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OBJECTIVE: While biologics have been used for the patients with psoriatic arthritis, there remains to be unknown concerning long-term retention rates. This study aims to present real-world data about long-term retention rates of biologics for the patients with psoriatic arthritis, and to undertake an analysis of the contributing factors. METHODS: We examined retention rates and the reasons for discontinuation for biologics (adalimumab, certolizumab pegol, secukinumab, and ixekizumab) in 146 prescriptions (of which, 109 prescriptions were as naive) at our hospital since March 2010. RESULTS: Throughout the entire course of the study, the 10-year retention rates were approximately 70% for adalimumab, 50% for ixekizumab, and 40% for secukinumab. When evaluating retention rates in the biologic-naïve subgroups, the 10-year retention rates were all approximately 70%. Regarding certolizumab pegol, the 3-year retention rate was approximately 75%. For adalimumab, a higher degree of arthritis at the initiation of treatment was found to correlate with an increased likelihood of secondary inefficacy. The main reason for discontinuation was secondary inefficacy, except for ixekizumab. CONCLUSIONS: Each biologic exhibited a favourable long-term retention rate. The main reason for discontinuation was secondary inefficacy. Regarding adalimumab, secondary inefficacy was linked to the extent of arthritis upon treatment initiation.
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CONTEXT: Tangnaikang (TNK) is a Chinese herbal formulation that has lipid-lowering effects, but its effect on reducing obesity has not been studied. OBJECTIVE: To observe the effect of TNK on obesity and explore its effect on gut microbiota of obese rats. MATERIALS AND METHODS: The SHR/NDmcr-cp rats were divided into three groups: (1) 3.24 g/kg TNK (High TNK), (2) 1.62 g/kg TNK (Low TNK), and (3) an untreated control (CON). Wistar-Kyoto rats were used as normal controls (WKY). After 8 weeks of TNK oral administration, body weight, abdominal circumference, triglycerides (TC) and total cholesterol (CHO) were measured. Gut microbiota diversity was studied by 16S rDNA sequencing, and metagenomes analysis was conducted to determine alteration in functional gene expression. RESULTS: The body weight (496.60 ± 6.0 g vs. 523.40 ± 5.6 g), abdomen circumference (24.00 ± 0.11 cm vs. 24.87 ± 0.25 cm), TC (3.04 ± 0.16 mmol/L vs. 4.97 ± 0.21 mmol/L), CHO (2.42 ± 0.15 mmol/L vs. 2.84 ± 0.09 mmol/L) of rats in the High TNK group were decreased significantly (all p < 0.05). TNK administration regulates intestinal flora, up-regulates Eisenbergiella and down-regulates Clostridium_sensu_stricto_1, which is beneficial to the production of short-chain fatty acids (SCFAs). Metagenomes analysis shows that TNK is closely related to the fatty acid synthesis pathway. DISCUSSION AND CONCLUSIONS: TNK can regulate gut microbiota to reduce obesity, which may be related to fatty acid metabolism. Our research supports the clinical application of TNK preparation and provides a new perspective for the treatment of obesity.
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Diabetes Mellitus , Medicamentos de Ervas Chinesas , Microbioma Gastrointestinal , Animais , Peso Corporal , Colesterol/farmacologia , DNA Ribossômico/farmacologia , Diabetes Mellitus/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Ácidos Graxos Voláteis , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , TriglicerídeosRESUMO
A 57-year-old man had a 2-year history of a painful nodule on the right sole. Physical examination revealed an 8 × 8 mm hyperkeratotic plaque with a central fissure. Excisional biopsy disclosed epithelial invagination surrounded by the acanthotic epidermis with parakeratotic hyperkeratosis and focal hypergranulosis. The invaginated epithelium lacked a cornified layer and was composed of a mixture of small basaloid squamous cells and goblet cells showing tubular structures. The patient was diagnosed with mucinous syringometaplasia. Our literature review established that surrounding acanthosis with hyperkeratosis typically tends to conceal mucinous syringometaplastic changes. Because mucinous syringometaplasia often presents as an asymptomatic papule/nodule with no distinct ulcer, fissure, or depressed area, cases may be overlooked.
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Neoplasias Císticas, Mucinosas e Serosas/patologia , Paraceratose/patologia , Pele/patologia , Neoplasias das Glândulas Sudoríparas/patologia , Biomarcadores Tumorais/análise , Biópsia , Pé , Humanos , Imuno-Histoquímica , Masculino , Metaplasia , Pessoa de Meia-Idade , Neoplasias Císticas, Mucinosas e Serosas/química , Pele/química , Neoplasias das Glândulas Sudoríparas/químicaRESUMO
(1) Background: Recent studies have investigated the expression of taste-related genes in the organs of various animals, including humans; however, data for additional taxa are needed to facilitate comparative analyses within and among species. (2) Methods: We investigated the expression of taste-related genes in the intestines of rhesus macaques, the non-human primates most commonly used in experimental models. (3) Results: Based on RNAseq and qRT-PCR, genes encoding bitter taste receptors and the G-protein gustducin were expressed in the gut of rhesus macaques. RNAscope analysis showed that one of the bitter receptors, TAS2R38, was expressed in some cells in the small intestine, and immunohistochemical analysis revealed the presence of T2R38-positive cells in the villi of the intestines. (4) Conclusions: These results suggest that bitter receptors are expressed in the gut of rhesus macaques, supporting the use of macaques as a model for studies of human taste, including gut analyses.
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Cálcio/metabolismo , Mucosa Intestinal/metabolismo , Intestino Delgado/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Paladar/fisiologia , Animais , Humanos , Macaca mulatta , RNA-Seq , Receptores Acoplados a Proteínas G/genéticaRESUMO
Mitochondria uncoupling protein2 (UCP2) expressed ubiquitously is a key molecule of energy metabolism. Insulin-like growth factor-1 (IGF-1) is a hormone, a target molecule of growth hormone (GH) signal pathway, which is also known as the drug "mecasermin" for clinical usages. IGF-1 is seemed to be closely related to metabolic diseases, such as adult GH deficiency. However, there has not been reports depicted possible relationship with each other. So, we sought to elucidate the mechanisms by which expression of UCP2 is regulated by IGF-1 via FOXO1. The findings suggested that three sequences in the consensus UCP2 promoter play complementary functional roles in the functional expression of FOXO1. So, we found that FOXO1 is involved in IGF-1-mediated energy metabolism greater than that of direct action of GH via STAT5. Our findings suggested that IGF-1 was involved in energy metabolism by regulating the expression of UCP2 via the PI3K/Akt/FOXO1 pathway.
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Proteína Forkhead Box O1/metabolismo , Hormônio do Crescimento/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Proteína Desacopladora 2/metabolismo , Células 3T3-L1 , Tecido Adiposo/metabolismo , Animais , Metabolismo Energético , Regulação da Expressão Gênica , Células HEK293 , Células Hep G2 , Humanos , Camundongos , Mitocôndrias/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Regiões Promotoras Genéticas , Receptor IGF Tipo 1/metabolismo , Fator de Transcrição STAT5/metabolismo , Proteínas Supressoras de Tumor/metabolismoRESUMO
Cigarette smoke extract (CSE) contains many toxicants and may derange the physiological processes, such as cholesterol metabolism. We examined the impact of CSE on transcriptional regulation mediated peroxisome proliferator-activated receptors (PPARs) and its interaction with cofactors to elucidate differences in the molecular mechanism between CSE and other agonists of PPARs. We constructed several mutant PPARs (mPPARs) with amino acid substitution in the ligand-binding domain, which according to the molecular modeling, may affect the binding of agonists. In transient expression assays, each wild-type peroxisome proliferator-activated receptor (PPAR) mediated transcription stimulated by CSE was faintly yet significantly elevated compared to the control. The CSE-induced transcriptional activation was abolished in the H323A, H323Y, S342A, and H449A mPPARγs, although the activation elevated by pioglitazone was reserved. In the mPPARγ with Y473A and mPPARß/δs with H286Y and Y436A, the pioglitazone-induced or L165041-activated transcriptional elevations were decreased and were lower than that of CSE-induced stimulation. These results suggested that CSE activated both mutant PPARs to be selectively different from those ligands. Mammalian two-hybrid assay illustrated that CSE could mildly recruit SRC1 or GRIP1 to the wild-type PPARγ. Representative ingredients, such as acrolein and crotonaldehyde present in CSE, could stimulate PPAR isoforms even at the toxicological concentrations and might possibly contribute to stimulatory effects. CSE mildly regulates the cholesterol metabolism-related genes, such as low density lipoprotein (LDL) receptor and Liver X receptor (LXR)ß. In conclusion, these CSE effects the nuclear hormone receptors and their cofactors thereby disturbing metabolic phenomena. Therefore, CSE might be involved in cholesterol metabolism.
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Nicotiana , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Fumaça , Substituição de Aminoácidos , Linhagem Celular , LDL-Colesterol/metabolismo , Humanos , Receptores X do Fígado/genética , Receptores Ativados por Proliferador de Peroxissomo/genética , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Receptores Citoplasmáticos e Nucleares/genética , Receptores de LDL/genéticaRESUMO
Cigarette smoke contains over 4800 compounds, including at least 200 toxicants or endocrine disruptors. Currently, effects of cigarette smoke on thyroid hormone (TH) levels remains to be clarified. Here, we demonstrate that cigarette smoke extract (CSE) possesses thyroid hormone properties and acts synergistically as a partial agonist for thyroid hormone receptors (TRs) in the presence of TH. In transient gene expression experiments, CSE stimulated transcriptional activity with TH in a dose-dependent manner. Stimulatory effects were observed with physiological TH concentrations, although CSE did not activate TRs without TH. CSE (5%) dissolved in phosphate-buffered saline (PBS) supplemented with 1 nM TH was approximately comparable to 3.2±0.1 and 2.3±0.2 nM of TRα1 and TRß1, respectively. To illustrate probable mechanisms of the CSE agonistic activity, effects on TR mediated transcriptional functions with cofactors were investigated. With a mammalian two-hybrid assay, CSE recruited the nuclear coactivators glucocorticoid receptor interacting protein 1 (GRIP1) and steroid receptor coactivator 1 (SRC1) to the TR. Unsaturated carbonyl compounds, acrolein, crotonaldehyde, and methyl vinyl ketone, representative constituents of CSE, retained such agonistic properties and possibly contributed to stimulatory effects. The results suggest that CSE recruits a transcriptional activator and may reinforce TH binding to the TR additively, resulting in gene expression. CSE partially agonizes TH action and may disturb the function of various nuclear hormone receptor types and their cofactors to disrupt the physiological processes.
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Nicotiana/efeitos adversos , Receptores dos Hormônios Tireóideos/efeitos dos fármacos , Fumaça/efeitos adversos , Hormônios Tireóideos/farmacologia , Transcrição Gênica/efeitos dos fármacos , Proteínas de Transporte/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Humanos , Malato Desidrogenase/biossíntese , Proteínas do Tecido Nervoso/efeitos dos fármacos , Coativador 1 de Receptor Nuclear/genética , Receptores dos Hormônios Tireóideos/genética , Fumaça/análise , Receptores alfa dos Hormônios Tireóideos/efeitos dos fármacos , Receptores alfa dos Hormônios Tireóideos/genética , Receptores beta dos Hormônios Tireóideos/efeitos dos fármacos , Receptores beta dos Hormônios Tireóideos/genética , Nicotiana/químicaAssuntos
Implante Mamário/efeitos adversos , Implantes de Mama/efeitos adversos , Dermatomiosite/etiologia , Silicones/efeitos adversos , Adulto , Implante Mamário/instrumentação , Dermatomiosite/diagnóstico , Dermatomiosite/cirurgia , Remoção de Dispositivo , Feminino , Humanos , Resultado do TratamentoRESUMO
BACKGROUND: The impact of vitamin D3 (VD3) on obesity has been reported in the past. Our study was aimed at investigating the possible mechanisms by which VD3 affects obesity induced by a high fat diet. METHODS: Eight-week-old C57BL/6 J male mice were fed a normal- or high-fat diet for 9 weeks and were treated with a gavage of vehicle (corn oil) or cholecalciferol (50 µg/kg, daily). Body weight, white adipose tissue weight, blood lipid and glucose levels were measured. In addition, we investigated the expression of 1,25(OH)2D3 (calcitriol)/VDR-regulated genes involved in energy and lipid metabolism, such as of uncoupling protein 3 (UCP3), by using qRT-PCR in the liver, adipose tissue, skeletal muscle and C2C12, L6, and H-EMC-SS cells. We also measured UCP3 promoter transcription in the same cell lines using a Dual Luciferase Assay. Furthermore, we analyzed the binding site consensus sequences of VDR on the UCP3 promoter. RESULTS: Mice consuming a high-fat diet treated with cholecalciferol had lower body weight and adipose tissue weight and higher expression of UCP3 compared to the other treatment groups. Changes in the expression of genes correlated with calcitriol/VDR. Luciferase activity was dose-dependently associated with calcitriol/VDR levels. We confirmed the functional VDR binding site consensus sequences at -2200, -1561, -634, and +314 bp in the UCP3 promoter region. CONCLUSION: We suggest that VD3/VDR inhibits weight gain by activating UCP3 in the muscles.
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Calcitriol/farmacologia , Colecalciferol/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas Musculares/biossíntese , Músculo Esquelético/metabolismo , Obesidade/metabolismo , Receptores de Calcitriol/metabolismo , Proteína Desacopladora 3/biossíntese , Animais , Gorduras na Dieta/efeitos adversos , Gorduras na Dieta/farmacologia , Masculino , Camundongos , Proteínas Musculares/genética , Músculo Esquelético/patologia , Obesidade/induzido quimicamente , Obesidade/genética , Obesidade/patologia , Receptores de Calcitriol/genética , Proteína Desacopladora 3/genéticaAssuntos
Temperatura Baixa , Gelo , Urticária/sangue , Urticária/diagnóstico , Adulto , Feminino , HumanosAssuntos
Antialérgicos/uso terapêutico , Basófilos/efeitos dos fármacos , Omalizumab/uso terapêutico , Hipersensibilidade a Trigo/tratamento farmacológico , Adulto , Idoso , Antialérgicos/farmacologia , Basófilos/imunologia , Feminino , Gliadina/imunologia , Humanos , Imunoglobulina E/imunologia , Pessoa de Meia-Idade , Omalizumab/farmacologia , Proteínas de Plantas/imunologia , Triticum/imunologia , Hipersensibilidade a Trigo/imunologiaRESUMO
Background: Obesity is closely associated with several chronic diseases, and adipose tissue plays a major role in modulating energy metabolism. Objective: This study aimed to determine whether Mate, derived from I. paraguariensis A.St.-Hil., ameliorates lipid metabolism in 3T3-L1 adipocytes and high-fat diet (HFD)-fed obese Sprague-Dawley (SD) rats. Design: 3T3-L1 adipocytes were cultured for 7 days, following which intracellular lipid accumulation and expression levels of lipid metabolism-related factors were examined. Dorsomorphin was used to investigate the potential pathways involved, particularly the adenosine monophosphate-activated protein kinase (AMPK)- dependent pathway. Mate was administered to rat HFD-fed obese SD models for 8 consecutive weeks. The expression of lipid metabolism-related factors in the organs and tissues collected from dissected SD rats was evaluated. Results: Mate suppressed intracellular lipid accumulation in 3T3-L1 adipocytes, increased the protein and gene expression levels of AMPK, hormone sensitive lipase (HSL), calmodulin kinase kinase (CaMKK), liver kinase B1 (LKB1), protein kinase A (PKA), CCAAT/enhancer binding protein ß (C/EBPß), insulin receptor b (IRß), and insulin receptor substrate 1 (IRS1) (Tyr465), and decreased those of sterol regulatory element binding protein 1C (Srebp1c), fatty acid synthase (FAS), peroxisome-activated receptor γ (PPARγ), and IRS1 (Ser1101). Furthermore, an AMPK inhibitor abolished the effects exerted by Mate on intracellular lipid accumulation and HSL and FAS expression levels. Mate treatment suppressed body weight gain and improved serum cholesterol levels in HFD-fed obese SD rats. Treatment with Mate increased the protein and gene expression levels of AMPK, PKA, Erk1/Erk2 (p44/p42), and uncoupling protein 1 and reduced those of mammalian target of rapamycin, S6 kinase, Srebp1c, ap2, FAS, Il6, Adiponectin, Leptin, and Fabp4 in rat HFD-fed obese SD models. Discussion and conclusions: Mate suppressed intracellular lipid accumulation in 3T3-L1 adipocytes and improved lipid metabolism in the epididymal adipose tissue of HFD-fed obese SD rats via the activation of AMPK-dependent and insulin signaling pathways.
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OBJECTIVES: Adalimumab, a fully human anti-tumor necrosis factor monoclonal antibody, was retrospectively evaluated for its effect on musculoskeletal manifestations and health-related quality of life in patients with psoriatic arthritis (PsA) during daily clinical practice. METHODS: Patients who initiated adalimumab therapy after March 2010 were followed for at least 24 weeks with the clinical outcome measures. Eleven patients, all men with a mean age of 45.4 years, had mean psoriasis durations of 16.2 and 8.4 years at baseline. RESULTS: After 24 weeks, 72.7, 63.6, and 45.5 % of the patients met the ACR 20, 50, and 70 response criteria, respectively, while 81.8 % achieved the PsA response criteria. Disease Activity Score using the 28-joint count and CRP declined from 3.2 ± 1.2 at baseline to 1.3 ± 0.4 at week 24 (P < 0.01). The Bath Ankylosing Spondylitis Disease Activity Index and Bath Ankylosing Spondylitis Functional Index scores also decreased significantly (both P values were <0.01). After 24 weeks, three out of eight dimensions of the Medical Outcomes Study 36-Item Short Form Health Survey and Physical Component Summary were significantly improved (all P values were <0.05). CONCLUSIONS: Adalimumab exerted its effect as early as week 4, and it was sustained until the end of the 24-week observation period in the PsA patients.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Psoriásica/tratamento farmacológico , Espondilite Anquilosante/tratamento farmacológico , Adalimumab , Adulto , Artrite Psoriásica/psicologia , Avaliação da Deficiência , Nível de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Estudos Retrospectivos , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
Numerous clinical trials of sirolimus, an inhibitor of mechanistic/mammalian target of rapamycin complex 1, for the treatment of vascular malformations have been conducted. However, aside from lymphatic malformations, the efficacy of sirolimus for venous and capillary malformations has not been established. Moreover, no generalized venous or capillary malformations have been treated with topical sirolimus. To evaluate the safety and efficacy of topical sirolimus for venous and capillary malformations and to compare the efficacy of topical and systemic sirolimus therapy, an open-label single-arm pilot study with 0.2% sirolimus gel was conducted from July 19, 2019, to January 30, 2020, in four patients diagnosed with different vascular malformations (blue rubber bleb nevus syndrome, common venous malformation, phakomatosis pigmentovascularis type IVb, and angiokeratoma in Fabry disease). The primary endpoint was the safety evaluation of sirolimus gel. The main secondary endpoint was the improvement rate evaluated by the Central Judgment Committee at 12 weeks using photographs. No adverse events were observed. Blood sirolimus was not detected in any patient. Two patients (50%) had mild improvement, and the remaining two patients (50%) showed no change after 12 weeks of treatment. Blue rubber bleb nevus syndrome, a generalized venous malformation, showed the greatest response. In conclusion, 0.2% sirolimus gel was found to be as clinically effective as systemic sirolimus treatment in patients with venous and capillary malformations and more effective for early active lesions, even systemic venous malformations.
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Nevo Azul , Neoplasias Cutâneas , Malformações Vasculares , Humanos , Sirolimo , Projetos Piloto , Imunossupressores/uso terapêutico , Neoplasias Cutâneas/diagnóstico , Nevo Azul/diagnóstico , Malformações Vasculares/tratamento farmacológicoRESUMO
Pustulotic arthro-osteitis (PAO) is a rare chronic inflammatory arthropathy associated with palmoplantar pustulosis. The pathogenesis of PAO remains unclear. The most common musculoskeletal involvement in PAO is ossification of the sternoclavicular joints. A combination of parietal inflammation and hyperostosis-induced mechanical compression in this region is hypothesized to contribute to multiple venous thrombosis. Here, we present a 66-year-old man with PAO-associated multiple venous occlusion who was successfully treated with guselkumab. We also discuss its clinical manifestation and cause by reviewing the literature.
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Osteíte , Psoríase , Dermatopatias Vesiculobolhosas , Doenças Vasculares , Masculino , Humanos , Idoso , Osteíte/etiologia , Psoríase/complicações , Psoríase/diagnóstico , Psoríase/tratamento farmacológico , Inflamação , Dermatopatias Vesiculobolhosas/complicações , Doença Aguda , Doença CrônicaRESUMO
Plasmalogen, a phospholipid, exhibits preventive and therapeutic effects on dementia. Phospholipids improve fat metabolism, but it is unknown whether plasmalogen has an effect on fat metabolism. In this study, the effects of plasmalogen were determined by administering plasmalogen to KK-Ay mice. As a result, weight gain was significantly suppressed in the plasmalogen-treated group compared with the control group from 7 wk after the start of administration. In addition, plasmalogen administration increased uncoupling protein 1 (UCP1) expression in brown adipose tissue. The effect is thought to result from liver kinase B1 (LKB1)/AMP-activated protein kinase (AMPK)/PR domain containing 16 (PRDM16)/peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) pathway activation via adrenergic ß3 receptors. Furthermore, the expression of the carnitine palmitoyltransferase-1 (CPT-1) gene associated with thermogenic factors and ß-oxidation was increased. We investigated the browning of white adipose tissue, but no increase in UCP1 gene expression was observed in perirenal adipose tissue, epididymis adipose tissue, mesenteric adipose tissue and inguinal region white adipose tissue. In contrast, plasmalogen increased the activity of AMPK, which is a central enzyme in lipid metabolism, in perirenal adipose tissue. Furthermore, the activity of the protein kinase A (PKA)/LKB1/AMPK/acetyl-coenzyme A carboxylase (ACC), stearoyl-CoA desaturase-1 (SCD-1), and hormone-sensitive lipase (HSL) pathways was confirmed. Plasmalogen may inhibit weight gain by activating brown fat to increase heat production, inhibiting lipid synthesis, and promoting lipolysis in white fat.
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Tecido Adiposo Marrom , Plasmalogênios , Proteínas Quinases Ativadas por AMP/metabolismo , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Masculino , Camundongos , Plasmalogênios/metabolismo , Plasmalogênios/farmacologia , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo , Aumento de PesoRESUMO
Excess body weight and hyperlipidaemia cause severe health problems and have social implications. Amycenone is an active substance extracted from Yamabushitake mushrooms with no reports of its activity against excess body weight and hyperlipidaemia. This research clarifies the effects and mechanisms of action of amycenone on the inhibition of body weight excess and hyperlipidaemia attenuation using KK-Ay mice. Amycenone or water was administered to 8-week-old male KK-Ay mice by gavage for 8 weeks. Their body weight and food intake were recorded during the experiment. At the end of the experimental period, the mice were dissected, and blood samples, lipid metabolism-related organs and tissues were collected and stored for further analysis. Amycenone treatment suppressed body weight gain and improved serum levels of fasting blood glucose and non-esterified fatty acids. Additionally, serum and hepatic cholesterol and triacylglycerol levels were reduced after this treatment, whereas the phosphorylation levels of AMPK, PKA and HSL increased and the expression level of FAS decreased. The protein level of C/EBPß and gene expression level of Cpt1 were higher in the perirenal adipose tissue of amycenone-treated KK-Ay mice. Furthermore, amycenone phosphorylated AMPK, PKA and ACC, and PPARγ expression was lower in the mesenteric adipose tissue. The phosphorylation levels of AMPK, LKB1, PKA and ACC were also induced, and FAS expression level was reduced in the liver of the amycenone-treated group. Amycenone could reduce excess body weight and attenuate hyperlipidaemia in KK-Ay mice by inhibiting lipogenesis and promoting lipolysis through lipid metabolism pathway stimulation and fatty acid ß-oxidation acceleration.
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Diabetes Mellitus Experimental , Hiperlipidemias , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Peso Corporal , Ácidos Graxos , Hiperlipidemias/tratamento farmacológico , Lipogênese , Lipólise , Masculino , Camundongos , Camundongos Obesos , Obesidade/tratamento farmacológico , Extratos VegetaisRESUMO
BACKGROUND: Body weight gain is a social issue all over the world. When body weight increased, hepatic fat accumulation also increased and it causes fatty liver disease. Therefore, developing a new treatment method and elucidating its mechanism is necessary. L-citrulline (L-Cit) is a free amino acid found mainly in watermelon. No reports regarding its effects on the improvement of hepatic steatosis and fibrogenesis are currently available. The aim of this study was to clarify the effect and the mechanism of L-Cit on inhibition of body weight gain and hepatic fat accumulation in high-fat and high-cholesterol fed SHRSP5/Dmcr rats. METHODS: L-Cit or water (controls) was administered to six-week-old male SHRSP5/Dmcr rats by gavage for nine weeks. We recorded the level of body weight and food intake while performing the administration and sacrificed rats. After that, the blood and lipid metabolism-related organs and tissues were collected and analyzed. RESULTS: L-Cit treatment reduced body weight gain and hepatic TC and TG levels, and serum levels of AST and ALT. L-Cit enhanced AMPK, LKB1, PKA, and hormone-sensitive lipase (HSL) protein phosphorylation levels in the epididymal fat. L-Cit treatment improved steatosis as revealed by HE staining of liver tissues and enhanced AMPK and LKB1 phosphorylation levels. Moreover, activation of Sirt1 was higher, while the liver fatty acid synthase (FAS) level was lower. Azan staining of liver sections revealed a reduction in fibrogenesis following L-Cit treatment. Further, the liver levels of TGF-ß, Smad2/3, and α-SMA, fibrogenesis-related proteins and genes, were lower in the L-Cit-treated group. CONCLUSIONS: From the results of analysis of the epididymal fat and the liver, L-Cit inhibits body weight gain and hepatic fat accumulation by activating lipid metabolism and promoting fatty acid ß-oxidation in SHRSP5/Dmcr rats.
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Background: Pre-clinical research studies have shown that Madecassoside (MA) has favorable therapeutic effects on arthritis, acne, vitiligo and other diseases. However, the effects of MA on obesity have not yet been studied. This study mainly aimed to investigate the effects of MA in protecting against obesity and its underlying mechanism in reducing obesity. Methods: Obese diabetic KKay/TaJcl mice model was adopted to the study. The body weight of all animals was recorded daily, and the blood glucose, blood lipid, and serum aminotransferase levels were examined, respectively. The expression of P-AMPK, SIRT1, P-LKB1, P-ACC, and P-HSL in abdominal fat, mesenteric fat, and epididymal fat was measured by western blotting, and the levels of PPARα, CPT1a, PGC-1α, UCP-1, Cidea, Cox7a1, and Cox8b were examined by real-time quantitative PCR (RT-qPCR). Results: The results revealed that the body weight of the mice in MA group was significantly reduced, and the body mass index (BMI) showed significant difference between the two groups after 8 weeks of MA treatment. Further research revealed that it affected the mesenteric fat and epididymis fat by activating SIRT1/AMPK signaling pathway, and then promoted fatty acid oxidation of epididymal fat (PPARα ↑, CPT1a↑, and PGC-1α↑). Last but not the least, it also promoted the expression of UCP-1 and stimulated thermoregulatory genes (Cidea, Cox7a1, and Cox8b) in brown fat and mesenteric fat. Conclusions: Taken together, these findings suggest that MA can inhibit the weight gain in obese diabetic mice, and reduce triglyceride levels, inhibit lipogenesis of mesenteric fat, promote epididymal fat lipolysis and fatty acid oxidation. Furthermore, MA treatment might promote mesenteric fat browning and activate mitochondrial function in brown fat as well as mesenteric fat.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Regulação da Expressão Gênica , Transdução de Sinais , Sirtuína 1/metabolismo , Termogênese/genética , Triterpenos/farmacologia , Aumento de Peso/genética , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Marrom/metabolismo , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Glicemia/metabolismo , Índice de Massa Corporal , Carboidratos , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Epididimo/efeitos dos fármacos , Epididimo/metabolismo , Ácido Graxo Sintases/genética , Ácido Graxo Sintases/metabolismo , Ácidos Graxos/metabolismo , Comportamento Alimentar/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Lipólise/efeitos dos fármacos , Lipólise/genética , Masculino , Mesentério/metabolismo , Camundongos , Tamanho do Órgão/efeitos dos fármacos , Oxirredução , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais/efeitos dos fármacos , Termogênese/efeitos dos fármacos , Triglicerídeos/sangue , Aumento de Peso/efeitos dos fármacosRESUMO
BACKGROUND: Recent studies have demonstrated that genes related to bitter taste receptors (TAS2Rs) on various chromosomes are expressed in extra-oral organs of various animals. The bitter taste receptor TAS2R14 is conserved among primate species and shows broad ligand sensitivity. Mice have a number of orthologues to primate TAS2R14 located in tandem on chromosome 16; however, their expression patterns are not unique. OBJECTIVE: We characterized the expression of TAS2R14 in various cell types in the intestines of the rhesus macaque and evaluated its role in hormone production in the gut. METHODS: TAS2R14 expression was examined in the intestines of rhesus macaques, a common non-human primate model, by RT-qPCR and immunohistochemical staining. RESULTS: Mean expression levels of TAS2R14 in the duodenum, ileum, and colon were similar to each other and were lower than those in circumvallate papillae. An immunohistochemical analysis revealed TAS2R14 immunoreactivity in enteroendocrine cells positive for cholecystokinin, serotonin, and the G protein GNAT3. CONCLUSION: These results suggest that primate TAS2R14 is broadly expressed in the intestine, mainly in enteroendocrine cells, and promotes gut hormone secretion in response to bitter stimuli.