Phosphodiesterase 8 (PDE8): Distribution and Cellular Expression and Association with Alzheimer's Disease.

Phosphodiesterase 8 (PDE8), as a member of PDE superfamily, specifically promotes the hydrolysis and degradation of intracellular cyclic adenosine monophosphate (cAMP), which may be associated with pathogenesis of Alzheimer's disease (AD). However, little is currently known about potential role in the central nervous system (CNS). Here we investigated the distribution and expression of PDE8 in brain of mouse, which we believe can provide evidence for studying the role of PDE8 in CNS and the relationship between PDE8 and AD. Here, C57BL/6J mice were used to observe the distribution patterns of two subtypes of PDE8, PDE8A and PDE8B, in different sexes in vivo by western blot (WB). Meanwhile, C57BL/6J mice were also used to demonstrate the distribution pattern of PDE8 in selected brain regions and localization in neural cells by WB and multiplex immunofluorescence staining. Furthermore, the triple transgenic (3×Tg-AD) mice and wild type (WT) mice of different ages were used to investigate the changes of PDE8 expression in the hippocampus and cerebral cortex during the progression of AD. PDE8 was found to be widely expressed in multiple tissues and organs including heart, kidney, stomach, brain, and liver, spleen, intestines, and uterus, with differences in expression levels between the two subtypes of PDE8A and PDE8B, as well as two sexes. Meanwhile, PDE8 was widely distributed in the brain, especially in areas closely related to cognitive function such as cerebellum, striatum, amygdala, cerebral cortex, and hippocampus, without differences between sexes. Furthermore, PDE8A was found to be expressed in neuronal cells, microglia and astrocytes, while PDE8B is only expressed in neuronal cells and microglia. PDE8A expression in the hippocampus of both female and male 3×Tg-AD mice was gradually increased with ages and PDE8B expression was upregulated only in cerebral cortex of female 3×Tg-AD mice with ages. However, the expression of PDE8A and PDE8B was apparently increased in both cerebral cortex and hippocampus in both female and male 10-month-old 3×Tg-AD mice compared WT mice. These results suggest that PDE8 may be associated with the progression of AD and is a potential target for its prevention and treatment in the future.

Effects of genetic polymorphisms on the pharmacokinetics and pharmacodynamics of proton pump inhibitors.

Proton pump inhibitors (PPIs) are used widely for the treatment of acid-related disorders. Despite their excellent efficacy and tolerance, the pharmacodynamics and pharmacokinetics of PPIs are affected by each patient's CYP2C19 and gastric H+,K+-ATPase genotype. The aim of this review was to analyze the effect of genetic polymorphisms on the pharmacodynamic and pharmacokinetic properties of PPIs. The gastric acid-suppressive effect of PPIs is affected by both gastric H+,K+-ATPase and CYP2C19 polymorphisms, although gastric H+,K+-ATPase polymorphisms may have larger effects. Ilaprazole and rabeprazole show relatively small differences in the pharmacokinetic and pharmacodynamic properties and clinical efficacy among the different CYP2C19 genotypes. Compared with oral administration, the intravenous infusion of PPIs is less affected by CYP2C19 polymorphism. At the same dose, each enantiomer has less variation among different CYP2C19 genotypes than a racemate mixture.

Simultaneous enantioselective determination of omeprazole, rabeprazole, lansoprazole, and pantoprazole enantiomers in human plasma by chiral liquid chromatography-tandem mass spectrometry.

Proton pump inhibitors, including omeprazole, rabeprazole, lansoprazole, and pantoprazole, achieved simultaneous enantioselective determination in the human plasma by chiral liquid chromatography-tandem mass spectrometry. The four corresponding stable isotope-labeled proton pump inhibitors were adopted as the internal standards. Each enantiomer and the internal standards were extracted with acetonitrile containing 0.1% ammonia, then separated with a Chiralpak IC column (5 µm, 4.6 mm × 150 mm) within 10 min. The mobile phase was composed of acetonitrile-ammonium acetate (10 mM) containing 0.2% acetic acid (50:50, v/v). To quantify all enantiomers, an API 4000 tandem mass spectrometer was used, and multiple reaction monitoring transitions were performed on m/z 360.1→242.1, 384.1→200.1, 370.1→252.1, and 346.1→198.1, respectively. No significant matrix effect was observed for all analytes. The calibration curve for all enantiomers were linear from 1.25 to 2500 ng/mL. The precisions for intra- and inter-run were < 14.2%, and the accuracy fell in the interval of -5.3 to 8.1%. Stability of samples was confirmed under the storage and processing conditions. The developed method was also suitable for separation and determination of ilaprazole enantiomers. The validated method combining the equilibrium dialysis method was applied to the protein binding ratio studies of four pairs proton pump inhibitor enantiomers in human plasma.

Impact of 14 types of genetic polymorphisms on antihypertensive efficacy of felodipine in healthy Chinese subjects
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OBJECTIVE: This study evaluated different influences of 14 single nucleotide polymorphisms (SNPs) and demographic factors leading to individual differences in the antihypertensive efficacy of felodipine in healthy Chinese subjects. MATERIALS AND METHODS: 24 subjects were sequenced for candidate SNPs. Plasma samples were obtained as clinical trial protocol, and were determined by a HPLC-MS/MS method. Pharmacokinetic parameters were calculated by WinNonlin 6.0. Statistical analysis was mainly performed by SPSS 22.0. A multiple linear regression model provided different weight coefficients of different demographic and genetic factors. RESULTS: The trend of Cmax is almost consistent with AUCss increase, but tmax of individuals is different; the antihypertensive effect of felodipine is individually different. A significant association was observed between systolic blood pressure decrease (ΔSBP) and SNPs of CACNA1C, CACNA1D, GNB3 respectively, while CACNA1C and CACNA1 were associated with diastolic blood pressure decrease (ΔDBP). CYP3A5 rs766746 and CYP3A4 rs2242480 were linked with Cmax and AUCss, and ABCB1 rs1045642 was associated with T1/2. Significant relationships were shown between AUCss and ΔSBP (p = 0.022) as well as Cmax and ΔSBP (p = 0.015). CONCLUSION: The efficacy of felodipine is individually different, influenced especially by CACNA1C rs1051375 and ABCB1 rs1045642. ΔDBP is associated with ΔSBP in multiple-dosing of felodipine in healthy Chinese subjects.

Melatonin attenuates nicotine-induced autophagy and neurological changes by decreasing the production of reactive oxygen species.

Purpose: The aim of this study was to explore the mechanism of neurological changes underlying the toxicity of nicotine.Materials and methods: Rat pheochromocytoma 12 (PC12) cells and human neuroglia (HM) cells were used. The ROS levels of the cells were detected by the FACScan. Autophagy flux was monitored by a tandem monomeric RFP-GFP-tagged LC3 lentivirus. The autophagic proteins LC3, SQSTM1/p62 and Beclin1 were detected by western blot assay. In order to evaluate the effects of nicotine and melatonin on the morphological changes of neurons, primary cortical neurons were obtained and immunocytochemistry of TUBB3 tubulin were conducted.Results: Nicotine increased the levels of reactive oxygen species (ROS) in PC12 and HM cells in a concentration-dependent manner. Microscopy showed increased autophagic flux in nicotine-treated PC12 cells. Subsequent western blotting results showed that nicotine induced increase in the levels of LC3B-II and Beclin1, and decreased SQSTM1/p62 in a concentration-dependent manner. Finally, nicotine treatment reduced the length of TUBB3-positive axons and dendrites. Melatonin, a mitochondrially targeted antioxidant, reduced the ROS level, and blocked autophagy activation and the morphologic structural changes induced by nicotine.Conclusions: Our results suggested that the role of nicotine in neuronal toxicity maybe through the induction of ROS and the subsequent activation of autophagy. These effects could be restored by melatonin.

Comparison of the gastric acid inhibition function among lansoprazole, pantoprazole, and their respective stereoisomers in healthy Chinese subjects
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OBJECTIVE: This study was conducted to evaluate the difference in acid inhibition function among lansoprazole (LPZ), pantoprazole (PPZ), and their respective stereoisomers following single and multiple intravenous doses in healthy Chinese subjects. MATERIALS AND METHODS: The dosage groups were set as follows: 30 mg single and multiple intravenous administrations of LPZ or R-LPZ, 40 mg single and multiple intravenous administrations of PPZ or S-PPZ. Subjects received an intravenous infusion of LPZ, R-LPZ, PPZ, or S-PPZ injection in sterile saline solution (100 mL/h, 60 minutes), respectively. The intragastric pH was sampled every second for 24 hours at baseline and for 24 hours after drug administration. The baseline-adjusted pharmacodynamic (PD) parameters include ΔMean (pH), ΔMedian (pH), ΔTpH≥3 (%), ΔTpH≥4 (%), ΔTpH≥6 (%), and ΔAUECph-tτ1-τ2. The PD parameters were evaluated in different time intervals (0 - 24 hours, 0 - 4 hours and 14 - 24 hours). RESULTS: After a single dose, the ΔTpH≥4 (%) of R-LPZ, LPZ, S-PPZ and PPZ was 56.6 ± 19.6, 53.1 ± 23.3, 35.6 ± 24.9 and 26.8 ± 30.2, respectively. The ΔTpH≥6 (%) was 50.7 ± 26.1, 41.4 ± 26.2, 25.4 ± 24.9 and 22.1 ± 27.6, respectively. The ΔAUECph-τ1-τ was 45,564 ± 16,107, 41,798 ± 16,153, 31,914 ± 17,304 and 20,744 ± 21,500, respectively. Statistically significant differences were found with R-LPZ vs. S-PPZ, R-LPZ vs. PPZ, LPZ vs. S-PPZ and LPZ vs. PPZ. The average TpH≥4 of R-LPZ, LPZ, S-PPZ, and PPZ was (47.2 ± 26.1) minutes, (49.6 ± 19.3) minutes, (56.1 ± 23.7) minutes, and (72.1 ± 27.3) minutes, respectively. Statistically significant differences were found with R-LPZ vs. PPZ (p = 0.009) and LPZ vs. PPZ (p = 0.019). After multiple doses, the ΔTpH≥4 (%) of R-LPZ, LPZ, S-PPZ, and PPZ was 71.7 ± 20.2, 63.5 ± 19.4, 59.5 ± 17.8 and 64.0 ± 22.4, respectively. The ΔTpH≥6 (%) was 64.0 ± 22.2, 52.0 ± 19.2, 49.6 ± 20.4 and 50.9 ± 23.8, respectively. The ΔAUECph-τ1-τ was 326,149 ± 94,839, 288,565 ± 93,279, 296,189 ± 83,412 and 300,960 ± 108,057, respectively. No statistically significant differences were found in baseline-adjusted PD parameters during all time periods after multiple doses. CONCLUSION: After a single dose, the mean gastric pH inhibition value of R-LPZ was the highest, followed by LPZ, then S-PPZ and PPZ. R-LPZ and LPZ provided significantly better pH control compared with PPZ and S-PPZ in healthy subjects. The onset time of R-LPZ was the fastest and R-LPZ can provide better acid inhibition during sleeping time. After multiple doses, the mean values in all PD parameters of R-LPZ were the highest, the values of LPZ, S-PPZ, and PPZ were similar. However, no significant difference was found in acid inhibition among these four drugs after multiple doses.

Safety, pharmacokinetics, and pharmacodynamics of S-(-)-pantoprazole sodium injections after single and multiple intravenous doses in healthy Chinese subjects.

PURPOSE: The objective of this study was to evaluate the safety, pharmacokinetics, and pharmacodynamics of S-(-)-pantoprazole (PPZ) sodium injections following single and multiple intravenous doses in healthy Chinese subjects. METHODS: The dosage groups were set as followed: 20 mg of single and multiple intravenous administration of S-(-)-PPZ, 40 mg of single and multiple intravenous administration of S-(-)-PPZ or pantoprazole, and 80 mg of single dosage group of S-(-)-PPZ. Subjects were sampled for pharmacokinetic analysis and were monitored for 24-h intragastric pH prior to and 48-h intragastric pH after administration for the pharmacodynamic study. The pharmacokinetic and pharmacodynamic parameters were compared between S-(-)-PPZ and PPZ. Safety was evaluated on the basis of adverse events, vital signs, laboratory tests, and physical examination. RESULTS: All adverse events were mild and of limited duration. Maximum plasma concentration and area under the concentration-time curve for S-(-)-PPZ were dose proportional over the range of 20-80 mg following a single intravenous administration. Elimination rate constant and half-life observed statistical difference from a single dose to multiple doses in 40 mg of S-(-)-PPZ groups. After administration of a single dose, the mean 24-h intragastric pH value was observed higher in 80-mg group than in 40- and 20-mg groups. Slightly increase of intragastric pH was found after a single dose of 40 mg S-(-)-PPZ than 40 mg PPZ; however, the differences were not statistically significant. CONCLUSIONS: Twice daily of 40 mg S-(-)-PPZ sodium injections is effective in achieving satisfying acid inhibition. Compared with plasma R-(+)-PPZ levels, most subjects presented more potent and prolonged suppression of gastric acid of S-(-)-PPZ, while a few subjects showed faster metabolic rate of S-(-)-PPZ in vivo.

Stereoselective pharmacokinetics of (R)-(+)- and (S)-(-)-rabeprazole in human using chiral LC-MS/MS after administration of rabeprazole sodium enteric-coated tablet.

Rabeprazole is an effective proton pump inhibitor to treat acid-related diseases. To achieve the simultaneous determination of rabeprazole enantiomers in human plasma, a chiral LC-MS/MS method was developed and validated. Acetonitrile including 0.1% ammonium were used as protein precipitating agent. Analytes were separated within 8 minutes on a Chiralpak IC column (4.6 mm × 150 mm, 5 µm). The mobile phase was 10 mM ammonium acetate including 0.2% acetic acid-acetonitrile (35:65, v/v). An API 4000 mass spectrometer was used as detector for the analysis, and the multiple reactions monitoring transitions of m/z 360.1 â†’ 242.2 and 346.1 â†’ 198.1 were opted for quantifying rabeprazole enantiomers and internal standard. Matrix effects were not apparent for each enantiomer and internal standard (esomeprazole), the calibration curves were linear over the concentration of 0.500 to 400 ng·mL-1 , the intra-run precisions were below 5.4%, the inter-run precisions were below 9.9%, and the accuracy was between -9.2% and 9.3%. There was no chiral inversion observed during sample storage, preparation procedure, and analysis, demonstrating that analytes were stable in this study. This method was applied to the stereoselective pharmacokinetic study of (R)-(+)- and (S)-(-)-rabeprazole after oral administration of 10-mg rabeprazole sodium enteric-coated tablet in healthy Chinese subjects.

Relationship between inflammation and progression of an abdominal aortic aneurysm in a rabbit model based on 18F-FDG PET/CT imaging.

OBJECTIVE: To explore the relationship between abdominal aortic aneurysm development and inflammation in the rabbit through the establishment of a rabbit infrarenal abdominal aortic aneurysm model and the use of 18F-FDG PET/CT imaging. METHODS: Twenty male New Zealand rabbits were administered an elastase intracavity perfusion to induce an infrarenal abdominal aortic aneurysm model. Prior to surgery, the rabbits underwent abdominal aorta ultrasonic testing and blood collection from the ear veins. Of the original 20 rabbits, 10 rabbits were euthanized two weeks after the operation following ultrasonic testing, PET/CT scanning and blood collection, and their arterial tissue samples were prepared for pathological and immunohistochemical staining. The remaining 10 rabbits were euthanized four weeks after the operation following ultrasonic testing, PET/CT scanning and blood collection, and the arterial tissue samples were prepared for pathological and immunohistochemical staining. RESULTS: Compared with the preoperative measurement, the maximum growth rate of the aneurysm diameter is 89.21 ± 0.02% (the absolute increase in diameter is 2.040 ± 0.376 mm) two weeks after the operation. Compared with the two-week postoperative value, the maximum growth rate of the aneurysm diameter is 15.8 ± 0.01% (the absolute increase in diameter is 0.684 ± 0.115 mm) four weeks after the operation. Compared with the preoperative values, the blood MMP-2 and MMP-9 levels significantly increase two weeks after surgery, P < 0.05. Compared with the two-week postoperative values, the blood MMP-2 and MMP-9 levels significantly decrease after four weeks post-surgery, P < 0.05. At two weeks after the operation, the SUVmax and the TBR of the 18F-FDG PET/CT of the AAA wall are 0.90 ± 0.03 and 1.19 ± 0.09, respectively. At four weeks after the operation, the SUVmax and the TBR of the 18F-FDG PET/CT of the AAA wall are 0.35 ± 0.05 and 1.15 ± 0.12, respectively. Compared with two weeks after the operation, the SUVmax significantly decreases at four weeks after the operation, P < 0.05. Compared with two weeks after the operation, there is no significant difference in the TBR at four weeks after the operation, P > 0.05. Immunohistochemical staining shows that the CD68-positive cell rate at four weeks after the operation significantly decreases ( P < 0.05) compared with the CD68-positive cell rate at two weeks after the operation. CONCLUSION: In the early stages of abdominal aortic aneurysm development, the inflammatory response of the arterial wall is significant, the local metabolic activity is strengthened, the SUVmax value of 18F-FDG is high, and the abdominal aortic aneurysm diameter experiences rapid growth. In the later stages of abdominal aortic aneurysm development, the diameter continues to increase; however, there are decreases in the wall inflammatory response, the local metabolic activity, and the SUVmax value of 18F-FDG. Thus, inflammation plays an important role in the early development of abdominal aortic aneurysm.

[Development of human embryonic stem cell platforms for human health-safety evaluation].

The human embryonic stem cells (hESCs) serve as a self-renewable, genetically-healthy, pluripotent and single source of all body cells, tissues and organs. Therefore, it is considered as the good standard for all human stem cells by US, Europe and international authorities. In this study, the standard and healthy human mesenchymal progenitors, ligament tissues, cardiomyocytes, keratinocytes, primary neurons, fibroblasts, and salivary serous cells were differentiated from hESCs. The human cellular health-safety of NaF, retinoic acid, 5-fluorouracil, dexamethasone, penicillin G, adriamycin, lead acetate PbAc, bisphenol A-biglycidyl methacrylate (Bis-GMA) were evaluated selectively on the standardized platforms of hESCs, hESCs-derived cardiomyocytes, keratinocytes, primary neurons, and fibroblasts. The evaluations were compared with those on the currently most adopted cellular platforms. Particularly, the sensitivity difference of PM2.5 toxicity on standardized and healthy hESCs derived fibroblasts, currently adopted immortalized human bronchial epithelial cells Beas-2B and human umbilical vein endothelial cells (HUVECs) were evaluated. The RESULTS showed that the standardized hESCs cellular platforms provided more sensitivity and accuracy for human cellular health-safety evaluation.

Pim-2 Modulates Aerobic Glycolysis and Energy Production during the Development of Colorectal Tumors.

Tumor cells have higher rates of glucose uptake and aerobic glycolysis to meet energy demands for proliferation and metastasis. The characteristics of increased glucose uptake, accompanied with aerobic glycolysis, has been exploited for the diagnosis of cancers. Although much progress has been made, the mechanisms regulating tumor aerobic glycolysis and energy production are still not fully understood. Here, we demonstrate that Pim-2 is required for glycolysis and energy production in colorectal tumor cells. Our results show that Pim-2 is highly expressed in colorectal tumor cells, and may be induced by nutrient stimulation. Activation of Pim-2 in colorectal cells led to increase glucose utilization and aerobic glycolysis, as well as energy production. While knockdown of Pim-2 decreased energy production in colorectal tumor cells and increased their susceptibility to apoptosis. Moreover, the effects of Pim-2 kinase on aerobic glycolysis seem to be partly dependent on mTORC1 signaling, because inhibition of mTORC1 activity reversed the aerobic glycolysis mediated by Pim-2. Our findings suggest that Pim-2-mediated aerobic glycolysis is critical for monitoring Warburg effect in colorectal tumor cells, highlighting Pim-2 as a potential metabolic target for colorectal tumor therapy.

CD206 modulates the role of M2 macrophages in the origin of metastatic tumors.

Tumor metastasis is a key factor affecting the life of patients with malignant tumors. For the past hundred years, scientists have focused on how to kill cancer cells and inhibit their metastasis in vivo, but few breakthroughs have been made. Here we hypothesized a novel mode for cancer metastasis. We show that the phagocytosis of apoptotic tumor cells by macrophages leads to their polarization into the M2 phenotype, and that the expression of stem cell related as well as drug resistance related genes was induced. Therefore, it appears that M2 macrophages have "defected" and have been transformed into the initial "metastatic cancer cells", and thus are the source, at least in part, of the distal tissue tumor metastasis. This assumption is supported by the presence of fused cells with characteristics of both macrophage and tumor cell observed in the peripheral blood and ascites of patients with ovarian cancer. By eliminating the expression of CD206 in M2 macrophages using siRNA, we show that the growth and metastasis of tumors was suppressed using both in vitro cell line and with experimental in vivo mouse models. In summary, we show that M2 macrophages in the blood circulation underwent a "change of loyalty" to become "cancer cells" that transformed into distal tissue metastasis, which could be suppressed by the knockdown of CD206 expression.

Methyltransferase K-D-K-E motif influences the intercellular transmission of Newcastle disease virus.

We previously demonstrated that two methyltransferase motifs, K-D-K-E and G-G-D, affect the pathogenicity of Newcastle disease virus (NDV) by regulating mRNA translation and virus transmission. Here, we compared the infectious centre area produced by the NDV strain, rSG10, and methyltransferase motifs mutant rSG10 strains in DF-1 cells. The results show that intercellular transmission was attenuated by methyltransferase motif mutations. We further determined the ability of mutant viruses to spread in cell-free and cell-to-cell situations. Cell-free transmission of rSG10-K1756A was not reduced, indicating that cell-to-cell transmission of rSG10-K1756A was decreased. Using a donor and target system, we demonstrated that NDV can spread from cell-to-cell directly. Furthermore, by comparing the protein distribution area of three strains when treated with 2% agar overlay, we found that rSG10-K1756A was defective in cell-to-cell transmission. Tunnelling nanotubes (TNTs) are an important mode for cell-to-cell transmission. Treatment of cells with cytochalasin D (CytoD) or nocodazole to inhibit the formation of TNTs, reduced protein levels in all strains, but rSG10-K1756A was the least affected. These results indicate that mutation of the K-D-K-E motif is likely to restricted the spread of NDV via TNTs. Finally, we observed that matrix protein (M) and fusion protein (F) promoted the formation of cellular extensions, which may be involved in the cell-to-cell spread of NDV. Our research reveals a novel mechanism by which methyltransferase motifs affect the cell-to-cell spread of NDV and provides insight into dissemination of paramyxoviruses.

Short-term effect of 0.01% atropine sulphate eye gel on myopia progression in children.

AIM: To investigate the effect of 0.01% atropine sulphate eye gel on myopia progression and axial elongation in a 6-month treatment in children. METHODS: Totally 185 children aged 6-12y with binocular myopia of 3.0 D or less in both eyes were enrolled in this prospective cohort study. The atropine group (n=125) received one drop of 0.01% atropine sulphate eye gel in each eye before bedtime daily. The control group included 60 matched children without drug intervention during the same period. The spherical equivalent and axial length was recorded at baseline and the sixth month of treatment. The efficacy was evaluated by the change of the spherical equivalent and axial length. Adverse events were also recorded. RESULTS: The average spherical equivalent and axial length at baseline were not statistically significant between the atropine group (-1.64±0.80 D, 24.13±0.76 mm) and the control group (-1.59±0.94 D, 24.06±0.77 mm, P>0.05). After 6mo, there was significantly difference in the spherical equivalent progression between the atropine and the control group (-0.27±0.33 vs -0.60±0.35 D, P<0.001), with a relative reduction of 55.0% in myopia progression. The increase in axial elongation in the atropine group was significantly less than control group (0.19±0.14 vs 0.26±0.14 mm, P<0.001), with a relative reduction of 26.9% in axial length. The 84.4% and 38.4% of the eyes progressed by less than 0.50 D and remained stable in the atropine group, compared with 51.7% and 4.2% in the control group. No adverse events were observed. CONCLUSION: Atropine sulphate eye gel 0.01% can slow down myopia progression and axial elongation in children with a 6-month treatment.

Living near greenness is associated with higher bone strength: A large cross-sectional epidemiological study in China.

BACKGROUND: Living near green spaces may benefit various health outcomes. However, no studies have investigated the greenness-bone linkage in the general population. Moreover, to which extent ambient air pollution (AAP), physical activity (PA), and body mass index (BMI) mediate this relationship remains unclear. We aimed to explore the association between greenness and bone strength and the potential mediating roles of AAP, PA, and BMI in Chinese adults. METHODS: This cross-sectional analysis enrolled 66,053 adults from the China Multi-Ethnic Cohort in 2018-2019. The normalized difference vegetation index (NDVI) and enhanced vegetation index (EVI) were employed to define residential greenness. The calcaneus quantitative ultrasound index (QUI) was used to indicate bone strength. Multiple linear regression models and mediation analyses were used to estimate the residential greenness-bone strength association and potential pathways operating through AAP (represented by PM2.5 [particulate matter <2.5 µm in diameter]), PA, and BMI. Stratification analyses were performed to identify susceptible populations. RESULTS: Higher residential exposure to greenness was significantly associated with an increase in QUI, with changes (95% confidence interval) of 3.28 (3.05, 3.50), 3.57 (3.34, 3.80), 2.68 (2.46, 2.90), and 2.93 (2.71, 3.15) for every interquartile range increase in NDVI500m, NDVI1000m, EVI500m, and EVI1000m, respectively. Sex, urbanicity, annual family income, smoking, and drinking significantly modified the association of greenness-bone strength, with more remarkable associations in males, urban residents, subjects from wealthier families, smokers, and drinkers. For the NDVI500m/EVI500m-QUI relationship, the positive mediating roles of PM2.5 and PA were 6.70%/8.50 and 2.43%/2.69%, respectively, whereas those negative for BMI and PA-BMI were 0.88%/1.06% and 0.05%/0.05%, respectively. CONCLUSION: Living in a greener area may predict higher bone strength, particularly among males, urban residents, wealthier people, smokers, and drinkers. AAP, PA, BMI, and other factors may partially mediate the positive association. Our findings underscore the importance of optimizing greenness planning and management policies.

Levels of Apelin-12, AT1R, and AGT are correlated with degree of renal fibrosis in patients with immunoglobulin A nephropathy.

BACKGROUND: To explore the relationship between the degree of renal fibrosis in patients with immunoglobulin A nephropathy (IgAN) and their levels of Apelin-12, Average Optical Density of angiotensin II type 1 receptor (AODAT1R), and angiotensinogen (AGT). METHODS: A total of 156 patients with IgAN diagnosed by renal biopsy in our hospital were selected and divided into a T0 group (54 cases), T1 group (49 cases) and T2 group (53 cases). The levels of Apelin-12, AT1R, and AGT were compared among the three groups, and the relationship between the above three indicators and degree of renal fibrosis was analyzed among patients with IgAN. RESULTS: The AODAT1R and AGT level in the T2 group and T1 groups were significantly higher than those of the T0 group, and the Apelin-12 level of patients in the T2 group and T1 groups were significantly lower than that in T0 group. Significances of the same trend were observed among all the above indicators between the T2 group and T1 group. ROC curves showed that when the cutoff value of Apelin-12 was 2.36 µg/L, the area under curve (AUC), sensitivity, and specificity of T0-T1T2 were 0.889, 92.00%, and 88.00%, respectively. When the cut-off value of AODAT1R was 0.065, the AUC, sensitivity, and specificity were 0.706, 76.00%, and 76.00%, respectively, and when the cut-off value of AGT was 47.26 ng/mL, the AUC, sensitivity, and specificity were 0.899, 84.00%, and 88.00%, respectively. When the cutoff value of Apelin-12 was 0.92 µg/L, the AUC, sensitivity, and specificity of T0T1-T2 were 0.819, 84.62%, and 87.50%, respectively, and when the cutoff value of AODAT1R was 0.079, the AUC, sensitivity, and specificity were 0.699, 76.92%, and 79.17%, respectively. When the cut-off value of AGT was 92.96 ng/mL, the AUC, sensitivity, and specificity were 0.893, 84.62%, and 91.67%, respectively. CONCLUSIONS: Apelin-12 decreased with disease progression, while AT1R and AGT increased. The changes of levels of Apelin-12, AT1R, and AGT have certain significance in judging the degree of renal fibrosis in patients with IgA nephropathy, and the change of level of AGT has the highest correlation with the degree of renal fibrosis.

Electroacupuncture Attenuates Neuropathic Pain and Comorbid Negative Behavior: The Involvement of the Dopamine System in the Amygdala.

Neuropathic pain (NeuP) is an important clinical problem accompanying negative mood symptoms. Neuroinflammation in the amygdala is critically involved in NeuP, and the dopamine (DA) system acts as an important endogenous anti-inflammatory pathway. Electroacupuncture (EA) can improve the clinical outcomes in NeuP, but the underlying mechanisms have not been fully elucidated. This study was designed to assess the effectiveness of EA on pain and pain-related depressive-like and anxiety-like behaviors and explore the role of the DA system in the effects of EA. Male Sprague-Dawley rats were subjected to the chronic constrictive injury (CCI) model to induce NeuP. EA treatment was carried out for 30 min once every other day for 3 weeks. The results showed that CCI caused mechanical hyperalgesia and depressive and anxiety-like behaviors in rats and neuroinflammation in the amygdala, such as an increased protein level of TNFα and IL-1ß and activation of astrocytes. EA treatment significantly improved mechanical allodynia and the emotional dysfunction induced by CCI. The effects of EA were accompanied by markedly decreased expression of TNFα, IL-1ß, and glial fibrillary acid protein (GFAP) in the amygdala. Moreover, EA treatment reversed CCI-induced down-regulation of DA concentration, tyrosine hydroxylase (TH) expression, and DRD1 and DRD2 receptors. These results suggest that EA-ameliorated NeuP may possibly be associated with the DA system to inhibit the neuroinflammation in the amygdala.

Corosolic acid and its structural analogs: A systematic review of their biological activities and underlying mechanism of action.

BACKGROUND: The corosolic acid (CA), also known as plant insulin, is a pentacyclic triterpenoid extracted from plants such as Lagerstroemia speciosa. It has been shown to have anti-diabetic, anti-inflammatory and anti-tumor effects. Its structural analogs ursolic acid (UA), oleanolic acid (OA), maslinic acid (MA), asiatic acid (AA) and betulinic acid (BA) display similar individual pharmacological activities to those of CA. However, there is no systematic review documenting pharmacological activities of CA and its structural analogues. This study aims to fill this gap in literature. PURPOSE: This systematic review aims to summarize the medical applications of CA and its analogues. METHODS: A systematic review summarizes and compares the extraction techniques, pharmacokinetic parameters, and pharmacological effects of CA and its structural analogs. Hypoglycemic effect is one of the key inclusion criteria for searching Web of Science, PubMed, Embase and Cochrane databases up to October 2020 without language restrictions. 'corosolic acid', 'ursolic acid', 'oleanolic acid', 'maslinic acid', 'asiatic acid', 'betulinic acid', 'extraction', 'pharmacokinetic', 'pharmacological' were used to extract relevant literature. The PRISMA guidelines were followed. RESULTS: At the end of the searching process, 140 articles were selected for the systematic review. Information of CA and five of its structural analogs including UA, OA, MA, AA and BA were included in this review. CA and its structural analogs are pentacyclic triterpenes extracted from plants and they have low solubilities in water due to their rigid scaffold and hydrophobic properties. The introduction of water-soluble groups such as sugar or amino groups could increase the solubility of CA and its structural analogs. Their biological activities and underlying mechanism of action are reviewed and compared. CONCLUSION: CA and its structural analogs UA, OA, MA, AA and BA are demonstrated to show activities in lowering blood sugar, anti-inflammation and anti-tumor. Their oral absorption and bioavailability can be improved through structural modification and formulation design. CA and its structural analogs are promising natural product-based lead compounds for further development and mechanistic studies.

Effects of ABCB1, UGT1A1, and UGT1A9 Genetic Polymorphisms on the Pharmacokinetics of Sitafloxacin Granules in Healthy Subjects.

Sitafloxacin, a new fluoroquinolone, has strong antibacterial activity. We evaluated the effects of sitafloxacin granules in single-dose and multidose cohorts and the effects of ABCB1, UGT1A1, and UGT1A9 genetic polymorphisms on the pharmacokinetics (PK) of sitafloxacin in healthy subjects. The single-dose study included 3 fasted cohorts receiving 50, 100, and 200 mg of sitafloxacin granules and 1 cohort receiving 50 mg of sitafloxacin granules with a high-fat meal. The multidose study included 1 cohort receiving 100 mg of sitafloxacin granules once daily for 5 days. PK parameters were calculated using noncompartmental parameters based on concentration-time data. The genotypes for ABCB1, UGT1A1, and UGT1A9 single-nucleotide polymorphisms were determined using Sanger sequencing. Subsequently, the association between sitafloxacin PK parameters and target single-nucleotide polymorphisms was analyzed. Sitafloxacin granules were well tolerated up to 200 and 100 mg in the single-dose and multidose studies, respectively. Sitafloxacin AUC and Cmax increased linearly within the detection range, and a steady state was reached within 3 days after the administration of multiple oral doses. Our findings showed that Cmax was lower in the ABCB1 (rs1045642) mutation group, whereas t1/2 was longer in the UGT1A1 (rs2741049) and UGT1A9 (rs3832043) mutation groups. In conclusion, sitafloxacin granules were safe at single doses and multiple doses up to 200 and 100 mg/day, respectively, with a linear plasma PK profile. However, ABCB1 (rs1045642), UGT1A1 (rs2741049), and UGT1A9 (rs3832043) genetic polymorphisms are likely to influence the Cmax or t1/2 and thereby merit further clinical evaluation.

[Effects of ant disturbance on soil organic carbon cycle: A review.] / èš‚èšæ‰°åŠ¨å¯¹åœŸå£¤æœ‰æœºç¢³å¾ªçŽ¯è¿‡ç¨‹çš„å½±å“ç ”ç©¶è¿›å±•.

The impact of ants, as consumer and decomposer in ecosystems, on soil organic carbon pool is a hotspot in soil fauna research. Recently, effects of ants on soil organic carbon pool dynamics have been mainly documented in terms of soil macro-elements storage, physical and chemical properties, and microbial community. We summarized the effects of ant disturbance on soil organic carbon cycle. Ant nesting alters microhabitat, microclimate, and physicochemical properties of ant nested soils. By re-shaping soil microbial community structure, regulating the succession process and pattern of vegetation, ant nesting directly or indirectly affects the source, allocation, stability, and microcosmic molecular characteristics of soil organic carbon, scaling from micro, local, to landscape scale. In the future, more attentions should be paid on quantifying the contribution of ant disturbance combined with the fluctuations in environmental factors to soil carbon flux dynamics, establishing quantitative model to link and unify ant-induced soil carbon cycle process, and clari-fying mechanisms underlying the impacts of ants on the stability of soil organic carbon pool, and finally revealing the "ecological engineers" role of ants in regulating soil organic carbon cycling.