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1.
Trials ; 22(1): 595, 2021 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-34488845

RESUMO

BACKGROUND: Chronic lower limb ischemia develops earlier and more frequently in patients with type 2 diabetes mellitus. Diabetes remains the main cause of lower-extremity non-traumatic amputations. Current medical treatment, based on antiplatelet therapy and statins, has demonstrated deficient improvement of the disease. In recent years, research has shown that it is possible to improve tissue perfusion through therapeutic angiogenesis. Both in animal models and humans, it has been shown that cell therapy can induce therapeutic angiogenesis, making mesenchymal stromal cell-based therapy one of the most promising therapeutic alternatives. The aim of this study is to evaluate the feasibility, safety, and efficacy of cell therapy based on mesenchymal stromal cells derived from adipose tissue intramuscular administration to patients with type 2 diabetes mellitus with critical limb ischemia and without possibility of revascularization. METHODS: A multicenter, randomized double-blind, placebo-controlled trial has been designed. Ninety eligible patients will be randomly assigned at a ratio 1:1:1 to one of the following: control group (n = 30), low-cell dose treatment group (n = 30), and high-cell dose treatment group (n = 30). Treatment will be administered in a single-dose way and patients will be followed for 12 months. Primary outcome (safety) will be evaluated by measuring the rate of adverse events within the study period. Secondary outcomes (efficacy) will be measured by assessing clinical, analytical, and imaging-test parameters. Tertiary outcome (quality of life) will be evaluated with SF-12 and VascuQol-6 scales. DISCUSSION: Chronic lower limb ischemia has limited therapeutic options and constitutes a public health problem in both developed and underdeveloped countries. Given that the current treatment is not established in daily clinical practice, it is essential to provide evidence-based data that allow taking a step forward in its clinical development. Also, the multidisciplinary coordination exercise needed to develop this clinical trial protocol will undoubtfully be useful to conduct academic clinical trials in the field of cell therapy in the near future. TRIAL REGISTRATION: ClinicalTrials.gov NCT04466007 . Registered on January 07, 2020. All items from the World Health Organization Trial Registration Data Set are included within the body of the protocol.


Assuntos
COVID-19 , Diabetes Mellitus Tipo 2 , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Mesenquimais , Noma , Tecido Adiposo , Animais , Ensaios Clínicos Fase II como Assunto , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/terapia , Método Duplo-Cego , Humanos , Isquemia/diagnóstico , Isquemia/terapia , Estudos Multicêntricos como Assunto , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , SARS-CoV-2 , Resultado do Tratamento
2.
Antioxidants (Basel) ; 10(9)2021 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-34573040

RESUMO

The optimization of conditions to promote the stemness of pluripotent cells in vitro is instrumental for their use in advanced therapies. We show here that exposure of human iPSCs and human ESCs to low concentrations of the chemical NO donor DETA/NO leads to stabilization of hypoxia-inducible factors (HIF-1α and HIF-2α) under normoxia, with this effect being dependent on diminished Pro 402 hydroxylation and decreased degradation by the proteasome. Moreover, the master genes of pluripotency, NANOG and OCT-4, were upregulated. NO also induces a shift in the metabolic profile of PSCs, with an increased expression of hypoxia response genes in glycolysis. Furthermore, a reduction in the mitochondrial membrane potential with lower oxygen consumption and increased expression of mitochondrial fusion regulators, such as DRP1, was observed. The results reported here indicate that NO mimics hypoxia response in human PSCs and enhances their stemness properties when cultured under normoxic conditions.

3.
Oper Orthop Traumatol ; 33(5): 405-421, 2021 Oct.
Artigo em Alemão | MEDLINE | ID: mdl-34529101

RESUMO

For surgeons in the clinic and practice, the handling of suture material is the "daily bread". Therefore, one might assume that knowledge of this material is competent and comprehensive. However, daily experience shows a different picture. Often, the knowledge regarding needle shape, needle composition as well as needle size is only marginal and the surgeon has to rely on the knowledge of his OR nurse.The choice of needle is critical for each surgical step and each tissue; however, the use of the correct suture material in relation to the tissue to be sutured is essential, not only with respect to the quality of the suture but also with respect to the traumatization of the tissue. Depending on the tissue, different requirements must be placed on or taken into account for both the needle and the sutures. The purpose of this article is to provide the most essential and basic knowledge, such as the influence of needle shape and dimensions, effect of atraumatic or traumatic (so called sharp) needles on the tissue and shape of the needle tip. The interaction between the needle holder and the needle and the surgeon's hand in different applications is presented. In this present article, the main focus is on the needle and needle holder. A follow-up article specifically dedicated to sutures is being planned. The article does not claim to be 100% complete but the most essential, everyday questions should be clarified.


Assuntos
Agulhas , Ortopedia , Humanos , Instrumentos Cirúrgicos , Técnicas de Sutura , Suturas , Resultado do Tratamento
4.
Foods ; 10(8)2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-34441565

RESUMO

Liver fibrosis can be caused by non-alcoholic steatohepatitis (NASH), among other conditions. We performed a study to analyze the effects of a nontoxic, water-soluble extract of the edible mushroom Agaricus bisporus (AB) as a potential inhibitor of fibrosis progression in vitro using human hepatic stellate cell (LX2) cultures and in vivo in LDLR-/- mice. Treatment of LX2 cells with the AB extract reduced the levels of fibrotic and oxidative-related markers and increased the levels of GATA4 expression. In LDLR-/- mice with high-fat diet (HFD)-induced liver fibrosis and inflammation, the progression of fibrosis, oxidative stress, inflammation, and apoptosis were prevented by AB extract treatment. Moreover, in the mouse model, AB extract could exert an antiatherogenic effect. These data suggest that AB mushroom extract seems to exert protective effects by alleviating inflammation and oxidative stress during the progression of liver fibrosis, possibly due to a decrease in Toll-like receptor 4 (TLR4) expression and a reduction in Nod-like receptor protein 3 (NLRP3) inflammasome activation. In addition, we observed a potential atheroprotective effect in our mouse model.

5.
Ann Anat ; 239: 151803, 2021 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-34265384

RESUMO

INTRODUCTION: Thyroid ima artery is a variant artery found on the anterior surface of the trachea. The aim of this meta-analysis was to obtain pooled prevalence data of the thyroid ima artery and discuss its clinical importance especially for tracheostomy. METHODS: A systematic literature search was performed through five electronic databases until May 2021. A set of inclusion and exclusion criteria based on AQUA guidelines were used to select relevant studies. Meta-analysis, subgroup analyses, meta-regression, and tests for publication bias were performed. Factors that influence the prevalence of the thyroid ima artery were detected using simple and interpretable machine learning (linear regression and K means). RESULTS: Thirty-six studies with a total of 4335 subjects met the inclusion criteria. The prevalence of the thyroid ima artery was 3.8% (95% CI: 0.027-0.049, I2=56.2%). Machine learning identified age, region and year of publication as potential covariates. Subgroup analysis showed that the prevalence of the thyroid ima artery was 4.5 times higher in fetuses (14.8%) than adults (3.3%) (z=-6.76, p<0.01). There was a significant negative correlation between the adult prevalence of the thyroid ima artery and the year of publication (Pearson's r=-0.354, p=0.040) thereby suggesting a decline in thyroid ima artery prevalence over time. This artery, if present, may originate from the brachiocephalic trunk (74%), right common carotid artery (9.6%), arch of aorta (7.7%), right internal thoracic artery (4.8%), left common carotid artery (1.9%) and left internal thoracic artery (1.9%). CONCLUSION: In addition to evidence-based synthesis of the thyroid ima artery, this study is the first ever study to report the decreasing prevalence over time of a human body structure in the postnatal life. Knowledge of the thyroid ima artery is of vital importance for surgeons to avoid accidental hemorrhage during tracheostomy.

6.
Theranostics ; 11(14): 6983-7004, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093866

RESUMO

Rationale: We recently demonstrated that the 'Metabesity' factor HMG20A regulates islet beta-cell functional maturity and adaptation to physiological stress such as pregnancy and pre-diabetes. HMG20A also dictates central nervous system (CNS) development via inhibition of the LSD1-CoREST complex but its expression pattern and function in adult brain remains unknown. Herein we sought to determine whether HMG20A is expressed in the adult CNS, specifically in hypothalamic astrocytes that are key in glucose homeostasis and whether similar to islets, HMG20A potentiates astrocyte function in response to environmental cues. Methods: HMG20A expression profile was assessed by quantitative PCR (QT-PCR), Western blotting and/or immunofluorescence in: 1) the hypothalamus of mice exposed or not to either a high-fat diet or a high-fat high-sucrose regimen, 2) human blood leukocytes and adipose tissue obtained from healthy or diabetic individuals and 3) primary mouse hypothalamic astrocytes exposed to either high glucose or palmitate. RNA-seq and cell metabolic parameters were performed on astrocytes treated or not with a siHMG20A. Astrocyte-mediated neuronal survival was evaluated using conditioned media from siHMG20A-treated astrocytes. The impact of ORY1001, an inhibitor of the LSD1-CoREST complex, on HMG20A expression, reactive astrogliosis and glucose metabolism was evaluated in vitro and in vivo in high-fat high-sucrose fed mice. Results: We show that Hmg20a is predominantly expressed in hypothalamic astrocytes, the main nutrient-sensing cell type of the brain. HMG20A expression was upregulated in diet-induced obesity and glucose intolerant mice, correlating with increased transcript levels of Gfap and Il1b indicative of inflammation and reactive astrogliosis. Hmg20a transcript levels were also increased in adipose tissue of obese non-diabetic individuals as compared to obese diabetic patients. HMG20A silencing in astrocytes resulted in repression of inflammatory, cholesterol biogenesis and epithelial-to-mesenchymal transition pathways which are hallmarks of reactive astrogliosis. Accordingly, HMG20A depleted astrocytes exhibited reduced mitochondrial bioenergetics and increased susceptibility to apoptosis. Neuron viability was also hindered in HMG20A-depleted astrocyte-derived conditioned media. ORY1001 treatment rescued expression of reactive astrogliosis-linked genes in HMG20A ablated astrocytes while enhancing cell surface area, GFAP intensity and STAT3 expression in healthy astrocytes, mimicking the effect of HMG20A. Furthermore, ORY1001 treatment protected against obesity-associated glucose intolerance in mice correlating with a regression of hypothalamic HMG20A expression, indicative of reactive astrogliosis attenuation with improved health status. Conclusion: HMG20A coordinates the astrocyte polarization state. Under physiological pressure such as obesity and insulin resistance that induces low grade inflammation, HMG20A expression is increased to induce reactive astrogliosis in an attempt to preserve the neuronal network and re-establish glucose homeostasis. Nonetheless, a chronic metabesity state or functional mutations will result in lower levels of HMG20A, failure to promote reactive astrogliosis and increase susceptibility of neurons to stress-induced apoptosis. Such effects could be reversed by ORY1001 treatment both in vitro and in vivo, paving the way for a new therapeutic approach for Type 2 Diabetes Mellitus.


Assuntos
Astrócitos/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Gliose/metabolismo , Proteínas de Grupo de Alta Mobilidade/metabolismo , Hipotálamo/metabolismo , Neurônios/metabolismo , Obesidade/metabolismo , Tecido Adiposo/metabolismo , Adulto , Animais , Sobrevivência Celular/efeitos dos fármacos , Proteínas Correpressoras/antagonistas & inibidores , Dieta Hiperlipídica , Proteína Glial Fibrilar Ácida/metabolismo , Glucose/metabolismo , Proteínas de Grupo de Alta Mobilidade/antagonistas & inibidores , Proteínas de Grupo de Alta Mobilidade/genética , Histona Desmetilases/antagonistas & inibidores , Humanos , Interleucina-1beta/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Mitocôndrias/genética , Mitocôndrias/metabolismo , Proteínas do Tecido Nervoso/antagonistas & inibidores , RNA Interferente Pequeno , RNA-Seq
7.
Handchir Mikrochir Plast Chir ; 53(3): 267-275, 2021 Jun.
Artigo em Alemão | MEDLINE | ID: mdl-34134159

RESUMO

Pyogenic flexor tenosynovitis (PFT) is still the most serious infections of the hand. If the typical cardinal signs of PFT according to Kanavel exist, the indication for surgery should be made immediately. The consequential damage of a delayed surgery with enormous restrictions on the movement of the fingers due to the destruction of the sliding layers and massive adhesions are so serious that conservative therapy attempts are very difficult to justify. The results of Hand therapy after delayed surgery are often disappointing. The rapid surgical intervention and the early opening and relief as well as the irrigation of the tendon sheath can end the disease, the destruction of the sliding layers and the severe pain almost immediately. Quick recognition and quick action are important. With early intervention, normal hand function can often be completely restored.


Assuntos
Tenossinovite , Dedos/cirurgia , Mãos/cirurgia , Humanos , Tenossinovite/diagnóstico , Tenossinovite/cirurgia
8.
Oper Orthop Traumatol ; 33(3): 183-199, 2021 Jun.
Artigo em Alemão | MEDLINE | ID: mdl-34106290

RESUMO

OBJECTIVE: Creation of a pain-free, flexible and stable (pseudo) joint between the carpus and the base of the 1st metacarpal bone. INDICATIONS: Painful carpometacarpal (CMC)­I joint due to primary or secondary osteoarthritis, CMC­I instability. CONTRAINDICATIONS: Carpal instability, local infection, tumors. SURGICAL TECHNIQUE: Resection of the trapezium (and of the arthritic joint surfaces in CMC­I and STT [scaphoid-trapezium-trapezoid-joint]), stabilization of the base of the 1st metacarpal bone by suspension with a distally pedicled strip of the flexor carpi radialis tendon or variants thereof. POSTOPERATIVE MANAGEMENT: Immobilization in a splint for 3-5 weeks, followed by hand therapy. RESULTS: Worldwide for almost 40 years, regardless of the exact technique, almost always (90%) significant pain reduction, increased strength in the grip and slightly less in the pinch grip, very good mobility, 85-95% very satisfied patients and very good long-term results.


Assuntos
Articulações Carpometacarpais , Trapézio , Artroplastia , Articulações Carpometacarpais/diagnóstico por imagem , Articulações Carpometacarpais/cirurgia , Humanos , Ligamentos , Tendões/cirurgia , Polegar/cirurgia , Trapézio/diagnóstico por imagem , Trapézio/cirurgia , Resultado do Tratamento
9.
Sci Rep ; 11(1): 8250, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33859314

RESUMO

Dietary fatty acids play a role in the pathogenesis of obesity-associated non-alcoholic fatty liver disease (NAFLD), which is associated with insulin resistance (IR). Fatty acid composition is critical for IR and subsequent NAFLD development. Extra-virgin olive oil (EVOO) is the main source of monounsaturated fatty acids (MUFA) in Mediterranean diets. This study examined whether EVOO-containing high fat diets may prevent diet-induced NAFLD using Ldlr-/-. Leiden mice. In female Ldlr-/-.Leiden mice, the effects of the following high fat diets (HFDs) were examined: a lard-based HFD (HFD-L); an EVOO-based HFD (HFD-EVOO); a phenolic compounds-rich EVOO HFD (HFD-OL). We studied changes in body weight (BW), lipid profile, transaminases, glucose homeostasis, liver pathology and transcriptome. Both EVOO diets reduced body weight (BW) and improved insulin sensitivity. The EVOOs did not improve transaminase values and increased LDL-cholesterol and liver collagen content. EVOOs and HFD-L groups had comparable liver steatosis. The profibrotic effects were substantiated by an up-regulation of gene transcripts related to glutathione metabolism, chemokine signaling and NF-kappa-B activation and down-regulation of genes relevant for fatty acid metabolism. Collectivelly, EVOO intake improved weight gain and insulin sensitivity but not liver inflammation and fibrosis, which was supported by changes in hepatic genes expression.

10.
J Hepatol ; 75(1): 34-45, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33571553

RESUMO

BACKGROUND & AIMS: Perturbations of intracellular magnesium (Mg2+) homeostasis have implications for cell physiology. The cyclin M family, CNNM, perform key functions in the transport of Mg2+ across cell membranes. Herein, we aimed to elucidate the role of CNNM4 in the development of non-alcoholic steatohepatitis (NASH). METHODS: Serum Mg2+ levels and hepatic CNNM4 expression were characterised in clinical samples. Primary hepatocytes were cultured under methionine and choline deprivation. A 0.1% methionine and choline-deficient diet, or a choline-deficient high-fat diet were used to induce NASH in our in vivo rodent models. Cnnm4 was silenced using siRNA, in vitro with DharmaFECT and in vivo with Invivofectamine® or conjugated to N-acetylgalactosamine. RESULTS: Patients with NASH showed hepatic CNNM4 overexpression and dysregulated Mg2+ levels in the serum. Cnnm4 silencing ameliorated hepatic lipid accumulation, inflammation and fibrosis in the rodent NASH models. Mechanistically, CNNM4 knockdown in hepatocytes induced cellular Mg2+ accumulation, reduced endoplasmic reticulum stress, and increased microsomal triglyceride transfer activity, which promoted hepatic lipid clearance by increasing the secretion of VLDLs. CONCLUSIONS: CNNM4 is overexpressed in patients with NASH and is responsible for dysregulated Mg2+ transport. Hepatic CNNM4 is a promising therapeutic target for the treatment of NASH. LAY SUMMARY: Cyclin M4 (CNNM4) is overexpressed in non-alcoholic steatohepatitis (NASH) and promotes the export of magnesium from the liver. The liver-specific silencing of Cnnm4 ameliorates NASH by reducing endoplasmic reticulum stress and promoting the activity of microsomal triglyceride transfer protein.

12.
Unfallchirurg ; 123(2): 114-125, 2020 Feb.
Artigo em Alemão | MEDLINE | ID: mdl-31822942

RESUMO

The secondary reconstruction of flexor tendons is in most cases very demanding and tedious. The indications, selection of the correct surgical procedure, operative technique and further treatment have to be individually adjusted and are mostly very difficult. Due to the previous operations unpleasant surprises may occur intraoperatively, which must be recognized and treated by the surgeon. Nevertheless, a significant improvement of the function of the whole hand can be achieved for most patients, e.g. by a two-stage flexor tendon transplantation or other techniques described in this article.


Assuntos
Traumatismos dos Dedos , Traumatismos da Mão , Procedimentos Ortopédicos , Traumatismos dos Tendões , Traumatismos dos Dedos/cirurgia , Mãos , Traumatismos da Mão/cirurgia , Humanos , Traumatismos dos Tendões/cirurgia
13.
J Pathol ; 250(4): 362-373, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31875961

RESUMO

Pancreatic heterotopia is defined as pancreatic tissue outside its normal location in the body and anatomically separated from the pancreas. In this work we have analyzed the stomach glandular epithelium of Gata4 flox/flox ; Pdx1-Cre mice (Gata4KO mice). We found that Gata4KO glandular epithelium displays an atypical morphology similar to the cornified squamous epithelium and exhibits upregulation of forestomach markers. The developing gastric units fail to form properly, and the glandular epithelial cells do not express markers of gastric gland in the absence of GATA4. Of interest, the developing glands of the Gata4KO stomach express pancreatic cell markers. Furthermore, a mass of pancreatic tissue located in the subserosa of the Gata4KO stomach is observed at adult stages. Heterotopic pancreas found in Gata4-deficient mice contains all three pancreatic cell lineages: ductal, acinar, and endocrine. Moreover, Gata4 expression is downregulated in ectopic pancreatic tissue of some human biopsy samples. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Assuntos
Células Epiteliais/patologia , Fator de Transcrição GATA4/genética , Pâncreas/patologia , Animais , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Mucosa Gástrica/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/genética , Humanos , Camundongos Transgênicos , Organogênese/fisiologia
14.
Eur J Gastroenterol Hepatol ; 32(5): 626-634, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31725030

RESUMO

BACKGROUND AND AIM: Body composition has emerged as a prognostic factor for end-stage liver disease. We therefore investigated muscle mass, body fat and other clinical-pathological variables as predictors of posttransplant survival. METHODS: A total of 368 patients, who underwent orthotopic liver transplantation (OLT) at our institution, were assessed prior to OLT and followed for a median of 9.0 years (range 2.0-10.0 years) after OLT. Psoas, erector spinae and the combined paraspinal muscle area, as well as the corresponding indices normalized by body-height squared, were quantified by a lumbar (L3) cross-sectional computed tomography. In addition, absolute body fat and bone density were estimated by the same computed tomography approach. RESULTS: Paraspinal muscle index (PSMI) (hazard ratio 0.955, P = 0.039) and hepatitis C (hazard rati 1.498, P = 0.038) were independently associated with post-OLT mortality. In contrast, body fat and bone density did not significantly affect post-OLT outcome (P > 0.05). The PSMI also predicted one-year posttransplant mortality with a receiver operating characteristics-area under the curve of 0.671 [95% confidence interval (CI) 0.589-0.753, P < 0.001) in male patients and outperformed individual psoas and erector spinae muscle group assessments in this regard. In male patients, a defined PSMI cutoff (<18.41 cm/m) was identified as suitable determinant for sarcopenia and posttransplant one-year mortality. In female OLT-recipients, however, sarcopenia was not predictive for patient survival und a women-specific cutoff could not be derived from this study. CONCLUSIONS: Taken together this analysis provides evidence, which PSMI is a relevant marker for muscle mass and that sarcopenia is an independent predictor of early post-OLT survival in male patients.


Assuntos
Doença Hepática Terminal/cirurgia , Transplante de Fígado , Sarcopenia , Adulto , Anatomia Transversal , Composição Corporal , Doença Hepática Terminal/complicações , Doença Hepática Terminal/diagnóstico por imagem , Feminino , Humanos , Transplante de Fígado/efeitos adversos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Sarcopenia/diagnóstico por imagem , Sarcopenia/etiologia , Tomografia Computadorizada por Raios X
15.
Front Immunol ; 11: 609961, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33633730

RESUMO

Snakebite envenoming is a global neglected disease with an incidence of up to 2.7 million new cases every year. Although antivenoms are so-far the most effective treatment to reverse the acute systemic effects induced by snakebite envenoming, they have a limited therapeutic potential, being unable to completely neutralize the local venom effects. Local damage, such as dermonecrosis and myonecrosis, can lead to permanent sequelae with physical, social, and psychological implications. The strong inflammatory process induced by snake venoms is associated with poor tissue regeneration, in particular the lack of or reduced skeletal muscle regeneration. Mesenchymal stromal cells (MSCs)-based therapies have shown both anti-inflammatory and pro-regenerative properties. We postulate that using allogeneic MSCs or their cell-free products can induce skeletal muscle regeneration in snakebite victims, improving all the three steps of the skeletal muscle regeneration process, mainly by anti-inflammatory activity, paracrine effects, neovascularization induction, and inhibition of tissue damage, instrumental for microenvironment remodeling and regeneration. Since snakebite envenoming occurs mainly in areas with poor healthcare, we enlist the principles and potential of MSCs-based therapies and discuss regulatory issues, good manufacturing practices, transportation, storage, and related-procedures that could allow the administration of these therapies, looking forward to a safe and cost-effective treatment for a so far unsolved and neglected health problem.


Assuntos
Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/metabolismo , Desenvolvimento Muscular , Músculo Esquelético/fisiopatologia , Regeneração , Mordeduras de Serpentes/cirurgia , Animais , Humanos , Mediadores da Inflamação/metabolismo , Transplante de Células-Tronco Mesenquimais/efeitos adversos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Necrose , Fenótipo , Transdução de Sinais , Mordeduras de Serpentes/diagnóstico , Mordeduras de Serpentes/metabolismo , Mordeduras de Serpentes/fisiopatologia , Resultado do Tratamento
16.
Aging (Albany NY) ; 11(18): 7746-7779, 2019 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-31518338

RESUMO

An inverse correlation between thyroid hormone levels and longevity has been reported in several species and reduced thyroid hormone levels have been proposed as a biomarker for healthy aging and metabolic fitness. However, hypothyroidism is a medical condition associated with compromised health and reduced life expectancy. Herein, we show, using wild-type and the Pax8 ablated model of hypothyroidism in mice, that hyperthyroidism and severe hypothyroidism are associated with an overall unhealthy status and shorter lifespan. Mild hypothyroid Pax8 +/- mice were heavier and displayed insulin resistance, hepatic steatosis and increased prevalence of liver cancer yet had normal lifespan. These pathophysiological conditions were precipitated by hepatic mitochondrial dysfunction and oxidative damage accumulation. These findings indicate that individuals carrying mutations on PAX8 may be susceptible to develop liver cancer and/or diabetes and raise concerns regarding the development of interventions aiming to modulate thyroid hormones to promote healthy aging or lifespan in mammals.


Assuntos
Envelhecimento/metabolismo , Fígado Gorduroso/patologia , Resistência à Insulina/fisiologia , Neoplasias Hepáticas/patologia , Fígado/patologia , Hormônios Tireóideos/sangue , Animais , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Fígado/metabolismo , Neoplasias Hepáticas/sangue , Masculino , Camundongos , Camundongos Knockout , Fator de Transcrição PAX8/genética , Fator de Transcrição PAX8/metabolismo
17.
Sci Rep ; 9(1): 11311, 2019 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-31383924

RESUMO

Dietary composition plays an important role in the pathophysiology of type 2 diabetes. Monounsaturated fatty acid consumption has been positively associated with improved insulin sensitivity and ß-cell function. We examined whether an extra virgin olive oil (EVOO) high fat diet (HFD) can improve glucose homeostasis. C57BL/6J mice were fed a standard diet or a lard-based HFD to induce type 2 diabetes. Then, HFD mice were fed with three different based HFD (lard, EVOO and EVOO rich in phenolic compounds) for 24 weeks. HFD-EVOO diets significantly improved glycemia, insulinemia, glucose tolerance, insulin sensitivity and insulin degradation. Moreover, EVOO diets reduced ß-cell apoptosis, increased ß-cell number and normalized islet glucose metabolism and glucose induced insulin secretion. No additional effects were observed by higher levels of phenolic compounds. Thus, EVOO intake regulated glucose homeostasis by improving insulin sensitivity and pancreatic ß-cell function, in a type 2 diabetes HFD animal model.


Assuntos
Diabetes Mellitus Tipo 2/dietoterapia , Dieta Hiperlipídica/métodos , Resistência à Insulina , Células Secretoras de Insulina/metabolismo , Azeite de Oliva/uso terapêutico , Animais , Glicemia/metabolismo , Células Cultivadas , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Modelos Animais de Doenças , Glucose/metabolismo , Insulina/metabolismo , Secreção de Insulina , Masculino , Camundongos Endogâmicos C57BL
18.
Diabetologia ; 62(9): 1667-1680, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31250031

RESUMO

AIMS/HYPOTHESIS: Bisphenol-A (BPA) is a widespread endocrine-disrupting chemical that has been associated with type 2 diabetes development. Low doses of BPA modify pancreatic beta cell function and induce insulin resistance; some of these effects are mediated via activation of oestrogen receptors α (ERα) and ß (ERß). Here we investigated whether low doses of BPA regulate the expression and function of ion channel subunits involved in beta cell function. METHODS: Microarray gene profiling of isolated islets from vehicle- and BPA-treated (100 µg/kg per day for 4 days) mice was performed using Affymetrix GeneChip Mouse Genome 430.2 Array. Expression level analysis was performed using the normalisation method based on the processing algorithm 'robust multi-array average'. Whole islets or dispersed islets from C57BL/6J or oestrogen receptor ß (ERß) knockout (Erß-/-) mice were treated with vehicle or BPA (1 nmol/l) for 48 h. Whole-cell patch-clamp recordings were used to measure Na+ and K+ currents. mRNA expression was evaluated by quantitative real-time PCR. RESULTS: Microarray analysis showed that BPA modulated the expression of 1440 probe sets (1192 upregulated and 248 downregulated genes). Of these, more than 50 genes, including Scn9a, Kcnb2, Kcnma1 and Kcnip1, encoded important Na+ and K+ channel subunits. These findings were confirmed by quantitative RT-PCR in islets from C57BL/6J BPA-treated mice or whole islets treated ex vivo. Electrophysiological measurements showed a decrease in both Na+ and K+ currents in BPA-treated islets. The pharmacological profile indicated that BPA reduced currents mediated by voltage-activated K+ channels (Kv2.1/2.2 channels) and large-conductance Ca2+-activated K+ channels (KCa1.1 channels), which agrees with BPA's effects on gene expression. Beta cells from ERß-/- mice did not present BPA-induced changes, suggesting that ERß mediates BPA's effects in pancreatic islets. Finally, BPA increased burst duration, reduced the amplitude of the action potential and enlarged the action potential half-width, leading to alteration in beta cell electrical activity. CONCLUSIONS/INTERPRETATION: Our data suggest that BPA modulates the expression and function of Na+ and K+ channels via ERß in mouse pancreatic islets. Furthermore, BPA alters beta cell electrical activity. Altogether, these BPA-induced changes in beta cells might play a role in the diabetogenic action of BPA described in animal models.


Assuntos
Compostos Benzidrílicos/farmacologia , Diabetes Mellitus Tipo 2/metabolismo , Receptor beta de Estrogênio/metabolismo , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Fenóis/farmacologia , Animais , Receptor alfa de Estrogênio/metabolismo , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Potássio/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Sódio/metabolismo
19.
Front Immunol ; 10: 1151, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31231366

RESUMO

Cell therapy is a progressively growing field that is rapidly moving from preclinical model development to clinical application. Outcomes obtained from clinical trials reveal the therapeutic potential of stem cell-based therapy to deal with unmet medical treatment needs for several disorders with no therapeutic options. Among adult stem cells, mesenchymal stem cells (MSCs) are the leading cell type used in advanced therapies for the treatment of autoimmune, inflammatory and vascular diseases. To date, the safety and feasibility of autologous MSC-based therapy has been established; however, their indiscriminate use has resulted in mixed outcomes in preclinical and clinical studies. While MSCs derived from diverse tissues share common properties depending on the type of clinical application, they markedly differ within clinical trials in terms of efficacy, resulting in many unanswered questions regarding the application of MSCs. Additionally, our experience in clinical trials related to critical limb ischemia pathology (CLI) shows that the therapeutic efficacy of these cells in different animal models has only been partially reproduced in humans through clinical trials. Therefore, it is crucial to develop new research to identify pitfalls, to optimize procedures and to clarify the repair mechanisms used by these cells, as well as to be able to offer a next generation of stem cell that can be routinely used in a cost-effective and safe manner in stem cell-based therapies targeting CLI.

20.
Mol Ther ; 26(11): 2696-2709, 2018 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-30195725

RESUMO

Diabetes is a chronic metabolic disorder that affects 415 million people worldwide. This pathology is often associated with long-term complications, such as critical limb ischemia (CLI), which increases the risk of limb loss and mortality. Mesenchymal stromal cells (MSCs) represent a promising option for the treatment of diabetes complications. Although MSCs are widely used in autologous cell-based therapy, their effects may be influenced by the constant crosstalk between the graft and the host, which could affect the MSC fate potential. In this context, we previously reported that MSCs derived from diabetic patients with CLI have a defective phenotype that manifests as reduced fibrinolytic activity, thereby enhancing the thrombotic risk and compromising patient safety. Here, we found that MSCs derived from diabetic patients with CLI not only exhibit a prothrombotic profile but also have altered multi-differentiation potential, reduced proliferation, and inhibited migration and homing to sites of inflammation. We further demonstrated that this aberrant cell phenotype is reversed by the platelet-derived growth factor (PDGF) BB, indicating that PDGF signaling is a key regulator of MSC functionality. These findings provide an attractive approach to improve the therapeutic efficacy of MSCs in autologous therapy for diabetic patients.


Assuntos
Diabetes Mellitus/genética , Inflamação/genética , Células-Tronco Mesenquimais/metabolismo , Proteínas Proto-Oncogênicas c-sis/genética , Animais , Diferenciação Celular/genética , Proliferação de Células/genética , Terapia Baseada em Transplante de Células e Tecidos/métodos , Células Cultivadas , Complicações do Diabetes/genética , Complicações do Diabetes/patologia , Complicações do Diabetes/terapia , Diabetes Mellitus/metabolismo , Diabetes Mellitus/patologia , Diabetes Mellitus/terapia , Humanos , Inflamação/patologia , Inflamação/terapia , Camundongos , Camundongos SCID , Osteogênese/genética , Fenótipo , Proteínas Proto-Oncogênicas c-sis/uso terapêutico , Transdução de Sinais , Cicatrização/genética
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