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.].

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*

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.

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

Substantial progress in the use of chemo-photodynamic nano-drug delivery systems (nano-DDS) for the treatment of the malignant breast cancer has been achieved. The inability to customize precise nanostructures, however, has limited the therapeutic efficacy of the prepared nano-DDS to date. Here, we report a structurally defined tandem-responsive chemo-photosensitive co-nanoassembly to eliminate primary breast tumor and prevent lung metastasis. This both-in-one co-nanoassembly is prepared by assembling a biocompatible photosensitive derivative (pheophorbide-diphenylalanine peptide, PPA-DA) with a hypoxia-activated camptothecin (CPT) prodrug [(4-nitrophenyl) formate camptothecin, N-CPT]. According to computational simulations, the co-assembly nanostructure is not the classical core-shell type, but consists of many small microphase regions. Upon exposure to a 660 nm laser, PPA-DA induce high levels of ROS production to effectively achieve the apoptosis of normoxic cancer cells. Subsequently, the hypoxia-activated N-CPT and CPT spatially penetrate deep into the hypoxic region of the tumor and suppress hypoxia-induced tumor metastasis. Benefiting from the rational design of the chemo-photodynamic both-in-one nano-DDS, these nanomedicines exhibit a promising potential in the inhibition of difficult-to-treat breast tumor metastasis in patients with breast cancer.

Objective:To study the incidence, clinical features and genetic mutation profiles of neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) using screening strategy.Methods:From September 2015 to September 2020, neonates in Xuzhou area were prospectively screened for genetic metabolic diseases using tandem mass spectrometry. Suspected infants were further confirmed using urinary organic acid test and SLC25A13 gene mutation analysis. The clinical manifestations, biochemical and gene mutation results, treatment and prognosis of the confirmed cases were analyzed.Results:A total of 468,494 live-birth newborns were screened with 112 cases suspected and 95 cases received urinary organic acid test and SLC25A13 gene mutation analysis. 13 cases of NICCD were diagnosed with a prevalence of 1/36,038. Most confirmed cases presented with delayed disappearance of neonatal jaundice, feeding difficulties and poor weight gain. Biochemical changes included increased bile acid, abnormal liver enzymes, increased alpha-fetoprotein, hypoglycemia, decreased hemoglobin, abnormal coagulation function and increased blood ammonia. Tandem mass spectrometry showed increased citrulline, methionine, arginine, tyrosine and phenylalanine, and in some cases with slightly increased acylcarnitine. Urine organic acid analysis mainly showed increased 4-hydroxyphenyllactic acid and 4-hydroxyphenylpyruvate. All confirmed cases received genetic mutation tests and a total of 13 mutation loci were detected, including c.852_855delTATG, c.511dupG, c.1638_1660dup, IVS16ins3kb, c.1078C>T, c. 615+5G>A, c.742G>A, c.44G>A, c.1311+1G>A, c.1399C>T, c.889G>T, c.1177+1G>A, c.1841+3_1841+4del, among which, c.852_855delTATG was the most common one. A total of 5 novel mutation loci were discovered in this study with c.1841+3_1841+4del, c.511dupG and c.889G>T predicted as pathogenic variants. Special formula of lactose-free and fortified medium-chain triglyceride (MCT) were used in confirmed cases and most of the symptoms were relieved within 1 year and abnormal indicators significantly improved.Conclusions:The prevalence of NICCD in Xuzhou was 1/36,038. c.852_855delTATG mutation is the most frequent one. Five novel mutation loci are discovered, expanding the SLC25A13 gene mutation spectrum. Most infants with NICCD have a good prognosis, requiring early diagnosis, treatment and life-long follow-up.

Objective:To study the clinical features and genetic characteristics of isobutyryl-CoA dehydrogenase deficiency (IBDD) of neonates in Xuzhou area.Methods:From October 2016 to October 2021, neonates diagnosed with IBDD using tandem mass spectrometry in Xuzhou area were retrospectively studied. Their clinical phenotypes and genotypes, clinical diagnosis, treatment and follow-up were analyzed.Results:A total of 510 057 neonates were screened and 10 cases of IBDD were diagnosed. The 10 IBDD cases showed increased butyryl carnitine (C4), C4/C2 and C4/C3 during screening and follow-up tests. One case had transient elevated transaminase and one case showed delayed language development. The other 8 cases were otherwise normal. A total of 16 mutation loci of acyl-CoA dehydrogenase 8 (ACAD8) gene were found, including 10 unreported loci: c.567+8C>T, c.213G>T, c.553C>T, c.1190T>C, c.1060G>A, c.494G>A, c.771C>A, c.962A>T, c.715A>G and c.731G>A. Genetic mutations were found in Exon 3, Exon 4, Exon 5, Intron 5, Exon 7, Exon 9 and Exon 10. The hot spots of mutations were c.1176G>T, c. 286G>A and c.1000C>T.Conclusions:IBDD is a rare disease without specific clinical manifestations. Neonatal metabolic disease screening combined with urinary organic acid tests and genetic sequencing can be used for early detection and diagnosis of IBDD. No serious adverse outcome is found in IBDD patients during short-term follow-up, however, long-term follow-up is recommended.

Objective:To establish a disease risk prediction model for the newborn screening system of inherited metabolic diseases by artificial intelligence technology.Methods:This was a retrospectively study. Newborn screening data ( n=5 907 547) from February 2010 to May 2019 from 31 hospitals in China and verified data ( n=3 028) from 34 hospitals of the same period were collected to establish the artificial intelligence model for the prediction of inherited metabolic diseases in neonates. The validity of the artificial intelligence disease risk prediction model was verified by 360 814 newborns ' screening data from January 2018 to September 2018 through a single-blind experiment. The effectiveness of the artificial intelligence disease risk prediction model was verified by comparing the detection rate of clinically confirmed cases, the positive rate of initial screening and the positive predictive value between the clinicians and the artificial intelligence prediction model of inherited metabolic diseases. Results:A total of 3 665 697 newborns ' screening data were collected including 3 019 cases ' positive data to establish the 16 artificial intelligence models for 32 inherited metabolic diseases. The single-blind experiment ( n=360 814) showed that 45 clinically diagnosed infants were detected by both artificial intelligence model and clinicians. A total of 2 684 cases were positive in tandem mass spectrometry screening and 1 694 cases were with high risk in artificial intelligence prediction model of inherited metabolic diseases, with the positive rates of tandem 0.74% (2 684/360 814)and 0.46% (1 694/360 814), respectively. Compared to clinicians, the positive rate of newborns was reduced by 36.89% (990/2 684) after the application of the artificial intelligence model, and the positive predictive values of clinicians and artificial intelligence prediction model of inherited metabolic diseases were 1.68% (45/2 684) and 2.66% (45/1 694) respectively. Conclusion:An accurate, fast, and the lower false positive rate auxiliary diagnosis system for neonatal inherited metabolic diseases by artificial intelligence technology has been established, which may have an important clinical value.

Objective:To investigate the value of rate-pressure product (RPP) in predicating the prognosis of postural tachycardia syndrome (POTS) in children.Methods:Fifty-three children (26 males and 27 females) aged 5 to 15 who had syncope of unknown reasons or presyncope and were diagnosed with POTS by head-up tilt test (HUTT) at the Children′s Syncope Specialist Clinic, the Second Xiangya Hospital, Central South University from April 2012 to May 2019 were selected as the POTS group.Thirty-eight children aged 5 to 16 (19 males and 19 females) who underwent medical examinations at the Children′s Health Specialist Clinic of the Second Xiangya Hospital, Central South University over the same period were enrolled as controls (control group). POTS children were followed up after intervention and they were divided into the response group ( n=40) and the non-response group ( n=13) according to the follow-up results.The products (RPP0, RPP5, RPP10) of the heart rate (HR0, HR5, HR10) and systolic blood pressure (SBP0, SBP5, SBP10) at baseline (HUTT 0 min), HUTT 5 min and HUTT 10 min were calculated.Statistical analysis was performed using SPSS 22.0 software and EmpowerStats software. Results:(1) There was no statistical difference in age and gender between the POTS group and the control group (all P> 0.05). (2) HR5 [(115.45±14.50) times/min vs.(95.79±13.89) times/min], HR10 [(120.57±16.13) times/min vs.(96.05±12.43) times/min], RPP5 (12 814.55±2 304.56 vs.10 371.42±1 910.20), and RPP10 (13 449.17±2 360.40 vs.10 523.18±1 771.48) in the POTS group were significantly higher than those in the control group( t=0.799, 7.842, 5.747, 6.446, all P<0.01). No statistical difference of HR0 and RPP0 was observed between the 2 groups (all P>0.05). (3) In the POTS group: HR5 [(98.73±12.43) times/min vs.(113.77±17.65) times/min], HR10 [(96.90±13.96) times/min vs.(119.08±13.52) times/min], RPP5 (11 125.45±1 952.35 vs.12 914.69±3 192.12) and RPP10 (10 819.58± 2 144.26 vs.13 375.46±2 807.01) in the response group were significantly lower than those in the non-response group( t=3.406, 5.012, 2.432, 3.455, all P<0.01). HR0 and RPP0 were no significantly different between the 2 groups(all P>0.05). (4) When SBP10<114 mmHg(1 mmHg= 0.133 kPa), the probability of response after POTS intervention increased by 10% with every 1 mmHg increase in SBP10, and there was a non-linear relationship between the 2 group ( P<0.05). (5) The receiver operating characteristic curve suggested that when RPP5 was 11 548.50, the sensitivity and specificity to predict the response after POTS intervention were 81.82% and 61.70%, respectively.When RPP10 was 10 988.00, the sensitivity and specificity were 77.78% and 86.21%, respectively. Conclusions:RPP is closely related to the intervention effect of POTS in children.RPP5 and RPP10 can predict the prognosis of POTS in children.There is a non-linear relationship between SBP10 and the intervention effect of POTS in children.