Stress-induced dynamic regulation of mitochondrial STAT3 and its association with cyclophilin D reduces mitochondrial ROS production

Signal Transducer and Activator of Transcription 3 (STAT3) has been tied to various physiological and pathological functions, mainly as a transcription factor that translocates to the nucleus upon tyrosine phosphorylation induced by cytokine stimulation. In addition, a small pool of STAT3 resides in the mitochondria where it serves as a sensor for various metabolic stressors including reactive oxygen species (ROS). Mitochondrially-localized STAT3 largely exerts its effects through direct or indirect regulation of the activity of the electron transport chain (ETC). It has been assumed that STAT3 amounts in the mitochondria are static. We showed that various stimuli, including oxidative stress and cytokines, triggered a signaling cascade that resulted in a rapid loss of mitochondrially-localized STAT3. Recovery of the mitochondrial pool of STAT3 over time depended upon phosphorylation of Ser727 in STAT3 and new protein synthesis. Under these conditions, mitochondrially-localized STAT3 also became competent to bind to cyclophilin D (CypD). Binding of STAT3 to CypD was mediated by the N-terminus of STAT3, which was also important for reducing mitochondrial ROS production after oxidative stress. These results outline a role for mitochondrially-localized STAT3 in sensing and responding to external stimuli

Inactivity of Peptidase ClpP Causes Primary Accumulation of Mitochondrial Disaggregase ClpX with Its Interacting Nucleoid Proteins, and of mtDNA

From MDPI via Jisc Publications RouterHistory: accepted 2021-11-25, pub-electronic 2021-11-29Publication status: PublishedFunder: German Network for Mitochondrial Disorders; Grant(s): mitoNET, 01GM1906D, R01HL148153Funder: Action Medical Research; Grant(s): GN2494Funder: Office of the Assistant Secretary for Health; Grant(s): W81XWH-17-1-0052, W81XWH-20-1-0150Biallelic pathogenic variants in CLPP, encoding mitochondrial matrix peptidase ClpP, cause a rare autosomal recessive condition, Perrault syndrome type 3 (PRLTS3). It is characterized by primary ovarian insufficiency and early sensorineural hearing loss, often associated with progressive neurological deficits. Mouse models showed that accumulations of (i) its main protein interactor, the substrate-selecting AAA+ ATPase ClpX, (ii) mitoribosomes, and (iii) mtDNA nucleoids are the main cellular consequences of ClpP absence. However, the sequence of these events and their validity in human remain unclear. Here, we studied global proteome profiles to define ClpP substrates among mitochondrial ClpX interactors, which accumulated consistently in ClpP-null mouse embryonal fibroblasts and brains. Validation work included novel ClpP-mutant patient fibroblast proteomics. ClpX co-accumulated in mitochondria with the nucleoid component POLDIP2, the mitochondrial poly(A) mRNA granule element LRPPRC, and tRNA processing factor GFM1 (in mouse, also GRSF1). Only in mouse did accumulated ClpX, GFM1, and GRSF1 appear in nuclear fractions. Mitoribosomal accumulation was minor. Consistent accumulations in murine and human fibroblasts also affected multimerizing factors not known as ClpX interactors, namely, OAT, ASS1, ACADVL, STOM, PRDX3, PC, MUT, ALDH2, PMPCB, UQCRC2, and ACADSB, but the impact on downstream metabolites was marginal. Our data demonstrate the primary impact of ClpXP on the assembly of proteins with nucleic acids and show nucleoid enlargement in human as a key consequence

Stress-induced decreases in local cerebral glucose utilization in specific regions of the mouse brain

BACKGROUND: Restraint stress in rodents has been reported to activate the hypothalamic-pituitary-adrenocortical (HPA) axis and to increase c-fos expression in regions that express components of the corticotropin-releasing factor (CRF) system. We have previously reported that acute central administration of CRF increased a measure of relative local cerebral glucose utilization (LCGU), a measure of neuronal activity in specific brain regions, and activated the HPA axis in mice. It was hypothesized that the involvement of the CRF system in the stress response would lead to similar changes in relative LCGU after restraint stress. In the present studies the effect of restraint stress on relative LCGU and on the HPA axis in C57BL/6N mice were examined. FINDINGS: Restraint stress activated the HPA axis in a restraint-duration dependent manner, but in contrast to the reported effects of CRF, significantly decreased relative LCGU in frontal cortical, thalamic, hippocampal and temporal dissected regions. These findings support evidence that stressors enforcing limited physical activity reduce relative LCGU, in contrast to high activity stressors such as swim stress. CONCLUSIONS: In conclusion, the present studies do not support the hypothesis that stress-induced changes in relative LCGU are largely mediated by the CRF system. Further studies will help to delineate the role of the CRF system in the early phases of the relative LCGU response to stress and investigate the role of other neurotransmitter systems in this response

Toxicidade dérmica e oftálmica do extrato hidroalcoholico de Curcuma longa, Linn (Curcuvet) em modelos in vivo

Transforming medicinal plants into industrializable and marketable products involves meeting numerous regulatory requirements regarding the quality, safety, efficacy and stability of the proposed formulation. In this context, the product Curcuvet (antiseptic and healing solution obtained from the hydroalcoholic extract of C. longa) needs to demonstrate its safety before being legally used in veterinary clinical practice. Therefore, the present work aimed to evaluate in vivo the dermal and ophthalmic toxic potentialities of the product. To achieve this, three in vivo investigations were carried out: acute dermal toxicity, primary dermal irritancy and ophthalmic irritancy according to the standards described by the Organization for Economic Cooperation and Development (OECD) No. 434, 404 and 405, respectively. The Curcuvet product in all tests was administered as a single dose, superficially on both skin (Sprague Dawley rat and F1 rabbits) and ocular mucosa (New Zealand albino rabbits). The Curcuvet product was not irritating to the skin of rats and rabbits, but not to the ocular structures, which were severely damaged, reaching an irritancy index of 110. It is concluded that the Curcuvet formulation, administered in single dose, was not a dermal irritant and a severe ophthalmic irritant.Transformar las plantas medicinales en productos industrializables y comercializables implica cumplir numerosas exigencias regulatorias, sobre calidad, seguridad, eficacia y estabilidad de la formulación propuesta. En este contexto, el producto Curcuvet (solución antiséptica y cicatrizante obtenida a partir del extracto hidroalcohólico de C. longa) necesita demostrar su inocuidad antes de utilizarse legalmente en la práctica clínica veterinaria. Por tanto, el presente trabajo tuvo como objetivo evaluar in vivo las potencialidades tóxicas dérmica y oftálmica del producto. Para lograrlo se realizaron tres investigaciones in vivo: toxicidad aguda dérmica, irritabilidad dérmica primaria e irritabilidad oftálmica según las normas descritas por la Organización para la Cooperación Económica y el Desarrollo (OECD) No. 434, 404 y 405 respectivamente. El producto Curcuvet en todos los ensayos fue administrado en dosis única, de forma superficial tanto en piel (rata Sprague Dawley y conejos F1) como en mucosa ocular (conejos albinos Nueva Zelanda). El producto Curcuvet no resultó irritante para la piel de ratas y conejos, no así para las estructuras oculares, las cuales fueron severamente dañadas, alcanzándose un índice de irritabilidad de 110. Se concluye que la formulación Curcuvet administrado en dosis única, resultó no irritante dérmico e irritante severo oftálmico.A transformação de plantas medicinais em produtos industrializáveis e comercializáveis envolve o cumprimento de inúmeros requisitos regulamentares sobre qualidade, segurança, eficácia e estabilidade da formulação proposta. Neste contexto, o produto Curcuvet (uma solução anti-séptica e curativa obtida a partir do extrato hidroalcoólico de C. longa) precisa demonstrar sua segurança antes de poder ser legalmente utilizado na prática clínica veterinária. Portanto, o presente trabalho visou avaliar o potencial tóxico dérmico e oftálmico do produto in vivo. Para isso, foram realizadas três investigações in vivo: toxicidade dérmica aguda, irritação dérmica primária e irritação oftalmológica de acordo com as normas descritas pela Organização para Cooperação e Desenvolvimento Econômico (OCDE) No. 434, 404 e 405, respectivamente. O curcuvet em todos os testes foi administrado como dose única, superficialmente tanto à pele (rato Sprague Dawley e coelhos F1) quanto à mucosa ocular (coelhos albinos da Nova Zelândia). O Curcuvet não era irritante para a pele de ratos e coelhos, mas não para as estruturas oculares, que estavam gravemente danificadas, atingindo um índice de irritação de 110. Conclui-se que a formulação Curcuvet, administrada em doses únicas, era não-irritante para a pele e severamente irritante para a mucosa oftálmica

The Global Burden of Snakebite: A Literature Analysis and Modelling Based on Regional Estimates of Envenoming and Deaths

Janaka de Silva and colleagues estimate that globally at least 421,000 envenomings and 20,000 deaths occur each year due to snakebite

Human dopaminergic neurons lacking PINK1 exhibit disrupted dopamine metabolism related to vitamin B6 co-factors

PINK1 loss-of-function mutations cause early onset Parkinson disease. PINK1-Parkin mediated mitophagy has been well studied, but the relevance of the endogenous process in the brain is debated. Here, the absence of PINK1 in human dopaminergic neurons inhibits ionophore-induced mitophagy and reduces mitochondrial membrane potential. Compensatory, mitochondrial renewal maintains mitochondrial morphology and protects the respiratory chain. This is paralleled by metabolic changes, including inhibition of the TCA cycle enzyme mAconitase, accumulation of NAD+, and metabolite depletion. Loss of PINK1 disrupts dopamine metabolism by critically affecting its synthesis and uptake. The mechanism involves steering of key amino acids toward energy production rather than neurotransmitter metabolism and involves cofactors related to the vitamin B6 salvage pathway identified using unbiased multi-omics approaches. We propose that reduction of mitochondrial membrane potential that cannot be controlled by PINK1 signaling initiates metabolic compensation that has neurometabolic consequences relevant to Parkinson disease

Improved functionalization of oleic acid-coated iron oxide nanoparticles for biomedical applications

Superparamagnetic iron oxide nanoparticles can providemultiple benefits for biomedical applications in aqueous environments such asmagnetic separation or magnetic resonance imaging. To increase the colloidal stability and allow subsequent reactions, the introduction of hydrophilic functional groups onto the particles’ surface is essential. During this process, the original coating is exchanged by preferably covalently bonded ligands such as trialkoxysilanes. The duration of the silane exchange reaction, which commonly takes more than 24 h, is an important drawback for this approach. In this paper, we present a novel method, which introduces ultrasonication as an energy source to dramatically accelerate this process, resulting in high-quality waterdispersible nanoparticles around 10 nmin size. To prove the generic character, different functional groups were introduced on the surface including polyethylene glycol chains, carboxylic acid, amine, and thiol groups. Their colloidal stability in various aqueous buffer solutions as well as human plasma and serum was investigated to allow implementation in biomedical and sensing applications.status: publishe

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p<0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (<1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (<1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Factores genéticos, inmunológicos y ambientales asociados a la autoinmunidad Genetic, immunologic and environmental factors associated with autoimmunity

La autoinmunidad se caracteriza por una pérdida de la tolerancia inmunológica que produce la destrucción de células y tejidos propios. El sistema del complejo mayor de histocompatibilidad posee una fuerte asociación con las enfermedades autoinmunes aunque determinados genes que codifican para citoquinas y moléculas coestimuladoras incrementan la susceptibilidad genética. Estudios de concordancia entre gemelos monocigóticos demuestran el papel de los factores ambientales en la aparición de las enfermedades autoinmunes. A pesar de los avances científicos producidos en esta área de investigación, los mecanismos subyacentes de estas afecciones son desconocidos. El objetivo deeste trabajo es exponer de forma sintetizada el papel de los factores genéticos, inmunológicos y ambientales en la autoinmunidad.The autoimmunity is characterized by a loss of immunologic tolerance producing the destruction of cells and own tissues. The major complex system of histocompatibility has a close association with the autoimmune diseases although determined genes codifying for cytokines and co-stimulators molecules increase the genetic susceptibility. Concordance studies among monozygotic twins demonstrate the role of environmental factors in appearance of autoimmune diseases. Despite the scientific advances achieved in this research field, the underlying mechanisms of these affections are unknown. The objective of present paper is to expose in a summarized way the role of the genetic, immunologic and environmental factors in autoimmunity