Cellular senescence, stable cell cycle arrest that can be triggered in normal cells in response to various intrinsic and extrinsic stressors, has been highlighted as one of the most important mechanisms involved in kidney diseases. It not only serves as a fundamental biological process promoting normal organogenesis and successful wound repair but also contributes to organ dysfunction, tissue fibrosis, and the generalized aging phenotype. Moreover, senescent cells exhibit reduced regenerative capacity, which impairs renal function recovery from injuries. Importantly, senescent cells are involved in immune regulation via secreting a diverse array of proinflammatory and profibrotic factors known as senescence-associated secretory phenotype (SASP) with autocrine, paracrine, and endocrine activities. Thus, eliminating detrimental senescent cells or inhibiting SASP production holds great promise for developing innovative therapeutic strategies for kidney diseases. In this review, we summarize the current knowledge of the intricate mechanisms and hallmarks of cellular senescence in kidney diseases and emphasize novel therapeutic targets, including epigenetic regulators, G protein-coupled receptors, and lysosome-related proteins. Particularly, we highlight the recently identified senotherapeutics, which provide new therapeutic strategies for treating kidney diseases.
Humans ; Cellular Senescence/genetics* ; Kidney Diseases/pathology* ; Senescence-Associated Secretory Phenotype/physiology* ; Animals ; Epigenesis, Genetic/physiology*

Positron emission tomography (PET) now plays an important role in the research and development (R&D) of central nervous system (CNS) drugs. PET could characterize the biodistribution, pharmacokinetics, and receptor binding of CNS drugs quantitatively. The present review summarized the quantitative methods of PET used in the pharmacokinetics and receptor occupancy analysis of CNS drugs. Moreover, the present review listed various applications of PET supporting R&D of CNS drugs, which could provide a new direction for the R&D of CNS drugs.

OBJECTIVE To study the inhibitory effect and mechanism of curcumin and its derivatives A and B on TGF-β induced LX-2 cell fibrosis. METHODS Established the liver fibrosis model of LX-2 cells induced by TGF-β(10 ng·mL−1).The effects on cell proliferation were detected by CCK-8. The effects on cell apoptosis was detected by flow cytometry. The effects on fibrosis related factors(Collagen I, Collagen Ⅳ, Fibronectin, Vimentin, α-SMA, PDGFRβ, TGFβR1, TGFβR2, MMP2, MMP9, TIMP1 and TIMP2) protein expression and gene transcription levels were detected by Western blotting and q-PCR. RESULTS The curcumin and its derivative A and B had the inhibition effects on normal LX-2 cells, and the IC25 values were 15.7, 2.6, 10.2 μmol·L−1, respectively. Compared to the model group, the curcumin(15.7 μmol·L−1) and its derivative A(2.6 μmol·L−1) and B(10.2 μmol·L−1) had the significant inhibition effects on cell proliferation of the TGF-β induced LX-2 cells(P<0.05). The cell apoptosis rate of curcumin derivative B group was higher than the model group(P<0.05). Collagen I, Fibronectin, Vimentin, α-SMA, TGFβR1 and TIMP-1 protein expression levels in curcumin group were lower, while the protein expression level of MMP-9 was higher(P<0.05). The protein expression levels of Collagen I, Collagen IV, Fibronectin, Vimentin, α-SMA, TIMP-1 and TIMP-2 in curcumin derivative A group were lower, while the protein expression level of MMP-2 was higher(P<0.05). The protein expression levels of Collagen I, Collagen IV, Fibronectin, Vimentin, α-SMA, PDGFRβ, TGFβR1, TGFβR2, TIMP-1 and TIMP-2 in curcumin derivative B group were lower, while the protein expression level of MMP-2 was higher(P<0.05). The gene transcription levels of Collagen I, Fibronectin, α-SMA and TIMP-1 in curcumin group were lower(P<0.05). The gene transcription levels of Collagen I, Fibronectin and α-SMA in curcumin derivative A and B groups were lower(P<0.05). CONCLUSION Curcumin and its derivatives A and B inhibit the abnormal activation and proliferation of TGF-β-induced LX-2 cells, inhibit the excessive secretion and accumulation of its extracellular matrix components, and promote its degradation, thus playing an anti-fibrotic effect in vitro, especially the curcumin derivative B.

BACKGROUND:De novo adipose regeneration induced by small extracellular vesicles has become a promising method for repairing soft tissue defects.However,due to different animal models and small extracellular vesicle application dosages,it is difficult to quantitatively compare the therapeutic effect of small extracellular vesicles from various sources on adipose regeneration. OBJECTIVE:To compare the regenerative effects of small extracellular vesicles derived from stem cells and small extracellular vesicles from tissue. METHODS:Small extracellular vesicles derived from adipose-derived stem cells and from adipose tissue were isolated by ultracentrifugation.The particle number,particle size,morphology,and protein expression of small extracellular vesicles were identified by nanoparticle tracking analysis,transmission electron microscopy and western blot assay.A quantitative and evaluative subcutaneous model for adipose regeneration in C57 mice was established using a customized silicone tube.The regenerative effects of induced de novo adipose were compared by cell counting and hematoxylin-eosin staining. RESULTS AND CONCLUSION:(1)Small extracellular vesicles derived from adipose-derived stem cells and from adipose tissue were isolated by ultracentrifugation.Both small extracellular vesicles were round-shape in transmission electron microscopy with particle size between 50-200 nm,and abundant with the small extracellular vesicles marker protein CD81,CD63 and TSG101.(2)An equal number of small extracellular vesicles were mixed with matrigel in customized silicone tubes,implanted subcutaneously in the back of mice to establish a cell-free and quantifiable adipose regeneration model.(3)On days 3 and 7 after implantation,the results of cell counting and hematoxylin-eosin staining showed that both small extracellular vesicle groups recruited more host cells than the blank group,and the small extracellular vesicles derived from adipose tissue group were superior to the small extracellular vesicles derived from adipose-derived stem cell group.(4)4 weeks after implantation,hematoxylin-eosin staining of the contents in silicone tubes showed that small extracellular vesicles induced de novo adipose regeneration in vivo,and the small extracellular vesicles derived from adipose tissue group were superior to the small extracellular vesicles derived from adipose-derived stem cell group.The above results indicated that small extracellular vesicles derived from tissues have a superior effect on inducing de novo adipose regeneration compared to small extracellular vesicles derived from stem cells.

Objective:To explore the relationship among suicide risk,distress tolerance,and resilience in pa-tients with depression.Methods:A total of 130 patients with depression who met the Diagnostic and Statistical Manual of Mental Disorders,Fifth Edition(DSM-5)diagnostic criteria were included.The Chinese version of the Mini International Neuropsychiatric Interview(MINI)suicide module was used to assess suicide risk.According to the interview results,the patients with depression were divided into suicide risk group(98 cases)and non-suicide risk group(32 cases).The Hamilton Depression Rating Scale(HAMD),Distress Tolerance Scale(DTS),10-item Connor-Davidson Resilience Scale(CD-RISC-10)were used to assess severity of depressive symptoms,level of distress tolerance and resilience,respectively.Results:The DTS total scores were positively correlated with the CD-RISC-10 total scores(r=0.50,P＜0.01).The total scores of MINI suicide module were negatively correlated with the total scores of DTS and CD-RISC-10(r=-0.34,-0.34,Ps＜0.01).Distress tolerance had a direct effect on suicide risk(β=-0.26,P＜0.05),and resilience played a mediating effect on the relationship between distress tolerance and suicide risk(β=-0.13,P＜0.05),and the mediating effect accounted for 33.5％of the total effect.Conclusion:Patients with depression with lower levels of distress tolerance may have higher suicide risk,and resilience may play a partially mediating role in the relationship between distress tolerance and suicide risk.

Purpose/Significance To explore the application and predictive accuracy of various models in predicting the risk of ather-osclerosis in diabetic patients.Method/Process Based on the biochemical data table from the"Diabetes Complications Warning Dataset"provided by the National Population Health Science Data Center,MATLAB software is used to construct risk prediction models for diabe-tes-induced atherosclerosis.The models are built by using k-nearest neighbors(KNN),decision trees,backpropagation(BP)neural networks,and Naive Bayes algorithms,and which are subjected to comparative analysis.Result/Conclusion In terms of effectiveness,the predictive accuracy of Naive Bayes algorithm is the highest(61.6％),followed by the decision tree model(58.2％),the KNN mod-el(57.7％),and the BP neural network model(55.9％).The results of the confusion matrix and the receiver operating characteristic(ROC)curve indicate that the Naive Bayes model performs best.When comparing the models in terms of effectiveness,performance and stability,the Naive Bayes model is superior.

Objective:To establish a determination method for sodium hyaluronate injection.Methods:Sodium hyaluronate was specifically hydrolyzed by hyaluronidase,and the optimal enzymolysis conditions were enzymolysis at 37 ℃ for 4 h at 100 IU·mg-1 of enzyme reaction concentration.The analysis was performed on a of Shodex sug-ar SH1011 column(300 mm ×8 mm,6 μm)with a mobile phase of 1％H3PO4 at a flow rate of 0.6 mL·min-1.The eluent was detected at 230 nm.Results:Linear ranges were 101.38-1 013.76 μg·mL-1(r=0.999 5),RSDs of precision,stability and repeatability tests were lower than 1％,and average recovery was 100.4％,RSD=2.0％(n=9).The RAD of determination results of this method and colorimetric was 0.1％-1.2％.Conclusions:The method is accurate and reproducible,and can be used for the determination of sodium hyalur-onate injection.

Carcinoma-associated fibroblasts (CAFs) are the main cellular components of the tumor microenvironment and promote cancer progression by modifying the extracellular matrix (ECM). The tumor-associated ECM is characterized by collagen crosslinking catalyzed by lysyl oxidase (LOX). Small extracellular vesicles (sEVs) mediate cell-cell communication. However, the interactions between sEVs and the ECM remain unclear. Here, we demonstrated that sEVs released from oral squamous cell carcinoma (OSCC)-derived CAFs induce collagen crosslinking, thereby promoting epithelial-mesenchymal transition (EMT). CAF sEVs preferably bound to the ECM rather than being taken up by fibroblasts and induced collagen crosslinking, and a LOX inhibitor or blocking antibody suppressed this effect. Active LOX (αLOX), but not the LOX precursor, was enriched in CAF sEVs and interacted with periostin, fibronectin, and bone morphogenetic protein-1 on the surface of sEVs. CAF sEV-associated integrin α2β1 mediated the binding of CAF sEVs to collagen I, and blocking integrin α2β1 inhibited collagen crosslinking by interfering with CAF sEV binding to collagen I. CAF sEV-induced collagen crosslinking promoted the EMT of OSCC through FAK/paxillin/YAP pathway. Taken together, these findings reveal a novel role of CAF sEVs in tumor ECM remodeling, suggesting a critical mechanism for CAF-induced EMT of cancer cells.
Humans ; Paxillin/metabolism* ; Protein-Lysine 6-Oxidase/metabolism* ; Carcinoma, Squamous Cell/pathology* ; Epithelial-Mesenchymal Transition ; Integrin alpha2beta1/metabolism* ; Mouth Neoplasms/pathology* ; Collagen/metabolism* ; Fibroblasts ; Extracellular Vesicles/metabolism* ; Cell Line, Tumor ; Tumor Microenvironment

OBJECTIVE To evaluate the incidence of nephrotoxicity in patients with drug-resistant Gram-negative bacterial infections after the use of polymyxin， and to provide evidence-based reference for clinical rational drug use. METHODS PubMed， Embase， Web of Science， the Cochrane Library， Wanfang database， CNKI， VIP and SinoMed were searched to collect randomized controlled trials （RCTs） or cohort studies about the polymyxin （trial group） versus other antibiotics （control group） or polymyxin B （trial group） versus polymyxin E （control group）. After literature screening， data extraction and quality evaluation， RevMan 5.4.1 software was used for meta-analysis. RESULTS A total of 37 studies were included， including 4 RCTs and 33 cohort studies， with a total of 5 871 patients. The meta-analysis results showed that in RCT [RR＝2.64，95%CI （1.43，4.87），P＝0.002] and in cohort studies [RR＝1.59， 95%CI （1.27， 1.98）， P＜0.000 1]， the incidence of nephrotoxicity in the trial group was significantly higher than control group. The results of the subgroup analysis of cohort studies showed that the incidence of nephrotoxicity in the trial group （receiving polymyxin） was significantly higher than control group （receiving new β-lactam and β-lactamase inhibitors and tigecycline）； when Kidney Disease Improving Global Outcomes （KDIGO）， renal replacement therapy or 0.5 times increase in serum creatinine were used as the standard of nephrotoxicity， the incidence of nephrotoxicity in the trial group was significantly higher than the control group （P＜0.05）. The incidence of nephrotoxicity in patients receiving polymyxin E was significantly higher than those using polymyxin B [RR＝0.57， 95%CI （0.39，0.84）， P＝0.005]. CONCLUSIONS In the treatment of drug-resistant Gram-negative bacteria infections， the incidence of nephrotoxicity caused by polymyxin is relatively high. The TYU108F）； incidence of nephrotoxicity caused by polymyxin E is higher than polymyxin B.

Public hospitals stand in need of strengthening cost control and improving operational efficiency to balance public welfare and economic benefits.Taking practice and exploration of ultrasound department as an exam-ple,it integrates the advantages of TDABC with cost management.Take the merits of time driver and activity driver,realizes direct cost accounting under the clinical pathway,strengthen capacity management capabilities un-der the integration of industry and finance,with a view to providing a powerful cost control tool for public hospitals to sensibly respond to pricing reform and reasonably make operational decisions.