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The association of diabetes with cognitive dysfunction has at least 60 years of history, which started with the observation that children with type 1 diabetes mellitus (T1D), who had recurrent episodes of hypoglycemia and consequently low glucose supply to the brain, showed a deficit of cognitive capacity. Later, the growing incidence of type 2 diabetes mellitus (T2D) and dementia in aged populations revealed their high association, in which a reduced neuronal glucose supply has also been considered as a key mechanism, despite hyperglycemia. Here, we discuss the role of glucose in neuronal functioning/preservation, and how peripheral blood glucose accesses the neuronal intracellular compartment, including the exquisite glucose flux across the blood-brain barrier (BBB) and the complex network of glucose transporters, in dementia-related areas such as the hippocampus. In addition, insulin resistance-induced abnormalities in the hippocampus of obese/T2D patients, such as inflammatory stress, oxidative stress, and mitochondrial stress, increased generation of advanced glycated end products and BBB dysfunction, as well as their association with dementia/Alzheimer's disease, are addressed. Finally, we discuss how these abnormalities are accompained by the reduction in the expression and translocation of the high capacity insulin-sensitive glucose transporter GLUT4 in hippocampal neurons, which leads to neurocytoglycopenia and eventually to cognitive dysfunction. This knowledge should further encourage investigations into the beneficial effects of promising therapeutic approaches which could improve central insulin sensitivity and GLUT4 expression, to fight diabetes-related cognitive dysfunctions.

Total absence of adipose tissue (lipoatrophy) is associated with the development of severe metabolic disorders including hepatomegaly and fatty liver. Here, we sought to investigate the impact of severe lipoatrophy induced by deletion of peroxisome proliferator-activated receptor gamma (PPARγ) exclusively in adipocytes on lipid metabolism in mice. Untargeted lipidomics of plasma, gastrocnemius and liver uncovered a systemic depletion of the essential linoleic (LA) and α-linolenic (ALA) fatty acids from several lipid classes (storage lipids, glycerophospholipids, free fatty acids) in lipoatrophic mice. Our data revealed that such essential fatty acid depletion was linked to increased: 1) capacity for liver mitochondrial fatty acid β-oxidation (FAO), 2) citrate synthase activity and coenzyme Q content in the liver, 3) whole-body oxygen consumption and reduced respiratory exchange rate in the dark period, and 4) de novo lipogenesis and carbon flux in the TCA cycle. The key role of de novo lipogenesis in hepatic steatosis was evidenced by an accumulation of stearic, oleic, sapienic and mead acids in liver. Our results thus indicate that the simultaneous activation of the antagonic processes FAO and de novo lipogenesis in liver may create a futile metabolic cycle leading to a preferential depletion of LA and ALA. Noteworthy, this previously unrecognized cycle may also explain the increased energy expenditure displayed by lipoatrophic mice, adding a new piece to the metabolic regulation puzzle in lipoatrophies., 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 paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objectives: The aim of this study is to evaluate the effects of transcranial direct current stimulation (tDCS) on central and peripheral fatigue in recreational runners., Design: This is a clinical randomized, sham-controlled, triple-blind, crossover study. Twenty adult runners will be randomized on the first day of the intervention to receive active or sham tDCS before fatigue protocol. After 1 wk, the participants will receive the opposite therapy to the one that they received on the first day. The tDCS, 2 mA, will be applied for 20 mins over the motor cortex. The fatigue protocol will be performed after tDCS, in which the participant should perform concentric knee flexion/extension contractions until reaching three contractions at only 50% of maximum voluntary contraction. Central fatigue will be evaluated with the motor evoked potential of the quadriceps muscle; peripheral fatigue with the peak torque (N.m) using an isokinetic dynamometer; the electrical activity of the quadriceps muscle using surface electromyography (Hz); blood lactate level (mmol/L); and the subjective perception of effort (Borg scale). All evaluations will be repeated before and after the interventions., Conclusion: This study will evaluate the effect of tDCS on fatigue in runners, possibly determining an application protocol for this population., Competing Interests: Financial disclosure statements have been obtained, and no conflicts of interest have been reported by the authors or by any individuals in control of the content of this article., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Deletion of mechanistic target of rapamycin complex 2 (mTORC2) essential component rapamycin insensitive companion of mTOR (Rictor) by a Cre recombinase under control of the broad, nonadipocyte-specific aP2/FABP4 promoter impairs thermoregulation and brown adipose tissue (BAT) glucose uptake on acute cold exposure. We investigated herein whether adipocyte-specific mTORC2 deficiency affects BAT and inguinal white adipose tissue (iWAT) signaling, metabolism, and thermogenesis in cold-acclimated mice. For this, 8-wk-old male mice bearing Rictor deletion and therefore mTORC2 deficiency in adipocytes (adiponectin-Cre) and littermates controls were either kept at thermoneutrality (30 ± 1°C) or cold-acclimated (10 ± 1°C) for 14 days and evaluated for BAT and iWAT signaling, metabolism, and thermogenesis. Cold acclimation inhibited mTORC2 in BAT and iWAT, but its residual activity is still required for the cold-induced increases in BAT adipocyte number, total UCP-1 content and mRNA levels of proliferation markers Ki67 and cyclin 1 D, and de novo lipogenesis enzymes ATP-citrate lyase and acetyl-CoA carboxylase. In iWAT, mTORC2 residual activity is partially required for the cold-induced increases in multilocular adipocytes, mitochondrial mass, and uncoupling protein 1 (UCP-1) content. Conversely, BAT mTORC1 activity and BAT and iWAT glucose uptake were upregulated by cold independently of mTORC2. Noteworthy, the impairment in BAT and iWAT total UCP-1 content and thermogenic capacity induced by adipocyte mTORC2 deficiency had no major impact on whole body energy expenditure in cold-acclimated mice due to a compensatory activation of muscle shivering. In conclusion, adipocyte mTORC2 deficiency impairs, through different mechanisms, BAT and iWAT total UCP-1 content and thermogenic capacity in cold-acclimated mice, without affecting glucose uptake and whole body energy expenditure. NEW & NOTEWORTHY BAT and iWAT mTORC2 is inhibited by cold acclimation, but its residual activity is required for cold-induced increases in total UCP-1 content and thermogenic capacity, but not glucose uptake and mTORC1 activity. The impaired BAT and iWAT total UCP-1 content and thermogenic capacity induced by adipocyte mTORC2 deficiency are compensated by activation of muscle shivering in cold-acclimated mice.

Purpose: This study evaluated the effect of the design of the light-curing unit (LCU) and mouth opening on the properties of bulk-fill resin-based composites (RBCs)., Materials and Methods: Eighty molars received a mesio-occlusal-distal preparation and were restored using two different bulk-fill RBCs, Opus Bulk Fill APS (FGM) and Filtek Bulk Fill One (3M Oral Care), using two different designs of LCU, straight (Valo Cordless [Ultradent]) and angled (Radii-Cal [SDI]). Two mouth openings of 25 and 45 mm at the incisors were used. Forty samples were sectioned mesiodistally. One half was immersed in tetrahydrofuran to examine the effect of the solvent on the RBCs (SE), and the other half to measure the degree of conversion (DC) in proximal and occlusal boxes using Fourier Transform Infrared spectroscopy. The other 40 samples were subjected to thermomechanical fatigue and immersed in silver nitrate to examine the gingival margin integrity (GMI) using SEM. The irradiance (mW/cm2) and emission spectrum (mW/cm2/nm) from the LCUs were measured using a MARC Resin Calibrator (BlueLight Analytics). DC data were analyzed by 3-way ANOVA and Tukey's test; SE and GMI were analyzed by an ANOVA on Ranks and Dunn test (α = 0.05)., Results: The DC values were similar in the occlusal and proximal boxes when using Valo Cordless, irrespective of RBC and the mouth opening used. Lower DC values were measured in proximal boxes when using Radii-Cal. The mouth opening had a greater effect on the irradiance delivered by Radii-Cal. Radii-Cal with 25-mm mouth opening had greater SE and GMI values, whereas the SE and GMI values obtained with Valo Cordless were unaffected by mouth opening., Conclusion: The choice of LCU did not influence the properties of tested bulk-fill RBCs when the 45-mm mouth opening was used. However, when using the 25-mm mouth opening, the choice of LCU did influence the properties of the RBCs.

Background: Novel coronavirus disease (COVID-19) morbidity is not restricted to the respiratory system, but also affects the nervous system. Non-invasive neuromodulation may be useful in the treatment of the disorders associated with COVID-19. Objective: To describe the rationale and empirical basis of the use of non-invasive neuromodulation in the management of patients with COVID-10 and related disorders. Methods: We summarize COVID-19 pathophysiology with emphasis of direct neuroinvasiveness, neuroimmune response and inflammation, autonomic balance and neurological, musculoskeletal and neuropsychiatric sequela. This supports the development of a framework for advancing applications of non-invasive neuromodulation in the management COVID-19 and related disorders. Results: Non-invasive neuromodulation may manage disorders associated with COVID-19 through four pathways: (1) Direct infection mitigation through the stimulation of regions involved in the regulation of systemic anti-inflammatory responses and/or autonomic responses and prevention of neuroinflammation and recovery of respiration; (2) Amelioration of COVID-19 symptoms of musculoskeletal pain and systemic fatigue; (3) Augmenting cognitive and physical rehabilitation following critical illness; and (4) Treating outbreak-related mental distress including neurological and psychiatric disorders exacerbated by surrounding psychosocial stressors related to COVID-19. The selection of the appropriate techniques will depend on the identified target treatment pathway. Conclusion: COVID-19 infection results in a myriad of acute and chronic symptoms, both directly associated with respiratory distress (e.g., rehabilitation) or of yet-to-be-determined etiology (e.g., fatigue). Non-invasive neuromodulation is a toolbox of techniques that based on targeted pathways and empirical evidence (largely in non-COVID-19 patients) can be investigated in the management of patients with COVID-19., (Copyright © 2020 Baptista, Baltar, Okano, Moreira, Campos, Fernandes, Brunoni, Badran, Tanaka, de Andrade, da Silva Machado, Morya, Trujillo, Swami, Camprodon, Monte-Silva, Sá, Nunes, Goulardins, Bikson, Sudbrack-Oliveira, de Carvalho, Duarte-Moreira, Pagano, Shinjo and Zana.)

Scope: Glucose homeostasis and progression of nonalcoholic fatty liver disease (NAFLD) and hepatomegaly in severe lipoatrophic mice and their modulation by intake of a diet rich in omega 3 (n-3) fatty acids (HFO) are evaluated., Methods and Results: Severe lipoatrophic mice induced by PPAR-γ deletion exclusively in adipocytes (A-PPARγ KO) and littermate controls (A-PPARγ WT) are evaluated for glucose homeostasis and liver mass, proteomics, lipidomics, inflammation, and fibrosis. Lipoatrophic mice are heavier than controls, severely glucose intolerant, and hyperinsulinemic, and develop NAFLD characterized by increased liver glycogen, triacylglycerol, and diacylglycerol contents, mitotic index, apoptosis, inflammation, steatosis score, fibrosis, and fatty acid synthase (FAS) content and activity. Lipoatrophic mice also display liver enrichment with monounsaturated in detriment of polyunsaturated fatty acids including n-3 fatty acids, and increased content of cardiolipin, a tetracyl phospholipid exclusively found at the mitochondria inner membrane. Administration of a high-fat diet rich in n-3 fatty acids (HFO) to lipoatrophic mice enriches liver with n-3 fatty acids, reduces hepatic steatosis, FAS content and activity, apoptosis, inflammation, and improves glucose homeostasis., Conclusion: Diet enrichment with n-3 fatty acids improves glucose homeostasis and reduces liver steatosis and inflammation without affecting hepatomegaly in severe lipoatrophic mice., (© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Scope: The mechanisms and involvement of uncoupling protein 1 (UCP1) in the protection from obesity and insulin resistance induced by intake of a high-fat diet rich in omega-3 (n-3) fatty acids are investigated., Methods and Results: C57BL/6J mice are fed either a low-fat (control group) or one of two isocaloric high-fat diets containing either lard (HFD) or fish oil (HFN3) as fat source and evaluated for body weight, adiposity, energy expenditure, glucose homeostasis, and inguinal white and interscapular brown adipose tissue (iWAT and iBAT, respectively) gene expression, lipidome, and mitochondrial bioenergetics. HFN3 intake protected from obesity, glucose and insulin intolerances, and hyperinsulinemia. This is associated with increased energy expenditure, iWAT UCP1 expression, and incorporation of n-3 eicosapentaenoic and docosahexaenoic fatty acids in iWAT and iBAT triacylglycerol. Importantly, HFN3 is equally effective in reducing body weight gain, adiposity, and glucose intolerance and increasing energy expenditure in wild-type and UCP1-deficient mice without recruiting other thermogenic processes in iWAT and iBAT, such as mitochondrial uncoupling and SERCA-mediated calcium and creatine-driven substrate cyclings., Conclusion: Intake of a high-fat diet rich in omega-3 fatty acids protects both wild-type and UCP1-deficient mice from obesity and insulin resistance by increasing energy expenditure through unknown mechanisms., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Objective: We investigated whether PPARγ modulates adipose tissue BCAA metabolism, and whether this mediates the attenuation of obesity-associated insulin resistance induced by pharmacological PPARγ activation., Methods: Mice with adipocyte deletion of one or two PPARγ copies fed a chow diet and rats fed either chow, or high fat (HF) or HF supplemented with BCAA (HF/BCAA) diets treated with rosiglitazone (30 or 15 mg/kg/day, 14 days) were evaluated for glucose and BCAA homeostasis., Results: Adipocyte deletion of one PPARγ copy increased mice serum BCAA and reduced inguinal white (iWAT) and brown (BAT) adipose tissue BCAA incorporation into triacylglycerol, as well as mRNA levels of branched-chain aminotransferase (BCAT)2 and branched-chain α-ketoacid dehydrogenase (BCKDH) complex subunits. Adipocyte deletion of two PPARγ copies induced lipodystrophy, severe glucose intolerance and markedly increased serum BCAA. Rosiglitazone abolished the increase in serum BCAA induced by adipocyte PPARγ deletion. In rats, HF increased serum BCAA, such levels being further increased by BCAA supplementation. Rosiglitazone, independently of diet, lowered serum BCAA and upregulated iWAT and BAT BCAT and BCKDH activities. This was associated with a reduction in mTORC1-dependent inhibitory serine phosphorylation of IRS1 in skeletal muscle and whole-body insulin resistance evaluated by HOMA-IR., Conclusions: PPARγ, through the regulation of both BAT and iWAT BCAA catabolism in lipoeutrophic mice and muscle insulin responsiveness and proteolysis in lipodystrophic mice, is a major determinant of circulating BCAA levels. PPARγ agonism, therefore, may improve whole-body and muscle insulin sensitivity by reducing blood BCAA, alleviating mTORC1-mediated inhibitory IRS1 phosphorylation., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Electromyographic biofeedback (EMG-BF) has been applied to treat different types of peripheral nerve injuries (PNI). However, despite the clinical practice widespread use its evidence is controversial. With the objective of summarize the available evidence on the electromyographic biofeedback effectiveness and efficacy to help motor function recovery after PNI an integrative review was performed. A secondary objective was to identify the conceptual framework and strategies of EMG-BF intervention, and the quality of technical description of EMG-BF procedures. To conduct this integrative review a systematic search of the literature was performed between October 2013 and July 2018, in PUBMED, ISI and COCHRANE databases for EMG-BF original studies in PNI patients of any etiology, in English, Portuguese, Spanish or French, published after 1990. Exclusion criteria were poor description of EMG-BF treatment, associated treatment that could impair EMG-BF effect, inclusion of non-PNI individuals and case studies design. The PEDro scale was used to evaluate study quality of randomized clinical trials (RCTs) included. This resulted in 71 potential articles enrolled to full reading, although only nine matched the inclusion criteria. PNI included facial paralysis, acute sciatic inflammation and carpal tunnel syndrome. The average quality score of the included RCTs was five, corresponding to low methodological quality. Due to the small number of included articles, low quality studies and heterogeneity of interventions, outcomes and population we concluded that there is limited evidence of EMG-BF effectiveness and efficacy for motor function recovery in PNI patients.

Lysophosphatidic acid (LPA) plays a critical role in the proliferation and migration of colon cancer cells; however, the downstream signaling events underlying these processes remain poorly characterized. The aim of this study was to investigate the signaling pathways triggered by LPA to regulate the mechanisms involved in the progression of colorectal cancer (CRC). We have used three cell line models of CRC, and initially analyzed the expression profile of LPA receptors (LPAR). Then, we treated the cells with LPA and events related to their tumorigenic potential, such as migration, invasion, anchorage-independent growth, proliferation as well as apoptosis and cell cycle were evaluated. We used the Chip array technique to analyze the global gene expression profiling that occurs after LPA treatment, and we identified cell signaling pathways related to the cell cycle. The inhibition of these pathways verified the conclusions of the transcriptomic analysis. We found that the cell lines expressed LPAR1, -2 and -3 in a differential manner and that 10 μM LPA did not affect cell migration, invasion and anchorage-independent growth, but it did induce proliferation and cell cycle progression in HCT-116 cells. Although LPA in this concentration did not induce transcriptional activity of β-catenin, it promoted the activation of Rho and STAT-3. Moreover, ROCK and STAT-3 inhibitors prevented LPA-induced proliferation, but ROCK inhibition did not prevent STAT-3 activation. Finally, we observed that LPA regulates the expression of genes related to the cell cycle and that the combined inhibition of ROCK and STAT-3 prevented cell cycle progression and increased the LPA-induced expression of cyclins E1, A2 and B1 to a greater degree than either inhibitor alone. Overall, these results demonstrate that LPA increases the proliferative potential of colon adenocarcinoma HCT-116 cells through a mechanism involving cooperation between the Rho-ROCK and STAT3 pathways involved in cell cycle control.

The present study evaluated the efficacy of superstimulation with p-FSH (Folltropin) before the ovum pick-up (OPU) on IVP in lactating and nonlactating Holstein donors. A total of 30 Holstein cows (15 lactating and 15 nonlactating) were blocked by lactation status to one of two groups (control or p-FSH), in a cross-over design. On a random day of the estrous cycle, all cows received an intravaginal progesterone device and 2.0 mg IM of estradiol benzoate (Day 0). Cows in the control group received no further treatment, whereas cows in the p-FSH group received a total dosage of 200 mg of p-FSH on Days 4 and 5 in four decreasing doses 12 hours apart (57, 57, 43, and 43 mg). On Day 7, the progesterone device was removed, and OPU was conducted in both groups (40 hours after the last p-FSH injection in the p-FSH-treated group). There was no difference between groups (P = 0.92) in the numbers of follicles that were aspirated per OPU session (17.2 ± 1.3 vs. 17.1 ± 1.1 in control and p-FSH-treated cows, respectively); however, p-FSH-treated cows had a higher (P < 0.001) percentage of medium-sized follicles (6-10 mm) at the time of the OPU (55.1%; 285/517) than control cows (20.8%; 107/514). Although recovery rate was lower (60.0%, 310/517 vs. 69.8%, 359/514; P = 0.002), p-FSH-treated cows had a higher blastocyst production rate (34.5%, 89/258 vs. 19.8%, 55/278; P < 0.001) and more transferable embryos per OPU session were produced in the p-FSH group (3.0 ± 0.5 vs. 1.8 ± 0.4; P = 0.02). Regardless of treatment, non-lactating cows had a higher blastocyst rate (41.9%, 106/253 vs. 13.4%, 38/283; P = 0.001) and produced more transferable embryos per OPU session (3.5 ± 0.5 vs. 1.3 ± 0.3; P = 0.003) than lactating cows. Thus, superstimulation of Holstein donors with p-FSH before OPU increased the efficiency of IVP. In addition, non-lactating donors had higher percentage of in vitro blastocyst development and produced more embryos per OPU session than lactating cows., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: To determine if resistive exercise protocol can modulate Tnf-α, SOCS3 and glucose transporter GLUT4 genes expression in skeletal muscle, and peripheral insulin sensitivity in obese rats induced by hyperlipidic diet., Materials and Methods: Wistar obese rats induced by hyperlipidic diet were subjected a resistive exercise protocol as jump squat. Insulin sensitivity and mRNA content of Tnf-α, SOCS3 and GLUT4 were assayed and compared among the groups: obese sedentary (OS) and exercised (OE), control sedentary (CS) and exercised (CE)., Results: The mRNA content of Tnf-α and SOCS3 has increased in skeletal muscle from OS and has decreased in OE group. The protein and GLUT4 mRNA contents were correlated but they did not change among the groups. Peripheral insulin sensitivity has increased in the OE compared to OS group., Conclusion: The resistive exercise reverses the peripheral insulin resistance and the inflammatory state in skeletal muscle from diet-induced obese rats.

Introduction: Nephroureterectomy for transplantation has increased owing to the greater number of deceased donors. Anatomic variations may complicate the procedure or, if unrecognized, compromise the viability of kidneys for transplantation., Methods: We reviewed 254 surgical descriptions of nephroureterectomy specimens from January 2008 to December 2009. All organs collected according by standard techniques were evaluated for age, cause of death, renal function, frequency of injury during the procedure, as well as variations in the vascular and collecting systems., Results: The mean donor age was 42 years (range, 2-74). The mean serum creatinine was 1.2 mg/dL (range, 1.0-7.0). The causes of death were cerebrovascular cause (stroke; n = 130), traumatic brain injury (n = 81) or other cause (n = 43). Among the anatomic variations: 8.6% (n = 22) were right arterial anatomical variations: 19 cases with 2 arteries and 3 cases with 3 arteries. In 25 cases (9.8%) the identified variation was the left artery: 2 arteries (n = 23), 3 arteries (n = 1) and 4 arteries (n = 1). We observed 9.8% on right side and 1.5% on left side venous anatomic variations, including 24 cases with 2 veins on the right side and 4 cases with 2 veins on the left side. Three cases of a retroaortic left renal vein and 1 case of a retro necklace vein (anterior and posterior to the aorta). Two cases of ureteral duplication were noted on the left and 1 on the right kidney. There were 3 horseshoe and 1 pelvic kidney. In 7.5% of cases, an injury to the graft included ureteral (n = 3), arterial (n = 10), or venous (n = 6)., Conclusion: The most common anatomic variation was arterial (17.8%). Duplication of the renal vein was more frequent on the right. The high incidences of anatomic variations require more attention in the dissection of the renal hilum to avoid an injury that may compromise the graft., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: To evaluate the copaiba oil effect on urea and creatinine levels in rats submitted to kidney ischemia and reperfusion syndrome., Methods: Eighteen Wistar rats (Rattus norvegicus albinus), aged between 90 and 120 days, weight between 200 g and 250 g, were allocated in 2 groups (n=9) and submitted to 50 minutes of renal ischemia and reperfusion and treated or not with copaiba oil (0.63 ml/kg daily seven days before ischemia). The nitrogen excrements were assessed at 24, 48 and 72 hours after ischemia period., Results: The urea serum level was smaller (p d" 0,05) at 24 and 48 hours, and the creatinine serum level was smaller at 48 hours in animals treated with copaiba oil (GIRC) than the GIR., Conclusion: The copaiba oil decreased significantly the urea serum level at 24 and 48 hours and the creatinine level at 48 hours after kidney ischemia and reperfusion in rats.