antioxidants commonly found in our daily diet have demonstrated significant benefits for human health and various diseases by counteracting the impact of reactive oxygen and nitrogen species. Their chemical properties enable a range of biological actions, including antihypertensive, antimicrobial, anti-inflammatory, anti-fibrotic, and anticancer effects. Despite promising outcomes from preclinical studies, ongoing debate persists regarding their reproducibility in human clinical models. This controversy largely stems from a lack of understanding of the pharmacokinetic properties of these compounds, coupled with the predominant focus on monotherapies in research, neglecting potential synergistic effects arising from combining different antioxidants. This study aims to provide an updated overview of natural antioxidants, operating under the hypothesis that a multitherapeutic approach surpasses monotherapy in efficacy. Additionally, this study underscores the importance of integrating these antioxidants into the daily diet, as they have the potential to prevent the onset and progression of various diseases. To reinforce this perspective, clinical findings pertaining to the treatment and prevention of non-alcoholic fatty liver disease and conditions associated with ischemia and reperfusion phenomena, including myocardial infarction, postoperative atrial fibrillation, and stroke, are presented as key references.