The effect of valproic acid on SLC5A8 expression in gonad-intact and gonadectomized rat thymocytes.

BACKGROUND: Valproic acid (VPA) pharmacological mechanisms are related to the anti-inflammatory and anti-viral effects. VPA is a histone deacetylases inhibitor and serves a role in its immunomodulatory impacts. VPA has complex effects on immune cell's mitochondrial metabolism. The SLC5A8 transporter of short fatty acids has an active role in regulating mitochondrial metabolism. The study aimed to investigate whether SLC5A8 expresses the sex-related difference and how SLC5A8 expression depends on gonadal hormones, VPA treatment, and NKCC1 expression in rat thymocytes. METHODS: Control groups and VPA-treated gonad-intact and gonadectomized Wistar male and female rats were investigated (n = 6 in a group). The VPA 300 mg/kg/day in drinking water was given for 4 weeks. The SLC5A8 (Slc5a8 gene) and NKCC1 (Slc12a2 gene) RNA expressions were determined by the RT-PCR method. RESULTS: The higher Slc5a8 expression was found in the gonad-intact males than respective females (p = 0.004). VPA treatment decreased the Slc5a8 expression in gonad-intact and castrated males (p = 0.02 and p = 0.03, respectively), and increased in gonad-intact female rats compared to their control (p = 0.03). No significant difference in the Slc5a8 expression between the ovariectomized female control and VPA-treated females was determined (p > 0.05). VPA treatment alters the correlation between Slc5a8 and Slc12a2 gene expression in thymocytes of gonad-intact rats. CONCLUSION: VPA effect on the Slc5a8 expression in rat thymocytes is gender- and gonadal hormone-dependent.

The Effectiveness of Dichloroacetate on Human Glioblastoma Xenograft Growth Depends on Na+ and Mg2+ Cations.

The study's aim was to investigate the effectiveness of sodium dichloroacetate (NaDCA) or magnesium dichloroacetate (MgDCA) on adult U87 MG and pediatric PBT24 cell lines glioblastoma (GB) xenografts in a chicken chorioallantoic membrane (CAM) model. The study groups were: treated with 10 mM, 5 mM of NaDCA, and 5 mM, 2.5 mM of MgDCA, and controls. The U87 MG and PBT24 xenografts growth, frequency of tumor invasion into CAM, CAM thickening, and the number of blood vessels in CAM differed depending on the dichloroacetate salt treatment. NaDCA impact on U87 MG and PBT24 tumor on proliferating cell nunclear antigen (PCNA) and enhancer of zeste homolog 2 (EZH2) expression in the tumor was different, depending on the NaDCA dose. The 5 mM MgDCA impact was more potent and had similar effects on U87 MG and PBT24 tumors, and its impact was also reflected in changes in PCNA and EZH2 expression in tumor cells. The U87 MG and PBT24 tumor response variations to treatment with different NaDCA concentration on tumor growth or a contrast between NaDCA and MgDCA effectiveness may reflect some differences in U87 MG and PBT24 cell biology.

The Importance of Gender-Related Anticancer Research on Mitochondrial Regulator Sodium Dichloroacetate in Preclinical Studies In Vivo.

Sodium dichloroacetate (DCA) is an investigational medicinal product which has a potential anticancer preparation as a metabolic regulator in cancer cells' mitochondria. Inhibition of pyruvate dehydrogenase kinases by DCA keeps the pyruvate dehydrogenase complex in the active form, resulting in decreased lactic acid in the tumor microenvironment. This literature review displays the preclinical research data on DCA's effects on the cell pyruvate dehydrogenase deficiency, pyruvate mitochondrial oxidative phosphorylation, reactive oxygen species generation, and the Na+-K+-2Cl- cotransporter expression regulation in relation to gender. It presents DCA pharmacokinetics and the hepatocarcinogenic effect, and the safety data covers the DCA monotherapy efficacy for various human cancer xenografts in vivo in male and female animals. Preclinical cancer researchers report the synergistic effects of DCA combined with different drugs on cancer by reversing resistance to chemotherapy and promoting cell apoptosis. Researchers note that female and male animals differ in the mechanisms of cancerogenesis but often ignore studying DCA's effects in relation to gender. Preclinical gender-related differences in DCA pharmacology, pharmacological mechanisms, and the elucidation of treatment efficacy in gonad hormone dependency could be relevant for individualized therapy approaches so that gender-related differences in treatment response and safety can be proposed.

Valproic Acid Inhibits NA-K-2CL Cotransporter RNA Expression in Male But Not in Female Rat Thymocytes.

OBJECTIVE: The NKCC1 is a recognized tumorigenesis marker as it is important for tumor cell proliferation, differentiation, apoptosis, and tumor progression. The study aim was to investigate the effect of sodium valproate (VPA) on thymus NKCC1 RNA expression. MATERIAL AND METHODS: Wistar rats, age 4 to 5 weeks, were investigated in the control and VPA-treated male and female gonad-intact and castrated groups. The treatment duration with VPA 300 mg/kg/d was 4 weeks. Rat thymus was weighted; its lobe was taken for the expression of NKCC1 RNA determined by the real-time polymerase chain reaction method. RESULTS: The RNA expression of the Slc12a2 gene was found to be significantly higher in the gonad-intact male control compared with the gonad-intact female control (P = .04). There was a gender-related VPA treatment effect on NKCC1 RNA expression in thymus: The Slc12a2 gene RNA expression level was found to be decreased in VPA-treated gonad-intact males (P = .015), and no significant VPA effects were found in the castrated males and in the gonad-intact and castrated females compared with the respective controls (P > .05). CONCLUSIONS: The study showed a gender-related difference in the NKCC1 RNA expression in rat thymus. The VPA decreases the NKCC1 expression in the thymus only in gonad-intact male rats. The NKCC1 RNA expression downregulation by VPA could be important for further VPA pharmacological studies in oncology.

Gender-Related Effect of Sodium Dichloroacetate on the Number of Hassall's Corpuscles and RNA NKCC1 Expression in Rat Thymus.

The aim was to investigate the effect of dichloroacetate (DCA) on thymus weight, Hassall's corpuscle number (HCs), and NKCC1 RNA expression in Wistar rats aged 4-5 weeks. They were investigated in the controls and DCA-treated gonad-intact and castrated males and females. The treatment lasted 4 weeks with DCA 200 mg/kg/day. At the end of the experiment, rat thymus was weighted, and its lobe was taken for the expression of NKCC1 RNA determined by the PCR method and of Hassall's corpuscles by immunohistochemistry. DCA caused a thymus weight decrease in DCA-treated gonad-intact rats of both genders as compared with their controls (p < 0.05), and no such impact was found in castrated DCA-treated males and females. DCA caused an increase of the HCs in gonad-intact males (p < 0.05), and no such increase in the DCA-treated gonad-intact females was found. There was gender-related difference in the HCs when comparing DCA-treated gonad-intact males and females: males showed significantly higher HCs (p < 0.05); no gender-related differences were found in the castrated DCA-treated groups. The Slc12a2 gene RNA expression level was found to be significantly decreased only in gonad-intact and in castrated DCA-treated males. The authors discuss the gender-related DCA effects on the thymus.

Sodium Dichloroacetate Pharmacological Effect as Related to Na-K-2Cl Cotransporter Inhibition in Rats.

The study objective was to investigate a possible sodium dichloroacetate (DCA) pharmacological mechanism causing an increase in diuresis in rats. The aim was to define characteristics of 24-hour urinary Na+, K+, Cl-, Ca2+, and Mg2+ excretion in Wistar male rats and to evaluate effect of a single-dose DCA and repeated DCA dosage on diuresis. Six control and 6 DCA-treated male rats aged 5 to weeks after a single DCA dose and repeated dosage were tested. The single DCA dose treatment caused a significantly higher 24-hour diuresis when compared to control (P < .05), and it was related to increased Cl-, Na+, and K+ urine excretion and a significant increase in Ca2+ and Mg2+ excretion (P < .05); after the repeated 4-week DCA dosage, the diuresis was not increased, but the excretion of the Na+, Cl-, Ca2+, and Mg2+ ions was significantly higher. Kidney immunohistochemistry has revealed that DCA continuous treatment results in an increase in the size of Henle loop thick ascending limb epithelial cells (P < .001). The study results show a significantly reduced RNA expression of Na-K-2Cl co-transporter (NKCC1) in thymus of 4-week DCA-treated rats (P < .03). The study data have indicated a possible mechanism of such pharmacological effect to be NKCC inhibition.

ABO blood group polymorphism has an impact on prostate, kidney and bladder cancer in association with longevity.

The aim of the present study was to assess the ABO blood group polymorphism association with prostate, bladder and kidney cancer, and longevity. The following data groups were analyzed: Prostate cancer (n=2,200), bladder cancer (n=1,530), renal cell cancer (n=2,650), oldest-old (n=166) and blood donors (n=994) groups. The data on the ABO blood type frequency and odds ratio in prostate cancer patients revealed a significantly higher blood group B frequency (P<0.05); the pooled men and women, separate men bladder cancer risk was significantly associated with the blood group B (P<0.04); however, no such association was identified in the female patients. The blood group O was observed to have a significantly decreased risk of bladder cancer for females (P<0.05). No significance for the ABO blood group type in the studied kidney cancer patients was identified. A comparison of the oldest-old and blood donor groups revealed that blood group A was significantly more frequent and blood type B was significantly rarer in the oldest-olds (P<0.05). The results of the present study indicated that blood type B was associated with the risk of prostate and bladder cancer, and could be evaluated as a determinant in the negative assocation with longevity. Blood types O and A may be positive factors for increasing the oldest-old age likelihood. The clustering analysis by the ABO type frequency demonstrated that the oldest-olds comprised a separate cluster of the studied groups.