ObjectiveTo investigate the mechanism of liver injury induced by tripterygium glycosides tablets （TG） and the molecular mechanism of compound glycyrrhizin tablets （CG） in alleviating the abnormalities of cholesterol metabolism caused by TG via cholesterol metabolism. MethodsAccording to the body weights， male Sprague-Dawley （SD） rats were randomly grouped as follows： control （pure water）， low-dose TG （TG-L， 189.0 mg·kg^-1·d^-1）， high-dose TG （TG-H， 472.5 mg·kg^-1·d^-1）， TG-L+CG （189.0 mg·kg^-1·d^-1 TG + 20.25 mg·kg^-1·d^-1 CG）， and TG-H+CG （472.5 mg·kg^-1·d^-1 TG + 20.25 mg·kg^-1·d^-1 CG）， with 6 rats in each group. Rats were administrated with corresponding drugs once daily for 3 weeks. At the end of the last administration， the mRNA and protein levels of liver X receptor-alpha （LXR-α）， low-density lipoprotein receptor （LDLR）， adenosine triphosphate-binding cassette transporter A1 （ABCA1）， adenosine triphosphate-binding cassette transporter G1 （ABCG1）， 3-hydroxy-3-methylglutaryl coenzyme A reductase （HMGCR）， cholesterol 7α-hydroxylase （CYP7A1）， cholesterol 12α-hydroxylase （CYP8B1）， and sterol 27-hydroxylase （CYP27A1） in the liver tissue were determined by Real-time PCR and Western blotting， respectively. The level of 3-hydroxy-3-methylglutaryl coenzyme A reductase （HMG-CoAR）， a regulatory enzyme of cholesterol synthesis， was measured by enzyme-linked immunosorbent assay （ELISA）. HepG2 cells were used to observe the effect of TG on the cell proliferation in vitro. Specifically， HepG2 cells were grouped as follows： Low-dose TG （TG-l， 15 mg·L^-1）， medium-dose TG （TG-m， 45 mg·L^-1）， high-dose TG （TG-h， 135 mg·L^-1）， fenofibrate （FB， 10 μmol·L^-1）， CG extract， TG-h+FB （135 mg·L^-1 TG + 10 μmol·L^-1 FB）， TG-m+FB （45 mg·L^-1 TG + 10 μmol·L^-1 FB）， TG-l+FB （15 mg·L^-1 TG + 10 μmol·L^-1 FB）， TG-h+CG （135 mg·L^-1 TG + 60 μmol·L^-1 CG）， TG-m+CG （45 mg·L^-1 TG + 60 μmol·L^-1 CG）， and TG-l+CG （15 mg·L^-1 TG + 60 μmol·L^-1 CG）. The mRNA and protein levels of LXR-α， ABCG1， LDLR， CYP7A1， CYP8B1， and CYP27A1 in HepG2 cells were determined by Real-time PCR and Western blotting， respectively. ResultsThe rat experiment showed that compared with the control group， the TG-H group showed down-regulated mRNA levels of CYP7A1， CYP8B1， and CYP27A1 in the liver tissue （P<0.05， P<0.01）， which were up-regulated by the application of CG （P<0.05， P<0.01）， and the TG-H+CG group showed up-regulated mRNA level of LDLR （P<0.01）. Compared with the control group， the TG-L and TG-H groups showed down-regulated protein levels of LDLR， CYP7A1， and CYP8B1 in the liver tissue （P<0.05， P<0.01）. In addition， the protein levels of ABCG1 and LXR-α were down-regulated in the TG-H and TG-L groups， respectively （P<0.05）. Compared with TG alone， TG+CG up-regulated the protein levels of ABCG1 and LDLR （P<0.05， P<0.01）， and the protein levels of CYP7A1 and CYP8B1 in the TG-H+CG group were up-regulated （P<0.05， P<0.01）. The cell experiment showed that compared with the control group， the TG-h group presented up-regulated mRNA level of LXR-α （P<0.01）， and the TG-m and TG-h groups showcased down-regulated mRNA levels of LDLR and CYP7A1 （P<0.01） and up-regulated mRNA level of CYP27A1 （P<0.01） in HepG2 cells. The combination of CG with TG restored the above changes （P<0.01）. Western blotting results showed that compared with the control group， the TG-m and TG-h groups showed down-regulated protein levels of LXR-α， ABCG1， LDLR， CYP7A1， CYP8B1， and CYP27A1 in HepG2 cells （P<0.01）. Compared with the TG-h group， the TG-h+CG group showed up-regulated protein level of LDLR （P<0.05）. Compared with the TG-m group， the TG-m+CG group showcased up-regulated protein levels of LDLR， ABCG1， CYP7A1， and CYP27A1 （P<0.05， P<0.01）. ConclusionThe administration of TG at 189.0， 472.5 mg·kg^-1 for 3 weeks could modulate the signaling pathways associated with cholesterol efflux， endocytosis， and cholesterol biotransformation in hepatocytes， leading to the accumulation of cholesterol and subsequent liver injury in rats. CG could ameliorate the liver injury induced by lipid metabolism disorders caused by TG by up-regulating the expression of LXR-α， LDLR， ABCG1， CYP7A1， CYP8B1， and CYP27A1 to promote cholesterol biotransformation.

AIM: To investigate the abnormal conditions and change patterns of accommodative facility in patients with different refractive states before and after small incision lenticule extraction(SMILE)surgery.METHODS:A prospective clinical cohort study was conducted. A total of 59 patients(118 eyes)who underwent SMILE surgery and had visual function files established in our hospital from June to December 2023 were randomly selected, including 37 males and 22 females, aged 18-35 years(with an average age of 25.19±5.65 years). According to the preoperative spherical equivalent(SE), they were divided into two groups: the low-to-moderate myopia group(SE≥-6.00 DS)with 40 patients(80 eyes), and the high myopia group(SE<-6.00 DS)with 19 patients(38 eyes). The monocular and binocular accommodative facility before surgery and at 1 wk and 1 mo after surgery were compared, and the changes in accommodative facility before and after SMILE surgery in the two groups of patients were analyzed.RESULTS:All surgeries were completed successfully. In the low-to-moderate myopia group, 33 cases(66 eyes)completed the 1-month follow-up after surgery, with a loss to follow-up rate of 17.5%(7/40). In the high myopia group, 15 patients(30 eyes)completed the 1-month follow-up after surgery, with a loss to follow-up rate of 21.1%(4/19). After SMILE surgery, the uncorrected visual acuity and SE of both low-to-moderate myopia and high myopia were significantly improved(all P<0.05). The accommodative facility of the right eyes in all the patients at 1 mo after surgery was better than that before surgery and at 1 wk after surgery(P=0.002, 0.006), the accommodative facility of the left eyes was significantly increased at 1 mo after surgery than that at 1 wk after surgery(P=0.005), and the binocular accommodative facility at 1 mo after surgery was significantly increased compared with that before surgery(P<0.017). Furthermore, there were statistical significance in accommodative facility of the right eyes in the low-to-moderate group at 1 mo compared with that before surgery and at 1 wk after surgery(P=0.011, 0.004); it was significantly increased in the left eyes at 1 mo after surgery compared with that at 1 wk after surgery(P=0.001), and binocular accommodative facility at 1 mo after surgery was significantly better than that before surgery(P<0.001). Furthermore, there was no statistical significance in the right, left and binocular accommodative facility of patients in the high myopia group(all P>0.017).CONCLUSION: After SMILE surgery, the monocular accommodative facility shows a transient decrease and then exceeds the preoperative level at 1 mo after surgery, and the binocular accommodative facility gradually improves after surgery. SMILE surgery has a positive impact on the monocular and binocular accommodative facility in patients with low-to-moderate myopia, but has no significant impact on the accommodative facility in patients with high myopia. It is of clinical significance to strengthen the detection of monocular and binocular accommodative facility before and after SMILE surgery.

To investigate the association between neutrophil to lymphocyte ratio (NLR) andestimated glomerular filtration rate (eGFR) in patients with diabetes using large-scale data.

ObjectiveTo investigate the effect and molecular mechanism of exosomes derived from bone marrow mesenchymal stem cells（BMSC-exos） modified with Bushen Yisui capsule（BSYS）-containing serum on promoting the differentiation and maturation of OLN-93 oligodendrocytes by regulating miR-15b/Wnt signaling pathway. MethodsOLN-93 cells were divided into 5 groups， including the normal（NC） group， BMSC-exos group， BSYS-BMSC-exos group， BSYS-BMSC+LV-miR-15b-5p inhibitor-exos group， and BSYS-BMSC+LV-miR-15b-5p NC-exos group. DiR staining was used to observe the uptake of Exos by OLN-93 cells. The effective dosage of BSYS-BMSC-exos on OLN-93 cells was assessed by cell proliferation and activity assay（CCK-8）. Stable BMSCs lentiviral transfection strains were established to inhibit miR-15b-5p expression in both BMSCs and their exos， and transfection efficiency was verified by real-time fluorescent quantitative polymerase chain reaction（Real-time PCR） detection of miR-15b-5p. The expressions of 2′，3′-cyclic nucleotide 3′-phosphodiesterase（CNPase） and myelin proteolipid protein（PLP） in OLN-93 cells were detected by immunocytochemistry（ICC） and Western blot. The mRNA expressions of miR-15b-5p and Wnt3a in OLN-93 cells were detected by Real-time PCR， and the protein expression of Wnt3a was measured by Western blot. The expression levels of key molecules in the Wnt/β-catenin signaling pathway of OLN-93 cells， including glycogen synthase kinase（GSK）-3β， β-catenin， and T-cell specific transcription factor 4/transcription factor 7-like 2（TCF4/TCF7L2）， were measured by Real-time PCR and Western blot. ResultsDiR-labeled Exos were efficiently taken up by OLN-93 cells. The CCK-8 assay results indicated that 20 mg·L^-1 of BSYS-BMSC-exos exhibited the most significant effect in enhancing OLN-93 cell viability（P<0.01） and this dosage was selected for subsequent experiments. Following lentiviral transfection of BMSCs， Real-time PCR results revealed that miR-15b-5p was significantly suppressed in BMSCs（P<0.01）， and miR-15b-5p was also notably inhibited in BSYS-BMSC-exos（P<0.01）. ICC analysis further revealed an increase in the number of differentiated， mature CNPase and PLP-positive cells following BSYS-BMSC-exos treatment（P<0.01）. Western blot results demonstrated that the protein expression of CNPase and PLP was significantly enhanced with BSYS-BMSC-exos treatment（P<0.01）. Additionally， BSYS-BMSC-exos also increased the expression levels of miR-15b-5p and p-β-catenin proteins in OLN-93 cells， while decreased the mRNA and protein expressions of Wnt3a， as well as the mRNA expressions of β-catenin and TCF4/TCF7L2， and the protein expression level of p-GSK-3β（Ser9） was significantly reduced（P<0.05， P<0.01）. After the transfection of miR-15b-5p inhibitor into BSYS-BMSC-exos， the above effects were significantly diminished（P<0.05， P<0.01）. ConclusionBSYS-BMSC-exos facilitate the differentiation and maturation of OLN-93 cells， and its mechanism is related to the upregulation of miR-15b-5p in OLN-93 cells， which inhibits the expression of Wnt3a and thereby suppresses the Wnt signaling pathway.

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

Poly(ADP-ribose) polymerase 1 (PARP1) is a multifunctional protein involved in diverse cellular functions, notably DNA damage repair. Pharmacological inhibition of PARP1 has therapeutic benefits for various pathologies. Despite the increased use of PARP inhibitors, challenges persist in achieving PARP1 selectivity and effective blood-brain barrier (BBB) penetration. The development of a PARP1-specific positron emission tomography (PET) radioligand is crucial for understanding disease biology and performing target occupancy studies, which may aid in the development of PARP1-specific inhibitors. In this study, we leverage the recently identified PARP1 inhibitor, AZD9574, to introduce the design and development of its ¹⁸F-isotopologue ([¹⁸F]AZD9574). Our comprehensive approach, encompassing pharmacological, cellular, autoradiographic, and in vivo PET imaging evaluations in non-human primates, demonstrates the capacity of [¹⁸F]AZD9574 to specifically bind to PARP1 and to successfully penetrate the BBB. These findings position [¹⁸F]AZD9574 as a viable molecular imaging tool, poised to facilitate the exploration of pathophysiological changes in PARP1 tissue abundance across various diseases.

Flavonoids, the key active compounds in Epimedii Folium, have both protective and toxic effects on the liver. Their hepatoprotective effects are associated with reducing lipid accumulation and oxidative stress, which contribute to the management of various liver conditions. In contrast, the mechanisms driving Epimedii Folium-induced hepatotoxicity are less understood but likely involve oxidative stress and pyroptosis. Pharmacokinetic studies, especially on icaritin, indicate that it undergoes isopentenyl dehydrogenation, glycosylation, and glucuronidation in vivo, contributing to its pharmacological effects. However, intermediate metabolites of icaritin may interact with biomolecules, potentially leading to liver toxicity. This review offers a detailed examination of the dual effects of Epimedii Folium flavonoids on liver function, emphasizing recent discoveries in their hepatoprotective and hepatotoxic pathways. We also summarize and discuss the pharmacokinetics of these flavonoids, highlighting how their metabolism affects therapeutic efficacy and toxicity. Lastly, we propose strategies to mitigate liver injury, providing new perspectives on the safe use of Epimedii Folium.

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.

Background and objective Both of lung cancer incidence and mortality rank first among all cancers in China.Previous lung cancer screening trials were mostly selective screening for high-risk groups such as smokers.Non-smoking women accounted for a considerable proportion of lung cancer cases in Asia.This study aimed to evaluate the outcome of community-based mass screening in Guangzhou and identify the high-risk factors for lung cancer.Methods Residents aged 40-74 years in Guangzhou were screened with low-dose computed tomography(LDCT)for lung cancer and the pulmonary nodules were classified and managed according to China National Lung Cancer Screening Guideline with Low-dose Computed Tomography(2018 version).The detection rate of positive nodules was calculated.Before the LDCT examination,residents were required to complete a"lung cancer risk factors questionnaire".The risk factors of the questionnaire were analyzed by least absolute shrinkage and selection operator(LASSO)penalized Logistic regression analysis.Results A total of 6256 residents were included in this study.1228 positive nodules(19.63％)and 117 lung cancers were confirmed,including 6 cases of Tis,103 cases of stage Ⅰ(accounting for 88.03％of lung cancer).The results of LASSO penalized Logistic regression analysis indicated that age ≥50 yr(OR=1.07,95％CI:1.06-1.07),history of cancer(OR=3.29,95％CI:3.22-3.37),textile industry(OR=1.10,95％CI:1.08-1.13),use coal for cooking in childhood(OR=1.14,95％CI:1.13-1.16)and food al-lergy(OR=1.10,95％CI:1.07-1.13)were risk factors of lung cancer for female in this district.Conclusion This study highlighted that numerous early stages of lung cancer cases were detected by LDCT,which could be applied to screen-ing of lung cancer in women.Besides,age ≥50 yr,personal history of cancer,textile industry and use coal for cooking in childhood are risk factors for women in this district,which suggested that it's high time to raise the awareness of early lung cancer screening in this group.