MRGPRX2 antagonists possess the potential for the treatment of allergic rhinitis, atopic dermatitis, and chronic urticaria. Previously, we identified a class of diaryl urea (DPU) MRGPRX2 antagonists with sub-micromolar IC₅₀ values in vitro. However, the structure-activity relationship remains unclear. Herein, we adopted a "relative symmetry with electronegativity of different key-groups" strategy for further modification of DPUs to achieve a promising MRGPRX2 antagonist with higher activity and safety. Electrostatic potential energy analysis and biological evaluation revealed that B-1023 and B-5023, that possess relatively symmetric electron-withdrawing substituents, remarkable inhibited mast cell degranulation at a sub-micromolar IC₅₀ in vitro and alleviated anaphylactic symptoms. Furthermore, B-1023, mitigated antigen-induced pulmonary inflammation (AIPI) in mice and competitively bonded to MRGPRX2. In summary, the "relative symmetry with electronegativity of different key-groups" strategy provided a drug design pattern for MRGPRX2 antagonists and identified promising antiallergic precursors for AIPI treatment.

Idiopathic pulmonary fibrosis (IPF), a chronic interstitial lung disease, is characterized by aberrant wound healing, excessive scarring and the formation of myofibroblastic foci. Although the role of alternative splicing (AS) in the pathogenesis of organ fibrosis has garnered increasing attention, its specific contribution to pulmonary fibrosis remains incompletely understood. In this study, we identified an up-regulation of serine/arginine-rich splicing factor 7 (SRSF7) in lung fibroblasts derived from IPF patients and a bleomycin (BLM)-induced mouse model, and further characterized its functional role in both human fetal lung fibroblasts and mice. We demonstrated that enhanced expression of Srsf7 in mice spontaneously induced alveolar collagen accumulation. Mechanistically, we investigated alternative splicing events and revealed that SRSF7 modulates the alternative splicing of pyruvate kinase (PKM), leading to metabolic dysregulation and fibroblast activation. In vivo studies showed that fibroblast-specific knockout of Srsf7 in conditional knockout mice conferred resistance to bleomycin-induced pulmonary fibrosis. Importantly, through drug screening, we identified lomitapide as a novel modulator of SRSF7, which effectively mitigated experimental pulmonary fibrosis. Collectively, our findings elucidate a molecular pathway by which SRSF7 drives fibroblast metabolic dysregulation and propose a potential therapeutic strategy for pulmonary fibrosis.

Learning-associated functional plasticity at hippocampal synapses remains largely unexplored. Here, in a single session of reward-based trace conditioning, we examine learning-induced synaptic plasticity in the dorsal CA1 hippocampus (dCA1). Local field-potential recording combined with selective optogenetic inhibition first revealed an increase of dCA1 synaptic responses to the conditioned stimulus (CS) induced during conditioning at both Schaffer collaterals to the stratum radiatum (Rad) and temporoammonic input to the lacunosum moleculare (LMol). At these dCA1 inputs, synaptic potentiation of CS-responding excitatory synapses was further demonstrated by locally blocking NMDA receptors during conditioning and whole-cell recording sensory-evoked synaptic responses in dCA1 neurons from naive animals. An overall similar time course of the induction of synaptic potentiation was found in the Rad and LMol by multiple-site recording; this emerged later and saturated earlier than conditioned behavioral responses. Our experiments demonstrate a cued memory-associated dCA1 synaptic plasticity induced at both Schaffer collaterals and temporoammonic pathways.
Animals ; CA1 Region, Hippocampal/physiology* ; Male ; Association Learning/physiology* ; Neuronal Plasticity/physiology* ; Cues ; Memory/physiology* ; Synapses/physiology* ; Conditioning, Classical/physiology* ; Excitatory Postsynaptic Potentials/physiology* ; Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors* ; Rats ; Optogenetics

Objective:To investigate the distribution of pathological types of unilateral primary aldosteronism, and to explore the clinical characteristics and prognosis of patients with different pathological types.Methods:A total of 241 patients with unilateral primary aldosteronism who underwent adrenal surgery were included in this study. The clinical data and postoperative follow-up data were collected, and the postoperative tissue sections were stained with HE and aldosterone synthase. According to the staining results, pathological types of 241 patients were classified, and the clinical characteristics and surgical prognosis of patients with unilateral primary aldosteronism were compared.Results:According to the international histopathology consensus for unilateral primary aldosteronism, among 241 patients with unilateral primary aldosteronism, 223 were classical(92.5%), 17 were non-classical(7.1%), and 1 was aldosterone producing carcinoma(0.4%). Among classical cases, 189 were aldosterone producing adenoma and 34 were aldosterone producing nodule. In the non-classical cases, 8 cases were multiple aldosterone producing nodule and 9 cases were multiple aldosterone producing nodule. Compared with the classical group, the non-classical group had a longer duration of hypertension(9.0 vs 5.0 years, P=0.062) and a lower baseline plasma aldosterone concentration(273 vs 305 pg/mL, P=0.147), but the difference was not significant. There was no significant difference between the two groups in the proportion of patients who achieved a complete biochemical response after surgery(98% vs 92.3%, P=0.281), but the proportion of patients who achieved a complete clinical response was significantly lower in the non-classical group(23.1% vs 52.9%, P=0.046). Conclusion:The pathological types of unilateral primary aldosteronism are predominantly classical, with aldosterone-producing adenoma being the most common. There were no significant differences in the clinical characteristics and postoperative biochemical remission rates between classical and non-classical patients, but the clinical prognosis of the latter was inferior to the former.

Objective To investigate the mechanism of Gastrodiae Rhizoma-Salviae Miltiorrhizae Radix et Rhizoma drug pair in the treatment of hypertension based on the network pharmacology method and animal experiment verification.Methods(1)TCMSP,BATMAN and TCMIP databases were used to screen the active components and targets of Gastrodiae Rhizoma-Salviae Miltiorrhizae Radix et Rhizoma drug pair.The hypertension-related targets were obtained by searching the Drugbank,Genecard,TTD and Disgenet databases.The intersection(common target)of the active component target and the target related to hypertension disease was taken,and the obtained intersection target was the potential target of Gastrodiae Rhizoma-Salviae Miltiorrhizae Radix et Rhizoma drug pair for the treatment of hypertension.The active ingredients and their targets of Gastrodiae Rhizoma-Salviae Miltiorrhizae Radix et Rhizoma drug pair were imported into Cytoscape 3.9.1 software to construct a'Chinese medicines-active ingredients-targets'network and screen key active ingredients.The protein-protein interaction(PPI)network of potential targets was constructed to screen potential core targets.The Metascape platform was used to analyze the GO function and KEGG pathway enrichment of potential targets.The key active components and potential core targets were selected for molecular docking verification.(2)Thirty male spontaneously hypertensive rats(SHR)were randomly divided into model group,western medicine group(Candesartan Cilexetil,0.72 mg·kg-1)and low-,medium-and high-dose groups of Gastrodiae Rhizoma-Salviae Miltiorrhizae Radix et Rhizoma(2.25,4.50,9.00 g·kg-1).Another male WKY rats were selected as blank group,with 6 rats in each group,once a day for 8 weeks.The systolic blood pressure of rat tail artery was detected before administration and 2,4,6 and 8 weeks after drug intervention.The pathological changes of thoracic aorta were observed by HE staining.The protein expression levels of GRP78,CHOP and Caspase-12 in aorta abdominalis were detected by Western Blot.Results(1)A total of 83 active components of Gastrodiae Rhizoma-Salviae Miltiorrhizae Radix et Rhizoma were obtained,and 158 potential targets(intersection targets)for the treatment of hypertension were screened out.Five key active ingredients:p-hydroxybenzoic acid,4-hydroxybenzylamine,tanshinone I,tanshinone,γ-sitosterol;6 potential core targets:IL6,TNF,CASP3,JUN,PTGS2,IL1B;GO functional enrichment analysis obtained 1 826 biological process items,89 cell component items,and 199 molecular function items.KEGG pathway enrichment analysis obtained 186 pathways,mainly involving neuroactive ligand-receptor interaction,calcium signaling pathway,inflammatory response(such as TNF and MAPK signaling pathway),vascular protection(such as HIF-1 and cAMP signaling pathway),oxidative stress(such as PI3K-Akt signaling pathway)and other signaling pathways.Tanshinone I and tanshinone had strong binding force to 6 potential core targets,and γ-sitosterol had strong binding force to IL6,CASP3,JUN,PTGS2 and IL1B.(2)Compared with the blank group,the systolic blood pressure of the model group was significantly increased(P＜0.01).The thoracic aortic endothelial injury was obvious,the endothelial cell morphology was abnormal,swelling and exfoliated cells could be seen,the intima of the tissue was disordered,the intima structure was incomplete,and the intima was thickened.The protein expressions of GRP78,CHOP and Caspase-12 in abdominal aorta were significantly increased(P＜0.01).Compared with the model group,the systolic blood pressure of the rats in the administration group was significantly decreased(P＜0.01);the injury of thoracic aorta was alleviated,and the morphology,intima structure and thickness of endothelial cells were improved to varying degrees.The protein expressions of GRP78,CHOP and Caspase-12 in abdominal aorta were significantly decreased(P＜0.01).Conclusion Gastrodiae Rhizoma-Salviae Miltiorrhizae Radix et Rhizoma drug pair may act on core targets such as IL6,TNF,CASP3,JUN,PTGS2,and IL1B through key active components such as p-hydroxybenzoic acid,tanshinone,and γ-sitosterol,and regulate key signaling pathways such as TNF signaling pathway,MAPK signaling pathway,PI3K-Akt signaling pathway,and PERK signaling pathway to improve vascular endothelial dysfunction,inhibit endoplasmic reticulum stress,and lower blood pressure.

This article summarized the experience of Professor Xiong Jibai,a national TCM master,in treating pulmonary nodules based on the theory of"body fluids and blood stasis mixing"in Huang Di Nei Jing.Professor Xiong Jibai believes that the basic pathogenesis of pulmonary nodules is that"body fluids and blood stasis mixing"accumulate in lung collaterals,and the fundamental pathological factor is phlegm and blood stasis.Xiong's treatment is based on dissipating phlegm and activating qi,activating blood circulation and resolving masses,paying attention to syndrome differentiation and treatment,examining syndromes and seeking causes,flexibly selecting prescriptions and treating both symptoms and root causes;attaching importance to maintaining healthy qi,preventing both illness and change,and preventing recovery after illness.Clinical medical records were attached to prove the clinical thinking and medication characteristics.

Objective:To compare the prevalence of frailty and related factors in middle-aged and elderly people aged ≥45 years in island and mountainous areas of Taizhou, Zhejiang Province.Methods:Based on cross-sectional design, stratified cluster sampling and quota sampling methods were adopted. One administrative district was randomly selected from each of six coastal and three inland administrative districts in Taizhou during July to August, representing two different geographical terrains. In the island area (Jiaojiang District), all residents aged ≥45 years were included by cluster sampling. In the mountainous area (Xianju County), participants were selected through quota sampling, with same gender and age distributions. Data about their demographic characteristics, lifestyle and health-related factors were collected through questionnaire surveys and laboratory examinations. The prevalence of frailty was assessed using the Fried frailty phenotype scale. Hierarchical analysis and multivariate logistic regression analysis were used to compare the influencing factors of frailty.Results:A total of 1 011 local residents were studied, in whom island and mountainous residents accounted for 48.1% (486/1 011) and 51.9% (525/1 011) respectively; men and women accounted for 45.9% (464/1 011) and 54.1% (547/1 011) respectively. Middle-aged (45-49 years), younger elderly (60-74 years), and older elderly (≥75 years) residents accounted for 38.6% (390/1 011), 44.6% (451/1 011), and 16.8% (170/1 011) respectively. The overall prevalence rate of frailty was 3.6% (36/1 011), the prevalence rate was 3.7% (17/464) in men and 3.5% (19/547) in women. The prevalence rates in age groups 45-59,60-74 years and ≥75 years were 0.3% (1/390), 2.2% (10/451), and 14.7% (25/170), respectively. The prevalence rates of frailty and pre-frailty in island area were 6.0% (29/486) and 39.1% (190/486), respectively, which was higher than those in mountainous area (1.3%, 7/525) and (30.9%, 162/525). After adjusting for potential confounding factors, the risk for frailty in island residents was significantly higher than that in mountainous residents (a OR=1.55,95% CI: 1.07-2.25, P=0.019). In island area, older age (60-74 years:a OR=2.52,95% CI: 1.56-4.13; ≥75 years:a OR=11.65,95% CI:5.38-26.70), being women (a OR=1.94,95% CI: 1.20-3.17), suffering from depression (a OR=1.09,95% CI:1.02-1.17) were associated with frailty symptoms. In mountainous area, older age was also associated with an increased risk of frailty symptoms, but the OR value was lower than those in island area (60-74 years: a OR=1.74,95% CI:1.04-2.94;≥75 years: a OR=4.78,95% CI:2.45-9.50). Polydrug use (a OR=2.08,95% CI: 1.14-3.80) and suffering from depression (a OR=1.10,95% CI: 1.02-1.18) had significant positive association with frailty symptoms. Higher education level had significant negative association with frailty symptoms (junior high school: a OR=0.40,95% CI: 0.21-0.75; senior high school and technical secondary school: a OR=0.29,95% CI: 0.15-0.53; college or above:a OR=0.22,95% CI: 0.11-0.42). Conclusions:The prevalence of frailty in middle-aged and elderly community residents was significantly higher in island area than in mountainous area in Taizhou. The frailty-related factors varied with area. The elderly people (≥75 years) and women in island area had higher risk for frailty. Older age and suffering from depression were the independent risk factors for frailty. It is necessary to pay attention to the health risk factors and special environment in island area, and take comprehensive intervention measures to delay the process of debilitation and improve the quality of life of middle-aged and elderly people.

目的：探讨LINC00958/血管内皮生长因子C（VEGF-C）信号通路在宫颈癌的淋巴管生成和淋巴转移中的作用。方法：从2020年9月至2022年9月期间在河南省人民医院接受手术的患者中收集了42例宫颈癌组织标本，通过qPCR检测宫颈癌组织和宫颈癌细胞（Hela、C33A、SiHa、Caski）中LINC00958的表达情况。将LINC00958过表达载体（LINC00958组）或对照载体（CMV组）转染Caski细胞，敲减LINC00958（shLINC00958组）、VEGF-C（shVEGF-C组）的shRNA序列或阴性对照shRNA（shNC组）转染SiHa细胞。分别通过CCK-8法、Transwell实验检测过表达或敲减LINC00958对宫颈癌细胞增殖、迁移和侵袭的影响。观察转染后细胞的培养上清液对人淋巴管内皮细胞（HLEC）淋巴管形成能力的影响。建立小鼠腘淋巴结转移模型，观察过表达LINC00958或同时敲减VEGF-C对宫颈癌淋巴结转移的影响。结果：LINC00958在宫颈癌组织中呈高表达（P<0.001），高水平的LINC00958与大肿瘤、晚期肿瘤分级、浸润深度和淋巴转移有关联（P<0.05或P<0.01）。与正常人宫颈上皮细胞ende1617相比，宫颈癌细胞中LINC00958水平均显著升高（P<0.01或P<0.001）。shLINC00958组SiHa细胞的增殖、迁移、侵袭能力及其培养上清液的促HLEC淋巴管形成能力均显著低于shNC组（P<0.05、P<0.01或P<0.001），LINC00958组Caski细胞的增殖、迁移、侵袭能力及其培养上清液的促HLEC淋巴管形成能力显著高于CMV组（P<0.05、P<0.01或P<0.001）。通过RNA下拉、RNA免疫沉淀实验发现宫颈癌细胞中LINC00958能够特异性结合VEGF-C。LINC00958+shVEGF-C组Caski细胞的增殖、迁移、侵袭能力及其培养上清液的促淋巴管形成能力显著低于LINC00958组（P<0.01或P<0.001）；在小鼠腘淋巴结转移模型中，LINC00958+shVEGF-C组中小鼠腘窝淋巴结的体积和VEGF-C蛋白、N-cadherin蛋白以及LYVE-1的阳性细胞比例均显著低于LINC00958组（均P<0.001）。结论：LINC00958通过直接与VEGF-C蛋白相互作用增强宫颈癌细胞的增殖、侵袭、淋巴管生成能力，促进小鼠腘淋巴结转移模型的淋巴结转移。

Benign prostatic hyperplasia(BPH)is one of the major chronic complications of type 2 diabetes mellitus(T2DM),and sex steroid hormones are common risk factors for the occurrence of T2DM and BPH.The profiles of sex steroid hormones are simultaneously quantified by LC-MS/MS in the clinical serum of patients,including simple BPH patients,newly diagnosed T2DM patients,T2DM complicated with BPH patients and matched healthy individuals.The G protein-coupled estrogen receptor(GPER)inhibitor G15,GPER knockdown lentivirus,the YAP1 inhibitor verteporfin,YAP1 knockdown/overexpression lentivirus,targeted metabolomics analysis,and Co-IP assays are used to investigate the molecular mechanisms of the disrupted sex steroid hormones homeostasis in the pathological process of T2DM complicated with BPH.The homeostasis of sex steroid hormone is disrupted in the serum of patients,accompanying with the proliferated prostatic epithelial cells(PECs).The sex steroid hormone metabolic profiles of T2DM patients complicated with BPH have the greatest degrees of separation from those of healthy individuals.Elevated 17β-estradiol(E2)is the key contributor to the disrupted sex steroid hormone homeostasis,and is significantly positively related to the clinical characteristics of T2DM patients complicated with BPH.Activating GPER by E2 via Hippo-YAP1 signaling exacerbates high glucose(HG)-induced PECs prolifer-ation through the formation of the YAP1-TEAD4 heterodimer.Knockdown or inhibition of GPER-mediated Hippo-YAP1 signaling suppresses PECs proliferation in HG and E2 co-treated BPH-1 cells.The anti-proliferative effects of verteporfin,an inhibitor of YAP1,are blocked by YAP1 overexpression in HG and E2 co-treated BPH-1 cells.Inactivating E2/GPER/Hippo/YAP1 signaling may be effective at delaying the progression of T2DM complicated with BPH by inhibiting PECs proliferation.

Objective:To analyze the evaluation of the application effect and deficiency of nurses acting as standardized parents in the graduation examination of standardized residency training of pediatrics and further improve and promote the level of standardized parents.Methods:A questionnaire survey was used to collect the scores of nurse standardized parents by students and examiners who took part in the graduation examination of standardized residency training of pediatrics in 2021. And the self-evaluation scores of standardized parents were collected. Counting data were represented by the number of cases and composition ratio. A Chi-square test was used to compare the rates.Results:A total of 125 questionnaires from students and 37 questionnaires from nurse standardized parents were collected, and the overall satisfaction (very satisfied + satisfied) of standardized parents reached 121 (96.80%). In the three dimensions of simulation ability, compliance with question-and-answer rules, and simulated attitude, students believed that the consistency between standardized parents and actual parents in simulated altitude was lower than that in the simulation ability and compliance with question-and-answer rules ( P=0.007, P=0.001). The overall satisfaction of standardized parents (very satisfied + satisfied) reached 87.38% (388/444). There were 26 (70.27%) nurse standardized parents who had the lowest satisfaction with their own performance ability, followed by 28 (75.68%) cases of imitation ability and 30 (81.08%) cases of adaptability. Conclusions:It is feasible to adopt nurse standardized parents in the assessment of standardized residency training of pediatrics, and both students and examiners have higher satisfaction. The next step is to improve the training of nurses standardized parents in the attitude of simulation and, at the same time, enhance the training of imitation ability and adaptability, so as to further expand the construction of standardized parents.