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Nature Communications published a correction notice for the article "Hypothalamic S1P/S1PR1 axis controls energy homeostasis." The correction addressed errors in the Western blot images of Tubulin and S1PR1 from specific brain regions in Figure 4C. The corrected version of the figure has been updated in the online versions of the article. The authors of the study are Vagner R. R. Silva, Thayana O. Micheletti, Gustavo D. Pimentel, and others. [Extracted from the article]

Evidence demonstrates that exogenous nitric oxide (NO) and the NO produced by inducible nitric oxide synthase (iNOS) can induce insulin resistance in muscle. Here, we investigated whether this insulin resistance could be mediated by S-nitrosation of proteins involved in early steps of the insulin signal transduction pathway. Exogenous NO donated by S-nitrosoglutathione (GSNO) induced in vitro and in vivo S-nitrosation of the insulin receptor beta subunit (IRbeta) and protein kinase B/Akt (Akt) and reduced their kinase activity in muscle. Insulin receptor substrate (IRS)-1 was also rapidly S-nitrosated, and its expression was reduced after chronic GSNO treatment. In two distinct models of insulin resistance associated with enhanced iNOS expression-diet-induced obesity and the ob/ob diabetic mice-we observed enhanced S-nitrosation of IRbeta/IRS-1 and Akt in muscle. Reversal of S-nitrosation of these proteins by reducing iNOS expression yielded an improvement in insulin action in both animal models. Thus, S-nitrosation of proteins involved in insulin signal transduction is a novel molecular mechanism of iNOS-induced insulin resistance. [ABSTRACT FROM AUTHOR]

Accumulating evidence has demonstrated that S-nitrosation of proteins plays a critical role in several human diseases. Here, we explored the role of inducible nitric oxide synthase (iNOS) in the S-nitrosation of proteins involved in the early steps of the insulin-signaling pathway and insulin resistance in the skeletal muscle of aged mice. Aging increased iNOS expression and S-nitrosation of major proteins involved in insulin signaling, thereby reducing insulin sensitivity in skeletal muscle. Conversely, aged iNOS-null mice were protected from S-nitrosation--induced insulin resistance. Moreover, pharmacological treatment with an iNOS inhibitor and acute exercise reduced iNOS-induced S-nitrosation and increased insulin sensitivity in the muscle of aged animals. These findings indicate that the insulin resistance observed in aged mice is mainly mediated through the S-nitrosation of the insulin-signaling pathway. [ABSTRACT FROM AUTHOR]

Objective: Insulin resistance in diet-induced obesity (DIO) is associated with a chronic systemic low-grade inflammation, and Toll-like receptor 4 (TLR4) plays an important role in the link among insulin resistance, inflammation, and obesity. The current study aimed to analyze the effect of exercise on TLR4 expression and activation in obese rats and its consequences on insulin sensitivity and signaling.Research Design and Methods: The effect of chronic and acute exercise was investigated on insulin sensitivity, insulin signaling, TLR4 activation, c-Jun NH(2)-terminal kinase (JNK) and IκB kinase (IKKβ) activity, and lipopolysaccharide (LPS) serum levels in tissues of DIO rats.Results: The results showed that chronic exercise reduced TLR4 mRNA and protein expression in liver, muscle, and adipose tissue. However, both acute and chronic exercise blunted TLR4 signaling in these tissues, including a reduction in JNK and IKKβ phosphorylation and IRS-1 serine 307 phosphorylation, and, in parallel, improved insulin-induced IR, IRS-1 tyrosine phosphorylation, and Akt serine phosphorylation, and reduced LPS serum levels.Conclusions: Our results show that physical exercise in DIO rats, both acute and chronic, induces an important suppression in the TLR4 signaling pathway in the liver, muscle, and adipose tissue, reduces LPS serum levels, and improves insulin signaling and sensitivity. These data provide considerable progress in our understanding of the molecular events that link physical exercise to an improvement in inflammation and insulin resistance. [ABSTRACT FROM AUTHOR]

OBJECTIVE--A high-protein diet (HPD) is known to promote the reduction of body fat, but the mechanisms underlying this change are unclear. AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) function as majors regulators of cellular metabolism that respond to changes in energy status, and recent data demonstrated that they also play a critical role in systemic energy balance. Here, we sought to determine whether the response of the AMPK and mTOR pathways could contribute to the molecular effects of an HPD. RESEARCH DESIGN AND METHODS--Western blotting, confocal microscopy, chromatography, light microscopy, and RT-PCR assays were combined to explore the anorexigenic effects of an HPD. RESULTS--An HPD reduced food intake and induced weight loss in both normal rats and ob/ob mice. The intracerebroventricular administration of leucine reduced food intake, and the magnitude of weight loss and reduction of food intake in a leucine-supplemented diet are similar to that achieved by HPD in normal rats and in ob/ob mice, suggesting that leucine is a major component of the effects of an HPD. Leucine and HPD decrease AMPK and increase mTOR activity in the hypothalamus, leading to inhibition of neuropeptide Y and stimulation of pro-opiomelanocortin expression. Consistent with a cross-regulation between AMPK and mTOR to control food intake, our data show that the activation of these enzymes occurs in the same specific neuronal subtypes. CONCLUSIONS--These findings provide support for the hypothesis that AMPK and roTOR interact in the hypothalamus to regulate feeding during HPD in a leucine-dependent manner. Diabetes 57:594-605, 2008 [ABSTRACT FROM AUTHOR]

Obesity is associated with insulin resistance and a state of abnormal inflammatory response. The Toll-like receptor (TLR)4 has an important role in inflammation and immunity, and its expression has been reported in most tissues of the body, including the insulin-sensitive ones. Because it is activated by lipopolysaccharide and saturated fatty acids, which are inducers of insulin resistance, TLR4 may be a candidate for participation in the cross-talk between inflammatory and metabolic signals. Here, we show that C3H/HeJ mice, which have a loss-of-function mutation in TLR4, are protected against the development of diet-induced obesity. In addition, these mice demonstrate decreased adiposity, increased oxygen consumption, a decreased respiratory exchange ratio, improved insulin sensitivity, and enhanced insulin-signaling capacity in adipose tissue, muscle, and liver compared with control mice during high-fat feeding. Moreover, in these tissues, control mice fed a high-fat diet show an increase in IκB kinase complex and c-Jun NH2-terminal kinase activity, which is prevented in C3H/HeJ mice. In isolated muscles from C3H/ HeJ mice, protection from saturated fatty acid-induced insulin resistance is observed. Thus, TLR4 appears to be an important mediator of obesity and insulin resistance and a potential target for the therapy of these highly prevalent medical conditions. Diabetes 56:1986-1998, 2007 [ABSTRACT FROM AUTHOR]

The actions of acetylcholine (ACh) on endothelium mainly are mediated through muscarinic receptors, which are members of the G protein-coupled receptor family. In the present study, we show that ACh induces rapid tyrosine phosphorylation and activation of Janus kinase 2 (JAK2) in rat aorta. Upon JAK2 activation, tyrosine phosphorylation of insulin receptor substrate (IRS)-1 is detected. In addition, ACh induces JAK2/IRS-1 and IRS-1/phosphatidylinositol (PI) 3-kinase associations, downstream activation of Akt/protein kinase B, endothelial cell-nitric oxide synthase (eNOS), and extracellular signal-regulated kinase (ERK)-1/2. The pharmacological blockade of JAK2 or PI 3-kinase reduced ACh-stimulated eNOS phosphorylation, NOS activity, and aorta relaxation. These data indicate a new signal transduction pathway for IRS-1/PI 3-kinase/Akt/ eNOS activation and ERK1/2 by means of JAK2 tyrosine phosphorylation stimulated by ACh in vessels. Moreover, we demonstrate that in aorta of obese rats (high-fat diet), there is an impairment in the insulin- and ACh-stimulated IRS-1/PI 3-kinase pathway, leading to reduced activation with lower protein levels of eNOS associated with a hyper-activated ERK/mitogen-activated protein kinase pathway. These results suggest that in aorta of obese rats, there not only is insulin resistance but also ACh resistance, probably mediated by a common signaling pathway that controls the activity and the protein levels of eNOS. Diabetes 56: 1014-1024, 2007 [ABSTRACT FROM AUTHOR]

Prolonged exercise of medium to high intensity is known to promote a substantial effect on the energy balance of rats. In male rats, moderately to severely intense programs lead to a reduction in food intake. However, the exact causes for the appetite-suppressive effects of exercise are not known. Here, we show that intracerebroventricular insulin or leptin infusion reduced food intake in exercised rats to a greater extent than that observed in control animals. Exercise was associated with a markedly increased phosphorylation/activity of several proteins involved in leptin and insulin signal transduction in the hypothalamus. The regulatory role of interleukin (IL)-6 in mediating the increase in leptin and insulin sensitivity in hypothalamus was also investigated. Treatment with insulin or leptin markedly reduced food intake in exercised rats that were pretreated with vehicle, although no increase in sensitivity to leptin- and insulin-induced anorexia after pretreatment with anti-IL-6 antibody was detected. The current study provides direct measurements of leptin and insulin signaling in the hypothalamus and documents increased sensitivity to these hormones in the hypothalamus of exercised rats in an IL-6-dependent manner. These findings provide support for the hypothesis that the appetite-suppressive actions of exercise may be mediated by the hypothalamus. Diabetes 55:2554-2561, 2006 [ABSTRACT FROM AUTHOR]

Chronic leptin treatment markedly enhances the effect of insulin on hepatic glucose production unproportionally with respect to body weight loss and increased insulin sensitivity. In the present study the cross-talk between insulin and leptin was evaluated in rat liver. Upon stimulation of JAK2 tyrosine phosphorylation, leptin induced JAK2 co-immunoprecipitation with STAT3, STAT5b, IRS-1 and IRS-2. This phenomenon parallels the leptin-induced tyrosine phosphorylation of STAT3, STAT5b, IRS-1 and IRS-2. Acutely injected insulin stimulated a mild increase in tyrosine phosphorylation of JAK2, STAT3 and STAT5b. Leptin was less effective than insulin in stimulating IRS phosphorylation and their association with PI 3-kinase. Simultaneous treatment with both hormones yielded no change in maximal phosphorylation of STAT3, IRS-1, IRS-2 and Akt, but led to a marked increase in tyrosine phosphorylation of JAK2 and STAT5b when compared with isolated administration of insulin or leptin. This indicates that there is a positive cross-talk between insulin and leptin signaling pathways at the level of JAK2 and STAT5b in rat liver. [ABSTRACT FROM AUTHOR]

A correction to the article "Exercise Improves Insulin and Leptin Sensitivity in Hypothalamus of Wistar Rats" by Marcelo B. S. Flores, Maria Fernanda A. Fernandes, Eduardo R. Ropelle, and colleagues is presented.

A correction to the article "Loss-of-Function Mutation in Toll-Like Receptor 4 Prevents Diet-Induced Obesity and Insulin Resistance" by Daniela M. L. Tsukumo, Marco A. Carvalho-Filho, Jose B. C. Carvalheira, and colleagues is presented.

A correction to the article "Physical Exercise Reduces Circulating Lipopolysaccharide and TLR4 Activation and Improves Insulin Signaling in Tissues of DIO Rats" by Alexandre G. Oliveira, Bruno M. Carvalho, Natalia Tobar, and colleagues is presented.

An expression of concern from the journal for the article "A Central Role for Neuronal AMP-Activated Protein Kinase (AMPK) and Mammalian Target of Rapamycin (mTOR) in High-Protein Diet-Induced Weight Loss" by Eduardo R. Ropelle, Jose Pauli, Maria Fernanda A. Fernandes, and colleagues is presented.

Background: Adipose tissue radiodensity and metabolic activity may influence COVID-19 outcomes. This study evaluated the association between adipose tissue characteristics and clinical outcomes in COVID-19 patients., Methods: Two retrospective cohorts of hospitalized COVID-19 patients were analyzed. Subcutaneous adipose tissue radiodensity (SATR) and visceral adipose tissue radiodensity were assessed by computed tomography. Fluorine-18-labelled fluorodeoxyglucose PET/computed tomography measured adipose tissue metabolic activity. Associations with mortality, length of stay, ventilation requirement, and complications were examined using regression analyses., Results: High SATR was independently associated with increased mortality risk (OR: 2.70; P = 0.033), longer hospitalization (P < 0.001), higher rates of mechanical ventilation (P = 0.007), and complications: acute kidney injury (P = 0.001), secondary infection (P = 0.007), shock (P = 0.010), and pulmonary embolism (P = 0.011). SATR positively correlated with SAT glucose uptake (ρ = 0.52) and negatively with leptin levels (ρ = -0.48)., Conclusions: Elevated SATR at COVID-19 diagnosis predicts disease severity and worse outcomes. SATR is a potential prognostic biomarker for acute and chronic inflammatory conditions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background and Objectives: We aim to verify the use of ML algorithms to predict patient outcome using a relatively small dataset and to create a nomogram to assess in-hospital mortality of patients with COVID-19., Methods: A database of 200 COVID-19 patients admitted to the Clinical Hospital of State University of Campinas (UNICAMP) was used in this analysis. Patient features were divided into three categories: clinical, chest abnormalities, and body composition characteristics acquired by computerized tomography. These features were evaluated independently and combined to predict patient outcomes. To minimize performance fluctuations due to low sample number, reduce possible bias related to outliers, and evaluate the uncertainties generated by the small dataset, we developed a shuffling technique, a modified version of the Monte Carlo Cross Validation, creating several subgroups for training the algorithm and complementary testing subgroups. The following ML algorithms were tested: random forest, boosted decision trees, logistic regression, support vector machines, and neural networks. Performance was evaluated by analyzing Receiver operating characteristic (ROC) curves. The importance of each feature in the determination of the outcome predictability was also studied and a nomogram was created based on the most important features selected by the exclusion test., Results: Among the different sets of features, clinical variables age, lymphocyte number and weight were the most valuable features for prognosis prediction. However, we observed that skeletal muscle radiodensity and presence of pleural effusion were also important for outcome determination. Integrating these independent predictors was successfully developed to accurately predict mortality in COVID-19 in hospital patients. A nomogram based on these five features was created to predict COVID-19 mortality in hospitalized patients. The area under the ROC curve was 0.86 ± 0.04., Conclusion: ML algorithms can be reliable for the prediction of COVID-19-related in-hospital mortality, even when using a relatively small dataset. The success of ML techniques in smaller datasets broadens the applicability of these methods in several problems in the medical area. In addition, feature importance analysis allowed us to determine the most important variables for the prediction tasks resulting in a nomogram with good accuracy and clinical utility in predicting COVID-19 in-hospital mortality., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Purpose: COVID-19 caused a disruption in cancer management around the world, resulting in an estimated excess burden secondary to screening disruption and excess lag time for treatment initiation., Methods: We gathered information from primary reimbursement data sets of the public health system of São Paulo, Brazil, from April 2020 to November 2021, and compared these data with those of the pre-COVID-19 period. We used an interrupted time series model to estimate the effect of the COVID-19 pandemic on the rate of key procedures of breast and cervical cancer health care chain., Results: We estimated that 1,149,727, 2,693, and 713,616 pap smears, conizations, and mammograms, respectively, were missed or delayed during the COVID-19 pandemic, compared with those in the years immediately before the COVID-19 stay-at-home restrictions. Specifically, we observed an acute decrease of procedures after the COVID-19 stay-at-home restrictions, with a trend to recovery in the long term. Regarding the systemic treatment analysis, we observed a 25% reduction in the rate of initiation of adjuvant systemic treatment for early breast cancer (stage I/II). However, we did not find a clear effect on the other settings of systemic treatment for breast cancer. We estimated an excess of 156 patients starting palliative care for cervical cancer after the COVID-19 stay-at-home restrictions., Conclusion: The COVID-19 pandemic significantly reduced the performance rate of pap smears, conizations, and mammograms. The initiation of adjuvant treatment for early-stage breast cancer was most susceptible to COVID-19's health system disruption. Furthermore, the downward trend of treatment of advanced cervical cancer was interrupted. Therefore, public health policies are urgently needed to decrease the incidence of advanced cervical and breast cancers caused by delayed diagnosis and treatment initiation.The COVID-19 control policies resulted in reduction of cancer patients' delivery of care. This study evaluated the pandemic's influence in key procedures of breast and cervical cancer chain of care in São Paulo, Brazil. We observed a substantial reduction in the number of mammograms, pap smears, and conizations performed since the onset of the COVID-19 pandemic. In addition, stage I and II breast cancer adjuvant treatment presented a reduced realization rate, whereas palliative treatment delivered for advanced cervical cancer increased. Our results support the need for public health policies focused on mitigating the long-term effects of COVID-19 in cancer-related mortality., Competing Interests: Mateus B.O. DuarteEmployment: UNIMED Campo Grande, UNIMED Uberlândia, Kantar Health José B.C. CarvalheiraHonoraria: Boehringer Ingelheim, Ipsen, BayerConsulting or Advisory Role: AbbottTravel, Accommodations, Expenses: Ipsen, Roche, MSD OncologyNo other potential conflicts of interest were reported.