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Endometriosis (EMS) is a chronic benign inflammatory disease characterized by the growth of endometrial-like tissue in aberrant locations outside of the uterine cavity. Angiogenesis and abnormal immune responses are the fundamental requirements of endometriotic lesion survival in the peritoneal cavity. Follistatin-like I (FSTL1) is a secreted glycoprotein that exhibits varied expression levels in cardiovascular disease, cancer and arthritis. However, the role of FSTL1 in the development of EMS remains to be fully elucidated. Results of the present study demonstrated that the expression of FSTL1 was significantly increased in ectopic endometrial stromal cells (ESCs) and peritoneal fluid from patients with EMS, compared to the control group. Both conditions of hypoxia and estrogen treatment induced human ESCs to produce increased levels of FSTL1 and disco-interacting protein 2 homolog A (DIP2A). Furthermore, the expression levels of DIP2A, IL8 and IL1ß were increased in FSTL1 overexpressed HESCs. Additionally, FSTL1 treatment increased the proliferation of HUVECs in a dose-dependent manner in vitro and markedly increased the tube formation of HUVECs. Moreover, treatment with FSTL1 facilitated M1 polarization of macrophages, increased the secretion of proinflammatory factors and inhibited the expression of scavenger receptor CD36. Results of the present study suggested that the elevated expression of FSTL1 may play a key role in accelerating the development of EMS via enhancing the secretion of proinflammatory factors and promoting angiogenesis.
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Endometriose , Proteínas Relacionadas à Folistatina , Endometriose/patologia , Endométrio/patologia , Feminino , Folistatina , Proteínas Relacionadas à Folistatina/genética , Proteínas Relacionadas à Folistatina/metabolismo , Proteínas Relacionadas à Folistatina/farmacologia , Humanos , Neovascularização Patológica/patologiaRESUMO
The corticotropin-releasing hormone (CRH) family is widely distributed among the central nervous system and peripheral tissues, such as the digestive, cardiovascular, immune, reproductive, endocrine systems. The CRH family members are widely involved in the regulation of human cell biological processes, immune response, and regulation of inflammatory processes that can affect the occurrence and development of tumors. At present, CRH family members and their receptors can be detected in many tumor tissues, and some people think that members of the CRH family may be potential tumor treatment targets as they can affect cellular processes, such as proliferation, migration, invasion, and apoptosis. However currently, there is no systematic introduction to the relationship between the CRH family and various tumors. This review introduces the molecular regulation of the CRH family in tumor formation and seeks further targeted therapy.
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Hormônio Liberador da Corticotropina , Neoplasias , Apoptose , Humanos , Receptores de Hormônio Liberador da CorticotropinaRESUMO
Bile acid (BA) signaling regulates fatty acid metabolism. BA dysregulation plays an important role in the development of metabolic disease. However, BAs in relation to fatty acids have not been fully investigated in obesity-related metabolic disorders. A targeted metabolomic measurement of serum BA and free fatty acid profiles was applied to sera of 381 individuals in 2 independent studies. The results showed that the ratio of dihomo-γ-linolenic acid (DGLA) to deoxycholic acid (DCA) species (DCAS) was significantly increased in obese individuals with type 2 diabetes (T2DM) from a case-control study and decreased in the remission group of obese subjects with T2DM after metabolic surgery. The changes were closely associated with their metabolic status. These results were consistently confirmed in both serum and liver of mice with diet-induced obesity, implying that such a metabolic alteration in circulation reflects changes occurring in the liver. In vitro studies of human liver L-02 cell lines under BA treatment revealed that DCA and its conjugated form, TDCA, significantly inhibited mRNA expression of fatty acid transport protein 5 in the presence of DGLA, which was involved in hepatocyte DGLA uptake. Thus, the DGLA:DCAS ratio may be a promising biomarker for metabolic abnormalities in obesity.-Lei, S., Huang, F., Zhao, A., Chen, T., Chen, W., Xie, G., Zheng, X., Zhang, Y., Yu, H., Zhang, P., Rajani, C., Bao, Y., Jia, W., Jia, W. The ratio of dihomo-γ-linolenic acid to deoxycholic acid species is a potential biomarker for the metabolic abnormalities in obesity.
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Ácido 8,11,14-Eicosatrienoico/metabolismo , Ácido Desoxicólico/metabolismo , Obesidade/sangue , Adulto , Animais , Biomarcadores , Linhagem Celular , Ácido Desoxicólico/química , Dieta Hiperlipídica/efeitos adversos , Feminino , Teste de Tolerância a Glucose , Hepatócitos/metabolismo , Humanos , Resistência à Insulina , Masculino , CamundongosRESUMO
BACKGROUND: Intestinal bacteria are known to regulate bile acid (BA) homeostasis via intestinal biotransformation of BAs and stimulation of the expression of fibroblast growth factor 19 through intestinal nuclear farnesoid X receptor (FXR). On the other hand, BAs directly regulate the gut microbiota with their strong antimicrobial activities. It remains unclear, however, how mammalian BAs cross-talk with gut microbiome and shape microbial composition in a dynamic and interactive way. RESULTS: We quantitatively profiled small molecule metabolites derived from host-microbial co-metabolism in mice, demonstrating that BAs were the most significant factor correlated with microbial alterations among all types of endogenous metabolites. A high-fat diet (HFD) intervention resulted in a rapid and significant increase in the intestinal BA pool within 12 h, followed by an alteration in microbial composition at 24 h, providing supporting evidence that BAs are major dietary factors regulating gut microbiota. Feeding mice with BAs along with a normal diet induced an obese phenotype and obesity-associated gut microbial composition, similar to HFD-fed mice. Inhibition of hepatic BA biosynthesis under HFD conditions attenuated the HFD-induced gut microbiome alterations. Both inhibition of BAs and direct suppression of microbiota improved obese phenotypes. CONCLUSIONS: Our study highlights a liver-BA-gut microbiome metabolic axis that drives significant modifications of BA and microbiota compositions capable of triggering metabolic disorders, suggesting new therapeutic strategies targeting BA metabolism for metabolic diseases.
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Ácidos e Sais Biliares/metabolismo , Microbioma Gastrointestinal/fisiologia , Isoxazóis/farmacologia , Receptores Citoplasmáticos e Nucleares/agonistas , Animais , Ácidos e Sais Biliares/administração & dosagem , Dieta Hiperlipídica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Transdução de SinaisRESUMO
This study aimed to observe the general state and changes in pathophysiological indexes of multiple cerebral infarction rat model with Qi-deficienty and Blood-stasis syndrome. Rats were randomly divided into 4 groups(with 30 in each group): the normal group, the sham group, the model group and the Yiqi Huoxue recipe group. Rats in the model group and Yiqi Huoxue group were provided with interruptable sleep deprivation for 7 days before the multiple cerebral infarction operation, and followed by another 4 weeks of sleep deprivation; rats in the Yiqi Huoxue group were intragastrically administrated with drug at a dose of 26 g·kg⻹, once a day for 4 weeks. The general state was observed, and the pathophysiological indexes were measured at 48 h, 2 weeks and 4 weeks after administration. The results showed that rats in the normal group and the sham group represented a good general state and behaviors, with a normal morphological structure of brain tissues; rats in the model group featured yellow fur, depression, accidie, loose stools and movement disorder, with obvious brain histomorphological damage, which became aggravated with the increase of modeling time; rats in the Yiqi Huoxue group showed release in the general state and above indexes. Compared with the sham group at three time points, rats in the model group showed decrease in body weight, exhaustive swimming time and RGB value of tongue surface image, and increase in whole blood viscosity of the shear rate under 5, 60 and 150 S⻹, reduction in cerebral cortex Naâº-Kâº-ATPase, Ca²âº-ATPase activity and contents of 5-HT, rise in TXB2 levels and decline in 6-keto-PGF1a in serum(P<0.05, P<0.01). Compared with the model group, rats in the Yiqi Huoxue group showed alleviations in the above indexes at 2 w and 4 w(P<0.05, P<0.01). The results showed that the characterization and pathophysiological indexes in the multiple cerebral infarction rat model with Qi-deficiency and blood-stasis syndrome were deteriorated; Yiqi Huoxue recipe could significantly alliviate the abnormal conditions, which suggested of the model was stable and reliable and the pathophysiologic evolutionary mechanism might be related to energy metabolism dysfunction, vasoactive substance abnormality and changes in neurotransmitters.
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Infarto Cerebral/fisiopatologia , Medicamentos de Ervas Chinesas/farmacologia , Metabolismo Energético , Animais , ATPases Transportadoras de Cálcio/metabolismo , Medicina Tradicional Chinesa , Qi , Ratos , ATPase Trocadora de Sódio-Potássio/metabolismoRESUMO
Dysregulated bile acids (BAs) are closely associated with liver diseases and attributed to altered gut microbiota. Here, we show that the intrahepatic retention of hydrophobic BAs including deoxycholate (DCA), taurocholate (TCA), taurochenodeoxycholate (TCDCA), and taurolithocholate (TLCA) were substantially increased in a streptozotocin and high fat diet (HFD) induced nonalcoholic steatohepatitis-hepatocellular carcinoma (NASH-HCC) mouse model. Additionally chronic HFD-fed mice spontaneously developed liver tumors with significantly increased hepatic BA levels. Enhancing intestinal excretion of hydrophobic BAs in the NASH-HCC model mice by a 2% cholestyramine feeding significantly prevented HCC development. The gut microbiota alterations were closely correlated with altered BA levels in liver and feces. HFD-induced inflammation inhibited key BA transporters, resulting in sustained increases in intrahepatic BA concentrations. Our study also showed a significantly increased cell proliferation in BA treated normal human hepatic cell lines and a down-regulated expression of tumor suppressor gene CEBPα in TCDCA treated HepG2 cell line, suggesting that several hydrophobic BAs may collaboratively promote liver carcinogenesis.
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Ácidos e Sais Biliares/metabolismo , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/metabolismo , Animais , Carcinogênese/metabolismo , Carcinogênese/patologia , Linhagem Celular , Ácido Desoxicólico/metabolismo , Dieta Hiperlipídica , Feminino , Microbioma Gastrointestinal , Células Hep G2 , Humanos , Neoplasias Hepáticas/microbiologia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas Experimentais/etiologia , Neoplasias Hepáticas Experimentais/metabolismo , Neoplasias Hepáticas Experimentais/microbiologia , Neoplasias Hepáticas Experimentais/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/microbiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Gravidez , Estreptozocina , Ácido Tauroquenodesoxicólico/metabolismo , Ácido Taurocólico/metabolismo , Ácido Taurolitocólico/metabolismoRESUMO
The presence of extensive infiltrated macrophages with impaired phagocytosis is widely recognised as a significant regulator for the development of endometriosis (EMs). Nevertheless, the metabolic characteristics and the fundamental mechanism of impaired macrophage phagocytosis are yet to be clarified. Here, we observe that there is the decreased expression of haematopoietic cellular kinase (HCK) in macrophage of peritoneal fluid from EMs patients, which might be attributed to high oestrogen and hypoxia condition. Of note, HCK deficiency resulted in impaired macrophage phagocytosis, and increased number and weight of ectopic lesions in vitro and in vivo. Mechanistically, this process was mediated via regulation of glutamine metabolism, and further upregulation of macrophage autophagy in a c-FOS/c-JUN dependent manner. Additionally, macrophages of EMs patients displayed insufficient HCK, excessive autophagy and phagocytosis dysfunction. In therapeutic studies, supplementation with glutamine-pre-treated macrophage or Bafilomycin A1 (an autophagy inhibitor)-pre-treated macrophage leads to the induction of macrophage phagocytosis and suppression of EMs development. This observation reveals that the aberrant HCK-glutamine-autophagy axis results in phagocytosis obstacle of macrophage and further increase the development risk of Ems. Additionally, it offers potential therapeutic approaches to prevent EMs, especially patients with insufficient HCK and macrophage phagocytosis dysfunction.
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American mink (Neovison vison) develop fatty liver quickly in response to food deprivation, which results in preferential mobilisation of n-3 PUFA. The altered n-3:n-6 PUFA ratio in the liver may activate the endocannabinoid system resulting in increased lipid synthesis. The objective of the present study was to investigate the effects of feeding intensity (80 or 120% RDA), dietary fat source (n-3, n-6 or n-9 fatty acids (FA)) and short-term fasting (1-7 d) on hepatic de novo lipogenesis (DNL) and the development of fatty liver in mink. Significantly elevated expression of mRNA encoding for acetyl-CoA carboxylase-1 (ACC-1) and FA synthase (FAS) was observed in the liver of mink fasted for 5-7 d, while upon re-feeding for 28 d after a 7 d food deprivation, DNL returned to pre-fasting levels. The females had a higher expression of ACC-1 and FAS mRNA than the males. In the non-fasted animals, dietary fat source and feeding intensity had significant effects on ACC-1 mRNA. The highest levels were observed in the mink fed the rapeseed oil (n-9) diet at 80% RDA, while the lowest levels were seen when the same diet was fed at 120% RDA. For FAS, the highest gene expression was seen in the fasted mink fed at 80% RDA and the lowest in the non-fasted mink fed at 80%. It is concluded that short-term food deprivation induces hepatic lipidosis in mink and that during this process, hepatic DNL further exacerbates liver fat accumulation.
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Gorduras na Dieta/farmacologia , Ingestão de Energia , Jejum/fisiologia , Fígado Gorduroso/etiologia , Lipogênese/efeitos dos fármacos , Fígado/efeitos dos fármacos , Óleos de Plantas/farmacologia , Acetil-CoA Carboxilase/genética , Acetil-CoA Carboxilase/metabolismo , Fenômenos Fisiológicos da Nutrição Animal/genética , Animais , Gorduras na Dieta/administração & dosagem , Gorduras na Dieta/metabolismo , Ácido Graxo Sintases/genética , Ácido Graxo Sintases/metabolismo , Ácidos Graxos Monoinsaturados , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Feminino , Privação de Alimentos , Expressão Gênica/efeitos dos fármacos , Lipidoses , Fígado/metabolismo , Masculino , Vison , Política Nutricional , Óleos de Plantas/administração & dosagem , Óleos de Plantas/metabolismo , RNA Mensageiro/metabolismo , Óleo de Brassica napus , Fatores SexuaisRESUMO
Endometriosis (EMs) is characterized as an estrogen-dependent disease. Whereas, the underlying mechanism for activated estrogen biosynthesis in EMs lesions is largely unknown. We analyzed cholesterol metabolism and estrogen biosynthesis condition of EMs lesions by biological information analysis of GEO datasets, and further verified both in vitro and in vivo by constructing EMs models with uterus fragments from donors of PRNP knockout mouse (Prnp-/-, KO119), Octapeptide repeat region of PRNP knockout mouse (KO120) and PRNP transgenic mouse (Tg20). We found that transcriptome of cholesterol metabolism and estrogen-converting enzymes were disturbed in EMs patients, and cellular cholesterol concentration and local estradiol level were substantially increased in EMs lesions, as well as the high level of prion (PrPC, encoded by PRNP). Notably, 17-ß estradiol stimulation significantly up-regulated PrPC expression in endometrial stromal cells (ESC) and PrPC promoted the proliferative, migratory and invasive abilities of ESC, and was further verified to accelerate EMs progression in mouse models. More importantly, PrPC promoted cholesterol accumulation and activated estrogen biosynthesis of ESC in a PPARα pathway-dependent manner. Taken together, this study suggests that PrPC-cholesterol metabolism/estrogen biosynthesis contributes to the progression of EMs by negatively regulating PPARα pathway, and could be potential therapeutic targets for EMs intervention.
Assuntos
Endometriose , Animais , Endometriose/genética , Endometriose/metabolismo , Estradiol , Estrogênios/metabolismo , Feminino , Humanos , Camundongos , PPAR alfa/metabolismo , Células Estromais/metabolismoRESUMO
Purpose: This study aims to investigate the renal protective effect of glucagon-like peptide 1 receptor agonist (GLP-1RA) on improving renal tubular damage in diabetic kidney disease (DKD) and to explore the potential mechanism of GLP-1RA on renal tubular protection. Methods: Long-acting GLP-1RA was used to treat DKD mice for 12 weeks. The label-free quantitative proteomic analysis of renal proteins was conducted to explore the differentially expressed proteins (DEPs) in the renal tissues of the control, DKD and GLP-1RA groups. The DEPs and markers of renal tubular injury were verified by qPCR in vivo and in vitro. The expression of glucagon-likepeptide-1 receptor (GLP-1R) in renal tubules was determined by immunofluorescence staining. Results: GLP-1RA treatment significantly improved the tubular damages in kidney tissues of DKD mice and mTEC cells stimulated by high glucose (HG). Proteomics analysis revealed that 30 proteins in kidney tissue were differentially expressed among three groups. Seminal vesicle secretory protein 6 (SVS6) was the most differentially expressed protein in kidney tissues among three groups of mice. The expression changes of Svs6 mRNA in vitro and in vivo detected by qPCR were consistent with the results of proteomic analysis. Furthermore, reduction of Svs6 expression by SVS6 siRNA could attenuate HG-stimulated tubular injury in mTEC cells. Immunofluorescence staining also found that GLP-1R was widely expressed in renal tubules in vitro and in vivo. Conclusion: GLP-1RA significantly improved renal tubular damage in DKD mice. SVS6 may be a potential therapeutic target for GLP-1RA in the treatment of DKD.
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Objective: To identify an efficacious intervention on treating adolescents with overweight and obesity, this might result in health benefits. Methods: Adolescents with overweight or obesity aged 10-17 years with BMI percentile ≥85th were included in this historical observational analysis. Subjects used an entirely remote weight loss program combining mobile applications, frequent self-weighing, and calorie restriction with meal replacement. Body weight changes were evaluated at 42, 60, 90, and 120 days using different metrics including absolute body weight, BMI, and BMI z-score. Chi-square or Fisher exact tests (categorical variables) and Student's t-test (continuous variables) were used to compare subjects. Results: In total, 2,825 participants, mean age 14.4 ± 2.2 years, (54.8% girls), were included from October 27, 2016, to December 31, 2017, in mainland China; 1355 (48.0%) had a baseline BMI percentile ≥97th. Mean BMI and BMI z-score were 29.20 ± 4.44 kg/m2 and 1.89 ± 0.42, respectively. At day 120, mean reduction in body weight, BMI, and BMI z-score was 8.6 ± 0.63 kg, 3.13 ± 0.21 kg/m2, and 0.42 ± 0.03; 71.4% had lost ≥5% body weight, 69.4% of boys and 73.2% of girls, respectively. Compared with boys, girls achieved greater reduction on BMI z-score at all intervals (p < 0.004 for all comparisons). Higher BMI percentile at baseline and increased frequency of use of the mobile application were directly associated with more significant weight loss. Conclusions: An entirely remote digital weight loss program is effective in facilitating weight loss in adolescents with overweight or obesity in the short term and mid term.
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Obesidade Infantil , Programas de Redução de Peso , Adolescente , Índice de Massa Corporal , Criança , Feminino , Humanos , Masculino , Sobrepeso/epidemiologia , Sobrepeso/terapia , Obesidade Infantil/epidemiologia , Obesidade Infantil/prevenção & controle , Redução de PesoRESUMO
OBJECTIVES: Endometriosis (EMS) is a benign disease that is related to estrogen, immune disorders and inflammation. The purpose of this research was to determine the expression of CD200 in EMS and to clarify its role in the pathogenesis of the disease. METHODS: The levels of serum CD200 in patients with and without EMS were determined by ELISA. Furthermore, the expression of CD200 in normal eutopic endometrium and ectopic endometrium was detected by immunohistochemistry and western blotting. The CD200 receptor (CD200R) in macrophages in peritoneal fluid (pMØ) obtained from controls and patients with EMS was examined by western blotting. CD200 expression in human endometrial stromal cells (HESCs) stimulated with 17ß-estradiol (E2) was measured by western blotting. Furthermore, macrophages were stimulated with different concentrations of CD200 and the effect on phagocytosis was analyzed. RESULTS: The plasma CD200 levels of patients with EMS was significantly increased compared with controls (P = 0.0173, 95%CI [18.75, 159.6]). Compared with normal eutopic endometrium, the expression of CD200 was significantly increased in ectopic endometrial tissues. The CD200R expression in pMØ obtained from patients with EMS was increased compared with the controls (P = 0.0244). CD200 expression in HESCs stimulated with E2 was up-regulated. As the levels of CD200 increased, macrophage phagocytosis in vitro gradually decreased. CONCLUSIONS: CD200 is an estrogen-induced molecule that impairs macrophage phagocytosis and may contribute to the immune escape of ectopic lesions in EMS.
Assuntos
Antígenos CD/metabolismo , Endometriose/imunologia , Endométrio/patologia , Fagocitose/imunologia , Adolescente , Adulto , Estudos de Casos e Controles , Endometriose/patologia , Endometriose/cirurgia , Endométrio/citologia , Endométrio/imunologia , Endométrio/cirurgia , Estrogênios/metabolismo , Feminino , Humanos , Tolerância Imunológica , Macrófagos/imunologia , Células Estromais/metabolismo , Regulação para Cima , Adulto JovemRESUMO
T-type Ca(2+) currents have been detected in cells from the external muscular layers of gastrointestinal smooth muscles and appear to contribute to the generation of pacemaker potentials in interstitial cells of Cajal from those tissues. However, the Ca(2+) channel alpha subunit responsible for these currents has not been determined. We established that the alpha subunit of the alpha(1H) Ca(2+) channel is expressed in single myocytes and interstitial cells of Cajal using reverse transcription and polymerase chain reaction from whole tissue, laser capture microdissected tissue and single cells isolated from the mouse jejunum. Whole-cell voltage clamp recordings demonstrated that a nifedipine and Cd(2+) resistant, mibefradil-sensitive current is present in myocytes dissociated from the jejunum. Electrical recordings from the circular muscle layer demonstrated that mibefradil reduced the frequency and initial rate of rise of the electrical slow wave. Gene targeted knockout of both alleles of the cacna1h gene, which encodes the alpha(1H) Ca(2+) channel subunit, resulted in embryonic lethality because of death of the homozygous knockouts prior to E13.5 days in utero. We conclude that a channel with the pharmacological and molecular characteristics of the alpha(1H) Ca(2+) channel subunit is expressed in interstitial cells of Cajal and myocytes from the mouse jejunum, and that ionic conductances through the alpha(1H) Ca(2+) channel contribute to the upstroke of the pacemaker potential. Furthermore, the survival of mice that do not express the alpha(1H) Ca(2+) channel protein is dependent on the genetic background and targeting approach used to generate the knockout mice.
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Canais de Cálcio Tipo T/metabolismo , Células Intersticiais de Cajal/metabolismo , Jejuno/citologia , Células Musculares/metabolismo , Subunidades Proteicas/metabolismo , Animais , Canais de Cálcio Tipo T/genética , Cruzamentos Genéticos , Feminino , Feto/efeitos dos fármacos , Feto/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Genótipo , Células Intersticiais de Cajal/efeitos dos fármacos , Ativação do Canal Iônico/efeitos dos fármacos , Masculino , Mibefradil/farmacologia , Camundongos , Camundongos Knockout , Células Musculares/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Músculo Liso/metabolismo , Subunidades Proteicas/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
On 2 separate occasions at least 1 week apart, 6 independent observers studied errors in identification of the transepicondylar axis (TEA) using computed tomography in 10 cadaveric knees. The reference surgical TEA was established by dissection of specimens. We found an average error of 2.6 degrees (external rotation) when the TEA was identified by computed tomography. The error was significantly smaller when the TEA was identified by using a conventional axial image than when a 3-dimensional reconstruction image was used (P < .001, paired t test). No significant intraobserver error (P = .814, Wilcoxon rank test) was found when the measurement was performed using conventional 2-dimensional computed tomography images. However, significant interobserver difference was evident (P < .001, Friedman test).
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Fêmur/anatomia & histologia , Processamento de Imagem Assistida por Computador/estatística & dados numéricos , Imageamento Tridimensional/estatística & dados numéricos , Articulação do Joelho/anatomia & histologia , Artroplastia do Joelho , Fêmur/diagnóstico por imagem , Humanos , Articulação do Joelho/diagnóstico por imagem , Variações Dependentes do Observador , Radiografia , Tomógrafos ComputadorizadosRESUMO
BACKGROUND AND PURPOSE: Ursodeoxycholic acid (UDCA) is the first-line treatment for primary biliary cholangitis, but its effects on the enterohepatic circulation of bile acid (BA) have been under-investigated. Therefore, we studied the influence of UDCA on BA enterohepatic circulation in vivo and the mechanisms by which UDCA affects the BA kinetics. EXPERIMENTAL APPROACH: Mice were treated with UDCA and other BAs to observe changes in BA pool and BA transporters involved in enterohepatic circulation. Isotope dilution techniques and biochemical analyses were applied to study BA kinetics after oral administration of UDCA, and the mechanism involved. KEY RESULTS: Oral administration of UDCA in mice reduced the overall BA pool and produced a unique BA profile with high-abundance conjugated UDCA species, including tauroursodeoxycholic acid (TUDCA) and GUDCA. We found increased expression of several main BA transporters in the ileum and liver. BA kinetic experiment showed that feeding UDCA shortened cycling time of BA and accelerated BA enterohepatic circulation. Additionally, we found evidence that the effect of UDCA administration on accelerating BA enterohepatic circulation was due to the inhibition of farnesoid X receptor (FXR) signalling in the ileum and FGF15/19 in the liver. CONCLUSION AND IMPLICATIONS: Oral administration of UDCA produced a unique BA profile with high-abundance TUDCA and GUDCA and significantly accelerated BA enterohepatic circulation through the inhibition of intestinal FXR signalling and reduced level of FGF15/19, which in turn, induced the expression of BA transporters in the liver. These findings highlight a critical role for UDCA in maintaining the homeostasis of BA enterohepatic circulation in vivo.
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Fígado/metabolismo , Ácido Ursodesoxicólico/metabolismo , Animais , Proteínas de Transporte/metabolismo , Linhagem Celular , Fatores de Crescimento de Fibroblastos/metabolismo , Humanos , Íleo/metabolismo , Masculino , Glicoproteínas de Membrana/metabolismo , Camundongos Endogâmicos C57BL , Receptores Citoplasmáticos e Nucleares/metabolismoRESUMO
Pu-erh tea has been extensively reported to possess lipid lowering effects but the underlying mechanisms remained unclear. Free fatty acids (FFAs) are generally correlated with the development of obesity, leading to increased risk for type 2 diabetes mellitus and cardiovascular diseases. To investigate whether Pu-erh tea treatment alters FA metabolism, we treated HFD induced obese mice with Pu-erh tea for 22 weeks and analyzed FFA profiles of experimental mice using a UPLC-QTOF-MS platform. Results showed remarkable changes in metabolic phenotypes and FFA compositions in mice treated with or without Pu-erh tea. HFD induced a marked obese phenotype in mice as revealed by significantly increased body weight, liver and adipose tissue weight, lipid levels in serum and liver, and these parameters were markedly reduced by Pu-erh tea treatment. Several FFA or FFA ratios, such as DGLA, palmitoleic acid, and OA/SA ratio, were significantly increased while the levels of SA/PA and AA/DGLA were significantly reduced in HFD-induced obese mice. Interestingly, these differential FFAs or FFA ratios were previous identified as key markers in human obese subjects, and their changes observed in the HFD group were reversed by Pu-erh tea treatment. Moreover, a panel of FFA markers including C20:3 n6/C18:3 n6 and C20:3 n6/C20:2 n6, C18:3 n6/C18:2 n6, C18:3 n3/C18:2 n6 and C24:1 n9/C22:1 n9, which were previously identified as biomarkers in predicting the remission of obesity and diabetes in human subjects who underwent metabolic surgery procedures, were reversed by Pu-erh tea intervention. Pu-erh tea significantly improved glucose homeostasis and insulin tolerance compared to the HFD group. Additionally, Pu-erh tea treatment significantly decreased FFA synthesis genes and increased the expression of genes involved in FFA uptake and ß-oxidation including FATP2, FATP5, PPARα, CPT1α, and ACOX-1. These finding confirmed the beneficial effects of Pu-erh tea on regulating lipid and glucose metabolism, and further validated a panel of FFA markers with diagnostic and prognostic value for obesity and diabetes.
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PROBLEM: Decidual stromal cells (DSCs) are important origins of cytokines to modulate maternal-fetal immunotolerance and provide a feasible environment for embryo implantation and development. Interleukin (IL)-24 is a multifunctional cancer killing cytokine and a pleiotropic immunoregulator with complex potency according to tissue or cell types. Its role in establishment and maintenance of normal pregnancy is largely unknown. The aim of our study was to investigate the function and significance of IL-24 and its receptor in the coordination between DSCs and natural killer cells (NK) in early pregnancy. METHOD OF STUDY: The levels of IL-24 in DSC, endometrial stromal cell (ESC), peripheral blood NK cells (pNK), or decidual NK cells (dNK) culture supernatants were detected by enzyme-linked immunosorbent assay (ELISA), and the levels of IL-24 receptors were determined by real-time reverse transcriptase-polymerase chain reaction (RT-PCR) and flow cytometry assays. The effect of IL-24 on the functions of decidual NK cells was analyzed by flow cytometry assays in vitro. RESULTS: The concentration of IL-24 in culture supernatant of DSCs was significantly higher than that of ESCs. Both eNK (endometrial NK cells) and dNK highly expressed IL-24 receptors (IL-20R1 and IL-22R1), especially on CD56dim eNK. However, there were extremely low levels of IL-20R1 and IL-22R1 on pNK. Recombinant human IL-24 or DSCs-secreted IL-24 downregulated the levels of CD16, Granzyme B, perforin, and interferon (IFN)-γ and upregulated the levels of inhibitory receptors killer-cell immunoglobulin-like receptor (KIR)2DL1 and KIR3DL1, or immunotolerant or angiogenic cytokines (eg, transforming growth factor (TGF)-ß, IL-10, and IL-8), and elevated the percentage of CD56bright CD16- dNK in vitro. CONCLUSION: These data suggest that DSCs promote the differentiation of CD56bright CD16- NK with high levels of inhibitory receptors, immunotolerant, and angiogenic cytokines by secreting IL-24 during decidualization in early pregnancy.
Assuntos
Decídua/citologia , Interleucinas/imunologia , Células Matadoras Naturais/imunologia , Células Estromais/imunologia , Adulto , Antígeno CD56/imunologia , Diferenciação Celular , Células Cultivadas , Técnicas de Cocultura , Decídua/imunologia , Feminino , Humanos , Gravidez , Adulto JovemRESUMO
Pu-erh tea displays cholesterol-lowering properties, but the underlying mechanism has not been elucidated. Theabrownin is one of the most active and abundant pigments in Pu-erh tea. Here, we show that theabrownin alters the gut microbiota in mice and humans, predominantly suppressing microbes associated with bile-salt hydrolase (BSH) activity. Theabrownin increases the levels of ileal conjugated bile acids (BAs) which, in turn, inhibit the intestinal FXR-FGF15 signaling pathway, resulting in increased hepatic production and fecal excretion of BAs, reduced hepatic cholesterol, and decreased lipogenesis. The inhibition of intestinal FXR-FGF15 signaling is accompanied by increased gene expression of enzymes in the alternative BA synthetic pathway, production of hepatic chenodeoxycholic acid, activation of hepatic FXR, and hepatic lipolysis. Our results shed light into the mechanisms behind the cholesterol- and lipid-lowering effects of Pu-erh tea, and suggest that decreased intestinal BSH microbes and/or decreased FXR-FGF15 signaling may be potential anti-hypercholesterolemia and anti-hyperlipidemia therapies.
Assuntos
Ácidos e Sais Biliares/metabolismo , Catequina/análogos & derivados , Alimentos Fermentados , Microbioma Gastrointestinal/efeitos dos fármacos , Hipercolesterolemia/metabolismo , Chá , Adulto , Amidoidrolases/metabolismo , Animais , Catequina/farmacologia , Ácido Quenodesoxicólico/metabolismo , Colesterol/metabolismo , Dieta Hiperlipídica , Transplante de Microbiota Fecal , Fatores de Crescimento de Fibroblastos/efeitos dos fármacos , Fatores de Crescimento de Fibroblastos/metabolismo , Microbioma Gastrointestinal/genética , Microbioma Gastrointestinal/fisiologia , Humanos , Íleo/efeitos dos fármacos , Íleo/metabolismo , Lipogênese/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Metabolômica , Camundongos , Extratos Vegetais/farmacologia , RNA Ribossômico 16S , Receptores Citoplasmáticos e Nucleares/efeitos dos fármacos , Receptores Citoplasmáticos e Nucleares/metabolismo , Transdução de Sinais , Adulto JovemRESUMO
Emerging evidence points to a strong association between sex and gut microbiota, bile acids (BAs), and gastrointestinal cancers. Here, we investigated the mechanistic link between microbiota and hepatocellular carcinogenesis using a streptozotocin-high fat diet (STZ-HFD) induced nonalcoholic steatohepatitis-hepatocellular carcinoma (NASH-HCC) murine model and compared results for both sexes. STZ-HFD feeding induced a much higher incidence of HCC in male mice with substantially increased intrahepatic retention of hydrophobic BAs and decreased hepatic expression of tumor-suppressive microRNAs. Metagenomic analysis showed differences in gut microbiota involved in BA metabolism between normal male and female mice, and such differences were amplified when mice of both sexes were exposed to STZ-HFD. Treating STZ-HFD male mice with 2% cholestyramine led to significant improvement of hepatic BA retention, tumor-suppressive microRNA expressions, microbial gut communities, and prevention of HCC. Additionally the sex-dependent differences in BA profiles in the murine model can be correlated to the differential BA profiles between men and women during the development of HCC. These results uncover distinct male and female profiles for gut microbiota, BAs, and microRNAs that may contribute to sex-based disparity in liver carcinogenesis, and suggest new possibilities for preventing and controlling human obesity-related gastrointestinal cancers that often exhibit sex differences.
Assuntos
Bactérias/classificação , Carcinoma Hepatocelular/microbiologia , Dieta Hiperlipídica/efeitos adversos , Neoplasias Hepáticas/microbiologia , Metagenômica/métodos , Hepatopatia Gordurosa não Alcoólica/microbiologia , Estreptozocina/efeitos adversos , Animais , Ácidos e Sais Biliares/metabolismo , Carcinoma Hepatocelular/induzido quimicamente , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Resina de Colestiramina/farmacologia , Resina de Colestiramina/uso terapêutico , Modelos Animais de Doenças , Feminino , Microbioma Gastrointestinal/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Incidência , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/genética , Masculino , Camundongos , MicroRNAs/genética , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Fatores SexuaisRESUMO
OBJECTIVE: To explore the role of angiotensin II (Ang II)-Notch signaling in high glucose-induced secretion of extracellular matrix of rat mesangial cells (RMCs) and to further investigate the protective effect of valsartan (one of Ang II receptor blockers) on kidney. METHODS: Subcultured RMCs were divided into groups as follows: normal glucose group (5.5 mmol/L glucose); high glucose group (30 mmol/L glucose); high concentration of mannitol as osmotic control group (5.5 mmol/L glucose and 24.5 mmol/L mannitol); normal glucose plus 1 µmol/L N-[N-(3, 5-difluorophenacetyl)-L-alanyl ]-S-phenylglycine t-butyl ester (DAPT) group; normal glucose plus (1, 5, 10) µmol/L valsartan group; high glucose plus 1 µmol/L DAPT group; high glucose plus (1, 5, 10) µmol/L valsartan group. Cells and supernatants were harvested after 12, 24 and 48 hours. Notch1 expression was examined by Western blotting. Secretion of transforming growth factor (TGF-ß) and fibronectin (FN) were detected by ELISA. RESULTS: Compared to the normal glucose group, Notch1 expression was elevated in the high glucose group after 12 hours, and peaked at 24 hours. Besides, secretion of TGF-ß and FN were much higher in the high glucose group than in the normal glucose group in a time-dependent manner. Compared to the untreated group, Notch1 expression decreased in a dose-dependent manner in the valsartan or DAPT treated group under high glucose after 24 hours. After pre-treatment by either valsartan or DAPT in the high glucose group, secretion of TGF-ß and FN obviously decreased as compared to the untreated group. CONCLUSION: Hyperglycemia could stimulate activation of Notch signaling in cultured RMCs, which may increase secretion of downstream fibrotic factors such as TGF-ß and FN. Valsartan may decrease the secretion of downstream FN in a dose-dependent manner via inhibiting AngII-Notch signaling.