Cyclin-dependent kinase 9 (CDK9) is a member of the transcription CDK subfamily and plays a role in transcriptional regulation. Selective CDK9 degraders possess potent clinical advantages over reversible CDK9 inhibitors. Herein, we report the first ATG101-recruiting selective CDK9 degrader, AZ-9, based on the hydrophobic tag kinesin degradation technology. AZ-9 showed significant degradation effects and selectivity toward other homologous cell cycle CDKs in vitro and in vivo, which could also affect downstream related phenotypes. Mechanism research revealed that AZ-9 recruits ATG101 to initiate the autophagy-lysosome pathway, and forms autophagosomes through the recruitment of LC3, which then fuses with lysosomes to degrade CDK9 and the partner protein Cyclin T1. These dates validated the existence of non-proteasomal degradation pathway of hydrophobic driven protein degradation strategy for the first time, which might provide research ideas for chemical induction intervention on other types of pathogenic proteins.

[This corrects the article DOI: 10.1016/j.apsb.2021.08.008.].

BACKGROUND:There are many problems to completely transform clinical diseases into animal models,but the ideal animal model is the premise of the mechanism research of cervical spondylosis,and it is very important to select the appropriate animal model of cervical spondylosis.OBJECTIVE:To analyze the species,sex,age,type of cervical spondylosis model and its internal molecular mechanism of animal models of cervical spondylosis in detail so as to explore how to select suitable animal models for experimental research of cervical spondylosis.METHODS:PubMed,Medline,Embase,Web of Science,WanFang,VIP,and CNKI databases were searched with Chinese and English search terms"cervical spondylosis,cervical spondylotic myelopathy,cervical spondylotic radiculopathy,cervical spondylosis of vertebral artery type,neck type cervical spondylosis,unbalanced dynamic and static forces,joint injury,neck pain,animal model."According to the inclusion and exclusion criteria,the literature was screened,and finally 61 articles were included for review and analysis.RESULTS AND CONCLUSION:Rats are the most commonly used animals,and males seem to be more popular.It is recommended to use young adult animals.According to the characteristics of molding,cervical spondylosis models were divided into cervical spondylotic myelopath,cervical spondylotic radiculopathy,neck type cervical spondylosis,and other type cervical spondylosis.The advantages and disadvantages of various modeling methods were evaluated.Based on the studies of existing animal models,the molecular mechanism of cervical spondylosis was summarized.Therapeutic signals mediate nuclear factor-κB,phosphatidylinositol-3 kinase/protein kinase B,mitogen-activated protein kinase,and other pathways to regulate the biological processes of inflammation,apoptosis and autophagy of spinal cord,nerve root,intervertebral disc,muscle and other tissues,and ultimately delay the progression of cervical spondylosis.The quality of some studies is poor,and the clinical compatibility is not high.In the future,it is necessary to further standardize the animal model of cervical spondylosis,formulate relevant guidelines,improve the credibility of the research results,and lay a solid foundation for further human clinical trials.

BACKGROUND:There are many problems to completely transform clinical diseases into animal models,but the ideal animal model is the premise of the mechanism research of cervical spondylosis,and it is very important to select the appropriate animal model of cervical spondylosis.OBJECTIVE:To analyze the species,sex,age,type of cervical spondylosis model and its internal molecular mechanism of animal models of cervical spondylosis in detail so as to explore how to select suitable animal models for experimental research of cervical spondylosis.METHODS:PubMed,Medline,Embase,Web of Science,WanFang,VIP,and CNKI databases were searched with Chinese and English search terms"cervical spondylosis,cervical spondylotic myelopathy,cervical spondylotic radiculopathy,cervical spondylosis of vertebral artery type,neck type cervical spondylosis,unbalanced dynamic and static forces,joint injury,neck pain,animal model."According to the inclusion and exclusion criteria,the literature was screened,and finally 61 articles were included for review and analysis.RESULTS AND CONCLUSION:Rats are the most commonly used animals,and males seem to be more popular.It is recommended to use young adult animals.According to the characteristics of molding,cervical spondylosis models were divided into cervical spondylotic myelopath,cervical spondylotic radiculopathy,neck type cervical spondylosis,and other type cervical spondylosis.The advantages and disadvantages of various modeling methods were evaluated.Based on the studies of existing animal models,the molecular mechanism of cervical spondylosis was summarized.Therapeutic signals mediate nuclear factor-κB,phosphatidylinositol-3 kinase/protein kinase B,mitogen-activated protein kinase,and other pathways to regulate the biological processes of inflammation,apoptosis and autophagy of spinal cord,nerve root,intervertebral disc,muscle and other tissues,and ultimately delay the progression of cervical spondylosis.The quality of some studies is poor,and the clinical compatibility is not high.In the future,it is necessary to further standardize the animal model of cervical spondylosis,formulate relevant guidelines,improve the credibility of the research results,and lay a solid foundation for further human clinical trials.

Intestinal dysbiosis and disrupted bile acid(BA)homeostasis are associated with obesity,but the precise mechanisms remain insufficiently explored.Hepatic protein phosphatase 1 regulatory subunit 3G(PPP1R3G)plays a pivotal role in regulating glycolipid metabolism;nevertheless,its obesity-combatting potency remains unclear.In this study,a substantial reduction was observed in serum PPP1R3G levels in high-body mass index(BMI)and high-fat diet(HFD)-exposed mice,establishing a positive correlation between PPP1R3G and non-12α-hydroxylated(non-12-OH)BA content.Additionally,hepatocyte-specific overexpression of Ppp1r3g(PPP1R3G HOE)mitigated HFD-induced obesity as evidenced by reduced weight,fat mass,and an improved serum lipid profile;hepatic steatosis alleviation was confirmed by normalized liver enzymes and histology.PPP1R3G HOE considerably impacted systemic BA homeostasis,which notably increased the non-12-OH BAs ratio,particularly lithocholic acid(LCA).16S ribosomal DNA(16S rDNA)sequencing assay indicated that PPP1R3G HOE reversed HFD-induced gut dysbiosis by reducing the Firmicutes/Bacteroidetes ratio and Lactobacillus population,and elevating the relative abundance of Blautia,which exhibited a positive correlation with serum LCA levels.A fecal microbiome transplantation test confirmed that the anti-obesity effect of hepatic PPP1R3G was gut microbiota-dependent.Mechanistically,PPP1R3G HOE markedly suppressed hepatic cholesterol 7α-hydroxylase(CYP7A1)and sterol-12α-hydroxylase(CYP8B1),and concurrently upregulated oxysterol 7-α hydroxylase and Takeda G protein-coupled BA receptor 5(TGR5)expression under HFD conditions.Furthermore,LCA administration significantly mitigated the HFD-induced obesity phenotype and elevated non-12-OH BA levels.These findings emphasize the significance of hepatic PPP1R3G in ameliorating diet-induced adiposity and hepatic steatosis through the gut microbiota-BA axis,which may serve as potential ther-apeutic targets for obesity-related disorders.

Critical care medicine-related treatment is an interdisciplinary and multi-professional process,often leading to secondary or concomitant mental disorders in clinical practice.Currently,there is no consensus on the pharmacological treatment of related mental illnesses in China.The Chinese Society of Psychosomatic Medicine collaborated with the Critical Care Medicine expert group to form a consensus writing expert group.After a systematic review of relevant literature,summarizing published domestic and foreign literature,and extensive discussions,the consensus was developed.The consensus elaborates on the principles and processes of the standardized use of psychotropic drugs in critical care medicine,as well as the clinical indications,precautions,and specific drug selection of various psychiatric medications,providing feasible suggestions and guidance for the clinical application of psychiatric medications in the intensive care unit.

Oleanolic acid (OA), a pentacyclic triterpenoid, exhibits a broad spectrum of biological activities, including antitumor, antiviral, antibacterial, anti-inflammatory, hepatoprotective, hypoglycemic, and hypolipidemic effects. Since its initial isolation and identification, numerous studies have reported on the structural modifications and pharmacological activities of OA and its derivatives. Despite this, there has been a dearth of comprehensive reviews in the past two decades, leading to challenges in subsequent research on OA. Based on the main biological activities of OA, this paper comprehensively summarized the modification strategies and structure-activity relationships (SARs) of OA and its derivatives to provide valuable reference for future investigations into OA.
Oleanolic Acid ; Structure-Activity Relationship ; Anti-Inflammatory Agents/pharmacology* ; Triterpenes ; Anti-Bacterial Agents/pharmacology*

Humans ; Aripiprazole/therapeutic use* ; Schizophrenia/drug therapy* ; Antipsychotic Agents/therapeutic use* ; Risperidone ; China ; Treatment Outcome

Objective: To analyze the status of noise hazard in workplace of key industries in Guangdong Province. Methods: A total of 1 061 enterprises from 14 key industries in 21 prefecture-level cities in Guangdong Province were selected as the research subjects using stratified sampling method. The occupational health survey was carried out, and the noise intensity in the workplace was detected. Results: There were 12 606 workplaces and 5 570 work sites involved among 1 061 enterprises. The median and the 0-100th percentile value ［M (P₀-P₁₀₀)］ of noise intensity in workplace were 82.6 (46.5-112.6) dB(A), and 35.03% of the workplace exceeded the national noise intensity standard. The regions and industry with the highest rate of noise exceeded the national noise intensity standard in workplace were in the northern part of Guangdong and the stone processing industry respectively. The M (P₀-P₁₀₀) of noise intensity in the work sites was 83.7 (47.5-106.2) dB(A), and 36.00% of the work sites exceeded the national noise intensity standard. The regions and industry with the highest rate of noise exceeded the national noise intensity standard in work sites were in the Pearl River Delta region and the ferrous metal mining and dressing industry respectively. The rate of noise protection facilities setting was 66.45%, and the validity of personal protection was 61.73%. The occupational medical examination was performed in 73.24% of the research subjects, and 3.25% of the result was abnormal. The industry with the highest occupational medical examination rate was nonferrous metal smelting and rolling processing, and the industry with the highest abnormal rate of occupational medical examination was stone processing industry. Conclusion: Noise hazards in workplaces of key industries in Guangdong Province are relatively severe, necessitating strengthened supervision and management, noise control measures, and efforts to reduce noise exposure levels in workplaces and work sites.

Objective To investigate the level of finger systolic blood pressure (FSBP) in healthy young adults. Methods A total of 28 healthy young adults were selected as the study subjects by convenient sampling method. The FSBP of the study subjects was detected at 30 and 10 ℃, and the FSBP index (F_i) was calculated. Results The FSBP of the study subjects at 30 and 10 ℃ were (102.0±16.5) and (104.4±15.2) mmHg, respectively. The FSBP in male group at 30 and 10 ℃ was (99.6±18.6) and (107.2±17.0) mmHg, respectively. The FSBP in female group at 30 and 10 ℃ was (104.4±13.9) and (101.5±2.8) mmHg, respectively. The results of factorial analysis showed that the interaction between gender and temperature on FSBP was statistically significant (P<0.05). FSBP in male group was higher at 10 than 30 ℃ (P<0.05) and higher than female group at 10 ℃ (P<0.05). There was no statistical significance for the main effect of gender, temperature, finger, or the interaction effect of gender and finger, temperature and finger for FSBP (all P>0.05). The average F_i of the study subjects was (98.0±16.6)%, with males and females having the average F_i of (100.7±20.7) % and (95.2±10.6) % respectively. The results of factorial analysis of variance showed that there was no significant difference on F_i in the main effect gender and fingers or the interaction effect between them(all P>0.05). Conclusion The FSBP test could be used as a detection method for assessing peripheral microcirculation function in Chinese population. However, further research is needed to establish reference ranges and influencing factors.