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Nescient helix-loop-helix 2 (NHLH2) is a hypothalamic transcription factor that controls the expression of prohormone convertase 1/3, therefore having an impact on the processing of proopiomelanocortin and thus on energy homeostasis. Studies have shown that KO ofNhlh2results in increased body mass, reduced physical activity, and hypogonadism. In humans, a polymorphism of theNHLH2gene is associated with obesity; and in Prader–Willi syndrome, a condition characterized by obesity, hypogonadism and behavioral abnormalities, the expression of NHLH2 is reduced. Despite clinical and experimental evidence suggesting that NHLH2 could be a good target for the treatment of obesity, no previous study has evaluated the impact of NHLH2 overexpression in obesity. Here, in mice fed a high-fat diet introduced right after the arcuate nucleus intracerebroventricular injection of a lentivirus that promoted 40% increase in NHLH2, there was prevention of the development of obesity by a mechanism dependent on the reduction of caloric intake. When hypothalamic overexpression of NHLH2 was induced in previously obese mice, the beneficial impact on obesity-associated phenotype was even greater; thus, there was an 80% attenuation in body mass gain, reduced whole-body adiposity, increased brown adipose tissue temperature, reduced hypothalamic inflammation, and reduced liver steatosis. In this setting, the beneficial impact of hypothalamic overexpression of NHLH2 was a result of combined effects on caloric intake, energy expenditure, and physical activity. Moreover, the hypothalamic overexpression of NHLH2 reduced obesity-associated anxiety/depression behavior. Thus, we provide an experimental proof of concept supporting that hypothalamic NHLH2 is a good target for the treatment of obesity.SIGNIFICANCE STATEMENTObesity is a highly prevalent medical condition that lacks an effective treatment. The main advance provided by this study is the demonstration of the beneficial metabolic and behavioral outcomes resulting from the overexpression of NHLH2 in the hypothalamus. When NHLH2 was overexpressed simultaneously with the introduction of a high-fat diet, there was prevention of obesity by a mechanism dependent on reduced caloric intake. Conversely, when NHLH2 was overexpressed in previously obese mice, there was reduction of the obese phenotype because of a combination of reduced caloric intake, increased physical activity, and increased thermogenesis. In addition, the overexpression of NHLH2 reduced anxiety/depression-like behavior. Thus, NHLH2 emerges as a potential target for the combined treatment of obesity and its associated anxiety/depression-like behavior.

Background SARS-CoV-2, the virus that causes COVID-19, enters the cells through a mechanism dependent on its binding to angiotensin-converting enzyme 2 (ACE2), a protein highly expressed in the lungs. The putative viral-induced inhibition of ACE2 could result in the defective degradation of bradykinin, a potent inflammatory substance. We hypothesize that increased bradykinin in the lungs is an important mechanism driving the development of pneumonia and respiratory failure in COVID-19. Methods This is a phase II, single-center, three-armed parallel-group, open-label, active control superiority randomized clinical trial. One hundred eighty eligible patients will be randomly assigned in a 1:1:1 ratio to receive either the inhibitor of C1e/kallikrein 20 U/kg intravenously on day 1 and day 4 plus standard care; or icatibant 30 mg subcutaneously, three doses/day for 4 days plus standard care; or standard care alone, as recommended in the clinical trials published to date, which includes supplemental oxygen, non-invasive and invasive ventilation, antibiotic agents, anti-inflammatory agents, prophylactic antithrombotic therapy, vasopressor support, and renal replacement therapy. Discussion Accumulation of bradykinin in the lungs is a common side effect of ACE inhibitors leading to cough. In animal models, the inactivation of ACE2 leads to severe acute pneumonitis in response to lipopolysaccharide (LPS), and the inhibition of bradykinin almost completely restores the lung structure. We believe that inhibition of bradykinin in severe COVID-19 patients could reduce the lung inflammatory response, impacting positively on the severity of disease and mortality rates. Trial registration Brazilian Clinical Trials Registry Universal Trial Number (UTN) U1111-1250-1843. Registered on May/5/2020.

SARS-CoV-2, the pathogenic agent of COVID-19, employs angiotensin converting enzyme-2 (ACE2) as its cell entry receptor. Clinical data reveal that in severe COVID-19, SARS-CoV-2 infects the lung, leading to a frequently lethal triad of respiratory insufficiency, acute cardiovascular failure, and coagulopathy. Physiologically, ACE2 plays a role in the regulation of three systems that could potentially be involved in the pathogenesis of severe COVID-19: the kinin–kallikrein system, resulting in acute lung inflammatory edema; the renin–angiotensin system, promoting cardiovascular instability; and the coagulation system, leading to thromboembolism. Here we assembled a healthy human lung cell atlas meta-analysis with ~ 130,000 public single-cell transcriptomes and show that key elements of the bradykinin, angiotensin and coagulation systems are co-expressed with ACE2 in alveolar cells and associated with their differentiation dynamics, which could explain how changes in ACE2 promoted by SARS-CoV-2 cell entry result in the development of the three most severe clinical components of COVID-19.

Objetivo: Avaliar o grau de suporte social percebido e sua relação com o autocuidado e o controle glicêmico dos indiví­duos diabéticos tipo 2. Metodologia: Pesquisa transversal, realizada com 154 indiví­duos diabéticos com idade superior a 18 anos, acompanhados em unidades de saúde. Foram analisadas variáveis sociodemográficas, antropométricas, clí­nicas, de autocuidado e de suporte social relacionadas ao controle glicêmico. Para a análise das variáveis de caráter genérico, foi realizado um estudo de frequência simples e calculadas as medidas de tendência central. Para verificar a associação das comorbidades com o controle glicêmico foi utilizado o teste Qui-quadrado. Resultados: Os participantes atingiram boa pontuação em algumas atividades do autocuidado e, apesar de terem pouco apoio social, se sentiam satisfeitos. Ao se associar as atividades de autocuidado com o suporte social recebido, não houve associação estatisticamente significativa. Conclusão: Houve associação entre algumas comorbidades, como Hipertensão, obesidade, nefropatias, depressão e o uso de insulina com o controle glicêmico, o que reforça a necessidade de estimular cada vez mais a busca do controle entre os indiví­duos com diabetes tipo 2.

Significance: Optimal skin wound healing is crucial for maintaining tissue homeostasis, particularly in response to an injury. The skin immune system is under regulation of mediators such as bioactive lipids and cytokines that can initiate an immune response with controlled inflammation, followed by efficient resolution. However, nutritional deficiency impacts wound healing by hindering fibroblast proliferation, collagen synthesis, and epithelialization, among other crucial functions. In this way, the correct nutritional support of bioactive lipids and of other essential nutrients plays an important role in the outcome of the wound healing process. Recent Advances and Critical Issues: Several studies have revealed the potential role of lipids as a treatment for the healing of skin wounds. Unsaturated fatty acids such as linoleic acid, α-linolenic acid, oleic acid, and most of their bioactive products have shown an effective role as a topical treatment of chronic skin wounds. Their effect, when the treatment starts at day 0, has been observed mainly in the inflammatory phase of the wound healing process. Moreover, some of them were associated with different dressings and were tested for clinical purposes, including pluronic gel, nanocapsules, collagen films and matrices, and polymeric bandages. Therefore, future research is still needed to evaluate these dressing technologies in association with different bioactive fatty acids in a wound healing context. Future Directions: This review summarizes the main results of the available clinical trials and basic research studies and provides evidence-based conclusions. Together, current data encourage the use of bioactive fatty acids for an optimal wound healing resolution.

Currently, experimental animals are widely used in biological and medical research. However, the scientific community has raised several bioethical concerns, such as the number of animals required to achieve reproducible and statistically relevant results. These concerns involve aspects related to pain, discomfort, and unwanted animal loss. Retrospectively, we compare two different approaches for anesthesia dosage: a mobile app for dose calculation and a standard dose calculation. A total of 939 C57BL/6J and Swiss mice were analyzed. We collected data on intraoperative and anesthesia-related mortality as described in electronic or physical handwritten records. Our results showed that the mobile app approach significantly reduces anesthetic-related deaths upon using doses of ketamine and xylazine. The results suggest that anesthesia-related mortality can be minimized even more using information technology approaches, helping to solve an old but transversal challenge for researchers working with experimental mice. The mobile app is a free and open code which could be implemented worldwide as an essential requirement for all anesthetic procedures in mice using xylazine and ketamine combination. As an open code app, the Labinsane initiative could also represent the starting point to unify and validate other anesthetic procedures in different species and strains.

As the worldwide vaccination, it is imperative to minimize vaccine wastage by effectively using all doses available. Vaccine wastage can occur at multiple points during the vaccination process, but it is mainly because the device dead space and the filling process technique. However, there are no studies discussing the waste volume effect of COVID-19 vaccines in clinical practice. There is an increasing COVID-19 vaccine demand that we estimate up to several billion dual doses. The objective of this study was to assess the number of 0.3mL doses obtained from a multiple-dose vial using 1ml and 3ml syringes with different type of needles replicating the first COVID-19 vaccination protocol.Our results suggest that it is possible to obtain six or seven doses from each vial instead five. We provide evidence to optimize between 20% and 40% additional vaccine doses per vial if the current 5-dose vials are used, making scarce supplies go further.It is our duty, as researchers, to ensure the efficacy and efficiency of the worldwide COVID-19 vaccination process. However, if standard syringes-needles and technique are used, there may not be sufficient volume to draw extra doses from a single vial.

Background: Coronavirus disease 19 (COVID-19) can develop into a severe respiratory syndrome that results in up to 40% mortality. Acute lung inflammatory edema is a major pathological finding in autopsies explaining O2 diffusion failure and hypoxemia. Only dexamethasone has been shown to reduce mortality in severe cases, further supporting a role for inflammation in disease severity. SARS-CoV-2 enters cells employing angiotensin-converting enzyme 2 (ACE2) as a receptor, which is highly expressed in lung alveolar cells. ACE2 is one of the components of the cellular machinery that inactivates the potent inflammatory agent bradykinin, and SARS-CoV-2 infection could interfere with the catalytic activity of ACE2, leading to the accumulation of bradykinin. Methods: In this case control study, we tested two pharmacological inhibitors of the kinin–kallikrein system that are currently approved for the treatment of hereditary angioedema, icatibant, and inhibitor of C1 esterase/kallikrein, in a group of 30 patients with severe COVID-19. Results: Neither icatibant nor inhibitor of C1 esterase/kallikrein resulted in changes in time to clinical improvement. However, both compounds were safe and promoted the significant improvement of lung computed tomography scores and increased blood eosinophils, which are indicators of disease recovery. Conclusions: In this small cohort, we found evidence for safety and a beneficial role of pharmacological inhibition of the kinin–kallikrein system in two markers that indicate improved disease recovery.

Dear Editor,COVID-19 was first reported in December, 2019 in Wuhan, China, and rapidly spread across the globe 1. It has affected more than 6.4 million people and has led to the death of over 370 thousand as of June 2, 2020 (www.who.org). Severely affected patients present fever, dry cough, dyspnea, and fatigue, which are commonly associated with the development of pneumonia and acute respiratory distress syndrome (ARDS) 2. Advanced age, ischemic and congestive heart disease, hypertension, diabetes, and chronic obstructive pulmonary disease (COPD) are the most important independent predictors of death 2,3. As with other infectious diseases affecting the respiratory tract, asthma has been cited as a potential risk factor for severe COVID-194-6; however, no previous study has addressed this specific question.Here, we systematically reviewed all papers published on COVID-19 since its emergence in December 2019 to May 18, 2020, looking into the description of asthma as a premorbid condition and its putative association with severe progression of the disease.Two authors, NFM and CPJ, independently identified cross-sectional and longitudinal studies published before May 18, 2020, that reported on the prevalence of asthma as a premorbid condition of severe COVID-19 by systematically searching PubMed-NCBI database. We restricted the search for PubMed-NCBI because COVID-19 is a new medical condition and, currently, PubMed-NCBI covers more than 90% of MEDLINE providing a widely accessible biomedical resource 7. For database searches, language of the article was restricted to English. Search terms included the following: COVID-19 (COVID, COVID 19) ornCov or novel coronavirus or Sars-Cov-2 in the title and clinical characteristics or asthma anywhere in the text. Three authors, EM, EPA, and LAV, resolved eventual discrepancies by discussion and adjudication.We found 458 articles that met the initial inclusion search criteria (Supplementary Figure 1). All articles were assessed by authors and 290 were excluded (Supplementary Table 1) due to one or more of the following criteria: editorials; metanalyses; systematic reviews; commentaries; letters to the Editor; no description of patient’s clinical characteristics or premorbid conditions; and main text in a language other than English.The remaining 150 articles were included in the study. Supplementary Table 2 depicts the details of all articles analyzed. As a whole, the articles described the clinical aspects of 36,072 COVID-19 patients. One hundred and seven studies mentioned the existence of other respiratory premorbidities except for asthma. Asthma was mentioned as a premorbid condition in only eighteen studies (Table 1). There was a total of 8,690 patients included in the studies mentioning asthma, and 655 patients were previously diagnosed with asthma. In most of the studies describing other respiratory illnesses, COPD was the leading diagnosis.Based on the current medical records, we conclude that 7.5% of patients included in articles describing the clinical characteristics of COVID-19 patients and citing asthma were previously diagnosed with asthma. If all studies providing any clinical description of COVID-19 comorbidities are taken into consideration, asthma was present in only 1.8% of patients. These numbers are far less than expected considering the prevalence of asthma in the world. According to the World Asthma Report (http://www.globalasthmareport.org), there were as many as 339 million people living with asthma in the world in 2018, which corresponds to 4.4% of the world’s population.In conclusion, asthma does not seem to be an important premorbid condition in COVID-19 patients; or, conversely, it could be a protective factor, as previously proposed 8. The findings herein reported could be an epidemiological truth that should be further explored in mechanistic studies or could be due to the fact that researchers are not properly investigating and describing the premorbidities in COVID-19 patients. Whatever the reasons, the medical community should be aware of the implications of missing the diagnosis of a potentially severe respiratory disease such as asthma that could worsen the prognosis of COVID-19 patients.Acknowledgements. NFM was supported by The Sao Paulo Research Foundation (grant: 2016/17810-3), and CPJ was supported by Coordination for the Improvement of Higher Education Personnel (CAPES) grant: 1744875 and 88882.434715/2019-01. EM, LAV and EPA are supported by grants from Sao Paulo Research Foundation (grants: 2013/07607-8 and 2020/) and Brazilian National Council of Scientific and Technological Development (CNPq).Ethics. The study does not require ethical approval because the systematic review is based on published research and the original data are anonymous.

Coronavirus disease-19 (COVID-19) can develop into a severe respiratory syndrome that results in up to 40% mortality. Acute lung inflammatory edema is a major pathological finding in autopsies explaining O2 diffusion failure and hypoxemia. Only dexamethasone has been shown to reduce mortality in severe cases, further supporting a role for inflammation in disease severity. SARS-CoV-2 enters cells employing angiotensin converting enzyme 2 (ACE2) as a receptor, which is highly expressed in lung alveolar cells. ACE2 is one of the components of the cellular machinery that inactivates the potent inflammatory agent bradykinin, and SARS-CoV-2 infection could interfere with the catalytic activity of ACE2, leading to accumulation of bradykinin. In this open-label, randomized clinical trial, we tested two pharmacological inhibitors of the kinin-kallikrein system that are currently approved for the treatment of hereditary angioedema, icatibant and inhibitor of C1 esterase/kallikrein, in a group of 30 patients with severe COVID-19. Neither icatibant nor inhibitor of C1 esterase/kallikrein resulted in significant changes in disease mortality and time to clinical improvement. However, both compounds promoted significant improvement of lung computed tomography scores and increased blood eosinophils, which has been reported as an indicator of disease recovery. In this small cohort, we found evidence for a beneficial role of pharmacological inhibition of the kinin-kallikrein system in two markers that indicate improved disease recovery.

SARS-CoV-2, the pathogenic agent of COVID-19, employs angiotensin converting enzyme-2 (ACE2) as its cell entry receptor. Clinical data reveal that in severe COVID-19, SARS-CoV-2 infects the lung, leading to a frequently lethal triad of respiratory insufficiency, acute cardiovascular failure, and coagulopathy. Physiologically, ACE2 plays a role in the regulation of three systems that could potentially be involved in the pathogenesis of severe COVID-19: the kinin-kallikrein system, resulting in acute lung inflammatory edema; the renin-angiotensin system, promoting cardiovascular instability; and the coagulation system, leading to thromboembolism. Here we analyzed ~130,000 human lung single-cell transcriptomes and show that key elements of the kinin-kallikrein, renin-angiotensin and coagulation systems are co-expressed with ACE2 in alveolar cells, which could explain how changes in ACE2 promoted by SARS- CoV-2 cell entry result in the development of the three most severe clinical components of COVID-19.

Recent studies have indicated that systemic topiramate can induce an improvement on the aesthetic appearance of skin scars. Here, we evaluated topical topiramate as an agent to improve wound healing in C57/BL6 mice. Mice were inflicted with a 6.0 mm punch to create two wounds in the skin of the dorsal region. Thereafter, mice were randomly assigned to either vehicle or topical topiramate (20 µl of 2% cream) once a day for 14 days, beginning on the same day as wound generation. We analyzed the wound samples over real-time PCR, Western blotting, and microscopy. There was no effect of the topiramate treatment on the time for complete reepithelization of the wound. However, on microscopic analysis, topiramate treatment resulted in increased granulation tissue, thicker epidermal repair, and improved deposition of type I collagen fibers. During wound healing, there were increased expressions of anti-inflammatory markers, such as IL-10, TGF-β1, and reduced expression of the active form of JNK. In addition, topiramate treatment increased the expression of active forms of two intermediaries in the insulin-signaling pathway, IRS-1 and Akt. Finally, at the end of the wound-healing process, topiramate treatment resulted in increased expression of SOX-2, a transcription factor that is essential to maintain cell self-renewal of undifferentiated embryonic stem cells. We conclude that topical topiramate can improve the overall quality of wound healing in the healthy skin of mice. This improvement is accompanied by reduced expression of markers involved in inflammation and increased expression of proteins of the insulin-signaling pathway.

Background The consumption of large amounts of dietary fats activates an inflammatory response in the hypothalamus, damaging key neurons involved in the regulation of caloric intake and energy expenditure. It is currently unknown why the mediobasal hypothalamus is the main target of diet-induced brain inflammation. We hypothesized that dietary fats can damage the median eminence blood/spinal fluid interface. Methods Swiss mice were fed on a high-fat diet, and molecular and structural studies were performed employing real-time PCR, immunoblot, immunofluorescence, transmission electron microscopy, and metabolic measurements. Results The consumption of a high fat diet was sufficient to increase the expression of inflammatory cytokines and brain-derived neurotrophic factor in the median eminence, preceding changes in other circumventricular regions. In addition, it led to an early loss of the structural organization of the median eminence β1-tanycytes. This was accompanied by an increase in the hypothalamic expression of brain-derived neurotrophic factor. The immunoneutralization of brain-derived neurotrophic factor worsened diet-induced functional damage of the median eminence blood/spinal fluid interface, increased diet-induced hypothalamic inflammation, and increased body mass gain. Conclusions The median eminence/spinal fluid interface is affected at the functional and structural levels early after introduction of a high-fat diet. Brain-derived neurotrophic factor provides an early protection against damage, which is lost upon a persisting consumption of large amounts of dietary fats. Electronic supplementary material The online version of this article (10.1186/s12974-017-1046-8) contains supplementary material, which is available to authorized users.

Pressure ulcers (PrUs)* are chronic wounds caused by a combination of factors, such as repetitive ischemia perfusion injury, bacterial colonization of the wound bed, local tissue hypoxia, or an altered cellular and systemic stress response. The objectives of this study were to analyze fragments of devitalized tissue of Stages III and IV PrUs and compare them with healthy tissue to evaluate the expression of the genes involved in wound inflammation. Samples of healthy skin from patients undergoing plastic surgery (n = 3) were collected, as well as from patients with devitalized tissue from Stages III and IV PrUs (n = 3) by means of sharp debridement. Gene expression analysis identified 5 up-regulated genes and 6 down-regulated genes in the devitalized tissue. Fibroblast cultures treated with devitalized tissue extract showed less attraction and cellular growth compared with the control group. Western blotting analysis showed a tendency of 3 particular genes to decrease in cell cultures treated with devitalized tissue extract. This study demonstrates that all of these mediators stimulate and promote inflammation in the wound bed and that a better understanding of the mechanisms of chronic wound development could lead to novel therapeutic strategies.

Interleukin-6 (IL-6) is a unique cytokine that can play both pro- and anti-inflammatory roles depending on the anatomical site and conditions under which it has been induced. Specific neurons of the hypothalamus provide important signals to control food intake and energy expenditure. In individuals with obesity, a microglia-dependent inflammatory response damages the neural circuits responsible for maintaining whole-body energy homeostasis, resulting in a positive energy balance. However, little is known about the role of IL-6 in the regulation of hypothalamic microglia. In this systematic review, we asked what types of conditions and stimuli could modulate microglial IL-6 expression in murine model. We searched the PubMed and Web of Science databases and analyzed 13 articles that evaluated diverse contexts and study models focused on IL-6 expression and microglia activation, including the effects of stress, hypoxia, infection, neonatal overfeeding and nicotine exposure, lipopolysaccharide stimulus, hormones, exercise protocols, and aging. The results presented in this review emphasized the role of “injury-like” stimuli, under which IL-6 acts as a proinflammatory cytokine, concomitant with marked microglial activation, which drive hypothalamic neuroinflammation. Emerging evidence indicates an important correlation of basal IL-6 levels and microglial function with the maintenance of hypothalamic homeostasis. Advances in our understanding of these different contexts will lead to the development of more specific pharmacological approaches for the management of acute and chronic conditions, like obesity and metabolic diseases, without disturbing the homeostatic functions of IL-6 and microglia in the hypothalamus.

The healing time of burn wounds depends on surface area and depth of the burn and associated comorbidities. Diabetes mellitus (DM) causes delays in the healing process by extending the inflammatory phase. Treatment with topical insulin can improve the inflammatory phase, restore metabolic dysregulation, and modulate impaired cellular signaling in burn wounds. The objective of this study was to evaluate markers of the inflammatory and proliferative phases of second-degree burns after topical insulin treatment in diabetic rats. Type I DM was induced with streptozotocin in male Wistar rats. The animals’ backs were shaved and subjected to thermal burning. Rats were randomized into two groups: control diabetic (DC) and insulin diabetic (DI). At Days 7 and 14 postburn, rats were euthanized, and wound-tissue sections were evaluated by hematoxylin and eosin, Weigert, and Verhöeff staining, immunohistochemistry-paraffin, and enzyme-linked immunosorbent assay. A significant increase in reepithelialization was seen on Days 7 and 14 in DI versus DC rats. On Day 7, interleukin (IL)-1β, IL-6, monocyte chemotactic protein (MCP)-1, and F4/80 expression were increased in DI versus DC rats. On Day 14, MCP-1 expression was decreased and F4/80 increased in DI versus DC rats. On Days 7 and 14, Ki-67, transforming growth factor-β1, vascular endothelial growth factor expression, and formation of elastic fibers were increased in DI versus DC rats. Topical insulin modulates burn-wound healing in diabetic animals by balancing inflammation and promoting angiogenesis and formation of elastic fibers.

Wound healing is severely affected in hyperglycemia and other metabolic conditions. Finding new therapeutic approaches that accelerate wound healing and improve the quality of the scar may reduce the morbidity commonly associated with skin lesions in diabetes. This study evaluated the effect of topical topiramate (TPM) on wound healing in C57 mice. Streptozotocin-induced hyperglycemic mice were subjected to a wound on the back and randomly allocated for treatment with either vehicle or topical TPM cream (2%) once a day for 14 days. Polymerase chain reaction, Western blotting, and microscopy were performed for the analysis. TPM improved wound healing (complete resolution at Day 10, 98% ± 5 for TPM vs. 81% ± 28 for vehicle), increased organization and deposition of collagen Type I, and enhanced the quality of the scars as determined by microscopy. In addition, TPM modulated the expression of cytokines and proteins of the insulin-signaling pathway: In early wound-healing stages, expression of interleukin-10, an anti-inflammatory marker, increased, whereas at the late phase, the pro-inflammatory markers tumor necrosis factor-α and monocyte chemoattractant protein-1 increased and there was increased expression of a vascular endothelial growth factor. Proteins of the insulin-signaling pathway were stimulated in the late wound-healing phase. Topical TPM improves the quality of wound healing in an animal model of hyperglycemia. The effect of TPM is accompanied by modulation of inflammatory and growth factors and proteins of the insulin-signaling pathway. Therefore, topical TPM presents as a potential therapeutic agent in skin wounds in patients with hyperglycemia.

Selected subpopulations of hypothalamic neurons play important roles in the regulation of whole body energy homeostasis. Studies have shown that the saturated fats present in large amounts in western diets can activate an inflammatory response in the hypothalamus, affecting the capacity of such neurons to respond appropriately to satiety and adipostatic signals. In the first part of this review, we will explore the mechanisms behind saturated fatty acid-induced hypothalamic dysfunction. Next, we will present and discuss recent studies that have identified the mechanisms that mediate some of the anti-inflammatory actions of unsaturated fatty acids in the hypothalamus and the potential for exploring these mechanisms to prevent or treat obesity.

Background and Purpose: Assessing the stress of patient with diabetes requires reliable and valid instruments. This study evaluated the measurement properties of the Brazilian version of the Diabetes Distress Scale (B-DDS). Methods: This cross-sectional study enrolled 139 patients with Type 2 diabetes mellitus (DM2) receiving outpatient treatment. Reliability and construct validity were estimated through convergent validity and confirmatory factor analysis. Results: Evidence of reliability was obtained—Cronbach alpha = .87 and intraclass correlation coefficient (ICC) = .93. Significant positive correlations of moderate-to-strong magnitudes were observed between the dimensions of the DDS and the total score of the PAID; the confirmatory factor analysis supported the four dimensions of the original instrument. Conclusions: The B-DDS is reliable and valid for evaluation of the stress related to diabetes mellitus.

Emerging data demonstrate that microglia activation plays a pivotal role in the development of hypothalamic inflammation in obesity. Early after the introduction of a high-fat diet, hypothalamic microglia undergo morphological, and functional changes in response to excessive dietary saturated fats. Initially the resident microglia are affected; however, as diet-induced obesity persists, bone marrow-derived myeloid cells gradually replace resident microglia. Genetic and pharmacological approaches aimed at dampening the inflammatory activity in the hypothalamus of experimental models of obesity have proven beneficial to correct the obese phenotype and improve metabolic abnormalities commonly associated with obesity. These approaches provide an experimental proof-of-concept that hypothalamic inflammation is central to the pathophysiology of obesity; understanding the details of the roles played by microglia in this process may help the development of preventive and therapeutic advances in the field. In this review, we discuss the potential mechanisms underlying hypothalamic microglial activation in high-fat induced obesity.

Background The consumption of large amounts of dietary fats induces hypothalamic inflammation and impairs the function of the melanocortin system, leading to a defective regulation of caloric intake and whole-body energy expenditure. In mice fed a high-fat diet (HFD), TGF-β1 expression was increased and NF-κB signaling was activated in proopiomelanocortin neurons, which plays an important role in the obesity-associated hypothalamic inflammation scenario. However, whether excessive hypothalamic TGF-β1 impairs energy homeostasis remains unclear. Objectives We aimed to investigate the role of diet-induced hypothalamic TGF-β1 on inflammation and whole-body energy homeostasis. Methods A TGF-β1 inhibitory lentiviral shRNA particle was stereotaxically injected bilaterally in the arcuate nucleus (ARC) of C57BL/6 mice fed a HFD. We assessed changes in body mass and adiposity, food intake, inflammatory markers, and the function of energy and glucose metabolism. Results TGF-β1 down-regulation in the ARC-attenuated body-mass gain, reduced fat-mass accumulation, decreased hypothalamic inflammatory markers, and protected against HFD-induced lipohypertrophy of brown adipose tissue. In addition, the inhibition of hypothalamic TGF-β1 increased the locomotor activity and improved whole-body lipid metabolism, which attenuated hepatic fat accumulation and serum triglyceride levels. No changes were observed in food intake and glucose homeostasis. Conclusion Hypothalamic TGF-β1 down-regulation attenuates hypothalamic inflammation and improves energy metabolism, resulting in lower body-mass gain and lower fat-mass accumulation, which protects mice from the development of obesity. Our data suggest that modulation of hypothalamic TGF-β1 expression might be an effective strategy to treat obesity.

The aim of this study is to investigate the prevalence of potential drug-drug interactions (PDDIs), as well as classifying them in relation to level of severity, scientific evidence, time of onset, and potential clinical impact in adult and older adult patients with diabetes mellitus 2 (DM2). This cross-sectional study was conducted in a tertiary care outpatient center. The consecutive sample was made up of 140 patients with DM2. The Anatomical-Therapeutic-Chemical Classification was used for classifying the classes of medications. The PDDIs were analyzed using the DRUG-REAX® system. The relationships between PDDI and the associated factors were ascertained using a multiple logistic regression model. The prevalence of total PDDI was 75 %, and the prevalence of major severity PDDI was 20.7 %. Simvastatin (30.8 %), captopril/enalapril (12.8 %), and oral anti-diabetics/insulin (12.8 %) were the medications which were most involved in the major PDDI, bringing relevant potential clinical impacts such as rhabdomyolysis, hyperkalemia, and important glycemic alterations. Polypharmacy was associated with PDDI (adjusted odds ratio = 10.46, 95 % confidence interval = 4.10–26.71). Diabetics were highly exposed to clinically significant PDDI. It is important that health professionals should be aware of the risks related to PDDI, so that measures may be implemented in order to assure safe care for the patient.

The development of new methods to improve skin wound healing may affect the outcomes of a number of medical conditions. Here, we evaluate the molecular and clinical effects of topical 5-azacytidine on wound healing in rats. 5-Azacytidine decreases the expression of follistatin-1, which negatively regulates activins. Activins, in turn, promote cell growth in different tissues, including the skin. Eight-week-old male Wistar rats were submitted to 8.0-mm punch-wounding in the dorsal region. After 3 days, rats were randomly assigned to receive either a control treatment or the topical application of a solution containing 5-azacytidine (10 mM) once per day. Photo documentation and sample collection were performed on days 5, 9, and 15. Overall, 5-azacytidine promoted a significant acceleration of complete wound healing (99.7% ± 0.7.0 vs. 71.2% ± 2.8 on day 15; n = 10; p

Skin-wound healing is a complex and dynamic biological process involving inflammation, proliferation, and remodeling. Recent studies have shown that statins are new therapeutical options because of their actions, such as anti-inflammatory and antioxidant activity, on vasodilation, endothelial dysfunction and neoangiogenesis, which are independent of their lipid-lowering action. Our aim was to investigate the effect of atorvastatin on tissue repair after acute injury in healthy animals. Rats were divided into four groups: placebo-treated (P), topical atorvastatin-treated (AT), oral atorvastatin-treated (AO), topical and oral atorvastatin-treated (ATO). Under anesthesia, rats were wounded with an 8-mm punch in the dorsal region. Lesions were photographed on Days 0, 1, 3, 7, 10, 12, and 14 post-injury and samples taken on Days 1, 3, 7, and 14 for protein-expression analysis of insulin receptor substrate (IRS)-1, phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt), glycogen synthase kinase (GSK)-3, endothelial nitric oxide synthase (eNOS), vascular endothelial growth factor (VEGF), extracellular signal-regulated kinase (ERK), interleukin (IL)-10, IL-1β, IL-6, and tumor necrosis factor (TNF)-α. Upon macroscopic examination, we observed significant reductions of lesion areas in groups AT, AO, and ATO compared to the P group. Additionally, AT and AO groups showed increased expression of IRS-1, PI3K, Akt, GSK-3, and IL-10 on Days 1 and 3 when compared with the P group. All atorvastatin-treated groups showed higher expression of IRS-1, PI3K, Akt, GSK-3, IL-10, eNOS, VEGF, and ERK on Day 7. On Days 1, 3, and 7, all atorvastatin-treated groups showed lower expression of IL-6 and TNF-α when compared with the P group. We conclude that atorvastatin accelerated tissue repair of acute lesions in rats and modulated expressions of proteins and cytokines associated with cell-growth pathways.

The above-cited article has been retracted by the American Diabetes Association, the publisher of Diabetes. This article was previously the subject of an expression of concern in the March 2015 issue of the journal (Diabetes 2015;64:1068–1070. DOI: 10.2337/db15-ec03). As noted in the March 2015 expression of concern, the American Diabetes Association asked the corresponding author’s institution, the University of Campinas, to review the following issues with the article: The Association also asked the University of Campinas to review several discrepancies between source images previously provided by the corresponding …

The healing process is complex in diabetic wounds, and the healing mechanism of burn wounds is different from that of incisional or excisional wounds. Data from our previous study indicated that topical insulin cream reduced wound closure time in diabetic rats. Our aim was to investigate the effect of topical insulin cream on wound healing following second-degree burns in control and diabetic rats. Rats were divided into four groups: control (nondiabetic) rats treated with placebo (CP), control (nondiabetic) rats treated with topical insulin cream (CI), diabetic rats treated with placebo (DP), and diabetic rats treated with topical insulin cream (DI). The wounds were assessed at 4 time points (1, 7, 14, and 26 days) post-wounding for morphometric analysis of wound sections stained with hematoxylin/eosin, α-smooth muscle actin, and Picrosirius red to evaluate general aspects of the wound, inflammatory infiltrate, blood vessels, and Types I and III collagen fibers. Histological analysis showed that topical insulin cream increased the inflammatory cell infiltrate in the DI group (at 7 and 14 days postburn, p < .05) and blood vessels (at 14 days postburn, p < .05) to levels similar to those of groups CP and CI. Wounds treated with topical insulin cream (CI and DI groups) showed significantly stronger staining for fibrillar collagen than wounds of the DP group. The use of topical insulin may reduce the duration of the inflammatory phase; improve wound reepithelialization, tissue granulation, and wound contraction; and increase collagen deposition in second-degree burns in healthy and diabetic animals.

La finalidad de esta actualización fue plantear el mecanismo molecular y celular del proceso de cicatrización de heridas cutáneas en individuos con diabetes mellitus. El proceso de restauración tecidual en individuos con diabetes mellitus es lentificado, la producción excesiva de Especies Reactivas de Oxigenio, reducción del Óxido Nítrico, reducción de la respuesta a los Factores de Crecimiento y de las proteínas de la vía de señalización de la insulina hacen parte de este proceso. El éxito en el tratamiento de heridas de dificil cicatrización depende del conocimiento de los factores que interfieren en este proceso, lo cual junto a la práctica clínica traerá al enfermero subsidios para prevención, intervenciones y elección de medidas adecuadas para el cuidado y tratamiento de heridas en pacientes con diabetes mellitus. The objective of this updating study was to address the molecular and cellular process of the healing of cutaneous wounds in individuals with diabetes mellitus. The process of tissue repair in individuals with diabetes mellitus is slowed down; the excessive production of Reactive oxygen species, the reduction of Nitric Oxide, the reduction in the response to Growth Factors and the reduction in the proteins of the insulin signalling route are all involved in this process. Success in treating wounds which are having difficulty in healing depends on knowledge of the factors which interfere in this process, which, allied with clinical practice, provides the nurse with support for prevention, interventions and choice of appropriate dressings for the care and treatment of wounds in patients with diabetes mellitus. O objetivo desta atualização foi abordar o mecanismo molecular e celular do processo de cicatrização de feridas cutâneas em indivíduos com diabetes mellitus. O processo de reparo tecidual em indivíduos com diabetes mellitus é lentificado, a produção excessiva de Espécies Reativas de Oxigênio, diminuição do Óxido Nítrico, diminuição da reposta aos Fatores de Crescimento e das proteínas da via de sinalização da insulina estão envolvidos neste processo. O sucesso no tratamento de feridas de difícil cicatrização depende do conhecimento dos fatores que interferem neste processo, que aliado à prática clínica trará ao enfermeiro subsídios para prevenção, intervenções e escolha de coberturas adequadas para o cuidado e tratamento de feridas em pacientes com diabetes mellitus.

Aim: identifying taxonomy II nursing diagnoses from the North American Nursing Diagnoses Association International using nursing records associated with outpatient diabetic treatment. Method: a descriptive and retrospective study. Data obtained from 35 patients’ medical charts, using a tool devised by the authors and analyzed using relative and absolute frequencies. Result: from eight diagnoses, three of the following showed up in more than 50% of the samples: Ineffective health maintenance; Imbalanced nutrition - more than body requirements; Sedentary lifestyle. Discussion: The findings show that these three diagnoses relate to a very important and unique issue in treating diabetic patients: the difficulty on the part of patients to adhere to treatment and self-care. Conclusion: The findings show that nursing diagnoses are useful with regard to identifying phenomena that require attention in specific treatment contexts, as well as acting as a guide in terms of the assistance offered.

Autophagy is a highly regulated process that has an important role in the control of a wide range of cellular functions, such as organelle recycling, nutrient availability and tissue differentiation. A recent study has shown an increased autophagic activity in the adipose tissue of obese subjects, and a role for autophagy in obesity-associated insulin resistance was proposed. Body mass reduction is the most efficient approach to tackle insulin resistance in over-weight subjects; however, the impact of weight loss in adipose tissue autophagy is unknown. Adipose tissue autophagy was evaluated in mice and humans. First, a mouse model of diet-induced obesity and diabetes was maintained on a 15-day, 40% caloric restriction. At baseline, markers of autophagy were increased in obese mice as compared with lean controls. Upon caloric restriction, autophagy increased in the lean mice, whereas it decreased in the obese mice. The reintroduction of ad libitum feeding was sufficient to rapidly reduce autophagy in the lean mice and increase autophagy in the obese mice. In the second part of the study, autophagy was evaluated in the subcutaneous adipose tissue of nine obese-non-diabetic and six obese-diabetic subjects undergoing bariatric surgery for body mass reduction. Specimens were collected during the surgery and approximately 1 year later. Markers of systemic inflammation, such as tumor necrosis factor-1α, interleukin (IL)-6 and IL-1β were evaluated. As in the mouse model, human obesity was associated with increased autophagy, and body mass reduction led to an attenuation of autophagy in the adipose tissue. Obesity and caloric overfeeding are associated with the defective regulation of autophagy in the adipose tissue. The studies in obese-diabetic subjects undergoing improved metabolic control following calorie restriction suggest that autophagy and inflammation are regulated independently.

Background Wound healing is impaired in diabetes mellitus, but the mechanisms involved in this process are virtually unknown. Proteins belonging to the insulin signaling pathway respond to insulin in the skin of rats. Objective The purpose of this study was to investigate the regulation of the insulin signaling pathway in wound healing and skin repair of normal and diabetic rats, and, in parallel, the effect of a topical insulin cream on wound healing and on the activation of this pathway. Research Design and Methods We investigated insulin signaling by immunoblotting during wound healing of control and diabetic animals with or without topical insulin. Diabetic patients with ulcers were randomized to receive topical insulin or placebo in a prospective, double-blind and placebo-controlled, randomized clinical trial (NCT 01295177) of wound healing. Results and Conclusions Expression of IR, IRS-1, IRS-2, SHC, ERK, and AKT are increased in the tissue of healing wounds compared to intact skin, suggesting that the insulin signaling pathway may have an important role in this process. These pathways were attenuated in the wounded skin of diabetic rats, in parallel with an increase in the time of complete wound healing. Upon topical application of insulin cream, the wound healing time of diabetic animals was normalized, followed by a reversal of defective insulin signal transduction. In addition, the treatment also increased expression of other proteins, such as eNOS (also in bone marrow), VEGF, and SDF-1α in wounded skin. In diabetic patients, topical insulin cream markedly improved wound healing, representing an attractive and cost-free method for treating this devastating complication of diabetes. Trial Registration ClinicalTrials.gov NCT01295177

The prevalence of obesity has grown to an alarming magnitude, affecting more than 300 million humans worldwide. Although in most instances obesity is caused by excessive caloric consumption, only recently have we begun to understand the mechanisms involved in the loss of balance between caloric intake and energy expenditure. In the hypothalamus, groups of specialized neurons provide the signals that, under physiological conditions, determine the stability of body mass. Recent studies have shown that under certain environmental and genetic conditions, this equilibrium is lost and body adiposity may increase. Here, we review the work that provided the basis for the current understanding of hypothalamic dysfunction and the genesis of obesity.

Obesity is one of the most prevalent diseases in the modern world. It results from the progressive loss of balance between food intake and whole body energy expenditure. Recent studies have shown that consumption of fat-rich diets induces hypothalamic inflammation and dysfunction which is characterized by defective response to anorexygenic and thermogenic hormones, such as leptin and insulin, leading to anomalous neurotransmitter production and favoring body mass gain. In this chapter, we present the main recent advances in this rapidly evolving field, focusing on the role of hypothalamic inflammation on the genesis of obesity.

TNF-alpha plays an important role in obesity-linked insulin resistance and diabetes mellitus by activating at least two serine kinases capable of promoting negative regulation of key elements of the insulin signaling pathway. Pharmacological inhibition of TNF-alpha is currently in use for the treatment of rheumatoid and psoriatic arthritis, and some case reports have shown clinical improvement of diabetes in patients treated with the TNF-alpha blocking monoclonal antibody infliximab. The objective of this study was to evaluate the effect of infliximab on glucose homeostasis and insulin signal transduction in an animal model of diabetes. Diabetes was induced in Swiss mice by a fat-rich diet. Glucose and insulin homeostasis were evaluated by glucose and insulin tolerance tests and by the hyperinsulinemic-euglycemic clamp. Signal transduction was evaluated by immunoprecipitation and immunoblotting assays. Short-term treatment with infliximab rapidly reduced blood glucose and insulin levels and glucose and insulin areas under the curve during a glucose tolerance test. Furthermore, infliximab increased the glucose decay constant during an insulin tolerance test and promoted a significant increase in glucose infusion rate during a hyperinsulinemic-euglycemic clamp. In addition, the clinical outcomes were accompanied by improved insulin signal transduction in muscle, liver, and hypothalamus, as determined by the evaluation of insulin-induced insulin receptor, insulin receptor substrate-1, and receptor substrate-2 tyrosine phosphorylation and Akt and forkhead box protein O1 serine phosphorylation. Thus, pharmacological inhibition of TNF-alpha may be an attractive approach to treat severely insulin-resistant patients with type 2 diabetes mellitus.

The effect of visceral fat removal upon glucose homeostasis, insulin signal transduction, and serum adipokine levels in an animal model of diet-induced obesity and diabetes mellitus (DIO) was evaluated. Swiss mice were initially divided into two groups fed with regular rodent chow or with chow containing 24 g% saturated fat (DIO). DIO mice became obese and overtly diabetic after 8 weeks. DIO mice were then divided into three groups: control, sham, and visceral (epididymal and perinephric) fat removal. All groups were submitted to evaluation of basal glucose and insulin levels and i.p. insulin tolerance test. Insulin signal transduction in muscle was evaluated by immunoprecipitation and immunoblot, and serum adipokine levels were determined by ELISA. DIO mice became diabetic (228 versus 115 mg/dl), hyperinulinemic (7.59 versus 3.15 ng/ml) and insulin resistant (Kitt 2.88 versus 4.97%/min) as compared with control. Visceral fat removal partially reverted all parameters (147 mg/dl glucose; 3.82 ng/ml insulin; and 4.20%/min Kitt). In addition, visceral fat removal completely reversed the impairment of insulin signal transduction through insulin receptor, insulin receptor substrate (IRS)-1, IRS-2 and Akt in muscle. Finally, serum levels of the pro-inflammatory cytokines tumour necrosis factor-α, interleukin (IL)-1β and IL-6 were significantly increased, while adiponectin levels were significantly reduced in DIO mice. After visceral fat removal the levels of adipokines returned to near control levels. The present study shows that removal of visceral fat improves insulin signal transduction and glucose homeostasis in an animal model of diet-induced obesity and diabetes mellitus and these metabolic and molecular outcomes are accompanied by the restoration of adipokine levels.

To investigate whether insulin and leptin share common intracellular signal transduction pathways and to determine whether these hormonal signaling systems modulate each other's action in rat hypothalamus.Male Wistar rats were studied after chronic implantation of an intracerebroventricular catheter into the third ventricle. Immunoprecipitation and immunoblotting were used to examine the activation of insulin and leptin signaling molecules in the rat hypothalamus.Insulin alone is able to produce molecular activation of insulin receptor substrates (IRSs)/phosphatidylinositol 3-kinase (PI 3-kinase)/Akt and mitogen-activated protein (MAP) kinase signaling pathways in hypothalamus, whereas leptin alone activates MAP kinase and IRSs/PI 3-kinase signaling with no effect on Akt. Combined infusion of leptin and insulin provokes a dual action. There was no quantitative potentialization of any single hormone's action on the elements of the insulin signaling pathway, IRSs/PI 3-kinase/Akt, and MAP kinase. Conversely, leptin plus insulin leads to quantitative potentialization of molecular signaling through the Janus kinase/signal transducer and activator of transcription pathway.We provide evidence for a convergence of leptin and insulin signaling at the level of IRSs-PI 3-kinase and a divergence at the level of Akt. Moreover, our results indicate a direct and positive cross-talk between insulin and leptin at the level of Janus kinase 2 and signal transducer and activator of transcription 3 tyrosine phosphorylation. This mechanism may serve to potentiate the activity of both insulin and leptin pathways and to increase stimulation in physiological processes such as the control of food intake and body weight, which are under the combined control of insulin and leptin.