[Pharmacokinetics and tissue distribution of four alkaloids in Ermiao Pills and Sanmiao Pills in normal and arthritic model rats].

This work aimed to investigate the differences of pharmacokinetics and tissue distribution of four alkaloids in Ermiao Pills and Sanmiao Pills in normal and arthritic model rats. The rat model of arthritis was established by injecting Freund's complete adjuvant, and ultra-high performance liquid chromatography-tandem mass spectrometry(UPLC-MS/MS) in the positive ion multiple reaction monitoring(MRM) mode was used for the determination of four alkaloids in plasma and tissues of normal and arthritic rats after administration of Ermiao Pills and Sanmiao Pills, respectively. The differences in pharmacokinetics and tissue distribution of the four active components were compared, and the effect of Achyranthis Bidentatae Radix on the major components of Sanmiao Pills was explored. This study established an UPLC-MS/MS for simultaneous determination of four alkaloids, and the specificity, linearity, accuracy, precision, and stability of this method all met the requirements. Pharmacokinetics study found that as compared with normal rats, the AUC and C_(max) of phellodendrine, magnoflorine, berberine and palmatine in model rats were significantly decreased after administration of Ermiao Pills, the clearance rate CL/F was significantly increased, and the distribution and tissue/plasma concentration ratio of the four alkaloids in the liver, kidney, and joint were significantly reduced. Achyranthis Bidentatae Radix increased the AUC of phellodendrine, berberine, and palmatine, reduced the clearance rate, and significantly increased the distribution of the four alkaloids in the liver, kidney, and joints in arthritic rats. However, it had no significant effect on the pharmacokinetics and tissue distribution of the four alkaloids in normal rats. These results suggest that Achyranthis Bidentatae Radix may play a guiding role in meridian through increasing the tissue distribution of effective components in Sanmiao Pills under arthritis states.

Rutaecarpine enhances the anti-diabetic activity and hepatic distribution of metformin via up-regulation of Oct1 in diabetic rats.

Diabetes mellitus is a chronic metabolic disorder with multiple complications, patients who receive metformin may have a simultaneous intake of herbal medicine containing rutaecarpine due to cardiovascular protection and hypolipidemic effects of rutaecarpine. There might be drug interactions between metformin and rutaecarpine. This study aimed to investigate the effects of rutaecarpine on the pharmacodynamics and pharmacokinetics of metformin in diabetic rats.The diabetic rat model was induced with high-fat diet and low dose streptozotocin. Metformin with or without rutaecarpine was administered by oral gavage for 42 days. Pharmacodynamics and pharmacokinetics parameters were evaluated.The pharmacodynamics results revealed that co-administration of rutaecarpine with metformin resulted in a remarkable reduction of serum glucose and lipid profiles in diabetic rats compared to metformin treated alone. The pharmacokinetics results showed that co-treatments of rutaecarpine with metformin did not affect the systemic exposure and renal distribution of metformin, but increased metformin concentration in liver. Furthermore, rutaecarpine increased Oct1-mediated metformin uptake into hepatocytes by upregulation of Oct1 expression in the liver.The above data indicate that rutaecarpine enhanced the anti-diabetic effect of metformin, which may be associated with the increased hepatic distribution of metformin through up-regulation of Oct1 in response to rutaecarpine.

Involvement of organic anion-transporting polypeptides and organic cation transporter in the hepatic uptake of jatrorrhizine.

Jatrorrhizine possesses a wide spectrum of pharmacological activities. However, the mechanism underlying hepatic uptake of jatrorrhizine remains unclear.Rat liver slices, isolated rat hepatocytes and human embryonic kidney 293 (HEK293) cells stably expressing human organic anion-transporting polypeptide (OATP) and organic cation transporter (OCT) were used to evaluate the hepatic uptake of jatrorrhizine in this study.Uptake of jatrorrhizine in rat liver slices and isolated rat hepatocytes was significantly inhibited by glycyrrhizic acid (Oatp1b2 inhibitor) and prazosin (Oct1 inhibitor), but not by ibuprofen (Oatp1a1 inhibitor) or digoxin (Oatp1a4 inhibitor). Uptake of jatrorrhizine in OATP1B3 and OCT1-HEK293 cells indicated a saturable process with the Km of 8.20 ± 1.28 and 4.94 ± 0.55 µM, respectively. However, the transcellular transport of jatrorrhizine in OATP1B1-HEK293 cells was not observed. Rifampicin (OATP inhibitor) for OATP1B3-HEK293 cells and prazosin for OCT1-HEK293 cells could inhibit the uptake of jatrorrhizine with the IC50 of 5.49 ± 1.05 and 2.77 ± 0.72 µM, respectively.The above data indicate that hepatic uptake of jatrorrhizine is involved in both OATP and OCT, which may have important roles in jatrorrhizine liver disposition and potential drug-drug interactions.

The Hydraulic Driving Mechanisms of Cyanobacteria Accumulation and the Effects of Flow Pattern on Ecological Restoration in Lake Dianchi Caohai.

Due to rapid increases in socioeconomic development and the human population over the past few decades, the shallow lakes in China have suffered from eutrophication and poor water quality. The conditions in Lake Dianchi Caohai, which is in the northern part of Lake Dianchi, are considered the most serious. The ecological restoration of Lake Dianchi Caohai began in the late 1980s. Lake managers and the public have been puzzled by the lack of a significant response of the water quality to the flow pattern despite the tremendous investment in water quality improvements. Therefore, lake managers desperately need to understand the responses of pollutant behaviors to proposed management measures. In this paper, a depth-averaged two-dimensional hydrodynamic and water quality model based on hydrological data, measured lake bed elevation, and water quality data is developed to simulate the flow field and water quality of Lake Dianchi Caohai. This model was validated using water quality data from the Caohaizhongxin site in 2016, and a close agreement was found between the model results and observations. Wind-driven circulation in Lake Dianchi Caohai was observed in the model results, which revealed that the lake flow pattern was dominated by wind-driven circulation, while the inflow/outflow played only a subsidiary role during this period. The formation of the wind-driven current in Lake Dianchi Caohai could be roughly divided into three stages. The hydrodynamic processes connected with the distribution of chlorophyll a are evaluated and discussed to adequately understand the hydraulic mechanisms driving the accumulation of cyanobacteria. Moreover, we designed three scenarios after comparing all possible operation scenarios to analyze the contributions of each different operation scenario to the water quality improvements. The optimal ecological operation scenario which has the best impacts on the water quality, especially the reduction in Chla and NH3-N concentration, is proposed based on our comprehensive analysis. The water quality improvement and management suggestions proposed in this paper are based on lake flow patterns and make up for previous studies that did not consider the effects of hydraulic characteristics on water quality improvement in Lake Dianchi Caohai.

[Effect of Saposhnikoviae Radix on pharmacokinetics and tissue distributions of active components in Tongxie Yaofang in rats].

Tongxie Yaofang (TXYF) is a famous formula that has been used for treating gastrointestinal diseases in traditional Chinese medicine(TCM). Saposhnikoviae Radix is considered as a meridian guiding drug in TXYF and could enhance the effectiveness of prescription. However, the scientific evidence for this effect is still not clear. To reveal the interactions of Saposhnikoviae Radix with other herbs, we conducted this study on the pharmacokinetic profile and tissue distribution of active ingredients of TXYF in rats. The concentrations of four components in blood and tissues were determined by UPLC-MS/MS after oral administration with TXYF. The detection was carried out by electrospray ionization mass spectrometry in the multiple reaction monitoring (MRM) mode. The positive and negative ion switching technique was performed in the same analysis. The results revealed that Saposhnikoviae Radix could enhance Cmax, AUC0-t, and AUC0-∞ of paeoniflorin and hesperidin, and increase the distribution of atractylenolide-I, paeoniflorin and hesperidin in liver, spleen, brain and small intestine. Saposhnikoviae Radix increased the ratio of brain to blood concentrations of atractylenolide-I, paeoniflorin and hesperidin. Meanwhile, it reduced the ratio of lung to blood concentrations of atractylenolide-I and paeoniflorin. Saposhnikoviae Radix, and may enhance the effectiveness of prescriptions by promoting distribution of other herbs in brain.

Reliability and validity of the quality of life-Alzheimer disease Chinese version.

OBJECTIVES: To evaluate the psychometric properties of the quality of life-Alzheimer disease (QOL-AD) Chinese version in patients with dementia in mainland, China and to compare patient and caregiver reports of patient QOL. METHODS: The QOL-AD Chinese version was established following standard guidelines for cross-cultural adaptation of measures. The reliability was assessed by internal consistency and test-retest reliability. The validity included construct and convergent validity. A paired Student t test was performed to determine differences between patient reports and caregiver reports. RESULTS: The reliability for both patient and caregiver reports on the QOL-AD was good (Cronbach α values of 0.66 and 0.87; intraclass correlation coefficients of 0.84 and 0.90 for patient and caregiver reports, respectively). The validity of patient and caregiver reports was supported by correlation with domain measures. All of the multitrait-multimethod correlations demonstrated a high relationship between patient reports and caregiver reports, ranging from 0.26 to 0.55. The caregivers rated patient QOL significantly higher than did the patients. CONCLUSION: The findings support the use of the Chinese version of the QOL-AD as a generic instrument to measure QOL of AD in mainland China. Further research is needed to clarify the relationship between patient and caregiver reports of patient QOL.

Effect of total dissolved gas supersaturated water on early life of David's schizothoracin (Schizothorax davidi).

The effect of total dissolved gas (TDG) supersaturation on fish living downstream of dams is one of the main ecological risks of high dam construction. A strategy for mitigating the negative effects is needed urgently since many high dams are under construction in the upper reaches of the Yangtze River in China. Experiments on the hatching process of David's schizothoracin were carried out and the results show that the hatching rate decreased with increasing TDG levels, and that most eggs hatched within a very short time in the higher TDG saturation groups. By using a stereomicroscope, damages to the head, yolk sac, body, anus, etc. were found in larvae which hatched in TDG supersaturated water. Results show that the lesion rate increased with increasing TDG levels. Furthermore, 7-d-old David's schizothoracin were exposed to TDG supersaturated water levels of 100%, 105%, 110%, 115%, 120%, 125%, 130%, 135%, and 140% for testing their tolerance to TDG supersaturation. We found that the median lethal concentrations (LC50) for 13, 14, 20, 35, 52, 73, and 96 h exposure were 138%, 138%, 134%, 130%, 129%, 128%, and 126%, respectively. The median lethal times (LT50) were 7.49, 11.04, 19.25, and 35.38 h for exposure to water with TDG levels of 145%, 140%, 135%, and 130%, respectively.

Impact of sub-chronic aluminium-maltolate exposure on catabolism of amyloid precursor protein in rats.

OBJECTIVE: To investigate the impact of sub-chronic Aluminium-maltolate [Al(mal)3] exposure on the catabolism of amyloid precursor protein (APP) in rats. METHODS: Forty adult male Sprague-Dawley (SD) rats were randomly divided into five groups: the control group, the maltolate group (7.56 mg/kg BW), and the Al(mal)3 groups (0.27, 0.54, and 1.08 mg/kg BW, respectively). Control rats were administered with 0.9% normal saline through intraperitoneal (i.p.) injection. Maltolate and Al(mal)3 were administered to the rats also through i.p. injections. Administration was conducted daily for two months. Rat neural behavior was examined using open field tests (OFT). And the protein expressions and their mRNAs transcription related with APP catabolism were studied using enzyme-linked immunosorbent assay (ELISA) and real-time polymerase chain reaction (RT-PCR). RESULTS: The expressions of APP, ß-site APP cleaving enzyme 1 (BACE1) and presenilin-1 (PS1) proteins and their mRNAs transcription increased gradually with the increase of Al(mal)3 doses (P<0.05). The enzyme activity of BACE1 in the 0.54 and 1.08 mg/kg Al(mal)3 groups increased significantly (P<0.05). The expression of ß-amyloid protein (Aß) 1-40 gradually decreased while the protein expression of Aß1-42 increased gradually with the increase of Al(mal)3 doses (P<0.05). CONCLUSION: Result from our study suggested that one of the possible mechanisms that Al(mal)3 can cause neurotoxicity is that Al(mal)3 can increase the generation of Aß1-42 by facilitating the expressions of APP, ß-, and γ-secretase.

[Effect of aluminum exposure on cognitive function in electrolytic workers and its influential factors].

OBJECTIVE: To clarify the effect of aluminum exposure on the cognitive function in electrolytic workers and the prevalence of mild cognitive impairment (MCI) among them by prevalence survey, and to investigate its influential factors. METHODS: Sixty-six retired workers from the electrolysis workshop of an electrolytic aluminum plant were selected as an aluminum exposure group, while 70 retired workers from a flour mill in the same region were selected as a control group. MCI patients were screened out by Mini-Mental State Examination (MMSE); the blood aluminum level was measured by inductively coupled plasma-mass spectrometry; multivariate statistical analysis was used to investigate the influential factors for MMSE scores and the correlation between blood aluminum level and MCI prevalence. RESULTS: The aluminum exposure group showed a significantly higher blood aluminum level than the control group (25.18 ± 2.65 µg/L vs 9.97 ± 2.83 µg/L, P < 0.01). The total MMSE score of the aluminum exposure group (26.13 ± 2.57) was significantly lower than that of the control group (27.89 ± 1.91) (P < 0.05), particularly the scores on time and place orientation, short-term memory, calculation ability, and language skill (P < 0.05). The detection rate of MCI was significantly higher in the aluminum exposure group (18.2%) than in the control group (5.7%) (P < 0.01). The main influential factors for MMSE scores were gender, age, education level, and blood aluminum level. The logistic regression analysis indicated that the MCI prevalence was significantly correlated with blood aluminum level in the study population (OR = 1.168, P < 0.01). CONCLUSION: Long-term exposure to aluminum can cause cognitive disorders in electrolytic workers and may be one of the risk factors for MCI. Advanced age, male, low education level, and high blood aluminum level may be high-risk factors for cognitive impairment.

Multi-state Markov model in outcome of mild cognitive impairments among community elderly residents in Mainland China.

BACKGROUND: Although knowledge of established risk factors for Alzheimer's disease (AD) can logically contribute to the search for predictors of the progression of cognitive impairment, it has not yet been firmly established where in the cognitive impairment process these risk factors exert their effects and how to predict quantitatively for the progression of mild cognitive impairments (MCI) to AD. This study aimed to determine whether known risk factors increased the risk of progression from MCI to AD and to make prediction based on transition probabilities. METHODS: Based on ten examinations of 600 community-dwelling MCI residents and cognitive assessments to classify individuals into MCI, global impairment, and AD, a multi-state Markov Cox's regression model was used and the hazard ratios with their confidence intervals and transition probabilities were estimated. RESULTS: Multivariate analysis showed that gender, age, and hypertension were statistically significant predictors of transition from MCI to global impairment; age, education, and reading statistically influenced transition from global impairment to MCI; gender, age, hypertension, diabetes, and apolipoprotein E geneε4 status were statistically associated with transition from global impairment to AD. Subjects at MCI were more likely (67%) to remain in that cognitive state at the next cognitive assessment than to transition to cognitive deterioration. For global impairment, probability of remaining in the same state was only 18% and that of forward transition was three times more likely than that of backward transition. CONCLUSIONS: Known risk factors influenced differently for different transitions. Transition from global impairment was more likely to worsen to severe cognitive deterioration than transition from MCI.

Aluminium-maltolate-induced impairment of learning, memory and hippocampal long-term potentiation in rats.

Recently, aluminium (Al) has been proposed to be one of the environmental factors responsible for cause Alzheimer's disease (AD). However, the relationship between Al and AD is controversial. To investigate the effects of subchronic Aluminium-maltolate (Al (mal)(3)) exposure on the behavioral, electrophysiological functions. Forty Sprague-Dawley (SD) rats were randomly distributed into five groups. Over two months, rats in the saline group received daily intraperitoneal (i.p.) injections 0.9% saline, rats in the maltolate group received 7.56 mg/kg maltolate, and rats in the 0.27, 0.54, 1.08 mg/kg Al (mal)(3) groups received i.p. administrations of these three doses, respectively. Neural behavior was assessed in Morris water maze. Long-term potentiation (LTP) in hippocampus was recorded. Al content in the neocortex was determined using a graphite furnace atomic absorption spectrophotometer. Our studies indicate that subchronic Al (mal)(3) exposure significantly impaired spatial learning and memory abilities, suppressed the LTP in the CA1 hippocampal area, and elevated Al levels in cerebral cortex in a dose-dependent fashion. In conclusion, low doses of Al (mal)(3) can still lead to dramatic Al accumulation in the brain, severely impair learning and memory capacities, and hippocampal LTP.

[Multi-state Markov model in expressing the outcome of mild cognitive impairment among community-based elderly residents].

OBJECTIVE: To introduce the Multi-state Markov model in studying the outcome prediction of mild cognitive impairment (MCI). METHODS: Based on the intelligence quotient (IQ) changes that reflecting the trends in cognitive function in the patients under follow-up program, we constructed a four states model and used Multi-state Markov model to analyze the patients. RESULTS: Among 600 MCI patients, there were 174 (29.0%) males and 426 (71.0%) females, with age range of 65-90 years-old (average 69.7 ± 6.6). For univariate analysis, gender, age, education level, marital status, smoking, household income, cerebral hemorrhage, hypertension, high cholesterol, diabetes, LDL-C, SBP and DBP were found to be associated with cognitive function. For multivariate analysis, female, older age, cerebral hemorrhage and higher SBP were shown to be the risk factors for transition from the state of cognitive stability to the state of severe deterioration, and their coefficients were 0.762, 0.366, 0.885, and 0.069, respectively. Age (0.038) could influence the transition from the state of cognitive stability to slight deterioration. Higher education level was shown to be the protective factor for these transitions (-0.219 and -0.297). Transition intensity from the state of cognitive stability to the state of slight and severe deterioration was 1.2 times that of transition to the state of improving. Transition intensity from state of slight deterioration to cognitive stability was 11.4 times that of transition to severe deterioration. CONCLUSION: Multi-state Markov model was an effective tool in dealing with longitudinal data.