Pulmonary fibrosis（PF） is a progressive and life-threatening disease with limited therapeutic options， highlighting the urgent need for innovative drug discovery strategies. To address this challenge， the authors propose the formula-originated rational intelligent screening&translation（FIRST）， a systematic framework for developing anti-fibrotic monomers derived from classical traditional Chinese medicine（TCM）. The strategy integrates three key dimensions， including tissue-oriented intelligent screening of active compounds， structural optimization based on drug-target spatial interactions and plant biosynthetic pathways， and cross-scale validation of drug. We further highlight its applications in discovering tissue-oriented novel drugs from clinically validated TCM， the development and mechanistic elucidation of anti-fibrotic therapeutics， as well as the clinical translation and secondary development of candidate drugs. This strategy paves the way for first-in-class， formula-derived monomeric drugs with defined structures， clarified mechanisms， and proven safety， offering a transformative avenue to meet the urgent therapeutic needs of PF and setting a new paradigm for TCM-based drug innovation.

Pulmonary fibrosis（PF） is a progressive and life-threatening disease with limited therapeutic options， highlighting the urgent need for innovative drug discovery strategies. To address this challenge， the authors propose the formula-originated rational intelligent screening&translation（FIRST）， a systematic framework for developing anti-fibrotic monomers derived from classical traditional Chinese medicine（TCM）. The strategy integrates three key dimensions， including tissue-oriented intelligent screening of active compounds， structural optimization based on drug-target spatial interactions and plant biosynthetic pathways， and cross-scale validation of drug. We further highlight its applications in discovering tissue-oriented novel drugs from clinically validated TCM， the development and mechanistic elucidation of anti-fibrotic therapeutics， as well as the clinical translation and secondary development of candidate drugs. This strategy paves the way for first-in-class， formula-derived monomeric drugs with defined structures， clarified mechanisms， and proven safety， offering a transformative avenue to meet the urgent therapeutic needs of PF and setting a new paradigm for TCM-based drug innovation.

The interaction between m⁶A-methylated RNA and chromatin modification remains largely unknown. We found that targeted inhibition of bromodomain-containing protein 4 (BRD4) by siRNA or its inhibitor (JQ1) significantly decreases mRNA m⁶A levels and suppresses the malignancy of breast cancer (BC) cells via increased expression of demethylase AlkB homolog 5 (ALKBH5). Mechanistically, inhibition of BRD4 increases the mRNA stability of ALKBH5 via enhanced binding between its 3' untranslated regions (3'UTRs) with RNA-binding protein RALY. Further, BRD4 serves as a scaffold for ubiquitin enzymes tripartite motif containing-21 (TRIM21) and ALKBH5, resulting in the ubiquitination and degradation of ALKBH5 protein. JQ1-increased ALKBH5 then demethylates mRNA of extra spindle pole bodies like 1 (ESPL1) and reduces binding between ESPL1 mRNA and m⁶A reader insulin like growth factor 2 mRNA binding protein 3 (IGF2BP3), leading to decay of ESPL1 mRNA. Animal and clinical studies confirm a critical role of BRD4/ALKBH5/ESPL1 pathway in BC progression. Further, our study sheds light on the crosstalks between histone modification and RNA methylation.

Biomolecular condensates are formed through phase separation of biomacromolecules such as proteins and RNAs. These condensates exhibit liquid-like properties that can futher transition into more stable material states. They form complex internal structures via multivalent weak interactions, enabling precise spatiotemporal regulations. However, the use of inconsistent and non-standardized terminology has become increasingly problematic, hindering academic exchange and the dissemination of scientific knowledge. Therefore, it is necessary to discuss the terminology related to biomolecular condensates in order to clarify concepts, promote interdisciplinary cooperation, enhance research efficiency, and support the healthy development of this field.

Objective:To assess the presence of chemotherapy-induced abnormal myocardial perfusion using SPECT myocardial perfusion imaging (MPI) in patients with malignant hematologic diseases before hematopoietic stem cell transplantation (HSCT), and to explore its predictive value for mid-to-long-term mortality risk after transplantation.Methods:From March 2016 to August 2022, 139 patients with malignant hematologic diseases (80 males, 59 females; age (45.7±13.0) years) who underwent resting MPI to assess the presence of chemotherapy-induced abnormal myocardial perfusion before HSCT at the First People′s Hospital of Changzhou were prospectively included. Baseline-data were collected and patients were followed up for mid-to-long-term (≥100d) adverse outcomes after transplantation. Overall survival (OS) of each patient was recorded. The χ2 test and independent-sample t test were used for data analysis. Cox regression analysis was utilized to identify independent risk factors affecting OS. Kaplan-Meier method and log-rank test were used for survival analysis. Results:The median follow-up time of 139 patients was 41.6(19.5, 65.6) months, with all-cause mortality of 28.8%(40/139), and the cardiovascular mortality was 42.5%(17/40). The prior cardiotoxic therapies rate (anthracycline dose ≥250mg/m 2) was higher in the death group compared to that in the survival group (15.0% (6/40) vs 5.1% (5/99); χ2=3.87, P=0.049). Pre-transplant abnormal myocardial perfusion rate was also higher in the death group compared to that in the survival group (55.0%(22/40) vs 22.2%(22/99); χ2=15.19, P<0.001). But pre-transplant left ventricular ejection fraction (LVEF) was lower in the death group compared to that in the survival group ((60.4±5.2)% vs (62.9±3.9)%; t=-3.07, P=0.003). Cox multivariate regression analysis showed that the abnormal myocardial perfusion indicated by MPI before transplantation was an independent risk factor affecting OS after HSCT in patients with malignant hematologic diseases (hazard rate ( HR)=2.70, 95% CI: 1.33-5.46, P=0.006). Kaplan-Meier analysis showed the 1-, 2-, 5-year OS rates of patients with the abnormal myocardial perfusion and the normal myocardial perfusion were 73.5%, 69.1%, 49.2% and 94.6%, 89.9%, 81.6%, respectively, with significant difference ( χ2=17.01, P<0.001). Conclusions:Patients with abnormal myocardial perfusion detected by MPI before HSCT for malignant hematologic diseases have a poorer prognosis, characterized by lower post-transplantation OS rates. The utilization of MPI for assessing abnormal myocardial perfusion before transplantation in patients with malignant hematologic diseases can aid in predicting the mid-to-long-term mortality risk after transplantation.

Objective:To evaluate the early outcomes of total hip arthroplasty (THA) and discuss the revisions post THA in the treatment for Kashin-Beck disease (KBD) with severe hip problems.Methods:This retrospective cohort study enrolled 50 patients (64 hips) with a mean age of 52.4±8.7 years, including 25 male patients and 25 female patients (36 left hips and 28 right hips), who were diagnosed as KBD with hip problems and received THA at Arthritis Clinical and Research Centre, Peking University People's Hospital from October 2019 to January 2024. The leg length discrepancy (LLD), femoral offset (FO), abduction angle and anteversion angle were calculated preoperatively and one week post-operation. The postoperative radiological indexes and the functional outcomes in the last follow-up were compared with the preoperative assessment.Results:The surgical duration was 105(80, 120) min and the bleeding amount was 300(200, 400) ml. All the cases were followed up for an average of 37 months (ranging from 21 to 44 months). Significant differences were found on postoperative radiological images, with LLD improving to 0.50±0.78 cm from a preoperative value of -1.36±0.79 cm, and FO increasing to 3.28±1.01 cm from 2.72±0.83 cm ( P<0.05). The mean postoperative abduction angle and anteversion angle were 42.5°±7.7° and 15.1°±5.9°, respectively. A total of 71.8% and 95.3% hips fell within the Lewinnek safe zones of abduction angle and anteversion angle, respectively. In terms of functional outcomes, the average range of motion improved significantly to 185°(173°, 210°) from a preoperative value of 99°(76°, 123°), and the Harris Hip Score increased from 35(26, 43) preoperatively to 70(63, 80) postoperatively ( P<0.05). During the follow-up, there were complications for two cases of femoral stem loosening, one case of periprosthetic femoral fracture, one case of hip dislocation, and one case of acetabular component loosening with hip subluxation. Additionally, seven patients exhibited Trendelenburg gait. A total of five hips required revision surgery due to severe complications, including two cases of femoral stem loosening, one case of periprosthetic femoral fracture, one case of hip dislocation, and one case of acetabular component loosening with subluxation. Conclusions:Patients with KBD demonstrated significant early improvements in both radiological and functional outcomes following THA.

Spermatogenesis is a fundamental process that requires a tightly controlled epigenetic event in spermatogonial stem cells (SSCs). The mechanisms underlying the transition from SSCs to sperm are largely unknown. Most studies utilize gene knockout mice to explain the mechanisms. However, the production of genetically engineered mice is costly and time-consuming. In this study, we presented a convenient research strategy using an RNA interference (RNAi) and testicular transplantation approach. Histone H3 lysine 9 (H3K9) methylation was dynamically regulated during spermatogenesis. As Jumonji domain-containing protein 1A (JMJD1A) and Jumonji domain-containing protein 2C (JMJD2C) demethylases catalyze histone H3 lysine 9 dimethylation (H3K9me2), we firstly analyzed the expression profile of the two demethylases and then investigated their function. Using the convenient research strategy, we showed that normal spermatogenesis is disrupted due to the downregulated expression of both demethylases. These results suggest that this strategy might be a simple and alternative approach for analyzing spermatogenesis relative to the gene knockout mice strategy.
Spermatogenesis/physiology* ; Animals ; Male ; Mice ; Epigenesis, Genetic ; Jumonji Domain-Containing Histone Demethylases/metabolism* ; Histones/metabolism* ; RNA Interference ; Testis/metabolism* ; Methylation ; Mice, Knockout ; Histone Demethylases

OBJECTIVE: To explore the effects of electroacupuncture (EA) on pregnancy outcomes after assisted reproduction and mitochondrial function of granulosa cells (GCs) in patients with polycystic ovary syndrome (PCOS) and phlegm-dampness syndrome. METHODS: In this randomized controlled trial, 90 infertile women with PCOS and phlegm-dampness syndrome were recruited between August 2022 and December 2022. Patients were randomly assigned to the EA and control groups using a random sequence of codes in the order of enrolment, with 45 in in each group. Both groups underwent the ovarian stimulation protocol. The patients in the EA group received EA therapy including Zhongwan (CV 12), Qihai (CV 6), bilateral Xuehai (SP 10), Sanyinjiao (SP 6), Yinlingquan (SP 9), Tianshu (ST 25), Zusanli (ST 36), and Fenglong (ST 40), and the patients in the control group was treated with pseudo-acupuncture. The intervention was 25 min twice a week for a total of 6 times until the trigger day after menstruation had ended in the cycle before oocyte retrieval. The primary outcomes were clinical pregnancy rate (CPR) and the number of high-quality embryos. The secondary outcomes were (1) pregnancy-related indicators, including fresh embryo transfer rate (ETR), ovarian hyperstimulation syndrome (OHSS) rate, early pregnancy loss rate (ePLR), ectopic pregnancy rate, live birth rate (LBR), and cumulative CPR; (2) mitochondrial autophagy and mitochondrial membrane potential (MMP) in GCs; and (3) scoring for Chinese medicine syndrome. Adverse events to assess clinical safety were also monitored. RESULTS: The cumulative CPR was significantly higher in the EA group (42/45, 93.3%) than in the control group (38/45, 84.4%, P=0.036). The number of high-quality embryos and fresh ETR in the EA group were higher than those in the control group (3.80±1.65 vs. 2.44±1.34, P<0.001; 46.7% vs 24.4%, P=0.028). Ectopic pregnancies were not observed in either group. There were no significant differences in the fresh CPR, OHSS rate, ePLR or LBR between the two groups (P>0.05). Compared with the control group, the EA group showed lower expression levels of miR-146a-5p mRNA and P62 protein in GCs and higher levels of MMP and the LC3-II/LC3-I protein ratio (all P<0.01). The phlegm-dampness syndrome scores of the EA group were significantly lower than those of the control group (P<0.01). CONCLUSIONS EA significantly improved pregnancy outcomes in patients with PCOS and phlegm dampness syndrome. Mechanistically, this effect may be related to EA in decreasing miR-146a-5p mRNA expression, promoting mitochondrial autophagy in GCs, and improving mitochondrial function, which may contribute to improved oocyte quality. (Trial registration No. ChiCTR2200062915).
Humans ; Female ; Polycystic Ovary Syndrome/therapy* ; Pregnancy ; Electroacupuncture ; Granulosa Cells/metabolism* ; Adult ; Mitochondria/metabolism* ; Pregnancy Outcome ; Pregnancy Rate ; Reproductive Techniques, Assisted ; Infertility, Female/therapy*

Pyroptosis is an identified programmed cell death that has been highly linked to endoplasmic reticulum (ER) dynamics. However, the crucial proteins for modulating dynamic ER membrane curvature change that trigger pyroptosis are currently not well understood. In this study, a biotin-labeled chemical probe of potent pyroptosis inducer α-mangostin (α-MG) was synthesized. Through protein microarray analysis, reticulon-4 (RTN4/Nogo), a crucial regulator of ER membrane curvature, was identified as a target of α-MG. We observed that chemically induced proteasome degradation of RTN4 by α-MG through recruiting E3 ligase UBR5 significantly enhances the pyroptosis phenotype in cancer cells. Interestingly, the downregulation of RTN4 expression significantly facilitated a dynamic remodeling of ER membrane curvature through a transition from tubules to sheets, consequently leading to rapid fusion of the ER with the cell plasma membrane. In particular, the ER-to-plasma membrane fusion process is supported by the observed translocation of several crucial ER markers to the "bubble" structures of pyroptotic cells. Furthermore, α-MG-induced RTN4 knockdown leads to pyruvate kinase M2 (PKM2)-dependent conventional caspase-3/gasdermin E (GSDME) cleavages for pyroptosis progression. In vivo, we observed that chemical or genetic RTN4 knockdown significantly inhibited cancer cells growth, which further exhibited an antitumor immune response with anti-programmed death-1 (anti-PD-1). In translational research, RTN4 high expression was closely correlated with the tumor metastasis and death of patients. Taken together, RTN4 plays a fundamental role in inducing pyroptosis through the modulation of ER membrane curvature remodeling, thus representing a prospective druggable target for anticancer immunotherapy.
Pyroptosis/immunology* ; Humans ; Endoplasmic Reticulum/immunology* ; Animals ; Nogo Proteins/antagonists & inhibitors* ; Mice ; Cell Line, Tumor ; Xanthones/pharmacology* ; Neoplasms/pathology* ; Mice, Nude

Abstract In recent years, the prevalence of overweight and obesity among children and adolescents has risen rapidly, posing a serious threat to their physical and mental health. To provide scientific, systematic, and standardized weight management guidance for overweight and obese children and adolescents, the study focuses on the core concept of healthy lifestyle intervention, integrates multidisciplinary expert opinions and research findings,and proposes a comprehensive multidisciplinary intervention framework covering scientific exercise intervention, precise nutrition and diet, optimized sleep management, and standardized psychological support. It calls for the establishment of a multi agent collaborative management mechanism led by the government, implemented by families, fostered by schools, initiated by individuals, optimized by communities, reinforced by healthcare, and coordinated by multiple stakeholders. Emphasizing a child and adolescent centered approach, the consensus advocates for comprehensive, multi level, and personalized guidance strategies to promote the internalization and maintenance of a healthy lifestyle. It serves as a reference and provides recommendations for the effective prevention and control of overweight and obesity, and enhancing the health level of children and adolescents.