Down-regulation of XBP1s alleviates the senescence of renal tubular epithelial cells induced by hypoxia/reoxygenation through Sirt3/SOD2/mtROS signaling pathway / 器官移植

Objective To investigate the role and mechanism of spliced X-box binding protein 1 (XBP1s) in the senescence of primary renal tubular epithelial cells induced by hypoxia/reoxygenation (H/R). Methods Primary renal tubular epithelial cells were divided into the normal control group (NC group), H/R group, empty adenovirus negative control group (Ad-shNC group), targeted silencing XBP1s adenovirus group (Ad-shXBP1s group), empty adenovirus+H/R treatment group (Ad-shNC+H/R group) and targeted silencing XBP1s adenovirus+H/R treatment group (Ad-shXBP1s +H/R group), respectively. The expression levels of XBP1s in the NC, H/R, Ad-shNC and Ad-shXBP1s groups were measured. The number of cells stained with β-galactosidase, the expression levels of cell aging markers including p53, p21 and γH2AX, and the levels of reactive oxygen species (ROS), malondialdehyde (MDA) and superoxide dismutase (SOD) were determined in the Ad-shNC, Ad-shNC+H/R and Ad-shXBP1s+H/R groups. Chromatin immunoprecipitation was employed to verify Sirtuin 3 (Sirt3) of XBP1s transcription regulation, and the expression levels of Sirt3 and downstream SOD2 after down-regulation of XBP1s were detected. Mitochondrial reactive oxygen species (mtROS) were detected by flow cytometry. Results Compared with the NC group, the expression level of XBP1s was up-regulated in the H/R group. Compared with the Ad-shNC group, the expression level of XBP1s was down-regulated in the Ad-shXBP1s group (both P<0.001). Compared with the Ad-shNC group, the number of cells stained with β-galactosidase was increased, the expression levels of p53, p21 and γH2AX were up-regulated, the levels of ROS, MDA and mtROS were increased, the SOD activity was decreased, the expression level of Sirt3 was down-regulated, and the ratio of Ac-SOD2/SOD2 was increased in the Ad-shNC+H/R group. Compared with the Ad-shNC+H/R group, the number of cells stained with β-galactosidase was decreased, the expression levels of p53, p21 and γH2AX were down-regulated, the levels of ROS, MDA and mtROS were decreased, the SOD activity was increased, the expression level of Sirt3 was up-regulated and the ratio of Ac-SOD2/SOD2 was decreased in the Ad-shXBP1s+H/R group (all P<0.05). Conclusions Down-regulation of XBP1s may ameliorate the senescence of primary renal tubular epithelial cells induced by H/R, which probably plays a role through the Sirt3/SOD2/mtROS signaling pathway.

Research progress on molecular mechanism of traditional chinese medicine active ingredients interfering bone marrow mesenchymal stem cells senescence / 中国临床药理学与治疗学

The senescence of bone marrow mesenchymal stem cells (BM-MSCs) will induce age-related bone tissue degeneration and chronic inflammation, and reduce its application effect for cell therapy. More and more active ingredients of traditional chinese medicine have been proved to intervene BM - MSCs senescence, playing an important role in bone diseases prevention and treatment, and improving the therapeutic effect of BM-MSCs. In this paper, the latest research progress on the molecular mechanism of traditional chinese medicine active ingredients interfering BM-MSCs senescence was summarized, in order to provide new direction and reference basis for senescence intervention research and clinical application improvement of BM-MSCs.

Lycium barbarian seed oil activates Nrf2/ARE pathway to reduce oxidative damage in testis of subacute aging rats / 中国药理学通报

Aim To explore the effects of Lycium berry seed oil on Nrf2/ARE pathway and oxidative damage in testis of subacute aging rats. Methods Fifty out of 60 male SD rats, aged 8 weeks, were subcutaneously injected with 125 mg • kg"D-galactosidase in the neck for 8 weeks to establish a subacute senescent rat model. The presence of senescent cells was observed using P-galactosidase ((3-gal), while testicular morphology was examined using HE staining. Serum levels of testosterone (testosterone, T), follicle-stimulating hormone ( follicle stimulating hormone, FSH ) , luteinizing hormone ( luteinizing hormone, LH ) , superoxide dis-mutase ( superoxide dismutase, SOD ) , glutathione ( glutathione, GSH) and malondialdehyde ( malondial-dehyde, MDA) were measured through ELISA, and the expressions of factors related to aging, oxidative damage, and the Nrf2/ARE pathway were assessed via immunohistochemical analysis and Western blotting. Results After successfully identifying the model, the morphology of the testis was improved and the intervention of Lycium seed oil led to a down-regulation in the expression of [3-gal and -yH2AX. The serum levels of SOD, GSH, T, and FSH increased while MDA and LH decreased (P 0. 05) . Additionally, there was an up-regulated expression of Nrf2, GCLC, NQOl, and SOD2 proteins in testicular tissue ( P 0. 05 ) and nuclear expression of Nrf2 in sertoli cells. Conclusion Lycium barbarum seed oil may reduce oxidative damage in testes of subacute senescent rats by activating the Nrf2/ARE signaling pathway.

Research progress on bone metabolism and molecular mechanisms in accelerated aging SAMP6 mice / 中国药理学通报

Senile osteoporosis (SOP) is a systemic bone disease characterized by increased susceptibility to fractures. The pathogenesis of SOP is complex and not well understood. Currently, the rapid aging model mouse, senescence accelerated mouse prone 6 (SAMP6), is an ideal model for studying the mechanisms of SOP development and exploring its prevention and treatment. This model exhibits characteristics including increased bone fragility, degradation of bone microstructure, loss of bone matrix, and abnormal metabolism and dysfunction of bone cells, faithfully replicating the process of SOP occurrence and progression at both macroscopic and microscopic levels.

Effects of fractionated low-dose ionizing radiation in the induction of EA.hy926 cell senescence / 中国辐射卫生

Objective To investigate the mechanism of fractionated low-dose ionizing radiation (LDIR) in the induction of EA.hy926 cell senescence. Methods EA.hy926 cells were irradiated with X-ray at 0, 50, 100, and 200 mGy × 4, respectively, and cultured for 24, 48, and 72 h. Several indicators were measured, including the levels of cellular senescence-associated β-galactosidase (SA-β-gal) staining, mRNA levels of senescence-associated cell cycle protein-dependent kinase inhibitor genes CDKN1A and CDKN2A, reactive oxygen species (ROS), total antioxidant capacity (T-AOC), and phosphorylated H2A histone family member X (γ-H2AX). Results After 4 fractionated LDIR, compared with the control group, the treatment groups showed increased nucleus area, blurred cell edge, and increased SA-β-gal positive area (P < 0.05) at 24, 48 and 72 h. After 4 fractionated LDIR, the mRNA level of CDKN1A increased in the 100 and 200 mGy × 4 groups at 24 and 48 h (P < 0.05), and CDKN2A mRNA level increased in the 100 and 200 mGy × 4 groups at 48 and 72 h (P < 0.05). The fluorescence intensity of ROS increased in treatment groups at 24, 48, and 72 h after 4 fractionated LDIR (P < 0.05). After 4 fractionated LDIR, the T-AOC level increased in the 100 and 200 mGy × 4 groups at 24 h (P < 0.05), and T-AOC level increased in all treatment groups at 48 and 72 h (P < 0.05). After 4 fractionated LDIR, γ-H2AX fluorescence intensity increased in all treatment groups at 24 h (P < 0.05), and the fluorescence intensity increased in the 100 and 200 mGy × 4 groups at 48 and 72 h (P < 0.05). Conclusion Fractionated LDIR can induce cellular senescence in EA.hy926 cells by impacting the cellular oxidation-antioxidation and oxidative damage levels, and the effects were relatively evident at 100 and 200 mGy.

Anti-cancer Effect of Traditional Chinese Medicine in Regulating Cellular Senescence： A Review / 中国实验方剂学杂志

In recent years， the incidence and mortality rates of cancer have been increasing， posing a serious threat to human health. Western medicine mainly uses treatments such as surgical resection， chemotherapy， immunotherapy and targeted therapy， but they are prone to complications， drug resistance and adverse reactions. A growing number of studies have shown that traditional Chinese medicine has obvious advantages in the treatment of cancer， reducing the recurrence rate of cancer and improving the quality of survival of patients. Cellular senescence refers to a state of irreversible cell cycle growth arrest when cells cease to proliferate after a limited number of divisions， resulting in a decline in cell proliferation and differentiation capacities and physiological functions， accompanied by morphological changes such as flattening and multinuclear morphology. At the molecular level， it shows increased expression of DNA damage-related genes， reduced expression of cell cycle-related factors and significant secretory activity. The malignant development of cancer is closely related to cellular senescence. With the increasing number of cancer cell proliferation， cancer-related genes undergo continuous mutations， freeing them from cellular senescence and thus achieving unlimited proliferation. Through recent studies， it has been found that induction of tumor cell senescence， possibly through modulation of cellular DNA damage， cell cycle arrest and senescence-associated secretory phenotype （SASP）， which converts the suppressive immune tumor microenvironment to an activated immune tumor microenvironment and thus reverses the escape of tumor cell senescence， is a promising strategy for cancer therapy. However， the mechanism of cellular senescence in cancer progression is not fully understood， especially the anti-cancer role played by traditional Chinese medicine in regulating cellular senescence. This article summarized and concluded the specific molecular mechanisms of cellular senescence， the role of cellular senescence in cancer progression， and the mechanism of anti-cancer effects of traditional Chinese medicine based on cellular senescence from the perspective of regulating cellular senescence， with a view to providing ideas and methods for the anti-cancer effects of traditional Chinese medicine and the development of new drugs.

Genética y genómica de la longevidad y el envejecimiento / Genetics and genomics of longevity and aging

El envejecimiento y la longevidad son procesos que involucran una serie de factores genéticos, bioquímicos y ambientales. En esta revisión se tratan algunas cuestiones sobre estos dos procesos biológicos y epigenéticos. Se presentan los genes más importantes en estos procesos, así como se ejemplifican enfermedades que presentan un aceleramiento o falla en la longevidad y el envejecimiento. Se usa el análisis inteligente de datos para hallar interacciones de proteínas/genes que expliquen estos dos fenómenos biológicos.

Aging and longevity are processes that involve a series of genetic, biochemical and environmental factors. This review addresses some issues about these two biological and epigenetic processes. The most important genes in these processes are presented, as well as diseases that present an acceleration or failure in longevity and aging. Intelligent data analysis is used to find protein/gene interactions that explain these two biological phenomena.

Senescence in oral lichen planus as assessed by the immunohistochemical evaluation of senescence marker protein-30 (Regucalcin)

Background: Oral lichen planus is a T-cell-mediated chronic inflammatory disease affecting approximately 1% to 2% of the population, the etiology of which is currently unknown. The objectives of this study were to observe if senescence occurs in oral lichen planus, through the assessment of the immunohistochemical expression of a novel marker for senescence called Senescence marker protein-30 or regucalcin, and compare the expression to that in oral lichenoid reaction and non-specific inflammation. Subjects and Methods: The study material consisted of 30 cases of oral lichen planus, 15 cases of oral lichenoid reaction and 15 cases of non-specific inflammation. The number of positive cells in ten randomly selected high power fields were counted in the epithelium and the connective tissue separately and the mean was determined. Results: Mann–Whitney U test was used to statistically analyze if there was any significant difference in the expression of Senescence marker protein-30 between oral lichen planus, oral lichenoid reaction and non-specific inflammation. Even though a greater expression was seen in the oral lichen planus cases than oral lichenoid reaction, the difference in both the epithelium and connective tissue was not statistically significant. Conclusion: This study shows that in addition to the already known mechanisms like apoptosis and increased cell proliferation rates, the activated T-lymphocytes may also trigger a senescent change in the cells of oral lichen planus. As with the other mechanisms, this is also seen only in a small proportion of the cases.

Downregulated miR-181a alleviates H2O2-induced oxidative stress and cellular senescence by targeting PDIA6 in human foreskin fibroblasts

Abstract Background Oxidative stress is strongly associated with cellular senescence. Numerous studies have indicated that microRNAs (miRNAs) play a critical part in cellular senescence. MiR-181a was reported to induce cellular senescence, however, the potential mechanism of miR-181a in hydrogen peroxide (H2O2)-induced cellular senescence remains obscure. Objective The aim of this study is to investigate the role and regulatory mechanism of miR-181a in H2O2-induced cellular senescence. Methods Human foreskin fibroblasts (HFF) transfected with miR-181a inhibitor/miR-NC with or without H2O2 treatment were divided into four groups: control + miR-NC/miR-181a inhibitor, H2O2 + miR-NC/miR-181a inhibitor. CCK-8 assay was utilized to evaluate the viability of HFF. RT-qPCR was used to measure the expression of miR-181a and its target genes. Protein levels of protein disulfide isomerase family A member 6 (PDIA6) and senescence markers were assessed by western blotting. Senescence-associated β-galactosidase (SA-β-gal) staining was applied for detecting SA-β-gal activity. The activities of SOD, GPx, and CAT were detected by corresponding assay kits. The binding relation between PDIA6 and miR-181a was identified by luciferase reporter assay. Results MiR-181a inhibition suppressed H2O2-induced oxidative stress and cellular senescence in HFF. PDIA6 was targeted by miR-181a and lowly expressed in H2O2-treated HFF. Knocking down PDIA6 reversed miR-181a inhibition-mediated suppressive impact on H2O2-induced oxidative stress and cellular senescence in HFF. Study limitations Signaling pathways that might be mediated by miR-181a/PDIA6 axis were not investigated. Conclusion Downregulated miR-181a attenuates H2O2-induced oxidative stress and cellular senescence in HFF by targeting PDIA6.

Chronic Injury of Mice Bone Marrow Multipotent Hematopoietic Progenitor Cells Induced by Ionizing Radiation / 中国实验血液学杂志

OBJECTIVE@#To explore the chronic injury and its possible mechanism of ionizing radiation on multipotent hematopoietic progenitor cells (MPPs) by determining the related indicators of MPPs in bone marrow of mice post-radiation.@*METHODS@#Sixteen C57BL/6 adult mice were randomly divided into normal control and irradiation groups, 8 mice in each group. The mice in irradiation group were exposed to 6 Gy X-ray. The proportion of bone marrow MPPs, their apoptosis and proliferation 2 months after irradiation were detected by flow cytometry. Mitochondrial activity and levels of reactive oxygen species (ROS) in each MPPs population were detected by Mitotracker Red and DCFDA probes, and the senescent state of MPPs in the bone marrow was analyzed.@*RESULTS@#Ionizing radiation could reduce the proportion of MPPs in mouse bone marrow. The proportions and numbers of MPP1, MPP3 and MPP4 in the bone marrow were significantly decreased after whole-body irradiation with 6 Gy X-ray (P<0.05). In addition, radiation significantly reduced the colony-forming capacity of MPPs in bone marrow (P<0.05), the proportions of apoptotic cells in the MPP1 and MPP4 cell populations increased significantly in the bone marrow (P<0.05). The activity of mitochondria was significantly reduced in the bone marrow MPP2, MPP3 and MPP4 cell populations compared with that of the control group (P<0.05). It was also found that the radiation could significantly increase the ROS levels of MPPs in bone marrow, and the content of ROS in the MPP2, MPP3 and MPP4 cell population of the bone marrow was significantly increased(P<0.05). The senescent cells ratios of MPP1, MPP3 and MPP4 cells in the bone marrow after irradiation were significantly higher than those in the control group (P<0.05).@*CONCLUSION@#Ionizing radiation can cause chronic MPPs damage in mice, which is closely associated with persistent oxidative stress, cells apoptosis, and cellular senescence.

Research advances in the association between metabolic associated fatty liver and type 2 diabetes mellitus and the mechanism of comorbidity / 临床肝胆病杂志

There are gradual increases in the incidence rates of metabolic associated fatty liver disease （MAFLD） and type 2 diabetes mellitus （T2DM）， with close relationship and mutual interaction between the two diseases， but the specific mechanism is still unclear. Studies have shown that T2DM and MAFLD may cause aggravation of each other through insulin resistance， inflammation， some hepatocyte factors， and cellular senescence and protect each other through some hepatocyte factors. Further research on the association between T2DM and MAFLD and the mechanism of comorbidity is of great significance for the clinical prevention and treatment of the two diseases.

Construction and Validation of A Risk Model for Predicting Prognosis and Immunotherapy Response of Bladder Cancer Based on Cellular Senescence-related Genes / 肿瘤防治研究

Objective To evaluate the prognosis and immunotherapy response of patients with bladder cancer by constructing a risk-score model of cellular senescence-related signature (SRS), as well as to explore the clinical application value of SRS in bladder cancer. Methods Senescence genes were screened from TCGA-BLCA, and cellular SRS genes were screened according to LASSO regression. A bladder cancer risk-score model was constructed based on the SRS genes to analyze the survival difference and model-fit degree of TCGA-BLCA high- and low-risk groups. Univariable and multivariable Cox regression was used to analyze the prognostic risk factors of bladder cancer. Overall survival differences of high- and low-risk groups in GEO-BLCA database were verified, and variations in immunotherapy responses were analyzed in IMvigor210 databases. According to the result of β-gal chromogenic reaction in bladder cancer and normal paracancer tissues, the existence of cell senescence was determined. Results Eight marker genes were screened, and patients were divided into high- and low-risk groups according to the median risk score constructed by the marker genes. The 5-year survival rate of high risk group was lower than that of low risk group (training and validation sets P < 0.05). The area under the ROC curve of TCGA-BLCA in 1-, 3-, and 5-year were 0.657, 0.660, and 0.688, and those for GSE13507 were 0.665, 0.665, and 0.613, respectively. SRS risk score can be used as an independent risk factor for the prognosis of patients with bladder cancer. The SRS risk score in the response group was lower than that in the non-response group during bladder cancer immunotherapy (P < 0.05). The β-gal staining of bladder cancer tissue was positive, but the β-gal staining of adjacent normal tissue was negative. Conclusion Cell senescence occurs in bladder cancer tissues. SRS risk score can predict the clinical prognosis of patients with bladder cancer, and patients with low score can benefit from immunotherapy. SRS is a reliable biomarker for the prognosis and immunotherapy response of bladder cancer.

Expression of TIGIT, PD-1 and HLA-DR/CD38 markers on CD8-T cells of children and adolescents infected with HIV and uninfected controls

ABSTRACT Immune exhaustion and senescence are scarcely studied in HIV-pediatric patients. We studied the circulatory CD8 T cells activation/exhaustion and senescent phenotype of children and adolescents vertically infected with HIV or uninfected controls based on the expression of human leukocyte antigen (HLA-DR), CD38, T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT), programmed death 1 (PD-1) and CD57 by flow cytometry, during approximately one year. Eleven HIV-infected (HI) and nine HIV-uninfected (HU) children/adolescents who received two doses or one dose of meningococcal C conjugate vaccine (MenC), respectively, were involved in this study. Blood samples were collected before the immunization (T0), 1-2 months after the first dose (T1), and 1-2 months after the second dose (T2), which was administered approximately one year after the first one. HI patients not receiving combined antiretroviral therapy (cART) showed a higher frequency of CD8 T cells TIGIT+, PD-1+ or CD57+, as well as a higher frequency of CD8 T cells co-expressing CD38/HLA-DR/TIGIT or CD38/HLA-DR/PD-1 when compared to HI treated or HU individuals, at all times that they were assessed. CD8 T cells co-expressing CD38/DR/TIGIT were inversely correlated with the CD4/CD8 ratio but positively associated with viral load. The co-expression of CD38/DR/TIGIT or CD38/DR/PD-1 on CD8 T cells was also inversely associated with the CD4 T cells expressing co-stimulatory molecules CD127/CD28. The results showed a higher expression of exhaustion/senescence markers on CD8 T cells of untreated HI children/adolescents and its correlations with viral load.

O efeito do tratamento com rapamicina em órgãos linfoides de camundongos propensos à senescência acelerada / The effect of rapamycin treatment on lymphoid organs of senescence accelerated mice prone

Envelhecer compreende um fenômeno complexo, natural e irreversível, que submete o organismo a inúmeras alterações nos processos biológicos, fisiológicos, ambientais, psicológicos, comportamentais e sociais. Esse processo é caracterizado por um declínio gradual dos mecanismos homeostáticos do organismo, intimamente relacionados com o estado senescente. A senescência, quando diz respeito ao sistema imunológico, é denominada de imunossenescência, que pode ser definida como uma parada estável do ciclo celular associada a mudanças, com uma resposta que limita a proliferação de células envelhecidas ou danificadas. A autofagia está diretamente relacionada com a manutenção do fenótipo senescente, em que a atividade autofágica exerce um papel essencial e ativo na influência da biossíntese de proteínas e organelas. Essa via é regulada naturalmente pela proteína mTOR e quimicamente pelo fármaco rapamicina. Assim, pretendemos investigar: (1) as alterações no perfil corporal e hematimêtrico dos animais ao longo do tratamento com rapamicina; (2) avaliar o perfil de citocinas; (3) observar as modificações histológicas em órgãos linfoides primários e secundário; (4) analisar as populações de células linfoides e mieloides; e (5) avaliar a capacidade proliferativa de linfócitos in vitro. Camundongos SAMP-8 e SAMR-1 foram tratados com rapamicina durante dois meses. A mensuração da massa corporal e análises hematológicas foram realizadas antes e durante o tratamento. Amostras de soro, medula óssea, timo e baço foram analisados em ensaios de ELISA, histologia, população e subpopulações de células. Alterações na massa corporal, parâmetros hematológicos e celularidade de células foram nítidas entre os dois modelos utilizados. Diferenças também foram percebidas na detecção de citocinas IL-1ß. IL-6 e TNF-α, com resultados significantes nas amostras de baço, timo e medula óssea. As citocinas IL-7 e IL-15 apresentaram diferenças de secreção entre os grupos, sendo a primeira maior detectada em camundongos com senescência acelerada tratados com rapamicina. Em nossa análise histológica observamos que os camundongos SAM-P8 apresentaram involução tímica. E nas subpopulações de linfócitos T do baço, células TCD4+ e TCD8+ estavam, respectivamente, em maior e menor quantidade nos camundongos SAM-P8 tratados com rapamicina. Dessa forma, o camundongo da linhagem SAM-P8 é um excelente modelo para se estudar as alterações da senescência, em que o mesmo apresenta características fisiológicas distintas dos camundongos utilizados como controle (SAM-R1). Além disso, verificamos que a dose de rapamicina empregada não desencadeou alterações que pudessem comprometer a resposta imunológica desses camundongos, bem como na possibilidade de atuar na resposta contra os efeitos complexos do envelhecimento

Aging comprises a complex, natural, and irreversible phenomenon, which subjects the organism to countless alterations in biological, physiological, environmental, psychological, behavioral, and social processes. This process is characterized by a gradual decline in the organism's homeostatic mechanisms, closely related to senescence effects. Senescence, when it concerns the immune system, is called immunosenescence, which can be defined as a stable cell cycle arrest associated with changes and is a response that limits the proliferation of aged or damaged cells. Autophagy is a genetically regulated, conserved cellular process and a metabolic pathway essential for maintaining cellular homeostasis, which plays a constitutive and active role in controlling the biosynthesis of proteins and organelles. This pathway is regulated naturally by mTOR or chemically by the drug rapamycin, having a direct relationship with cellular homeostasis and maintenance of the senescent phenotype. Thus, we intend to investigate: (1) the changes in the body and hematimetic profile of the animals throughout the rapamycin treatment; (2) evaluate the cytokine profile; (3) observe histological changes in primary and secondary lymphoid organs; (4) analyze lymphoid and myeloid cell populations; and (5) evaluate the proliferative capacity of lymphocytes in vitro. SAMP-8 and SAMR-1 mice were treated with rapamycin for two months. Body mass measurement and hematological analyses were performed before and during treatment. Serum, bone marrow, thymus and spleen samples were analyzed in ELISA assays, histology, cell population and subpopulations. Changes in body mass, hematological parameters, and cellularity were clear between the two models used. Differences were also noticed in the detection of cytokines IL-1ß. IL-6 and TNF-α, with significant results in the spleen, thymus and bone marrow samples. The cytokines IL-7 and IL-15 showed differences in secretion between groups, the former being higher detected in mice with accelerated senescence treated with rapamycin. In our histological analysis we observed that SAM-P8 mice showed thymic involution. And in the spleen T-lymphocyte subpopulations, TCD4+ and TCD8+ cells were, respectively, in higher and lower quantities in SAM-P8 mice treated with rapamycin. Thus, the SAM-P8 mouse is an excellent model to study the changes of senescence, since it presents physiological characteristics different from the control mice (SAM-R1). Furthermore, we verified that the dose of rapamycin used did not trigger changes that could compromise the immune response of these mice, as well as the possibility of acting in the modulatory response against the complex effects of aging

Cellular senescence and type 2 diabetes / 中华内分泌代谢杂志

Cellular senescence is a state in which cells enter permanent cell cycle arrest, which is characterized by senescence-associated secretory phenotype secretion, macromolecular damage, metabolic dysregulation and so on. Recent studies have shown a close relationship between cellular senescence and type 2 diabetes. On the one hand, the glycolipotoxic microenvironment of type 2 diabetes can accelerate cell senescence and accumulation. On the other hand, cellular senescence can promote the development of type 2 diabetes. For example, senescence of pancreatic β-cells leads to β-cell dysfunction and adipocytes senescence results in the secretion of pro-inflammatory cytokines, causing disturbances in lipid metabolism and exacerbating insulin resistance. Moreover, senescence of endothelial cells, retinal endothelial cells, and other cell types contributes to the occurrence of chronic complications in diabetes. Cellular senescence is not only an important factor in the onset of type 2 diabetes but also a consequence of its progression. Targeting cellular senescence holds promise as a new strategy for the treatment of type 2 diabetes.

Effect of autophagic core protein Atg101 on adipocyte senescence / 中华内分泌代谢杂志

Objective:To investigate the effect of autophagy related gene Atg101 on white adipocyte senescence.Methods:An Atg101 knockdown model of 3T3-L1 mature adipocytes was constructed to probe the effect of Atg101 on autophagy-related proteins LC3 and p62 protein. The RNA-seq database of human subcutaneous adipose tissue was constructed and analyzed, and the co-expressed gene set was predicted based on the pearson correlation coefficient( R2>0.4, P<0.05) between FPKM values of Atg101 and other gene, followed by KEGG and Reactome enrichment analysis. Young mouse(8 weeks old) and old mouse(18 months old) models were established, and the expression levels of Atg101 in inguinal white adipose tissue and epididymal white adipose tissue were detected by quantitative real-time PCR(RT-qPCR) and Western blot. Furthermore, the differences in white adipocyte senescence-associated secretory phenotype(SASP), cell cycle and mitochondrial homeostasis-related genes were detected by RNA-seq, Western blot, and RT-qPCR to analyze the effects of Atg101 silencing on adipocyte senescence. Results:The autophagy-related protein LC3-Ⅱ expression was significantly decreased and p62 protein was induced after Atg101 was knockdowned in 3T3-L1 adipocytes, suggesting impaired cell autophagy. KEGG enrichment analysis revealed that Atg101 co-expressed gene set was mainly enriched in autophagy and senescence-related pathways; Reactome enrichment analysis revealed that this gene set was associated with multiple cell cycle signaling pathways. RT-qPCR and Western blot confirmed that both mRNA and protein levels of Atg101 were down-regulated in inguinal white adipose tissue of aging mice, and protein levels in epididymal white adipose tissue were also significantly reduced. Finally, it was further confirmed that SASP-related genes were induced after Atg101 knockdown in white adipocytes, and cell cycle-specific gene expression was restricted and cytokine-dependent protein kinase inhibitors p16 and p21 expressions were significantly increased, while mitochondrial homeostasis regulatory genes were also suppressed.Conclusions:Knockdown of Atg101 may regulate white adipocyte senescence by inhibiting autophagic activity, presenting impaired mitochondrial homeostasis.

Characteristics, cellular and molecular mechanisms of renal aging and nutritional intervention strategies / 中华老年医学杂志

Renal aging is a gradual process of degenerative changes in tissue structure and physiological function and is closely related to the occurrence and development of acute kidney injury(AKI)and chronic kidney disease(CKD). The cellular and molecular mechanisms of renal aging mainly include cellular senescence and reduced autophagy, and are regulated by nutritional factors.Promoting reasonable and moderate energy-and protein-restricted diets, strengthening the supervision of food additives and preservatives, cultivating safety awareness of residents, and strictly controlling the daily salt intake are potential nutritional intervention strategies to prevent and delay renal aging.Given the limited number of studies, there is an urgent need to further explore the effectiveness of the above strategies to provide a new evidence-based approach to formulating precise and feasible personalized nutritional intervention programs.

Mechanism of racanisodamine on alleviating radiation-induced lung injury in mice / 中华放射医学与防护杂志

Objective:To investigate the protective effect of racanisodamine on lung injury in mice exposed to irradiation.Methods:C57BL/6 mice were randomly divided into control group, racanisodamine group, 18 Gy irradiation group (model group) and racanisodamine combined with 18 Gy irradiation group (treatment group), with 5 mice in each group. The mice in the treatment group received racanisodamine (5 mg/kg) intraperitoneally 3 d before irradiation and contained the whole experiments. Then, single chest irradiation of 18 Gy X-rays was performed both in the model and treatment groups. The racanisodamine group and treatment group received racanisodamine intraperitoneally once a day until 6 weeks after irradiation. The mice were killed at 6 weeks after irradiation. The lung histopathology was observed by HE staining. Serum and bronchial alveolar lavage fluid (BALF) inflammatory cytokines such as TNF-α, IL-1β and IL-6 were determined by ELISA method. Cell senescence was detected by SA-β-Gal staining. The expressions of Nrf2, p-Nrf2 and p62 in lung tissue were performed by immunehistochemistry and Western blot assays.Results:Compared with the model group, the scores of HE staining were decreased ( t=8.66, P<0.01), the number of infiltrated inflammatory cells in BALF were decreased ( t=10.70, P<0.01), and protein concentration in BALF had lower levels ( t=6.75, P<0.01), the serum TNF-α, IL-1β and IL-6 were decreased significantly ( t=8.17, 4.58, 6.54, P<0.01), the activity of SA-β-gal was decreased, and the expressions of Nrf2, p-Nrf2 were enhanced ( t=6.42, 7.30, P<0.01), while the expression of p62 was reduced ( t=4.62, P<0.01) in the treatment group. Conclusions:Racanisodamine plays the protective effect of radiation-induced lung injury by alleviating inflammation associating with the activating of Nrf2-related pathway, which reversed radiation-induced cell senescence.

Research progress on the role and mechanism of premature cellular senescence on wound healing in radiation-induced skin injury / 中华放射医学与防护杂志

Radiation skin injury can be induced by medical exposure, occupational exposure, and emergency exposure. Many relevant studies focused on the prevention and treatment of radiation-induced skin injury, but the underlying molecular mechanisms have not been fully clarified. It has been demonstrated that radiation-induced premature cellular senescence is involved in radiation skin injury. To discuss the relationship between radiation-induced premature cellular senescence and radiation-induced skin injury, this paper reviewed the mechanism of radiation-induced skin injury, the promotion of premature cellular senescence and related signal pathways, and the role of premature cellular senescence in wound healing.

Research progress of cellular senescence in glaucoma / 中华实验眼科杂志

Cellular senescence is a response process in which cells are activated by ischemia, hypoxia, oxidative stress, DNA damage, reactive oxygen species deposition and other stimulations.Senescent cells markers include such as senescence-associated β-galactosidase (SA-β-gal) activation, P16INK4a upregualtion, senescence-associated heterochromatic foci (SAHF) accumulation, senescence-associated secretory phenotype (SASP) generation, telomere shortening and so on.P16INK4a/Rb and P19 ARF/P53/P21 Cip1 pathways are two classic cell senescence signaling pathways, which are interconnected and independent on each other.In recent years, glaucoma is considered as a blinding eye disease associated with cell senescence.Research on cell senescence in glaucoma mainly focuses on trabecular meshwork and Schlemm cannel endothelial cells senescence leading to increased resistance of aqueous humor outflow pathway, and the mechanism of retinal ganglion cells senescence and treatment in glaucoma.As an irreversible stage before cell death, deeper study on the mechanism of retinal ganglion cells senescence, and specific blocking of cell senescence will provide a new target for reducing the aqueous humor outflow resistance and protecting the optic nerve in glaucoma.This article reviewed characteristics, inducements, molecular signaling pathways of cellular senescence in glaucoma.