Mild inhibition of mitochondrial respiration extends the lifespan of many species. In Caenorhabditis elegans, reactive oxygen species (ROS) promote longevity by activating hypoxia-inducible factor 1 (HIF-1) in response to reduced mitochondrial respiration. However, the physiological role and mechanism of ROS-induced longevity are poorly understood. Here, we show that a modest increase in ROS increases the immunity and lifespan of C. elegans through feedback regulation by HIF-1 and AMP-activated protein kinase (AMPK). We found that activation of AMPK as well as HIF-1 mediates the longevity response to ROS. We further showed that AMPK reduces internal levels of ROS, whereas HIF-1 amplifies the levels of internal ROS under conditions that increase ROS. Moreover, mitochondrial ROS increase resistance to various pathogenic bacteria, suggesting a possible association between immunity and long lifespan. Thus, AMPK and HIF-1 may control immunity and longevity tightly by acting as feedback regulators of ROS.aging | mitochondria | immunity | reactive oxygen species | C. elegans M itochondria are essential for various physiological processes, including energy production, apoptosis, metabolism, and signaling (1). Thus, it is not surprising that defects in mitochondrial function are linked to many diseases. Interestingly, however, mild inhibition of mitochondrial respiration increases the lifespans of many organisms (2, 3). In particular, genetic inhibition of components of the mitochondrial electron transport chain (ETC) increases longevity of the roundworm Caenorhabditis elegans. For example, mutations in clk-1 (a ubiquinone hydroxylase) and isp-1 (iron-sulfur protein 1 in the mitochondrial complex III) extend the lifespans of worms (4, 5). Longevity resulting from mitochondrial ETC inhibition also has been observed in Drosophila (6, 7) and mice (8, 9). Thus, the mechanisms responsible for longevity may be evolutionarily conserved.Key genetic factors that mediate longevity caused by reduced mitochondrial respiration in C. elegans have been identified recently (10-17). However, the mechanisms are not completely understood. Hypoxia-inducible factor 1 (HIF-1), the master transcriptional regulator of cellular responses to hypoxia, is one of the mediators of longevity caused by inhibition of mitochondrial respiration in C. elegans (12). The physiological importance of HIF-1α in humans is underscored by the fact that mutations in VHL, the von HippelLindau tumor suppressor gene, which encodes an E3-ubiquitin ligase component required for the degradation of HIF-1, lead to an inherited form of cancer (18,19). HIF-1 regulates adaptation to low oxygen and various other biological processes, including axon guidance, immunity, iron homeostasis, and aging (20-29). Increased levels of HIF-1 by vhl-1 mutations or by overexpression of HIF-1 lengthen the lifespan of C. elegans (27, 28). In addition, we previously showed that inhibition of mitochondrial respiration promotes longevity by elevating reactive oxygen species (ROS) levels and incr...

SUMMARYHistamine is a major inflammatory molecule released from the mast cell, and is known to activate endothelial cells. However, its ability to modulate endothelial responses to bacterial products has not been evaluated. In this study we determined the ability of histamine to modulate inflammatory responses of endothelial cells to Gram-negative and Gram-positive bacterial cell wall components and assessed the role of Toll-like receptors (TLR) 2 and 4 in the co-operation between histamine and bacterial pathogens. Human umbilical vein endothelial cells (HUVEC) were incubated with lipopolysaccharide (LPS), lipoteichoic acid (LTA), or peptidoglycan (PGN) in the presence or absence of histamine, and the expression and release of interleukin-6 (IL-6), and NF-jB translocation were determined. The effect of histamine on the expression of mRNA and proteins for TLR2 and TLR4 was also evaluated. Incubation of HUVEC with LPS, LTA and PGN resulted in marked enhancement of IL-6 mRNA expression and IL-6 secretion. Histamine alone markedly enhanced IL-6 mRNA expression in HUVEC, but it did not stimulate proportional IL-6 release. When HUVEC were incubated with LPS, LTA, or PGN in the presence of histamine marked amplification of both IL-6 production and mRNA expression was noted. HUVEC constitutively expressed TLR2 and TLR4 mRNA and proteins, and these were further enhanced by histamine. The expression of mRNAs encoding MD-2 and MyD88, the accessory molecules associated with TLR signalling, were unchanged by histamine treatment. These results demonstrate that histamine up-regulates the expression of TLR2 and TLR4 and amplifies endothelial cell inflammatory responses to Gram-negative and Gram-positive bacterial components.

BackgroundMajor depressive disorder (MDD) is a mixed disorder with the highly irregular course, inconsistent response to treatment and has no well-known mechanism for the pathophysiology. Major causes of depression are genetic, neurobiological, and environmental. However, over the past few years, altered serum levels of macro-minerals (MM) and trace elements (TE) have been recognized as major causative factors to the pathogenesis of many mental disorders. The purpose of this study was to determine the serum levels of MM (calcium and magnesium) and TE (copper, iron, manganese, selenium, and zinc) in MDD patients and find out their associations with depression risk.MethodsThis prospective case-control study recruited 247 patients and 248 healthy volunteers matched by age and sex. The serum levels of MM and TE were analyzed by atomic absorption spectroscopy (AAS). Statistical analysis was performed with independent sample t-tests and Pearson’s correlation test.ResultsWe found significantly decreased concentrations of calcium and magnesium, iron, manganese, selenium, and zinc in MDD patients compared with control subjects (p < 0.05). But the concentration of copper was significantly increased in the patients than control subjects (p < 0.05). Data obtained from different inter-element relations in MDD patients and control subjects strongly suggest that there is a disturbance in the element homeostasis.ConclusionOur study suggests that altered serum concentrations of MM and TE are major contributing factors for the pathogenesis of MDD. Alterations of these elements in serum levels of MDD patients arise independently and they may provide a prognostic tool for the assessment of depression risk.

BackgroundThe number of tribes present within Bangladesh has been estimated to approximate one hundred and fifty. Information on traditional medicinal practices, particularly of the smaller tribes and their clans is lacking. It was the objective of the study to document the tribal medicinal practices of the Deb barma clan of the Tripura tribe, which clan can be found residing in Dolusora Tripura Palli of Moulvibazar district of Bangladesh. A further objective was to determine the extent of the community households who still prefer traditional treatment to other forms of treatment, particularly allopathic treatment.MethodsInterviews of the tribal healer and the tribal community regarding their ethnomedicinal practices were carried out with the help of a semi-structured questionnaire and the guided field-walk method. All together 67 clan members were interviewed including the Headman, tribal healer, 19 Heads of households and 46 other adult members of the clan. Information on number of members of household, their age, gender, educational status, occupation of working household members and preferred mode of treatment was obtained through the semi-structured questionnaire. In the guided field-walk method, the healer took the interviewers on field-walks through areas from where he collected his medicinal plants, pointed out the plants, and described their uses.ResultsThe clan had a total of 135 people distributed into 20 households and had only one traditional healer. Use of medicinal plants, wearing of amulets, and worship of the evil god ‘Bura debta’ constituted the traditional medicinal practices of the clan for treatment of diseases. The healer used a total of 44 medicinal plants distributed into 34 families for treatment of various ailments like pain, coughs, cold, gastrointestinal disorders, cuts and wounds, diabetes, malaria, heart disorders, and paralysis.ConclusionsAvailable scientific reports validate the use of a number of plants by the traditional healer. A number of the plants used by the clan healer had reported similar uses in Ayurveda, but differ considerably in their therapeutic uses from that reported for other tribes in Bangladesh. The present survey also indicated that in recent years the Deb barma clan members are inclining more towards allopathic medicine.

WIP1 (wild-type p53-induced phosphatase 1) functions as a homeostatic regulator of the ataxia telangiectasia mutated (ATM)-mediated signaling pathway in response to ionizing radiation (IR). Here we identify homeodomain-interacting protein kinase 2 (HIPK2) as a protein kinase that targets WIP1 for phosphorylation and proteasomal degradation. In unstressed cells, WIP1 is constitutively phosphorylated by HIPK2 and maintained at a low level by proteasomal degradation. In response to IR, ATM-dependent AMPKα2-mediated HIPK2 phosphorylation promotes inhibition of WIP1 phosphorylation through dissociation of WIP1 from HIPK2, followed by stabilization of WIP1 for termination of the ATM-mediated double-strand break (DSB) signaling cascade. Notably, HIPK2 depletion impairs IR-induced γ-H2AX foci formation, cell-cycle checkpoint activation, and DNA repair signaling, and the survival rate of hipk2+/- mice upon γ-irradiation is markedly reduced compared to wild-type mice. Taken together, HIPK2 plays a critical role in the initiation of DSB repair signaling by controlling WIP1 levels in response to IR.