Galectins control MTOR and AMPK in response to lysosomal damage to induce autophagy

The Ser/Thr protein kinase MTOR (mechanistic target of rapamycin kinase) regulates cellular metabolism and controls macroautophagy/autophagy. Autophagy has both metabolic and quality control functions, including recycling nutrients at times of starvation and removing dysfunctional intracellular organelles. Lysosomal damage is one of the strongest inducers of autophagy, and yet mechanisms of its activation in response to lysosomal membrane damage are not fully understood. Our recent study has uncovered a new signal transduction system based on cytosolic galectins that elicits autophagy by controlling master regulators of metabolism and autophagy, MTOR and AMPK, in response to lysosomal damage. Thus, intracellular galectins are not, as previously thought, passive tags recognizing damage to guide selective autophagy receptors, but control the activation state of AMPK and MTOR in response to endomembrane damage.

Abbreviations: MTOR: mechanistic target of rapamycin kinase; AMPK: AMP-activated protein kinase / Protein Kinase AMP-Activated; SLC38A9: Solute Carrier Family 38 Member 9; APEX2: engineered ascorbate peroxidase 2; RRAGA/B: Ras Related GTP Binding A or B; LAMTOR1: Late Endosomal/Lysosomal Adaptor, MAPK and MTOR Activator 1; LGALS8: Lectin, Galactoside-Binding, Soluble, 8 / Galectin 8; LGALS9: Lectin, Galactoside-Binding, Soluble, 9 / Galectin 9; TAK1: TGF-Beta Activated Kinase 1 / Mitogen-Activated Protein Kinase Kinase Kinase 7 (MAP3K7); STK11/LKB1: Serine/Threonine Kinase 11 / Liver Kinase B1; ULK1: Unc-51 Like Autophagy Activating Kinase 1.     

Flower colour variation in the montane plant Gentiana lutea L. (Gentianaceae) is unrelated to abiotic factors

Background: Flower colour variation among populations may result from the spatial variation of selective agents. The structure of phenotypic variation informs on the ecological processes related to this variation. Variation in floral traits is mainly attributed to variation in the pollinator fauna, while variation in vegetative traits is usually linked to abiotic factors or herbivores.

Aims: We investigated the geographical variation of flower colour (and correlated traits) in Gentiana lutea and the relationship with the variation in abiotic factors.

Methods: Phenotypic variation (flower colour, petal length, petal width, stalk length, leaf length, flower number, petal number and number of basal leaves) was assessed in 429 plants of 12 populations located at north-west Iberia. Additionally, we obtained data on the geographical coordinates, elevation, temperature, rainfall and radiation for each population.

Results: Populations mostly differed in flower colour, from orange to yellow from west to the east. Abiotic factors were unrelated to variation in either floral or vegetative traits.

Conclusions: Phenotypic variation among G. lutea populations does not result from adaptation to environmental factors. Other factors, such as historical events or selective pressure exerted by biotic interactions, might explain the flower colour variation in G. lutea along the Cantabrian Range.     

EGFR signaling and autophagy dependence for growth,survival, and therapy resistance

The epidermal growth factor receptor (EGFR) is amplified or mutated in various human epithelial tumors. Its expression and activation leads to cell proliferation, differentiation, and survival. Consistently, EGFR amplification or expression of EGFR variant 3 (EGFRvIII) is associated with resistance to conventional cancer therapy through activation of pro-survival signaling and DNA-repair mechanisms. EGFR targeting has successfully been exploited as strategy to increase treatment efficacy. Nevertheless, these targeting strategies have only been proven effective in a limited percentage of human tumors.

Recent knowledge indicates that EGFR deregulated tumors display differences in autophagy and dependence on autophagy for growth and survival and the use of autophagy to increase resistance to EGFR-targeting drugs. In this review the dependency on autophagy and its role in mediating resistance to EGFR-targeting agents will be discussed. Considering the current knowledge, autophagy inhibition could provide a novel strategy to enhance therapy efficacy in treatment of EGFR deregulated tumors.     

Mutation in the beta3 subunit of Guanine nucleotide-binding protein (GNB3) gene is not associated with Type II diabetes mellitus risk: a case–control study of a North Indian population

Context: Genetics play a major role in development and pathophysiology of Type 2 diabetes mellitus (T2DM).

Objective: To asses the association of Guanine nucleotide-binding protein (GNB3) (C825T) gene's polymorphism with T2DM.

Materials and methods: A case–control study including 400 North Indians was performed using Polymerase Chain Reaction–Restriction Fragment Length Polymorphism (PCR-RFLP) approach to analyze genetic polymorphism.

Results: No significant difference was observed in genotype and allele frequencies of GNB3 gene on comparing cases with controls.

Discussion: Our study is in agreement with studies on Polish, Japanese, Hispanic-American and Danish populations who observed no significant association between GNB3 (C825T) polymorphism and T2DM.

Conclusion: GNB3 (C825T) polymorphism is not associated with T2DM.     

Resilience,vulnerability and conservation strategies in high-mountain pine forests in the Gredos Range,central Spain

Background: High-mountain pine forests and broom communities in central Spain today have led to contrasting interpretations of their natural or human-induced origin.

Aims: We evaluated the vulnerability and resilience of high-mountain Pinus sylvestris/P. nigra forests and derived Cytisus broom scrub communities to climate and anthropogenic disturbances.

Methods: We assessed historical transitions from forest to scrub and their relation to climate and human influences, using a multi-proxy paleoenvironmental study (pollen, non-pollen palynomorphs, charcoal, magnetic susceptibility) in three mires in the Gredos Range, western Iberian Central System.

Results: High percentages of Pinus sylvestris/nigra pollen and the identification of their macro remains demonstrated that high-mountain pine forests have been present in the oromediterranean bioclimatic belt of the Gredos Range since the mid-Holocene. After that, a major human-induced decline, enhanced by climate conditions, has led to their gradual replacement by broom communities.

Conclusions: Broom communities are derived from ancient pine forests that were intensively transformed by human activities after 700 cal year BP, and largely disappeared by ca. 500 cal yr BP. Today’s landscape, dominated by broom scrub and grasslands with scattered stands of pines, shows high resilience and provides suitable refugia for a rich mountain biodiversity which deserves a further protection.     

Aberrant methylation of nucleotide excision repair genes is associated with chronic arsenic poisoning

Objective: To define whether aberrant methylation of DNA repair genes is associated with chronic arsenic poisoning.

Methods: Hundred and two endemic arsenicosis patients and 36 healthy subjects were recruited. Methylight and bisulfite sequencing (BSP) assays were used to examine the methylation status of ERCC1, ERCC2 and XPC genes in peripheral blood lymphocytes (PBLs) and skin lesions of arsenicosis patients and NaAsO₂-treated HaCaT cells.

Results: Hypermethylation of ERCC1 and ERCC2 and suppressed gene expression were found in PBLs and skin lesions of arsenicosis patients and was correlated with the level of arsenic exposure. Particularly, the expression of ERCC1 and ERCC2 was associated with the severity of skin lesions. In vitro studies revealed an induction of ERCC2 hypermethylation and decreased mRNA expression in response to NaAsO₂ treatment.

Conclusion: Hypermethylation of ERCC1 and ERCC2 and concomitant suppression of gene expression might be served as the epigenetic marks associated with arsenic exposure and adverse health effects.     

Dynamic variation of histone H3 trimethyl Lys4 (H3K4me3) and heterochromatin protein 1 (HP1) with employment length in nickel smelting workers

Objective: To investigate the dynamic variation in H3K4me3 and HP1 with employment length in nickel smelting workers.

Methods: Blood samples were collected from 140 nickel smelting workers and 140 age-matched office workers to test for H3K4me3, and HP1 levels.

Results: H3K4me3 was statistically significantly different (p?<?0.05) between the two groups and positively correlated with employment length (r_s?=_?0.267). HP1 was not correlated with employment length (p?=?0.066) but was significantly different between the two groups.

Conclusions: Chronic exposure to nickel can induce oxidative damage, and increase H3K4me3 expression and inhibit HP1 expression.     

Book reviews

Patterns of thought in Africa and the West: Essays on magic, religion and science , by Robin Horton. Cambridge University Press, Cambridge, 1997. xi, 471pp., figures, notes, bibliography, index. ISBN 0–521–36926–6 (paperback).

Women's experiences with HIV/AIDS: An international perspective , edited by Lynellyn D. Long and E. Maxine Ankrah. Columbia University Press, New York, 1996. x, 426pp., tables, references, notes on contributors, index. ISBN 0–231–10605‐X (paperback).

A healing place: Indigenous visions for personal empowerment and community recovery , by Kayleen M. Hazelhurst. Central Queensland University Press, Rockhampton, 1996. xiii, 274pp., notes, illustrations, references. ISBN 0–908140–87–8 (paperback).

Reading the skin: Adornment, display and society among the Wahgi , by Michael O'Hanlon. Crawford House Press, Bathurst, 1989. 139pp., map, photographs, orthography and kinship terms, glossary, notes, bibliography, index. ISBN 1–86333–003–8 (hardback).

Paradise: Portraying the New Guinea Highlands , by Michael O'Hanlon. Crawford House Press, Bathurst, 1993. 99pp., maps, photographs, notes, bibliography, index. ISBN 1–86333–078‐X (paperback).

To sing with pigs is human: The concept of person in Papua New Guinea , by Jane C. Goodale. University of Washington Press, Seattle, 1995. xvi, 269pp., map, tables, figure, musical scores, photographs, bibliography, index. ISBN 0–295–94736–2 (paperback).

Resplendent sites, discordant voices: Sri Lankans and international tourism , by Malcolm Crick. Harwood Academic Publishers, Chur, 1994. x, 237pp., maps, tables, photographs, bibliography, index. ISBN 3–7186–5564–0 (hardback).

Impasse of the angels: Scenes from a Moroccan space of memory , by Stefania Pandolfo. University of Chicago Press, Chicago, 1997. xi, 389pp., photograph, notes, index. ISBN 0–226–64532–0 (paperback).

Mal'uocchiu: Ambiguity, evil eye, and the language of distress , by Sam Migliore. University of Toronto Press, Toronto, 1997. xiv, 159pp., tables, figures, glossary, notes, bibliography, index. ISBN 0–8020–7922–9 (paperback).

Satmar: Two generations of an urban island: The life, thought and culture of an Hasidic Jewish community in America , by Israel Rubin. Peter Lang, New York, 1997. xii, 341pp., tables, figures, notes, index. ISBN 0–8204–0759–3 (hardback).

UFO crash at Roswell: The genesis of a modern myth , by Benson Saler, Charles A. Ziegler and Charles B. Moore. Smithsonian Institution Press, Washington DC, 1997. xii, 198pp., maps, tables, figures, appendices, notes, bibliography, index. ISBN 1–56098–751–0 (hardback).     

Predictors of leptin concentration and association with cardiovascular risk in patients with coronary artery disease: results from the AtheroGene study

Context: Leptin is produced in white adipose tissue, but also in human coronary atherosclerotic lesions.

Objective: The aim of this study is to assess the prognostic value of leptin in patients with proven coronary artery disease (CAD) (N?=?1907).

Methods: AtheroGene is a contemporary CAD cohort study (N?=?3229). Median follow-up time was 3.8 (Quartile 1/3 with 2.8/4.9) years.

Results: Leptin concentration was associated with a hazard ratio (HR) for the fully adjusted model of HR?=?1.32 in women but was not significant in men. The endpoint cardiovascular death and non-fatal myocardial infarction was observed in 167 patients.

Conclusion: In women with known CAD, increased leptin concentration is useful for predicting cardiovascular death and non-fatal myocardial infarction.     

JNK pathway in osteoarthritis: pathological and therapeutic aspects

Context: Osteoarthritis (OA) is a common chronic degenerative joint disease resulting in physical disability and reduced quality of life. Different biochemical signaling pathways are involved in the progression of OA, including the c-Jun NH2-terminal kinase (JNK) signal transduction pathway.

Objective: In this study, we have reviewed the recent updates on the association of JNK pathway with OA.

Methods: In this review, we have explored the databases like PubMed, Google Scholar, Medline, Scopus, etc., and collected the most relevant papers of JNK signaling pathway involved in the pathogenesis and therapeutics of OA

Results: JNK has been shown by scientific studies to be activated (phosphorylated) in OA that can play a key role in the cartilage destruction. Activation of JNK causes the phosphorylation of c-Jun that causes decreased proteoglycan synthesis and enhanced production of matrix metalloproteinase 13 (MMP-13). Overproduction of MMP-13 by chondrocytes plays a central role in cartilage degeneration in OA. Thus, targeting JNK pathway might be a promising therapeutic application for the prevention and treatment of OA. A number of JNK-inhibitors have been used in vitro and in vivo studies; however, not yet been translated into human use.

Conclusions: This review study indicates that JNK pathway plays an important role in development and progression of OA, and targeting the JNK pathway might be a potential approach for the treatment of OA in future.