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1.
Microbiome ; 10(1): 96, 2022 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-35739571

RESUMO

BACKGROUND: Bariatric surgery remains the most effective therapy for adiposity reduction and remission of type 2 diabetes. Although different bariatric procedures associate with pronounced shifts in the gut microbiota, their functional role in the regulation of energetic and metabolic benefits achieved with the surgery are not clear. METHODS: To evaluate the causal as well as the inherent therapeutic character of the surgery-altered gut microbiome in improved energy and metabolic control in diet-induced obesity, an antibiotic cocktail was used to eliminate the gut microbiota in diet-induced obese rats after gastric bypass surgery, and gastric bypass-shaped gut microbiota was transplanted into obese littermates. Thorough metabolic profiling was combined with omics technologies on samples collected from cecum and plasma to identify adaptions in gut microbiota-host signaling, which control improved energy balance and metabolic profile after surgery. RESULTS: In this study, we first demonstrate that depletion of the gut microbiota largely reversed the beneficial effects of gastric bypass surgery on negative energy balance and improved glucolipid metabolism. Further, we show that the gastric bypass-shaped gut microbiota reduces adiposity in diet-induced obese recipients by re-activating energy expenditure from metabolic active brown adipose tissue. These beneficial effects were linked to improved glucose homeostasis, lipid control, and improved fatty liver disease. Mechanistically, these effects were triggered by modulation of taurine metabolism by the gastric bypass gut microbiota, fostering an increased abundance of intestinal and circulating taurine-conjugated bile acid species. In turn, these bile acids activated gut-restricted FXR and systemic TGR5 signaling to stimulate adaptive thermogenesis. CONCLUSION: Our results establish the role of the gut microbiome in the weight loss and metabolic success of gastric bypass surgery. We here identify a signaling cascade that entails altered bile acid receptor signaling resulting from a collective, hitherto undescribed change in the metabolic activity of a cluster of bacteria, thereby readjusting energy imbalance and metabolic disease in the obese host. These findings strengthen the rationale for microbiota-targeted strategies to improve and refine current therapies of obesity and metabolic syndrome. Video Abstract Bariatric Surgery (i.e. RYGB) or the repeated fecal microbiota transfer (FMT) from RYGB donors into DIO (diet-induced obesity) animals induces shifts in the intestinal microbiome, an effect that can be impaired by oral application of antibiotics (ABx). Our current study shows that RYGB-dependent alterations in the intestinal microbiome result in an increase in the luminal and systemic pool of Taurine-conjugated Bile acids (TCBAs) by various cellular mechanisms acting in the intestine and the liver. TCBAs induce signaling via two different receptors, farnesoid X receptor (FXR, specifically in the intestines) and the G-protein-coupled bile acid receptor TGR5 (systemically), finally resulting in metabolic improvement and advanced weight management. BSH, bile salt hydrolase; BAT brown adipose tissue.


Assuntos
Diabetes Mellitus Tipo 2 , Derivação Gástrica , Microbiota , Tecido Adiposo/metabolismo , Animais , Ácidos e Sais Biliares , Glicemia , Dieta , Obesidade/metabolismo , Obesidade/cirurgia , Ratos , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Taurina , Termogênese
2.
Mol Metab ; 48: 101214, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33741533

RESUMO

OBJECTIVE: Hypothalamic inflammation and endoplasmic reticulum (ER) stress are extensively linked to leptin resistance and overnutrition-related diseases. Surgical intervention remains the most efficient long-term weight-loss strategy for morbid obesity, but mechanisms underlying sustained feeding suppression remain largely elusive. This study investigated whether Roux-en-Y gastric bypass (RYGB) interacts with obesity-associated hypothalamic inflammation to restore central leptin signaling as a mechanistic account for post-operative appetite suppression. METHODS: RYGB or sham surgery was performed in high-fat diet-induced obese Wistar rats. Sham-operated rats were fed ad libitum or by weight matching to RYGB via calorie restriction (CR) before hypothalamic leptin signaling, microglia reactivity, and the inflammatory pathways were examined to be under the control of gut microbiota-derived circulating signaling. RESULTS: RYGB, other than CR-induced adiposity reduction, ameliorates hypothalamic gliosis, inflammatory signaling, and ER stress, which are linked to enhanced hypothalamic leptin signaling and responsiveness. Mechanistically, we demonstrate that RYGB interferes with hypothalamic ER stress and toll-like receptor 4 (TLR4) signaling to restore the anorexigenic action of leptin, which most likely results from modulation of a circulating factor derived from the altered gut microbial environment upon RYGB surgery. CONCLUSIONS: Our data demonstrate that RYGB interferes with hypothalamic TLR4 signaling to restore the anorexigenic action of leptin, which most likely results from modulation of a circulating factor derived from the post-surgical altered gut microbial environment.


Assuntos
Derivação Gástrica/métodos , Microbioma Gastrointestinal , Hipotálamo/metabolismo , Leptina/metabolismo , Microglia/metabolismo , Neurônios/metabolismo , Obesidade Mórbida/cirurgia , Transdução de Sinais , Redução de Peso , Animais , Restrição Calórica , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Inflamação/metabolismo , Masculino , Obesidade Mórbida/etiologia , Ratos , Ratos Wistar , Resultado do Tratamento
3.
Thyroid ; 30(8): 1205-1216, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32188347

RESUMO

Background: Tachycardia, cardiac hypertrophy, and elevated body temperature are major signs of systemic hyperthyroidism, which are considered to reflect the excessive thyroid hormone (TH) action in the respective peripheral tissues. However, recent observations indicate that the central actions of TH also contribute substantially to cardiovascular regulation and thermogenesis. Methods: In this study, we dissect the individual contributions of peripheral TH action versus the central effects in body temperature regulation and cardiovascular functions by taking advantage of mice lacking the TH transporters monocarboxylate transporter 8 (MCT8) and organic anion transporting polypeptide 1C1 (OATP1C1) (M/O double knock-out [dko]), which exhibit elevated serum triiodothyronine (T3) levels while their brain is in a profoundly hypothyroid state. We compared these animals with wild-type (WT) mice that were treated orally with T3 to achieve similarly elevated serum T3 levels, but are centrally hyperthyroid. For the studies, we used radiotelemetry, infrared thermography, gene expression profiling, Western blot analyses, and enzyme linked immunosorbent assays (ELISA) assays. Results: Our analyses revealed mild hyperthermia and cardiac hypertrophy in T3-treated WT mice but not in M/O dko animals, suggesting that central actions of TH are required for these hyperthyroid phenotypes. Although the average heart rate was unaffected in either model, the M/O dko exhibited an altered heart rate frequency distribution with tachycardic bursts in active periods and bradycardic episodes during resting time, demonstrating that the stabilization of heart rate by the autonomic nervous system can be impaired in centrally hypothyroid animals. Conclusions: Our studies unravel distinct phenotypical traits of hyperthyroidism that depend on an intact central nervous system, and provide valuable insight into the cardiovascular pathology of the Allan-Herndon-Dudley syndrome, a condition caused by the lack of MCT8 in humans.


Assuntos
Cardiomegalia/metabolismo , Febre/metabolismo , Frequência Cardíaca , Hipotireoidismo/complicações , Hormônios Tireóideos/metabolismo , Animais , Cardiomegalia/prevenção & controle , Cruzamentos Genéticos , Ensaio de Imunoadsorção Enzimática , Perfilação da Expressão Gênica , Glicogênio/metabolismo , Lipólise , Fígado/metabolismo , Masculino , Deficiência Intelectual Ligada ao Cromossomo X/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transportadores de Ácidos Monocarboxílicos/genética , Hipotonia Muscular/metabolismo , Atrofia Muscular/metabolismo , Fenótipo , Telemetria , Termogênese , Termografia , Fatores de Tempo , Tri-Iodotironina/sangue
4.
Zool Res ; 41(1): 3-19, 2020 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-31840949

RESUMO

Hypobaric hypoxia (HH) exposure can cause serious brain injury as well as life-threatening cerebral edema in severe cases. Previous studies on the mechanisms of HH-induced brain injury have been conducted primarily using non-primate animal models that are genetically distant to humans, thus hindering the development of disease treatment. Here, we report that cynomolgus monkeys ( Macacafascicularis) exposed to acute HH developed human-like HH syndrome involving severe brain injury and abnormal behavior. Transcriptome profiling of white blood cells and brain tissue from monkeys exposed to increasing altitude revealed the central role of the HIF-1 and other novel signaling pathways, such as the vitamin D receptor (VDR) signaling pathway, in co-regulating HH-induced inflammation processes. We also observed profound transcriptomic alterations in brains after exposure to acute HH, including the activation of angiogenesis and impairment of aerobic respiration and protein folding processes, which likely underlie the pathological effects of HH-induced brain injury. Administration of progesterone (PROG) and steroid neuroprotectant 5α-androst-3ß,5,6ß-triol (TRIOL) significantly attenuated brain injuries and rescued the transcriptomic changes induced by acute HH. Functional investigation of the affected genes suggested that these two neuroprotectants protect the brain by targeting different pathways, with PROG enhancing erythropoiesis and TRIOL suppressing glutamate-induced excitotoxicity. Thus, this study advances our understanding of the pathology induced by acute HH and provides potential compounds for the development of neuroprotectant drugs for therapeutic treatment.


Assuntos
Androstanóis/farmacologia , Hipóxia/veterinária , Macaca fascicularis , Doenças dos Macacos/prevenção & controle , Progesterona/farmacologia , Transcriptoma , Androstanóis/administração & dosagem , Animais , Encefalopatias/prevenção & controle , Encefalopatias/veterinária , Cálcio/metabolismo , Regulação da Expressão Gênica , Hipóxia/patologia , Leucócitos/metabolismo , Masculino , Fármacos Neuroprotetores/farmacologia , Pressão , Progesterona/administração & dosagem
5.
Int J Pharm ; 495(2): 728-37, 2015 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-26417849

RESUMO

The resistance of Helicobacter pylori to classical antimicrobial treatment has become increasingly common, whereupon biofilms are considered to play an important role in the resistance mechanism. Here 10.2% of amoxicillin (AMX) and a novel anti H. pylori adhesion material pectin sulfate (PECS) loaded lipid polymer nanoparticles (LPN) were prepared, with rhamnolipid and phospholipids as the outer mixed lipids layer (RHL-PC-LPN). The size of RHL-PC-LPN was around 200 nm, was negatively-charged, and showed sustained and complete drug release within 24h. In an in vitro study, H. pylori biofilm models were successfully established. RHL-PC-LPN, superior to PC-LPN (employing phospholipids only as the outer lipid layer), PECS+AMX (mixture of PECS and AMX) and AMX only, was proven to significantly eradicate H. pylori in the biofilm form. In accordance to our previous results, the RHL-PC-LPN group, together with the PC-LPN and PECS+AMX group, inhibited H. pylori from adhering to AGS cells. Investigating the underlying mechanisms contributing to the death of H. pylori caused by RHL-PC-LPN, we found that LPN could lower the antibiotic minimal inhibition concentration (MIC) to biofilm form from 125 µg/ml to 15.6 µg/ml. Furthermore, FITC-ConA labeled extracellular polymeric substances (EPS) were decreased in the RHL-PC-LPN group observed by a laser scanning confocal microscope. Therefore, we conclude that employing the mixed lipids of rhamnolipid and phospholipids as the outer layer of nanoparticles and PECS as the inner core produces a system capable of significantly disrupting H. pylori biofilm by eliminating the EPS as well as inhibiting the adherence and colonization of bacteria.


Assuntos
Amoxicilina/administração & dosagem , Antibacterianos/administração & dosagem , Helicobacter pylori/efeitos dos fármacos , Nanopartículas , Amoxicilina/farmacologia , Antibacterianos/farmacologia , Biofilmes/efeitos dos fármacos , Linhagem Celular Tumoral , Química Farmacêutica , Preparações de Ação Retardada , Liberação Controlada de Fármacos , Farmacorresistência Bacteriana , Glicolipídeos/química , Humanos , Testes de Sensibilidade Microbiana , Pectinas/química , Fosfolipídeos/química , Polímeros/química
6.
Mol Endocrinol ; 28(12): 1961-70, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25389909

RESUMO

Monocarboxylate transporter 8 (MCT8) transports thyroid hormone (TH) across the plasma membrane. Mutations in MCT8 result in the Allan-Herndon-Dudley syndrome, comprising severe psychomotor retardation and elevated serum T3 levels. Because the neurological symptoms are most likely caused by a lack of TH transport into the central nervous system, the administration of a TH analog that does not require MCT8 for cellular uptake may represent a therapeutic strategy. Here, we investigated the therapeutic potential of the biologically active T3 metabolite Triac (TA3) by studying TA3 transport, metabolism, and action both in vitro and in vivo. Incubation of SH-SY5Y neuroblastoma cells and MO3.13 oligodendrocytes with labeled substrates showed a time-dependent uptake of T3 and TA3. In intact SH-SY5Y cells, both T3 and TA3 were degraded by endogenous type 3 deiodinase, and they influenced gene expression to a similar extent. Fibroblasts from MCT8 patients showed an impaired T3 uptake compared with controls, whereas TA3 uptake was similar in patient and control fibroblasts. In transfected cells, TA3 did not show significant transport by MCT8. Most importantly, treatment of athyroid Pax8-knockout mice and Mct8/Oatp1c1-double knockout mice between postnatal days 1 and 12 with TA3 restored T3-dependent neural differentiation in the cerebral and cerebellar cortex, indicating that TA3 can replace T3 in promoting brain development. In conclusion, we demonstrated uptake of TA3 in neuronal cells and in fibroblasts of MCT8 patients and similar gene responses to T3 and TA3. This indicates that TA3 bypasses MCT8 and may be used to improve the neural status of MCT8 patients.


Assuntos
Deficiência Intelectual Ligada ao Cromossomo X/tratamento farmacológico , Deficiência Intelectual Ligada ao Cromossomo X/metabolismo , Hipotonia Muscular/tratamento farmacológico , Hipotonia Muscular/metabolismo , Atrofia Muscular/tratamento farmacológico , Atrofia Muscular/metabolismo , Tri-Iodotironina/análogos & derivados , Animais , Transporte Biológico/efeitos dos fármacos , Células COS , Diferenciação Celular/fisiologia , Linhagem Celular Tumoral , Células Cultivadas , Chlorocebus aethiops , Humanos , Técnicas In Vitro , Proteínas de Membrana Transportadoras , Camundongos , Camundongos Knockout , Transportadores de Ácidos Monocarboxílicos , Proteínas de Transporte de Cátions Orgânicos/genética , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Simportadores , Tri-Iodotironina/genética , Tri-Iodotironina/metabolismo , Tri-Iodotironina/uso terapêutico
7.
Steroids ; 78(10): 996-1002, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23811019

RESUMO

Ischemic stroke is a leading cause of death worldwide, yet therapies are limited. During periods of ischemia following reperfusion in ischemic stroke, not only loss of energy supply, but a few other factors including mitochondrial dysfunction and oxidative stress also make vital contribution to neuronal injury. Here we synthesized a steroid compound 5α-androst-3ß,5,6ß-triol by 3 steps starting from dehydroepiandrosterone and examined its effect on mitochondrial function and oxidative stress in primary cultured cortical neurons exposed to hypoxia followed by reoxygenation. 5α-Androst-3ß,5,6ß-triol dose-dependently protected cortical neurons from hypoxia/reoxygenation exposure. Rates of reduction in neuronal viability, loss of mitochondrial membrane potential, disruption of ATP production and oxidative stress were ameliorated in 5α-androst-3ß,5,6ß-triol pretreated cultures. In summary, these results suggest that 5α-androst-3ß,5,6ß-triol is neuroprotective against hypoxia/reoxygenation induced neuronal injuries through mediation of mitochondrial function and oxidative stress.


Assuntos
Androstanóis/farmacologia , Mitocôndrias/fisiologia , Neurônios/fisiologia , Fármacos Neuroprotetores/farmacologia , Trifosfato de Adenosina/metabolismo , Animais , Hipóxia Celular/efeitos dos fármacos , Células Cultivadas , Desidroepiandrosterona/farmacologia , Avaliação Pré-Clínica de Medicamentos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Estresse Oxidativo , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo
8.
Biosens Bioelectron ; 26(7): 3167-74, 2011 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-21227679

RESUMO

We have recently applied surface-enhanced Raman spectroscopy (SERS) for blood plasma analysis for non-invasive nasopharyngeal cancer detection and obtained good preliminary results. The aim of this study was to develop a more robust SERS spectroscopy based blood plasma analysis method for non-invasive gastric cancer detection. The effect of different laser polarizations (non-polarized, linear-polarized, right-handed circularly polarized, and left-handed circularly polarized) on blood plasma SERS spectroscopy was explored for the first time. Silver nanoparticles as the SERS-substrate were directly mixed with blood plasma to enhance the Raman scattering of various biomolecular constituents. High quality SERS spectra were obtained using a fiber optic probe and a dispersive type near infrared Raman system. Blood plasma samples from gastric cancer patients (n=32) and healthy subjects (n=33) were analyzed. The diagnostic performance for differentiating gastric cancer plasma from normal plasma was evaluated. Principal component analysis combined with linear discriminant analysis (LDA) of the obtained spectral data was used to develop diagnostic algorithms. Classification results obtained from cross-validation of the LDA model based on the four spectral data sets of different laser polarizations demonstrated different diagnostic sensitivities and specificities: 71.9% and 72.7% for non-polarized laser excitation, 75% and 87.9% for linear-polarized laser excitation, 81.3% and 78.8% for right-handed circularly polarized laser excitation, 100% and 97% for left-handed circularly polarized laser excitation. The results from this exploratory study demonstrated that plasma SERS spectroscopy with left-handed circularly polarized laser excitation has great promise of becoming a clinically useful diagnostic tool for non-invasive gastric cancer detection.


Assuntos
Plasma/química , Análise Espectral Raman/métodos , Neoplasias Gástricas/diagnóstico , Adulto , Análise Discriminante , Desenho de Equipamento , Humanos , Lasers , Pessoa de Meia-Idade , Nanopartículas/química , Análise de Componente Principal , Sensibilidade e Especificidade , Prata/química , Análise Espectral Raman/instrumentação , Adulto Jovem
9.
Brain Res ; 1373: 160-71, 2011 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-21163255

RESUMO

Acupuncture has been applied in the clinic to treat visceral pain for a long time. However, the underlying mechanism still remains unknown. In the present study, extrasegmental analgesia of electroacupuncture (EA) at orofacial acupoints on visceral pain rats was investigated. The results revealed that nociceptive EA stimulation applied at heterotopic acupoints or nonacupoints to activate A(δ) and/or C fibers induced c-fos expression in the paratrigeminal nucleus (PTN) and significantly inhibited acetic acid-induced abdominal contractions and c-fos expression in the nucleus of the solitary tract (NTS). However, non-nociceptive EA or non-EA stimulation applied at heterotopic acupoints was totally ineffective. After infraorbital nerves transaction or pretreated by capsaicin, the EA analgesia was dramatically inhibited. Snake venom pretreatment had no influence on this analgesia. Consequently, heterotopic EA stimulation trigger the pain-inhibiting effect of diffuse noxious inhibitory controls (DNIC), in which PTN-NTS secondary neural pathway may be involved and small-diameter (A(δ) and/or C) fibers are crucial.


Assuntos
Analgesia/métodos , Eletroacupuntura/métodos , Manejo da Dor , Vísceras/inervação , Ácido Acético/efeitos adversos , Pontos de Acupuntura , Vias Aferentes/efeitos dos fármacos , Vias Aferentes/fisiologia , Animais , Capsaicina/farmacologia , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/fisiologia , Masculino , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/inervação , Fibras Nervosas/fisiologia , Dor/induzido quimicamente , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Sprague-Dawley , Venenos de Serpentes/farmacologia , Núcleo Solitário/metabolismo , Núcleos do Trigêmeo/metabolismo
10.
Biosens Bioelectron ; 25(11): 2414-9, 2010 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-20427174

RESUMO

A surface-enhanced Raman spectroscopy (SERS) method was developed for blood plasma biochemical analysis for the first time with the aim to develop a simple blood test for non-invasive nasopharyngeal cancer detection. Silver nanoparticles (Ag NP) as the SERS-active nanostructures were directly mixed with blood plasma to enhance the Raman scattering signals of various biomolecular constituents such as proteins, lipids, and nucleic acids. High quality SERS spectrum from blood plasma-Ag NP mixture can be obtained within 10s using a Renishaw micro-Raman system. SERS measurements were performed on two groups of blood plasma samples: one group from patients (n=43) with pathologically confirmed nasopharyngeal carcinomas (WHO type I, II, and III) and the other group from healthy volunteers (control subjects, n=33). Tentative assignments of the Raman bands in the measured SERS spectra suggest interesting cancer specific biomolecular differences, including an increase in the relative amounts of nucleic acid, collagen, phospholipids and phenylalanine and a decrease in the percentage of amino acids and saccharide contents in the blood plasma of nasopharyngeal cancer patients as compared to that of healthy subjects. Principal component analysis (PCA) of the measured SERS spectra separated the spectral features of the two groups into two distinct clusters with little overlaps. Linear discriminate analysis (LDA) based on the PCA generated features differentiated the nasopharyngeal cancer SERS spectra from normal SERS spectra with high sensitivity (90.7%) and specificity (100%). The results from this exploratory study demonstrated great potentials for developing SERS blood plasma analysis into a novel clinical tool for non-invasive detection of nasopharyngeal cancers.


Assuntos
Biomarcadores Tumorais/sangue , Técnicas Biossensoriais/métodos , Análise Química do Sangue/métodos , Neoplasias Nasofaríngeas/sangue , Neoplasias Nasofaríngeas/diagnóstico , Análise Espectral Raman/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
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