Cancer is characterized by abnormal cell proliferation. Cyclins and cyclin-dependent kinases (CDKs) have been recognized as essential regulators of the intricate cell cycle, orchestrating DNA replication and transcription, RNA splicing, and protein synthesis. Dysregulation of the CDK pathway is prevalent in the development and progression of human cancers, rendering cyclins and CDKs attractive therapeutic targets. Several CDK4/6 inhibitors have demonstrated promising anti-cancer efficacy and have been successfully translated into clinical use, fueling the development of CDK-targeted therapies. With this enthusiasm for finding novel CDK-targeting anti-cancer agents, there have also been exciting advances in the field of targeted protein degradation through innovative strategies, such as using proteolysis-targeting chimera, heat shock protein 90 (HSP90)‍-mediated targeting chimera, hydrophobic tag-based protein degradation, and molecular glue. With a focus on the translational potential of cyclin- and CDK-targeting strategies in cancer, this review presents the fundamental roles of cyclins and CDKs in cancer. Furthermore, it summarizes current strategies for the proteasome-dependent targeted degradation of cyclins and CDKs, detailing the underlying mechanisms of action for each approach. A comprehensive overview of the structure and activity of existing CDK degraders is also provided. By examining the structure‍‒‍activity relationships, target profiles, and biological effects of reported cyclin/CDK degraders, this review provides a valuable reference for both CDK pathway-targeted biomedical research and cancer therapeutics.
Humans ; Neoplasms/metabolism* ; Cyclin-Dependent Kinases/antagonists & inhibitors* ; Cyclins/metabolism* ; Proteolysis ; Antineoplastic Agents/pharmacology* ; Molecular Targeted Therapy ; Proteasome Endopeptidase Complex/metabolism* ; Animals

Abstract Alzheimer′s disease(AD) is a common neurodegenerative disease. It has been found that AD is related to various pathogenic factors such as genetics, cardiovascular and cerebrovascular disease, and excessive phosphorylation of tau protein. However, no definitive conclusions on its pathogenesis have been reached. In this paper, the research progress on the pathogenesis of AD inC.elegansmodel and the therapeutic effects of traditional Chinese medicine extracts on AD are reviewed, providing a basis for further research on the alleviating effects of Chinese medicine extracts on AD.

Objective To investigate the epidemiological characteristics and mutation spectrum of monogenic diseases in Chinese population through a large-scale,multicenter carrier screening.Methods This study was conducted among a total of 33 104 participants(16 610 females)from 12 clinical centers across China.Carrier status for 223 genes was analyzed using high-throughput sequencing and different PCR methods.Results The overall combined carrier frequency was 55.58%for 197 autosomal genes and 1.84%for 26 X-linked genes in these participants.Among the 16 669 families,874 at-risk couples(5.24%)were identified.Specifically,584 couples(3.50%)were at risk for autosomal genes,306(1.84%)for X-linked genes,and 16 for both autosomal and X-linked genes.The most frequently detected autosomal at-risk genes included GJB2(autosomal recessive deafness type 1A,393 couples),HBA1/HBA2(α-thalassemia,36 couples),PAH(phenylketonuria,14 couples),and SMN1(spinal muscular atrophy,14 couples).The most frequently detected X-linked at-risk genes were G6PD(G6PD deficiency,236 couples),DMD(Duchenne muscular dystrophy,23 couples),and FMR1(fragile X syndrome,17 couples).After excluding GJB2 c.109G>A,the detection rate of at-risk couples was 3.91%(651/16 669),which was lowered to 1.72%(287/16 669)after further excluding G6PD.The theoretical incidence rate of severe monogenic birth defects was approximately 4.35‰(72.5/16 669).Screening for a battery of the top 22 most frequent genes in the at-risk couples could detect over 95%of at-risk couples,while screening for the top 54 genes further increased the detection rate to over 99%.Conclusion This study reveals the carrier frequencies of 223 monogenic genetic disorders in the Chinese population and provides evidence for carrier screening strategy development and panel design tailored to the Chinese population.In carrier testing,genetic counseling for specific genes or gene variants can be challenging,and the couples need to be informed of these difficulties before testing and provided with options for not screening these genes or gene variants.

Objective To investigate the epidemiological characteristics and mutation spectrum of monogenic diseases in Chinese population through a large-scale,multicenter carrier screening.Methods This study was conducted among a total of 33 104 participants(16 610 females)from 12 clinical centers across China.Carrier status for 223 genes was analyzed using high-throughput sequencing and different PCR methods.Results The overall combined carrier frequency was 55.58%for 197 autosomal genes and 1.84%for 26 X-linked genes in these participants.Among the 16 669 families,874 at-risk couples(5.24%)were identified.Specifically,584 couples(3.50%)were at risk for autosomal genes,306(1.84%)for X-linked genes,and 16 for both autosomal and X-linked genes.The most frequently detected autosomal at-risk genes included GJB2(autosomal recessive deafness type 1A,393 couples),HBA1/HBA2(α-thalassemia,36 couples),PAH(phenylketonuria,14 couples),and SMN1(spinal muscular atrophy,14 couples).The most frequently detected X-linked at-risk genes were G6PD(G6PD deficiency,236 couples),DMD(Duchenne muscular dystrophy,23 couples),and FMR1(fragile X syndrome,17 couples).After excluding GJB2 c.109G>A,the detection rate of at-risk couples was 3.91%(651/16 669),which was lowered to 1.72%(287/16 669)after further excluding G6PD.The theoretical incidence rate of severe monogenic birth defects was approximately 4.35‰(72.5/16 669).Screening for a battery of the top 22 most frequent genes in the at-risk couples could detect over 95%of at-risk couples,while screening for the top 54 genes further increased the detection rate to over 99%.Conclusion This study reveals the carrier frequencies of 223 monogenic genetic disorders in the Chinese population and provides evidence for carrier screening strategy development and panel design tailored to the Chinese population.In carrier testing,genetic counseling for specific genes or gene variants can be challenging,and the couples need to be informed of these difficulties before testing and provided with options for not screening these genes or gene variants.

ObjectiveBased on network pharmacology and transcriptomics， the mechanism of Zishen Qinggan prescription （ZSQGF） in improving glucose and lipid metabolism in type 2 diabetes （T2DM） model rats was explored. MethodBased on network pharmacology analysis of the differential genes between ZSQGF and T2DM， gene ontology（GO）analysis and Kyoto encyclopedia of genes and genomes（KEGG） analysis were conducted， and molecular docking analysis was used to verify the binding between components and targets. A T2DM rat model was established by high-fat feeding and injection of streptozotocin （STZ）. The rats were randomly divided into the control group， model group， metformin （Met， 72 mg·kg^-1） group， and ZSQGF high-， medium-， and low-dose groups （ZSQGF-H， ZSQGF-M， and ZSQGF-L， with 4.8， 2.4， and 1.2 g·kg^-1 raw drug in the solution）. The living status of rats was monitored and the levels of total cholesterol （TC）， total triglycerides （TG）， high density lipoprotein cholesterol （HDL-C）， low-density lipoprotein cholesterol （LDL-C）， aspartate aminotransferase （AST）， and alanine aminotransferase （ALT） in rat serum were detected. The liver tissues were subjected to Hematoxylin eosin（HE） staining and oil red O staining. The differential genes were analyzed through transcriptomics， GO and KEGG analysis， and the protein-protein interaction（PPI） network was obtained to screen key targets. With network pharmacology and transcriptomics analysis results， the protein pathways were identified. The expression levels of nuclear factor-κB （NF-κB）， matrix metalloproteinase（MMP）-1 and MMP-9 proteins in liver tissues were detected by Western blot. The mRNA expression of B-cell lymphoma-2（Bcl-2） modifying factor（BMF）， nicotinamide adenine dinucleotide phosphate （NADPH） oxidase 4 （NOX4）， and fatty acid synthase（FASN） was detected by real-time polymerase chain reaction（Real-time PCR）. The expression of MMP-1 and MMP-9 in the liver was detected by immunofluorescence staining. ResultTranscriptomics and network pharmacology analysis suggested that ZSQGF may protect the liver through the glucose and lipid metabolism pathway and the inflammation pathway. Experiments showed that after 8 weeks of administration， the body weight， blood sugar， serum indicators， and pathological staining results of rats were improved. Western blot results indicated a decrease in the relative expression levels of NF-κB， MMP-1 and MMP-9 proteins in the liver. Real-time PCR results showed a decrease in the transcriptional expression of BMF， NOX4， and FASN in the ZSQGF-H group， while immunofluorescence staining results present decreased expression of MMP-1 and MMP-9 in the ZSQGF groups. ConclusionZSQGF can improve the glucose and lipid metabolism by inhibiting the expression of FASN， reducing lipid synthesis， and regulating the NF-κB signaling pathway.

Objective:To investigate the effects of gene silencing inducible cyclooxygenase-2 (COX-2) combined with hyperbaric oxygen (HBO) on neuronal cell edema, apoptosis, autophagy and neural functional recovery in rats with intracerebral hemorrhage.Methods:SPF-grade adult male SD rats ( n=96) were used to establish a cerebral hemorrhage model through stereotactic injection of thrombin VII into the caudate nucleus. They were randomized (random number) into 4 groups ( n=24/group): control group, hyperbaric oxygen (HBO) group, COX-2 RNAi group and combined group (COX-2 RNAi+HBO). The siRNA plasmid targeting silencing COX-2 gene expression was constructed. After group treatment, the four rats were randomly selected from each group for testing in each category. Postoperative day 1, 7, and 14 were assessed using the modified neurological severity score (mNSS) for evaluating neurofunctional deficits. On the 7th day, the water content of the brain tissue was measured using the dry/wet weight method. The blood-brain barrier permeability was assessed using the Evans method. Annexin V and TUNEL assays were employed to assess the apoptotic rate of neural cells. The mRNA expression level of COX-2 in brain tissue was determined using the RT-PCR method. The protein expression levels of Beclin-1, COX-2, aquaporin 4 (AQP-4), B cell lymphoma/lewkmia-2 (Bcl-2), caspase-3, hypoxia-inducible factor-1α (HIF-1α) and matrix metalloprotein-2/9 (MMP-2/9) were detected by Western blot (WB). SPSS software was used for data analysis. One-way ANOVA was used for inter group comparisons and LSD- t test was used for further pairwise comparison. Results:The SD rat intracerebral hemorrhage model and plasmid construction were successfully achieved. The mNSS scores were significantly decreased in COX-2 RNAi, HBO and combined groups compared with control group on the 7th day and 14th day (all P<0.01), especially in combined group ( P<0.01). The contents of Evans blue and the water content of brain tissue of all treatment groups were significantly lower than those in control group (all P<0.05), especially in combined group ( P<0.01). The apoptotic rate of neural cells decreased in all treatment groups compared with the control group (all P<0.05), and the combined group decreased the most ( P<0.01). The mRNA expression levels of COX-2 were significantly decreased in all treatment groups compared with the control group (all P<0.01), and combined group silenced COX-2 expression most obviously ( P<0.05). The results of WB showed that the protein expression levels of Beclin-1, COX-2, AQP-4, Caspase-3, HIF-1α, MMP-2/9 were significantly lower than control group (all P<0.05), while the expression of Bcl-2 was increased in all treatment groups (all P<0.01). Among them, the combined group exhibited the most pronounced trend ( P<0.01). Conclusions:Gene silencing of COX-2 in combination with hyperbaric oxygen therapy can effectively restore neurological function in rats with cerebral hemorrhage. The mechanism may be associated with reduced blood-brain barrier permeability, alleviated brain edema, and inhibition of neuronal apoptosis and autophagy.

The Spt-Ada-Gcn5-acetyltransferase (SAGA) is an ancillary transcription initiation complex which is highly conserved. The ADA1 (alteration/deficiency in activation 1, also called histone H2A functional interactor 1, HFI1) is a subunit in the core module of the SAGA protein complex. ADA1 plays an important role in plant growth and development as well as stress resistance. In this paper, we performed genome-wide identification of banana ADA1 gene family members based on banana genomic data, and analyzed the basic physicochemical properties, evolutionary relationships, selection pressure, promoter cis-acting elements, and its expression profiles under biotic and abiotic stresses. The results showed that there were 10, 6, and 7 family members in Musa acuminata, Musa balbisiana and Musa itinerans. The members were all unstable and hydrophilic proteins, and only contained the conservative SAGA-Tad1 domain. Both MaADA1 and MbADA1 have interactive relationship with Sgf11 (SAGA-associated factor 11) of core module in SAGA. Phylogenetic analysis revealed that banana ADA1 gene family members could be divided into 3 classes. The evolution of ADA1 gene family members was mostly influenced by purifying selection. There were large differences among the gene structure of banana ADA1 gene family members. ADA1 gene family members contained plenty of hormonal elements. MaADA1-1 may play a prominent role in the resistance of banana to cold stress, while MaADA1 may respond to the Panama disease of banana. In conclusion, this study suggested ADA1 gene family members are highly conserved in banana, and may respond to biotic and abiotic stress.
Musa/genetics* ; Phylogeny ; Fungal Proteins ; Cell Nucleus ; Histones ; Stress, Physiological/genetics*

Objective:To explore the regulatory effect of Suaeda salsa on renal apoprosis inhibitor of macrophage (AIM) and macrophage polarization in diabetes kidney disease (DKD) model rats.Methods:A DKD rat model was established using a high-sugar and high-fat diet combined with intraperitoneal injection of streptozotocin (STZ). The rats were divided into model group, metformin group, and Suaeda salsa high-, medium-, and low-dosage groups using a random number table method, with 8 mice in each group. The normal group was set with 8 rats in this group. The metformin group was given 85.71 mg/kg of metformin solution by gavage, while the Suaeda salsa high-, medium-, and low-dosage groups were given 3.08, 1.54, and 0.77 g/kg of Suaeda salsa suspension by gavage (raw dosage). The normal group and model group were given equal volumes of saline by gavage, once a day, administered by gavage for 12 weeks of intervention. Fasting blood glucose (FBG) and glucose tolerance (OGTT) were measured, and the area under the curve (AUC) was calculated; the levels of glycosylated hemoglobin (HbA1c) and glycosylated serum protein (GSP) were detected; urea nitrogen (BUN), serum creatinine (SCr), and 24-hour urine protein (24 hUP) were detected; HE staining was used to observe the pathological morphology of the kidneys; Masson and PAS staining were used to observe renal tissue fibrosis; Western blot method was used for detecting AIM, CD206, CD86, TNF-α and IL-10 protein levels in renal tissue; Immunofluorescence was used to detect the average optical density values of AIM, CD206, and CD86 proteins in renal tissue.Results:Compared with the model group, the FBG, OGTT AUC, HbA1c, GSP of each dosage group of Suaeda salsa decreased ( P<0.01); the expression levels of AIM, CD206, and IL-10 proteins in renal tissue increased ( P<0.01 or P<0.05), while the expression levels of CD86 and TNF-α protein significantly decreased ( P<0.01 or P<0.05); HE, Masson, and PAS staining results showed that compared with the model group, the changes in renal microvasculature and renal fibrosis of rats in each dosage group of Suaeda salsa were improved. Conclusion:Suaeda salsa may regulate AIM, promote polarization of M2 macrophages, improve the inflammatory microenvironment of macrophages, thereby lowering blood lipids of DKD rats, and improving renal pathological damage.

Objective:To establish an early prediction model based on triglyceride glucose index (TyG) and procalcitonin (PCT) for patients of acute pancreatitis (AP) complicated with acute kidney injury (AKI), and evaluate the diagnostic value of prediction model.Methods:This study was a single center prospective study. AP patients were recruited from the Emergency Department at Peking University People’s Hospital from January to December 2022. The observation endpoint was 14 days after the diagnosis of acute pancreatitis, patients were divided into AKI and control (no AKI) groups according to the observation endpoint. The general characteristics, clinical laboratory examinations, complications, and clinical scores were compared. The risk for AKI development was determined using logistic analyses to establish a risk prediction model. The receiver operating characteristic curve was drawn and the area under the curve (AUC) was calculated. The diagnostic sensitivity and specificity of the model were calculated, and the diagnostic value of the model was compared with that of Ranson score, APACHEⅡ score and BISAP score.Results:A total of 258 patients were selected for this study, including 79 in the AKI group and 179 in the control group. There was no significant difference in serum creatinine and blood urea nitrogen levels between the two groups. Compared with the control group, the AKI group had a higher proportion of males, older age, and had a higher proportion of hypertension. The ratio of neutrophil/lymphocyte ratio, PCT, and TyG were significantly increased. The Ranson score, APACHE Ⅱ score, and BISAP score were higher, and more patients had ARDS and serous fluid accumulation in the later period. Multivariate logistic regression showed that age ( OR=1.071, 95% CI: 1.020-1.125, P=0.006), increased TyG index ( OR=2.632, 95% CI: 1.423-4.866, P=0.002), and elevated PCT ( OR=1.275, 95% CI: 1.067-1.524, P=0.008) were risk factors for AKI in AP patients. According to the risk factors, forecast the AP patients complicated with AKI risk assessment model is established: Logistic (AKI/AP) = -16.697+0.069×age+ 0.968×TyG+0.243×PCT. The sensitivity and specificity of the model for predicting AKI in AP were 79.75% and 96.65%, respectively, and the AUC was 0.856 (95% CI: 0.790-0.922). The predictive ability was better than that of Ranson score, BISAP score and APACHE Ⅱ score (AUC: 0.856 vs. 0.691 vs. 0.745 vs. 0.705, P=0.041). Conclusion:The prediction model based on age, TyG and PCT was valuable for the prediction of AP concurrent AKI in early stage.

Objective To investigate the causal association of liver function and lipid metabolism levels with sleep disorders based on the Mendelian randomization analysis.Methods The analysis was conducted using the data from genome-wide association studies,with the exposure factors of liver function and lipid metabolism levels(alanine aminotransferase[ALT],aspartate aminotransferase[AST],gamma-glutamyl transpeptidase[GGT],albumin[Alb],serum total protein[TP],total bilirubin[TBil],alkaline phosphatase[ALP],triglyceride[TG],triglyceride-to-glycerol-3-phosphate[TG/G3P]ratio,total cholesterol[TC],high-density lipoprotein cholesterol[HDL-C],low-density lipoprotein cholesterol[LDL-C],poly-unsaturated fatty acids[PUFA],total fatty acids[TFA],PUFA/TFA ratio)and the outcome factor of sleep disorders(nonorganic).The regression models including inverse variance weighted,MR-Egger,Simple mode,weighted median,and Weighted mode were used to perform the Mendelian randomization analysis.Results Serum Alb(odds ratio[OR]=0.728,95%confidence interval[CI]:0.535-0.989,P＜0.05),HDL-C(OR=0.879,95%CI:0.784-0.986,P＜0.05),and PUFA/TFA ratio(OR=0.800,95%CI:0.642-0.998,P＜0.05)were negatively associated with sleep disorders,while TG/G3P ratio(OR=1.222,95%CI:1.044-1.431,P＜0.05)was positively associated with sleep disorders.The results of Mendelian randomization did not show a causal association of ALT,AST,GGT,TP,TBil,ALP,TG,TC,LDL-C,PUFA,and TFA with sleep disorders(all P＞0.05).The results of the MR-Egger intercept test showed no pleiotropy(P＞0.05),and Mendelian randomization was a valid method for causal inference in this study.Conclusion According to the results of the Mendelian randomization analysis,liver function and lipid metabolism show significant association with sleep disorders.Liver function and lipid metabolism can be used as indicators for predicting the risk of sleep disorders and performing intervention.