Confining Conversion Chemistry in Intercalation Host for Aqueous Batteries.

Conversion-type anode materials with high theoretical capacities play a pivotal role in developing future aqueous rechargeable batteries (ARBs). However, their sustainable applications have long been impeded by the poor cycling stability and sluggish redox kinetics. Here we show that confining conversion chemistry in intercalation host could overcome the above challenges. Using sodium titanates as a model intercalation host, an integrated layered anode material of iron oxide hydroxide-pillared titanate (FeNTO) is demonstrated. The conversion reaction is spatially and kinetically confined within sub-nano interlayer, enabling superlow redox polarization (ca. 4-6 times reduced), ultralong lifespan (up to 8700 cycles) and excellent rate performance. Notably, the charge compensation of interlayer via universal cation intercalation into host endows FeNTO with the capability of operating well in a broad range of aqueous electrolytes (Li+, Na+, K+, Mg2+, Ca2+, etc.). We further demonstrate the large-scale synthesis of FeNTO thin film and powder, and rational design of quasi-solid-state high-voltage ARB pouch cells powering wearable electronics against extreme mechanical abuse. This work demonstrates a powerful confinement means to access disruptive electrode materials for next-generation energy devices.

Targeting SOCS2 alleviates myocardial fibrosis by reducing nuclear translocation of ß-catenin.

BACKGROUND: Myocardial fibrosis is an important pathological feature of dilated cardiomyopathy (DCM). The roles of SOCS2 in fibrosis of different organs are controversial. Herein, we investigated the function and potential mechanism of SOCS2 in myocardial fibrosis. METHODS: Bioinformatics, immunohistochemistry (IHC), immunofluorescence (IF), western blot (WB), real-time fluorescence quantitative PCR (qPCR), rat primary myocardial fibroblasts (rCFs) culture, doxorubicin (DOX) induced mouse dilated cardiomyopathy (DCM) model, and in vivo adeno-associated virus (AAV) infection were used to explore the role of SOCS2 in DCM. RESULTS: Bioinformatics analysis showed that SOCS2 was positively correlated with fibrosis related factors. SOCS2 was significantly upregulated in patients and mice with DCM. In vivo experiments showed that targeted inhibition of cardiac SOCS2 could improve mouse cardiac function and alleviate myocardial fibrosis. Further research demonstrated that SOCS2 promoted the transformation of myofibroblasts. Knockdown of SOCS2 reduced the nuclear localization of ß-catenin, which inhibited the fibrogenic effect of Wnt/ß-catenin pathway. In addition, bioinformatics analysis suggested that lymphoid enhancer binding factor 1 (LEF1) was significantly positively correlated with SOCS2. Finally, dual luciferase assays demonstrated that LEF1 could bind to the promoter region of SOCS2, thereby mediating its transcriptional activation. CONCLUSION: SOCS2 could activate the Wnt/ß-catenin by regulating the nuclear translocation of ß-catenin, which induces the transcriptional activation of SOCS2. Overall, these results indicated a positive feedback activation phenomenon between SOCS2, ß-catenin and LEF1 in DCM. These results suggested that inhibition of SOCS2 could effectively alleviate the progression of myocardial fibrosis and improve cardiac function.

Thrombocytopenia developed in intensive care unit for congenital heart disease: incidence, risk factors, and outcomes.

BACKGROUND: Thrombocytopenia is common for patients in the intensive care unit (ICU) and is associated with adverse outcomes. ICU thrombocytopenia in pediatric patients who underwent cardiac surgeries with cardiopulmonary bypass (CPB) is inadequately studied. OBJECTIVES: We aimed to investigate the incidence, risk factors, and prognostic role of ICU thrombocytopenia after congenital cardiac surgeries with CPB. METHODS: A retrospective study involving 11 761 patients was conducted. Patients were categorized into 4 groups of thrombocytopenia based on platelet counts tested during ICU: non (>150 × 109/L), mild (100-150 × 109/L), moderate (50-100 × 109/L), and severe (<50 × 109/L). Logistic and Cox regression analyses were utilized to explore the risk factors of thrombocytopenia and the association of ICU thrombocytopenia with 30-day mortality. RESULTS: ICU thrombocytopenia was observed in 4007 patients (34.1%), with mild, moderate, and severe thrombocytopenia occurring in 2773 (23.6%), 987 (8.4%), and 247 (2.1%) patients, respectively. Younger age, cyanotic congenital heart disease, CPB duration, and preoperative laboratory findings (red blood cell, thrombocytopenia, red cell distribution width, hematocrit, and coagulation disorder) were identified as independent risk factors of ICU thrombocytopenia. Patients with moderate (hazard ratio [95% CI]: 11.38 [3.02-42.87]; P < .001) and severe thrombocytopenia (hazard ratio [95% CI]: 49.54 [13.11-187.14]; P < .001) had a significantly higher risk of 30-day mortality. Furthermore, with the increase in the severity of ICU thrombocytopenia, there was an incremental increase in the incidence of postoperative critical bleeding and thrombosis, perioperative blood transfusions, length of ICU stays, and duration of mechanical ventilation. CONCLUSION: ICU thrombocytopenia occurred in one-third of children after congenital cardiac surgery with CPB, and it was associated with multiple adverse outcomes.

Effect of Inconel 718 Filler on the Microstructure and Mechanical Properties of Inconel 690 Joint by Ultrasonic Frequency Pulse Assisted TIG Welding.

Ultrasonic frequency pulse assisted TIG welding (UFP-TIG) experiments were conducted to join Inconel 690 alloy (IN690) by adding Inconel 718 alloy (IN718) as the filler. The effect of the filler on the microstructure, mechanical properties, and ductility dip cracking (DDC) susceptibility of IN690 joints were investigated. The results show that a variety of precipitates, including MC-type carbide and Laves phases, are formed in the weld zone (WZ), which are uniformly dispersed in the interdendritic region and grain boundaries (GBs). The increase in the thickness of the IN718 filler facilitates the precipitation and growth of Laves phases and MC carbides. However, the formation of Laves phases in the WZ exhibits a lower bonding force with the matrix and deteriorates the tensile strength of IN690 joints. Due to the moderate content of Laves phases in the WZ, the IN690 joint with 1.0 mm filler reaches the maximum tensile strength (627 MPa), which is about 96.5% of that of the base metal (BM). The joint with 1.0 mm filler also achieves the highest elongation (35.4%). In addition, the strain-to-fracture tests indicate that the total length of cracks in the joint with the IN718 filler decreases by 66.49% under a 3.8% strain. As a result, the addition of the IN718 filler significantly improves the mechanical properties and DDC resistance of IN690 joints.

Cardiomyocyte-specific Tbk1 deletion aggravated chronic doxorubicin cardiotoxicity via inhibition of mitophagy.

Doxorubicin (Dox) use is limited by Dox-induced cardiotoxicity. TANK-blinding kinase 1 (TBK1) is an important kinase involved in the regulation of mitophagy, but the role of TBK1 in cardiomyocytes in chronic Dox-induced cardiomyopathy remains unclear. Cardiomyocyte-specific Tbk1 knockout (Tbk1CKO) mice received Dox (6 mg/kg, injected intraperitoneally) once a week for 4 times, and cardiac assessment was performed 4 weeks after the final Dox injection. Adenoviruses encoding Tbk1 or containing shRNA targeting Tbk1, or a TBK1 phosphorylation inhibitor were used for overexpression or knockdown of Tbk1, or inhibit phosphorylation of TBK1 in isolated primary cardiomyocytes. Our results revealed that moderate Dox challenge decreased TBK1 phosphorylation (with no effect on TBK1 protein levels), resulting in compromised myocardial function, obvious mortality and overt interstitial fibrosis, and the effects were accentuated by Tbk1 deletion. Dox provoked mitochondrial membrane potential collapse and oxidative stress, the effects of which were exacerbated and mitigated by Tbk1 knockdown, specific inhibition of phosphorylation and overexpression, respectively. However, Tbk1 （Ser172A） overexpression did not alleviate these effects. Further scrutiny revealed that TBK1 exerted protective effects on mitochondria via SQSTM1/P62-mediated mitophagy. Tbk1 overexpression mediated cardioprotective effects on Dox-induced cardiotoxicity were cancelled off by Sqstm1/P62 knockdown. Moreover, TBK1-mitophagy-mitochondria cascade was confirmed in heart tissues from dilated cardiomyopathy patients. Taken together, our findings denoted a pivotal role of TBK1 in Dox-induced mitochondrial injury and cardiotoxicity possibly through its phosphorylation and SQSTM1/P62-mediated mitophagy.

Norepinephrine or phenylephrine for the prevention of post-spinal hypotension after caesarean section: A double-blinded, randomized, controlled study of fetal heart rate and fetal cardiac output.

STUDY OBJECTIVE: Spinal anesthesia often causes hypotension, with consequent risk to the fetus. The use of vasopressor agents has been highly recommended for the prevention of spinal anesthesia-induced hypotension during caesarean delivery. Many studies have shown that norepinephrine can provide more stable maternal hemodynamics than phenylephrine. We therefore tested the hypothesis that norepinephrine preserves fetal circulation better than phenylephrine when used to treat maternal hypotension consequent to spinal anesthesia. DESIGN: Prospective, randomized, double-blinded study. SETTING: Operating room. PATIENTS: We recruited 223 parturients with uncomplicated singleton pregnancies who were scheduled for elective caesarean section under combined spinal-epidural anesthesia. INTERVENTIONS: The patients received prophylactic intravenous infusion of either 0.08 µg/kg/min norepinephrine or 0.5 µg/kg/min phenylephrine for prevention of spinal anesthesia-induced hypotension. MEASUREMENTS: Changes in fetal heart rate and fetal cardiac output before and after spinal anesthesia were measured using noninvasive Doppler ultrasound. MAIN RESULTS: 90 subjects who received norepinephrine infusion and 93 subjects who received phenylephrine infusion were ultimately analyzed in the present study. The effects of norepinephrine and phenylephrine on the change of fetal heart rate and fetal cardiac output at 3 and 6 min after spinal block were similar. Although there was a statistically significant decrease in fetal cardiac output at 6 min after subarachnoid block initiation in both the norepinephrine group (mean difference 0.02 L/min; 95% CI, 0-0.04 L/min; P = 0.03) and the phenylephrine group (mean difference 0.02 L/min; 95% CI, 0-0.04 L/min; P = 0.02), it remained within the normal range. CONCLUSIONS: Prophylactic infusion of comparable doses of phenylephrine or norepinephrine has similar effects on fetal heart rate and cardiac output changes after spinal anesthesia. Neither phenylephrine nor norepinephrine has meaningful detrimental effects on fetal circulation or neonatal outcomes.

Unsupervised domain adaptation multi-level adversarial learning-based crossing-domain retinal vessel segmentation.

BACKGROUND: The retinal vasculature, a crucial component of the human body, mirrors various illnesses such as cardiovascular disease, glaucoma, and retinopathy. Accurate segmentation of retinal vessels in funduscopic images is essential for diagnosing and understanding these conditions. However, existing segmentation models often struggle with images from different sources, making accurate segmentation in crossing-source fundus images challenging. METHODS: To address the crossing-source segmentation issues, this paper proposes a novel Multi-level Adversarial Learning and Pseudo-label Denoising-based Self-training Framework (MLAL&PDSF). Expanding on our previously proposed Multiscale Context Gating with Breakpoint and Spatial Dual Attention Network (MCG&BSA-Net), MLAL&PDSF introduces a multi-level adversarial network that operates at both the feature and image layers to align distributions between the target and source domains. Additionally, it employs a distance comparison technique to refine pseudo-labels generated during the self-training process. By comparing the distance between the pseudo-labels and the network predictions, the framework identifies and corrects inaccuracies, thus enhancing the accuracy of the fine vessel segmentation. RESULTS: We have conducted extensive validation and comparative experiments on the CHASEDB1, STARE, and HRF datasets to evaluate the efficacy of the MLAL&PDSF. The evaluation metrics included the area under the operating characteristic curve (AUC), sensitivity (SE), specificity (SP), accuracy (ACC), and balanced F-score (F1). The performance results from unsupervised domain adaptive segmentation are remarkable: for DRIVE to CHASEDB1, results are AUC: 0.9806, SE: 0.7400, SP: 0.9737, ACC: 0.9874, and F1: 0.8851; for DRIVE to STARE, results are AUC: 0.9827, SE: 0.7944, SP: 0.9651, ACC: 0.9826, and F1: 0.8326. CONCLUSION: These results demonstrate the effectiveness and robustness of MLAL&PDSF in achieving accurate segmentation results from crossing-domain retinal vessel datasets. The framework lays a solid foundation for further advancements in cross-domain segmentation and enhances the diagnosis and understanding of related diseases.

BOLERO-5: a phase II study of everolimus and exemestane combination in Chinese post-menopausal women with ER + /HER2- advanced breast cancer.

BACKGROUND: The global BOLERO-2 trial established the efficacy and safety of combination everolimus (EVE) and exemestane (EXE) in the treatment of estrogen receptor positive (ER +), HER2-, advanced breast cancer (ABC). BOLERO-5 investigated this combination in a Chinese population (NCT03312738). METHODS: BOLERO-5 is a randomized, double-blind, multicenter, placebo controlled, phase II trial comparing EVE (10 mg/day) or placebo (PBO) in combination with EXE (25 mg/day). The primary endpoint was progression-free survival (PFS) per investigator assessment. Secondary endpoints included PFS per blinded independent review committee (BIRC), overall survival (OS), overall response rate (ORR), clinical benefit rate (CBR), pharmacokinetics, and safety. RESULTS: A total of 159 patients were randomized to EVE + EXE (n = 80) or PBO + EXE (n = 79). By investigator assessment, treatment with EVE + EXE prolonged median PFS by 5.4 months (HR 0.52; 90% CI 0.38, 0.71), from 2.0 months (PBO + EXE; 90% CI 1.9, 3.6) to 7.4 months (EVE + EXE; 90% CI 5.5, 9.0). Similar results were observed following assessment by BIRC, with median PFS prolonged by 4.3 months. Treatment with EVE + EXE was also associated with improvements in ORR and CBR. No new safety signals were identified in BOLERO-5, with the incidence of adverse events in Chinese patients consistent with the safety profile of both drugs. CONCLUSION: The efficacy and safety results of BOLERO-5 validate the findings from BOLERO-2, and further support the use of EVE + EXE in Chinese post-menopausal women with ER + , HER2- ABC. NCT03312738, registered 18 October 2017.

In Vitro Investigations into the Potential Drug Interactions of Pseudoginsenoside DQ Mediated by Cytochrome P450 and Human Drug Transporters.

Pseudoginsenoside DQ (PDQ), an ocotillol-type ginsenoside, is synthesized with protopanaxadiol through oxidative cyclization. PDQ exhibits good anti-arrhythmia activity. However, the inhibitory effect of PDQ on the cytochrome 450 (CYP450) enzymes and major drug transporters is still unclear. Inhibition of CYP450 and drug transporters may affect the efficacy of the drugs being used together with PDQ. These potential drug-drug interactions (DDIs) are essential for the clinical usage of drugs. In this study, we investigated the inhibitory effect of PDQ on seven CYP450 enzymes and seven drug transporters with in vitro models. PDQ has a significant inhibitory effect on CYP2C19 and P-glycoprotein (P-gp) with a half-inhibitory concentration (IC50) of 0.698 and 0.41 µM, respectively. The inhibition of CYP3A4 and breast cancer-resistant protein (BCRP) is less potent, with IC50 equal to 2.02-6.79 and 1.08 µM, respectively.

Screening parameters for diagnosing primary aldosteronism in patients with moderate to severe obstructive sleep apnea hypopnea syndrome and resistant hypertension.

Background: Patients with obstructive sleep apnea hypopnea syndrome (OSAHS) combined with resistant hypertension (RH) have a high risk of developing primary aldosteronism (PA). This study investigated the aldosterone-renin ratio (ARR), plasma aldosterone concentration (PAC), and plasma renin activity (PRA) to determine the optimal cutoff values for PA diagnosis in patients with OSAHS combined with RH. Methods: Patients diagnosed with moderate and severe OSAHS combined with RH were recruited from the inpatient clinic of the Department of Endocrinology at Ji'an Central Hospital between October 2020 and April 2023. The included patients were divided into PA and no-PA groups. Diagnostic accuracy measures were calculated for each group, and receiver operating characteristic (ROC) curves were generated. Results: A total of 241 patients were included, of which 103 had positive ARR screening results in the diagnostic accuracy analysis and 66 were diagnosed with PA. PAC and ARR showed moderate predictive capacity for PA, with area under the curve (AUC) values of 0.66 [95% confidence interval (CI): 0.55-0.77] and 0.72 (95% CI: 0.63-0.82), respectively, while PRA exhibited a limited predictive capacity (AUC = 0.51, 95% CI: 0.40-0.63). Using 45 as the optimal cutoff value for ARR, the sensitivity was 86% and the specificity was 52%. The optimal cutoff value for PAC was 17, with a sensitivity of 78% and a specificity of 55%. Notably, in patients with severe OSAHS, ARR at screening demonstrated significant predictive value for PA, with an AUC of 0.84 (95% CI: 0.72-0.96), a sensitivity of 85%, and a specificity of 76%. Conversely, in patients with moderate OSAHS, only ARR demonstrated significant predictive value for PA diagnosis, while PAC did not demonstrate notable diagnostic value. Conclusion: ARR and PAC are initial screening tools for PA, facilitating early detection, particularly in low-resource settings. In patients with OSAHS and RH, the ARR and PAC thresholds for PA diagnosis may require more stringent adjustment.

Narazaciclib, a novel multi-kinase inhibitor with potent activity against CSF1R, FLT3 and CDK6, shows strong anti-AML activity in defined preclinical models.

CSF1R is a receptor tyrosine kinase responsible for the growth/survival/polarization of macrophages and overexpressed in some AML patients. We hypothesized that a novel multi-kinase inhibitor (TKi), narazaciclib (HX301/ON123300), with high potency against CSF1R (IC50 ~ 0.285 nM), would have anti-AML effects. We tested this by confirming HX301's high potency against CSF1R (IC50 ~ 0.285 nM), as well as other kinases, e.g. FLT3 (IC50 of ~ 19.77 nM) and CDK6 (0.53 nM). An in vitro proliferation assay showed that narazaciclib has a high growth inhibitory effect in cell cultures where CSF1R or mutant FLT3-ITD variants that may be proliferation drivers, including primary macrophages (IC50 of 72.5 nM) and a subset of AML lines (IC50 < 1.5 µM). In vivo pharmacology modeling of narazaciclib using five AML xenografts resulted in: inhibition of MV4-11 (FLT3-ITD) subcutaneous tumor growth and complete suppression of AM7577-PDX (FLT3-ITD/CSF1Rmed) systemic growth, likely due to the suppression of FLT3-ITD activity; complete suppression of AM8096-PDX (CSF1Rhi/wild-type FLT3) growth, likely due to the inhibition of CSF1R ("a putative driver"); and nonresponse of both AM5512-PDX and AM7407-PDX (wild-type FLT3/CSF1Rlo). Significant leukemia load reductions in bone marrow, where disease originated, were also achieved in both responders (AM7577/AM8096), implicating that HX301 might be a potentially more effective therapy than those only affecting peripheral leukemic cells. Altogether, narazaciclib can potentially be a candidate treatment for a subset of AML with CSF1Rhi and/or mutant FLT3-ITD variants, particularly second generation FLT3 inhibitor resistant variants.

Exploring personalized treatment for cardiac graft rejection based on a four-archetype analysis model and bioinformatics analysis.

Heart transplantation is the gold standard for treating patients with advanced heart failure. Although improvements in immunosuppressive therapies have significantly reduced the frequency of cardiac graft rejection, the incidences of T cell-mediated rejection (TCMR) and antibody-mediated rejection remain almost unchanged. A four-archetype analysis (4AA) model, developed by Philip F. Halloran, illustrated this problem well. It provided a new dimension to improve the accuracy of diagnoses and an independent system for recalibrating the histology guidelines. However, this model was based on the invasive method of endocardial biopsy, which undoubtedly increased the postoperative risk of heart transplant patients. Currently, little is known regarding the associated genes and specific functions of the different phenotypes. We performed bioinformatics analysis (using machine-learning methods and the WGCNA algorithm) to screen for hub-specific genes related to different phenotypes, based Gene Expression Omnibus accession number GSE124897. More immune cell infiltration was observed with the ABMR, TCMR, and injury phenotypes than with the stable phenotype. Hub-specific genes for each of the four archetypes were verified successfully using an external test set (accession number GSE2596). Logistic-regression models based on TCMR-specific hub genes and common hub genes were constructed with accurate diagnostic utility (area under the curve > 0.95). RELA, NFKB1, and SOX14 were identified as transcription factors important for TCMR/injury phenotypes and common genes, respectively. Additionally, 11 Food and Drug Administration-approved drugs were chosen from the DrugBank Database for each four-archetype model. Tyrosine kinase inhibitors may be a promising new option for transplant rejection treatment. KRAS signaling in cardiac transplant rejection is worth further investigation. Our results showed that heart transplant rejection subtypes can be accurately diagnosed by detecting expression of the corresponding specific genes, thereby enabling precise treatment or medication.

Randomized Double-Blinded Comparison of Intermittent Boluses Phenylephrine and Norepinephrine for the Treatment of Postspinal Hypotension in Patients with Severe Pre-Eclampsia During Cesarean Section.

Background: Norepinephrine has fewer negative effects on heart rate (HR) and cardiac output (CO) for treating postspinal hypotension (PSH) compared with phenylephrine during cesarean section. However, it remains unclear whether fetuses from patients with severe pre-eclampsia could benefit from the superiority of CO. The objective of this study was to compare the safety and efficacy of intermittent intravenous boluses of phenylephrine and norepinephrine used in equipotent doses for treating postspinal hypotension in patients with severe pre-eclampsia during cesarean section. Methods: A total of 80 patients with severe pre-eclampsia who developed PSH predelivery during cesarean section were included. Eligible patients were randomized at a 1:1 ratio to receive either phenylephrine or norepinephrine for treating PSH. The primary outcome was umbilical arterial pH. Secondary outcomes included other umbilical cord blood gas values, Apgar scores at 1 and 5 min, changes in hemodynamic parameters including CO, mean arterial pressure (MAP), HR, stroke volume (SV), and systemic vascular resistance (SVR), the number of vasopressor boluses required, and the incidence of bradycardia, hypertension, nausea, vomiting, and dizziness. Results: No significant difference was observed in umbilical arterial pH between the phenylephrine and norepinephrine groups (7.303±0.38 vs 7.303±0.44, respectively; P=0.978). Compared with the phenylephrine group, the overall CO (P=0.009) and HR (P=0.015) were greater in the norepinephrine group. The median [IQR] total number of vasopressor boluses required was comparable between the two groups (2 [1 to 3] and 2 [1 to 3], respectively; P=0.942). No significant difference was found in Apgar scores or the incidence of maternal complications between groups. Conclusion: A 60 µg bolus of phenylephrine and a 4.5 µg bolus of norepinephrine showed similar neonatal outcomes assessed by umbilical arterial pH and were equally effective when treating PSH during cesarean section in patients with severe pre-eclampsia. Norepinephrine provided a higher maternal CO and a lower incidence of bradycardia.

Novel applications of Yinhua Miyanling tablets in ulcerative colitis treatment based on metabolomics and network pharmacology.

BACKGROUND: Yinhua Miyanling tablets (YMT), comprising 10 Chinese medicinal compounds, is a proprietary Chinese medicine used in the clinical treatment of urinary tract infections. Medicinal compounds, extracts, or certain monomeric components in YMT all show good effect on ulcerative colitis (UC). However, no evidence supporting YMT as a whole prescription for UC treatment is available. PURPOSE: To evaluate the anti-UC activity of YMT and elucidate the underlying mechanisms. The objective of the study was to provide evidence for the add-on development of YMT to treat UC. METHODS: First, YMT's protective effect on the intestinal barrier was evaluated using a lipopolysaccharide (LPS)-induced Caco-2 intestinal injury model. Second, the UC mouse model was established using dextran sodium sulfate (DSS) to determine YMT's influence on symptoms, inflammatory factors, intestinal barrier, and histopathological changes in the colon. Third, an integrated method combining metabolomics and network pharmacology was employed to screen core targets and key metabolic pathways with crucial roles in YMT's therapeutic effect on UC. Molecular docking was employed to identify the key targets with high affinity. Finally, western blotting was performed to validate the mechanism of YMT action against UC. RESULTS: YMT enhanced the transepithelial electrical resistance value and improved the expression of proteins of the tight junctions dose-dependently in LPS-induced Caco-2 cells. UC mice treated with YMT exhibited alleviated pathological lesions of the colon tissue in the in vivo pharmacodynamic experiments. The colonic lengths tended to be normal, and the levels of inflammatory factors (TNF-α, IL-6, and iNOS) along with those of the core enzymes (MPO, MDA, and SOD) improved. YMT effectively ameliorated DSS-induced colonic mucosal injury; pathological changes along with ultrastructure damage were significantly alleviated (evidenced by a relatively intact colon tissue, recovery of epithelial damage, repaired gland, reduced infiltration of inflammatory cells and epithelial cells arranged closely with dense microvilli). Seven key targets (IL-6, TNF-α, MPO, COX-2, HK2, TPH, and CYP1A2) and four key metabolic pathways (arachidonic acid metabolism, linoleate metabolism, glycolysis, and gluconeogenesis and tyrosine biosynthesis) were identified to play vital roles in the treatment on UC using YMT. CONCLUSIONS: YMT exerts beneficial therapeutic effects on UC by regulating multiple endogenous metabolites, targets, and metabolic pathways, suggestive of its potential novel application in UC treatment.

Pyxinol Fatty Acid Ester Derivatives J16 against AKI by Selectively Promoting M1 Transition to M2c Macrophages.

Acute kidney injury (AKI) is a common, multicause clinical condition that, if ignored, often progresses to chronic kidney disease (CKD) and end-stage kidney disease, with a mortality rate of 40-50%. However, there is a lack of universal treatment for AKI. Inflammation is the basic pathological change of early kidney injury, and inflammation can exacerbate AKI. Macrophages are the primary immune cells involved in the inflammatory microenvironment of kidney disease. Therefore, regulating the function of macrophages is a crucial breakthrough for the AKI intervention. Our team chemically modified pyxinol, an ocotillol-type ginsenoside, to prepare PJ16 with higher solubility and bioavailability. In vitro, using a model of macrophages stimulated by LPS, it was found that PJ16 could regulate macrophage function, including inhibiting the secretion of inflammatory factors, promoting phagocytosis, inhibiting M1 macrophages, and promoting M1 transition to the M2c macrophage. Further investigation revealed that PJ16 may shield renal tubular epithelial cells (HK-2) damaged by LPS in vitro. Based on this, PJ16 was validated in the animal model of unilateral ureteral obstruction, which showed that it improves renal function and inhibits renal tissue fibrosis by decreasing inflammatory responses, reducing macrophage inflammatory infiltration, and preferentially upregulating M2c macrophages. In conclusion, our study is the first to show that PJ16 resists AKI and fibrosis by mechanistically regulating macrophage function by modulating the phenotypic transition from M1 to M2 macrophages, mainly M2c macrophages.

HTRA1-driven detachment of type I collagen from endoplasmic reticulum contributes to myocardial fibrosis in dilated cardiomyopathy.

BACKGROUND: The aberrant secretion and excessive deposition of type I collagen (Col1) are important factors in the pathogenesis of myocardial fibrosis in dilated cardiomyopathy (DCM). However, the precise molecular mechanisms underlying the synthesis and secretion of Col1 remain unclear. METHODS AND RESULTS: RNA-sequencing analysis revealed an increased HtrA serine peptidase 1 (HTRA1) expression in patients with DCM, which is strongly correlated with myocardial fibrosis. Consistent findings were observed in both human and mouse tissues by immunoblotting, quantitative reverse transcription polymerase chain reaction (qRT-PCR), immunohistochemistry, and immunofluorescence analyses. Pearson's analysis showed a markedly positive correlation between HTRA1 level and myocardial fibrosis indicators, including extracellular volume fraction (ECV), native T1, and late gadolinium enhancement (LGE), in patients with DCM. In vitro experiments showed that the suppression of HTRA1 inhibited the conversion of cardiac fibroblasts into myofibroblasts and decreased Col1 secretion. Further investigations identified the role of HTRA1 in promoting the formation of endoplasmic reticulum (ER) exit sites, which facilitated the transportation of Col1 from the ER to the Golgi apparatus, thereby increasing its secretion. Conversely, HTRA1 knockdown impeded the retention of Col1 in the ER, triggering ER stress and subsequent induction of ER autophagy to degrade misfolded Col1 and maintain ER homeostasis. In vivo experiments using adeno-associated virus-serotype 9-shHTRA1-green fluorescent protein (AAV9-shHTRA1-GFP) showed that HTRA1 knockdown effectively suppressed myocardial fibrosis and improved left ventricular function in mice with DCM. CONCLUSIONS: The findings of this study provide valuable insights regarding the treatment of DCM-associated myocardial fibrosis and highlight the therapeutic potential of targeting HTRA1-mediated collagen secretion.

Bendable quasi-solid-state aqueous sodium-ion batteries operated at -30 °C.

Aqueous sodium-ion batteries (ASIBs) have garnered considerable attention for large-scale energy storage because of inherent safety and the Na abundance. Nonetheless, the solidification of aqueous electrolytes under sub-zero conditions results in diminished ionic conductivity and increased viscosity, hindering the electrochemical performance and versatility of ASIBs. Herein, we introduce a novel freeze-tolerant ASIB using antifreezing ethylene glycol-polyacrylamide-sodium perchlorate hydrogel electrolyte, paired with new couple of Na3MnTi(PO4)3 cathode and Fe-based anode. The addition of ethylene glycol in the electrolyte enhances ionic conductivity at cold temperatures and optimizes electrode capacity by reduced hydrogen bonding within the water molecules and a decline in free water activity. The pronounced interaction between ethylene glycol and water, combined with the cooperative effect of the crosslinked polyacrylamide network, enables the hydrogel electrolyte to effectively suppress water solidification and maintain better water-retaining capability, achieving remarkable mechanical extensibility and good ionic conductivity (2.5 mS cm-1) at - 40 °C. Consequently, the ASIB equipped with hydrogel electrolyte delivers high energy density of 43.6 Wh kg-1 and retains 64 % at - 30 °C. Furthermore, the flexible ASIB demonstrates robust mechanical durability when bent or compressed, efficiently powering electronic devices even at - 30 °C. Our findings will pave the way for advancing low-temperature ASIBs with hydrogel-based electrolytes.