Humans ; Protein Binding ; Receptors, Steroid ; agonists ; antagonists & inhibitors ; metabolism ; physiology

The development of chronic liver disease can be promoted by excessive fat accumulation, dysbiosis, viral infections and persistent inflammatory responses, which can lead to liver inflammation, fibrosis and carcinogenesis. An in-depth understanding of the etiology leading to chronic liver disease and the underlying mechanisms influencing its development can help identify potential therapeutic targets for targeted treatment. Orphan nuclear receptors (ONRs) are receptors that have no corresponding endogenous ligands to bind to them. The study of these ONRs and their biological properties has facilitated the development of synthetic ligands, which are important for investigating the effective targets for the treatment of a wide range of diseases. In recent years, it has been found that ONRs are essential for maintaining normal liver function and their dysfunction can affect a variety of liver diseases. ONRs can influence pathophysiological activities such as liver lipid metabolism, inflammatory response and cancer cell proliferation by regulating hormones/transcription factors and affecting the biological clock, oxidative stress, etc. This review focuses on the regulation of ONRs, mainly including retinoid related orphan nuclear receptors (RORs), pregnane X receptor (PXR), leukocyte cell derived chemotaxin 2 (LECT2), Nur77, and hepatocyte nuclear factor 4α (HNF4α), on the development of different types of chronic liver diseases in different ways, in order to provide useful references for the therapeutic strategies of chronic liver diseases based on the regulation of ONRs.
Humans ; Orphan Nuclear Receptors/metabolism* ; Receptors, Steroid/physiology* ; Ligands ; Liver ; Liver Diseases ; Intercellular Signaling Peptides and Proteins

Cholestatic liver diseases are characterized by impairments of bile flows and accumulations of biliary constituents such as bile acids and bilirubin. The changes of phase I and II metabolism and the hepatobiliary transport system minimize cholestatic liver injury. These adaptive responses are transcriptionally regulated by several nuclear receptors. Recent studies have revealed that the pregnane X receptor (PXR) and the constitutive androstane receptor (CAR) are key nuclear receptors for regulating many of the adaptive responses noted in cholestasis. PXR and CAR coordinately regulate not only bile acid metabolism and transport, but also bilirubin clearance. PXR and CAR ligands may be useful in the future for the treatment of cholestatic liver disease.
Transcription Factors/metabolism/*physiology ; Receptors, Steroid/metabolism/*physiology ; Receptors, Cytoplasmic and Nuclear/metabolism/*physiology ; Humans ; Cholestasis/metabolism/*physiopathology

Endocrine hormones are important factors in maintaining pregnancy as well as initiation of parturition. Progesterone is the major hormone maintaining myometrium quiescence, while glucocorticoids, prostaglandins and estrogen are among the major hormones involved in the initiation of parturition. Therefore progesterone withdrawal at the end of pregnancy is the prerequisite for the initiation of parturition. However, unlike most of the other species of mammals that the withdrawal of progesterone is achieved via reduction of progesterone synthesis or increased conversion of progesterone to estrogen, some mammals including the primates maintain high progesterone level throughout gestation and even during parturition. Accumulating lines of evidence indicate that the withdrawal of progesterone in human being is attained via the changes of the expression ratio of progesterone receptor subtypes and the changes of co-activators required for the activation of transcriptional activity of progesterone receptor. Here we reviewed the three major mechanisms, namely luteolysis, upregulation of placental P450c17 hydroxylase and changes of progesterone receptor functions, underlying progesterone withdrawal in late pregnancy in mammals.
Animals ; Female ; Humans ; Luteolysis ; physiology ; Parturition ; metabolism ; physiology ; Pregnancy ; Pregnancy Trimester, Third ; metabolism ; physiology ; Progesterone ; metabolism ; Receptors, Progesterone ; metabolism ; physiology ; Species Specificity ; Steroid 17-alpha-Hydroxylase ; metabolism

OBJECTIVETo investigate whether pregnane X receptor (PXR) is involved in the induction of rat hepatic cytochrome P450 3A1/2 by zolmitriptan.

METHODSThe induction effects of zolmitriptan were investigated in three concentrations (100 micromol L(-1)), 50 micromolL(-1)) and 10 micromol L(-1))) using luciferase report gene method based on PXR. Pregnenolone-16 alpha-carbonitrile (PCN) was used as the positive control and the solvent DMSO as the negative control.

RESULTCompared with the negative groups, the positive and high level zolmitriptan groups exhibited a significant induction effect on CYP 3A1, the activity increased to 1.93 and 1.96 times, respectively (P<0.05). The positive, middle level and low level zolmitriptan groups exhibited a significant induction effect on CYP 3A2, the activity increase to 2.51, 2.10 and 1.63 times, respectively (P<0.01, <0.05 ).

CONCLUSIONZolmitriptan can significantly induce CYP 3A2 in low and middle concentrations and induce CYP 3A1 in high concentration.PXR is involved in the induction of CYP 3A1/2 by zolmitriptan.

Animals ; Cytochrome P-450 CYP3A ; drug effects ; metabolism ; Liver ; enzymology ; metabolism ; Oxazolidinones ; pharmacology ; Rats ; Receptors, Steroid ; metabolism ; physiology ; Tryptamines ; pharmacology

OBJECTIVETo investigate the variation of sex hormone and its receptor level in elderly male patients with coronary heart disease (CHD) and to evaluate the correlations between CHD and sex hormone as well as sex hormone receptor.

METHODSAltogether 139 male CHD patients (CHD group) aged 60-92 years and 400 healthy men (control group) aged 60-90 years were included in this cross sectional study. The plasma concentrations of dehydroepiandrosterone sulfate (DHEAS), total testosterone (TT), free testosterone (FT), estradiol (E2), sex hormone binding globulin (SHBG), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) were measured. The androgen receptor (AR) was tested by flow cytometry. Correlations between CHD and levels of sex hormones and AR were analyzed.

RESULTSCompared with the control group, the levels of DHEAS, TT, FT, SHBG, and the fluorescence intensity of AR in the CHD group significantly reduced (P < 0.05), while the levels of FSH and E2 significantly increased (P < 0.01). Age was negatively correlated with TT (r = -0.28, P = 0.00) and FT (r = -0.17, P = 0.01), while it was positively correlated with SHBG (r = 0.14, P = 0.04) and E2 (r = 0.33, P = 0.00). AR fluorescence intensity was negatively correlated with systolic blood pressure (r = -0.12, P = 0.01). Binary logistic regression analysis showed that TT, SHBG, and AR were all negatively correlated with CHD (P < 0.05).

CONCLUSIONSElderly male patients with CHD are found to have low levels of DHEAS, TT, FT, SHBG, and AR, while high concentrations of E2 and FSH. Low levels of TT and SHBG may be the potential risk factors of CHD in elderly men.

Aged ; Aged, 80 and over ; Aging ; blood ; physiology ; Anthropometry ; Coronary Disease ; metabolism ; physiopathology ; Cross-Sectional Studies ; Gonadal Steroid Hormones ; blood ; Humans ; Male ; Middle Aged ; Receptors, Androgen ; metabolism ; Risk Factors

Nuclear receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are originally characterized as transcription factors regulating many target genes. Recent works have revealed that these nuclear receptors play critical roles in regulating genes that encode drug metabolism enzymes and modulating hepatic energy metabolism, such as down-regulating gluconeogenesis, fatty acid oxidation, and ketogenesis, as well as up-regulating lipogenesis. Studies on PXR and CAR have important implication on drug-drug interaction (DDI) and potential disease treatment targets.
Animals ; Drug Interactions ; Energy Metabolism ; Glucose ; metabolism ; Glucose-6-Phosphate ; metabolism ; Humans ; Inflammation ; metabolism ; Lipid Metabolism ; Liver ; metabolism ; NF-kappa B ; metabolism ; Receptors, Cytoplasmic and Nuclear ; physiology ; Receptors, Steroid ; physiology

Estrogen is a steroid and the predominant female sex hormone in the body. Ovariectomised (OVX) adult female rats exhibit greater myocardial injury compared to the sham rats following ischemic insult in the presence of beta-adrenoceptor stimulation. Estrogen replacement restores the response of OVX female rats to ischemic/beta-adrenoceptor stimulation to that of normal female rats, providing evidence for a cardioprotective role of estrogen during ischemic insult. The protective effect is due to down-regulation of the beta(1)-adrenoceptor. There is also evidence that estrogen suppresses the expression and activity of protein kinase A (PKA), a second messenger of the G(s) protein/adenylyl cyclase/cAMP/PKA pathway which ultimately influences contractile function. There is also preliminary evidence that estrogen may suppress the activity of Ca(2+)/calmodulin kinase II deltac isoform (CaMKII-deltac), another downstream second messenger of the beta(1)-adrenoceptor pathway, which is involved in PKA-independent cell apoptosis. Acute administration of estrogen at physiological level could inhibit myocardial beta(1)-adrenoceptor and attenuate Ca(2+) influx independent of the estrogen receptor. In addition, brain studies also show estrogen inhibits the activities activated by the beta-adrenoceptor in brain regions responsible for the regulation of arterial blood pressure. Thus, it can be appreciated that the interaction between estrogen and the beta(1)-adrenoceptor and its signaling pathways is a complex one. Estrogen plays an important role not only in reproduction but also in other regulatory functions such as cardioprotection.
Animals ; Cyclic AMP-Dependent Protein Kinases ; Down-Regulation ; Estrogens ; physiology ; Female ; Gonadal Steroid Hormones ; Heart ; physiology ; Heart Diseases ; prevention & control ; Myocardium ; Rats ; Rats, Sprague-Dawley ; Receptors, Adrenergic, beta-1 ; physiology ; Signal Transduction

As the first line of immune defense for Mycobacterium tuberculosis (Mtb), macrophages also provide a major habitat for Mtb to reside in the host for years. The battles between Mtb and macrophages have been constant since ancient times. Triggered upon Mtb infection, multiple cellular pathways in macrophages are activated to initiate a tailored immune response toward the invading pathogen and regulate the cellular fates of the host as well. Toll-like receptors (TLRs) expressed on macrophages can recognize pathogen-associated-molecular patterns (PAMPs) on Mtb and mediate the production of immune-regulatory cytokines such as tumor necrosis factor (TNF) and type I Interferons (IFNs). In addition, Vitamin D receptor (VDR) and Vitamin D-1-hydroxylase are up-regulated in Mtb-infected macrophages, by which Vitamin D participates in innate immune responses. The signaling pathways that involve TNF, type I IFNs and Vitamin D are inter-connected, which play critical roles in the regulation of necroptosis, apoptosis, and autophagy of the infected macrophages. This review article summarizes current knowledge about the interactions between Mtb and macrophages, focusing on cellular fates of the Mtb-infected macrophages and the regulatory molecules and cellular pathways involved in those processes.
Animals ; Apoptosis ; Autophagy ; Humans ; Interferon Type I ; metabolism ; Macrophages ; immunology ; metabolism ; Mycobacterium tuberculosis ; physiology ; Receptors, Calcitriol ; metabolism ; Steroid Hydroxylases ; metabolism ; Toll-Like Receptors ; metabolism ; Tuberculosis ; immunology ; metabolism ; pathology ; Tumor Necrosis Factors ; metabolism

Animals ; Bridged Bicyclo Compounds ; metabolism ; Cytochrome P-450 CYP3A ; biosynthesis ; genetics ; Drug Design ; Drug Interactions ; Enzyme Induction ; Humans ; Lithocholic Acid ; metabolism ; Phloroglucinol ; analogs & derivatives ; metabolism ; Receptors, Cytoplasmic and Nuclear ; genetics ; metabolism ; physiology ; Receptors, Steroid ; genetics ; physiology ; Signal Transduction ; Terpenes ; metabolism ; Transcription Factors ; genetics ; metabolism