Mesenchymal Stem Cells and Extracellular Vesicles: Therapeutic Potential in Organ Transplantation.

At present, organ transplantation remains the most appropriate therapy for patients with end-stage organ failure. However, the field of organ transplantation is still facing many challenges, including the shortage of organ donors, graft function damage caused by organ metastasis, and antibody-mediated immune rejection. It is therefore urgently necessary to find new and effective treatment. Stem cell therapy has been regarded as a "regenerative medicine technology." Mesenchymal stem cells (MSCs), as the most common source of cells for stem cell therapy, play an important role in regulating innate and adaptive immune responses and have been widely used in clinical trials for the treatment of autoimmune and inflammatory diseases. Increasing evidence has shown that MSCs mainly rely on paracrine pathways to exert immunomodulatory functions. In addition, mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) are the main components of paracrine substances of MSCs. Herein, an overview of the application of the function of MSCs and MSC-EVs in organ transplantation will focus on the progress reported in recent experimental and clinical findings and explore their uses for graft preconditioning and recipient immune tolerance regulation. Additionally, the limitations on the use of MSC and MSC-EVs are also discussed, covering the isolation of exosomes and preservation techniques. Finally, the opportunities and challenges for translating MSCs and MSC-EVs into clinical practice of organ transplantation are also evaluated.

Haplotype-resolved genome of Prunus zhengheensis provides insight into its evolution and low temperature adaptation in apricot.

Prunus zhengheensis, an extremely rare population of apricots, originated in warm South-East China and is an excellent material for genetic breeding. However, most apricots and two related species (P. sibirica, P. mandshurica) are found in the cold northern regions in China and the mechanism of their distribution is still unclear. In addition, the classification status of P. zhengheensis is controversial. Thus, we generated a high-quality haplotype-resolved genome for P. zhengheensis, exploring key genetic variations in its adaptation and the causes of phylogenetic incongruence. We found extensive phylogenetic discordances between the nuclear and organelle phylogenies of P. zhengheensis, which could be explained by incomplete lineage sorting. A 242.22-Mb pan-genome of the Armeniaca section was developed with 13 chromosomal genomes. Importantly, we identified a 566-bp insertion in the promoter of the HSFA1d gene in apricot and showed that the activity of the HSFA1d promoter increased under low temperatures. In addition, HSFA1d overexpression in Arabidopsis thaliana indicated that HSFA1d positively regulated plant growth under chilling. Therefore, we hypothesized that the insertion in the promoter of HSFA1d in apricot improved its low-temperature adaptation, allowing it to thrive in relatively cold locations. The findings help explain the weather adaptability of Armeniaca plants.

Normothermic Ex Vivo Heart Perfusion With Exosomes From Human Umbilical Cord Mesenchymal Stem Cells Improves Graft Function in Donation After Circulatory Death Hearts.

BACKGROUND: This study aimed to investigate the cardioprotective effect of exosomes derived from human umbilical cord mesenchymal stem cells on donation after circulatory death (DCD) hearts preserved with normothermic ex vivo heart perfusion (EVHP) in a rat heart transplantation model. METHODS: Thirty-two male Lewis rats were divided into 2 groups: the control group and the exosome group. The donor-heart rats were subjected to the DCD procedure by suffering a 15-min warm ischemia injury, subsequently preserved with EVHP for 90 min, and then transplanted into recipients via abdominal heterotopic heart transplantation. Vehicle or exosome was added into the perfusate of normothermic EVHP in the control or exosome group. We evaluated left ventricular graft function, myocardial inflammation, and myocardial apoptosis of the donor heart 1.5 h after heart transplantation. Furthermore, we investigate the alternation of myocardial gene expression in the donor hearts between both groups by transcriptome sequencing. RESULTS: The treatment with exosome significantly enhanced cardiac function through increasing left ventricular developed pressure, dp/dtmax, and dp/dtmin of DCD hearts at 90 min after heart transplantation compared with the control group. The myocardial cells in the exosome group exhibited an orderly arrangement without obvious edema. Furthermore, exosome added into perfusate in the exosome group significantly attenuated the level of inflammatory response and apoptosis. Transcriptome sequencing and RT-qPCR showed the phosphoinositide 3-kinase/protein kinase B pathway was activated after exosome treatment. CONCLUSIONS: Normothermic EVHP combined with exosome can be a promising and novel DCD heart preservation strategy, alleviating myocardial ischemia-reperfusion injury in the DCD heart.

AGAMOUS-LIKE24 controls pistil number in Japanese apricot by targeting the KNOTTED1-LIKE gene KNAT2/6-a.

The formation of multi-pistil flowers reduces the yield and quality in Japanese apricot (Prunus mume). However, the molecular mechanism underlying the formation of multi-pistil flowers remains unknown. In the current study, overexpression of PmKNAT2/6-a, a class I KNOTTED1-like homeobox (KNOX) member, in Arabidopsis (Arabidopsis thaliana) resulted in a multi-pistil phenotype. Analysis of the upstream regulators of PmKNAT2/6-a showed that AGAMOUS-like 24 (PmAGL24) could directly bind to the PmKNAT2/6-a promoter and regulate its expression. PmAGL24 also interacted with Like Heterochromatin Protein 1 (PmLHP1) to recruit lysine trimethylation at position 27 on histone H3 (H3K27me3) to regulate PmKNAT2/6-a expression, which is indirectly involved in multiple pistils formation in Japanese apricot flowers. Our study reveals that the PmAGL24 transcription factor, an upstream regulator of PmKNAT2/6-a, regulates PmKNAT2/6-a expression via direct and indirect pathways and is involved in the formation of multiple pistils in Japanese apricot.

Allelic variation of PmCBF03 contributes to the altitude and temperature adaptability in Japanese apricot (Prunus mume Sieb. et Zucc.).

Japanese apricot is an important subtropical deciduous fruit tree in China, widely distributed in different altitude areas. How does it adapt to the different temperature environments in these areas? In this study, we identified a low-temperature transcription factor PmCBF03 on chromosome 7 through adaptive analysis of populations at different altitudes, which has an early termination single nucleotide polymorphism mutation. There were two different types of variation, PmCBF03A type in high-altitude areas and PmCBF03T type in low-altitude areas. PmCBF03A gene increased the survival rate, Fv/Fm values, antioxidant enzyme activity, and expression levels of antioxidant enzyme genes, and reducing electrolyte leakage and accumulation of reactive oxygen species in transgenic Arabidopsis under low temperature and freezing stress. Simultaneously, PmCBF03A gene promoted the dormancy of transgenic Arabidopsis seeds than wild-type. Biochemical analysis demonstrated that PmCBF03A directly bound to the DRE/CRT element in the promoters of the PmCOR413, PmDAM6 and PmABI5 genes, promoting their transcription and enhanced the cold resistance and dormancy of the overexpressing PmCBF03A lines. While PmCBF03T gene is unable to bind to the promoters of PmDAM6 and PmABI5 genes, leading to early release of dormancy to adapt to the problem of insufficient chilling requirement in low-altitude areas.

Opportunities and Perspectives for Three Dimensional Culture of Mesenchymal Stem Cell-Derived Exosomes.

Exosomes are nanosized extracellular vesicles (EVs) that participate in intercellular communication through surface proteins and the delivery of internal cargo. The exosomes have gained attention for their potential as disease biomarkers and therapeutic agents. The therapeutic ability of exosomes has been verified by copious previous studies. Effective methods for extensive clinical applications are being researched for exosome-based regenerative therapies, including the application of 3D cultures to enhance exosome production and secretion, which can resolve limited exosome secretion from the parent cells. Cell culture has emerged as a crucial approach for biomedical research because of its many benefits. Both well-established continuous cell lines and primary cell cultures continue to be invaluable for basic research and clinical application. Previous studies have shown that three-dimensional cultured exosomes (3D-Exo) improve therapeutic properties and yields compared with traditional culture systems. Since the majority of studies have focused on exosomes derived from mesenchymal stem cells (MSC-Exo), this review will also concentrate on MSC-Exo. In this review, we will summarize the advantages of 3D-Exo and introduce the 3D culture system and methods of exosome isolation, providing scientific strategies for the diagnosis, treatment, and prognosis of a wide variety of diseases.

Nadir oxygen delivery during cardiopulmonary bypass in acute type A aortic dissection repair.

Background: Acute type A aortic dissection (ATAAD) is associated with high mortality. Previous studies found that maintaining a high level of oxygen delivery (DO2) could decrease the postoperative mortality, but the minimum threshold of DO2 remained unclear. The present study aimed to investigate the relationship between maintaining intraoperative DO2 ≥280 mL/(min·m2) and the 90-day postoperative mortality of ATAAD patients. Methods: The clinical data of 178 ATAAD patients who underwent Sun's procedure in our center from January 2018 to July 2022 were retrospectively analyzed in the present cohort study. The included patients were divided into hypoxic group [DO2 <280 mL/(min·m2)] and normoxic group [DO2 ≥280 mL/(min·m2)]. The primary endpoint was the 90-day all-cause mortality, and the secondary endpoints were postoperative mechanical ventilation time, the application of continuous renal replacement therapy (CRRT), brain complications, and other postoperative complications. Results: Among all the patients, a total of 23 patients died 90 days postoperatively. Compared with the hypoxic group, blood flow, hematocrit (HCT), DO2, and DO2/VO2 ratio during cardiopulmonary bypass (CPB) were significantly higher, while the need for CRRT and the 90-day mortality were significantly lower in the normoxic group. The median follow-up time was 4 months. Kaplan-Meier curve indicated that the survival rate of ATAAD patients in the normoxic group was significantly higher. Univariate cox regression analysis demonstrated that 90-day mortality was reduced by 72.1% in the normoxic group. Conclusions: Maintaining DO2 ≥280 mL/(min·m2) during CPB by increasing CPB flow and HCT level is associated with decreased 90-day mortality of ATAAD patients.

Synergetic EGCG and coenzyme Q10 DSPC liposome nanoparticles protect against myocardial infarction.

At the site of myocardial infarction (MI), various phenomena such as oxidative stress and myocardial apoptosis can be observed. Both epigallocatechin gallate (EGCG) and coenzyme Q10 (CoQ10) exhibit antioxidant and anti-inflammatory effects. Macrophages have demonstrated a higher internalization rate of cationic liposomes, thereby increasing their bioavailability. This study utilized EGCG in synergy with CoQ10 as an antioxidant agent and distearyl phosphatidylcholine (DSPC) as the carrier, to create liposome nanoparticles known as CE-LNPs. The CE-LNPs exhibited favorable biocompatibility and were effectively engulfed by macrophages in vitro. In addition, the CE-LNPs effectively eradicated reactive oxygen species (ROS) in hypoxic cardiomyocytes, mitigated myocardial cell apoptosis, and sustained the functionality and proliferation of myocardial cells. The anti-apoptotic effect of the CE-LNPs was further validated through TUNEL and Annexin V FITC/PI experiments. The therapeutic efficacy of CE-LNPs was evaluated in a murine model of MI. CE-LNPs demonstrated a significant reduction in scar area in vivo, facilitating cardiac repair and improving cardiac function. These findings provide evidence that EGCG synergistically combined with CoQ10 in DSPC liposome nanoparticles offers protection against MI.

Unilateral cerebral arterial tortuosity: Associated with aneurysm occurrence, but potentially inversely associated with aneurysm rupture.

PURPOSE: To investigate the association of tortuosity of the main cerebral arteries with intracranial aneurysm (IA) occurrence and rupture. To investigate the relationship between arterial tortuosity and aneurysm morphology as well as conventional risk factors of vascular diseases. METHODS: Three subject groups were analyzed in this study: Patients with ruptured IAs, patients with unruptured IAs, and healthy subjects. The groups were matched by sex and age using tendency score matching. Their intracranial magnetic resonance angiography (MRA) images were collected retrospectively. The intracranial arterial structures were segmented from the MRA images. Arterial tortuosity was measured and statistically compared between the different subject groups and different vessels. Correlation analysis was conducted between arterial tortuosity and clinical risk factors as well as aneurysm morphology. RESULTS: 120 patients were included in the study (average age: 67.5 years; 60% female), 40 for each group after matching. The tortuosity of the aneurysm-bearing artery was significantly greater than that of the contralateral artery in both the ruptured and unruptured IA groups (p < 0.001). There was no significant association between clinical risk factors (history of hypertension, hyperlipidemia, diabetes, smoking, and alcohol use) and arterial tortuosity. There were significant negative correlations between aneurysm-bearing artery tortuosity and aneurysm morphological features such as maximal diameter (p = 0.0011), neck diameter (p < 0.0001), maximum height (p = 0.0024), and size ratio (p = 0.0269). CONCLUSION: The occurrence of cerebral aneurysms correlates to increased unilateral arterial tortuosity, but the risk of aneurysm enlargement/rupturing decreases with greater arterial tortuosity. Abnormal tortuosity may be congenital as tortuosity has no clear connection with acquired common risk factors of vascular diseases.

Upregulation of P2Y14 receptor in neutrophils promotes inflammation after myocardial ischemia/reperfusion injury.

BACKGROUND: P2Y14 receptor is expressed in neutrophils and is involved in activation of inflammatory signaling. However, the expression and function of P2Y14 receptor in neutrophils after myocardial infarction/reperfusion (MIR) injury remain to be elucidated. METHODS: In this research, rodent and cellular models of MIR were used to detect the involvement and function of P2Y14 receptor, as well as the regulation of inflammatory signaling via P2Y14 receptor in neutrophils post-MIR. RESULTS: In the early stage post MIR, the expression of P2Y14 receptor was upregulated in CD4+Ly-6G+ neutrophils. Additionally, the expression of P2Y14 receptor was highly induced in neutrophils subjected to uridine 5'-diphosphoglucose (UDP-Glu), which is proven to be secreted by cardiomyocytes during ischemia and reperfusion. Our results also showed the beneficial role of P2Y14 receptor antagonist PPTN in counteracting inflammation via promoting polarization of neutrophils to N2 phenotype in the infarct area of the heart tissue after MIR. CONCLUSION: These findings prove that the P2Y14 receptor is involved in the regulation of inflammation in the infarct area after MIR, and establish a novel signaling pathway concerning the interplay between cardiomyocytes and neutrophils in the heart tissue.

Macrophage polarization states in atherosclerosis.

Atherosclerosis, a chronic inflammatory condition primarily affecting large and medium arteries, is the main cause of cardiovascular diseases. Macrophages are key mediators of inflammatory responses. They are involved in all stages of atherosclerosis development and progression, from plaque formation to transition into vulnerable plaques, and are considered important therapeutic targets. Increasing evidence suggests that the modulation of macrophage polarization can effectively control the progression of atherosclerosis. Herein, we explore the role of macrophage polarization in the progression of atherosclerosis and summarize emerging therapies for the regulation of macrophage polarization. Thus, the aim is to inspire new avenues of research in disease mechanisms and clinical prevention and treatment of atherosclerosis.

Normothermic ex vivo heart perfusion with NLRP3 inflammasome inhibitor Mcc950 treatment improves cardiac function of circulatory death hearts after transplantation.

Background: The utilization of donation after circulatory death (DCD) hearts can enlarge the donor pool. However, DCD hearts suffer from serious ischemia/reperfusion injury (IRI). Recent studies found that the activation of NLRP3 inflammasome could play a significant role in organ IRI. Mcc950, which is a novel inhibitor of the NLRP3 inflammasome, can be applied to treat various kinds of cardiovascular diseases. Therefore, we hypothesized that the treatment of mcc950 could protect DCD hearts preserved with normothermic ex vivo heart perfusion (EVHP) against myocardial IRI via inhibiting NLRP3 inflammasome in a rat heart transplantation model of DCD. Methods: Donor-heart rats were randomly divided into four groups: Control group; Vehicle group; MP-mcc950 group; and MP + PO-mcc950 group. Mcc950 was added into the perfusate of normothermic EVHP in the MP-mcc950 and MP + PO-mcc950 groups, and was injected into the left external jugular vein after heart transplantation in the MP + PO-mcc950 group. Cardiac functional assessment was performed. The level of oxidative stress, inflammatory response, apoptosis, and NLRP3 inflammasome-associated protein of donor hearts were evaluated. Results: The treatment with mcc950 significantly increased the developed pressure (DP), dP/dtmax, and dP/dtmin of the left ventricular of DCD hearts at 90 min after heart transplantation in both MP-mcc950 and MP + PO-mcc950 groups. Furthermore, mcc950 added into perfusate and injected after transplantation in both MP-mcc950 and MP + PO-mcc950 groups significantly attenuated the level of oxidative stress, inflammatory response, apoptosis, and NLRP3 inflammasome compared with the vehicle group. Conclusions: Normothermic EVHP combined with mcc950 treatment can be a promising and novel DCD heart preservation strategy, which can alleviate myocardial IRI via inhibiting NLRP3 inflammasome.

Genome-Wide Identification of the KNOX Gene Family in Japanese Apricot (Prunus mume Sieb. et Zucc.) and Functional Characterization of PmKNAT2 Genes.

The Knotted1-like Homeobox gene is crucial for plant morphological development and growth. Physicochemical characteristics, phylogenetic relationships, chromosomal localization, cis-acting elements, and tissue-specific expression patterns of the 11 PmKNOX genes found in the Japanese apricot genome in this study were examined. Proteins of 11 PmKNOX were soluble proteins with isoelectric points between 4.29 and 6.53, molecular masses between 15.732 and 44.011 kDa, and amino acid counts between 140 and 430. The identified PmKNOX gene family was split into three subfamilies by jointly constructing the phylogenetic tree of KNOX proteins in Japanese apricot and Arabidopsis thaliana. Combined outcomes of the analyzed conserved motifs and gene structures of the 11 PmKNOX genes from the same subfamily displayed comparable gene structure and motif patterns. The 11 PmKNOX members were distributed across six chromosomes, while two sets of PmKNOX genes were found to be collinear. Analysis of the 2000 bp promoter upstream of the coding region of the PmKNOX gene revealed that most PmKNOX genes might be involved in the physiological metabolism, growth and development processes of plants. The PmKNOX gene expression profile revealed that these genes were expressed at varying levels in different tissues, and most of them were linked to the meristems of leaf and flower buds, suggesting that PmKNOX may be involved in plants' apical meristems. In Arabidopsis thaliana, functional validation of PmKNAT2a and PmKNAT2b revealed that these two genes might be involved in regulating leaf and stem development. In addition to laying the groundwork for future research on the function of these genes, understanding the evolutionary relationships between members of the PmKNOX gene family provides opportunities for future breeding in Japanese apricots.

Alpha-1-Antitrypsin Protects Vascular Grafts of Brain-Dead Rats Against Ischemia/Reperfusion Injury.

INTRODUCTION: Endothelial dysfunction is a potential side effect of brain death (BD). Ischemia/reperfusion (IR) injury during heart transplantation may lead to further endothelial damage. Protective effects of alpha-1-antitrypsin (AAT), a human neutrophil serine protease inhibitor, have been demonstrated against IR injury. We hypothesized that AAT protects brain-dead rats' vascular grafts from IR injury. METHODS: Donor rats were subjected to BD by inflation of a subdural balloon. After 5.5 h, aortic rings were immediately mounted in organ baths (BD, n = 6 rats) or preserved in saline, supplemented either with vehicle (BD-IR, n = 8 rats) or AAT (BD-IR + AAT, n = 14 rats) for 24 h. During organ bath experiment, rings from both IR groups were exposed to hypochlorite to simulate warm reperfusion-associated endothelial injury. Endothelial function was measured ex vivo. Immunohistochemical staining for caspases was carried out and DNA-strand breaks were evaluated using terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling. Data are presented as median (interquartile range). RESULTS: AAT improved IR-induced decreased maximum endothelium-dependent vasorelaxation to acetylcholine in the BD-IR + AAT aortas compared to the BD-IR group (BD: 83 (9-28) % versus BD-IR: 49 (39-60) % versus BD-IR + AAT: 64 (24-42) %, P < 0.05). Additionally, an increase in the rings' sensitivity to acetylcholine was noted after AAT (pD2-value: BD-IR + AAT: 7.35 (7.06-7.89) versus BD-IR: 6.96 (6.65-7.21), P < 0.05). Caspase-3, -8, -9, and -12 immunoreactivity and the number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cells were significantly decreased by AAT. CONCLUSIONS: AAT alleviates endothelial dysfunction, prevents increased caspase-3, -8, -9, and -12 levels, and decreases apoptotic DNA breakage due to BD and IR injury. This suggests that AAT treatment may be therapeutically beneficial to reduce IR-induced vascular damage.

Anti-Oxidative, Anti-Apoptotic, and M2 Polarized DSPC Liposome Nanoparticles for Selective Treatment of Atherosclerosis.

Purpose: Oxidative stress is one of the main pathogenic factors of atherosclerosis. However, no antioxidants have brought positive effects on the treatment of atherosclerosis. To selectively treat atherosclerosis, various means such as antioxidation, anti-apoptosis, and M2 polarization are used. The ultimate goal is that multiple regulatory pathways can help to treat atherosclerosis. Patients and Methods: In this study, Simvastatin (SIM) as a model drug, EGCG as an antioxidant agent, and distearyl phosphatidylcholine (DSPC) as major carriers were used to make liposome nanoparticles (SE-LNPs). The cytotoxicity, phagocytosis, antioxidant, and anti-apoptotic properties of nanoparticles were tested in vitro. ApoE-/- atherosclerotic mice were treated with nanoparticles. The changes of aortic Oil red staining, blood lipid, HE, and Masson sections of the aortic root were observed. Results: SE-LNPs exhibited a sustained release profile, potentially enabling the accumulation of the majority amount of drugs at the atherosclerotic plaque. The phagocytosis effect was stronger in RAW. The anti-oxidative and anti-apoptotic effects of the formulation were verified in vitro. SE-LNPs promoted the polarization of M2 macrophages. The therapeutic effect of SE-LNPs was assessed in the ApoE-/- mice model of atherosclerosis. SE-LNPs reduced reactive oxygen species and lipids in vivo. The results of Oil red staining, blood lipid, HE, and Masson sections of the aortic root showed the recovery of the focus. Conclusion: Studies have shown that SE-LNPs could resist oxidation, and apoptosis, promote M2 polarization, and reduce blood lipids and lesions, which is a reliable and selective treatment for atherosclerosis.

Follow-Up Infarct Volume Prediction by CTP-Based Hypoperfusion Index, and the Discrepancy between Small Follow-Up Infarct Volume and Poor Functional Outcome-A Multicenter Study.

(1) Background: Follow-up infarct volume (FIV) may have implications for prognostication in acute ischemic stroke patients. Factors predicting the discrepancy between FIV and 90-day outcomes are poorly understood. We aimed to develop a comprehensive predictive model of FIV and explore factors associated with the discrepancy. (2) Methods: Patients with acute anterior circulation large vessel occlusion were included. Baseline clinical and CT features were extracted and analyzed, including the CTP-based hypoperfusion index (HI) and the NCCT-based e-ASPECT, measured by automated software. FIV was assessed on follow-up NCCT at 3−7 days. Multiple linear regression was used to construct the predictive model. Subgroup analysis was performed to explore factors associated with poor outcomes (90-mRS scores 3−6) in small FIV (<70 mL). (3) Results: There were 170 patients included. Baseline e-ASPECT, infarct core volume, hypoperfusion volume, HI, baseline international normalized ratio, and successful recanalization were associated with FIV and included in constructing the predictive model. Baseline NIHSS, baseline hypertension, stroke history, and current tobacco use were associated with poor outcomes in small FIV. (4) Conclusions: A comprehensive predictive model (including HI) of FIV was constructed. We also emphasized the importance of hypertension and smoking status at baseline for the functional outcomes in patients with a small FIV.

Hepatocyte-specific TMEM16A deficiency alleviates hepatic ischemia/reperfusion injury via suppressing GPX4-mediated ferroptosis.

Ischemia/reperfusion (I/R)-induced liver injury with severe cell death is a major complication of liver transplantation. Transmembrane member 16A (TMEM16A), a component of hepatocyte Ca2+-activated chloride channel, has been implicated in a variety of liver diseases. However, its role in hepatic I/R injury remains unknown. Here, mice with hepatocyte-specific TMEM16A knockout or overexpression were generated to examine the effect of TMEM16A on hepatic I/R injury. TMEM16A expression increased in liver samples from patients and mice with I/R injury, which was correlated with liver damage progression. Hepatocyte-specific TMEM16A knockout alleviated I/R-induced liver damage in mice, ameliorating inflammation and ferroptotic cell death. However, mice with hepatic TMEM16A overexpression showed the opposite phenotype. In addition, TMEM16A ablation decreased inflammatory responses and ferroptosis in hepatocytes upon hypoxia/reoxygenation insult in vitro, whereas TMEM16A overexpression promoted the opposite effects. The ameliorating effects of TMEM16A knockout on hepatocyte inflammation and cell death were abolished by chemically induced ferroptosis, whereas chemical inhibition of ferroptosis reversed the potentiated role of TMEM16A in hepatocyte injury. Mechanistically, TMEM16A interacted with glutathione peroxidase 4 (GPX4) to induce its ubiquitination and degradation, thereby enhancing ferroptosis. Disruption of TMEM16A-GPX4 interaction abrogated the effects of TMEM16A on GPX4 ubiquitination, ferroptosis, and hepatic I/R injury. Our results demonstrate that TMEM16A exacerbates hepatic I/R injury by promoting GPX4-dependent ferroptosis. TMEM16A-GPX4 interaction and GPX4 ubiquitination are therefore indispensable for TMEM16A-regulated hepatic I/R injury, suggesting that blockades of TMEM16A-GPX4 interaction or TMEM16A inhibition in hepatocytes may represent promising therapeutic strategies for acute liver injury.

Normothermic Ex Vivo Heart Perfusion with Mesenchymal Stem Cell-Derived Conditioned Medium Improves Myocardial Tissue Protection in Rat Donation after Circulatory Death Hearts.

Objective: Adopting hearts from donation after circulatory death (DCD) is a promising approach to enlarge the donor pool. Nevertheless, DCD hearts experience severe warm ischemia/reperfusion (I/R) injury. Recent studies have demonstrated that conditioned medium (CM) derived from bone marrow mesenchymal stem cells (BMSCs) has the potential of reducing organ I/R injury. Therefore, we investigated whether DCD heart preservation with normothermic ex vivo heart perfusion (EVHP) and BMSCs-CM treatment could alleviate myocardial warm I/R injury in the DCD hearts. Methods: We randomly divided donor rats into two groups: (1) DCD-Control group and (2) DCD-CM group. Before DCD heart preservation with the normothermic EVHP system for 105 minutes, rats suffered from a 25-minute warm ischemia injury in the DCD procedure. Vehicle or CM (300 µl) was added to the perfusate at the beginning of the perfusion process. The cardiac function of DCD hearts in the DCD-Control and DCD-CM groups was measured every 30 minutes. Besides, non-DCD hearts were harvested from the beating-heart rats. Results: The antibody array demonstrated that the CM contained 14 bioactive factors involved in apoptosis, inflammation, and oxidative stress. Warm ischemia injury resulted in a significant increase in the level of oxidative stress, inflammation, and apoptosis in the DCD hearts of DCD-Control group. Furthermore, compared with the DCD-Control group, CM treatment increased the developed pressure, dP/dtmax and dP/dtmin of the left ventricular in the DCD hearts during a 90-minute EVHP. Moreover, the administration of CM attenuated the level of oxidative stress, inflammation, and apoptosis in the DCD hearts of the DCD-CM group. Conclusions: Normothermic EVHP combined with CM treatment can alleviate warm I/R injury in the DCD hearts by decreasing the level of oxidative stress, inflammatory response, and apoptosis, which might alleviate the shortage of donor hearts by adopting DCD hearts.

2D Catalysts for CO2 Photoreduction: Discussing Structure Efficiency Strategies and Prospects for Scaled Production Based on Current Progress.

Currently, the excessive consumption of fossil fuels is accompanied by massive emissions of CO2 , leading to severe energy shortages and intensified global warming. It is of great significance to develop and use renewable clean energy while reducing the concentration of CO2 in the atmosphere. Photocatalytic technology is a promising strategy for carbon dioxide conversion. Clearly, the achievement of the above goals largely depends on the design and construction of catalysts. This review is mainly focused on the application of 2D materials for photocatalytic CO2 reduction. The contribution of synthetic strategies to their structure and performance is emphasized. Finally, the current challenges, and prospects of 2D materials for photoreduction of CO2 with high efficiency, even for practical applications are discussed. It is hoped that this review can provide some guidance for the rational design, controllable synthesis of 2D materials, and their application for efficient photocatalytic CO2 reduction.