Differential manifestations of anhedonia in people with social anhedonia and subsyndromal depression.

Empirical findings suggested that anhedonia, a reduced capability to access pleasure and a core symptom in both schizophrenia and the major depressive disorder, can be present in people with high levels of social anhedonia and people with subsyndromal depression. Few studies have adopted a multidimensional framework to investigate anhedonia in these subclinical samples. We recruited 35 participants with high social anhedonia (SA), 53 participants with subsyndromal depression (SD), 20 participants with co-occurrence of both traits (CO), and 47 participants with low levels of both traits (CN) to complete a self-report questionnaire capturing the pleasure experience, and the Monetary Incentives Delay (MID) Task and the Social Incentives Delay (SID) Task capturing the motivation of reward. Results indicated that people with SA, SD and CO exhibited lower abstract anticipatory pleasure compared to CN. Moreover, people with SD and CO exhibited specific impairment in response to social incentives. Together, our findings characterized the multidimensional features of anhedonia performances of subclinical samples with SA, SD and CO, which may contribute to the formulation of early identification of at-risk groups.

Enhanced electrocatalytic activity in MOFs-derived 3D hollow NiCo-LDH nanocages decorated porous biochar for simultaneously ultra-sensitive electrochemical sensing of Cu2+ and Hg2.

Layered double hydroxides (LDHs) have attracted significant attention due to their compositional and structural flexibility. However, it is challenging but meaningful to design and fabricate hierarchical mixed-dimensional LDHs with synergistic effects to increase the electrical conductivity of LDHs and promote the intrinsic activity. Herein, 3D hollow NiCo-LDH nanocages decorated porous biochar (3D NiCo-LDH/PBC) has been synthesized by using ZIF-67 as precursor, which was utilized for constructing electrochemical sensing platform to realize simultaneous determination of Cu2+ and Hg2+. The 3D NiCo-LDH/PBC possessed the characteristics of hollow material and three-dimensional porous material, revealing a larger surface area, more exposed active sites, and faster electron transfer, which is beneficial to enhancing its electrochemical performance. Consequently, the developed sensor displayed good performance for simultaneously detecting Cu2+ and Hg2+ with ultra-low limit of detection (LOD) of 0.03 µg L-1 and 0.03 µg L-1, respectively. The proposed sensor also demonstrated excellent stability, repeatability and reproducibility. Furthermore, the sensor can be successfully used for the electrochemical analysis of Cu2+ and Hg2+ in lake water sample with satisfactory recovery, which is of great feasibility for practical application.

G-quadruplex-Based Artificial Transmembrane Channels Induce Cancer Cell Apoptosis by Perturbing Potassium Ion Homeostasis.

Transmembrane ion transport modality has received a widespread attention due to its apoptotic activation toward anticancer cell activities. In this study, G-quadruplex-based potassium-specific transmembrane channels have been developed to facilitate the intracellular K+ efflux, which perturbs the cellular ion homeostasis thereby inducing cancer cell apoptosis. Cholesterol-tag, a lipophilic anchor moiety, serves as a rudiment for the G-quadruplex immobilization onto the membrane, while G-quadruplex channel structure as a transport module permits ion binding and migration along the channels. A c-Myc sequence tagged with two-cholesterol is designed as a representative lipophilic G-quadruplex, which forms intramolecular parallel G-quadruplex with three stacks of G-quartets (Ch2-Para3). Fluorescence transport assay demonstrates Ch2-Para3 a high transport activity (EC50 = 10.9 × 10-6 m) and an ion selectivity (K+/Na+ selectivity ratio of 84). Ch2-Para3 mediated K+ efflux in cancer cells is revealed to purge cancer cells through K+ efflux-mediated cell apoptosis, which is confirmed by monitoring the changes in membrane potential of mitochondria, leakage of cytochrome c, reactive oxygen species yield, as well as activation of a family of caspases. The lipophilic G-quadruplex exhibits obvious antitumor activity in vivo without systemic toxicity. This study provides a functional scheme aimed at generating DNA-based selective artificial membrane channels for the purpose of regulating cellular processes and inducing cell apoptosis, which shows a great promising for anticancer therapy in the future.

Small vessel disease burden and prognosis of recent subcortical ischaemic stroke differ by parent artery atherosclerosis.

BACKGROUND AND PURPOSE: Parent artery atherosclerosis is an important aetiology of recent subcortical ischaemic stroke (RSIS). However, comparisons of RSIS with different degrees of parent artery atherosclerosis are lacking. METHODS: Prospectively collected data from our multicentre cohort (all were tertiary centres) of the Stroke Imaging Package Study between 2015 and 2017 were retrospectively reviewed. The patients with RSIS defined as a single clinically relevant diffusion-weighted imaging positive lesion in the territory of lenticulostriate arteries were categorized into three subgroups: (1) normal middle cerebral artery (MCA) on magnetic resonance angiography and high-resolution magnetic resonance imaging (HR-MRI); (2) low-grade MCA atherosclerosis (normal or <50% stenosis on magnetic resonance angiography and with MCA plaques on HR-MRI); (3) steno-occlusive MCA atherosclerosis (stenosis ≥50% or occlusion). The primary outcome was 90-day functional dependence (modified Rankin Scale score >2). The clinical and imaging findings were compared between subgroups. RESULTS: A total of 239 patients (median age 60.0 [52.0-67.0] years, 72% male) were enrolled, including 140 with normal MCA, 64 with low-grade MCA atherosclerosis and 35 with steno-occlusive MCA atherosclerosis. Patients with steno-occlusive MCA atherosclerosis had the largest infarct volume. Low-grade MCA atherosclerosis was independently associated with cerebral microbleeding, more severe perivascular spaces in basal ganglia and higher total cerebral small vessel disease burden. Low-grade MCA atherosclerosis was an independent determinant of 90-day functional dependence (odds ratio 3.897; 95% confidence interval 1.309-11.604). CONCLUSIONS: Our study suggested RSIS with varying severity of parent artery atherosclerosis exhibits distinctive clinical and neuroimaging characteristics, with low-grade MCA atherosclerosis associating with higher cerebral small vessel disease burden and worse prognosis.

Prevalence of intrinsic capacity decline among community-dwelling older adults: a systematic review and meta-analysis.

BACKGROUND: The concept of intrinsic capacity (IC) was introduced to define healthy aging and active aging based on functional capacity, yet there is limited understanding of the risk of IC decline at a population level. AIMS: To consolidate existing evidence for rates of IC decline and risk factors among community-dwelling adults 60 years or older. METHODS: According to the PRISMA guidelines, the literature search was independently conducted by two researchers in 8 databases from inception to January 2024 without language restrictions using combinations of free words and subject words. Qualities of included studies were assessed using Joanna Briggs Institute's (JBI's) critical appraisal checklist for prevalence studies. To pool the data, a random-effect meta-analysis was performed, followed by subgroup analysis and sensitivity analysis. All analyses were performed by Stata14.0. RESULTS: From 1594 records, 15 studies were extracted with 33,070 participants for meta-analysis. The pooled prevalence of IC decline in community settings was 67.8% (95% CI: 57.0-78.5%; P < 0.001). The prevalence of IC decline in China (66.0%; 95% CI: 53.2-78.9%) was found to be slightly lower than in other countries/regions (73.0%; 95% CI: 59.8-86.3%); however, this difference was not statistically significant. Other subgroup analyses revealed no statistically significant differences in prevalence. Age, hypertension, diabetes, gender, education level, living status, smoking, regular exercise, marital status, and osteoarthritis are associated with IC decline. CONCLUSION: More than two-thirds of older adults in the community are affected by IC decline, and age, hypertension, diabetes, female sex, low education level, living alone, smoking, irregular exercise, unmarried, and osteoarthritis are all risk factors for IC decline.

Long-term safety and influence on growth in patients receiving sirolimus: a pooled analysis.

BACKGROUND: Sirolimus is increasingly utilized in treating diseases associated with mTOR pathway overactivation. Despite its potential, the lack of evidence regarding its long-term safety across all age groups, particularly in pediatric patients, has limited its further application. This study aims to assess the long-term safety of sirolimus, with a specific focus on its impact on growth patterns in pediatric patients. METHODS: This pooled analysis inlcudes two prospective cohort studies spanning 10 years, including 1,738 participants (aged 5 days to 69 years) diagnosed with tuberous sclerosis and/or lymphangioleiomyomatosis. All participants were mTOR inhibitor-naive and received 1 mg/m²/day of sirolimus, with dose adjustments during a two-week titration period to maintain trough blood concentrations between 5 and 10 ng/ml (maximum dose 2 mg). Indicators of physical growth, hematopoietic, liver, renal function, and blood lipid levels were all primary outcomes and were analyzed. The adverse events and related management were also recorded. RESULTS: Sirolimus administration did not lead to deviations from normal growth ranges, but higher doses exhibited a positive association with Z-scores exceeding 2 SD in height, weight, and BMI. Transient elevations in red blood cell and white blood cell counts, along with hyperlipidemia, were primarily observed within the first year of treatment. Other measured parameters remained largely unchanged, displaying only weak correlations with drug use. Stomatitis is the most common adverse event (920/1738, 52.9%). In adult females, menstrual disorders were observed in 48.5% (112/217). CONCLUSIONS: Sirolimus's long-term administration is not associated with adverse effects on children's physical growth pattern, nor significant alterations in hematopoietic, liver, renal function, or lipid levels. A potential dose-dependent influence on growth merits further exploration. TRIAL REGISTRATION: Pediatric patients: Chinese clinical trial registry, No. ChiCTR-OOB-15,006,535. Adult patients: ClinicalTrials, No. NCT03193892.

Characterization of the components in plasma EVs unveiling the link between EVs-derived complement C3 with the severity and initial treatment response of profound sudden sensorineural hearing loss.

BACKGROUND: Sudden sensorineural hearing loss (SSNHL) is characterized by rapid, unexplained loss of hearing within a 72-hour period and exhibits a high incidence globally. Despite this, the outcomes of therapeutic interventions remain largely unpredictable, especially for those with profound hearing loss. Extracellular vesicles (EVs), nano-sized entities containing biological materials, are implicated in the development of numerous diseases. The specific relationship between EVs and both the severity and treatment effectiveness of SSNHL, however, is not well understood. METHODS: This study involved the analysis of medical records from the Department of Otolaryngology (September 1, 2020 - December 31, 2022) of patients diagnosed with SSNHL according to the 2015 Guidelines for Diagnosis and Treatment of Sudden Deafness in China. Peripheral blood samples from patients with various types of SSNHL before and after treatment were collected, alongside samples from healthy volunteers serving as controls. Plasma EVs were isolated using gel rejection chromatography and analyzed for concentration, marker presence, and morphology using Nanosight, Western blot, and transmission electron microscopy (TEM), respectively. Proteomics and miRNA assessments were conducted to identify differentially expressed proteins and miRNAs in the plasma EVs of SSNHL patients and healthy volunteers. Key proteins were further validated through Western blot analysis. Enzyme-linked immunosorbent assay (ELISA) was utilized to determine the levels of complement C3 in plasma EVs, and correlation analyses were performed with audiological data pre- and post-treatment. RESULTS: Plasma from SSNHL patients of varying types was collected and their EVs were successfully isolated and characterized. Proteomic analysis revealed that complement C3 levels in the plasma EVs of patients with profound SSNHL were significantly higher compared to healthy controls. Differential expression of miRNAs in plasma EVs and their related functions were also identified. The study found that the level of complement C3 in plasma EVs, but not the total plasma complement C3, positively correlated with the severity of SSNHL in patients exhibiting positive therapeutic responses, particularly in those with initially lower levels of EV-associated complement C3. After treatment, complement C3 level was decreased in patients with initially higher levels of EV-associated complement C3. No significant correlation was observed between changes in plasma EV-derived complement C3 levels and the degree of hearing loss in either responders or non-responders among patients with profound SSNHL. CONCLUSION: Differential profiles of proteins and miRNAs were identified in patients with profound SSNHL. Notably, plasma EV-derived complement C3 was linked to both the severity and early treatment effectiveness of patients with profound SSNHL.

Development of an Investigation Form for Hemodialysis Infection Outbreak: Identifying Sources in the Early Stage.

OBJECTIVE: To develop an investigation form for hemodialysis infection outbreak, and to identify sources of outbreak in early stage. METHODS: After an exhaustive literature review, we used the Delphi method to determine the indicators and relative risk scores of the assessment tools through two rounds of specialist consultation and overall consideration of the opinions and suggestions of 18 specialists. RESULTS: A total of 87 studies of hemodialysis infection outbreaks were eligible for inclusion. The mean authority coefficient (Cr) was 0.89. Kendall's W coefficient of the specialist consultation was 0.359 after two rounds of consultation (p <0.005), suggesting that the specialists had similar opinions. Based on 4 primary items and 13 secondary items of the source of hemodialysis infection outbreak, and tripartite distribution characteristics of infected patients, we constructed the investigation form. CONCLUSIONS: The investigation form can be used at the early stage of the cluster of cases, it's a prerequisite for taking effective control measures, avoiding hemodialysis infection outbreak occurrence. However, the effect of the investigation form needs to be further evaluated.

Association of serum uric acid with male sexual hormones and erectile dysfunction: a bidirectional 2-sample Mendelian randomization analysis.

Background: Observational studies indicated that serum uric acid (SUA) was associated with male sexual hormones and erectile dysfunction (ED). However, their relationship was still heterogeneous. Aim: This study conducted 2-sample univariate mendelian randomization (UVMR) and multivariate mendelian randomization (MVMR) to explore the causal relationship between SUA and sexual hormones as well as ED. Methods: Genetic variants associated with SUA were derived from the UK Biobank database (N = 437 354). Outcomes from the IEU Open GWAS and summary data sets were sexual hormones (sex hormone-binding globulin [SHBG], testosterone, estradiol [E2], follicle-stimulating hormone, luteinizing hormone) and ED, with 3301 to 625 650 participants. UVMR analysis primarily utilized the inverse variance weighted method, complemented by MVMR analysis. Thorough sensitivity analyses were carried out to ensure the reliability of results. Moreover, mediation analysis was conducted to estimate the mediated effect between SUA and outcomes. Outcomes: The primary outcomes included results of UVMR and MVMR analysis and mediation analysis, along with sensitivity analyses involving the Cochran Q test, the MR Egger intercept test, leave-1-out analysis, and the MR-PRESSO method (mendelian randomization pleiotropy residual sum and outlier). Results: UVMR analysis revealed that an elevated SUA level could decrease levels of SHBG (ß = -0.10, P = 1.70 × 10-7) and testosterone (ß = -0.10, P = 5.94 × 10-3) and had a positive causal effect on ED (odds ratio, 1.10; P = .018). According to reverse mendelian randomization results, increased levels of SHBG (ß = -0.06, P = 4.82 × 10-4) and E2 (ß = -0.04, P = .037) could also reduce SUA levels. As shown by MVMR analysis, SUA had a negative effect on SHBG and testosterone levels (P < .05), while the significant causal relationship between SUA and ED disappeared. Furthermore, SHBG mediated 98.1% of the effect of SUA on testosterone levels. Results of other mendelian randomization analyses were not statistically significant. No pleiotropy was found by sensitivity analysis in this study. Clinical Implications: Given the causal relationship between SUA and sexual hormones, we must focus on SUA and E2 levels in men, especially patients with hypogonadism and ED. Strengths and Limitations: This study evaluated the causal effect of SUA on male sexual hormones and ED genetically for the first time, clarifying the common biases in observational studies and confirming the negative relationship between SUA and testosterone level. Limitations include a population based on European ancestry, some crossover of the samples, and unobserved confounding factors. Conclusion: Genetic studies provide evidence for the causal relationship between SUA and male sexual hormones (SHBG, testosterone, E2), while the relationship between SUA and ED should be further evaluated.

Understanding the deficiency in inertial confinement fusion hohlraum x-ray flux predictions using experiments at the National Ignition Facility.

The predicted implosion performance of deuterium-tritium fuel capsules in indirect-drive inertial confinement fusion experiments relies on precise calculations of the x-ray drive in laser-heated cavities (hohlraums). This requires accurate, spectrally dependent simulations of laser to x-ray conversion efficiencies and x-ray absorption losses to the hohlraum wall. A set of National Ignition Facility experiments have identified a cause for the long-standing hohlraum "drive deficit" as the overprediction of gold emission at ∼2.5 keV in nonlocal thermodynamic equilibrium coronal plasma regions within the hohlraum. Reducing the emission and absorption opacity in this spectral region by ∼20% brings simulations into agreement with measured x-ray fluxes and spectra.

Exploring the role of non-canonical splice site variants in aberrant splicing associated with reproductive genetic disorders.

Whole-exome sequencing (WES) is frequently utilized in diagnosing reproductive genetic disorders to identify various genetic variants. Canonical ±1,2 splice sites are typically considered highly pathogenic, while variants at the 5' or 3' ends of exon boundaries are often considered synonymous or missense variants, with their potential impact on abnormal gene splicing frequently overlooked. In this study, we identified five variants located at the last two bases of the exons and two canonical splicing variants in five distinct families affected by reproductive genetic disorders through WES. Minigene analysis, RT-PCR and Quantitative Real-time PCR (RT-qPCR) confirmed that all seven variants induced aberrant splicing, with six variants altering gene transcriptional expression levels. These findings underscore the crucial role of splice variants, particularly non-canonical splice sites variants, in reproductive genetic disorders, with all identified variants classified as pathogenic.

Neutrophil extracellular traps induce intrahepatic thrombotic tendency and liver damage in cholestatic liver disease.

BACKGROUND: Cholestatic liver diseases induce local and systemic hypercoagulation, with neutrophil extracellular traps (NETs) serving as major drivers. These NETs have been linked to decreased liver function in patients with obstructive jaundice. However, the impact of NETs on liver hypercoagulation in cholestatic liver disease remains unknown. METHODS: We utilized bile duct ligation to create experimental mice and analyzed NETs formation in the liver. Fibrin deposition, tissue factor expression, and inflammation in the liver were visualized through western blot and immunohistochemical techniques. LSECs were incubated with isolated NETs, and we detected endothelial procoagulant activity using coagulation protein production assays and measuring endothelial permeability. In both in vivo and in vitro settings, DNase I was applied to clarify the effect of NETs on intrahepatic hypercoagulability, hepatotoxicity, LSEC, and macrophage activation or injury. RESULTS: Bile duct ligation mice exhibited significantly increased levels of NETs in liver tissue, accompanied by neutrophil infiltration, tissue necrosis, fibrin deposition, and thrombophilia compared to sham mice. Notably, NETs resulted in phosphatidylserine and tissue factor exposure on LSEC, enhancing coagulation Factor Xa and thrombin production. The enhanced procoagulant activity could be reversed by degrading NETs with DNase I. Additionally, NETs-induced permeability changes in LSECs, characterized by increased VE-cadherin expression and F-actin retraction, which could be rescued by DNase I. Meanwhile, NET formation is associated with KC activation and the formation of inflammatory factors. CONCLUSIONS: NETs promote intrahepatic activation of coagulation and inflammation, leading to liver tissue injury. Strategies targeting NET formation may offer a potential therapeutic approach for treating cholestatic liver disease.

Characterization of a novel multi-resistant Pseudomonas juntendi strain from China with chromosomal blaVIM-2 and a megaplasmid coharboring blaIMP-1-like and blaOXA-1.

BACKGROUND: Pseudomonas juntendi is a newly identified opportunistic pathogen, of which we have limited understanding. P. juntendi strains are often multidrug resistant, which complicates clinical management of infection. METHODS: A strain of Pseudomonas juntendi (strain L4326) isolated from feces was characterized by MALDI-TOF-MS and Average Nucleotide Identity BLAST. This strain was further subject to whole-genome sequencing and Maximum Likelihood phylogenetic analysis. The strain was phenotypically characterized by antimicrobial susceptibility testing and conjugation assays. RESULTS: We have isolated the novel P. juntendi strain L4236, which was multidrug resistant, but retained sensitivity to amikacin. L4236 harbored a megaplasmid that encoded blaOXA-1 and a novel blaIMP-1 resistance gene variant. P. juntendi strain L4236 was phylogenetically related to P. juntendi strain SAMN30525517. CONCLUSION: A rare P. juntendi strain was isolated from human feces in southern China with a megaplasmid coharboring blaIMP-1-like and blaOXA-1. Antimicrobial selection pressures may have driven acquisition of drug-resistance gene mutations and carriage of the megaplasmid.

Effects of the rice-mushroom rotation pattern on soil properties and microbial community succession in paddy fields.

Introduction: Currently, straw biodegradation and soil improvement in rice-mushroom rotation systems have attracted much attention. However, there is still a lack of studies on the effects of rice-mushroom rotation on yield, soil properties and microbial succession. Methods: In this study, no treatment (CK), green manure return (GM) and rice straw return (RS) were used as controls to fully evaluate the effect of Stropharia rugosoannulata cultivation substrate return (SRS) on soil properties and microorganisms. Results: The results indicated that rice yield, soil nutrient (organic matter, organic carbon, total nitrogen, available nitrogen and available potassium) and soil enzyme (urease, saccharase, lignin peroxidase and laccase) activities had positive responses to the rice-mushroom rotation. At the interannual level, microbial diversity varied significantly among treatments, with the rice-mushroom rotation significantly increasing the relative alpha diversity index of soil bacteria and enriching beneficial microbial communities such as Rhizobium, Bacillus and Trichoderma for rice growth. Soil nutrients and enzymatic activities were significantly correlated with microbial communities during rice-mushroom rotation. The fungal-bacterial co-occurrence networks were modular, and Latescibacterota, Chloroflexi, Gemmatimonadota and Patescibacteria were closely related to the accumulation of nutrients in the soil. The structural equation model (SEM) showed that fungal diversity responded more to changes in soil nutrients than did bacterial diversity. Discussion: Overall, the rice-mushroom rotation model improved soil nutrients and rice yields, enriched beneficial microorganisms and maintained microbial diversity. This study provides new insights into the use of S. rugosoannulata cultivation substrates in the sustainable development of agroecosystems.

The epithelial Na+ channel (ENaC) in ovarian granulosa cells modulates Ca2+ mobilization and gonadotrophin signaling for estrogen homeostasis and female fertility.

Ovarian granulosa cells are essential to gonadotrophin-regulated estrogen production, female cycle maintenance and fertility. The epithelial Na+ channel (ENaC) is associated with female fertility; however, whether and how it plays a role in ovarian cell function(s) remained unexplored. Here, we report patch-clamp and Na+ imaging detection of ENaC expression and channel activity in both human and mouse ovarian granulosa cells, which are promoted by pituitary gonadotrophins, follicle stimulating hormone (FSH) or luteinizing hormone (LH). Cre-recombinase- and CRISPR-Cas9-based granulosa-specific knockout of ENaC α subunit (Scnn1a) in mice resulted in failed estrogen elevation at early estrus, reduced number of corpus luteum, abnormally extended estrus phase, reduced litter size and subfertility in adult female mice. Further analysis using technologies including RNA sequencing and Ca2+ imaging revealed that pharmacological inhibition, shRNA-based knockdown or the knockout of ENaC diminished spontaneous or stimulated Ca2+ oscillations, lowered the capacity of intracellular Ca2+ stores and impaired FSH/LH-stimulated transcriptome changes for estrogen production in mouse and/or human granulosa cells. Together, these results have revealed a previously undefined role of ENaC in modulating gonadotrophin signaling in granulosa cells for estrogen homeostasis and thus female fertility.

Sciatic nerve stimulation alleviates neuropathic pain and associated neuroinflammation in the dorsal root ganglia in a rodent model.

BACKGROUND: Satellite glial cells (SGCs) in the dorsal root ganglia (DRG) play a pivotal role in the formation of neuropathic pain (NP). Sciatic nerve stimulation (SNS) neuromodulation was reported to alleviate NP and reduce neuroinflammation. However, the mechanisms underlying SNS in the DRG remain unclear. This study aimed to elucidate the mechanism of electric stimulation in reducing NP, focusing on the DRG. METHODS: L5 nerve root ligation (NRL) NP rat model was studied. Ipsilateral SNS performed 1 day after NRL. Behavioral tests were performed to assess pain phenotypes. NanoString Ncounter technology was used to explore the differentially expressed genes and cellular pathways. Activated SGCs were characterized in vivo and in vitro. The histochemical alterations of SGCs, macrophages, and neurons in DRG were examined in vivo on post-injury day 8. RESULTS: NRL induced NP behaviors including decreased pain threshold and latency on von Frey and Hargreaves tests. We found that following nerve injury, SGCs were hyperactivated, neurotoxic and had increased expression of NP-related ion channels including TRPA1, Cx43, and SGC-neuron gap junctions. Mechanistically, nerve injury induced reciprocal activation of SGCs and M1 macrophages via cytokines including IL-6, CCL3, and TNF-α mediated by the HIF-1α-NF-κB pathways. SNS suppressed SGC hyperactivation, reduced the expression of NP-related ion channels, and induced M2 macrophage polarization, thereby alleviating NP and associated neuroinflammation in the DRG. CONCLUSIONS: NRL induced hyperactivation of SGCs, which had increased expression of NP-related ion channels. Reciprocal activation of SGCs and M1 macrophages surrounding the primary sensory neurons was mediated by the HIF-1α and NF-κB pathways. SNS suppressed SGC hyperactivation and skewed M1 macrophage towards M2. Our findings establish SGC activation as a crucial pathomechanism in the gliopathic alterations in NP, which can be modulated by SNS neuromodulation.

Attenuation of renal fibrosis in mice due to lack of bombesin receptor-activated protein homologue.

Bombesin receptor-activated protein (BRAP), encoded by the C6orf89 gene in humans, is expressed in various cells with undefined functions. BC004004, the mouse homologue of C6orf89, has been shown to play a role in bleomycin-induced pulmonary fibrosis through the use of a BC004004 gene knockout mouse (BC004004-/-). In this study, we investigated the potential involvement of BRAP in renal fibrosis using two mouse models: unilateral ureteral obstruction (UUO) and type 2 diabetes mellitus induced by combination of a high-fat diet (HFD) and streptozocin (STZ). BRAP or its homologue was expressed in tubular epithelial cells (TECs) in the kidneys of patients with chronic kidney disease (CKD) and in BC004004+/+ mice. Compared to control mice, BC004004-/- mice exhibited attenuated renal injury and renal fibrosis after UUO or after HFD/STZ treatment. Immunohistochemistry and immunoblot analyses of the kidneys of BC004004+/+ mice after UUO surgery showed a more significant decrease in E-cadherin expression and a more significant increase in both α smooth muscle actin (α-SMA) and vimentin expression compared to BC004004-/- mice. Additionally, stimulation with transforming growth factor-ß1 (TGF-ß1) led to a more significant decrease in E-cadherin expression and a more significant increase in α-SMA and vimentin expression in isolated TECs from BC004004+/+ than in those from BC004004-/- mice. These results suggest that an enhanced epithelial-mesenchymal transition (EMT) process occurred in TECs in BC004004+/+ mice during renal injury, which might contribute to renal fibrosis. The loss of the BRAP homologue in BC004004-/- mice suppressed EMT activation in kidneys and contributed to the suppression of fibrosis during renal injury.

Conditioned medium of infrapatellar fat stem cells alleviates degradation of chondrocyte extracellular matrix and delays development of osteoarthritis.

Osteoarthritis (OA) is a common clinical chronic degenerative disease characteriszed by articular cartilage degeneration. Mesenchymal stem cells (MSCs) delay OA the development of OA mainly through paracrine effects. The conditioned medium (CM) of MSCs contains all the paracrine components of these cells, and many studies have demonstrated the anti-apoptotic and anti-inflammatory effects of CM in vitro. In this study, we investigated the effect of the CM of infrapatellar fat pad-derived MSCs (IPFSCs) on OA in vitro and in vivo, as well as and the potential underlying mechanisms. The results showed that injection of CM into the knee joint inhibited OA development in a rat model induced by destabilisation of the medial meniscus and anterior cruciate ligament transection. The CM increased the deposition of extracellular matrix-related components (type II collagen and Proteoglycan).In addition, CM inhibited the excessive production of pro-inflammatory mediators in human chondrocytes induced by IL-1 ß, including COX2, iNOS, TNF- α and IL-6, and reduced the production of MMP13 and ADAMTS5, thus protecting the degradation of extracellular matrix. The activation of PI3K/AKT/NF- κ B signalling pathway was induced by IL-1ß in chondrocytes, which was finally inhibited by CM-IPFSCs treatment. In summary, IPFSC-CM may have therapeutic potential for OA.

Molecular Responses of Anti-VEGF Therapy in Neovascular Age-Related Macular Degeneration: Integrative Insights From Multi-Omics and Clinical Imaging.

Purpose: The purpose of this study was to investigate the molecular mechanisms underlying anti-vascular endothelial growth factor (anti-VEGF) efficacy and response variability in neovascular age-related macular degeneration (nAMD) using longitudinal proteomic and metabolomic analysis alongside three-dimensional lesion measurements. Methods: In this prospective study, 54 treatment-naive patients with nAMD underwent "3+ pro re nata" (3+PRN) anti-VEGF regimens followed for at least 12 weeks. Aqueous humors were collected pre- and post-treatment for proteomic and metabolomic analysis. Three-dimensional optical coherence tomography (OCT) and OCT angiography assessed different types of nAMD lesion volumes and areas. Results: There were 1350 proteins and 1268 metabolites that were identified in aqueous humors, with 301 proteins and 353 metabolites significantly altered during anti-VEGF treatment, enriched in pathways of angiogenesis, energy metabolism, signal transduction, and neurofunctional regulation. Sixty-seven changes of (Δ) molecules significantly correlated with at least one type of ΔnAMD lesion. Notably, proteins FGA, TALDO1, and ASPH significantly decreased during treatment, with their reductions correlating with greater lesion regression in at least two lesion types. Conversely, despite that YIPF3 also showed significant downregulation, its decrease was associated with poorer regression in total nAMD lesion and subretinal hyper-reflective material. Conclusions: This study identifies FGA, TALDO1, and ASPH as potential key molecules in the efficacy of anti-VEGF therapy, whereas YIPF3 may be a key factor in poor response. The integration of longitudinal three-dimensional lesion analysis with multi-omics provides valuable insights into the mechanisms and response variability of anti-VEGF treatment in nAMD.

Metabolomics and serum pharmacochemistry combined with network pharmacology uncover the potential effective ingredients and mechanisms of Yin-Chen-Si-Ni Decoction treating ANIT-induced cholestatic liver injury.

ETHNOPHARMACOLOGICAL RELEVANCE: Yin-Chen-Si-Ni Decoction is a classical traditional Chinese medicine (TCM) prescription that is used clinically for treating cholestatic liver injury (CLI) and other hepatic diseases. However, the material basis and underlying mechanisms of YCSND are not clear. AIM OF THE STUDY: To investigate effective components and mechanisms of YCSND in the treatment of CLI using serum pharmacochemistry, metabolomics, and network pharmacology. MATERIALS AND METHODS: Biochemical indicators, liver index, and histopathology analysis were adopted to evaluate the protective effect of YCSND on ANIT-induced CLI rats. Then, a UPLC-Q-Exactive Orbitrap MS/MS analysis of the migrant components in serum and liver including prototype and metabolic components was performed in YCSND. In addition, a study of the endogenous metabolites using serum and liver metabolomics was performed to discover potential biomarkers, metabolic pathways, and associated mechanisms. Further, the network pharmacology oriented by in vivo migrant components was also used to pinpoint the active ingredients, core targets, and signaling pathways of YCSND. Finally, molecular docking and molecular dynamics simulation (MDS) were used to predict the binding ability between components and core targets, and a real-time qPCR (RT-qPCR) experiment was used to measure the mRNA expression of the core target genes. RESULTS: Pharmacodynamic studies suggest that YCSND could exert obvious hepatoprotective effects on CLI rats. Furthermore, 68 compounds, comprising 32 prototype components and 36 metabolic components from YCSND, were found by serum pharmacochemistry analysis. Network pharmacology combining molecular docking and MDS showed that apigenin, naringenin, 18ß-glycyrrhetinic acid, and isoformononetin have better binding ability to 6 core targets (EGFR, AKT1, IL6, MMP9, CASP3, PPARG). Additionally, PI3K, TNF-α, MAPK3, and six core target genes in liver tissues were validated with RT-qPCR. Metabolomics revealed the anti-CLI effects of YCSND by regulating four metabolic pathways of primary bile acid and biosynthesis, phenylalanine, tyrosine and tryptophan biosynthesis, taurine and hypotaurine metabolism, and arachidonic acid metabolism. Integrating metabolomics and network pharmacology identified four pathways related to CLI, including the PI3K-Akt, HIF-1, MAPK, and TNF signaling pathway, which revealed multiple mechanisms of YCSND against CLI that might involve anti-inflammatory and apoptosis. CONCLUSION: The research based on serum pharmacochemistry, network pharmacology, and metabolomics demonstrates the beneficial hepatoprotective effects of YCSND on CLI rats by regulating multiple components, multiple targets, and multiple pathways, and provides a potent means of illuminating the material basis and mechanisms of TCM prescriptions.