Moonlighting cell-surface GAPDH recruits apotransferrin to effect iron egress from mammalian cells

Iron (Fe, Fe) homeostasis is a tightly regulated process, involving precise control of iron influx and egress from cells. Although the mechanisms of its import into cells by iron carrier molecules are well characterized, iron export remains poorly understood. The current paradigm envisages unique functions associated with specialized macromolecules for its cellular import (transferrin receptors) or export (ferroportin, also known as SLC40A1). Previous studies have revealed that iron-depleted cells recruit glyceraldehyde-3- phosphate dehydrogenase (GAPDH), a multitasking, 'moonlighting' protein, to their surface for internalization of the iron carrier holotransferrin. Here, we report that under the converse condition of intracellular iron excess, cells switch the isoform of GAPDH on their surface to one that now recruits iron-free apotransferrin in close association with ferroportin to facilitate the efflux of iron. Increased expression of surface GAPDH correlated with increased apotransferrin binding and enhanced iron export from cells, a capability lost in GAPDH-knockdown cells. These findings were confirmed in vivo utilizing a rodent model of iron overload. Besides identifying for the first time an apotransferrin receptor, our work uncovers the two-way switching of multifunctional molecules to manage cellular micronutrient requirements

Targeting adenosine monophosphate-activated protein kinase (AMPK) in preclinical models reveals a potential mechanism for the treatment of neuropathic pain

Neuropathic pain is a debilitating clinical condition with few efficacious treatments, warranting development of novel therapeutics. We hypothesized that dysregulated translation regulation pathways may underlie neuropathic pain. Peripheral nerve injury induced reorganization of translation machinery in the peripheral nervous system of rats and mice, including enhanced mTOR and ERK activity, increased phosphorylation of mTOR and ERK downstream targets, augmented eIF4F complex formation and enhanced nascent protein synthesis. The AMP activated protein kinase (AMPK) activators, metformin and A769662, inhibited translation regulation signaling pathways, eIF4F complex formation, nascent protein synthesis in injured nerves and sodium channel-dependent excitability of sensory neurons resulting in a resolution of neuropathic allodynia. Therefore, injury-induced dysregulation of translation control underlies pathology leading to neuropathic pain and reveals AMPK as a novel therapeutic target for the potential treatment of neuropathic pain

Effectiveness of trigger point dry needling for plantar heel pain: study protocol for a randomised controlled trial

<p>Abstract</p> <p>Background</p> <p>Plantar heel pain (plantar fasciitis) is a common and disabling condition, which has a detrimental impact on health-related quality of life. Despite the high prevalence of plantar heel pain, the optimal treatment for this disorder remains unclear. Consequently, an alternative therapy such as dry needling is increasingly being used as an adjunctive treatment by health practitioners. Only two trials have investigated the effectiveness of dry needling for plantar heel pain, however both trials were of a low methodological quality. This manuscript describes the design of a randomised controlled trial to evaluate the effectiveness of dry needling for plantar heel pain.</p> <p>Methods</p> <p>Eighty community-dwelling men and woman aged over 18 years with plantar heel pain (who satisfy the inclusion and exclusion criteria) will be recruited. Eligible participants with plantar heel pain will be randomised to receive either one of two interventions, (i) real dry needling or (ii) sham dry needling. The protocol (including needling details and treatment regimen) was formulated by general consensus (using the Delphi research method) using 30 experts worldwide that commonly use dry needling for plantar heel pain. Primary outcome measures will be the pain subscale of the Foot Health Status Questionnaire and "first step" pain as measured on a visual analogue scale. The secondary outcome measures will be health related quality of life (assessed using the Short Form-36 questionnaire - Version Two) and depression, anxiety and stress (assessed using the Depression, Anxiety and Stress Scale - short version). Primary outcome measures will be performed at baseline, 2, 4, 6 and 12 weeks and secondary outcome measures will be performed at baseline, 6 and 12 weeks. Data will be analysed using the intention to treat principle.</p> <p>Conclusion</p> <p>This study is the first randomised controlled trial to evaluate the effectiveness of dry needling for plantar heel pain. The trial will be reported in accordance with the Consolidated Standards of Reporting Trials and the Standards for Reporting Interventions in Clinical Trials of Acupuncture guidelines. The findings from this trial will provide evidence for the effectiveness of trigger point dry needling for plantar heel pain.</p> <p>Trial registration</p> <p>Australian New Zealand 'Clinical Trials Registry'. <a href="http://www.anzctr.org.au/ACTRN12610000611022.aspx">ACTRN12610000611022</a>.</p

Membrane lipid composition differentially modulates the function of human plasma platelet activating factor-acetylhydrolase

Human plasma platelet activating factor-acetylhydrolase (HpPAF-AH) is a calcium-independent phospholipase that catalyzes the hydrolysis of ester bond at the sn-2 position of phospholipid substrates. The enzyme belongs to group VIIA of the phospholipase A 2 superfamily and is associated with the lipids. Circulating form of HpPAF-AH resides on the lipoprotein particles and acts on a wide variety of substrates, including oxidized phospholipids. In this study we have characterized the effect of lipid composition of the membrane vesicles on the function of purified HpPAF-AH. Lipid composition of the vesicles was varied by incorporating varying amounts of cholesterol in the matrix phospholipids, POPC and DPPC, and its effect on the membrane binding, membrane penetration and the activity of the enzyme was determined. Physicochemical properties of the phospholipid vesicles were characterized by using different fluorescent probes. For the first time our results show that (a) membrane binding of HpPAF-AH increases the activity of enzyme (interfacial activation) and (b) lipid composition of membrane vesicles, by changing the physicochemical properties, differentially modulates the binding, partial membrane penetration and the activity of the enzyme

Association between geomagnetic activity and surface temperature

104-106The possible relationship between surface temperatures and geomagnetic field variations has been studied. Daily surface temperature data for Pune for 1998 and 1999 are used in the study. Geomagnetic field variations data were collected using Proton Precession Magnetometer (PPM). In this study May, June, July (representing summer) and December, January, February (representing winter) data are utilized. The increase in surface temperatures in association with increase in geomagnetic field is observed to be more in winter than in summer