TR2 and TR4 Orphan Nuclear Receptors: An Overview.

Testicular nuclear receptors 2 and 4 (TR2, TR4), also known as NR2C1 and NR2C2, belong to the nuclear receptor superfamily and were first cloned in 1989 and 1994, respectively. Although classified as orphan receptors, several natural molecules, their metabolites, and synthetic compounds including polyunsaturated fatty acids (PUFAs), PUFA metabolites 13-hydroxyoctadecadienoic acid, 15-hydroxyeicosatetraenoic acid, and the antidiabetic drug thiazolidinediones can transactivate TR4. Importantly, many of these ligands/activators can also transactivate peroxisome proliferator-activated receptor gamma (PPARγ), also known as NR1C3 nuclear receptor. Both TR4 and PPARγ can bind to similar hormone response elements (HREs) located in the promoter of their common downstream target genes. However, these two nuclear receptors, even with shared ligands/activators and shared binding ability for similar HREs, have some distinct functions in many diseases they influence. In cancer, PPARγ inhibits thyroid, lung, colon, and prostate cancers but enhances bladder cancer. In contrast, TR4 inhibits liver and prostate cancer initiation but enhances pituitary corticotroph, liver, and prostate cancer progression. In type 2 diabetes, PPARγ increases insulin sensitivity but TR4 decreases insulin sensitivity. In cardiovascular disease, PPARγ inhibits atherosclerosis but TR4 enhances atherosclerosis through increasing foam cell formation. In bone physiology, PPARγ inhibits bone formation but TR4 increases bone formation. Together, the contrasting impact of TR4 and PPARγ on different diseases may raise a critical issue about drug used to target any one of these nuclear receptors.

Natural killer cells suppress enzalutamide resistance and cell invasion in the castration resistant prostate cancer via targeting the androgen receptor splicing variant 7 (ARv7).

Despite the success of androgen-deprivation therapy (ADT) with the newly developed anti-androgen enzalutamide (Enz, also known as MDV3100) to suppress castration resistant prostate cancer (CRPC) in extending patient survival by an extra 4.8 months, eventually patients die with the development of Enz resistance that may involve the induction of the androgen receptor (AR) splicing variant ARv7. Here we identify an unrecognized role of Natural Killer (NK) cells in the prostate tumor microenvironment that can be better recruited to the CRPC cells to suppress ARv7 expression resulting in suppressing the Enz resistant CRPC cell growth and invasion. Mechanism dissection revealed that CRPC cells, compared to normal prostate epithelial cells, could recruit more NK cells that might then lead to alterations of the microRNA-34 and microRNA-449 to suppress both ARv7 expression and ARv7-induced EZH2 expression to suppress CRPC cell invasion. Together, these results identify a new potential therapy using recruited NK cells to better suppress the Enz resistance and cell invasion in CRPC at the later enzalutamide resistant stage.

To complete its replication cycle, a shrimp virus changes the population of long chain fatty acids during infection via the PI3K-Akt-mTOR-HIF1α pathway.

White spot syndrome virus (WSSV), the causative agent of white spot disease (WSD), is a serious and aggressive shrimp viral pathogen with a worldwide distribution. At the genome replication stage (12 hpi), WSSV induces a metabolic rerouting known as the invertebrate Warburg effect, which boosts the availability of energy and biosynthetic building blocks in the host cell. Here we show that unlike the lipogenesis that is seen in cancer cells that are undergoing the Warburg effect, at 12 hpi, all of the long chain fatty acids (LCFAs) were significantly decreased in the stomach cells of WSSV-infected shrimp. By means of this non-selective WSSV-induced lipolysis, the LCFAs were apparently diverted into ß-oxidation and used to replenish the TCA cycle. Conversely, at 24 hpi, when the Warburg effect had ceased, most of the LCFAs were significantly up-regulated and the composition was also significantly altered. In crayfish these changes were in a direction that appeared to favor the formation of WSSV virion particles. We also found that, at 24 hpi, but not at 12 hpi, the PI3K-Akt-mTOR-HIF1α pathway induced the expression of fatty acid synthase (FAS), an enzyme which catalyzes the conversion of acetyl-CoA into LCFAs. WSSV virion formation was impaired in the presence of the FAS inhibitor C75, although viral gene and viral DNA levels were unaffected. WSSV therefore appears to use the PI3K-Akt-mTOR pathway to induce lipid biosynthesis at 24 hpi in order to support viral morphogenesis.

The Differential Effects of Anti-Diabetic Thiazolidinedione on Prostate Cancer Progression Are Linked to the TR4 Nuclear Receptor Expression Status.

The insulin sensitizers, thiazolidinediones (TZDs), have been used as anti-diabetic drugs since the discovery of their ability to alter insulin resistance through transactivation of peroxisome proliferator-activated receptors (PPARs). However, their side effects in hepatitis, cardiovascular diseases, and bladder cancer resulted in some selling restrictions in the USA and Europe. Here, we found that the potential impact of TZDs on the prostate cancer (PCa) progression might be linked to the TR4 nuclear receptor expression. Clinical surveys found that 9% of PCa patients had one allele TR4 deletion in their tumors. TZD increased cell growth and invasion in PCa cells when TR4 was knocked down. In contrast, TZD decreased PCa progression in PCa cells with wild type TR4. Mechanism dissection found that the Harvey Rat Sarcoma (HRAS) oncogene increased on TZD treatment of the TR4 knocked-down CWR22Rv1 and C4-2 cells, and interruption with HRAS inhibitor resulted in reversal of TZD-induced PCa progression. Together, these results suggest that TZD treatment may promote PCa progression depending on the TR4 expression status that may be clinically relevant since extra caution may be needed for those diabetic PCa patients receiving TZD treatment who have one allele TR4 deletion.

Pulmonary embolism in chronic obstructive pulmonary disease: a population-based cohort study.

BACKGROUND: To evaluate the incidence of pulmonary embolism (PE) in patients with chronic obstructive pulmonary disease (COPD) in Taiwan. METHODS: This was a retrospective population-based cohort study using data retrieved from Taiwan's National Health Insurance Research Database (2000 to 2008), which contains 99% of Taiwanese healthcare data. The evaluations included 355,878 COPD patients and 355,878 non-COPD patients for comparison. RESULTS: The incidence of PE in the COPD cohort was 12.31 per 10,000 person-years (1.37/10,000 persons/y), which was approximately 4-times higher than in the comparison cohort (0.35/10,000 persons/y). In the COPD cohort, risk of PE was higher in the young age group (20-59 y, HR 4.64, 95% CI 3.06-7.03) than in other age groups. Risk of PE was higher in patients with COPD combined with hypertension, coronary artery disease, and cancer, or those with previous operation (HR 4.16, 4.75, 4.56, and 4.50 respectively) than in those with COPD and no comorbidity. CONCLUSIONS: The overall incidence of PE is lower in Taiwan than in western countries. However, the prevalence of PE in COPD patients is higher than in non-COPD patients and increases with age. It is crucial to incorporate PE into the differential diagnosis of COPD exacerbation for clinical physicians.

Rheinheimera aquatica sp. nov., an antimicrobial activity producing bacterium isolated from freshwater culture pond.

A bacterial strain designated GR5(T) was isolated from freshwater culture pond in Taiwan during the screening of bacteria for antimicrobial compounds and characterized using the polyphasic taxonomic approach. Strain GR5(T) was Gram-negative, aerobic, greenish-yellow colored, rod-shaped, and motile by means of a polar single flagellum. Growth occurred at 10-40 degrees C (optimum, 35 degrees C), at pH 7.0-8.0 (optimum pH 8.0) and with 0-2.0% NaCl (optimum, 0.5-1.0%). The major fatty acids were C(16:1) omega7c (36.3%), C(16:0) (16.6%), C(12:0) 3-OH (12.5%) and C(18:1) omega7c (9.1%). The major respiratory quinone was Q-8. The DNA G+C content of the genomic DNA was 51.9 mol%. Phylogenetic analyses based on 16S rRNA gene sequences showed that strain GR5(T) belonged to the genus Rheinheimera and its most closely neighbours were Rheinheimera texasensis A62-14B(T) and Rheinheimera tangshanensis JA3-B52(T) with sequence similarities of 98.1 and 97.5%, respectively. The sequence similarities to any other recognized species within Gammaproteobacteria were less than 96.5%. The mean level of DNA-DNA relatedness between strain GR5(T) and R. texasensis A62-14B(T), the strain most closely related to the isolate, was 26.5 +/- 7.6 %. On the basis of the phylogenetic and phenotypic data, strain GR5(T) should be classified as representing a novel species, for which the name Rheinheimera aquatica sp. nov. is proposed. The type strain is GR5(T) (= BCRC 80081(T) = LMG 25379(T)).

Altered inflammatory responses in preterm children with cerebral palsy.

OBJECTIVE: Perinatal inflammatory responses contribute to periventricular leukomalacia (PVL) and cerebral palsy (CP) in preterm infants. Here, we examined whether preterm children with CP had altered inflammatory responses when school-aged. METHODS: Thirty-two preterm children with PVL-induced CP (mean [+/-standard deviation] age, 7.2 +/- 3.6 years) and 32 control preterm children with normal neurodevelopment (6.2 +/- 2.2 years) and matched for gestational age were recruited. We measured tumor necrosis factor (TNF)-alpha levels in the plasma and the supernatants of peripheral blood mononuclear cells (PBMCs) before and after lipopolysaccharide (LPS) stimulation, and proinflammatory gene expression in the PBMCs. RESULTS: TNF-alpha expression was significantly higher in the plasma (p < 0.001) and supernatants of LPS-stimulated PBMCs (p = 0.003) in the CP group than in the control group. After LPS stimulation, the intracellular TNF-alpha level in the PBMCs was significantly lower in the control group (p = 0.016) and significantly higher in the CP group (p = 0.01). The CP group also had, in their nonstimulated PBMCs, significantly higher mRNA levels of inflammatory molecules: toll-like receptor 4 (TLR-4) (p = 0.0023), TNF-alpha (p = 0.0016), transforming growth factor-beta-activated kinase 1 (p = 0.038), IkappaB kinase-gamma (p = 0.029), and c-Jun N-terminal kinase (p = 0.045). The TLR-4 mRNA levels in the PBMCs were highly correlated with TNF-alpha levels in LPS-stimulated PBMCs (Spearman rank correlation = 0.38, p = 0.03). INTERPRETATION: The finding that preterm children with PVL-induced CP have altered inflammatory responses indicates the possibility of programming effect of PVL or inflammation-related events during early life.

Time to rehospitalization in patients with major depressive disorder taking venlafaxine or fluoxetine.

OBJECTIVE: The combined serotonin-norepinephrine reuptake inhibitor, venlafaxine, has demonstrated better short-term efficacy than selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine in pooled analyses. This study aimed to compare venlafaxine and fluoxetine treatment in the long-term outcome measure, time to rehospitalization, in patients with major depressive disorder. Other clinical factors that may influence time to rehospitalization were also explored. METHOD: Han Chinese patients were admitted to the depression inpatient unit of a major psychiatric center in Taiwan from January 1, 2002, to December 31, 2003. Patients with major depressive disorder (DSM-IV) who showed favorable treatment response to venlafaxine (mean +/- SD dose = 116.5 +/- 42.5 mg/day; N = 122) or fluoxetine (mean +/- SD dose = 25.1 +/- 9.0 mg/day; N = 80) during hospitalization were followed up for 1 year after discharge under naturalistic conditions. The 2 treatment groups were similar in demographic and clinical characteristics: sex, age, age at illness onset, comorbid anxiety disorders, personality disorders, nicotine dependence, psychotic features, adjunctive antipsychotics use, duration of index hospitalization, and number of previous hospitalizations. Time to rehospitalization was measured by the Kaplan-Meier method. Possible associations of rehospitalization with other covariates were analyzed using the Cox proportional hazards regression model. RESULTS: No significant difference for the time to rehospitalization was found between the 2 groups by the log-rank test. The number of previous admissions (hazard ratio = 1.331, 95% CI = 1.153 to 1.538, p = .000), but not other factors, increased the risk of rehospitalization. CONCLUSION: The findings suggest that venlafaxine and fluoxetine have similar effects on time to rehospitalization in patients with major depressive disorder. The relatively low dose of venlafaxine may have contributed to the negative finding. Previous hospitalization history may raise the risk of rehospitalization. Longer-term, double-blind, randomized, fixed-dose studies are warranted to better delineate the effectiveness of different pharmacotherapeutic regimens for the outcomes of patients with major depressive disorder.

Mechanical ventilation may increase susceptibility to the development of bacteremia.

OBJECTIVE: We examined the hypothesis that mechanical ventilation with a potentially injurious strategy would predispose animals to the detrimental effects of subsequent instillation of bacteria. DESIGN: Interventional animal study. SETTING: A university hospital research laboratory. SUBJECTS: Fifty Sprague-Dawley male rats. INTERVENTIONS: Rats were anesthetized and randomized to receive a protective (tidal volume 7 mL/kg, positive end-expiratory pressure 5 cm H(2)O, n = 25) or an injurious ventilatory strategy (tidal volume 21 mL/kg, zero positive end-expiratory pressure, n = 25). Hemodynamics were similar during the 1-hr ventilation period in the two groups. Animals were then disconnected from the ventilator and Pseudomonas aeruginosa was instilled intratracheally before extubation. Thereafter, animals breathed spontaneously; mortality rate was assessed up to 48 hrs, at which time the animals were killed. MEASUREMENTS AND MAIN RESULTS: The 48-hr mortality rate was 28% in the protective group and 40% in the injurious group (p = not significant). A positive bacterial culture from the lung was obtained in 56% of the surviving rats in the low tidal volume group and 67% in the high tidal volume group (p =.059). A positive blood bacterial culture was found in 11% of the low tidal volume group and 33% in the high tidal volume group (p <.05). The absolute bacterial count in the blood was lower in the low tidal volume group compared with the high tidal volume group (p <.05). Concentrations of blood tumor necrosis factor-alpha and macrophage inflammatory protein-2, and lung macrophage inflammatory protein-2 at 48 hrs were significantly higher in the low tidal volume group than in the high tidal volume group. CONCLUSIONS: An injurious ventilatory strategy predisposes animals to subsequent bacteremia associated with an impaired host defense reflected by cytokine response.

Ventilation with negative airway pressure induces a cytokine response in isolated mouse lung.

UNLABELLED: We tested the hypothesis that, under relatively low tidal volume (VT) mechanical ventilation, continuing lung decruitment induced by negative end-expiratory pressure (NEEP) would increase the lung cytokine response, potentially contributing to lung injury. Mouse lungs were excised and randomly assigned to one of 3 different ventilatory strategies: 1) the zero end-expiratory pressure group served as a control, 2) the NEEP7 group received a NEEP of -7.5 cm H(2)O, and 3) the NEEP15 group received a NEEP of -15 cm H(2)O. In all 3 groups, a VT of 7 mL/kg was used. After 2 h of ventilation, lung lavage fluid was collected for measurements of tumor necrosis factor-alpha, monocyte chemoattractant protein-1, and lactate dehydrogenase. Increases in plateau pressure before and after mechanical ventilation were significantly greater in the NEEP15 group compared with the zero end-expiratory pressure group or NEEP7 group. Lung compliance was decreased in the NEEP15 compared with the other two groups. Concentrations of tumor necrosis factor-alpha, monocyte chemoattractant protein-1, and lactate dehydrogenase in lung lavage were larger in the NEEP15 group than in the other groups. Atelectatic lung during repeated collapse and reopening of lung units accentuates the lung cytokine response that may contribute to lung injury even during relatively low VT mechanical ventilation. IMPLICATIONS: Repeated closing and reopening of lung units induced by negative end-expiratory pressure resulted in lung inflammation and cell injury even under mechanical ventilation using a normal tidal volume. This finding may have clinical relevance in certain patients who are prone to atelectasis during mechanical ventilation.