Aging is the main risk factor for many chronic degenerative diseases and cancer. Increased senescent cell burden in various tissues is a major contributor to aging and age-related diseases. Recently, ...a new class of drugs termed senolytics were demonstrated to extending healthspan, reducing frailty and improving stem cell function in multiple murine models of aging. To identify novel and more optimal senotherapeutic drugs and combinations, we established a senescence associated β-galactosidase assay as a screening platform to rapidly identify drugs that specifically affect senescent cells. We used primary Ercc1
murine embryonic fibroblasts with reduced DNA repair capacity, which senesce rapidly if grown at atmospheric oxygen. This platform was used to screen a small library of compounds that regulate autophagy, identifying two inhibitors of the HSP90 chaperone family as having significant senolytic activity in mouse and human cells. Treatment of Ercc1
mice, a mouse model of a human progeroid syndrome, with the HSP90 inhibitor 17-DMAG extended healthspan, delayed the onset of several age-related symptoms and reduced p16
expression. These results demonstrate the utility of our screening platform to identify senotherapeutic agents as well as identified HSP90 inhibitors as a promising new class of senolytic drugs.The accumulation of senescent cells is thought to contribute to the age-associated decline in tissue function. Here, the authors identify HSP90 inhibitors as a new class of senolytic compounds in an in vitro screening and show that administration of a HSP90 inhibitor reduces age-related symptoms in progeroid mice.
Sarcomas is a group of heterogeneous malignant tumors originated from mesenchymal tissue and different types of sarcomas have disparate outcomes. The present study aims to identify the prognostic ...value of immune-related genes (IRGs) in sarcoma and establish a prognostic signature based on IRGs.
We collected the expression profile and clinical information of 255 soft tissue sarcoma samples from The Cancer Genome Atlas (TCGA) database and 2498 IRGs from the ImmPort database. The LASSO algorithm and Cox regression analysis were used to identify the best candidate genes and construct a signature. The prognostic ability of the signature was evaluated by ROC curves and Kaplan-Meier survival curves and validated in an independent cohort. Besides, a nomogram based on the IRGs and independent prognostic clinical variables was developed.
A total of 19 IRGs were incorporated into the signature. In the training cohort, the AUC values of signature at 1-, 2-, and 3-years were 0.938, 0.937 and 0.935, respectively. The Kaplan-Meier survival curve indicated that high-risk patients were significantly worse prognosis (P < 0.001). In the validation cohort, the AUC values of signature at 1-, 2-, and 3-years were 0.730, 0.717 and 0.647, respectively. The Kaplan-Meier survival curve also showed significant distinct survival outcome between two risk groups. Furthermore, a nomogram based on the signature and four prognostic variables showed great accuracy in whole sarcoma patients and subgroup analyses. More importantly, the results of the TF regulatory network and immune infiltration analysis revealed the potential molecular mechanism of IRGs.
In general, we identified and validated an IRG-based signature, which can be used as an independent prognostic signature in evaluating the prognosis of sarcoma patients and provide potential novel immunotherapy targets.
The overpressure of silo wall caused by granular materials under earthquake is one of the main reasons of silo damage. Two shaking table model tests were carried out with column supported silos and ...independent single silos, respectively. The seismic response of silo granular materials was analyzed first, and then the dynamic lateral pressure of silo wall under different levels of earthquake and overpressure coefficient were obtained. The results showed that the interaction between the granular materials and the silo wall in the group silos is related to the position of the individual silo. The seismic response of granular materials is linked with the spectral characteristics of seismic waves. The overpressure coefficients of the corner silo and the side silo are greater than that of the independent single silo with a 7% and 9% higher value, respectively. Apparently, the seismic response characteristics of the independent single silo are totally different from that of the group silos. It was concluded that when designing the wall of the group bin, the position of the bin should also be considered.
This paper investigates the shear performance of HDC beams reinforced with stirrups. The use of HDC led to limited crack propagation, multiple micro diagonal cracks between the load and support ...points, and ductile shear failure mode with significant nonlinear response, compared to reference specimens. The contribution of longitudinal reinforcement for shear strength of HCD specimens were larger than RC specimens. An average increment in shear strength of about 19% and a maximum value up to 40% was obtained. A modified formula for evaluating the shear capacity of HDC beam was proposed, and assessed with experimental results.
To improve the thermal insulation properties and toughness of concrete, the glazed hollow bead (GHB) and polyvinyl alcohol (PVA) fiber reinforced cementitious composites (GPCC) were investigated by ...orthogonal test, which includes six GHB mass percentage (20%, 40%, 60%, 80%,100%, 120%), three PVA volume fraction (1%, 1.5%, 2%) and water binder ratio (0.26, 0.30, 0.34). Compressive, split tensile strengths and thermal conductivity of GHB-PVA reinforced cementitious composites (GPCC) were tested, and the mechanism of fibers was analyzed from a microscopic perspective. The results revealed that the thermal insulation will be significantly improved with the increased content of GHB, but the compressive and split tensile strength will be decreased simultaneously. No obvious effect was found by the PVA fiber addition on its strength indexes, and the presence of GHB will affect the bridging action of PVA fibers. The water binder ratio has more effect on strengths than thermal conductivity. Based on the mechanical performance rather than the thermal insulation analysis test, the optimal mix proportions were proposed: mass percentage of 40% GHB, a volume fraction of 1.5% PVA fiber, and 0.26 water-binder ratio. Moreover, the anchoring and bridging effect of PVA fibers will effectively balance the stress generated by the shrinkage of cement paste, and inhibits or even prevents the development of cracks. However, a certain number of tiny cracks will be formed near the GHB, and between GHB and PVA fibers, which will cause local stretching and peeling of PVA, and shattering inside the GHB with the increase of external force. The findings of this study can provide a useful reference for the application of an insulated-bearing material with GHB and PVA fiber.
Hydroxytyrosol (HT) in extra-virgin olive oil is considered one of the most important polyphenolic compounds responsible for the health benefits of the Mediterranean diet for lowering incidence of ...cardiovascular disease, the most common and most serious complication of diabetes. We propose that HT may prevent these diseases by a stimulation of mitochondrial biogenesis that leads to enhancement of mitochondrial function and cellular defense systems. In the present study, we investigated effects of HT that stimulate mitochondrial biogenesis and promote mitochondrial function in 3T3-L1 adipocytes. HT over the concentration range of 0.1–10 μmol/L stimulated the promoter transcriptional activation and protein expression of peroxisome proliferator-activated receptor (PPAR) coactivator 1 alpha (PPARGC1α, the central factor for mitochondrial biogenesis) and its downstream targets; these included nuclear respiration factors 1 and 2 and mitochondrial transcription factor A, which leads to an increase in mitochondrial DNA (mtDNA) and in the number of mitochondria. Knockdown of
Ppargc1α by siRNA blocked HT's stimulating effect on Complex I expression and mtDNA copy number. The HT treatment resulted in an enhancement of mitochondrial function, including an increase in activity and protein expression of Mitochondrial Complexes I, II, III and V; increased oxygen consumption; and a decrease in free fatty acid contents in the adipocytes. The mechanistic study of the PPARGC1α activation signaling pathway demonstrated that HT is an activator of 5′AMP-activated protein kinase and also up-regulates gene expression of PPARα, CPT-1 and PPARγ. These data suggest that HT is able to promote mitochondrial function by stimulating mitochondrial biogenesis.
The walls of grain cottage silos are still being built by clay brick masonry featured with single-structure form, poor air tightness, large workload of manual masonry on site, and huge consumption of ...raw materials and burning materials, which is not conducive to energy saving and environmental protection. In order to study the mechanical function of the new wall under the action of grain side pressure, the static loading test was conducted on the model of scaled-down wall panel under the action of side pressure. The damage process, the damage pattern, and the bearing capacity of the wall panel were studied through the analysis of the crack development process and distribution law to reveal the force characteristics of the wall panel. The test results show that the span deflection of the “structure-insulation” integrated wall panel under the lateral pressure meets the requirement of the limit state of normal use; the inner and outer leaf wall panels can work together under the action of the joint; the ratio of the load borne by the inner and outer leaf wall panels is equal to the ratio of their stiffness; the flexural stiffness of the wall panels after cracking is proposed based on the combined effect analysis. Based on the analysis of the combined effect, the degradation factor of the wall panel after cracking is proposed, and the deflection calculation formula of the inner and outer leaf wall panel is established, which provides a theoretical basis for the design and the promotion of the “structure-insulation” integrated wall panel.
In our previous study, we found that pretreatment with lipoamide (LM) more effectively than alpha-lipoic acid (LA) protected retinal pigment epithelial (RPE) cells from the acrolein-induced damage. ...However, the reasons and mechanisms for the greater effect of LM than LA are unclear. We hypothesize that LM, rather than the more direct antioxidant LA, may act more as an indirect antioxidant. In the present study, we treated ARPE-19 cells with LA and LM and compared their effects on activation of mitochondrial biogenesis and induction of phase II enzyme systems. It is found that LM is more effective than LA on increasing mitochondrial biogenesis and inducing the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and its translocation to the nucleus, leading to an increase in expression or activity of phase II antioxidant enzymes (NQO-1, GST, GCL, catalase and Cu/Zn SOD). Further study demonstrated that mitochondrial biogenesis and phase II enzyme induction are closely coupled via energy requirements. These results suggest that LM, compared with the direct antioxidant LA, plays its protective effect on oxidative damage more as an indirect antioxidant to simultaneously stimulate mitochondrial biogenesis and induction of phase II antioxidant enzymes.
Rigorous control of substrate oxidation by humoral factors is essential for maintaining metabolic homeostasis. During feeding and fasting cycles, carbohydrates and fatty acids are the two primary ...substrates in oxidative metabolism. Here, we report a novel role for the peptide hormone adropin in regulating substrate oxidation preferences. Plasma levels of adropin increase with feeding and decrease upon fasting. A comparison of whole-body substrate preference and skeletal muscle substrate oxidation in adropin knockout and transgenic mice suggests adropin promotes carbohydrate oxidation over fat oxidation. In muscle, adropin activates pyruvate dehydrogenase (PDH), which is rate limiting for glucose oxidation and suppresses carnitine palmitoyltransferase-1B (CPT-1B), a key enzyme in fatty acid oxidation. Adropin downregulates PDH kinase-4 (PDK4) that inhibits PDH, thereby increasing PDH activity. The molecular mechanisms of adropin's effects involve acetylation (suggesting inhibition) of the transcriptional coactivator PGC-1α, downregulating expression of Cpt1b and Pdk4. Increased PGC-1α acetylation by adropin may be mediated by inhibiting Sirtuin-1 (SIRT1), a PGC-1α deacetylase. Altered SIRT1 and PGC-1α activity appear to mediate aspects of adropin's metabolic actions in muscle. Similar outcomes were observed in fasted mice treated with synthetic adropin. Together, these results suggest a role for adropin in regulating muscle substrate preference under various nutritional states.
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