Accelerated Dynamic Reconstruction in Metal-Organic Frameworks with Ligand Defects for Selective Electrooxidation of Amines to Azos Coupling with Hydrogen Production.

Electrosynthesis coupled hydrogen production (ESHP) mostly involves catalyst reconstruction in aqueous phase, but accurately identifying and controlling the process is still a challenge. Herein, we modulated the electronic structure and exposed unsaturated sites of metal-organic frameworks (MOFs) via ligand defect to promote the reconstruction of catalyst for azo electrosynthesis (ESA) coupled with hydrogen production overall reaction. The monolayer Ni-MOFs achieved 89.8 % Faraday efficiency and 90.8 % selectivity for the electrooxidation of 1-methyl-1H-pyrazol-3-amine (Pyr-NH2) to azo, and an 18.5-fold increase in H2 production compared to overall water splitting. Operando X-ray absorption fine spectroscopy (XAFS) and various in situ spectroscopy confirm that the ligand defect promotes the potential dependent dynamic reconstruction of Ni(OH)2 and NiOOH, and the reabsorption of ligand significantly lowers the energy barrier of rate-determining step (*Pyr-NH to *Pyr-N). This work provides theoretical guidance for modulation of electrocatalyst reconstruction to achieve highly selective ESHP.

Rapid and Widespread Distribution of Intranasal Small Extracellular Vesicles Derived from Mesenchymal Stem Cells throughout the Brain Potentially via the Perivascular Pathway.

Intranasal administration is a promising strategy to enhance the delivery of the sEVsomes-based drug delivery system to the central nervous system (CNS). This study aimed to explore central distributive characteristics of mesenchymal stem cell-derived small extracellular vesicles (MSC-sEVs) and underlying pathways. Here, we observed that intranasal MSC-sEVs were rapidly distributed to various brain regions, especially in the subcortex distant from the olfactory bulb, and were absorbed by multiple cells residing in these regions. We captured earlier transportation of intranasal MSC-sEVs into the perivascular space and found an increase in cerebrospinal fluid influx after intranasal administration, particularly in subcortical structures of anterior brain regions where intranasal sEVs were distributed more significantly. These results suggest that the perivascular pathway may underlie the rapid and widespread central delivery kinetics of intranasal MSC-sEVs and support the potential of the intranasal route to deliver MSC-sEVs to the brain for CNS therapy.

The Role of M1 and M2 Myocardial Macrophages in Promoting Proliferation and Healing via Activating Epithelial-to-Mesenchymal Transition.

(1) Background: The activation of sequential processes for the formation of permanent fibrotic tissue following myocardial infarction (MI) is pivotal for optimal healing of heart tissue. M1 and M2 macrophages are known to play essential roles in wound healing by the activation of cardiac fibroblasts after an episode of MI. However, the molecular and cellular mechanisms mediated by these macrophages in cellular proliferation, fibrosis, and wound healing remain unclear. (2) Methods: In the present study, we aimed to explore the mechanisms by which M1 and M2 macrophages contribute to cellular proliferation, fibrosis, and wound healing. Using both in vivo and cellular models, we examined the remodeling effects of M1 and M2 macrophages on infarcted cardiac fibroblasts and their role in promoting cardiac healing post-MI. (3) Results: Our findings indicate that M1 macrophages induce a proliferative effect on infarcted cardiac fibroblasts by exerting an anti-apoptotic effect, thereby preventing cell death. Moreover, M1 macrophages were found to activate the mechanism of epithelial-to-mesenchymal transition (EMT), resulting in wound healing and inducing the fibrotic process. The present findings suggest that M1 macrophages play a crucial role in promoting cardiac remodeling post-MI, as they activate the EMT pathway and contribute to increased collagen production and fibrotic changes. (4) Conclusions: The present study provides insights into molecular and cellular mechanisms mediated by M1 and M2 macrophages in cellular proliferation, fibrosis, and wound healing post-MI. Our findings highlight the critical role of M1 macrophages in promoting cardiac remodeling by activating the EMT pathway. Understanding these mechanisms can potentially result in the development of targeted therapies aimed at enhancing the healing process and improving outcomes following MI.

Ketogenic diet alleviates renal fibrosis in mice by enhancing fatty acid oxidation through the free fatty acid receptor 3 pathway.

Introduction: The ketogenic diet (KD), as a dietary intervention, has gained importance in the treatment of solid organ structural remodeling, but its role in renal fibrosis has not been explored. Methods: Male C57BL/6 mice were fed a normal diet or a KD for 6 weeks prior to unilateral ureteral obstruction (UUO), a well-established in vivo model of renal fibrosis in rodents. Seven days after UUO, serum and kidney samples were collected. Serum ß-hydroxybutyrate (ß-OHB) concentrations and renal fibrosis were assessed. NRK52E cells were treated with TGFß1, a fibrosis-inducing cytokine, and with or without ß-OHB, a ketone body metabolized by KD, to investigate the mechanism underlying renal fibrosis. Results: KD significantly enhanced serum ß-OHB levels in mice. Histological analysis revealed that KD alleviated structural destruction and fibrosis in obstructed kidneys and reduced the expression of the fibrosis protein markers α-SMA, Col1a1, and Col3a1. Expression of the rate-limiting enzymes involved in fatty acid oxidation (FAO), Cpt1a and Acox1, significantly decreased after UUO and were upregulated by KD. However, the protective effect of KD was abolished by etomoxir (a Cpt1a inhibitor). Besides, our study observed that KD significantly suppressed UUO-induced macrophage infiltration and the expression of IL-6 in the obstructive kidneys. In NRK52E cells, fibrosis-related signaling was increased by TGFß1 and reduced by ß-OHB. ß-OHB treatment restored the impaired expression of Cpt1a. The effect of ß-OHB was blocked by siRNA targeting free fatty acid receptor 3 (FFAR3), suggesting that ß-OHB might function through the FFAR3-dependent pathway. Discussion: Our results highlight that KD attenuates UUO-induced renal fibrosis by enhancing FAO via the FFAR3-dependent pathway, which provides a promising dietary therapy for renal fibrosis.

Broadening horizons in mechanisms, management, and treatment of diabetic kidney disease.

Diabetic kidney disease (DKD) is the first cause of end-stage kidney disease in patients with diabetes and its prevalence is increasing worldwide. It encompasses histological alterations that mainly affect the glomerular filtration unit, which include thickening of the basement membrane, mesangial cell proliferation, endothelial alteration, and podocyte injury. These morphological abnormalities further result in a persistent increase of urinary albumin-to-creatinine ratio and in a reduction of the estimated glomerular filtration rate. Several molecular and cellular mechanisms have been recognized, up to date, as major players in mediating such clinical and histological features and many more are being under investigation. This review summarizes the most recent advances in understanding cell death mechanisms, intracellular signaling pathways and molecular effectors that play a role in the onset and progression of diabetic kidney damage. Some of those molecular and cellular mechanisms have been already successfully targeted in preclinical models of DKD and, in some cases, strategies have been tested in clinical trials. Finally, this report sheds light on the relevance of novel pathways that may become therapeutic targets for future applications in DKD.

Low-dose vs. standard-dose alteplase for Chinese patients with acute ischemic stroke: A propensity score analysis.

Background and purpose: Previous studies have stimulated debates on low-dose alteplase administration in acute ischemic stroke (AIS) among the Asian population. We sought to evaluate the safety and efficacy of low-dose alteplase in Chinese patients with AIS using a real-world registry. Methods: We analyzed data from the Shanghai Stroke Service System. Patients receiving alteplase intravenous thrombolysis within 4.5 hours were included. These patients were divided into the low-dose alteplase group (0.55-0.65 mg/kg) and the standard-dose alteplase group (0.85-0.95 mg/kg). Baseline imbalances were adjusted by using the propensity score matching. The primary outcome was mortality or disability, which was defined as the modified Rankin scale (mRS) score ranging from 2 to 6 at discharge. The secondary outcomes were in-hospital mortality, symptomatic intracranial hemorrhage (sICH) and functional independence (mRS score 0-2). Results: From January 2019 to December 2020, a total of 1,334 patients were enrolled and 368 (27.6%) were treated with low-dose alteplase. The median age of the patients was 71 years, and 38.8% were female. Our study showed that the low-dose group had significantly higher rates of death or disability (adjusted odds ratio (aOR) = 1.49, 95% confidence interval (CI) [1.12, 1.98]) and less functional independence (aOR = 0.71, 95%CI [0.52, 0.97]) than the standard-dose group. There was no significant difference in sICH or in-hospital mortality between the standard-dose and low-dose alteplase groups. Conclusions: Low-dose alteplase was related to a poor functional outcome without lowering the risk of sICH, compared with standard-dose alteplase for AIS patients in China.

Liraglutide abrogates nephrotoxic effects of chemotherapies.

Acute kidney injury (AKI) is a common clinical complication. Cisplatin (Cis) is an effective chemotherapeutic drug; however, its acute nephrotoxicity often limits its application. The role of liraglutide (Lir), an agonist of the glucagon-like peptide-1 receptor (GLP-1R), has recently attracted increasing attention beyond glycemic regulation. This study showed that Lir significantly ameliorated Cis-induced kidney dysfunction and renal damage. However, this renoprotective effect was partially abolished in GLP-1R knockout (GLP-1R-/-) mice. Furthermore, we synthesized Lir metabolites, GLP-1 (9-37) and GLP-1 (28-37), and found that they also exerted reno-protective effects that were not impaired in GLP-1R-/- mice. We also demonstrated that Lir and its metabolites reduced cisplatin-induced apoptosis in human renal tubular epithelial cells (HK-2). After silencing GLP-1R expression in HK-2 cells with small interfering ribose nucleic acid (siRNA), the protective effect of Lir on HK-2 cells was inhibited, while the protective effects of GLP-1 (9-37) and GLP-1 (28-37) were not affected. Additionally, we demonstrated that Lir and its metabolites inhibited Cis-induced high-mobility group box 1 (HMGB1) nuclear-cytoplasmic translocation and release, and reduced inflammatory cytokines and HMGB1 receptor expression. The exogenous use of recombinant HMGB1 (rHMGB1) dramatically weakened the protective effects of Lir and its metabolites. In conclusion, our study shows that Lir significantly attenuated Cis-induced AKI through GLP-1R dependent and independent pathways, mediated by inhibiting nuclear-cytoplasmic translocation and release of HMGB1. Lir and its metabolites may be effective drugs for treating cisplatin-induced nephrotoxicity.

eATP and autoimmune diabetes.

PURPOSE OF REVIEW: The purine nucleotide adenosine triphosphate (ATP) is released into extracellular spaces as extracellular ATP (eATP) as a consequence of cell injury or death and activates the purinergic receptors. Once released, eATP may facilitate T-lymphocyte activation and differentiation. The purpose of this review is to elucidate the role of ATP-mediated signaling in the immunological events related to type 1 diabetes (T1D). RECENT FINDINGS: T lymphocytes mediate immune response during the onset of T1D and promote pancreatic islet or whole pancreas rejection in transplantation. Recent data suggest a potential role for eATP in early steps of T1D onset and of allograft rejection. In different preclinical experimental models and clinical trials, several drugs targeting purinergic signaling have been employed to abrogate lymphocyte activation and differentiation, thus representing an achievable treatment to prevent/revert T1D or to induce long-term islet allograft function. SUMMARY: In preclinical and clinical settings, eATP-signaling inhibition induces immune tolerance in autoimmune disease and in allotransplantation. In this view, the purinergic system may represent a novel therapeutic target for auto- and allo-immunity.

Boosting Hydrogen Production via Selective Two-electron Mild Electrochemical Oxidation of Tetrahydroisoquinolines Completely to Dihydroisoquinolines.

Different from the previous study that biomass derivatives replace water oxidation for enhancing hydrogen production, we found that mild oxidation was more conductive to cathodic hydrogen production. In this study, maximum Faradaic efficiency (>99 %) and lower energy consumption for hydrogen production was achieved by precisely controlling the two-electron mild electrochemical oxidation of tetrahydroisoquinolines (THIQs) to dihydroisoquinolines (DHIQs) in place of the four-electron deep oxidation to isoquinolines (IQs). Moreover, the high value-added DHIQs were prepared from THIQs with high selectivity (>99 %) at the low potential of 1.36 V. Operando electrochemical Raman and density functional theory proved that the high selectivity was attributed to the regulable active species of NiOOH induced by the interaction of Co and Fe for preferentially breaking C-H bond rather than N-H of THIQs. This novel method provides important insight into efficient biomass-assisted hydrogen production.

Glycyrrhizic acid improves tacrolimus-induced renal injury by regulating autophagy.

Tacrolimus (TAC)-induced renal injury is detrimental to long-term kidney function, but a treatment medication is not available. Glycyrrhizic acid (GA) is an active ingredient in licorice widely used to treat kidney disease. Thus, this study explored the mechanisms of renoprotection by GA on TAC-induced renal injury. C57BL/6 mice were subjected daily to TAC or a combination of TAC and GA for 4 weeks, and then renal function, histopathology, and autophagy were assessed to examine the effect of GA on a renal injury. Next, Human kidney proximal tubular epithelial (HK-2) cells were pretreated with GA for 2 h and then treated with TAC for 24 h. The effect of GA on TAC-induced HK-2 cell injury was assessed by measuring cell viability, apoptosis, autophagy, and lysosomes. Mice exposed to TAC and treated with GA had significantly greater improvements in renal function and tubulointerstitial fibrosis in comparison to mice not treated with GA. In addition, fibrosis-related protein expression, including α-smooth muscle actin and fibronectin, decreased after GA treatment. GA treatment also relieved autophagic clearance in TAC-induced renal injury. Several in vitro studies found that TAC inhibited cell viability, autophagy, lysosomal acidification, and promoted apoptosis. However, these results were less pronounced with GA pretreatment. In addition, bafilomycin A1 (which inhibits lysosomal function) reduced the protective effect of GA, indicating that lysosomal function plays an important role in this effect. Our data suggest that GA improves lysosomal function and regulates autophagy to protect against TAC-induced renal injury.

Effect of the Shanghai Stroke Service System (4S) on the quality of stroke care and outcomes: A prospective quality improvement project.

BACKGROUND: In China, disparities in the quality of stroke care still exist and implementing quality improvement is still a challenge. AIM: The aim of the study was to determine whether the intervention by Shanghai Stroke Service System (4S) has helped improve adherence to stroke care guidelines and patient outcome. METHODS: The 4S is a regional stroke network with real-time data extraction among its 61 stroke centers in Shanghai. A total of 11 key performance indicators (KPIs) were evaluated. The primary outcomes were a composite measure and an all-or-none measure of adherence to 11 KPIs. The secondary outcomes were length of hospital stay and in-hospital mortality. RESULTS: The study enrolled 92,395 patients (mean age 69.0 ± 12.5 years, 65.2% men) with acute ischemic stroke hospitalized within 7 days of onset in Shanghai from January 2015 to December 2020. More patients received guideline recommended care between 2018 and 2020 than those between 2015 and 2017 (composite measure 87.1% vs 83.6%; absolute difference 2.9%, 95% confidence interval (CI) = [2.7%, 3.2%], p < 0.001; all-or-none measure 49.2% vs 44.8% patients; absolute difference 3.5%, 95% CI = [2.7%, 4.2%], p < 0.001). Further analysis of individual KPIs showed an absolute increase in six KPIs ranging from 3.4% to 8.9% (p < 0.001 for all comparisons). Compared with 2015-2017, hospital length of stay was shorter (10.95 vs 11.90 days; absolute difference -1.08, 95% CI = [-1.18, -0.99], p < 0.001), and in-hospital mortality was significantly reduced (risk ratio (RR) = 0.88, 95% CI = [0.79, 0.98], p = 0.01) in 2018-2020. CONCLUSION: The 4S intervention was associated with increased adherence to the stroke care guidelines, which further translated to improved clinical outcomes. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02735226.

A Machine Learning-Based Risk Prediction Model for Post-Traumatic Stress Disorder during the COVID-19 Pandemic.

Background and Objectives: The COVID-19 pandemic has caused global public panic, leading to severe mental illnesses, such as post-traumatic stress disorder (PTSD). This study aimed to establish a risk prediction model of PTSD based on a machine learning algorithm to provide a basis for the extensive assessment and prediction of the PTSD risk status in adults during a pandemic. Materials and Methods: Model indexes were screened based on the cognitive-phenomenological-transactional (CPT) theoretical model. During the study period (1 March to 15 March 2020), 2067 Chinese residents were recruited using Research Electronic Data Capture (REDCap). Socio-demographic characteristics, PTSD, depression, anxiety, social support, general self-efficacy, coping style, and other indicators were collected in order to establish a neural network model to predict and evaluate the risk of PTSD. Results: The research findings showed that 368 of the 2067 participants (17.8%) developed PTSD. The model correctly predicted 90.0% (262) of the outcomes. Receiver operating characteristic (ROC) curves and their associated area under the ROC curve (AUC) values suggested that the prediction model possessed an accurate discrimination ability. In addition, depression, anxiety, age, coping style, whether the participants had seen a doctor during the COVID-19 quarantine period, and self-efficacy were important indexes. Conclusions: The high prediction accuracy of the model, constructed based on a machine learning algorithm, indicates its applicability in screening the public mental health status during the COVID-19 pandemic quickly and effectively. This model could also predict and identify high-risk groups early to prevent the worsening of PTSD symptoms.

The clinical, pathological, and genetic characteristics of lipid storage myopathy in northern China.

BACKGROUND: The lipid storage myopathy (LSM) diagnosis is based on the patient's clinical manifestations and muscle pathology. However, when genetic testing is lacking, there is a high rate of misdiagnosis of the disease. This study aimed to investigate the clinical and pathological features of genetically diagnosed LSM in northern China, analyze genetic mutations' characteristics, and improve the LSM diagnostic rate. METHODS: Twenty patients with LSM diagnosed were collected; meanwhile, the clinical data, muscle samples, and routine pathological staining of muscle specimens were collected. The morphological changes of muscle fibers were observed under an optical microscope. RESULTS: Among the included patients, 18 cases had ETFDH (HGNC ID: 3483) mutations, and two had PNPLA2 mutations. Family pedigree verification was performed on three patients with heterozygous mutations in the ETFDH gene complex. Histopathological staining showed that all patients had fine vacuoles in the muscle fibers, and some of them merged to form fissures, and the lipid droplets increased in cells. After therapy, 18 patients were associated with a favorable prognosis, and two patients were ineffective with the treatment of neutral lipid storage myopathy (NLSDM) caused by PNPLA2 mutation. DISCUSSION: The clinical manifestations of LSM are complex and diverse, mainly manifested by proximal muscle weakness and exercise intolerance in the extremities. The pathological images of LSM muscles are abnormal storage of lipid droplets in muscle fibers, primarily involving type I fibers. The LSM patients were mainly multiple acyl-CoA dehydrogenase deficiency (MADD) caused by the ETFDH gene mutation. It is necessary to perform an accurate typing diagnosis of LSM.

A potential novel inflammation biomarker for predicting the prognosis of decompensated liver cirrhosis.

OBJECTIVE: This study aimed to explore the prognostic value of the lymphocyte (LYM)-to-white blood cell (WBC) ratio (LWR) in patients with decompensated liver cirrhosis (DLC). METHODS: This study was conducted by recruiting 214 patients with DLC with different aetiologies (development cohort). Receiver operating characteristic (ROC) curve analyses were used to assess the predictive accuracy of the LWR, and Youden's index was used to determine the optimal cut-off values of the LWR based on the ROC curve. Next, patients were divided into high- and low-LWR groups according to the cut-off values. Multivariate logistic analyses were performed to determine the independent predictors for the 1-, 3- and 6-month mortality. Restricted cubic spline (RCS) was used to determine and visualize the association between LWR and the risk of death. We verified the predictive ability of LWR in the validation cohort of 139 patients. RESULTS: In the development cohort, there were 16 (7.5%), 22 (10.3%) and 30 patients (14.0%) who died at 1, 3 and 6 months, respectively. The LWR was significantly lower in non-survivors than in survivors and was an independent predictor of poor outcomes. The ROC analyses with the Delong test showed that the LWR had comparable predictive power with the Model for End-Stage Liver Disease (MELD) score, neutrophil-to-LYM ratio (NLR) and Chronic Liver Failure consortium score for acute decompensated (CLIF-C ADs). RCS showed a non-linear relationship between the LWR and the risk of death at 1 and 3 months, whereas a linear relationship was observed between the LWR and the risk of death at 6 months. We verified that the decreased LWR was an independent predictor of adverse outcomes at 3-, and 6-month follow-up endpoints in the validation cohort. CONCLUSIONS: Our findings indicate that a lower LWR is an independent factor for unfavourable outcomes and may serve as a potential novel prognostic predictor in patients with DLC.KEY MESSAGESThis study is the first report on the prognostic value of the lymphocyte (LYM)-to-white blood cell (WBC) ratio (LWR) in patients with decompensated liver cirrhosis (DLC).Decreased LWR is an independent factor for adverse outcomes in patients with DLC.

Neuregulin-4 attenuates diabetic cardiomyopathy by regulating autophagy via the AMPK/mTOR signalling pathway.

BACKGROUND: Diabetic cardiomyopathy is characterized by left ventricle dysfunction, cardiomyocyte apoptosis, and interstitial fibrosis and is a serious complication of diabetes mellitus (DM). Autophagy is a mechanism that is essential for maintaining normal heart morphology and function, and its dysregulation can produce pathological effects on diabetic hearts. Neuregulin-4 (Nrg4) is an adipokine that exerts protective effects against metabolic disorders and insulin resistance. The aim of this study was to explore whether Nrg4 could ameliorate DM-induced myocardial injury by regulating autophagy. METHODS: Four weeks after the establishment of a model of type 1 diabetes in mice, the mice received Nrg4 treatment (with or without an autophagy inhibitor) for another 4 weeks. The cardiac functions, histological structures and cardiomyocyte apoptosis were investigated. Autophagy-related protein levels along with related signalling pathways that regulate autophagy were evaluated. In addition, the effects of Nrg4 on autophagy were also determined in cultured primary cardiomyocytes. RESULTS: Nrg4 alleviated myocardial injury both in vivo and in vitro. The autophagy level was decreased in type 1 diabetic mice, and Nrg4 intervention reactivated autophagy. Furthermore, Nrg4 intervention was found to activate autophagy via the AMPK/mTOR signalling pathway. Moreover, when autophagy was suppressed or the AMPK/mTOR pathway was inhibited, the beneficial effects of Nrg4 were diminished. CONCLUSION: Nrg4 intervention attenuated diabetic cardiomyopathy by promoting autophagy in type 1 diabetic mice. Additionally, Nrg4 induced autophagy via the AMPK/mTOR signalling pathway.

Cerebral Angiography under Artificial Intelligence Algorithm in the Design of Nursing Cooperation Plan for Intracranial Aneurysm Patients in Craniotomy Clipping.

This research was to investigate the value of indocyanine green angiography (ICGA) based on maximum interclass variance (Otsu) method in the nursing plan of intracranial aneurysm clipping (ICAC) for intracranial aneurysm patients. An Otsu algorithm was selected to optimize the original images with the optimal threshold. In addition, the algorithm was applied to ICGA images of 86 patients with intracranial aneurysms, who were randomly divided into an experimental group (using ICGA + ICAC+ perioperative nursing) and a control group (ICAC + conventional nursing), to observe the clinical indicators, treatment, complications, nursing satisfaction, and quality of life of patients in two groups. The results showed that the mean square error (MSE), structural similarity (SSIM), and shape error (SE) were 3.71, 0.84, and 0.47, respectively. The length of hospital stay in the experimental group (19.9 ± 3.5 days) was significantly shorter than that in the control group (23.2 ± 3.0 days), the rate of excellent treatment was significantly higher than that in the control group, and the incidence of complications was lower. WHOQOL-BREF scores of the two groups after nursing intervention were higher than before, and the score in the experimental group was higher than the control group. In addition, the nursing satisfaction was also significantly higher in the experimental group, and the difference was statistically significant (P < 0.05). In conclusion, ICGA based on the Otsu method could effectively evaluate the cerebrovascular morphology during craniotomy and ICAP and improve the surgical efficacy. Combined with perioperative nursing intervention, it could greatly reduce the incidence of postoperative complications, improve the treatment effect and quality of life, and enhance the long-term prognosis.

Liraglutide Attenuates Hepatic Ischemia-Reperfusion Injury by Modulating Macrophage Polarization.

Ischemia-reperfusion injury (IRI) is a common complication associated with liver surgery, and macrophages play an important role in hepatic IRI. Liraglutide, a glucagon-like peptide-1 (GLP-1) analog primarily used to treat type 2 diabetes and obesity, regulates intracellular calcium homeostasis and protects the cardiomyocytes from injury; however, its role in hepatic IRI is not yet fully understood. This study aimed to investigate whether liraglutide can protect the liver from IRI and determine the possible underlying mechanisms. Our results showed that liraglutide pretreatment significantly alleviated the liver damage caused by ischemia-reperfusion (I/R), as evidenced by H&E staining, serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, and TUNEL staining. Furthermore, the levels of inflammatory cytokines elicited by I/R were distinctly suppressed by liraglutide pretreatment, accompanied by significant reduction in TNF-α, IL-1ß, and IL-6 levels. Furthermore, pretreatment with liraglutide markedly inhibited macrophage type I (M1) polarization during hepatic IRI, as revealed by the significant reduction in CD68+ levels in Kupffer cells (KCs) detected via flow cytometry. However, the protective effects of liraglutide on hepatic IRI were partly diminished in GLP-1 receptor-knockout (GLP-1R-/-) mice. Furthermore, in an in vitro study, we assessed the role of liraglutide in macrophage polarization by examining the expression profiles of M1 in bone marrow-derived macrophages (BMDMs) from GLP-1R-/- and C57BL/6J mice. Consistent with the results of the in vivo study, liraglutide treatment attenuated the LPS-induced M1 polarization and reduced the expression of M1 markers. However, the inhibitory effect of liraglutide on LPS-induced M1 polarization was largely abolished in BMDMs from GLP-1R-/- mice. Collectively, our study indicates that liraglutide can ameliorate hepatic IRI by inhibiting macrophage polarization towards an inflammatory phenotype via GLP-1R. Its protective effect against liver IRI suggests that liraglutide may serve as a potential drug for the clinical treatment of liver IRI.

EZH2 mitigates the cardioprotective effects of mesenchymal stem cell-secreted exosomes against infarction via HMGA2-mediated PI3K/AKT signaling.

BACKGROUND: Mesenchymal stem cell-derived exosomes (MSC-EXO) have emerged as novel therapeutic strategies for myocardial infarction (MI). However, many questions remain untouched and unanswered regarding their roles in myocardial fibrosis. This study aimed to probe the therapeutic effects of MSC-EXO on myocardial fibrosis after MI and possible mechanisms. METHODS: Myocardial tissues were obtained from MI rats, and myocardial cell viability, fibrosis, apoptosis, and epithelial-mesenchymal transition (EMT) were detected by immunohistochemistry, Masson's staining, TUNEL, and western blot. Bone marrow-derived MSCs and corresponding EXO were identified, and cardiac function were detected after treatment of MSC-EXO. Bioinformatics analysis and ChIP assay were conducted to detect the downstream genes of EZH2. EZH2 was upregulated alone or with HMGA2 overexpression in myocardial tissues of MI rats upon MSC-EXO treatment, and PI3K/AKT pathway activity in myocardial tissues was detected using western blot. RESULTS: The proliferative activity in myocardial tissues of MI rats was significantly decreased, along with accentuated fibrosis, increased collagen volume and EMT. MSC-EXO treatment resulted in partial restoration of cardiac function and reduced EZH2 expression in the myocardium of rats. EZH2 inhibited HMGA2 expression by increasing the H3K27me3 modification. PI3K/AKT pathway was altered under the influence of the EZH2/HMGA2 axis. EZH2 inhibited the effect of MSC-EXO on the recovery of cardiac function and accelerated fibrosis, while HMGA2 reversed the effect of EZH2 to reduce fibrosis and enhance cardiac function. CONCLUSION: MSC-EXO alleviated fibrosis in MI rats via inhibition of EZH2, whereas EZH2 inhibited HMGA2 expression and impaired the PI3K/AKT pathway.

Pharmacological targeting macrophage phenotype via gut-kidney axis ameliorates renal fibrosis in mice.

Renal fibrosis is a non-negligible pathological change in chronic kidney disease (CKD). Increasing evidence indicates that macrophage and gut-kidney axis are correlated with CKD. In this study, we manifest that pharmacological modulating macrophage phenotype via gut-kidney axis is conducive to the alleviation of renal fibrosis. Employing wild-type male mice with unilateral ureteral obstruction (UUO), renal fibrosis was dramatically mitigated in mice treated with antibiotics. And antibiotics application restricted the synthesis of intestinal flora metabolite Trimethylamine N-Oxide (TMAO). However, a 1.3% choline diet enhanced fibrosis. Then we further examined macrophage phenotype through the gut-kidney axis. In in vivo and in vitro culture experiments, the mRNA expression of Nos2, Tnf-α, Il-6, and Il-1ß increased under TMAO stimulation. Curbing the NLRP3 inflammasome countered TMAO-induced M1 polarization in bone marrow-derived macrophages. This finding demonstrates that NLRP3 plays a critical part in macrophage polarization. Because of the declining M1 polarization trend in the early stage, M2 macrophages undoubtedly decreased in the tissues. Our results revealed that some metabolites could regulate macrophage phenotype, which matters the severity of renal fibrosis. Thus, pharmacological targeting macrophage phenotype via gut-kidney axis may be a different strategy to treat renal fibrosis.

Prognostic nutritional index: A potential biomarker for predicting the prognosis of decompensated liver cirrhosis.

Background: Prognostic nutritional index (PNI) is an independent predictor of the prognosis of various diseases. However, the prognosis value of PNI in patients with decompensated liver cirrhosis (DLC) remains unknown. The study aimed to investigate the prognostic significance of PNI in patients with DLC. Methods: A total of 214 eligible patients were enrolled in the study's development cohort between January 2018 and March 2021. The clinical primary study endpoints were mortality at 3 and 6 months. Receiver operating characteristic (ROC) curve analysis was used to assess the PNI's prediction accuracy, and Youden's index was utilized to determine the PNI's optimal cut-off value. Moreover, based on the optimal cut-off value, patients were categorized into high and low PNI groups. Multivariate logistic regression analysis was used to determine independent risk factors for mortality, while the relationship between PNI and the risk of death was identified and demonstrated using restricted cubic splines (RCS). A validation cohort of 139 patients was to verify the predictive power of the PNI. Results: In the development cohort, the mortality rate at 3 and 6 months were 10.3% (22) and 14.0% (30), respectively. The PNI had comparable predictive power with the MELD score at all follow-up endpoints. Decreased PNI was an independent predictor of adverse prognosis at all follow-up endpoints. The RCS revealed a linear correlation between PNI and the risk of death. We confirmed that lower PNI was an independent predictor of poor prognosis in the validation cohort. Conclusion: The findings showed that lower PNI is an independent factor of poor outcomes and might be utilized as a potentially promising prognostic predictor in patients with DLC.