Physical Review B

https://www.cell.com/cell-metabolism/pdf/S1550-4131(15)00578-1.pdf

Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype

Ageing is a plastic process and can be successfully modulated by some biomedical approaches or pharmaceutics. In this manner it is possible to delay or even prevent some age-related pathologies. There are some defined interventions, which give promising results in animal models or even in human studies, resulting in lifespan elongation or healthspan improvement. One of the most promising targets for anti-ageing approaches are proteins belonging to the sirtuin family. Sirtuins were originally discovered as transcription repressors in yeast, however, nowadays they are known to occur in bacteria and eukaryotes (including mammals). In humans the family consists of seven members (SIRT1-7) that possess either mono-ADP ribosyltransferase or deacetylase activity. It is believed that sirtuins play key role during cell response to a variety of stresses, such as oxidative or genotoxic stress and are crucial for cell metabolism. Although some data put in question direct involvement of sirtuins in extending human lifespan, it was documented that proper lifestyle including physical activity and diet can influence healthspan via increasing the level of sirtuins. The search for an activator of sirtuins is one of the most extensive and robust topic of research. Some hopes are put on natural compounds, including curcumin. In this review we summarize the involvement and usefulness of sirtuins in anti-ageing interventions and discuss the potential role of curcumin in sirtuins regulation.

/pdf/sirtuins-a-promising-target-in-slowing-down-the-ageing-55zlxycswo.pdf

Sirtuins, a promising target in slowing down the ageing process

Cellular senescence is a process that results from a variety of stresses, leading to a state of irreversible growth arrest. Senescent cells accumulate during aging and have been implicated in promoting a variety of age-related diseases. Mitochondrial stress is an effective inducer of cellular senescence, but the mechanisms by which mitochondria regulate permanent cell growth arrest are largely unexplored. Here, we review some of the mitochondrial signaling pathways that participate in establishing cellular senescence. We discuss the role of mitochondrial reactive oxygen species (ROS), mitochondrial dynamics (fission and fusion), the electron transport chain (ETC), bioenergetic balance, redox state, metabolic signature, and calcium homeostasis in controlling cellular growth arrest. We emphasize that multiple mitochondrial signaling pathways, besides mitochondrial ROS, can induce cellular senescence. Together, these pathways provide a broader perspective for studying the contribution of mitochondrial stress to aging, linking mitochondrial dysfunction and aging through the process of cellular senescence.

https://www.onlinelibrary.wiley.com/doi/pdf/10.1111/acel.12287

Mitochondrial effectors of cellular senescence: beyond the free radical theory of aging.

https://www.cell.com/cell-metabolism/pdf/S1550-4131(16)30228-5.pdf

From Ancient Pathways to Aging Cells—Connecting Metabolism and Cellular Senescence

Carbohydrate metabolism changes during cellular senescence. Cytosolic malate dehydrogenase (MDH1) catalyzes the reversible reduction of oxaloacetate to malate at the expense of reduced nicotinamide adenine dinucleotide (NADH). Here, we show that MDH1 plays a critical role in the cellular senescence of human fibroblasts. We observed that the activity of MDH1 was reduced in old human dermal fibroblasts (HDFs) [population doublings (PD) 56], suggesting a link between decreased MDH1 protein levels and aging. Knockdown of MDH1 in young HDFs (PD 20) and the IMR90 human fibroblast cell line resulted in the appearance of significant cellular senescence features, including senescence-associated β-galactosidase staining, flattened and enlarged morphology, increased population doubling time, and elevated p16INK4A and p21CIP1 protein levels. Cytosolic NAD/NADH ratios were decreased in old HDFs to the same extent as in MDH1 knockdown HDFs, suggesting that cytosolic NAD depletion is related to cellular senescence. We found that AMP-activated protein kinase, a sensor of cellular energy, was activated in MDH1 knockdown cells. We also found that sirtuin 1 (SIRT1) deacetylase, a controller of cellular senescence, was decreased in MDH1 knockdown cells. These results indicate that the decrease in MDH1 and subsequent reduction in NAD/NADH ratio, which causes SIRT1 inhibition, is a likely carbohydrate metabolism-controlled cellular senescence mechanism.

Cytosolic malate dehydrogenase regulates senescence in human fibroblasts.

BACKGROUND Acute variceal bleeding is a serious complication of liver cirrhosis, which has an attendant mortality of approximately 60% over two years, and a variety of treatments, such as balloon tamponade, endoscopic varix ligation, sclerotherapy, histoacryl injection and vasoactive drugs, have been used. The aims of the present trial were to compare the effectiveness and complications of somatostatin and vasopressin in the treatment of acute variceal bleeding. METHODS Forty-three cirrhotic patients, with endoscopically proven acute variceal bleeding, were included in this trial. Both drugs were given as continuous intravenous infusions for 48 hours. Twenty patients received the somatostatin (250 mcg per hr after a bolus of 50 mcg) and twenty-three the vasopressin (0.4 units per min). RESULTS There were no significant differences between the two groups in relation to age, sex, etiology of cirrhosis, Child-Pugh classification, characteristics of bleeding episode, laboratory findings before randomization and units of transfused blood during therapy. Rebleeding, within 6 hours after beginning of therapy, was regarded as failure to control initial bleeding, and was observed in 3 (13.0%) of the patients who received vasopressin and in 1 (5.0%) treated with somatostatin (p > 0.05). Five patients in both the somatostatin (25.0%) and vasopressin (21.7%) groups rebled during the first 5 days following the initial therapy (p > 0.05). Meaningful complications related to the use of vasopressin were observed in 5 patients (chest pain or abdominal pain requiring nitroglycerin), but no complications were associated with the use of somatostatin (p < 0.05). The mortalities during hospitalization were similar in both the treatment groups. Two of the vasopressin and 1 of the somatostatin group died due to the uncontrolled rebleeding, and 1 of the vasopressin group died due to hepatic failure (2 weeks later after therapy). CONCLUSION This study showed no differences in the effectiveness of somatostatin and vasopressin, but the somatostatin group had a lower risk of the complications.

A prospective randomized controlled clinical trial comparing the effects of somatostatin and vasopressin for control of acute variceal bleeding in the patients with liver cirrhosis.

Machine-Readable Cataloging (MARC) is currently the most broadly used bibliographic
						standard for encoding and exchanging bibliographic data. However, MARC
						may not fully support representation of the dynamic nature and semantics
						of digital resources because of its rigid and single-layered linear
						structure. The Functional Requirements for Bibliographic Records (FRBR)
						model, which is designed to overcome the problems of MARC, does not
						provide sufficient data elements and adopts a predetermined hierarchy.
						A flexible structure for bibliographic data with detailed data elements
						is needed. Integrating MARC format with the hierarchical structure of
						FRBR is one approach to meet this need. The purpose of this research
						is to propose an approach that can facilitate interoperability between
						MARC and FRBR by providing a conceptual structure that can function
						as a mediator between MARC data elements and FRBR attributes.

/pdf/an-integrated-approach-to-metadata-interoperability-4sshf9x2z0.pdf

An Integrated Approach to Metadata Interoperability Construction of a Conceptual Structure between MARC and FRBR

In this study we explore the construction of a faceted vocabulary that can be used as a mechanism for organizing Web-based resources. After analyzing the manual process of faceted vocabulary construction using an existing organizational structure to identify heuristics for automating the construction process, we modeled a hybrid, semi-automatic approach to facet generation that integrates the strengths of manual and automatic methods.

/pdf/organizing-the-web-semi-automatic-construction-of-a-faceted-5fsxjlin90.pdf

Organizing the Web: Semi-Automatic Construction of a Faceted Scheme.

OBJECTIVES The evaluations of the pathogenetic roles of cell mediated immunity and of the preventive effect for disease progression with interferon(IFN) treatment in patients with chronic active hepatitis-B(CAH-B) are the objectives of this study. METHODS Thirty-two patients with CAH-B were treated with interferon alpha-2b(IFN alpha-2b) with prednisolone withdrawal and 30 control patients were treated with conventional hepatotonics for 6 months. Peripheral total T cell fractions and T cell subsets of the patients with CAH-B, treated with IFN alpha-2b with prednisolone withdrawal, were examined 1 month before administration of prednisolone, and compared with 12 normal controls for assessing the potential role of cellular immunity in the development of CAH-B. To estimate the effectiveness of IFN therapy for the patients with CAH-B, levels of various liver function tests, HBsAg, anti-HBs, HBeAg, anti-HBe, HBV DNA, anti-HCV and others were assessed for the treatment group and compared with control patients at pre- and post-treatment period each. RESULTS The value of CD4 was significantly lower in patients with CAH-B than normal controls (36.3 +/- 7.7% vs 42.1 +/- 5.7%, p < 0.05) and the value of CD8 was significantly higher in patients with CAH-B than normal controls (30.6 +/- 10.3% vs 24.3 +/- 5.2%, p < 0.05) before prednisolone administration. The patients in responder group (n = 26) had significantly lower CD4 cells compared with normal controls, but non-responders (n = 6) did not have. The levels of liver function test(LFT) in the patients with IFN alpha-2b treatment with prednisolone withdrawal were not different from the control patient group at pretreatment, but significantly lower than control patient group's after treatment, regardless of response to IFN alpha-2b treatment with prednisolone withdrawal. CONCLUSIONS The cellular immunity of the host may have a potential role in the pathogenesis of chronicity of hepatitis B infection. IFN alpha-2b treatment with prednisolone withdrawal may be regarded as one of the effective treatment modalities for the inhibition of disease progression in patients with CAH-B.

/pdf/t-cell-subsets-in-chronic-hepatitis-b-and-the-effect-of-ep4ceq33z3.pdf

Seung-Min Lee

Papers

Cytosolic malate dehydrogenase regulates senescence in human fibroblasts.

A prospective randomized controlled clinical trial comparing the effects of somatostatin and vasopressin for control of acute variceal bleeding in the patients with liver cirrhosis.

An Integrated Approach to Metadata Interoperability Construction of a Conceptual Structure between MARC and FRBR

Organizing the Web: Semi-Automatic Construction of a Faceted Scheme.

T cell subsets in chronic hepatitis B and the effect of prednisolone withdrawal and interferon alpha-2b.