Epidemiological study of Hepatitis C in people deprived of liberty

Introduction: The prevalence of hepatitis C (HCV) is high among prisoners. If untreated, a substantial number of patients progress to cirrhosis, hepatocarcinoma, or liver failure. World Health Organization aims to reduce the incidence of infection by 90% by 2030. Objective: To describe the prevalence of anti-HCV and sociodemographic and clinical aspects, related to the presence of the antibody, in the population deprived of liberty. Methods: Cross-sectional and epidemiological survey, with exploratory, observational, quantitative-analytical components. A simple random sample of 233 participants, with 95% Confidence Interval (CI) and, a 4% margin of error, was calculated for a population of 1,564 prisoners. The relationship between sociodemographic and clinical variables was evaluated, considering as outcome of the rapid test for anti-HCV results, using the associative measure Prevalence Ratio (PR) with a 95% CI. Results: 240 people participated. The prevalence of anti-HCV was 2%, and the use of injectable drugs (PR 14.75; PRIC95% 2.09-104.28), being born in the decades of 1951 to 1980 (PR 9.28; PRIC95% 1.06-81.57) and be co-infected with hepatitis B virus (PR 10.75; PRIC95% 1.66-69.65) were the aspects that presented a relevant prevalence ratio for the presence of the virus, which could be generalized to the population. Conclusion: This is a population that is difficult to access, the study is relevant because it contributes to preventive measures of public health in the prison system. Moreover, it shows the need to implement measures to prevent and contain the spread of HCV, aiming at the elimination of hepatitis C in this population.

Metabolic dysfunction induced by HFD + L-NAME preferentially affects hippocampal mitochondria, impacting spatial memory in rats.

High-fat diet-induced metabolic changes are not restricted to the onset of cardiovascular diseases, but also include effects on brain functions related to learning and memory. This study aimed to evaluate mitochondrial markers and function, as well as cognitive function, in a rat model of metabolic dysfunction. Eight-week-old male Wistar rats were subjected to either a control diet or a two-hit protocol combining a high fat diet (HFD) with the nitric oxide synthase inhibitor L-NAME in the drinking water. HFD plus L-NAME induced obesity, hypertension, and increased serum cholesterol. These rats exhibited bioenergetic dysfunction in the hippocampus, characterized by decreased oxygen (O2) consumption related to ATP production, with no changes in H2O2 production. Furthermore, OPA1 protein expression was upregulated in the hippocampus of HFD + L-NAME rats, with no alterations in other morphology-related proteins. Consistently, HFD + L-NAME rats showed disruption of performance in the Morris Water Maze Reference Memory test. The neocortex did not exhibit either bioenergetic changes or alterations in H2O2 production. Calcium uptake rate and retention capacity in the neocortex of HFD + L-NAME rats were not altered. Our results indicate that hippocampal mitochondrial bioenergetic function is disturbed in rats exposed to a HFD plus L-NAME, thus disrupting spatial learning, whereas neocortical function remains unaffected.

Association between religiosity/spirituality and substance use among homeless individuals.

BACKGROUND: Alcohol and illicit drug use are prevalent among homeless people. Religiosity and spirituality (RS) have been widely associated with lower consumption of substances. However, evidence of this relationship among homeless people is still scarce. AIMS: To evaluate the associations between RS and alcohol and illicit drug consumption among homeless people in a large Brazilian urban center. METHOD: This cross-sectional study was carried out in São Paulo city, Brazil. Aspects such as spirituality (FACIT-Sp12), religiosity (DUREL), spiritual-religious coping (Brief-RCOPE), and self-report questions concerning the current substance use (alcohol and illicit substances) were evaluated. Adjusted logistic regression models were used to assess the impact of RS beliefs on alcohol and illicit drug consumption. RESULTS: A total of 456 homeless people were included, of an average age of 44.5 (SD = 12.6) years. More than half of the participants consumed alcohol (55.7%) weekly and 34.2% used illicit drugs weekly. Adjusted logistic regression models identified that aspects of RS were associated with lower likelihood factors for alcohol and illicit drug use; conversely, negative spiritual religious coping (SRC) strategies were associated with a higher likelihood to use both. CONCLUSION: The prevalence of alcohol and illicit drug use among participants was high. RS and positive SRC were important protective factors for lower consumption of these substances. Conversely, negative SRC strategies were associated with risk factors.

4-Hydroxynonenal impairs miRNA maturation in heart failure via Dicer post-translational modification.

BACKGROUND AND AIMS: Developing novel therapies to battle the global public health burden of heart failure remains challenging. This study investigates the underlying mechanisms and potential treatment for 4-hydroxynonenal (4-HNE) deleterious effects in heart failure. METHODS: Biochemical, functional, and histochemical measurements were applied to identify 4-HNE adducts in rat and human failing hearts. In vitro studies were performed to validate 4-HNE targets. RESULTS: 4-HNE, a reactive aldehyde by-product of mitochondrial dysfunction in heart failure, covalently inhibits Dicer, an RNase III endonuclease essential for microRNA (miRNA) biogenesis. 4-HNE inhibition of Dicer impairs miRNA processing. Mechanistically, 4-HNE binds to recombinant human Dicer through an intermolecular interaction that disrupts both activity and stability of Dicer in a concentration- and time-dependent manner. Dithiothreitol neutralization of 4-HNE or replacing 4-HNE-targeted residues in Dicer prevents 4-HNE inhibition of Dicer in vitro. Interestingly, end-stage human failing hearts from three different heart failure aetiologies display defective 4-HNE clearance, decreased Dicer activity, and miRNA biogenesis impairment. Notably, boosting 4-HNE clearance through pharmacological re-activation of mitochondrial aldehyde dehydrogenase 2 (ALDH2) using Alda-1 or its improved orally bioavailable derivative AD-9308 restores Dicer activity. ALDH2 is a major enzyme responsible for 4-HNE removal. Importantly, this response is accompanied by improved miRNA maturation and cardiac function/remodelling in a pre-clinical model of heart failure. CONCLUSIONS: 4-HNE inhibition of Dicer directly impairs miRNA biogenesis in heart failure. Strikingly, decreasing cardiac 4-HNE levels through pharmacological ALDH2 activation is sufficient to re-establish Dicer activity and miRNA biogenesis; thereby representing potential treatment for patients with heart failure.

Commentary: Aldehyde dehydrogenase, redox balance and exercise physiology: What is missing?

Aldehyde dehydrogenase 2 (ALDH2) is a mitochondrial enzyme involved in reactive aldehyde detoxification. Approximately 560 million people (about 8% of the world's population) carry a point mutation in the aldehyde dehydrogenase 2 gene (ALDH2), identified as ALDH2*2, which leads to decreased ALDH2 catalytic activity. ALDH2*2 variant is associated with an accumulation of toxic reactive aldehydes and consequent disruption of cellular metabolism, which contributes to the establishment and progression of several degenerative diseases. Consequences of aldehyde accumulation include impaired mitochondrial functional, hindered anabolic signaling in the skeletal muscle, impaired cardiovascular and pulmonary function, and reduced osteoblastogenesis. Considering that aldehydes are endogenously produced through redox processes, it is expected that conditions that have a high energy demand, such as exercise, might be affected by impaired aldehyde clearance in ALDH2*2 individuals. Despite the large body of evidence supporting the importance of ALDH2 to ethanol metabolism, redox homeostasis and overall health, specific research investigating the impact of ALDH2*2 on phenotypes relevant to exercise performance are notoriously scarce. In this commentary, we highlight the consolidated knowledge on the impact of ALDH2*2 on physiological processes that are relevant to exercise.

Small-Molecule Inhibition of MuRF1 Prevents Early Disuse-Induced Diaphragmatic Dysfunction and Atrophy.

In clinical conditions such as diaphragm paralysis or mechanical ventilation, disuse-induced diaphragmatic dysfunction (DIDD) is a condition that poses a threat to life. MuRF1 is a key E3-ligase involved in regulating skeletal muscle mass, function, and metabolism, which contributes to the onset of DIDD. We investigated if the small-molecule mediated inhibition of MuRF1 activity (MyoMed-205) protects against early DIDD after 12 h of unilateral diaphragm denervation. Wistar rats were used in this study to determine the compound's acute toxicity and optimal dosage. For potential DIDD treatment efficacy, diaphragm contractile function and fiber cross-sectional area (CSA) were evaluated. Western blotting investigated potential mechanisms underlying MyoMed-205's effects in early DIDD. Our results indicate 50 mg/kg bw MyoMed-205 as a suitable dosage to prevent early diaphragmatic contractile dysfunction and atrophy following 12 h of denervation without detectable signs of acute toxicity. Mechanistically, treatment did not affect disuse-induced oxidative stress (4-HNE) increase, whereas phosphorylation of (ser632) HDAC4 was normalized. MyoMed-205 also mitigated FoxO1 activation, inhibited MuRF2, and increased phospho (ser473) Akt protein levels. These findings may suggest that MuRF1 activity significantly contributes to early DIDD pathophysiology. Novel strategies targeting MuRF1 (e.g., MyoMed-205) have potential therapeutic applications for treating early DIDD.

Efficacy of the argon plasma coagulation in patients with weight regain after gastric bypass: a randomized control trial.

Background and study aims Endoscopic procedure using argon plasma coagulation (APC) promotes a progressive reduction in gastrojejunal anastomosis diameter. The present study aimed to evaluate the efficacy of the APC in patients with weight regain in the postoperative periods of gastric bypass. Patients and methods This was a randomized controlled trial conducted with 66 patients who were randomly assigned selected (using lottery method) and divided into two groups: study group (SG), 38 patients (APC treatment); and control group (CG), 28 patients (only endoscopy procedure). We considered 30 days,180 days, and one year as short-term, medium-term, and long-term, respectively. The parameters analyzed were total weight loss (TWL), excess weight loss (%EWL), total weight loss (%TWL), and reduction of weight regain (%RWR). Furthermore, a biopsy for neoplastic histological changes was carried out for the APC group. For statistical analysis, values of P  < 0.05 were considered significant. Results The %TWL and %RWR were higher in the SG in short, medium, and long terms, when compared to the same periods in the CG ( P  < 0.001). One year after follow-up, the final weight did not reach the statistical difference between groups. Biopsy performed in SG 1 year after APC did not reveal neoplastic histological changes. Conclusions APC effectively treats weight regain after bariatric surgery in the short and medium-term. An important "new" weight gain was observed in the long-term, showing that obesity is a chronic disease that requires multidisciplinary and family care for life. Also, APC is a safe procedure with low adverse event rates.

Exercise preserves physical fitness during aging through AMPK and mitochondrial dynamics.

Exercise is a nonpharmacological intervention that improves health during aging and a valuable tool in the diagnostics of aging-related diseases. In muscle, exercise transiently alters mitochondrial functionality and metabolism. Mitochondrial fission and fusion are critical effectors of mitochondrial plasticity, which allows a fine-tuned regulation of organelle connectiveness, size, and function. Here we have investigated the role of mitochondrial dynamics during exercise in the model organism Caenorhabditis elegans. We show that in body-wall muscle, a single exercise session induces a cycle of mitochondrial fragmentation followed by fusion after a recovery period, and that daily exercise sessions delay the mitochondrial fragmentation and physical fitness decline that occur with aging. Maintenance of proper mitochondrial dynamics is essential for physical fitness, its enhancement by exercise training, and exercise-induced remodeling of the proteome. Surprisingly, among the long-lived genotypes we analyzed (isp-1,nuo-6, daf-2, eat-2, and CA-AAK-2), constitutive activation of AMP-activated protein kinase (AMPK) uniquely preserves physical fitness during aging, a benefit that is abolished by impairment of mitochondrial fission or fusion. AMPK is also required for physical fitness to be enhanced by exercise, with our findings together suggesting that exercise may enhance muscle function through AMPK regulation of mitochondrial dynamics. Our results indicate that mitochondrial connectivity and the mitochondrial dynamics cycle are essential for maintaining physical fitness and exercise responsiveness during aging and suggest that AMPK activation may recapitulate some exercise benefits. Targeting mechanisms to optimize mitochondrial fission and fusion, as well as AMPK activation, may represent promising strategies for promoting muscle function during aging.

Experiência no gerenciamento de pesquisa-ação sobre inquérito de hepatite C junto à comunidade carcerária / Experience in managing action research on hepatitis C survey in the prison community

Resumo Objetivou-se relatar a experiência no gerenciamento de pesquisa-ação sobre inquérito de hepatite C junto à comunidade carcerária no Triângulo Mineiro, Minas Gerais. A proposta foi desenvolvida entre março de 2019 e março de 2020, alcançando 240 pessoas, com o intuito de conter a disseminação do agravo por meio de inquérito, testagem e acompanhamento dos casos positivos. Adotou-se ação intersetorial, com articulação entre universidades, sociedade médica, hospital de ensino e Secretaria de Estado de Justiça e Segurança Pública. As estratégias para o gerenciamento da pesquisa-ação foram: cenários e atores do estudo, registro e formalização da atividade, aplicação dos testes e manejo dos internos reagentes. Dificuldades foram identificadas quanto à acomodação de rotinas entre equipe de pesquisadores e funcionamento próprio da penitenciária, o que exigiu treinamento ostensivo entre as partes e articulações gerenciais. Considera-se que o relato, quando destaca as estratégias adotadas para a condução da pesquisa, colabora para a organização de investigações futuras que visem acessar essa população ainda invisibilizada.

Abstract We aimed to report the experience in managing action research on hepatitis C investigation in the prison community in the Triângulo Mineiro region, Minas Gerais, Brazil. The proposal was developed from March 2019 to March 2020, reaching 240 people to contain the spread of the disease through a survey, testing, and monitoring of positive cases. We adopted intersectoral action with articulation between Universities, Medical Society, Teaching Hospital, and State Secretariat for Justice and Public Security. Strategies for the management of action research are described: study settings and stakeholders, registration and formalization of the activity, application of tests, and management of reagent inmates. We identified difficulties regarding the accommodation of routines among the research team and the proper functioning of the penitentiary, which required extensive training between the parties and managerial articulations. We consider that the report collaborates with the organization of future research aimed at accessing this still invisible population, the prison community when it highlights the strategies adopted to conduct the research.

Experience in managing action research on hepatitis C survey in the prison community. / Experiência no gerenciamento de pesquisa-ação sobre inquérito de hepatite C junto à comunidade carcerária.

We aimed to report the experience in managing action research on hepatitis C investigation in the prison community in the Triângulo Mineiro region, Minas Gerais, Brazil. The proposal was developed from March 2019 to March 2020, reaching 240 people to contain the spread of the disease through a survey, testing, and monitoring of positive cases. We adopted intersectoral action with articulation between Universities, Medical Society, Teaching Hospital, and State Secretariat for Justice and Public Security. Strategies for the management of action research are described: study settings and stakeholders, registration and formalization of the activity, application of tests, and management of reagent inmates. We identified difficulties regarding the accommodation of routines among the research team and the proper functioning of the penitentiary, which required extensive training between the parties and managerial articulations. We consider that the report collaborates with the organization of future research aimed at accessing this still invisible population, the prison community when it highlights the strategies adopted to conduct the research.

Objetivou-se relatar a experiência no gerenciamento de pesquisa-ação sobre inquérito de hepatite C junto à comunidade carcerária no Triângulo Mineiro, Minas Gerais. A proposta foi desenvolvida entre março de 2019 e março de 2020, alcançando 240 pessoas, com o intuito de conter a disseminação do agravo por meio de inquérito, testagem e acompanhamento dos casos positivos. Adotou-se ação intersetorial, com articulação entre universidades, sociedade médica, hospital de ensino e Secretaria de Estado de Justiça e Segurança Pública. As estratégias para o gerenciamento da pesquisa-ação foram: cenários e atores do estudo, registro e formalização da atividade, aplicação dos testes e manejo dos internos reagentes. Dificuldades foram identificadas quanto à acomodação de rotinas entre equipe de pesquisadores e funcionamento próprio da penitenciária, o que exigiu treinamento ostensivo entre as partes e articulações gerenciais. Considera-se que o relato, quando destaca as estratégias adotadas para a condução da pesquisa, colabora para a organização de investigações futuras que visem acessar essa população ainda invisibilizada.

Correlation Between Implant Positioning and Functional Outcomes in Partial Shoulder Resurfacing.

Objective The present study aimed to correlate functional outcomes and implant positioning in a case series of partial shoulder resurfacing arthroplasties. Methods A total of 25 patients were assessed for range of motion, functional outcome per the University of California at Los Angeles (UCLA) score and radiographic findings. Pre- and postoperative data were compared. In addition, patients were grouped according to the cervical-diaphyseal angle (CDA) determined by an anteroposterior radiography and to the retroversion angle (RVA) determined by an axillary radiography. A CDA from 130° to 140° and a RVA from 20° to 40° consisted in ideal positioning (anatomical standard). Data were analyzed using the Wilcoxon signed-rank test, analysis of variance (ANOVA) followed by the Kruskal-Wallis test or the Mann-Whitney test as appropriate. Results The mean follow-up time was 48.3 months (12 to 67 months). The postoperative functional score (31.5) was higher than the preoperative score (15.5) ( p < 0.001). In 6 patients, the implant was in anatomical positioning, while implant positioning was considered "nonstandard" in 19 subjects. Seven patients had a CDA < 130°, and 14 patients had a CDA ranging from 130° to 140°; in addition, the CDA was > 140° in 4 subjects. The RVA was up to 20° in 15 patients and ranged from 20° to 40° in 10 subjects. Using these criteria to group patients, the postoperative clinical-functional parameters were not statistically different from the preoperative findings ( p > 0.05). Conclusion Partial shoulder resurfacing results in significant postoperative functional recovery in patients with degenerative joint diseases. However, implant positioning assessed by CDA and RVA does not correlate with clinical-functional outcomes and, therefore, it is an inaccurate indicator of surgical success. Level of Evidence IV; Case Series.

Correlation Between Implant Positioning and Functional Outcomes in Partial Shoulder Resurfacing / Correlação entre posicionamento do implante das artroplastias parciais de recobrimento do ombro e os resultados funcionais

Abstract Objective The present study aimed to correlate functional outcomes and implant positioning in a case series of partial shoulder resurfacing arthroplasties. Methods A total of 25 patients were assessed for range of motion, functional outcome per the University of California at Los Angeles (UCLA) score and radiographic findings. Preand postoperative data were compared. In addition, patients were grouped according to the cervical-diaphyseal angle (CDA) determined by an anteroposterior radiography and to the retroversion angle (RVA) determined by an axillary radiography. A CDA from 130° to 140° and a RVA from 20° to 40° consisted in ideal positioning (anatomical standard). Data were analyzed using the Wilcoxon signed-rank test, analysis of variance (ANOVA) followed by the Kruskal-Wallis test or the Mann-Whitney test as appropriate. Results The mean follow-up time was 48.3 months (12 to 67 months). The postoperative functional score (31.5) was higher than the preoperative score (15.5) (p < 0.001). In 6 patients, the implant was in anatomical positioning, while implant positioning was considered "nonstandard" in 19 subjects. Seven patients had a CDA < 130°, and 14 patients had a CDA ranging from 130° to 140°; in addition, the CDA was > 140° in 4 subjects. The RVA was up to 20° in 15 patients and ranged from 20° to 40° in 10 subjects. Using these criteria to group patients, the postoperative clinical-functional parameters were not statistically different from the preoperative findings (p > 0.05). Conclusion Partial shoulder resurfacing results in significant postoperative functional recovery in patients with degenerative joint diseases. However, implant positioning assessed by CDA and RVA does not correlate with clinical-functional outcomes and, therefore, it is an inaccurate indicator of surgical success. Level of Evidence IV; Case Series.

Resumo Objetivo O objetivo do presente estudo é correlacionar os resultados funcionais de uma série de casos de artroplastias parciais de recobrimento do ombro com o posicionamento do implante. Métodos Um total de 25 pacientes foram avaliados em relação à amplitude de movimentos, à avaliação funcional pelo escore de Universidade da Califórnia Los Angeles (UCLA) e por análise radiográfica. Os dados pré- e pós-operatórios foram comparados. Adicionalmente, os pacientes foram agrupados quanto ao ângulo cérvico-diafisário (ACD) avaliado na radiografia em anteroposterior e quanto ao ângulo de retroversão (ARV) avaliado na radiografia em posição axilar. Foi considerado como posicionamento ideal (padrão anatômico) um ACD entre 130° e 140° e um ARV entre 20° e 40°. Os dados foram analisados pelo teste pareado de Wilcoxon, pela análise de variância (ANOVA, na sigla em inglês) seguida pelo pós-teste de Kruskal-Wallis ou pelo teste de Mann-Whitney, quando apropriado. Resultados O seguimento médio foi de 48,3 meses (12 a 67 meses). A avaliação funcional pós-operatória (31,5) foi melhor do que a pré-operatória (15,5) (p < 0,001). Seis pacientes apresentaram posicionamento anatômico do implante, enquanto 19 pacientes foram considerados "fora do padrão." Sete pacientes apresentaram um ACD < 130°, quatorze apresentaram um ACD entre 130° e 140°, e quatro apresentaram um ACD >140°. Quinze pacientes apresentaram um ARV ≤ 20°, e 10 entre 20° e 40°. Utilizando esses critérios para agrupar os pacientes, a comparação dos parâmetros da avaliação clínico-funcional pós-operatória não foi estatisticamente diferente (p > 0,05). Conclusão A artroplastia parcial de recobrimento do ombro oferece significativa recuperação funcional pós-operatória em pacientes com doenças degenerativas articulares. Entretanto, o posicionamento do implante avaliado pelos ACD e ARV não se correlaciona com o resultado clínico-funcional, sendo, portanto, uma medida imprecisa de sucesso da cirurgia. Nível de Evidência IV, Série de Casos.

Mitochondrial Dysfunction in Degenerative Diseases.

Mitochondria are major intracellular hubs distributed throughout the cell that play a key role in the spatiotemporal coordination and propagation of signalling events, ensuring that homeostasis is met at baseline or under environmental pressure [...].

A Selective Inhibitor of Cardiac Troponin I Phosphorylation by Delta Protein Kinase C (δPKC) as a Treatment for Ischemia-Reperfusion Injury.

Myocardial infarction is the leading cause of cardiovascular mortality, with myocardial injury occurring during ischemia and subsequent reperfusion (IR). We previously showed that the inhibition of protein kinase C delta (δPKC) with a pan-inhibitor (δV1-1) mitigates myocardial injury and improves mitochondrial function in animal models of IR, and in humans with acute myocardial infarction, when treated at the time of opening of the occluded blood vessel, at reperfusion. Cardiac troponin I (cTnI), a key sarcomeric protein in cardiomyocyte contraction, is phosphorylated by δPKC during reperfusion. Here, we describe a rationally-designed, selective, high-affinity, eight amino acid peptide that inhibits cTnI's interaction with, and phosphorylation by, δPKC (ψTnI), and prevents tissue injury in a Langendorff model of myocardial infarction, ex vivo. Unexpectedly, we also found that this treatment attenuates IR-induced mitochondrial dysfunction. These data suggest that δPKC phosphorylation of cTnI is critical in IR injury, and that a cTnI/δPKC interaction inhibitor should be considered as a therapeutic target to reduce cardiac injury after myocardial infarction.

Autophagy deficiency abolishes liver mitochondrial DNA segregation.

Mutations in the mitochondrial genome (mtDNA) are ubiquitous in humans and can lead to a broad spectrum of disorders. However, due to the presence of multiple mtDNA molecules in the cell, co-existence of mutant and wild-type mtDNAs (termed heteroplasmy) can mask disease phenotype unless a threshold of mutant molecules is reached. Importantly, the mutant mtDNA level can change across lifespan as mtDNA segregates in an allele- and cell-specific fashion, potentially leading to disease. Segregation of mtDNA is mainly evident in hepatic cells, resulting in an age-dependent increase of mtDNA variants, including non-synonymous potentially deleterious mutations. Here we modeled mtDNA segregation using a well-established heteroplasmic mouse line with mtDNA of NZB/BINJ and C57BL/6N origin on a C57BL/6N nuclear background. This mouse line showed a pronounced age-dependent NZB mtDNA accumulation in the liver, thus leading to enhanced respiration capacity per mtDNA molecule. Remarkably, liver-specific atg7 (autophagy related 7) knockout abolished NZB mtDNA accumulat ion, resulting in close-to-neutral mtDNA segregation through development into adulthood. prkn (parkin RBR E3 ubiquitin protein ligase) knockout also partially prevented NZB mtDNA accumulation in the liver, but to a lesser extent. Hence, we propose that age-related liver mtDNA segregation is a consequence of macroautophagic clearance of the less-fit mtDNA. Considering that NZB/BINJ and C57BL/6N mtDNAs have a level of divergence comparable to that between human Eurasian and African mtDNAs, these findings have potential implications for humans, including the safe use of mitochondrial replacement therapy.Abbreviations: Apob: apolipoprotein B; Atg1: autophagy-related 1; Atg7: autophagy related 7; Atp5a1: ATP synthase, H+ transporting, mitochondrial F1 complex, alpha subunit 1; BL6: C57BL/6N mouse strain; BNIP3: BCL2/adenovirus E1B interacting protein 3; FCCP: carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; MAP1LC3A: microtubule-associated protein 1 light chain 3 alpha; MAP1LC3B: microtubule-associated protein 1 light chain 3 beta; mt-Atp8: mitochondrially encoded ATP synthase 8; MT-CO1: mitochondrially encoded cytochrome c oxidase I; MT-CO2: mitochondrially encoded cytochrome c oxidase II; mt-Co3: mitochondrially encoded cytochrome c oxidase III; mt-Cytb: mitochondrially encoded cytochrome b; mtDNA: mitochondrial DNA; MUL1: mitochondrial ubiquitin ligase activator of NFKB 1; nDNA: nuclear DNA; Ndufa9: NADH:ubiquinone oxireductase subunit A9; NDUFB8: NADH:ubiquinone oxireductase subunit B8; Nnt: nicotinamide nucleotide transhydrogenase; NZB: NZB/BINJ mouse strain; OXPHOS: oxidative phosphorylation; PINK1: PTEN induced putative kinase 1; Polg2: polymerase (DNA directed), gamma 2, accessory subunit; Ppara: peroxisome proliferator activated receptor alpha; Ppia: peptidylprolyl isomerase A; Prkn: parkin RBR E3 ubiquitin protein ligase; P10: post-natal day 10; P21: post-natal day 21; P100: post-natal day 100; qPCR: quantitative polymerase chain reaction; Rpl19: ribosomal protein L19; Rps18: ribosomal protein S18; SD: standard deviation; SEM: standard error of the mean; SDHB: succinate dehydrogenase complex, subunit B, iron sulfur (Ip); SQSTM1: sequestosome 1; Ssbp1: single-stranded DNA binding protein 1; TFAM: transcription factor A, mitochondrial; Tfb1m: transcription factor B1, mitochondrial; Tfb2m: transcription factor B2, mitochondrial; TOMM20: translocase of outer mitochondrial membrane 20; UQCRC2: ubiquinol cytochrome c reductase core protein 2; WT: wild-type.

Effect of FKBP12-Derived Intracellular Peptides on Rapamycin-Induced FKBP-FRB Interaction and Autophagy.

Intracellular peptides (InPeps) generated by proteasomes were previously suggested as putative natural regulators of protein-protein interactions (PPI). Here, the main aim was to investigate the intracellular effects of intracellular peptide VFDVELL (VFD7) and related peptides on PPI. The internalization of the peptides was achieved using a C-terminus covalently bound cell-penetrating peptide (cpp; YGRKKRRQRRR). The possible inhibition of PPI was investigated using a NanoBiT® luciferase structural complementation reporter system, with a pair of plasmids vectors each encoding, simultaneously, either FK506-binding protein (FKBP) or FKBP-binding domain (FRB) of mechanistic target of rapamycin complex 1 (mTORC1). The interaction of FKBP-FRB within cells occurs under rapamycin induction. Results shown that rapamycin-induced interaction between FKBP-FRB within human embryonic kidney 293 (HEK293) cells was inhibited by VFD7-cpp (10-500 nM) and FDVELLYGRKKRRQRRR (VFD6-cpp; 1-500 nM); additional VFD7-cpp derivatives were either less or not effective in inhibiting FKBP-FRB interaction induced by rapamycin. Molecular dynamics simulations suggested that selected peptides, such as VFD7-cpp, VFD6-cpp, VFAVELLYGRKKKRRQRRR (VFA7-cpp), and VFEVELLYGRKKKRRQRRR (VFA7-cpp), bind to FKBP and to FRB protein surfaces. However, only VFD7-cpp and VFD6-cpp induced changes on FKBP structure, which could help with understanding their mechanism of PPI inhibition. InPeps extracted from HEK293 cells were found mainly associated with macromolecular components (i.e., proteins and/or nucleic acids), contributing to understanding InPeps' intracellular proteolytic stability and mechanism of action-inhibiting PPI within cells. In a model of cell death induced by hypoxia-reoxygenation, VFD6-cpp (1 µM) increased the viability of mouse embryonic fibroblasts cells (MEF) expressing mTORC1-regulated autophagy-related gene 5 (Atg5), but not in autophagy-deficient MEF cells lacking the expression of Atg5. These data suggest that VFD6-cpp could have therapeutic applications reducing undesired side effects of rapamycin long-term treatments. In summary, the present report provides further evidence that InPeps have biological significance and could be valuable tools for the rational design of therapeutic molecules targeting intracellular PPI.

Mitochondrial Fusion, Fission, and Mitophagy in Cardiac Diseases: Challenges and Therapeutic Opportunities.

Significance: Mitochondria play a critical role in the physiology of the heart by controlling cardiac metabolism, function, and remodeling. Accumulation of fragmented and damaged mitochondria is a hallmark of cardiac diseases. Recent Advances: Disruption of quality control systems that maintain mitochondrial number, size, and shape through fission/fusion balance and mitophagy results in dysfunctional mitochondria, defective mitochondrial segregation, impaired cardiac bioenergetics, and excessive oxidative stress. Critical Issues: Pharmacological tools that improve the cardiac pool of healthy mitochondria through inhibition of excessive mitochondrial fission, boosting mitochondrial fusion, or increasing the clearance of damaged mitochondria have emerged as promising approaches to improve the prognosis of heart diseases. Future Directions: There is a reasonable amount of preclinical evidence supporting the effectiveness of molecules targeting mitochondrial fission and fusion to treat cardiac diseases. The current and future challenges are turning these lead molecules into treatments. Clinical studies focusing on acute (i.e., myocardial infarction) and chronic (i.e., heart failure) cardiac diseases are needed to validate the effectiveness of such strategies in improving mitochondrial morphology, metabolism, and cardiac function. Antioxid. Redox Signal. 36, 844-863.

Accuracy of the clinical indicators for Readiness for enhanced health management.

PURPOSE: to analyze accuracy measures of the clinical indicators of Readiness for enhanced health management in patients with arterial hypertension and/or diabetes mellitus METHODS: prospective diagnostic accuracy study conducted with 359 patients with hypertension and/or diabetes mellitus, followed up in primary healthcare. Stratified random sampling was used to recruit participants. An assessment form was applied with sociodemographic data, health conditions, and information related to the clinical indicators under investigation. Sensitivity, specificity, predictive values, and likelihood ratios were analyzed FINDINGS: the sample was composed of 359 participants. The prevalence of Readiness for enhanced health management was 93.8%. There was a statistically significant association between the diagnosis and age under 60 years (p < 0.001), having only one chronic condition (p < 0.001), having normal blood pressure (p = 0.017) and blood glucose (p = 0.013) values, and having a nonsedentary (p = 0.026) and nonalcoholic (p = 0.044) lifestyle. All clinical indicators had high predictive values in predicting the nursing diagnosis under investigation. The indicator expresses desire to enhance management of symptoms was the most sensitive (99.7%) and specific (100%). The indicator expresses desire to enhance management of prescribed regimens was also highly specific (100%) CONCLUSION: all clinical indicators were accurate in predicting Readiness for enhanced health management IMPLICATIONS FOR NURSING PRACTICE: knowing which clinical indicators and sociodemographic/clinical characteristics best predict Readiness for enhanced health management, nurses in primary care can better plan nursing interventions and direct their goals.