Cytokines are involved in the immunopathogenesis of nonalcoholic fatty liver disease (NAFLD), but the relationship between them and clinical parameters of NAFLD progression is still unknown. Using ...flow cytometry, we evaluated the plasma levels of IL-1β, IL-6, IL-12, TNF and IL-10 and their association with clinical and biochemical parameters of liver function during simple steatosis (NAFL) and nonalcoholic steatohepatitis (NASH) in biopsy-proven patients. The NASH patients showed higher levels of IL-6 associated with a lower IL-10/IL-6 ratio. Besides heatmaps were similar in the NAFL and NASH groups, the same did not occur in signature curves, the NASH patients were high producers to IL-12 and IL-6 while the NAFL patients were not high producers of any cytokines evaluated. Integrative biomarker network analysis revealed that cytokines are differently correlated with clinical parameters, while IL-12, IL-10 presented moderate and negative correlations with glycemic and lipid profile in the NAFL group. The NASH group IL-12 and TNF revealed stronger and positive correlations with transient elastography parameters and NAFLD liver fibrosis score. These data suggest that IL-6 and IL-10 might act in chronic inflammation and insulin resistance whereas IL-12 and TNF may be involved in promoting liver damage and NAFLD progression. Plasma concentration analysis of these molecules and their association with clinical parameters can be used as new biomarkers to monitoring NAFLD progression and to reflect NASH development.
Shift work was recently described as a factor that increases the risk of Type 2 diabetes mellitus. In addition, rats born to mothers subjected to a phase shift throughout pregnancy are glucose ...intolerant. However, the mechanism by which a phase shift transmits metabolic information to the offspring has not been determined. Among several endocrine secretions, phase shifts in the light/dark cycle were described as altering the circadian profile of melatonin production by the pineal gland. The present study addresses the importance of maternal melatonin for the metabolic programming of the offspring.
Female Wistar rats were submitted to SHAM surgery or pinealectomy (PINX). The PINX rats were divided into two groups and received either melatonin (PM) or vehicle. The SHAM, the PINX vehicle and the PM females were housed with male Wistar rats. Rats were allowed to mate and after weaning, the male and female offspring were subjected to a glucose tolerance test (GTT), a pyruvate tolerance test (PTT) and an insulin tolerance test (ITT). Pancreatic islets were isolated for insulin secretion, and insulin signaling was assessed in the liver and in the skeletal muscle by western blots. We found that male and female rats born to PINX mothers display glucose intolerance at the end of the light phase of the light/dark cycle, but not at the beginning. We further demonstrate that impaired glucose-stimulated insulin secretion and hepatic insulin resistance are mechanisms that may contribute to glucose intolerance in the offspring of PINX mothers. The metabolic programming described here occurs due to an absence of maternal melatonin because the offspring born to PINX mothers treated with melatonin were not glucose intolerant.
The present results support the novel concept that maternal melatonin is responsible for the programming of the daily pattern of energy metabolism in their offspring.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Melatonin can contribute to glucose homeostasis either by decreasing gluconeogenesis or by counteracting insulin resistance in distinct models of obesity. However, the precise mechanism through which ...melatonin controls glucose homeostasis is not completely understood. Male Wistar rats were administered an intracerebroventricular (icv) injection of melatonin and one of following: an icv injection of a phosphatidylinositol 3-kinase (PI3K) inhibitor, an icv injection of a melatonin receptor (MT) antagonist, or an intraperitoneal (ip) injection of a muscarinic receptor antagonist. Anesthetized rats were subjected to pyruvate tolerance test to estimate in vivo glucose clearance after pyruvate load and in situ liver perfusion to assess hepatic gluconeogenesis. The hypothalamus was removed to determine Akt phosphorylation. Melatonin injections in the central nervous system suppressed hepatic gluconeogenesis and increased hypothalamic Akt phosphorylation. These effects of melatonin were suppressed either by icv injections of PI3K inhibitors and MT antagonists and by ip injection of a muscarinic receptor antagonist. We conclude that melatonin activates hypothalamus-liver communication that may contribute to circadian adjustments of gluconeogenesis. These data further suggest a physiopathological relationship between the circadian disruptions in metabolism and reduced levels of melatonin found in type 2 diabetes patients.
Fructose consumption causes insulin resistance and favors hepatic gluconeogenesis through mechanisms that are not completely understood. Recent studies demonstrated that the activation of ...hypothalamic 5′-AMP-activated protein kinase (AMPK) controls dynamic fluctuations in hepatic glucose production. Thus, the present study was designed to investigate whether hypothalamic AMPK activation by fructose would mediate increased gluconeogenesis. Both ip and intracerebroventricular (icv) fructose treatment stimulated hypothalamic AMPK and acetyl-CoA carboxylase phosphorylation, in parallel with increased hepatic phosphoenolpyruvate carboxy kinase (PEPCK) and gluconeogenesis. An increase in AMPK phosphorylation by icv fructose was observed in the lateral hypothalamus as well as in the paraventricular nucleus and the arcuate nucleus. These effects were mimicked by icv 5-amino-imidazole-4-carboxamide-1-β-d-ribofuranoside treatment. Hypothalamic AMPK inhibition with icv injection of compound C or with injection of a small interfering RNA targeted to AMPKα2 in the mediobasal hypothalamus (MBH) suppressed the hepatic effects of ip fructose. We also found that fructose increased corticosterone levels through a mechanism that is dependent on hypothalamic AMPK activation. Concomitantly, fructose-stimulated gluconeogenesis, hepatic PEPCK expression, and glucocorticoid receptor binding to the PEPCK gene were suppressed by pharmacological glucocorticoid receptor blockage. Altogether the data presented herein support the hypothesis that fructose-induced hypothalamic AMPK activation stimulates hepatic gluconeogenesis by increasing corticosterone levels.
The use of flubendazole (FBZ) in the treatment of lymphatic filariasis and onchocerciasis (two high incidence neglected tropical diseases) has been hampered by its poor aqueous solubility. A material ...consisting of binary flubendazole/maleic acid crystals (FBZ/MA), showing considerably improved solubility and dissolution rate relative to flubendazole alone, has been prepared in this work through solvent assisted mechanical grinding. The identification of FBZ/MA as a binary crystalline compound with salt character (proton transfer from MA to FBZ) relied on the combined results of powder X-ray diffraction, Raman spectroscopy, attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR), X-ray photoelectron spectroscopy (XPS), thermogravimetry (TG), and differential scanning calorimetry (DSC). Isothermal solution microcalorimetry studies further suggested that the direct formation of FBZ/MA from its precursors in the solid state is thermodynamically favored. A comparison of the in silico pharmacokinetic performance of the FBZ/MA with that of pure FBZ based on a rat fasted physiology model indicated that the absorption rate, mean plasma peak concentration, and absorption extension of FBZ/MA were ∼2.6 times, ∼1.4 times, and 60% larger, respectively, than those of FBZ. The results here obtained therefore suggest that the new FBZ/MA salt has a considerable potential for the development of stable and affordable pharmaceutical formulations with improved dissolution and pharmacokinetic properties. Finally, powder X-ray diffraction studies also led to the first determination of the crystal structure of FBZ.
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•The Cu deposition over Nb2O5 showed a high CO2 reduction capacity.•The Cu deposition decreases the recombination rate of the charges photogenerated.•The magnetron sputtering system ...provided a cluster of Cu highly dispersed.•The Nb2O5/Cu material showed high conversion for the methanol.
Herein we demonstrate that the deposition of a small loading of Cu nanoparticles (0.51 wt %) by DC-magnetron sputtering over niobium oxide (Nb2O5) increases its photocatalytic activity for the reduction of carbon dioxide (CO2) into methane (CH4), methanol (CH3OH), acetone (CH3COCH3), acetic acid (CH3COOH), isopropanol (CH3CH(OH)CH3) and formate (HCOO−). The improvement in the CO2 photoreduction of the Nb2O5/Cu can be attributed mainly to a reduction in the recombination rate of the electron-holes pairs photogenerated due to the electron trapping by Cu species as observed by the photoluminescence analysis, high dispersion of Cu, and high specific surface area of material even after addition Cu.
Abstract
Objective.
To establish the reference values for peripheral tissue perfusion of the triceps surae muscle assessed by Near-infrared spectroscopy (NIRS) at rest and in progressive effort.
...Approach.
A total of 288 apparently healthy individuals of both sexes were included; between 30 and 79 years of age; nonsmokers; without diagnosis of diabetes mellitus, systemic arterial hypertension, kidney disease, symptoms of angina and intermittent claudication, or any musculoskeletal alteration that would prevent physical exertion; and without diagnosis of Peripheral arterial disease (PAD) or other associated symptoms. All individuals performed anthropometric measurements, physical activity levels, and tissue oxygen saturation (StO
2
) assessments by NIRS during and after arterial occlusion maneuver and incremental shuttle walking test. The variables obtained by NIRS were presented in percentiles (P) for general comparison between sexes and for comparison between sexes according to age group. The relationship between the NIRS data and other variables was tested.
Main results.
Considering P50 and p<0.05, men had lower StO2 values, higher deoxygenation and reoxygenation (Tx-reox) rates at rest, and higher Tx-reox during progressive effort. There were correlations (p<0.0001) of body composition with the lowest StO2 and Tx-reox values and of functional capacity with Tx-reox in occlusion and Tx-reox.
Significance.
The percentiles presented can clinically assist in the diagnosis and monitoring of different health conditions; however, it is important to consider the individual’s sex, body composition, and functional capacity.
Abstract
The post-COVID-19 condition or ‘long COVID’ is a clinical and scientific challenge for society. In this regard, patients after COVID-19 recovery show a vast range of sequels including ...muscular, articular lesions, neurological, dermatological, and pulmonary issues. These clinical consequences are issues in the present and for the future. In this case, rehabilitation therapies based on photobiomodulation and combined therapies arise as excellent tools to solve it. Herein, we describe and discuss the perspectives on the use of light-based therapies such as photobiomodulation, photodynamic therapy and combined vacuum and laser therapy for rehabilitation of patients who present some sequelae of the COVID-19 infection. We did not intend to produce a comprehensive review; instead we highlight the most important and clinical protocols against these sequels. Moreover, the principles and mechanism of action of each light-based technique proposed were reported and discussed.
The renin–angiotensin system (RAS) plays a major role in cardiovascular diseases in postmenopausal women, but little is known about its importance to lower urinary tract symptoms. In this study we ...have used the model of ovariectomized (OVX) estrogen-deficient rats to investigate the role of RAS in functional and molecular alterations in the urethra and bladder.
Responses to contractile and relaxant agents in isolated urethra and bladder, as well as cystometry were evaluated in 4-month OVX Sprague–Dawley rats. Angiotensin-converting enzyme activity and Western blotting for AT1/AT2 receptors were examined.
Cystometric evaluations in OVX rats showed increases in basal pressure, capacity and micturition frequency, as well as decreased voiding pressure. Angiotensin II and phenylephrine produced greater urethral contractions in OVX compared with Sham group. Carbachol-induced bladder contractions were significantly reduced in OVX group. Relaxations of urethra and bladder to sodium nitroprusside and BAY 41-2272 were unaffected by OVX. Angiotensin-converting enzyme activity was 2.6-fold greater (p<0.05) in urethral tissue of OVX group, whereas enzyme activity in plasma and bladder remained unchanged. Expressions of AT1 and AT2 receptors in the urethra were markedly higher in OVX group. In bladder, AT1 receptors were not detected, whereas AT2 receptor expression was unchanged between groups. 17β-Estradiol replacement (0.1mg/kg, weekly) or losartan (30mg/kg/day) largely attenuated most of the alterations seen in OVX group.
Prolonged estrogen deprivation leads to voiding dysfunction and urethral hypercontractility that are associated with increased ACE activity and up-regulation of angiotensin AT1/AT2 receptor in the urethral tissue.
Strong evidence suggests that an adverse in utero and/or early postnatal environment impacts on long-term risk of developing type 2 diabetes. We showed previously that miR-126 is increased in adipose ...tissue of mouse offspring born to obese mothers which leads to impaired insulin signaling pathway by silencing IRS-1 at the translational level. However, the full spectrum of targets of miR-126 and consequently the consequences of its overexpression for adipose tissue function are unknown. The aim of the current study was therefore to identify novel targets of miR-126 using the proteomic technique, known as Pulsed Stable Isotope Labeling by Amino Acids (pSILAC). 3T3-L1-cells were transfected with miR-126 and their proteome compared to those transfected with a scrambled sequence. We detected 4567 proteins that were translated in adipocytes and of these 401 demonstrated a >1.3 fold decrease following over-expression of miR-126. Bioinformatic analysis revealed that 43 of these contained a miR-126 seed sequence in their 3’un-translated region. This included known miR-126 targets such as IRS-1 and VCAM-1 as well as novel targets. One of the largest changes in expression was observed for Lunapark and through the use of luciferase assays and western blotting we independently confirmed this was a direct target of miR-126. Lunapark is a key component for stabilization of nascent three-way junctions in the endoplasmic reticulum (ER). Consistent with this role we observed altered levels of mTOR and XBP1 in cells treated with miR-126, reflecting the presence of ER stress. Together, the results suggest that overexpression of miR-126 can lead to both ER stress and Insulin Resistance and therefore represent a novel link between two pathways that contribute to development and progression to T2DM.
Disclosure
J.A. Faria: None. D. Duque Guimaraes: None. L. Pantaleao: None. T.P. Ong: None. A. Ozanne: None.
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