Effects of plateau hypoxia on population pharmacokinetics and pharmacodynamics of metformin in patients with Type 2 diabetes. / 高原低氧对2åž‹ç³–å°¿ç— æ‚£è€ äºŒç”²åŒèƒç¾¤ä½“è¯åŠ¨å­¦å’Œè¯æ•ˆå­¦çš„å½±å“ï¼ˆè‹±æ–‡ï¼‰.

OBJECTIVES: Metformin is the basic drug for treating diabetes, and the plateau hypoxic environment is an important factor affecting the pharmacokinetics of metformin, but there have been no reports of metformin pharmacokinetic parameters in patients with diabetes mellitus type 2 (T2DM) in the high-altitude hypoxic environment. This study aims to investigate the effect of the hypoxic environment on the pharmacokinetics and assess the efficacy and safety of metformin administration in patients with Type 2 diabetes mellitus (T2DM). METHODS: A total of 85 patients with T2DM taking metformin tablets in the plateau group (n=32, altitude: 1 500 m) and control group (n=53, altitude: 3 800 m) were enrolled according to the inclusion and exclusion criteria, and 172 blood samples were collected in the plateau group and the control Group. A ultra-performance liquid chromatography/tandem mass spectrometry (UFLC-MS/MS) method was established to determine the blood concentration of metformin, and Phoenix NLME software was used to establish a model of pharmacokinetics of metformin in the Chinese T2DM population. The efficacy and serious adverse effects of metformin were compared between the 2 groups. RESULTS: The population pharmacokinetic modeling results showed that plateau hypoxia and age were the main covariates for model building, and the pharmacokinetic parameters were significantly different between the plateau and control groups (all P<0.05), including distribution volume (V), clearance (CL), elimination rate constant (Ke), half-life(T1/2), area under the curve (AUC), time to reach maximum concentration (Tmax). Compared with the control group, AUC was increased by 23.5%, Tmax and T1/2 were prolonged by 35.8% and 11.7%, respectively, and CL was decreased by 31.9% in the plateau group. The pharmacodynamic results showed that the hypoglycaemic effect of T2DM patients in the plateau group was similar to that in the control group, the concentration of lactic acid was higher in the plateau group than that in the control group, and the risk of lactic acidosis was increased after taking metformin in the plateau population. CONCLUSIONS: Metformin metabolism is slowed down in T2DM patients in the hypoxic environment of the plateau; the glucose-lowering effect of the plateau is similar, and the attainment rate is low, the possibility of having serious adverse effects of lactic acidosis is higher in T2DM patients on the plateau than on the control one. It is probably suggested that patients with T2DM on the plateau can achieve glucose lowering effect by extending the interval between medication doses and enhancing medication education to improve patient compliance.

Anti-hypoxic pharmacological effects of betelnut polyphenols. / æ§Ÿæ¦”å¤šé šçš„æŠ—ç¼ºæ°§è¯ç†ä½œç”¨.

Areca catechu L. medicinal materials and their preparations are widely used in clinical practice. Betelnut polyphenol is one of the main chemical components with antioxidant, anti-inflammatory, and antibacterial effects. With continuous increase of high altitude activities, tissue oxidative damage caused by high altitude hypoxia seriously affects the ability to work, and the studies on anti-hypoxia drugs are particularly important. Recent studies have shown that betelnut polyphenols have protective effects on oxidative stress injury caused by hypoxia via improving blood gas index of hypoxic organism, increasing superoxide dismutase glutathione catalase activity, and scavenging excessive free radicals. The effects of betelnut polyphenols against hypoxia and oxidative damage protection suggest that betelnut polyphenols can be used as potential anti-hypoxia drugs and posses clinical prospects.

The Emerging Role of RNA Modifications in the Regulation of Antiviral Innate Immunity.

Posttranscriptional modifications have been implicated in regulation of nearly all biological aspects of cellular RNAs, from stability, translation, splicing, nuclear export to localization. Chemical modifications also have been revealed for virus derived RNAs several decades before, along with the potential of their regulatory roles in virus infection. Due to the dynamic changes of RNA modifications during virus infection, illustrating the mechanisms of RNA epigenetic regulations remains a challenge. Nevertheless, many studies have indicated that these RNA epigenetic marks may directly regulate virus infection through antiviral innate immune responses. The present review summarizes the impacts of important epigenetic marks on viral RNAs, including N6-methyladenosine (m6A), 5-methylcytidine (m5C), 2'-O-methylation (2'-O-Methyl), and a few uncanonical nucleotides (A-to-I editing, pseudouridine), on antiviral innate immunity and relevant signaling pathways, while highlighting the significance of antiviral innate immune responses during virus infection.

Effects of salidroside on exercise tolerance of mice under high altitude hypoxia environment.

OBJECTIVE: To investigate the effect of salidroside on the exercise tolerance of mice under high altitude hypoxia environment. METHODS: C57BL/6J healthy male mice were randomly divided into normoxia control group, model control group, Rhodiola rosea capsule group and salidroside low-dose (5 mg/kg), medium-dose (10 mg/kg) and high-dose (20 mg/kg) groups, with 15 mice in each group. After 3 days, all groups (except the normoxia control group) entered a plateau with an altitude of 4010 m. After 1 day of hypoxia exposure, the exhausted swimming test was performed to determine the exhaustive time of mice; the pathological changes of liver and muscle tissue were observed with hematoxylin and eosin staining. The levels of malondialdehyde (MDA), hydrogen peroxide (H 2O 2), glutathione (GSH), total superoxide dismutase (T-SOD), glycogen, lactate and ATPase were measured and compared among groups. RESULTS: Compared with the normoxia control group, the exhaustive swimming time of the model control group was shortened ( P<0.05), the liver tissue and muscle tissue were pathologically damaged, the level of oxidative stress was significantly increased, the levels of sodium potassium ATPase and calcium magnesium ATPase were significantly increased. Compared with the model control group, the exhaustive swimming time of the mice in the Rhodiola rosea capsule group and salidroside groups was significantly prolonged ( P<0.05). The oxidative stress injury was alleviated, the contents of MDA, H 2O 2 and lactic acid in liver and muscle tissues decreased, the contents of GSH, liver glycogen and muscle glycogen increased, and the activities of T-SOD and ATPase increased (all P<0.05). CONCLUSION: Salidroside has significant anti-fatigue activity, and its anti-fatigue effect is related to the reduction of oxidative stress damage, the reduction of the accumulation of undesirable metabolites and the increase in the reserve of energy substances.

Nitrogen Supply Alters Rice Defense Against the Striped Stem Borer Chilo suppressalis.

Plant nutrition status is closely associated with plant defense against insect herbivores. However, the way nitrogen supply regulates rice anti-herbivore is not clear. This study investigated the effects of low (LN, 0.3 mM) and high (HN, 3 mM) nitrate levels on rice resistance against the striped stem borer Chilo suppressalis (SSB), one of the major destructive rice pests. Seven-day-old rice seedlings were cultured with different nitrate levels for 30 days and then inoculated with third instars of SSB. LN significantly enhanced rice anti-herbivore defense and lowered the total nitrogen content in the plants, but increased the content of free amino acids after SSB infestation. Additionally, LN significantly increased the accumulation of phenolic acids and flavonoids, especially lignin, resulting in enhanced constitutive defense in SSB-infested plants. SSB feeding led to a rapid accumulation of secondary metabolites. HN application led to the accumulation of metabolites derived from cinnamic acid, p-coumaric acid, p-coumaric CoA, feruloyl CoA, and apigenin, while LN led to the accumulation of metabolites derived from 3-dehydroquinic acid, phenylalanine, acetyl CoA, and aspartic acid. Collectively, our finding suggests that nitrogen deficiency enhances rice anti-herbivore defense via constitutive defense by the accumulation of phenolic acids and flavonoids.

Received Signal Strength-Based Indoor Localization Using Hierarchical Classification.

Commercial interests in indoor localization have been increasing in the past decade. The success of many applications relies at least partially on indoor localization that is expected to provide reliable indoor position information. Wi-Fi received signal strength (RSS)-based indoor localization techniques have attracted extensive attentions because Wi-Fi access points (APs) are widely deployed and we can obtain the Wi-Fi RSS measurements without extra hardware cost. In this paper, we propose a hierarchical classification-based method as a new solution to the indoor localization problem. Within the developed approach, we first adopt an improved K-Means clustering algorithm to divide the area of interest into several zones and they are allowed to overlap with one another to improve the generalization capability of the following indoor positioning process. To find the localization result, the K-Nearest Neighbor (KNN) algorithm and support vector machine (SVM) with the one-versus-one strategy are employed. The proposed method is implemented on a tablet, and its performance is evaluated in real-world environments. Experiment results reveal that the proposed method offers an improvement of 1.4% to 3.2% in terms of position classification accuracy and a reduction of 10% to 22% in terms of average positioning error compared with several benchmark methods.

Copper exposure enhances Spodoptera litura larval tolerance to ß-cypermethrin.

Environmental xenobiotics can influence the tolerance of insects to chemical insecticides. Heavy metals are widespread distributed, can be easily bio-accumulated in plants and subsequently within phytophagous insects via the food chains. However, less attention has been paid to the effect of heavy metal exposure on their insecticide tolerance. In this study, pre-exposure of copper (Cu, 25-100 mg kg-1) significantly enhanced the subsequent tolerance of Spodoptera litura to ß-cypermethrin, a widely used pyrethroid insecticide in crop field. Cytochrome P450 monooxygenases (CYPs) activities were cross-induced in larvae exposed to Cu and ß-cypermethrin, while the activities of glutathione S-transferase (GST) and carboxylesterase (CarE) were not affected. Application of piperonyl butoxide (PBO), a P450 synergist, effectively impaired the tolerance to ß-cypermethrin in Cu-exposed S. litura larvae with a synergistic ratio of 1.72, indicating that P450s contribute to larval tolerance to ß-cypermethrin induced by Cu exposure. Among the four CYP6AB family genes examined, only larval midgut-specific CYP6AB12 was found to be cross-induced by Cu and ß-cypermethrin. RNA interference (RNAi)-mediated silencing of CYP6AB12 effectively decreased the mRNA levels of the target gene, and significantly reduced the larval tolerance to ß-cypermethrin following exposure to Cu. These results showed that pre-exposure of heavy metal Cu enhanced larval tolerance to ß-cypermethrin in S. litura, possibly through the cross-induction of P450s. Our findings provide new insights on the relationship between heavy metals and chemical insecticides that may benefit both the risk evaluation of heavy metal contamination and development of pest management strategies.

Enhancement of Jasmonate-Mediated Antiherbivore Defense Responses in Tomato by Acetic Acid, a Potent Inducer for Plant Protection.

Acetic acid (AA) has been proved as a chemical that could prime the jasmonic acid (JA) signaling pathway for plant drought tolerance. In this study, the capability of AA for priming of tomato defense against a chewing caterpillar Spodoptera litura and its underlying molecular mechanism were evaluated. AA pretreatment significantly increased tomato resistance against S. litura larvae. Upon larval attack, tomato plants pretreated with AA exhibited increased transcript levels of defense-related genes and elevated activities of polyphenol oxidase (PPO) and peroxidase (POD), and accumulation of protease inhibitor. Moreover, AA pretreatment resulted in upregulated transcription of JA biosynthesis genes and elevated JA accumulation in tomato seedlings upon insect attack. Furthermore, an apparent loss of AA-induced resistance was observed in a JA pathway-impaired mutant suppressor of prosystemin-mediated responses8 (spr8). These results indicate that AA enhances jasmonate-mediated antiherbivore defense responses in tomato. This raises the possibility of use of AA, a basic and simple biochemical compound, as a promising inducer for management of agricultural pests.

Phosphoinositide 3-Kinase Promotes Oxidative Burst, Stomatal Closure and Plant Immunity in Bacterial Invasion.

Phosphoinositide 3-kinase (PI3K) plays a vital role in plant response to abiotic stress. However, the role of PI3K in plant immunity is largely unknown. This study showed that PI3K enhanced Arabidopsis resistance to Pseudomonas syringae pv tomato DC3000 (Pst DC3000) and Pst DC3000 (avrRpt2). Overexpression of AtVPS34 promoted stomatal closure while PI3K inhibitors blocked that after spray inoculation. Additionally, gene expression of AtVPS34 was increased upon infection by Pst DC3000 (avrRpt2), and SA upregulated AtVPS34 gene expression in this process. Furthermore, overexpression of AtVPS34 enhanced PR gene expression after syringe infiltration with Pst DC3000 (avrRpt2), while PI3K inhibitors inhibited that. The production of hydrogen peroxide and the expression of gene encoding antioxidant enzyme were both enhanced in AtVPS34 overexpressing lines after spray inoculation or syringe infiltration with Pst DC3000 (avrRpt2). Collectively, these results unraveled a novel and broad role of PI3K in plant immunity which promoted stomatal closure and PR gene expression possibly via regulating ROS production.

Metformin Regulating miR-34a Pathway to Inhibit Egr1 in Rat Mesangial Cells Cultured with High Glucose.

BACKGROUND: Activating AMPKα negatively regulates Egr1 to inhibit inflammatory cytokines in high glucose. miR-34a inhibition increases phosphorylated AMPKα through mediating SIRT1 to suppress the development of fatty liver. AIM OF THE STUDY: To clarify the function of Egr1 on the inflammation and fibrosis in high glucose-cultured MCs, as well as to explore the effects of metformin on miR-34a pathway and Egr1 expression. METHODS: We transfected MCs with miR-34a inhibitor. And MCs were transfected with small interfering RNA for silencing Egr1 and SIRT1. Quantitative real-time PCR was used to assay the transcription levels of Egr1 mRNA and miR-34a. Western blot was used to test the protein. And ELISA was used to measure inflammatory factors. RESULTS: High glucose upregulates Egr1 to aggravate the inflammation and fibrosis in MCs. miR-34a suppresses the activation of SIRT1/AMPKα and results in promoting Egr1 in high glucose-cultured MCs. Metformin attenuates high glucose-stimulated inflammation and fibrosis in MCs by regulating miR-34a-mediated SIRT1/AMPKα activity and the downstream Egr1 protein. CONCLUSION: We enriched the effects of miR-34a pathway regulating Egr1 in high glucose-cultured MCs. It provides a foundation for future researches considering Egr1 as a therapeutic target and a new direction for the clinical application of metformin in early DKD.

A Trajectory-Based Coverage Assessment Approach for Universal Sensor Networks.

To solve the problem of coverage performance assessment, this study proposes an evaluation method based on the trajectory of the target, which is applicable to universal sensor networks, including both heterogeneous and homogeneous sensor networks. Different from the traditional Voronoi algorithm, the proposed Improved Coverage Force Division (ICFD) plans a coverage force division map whichscales the qualitative coverage performancebasedon both covering intensities andlocations of the nodes. Furthermore, the Trajectory-based Evaluating Schedule (TES) is responsible for solving the quantitative coverage evaluationproblem by measuringthe resulting trajectories' Balance Values (BVs). A model of weak-point ranking conjoined in consideration of coverage force and distance can guide future deployment to compensate coverage. Comparative trials using the greedy algorithm, Voronoi algorithm, and the proposed TES verify that TES achieves the approximate results for two-stage and multistage heterogeneous sensor networks with acceptable difference and lower complexity, and it is superior to the Voronoi algorithm in homogeneous sensor networks interms of breaking the four-point circle block.

The changes of serum sKlotho and NGAL levels and their correlation in type 2 diabetes mellitus patients with different stages of urinary albumin.

OBJECTIVE: To investigate the changes of serum anti-aging protein Klotho and neutrophil gelatinase-associated lipocalin (NGAL) levels and their correlation in type 2 diabetes mellitus (T2DM) patients at different stages of diabetic kidney disease (DKD) determined by urinary albuminuria. METHODS: 462 cases with T2DM were divided into three groups: normoalbuminuric [N-UAlb; urinary albumin to creatinine ratio (UACR) < 30 mg/g, n=180], microalbuminuric [M-UAlb; UACR 30-300 mg/g, n = 158], macroalbuminuric [L-UAlb; UACR > 300 mg/g, n = 124]. The levels of serum soluble-Klotho (sKlotho), NGAL, 8-isoprostane prostaglandin F2α (8-iso-PGF2α), monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor-α (TNF-α), transforming growth factor-ß1 (TGF-ß1) were determined by enzyme-linked immunosorbent assay (ELISA) in all cases and 160 control subjects. RESULTS: Compared with control, serum sKlotho levels were significantly decreased (P < 0.001), and serum NGAL levels increased significantly (P < 0.001) in T2DM patients. Furthermore, serum sKlotho and NGAL levels were significantly negatively correlated (P < 0.001). Serum sKlotho levels negatively correlated with UACR, TG, CHO, LDL, 8-Iso-PGF2α, MCP-1, TNF-α, TGF-ß1 (P < 0.001), but positively correlated with LDL (P < 0.001). Serum NGAL levels positively correlated with UACR, 8-Iso-PGF2α, MCP-1, TNF-α, TGF-ß1 (P < 0.001). In addition, serum NGAL levels and LDL were significantly positively correlated (P = 0.005), and HDL was significantly negatively correlated (P < 0.001). CONCLUSION: Serum Klotho and NGAL levels may become new biomarkers of the early diagnosis of DKD in T2DM. Klotho may participate in the development of DKD pathological mechanism such as oxidative stress related to inflammation, renal fibrosis, lipid metabolic disorders, modulating the pathological process of diabetic kidney tissue. NGAL may play a part in these mechanisms.

[Childhood-onset myasthenia gravis: the analysis of influencing factors of therapeutic effect and prognosis].

OBJECTIVE: Though myasthenia gravis (MG) is a typical autoimmune disorder, there was some controversy on the treatment of the childhood-onset MG. By observing the efficacy of different therapies, the authors analyzed the affecting factors of prognosis in childhood-onset MG. METHOD: The retrospective data of 155 patients with childhood-onset MG (age of MG onset was less than 15 years) were collected from Department of Neurology, Beijing Tongren Hospital (January 2000 - February 2010). The patients were non-randomly divided according to their treatment into 3 groups (glucocorticoid, thymectomy and glucocorticoid combined with thymectomy groups). Postintervention status meeting the criteria of Myasthenia Gravis Foundation of America (MGFA) "complete stable remission, CSR", "pharmacologic remission, PR", "minimal manifestations, MM", or "Improved, I" was regarded as desirable response, which was used as primary indicator of observation. The authors assessed the efficacy of three therapies and analyzed the influencing factors of prognosis by using Chi-square test and Logistic regression. RESULT: At 3 months of treatment, glucocorticoid group showed the highest effective rate. At the end of 1 year or 2 years of treatment, glucocorticoid combined with thymectomy group showed the highest effective rate respectively. The generalization rate of MG at 2 years, 10 years and 20 years in childhood-onset ocular MG patients were 4.3%, 10.7%, and 41.5%, respectively. Of patients with generalization of MG, 48.1% occurred within 2 years, 92.6% within 20 years. Univariate analysis showed that in childhood-onset ocular MG patients, variables such as age at onset (> 10 years), LG-MG and with chronic fatigue were significantly associated with general MG conversion. Whereas multivariate analysis showed that patients with age at onset (> 10 years) and chronic muscle fatigue were apt to convert to generalized MG. CONCLUSION: Glucocorticoid appeared to have an effect that leads to early remission of symptoms in childhood-onset MG patients and glucocorticoid combined with thymectomy appeared to have better long-term effect. For those childhood-onset ocular MG patients with longer course of disease, older age of onset, chronic fatigue, or LG-MG, physicians should try to prevent the generalization of MG by immunosuppressive therapies.