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*

ObjectiveTo evaluate pharmacological effects of Shengmai injection（SMI）on cerebral ischemia and study its neuroprotective mechanism. MethodsMale specific pathogen-free （SPF） Sprague-Dawley （SD） rats were randomly divided into a sham group， a model group， a low-dose SMI group（3 mL·kg^-1）， a middle-dose SMI group（6 mL·kg^-1）， a high-dose SMI group（12 mL·kg^-1）， and a Ginaton group（4 mL·kg^-1）according to the random number table method， with 12 rats in each group. The rat model of cerebral ischemia-reperfusion（MCAO/R）was prepared via the suture method. The administration groups were intraperitoneally injected with corresponding concentrations of SMI or Ginaton injection after reperfusion， which was conducted for 3 consecutive days. The sham group and model group were administered the equivalent volume of physiological saline. The pharmacological effects of SMI on brain injury in MCAO/R rats were evaluated by neurological function scores， cerebral infarction area， hematoxylin-eosin （HE） staining， Nissl staining， terminal deoxynucleotidyl transferase dUTP nick-end labeling （TUNEL） staining， and Western blot. The dominant link and key protein of SMI treating cerebral injury were explored using proteomic analysis. The related mechanisms of SMI were further validated using enzyme-linked immunosorbent assay （ELISA）， Western blot， and chloride ion fluorescence probe with oxygen-glucose deprivation/reoxygenation（OGD/R）-treated PC12 cells and MCAO/R rats. ResultsCompared with the sham group， the model group showed significantly increased neurological function scores， cerebral infarction area， neuronal apoptosis rate， and expression levels of apoptosis related proteins （P<0.05， P<0.01）and significantly decreased density of Nissl bodies and neurons（P<0.01）. Compared with the model group， the SMI groups exhibited significantly decreased neurological function scores， cerebral infarction area， neuronal apoptosis rate， and expression levels of apoptosis related proteins （P<0.05， P<0.01）and significantly increased density of Nissl bodies and neurons （P<0.05）. The proteomic analysis results showed that oxidative stress and inflammatory response were important processes of SMI intervening in MCAO/R injury， and the chloride intracellular channel protein 1 （CLIC1） was one of key proteins in its action network. The levels of representative indicators of oxidative stress and inflammatory response in the MCAO/R rats of the SMI groups were significantly reduced， compared with those in the model group（P<0.05， P<0.01）， and the expression levels of CLIC1 and downstream NOD-like receptor protein 3 （NLRP3） decreased （P<0.01）. In addition， the experimental results based on the OGD/R PC12 cells showed that SMI significantly increased the cell survival rate（P<0.01） and significantly decreased the intracellular chloride ion concentration（P<0.05）. ConclusionSMI has neuroprotective effects. Oxidative stress and inflammatory response are key processes of SMI intervening in MCAO/R injury. The potential mechanism is closely related to the regulation of CLIC1.

OBJECTIVES: Exposure to rare earth elements (REEs) has been linked to various systemic diseases, but their impact on the offspring blood-brain barrier (BBB) via the gut-brain axis remains unclear. This study aims to investigate the effects of maternal exposure to neodymium oxide (Nd₂O₃) on the BBB integrity of offspring rats, and to evaluate the potential protective role of bifidobacterium tetrad viable tablets (BTVT) against Nd₂O₃-induced intestinal and BBB damage. METHODS: Healthy adult SD rats were mated at a 1:1 male-to-female ratio, with the day of vaginal plug detection marked as gestational day 0. A total of 60 pregnant rats were randomly assigned to the following groups: Control, 50 mg/(kg·d) Nd₂O₃, 100 mg/(kg·d) Nd₂O₃, 200 mg/(kg·d) Nd₂O₃, and 200 mg/(kg·d) Nd₂O₃ + BTVT group. Treatments were administered by daily oral gavage throughout pregnancy and lactation. On postnatal day 21 (weaning), offspring feces, brain, and colon tissues were collected. Hematoxylin and eosin (HE) staining was used to assess structural changes in brain and intestinal tissues. Short-chain fatty acids (SCFAs) in feces were quantified by gas chromatography-mass spectrometry (GC-MS). Evans Blue (EB) dye extravasation assessed BBB permeability. Gene and protein expression levels of tight junction proteins occludin and zonula occludens-1 (ZO-1) were measured by reverse transcription PCR (RT-PCR) and Western blotting (WB), respectively. Neodymium levels in brain tissue were determined via inductively coupled plasma mass spectrometry (ICP-MS). RESULTS: HE staining revealed that maternal Nd₂O₃ exposure caused mucosal edema, increased submucosal spacing, and lymphocyte infiltration in offspring colon, as well as neuronal degeneration and vacuolization in brain tissue. BTVT intervention alleviated these changes. GC-MS analysis showed that levels of acetic acid, propionic acid, butyric acid, and isobutyric acid significantly decreased, while valeric acid and isovaleric acid increased in offspring of Nd₂O₃-exposed mothers (P<0.05). BTVT significantly restored levels of acetic, propionic, and isobutyric acids and reduced valeric acid content (P<0.05). EB permeability was significantly elevated in Nd₂O₃-exposed offspring brains (P<0.05), but reduced with BTVT treatment (P<0.05). RT-PCR and WB showed downregulation of occludin and ZO-1 expression following Nd₂O₃ exposure (P<0.05), which was reversed by BTVT (P<0.05). ICP-MS results indicated significantly increased brain neodymium levels in offspring from all Nd₂O₃-exposed groups (P<0.05), while BTVT significantly reduced neodymium accumulation compared to the 200 mg/(kg·d) Nd₂O₃ group (P<0.05). CONCLUSIONS Maternal exposure to Nd₂O₃ during pregnancy and lactation disrupts intestinal health and BBB integrity in offspring, elevates brain neodymium accumulation, and induces neuronal degeneration. BTVT effectively mitigates Nd₂O₃-induced intestinal and BBB damage in offspring, potentially through modulation of the gut-brain axis.
Animals ; Female ; Blood-Brain Barrier/pathology* ; Pregnancy ; Rats, Sprague-Dawley ; Rats ; Male ; Neodymium/toxicity* ; Prenatal Exposure Delayed Effects/prevention & control* ; Lactation ; Maternal Exposure/adverse effects* ; Brain

Objective:To investigate the role of telomere length in the causal effects of immune-mediated diseases on liver fibrosis.Methods:Genome-wide association study (GWAS) data were extracted from open GWAS (https: //gwas.mrcieu.ac.uk) for a two-sample Mendelian randomization (MR) analysis. Five immune-mediated autoimmune diseases (rheumatoid arthritis, systemic lupus erythematosus, primary biliary cirrhosis, primary biliary cholangitis, and Crohn′s disease) individually and collectively were included as exposure factors, telomere length as a mediator, and liver fibrosis as the outcome. The Wald ratio and inverse variance weighted (IVW) methods were performed to assess causal effects. The MR-Egger intercept test was adopted to evaluate the level of horizontal pleiotropy. Multivariable MR was employed to quantify the proportion of the effect of immune-mediated diseases on liver fibrosis mediated by telomere length. And sensitivity analyses were performed to assess the robustness of the results.Results:The results of IVW analysis revealed that the overall category of immune-mediated diseases, rheumatoid arthritis, systemic lupus erythematosus, primary biliary cirrhosis, primary biliary cholangitis, and Crohn′s disease were causally related to the high risk of liver fibrosis, and the OR were 1.63 (95% confidence intervals (95% CI): 1.33 to 2.10), 1.28 (95% CI: 1.14 to 1.43), 1.34 (95% CI: 1.02 to 1.74), 1.36 (95% CI: 1.27 to 1.47), 1.37 (95% CI: 1.23 to 1.52), and 1.52 (95% CI: 1.15 to 2.01), respectively ( P<0.001, <0.001, =0.032, <0.001, <0.001, =0.003). Horizontal pleiotropy was detected in the association between Crohn′s disease and liver fibrosis (MR-Egger intercept test, P=0.025).The results of multivariable MR indicated that telomere length acted as a mediating factor in the causal relationship between liver fibrosis and the overall category of immune-mediated diseases, rheumatoid arthritis, systemic lupus erythematosus, primary biliary cholangitis ( OR=2.24, 95% CI: 1.41 to 3.56; OR=1.78, 95% CI: 1.03 to 3.06; OR=2.11, 95% CI: 1.31 to 3.40; OR=2.01, 95% CI: 1.06 to 3.80; P<0.001, =0.038, =0.002, =0.032, respectively ). Conclusion:The causal effects of the overall category of immune-mediated diseases, rheumatoid arthritis, systemic lupus erythematosus, and primary biliary cholangitis on liver fibrosis are mediated by telomere length.

OBJECTIVES: To analyze MYO1B expression in gastric cancer, its association with long-term prognosis and its role in regulating biological behaviors of gastric cancer cells. METHODS: We analyzed MYO1B expression in gastric cancer and its correlation with tumor grade, tumor stage, and patient survival using the Cancer Public Database. We also examined MYO1B expression with immunohistochemistry in gastric cancer and paired adjacent tissues from 105 patients receiving radical surgery and analyzed its correlation with cancer progression and postoperative 5-year survival of the patients. GO and KEGG enrichment analyses were used to explore the biological functions of MYO1B and the key pathways. In cultured gastric cancer cells, we examined the changes in cell proliferation, migration and invasion following MYO1B overexpression and knockdown. RESULTS: Data from the Cancer Public Database showed that MYO1B expression was significantly higher in gastric cancer tissues than in normal tissues with strong correlations with tumor grade, stage and patient prognosis (P<0.05). In the clinical tissue samples, MYO1B was significantly overexpressed in gastric cancer tissues in positive correlation with Ki67 expression (r=0.689, P<0.05) and the parameters indicative of gastric cancer progression (CEA ≥5 μg/L, CA19-9 ≥37 kU/L, G3-4, T3-4, and N2-3) (P<0.05). Kaplan-Meier analysis and multivariate Cox regression analysis suggested that high MYO1B expression was associated with decreased postoperative 5-year survival and was an independent risk factor (HR: 3.522, 95%CI: 1.783-6.985, P<0.05). MYO1B expression level was a strong predictor of postoperative survival (cut-off value: 3.11, AUC: 0.753, P<0.05). GO and KEGG analyses suggested that MYO1B may regulate cell migration and the mTOR signaling pathway. In cultured gastric cancer cells, MYO1B overexpression significantly enhanced cell proliferation, migration, and invasion and promoted the phosphorylation of Akt and mTOR. CONCLUSIONS High MYO1B expression promotes proliferation, migration and invasion of gastric cancer cells and is correlated with poor patient prognosis.
Humans ; Stomach Neoplasms/metabolism* ; Cell Proliferation ; Prognosis ; Cell Movement ; Myosin Type I/genetics* ; Neoplasm Invasiveness ; Cell Line, Tumor ; Female ; Male

Astragali Radix (AR), a traditional Chinese medicine (TCM), has demonstrated therapeutic efficacy against various diseases, including cardiovascular conditions, over centuries of use. While doxorubicin serves as an effective chemotherapeutic agent against multiple cancers, its clinical application remains constrained by significant cardiotoxicity. Research has indicated that AR exhibits protective properties against doxorubicin-induced cardiomyopathy (DIC); however, the specific bioactive components and underlying mechanisms responsible for this therapeutic effect remain incompletely understood. This investigation seeks to identify the protective bioactive components in AR against DIC and elucidate their mechanisms of action. Through network medicine analysis, astragaloside IV (AsIV) and formononetin (FMT) were identified as potential cardioprotective agents from 129 AR components. In vitro experiments using H9c2 rat cardiomyocytes revealed that the AsIV-FMT combination (AFC) effectively reduced doxorubicin-induced cell death in a dose-dependent manner, with optimal efficacy at a 1∶2 ratio. In vivo, AFC enhanced survival rates and improved cardiac function in both acute and chronic DIC mouse models. Additionally, AFC demonstrated cardiac protection while maintaining doxorubicin's anti-cancer efficacy in a breast cancer mouse model. Lipidomic and metabolomics analyses revealed that AFC normalized doxorubicin-induced lipid profile alterations, particularly by reducing fatty acid accumulation. Gene knockdown studies and inhibitor experiments in H9c2 cells demonstrated that AsIV and FMT upregulated peroxisome proliferator activated receptor γ coactivator 1α (PGC-1α) and PPARα, respectively, two key proteins involved in fatty acid metabolism. This research establishes AFC as a promising therapeutic approach for DIC, highlighting the significance of multi-target therapies derived from natural herbals in contemporary medicine.
Animals ; Doxorubicin/adverse effects* ; Saponins/administration & dosage* ; Isoflavones/pharmacology* ; Rats ; Cardiomyopathies/prevention & control* ; Mice ; Fatty Acids/metabolism* ; Myocytes, Cardiac/metabolism* ; Triterpenes/administration & dosage* ; Male ; Drugs, Chinese Herbal/administration & dosage* ; Humans ; Cardiotonic Agents/administration & dosage* ; Mice, Inbred C57BL ; Cell Line ; Astragalus Plant/chemistry* ; Astragalus propinquus

Objective:To investigate the mechanisms of S100 calcium binding protein A10 (S100A10) regulating the proliferation and inflammation of psoriatic keratinocytes by targeting nuclear factor-κB (NF-κB) and signal transduction and activator of transcription 3 (STAT3).Methods:Skin lesion tissues from psoriasis patients (10 cases) and normal skin tissues from healthy control (10 cases) who underwent plastic surgery at the Department of Dermatology and Medical Cosmetology, Honghui Hospital Affiliated to Xi′an Jiaotong University from January to June 2024 were collected. The pCMV plasmid and small interfering RNA plasmid were transfected into human immortalized epidermal HaCaT cells to establish the S100A10 overexpression group and the S100A10 knockdown group, respectively. Untreated HaCaT cells were used as the control group. NF-κB and STAT3 pathway inhibitors were added to the cells in the S100A10 overexpression group to create two subgroups: the S100A10 overexpression+NF-κB inhibitor group and the S100A10 overexpression+STAT3 inhibitor group. The effect of S100A10 on HaCaT cell proliferation was determined by cell counting kit-8 assay. The effect of S100A10 on HaCaT cell apoptosis was detected by extracellular phosphatidylserine binding protein V-fluorescein isothiocyanate/ propidium iodide double staining. The expression of S100A10 in normal skin tissue and skin lesion tissues of psoriasis patients was detected by Western blotting. The relative expression of apoptosis-related protein cysteine aspartic acid specific protease-3 (Caspase-3) and NF-κB and STAT3 pathway-related proteins phosphorylated NF-κB p65 (p-NF-κB p65) and phosphorylated STAT3 (p-STAT3) was detected. The effects of S100A10 on the relative expression of interleukin (IL)-6, tumor necrosis factor-α ( TNF-α), IL-1β, and CXC chemokine ligand 8 ( CXCL8) mRNA were detected by real-time reverse transcription-PCR. The effects of S100A10 on the levels of IL-6, TNF-α, IL-1β and CXCL8 in cell supernatant were detected by enzyme-linked immunosorbent assay. One-way analysis of variance and independent t test were used for data analysis. Results:The expression of S100A10 protein in the skin lesion tissues of psoriasis patients was higher than that in normal skin tissues (1.58±0.13 vs 1.00±0.09, P<0.05). Compared with the control group, the cell survival rates of the S100A10 knockdown group [(99.89±1.03)% vs (82.24±6.03)%], the relative expression of p-NF-κB p65 (0.47±0.06 vs 0.21±0.03) and p-STAT3 protein (0.59±0.12 vs 0.17±0.03), the relative expression of IL-6 (0.98±0.12 vs 0.63±0.07), TNF-α (0.97±0.13 vs 0.71±0.09), IL-1β (1.02±0.14 vs 0.51±0.09) and CXCL8 mRNA (1.01±0.16 vs 0.59±0.11), the levels of IL-6 [(27.69±3.47) pg/ml vs (13.65±2.11) pg/ml], TNF-α [(19.21±2.16) pg/ml vs (10.06±1.44) pg/ml], IL-1β [(15.52±1.03) pg/ml vs (5.17±0.96) pg/ml] and CXCL8 [(62.87±8.48) pg/ml vs (47.11±6.35) pg/ml] in the cell supernatant were lower (all P<0.05), and the cell apoptosis rate [(15.41±2.37)% vs (26.38±4.16)%] and Caspase-3 protein relative expression (0.31±0.04 vs 0.74±0.12) were higher (both P<0.05). The cell survival rates [(145.24±6.03)%], the relative expression of p-NF-κB p65 and p-STAT3 protein (2.37±0.25, 3.98±0.47), the relative expression of IL-6, TNF-α, IL-1β and CXCL8 mRNA (2.27±0.64, 3.31±0.61, 2.74±0.43, 3.11±0.48), the levels of IL-6, TNF-α, IL-1β and CXCL8 in the cell supernatant [(51.17±7.95), (33.65±4.19), (29.95±4.07), (79.97±10.32) pg/ml] in the S100A10 overexpression group were higher than those in the control group (all P<0.05), and the cell apoptosis rate [(5.09±0.73)%] and Caspase-3 protein relative expression (0.09±0.01) were lower than those in the control group (both P<0.05). The cell survival rates [(123.65±9.42)%, (122.94±8.14)%], the relative expression of p-NF-κB p65 (1.51±0.19, 1.49±0.21) and p-STAT3 protein (1.67±0.29, 1.69±0.31), the relative expression of IL-6 (1.69±0.14, 1.73±0.15), TNF-α (1.92±0.27, 1.94±0.25), IL-1β (1.85±0.16, 1.87±0.21) and CXCL8 mRNA (2.02±0.34, 2.01±0.39), the levels of IL-6 [(35.55±5.12), (36.18±5.24) pg/ml], TNF-α [(25.17±3.08), (25.23±3.17) pg/ml], IL-1β [(22.08±3.11), (22.11±3.24) pg/ml] and CXCL8 [(70.04±9.31), (70.11±10.29) pg/ml] in the cell supernatant in the S100A10 overexpression+NF-κB inhibitor group and the S100A10 overexpression+STAT3 inhibitor group were higher than those in S100A10 knockdown group (all P<0.05), and the cell apoptosis rates [(20.13±4.62)%, (20.21±4.91)%] and Caspase-3 protein relative expression (0.15±0.03, 0.16±0.04) were lower than those in S100A10 knockdown group (all P<0.05).The cell survival rates, the relative expression of p-NF-κB p65 and p-STAT3 protein, the relative expression of IL-6, TNF-α, IL-1β and CXCL8 mRNA, the levels of IL-6, TNF-α, IL-1β and CXCL8 in the cell supernatant in the S100A10 overexpression+NF-κB inhibitor group and the S100A10 overexpression+STAT3 inhibitor group were lower than those in S100A10 overexpression group (all P<0.05), and the cell apoptosis rates and Caspase-3 protein relative expression were higher than those in S100A10 overexpression group (all P<0.05). Conclusions:S100A10 may regulate the proliferation and inflammation of keratinocytes in psoriasis by targeting NF-κB and STAT3.

Objective To compare TyG index between the patients with CHF and ADHF to eluci-date the metabolic difference between these two stages.Methods A total of 1156 HF patients ad-mitted in Taizhou People's Hospital between January 2020 and December 2022 were enrolled,and according to 2021 ESC Guidelines for Diagnosis and Treatment of Acute and Chronic Heart Fail-ure,they were divided into CHF group(365 cases)and ADHF group(791 cases).The clinical da-ta,results of laboratory tests,and cardiovascular history were collected,and TyG index was calcu-lated.All-cause death outcome was observed in ADHF patients during a follow-up of 1 year.Results The TyG index was significantly lower in the ADHF group than the CHF group[8.27(7.99,8.62)vs 8.35(8.04,8.75),P=0.001].In the ADHF group,the TyG index was positively correlated with SBP,DBP,TC,TG,LDL-C,FPG,HbA1c,BMI,and LVEF,and negatively with age(P＜0.01).In the CHF group,the index was positively correlated with DBP,TC,TG,LDL-C,FPG,BMI,and HbA1c,and negatively with age(P＜0.05,P＜0.01).Both univariate and multiva-riate logistic regression analyses indicated that the TyG index was a protective factor for ADHF(OR=0.647,95％CI:0.503～0.832,P=0.001;OR=0.694,95％CI:0.536～0.898,P=0.005).Multivariate logistic regression analysis showed that the index in ADHF patients was a protective factor for one-year all-cause mortality(OR=0.483,95％CI:0.254-0.916;P=0.026).Conclusion TyG index might be regarded as an important marker for assessing the metabolic status in HF patients and predicting the prognosis in ADHF patients.

Objective To establish mouse models exposed to different doses of neodymium oxide via tracheal instillation,and to investigate the mechanisms underlying brain tissue damage induced by neodymium oxide exposure in mice.Methods Forty-eight male C57/BL6 mice were randomly assigned to four groups:the control group,the low-dose group,the medium-dose group,and the high-dose group.The low-dose,medium-dose,and high-dose groups received 62.5 mg/mL,125 mg/mL,and 250 mg/mL neodymium oxide,respectively,via non-exposed tracheal instillation.The control group received an equivalent volume of saline using the same administration method.After 35 days,the mice were euthanized,and brain tissues were collected.RT-PCR was used to assess the mRNA expression changes of Claudin-5 and Occludin.Western blot analysis was performed to evaluate the expression changes of Claudin-5 and Occludin tight junction proteins,as well as the expression changes of MMP-2 and MMP-9 in the brain tissues.Additionally,the expression of the RhoA/ROCK2 signaling pathway and downstream cofilin protein was examined.Changes in oxidative stress markers,including MDA,T-AOC,and NO,were measured using a kit method.Results The mRNA expression of Claudin-5 was significantly reduced in the middle-dose and high-dose groups compared to the control group(P<0.05).Similarly,the mRNA expression of Occludin was significantly lower in the low-dose,medium-dose,and high-dose groups compared to the control group(P<0.05).Additionally,the protein expression of Claudin-5,MMP-2,and Occludin was significantly decreased in the low-dose,medium-dose,and high-dose groups compared to the control group(P<0.05).The protein expression of MMP-9 and RhoA was also signifi-cantly lower in the medium-dose and high-dose groups compared to the control group(P<0.05).Furthermore,the protein expression of ROCK2 and p-cofilin in the high-dose group was significantly lower than that in the control group(P<0.05).The content of MDA and T-AOC was significantly lower in the medium-dose and high-dose groups compared to the control group(P<0.05),and the content of NO in the high-dose group was significantly lower than that in the control group(P<0.05).Conclusion Exposure to neodymium oxide results in increased permeability of the blood-brain barrier in mice,leading to oxidative stress,inflammatory responses,and activation of the RhoA/ROCK2 signaling pathway.