The CYP3A inducer dexamethasone affects the pharmacokinetics of sunitinib by accelerating its metabolism in rats.

Sunitinib, a novel anti-tumor small molecule targeting VEGFR, is prescribed for advanced RCC and GISTs. Sunitinib is primarily metabolized by the CYP3A enzyme. It is well-known that dexamethasone serves as a potent inducer of this enzyme system. Nonetheless, the effect of dexamethasone on sunitinib metabolism remains unclear. This study examined the effect of dexamethasone on the pharmacokinetics of sunitinib and its metabolite N-desethyl sunitinib in rats. The plasma levels of both compounds were measured using UHPLC-MS/MS. Pharmacokinetic parameters and metabolite ratio values were calculated. Compare to control group, the low-dose dexamethasone group and high-dose dexamethasone group decreased the AUC(0-t) values of sunitinib by 47 % and 45 %, respectively. Meanwhile, the AUC(0-t) values of N-desethyl sunitinib were increased by 2.2-fold and 2.4-fold in low-dose dexamethasone group and high-dose dexamethasone group, respectively. The CL values for sunitinib were both approximately 45 % higher in the two dexamethasone groups. Remarkably, metabolite ratio values increased over 5-fold in both low-dose dexamethasone group and high-dose dexamethasone group, indicating a significant enhancement of sunitinib metabolism by dexamethasone. Moreover, the total levels of sunitinib and its metabolite are also significantly increased. The impact of interactions on sunitinib metabolism, as observed with CYP3A inducers such as dexamethasone, is a crucial consideration for clinical practice. To optimize the dosage and prevent adverse drug events, therapeutic drug monitoring can be employed to avoid the toxicity from such interactions.

Inflammatory age and its impact on age-related health in older Chinese adults.

INTRODUCTION: A standardized measure for inflammaging is lacking. We introduced the inflammatory age (iAge) as a quantification method and explored its associations with age-related traits and diseases in an older Chinese cohort. METHODS: Inflammatory markers including white blood cell count (WBC), neutrophils, lymphocytes, monocytes, C-reactive protein, platelets and albumin were measured. Quantitative real-time polymerase chain reaction was used to measure telomere length. Traditional multivariable linear, partial least squares, and logistic regression were used. RESULTS: iAge was constructed based on WBC, neutrophils, monocytes and albumin, which were associated with telomere length independently. A higher iAge indicated a heavier aging-related inflammation burden. Per 1-year increase in iAge was associated with higher body mass index (ß 0.86 (95 % CI 0.67, 1.05) kg/m2), waist circumference (ß 2.37 (95 % CI 1.85, 2.90) cm), glycosylated hemoglobin A1c (ß 0.06 (95 % CI 0.02, 0.10) %), systolic blood pressure (ß 1.06 (95 % CI 0.10, 2.03) mmHg), triglycerides (ß 0.05 (95 % CI 0.01, 0.08) mmol/L), 10-year cardiovascular diseases risk (ß 0.05 (95 % CI 0.02, 0.08) %), diabetes (OR 1.22 (95 % CI 1.02, 1.46)), hypertension (OR 1.21 (95 % CI 1.04, 1.42)) and metabolic syndrome risks (OR 1.25 (95 % CI 1.04, 1.51)), and lower fasting plasma glucose (ß -0.016 (95 % CI -0.024, -0.007) mmol/L), total cholesterol (ß -0.06 (95 % CI -0.12, -0.01) mmol/L) and high-density lipoprotein cholesterol (ß -0.05 (95 % CI -0.07, -0.03) mmol/L). CONCLUSION: The newly introduced iAge, derived from inflammatory markers and telomere length, aligns with various metabolic dysfunctions and age-related disease risks, underscoring its potential ability in identifying aging-related phenotypes.

Association of fish and meat consumption with non-alcoholic fatty liver disease: Guangzhou Biobank Cohort Study.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. Unhealthy dietary habit is one of major risk factors of NAFLD. However, the associations between specific types of fish and meat consumption and NAFLD remain inconclusive. We explored the associations of fish and meat consumption with NAFLD risk in middle-aged and older Chinese. METHODS: We collected information on 1,862 participants aged 50 years or older from Guangzhou Biobank Cohort Study in 2009 to 2010. Fish and meat consumption was assessed using a validated food-frequency questionnaire. NAFLD was diagnosed by ultrasound. Multivariable logistic regression was used to examine the associations of fish and meat consumption with the presence of NAFLD. RESULTS: The average age was 61.0 (standard deviation = 6.5) years for the participants, 50.2% were women, and 37.2% were diagnosed with NAFLD. After adjusting for age, sex, education, family income, occupation, smoking status, drinking status, physical activity and several metabolic traits, compared with 0 serving/week (one serving = 50 g), fatty fish consumption of ≥ 3 servings/week showed higher odds of NAFLD (odds ratio (OR) and 95% confidence interval (CI): 1.64 (1.12, 2.39)). The highest (≥ 11 servings/week of red meat and poultry; ≥ 3 servings/week of processed meat) versus the lowest (0-3 servings/week of red meat and poultry; 0 serving/week of processed meat) consumption of all other types of meats, including red meat, poultry and processed meat, showed no association with NAFLD (1.17 (0.75, 1.81), 1.02 (0.42, 2.50) and 0.85 (0.50, 1.45), respectively). Aquatic and sea food, and red meat had negative indirect effects on NAFLD via systolic blood pressure and/or high-density lipoprotein cholesterol. Processed meat had positive indirect effects on NAFLD via body mass index, waist circumference, fasting plasma glucose and triglycerides. CONCLUSION: High consumption of fatty fish was associated with higher NAFLD risk. Our results, if causal, provide evidence that limiting consumption of fatty fish can be considered as part of NAFLD lifestyle prevention and treatment.

Free energy dissipation of the spontaneous gating of a single voltage-gated potassium channel.

Potassium channels mainly contribute to the resting potential and re-polarizations, with the potassium electrochemical gradient being maintained by the pump Na+/K+-ATPase. In this paper, we construct a stochastic model mimicking the kinetics of a potassium channel, which integrates temporal evolving of the membrane voltage and the spontaneous gating of the channel. Its stationary probability density functions (PDFs) are found to be singular at the boundaries, which result from the fact that the evolving rates of voltage are greater than the gating rates of the channel. We apply PDFs to calculate the power dissipations of the potassium current, the leakage, and the gating currents. On a physical perspective, the essential role of the system is the K+-battery charging the leakage (L-)battery. A part of power will inevitably be dissipated among the process. So, the efficiency of energy transference is calculated.

Analytical solution of the steady membrane voltage fluctuation caused by a single ion channel.

An analytical steady-state solution of the stochastic model describing the integrated dynamics of the membrane voltage and the gating of a single channel is presented. The voltage density function experiences bifurcation in the parameter space, and the threshold is determined by the comparison between the rates of the voltage evolution and that of the channel gating. It is singular at the reversal potential if the voltage evolves faster than the channel gating. As an application, the entropy production rate associated with the gating currents is calculated; its variation tendency in parameter space is consistent to that of the number of transitions counted from the sample paths. The analysis in this paper identifies the values of parameters that justify the formation of the voltage pulse and the efficient energy cost, which is associated with the singularity of the voltage density functions.

[Design, synthesis of quinolinone acid-containing compounds with anti-HIV integrase activity].

A series of novel quinolinone acid-containing compounds were designed and synthesized. Their structures were confirmed with 1H NMR and MS. The target compounds were tested for anti-HIV-1 integrase activities in vitro with enzyme linked immunosorbent assay (ELISA). The result showed that D-2, D-4 and D-7 have anti-integrase activity with IC50 < 100 micromol L(-1).

Sonic hedgehog-induced neural precursor proliferation after adult rodent spinal cord injury.

OBJECT: The glycoprotein molecule sonic hedgehog (Shh) has been shown to play a critical role in neuraxial development. To assess its role in the repair of demyelination following spinal cord injury (SCI), escalating doses of Shh were injected into demyelinated lesions in adult rat spinal cords. METHODS: Twenty-seven adult rats underwent thoracic laminectomy and chemical demyelination of the spinal cord dorsal columns without neurological deficit A subset of 20 rats was treated after 3 days by direct injection of Shh at two different doses. Rats were killed at 7 or 21 days after SCI, and tissue samples underwent immediate fixation or were placed into cell culture. Diffuse cellular proliferative responses throughout the gray and white matter were observed in up to 70% of Shh-treated rats. Proliferation around the central canal, believed to be derived from the ventricular ependyma consistent with neuronal stem cell induction, was demonstrated in up to 60% of the treated rats. No significant proliferation in these areas was detected in control rats. Dorsal areas of nestin-positive cells were also observed in 70% of rats treated with high doses of Shh, and these observations were reproduced in cell culture as well as in cultures of dorsal spinal cord explants. Cell counts revealed significant increases in the percentage of oligodendrocyte precursors and neurons in treated compared with control rats. CONCLUSIONS: Exogenous Shh administration promotes nestin-positive cell proliferation after SCI in adult rodents. These cells are believed to be derived from neural precursor cells. The populations of oligodendrocyte precursors and neurons were likewise increased in Shh-treated rats, suggesting that these cells may be derived from neural stem cells.