ObjectiveTo observe the intervention effect of Fufang Kangjiaolv capsules on anxiety-like behaviors in the rat model of chronic restraint stress （CRS） and explore the mechanism underlying the anti-anxiety effect via the microbiota-gut-brain axis. MethodsRats were assigned into blank， model， positive drug （diazepam， 1 mg·kg^-1）， and low-， medium-， and high-dose （0.75， 1.5， 3 g·kg^-1， respectively） Fufang Kangjiaolv capsules groups. After 14 days of administration， the elevated plus maze test， open field test， light and dark box test， and marble burying test were performed. Hematoxylin-eosin staining was employed to observe the pathological changes in the hippocampus and colon of rats， and Nissl staining was conducted to observe the damage of hippocampal neurons. The gut microbiota was analyzed by 16S rRNA gene sequencing. Real-time fluorescence quantitative polymerase chain reaction （Real-time PCR） was employed to determine the mRNA levels of zonula occludens-1 （ZO-1） and occludin in the colon of rats. The levels of tumor necrosis factor-α （TNF-α）， interleukin-6 （IL-6）， and interleukin-1β （IL-1β） in the colon， serum， and hippocampus were determined by enzyme-linked immunosorbent assay. Western blot was employed to determine the protein levels of ZO-1， occludin， nuclear factor-κB p65 （NF-κB p65） in the colon tissue and NF-κB p65 and brain-derived neurotrophic factor （BDNF） in the hippocampal tissue. ResultsCompared with the blank group， the model group showed reductions in the time and frequency ratio of rats entering the elevated plus maze， the time and frequency of rats entering the central area of the open field， the time of entering the open box， the times of passing through the light and dark box， and the number of unburied beads （P<0.05， P<0.01）. Compared with the model group， Fufang Kangjiaolv capsules ameliorated the anxiety of the model rats to varying degrees， and the high-dose group had the best effect， with increases in the proportions of time and frequency of rats entering the open arm in the elevated plus maze （P<0.05）， the number of rats entering the central area in the open field （P<0.05）， the time of entering the open box， the times of passing through the light and dark boxes， and the number of unburied beads （P<0.01）. Moreover， the high-dose group showed alleviated pathological damage of hippocampal neurons and colon. The results of 16S rRNA gene sequencing showed that the model group had increased relative abundance of Firmicutes， Deferribacterota， Romboutsia， and Phascolarctobacterium， while it had decreased relative abundance of Bavcteroidota and Lactobacillus. The drug administration groups showed increased relative abundance of Bavcteroidota， Bacteroides， norank f norank o Clostridia UCG-014， and Blautia and decreased relative abundance of Firmicutes and Deferribacterota. Compared with the blank group， the model group showed down-regulated protein and mRNA levels of ZO-1 and occludin in the colon （P<0.01）， elevated levels of TNF-α， IL-6， and IL-β in the colon， serum， and hippocampus （P<0.01）， up-regulated protein level of NF-κB p65 in the colon and hippocampus （P<0.01）， and down-regulated protein level of BDNF in the hippocampus （P<0.05）. Compared with the model group， high-dose Fufang Kangjiaolv capsules up-regulated the mRNA levels of ZO-1 and occludin in the colon （P<0.01）， lowered the levels of TNF-α， IL-6， and IL-β in the colon， serum， and hippocampus （P<0.01）， up-regulated the protein levels of ZO-1 （P<0.01） and occludin （P<0.05） in the colon， down-regulated the protein level of NF-κB p65 in the colon and hippocampus （P<0.05）， and up-regulated the protein level of BDNF in the hippocampus. ConclusionFufang Kangjiaolv capsules can reduce the anxiety-like behaviors in the rat model of CRS by regulating the gut microbiota disturbance， up-regulating the expression of tight junction proteins in the colon， repairing intestinal mucosal mechanical barrier， and down-regulating NF-κB/BDNF signaling pathway， thereby reducing peripheral and central inflammation. This study proves the hypothesis that Fufang Kangjiaolv capsules play an anti-anxiety role via the microbiota-gut-brain axis， providing a new idea for further research.

ObjectiveTo explore the clinical safety of Feilike Mixture （FLK） in the real world. MethodsThe safety of all children who received FLK from 29 institutions in 12 provinces between January 21，2021 and December 25，2021 was evaluated through prospective centralized surveillance and a nested case control study. ResultsA total of 3 035 juveniles were included. There were 29 research centers involved，which are distributed across 12 provinces，including one traditional Chinese medicine （TCM） hospital and 28 general hospitals. The average age among the juveniles was （4.77±3.56） years old，and the average weight was （21.81±12.97） kg. Among them，119 cases （3.92%） of juveniles had a history of allergies. Acute bronchitis was the main diagnosis for juveniles，with 1 656 cases （54.46%）. FLK was first used in 2 016 cases （66.43%），and 142 juvenile patients had special dosages，accounting for 4.68%. Among them，92 adverse drug reactions （ADRs） occurred，including 73 cases of gastrointestinal system disorders，10 cases of metabolic and nutritional disorders，eight cases of skin and subcutaneous tissue diseases，two cases of vascular and lymphatic disorders，and one case of systemic diseases and various reactions at the administration site. The manifestations of ADRs were mainly diarrhea，stool discoloration，and vomiting，and no serious ADRs occurred. The results of multi-factor analysis indicated that special dosages （the use of FLK）［odds ratio （OR） of 2.642， 95% confidence interval （CI） of 1.105-6.323］，combined administration： spleen aminopeptide （OR of 4.978， 95%CI of 1.200-20.655），and reason for combined administration： anti-infection （OR of 1.814， 95%CI of 1.071-3.075） were the risk factors for ADRs caused by FLK. Conclusion92 ADRs occurred among 3 035 juveniles using FLK. The incidence of ADRs caused by FLK was 3.03%，and the severity was mainly mild or moderate. Generally，the prognosis was favorable after symptomatic treatment such as drug withdrawal or dosage reduction，suggesting that FLK has good clinical safety.

[摘 要] 可变剪接是转录后水平的基因表达调控机制，也是导致真核生物转录组和蛋白质组多样性的重要途径。然而，可变剪接的异常是驱动肿瘤进展的重要推手。在肿瘤微环境中，肿瘤细胞、免疫细胞及肿瘤中其他类型细胞中mRNA的异常剪接，不仅参与塑造肿瘤细胞的恶性生物学行为和免疫逃逸，还促进支持肿瘤进展的免疫抑制性微环境的形成。靶向肿瘤相关剪接体组分、剪接调控因子、可变剪接产生的蛋白异构体和mRNA变异体，以及异常可变剪接产生的肿瘤新抗原已成为肿瘤治疗的新策略，已有基于可变剪接的肿瘤生物治疗项目进入到Ⅰ期临床研究阶段。基于可变剪接的肿瘤治疗面临安全性、长读测序和算法优化、核酸类药物递送等许多尚待解决的科学和技术问题，这些挑战的解决将为精准筛选肿瘤相关靶点和高免疫原性新抗原，突破传统疗法耐药瓶颈，增强免疫检查点阻断和CAR-T细胞等疗效提供新策略，开辟新领域。

Poly(ADP-ribosyl)ation (PARylation) is a specific form of post-translational modification (PTM) predominantly triggered by the activation of poly-ADP-ribose polymerase 1 (PARP1). However, the role and mechanism of PARylation in the advancement of acute kidney injury (AKI) remain undetermined. Here, we demonstrated the significant upregulation of PARP1 and its associated PARylation in murine models of AKI, consistent with renal biopsy findings in patients with AKI. This elevation in PARP1 expression might be attributed to trimethylation of histone H3 lysine 4 (H3K4me3). Furthermore, a reduction in PARylation levels mitigated renal dysfunction in the AKI mouse models. Mechanistically, liquid chromatography-mass spectrometry indicated that PARylation mainly occurred in receptor for activated C kinase 1 (RACK1), thereby facilitating its subsequent phosphorylation. Moreover, the phosphorylation of RACK1 enhanced its dimerization and accelerated the ubiquitination-mediated hypoxia inducible factor-1α (HIF-1α) degradation, thereby exacerbating kidney injury. Additionally, we identified a PARP1 proteolysis-targeting chimera (PROTAC), A19, as a PARP1 degrader that demonstrated superior protective effects against renal injury compared with PJ34, a previously identified PARP1 inhibitor. Collectively, both genetic and drug-based inhibition of PARylation mitigated kidney injury, indicating that the PARylated RACK1/HIF-1α axis could be a promising therapeutic target for AKI treatment.

Cemental tear is a rare and indetectable condition unless obvious clinical signs present with the involvement of surrounding periodontal and periapical tissues. Due to its clinical manifestations similar to common dental issues, such as vertical root fracture, primary endodontic diseases, and periodontal diseases, as well as the low awareness of cemental tear for clinicians, misdiagnosis often occurs. The critical principle for cemental tear treatment is to remove torn fragments, and overlooking fragments leads to futile therapy, which could deteriorate the conditions of the affected teeth. Therefore, accurate diagnosis and subsequent appropriate interventions are vital for managing cemental tear. Novel diagnostic tools, including cone-beam computed tomography (CBCT), microscopes, and enamel matrix derivatives, have improved early detection and management, enhancing tooth retention. The implementation of standardized diagnostic criteria and treatment protocols, combined with improved clinical awareness among dental professionals, serves to mitigate risks of diagnostic errors and suboptimal therapeutic interventions. This expert consensus reviewed the epidemiology, pathogenesis, potential predisposing factors, clinical manifestations, diagnosis, differential diagnosis, treatment, and prognosis of cemental tear, aiming to provide a clinical guideline and facilitate clinicians to have a better understanding of cemental tear.
Humans ; Dental Cementum/injuries* ; Consensus ; Diagnosis, Differential ; Cone-Beam Computed Tomography ; Tooth Fractures/therapy*

Ursodeoxycholic acid (UDCA) is a naturally occurring, low-toxicity, and hydrophilic bile acid (BA) in the human body that is converted by intestinal flora using primary BA. Solute carrier family 7 member 11 (SLC7A11) functions to uptake extracellular cystine in exchange for glutamate, and is highly expressed in a variety of human cancers. Retroperitoneal liposarcoma (RLPS) refers to liposarcoma originating from the retroperitoneal area. Lipidomics analysis revealed that UDCA was one of the most significantly downregulated metabolites in sera of RLPS patients compared with healthy subjects. The augmentation of UDCA concentration (≥25 μg/mL) demonstrated a suppressive effect on the proliferation of liposarcoma cells. [¹⁵N₂]-cystine and [¹³C₅]-glutamine isotope tracing revealed that UDCA impairs cystine uptake and glutathione (GSH) synthesis. Mechanistically, UDCA binds to the cystine transporter SLC7A11 to inhibit cystine uptake and impair GSH de novo synthesis, leading to reactive oxygen species (ROS) accumulation and mitochondrial oxidative damage. Furthermore, UDCA can promote the anti-cancer effects of ferroptosis inducers (Erastin, RSL3), the murine double minute 2 (MDM2) inhibitors (Nutlin 3a, RG7112), cyclin dependent kinase 4 (CDK4) inhibitor (Abemaciclib), and glutaminase inhibitor (CB839). Together, UDCA functions as a cystine exchange factor that binds to SLC7A11 for antitumor activity, and SLC7A11 is not only a new transporter for BA but also a clinically applicable target for UDCA. More importantly, in combination with other antitumor chemotherapy or physiotherapy treatments, UDCA may provide effective and promising treatment strategies for RLPS or other types of tumors in a ROS-dependent manner.

Objective To explore and establish the bacterial endotoxin limit value and testing method of the active pharmaceutical ingredient （API） of pentetic acid, and conduct methodological investigation. Methods Three batches of pentetic acid were used to establish the method for the determination of bacterial endotoxin, and interference test was conducted simultaneously. The sample was dissolved with commercially available alkaline regulator to a concentration of 4 mg/ml or lower, and then diluted with water for bacterial endotoxin test. Limulus reagent with sensitivity of 0.125 EU/ml or higher was selected and redissolved with commercially available magnesium ion buffer solution. And the endotoxin test was performed by gel method. Results The endotoxin limit of API of pentetic acid was determined as: less than 0.125 EU/mg. Conclusion The method established could be used for the control of bacterial endotoxin in API of pentetic acid.

Objective Exploring the antidiarrhea effect of new Ershen pills composed of nutmeg koji based on the spleen and kidney yang deficiency diarrhea mouse model.Methods KM mice were randomly divided into normal,model,Ershen pills Ⅰ(salt psoralen+bran-stewed nutmeg),Ershen pills Ⅱ(salt psoralen+nutmeg koji),Ershen pills Ⅲ(salt psoralen+nutmeg raw product),salt psoralen,and nutmeg koji groups.The combined modeling method of hydrocortisone+senna leaf was used to establish the diarrhea mouse model with spleen-kidney yang deficiency.General signs and pathological changes of each organ were observed.Various organ indexes,the small intestine propulsion rate,gastric residual rate,serum motilin(MTL),gastrin(GAS),adrenal ketone(CORT),thyroid stimulating hormone(TSH),testosterone(T),tumor necrosis factor-α(TNF-α),and interleukin 1β(IL-1β)were assessed.16S rDNA sequencing and data analysis were conducted for fecal microorganisms.Results After modeling,compared with the normal group,the weight and activity of mice in the model group were reduced,the small intestine propulsion rate was significantly increased,the gastric residual rate and organ indexes were significantly decreased,serum GAS,CORT,TSH,and T levels were significantly decreased,MTL,TNF-α,and IL-1β levels were significantly increased,and intestinal flora species diversity was decreased.After administration,the above indexes and symptoms were improved by various degrees in each administration group,and the Ershen pills Ⅱ group was better than Ershen pills Ⅰ,Ershen pills Ⅲ,salt-psoralea,and nutmeg koji groups.Conclusions Combined use of nutmeg koji and salt psoralen has a remarkable effect on diarrhea of spleen-kidney yang deficiency.Fermented nutmeg reduces its toxicity risk and enhances its effect of warming the spleen and preventing diarrhea,which facilitates the development of nutmeg koji.

Objective To summarize the medication law of TCM in the treatment of chronic bronchitis;To provide reference for clinical medication.Methods Medical records of patients with chronic bronchitis who were hospitalized in the Respiratory Department of the First Affiliated Hospital of Henan University of Chinese Medicine from January 1,2016 to December 31,2021 were extracted based on HIS electronic medical record data.After screening,the TCM prescriptions used by patients with chronic bronchitis were input into Excel 2019 to establish a database.Based on the software Lantern 5.0,the latent structure model was learned,hidden variables and explicit variables were obtained,and the model was interpreted.SPSS Modeler 18.0 was used to establish model points with Apriori algorithm for Chinese materia medica with a frequency greater than 6%,to obtain the association rules between drugs,and to analyze the medication law of TCM in treating chronic bronchitis.Results A total of 3 410 cases were included,involving 423 kinds of Chinese materia medica,with a cumulative frequency of 82 766 times.Among them,109 kinds of Chinese materia medica with a frequency of>6 % had a cumulative frequency of 69 845 times.The top five commonly used medicines were Fritillariae Cirrhosae Bulbus,Poria,Atractyodis Macrocephalae Rhizoma,Asteris Radix et Rhizoma,Citri Reticulatae Pericarpium,mainly with medicines of reducing cough and phlegm,antiasthmatic medicine,tonifying deficiency,clearing heat,relieving superficies,promoting blood circulation and removing blood stasis.The medicinal properties were warming,cold and mild,and the main tastes were bitter,sweet and pungent,and the meridians were mainly lung,spleen,liver and stomach meridians.Through analysis of latent structure,49 hidden variables and 149 hidden classes were obtained.Combined with professional knowledge,10 comprehensive clustering models and 21 core formulas were deduced,such as Sangbaipi Decoction,Xuefu Zhuyu Decoction,Xiaoqinglong Decoction,Erchen Decoction,Shashen Maidong Decoction,Liuwei Dihuang Pills,Yinqiao Powder,Zhisou Powder,Yupingfeng Powder,Xuefu Zhuyu Decoction combined with Daotan Decoction,etc.It was concluded that the chronic bronchitis syndrome included phlegm-heat stagnation lung syndrome,qi stagnation blood stasis syndrome,cold fluid attacking lung syndrome,phlegm-dampness accumulation lung syndrome,lung qi and yin deficiency syndrome,kidney yin deficiency syndrome,wind heat attacking lung syndrome,wind cold attacking lung syndrome,lung qi and spleen deficiency syndrome,phlegm stasis interjunction syndrome.A total of 41 strong association rules were screened in the analysis of association rules,including 5 strong association rules for two and 36 strong association rules for three.The high confidence rules were Saposheikovize Radix + Angelicae Sinensis Radix →Atractyodis Macrocephalae Rhizoma,Saposheikovize Radix + Codonopsis Radix → Atractyodis Macrocephalae Rhizoma,Codonopsis Radix + Citri Reticulatae Pericarpium → Atractyodis Macrocephalae Rhizoma;the higher degree of improvement were Bupleuri Radix + Mori Cortex → Scutellariae Radix,Perillae Fructus + Belamcandae Rhizoma → Fritillariae Cirrhosae Bulbus,Armeniacae Semen Amarum + Pinelliae Rhizoma → Citri Reticulatae Pericarpium,etc.Conclusion In the treatment of chronic bronchitis,TCM is mainly used to reduce phlegm,relieve cough and asthma,and the method of promoting blood circulation and removing blood stasis is commonly used to help eliminate phlegm.In addition,TCM pays attention to the application of methods such as tonifying lung and securing the exterior,invigorating spleen and benefiting qi.

Objective:To investigate the regulative effects of Streptococcus mutans (Sm) antisense vicK RNA (ASvicK) on the multi-species biofilm formed by three common oral streptococci (Sm, Streptococcus sanguinis, and Streptococcus gordonii) (Sm+Ss+Sg). Methods:ASvicK over-expression strain was constructed by using a recombinant plasmid, and three-species biofilm UA159+Ss+Sg and ASvicK+Ss+Sg were cultured. The phenotypes of biofilms were detected by scanning electron microscopy (SEM). Crystal violet (CV) assay was used to detect biofilm biomass. Lactate kit and anthrone-sulfuric acid colorimetric assay were used to determine the abilities of lactic acid and exopolysaccharides production, respectively. The proportions of three-species and expression levels of the cariogenic-related genes in biofilms were detected by TaqMan fluorescence quantitative PCR and real-time fluorescence quantitative PCR. A biofilm demineralization model of human enamel slabs was further constructed, and the hardness of enamel surface was detected.Results:Compared to UA159+Ss+Sg, over-expression of ASvicK could inhibit biofilm formation and lactic acid production in ASvicK+Ss+Sg biofilm significantly decreased by 78.93% ( P<0.001) and 62.23% ( P<0.001), respectively. With ASvicK over-expression, the amounts of water-insoluble and-soluble glucoses in ASvicK+Ss+Sg biofilm were reduced respectively by 39.13% ( P<0.001) and 68.00% ( P<0.001). Compared to the UA159+Ss+Sg Group, the proportion of Sm, the cariogenic bacteria, showed 33.00% reduction ( P<0.01) in Sm+Ss+Sg biofilm, and the gene expressions of cariogenic-relative genes vicK/X, gtfB/C/D, and ftf significantly decreased ( P<0.05). The micro-hardness value of enamel slabs after demineralization by ASvicK+Ss+Sg biofilm was significantly increased to 183.84% ( P<0.001). Conclusions:ASvicK over-expression could reduce the Sm proportion and weaken the cariogenicity of oral Streptococcus biofilm, thereby possibly slowing down the progression of caries.