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1.
Metab Brain Dis ; 39(1): 147-171, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37542622

RESUMO

Schizophrenia is a devastating neuropsychiatric disorder affecting 1% of the world population and ranks as one of the disorders providing the most severe burden for society. Schizophrenia etiology remains obscure involving multi-risk factors, such as genetic, environmental, nutritional, and developmental factors. Complex interactions of genetic and environmental factors have been implicated in the etiology of schizophrenia. This review provides an overview of the historical origins, pathophysiological mechanisms, diagnosis, clinical symptoms and corresponding treatment of schizophrenia. In addition, as schizophrenia is a polygenic, genetic disorder caused by the combined action of multiple micro-effective genes, we further detail several approaches, such as candidate gene association study (CGAS) and genome-wide association study (GWAS), which are commonly used in schizophrenia genomics studies. A number of GWASs about schizophrenia have been performed with the hope to identify novel, consistent and influential risk genetic factors. Finally, some schizophrenia susceptibility genes have been identified and reported in recent years and their biological functions are also listed. This review may serve as a summary of past research on schizophrenia genomics and susceptibility genes (NRG1, DISC1, RELN, BDNF, MSI2), which may point the way to future schizophrenia genetics research. In addition, depending on the above discovery of susceptibility genes and their exact function, the development and application of antipsychotic drugs will be promoted in the future.


Assuntos
Esquizofrenia , Humanos , Esquizofrenia/genética , Esquizofrenia/diagnóstico , Estudo de Associação Genômica Ampla , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único , Genômica , Proteínas de Ligação a RNA/genética
2.
CNS Neurosci Ther ; 29(11): 3460-3478, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37269088

RESUMO

INTRODUCTION: As a devastating neurological disease, spinal cord injury (SCI) results in severe tissue loss and neurological dysfunction. Pregnane X receptor (PXR) is a ligand-activated nuclear receptor with a major regulatory role in xenobiotic and endobiotic metabolism and recently has been implicated in the central nervous system. In the present study, we aimed to investigate the role and mechanism of PXR in SCI. METHODS: The clip-compressive SCI model was performed in male wild-type C57BL/6 (PXR+/+ ) and PXR-knockout (PXR-/- ) mice. The N2a H2 O2 -induced injury model mimicked the pathological process of SCI in vitro. Pregnenolone 16α-carbonitrile (PCN), a mouse-specific PXR agonist, was used to activate PXR in vivo and in vitro. The siRNA was applied to knock down the PXR expression in vitro. Transcriptome sequencing analysis was performed to discover the relevant mechanism, and the NRF2 inhibitor ML385 was used to validate the involvement of PXR in influencing the NRF2/HO-1 pathway in the SCI process. RESULTS: The expression of PXR decreased after SCI and reached a minimum on the third day. In vivo, PXR knockout significantly improved the motor function of mice after SCI, meanwhile, inhibited apoptosis, inflammation, and oxidative stress induced by SCI. On the contrary, activation of PXR by PCN negatively influenced the recovery of SCI. Mechanistically, transcriptome sequencing analysis revealed that PXR activation downregulated the mRNA level of heme oxygenase-1 (HO-1) after SCI. We further verified that PXR deficiency activated the NRF2/HO-1 pathway and PXR activation inhibited this pathway in vitro. CONCLUSION: PXR is involved in the recovery of motor function after SCI by regulating NRF2/HO-1 pathway.


Assuntos
Receptor de Pregnano X , Traumatismos da Medula Espinal , Animais , Masculino , Camundongos , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Receptor de Pregnano X/deficiência , Receptor de Pregnano X/genética , Traumatismos da Medula Espinal/genética , Traumatismos da Medula Espinal/metabolismo
3.
Acta Pharmacol Sin ; 44(10): 2075-2090, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37344564

RESUMO

Renal fibrosis is a common pathological feature of chronic kidney disease (CKD) with various etiologies, which seriously affects the structure and function of the kidney. Pregnane X receptor (PXR) is a member of the nuclear receptor superfamily and plays a critical role in regulating the genes related to xenobiotic and endobiotic metabolism in mammals. Previous studies show that PXR is expressed in the kidney and has protective effect against acute kidney injury (AKI). In this study, we investigated the role of PXR in CKD. Adenine diet-induced CKD (AD) model was established in wild-type and PXR humanized (hPXR) mice, respectively, which were treated with pregnenolone-16α-carbonitrile (PCN, 50 mg/kg, twice a week for 4 weeks) or rifampicin (RIF, 10 mg·kg-1·d-1, for 4 weeks). We showed that both PCN and RIF, which activated mouse and human PXR, respectively, improved renal function and attenuated renal fibrosis in the two types of AD mice. In addition, PCN treatment also alleviated renal fibrosis in unilateral ureter obstruction (UUO) mice. On the contrary, PXR gene deficiency exacerbated renal dysfunction and fibrosis in both adenine- and UUO-induced CKD mice. We found that PCN treatment suppressed the expression of the profibrotic Wnt7a and ß-catenin in AD mice and in cultured mouse renal tubular epithelial cells treated with TGFß1 in vitro. We demonstrated that PXR was colocalized and interacted with p53 in the nuclei of tubular epithelial cells. Overexpression of p53 increased the expression of Wnt7a, ß-catenin and its downstream gene fibronectin. We further revealed that p53 bound to the promoter of Wnt7a gene to increase its transcription and ß-catenin activation, leading to increased expression of the downstream profibrotic genes, which was inhibited by PXR. Taken together, PXR activation alleviates renal fibrosis in mice via interacting with p53 and inhibiting the Wnt7a/ß-catenin signaling pathway.


Assuntos
Receptor de Pregnano X , Insuficiência Renal Crônica , Via de Sinalização Wnt , Animais , Humanos , Camundongos , beta Catenina/metabolismo , Fibrose , Mamíferos/metabolismo , Receptor de Pregnano X/metabolismo , Receptores de Esteroides/genética , Receptores de Esteroides/metabolismo , Insuficiência Renal Crônica/induzido quimicamente , Insuficiência Renal Crônica/tratamento farmacológico , Transdução de Sinais , Proteína Supressora de Tumor p53/metabolismo , Rifampina/farmacologia
4.
Elife ; 122023 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-36722887

RESUMO

Hyperosmolarity of the renal medulla is essential for urine concentration and water homeostasis. However, how renal medullary collecting duct (MCD) cells survive and function under harsh hyperosmotic stress remains unclear. Using RNA-Seq, we identified SLC38A2 as a novel osmoresponsive neutral amino acid transporter in MCD cells. Hyperosmotic stress-induced cell death in MCD cells occurred mainly via ferroptosis, and it was significantly attenuated by SLC38A2 overexpression but worsened by Slc38a2-gene deletion or silencing. Mechanistic studies revealed that the osmoprotective effect of SLC38A2 is dependent on the activation of mTORC1. Moreover, an in vivo study demonstrated that Slc38a2-knockout mice exhibited significantly increased medullary ferroptosis following water restriction. Collectively, these findings reveal that Slc38a2 is an important osmoresponsive gene in the renal medulla and provide novel insights into the critical role of SLC38A2 in protecting MCD cells from hyperosmolarity-induced ferroptosis via the mTORC1 signalling pathway.


Assuntos
Sistemas de Transporte de Aminoácidos Neutros , Ferroptose , Animais , Camundongos , Sistemas de Transporte de Aminoácidos Neutros/metabolismo , Rim/metabolismo , Medula Renal/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo
5.
Int J Biol Sci ; 19(1): 294-310, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36594097

RESUMO

Acute kidney injury (AKI) is a pathological condition characterized by a rapid decrease in glomerular filtration rate and nitrogenous waste accumulation during hemodynamic regulation. Alisol B, from Alisma orientale, displays anti-tumor, anti-complement, and anti-inflammatory effects. However, its effect and action mechanism on AKI is still unclear. Herein, alisol B significantly attenuated cisplatin (Cis)-induced renal tubular apoptosis through decreasing expressions levels of cleaved-caspase 3 and cleaved-PARP and the ratio of Bax/Bcl-2 depended on the p53 pathway. Alisol B also alleviated Cis-induced inflammatory response (e.g. the increase of ICAM-1, MCP-1, COX-2, iNOS, IL-6, and TNF-α) and oxidative stress (e.g. the decrease of SOD and GSH, the decrease of HO-1, GCLC, GCLM, and NQO-1) through the NF-κB and Nrf2 pathways. In a target fishing experiment, alisol B bound to soluble epoxide hydrolase (sEH) as a direct cellular target through the hydrogen bond with Gln384, which was further supported by inhibition kinetics and surface plasmon resonance (equilibrium dissociation constant, K D = 1.32 µM). Notably, alisol B enhanced levels of epoxyeicosatrienoic acids and decreased levels of dihydroxyeicosatrienoic acids, indicating that alisol B reduced the sEH activity in vivo. In addition, sEH genetic deletion alleviated Cis-induced AKI and abolished the protective effect of alisol B in Cis-induced AKI as well. These findings indicated that alisol B targeted sEH to alleviate Cis-induced AKI via GSK3ß-mediated p53, NF-κB, and Nrf2 signaling pathways and could be used as a potential therapeutic agent in the treatment of AKI.


Assuntos
Injúria Renal Aguda , Cisplatino , Humanos , Cisplatino/toxicidade , NF-kappa B/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/metabolismo , Apoptose , Rim/metabolismo , Estresse Oxidativo , Inflamação/tratamento farmacológico , Inflamação/metabolismo
6.
Psychiatry Investig ; 20(12): 1168-1176, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38163656

RESUMO

OBJECTIVE: Schizophrenia is a complex and devastating psychiatric disorder with a strong genetic background. However, much uncertainty still exists about the role of genetic susceptibility in the pathophysiology of schizophrenia. TEA domain transcription factor 1 (TEAD1) is a transcription factor associated with neurodevelopment and has modulating effects on various nervous system diseases. In the current study, we performed a case-control association study in a Northeast Chinese Han population to explore the characteristics of pathogenic TEAD1 polymorphisms and potential association with schizophrenia. METHODS: We recruited a total of 721 schizophrenia patients and 1,195 healthy controls in this study. The 9 single nucleotide polymorphisms (SNPs) in the gene region of TEAD1 were selected and genotyped. RESULTS: The genetic association analyses showed that five SNPs (rs12289262, rs6485989, rs4415740, rs7113256, and rs1866709) were significantly different between schizophrenia patients and healthy controls in allele or/and genotype frequencies. After Bonferroni correction, the association of three SNPs (rs4415740, rs7113256, and rs1866709) with schizophrenia were still evident. Haplotype analysis revealed that two strong linkage disequilibrium blocks (rs6485989-rs4415740-rs7113256 and rs16911710-rs12364619-rs1866709) were globally associated with schizophrenia. Four haplotypes (C-C-C and T-T-T, rs6485989-rs4415740-rs7113256; G-T-A and G-T-G, rs16911710-rs12364619-rs1866709) were significantly different between schizophrenia patients and healthy controls. CONCLUSION: The current findings indicated that the human TEAD1 gene has a genetic association with schizophrenia in the Chinese Han population and may act as a susceptibility gene for schizophrenia.

7.
Front Physiol ; 14: 1252052, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38235388

RESUMO

Purpose: The aim of this study was to investigate the effect of blood flow restriction (BFR) combined with low-intensity resistance training (RT) on cardiovascular risk factors in obese individuals. Methods: Twenty-six male obese college students were recruited and randomly assigned to a control group (CON, n = 8), a low-intensity RT group (RT, n = 9), and a combined BFR training and low-intensity RT group (BFRT, n = 9). Results: The subjects in BFRT group showed significant reductions in body fat percentage and waist-to-hip ratio and a significant increase in lean mass and muscle mass; the peak torque, peak power, and endurance ratio of knee extensors and elbow flexors were significantly upregulated; the root mean square (RMS) for the medial femoral muscle, lateral femoral muscle and biceps significantly increased; the diastolic blood pressure (DBP) showed a significant decrease. The BFRT group also showed significant up-regulations in RMS of the difference between the adjacent R-R intervals (RMSSD), high-frequency power (HF) of parasympathetic modulatory capacity, the standard deviation of R-R intervals (SDNN) of overall heart rate variability (HRV) changes and low-frequency power (LF) of predominantly sympathetic activity. In addition, glycated hemoglobin (HbA1C), insulin resistance index (HOMA-IR) and fasting blood glucose (FBG) were all significantly downregulated in BFRT group. In parallel, low-density lipoprotein (LDL-C) significantly reduced while high-density lipoprotein (HDL-C) significantly increased in BFRT group. Conclusion: BFR combined with low-intensity RT training effectively improved body composition index, increased muscle mass, improved neuromuscular activation, enhanced muscle strength and endurance, which in turn improved abnormal glucolipid metabolism and enhanced cardiac autonomic regulation.

8.
Med Eng Phys ; 110: 103914, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36564139

RESUMO

Sidestep cutting is a critical movement in sports. However, biomechanical research on sidestep cutting has not hitherto reached a consensus. In order to investigate the effects of limb dominance and movement direction on ankle and subtalar joints during sidestep cutting, twelve physically active male participants were recruited in the present study. Trajectory and ground reaction force data were collected by the motion capture system and force platform. Kinematics, kinetics, and muscle forces information were obtained by running OpenSim. Two-way repeated measures ANOVA was performed with movement direction and limb dominance as independent variables. We found that movement direction had a significant effect on ankle dorsiflexion angle. In contrast, the factor of limb dominance had no effect on ankle and subtalar joints angles. For ankle joint moment, the plantarflexion moment was greater by performing a 45° sidestep cutting or using the dominant limb, while the subtalar joint moment was not affected by these two variables. In terms of muscle forces, the soleus of the dominant limb generated greater plantarflexion muscle force on the sagittal plane, while the non-dominant limb tended to contract more strongly (peroneus longus and peroneus brevis) on the frontal plane to stabilize the subtalar joint. Meanwhile, a smaller sidestep cutting angle made participants generate greater plantarflexion muscle forces (soleus and gastrocnemius). In conclusion, our findings indicated that participants should take limb dominance and movement direction into consideration for enhancing athletic performance and reducing the risk of injury during sidestep cutting.


Assuntos
Articulação do Tornozelo , Tornozelo , Masculino , Humanos , Articulação do Tornozelo/fisiologia , Extremidade Inferior/fisiologia , Movimento/fisiologia , Perna (Membro) , Fenômenos Biomecânicos
9.
Front Endocrinol (Lausanne) ; 13: 959902, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36111293

RESUMO

As a member of the nuclear receptor (NR) superfamily, pregnane X receptor (PXR; NR1I2) is a ligand-activated transcription factor that plays a crucial role in the metabolism of xenobiotics and endobiotics in mammals. The tissue distribution of PXR is parallel to its function with high expression in the liver and small intestine and moderate expression in the kidney, stomach, skin, and blood-brain barrier, which are organs and tissues in frequent contact with xenobiotics. PXR was first recognized as an exogenous substance receptor regulating metabolizing enzymes and transporters and functioning in detoxification and drug metabolism in the liver. However, further research revealed that PXR acts as an equally important endogenous substance receptor in the metabolism and homeostasis of endogenous substances. In this review, we summarized the functions of PXR in metabolism of different substances such as glucose, lipid, bile acid, vitamin, minerals, and endocrines, and also included insights of the application of PXR ligands (drugs) in specific diseases.


Assuntos
Receptor de Pregnano X , Receptores de Esteroides , Xenobióticos , Animais , Ácidos e Sais Biliares , Glucose , Ligantes , Lipídeos , Mamíferos/metabolismo , Receptor de Pregnano X/metabolismo , Receptores Citoplasmáticos e Nucleares , Receptores de Esteroides/fisiologia , Vitaminas , Xenobióticos/metabolismo
10.
Metab Brain Dis ; 37(5): 1365-1371, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35445959

RESUMO

Schizophrenia stands out as one of the most devastating psychiatric disorders. Previous findings have shown that schizophrenia is a polygenic genetic disorder. Thus, abnormal neurodevelopment and neurogenesis may be associated with the etiology of schizophrenia, so genes which affect these processes may be potential candidate genes of schizophrenia. Mitogen-activated protein kinase kinase kinase 4 (MAP3K4) gene is a member of the mitogen-activated protein kinase family. Taking into account previous findings, MAP3K4 plays a crucial role in the fundamental pathology of various nervous system diseases. In the present study, we aim to explore the association of MAP3K4 and schizophrenia in an independent case-control sample including 627 schizophrenic patients and 1175 healthy controls from a Northeast Chinese Han population. Both the allelic and genotypic association analyses showed that 6 SNPs in MAP3K4 were significantly associated with schizophrenia (rs590988, rs625977, rs9295134, rs12110787, rs1001808 and rs9355870). After rigorous Bonferroni correction, 4 SNPs (rs9295134, rs12110787, rs1001808 and rs9355870) were still significantly associated with the disease. The haplotype composed of these four SNPs also showed significantly global and individual association with schizophrenia. These results suggest that MAP3K4 is a susceptibility gene for schizophrenia in the Northeast Chinese Han population.


Assuntos
MAP Quinase Quinase Quinase 4/genética , Esquizofrenia , Estudos de Casos e Controles , China/epidemiologia , Predisposição Genética para Doença/genética , Genótipo , Haplótipos , Humanos , Polimorfismo de Nucleotídeo Único/genética , Esquizofrenia/genética
11.
Oxid Med Cell Longev ; 2022: 7502632, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35126820

RESUMO

AIM: The study is aimed at verifying miR-154-5p and Smurf1 combination in glomerular mesangial cells regulating TGFß1/Smad3 pathway-related protein ubiquitination in the model of diabetic rats renal tissues, primary mesangial cells, and cell lines. METHODS: The diabetic SD rat model and high-glucose-cultured primary mesangial cells and cell lines were established. miR-154-5p mimic and inhibitor, Smurf1 siRNA, and TGF ß 1/Smad3 inhibitor (SB431542) were pretreated to make the TGFß1/Smad3 pathway and ubiquitin changes. Fluorescence in situ hybridization was used for the miR-154-5p renal localization; molecular biological detection was adopted for cell proliferation, renal function, urine protein, and pathway proteins. After bioinformatics predicted binding sites, luciferase and Co-IP were used to detect miRNA and protein binding. RESULTS: miR-154-5p was significantly increased and mainly concentrated in the glomerular of renal cortex in well-established diabetic rat renal tissues. Rno-miR-154-5p combined Rno-Smurf1 3' UTR, while Smurf1 combined Smad3 directly. Meanwhile, miR-154-5p regulates TGFß1/Smad3-mediated cell proliferation via Smurf1 ubiquitination. CONCLUSION: miR-154-5p regulates the TGFß1/Smads pathway through Smurf1 ubiquitination and promotes the fibrosis process of diabetic kidney disease.


Assuntos
MicroRNAs/metabolismo , Transdução de Sinais , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Animais , Antagomirs/metabolismo , Proliferação de Células , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/metabolismo , Fibrose , Rim/metabolismo , Rim/patologia , Masculino , Células Mesangiais/citologia , Células Mesangiais/metabolismo , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Ligação Proteica , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/genética , Proteína Smad3/antagonistas & inibidores , Ubiquitina-Proteína Ligases/antagonistas & inibidores , Ubiquitina-Proteína Ligases/genética , Ubiquitinação
12.
EBioMedicine ; 76: 103855, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35123268

RESUMO

As a major social and economic burden for the healthcare system, kidney diseases contribute to the constant increase of worldwide deaths. A deeper understanding of the underlying mechanisms governing the etiology, development and progression of kidney diseases may help to identify potential therapeutic targets. As a superfamily of ligand-dependent transcription factors, nuclear receptors (NRs) are critical for the maintenance of normal renal function and their dysfunction is associated with a variety of kidney diseases. Increasing evidence suggests that ligands for NRs protect patients from renal ischemia/reperfusion (I/R) injury, drug-induced acute kidney injury (AKI), diabetic nephropathy (DN), renal fibrosis and kidney cancers. In the past decade, some breakthroughs have been made for the translation of NR ligands into clinical use. This review summarizes the current understanding of several important NRs in renal physiology and pathophysiology and discusses recent findings and applications of NR ligands in the management of kidney diseases.


Assuntos
Injúria Renal Aguda , Nefropatias Diabéticas , Traumatismo por Reperfusão , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/patologia , Nefropatias Diabéticas/patologia , Fibrose , Humanos , Rim/patologia , Rim/fisiologia , Receptores Citoplasmáticos e Nucleares/genética , Traumatismo por Reperfusão/patologia
13.
Gut ; 71(11): 2205-2217, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35173042

RESUMO

OBJECTIVE: Dysbiosis of the intestinal fungal community has been observed in inflammatory bowel disease (IBD); however, its potential role in IBD development and prevention remains unclear. Here, we explored the biological effects and molecular mechanisms of intestinal fungi isolated from human faeces on colitis in mice. DESIGN: Intestinal fungal strains with differential abundance in IBD were cultivated in human faeces and their effects on various mouse models of experimental colitis were evaluated. In addition, the bioactive metabolites secreted by the target fungus were accurately identified and their pharmacological effects and potential molecular targets were investigated in vitro and in vivo. RESULTS: The abundance of Candida spp was significantly higher in patients with IBD. After large-scale human intestinal fungal cultivation and functional analysis, Candida metapsilosis M2006B significantly attenuated various models of experimental colitis in wild-type, antibiotic-treated, germ-free, and IL10-/- mice by activating farnesoid X receptor (FXR). Among the seven acyclic sesquiterpenoids (F1-F7) identified as major secondary metabolites of M2006B, F4 and F5 attenuated colitis in mice by acting as novel FXR agonists. The therapeutic effects of M2006B and its metabolites on colitis via specific FXR activation were confirmed in Fxr -/- mice. CONCLUSION: This study revealed that C. metapsilosis M2006B significantly attenuated colitis in mice and identified two acyclic sesquiterpenoids (F4 and F5) as major active metabolites of M2006B. Notably, these metabolites were able to effectively treat experimental colitis by selectively activating FXR. Together, this study demonstrates that M2006B could be a beneficial intestinal fungus for treating and preventing IBD.


Assuntos
Colite , Doenças Inflamatórias Intestinais , Sesquiterpenos , Animais , Antibacterianos/uso terapêutico , Candida parapsilosis , Colite/tratamento farmacológico , Colite/metabolismo , Modelos Animais de Doenças , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Interleucina-10 , Camundongos , Camundongos Endogâmicos C57BL , Receptores Citoplasmáticos e Nucleares , Sesquiterpenos/farmacologia , Sesquiterpenos/uso terapêutico
15.
Phytochemistry ; 193: 112974, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34653908

RESUMO

Intestinal commensal fungi are vital to human health, and their metabolites play a key role in the reciprocal relationship. In the present work, eighteen alkaloids and seven monoterpenoids were isolated from the fermentation of the human intestinal fungus Penicillium oxalicum SL2, including seven undescribed alkaloids (penicilloxalines A-G), three undescribed monoterpenoids (penicilloxalines H-J), and fifteen reported compounds. The structures of the isolated compounds were identified by HRESIMS, 1D and 2D NMR, electronic circular dichroism spectra and quantum chemical calculations. Some metabolites displayed moderate agonistic effects against the pregnane X receptor (PXR), whereas (6R)3,7-dimethyl-6,7-dihydroxy-2(Z)-octenoic acid displayed a significant agonistic effect against the farnesoid X receptor (FXR) with an EC50 value of 0.43 µM, which was verified by investigating FXR downstream target genes and proteins, such as small heterodimer partner 1 (SHP1), fibroblast growth factor (FGF), and bile salt export pump (BSEP).


Assuntos
Penicillium , Receptor de Pregnano X , Receptores Citoplasmáticos e Nucleares , Humanos , Intestinos
16.
Sheng Li Xue Bao ; 73(5): 795-804, 2021 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-34708236

RESUMO

Farnesoid X receptor (FXR) has been identified as an inhibitor of platelet function and an inducer of fibrinogen protein complex. However, the regulatory mechanism of FXR in hemostatic system remains incompletely understood. In this study, we aimed to investigate the functions of FXR in regulating antithrombin III (AT III). C57BL/6 mice and FXR knockout (FXR KO) mice were treated with or without GW4064 (30 mg/kg per day). FXR activation significantly prolonged prothrombin time (PT) and activated partial thromboplastin time (APTT), lowered activity of activated factor X (FXa) and concentrations of thrombin-antithrombin complex (TAT) and activated factor II (FIIa), and increased level of AT III, whereas all of these effects were markedly reversed in FXR KO mice. In vivo, hepatic AT III mRNA and protein expression levels were up-regulated in wild-type mice after FXR activation, but down-regulated in FXR KO mice. In vitro study showed that FXR activation induced, while FXR knockdown inhibited, AT III expression in mouse primary hepatocytes. The luciferase assay and ChIP assay revealed that FXR can bind to the promoter region of AT III gene where FXR activation increased AT III transcription. These results suggest FXR activation inhibits coagulation process via inducing hepatic AT III expression in mice. The present study reveals a new role of FXR in hemostatic homeostasis and indicates that FXR might act as a potential therapeutic target for diseases related to hypercoagulation.


Assuntos
Antitrombina III , Hepatócitos , Receptores Citoplasmáticos e Nucleares , Animais , Coagulação Sanguínea , Fígado , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores Citoplasmáticos e Nucleares/genética
17.
Am J Physiol Renal Physiol ; 321(5): F617-F628, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34569253

RESUMO

The ligand-activated nuclear receptor, farnesoid X receptor (FXR), plays a pivotal role in regulating renal function. Activation of FXR by its specific agonists exerts renoprotective action in animals with acute kidney injury (AKI). In the present study, we aimed to identify naturally occurring agonists of FXR with potential as therapeutic agents in renal ischemia-reperfusion injury. In vitro and in vivo FXR activation was determined by a dual-luciferase assay, docking analysis, site-directed mutagenesis, and whole kidney transcriptome analysis. Wild-type (WT) and FXR knockout (FXR-/-) mice were used to determine the effect of potential FXR agonist on renal ischemia-reperfusion injury (IRI). We found that alisol B 23-acetate (ABA), a major active triterpenoid extracted from Alismatis rhizoma, a well-known traditional Chinese medicine, can activate renal FXR and induce FXR downstream gene expression in mouse kidney. ABA treatment significantly attenuated renal ischemia-reperfusion-induced AKI in WT mice but not in FXR-/- mice. Our results demonstrate that ABA can activate renal FXR to exert renoprotection against ischemia-reperfusion injury-induced AKI. Therefore, ABA may represent a potential therapeutic agent in the treatment of ischemic AKI.NEW & NOTEWORTHY In the present study, we found that alisol B 23-acetate (ABA), an identified natural farnesoid X receptor (FXR) agonist from the well-known traditional Chinese medicine Alismatis rhizoma, protects against ischemic acute kidney injury (AKI) in an FXR-dependent manner, as reflected by improved renal function, reduced renal tubular apoptosis, ameliorated oxidative stress, and suppressed inflammatory factor expression. Therefore, ABA may have great potential as a novel therapeutic agent in the treatment of AKI in the future.


Assuntos
Injúria Renal Aguda/prevenção & controle , Colestenonas/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Rim/efeitos dos fármacos , Receptores Citoplasmáticos e Nucleares/agonistas , Traumatismo por Reperfusão/prevenção & controle , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/patologia , Animais , Apoptose/efeitos dos fármacos , Modelos Animais de Doenças , Células HEK293 , Células Hep G2 , Humanos , Mediadores da Inflamação/metabolismo , Rim/metabolismo , Rim/patologia , Ligantes , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Estresse Oxidativo/efeitos dos fármacos , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Transdução de Sinais
18.
Diabetes Res Clin Pract ; 179: 109034, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34487756

RESUMO

AIM: To detect the expression levels of fasting serum fructose and ketohexokinase (KHK) in patients with type 2 diabetes mellitus (T2DM) at different stages of urinary albumin creatinine ratios (UACR) and serum uric acid (sUA). METHODS: 339 T2DM patients and 107 normal volunteers were divided into the normal uric acid (275 cases) and high uric acid group (171 cases) according to uric acid levels. T2DM patients were divided into the normal albuminuria group (118 cases, UACR < 30 mg/g), microalbuminuria group (112 cases, UACR 30-300 mg/g) and large amount of albuminuria group (109 cases, UACR > 300 mg/g). Levels of fasting serum fructose and KHK were detected and statistical analysis was carried out. RESULTS: Fasting serum fructose and KHK levels increased with the increase of UACR and sUA (P < 0.05). Correlation analysis showed that fasting serum fructose and KHK levels were positively correlated with UACR and sUA (P < 0.05). Ridge regression analysis showed that fasting serum fructose and KHK were also correlated with urinary albumin and uric acid (P < 0.05). CONCLUSION: Fasting serum fructose and KHK in endogenous fructose are associated with serum uric acid and urinary albumin levels in patients with T2DM. Trial number: ChiCTR2000039870.


Assuntos
Diabetes Mellitus Tipo 2 , Ácido Úrico , Albuminas , Albuminúria , Creatinina , Frutose , Humanos
19.
Biomed Res Int ; 2021: 8828677, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34235223

RESUMO

Analysis and diagnosis according to the collected physical data are an important part in the physical examination. Through the data analysis of the physical examination results and expert diagnoses, the physical condition of a specific physical examination unit can be achieved which may guide individual health development. However, in general, the application of physical examination data is insufficient in most of the current physical examination organizations. Therefore, in the present study, statistical analysis and intelligent diagnosis were applied to maximize the utilization of physical examination data. The physical examination data collected from different departments of Dalian University of Technology were statistically analyzed and then synthesized for stimulating the thinking mode and knowledge framework of medical experts by a learning model on machine, resulting in the construction of an intelligent physical examination diagnosis method with 93.4% accuracy confirmed by experts. In conclusion, a potential artificial intelligence model of psychical examination data on health analysis and intelligent diagnosis was established, which may become more and more accurate with data accumulation in the near future.


Assuntos
Inteligência Artificial , Diagnóstico por Computador/métodos , Reconhecimento Automatizado de Padrão , Exame Físico , Algoritmos , Índice de Massa Corporal , Interpretação Estatística de Dados , Lógica Fuzzy , Humanos , Lógica , Aprendizado de Máquina , Modelos Estatísticos , Reprodutibilidade dos Testes , Processamento de Sinais Assistido por Computador , Estatística como Assunto
20.
Acta Diabetol ; 58(11): 1551-1562, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34148121

RESUMO

AIM: The study is aimed to detect the expression of serum Sirtuin 6 (SIRT6) with different severities and urinary albumin creatinine ratios (UACR) in type 2 diabetes mellitus (T2DM) patients, thus exploring the association of SIRT6 together with glycolipid metabolism and urinary protein in the cross-sectional study. METHODS: T2DM patients (313 cases), pre-diabetic patients (102 cases), and healthy volunteers (100 cases) were selected. T2DM patients were divided into the normal albuminuria (103 cases, UACR < 30 mg/g), micro-albuminuria (106 cases, UACR 30-300 mg/g), and large amount of albuminuria group (104 cases, UACR > 300 mg/g) based on different UACR levels. The medical history was asked, biochemical indicators were detected, hematuria samples were taken, serum SIRT6 levels were detected, and detailed statistical analysis was conducted. RESULTS: FPG, 2 h-PG, HOMA-IR, HbA1c, and LDL-C increased, while ISI and HDL-C decreased with the aggravation of diabetic status (P < 0.05). HbA1c, UACR, TNFα, HIF1α, and SIRT6 increased with UACR in T2DM patients (P < 0.05). Correlation analysis demonstrated that SIRT6 was significantly positively correlated with glycolipid metabolism in the whole samples, and correlated with UACR, TNFα, and HIF1α in T2DM patients (P < 0.05). Ridge regression analysis showed that SIRT6 was a risk factor for both glycolipid metabolism and urinary protein (P < 0.05). CONCLUSION: SIRT6 increases with biomarkers in glycolipid metabolism and urinary protein in different severities of diabetes and UACR, which is expected to be a potential biomarker for early prediction and diagnosis related to glycolipid metabolism disorders and related nephropathy. Trial number: ChiCTR2000039808.


Assuntos
Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Estado Pré-Diabético , Sirtuínas , Albuminúria , Biomarcadores , Creatinina , Estudos Transversais , Nefropatias Diabéticas/diagnóstico , Humanos , Estado Pré-Diabético/diagnóstico
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