Objective To explore the mechanism of Qingda Granules(QDG)for alleviating brain damage in spontaneously hypertensive rats(SHRs).Methods Twelve 5-week-old SHRs were randomized into SHR control group and SHR+QDG group treated with QDG by gavage at the daily dose of 0.9 g/kg for 12 weeks.The control rats,along with 6 age-matched WKY rats,were treated with saline only.Blood pressure changes of the rats were monitored,and pathologies and neuronal apoptosis in the cerebral cortex were examined with HE staining and TUNEL staining.Cerebral cortical expressions of miR-124 and STAT3 mRNA were detected using RT-qPCR,and the protein expressions of NeuN,STAT3,Bcl-2,Bax,and cleaved caspase-3 were detected with immunohistochemistry and Western blotting.In a HT22 cell model of oxygen and glucose deprivation/reoxygenation(OGD/R),the effects of QDG on cell viability and apoptosis,expressions of miR-124 and STAT3 mRNA,and protein expressions of STAT3,Bcl-2,Bax,and cleaved caspase-3 were evaluated using CCK8 assay,Hoechst 33342 staining,RT-qPCR,and Western blotting.Results Compared with WKY rats,SHRs had significantly elevated systolic blood pressure,diastolic blood pressure and mean arterial pressure with significantly increased neuronal apoptosis in the cerebral cortex,reduced expressions of NeuN,miR-124 and Bcl-2,and enhanced expressions of STAT3,Bax and cleaved caspase-3(P＜0.05).All these changes in the SHRs were significantly ameliorated by treatment with QDG(P＜0.05).In the HT22 cell model,QDG treatment obviously reduced OGD/R-induced cell apoptosis,increased the expressions of miR-124 and Bcl-2,and suppressed the elevation of protein expressions of STAT3,Bax and cleaved caspase-3.Conclusion QDG inhibits cerebral cortical neuronal apoptosis and thereby attenuates brain damage in SHR rats by modulating the miR-124/STAT3 signaling axis.

Protein arginine methyltransferase 5 (PRMT5) acts as an oncogene in liver cancer, yet its roles and in-depth molecular mechanisms within the liver cancer immune microenvironment remain mostly undefined. Here, we demonstrated that disruption of tumor-intrinsic PRMT5 enhances CD8⁺ T-cell-mediated antitumor immunity both in vivo and in vitro. Further experiments verified that this effect is achieved through downregulation of the inhibitory immune checkpoint molecule, fibrinogen-like protein 1 (FGL1). Mechanistically, PRMT5 catalyzed symmetric dimethylation of transcription factor 12 (TCF12) at arginine 554 (R554), prompting the binding of TCF12 to FGL1 promoter region, which transcriptionally activated FGL1 in tumor cells. Methylation deficiency at TCF12-R554 residue downregulated FGL1 expression, which promoted CD8⁺ T-cell-mediated antitumor immunity. Notably, combining the PRMT5 methyltransferase inhibitor GSK591 with PD-L1 blockade efficiently inhibited liver cancer growth and improved overall survival in mice. Collectively, our findings reveal the immunosuppressive role and mechanism of PRMT5 in liver cancer and highlight that targeting PRMT5 could boost checkpoint immunotherapy efficacy.

Metabolic reprogramming plays a central role in tumors. However, the key drivers modulating reprogramming of gluconeogenesis/lipogenesis are poorly understood. Here, we try to identify the mechanism by which histone acetyltransferase 1 (HAT1) confers reprogramming of gluconeogenesis/lipogenesis in liver cancer. Diethylnitrosamine (DEN)/carbon tetrachloride (CCl₄)-induced hepatocarcinogenesis was hardly observed in HAT1-knockout mice. Multi-omics identified that HAT1 modulated gluconeogenesis and lipogenesis in liver. Protein phosphatase 2 scaffold subunit alpha (PPP2R1A) promoted gluconeogenesis and inhibited lipogenesis by phosphoenolpyruvate carboxykinase 1 (PCK1) serine 90 dephosphorylation to suppress the tumor growth. HAT1 succinylated PPP2R1A at lysine 541 (K541) to block the assembly of protein phosphatase 2A (PP2A) holoenzyme and interaction with PCK1, resulting in the depression of dephosphorylation of PCK1. HAT1-succinylated PPP2R1A contributed to the remodeling of gluconeogenesis/lipogenesis by PCK1 serine 90 phosphorylation, leading to the inhibition of gluconeogenic enzyme activity and activating sterol regulatory element-binding protein 1 (SREBP1) nuclear accumulation-induced lipogenesis gene expression, which enhanced the tumor growth. In conclusion, succinylation of PPP2R1A lysine 541 by HAT1 converses the role in modulation of gluconeogenesis/lipogenesis remodeling through PCK1 S90 phosphorylation to support liver cancer. Our finding provides new insights into the mechanism by which post-translational modifications (PTMs) confer the conversion of tumor suppressor function to oncogene.

Poly(ADP-ribose) polymerase 1 (PARP1) is a multifunctional protein involved in diverse cellular functions, notably DNA damage repair. Pharmacological inhibition of PARP1 has therapeutic benefits for various pathologies. Despite the increased use of PARP inhibitors, challenges persist in achieving PARP1 selectivity and effective blood-brain barrier (BBB) penetration. The development of a PARP1-specific positron emission tomography (PET) radioligand is crucial for understanding disease biology and performing target occupancy studies, which may aid in the development of PARP1-specific inhibitors. In this study, we leverage the recently identified PARP1 inhibitor, AZD9574, to introduce the design and development of its ¹⁸F-isotopologue ([¹⁸F]AZD9574). Our comprehensive approach, encompassing pharmacological, cellular, autoradiographic, and in vivo PET imaging evaluations in non-human primates, demonstrates the capacity of [¹⁸F]AZD9574 to specifically bind to PARP1 and to successfully penetrate the BBB. These findings position [¹⁸F]AZD9574 as a viable molecular imaging tool, poised to facilitate the exploration of pathophysiological changes in PARP1 tissue abundance across various diseases.

OBJECTIVES: To explore the mechanism of Qingda Granules (QDG) for alleviating brain damage in spontaneously hypertensive rats (SHRs). METHODS: Twelve 5-week-old SHRs were randomized into SHR control group and SHR+QDG group treated with QDG by gavage at the daily dose of 0.9 g/kg for 12 weeks. The control rats, along with 6 age-matched WKY rats, were treated with saline only. Blood pressure changes of the rats were monitored, and pathologies and neuronal apoptosis in the cerebral cortex were examined with HE staining and TUNEL staining. Cerebral cortical expressions of miR-124 and STAT3 mRNA were detected using RT-qPCR, and the protein expressions of NeuN, STAT3, Bcl-2, Bax, and cleaved caspase-3 were detected with immunohistochemistry and Western blotting. In a HT22 cell model of oxygen and glucose deprivation/reoxygenation (OGD/R), the effects of QDG on cell viability and apoptosis, expressions of miR-124 and STAT3 mRNA, and protein expressions of STAT3, Bcl-2, Bax, and cleaved caspase-3 were evaluated using CCK8 assay, Hoechst 33342 staining, RT-qPCR, and Western blotting. RESULTS: Compared with WKY rats, SHRs had significantly elevated systolic blood pressure, diastolic blood pressure and mean arterial pressure with significantly increased neuronal apoptosis in the cerebral cortex, reduced expressions of NeuN, miR-124 and Bcl-2, and enhanced expressions of STAT3, Bax and cleaved caspase-3 (P<0.05). All these changes in the SHRs were significantly ameliorated by treatment with QDG (P<0.05). In the HT22 cell model, QDG treatment obviously reduced OGD/R-induced cell apoptosis, increased the expressions of miR-124 and Bcl-2, and suppressed the elevation of protein expressions of STAT3, Bax and cleaved caspase-3. CONCLUSIONS QDG inhibits cerebral cortical neuronal apoptosis and thereby attenuates brain damage in SHR rats by modulating the miR-124/STAT3 signaling axis.
Animals ; Rats, Inbred SHR ; MicroRNAs/metabolism* ; STAT3 Transcription Factor/metabolism* ; Signal Transduction/drug effects* ; Drugs, Chinese Herbal/pharmacology* ; Rats ; Apoptosis/drug effects* ; Rats, Inbred WKY ; Male ; Hypertension

Objective:To evaluate the efficacy and safety of filiform-needle acupuncture(FA)in the treatment of poststroke urinary incontinence(PSUI).Methods:All published papers in PubMed,Excerpta Medica Database(EMBASE),Cochrane Library,Web of Science,China National Knowledge Infrastructure(CNKI),Chongqing VIP Database(VIP),Wanfang Data Knowledge Service Platform(Wanfang),and China Biology Medicine Disc(CBM)were retrieved by computer.The retrieval time was from each database's inception to December 9,2023.Meta-analysis and sensitivity analysis were performed using the Revman V5.4 software,and GARDE evaluation was performed using GRADEpro GDT.Dichotomous variables were analyzed by the relative risk(RR),and weighted mean difference(WMD)was used for continuous variables.Each effect size was expressed as a 95%confidence interval(CI).Results:A total of 14 studies were included,comprising a total of 1 259 patients.The findings of the meta-analysis showed that the improvements of the maximum bladder capacity[WMD=64.63,95%CI(41.73,87.53),P<0.00001],72 h urination frequency[WMD=-5.27,95%CI(-6.40,-4.13),P<0.00001],and 72 h urinary incontinence frequency[WMD=-1.62,95%CI(-2.60,-0.64),P=0.001]in PSUI patients by FA were superior compared to conventional therapy.FA plus rehabilitation therapy(RT)was superior to RT alone in improving the maximum bladder capacity[WMD=35.17,95%CI(28.31,42.03),P<0.00001],the International Consultation on Incontinence questionnaire short form(ICI-Q-SF)score[WMD=-2.66,95%CI(-3.28,-2.05),P<0.00001],and incontinence quality of life questionnaire(I-QOL)score[WMD=8.07,95%CI(3.28,12.32),P=0.0002].The incidence of adverse reactions in FA was higher than that in RT[RR=21.62,95%CI(4.04,115.71),P=0.0003],but the severity was mild and did not affect the integrity of the treatment.Conclusion:FA has better safety,and its improving effect on bladder urinary storage function and urinary incontinence symptoms in patients with PSUI is clear.Combined with RT,it can better improve the quality of life in the patients.However,more high-quality studies are still needed for further updates and verification.

Objective:To analyze the scientific research projects of health management disciplines in medical institutions in Beijing.Methods:This study was an observational study, and data was retrieved through computer between 2014 and 2023 from the scientific research data filling system of health management disciplines in medical institutions in Beijing region, which recorded the project name, project category, scientific research funding, institution, discipline, field, etc.. Excel 2016 was used to analyze the scientific research projects of health management disciplines in medical institutions in the Beijing region.Results:From 2014 to 2023, a total of 1 848 scientific research projects of health management disciplines in medical institutions in the Beijing region were initiated, with research funding of 1 204.775 million yuan. In terms of institutional categorization, they were mainly concentrated on central and municipal medical institutions, and in terms of research fields, there were 1 577 projects in Western medicine, with research funding of 1 133.240 million yuan, and 271 projects in Chinese medicine/combination of Chinese and Western medicine, with research funding of 71.535 million yuan. Cardiovascular diseases ranked first in the sub-discipline of Western medicine, and Chinese internal medicine ranked first in the sub-discipline of Chinese medicine.Conclusions:The scientific research projects of health management disciplines in medical institutions in Beijing are characterized by an imbalance in the distribution of institutions and the classification of funded sub-disciplines. The research innovation of health management in medical institutions needs to strengthen multidisciplinary cooperation and talent cultivation.

Under stress,the cold-inducible RNA-binding protein(CIRP)is translocated from the nucleus to the cytoplasm and subsequently released outside the cell.Extracellular CIRP(eCIRP),acting as a damage-associated mo-lecular pattern,amplifies inflammation through various mechanisms and leads to an uncontrolled inflammatory response,thereby contributing to the occurrence and progression of sepsis and other critical pathological processes.Certain CIRP-tar-geting drugs have demonstrated promising anti-sepsis effects through the reduction of CIRP expression,the decrease of eCIRP release,the neutralization of eCIRP,or the intervention in receptor binding.This review examines the release mechanism of CIRP and the role of eCIRP in the development of sepsis,with the aim of providing new insights for the pre-vention and treatment of sepsis by targeting eCIRP.

Objective:To investigate the distribution of CGG repeat numbers in the FMR1 gene among reproductive-age women in China, providing data reference for carrier screening and genetic counseling of Fragile X syndrome. Methods:This cross-sectional study recruited 16 610 reproductive-age women from 12 medical institutions between July 2022 and October 2023. Peripheral venous blood samples (3 mL) were collected, and genomic DNA was extracted. The number of CGG repeats in the FMR1 gene was determined using the triplet-primed polymerase chain reaction (TP-PCR) combined with capillary electrophoresis technology. Statistical analyses were performed to assess the prevalence and distribution of CGG repeat expansions. Results:Among 16 610 women of childbearing age, 5 684 (34.220%) women had the same number of CGG repeats in the two alleles of FMR1 gene, and 10 926 (65.780%) women had different numbers of repeats in the two alleles. Among the 33 220 FMR1 alleles in 16 610 women of reproductive age, the most common CGG repeat numbers were 29 [48.645% (16 160/33 220)] and 30 [26.276% (8 729/33 220)], while the most frequent CGG genotype was CGG 29/29 [24.726% (4 107/16 610)]. The CGG repeat numbers of FMR1 gene were normal in 16 498 women (99.326%). Among the 112 women (0.674%) with CGG repeat abnormities, 96 (0.578%) women were classified as intermediate carriers, 15 (0.090%) as premutation carriers, and 1 (0.006%) as a full mutation carrier, whose CGG genotype was (36, >200). Conclusion:In the general reproductive-age female population in China, the normal CGG repeat numbers of the FMR1 gene account for 99.326%, while the intermediate carrier rate is 0.578%, and the combined carrier rate of the premutation and full mutation types is 0.096%.

Following hemorrhagic shock,locally released chemotactic molecules attract neutrophils to rapidly migrate to the damaged tissues,while effectively bind,engulf and kill microorganisms,along with chromatin releasing and forming a substance deco-rated with a meshwork of microbicidal proteins and enzymes,a DNA-protein structure named neutrophil extracellular traps(NETs).The formation and degradation of NETs are regulated by multiple factors,and an imbalance in the formation and degradation of NETs plays a role in cellular damage and the aggregation of inflammatory factors,which is one of the main mechanisms of uncontrolled in-flammatory response and further aggravates organ damage.Studies have shown that NETs are involved in the process of hemorrhagic shock-induced organ damage,but the relevant mechanisms have not been fully elucidated.In this paper,we review the role of NETs in organ damage after hemorrhagic shock and the related mechanisms,and in order to understand the role of NETs and provide a refer-ence for new targets for the prevention and treatment of hemorrhagic shock.