IL-17A exacerbates corpus cavernosum fibrosis and neurogenic erectile dysfunction by inducing CSMC senescence via the mTORC2-ACACA pathway.

BACKGROUND: Neurogenic erectile dysfunction, characterized by neurological repair disorders and progressive corpus cavernosum fibrosis (CCF), is an unbearable disease with limited treatment success. IL-17A exhibits a complex role in tissue remodelling. Nevertheless, the precise role and underlying mechanisms of IL-17A in CCF under denervation remain unclear. METHODS: PCR array was employed to identified differentially expressed genes between neurogenic ED and normal rats. IL-17A expression and its main target cells were analyzed using Western blotting, immunofluorescence and immunohistochemistry. The phenotypic regulation of IL-17A on corpus cavernosum smooth muscle cells (CSMCs) was evaluated by cell cycle experiments and SA-ß-Gal staining. The mechanism of IL-17A was elucidated using non-target metabolomics and siRNA technique. Finally, IL-17A antagonist and ABT-263 (an inhibitor of B-cell lymphoma 2/w/xL) were utilized to enhance the therapeutic effect in a rat model of neurogenic ED. RESULTS: IL-17A emerged as the most significantly upregulated gene in the corpus cavernosum of model rats. It augmented the senescence transformation and fibrotic response of CSMCs, and exhibited a strong correlation with CCF. Mechanistically, IL-17A facilitated CCF by activating the mTORC2-ACACA signalling pathway, upregulating of CSMCs lipid synthesis and senescence transition, and increasing the secretion of fibro-matrix proteins. In vivo, the blockade of IL-17A-senescence signalling improved erectile function and alleviated CCF in neurogenic ED. CONCLUSIONS: IL-17A assumes a pivotal role in denervated CCF by activating the mTORC2-ACACA signalling pathway, presenting itself as a potential therapeutic target for effectively overcoming CCF and erection rehabilitation in neurogenic ED.

Erratum: Porphyrin-grafted Lipid Microbubbles for the Enhanced Efficacy of Photodynamic Therapy in Prostate Cancer through Ultrasound-controlled In Situ Accumulation: Erratum.

[This corrects the article DOI: 10.7150/thno.22469.].

The effect of instructional quality on reading achievement: The mediating role of reading engagement in China (B-S-J-Z) and the UK.

The present study aims to explore the mediating role of reading engagement between instructional quality and reading achievement in China (B-S-J-Z) and the UK, and the pedagogical transportation that has been implemented between China and the UK since 2014. Participants in this study were from PISA 2018 where 12,058 students were from China (B-S-J-Z) and 13,818 were from the UK. Structural equation modeling (SEM) was used to explore the relationships among instructional quality, reading engagement, and reading achievement. The effect of classroom management and cognitive activation on reading achievement was significantly mediated by enjoyment of reading in both China (B-S-J-Z) and the UK. Diversity of reading was found to positively mediate the relationships between classroom management and reading achievement, and between cognitive activation and reading achievement in China (B-S-J-Z), in contrast to the mediating role of reading strategy revealed in the UK. The findings have important implications in that educators from China (B-S-J-Z) and the UK should focus on improving students' reading interests, UK teachers may incorporate diverse sources in reading, and Chinese educators may try different reading teaching strategies. Meanwhile, educators and policymakers may give full consideration to implications based on the specific cultural background. Finally, the limitations and future directions are provided.

Structural basis for the ligand recognition and G protein subtype selectivity of kisspeptin receptor.

Kisspeptin receptor (KISS1R), belonging to the class A peptide-GPCR family, plays a key role in the regulation of reproductive physiology after stimulation by kisspeptin and is regarded as an attractive drug target for reproductive diseases. Here, we demonstrated that KISS1R can couple to the Gi/o pathway besides the well-known Gq/11 pathway. We further resolved the cryo-electron microscopy (cryo-EM) structure of KISS1R-Gq and KISS1R-Gi complexes bound to the synthetic agonist TAK448 and structure of KISS1R-Gq complex bound to the endogenous agonist KP54. The high-resolution structures provided clear insights into mechanism of KISS1R recognition by its ligand and can facilitate the design of targeted drugs with high affinity to improve treatment effects. Moreover, the structural and functional analyses indicated that conformational differences in the extracellular loops (ECLs), intracellular loops (ICLs) of the receptor, and the "wavy hook" of the Gα subunit may account for the specificity of G protein coupling for KISS1R signaling.

Research on the relationship between nurses' emergency public health response capacity and workplace resilience: A cross-sectional study.

Objective: This study aimed to investigate the factors influencing nurses' ability to respond to public health emergencies and understand the relationship between nurses' ability to respond to emergencies and workplace resilience. Methods: A cross-sectional study of 361 nurses from military hospitals was conducted from January 18 to September 6, 2022, using an online survey. The Infectious Diseases Emergency Response Capacity (IDERC) questionnaire and the Workplace Resilience Scale (WRS) were utilized, and sociodemographic information was also collected. Data were analyzed using descriptive statistics and frequency analysis. Differences between groups were identified by one-way analysis of variance, and linear regression was used to analyze the main factors influencing the infectious emergency response capacity. Results: The average infectious emergency response capacity score on the IDERC questionnaire and workplace resilience, measured by WRS, were 4.01 (SD = 0.76) and 3.85 (SD = 0.71), respectively, on a scale of 1-5, indicating high performance. Factors such as degree of education, nurses' service years and experience in epidemic prevention participation were found to be the main influencing factors of the score of IDERC. The level of workplace resilience showed a positive correlation with the capacity to respond to infectious disease, the score of WRS and the service year accounted for 63.6% of the variance in emergency response capabilities. Conclusion: The results indicate an urgent need to strengthen the training of nurses with lower degree of education, shorter service years, no prior work, or no experience of epidemic prevention participation, and hospitals should also prioritize improving nurses' workplace resilience through targeted interventions, enhancing their abilities in infectious disease prevention, preparation, first aid, and subsequent critical patient care.

Automatic wound closure system: closure of large wounds by stretching the skin around the wound.

Large-wound treatment often requires autologous skin grafting or skin flap transfer, causing iatrogenic secondary injuries. Thus, we have developed an automatic wound closure system that consists of a stretch module, microcontroller, and touch screen. Full-thickness wounds (8 × 14 cm) on Bama miniature pigs were manually closed by direct suture in control animals and with three different tension levels performed by the automatic device in the experimental animals. Wound-closure conditions, post-closure healing, and scars were evaluated. Post-operative microscopic changes in collagen fibers, local cell apoptosis, and changes in vascular density were compared between the two wound-closure techniques. In the control group and the first experimental group, which used a traction force of 15 N, primary wound closure could not be achieved. The other two experimental groups used a traction force of 30 N and 60 N and all wounds achieved primary closure. Collagen-fiber stretching was observed histologically in all groups and collagen-fiber breakdown occurred in some wounds when the traction force was 60 N. Scar hyperplasia was significantly reduced in the automatic wound closure system groups. The collagen content decreased, cell apoptosis increased, and vascular density decreased in local tissues in the early post-closure stage, but eventually recovered to normal-skin levels. In summary, we developed an automatic wound closure system that effectively and safely stretches dermal-collagen fibers under an appropriate traction force (30 N) and stretch wound-peripheral skin to cover the wound, achieve primary closure, and reduce scar hyperplasia.

Physical and psychological status of emergency assistance personnel at major public health events: a qualitative descriptive study.

BACKGROUND: Many personnel respond to natural disasters like earthquakes and tsunamis and frequent public health events like Ebola and COVID-19. However, research on emergency assistance personnel remains limited. This study aims to describe the perceived well-being among responders deployed in isolated or emergency international missions while providing practical references to intervene in developing similar missions. METHODS: For this qualitative phenomenological study, purposive sampling was used following the principle of maximum differentiation to select personnel deployed on an emergency mission for over a year. Data collection continued until data saturation. Phenomenologically semi-structured interviews helped explore the physical and psychological status of the participants with Colaizzi's method. RESULTS: Eleven personnel were interviewed after the mission, with four major themes being identified: 'perceived somatic change,' 'perceived emotional change,' 'behavioral change,' and 'coping with perceived change.' CONCLUSIONS: The mental health status of the emergency assistance personnel was affected by multiple factors from external and internal environments. The current study explored the physical and psychological feelings and emotions of emergency assistance personnel during an emergency mission. The study provided a practical reference for health management under similar missions. REGISTRATIONS: Not registered.

Course-based intra-articular injection of medical chitosan mitigates excessive deposition of triacylglycerides in the synovial tissue of the knee osteoarthritis.

BACKGROUND: This study aimed to investigate the clinical efficacy of intra-articular injections of medical chitosan for treating knee osteoarthritis (KOA) and measure the lipid metabolism profiles of the synovial tissue. METHODS: Sixty patients with KOA undergoing conservative treatment were recruited and randomized into two groups: one without pharmacological intervention (OA group) and the other receiving course-based intra-articular medical chitosan injections (CSI group). Quantitative lipidomic profile of synovial tissue was analyzed. Functional scores, including Kellgren-Lawrence rating (K-L), Visual Analog Scale (VAS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scoring, and American Knee Society (AKS) scoring were conducted. RESULTS: Survival from the initial conservative treatment to final knee arthroplasty was significantly longer in the CSI group compared to the OA group. Except for the presurgery VAS score, no statistically significant differences were observed in the other scores, including K-L, initial VAS, WOMAC, and AKS. However, the CSI group experienced more reductions in AKS-Knee subscores compared to the OA group. Compared to the CSI group, the OA group exhibited a significant upregulation in most differential lipids, particularly triacylglycerides (TAGs, 77%). The OA group had notably higher levels of long-chain unsaturated fatty acids. CONCLUSION: Intra-articular injection of medical chitosan significantly prolongs the survival period before knee arthroplasty and reduces the deposition of TAGs metabolites.

Research Progress of Central Serous Chorioretinopathy in Recent 20 Years Based on Visual Bibliometric Analysis.

OBJECTIVE: To dynamically track the publications on central serous chorioretinopathy (CSC) and depict the research status and hot spots to guide future research. METHODS: Gather all papers published in this area between 2004 and 2024 in the WOSCC databases comprehensively, assess their trends, and characterize the contributions of various nations, authors, institutions, and journals. In addition, VOSviewer, CiteSpace, and R software are used to obtain the most popular keywords for the topic. RESULTS: A total of 2,203 papers were published across 1,863 institutions in 59 countries. Among these, 6,907 authors contributed to publications in 300 journals and generated a total of 35,638 citations. The number of publications continues to grow steadily. Notably, Jay Chhablani's team/Lab stands out as the leading contributor with ownership of 84 publications. Through keyword network analysis and clustering techniques, risk factor-related clustering, imaging-related clustering, pathogenesis-related clustering, and treatment-related clustering were identified. Furthermore, keyword analysis has unveiled emerging frontier areas including pachychoroid disease, choroidal vasculature abnormalities, PDT therapy, and optical coherence tomography that have garnered increasing interest. CONCLUSION: This study presents a comprehensive review of central serous retinopathy research conducted in the past two decades, highlighting key trends and exploring emerging research frontiers within this field. As such, it provides valuable references and suggestions for researchers engaged in studying this topic.

Discriminative analysis of schizophrenia and major depressive disorder using fNIRS.

BACKGROUND: Research into the shared and distinct brain dysfunctions in patients with schizophrenia (SCZ) and major depressive disorder (MDD) has been increasing. However, few studies have explored the application of functional near-infrared spectroscopy (fNIRS) in investigating brain dysfunction and enhancing diagnostic methodologies in these two conditions. METHODS: A general linear model was used for analysis of brain activation following task-state fNIRS from 131 patients with SCZ, 132 patients with MDD and 130 healthy controls (HCs). Subsequently, seventy-seven time-frequency analysis methods were used to construct new features of fNIRS, followed by the implementation of five machine learning algorithms to develop a differential diagnosis model for the three groups. This model was evaluated by comparing it to both a diagnostic model relying on traditional fNIRS features and assessments made by two psychiatrists. RESULTS: Brain activation analysis revealed significantly lower activation in Broca's area, the dorsolateral prefrontal cortex, and the middle temporal gyrus for both the SCZ and MDD groups compared to HCs. Additionally, the SCZ group exhibited notably lower activation in the superior temporal gyrus and the subcentral gyrus compared to the MDD group. When distinguishing among the three groups using independent validation datasets, the models utilizing new fNIRS features achieved an accuracy of 85.90 % (AUC = 0.95). In contrast, models based on traditional fNIRS features reached an accuracy of 52.56 % (AUC = 0.66). The accuracies of the two psychiatrists were 42.00 % (AUC = 0.60) and 38.00 % (AUC = 0.50), respectively. CONCLUSION: This investigation brings to light the shared and distinct neurobiological abnormalities present in SCZ and MDD, offering potential enhancements for extant diagnostic systems.

Effects of dyadic care interventions for heart failure on patients' and caregivers' outcomes: A systematic review, meta-analysis and meta-regression.

BACKGROUND: The contemporary model for managing heart failure has been extended to a patient-family caregiver dyadic context. However, the key characteristics of the model that can optimise health outcomes for both patients and caregivers remain to be investigated. OBJECTIVES: This study aimed to identify the effects of dyadic care interventions on the behavioural, health, and health-service utilisation outcomes of patients with heart failure and their family caregivers and to explore how the intervention design characteristics influence these outcomes. DESIGN: This study involved systematic review, meta-analysis, and meta-regression techniques. METHODS: We performed a systematic review and meta-analysis, using 12 databases to identify randomised controlled trials or quasi-experimental studies published in English or Chinese between database inception and 31 December 2022. The considered interventions included those targeting patients with heart failure and their family caregivers to enhance disease management. Data synthesis was performed on various patient- and caregiver-related outcomes. The identified interventions were categorised according to their design characteristics for subgroup analysis. Meta-regression was performed to explore the relationship between care delivery methods and their effectiveness. RESULTS: We identified 48 studies representing 9171 patient-caregiver dyads. Meta-analyses suggested the positive effects of dyadic care interventions on patients' health outcomes [Hedges' g (95 % confidence interval {CI}): heart failure knowledge = 1.0 (0.26, 1.75), p = 0.008; self-care confidence = 0.45 (0.08, 0.83), p = 0.02; self-care maintenance = 1.12 (0.55, 1.70), p < 0.001; self-care management = 1.01 (0.54, 1.49), p < 0.001; anxiety = -0.18 (-0.34, -0.02), p = 0.03; health-related quality of life = 0.30 (0.08, 0.51), p < 0.001; hospital admission (risk ratio {95 % CI}: hospital admission = 0.79 (0.65, 0.97), p = 0.007; and mortality = 0.58 (0.36, 0.93), p = 0.02)]. Dyadic care interventions also improved the caregivers' outcomes [Hedges' g (95 % CI): social support = 0.67 (0.01, 1.32), p = 0.05; perceived burden = -1.43 (-2.27, -0.59), p < 0.001]. Although the design of the identified care interventions was heterogeneous, the core care components included enabling and motivational strategies to improve self-care, measures to promote collaborative coping within the care dyads, and nurse-caregiver collaborative practice. Incorporating the first two core components appeared to enhance the behavioural and health outcomes of the patients, and the addition of the last component reduced readmission. Interventions that engaged both patients and caregivers in care provision, offered access to nurses, and optimised continuity of care led to better patient outcomes. CONCLUSIONS: These findings demonstrate that dyadic care interventions can effectively improve disease management in a family context, resulting in better health outcomes for both patients and caregivers. Additionally, this study provides important insights into the more-effective design characteristics of these interventions. REGISTRATION NUMBER: The review protocol was registered in the PROSPERO International Prospective Register of Systematic Reviews (CRD42022322492).

A multicentre, randomised, double-blind, double-dummy, parallel-controlled, phase 3 clinical trial assessing the efficacy and safety of intravenous nemonoxacin malate vs. levofloxacin for community-acquired pneumonia in adult patients.

BACKGROUND: Nemonoxacin malate is a novel non-fluorinated quinolone for oral and intravenous (IV) administration. This phase 3, multicentre, randomised, double-blind, double-dummy, parallel-controlled clinical trial (NCT02205112) evaluated the efficacy and safety of IV nemonoxacin vs. levofloxacin for the treatment of community-acquired pneumonia (CAP) in adult patients. METHODS: Eligible patients were randomised to receive 500 mg nemonoxacin or levofloxacin via IV infusion, once daily for 7-14 days. The primary endpoint was the clinical cure rate at the test-of-cure (TOC) visit in the modified intent-to-treat (mITT) population. Secondary efficacy and safety were also compared between nemonoxacin and levofloxacin. RESULTS: Overall, 525 patients were randomised and treated with nemonoxacin (n = 349) or levofloxacin (n = 176). The clinical cure rate was 91.8% (279/304) for nemonoxacin and 85.7% (138/161) for levofloxacin in the mITT population (P > 0.05). The clinical efficacy of nemonoxacin was non-inferior to levofloxacin for treatment of CAP. Microbiological success rate with nemonoxacin was 88.8% (95/107) and with levofloxacin was 87.8% (43/49) (P > 0.05) at the TOC visit in the bacteriological mITT population. The incidence of drug-related adverse events (AEs) was 37.1% in the nemonoxacin group and 22.2% in the levofloxacin group. These AEs were mostly local reactions at the infusion site, nausea, elevated alanine aminotransferase/aspartate aminotransferase (ALT/AST), and QT interval prolongation. The nemonoxacin-related AEs were mostly mild and resolved after discontinuation of nemonoxacin. CONCLUSIONS: Nemonoxacin 500 mg IV once daily for 7-14 days is effective and safe and non-inferior to levofloxacin for treating CAP in adult patients.

Risk analysis for subsequent fracture of osteoporotic fractures in Chinese women over age 60: a nationwide cross-sectional study.

Prevention of subsequent fracture is a major public health challenge in the field of osteoporosis prevention and treatment, and older women are at high risk for osteoporotic fractures. This study aimed to examine factors associated with subsequent fracture in older Chinese women with osteoporosis. We collected data on 9212 older female patients with osteoporotic fractures from 580 medical institutions in 31 provinces of China. Higher odds of subsequent fractures were associated with age of 70-79 years (OR 1.218, 95% CI 1.049-1.414), age ≥ 80 (OR 1.455, 95% CI 1.222-1.732), index fracture site was vertebrae (OR 1.472, 95% CI 1.194-1.815) and hip (OR 1.286, 95% CI 1.041-1.590), index fracture caused by fall (OR 1.822, 95% CI 1.281-2.591), strain (OR 1.587, 95% CI 1.178-2.139), no inducement (OR 1.541, 95% CI 1.043-2.277), and assessed as high risk of fracture (OR 1.865, 95% CI 1.439-2.416), BMD T-score ≤ -2.5 (OR 1.725, 95% CI 1.440-2.067), history of surgery (OR 3.941, 95% CI 3.475-4.471) and trauma (OR 8.075, 95% CI 6.941-9.395). Low risk of fall (OR 0.681, 95% CI 0.513-0.904), use of anti-osteoporosis medication (AOM, OR 0.801, 95% CI 0.693-0.926), and women who had received fall prevention health education (OR 0.583, 95% CI 0.465-0.730) associated with lower risk. The areas under the curve of the prediction model was 0.818. The sensitivity was 67.0% and the specificity was 82.0%. The prediction model showed a good ability to predict the risk of subsequent fracture in older women with osteoporotic fractures and are suitable for early self-measurement which may benefit post-fracture management.

Pan-immune-inflammation value: a new prognostic index in operative laryngeal and pharyngeal carcinomas.

PURPOSE: This study aimed to further evaluate the potential value of Pan-Immune-Inflammation Value (PIV) as a prognostic marker in patients with laryngeal and pharyngeal tumors. METHODS: A total of 545 patients with laryngeal and pharyngeal tumors who underwent surgery at Qilu Hospital of Shandong University were included. We determined the optimal cutoff of PIV and divided the patients into two groups. The relationship between PIV and clinicopathological features was explored by the chi-square test and the Mann-Whitney U test. Survival analysis and Cox regression analysis were used to evaluate the relationship between PIV and overall survival (OS) and disease-free survival (DFS). We also compared the prognostic predictive value of PIV with other inflammation-related markers. Finally, we developed a simple scoring prediction model based on several independent prognostic parameters. RESULTS: We found that PIV was statistically associated with clinicopathological features such as tumor stage (p < 0.001), node stage (p = 0.001), postoperative chemotherapy (p = 0.026), and vascular thrombosis (p = 0.027). Survival analysis demonstrated a significant correlation between elevated PIV and reduced OS and DFS (p < 0.0001). Multivariate Cox regression analysis further confirmed PIV as a prognostic indicator (HR 2.507; 95% CI 1.343-4.681; p = 0.004), which is superior to SII, NLR, MLR and PLR. Three of the independent prognostic factors screened by multivariate Cox regression analysis were selected to be used to create a scoring system with a concordance index of 0.756. CONCLUSIONS: Elevated PIV is associated with poor prognosis in patients with laryngeal and pharyngeal tumors, suggesting that PIV may be an important adjunctive indicator for assessing patient prognosis. REGISTRATION INFORMATION: Registration number: KYLL-202307-001, date: July 2023.

Preventing and Mitigating Post-Traumatic Stress: A Scoping Review of Resilience Interventions for Military Personnel in Pre Deployment.

Purpose: Resilience is considered as a protective factor that can assist individuals to reduce post-traumatic stress reactions. In recent years, armies in many countries have widely implemented resilience training programs before deployment to prevent or reduce post-deployment combat stress reactions. Therefore, this study aims to review what is known about resilience interventions for military personnel in pre deployment. Methods: Based on Arskey and O'Malley's framework, a scoping review was completed. This review was performed through searching databases including PubMed, Embase, Web of Science, Medline and the Cochrane Library, and screening literature to extract data, finally summarizing the findings. Results: A total of 25 studies focusing on resilience interventions for military personnel in pre deployment were involved and analyzed using intervention approaches, outcome measures, intervention effects, and so on. Conclusion: Based on the existing evidence in this review, it is cautiously believed that the resilience intervention program for military personnel before deployment is effective. However, there is no single effective best method even the same type intervention can make different effects in different situations and populations. Therefore, the population differences and context should be fully considered in constructing and implementing program to build military personnel resilience.

A higher order PUF complex is central to regulation of C. elegans germline stem cells.

PUF RNA-binding proteins are broadly conserved stem cell regulators. Nematode PUF proteins maintain germline stem cells (GSCs) and, with key partner proteins, repress differentiation mRNAs, including gld-1. Here we report that PUF protein FBF-2 and its partner LST-1 form a ternary complex that represses gld-1 via a pair of adjacent FBF-2 binding elements (FBEs) in its 3ÚTR. One LST-1 molecule links two FBF-2 molecules via motifs in the LST-1 intrinsically-disordered region; the gld-1 FBE pair includes a well-established 'canonical' FBE and a newly-identified noncanonical FBE. Remarkably, this FBE pair drives both full RNA repression in GSCs and full RNA activation upon differentiation. Discovery of the LST-1-FBF-2 ternary complex, the gld-1 adjacent FBEs, and their in vivo significance predicts an expanded regulatory repertoire of different assemblies of PUF-partner complexes in nematode germline stem cells. It also suggests analogous PUF controls may await discovery in other biological contexts and organisms.

How do stressful life events affect medical students' academic adjustment? Parallel mediating mechanisms of anxiety and depression.

BACKGROUND: Medical students frequently face challenges in academic adjustment, necessitating effective support and intervention. This study aimed to investigate the impact of stressful life events on medical students' academic adjustment, focusing on the mediating roles of depression and anxiety. It also differentiated the impacts between at-risk students (those with academic failures) and their peers respectively. METHODS: This case-control study involved 320 at-risk medical students and 800 other students from a university in western China. Participants anonymously completed the scales of stressful life events, depression, anxiety, and academic adjustment. T-tests, ANOVA, Pearson correlation, and structural equation modeling were employed for statistical analysis. RESULTS: Depression and anxiety were significantly more prevalent in at-risk students (46.8% and 46.1%, respectively) than in controls (34.0% and 40.3%, respectively). Notably, at-risk students had poorer academic adjustment (t = 5.43, p < 0.001). The structural equation modeling had good fit indices and the results indicated that depression and anxiety fully mediated the effects of stressful life events on academic adjustment. For at-risk students, stressful life events significantly decreased academic adjustment through increased depression and anxiety (p < 0.001). Conversely, anxiety had a positive effect on academic adjustment in other students. CONCLUSION: Targeted interventions focusing on depression and anxiety could reduce the negative impact of stressful life events on medical students' academic adjustment. However, educators have to distinguish the differences between at-risk students and others.

Itaconate alleviates diet-induced obesity via activation of brown adipocyte thermogenesis.

Despite medical advances, there remains an unmet need for better treatment of obesity. Itaconate, a product of the decarboxylation of the tricarboxylic acid cycle intermediate cis-aconitate, plays a regulatory role in both metabolism and immunity. Here, we show that itaconate, as an endogenous compound, counteracts high-fat-diet (HFD)-induced obesity through leptin-independent mechanisms in three mouse models. Specifically, itaconate reduces weight gain, reverses hyperlipidemia, and improves glucose tolerance in HFD-fed mice. Additionally, itaconate enhances energy expenditure and the thermogenic capacity of brown adipose tissue (BAT). Unbiased proteomic analysis reveals that itaconate upregulates key proteins involved in fatty acid oxidation and represses the expression of lipogenic genes. Itaconate may provoke a major metabolic reprogramming by inducing fatty acid oxidation and suppression of fatty acid synthesis in BAT. These findings highlight itaconate as a potential activator of BAT-mediated thermogenesis and a promising candidate for anti-obesity therapy.

Evaluation of retinal microcirculation by optical coherence tomography angiography in patients with primary membranous nephropathy.

BACKGROUND: Primary membranous nephropathy (PMN) patients may experience retinal microvascular changes. However, current diagnostic methods for PMN are not accurate in analyzing these modifications. In the present study, optical coherence tomography angiography (OCTA) was used for quantitative measurement of microvascular changes in the eyes of PMN patients. METHODS: A total of 26 patients with PMN and 26 healthy control (HC) were evaluated in this cross-sectional study. Optical coherence tomography (OCT) and OCTA were used to collect retinal thickness (RT) and microvascular parameters in the macula and optic disk in the superficial capillary plexus (SCP) of all subjects. Clinical data were collected from the PMN group. The OCT and OCTA data for PMN and HC group were compared, and the correlation between the OCTA and clinical data in the PMN group was determined. RESULTS: Vascular density (VD) and perfusion density (PD) in the macular area of the PMN group were significantly lower than those of the HC group, especially in the temporal quadrant. No significant difference in the foveal avascular zone (FAZ), optic disc microvascular parameters, RT, and retinal nerve fiber layer (RNFL) thickness was observed between the two groups. Correlation was noted between VD and PD in the macular area and clinical indicators, such as serum creatinine, serum urea nitrogen, 24 h urine volume and urinary protein concentration. CONCLUSION: Microvascular alterations in PMN patients occurred before ocular symptoms. The present quantitative study proposed a measurement method for detecting early retinal vascular injury in PMN patients.

Human amniotic epithelial stem cell is a cell therapy candidate for preventing acute graft-versus-host disease.

Graft-versus-host disease (GVHD), an immunological disorder that arises from donor T cell activation through recognition of host alloantigens, is the major limitation in the application of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Traditional immunosuppressive agents can relieve GVHD, but they induce serious side effects. It is highly required to explore alternative therapeutic strategy. Human amniotic epithelial stem cells (hAESCs) were recently considered as an ideal source for cell therapy with special immune regulatory property. In this study, we evaluated the therapeutic role of hAESCs in the treatment of GVHD, based on our previous developed cGMP-grade hAESCs product. Humanized mouse model of acute GVHD (aGVHD) was established by injection of huPBMCs via the tail vein. For prevention or treatment of aGVHD, hAESCs were injected to the mice on day -1 or on day 7 post-PBMC infusion, respectively. We showed that hAESCs infusion significantly alleviated the disease phenotype, increased the survival rate of aGVHD mice, and ameliorated pathological injuries in aGVHD target organs. We demonstrated that hAESCs directly induced CD4+ T cell polarization, in which Th1 and Th17 subsets were downregulated, and Treg subset was elevated. Correspondingly, the levels of a series of pro-inflammatory cytokines were reduced while the levels of the anti-inflammatory cytokines were upregulated in the presence of hAESCs. We found that hAESCs regulated CD4+ subset polarization in a paracrine mode, in which TGFß and PGE2 were selectively secreted to mediate Treg elevation and Th1/Th17 inhibition, respectively. In addition, transplanted hAESCs preserved the graft-versus-leukemia (GVL) effect by inhibiting leukemia cell growth. More intriguingly, hAESCs infusion in HSCT patients displayed potential anti-GVHD effect with no safety concerns and confirmed the immunoregulatory mechanisms in the preclinical study. We conclude that hAESCs infusion is a promising therapeutic strategy for post-HSCT GVHD without compromising the GVL effect. The clinical trial was registered at www.clinicaltrials.gov as #NCT03764228.