Epidemiologic features and therapeutic strategies of kerion: A nationwide multicentre study.

BACKGROUND: Kerion is a severe type of tinea capitis that is difficult to treat and remains a public health problem. OBJECTIVES: To evaluate the epidemiologic features and efficacy of different treatment schemes from real-world experience. METHODS: From 2019 to 2021, 316 patients diagnosed with kerion at 32 tertiary Chinese hospitals were enrolled. We analysed the data of each patient, including clinical characteristics, causative pathogens, treatments and outcomes. RESULTS: Preschool children were predominantly affected and were more likely to have zoophilic infection. The most common pathogen in China was Microsporum canis. Atopic dermatitis (AD), animal contact, endothrix infection and geophilic pathogens were linked with kerion occurrence. In terms of treatment, itraconazole was the most applied antifungal agent and reduced the time to mycological cure. A total of 22.5% of patients received systemic glucocorticoids simultaneously, which reduced the time to complete symptom relief. Furthermore, glucocorticoids combined with itraconazole had better treatment efficacy, with a higher rate and shorter time to achieving mycological cure. CONCLUSIONS: Kerion often affects preschoolers and leads to serious sequelae, with AD, animal contact, and endothrix infection as potential risk factors. Glucocorticoids, especially those combined with itraconazole, had better treatment efficacy.

CD3, CD8, IFN-γ, tumor and stroma inflammatory cells as prognostic indicators for surgically resected SCLC: evidences from a 10-year retrospective study and immunohistochemical analysis.

Current clinical guidelines limit surgical intervention to patients with cT1-2N0M0 small cell lung cancer (SCLC). Our objective was to reassess the role of surgery in SCLC management, and explore novel prognostic indicators for surgically resected SCLC. We reviewed all patients diagnosed with SCLC from January 2011 to April 2021 in our institution. Survival analysis was conducted using the Kaplan-Meier method, and independent prognostic factors were assessed through the Cox proportional hazard model. In addition, immunohistochemistry (IHC) staining was performed to evaluate the predictive value of selected indicators in the prognosis of surgically resected SCLC patients. In the study, 177 SCLC patients undergoing surgical resection were ultimately included. Both univariate and multivariate Cox analysis revealed that incomplete postoperative adjuvant therapy emerged as an independent risk factor for adverse prognosis (p < 0.001, HR 2.96). Survival analysis revealed significantly superior survival among pN0-1 patients compared to pN2 patients (p < 0.0001). No significant difference in postoperative survival was observed between pN1 and pN0 patients (p = 0.062). Patients with postoperative stable disease (SD) exhibited lower levels of tumor inflammatory cells (TIC) (p = 0.0047) and IFN-γ expression in both area and intensity (p < 0.0001 and 0.0091, respectively) compared to those with postoperative progressive disease (PD). Conversely, patients with postoperative SD showed elevated levels of stromal inflammatory cells (SIC) (p = 0.0453) and increased counts of CD3+ and CD8+ cells (p = 0.0262 and 0.0330, respectively). Survival analysis indicated that high levels of SIC, along with low levels of IFN-γ+ cell area within tumor tissue, may correlate positively with improved prognosis in surgically resected SCLC (p = 0.017 and 0.012, respectively). In conclusion, the present study revealed that the patients with pT1-2N1M0 staging were a potential subgroup of SCLC patients who may benefit from surgery. Complete postoperative adjuvant therapy remains an independent factor promoting a better prognosis for SCLC patients undergoing surgical resection. Moreover, CD3, CD8, IFN-γ, TIC, and SIC may serve as potential indicators for predicting the prognosis of surgically resected SCLC.

Activation of the cGMP/PKG/ERK signaling pathway associated with PDE5Is inhibits fibroblast activation by downregulating autophagy in early progressive benign prostatic hyperplasia.

PURPOSE: Benign prostatic hyperplasia (BPH) is one of the most prevalent diseases affecting aging males. However, approximately, 8% of the BPH patients under 50-year-old experience remarkably early progression, for reasons that remain elusive. Among the various factors implicated in promoting BPH advancement, the activation of fibroblasts and autophagy hold particular importance. Our research endeavors to explore the mechanisms behind the accelerated progression in these patients. METHODS: Immunohistochemistry and immunofluorescence were performed to detect the expression levels of LC3, p62, PDE5, and α-SMA in diverse BPH tissues and prostate stromal cells. The autophagy activator rapamycin, the autophagy suppressor chloroquine, and siRNA transfection were used to identify the impact of autophagy on fibroblast activation. RESULTS: Prostatic stromal fibroblasts in early progressive BPH tissues displayed activation of autophagy with an upregulation of LC3 and a concurrent downregulation of p62. After starvation or rapamycin treatment to a heightened level of autophagy, fibroblasts exhibited activation. Conversely, chloroquine treatment and ATG-7-knockdown effectively suppressed the level of autophagy and fibroblast activation. High expression of PDE5 was found in early progressive BPH stromal cells. The administration of PDE5 inhibitors (PDE5Is) hindered fibroblast activation through suppressing autophagy by inhibiting the ERK signaling pathway. CONCLUSION: Our findings suggest that autophagy plays a pivotal role in promoting BPH progression through fibroblast activation, while PDE5Is effectively suppress autophagy and fibroblast activation via the ERK signaling pathway. Nevertheless, further investigations are warranted to comprehensively elucidate the role of autophagy in BPH progression.

Safety, pharmacokinetics and pharmacodynamics of SHR-1703, an innovative long-acting anti-interleukin-5 monoclonal antibody, in healthy subjects: a randomized, double-blind, dose-escalation, placebo-controlled phase I study.

OBJECTIVE: SHR-1703 is a novel humanized IgG1 monoclonal antibody with high IL-5 affinity and prolonged half-life, aiming to control eosinophil-related diseases. The study intended to evaluate pharmacokinetics, pharmacodynamics, immunogenicity, safety, and tolerability of SHR-1703 in healthy subjects. METHODS: A single-center, randomized, double-blind, placebo-controlled, single-dose escalation phase I study was conducted. 42 subjects were allocated to sequentially receive single subcutaneous injection of 20, 75, 150, 300, and 400 mg SHR-1703 or placebo. RESULTS: After administration, SHR-1703 was slowly absorbed with median Tmax ranging from 8.5 to 24.5 days. Mean t1/2 in 150 to 400 mg doses was 86 to 100 days. Cmax and AUC increased in nearly dose-proportional pattern over range of 75 to 400 mg SHR-1703. After receiving SHR-1703, peripheral blood eosinophils (EOS) greatly decreased from baseline, which showed no significant change from baseline in placebo group. Magnitude and duration of reduction of EOS rose with increased dosing of SHR-1703. In 400 mg dose, remarkable efficacy of reducing EOS maintained up to approximately 6 months post single administration. Moreover, SHR-1703 exhibited low immunogenicity (2.9%), favorable safety, and tolerability in healthy subjects. CONCLUSION: Pharmacokinetics, pharmacodynamics, immunogenicity, safety, and tolerability of SHR-1703 support further clinical development of SHR-1703 in eosinophil-associated diseases. CLINICAL TRIAL REGISTRATION: The study was registered on the ClinicalTrials.gov (identifier: NCT04480762).

Spatial evolution of the proton-coupled Mott transition in correlated oxides for neuromorphic computing.

The proton-electron coupling effect induces rich spectrums of electronic states in correlated oxides, opening tempting opportunities for exploring novel devices with multifunctions. Here, via modest Pt-aided hydrogen spillover at room temperature, amounts of protons are introduced into SmNiO3-based devices. In situ structural characterizations together with first-principles calculation reveal that the local Mott transition is reversibly driven by migration and redistribution of the predoped protons. The accompanying giant resistance change results in excellent memristive behaviors under ultralow electric fields. Hierarchical tree-like memory states, an instinct displayed in bio-synapses, are further realized in the devices by spatially varying the proton concentration with electric pulses, showing great promise in artificial neural networks for solving intricate problems. Our research demonstrates the direct and effective control of proton evolution using extremely low electric field, offering an alternative pathway for modifying the functionalities of correlated oxides and constructing low-power consumption intelligent devices and neural network circuits.

Disruption of maternal vascular remodeling by a fetal endoretrovirus-derived gene in preeclampsia.

BACKGROUND: Preeclampsia, one of the most lethal pregnancy-related diseases, is associated with the disruption of uterine spiral artery remodeling during placentation. However, the early molecular events leading to preeclampsia remain unknown. RESULTS: By analyzing placentas from preeclampsia, non-preeclampsia, and twin pregnancies with selective intrauterine growth restriction, we show that the pathogenesis of preeclampsia is attributed to immature trophoblast and maldeveloped endothelial cells. Delayed epigenetic reprogramming during early extraembryonic tissue development leads to generation of excessive immature trophoblast cells. We find reduction of de novo DNA methylation in these trophoblast cells results in selective overexpression of maternally imprinted genes, including the endoretrovirus-derived gene PEG10 (paternally expressed gene 10). PEG10 forms virus-like particles, which are transferred from the trophoblast to the closely proximate endothelial cells. In normal pregnancy, only a low amount of PEG10 is transferred to maternal cells; however, in preeclampsia, excessive PEG10 disrupts maternal vascular development by inhibiting TGF-beta signaling. CONCLUSIONS: Our study reveals the intricate epigenetic mechanisms that regulate trans-generational genetic conflict and ultimately ensure proper maternal-fetal interface formation.

Factors predicting complications following open reduction and internal fixation of intra-articular distal radius fracture.

Objective: This study aimed to determine the incidence and predictors of the complications after open reduction and internal fixation (ORIF) of intra-articular distal radius fracture (IADRF) with a minimum follow-up of 12 months. Methods: Medical records and outpatient follow-up records were retrospectively reviewed to collect medical, surgical, and complication data on consecutive patients who had undergone an ORIF procedure for an IADRF between January 2019 and June 2022. Data included demographics, comorbidities, injury, surgical characteristics, and laboratory findings on admission. A multivariate logistic regression model was constructed to identify the significant predictors, with a composite of any complications occurring within 12 months after the operation as the outcome variable and potentially a range of clinical data as the independent variables. The magnitude of the relationship was indicated by the odds ratio (OR) and the 95% confidence interval (CI). Results: During the study period, 474 patients were included, and 64 had documented complications (n = 73), representing an accumulated rate of 13.5%. Among them, carpal tunnel syndrome was the most common, followed by tenosynovitis caused by tendon irritation/rupture, superficial or deep wound infection, complex regional pain syndrome (CRPS) type 1, radial shortening (≥4 mm), plate/screw problems, and others. The multivariate results showed the following factors significantly associated with increased risk of complications: experience of DRF surgery with <30 cases (OR: 2.2, 95% CI: 1.6-3.5), AO type C fracture (OR: 1.7, 95% CI: 1.2-2.9), initial lunate facet collapse of ≥5 mm (OR: 4.2, 95% CI: 1.4-8.9), and use of temporary external fixation before index surgery (OR: 2.4, 95% CI: 1.5-4.3). Conclusions: These findings may aid in patient counseling and quality improvement initiatives, and IADRF should be directed by an experienced surgeon.

Association between non-scarring alopecia and hypothyroidism: a bidirectional two-sample Mendelian randomization study.

Background: Non-scarring alopecia is typically represented by two main types: alopecia areata (AA) and androgenetic alopecia (AGA). While previous observational studies have indicated a link between non-scarring alopecia and hypothyroidism, the precise causal relationship remains uncertain. To determine the potential links between non-scarring alopecia and hypothyroidism, we conducted a bidirectional two-sample Mendelian randomization (MR) analysis. Methods: We used independent genetic instruments from the FinnGen consortium for AA (682 cases, 361,140 controls) and AGA (195 cases, 201,019 controls) to investigate the association with hypothyroidism in the UK Biobank study (22,687 cases, 440,246 controls). The primary analysis was performed using the inverse variance-weighted method. Complementary approaches were employed to evaluate the pleiotropy and heterogeneity. Results: Genetically predicted AA exhibited a positive causal effect on hypothyroidism (odds ratio [OR], 1.0017; 95% confidence interval [CI], 1.0004-1.0029; P = 0.0101). Additionally, hypothyroidism was found to be strongly correlated with an increase in the risk of AA (OR, 45.6839; 95% CI, 1.8446-1131.4271, P = 0.0196). However, no causal relationship was demonstrated between AGA and hypothyroidism. A sensitivity analysis validated the integrity of these causal relationships. Conclusion: This MR study supports a bidirectional causal link between AA and hypothyroidism. Nevertheless, additional research is needed to gain a more thorough comprehension of the causal relationship between non-scarring alopecia and hypothyroidism.

Clinical outcomes and clinico-pathological correlations in children with MPO-ANCA-associated glomerulonephritis showing renal arteritis.

The aim of this study was to evaluate the clinical features, pathological characteristics, and prognosis in myeloperoxidase (MPO)-antineutrophil cytoplasmic antibodies (ANCA)-associated glomerulonephritis (AAGN) with renal arteritis. The study involved 97 children from five pediatric clinical centers with MPO-AAGN who exhibited distinct clinical features. The patients were divided into AAGN-A+ and AAGN-A-, based on the presence or absence of arteritis, and the disparities in clinical, histopathological characteristics, and prognosis between the two groups was evaluated. In contrast to the AAGN-A- group, the children in the AAGN-A+ group exhibited more pronounced clinical symptoms and renal pathological injury. Arteritis positively moderately correlated with the serum creatinine, interleukin-6, urinary neutrophil gelatinase-associated lipocalin, negatively moderately correlated with serum complement C3. The renal survival rate in the AAGN-A+ group was significantly poorer than AAGN-A- group (χ2 = 4.278, p = 0.039). Arteritis showed a good predictive value for end-stage kidney disease (ESKD), and C3 deposition, ANCA renal risk score and arteritis were independent risk factors for the development of ESKD in children with MPO-AAGN. Arteritis is a significant pathological change observed in children with MPO-AAGN, and the formation of arteritis may be related to the inflammatory response and activation of the complement system.

Comparison of the Profile and Management of Chronic Pancreatitis between China and Western Countries: A Single-Center Experience and Literature Review.

OBJECTIVE: The etiology, clinical presentation, diagnosis, and treatment strategies of chronic pancreatitis (CP) vary significantly between countries. Specifically, the etiology and surgical approaches to treating CP differ between China and Western countries. Therefore, this study aims to compare the disparities in CP profiles and management based on our single-center experience and recent data from the West. METHODS: From January 2007 to December 2017, a total of 130 consecutive patients with histologically confirmed chronic pancreatitis (CP) underwent surgical treatment at the First Affiliated Hospital of Nanjing Medical University. The clinical features, etiology, risk factors, and operative procedures of these CP patients were analyzed and compared with recent data from Western countries. RESULTS: Our patient cohort was predominantly male (3.19:1), with a median age of 50.2 ± 9.8 years. Upper abdominal pain was the most common symptom, present in 102 patients (78.5%). The most common etiology was obstructive factors (47.7%), followed by alcohol (34.6%). The incidence of genic mutation was 2%, significantly lower than rates reported in Western research. Steatorrhea, weight loss, and jaundice were present in 6.9%, 18.5%, and 17.7% of patients, respectively. Pancreatic cysts or pseudocysts were diagnosed in 7 patients (5.4%). The following procedures were performed: Partington procedure in 33 patients (25.4%), Frey procedure in 17 patients (13.2%), Berne procedure in 5 patients (3.9%), Beger procedure in 1 patient (0.8%), pancreaticoduodenectomy in 17 patients (13.1%), pylorus-preserving pancreaticoduodenectomy in 18 patients (13.9%), middle pancreatectomy in 1 patient (0.8%), and distal pancreatectomy in 9 patients (6.9%). Choledochojejunostomy was performed in 14 patients (10.8%), gastroenterostomy in 2 (1.5%), and 15 patients (11.5%) underwent aspiration biopsy. CONCLUSION: Our study confirms that, etiologically, obstructive chronic pancreatitis (CP) is more frequent in the Chinese population than in Western populations. Although diagnostic instruments and operative procedures in China and Western countries are roughly comparable, slight differences exist in relation to diagnostic flowcharts/criteria and the indications and optimal timing of surgery.

A Novel LDLC Equation is Superior to the NIH LDLC Equation and the Friedewald Equation.

Background: LDLC equations have varying levels of underestimation for the calculated LDLC. Therefore, underestimating LDLC should be avoided as much as possible. We need to establish LDLC equations that underestimate LDLC as little as possible. Methods: We established the equations with a healthy cohort from Shuyang Hospital and validated the equations with an unselected patient cohort from The Second People's Hospital of Lianyungang. We established the novel LDLC equations by using the regression equation. The relationship between two markers was analysed using Pearson's approach. The 95% limits of measuring agreement within ±2 SD for the LDLC equations was performed using Bland‒Altman analysis. ROC curve analysis was used to predict LDLC levels and the accuracy of the LDLC equation for determining the direct LDLC levels at LDLC cut-offs was assessed. Results: We obtained two novel LDLC equations (LDL_nonHDLC equation=-0.899+1.195*nonHDLC-0.00347*nonHDLC2 and LDL_TC(total cholesterol) equation=-2.775+1.29*TC -0.00990* TC 2). The correlation coefficient between the novel LDLC equation and the direct LDLC measurements is not lower than that between the LDL_NIH equation and the direct LDLC measurements. The AUCs of our novel LDLC equations were greater than those of the LDL_NIH equation and the LDL_F equation at the LDLC cut-offs for clinical decision-making. The measuring agreement in the methods of the LDL_nonHDL equation is superior to that of the LDL_NIH equation. Conclusion: LDLC calculated by the novel LDL_nonHDL equation exhibited superiority over the LDL_NIH equation. Combining the LDL_NIH equation and our novel LDLC equation may improve accuracy and avoid undertreatment of high LDLC levels.

Degraders in epigenetic therapy: PROTACs and beyond.

Epigenetics refers to the reversible process through which changes in gene expression occur without changing the nucleotide sequence of DNA. The process is currently gaining prominence as a pivotal objective in the treatment of cancers and other ailments. Numerous drugs that target epigenetic mechanisms have obtained approval from the Food and Drug Administration (FDA) for the therapeutic intervention of diverse diseases; many have drawbacks, such as limited applicability, toxicity, and resistance. Since the discovery of the first proteolysis-targeting chimeras (PROTACs) in 2001, studies on targeted protein degradation (TPD)-encompassing PROTACs, molecular glue (MG), hydrophobic tagging (HyT), degradation TAG (dTAG), Trim-Away, a specific and non-genetic inhibitor of apoptosis protein (IAP)-dependent protein eraser (SNIPER), antibody-PROTACs (Ab-PROTACs), and other lysosome-based strategies-have achieved remarkable progress. In this review, we comprehensively highlight the small-molecule degraders beyond PROTACs that could achieve the degradation of epigenetic proteins (including bromodomain-containing protein-related targets, histone acetylation/deacetylation-related targets, histone methylation/demethylation related targets, and other epigenetic targets) via proteasomal or lysosomal pathways. The present difficulties and forthcoming prospects in this domain are also deliberated upon, which may be valuable for medicinal chemists when developing more potent, selective, and drug-like epigenetic drugs for clinical applications.

Barthel Index, SPAN-100, and NIHSS Studies on the Predictive Value of Prognosis in Patients With Thrombolysis.

OBJECTIVE: We mainly explore the predictive value of Barthel Index (BI), SPAN-100, and National Institute of Health stroke scale (NIHSS) scores on clinical prognosis and functional outcomes in thrombolytic patients and compare the differences in the predictive values of the above 3 scales so as to provide an effective basis to evaluate the prognosis of thrombolytic patients. METHODS: Data were collected from 212 patients with the first-onset AIS (acute ischemic stroke). The enrolled patients were treated with recombinant tissue plasminogen activator thrombolytic therapy and were divided into 2 groups according to the modified Rankin Scale (mRS) score at discharge: the prognosis group (mRS≤2 points) and the poor prognosis group (mRS≥3 points). Logistic multivariate analysis was used to analyze the predictors of poor prognosis in patients with thrombolysis. MedCalc software was used to plot receiver operating characteristic (ROC) curves, calculate the area under the ROC curve (AUC), and compare the prediction performance of the 3 scales by the Delong and colleagues' method, and the difference of P <0.05 was statistically significant. RESULTS: Logistic binary regression multivariate analysis suggested that BI was a predictor of poor prognosis for thrombolytic therapy in patients with AIS. The lower the BI score, the poorer the prognosis. The AUC for BI score was 0.862, 95% CI (0.808-0.906), NIHSS score AUC was 0.665, 95% CI (0.597-0.728), and SPAN-100 score AUC was 0.640, 95% CI (0.572-0.705). AUC comparison of 3 scoring ROC curves suggested statistically significant differences between BI and NIHSS ( PC =0.0000), BI and SPAN-100 ( PC =0.0000); no significant difference was observed between SPAN-100 and NIHSS ( PC =1.7997). CONCLUSIONS: Simple BI scores have a high prognostic value for thrombolytic therapy in AIS.

Integrating photothermal and plasmonic catalysis induced by near-infrared light for efficient reduction of 4-nitrophenol.

The reduction of 4-nitrophenol (4-NP) into 4-aminophenol (4-AP) is an important reaction in both chemical manufacturing and environmental protection. The design of a highly active, multifunctional and reusable catalyst for efficient 4-NP decontamination/valorization is therefore crucial to bring in economic and societal benefits. Herein, we achieve an efficient plasmonic-photothermal catalyst of Pd nanoparticles by growing them on graphene-polyelectrolytes self-assembly nanolayers via an in situ green reduction approach using polyelectrolyte as the reductant. The as-fabricated catalyst shows high catalytic behaviors and good stability (maintained over 92.5 % conversion efficiency after ten successive cycles) for 4-NP reduction under ultra-low catalyst dose. The rate constant and turnover frequency were calculated at 0.197 min-1 and 7.79 mmol g-1 min-1, respectively, which were much higher than those of most reported catalysts. Moreover, the as-prepared catalyst exhibited excellent photothermal conversion efficiency of ∼77 % and boosted 4-NP reduction by ∼2-fold under near-infrared irradiation (NIR). This study provides valuable insights into the design of greener catalytic materials and facilitates the development of multifunctional plasmonic-photothermal catalysts for diverse environmental, chemical, and energy applications using NIR.

Myeloid cell-associated aromatic amino acid metabolism facilitates CNS myelin regeneration.

Regulation of myeloid cell activity is critical for successful myelin regeneration (remyelination) in demyelinating diseases, such as multiple sclerosis (MS). Here, we show aromatic alpha-keto acids (AKAs) generated from the amino acid oxidase, interleukin-4 induced 1 (IL4I1), promote efficient remyelination in mouse models of MS. During remyelination, myeloid cells upregulated the expression of IL4I1. Conditionally knocking out IL4I1 in myeloid cells impaired remyelination efficiency. Mice lacking IL4I1 expression exhibited a reduction in the AKAs, phenylpyruvate, indole-3-pyruvate, and 4-hydroxyphenylpyruvate, in remyelinating lesions. Decreased AKA levels were also observed in people with MS, particularly in the progressive phase when remyelination is impaired. Oral administration of AKAs modulated myeloid cell-associated inflammation, promoted oligodendrocyte maturation, and enhanced remyelination in mice with focal demyelinated lesions. Transcriptomic analysis revealed AKA treatment induced a shift in metabolic pathways in myeloid cells and upregulated aryl hydrocarbon receptor activity in lesions. Our results suggest myeloid cell-associated aromatic amino acid metabolism via IL4I1 produces AKAs in demyelinated lesions to enable efficient remyelination. Increasing AKA levels or targeting related pathways may serve as a strategy to facilitate the regeneration of myelin in inflammatory demyelinating conditions.

Combination Therapy and Dual-Target Inhibitors Based on LSD1: New Emerging Tools in Cancer Therapy.

Lysine specific demethylase 1 (LSD1), a transcriptional modulator that represses or activates target gene expression, is overexpressed in many cancer and causes imbalance in the expression of normal gene networks. Over two decades, numerous LSD1 inhibitors have been reported, especially some of which have entered clinical trials, including eight irreversible inhibitors (TCP, ORY-1001, GSK-2879552, INCB059872, IMG-7289, ORY-2001, TAK-418, and LH-1802) and two reversible inhibitors (CC-90011 and SP-2577). Most clinical LSD1 inhibitors demonstrated enhanced efficacy in combination with other agents. LSD1 multitarget inhibitors have also been reported, exampled by clinical dual LSD1/histone deacetylases (HDACs) inhibitors 4SC-202 and JBI-802. Herein, we present a comprehensive overview of the combination of LSD1 inhibitors with various antitumor agents, as well as LSD1 multitarget inhibitors. Additionally, the challenges and future research directionsare also discussed, and we hope this review will provide new insight into the development of LSD1-targeted anticancer agents.

Gut microbiota dysbiosis and intestinal barrier impairment in diarrhea caused by cold drink and high-fat diet.

Cold drink and high-fat diet (CDHFD) are common diet patterns. However, the potential risks remain unclear. We investigated the effects of CDHFD in adult mice and explored the mechanisms of action. Twenty adult male mice were randomly divided into control and model groups, and the control group was fed a normal diet, whereas the model group was fed CDHFD for 28 days. We found that mice in the model group developed diarrhea symptoms accompanied by fatigue and weakness. Analysis of the intestinal flora revealed that the model group had a lower diversity and richness of microorganism species in the gut than the control group. Furthermore, the characteristic analysis indicated that CDHFD downregulated specific bacteria, such as norank_f_Muribaculaceae, Muribaculum, and Odoribacter, which are known to be associated with the systemic inflammatory response and mucosal barrier function. Blood tests showed that immune cells and inflammatory cytokines were significantly elevated in the model group, along with increased LPS induced by CDHFD. Pathological investigations demonstrated that CDHFD damages the intestinal mucosa while affecting the expression of tight junction proteins, including ZO-1, Claudin-1, Claudin-2, and Occludin, which may be attributed to the activation of the TRAF6/IκB/p65 signaling pathway. In conclusion, impaired gut microbial and mechanical barrier function is responsible for CDHFD-induced diarrhea. In this study, we constructed a model of diet-induced diarrhea by simulating human dietary patterns, evaluated the long-term effects of CDHFD on human intestinal barriers and immune systems, and revealed its mechanism of action based on chronic inflammation. This study validated the model's fit to provide an effective screening model for drug or functional food development.

Farnesoid X receptor activation protects against renal fibrosis via modulation of ß-catenin signaling.

OBJECTIVE: Activation of farnesoid X receptor (FXR), a bile acid nuclear receptor, may be implicated in the pathophysiology of diabetic nephropathy. We explored a possible role for FXR activation in preventing renal fibrosis in high fat diet (HFD)-fed mice. METHODS: We investigated the effects of HFD on mouse kidney and renal tubular epithelial cells both in vivo and in vitro, and observed the changes of FXR and ß-catenin pathway. FXR agonist was also used to alleviate this HFD-induced effect, and the interaction between FXR and ß-catenin was further verified. RESULTS: Mice were fed by a 60% kcal fat diet for 20 weeks developed the typical traits of metabolic syndrome with subsequent renal lipid accumulation and renal injury. Treatment with the FXR agonist CDCA or GW4064 decreased body weight, renal lipid accumulation, as well as renal injury. Moreover, renal ß-catenin signaling was activated and improved with FXR-agonist treatment in HFD-fed mice. To examine whether FXR affected ß-catenin signaling, and was involved in tubulo-interstitial fibrosis, we explored the FXR expression and function in ox-LDL induced-renal tubular injury. In rat proximal tubular epithelial cells (NRK-52E) stimulated by ox-LDL, FXR protein was decreased compared to control group, and phosphorylated (Ser675) ß-catenin was activated by ox-LDL in a dose- and time-dependent manner. Ox-LDL enhanced α-SMA and fibronectin expressions and reduced E-cadherin levels, whereas FXR agonism or FXR overexpression inhibited fibronectin and α-SMA expressions and restored E-cadherin. Moreover, FXR agonist treatment also decreased phosphorylated (Ser675) ß-catenin, nuclear translocation and ß-catenin-mediated transcription induced by ox-LDL in NRK-52E cells. We showed that FXR could bind with ß-catenin via the AF1 domain, and disrupt the assembly of the core ß-catenin/TCF4 complex. CONCLUSION: These experimental data suggest that FXR activation, via modulating ß-catenin signaling, may contribute to attenuating the development of lipid-mediated tubulo-interstitial fibrosis.

Promoting Piezocatalytic H2 O2 Production in Pure Water by Loading Metal-Organic Cage-Modified Gold Nanoparticles on Graphitic Carbon Nitride.

Piezocatalytic hydrogen peroxide (H2 O2 ) production is a green synthesis method, but the rapid complexation of charge carriers in piezocatalysts and the difficulty of adsorbing substrates limit its performance. Here, metal-organic cage-coated gold nanoparticles are anchored on graphitic carbon nitride (MOC-AuNP/g-C3 N4 ) via hydrogen bond to serve as the multifunctional sites for efficient H2 O2 production. Experiments and theoretical calculations prove that MOC-AuNP/g-C3 N4 simultaneously optimize three key parts of piezocatalytic H2 O2 production: i) the MOC component enhances substrate (O2 ) and product (H2 O2 ) adsorption via host-guest interaction and hinders the rapid decomposition of H2 O2 on MOC-AuNP/g-C3 N4 , ii) the AuNP component affords a strong interfacial electric field that significantly promotes the migration of electrons from g-C3 N4 for O2 reduction reaction (ORR), iii) holes are used for H2 O oxidation reaction (WOR) to produce O2 and H+ to further promote ORR. Thus, MOC-AuNP/g-C3 N4 can be used as an efficient piezocatalyst to generate H2 O2 at rates up to 120.21 µmol g-1 h-1 in air and pure water without using sacrificial agents. This work proposes a new strategy for efficient piezocatalytic H2 O2 synthesis by constructing multiple active sites in semiconductor catalysts via hydrogen bonding, by enhancing substrate adsorption, rapid separation of electron-hole pairs and preventing rapid decomposition of H2 O2 .