Naoxintong capsule accelerates mitophagy in cerebral ischemia-reperfusion injury via TP53/PINK1/PRKN pathway based on network pharmacology analysis and experimental validation.

ETHNOPHARMACOLOGICAL RELEVANCE: The incidence and mortality of cerebrovascular diseases are increasing year by year. Cerebral ischemia-reperfusion injury (CIRI) is common in patients with ischemic stroke. Naoxintong (NXT) is composed of a variety of Chinese medicines and has the ability to treat CIRI. AIM OF THE STUDY: The aim of this study is to investigate whether NXT regulates mitophagy in CIRI based on network pharmacology analysis and experimental validation. MATERIALS AND METHODS: Oxygen and glucose deprivation/re-oxygenation (OGD/R, 2/22 h) model of PC12 cells and transient middle cerebral artery occlusion (tMCAO, 2/22 h) model of rats were established. Pharmacodynamic indicators include neurological deficit score, 2,3,5-triphenyte-trazoliumchloride (TTC) staining, hematoxylin-eosin (HE) staining and cell viability. Network pharmacology was used to predict pharmacological mechanisms. Pharmacological mechanism indexes include transmission electron microscopy (TEM), drug affinity responsive target stability (DARTS), cellular thermal shift assay (CETSA), immunohistochemistry (IHC), western blot (WB) and immunofluorescence (IF). Kevetrin (an agonists of p53) and pifithrin-α (an inhibitor of p53) used to detect the key role of p53 in mitophagy of NXT. RESULTS: NXT (1% serum containing NXT and 110 mg/kg) improved the damage of OGD/R PC12 cells and tMCAO rats, and this protective effect was related to the anti-oxidation and ability to promote mitophagy of NXT. NXT and pifithrin-α increased the expression of promoting-mitophagy targets (PINK1, PRKN and LC3B) and inhibited the expression of inhibiting-mitophagy targets (p52) via restraining p53, and finally accelerated mitophagy caused by CIRI. CONCLUSION: This study demonstrates that NXT promotes mitophagy in CIRI through restraining p53 and promoting PINK1/PRKN in vivo and in vitro.

Melastoma dodecandrum lour. Protects against cerebral ischemia-reperfusion injury by ameliorating oxidative stress and endoplasmic reticulum stress.

ETHNOPHARMACOLOGICAL RELEVANCE: Melastoma dodecandrum Lour. (MD), a traditional Chinese medicine used by the She ethnic group, has been used to treat cerebral ischemia-reperfusion (CIR) injury due to its efficacy in promoting blood circulation and removing blood stasiss; however, the therapeutic effects and mechanisms of MD in treating CIR injury remain unclear. AIM: To investigate the protective effects of MD on CIR injury, in addition to its impact on oxidative stress, endoplasmic reticulum (ER) stress, and cell apoptosis. MATERIALS AND METHODS: The research was conducted using both cell experiments and animal experiments. The CCK-8 method, immunofluorescence staining, and flow cytometry were used to analyze the effects of MD-containing serum on oxygen-glucose deprivation/reperfusion (OGD/R)-induced PC12 cell viability, reactive oxygen species (ROS) clearance, anti-inflammatory, neuroprotection and inhibition of apoptosis. Furthermore, 2,3,5-Triphenyl tetrazolium chloride staining, hematoxylin and eosin staining, Nissl staining, and immunohistochemistry were used to detect infarct size, pathological changes, Nissl corpuscula and neuronal protein expression in middle cerebral artery occlusion (MCAO) rats. Polymerase chain reaction and Western Blotting were conducted in cell and animal experiments to detect the expression levels of ER stress-related genes and proteins. RESULTS: The MD extract enhanced the viability of PC12 cells under OGD/R modeling, reduced ROS and IL-6 levels, increased MBP levels, and inhibited cell apoptosis. Furthermore, MD improved the infarct area in MCAO rats, increased the number of Nissl bodies, and regulated neuronal protein levels including Microtubule-Associated Protein 2 (MAP-2), Myelin Basic Protein (MBP), Glial Fibrillary Acidic Protein (GFAP), and Neurofilament 200 (NF200). Additionally, MD could regulate the expression levels of oxidative stress proteins malondialdehyde (MDA), nitric oxide (NO), superoxide dismutase (SOD), and catalase (CAT). Both cell and animal experiments demonstrated that MD could inhibit ER stress-related proteins (GRP78, ATF4, ATF6, CHOP) and reduce cell apoptosis. CONCLUSION: This study confirmed that the therapeutic mechanism of the MD extract on CIR injury was via the inhibition of oxidative stress and the ER stress pathway, in addition to the inhibition of apoptosis.

Intestinal ischemia: A rare and less common complication after laparoscopic cholecystectomy-A case report and literature review.

Key Clinical Message: Patients with a history of persistent mesenteric ischemia should not undergo laparoscopy. Mesenteric ischemia must be kept in mind for patients who develop nonspecific abdominal symptoms following laparoscopic surgeries. Abstract: During laparoscopic cholecystectomy (LC), the rise in Intra-Abdominal Pressure due to carbon dioxide insufflation can reduce blood flow through splanchnic vessels, potentially leading to intestinal ischemia. A 72-year-old woman with a history of diabetes, hypertension, ischemic heart disease, and hyperlipidemia underwent LC. She was discharged but readmitted 4 days later due to peritonitis. Ischemic jejunum loops were found during surgery.

Alpha B-crystallin Ameliorates Imbalance of Redox Homeostasis, Inflammation and Apoptosis in an Acute Lung Injury Model with Rats.

Objective: Ischemia-reperfusion (IR) of the aorta is a significant contributor to the development of postoperative acute lung damage after abdominal aortic surgery. The aim of the present study was to examine the effect of alpha B-crystallin, a small heat shock protein (known as HspB5), on lung injury induced by abdominal aortic IR in rats. Methods: Male Sprague-Dawley rats were divided into three groups: control, ischemia-reperfusion (IR, 90 min ischemia and 180 min reperfusion), and alpha B-crystallin +IR. Alpha B-crystallin (50 µg/100 g) was intraperitoneally administered 1 h before IR. Lung tissue samples were obtained for histological and biochemical analyses of oxidative stress and cytokine and apoptosis parameters in plasma, lung tissues, and bronchoalveolar lavage (BAL) fluid. Results: The levels of malondialdehyde, reactive oxygen species, total oxidant status, tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1ß), nuclear factor kappa B (NFKß), caspase-9 (CASP-9), 8-hydroxy-2'-deoxyguanosine, total antioxidant status, superoxide dismutase, and interleukin-10 levels in lung tissues, plasma, and BAL fluid (p<0.05 versus control) increased in Aortic IR. However, alpha B-crystallin significantly reduced the lung tissue levels of oxidative, inflamatuvar, and apoptotic parameters in the plasma, lung tissues, and BAL fluid (p<0.05 versus aortic IR). Histopathological results showed that alpha B-crystallin ameliorated the morphological changes related to lung injury (p<0.001). Conclusion: Alpha B-crystallin substantially restored disrupted the redox balance, inflammation, and apoptotic parameters in rats exposed to IR. The cytoprotective effect of alpha B-crystallin on redox balance might be attributed to improved lung injury.

Correlation between prognosis and peripheral blood levels of NLRP3 and triglyceride-glucose index after myocardial ischemia-reperfusion injury.

OBJECTIVE: We aim to investigate the association between prognosis and outcomes following myocardial ischemia-reperfusion injury, as well as peripheral blood levels of NLRP3 and the triglyceride-glucose index (TyG). METHODS: A total of 100 patients who underwent emergency coronary intervention following myocardial infarction confirmed by coronary angiography at our hospital between October 2021 and May 2023 were included in this study. Patients were stratified into two groups based on their prognoses: the control group (n = 73), which did not experience new myocardial infarctions or require hospitalization for heart failure or suffer sudden cardiac death post-interventional treatment; and the observation group (n = 27), which experienced one or more cardiovascular events post-treatment. Patient demographics were obtained from clinical records while biochemical analyses assessed peripheral blood triglycerides, blood glucose levels, and TyG index. Additionally, ELISA measurements determined levels of NLRP3 as well as inflammatory factors IL-6, TNF-α, and CRP in peripheral blood samples. Cardiac function was evaluated according to NYHA standards. Univariable Cox regression analysis identified factors influencing patient prognosis while Pearson correlation analysis examined relationships among prognosis, outcomes following myocardial ischemia-reperfusion injury, TyG index, and peripheral blood NLRP3. RESULTS: No significant differences were observed in the general characteristics between the two patient groups (P > 0.05). However, the observation group exhibited higher levels of peripheral blood triglycerides, blood glucose, and TyG index compared to the control group (P < 0.05). Additionally, levels of NLRP3 and inflammatory factors IL-6, TNF-α, and CRP were elevated in the observation group compared to the control group (P < 0.05). Cardiac function impairment was more pronounced in the observation group (P < 0.05). Notably, TyG index and peripheral blood NLRP3 demonstrated higher risk ratios compared to other biomarkers (P < 0.05), indicating their significance in prognosis and outcomes. Elevated levels of NLRP3 and TyG index were associated with poorer recovery of cardiac function, increased rehospitalization rates, and higher mortality (P < 0.05). CONCLUSION: Elevated NLRP3 levels and an increased TyG index are strongly associated with impaired cardiac function and heightened risk of cardiovascular events. These findings suggest that these biomarkers may serve as crucial prognostic indicators following myocardial ischemia-reperfusion injury.

Infrapopliteal Surgical and Endovascular Intervention.

Infrapopliteal revascularization is generally performed for patients with chronic limb-threatening ischemia. As with revascularization in other fields, the indications for endovascular treatment (EVT) have expanded in recent years due to advances in endovascular devices and techniques. However, the optimal revascularization method must be selected based on (1) patient risk, (2) limb severity, and (3) anatomical pattern of disease. Therefore, vascular surgeons need to understand the characteristics of EVT and surgical treatment and improve their technical skills in both procedures. Here is an overview of the current methods of revascularization. (This is a translation of Jpn J Vasc Surg 2024; 33: 61-65).

Major Lower Limb Amputation for Chronic Limb-Threatening Ischemia Is Associated with Poor Long-Term Survival: 4-Year Follow-Up of a Single-Center Experience.

Objective: Despite advances in medicine, 30% of patients with chronic limb-threatening ischemia (CLTI) require major lower limb amputation (MLLA). The long-term outcome of this cohort is poorly described. Methods: In all, 154 patients undergoing MLLA for CLTI during 2018-2020 were analyzed for short-term and long-term outcomes and prosthesis use. Results: In total, 106 below-knee amputations and 48 above-knee amputations were followed up for a mean duration of 50 months (37-78). The mean age of the cohort was 63 years. The majority were male (60%) with multiple comorbidities, including diabetes (83.8%), hypertension (49.4%), ischemic heart disease (20%), and smoking (32.5%). An equal proportion underwent MLLA as primary (45%) or secondary (55%). 30-day mortality was 6%. The mean length of in-hospital stay was 18 days (3-56). Overall survival rates at 1st, 2nd, and 4th year were 73%, 64%, and 35%, respectively. On a multivariate regression analysis, a higher level of amputation had a significant impact on mortality (p = 0.015). 54% of amputees had a prosthetic limb. However, the primary use of prosthesis was for cosmesis, with only 12% mobile independently. Conclusions: MLLA for CLTI is associated with poor early and long-term survival. Prosthesis use and mobility are extremely poor in the Sri Lankan context.

Revision Surgery for Venous Graft Stenosis of SMA Bypass.

A 67-year-old male with postprandial abdominal pain for 4 months obtained medical attention for severe pain. He was diagnosed with small intestinal necrosis, secondary to chronic mesenteric ischemia by CT scan. We performed the surgery including a partial resection of the small intestine and left external iliac artery to the superior mesenteric artery bypass using saphenous vein graft. His symptoms improved after surgery. However, 5 months later, abdominal pain appeared after eating. A CT scan identified graft stenosis, leading to a revascularization. A synthetic vessel was used to perform the re-bypass surgery. Postoperatively, the patient's abdominal pain improved.

A Comprehensive Study of Risk Factors, Etiology, and Infarction Patterns in Cerebrovascular Accidents at a Tertiary Care Hospital in India.

Background Stroke is a debilitating cerebrovascular condition characterized by sudden neurological deficits. The incidence of stroke is rising in India, posing significant public health concerns. This study aims to examine the risk factors and etiology of stroke using the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification and analyze infarct areas in cerebrovascular accidents (CVA) at a tertiary care hospital. Methodology This cross-sectional, hospital-based observational study was conducted at Dr. D. Y. Patil Medical College, Hospital and Research Centre, Dr. D. Y. Patil Vidyapeeth (Deemed to Be University), Pune, India, from January 2023 to January 2024. The study included 100 adult patients diagnosed with CVA based on clinical and radiological criteria. Patients aged 18 years and older were eligible, while those with a history of head trauma or those below 18 years were excluded. The investigation protocol included routine biochemical assessments and radiological investigations, such as computed tomography (CT), magnetic resonance imaging (MRI) with angiography or venography, and Doppler ultrasound of bilateral carotid arteries. Results The study population consisted of 100 patients, with 84 males (84%) and 16 females (16%). Age distribution showed 44% were over 60 years old, 23% aged 51-60 years, 15% aged 31-40 years, 14% aged 41-50 years, and 4% aged 21-30 years. Hypertension was the most prevalent risk factor, affecting 75% of patients, with a higher occurrence in males (62%), compared to females (13%). Smoking was observed in 51% of patients, and alcohol consumption was seen in 50%. Other significant risk factors included dyslipidemia (39%), diabetes mellitus (33%), chronic kidney disease (11%), ischemic heart disease (10%), atrial fibrillation (4%), valvular heart disease (4%), and pregnancy or postpartum conditions (2%). Ischemic stroke was predominant, occurring in 80% of patients, while hemorrhagic stroke occurred in 20%. High occurrences of ischemic strokes were noted in the frontal lobe (41%), parietal lobe (37%), occipital lobe (27%), and temporal lobe (26%), with the internal capsule region also showing significant numbers (27%). According to the TOAST classification, the most prevalent cause of stroke in this study was undetermined etiology with two or more causes, accounting for 32% of cases, followed by large artery atherosclerosis, which accounted for 30%. Cardioembolic stroke was identified in 11% of the patients, with 4% due to atrial fibrillation, 3% due to acute myocardial infarction, 3% due to rheumatic valvular heart disease, and 1% due to infective endocarditis. Conclusion This study highlights the significant prevalence of hypertension, smoking, alcohol consumption, and hyperhomocysteinemia as major risk factors for stroke. Ischemic strokes were predominant, with high occurrences in the cerebral lobes and gangliocapsular region. These findings emphasize the need for targeted prevention strategies, including managing hypertension and lifestyle modifications such as smoking cessation and reducing alcohol consumption, to mitigate the risk of stroke. Effective management of blood pressure, lipid levels, and blood glucose is crucial for stroke prevention. Recognizing gender-specific differences and addressing comorbidities through an integrated approach can enhance patient outcomes and reduce the burden of stroke.

The role and possible mechanism of the ferroptosis-related SLC7A11/GSH/GPX4 pathway in myocardial ischemia-reperfusion injury.

BACKGROUND: Myocardial ischemia-reperfusion injury (MI/RI) is an unavoidable risk event for acute myocardial infarction, with ferroptosis showing close involvement. We investigated the mechanism of MI/RI inducing myocardial injury by inhibiting the ferroptosis-related SLC7A11/glutathione (GSH)/glutathione peroxidase 4 (GPX4) pathway and activating mitophagy. METHODS: A rat MI/RI model was established, with myocardial infarction area and injury assessed by TTC and H&E staining. Rat cardiomyocytes H9C2 were cultured in vitro, followed by hypoxia/reoxygenation (H/R) modeling and the ferroptosis inhibitor lipoxstatin-1 (Lip-1) treatment, or 3-Methyladenine or rapamycin treatment and overexpression plasmid (oe-SLC7A11) transfection during modeling. Cell viability and death were evaluated by CCK-8 and LDH assays. Mitochondrial morphology was observed by transmission electron microscopy. Mitochondrial membrane potential was detected by fluorescence dye JC-1. Levels of inflammatory factors, reactive oxygen species (ROS), Fe2+, malondialdehyde, lipid peroxidation, GPX4 enzyme activity, glutathione reductase, GSH and glutathione disulfide, and SLC7A11, GPX4, LC3II/I and p62 proteins were determined by ELISA kit, related indicator detection kits and Western blot. RESULTS: The ferroptosis-related SLC7A11/GSH/GPX4 pathway was repressed in MI/RI rat myocardial tissues, inducing myocardial injury. H/R affected GSH synthesis and inhibited GPX4 enzyme activity by down-regulating SLC7A11, thus promoting ferroptosis in cardiomyocytes, which was averted by Lip-1. SLC7A11 overexpression improved H/R-induced cardiomyocyte ferroptosis via the GSH/GPX4 pathway. H/R activated mitophagy in cardiomyocytes. Mitophagy inhibition reversed H/R-induced cellular ferroptosis. Mitophagy activation partially averted SLC7A11 overexpression-improved H/R-induced cardiomyocyte ferroptosis. H/R suppressed the ferroptosis-related SLC7A11/GSH/GPX4 pathway by inducing mitophagy, leading to cardiomyocyte injury. CONCLUSIONS: Increased ROS under H/R conditions triggered cardiomyocyte injury by inducing mitophagy to suppress the ferroptosis-related SLC7A11/GSH/GPX4 signaling pathway activation.

Beyond graft function impairment after liver transplantation: the prolonged cold ischemia time impact on recurrence of hepatocellular carcinoma after liver transplantation-a single-center retrospective study.

Purpose: Hepatocellular carcinoma (HCC) is one of the malignant tumors responsible for high mortality and recurrence rates. Although liver transplantation (LT) is an effective treatment option for HCC, ischemia-reperfusion injury (IRI) is a contributor to HCC recurrence after LT. Moreover, prolonged cold ischemia time (CIT) is a risk factor for IRI during LT, and there is insufficient clinical evidence regarding the impact of CIT on HCC recurrence after LT. Patients and Methods: This retrospective study analyzed 420 patients who underwent LT for HCC between February 2015 and November 2020 at The First Affiliated Hospital, Sun Yat-sen University. The duration of CIT was defined as the time from clamping of the donor aorta until portal reperfusion. Results: A total of 133 patients (31.7%) experienced tumor recurrence after LT, and CIT > 568 min was the independent risk factor for HCC recurrence (OR, 2.406; 95% CI [1.371-4.220]; p = 0.002). Multivariate Cox's regression analysis revealed that the recipients' gender, exceeding Milan criteria, poor differentiation, and alpha-fetoprotein (AFP) ≥400 ng/ml in CIT > 568 min group were independent risk factors for disease-free survival. The peak 7-day postoperative alanine aminotransferase (ALT) level (p < 0.001), the peak 7-day postoperative aspartate aminotransferase (AST) level (p < 0.001), the peak 7-day postoperative peak total bilirubin (TBIL) level (p = 0.012), and the incidence of early allograft dysfunction (EAD) (p = 0.006) were significantly higher in the CIT > 568 min group compared to the CIT ≤ 568 min group. Moreover, the amount of fresh frozen plasma (FFP) infusion during the operation increased (p = 0.02), and the time of mechanical ventilation postoperative was longer (p = 0.045). Conclusion: An effective strategy to improve the prognosis is to reduce CIT; this strategy lowers the recurrence of HCC in patients undergoing LT, especially those within the Milan criteria.

Near-infrared spectroscopy with a provocative maneuver to detect the presence of severe peripheral arterial disease.

Current assessment standards for peripheral arterial disease (PAD), such as the ankle brachial index, are limited in their utility and portability. Near-infrared spectroscopy (NIRS) has shown some promise in diagnosing PAD when used in conjunction with a provocative maneuver. The purpose of this study was to assess the viability of NIRS in conjunction with a transient leg elevation provocative maneuver for detecting severe PAD. This retrospective observational cross-sectional study assessed 57 limbs in 34 patients receiving routine vascular screening for PAD at Madigan Army Medical Center. The patient limbs were stratified into normal (n = 17), mild (n = 9), moderate (n = 16), and severe (n = 15) PAD groups based on the clinician assessments. Additionally, the patients were assessed with NIRS measurements taken with the patient in the supine position at rest and using a provocative leg raise maneuver of transient leg elevation of 45° for 60 seconds. The resting tissue oxygen saturation (StO2) and the change in StO2 (ΔStO2) from rest to elevation were recorded and compared between the PAD severity groups via independent measures analysis of variance with the Tukey honest significant difference post hoc test. The supine resting StO2 was not different between the normal (77.5% ± 7.7%), mild (72.5% ± 7.4%), moderate (72.0% ± 10.3%), and severe (74.2% ± 5.4%) PAD groups (P = .23). However, the ΔStO2 with transient leg elevation was significantly greater in the severe PAD group (-17.2% ± 6.0%) compared with the normal (-3.9% ± 4.8%), mild (-6.9% ± 4.7%), and moderate (-9.7% ± 5.2%) PAD groups (P < .002 for all). Similar results were observed in the changes in oxyhemoglobin and deoxyhemoglobin. The leg elevation protocol was also used for two patients before and after lower limb revascularization, which demonstrated that the ΔStO2 corresponded with the clinical assessment of PAD severity. Resting supine NIRS images were unable to detect any differences among normal and limbs with different PAD severity. However, NIRS imaging with 45° leg elevation for 60 seconds showed a significant difference between severe PAD compared healthy patients and those with mild to moderate PAD in a fast, precise, and accurate manner. These preliminary data support the use of NIRS and transient leg elevation as a tool to diagnose severe PAD but do not support the use of NIRS alone as a screening test for PAD. NIRS measurements with leg elevation might be a viable noninvasive, noncontact, and portable method of assessing severe PAD for home monitoring, in rural communities, and/or in standard clinical practice.

Ultra-Small Copper-Based Multienzyme-Like Nanoparticles Protect Against Hepatic Ischemia-Reperfusion Injury Through Scavenging Reactive Oxygen Species in Mice.

Hepatic ischemia-reperfusion injury (IRI) is a severe complication that occurs in the process of liver transplantation, hepatectomy, and other end-stage liver disease surgery, often resulting in the failure of surgery operation and even patient death. Currently, there is no effective way to prevent hepatic IRI clinically. Here, it is reported that the ultra-small copper-based multienzyme-like nanoparticles with catalase-like (CAT-like) and superoxide dismutase-like (SOD-like) catalytic activities significantly scavenge the surge-generated endogenous reactive oxygen species (ROS) and effectively protects hepatic IRI. Density functional theory calculations confirm that the nanoparticles efficiently scavenge ROS through their synergistic effects of the ultra-small copper SOD-like activity and manganese dioxides CAT-like activity. Furthermore, the results show that the biocompatible CMP NPs significantly protected hepatocytes from IRI in vitro and in vivo. Importantly, their therapeutic effect is much stronger than that of N-acetylcysteamine acid (NAC), an FDA-approved antioxidative drug. Finally, it is demonstrated that the protective effects of CMP NPs on hepatic IRI are related to suppressing inflammation and hepatocytic apoptosis and maintaining endothelial functions through scavenging ROS in liver tissues. The study can provide insight into the development of next-generation nanomedicines for scavenging ROS.

Exercise preconditioning mitigates brain injury after cerebral ischemia-reperfusion injury in rats by restraining TIMP1.

BACKGROUND: Cerebral ischemic disease is a common cerebrovascular disease, especially ischemic stroke. Exercise has protective functions on brain tissues following cerebral ischemia-reperfusion injury (CIRI), but its preventive effects and mechanisms in CIRI remain unclear. We aimed to investigate the effects and mechanisms of exercise preconditioning on CIRI. METHODS: The middle cerebral artery occlusion (MCAO) operation was prepared to establish CIRI rats. All rats were randomized into the MCAO, exercise (exercise preconditioning plus MCAO operation), vector (exercise preconditioning, MCAO operation plus intraventricular injection of empty vector), and tissue inhibitor of metalloprotease 1 overexpression (OE-TIMP1, exercise preconditioning, MCAO operation plus intraventricular injection of OE-TIMP1) groups. RESULTS: The results indicated that exercise preconditioning suppressed approximately 66.67% of neurological deficit scores and 73.79% of TIMP1 mRNA expression in MCAO rats, which were partially offset by OE-TIMP1. The protective effects of exercise against neuron death status and cerebral infarction size in MCAO rats were reversed by OE-TIMP1. It also confirmed that exercise weakened apoptosis and oxidative stress damage, with notable increases of B-cell lymphoma-2, superoxide dismutase, and glutathione peroxidase production, and evident decreases of BCL2-associated X, caspase 3, and malondialdehyde in MCAO rats, while these effects were partially reversed by OE-TIMP1. Additionally, the inhibitory effects of exercise on the protein levels of TIMP1, hypoxia-inducible factor-alpha, vascular endothelial growth factor receptor 2, vascular endothelial growth factor, and neurogenic locus notch homolog protein 1 in MCAO rats were partially reversed by OE-TIMP1. CONCLUSION: Altogether, exercise preconditioning had protective effects on CIRI by restraining TIMP1, which provided new therapeutic strategies for preventing CIRI.

Fibroblast growth factor 21 attenuates pulmonary ischemia/reperfusion injury via inhibiting endoplasmic reticulum stress-induced ferroptosis though FGFR1/PPARδ signaling pathway.

BACKGROUND: Acute lung injury is a critical life-threatening complication of pulmonary and cardiac surgery with a high rate of morbidity and mortality. Fibroblast growth factor 21 (FGF21) has been reported to play an important role in protecting vital organs from damage. This study aims to investigate the potential protective role and mechanism of FGF21 in pulmonary ischemia/reperfusion (I/R)-induced acute lung injury. METHODS: A pulmonary epithelial cell line was treated with hypoxia/regeneration (H/R) in vitro and a mouse model of acute lung injury was induced with pulmonary I/R in vivo. Lung injury after pulmonary I/R was compared between FGF21-konckout (KO) mice and wild-type (WT) mice. Recombinant FGF21 was administrated in vivo and in vitro to determine its therapeutic effect. RESULTS: Circulating levels of FGF21 in mice with pulmonary I/R injury were significantly higher than in those without pulmonary I/R injury. Lung injury was aggravated in FGF21-KO mice compared with WT mice and the administration of FGF21 alleviated lung injury in mouse treated with I/R and pulmonary epithelial cell injury treated with H/R. FGF21 treatment decreased endoplasmic reticulum (ER) stress, Fe2+ and lipid reactive oxygen species (ROS) contents and GPX4 expression and increased PTGS2 levels. Mechanistically, FGF21 upregulated the expression of FGFR1 and PPARδ, ameliorated ER stress and ER stress induced-ferroptosis. Furthermore, FGF21 increased the expression level of PPARδ in pulmonary epithelial cell exposed to H/R, which was inhibited by FGFR1 inhibitor (PD173074). The protective effects of FGF21 were abolished by co-treatment with PPARδ inhibitor (GSK0660), indicating FGF21 attenuated ER stress-induced ferroptosis by dependent on FGFR1/PPARδ signaling pathway. CONCLUSION: Our study reveals that FGF21 protects against pulmonary I/R injury via inhibiting ER stress-induced ferroptosis though FGFR1/PPARδ signaling pathway. Boosting endogenous FGF21 or the administration of recombinant FGF21 could be promising therapeutic strategies for pulmonary IRI.

Outcomes after Endovascular Revascularization for Chronic Limb Threatening Ischemia from the only Vascular Quality Initiative (VQI) Center in Asia.

INTRODUCTION: This study compares chronic limb-threatening ischemia (CLTI) disease characteristics and endovascular revascularization outcomes in a multi-ethnic Asian cohort versus their North American counterparts. METHODS: The Society for Vascular Surgery Vascular Quality Initiative (SVS VQI) registry database from the first and currently the only VQI center in Asia was reviewed to identify patients with CLTI who underwent endovascular revascularization between July 2019 and April 2024. Standardized VQI reporting variables were compared against benchmarks derived from all participating centers in North America. RESULTS: 2862 endovascular revascularization procedures from our center were benchmarked against 129347 procedures from 406 North American centers. Our cohort had a higher burden of comorbidities (diabetes mellitus, end-stage renal disease, cardiac disease) and presented with more advanced Wound, Ischemia, and Foot Infection (WIfI) stages. Our patients had more heavily calcified and longer (14.8 cm vs. 6.0 cm) diseased vessels with higher prevalence of multi-level (87% vs 54.6%), infrapopliteal (52.6% vs 38.9%) and inframalleolar (9.6% vs 2.4%) disease. Rates of technical success (92.7% vs 93%) and symptom improvement (39.1% vs 40.4%) were comparable between cohorts. However, 1-year mortality rates (28.9% vs 25.1%) and major amputation rates (13.3% vs 7.8%) were significantly higher. CONCLUSION: Short term outcomes of technical success and symptom relief in our center were comparable to benchmark North American outcomes despite having a cohort with more diseased vessels, higher WIfI stages and comorbidities. However, this cohort fared worse in longer term outcomes of 1-year mortality and major amputation rates. Further studies are required to elucidate the causes to improve these outcomes.

Quercetin as a therapeutic agent activate the Nrf2/Keap1 pathway to alleviate lung ischemia-reperfusion injury.

Lung ischemia-reperfusion injury (LIRI) causes oxidative stress, inflammation, and immune system activation. The Nrf2/Keap1/HO-1 pathway is important in cellular defense against these effects. Quercetin, a flavonoid with antioxidant, anti-inflammatory, and anti-cancer properties, has been investigated. Our aim in this study was to investigate the effect of quercetin on preventing lung ischemia-reperfusion injury and the role of the Nrf2/Keap1/HO-1 pathway. Sixty-four male Wistar rats were divided into four distinct groups(n = 16). Sham, lung ischemia-reperfusion (LIR), Saline + LIR, Quercetin + LIR (30 mg/kg i.p for a week before LIR). LIR groups were subjected to 60 min of ischemia (left pulmonary artery, vein, and bronchus) and 120 min of reperfusion. Our assessment encompassed a comprehensive analysis of various factors, including the evaluation of expression Nrf2, Keap1, and Heme Oxygenase-1 (HO-1) levels and NF-κB protein. Furthermore, we examined markers related to inflammation (interleukin-1ß and tumor necrosis factor alpha), oxidative stress (malondialdehyde, total oxidant status, superoxide dismutase, glutathione peroxidase, total antioxidant capacity), lung edema (Wet/dry lung weight ratio and total protein concentration), apoptosis (Bax and Bcl2 protein), and histopathological alterations (intra-alveolar edema, alveolar hemorrhage, and neutrophil infiltration). Our results show that ischemia-reperfusion results in heightened inflammation, oxidative stress, apoptosis, lung edema, and histopathological damage. Quercetin showed preventive effects by reducing these markers, acting through modulation of the Nrf2/Keap1 pathway and inhibiting the NF-κB pathway. This anti-inflammatory effect, complementary to the antioxidant effects of quercetin, provides a multifaceted approach to cell protection that is important for developing therapeutic strategies against ischemia-reperfusion injury and could be helpful in preventive strategies against ischemia-reperfusion.

Intraoperative indocyanine green fluorescence for precise resection of nonocclusive mesenteric ischemia: a case report and diagnostic considerations based on pathology findings.

BACKGROUND: Nonocclusive mesenteric ischemia (NOMI) is characterized by intestinal ischemia caused by spasms in the peripheral intestinal vessels without organic obstruction in the main mesenteric vessels. NOMI can be fatal in case of delayed diagnosis and treatment. Although the use of indocyanine green (ICG) fluorescence in assessing intestinal viability during NOMI surgery is well recognized, there is a paucity of reported cases using this technique. Herein, we present a case of NOMI that was successfully managed through accurate diagnosis and resection of the ischemic intestines guided by ICG fluorescence. CASE PRESENTATION: An 81-year-old man presented with abdominal pain. Contrast-enhanced computed tomography revealed intrahepatic portal vein gas, superior mesenteric vein gas, and terminal ileal edema. Considering these findings, the patient was diagnosed with NOMI and emergency surgery was performed. Intestinal edema was observed 30 cm upstream of the terminal ileum without serosal discoloration. ICG fluorescence revealed areas of normal perfusion as well as mild and moderate hypoperfusion. The small bowel, including the hypoperfusion area, was resected. As no clinical signs of residual bowel ischemia were observed during the postoperative course, a second-look operation was deemed unnecessary. Intraoperative ICG fluorescence and histopathological findings indicated mucosal edema in the mildly hypoperfused area and mucosal necrosis in the moderately hypoperfused area. CONCLUSIONS: This case highlights the use of intraoperative ICG fluorescence in the disease. ICG fluorescence is invaluable in assessing the extent of bowel ischemia and guiding precise resection. Thus, future efforts should focus on identifying accumulation of cases and quantification of ICG fluorescence intensity to further improve diagnostic performance.

TCD-Guided management in carotid endarterectomy: a retrospective study.

BACKGROUNDː: Stroke, primarily resulting from ischemic conditions, is the foremost cause of mortality and long-term impairment and is frequently associated with narrowing of the carotid arteries. Although carotid endarterectomy (CEA) is the treatment of choice, it carries the risk of cerebral ischemia and reduced blood flow. Transcranial Doppler (TCD) ultrasound offers a nonintrusive method to assess cerebral blood circulation during CEA, potentially enhancing surgical outcomes. The objective of this study was to assess the clinical utility and safety of TCD monitoring during CEA and to identify factors influencing postoperative complications. METHODS: This retrospective analysis included 158 CEA patients (from January 2021-August 2023) who underwent TCD monitoring and whose data were compared to historical standard care data. The primary outcomes were operation duration and artery occlusion time. Secondary outcomes included carotid shunt usage, seven-day postoperative complications, and six-month carotid artery patency. Logistic regression identified factors linked to adverse reactions, and a predictive model was evaluated with a receiver operating characteristic (ROC) curve. RESULTSː: Comparative analysis indicated significant reductions in both the duration of surgery (113.26 ± 7.29 min) and artery occlusion time (21.85 ± 2.92 min) for patients monitored with TCD (P < 0.001) and an increase in carotid shunt implementation (25% as opposed to traditional care). The observed postoperative complications were minor, with a nonsignificant trend that favored the use of TCD-monitored procedures (1% vs. historical rates). Factors such as patient age and plaque echogenicity were found to be predictive of postoperative issues, with plaque echogenicity emerging as a significant predictive factor (OR = 10.70, 95% CI: 2.14-202, P = 0.02) upon multivariate analysis. The predictive model exhibited high precision (AUC = 0.93). CONCLUSION: This retrospective evaluation suggested that TCD monitoring in the CEA may reduce procedural time and potentially decrease postoperative complications, supporting its use for personalized surgical planning.

Ozone therapy mitigates parthanatos after ischemic stroke.

BACKGROUND: Stroke is a leading cause of death worldwide, with oxidative stress and calcium overload playing significant roles in the pathophysiology of the disease. Ozone, renowned for its potent antioxidant properties, is commonly employed as an adjuvant therapy in clinical settings. Nevertheless, it remains unclear whether ozone therapy on parthanatos in cerebral ischemia-reperfusion injury (CIRI). This study aims to investigate the impact of ozone therapy on reducing parthanatos during CIRI and to elucidate the underlying mechanism. METHODS: Hydrogen peroxide (H2O2) was utilized to mimic the generation of reactive oxygen species (ROS) in SH-SY5Y cell reperfusion injury in vitro, and an in vivo ischemic stroke model was established. Ozone saline was introduced for co-culture or intravenously administered to mice. Apoptosis and oxidative stress were assessed using flow cytometry and immunofluorescence. Western blotting was utilized to examine the expression of parthanatos signature proteins. The mechanism by which ozone inhibits parthanatos was elucidated through inhibiting PPARg or Nrf2 activity. RESULTS: The findings demonstrated that ozone mitigated H2O2-induced parthanatos by either upregulating nuclear factor erythroid 2-related factor 2 (Nrf2) or activating peroxisome proliferator-activated receptorg (PPARg). Furthermore, through the use of calcium chelators and ROS inhibitors, it was discovered that ROS directly induced parthanatos and facilitated intracellular calcium elevation. Notably, a malignant feedback loop between ROS and calcium was identified, further amplifying the induction of parthanatos. Ozone therapy exhibited its efficacy by increasing PPARg activity or enhancing the Nrf2 translation, thereby inhibiting ROS production induced by H2O2. Concurrently, our study demonstrated that ozone treatment markedly inhibited parthanatos in stroke-afflicted mice. Additionally, ozone therapy demonstrated significant neuroprotective effects on cortical neurons, effectively suppressing parthanatos. CONCLUSIONS: These findings contribute valuable insights into the potential of ozone therapy as a therapeutic strategy for reducing parthanatos during CIRI, highlighting its impact on key molecular pathways associated with oxidative stress and calcium regulation.