Metformin decelerates aging clock in male monkeys.

In a rigorous 40-month study, we evaluated the geroprotective effects of metformin on adult male cynomolgus monkeys, addressing a gap in primate aging research. The study encompassed a comprehensive suite of physiological, imaging, histological, and molecular evaluations, substantiating metformin's influence on delaying age-related phenotypes at the organismal level. Specifically, we leveraged pan-tissue transcriptomics, DNA methylomics, plasma proteomics, and metabolomics to develop innovative monkey aging clocks and applied these to gauge metformin's effects on aging. The results highlighted a significant slowing of aging indicators, notably a roughly 6-year regression in brain aging. Metformin exerts a substantial neuroprotective effect, preserving brain structure and enhancing cognitive ability. The geroprotective effects on primate neurons were partially mediated by the activation of Nrf2, a transcription factor with anti-oxidative capabilities. Our research pioneers the systemic reduction of multi-dimensional biological age in primates through metformin, paving the way for advancing pharmaceutical strategies against human aging.

Resurrection of endogenous retroviruses during aging reinforces senescence.

Whether and how certain transposable elements with viral origins, such as endogenous retroviruses (ERVs) dormant in our genomes, can become awakened and contribute to the aging process is largely unknown. In human senescent cells, we found that HERVK (HML-2), the most recently integrated human ERVs, are unlocked to transcribe viral genes and produce retrovirus-like particles (RVLPs). These HERVK RVLPs constitute a transmissible message to elicit senescence phenotypes in young cells, which can be blocked by neutralizing antibodies. The activation of ERVs was also observed in organs of aged primates and mice as well as in human tissues and serum from the elderly. Their repression alleviates cellular senescence and tissue degeneration and, to some extent, organismal aging. These findings indicate that the resurrection of ERVs is a hallmark and driving force of cellular senescence and tissue aging.

Effect of Ginkgo biloba leaves on the removal efficiency of Cr(VI) in soil and its underlying mechanism.

Cr(VI) is a toxic, teratogenic, and carcinogenic heavy metal element in soil that poses major ecological and human health risks. In this study, microcosm tests combined with X-ray absorption near-edge spectra (XANES) and 16Sr DNA amplification techniques were used to explore the effect of Ginkgo biloba leaves on the removal efficiency of Cr(VI) in soil and its underlying mechanism. Ginkgo biloba leaves had a favorable remediation effect on soil varying in Cr(VI) contamination levels, and the optimal effect was observed when 5% Ginkgo biloba leaves were added. The occurrence state of Cr(VI) in soil before and after the addition of Ginkgo biloba leaves was analyzed by XANES, which revealed that Cr(VI) was fully converted to the more biologically innocuous Cr(III), and the hydroxyl-containing quercetin in Ginkgo biloba leaves was one of the primary components mediating this reduction reaction. The Cr(VI) content was significantly lower in non-sterilized soil than in sterilized soil, suggesting that soil microorganisms play a key role in the remediation process. The addition of Ginkgo biloba leaves decreased the α-diversity and altered the ß-diversity of the soil bacterial community. Actinobacteria was the dominant phylum in the soil remediated by Ginkgo biloba leaves; four genera of Cr(VI)-reducing bacteria were also enriched, including Agrococcus, Klebsiella, Streptomyces, and Microbacterium. Functional gene abundances predicted by PICRUST indicated that the expression of glutathione synthesis genes was substantially up-regulated, which might be the main metabolic pathway underlying the mitigation of Cr(VI) toxicity in soil by Cr(VI)-reducing bacteria. In sum, Ginkgo biloba leaves can effectively remove soil Cr(VI) and reduce Cr(VI) to Cr(III) via quercetin in soil, which also functions as a carbon source to drive the production of glutathione via Cr(VI)-reducing bacteria and mitigate Cr(VI) toxicity. The findings of this study elucidate the chemical and microbial mechanisms of Cr(VI) removal in soil by Ginkgo biloba leaves and provide insights that could be used to enhance the remediation of Cr(VI)-contaminated soil.

Integrated analysis of miRNA-mRNA regulatory networks of potato (Solanum tuberosum L.) in response to cadmium stress.

Cadmium (Cd) stress is a ubiquitous abiotic stress affecting plant growth worldwide and negatively impacting crop yield and food safety. Potato is the most important non-grain crop globally, but there is limited research available on the response of this crop to Cd stress. This study explored the coping mechanism for Cd stress in potato through analyses of miRNA and mRNA. Tissue culture seedlings (20-day-old) of potato variety 'Atlantic' were cultured for up to 48 h in liquid medium containing 5 mmol/L CdCl2, and phenotypic, physiological, and transcriptomic changes were observed at specific times. With the extension of Cd stress time, the potato leaves gradually wilted and curled, and root salicylic acid (SA), glutathione (GSH), and lignin contents and peroxidase (POD) activity increased, while indole-3-acetic acid (IAA) and zeatin (ZT) contents decreased. Using miRNA-seq, 161 existing miRNAs, 383 known miRNAs, and 7361 novel miRNAs were identified, and, 18 miRNAs were differentially expressed in response to Cd stress. Based on mRNA-seq, 7340 differentially expressed mRNAs (DEGs) were found. Through mRNA-miRNA integrated analysis, miRNA-target gene pairs consisting of 23 DEGs and 33 miRNAs were identified. Furthermore, "glutathione metabolism" "plant hormone signal transduction" and "phenylpropanoid biosynthesis" were established as crucial pathways in the Cd stress response of potato. Novel miRNAs novel-m3483-5p and novel-m2893-5p participate in these pathways through targeted regulation of cinnamic alcohol dehydrogenase (CAD; PG0005359) and alanine aminotransferase (POP; PG0024281), respectively. This study provides information that will help elucidate the complex mechanism of the Cd stress response in potato. Moreover, candidate miRNAs and mRNAs could yield new strategies for the development of Cd-tolerant potato breeding.

Rack1 mediates tyrosine phosphorylation of Anxa2 by Src and promotes invasion and metastasis in drug-resistant breast cancer cells.

BACKGROUND: Acquirement of resistance is always associated with a highly aggressive phenotype of tumor cells. Recent studies have revealed that Annexin A2 (Anxa2) is a key protein that links drug resistance and cancer metastasis. A high level of Anxa2 in cancer tissues is correlated to a highly aggressive phenotype. Increased Anxa2 expression appears to be specific in many drug-resistant cancer cells. The functional activity of Anxa2 is regulated by tyrosine phosphorylation at the Tyr23 site. Nevertheless, the accurate molecular mechanisms underlying the regulation of Anxa2 tyrosine phosphorylation and whether phosphorylation is necessary for the enhanced invasive phenotype of drug-resistant cells remain unknown. METHODS: Small interfering RNAs, small molecule inhibitors, overexpression, loss of function or gain of function, rescue experiments, Western blot, wound healing assays, transwell assays, and in vivo metastasis mice models were used to investigate the functional effects of Rack1 and Src on the tyrosine phosphorylation of Anxa2 and the invasion and metastatic potential of drug-resistant breast cancer cells. The interaction among Rack1, Src, and Anxa2 in drug-resistant cells was verified by co-immunoprecipitation assay. RESULTS: We demonstrated that Anxa2 Tyr23 phosphorylation is necessary for multidrug-resistant breast cancer invasion and metastasis. Rack1 is required for the invasive and metastatic potential of drug-resistant breast cancer cells through modulating Anxa2 phosphorylation. We provided evidence that Rack1 acts as a signal hub and mediates the interaction between Src and Anxa2, thereby facilitating Anxa2 phosphorylation by Src kinase. CONCLUSIONS: Our findings suggest a convergence point role of Rack1/Src/Anxa2 complex in the crosstalk between drug resistance and cancer aggressiveness. The interaction between Anxa2 and Rack1/Src is responsible for the association between drug resistance and invasive/metastatic potential in breast cancer cells. Thus, our findings provide novel insights on the mechanism underlying the functional linkage between drug resistance and cancer aggressiveness.

Including positive lymph node count in the AJCC N staging may be a better predictor of the prognosis of NSCLC patients, especially stage III patients: a large population-based study.

BACKGROUND: The study was designed to explore the value of including positive lymph node count in the TNM staging system of non-small cell lung cancer. PATIENTS AND METHODS: The X-tile model was applied to determine the cutoff values of positive lymph node count. Survival curves were generated using the Kaplan-Meier method and differences in survival among subgroups were examined using the log-rank test. The influence of different variables on overall survival and lung cancer-specific survival was further evaluated using univariate and multivariate Cox proportional hazard models. All statistical analyses were performed using SPSS version 22.0 (SPSS, Chicago, IL, USA). All p values were 2-sided and p < 0.05 was considered statistically significant. RESULTS: The overall survival and lung cancer-specific survival between stage IIIA and IIIB classified by the sixth edition TNM staging system show no statistically significant difference (p = 0.479 for overall survival; p = 0.081 for lung cancer specific survival). The X-tile model was used to screen three different cutoff values including nN = 0, nN1-3 and nN4-. The nN value is a significant independent prognostic factor that affects overall survival and lung cancer-specific survival of non-small cell lung cancer patients (all, p < 0.001). We obtained the hypothesized TNM sub-stages based on location and the number of PLN. There were significant differences between the hypothesized stage IIIA and IIIB regarding overall survival and lung cancer-specific survival (all, p < 0.001). CONCLUSIONS: It needs to be considered that N stage in combination with positive lymph node count may be used to predict the prognosis of non-small cell lung cancer for stage III cases with increased accuracy than category location-based stage.

Mechanism of ginsenoside Rg1 renal protection in a mouse model of d-galactose-induced subacute damage.

Context Ginseng is a widely used herbal medicine in China but its mechanism of action remains unclear. Objective The objectives of this work were to study the protective effect of ginsenoside Rg1 on subacute murine renal damage induced by d-galactose and its mechanism. Materials and methods C57BL/6J mice were injected with 120 mg/kg/d (sc) d-galactose for 1 week, followed by a combined treatment of Rg1 20 mg/kg/d (ip) and 120 mg/kg/d d-galactose (sc) for 5 weeks. Mice were injected with the 0.9% saline 0.2 mL/d (sc) and 120 mg/kg/d d-galactose (sc) for 6 weeks in the control group and the d-galactose group, respectively. After 6 weeks, urea, creatinine, uric acid, cystatin (Cys-C), senescence-associated ß-galactosidase (SA-ß-gal) staining positive kidney cells, superoxide dismutase (SOD), glutathione peroxidase (GSH-PX), malondialdehyde (MDA), glycation end products (AGEs) and 8-hydroxy-2 deoxyguanosine (8-OH-dG) were measured. Results Treatment with Rg1 ameliorated kidney function and aging state (urea from 17.19 ± 1.09 to 15.77 ± 1.22 mmol·L (-) (1), creatinine from 29.40 ± 5.72 to 22.60 ± 3.97 µmol·L (-) (1), uric acid from 86.80 ± 5.97 to 72.80 ± 10.61 µmol·L (-) (1), Cys-C from 0.23 ± 0.03 to 0.18 ± 0.05 mg·L (-) (1), ROD of SA-ß-gal from 56.32 ± 10.48 to 26.78 ± 7.34, SOD from 150.22 ± 19.07 to 190.56 ± 15.83 U·(mg·prot) (-1), MDA from 9.28 ± 1.59 to 3.17 ± 0.82 nmol·(mg·prot) (-1), GSH-PX from 15.68 ± 2.11 to 20.32 ± 2.96 U·(mg·prot) (-1) as well as regulated glomerulus morphology (glomerulus diameter from 775.77 ± 18.41 to 695.04 ± 14.61 µm, renal capsule width from 39.56 ± 3.51 to 31.42 ± 2.70 µm, glomerulus basement membrane from 206.03 ± 16.22 to 157.27 ± 15.70 nm, podocyte slit from 55.21 ± 8.55 to 37.63 ± 6.65 nm). Conclusions Ginsenoside Rg1 can antagonise d-galactose subacute renal damage in mice and this may occur due to alleviating oxidative stress injury.

Elevated STAT3 Signaling-Mediated Upregulation of MMP-2/9 Confers Enhanced Invasion Ability in Multidrug-Resistant Breast Cancer Cells.

The development of multidrug resistance greatly impedes effective cancer therapy. Recent advances in cancer research have demonstrated that acquisition of multidrug resistance by cancer cells is usually accompanied by enhanced cell invasiveness. Several lines of evidence indicated that cross activation of other signaling pathways during development of drug resistance may increase invasive potential of multidrug-resistant (MDR) cancer cells. However, the accurate mechanism of this process is largely undefined. In this study, to better understand the associated molecular pathways responsible for cancer progression induced by drug resistance, a MDR human breast cancer cell line SK-BR-3/EPR with P-glycoprotein overexpression was established using stepwise long-term exposure to increasing concentration of epirubicin. The SK-BR-3/EPR cell line exhibited decreased cell proliferative activity, but enhanced cell invasive capacity. We showed that the expression of metastasis-related matrix metalloproteinase (MMP)-2/9 was elevated in SK-BR-3/EPR cells. Moreover, SK-BR-3/EPR cells showed elevated activation of STAT3. Activation of STAT3 signaling is responsible for enhanced invasiveness of SK-BR-3/EPR cells through upregulation of MMP-2/9. STAT3 is a well-known oncogene and is frequently implicated in tumorigenesis and chemotherapeutic resistance. Our findings augment insight into the mechanism underlying the functional association between MDR and cancer invasiveness.

[Protective effect of Angelica sinensis polysaccharides on subacute renal damages induced by D-galactose in mice and its mechanism].

To explore the protective effect of Angelica sinensis polysaccharides(ASP) on subacute renal damages induced by D-galactose in mice and its mechanism. Male C57BL/6J mice were randomly divided into 3 groups, with 10 mice in each group. The D-galactose model group was subcutaneously injected with D-galactose (120 mg x kg(-1)), qd x 42; the ASP + D-galactose model group was intraperitoneally injected with ASP since the 8th day of the replication of the D-galactose model, qd x 35; and the normal control group was subcutaneously injected with saline at the same dose and time. On the 2nd day of after the injection, the peripheral blood was collected to measure the content of BUN, Crea, UA, Cys-C; paraffin sections were made to observe the renal histomorphology by HE staining; senescence-associated ß-g-alactosidase (SA-ß-Gal) stain was used to observe the relative optical density (ROD) in renal tissues; transmission electron microscopy was assayed to observe the renal ultrastructure; the renal tissue homogenate was prepared to measure the content of SOD, GSH-PX, MDA; the content of AGEs and 8-OH-dG were measured by ELISA. According to the result, compared with the D-galactose model group, the ASP + D-galactose model group showed obviously decreases in the content of BUN, Crea, UA, Cysc, AGES, 8-OH-dG, the number of hardening renal corpuscle, renal capsular space and renal tubular lumen, ROD of SA-ß-Gal staining positive kidney cells, mesangial cells, basement membrane thickness, podocyte secondary processes fusion and MDA and increases in the number of normal renal corpuscle, ribosome and rough endoplasmic reticulum in podocytes, the activity of SOD and GSH-PX. In Conclusion, A. sinensis polysaccharides can antagonize kidney subacute damages induced by D-galactose in mice. Its protective mechanism may be correlated with the inhibition of the oxidative stress injury.

Developing an institutional control framework for contaminated sites in China: An analytical case study.

Institutional controls, as an important measure for risk management of contaminated sites, is widely used in site management by the United States, Canada and European countries. At present, some regions in China have also begun to explore the implementation of institutional controls, but its path, safeguard mechanism, and tracking evaluation are still unclear. Based on China's unique contaminated site remediation control system and land management system, this paper proposes a framework for the whole life cycle institutional controls of China's contaminated sites: (1) evaluate the need for institutional controls; (2) establish the objectives of institutional controls; (3) identify the restrictive requirements of institutional controls; (4) establish the implementation form of institutional controls; and (5) regularly review the effectiveness of institutional controls. To demonstrate the applicability of the institutional control framework, a case demonstration study was conducted at a petrochemical contaminated site in China. By analyzing the information on residual pollutants after the implementation of risk management measures at the site, the exposure pathways and hazards in case of re-release, and the engineering facilities, we proposed eight restrictive requirements, including the prohibition of disturbing and damaging the clean and planted soil layers of the site and the protection of long-term monitoring wells. At the same time, we constructed a multi-departmental pathway to implement institutional controls in conjunction with ecological environment, natural resources and housing departments to ensure effective implementation of institutional controls. Eventually, we summarized a set of replicable and generalizable institutional controls application models, which provide valuable theoretical and practical support for China and other local governments in the implementation of institutional controls at contaminated sites.