新化合物Elixir-X对肝切及辐射所致衰老小鼠的抗衰老作用

目的 探讨蜂巢提取物Elixir-X对自然衰老及辐射衰老小鼠的影响，为Elixir-X的进一步研发提供药理学基础。方法 采用小鼠肝脏切除术建立自然衰老小鼠模型，将其分为空白对照组、Elixir-X组、白藜芦醇组及模型组，连续给药7 d后，检测小鼠70%肝脏切除后的再生过程中，衰老细胞、肝脏功能恢复与肝脏再生的变化，观察Elixir-X对自然衰老的影响；采用60CO辐射法建立辐射衰老小鼠模型，将其分为模型组、空白对照组、白藜芦醇组、Elixir-X高、低剂量组，通过检测小鼠肠隐窝干细胞再生、小肠绒毛结构以及衰老细胞的变化，对比不同剂量Elixir-X对辐射后衰老的影响。结果 在肝脏切除术的小鼠模型中，Elixir-X组的肝功能水平明显低于模型组的肝脏自然再生小鼠，显著促进了肝功能恢复（P＜0.05）；同时与模型组相比，Elixir-X组清除了肝脏切除后再生过程中产生的衰老细胞（P＜0.05），Ki-67的着色斑块明显增加，促进肝脏的再生，且肝血窦的扫描电镜影像结果中Elixir-X组肝血窦再生加快。60CO辐照小鼠模型中，与模型组相比，Elixir-X组有效促进辐照后肝脏功能恢复（P＜0.05），Elixir-X高剂量组体重也恢复到正常水平，与空白对照组无显著差异；与模型组相比，Elixir-X低剂量组小肠的β-Gal着色细胞减少，Elixir-X高剂量组甚至能更有效地减少衰老细胞（P＜0.05）；小肠HE染色的结果中，Elixir-X组小肠绒毛结构得到恢复；Ki-67的IHC染色中，与模型组相比，Elixir-X组着色板块更多，且着色区域都在肠隐窝干细胞位置。结论 Elixir-X能有效清除肝脏切除术引起的自然衰老与辐射引起的损伤性衰老细胞，对衰老具有显著地抑制作用。     

Fibroageing: An ageing pathological feature driven by dysregulated extracellular matrix-cell mechanobiology

Ageing is a multifactorial biological process leading to a progressive decline of physiological functions. The process of ageing includes numerous changes in the cells and the interactions between cell-cell and cell-microenvironment remaining as a critical risk factor for the development of chronic degenerative diseases. Systemic inflammation, known as inflammageing, increases as a consequence of ageing contributing to age-related morbidities. But also, persistent and uncontrolled activation of fibrotic pathways, with excessive accumulation of extracellular matrix (ECM) and organ dysfunction is markedly more frequent in the elderly. In this context, we introduce here the concept of Fibroageing, that is, the propensity to develop tissue fibrosis associated with ageing, and propose that ECM is a key player underlying this process. During ageing, molecules of the ECM become damaged through many modifications including glycation, crosslinking, and accumulation, leading to matrix stiffness which intensifies ageing-associated alterations. We provide a framework with some mechanistic hypotheses proposing that stiff ECM, in addition to the well-known activation of fibrotic positive feedback loops, affect several of the hallmarks of ageing, such as cell senescence and mitochondrial dysfunction, and in this context, is a key mechanism and a driver thread of Fibroageing.     

Anti-aging effect of DL-β-hydroxybutyrate against hepatic cellular senescence induced by D-galactose or γ-irradiation via autophagic flux stimulation in male rats

The present study aims to shed new light on anti-aging effect of DL-β-hydroxybutyrate (βOHB) against hepatic cellular senescence induced by d-galactose or γ-irradiation. The rats divided into 6 groups. Group 1, control, group 2, exposed to γ-ray (5 GY), group 3, injected by d-galactose (150 mg/kg) daily for consecutive 6 weeks, which regarded to induce the aging, group 4, injected intraperitoneal by β-hydroxybutyrate (βOHB) (72.8 mg/kg) daily for consecutive 14 days, group 5, exposed to γ-ray then treated with βOHB daily for consecutive 14 days, group 6, injected daily with d-galactose for consecutive 6 weeks, then treated with βOHB daily at the last two weeks of d-galactose. Aspartate amino transferase (AST), alanine amino transferase (ALT), Insulin, interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were estimated in serum. Moreover, protein expression of Microtubule-associated proteins 1A/1B light chain 3B (LC3-II/LC3-I) ratio, mechanistic target of rapamycin (mTOR), pAMPK, mRNA gene expression of 5′ AMP-activated protein kinase (AMPK), Nucleoporin p62 (p62), cyclin-dependent kinase inhibitor 1(P21^CIP1), cyclin-dependent kinase inhibitor 2A (p16^INK4a) and DNA fragmentation percentage were measured in liver tissue as a biomarker of cellular senescence. The results confirmed that βOHB modulated serum level of AST, ALT, insulin, IL-6 and TNF-α, protein expression of mTOR and LC3-II/LC3-I ratio, pAMPK and p62 in liver aging model induced by d-galactose or γ-irradiation. Histopathological examination results of liver tissue indicated coincidence with those recorded by molecular biochemical inspection. Taken together, these findings suggest that βOHB may be useful in combating hepatic cellular senescence induced by d-galactose or γ-irradiation via autophagy dependent mechanisms.     

Influence of resveratrol supplementation on IVF–embryo transfer cycle outcomes

Research questionDoes resveratrol, a polyphenolic compound, affect IVF–embryo transfer outcomes?DesignThis single-centre, cross-sectional retrospective study was designed to compare the outcomes of embryo transfer cycles in women receiving resveratrol supplementation (200 mg/day) continuously (RES group) with a control group (non-RES group). Of 8686 embryo transfer cycles, 1409 cycles with poor prognostic factors were excluded, including cycles in women aged ≥43 years and those with poor-quality embryos. The RES group (204 cycles, 102 women) was compared with the non-RES group (7073 cycles, 2958 women).ResultsAfter matching patients by age at the time of oocyte retrieval, grade and developmental stage of embryos, number of embryos transferred, and fresh or vitrified-warmed embryo transfer, multivariate logistic regression analysis showed that resveratrol supplementation is strongly associated with a decrease in clinical pregnancy rate [odds ratio (OR) 0.539, 95% confidence interval (CI) 0.341–0.853] and an increased risk of miscarriage (OR 2.602, 95% CI 1.070–6.325).ConclusionsResveratrol supplementation during embryo transfer cycles appears to be detrimental for pregnancy outcomes. An analysis of the supplementation protocol and randomized controlled studies are needed.     

Breast cancer treatment and its effects on aging

Breast cancer is the most common cancer of women in the United States. It is also proving to be one of the most treatable. Early detection, surgical intervention, therapeutic radiation, cytotoxic chemotherapies and molecularly targeted agents are transforming the lives of patients with breast cancer, markedly improving their survival. Although current breast cancer treatments are largely successful in producing cancer remission and extending lifespan, there is concern that these treatments may have long lasting detrimental effects on cancer survivors, in part, through their impact on non-tumor cells. Presently, the impact of breast cancer treatment on normal cells, its impact on cellular function and its effect on the overall function of the individual are incompletely understood. In particular, it is unclear whether breast cancer and/or its treatments are associated with an accelerated aging phenotype. In this review, we consider breast cancer survivorship from the perspective of accelerated aging, and discuss the evidence suggesting that women treated for breast cancer may suffer from an increased rate of physical and cognitive decline that likely corresponds with underlying vulnerabilities of genome instability, epigenetic changes, and cellular senescence.     

Endothelin-1 induces chondrocyte senescence and cartilage damage via endothelin receptor type B in a post-traumatic osteoarthritis mouse model

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Palbociclib induces DNA damage and inhibits DNA repair to induce cellular senescence and apoptosis in oral squamous cell carcinoma

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Sorafenib,rapamycin, and venetoclax attenuate doxorubicin-induced senescence and promote apoptosis in HCT116 cells

Emerging evidence has shown that the therapy-induced senescent growth arrest in cancer cells is of durable nature whereby a subset of cells can reinstate proliferative capacity. Promising new drugs named senolytics selectively target senescent cells and commit them into apoptosis. Accordingly, senolytics have been proposed as adjuvant cancer treatment to cull senescent tumor cells, and thus, screening for agents that exhibit senolytic properties is highly warranted. Our study aimed to investigate three agents, sorafenib, rapamycin, and venetoclax for their senolytic potential in doxorubicin-induced senescence in HCT116 cells. HCT116 cells were treated with one of the three agents, sorafenib (5 µM), rapamycin (100 nM), or venetoclax (10 µM), in the absence or presence of doxorubicin (1 µM). Senescence was evaluated using microscopy-based and flow cytometry-based Senescence-associated-β-galactosidase staining (SA-β-gal), while apoptosis was assessed using annexin V-FITC/PI, and Muse caspase-3/-7 activity assays. We screened for potential genes through which the three drugs exerted senolytic-like action using the Human Cancer Pathway Finder PCR array. The three agents reduced doxorubicin-induced senescent cell subpopulations and significantly enhanced the apoptotic effect of doxorubicin compared with those treated only with doxorubicin. The senescence genes IGFBP5 and BMI1 and the apoptosis genes CASP7 and CASP9 emerged as candidate genes through which the three drugs exhibited senolytic-like properties. These results suggest that the attenuation of doxorubicin-induced senescence might have shifted HCT116 cells to apoptosis by exposure to the tested pharmacological agents. Our work argues for the use of senolytics to reduce senescence-mediated resistance in tumor cells and to enhance chemotherapy efficacy.