BACKGROUND Type 1 diabetes(T1D) is associated with major chronic microvascular complications which contribute significantly to diabetes associated morbidity.The protein primarily responsible for glucose reabsorption i...BACKGROUND Type 1 diabetes(T1D) is associated with major chronic microvascular complications which contribute significantly to diabetes associated morbidity.The protein primarily responsible for glucose reabsorption in the kidney is sodium glucose co-transporter 2(SGLT2). Presently, SGLT2 inhibitors are widely used in diabetic patients to improve blood glucose levels and prevent cardiovascular and renal complications. Given the broad therapeutic application of SGLT2 inhibitors, we hypothesised that SGLT2 inhibition may exert its protective effects via alterations of the gut microbiome and tested this in a type 1 diabetic mouse model of diabetic retinopathy.AIM To determine whether the treatment with two independent SGLT2 inhibitors affects gut health in a type 1 diabetic mouse model.METHODS The SGLT2 inhibitors empagliflozin or dapagliflozin(25 mg/kg/d) or vehicle dimethylsulfoxide(DMSO) were administered to C57 BL/6 J, Akita, Kimba and Akimba mice at 10 wk of age for 8 wk via their drinking water. Serum samples were collected and the concentration of succinate and the short chain fatty acid(SCFA) butyric acid was measured using gas chromatography-mass spectrometry. Enzyme-linked immunosorbent assay(ELISA) was performed to determine the concentration of insulin and leptin. Furthermore, the norepinephrine content in kidney tissue was determined using ELISA. Pancreatic tissue was collected and stained with haematoxylin and eosin and analysed using brightfield microscopy.RESULTS Due to the presence of the Akita allele, both Akita and Akimba mice showed a reduction in insulin production compared to C57 BL/6 J and Kimba mice.Furthermore, Akita mice also showed the presence of apoptotic bodies within the pancreatic islets. The acinar cells of Akita and Akimba mice showed swelling which is indicative of acute injury or pancreatitis. After 8 wk of SGLT2 inhibition with dapagliflozin, the intermediate metabolite of gut metabolism known as succinate was significantly reduced in Akimba mice when compared to DMSO treated mice. In addition, empagliflozin resulted in suppression of succinate levels in Akimba mice. The beneficial SCFA known as butyric acid was significantly increased in Akita mice after treatment with dapagliflozin when compared to vehicle treated mice. The norepinephrine content in the kidney was significantly reduced with both dapagliflozin and empagliflozin therapy in Akita mice and was significantly reduced in Akimba mice treated with empagliflozin.In non-diabetic C57 BL/6 J and Kimba mice, serum leptin levels were significantly reduced after dapagliflozin therapy.CONCLUSION The inhibition of SGLT2 reduces the intermediate metabolite succinate, increases SCFA butyric acid levels and reduces norepinephrine content in mouse models of T1 D. Collectively, these improvements may represent an important mechanism underlying the potential benefits of SGLT2 inhibition in T1 D and its complications.展开更多
Accumulating evidence has demonstrated that the sodium-potassium-chloride co-transporter 1 and potassium-chloride co-transporter 2 have a role in the modulation of pain transmission at the spinal level through chlorid...Accumulating evidence has demonstrated that the sodium-potassium-chloride co-transporter 1 and potassium-chloride co-transporter 2 have a role in the modulation of pain transmission at the spinal level through chloride regulation in the pain pathway and by effecting neuronal excitability and pain sensitization. The present study aimed to investigate the analgesic effect of the speciifc sodium-potassium-chloride co-transporter 1 inhibitor bumetanide, and the change in spinal sodium-potassium-chloride co-transporter 1 and potassium-chloride co-transporter 2 expression in a rat model of incisional pain. Results showed that intrathecal bumetanide could decrease cumulative pain scores, and could increase thermal and mechanical pain thresholds in a rat model of incisional pain. Sodium-potassium-chloride co-transporter 1 expression in-creased in neurons from dorsal root ganglion and the deep laminae of the ipsilateral dorsal horn following incision. By contrast, potassium-chloride co-transporter 2 expression decreased in neurons of the deep laminae from the ipsilateral dorsal horn. These ifndings suggest that spinal sodium-potassium-chloride co-transporter 1 expression was up-regulated and spinal potassi-um-chloride co-transporter 2 expression was down-regulated following incision. Intrathecal bumetanide has analgesic effects on incisional pain through inhibition of sodium-potassi-um-chloride co-transporter 1.展开更多
Euglycemic diabetic ketoacidosis(EDKA)is a well-known complication of sodium-glucose co-transporter 2 inhibitors,and many cases with variable onset following the initiation of these agents are reported before,with a m...Euglycemic diabetic ketoacidosis(EDKA)is a well-known complication of sodium-glucose co-transporter 2 inhibitors,and many cases with variable onset following the initiation of these agents are reported before,with a median onset of approximately 2 wk.This letter discusses a 45-year-old lady who initially presented with ischemic stroke but developed EDKA 4 d after starting empagliflozin,a rare occurrence.The patient had severe metabolic acidosis that necessitated admission into the intensive care unit.Prompt discontinuation of empagliflozin and DKA management resulted in clinical recovery.展开更多
Sodium-glucose co-transporter 2(SGLT2)inhibitors are an insulin-independent class of oral antihyperglycemic medication and from recently established therapy in chronic heart failure patients.A rare,but potentially lif...Sodium-glucose co-transporter 2(SGLT2)inhibitors are an insulin-independent class of oral antihyperglycemic medication and from recently established therapy in chronic heart failure patients.A rare,but potentially life-threatening complication of SGLT2 inhibitor use is euglycemic diabetic ketoacidosis.We described a case of a middle-aged male patient with type 2 diabetes who developed metabolic ketoacidosis after a few days of empagliflozin administration.SGLT2 inhibitor related ketoacidosis presents with euglycemia or only modestly elevated glucose blood concentrations,which causes delayed detection and treatment of ketoacidosis.There are multiple possible risk factors and mechanism that might contribute to the pathogenesis of ketoacidosis.It is implied that SGLT2 inhibitor use and prescription by non-diabetologists(cardiologists,nephrologists,family physicians,etc.)will continue to grow in the future.It is important to inform the general cardiac public about this rare but serious side effect of SGLT2 inhibitors.展开更多
The rapid development and widespread use of ZnO nanoparticles(nZnO) in various industries have raised concerns about their potential environmental impact.Therefore,understanding the fate and role of nZnO in the natura...The rapid development and widespread use of ZnO nanoparticles(nZnO) in various industries have raised concerns about their potential environmental impact.Therefore,understanding the fate and role of nZnO in the natural environment is crucial for mitigating their hazardous effects on the environment and human safety.The purpose of the present study was to provide scientific support for understanding and eliminating the joint risk of nanoparticle and heavy metal pollution in the soil environment by revealing the co-transport characteristics of Cd(Ⅱ) and ZnO nanoparticles(nZnO) in soil under different ionic strength(IS) and pH.The impacts of different IS and pH on the co-transport of Cd(Ⅱ) and nZnO in a20 cm long with an inner diameter of 2.5 cm acrylic column packed with 10 cm high soil samples were investigated in the present study.In the above system,a500 μg L^(-1) Cd(Ⅱ) loaded nZnO suspension pulse with varying IS or pH was introduced into the soil column for leaching over 5 PVs,followed up by 5 PVs background solutions without nZnO.The IS was 1,10,or 50 mM NaCl,with pH6,or the pH was 6,7 or 8 with 1 mM NaCl.Meanwhile,Sedimentation experiments for nZnO,adsorption of Cd(Ⅱ) on soil,and nZnO,DLVO theory calculation for the same background condition were conducted.The presence of nZnO significantly increased the mobility of Cd(Ⅱ) as a result of its strong adsorption capacity for nZnO-associated Cd(Ⅱ).However,with the increase of IS,the co-transport of nZnO and Cd(Ⅱ) was decreased and the retention of nZnO in the soil column due to more nZnO attended to aggregate and sediment during the transport and the decrease in the adsorption capacity of nZnO for Cd(Ⅱ) by competition of Na^(+).When pH was 6,7,and 8,the co-transport of nZnO and Cd(Ⅱ) increased with higher pH due to the lower electrostatic attraction between nZnO and soil under higher pH.Meanwhile,the DLVO theory was fitted to describe the above co-transport process of nZnO and Cd(Ⅱ).More attention should be paid to the presence of nZnO on the migration of Cd(Ⅱ) in the natural soil to control the potential risk of nanoparticles and heavy metals to the environment.The risk of co-transport of nZnO and Cd(Ⅱ) might be controlled by adjusting IS and pH in the soil solution.展开更多
Three novel gem-dimethyl C-glucosides were designed as sodium-glucose co-transporter 2 （SGLT2） inhibitors, and their syntheses started from D-glucose and three 2-substituted-5-bromobenzoic acids were achieved via a ...Three novel gem-dimethyl C-glucosides were designed as sodium-glucose co-transporter 2 （SGLT2） inhibitors, and their syntheses started from D-glucose and three 2-substituted-5-bromobenzoic acids were achieved via a facile 8-step protocol, with the key step being anhydrous aluminum chloride-catalyzed Friedel-Crafts alkylation of tertiary alcohols and phenetol. These three SGLT2 inhibitors were evaluated in vivo with a mice oral glucose tolerance test （OGTT）, and the anti-hyperglycemic activities of all these three compounds were comparable with that of the positive control Dapagliflozin.展开更多
Canagliflozin(CANA)is a sodium-glucose co-transporter 2 inhibitor.One of the important mechanisms of CANA is the inhibitory effect on the glucose uptake in the proximal tubule of the nephron,and the other mechanism ca...Canagliflozin(CANA)is a sodium-glucose co-transporter 2 inhibitor.One of the important mechanisms of CANA is the inhibitory effect on the glucose uptake in the proximal tubule of the nephron,and the other mechanism can be the reduction of inflammatory cytokine expression monocytes and macrophages.It is proved by FDA for the management of type 2 diabetes.In the present work,we summarized the publication and clinical evidence of the CANA on healthy individuals and those with related metabolic diseases,such as type 1 and 2 diabetes,obesity,or cardiovascular and kidney diseases.This drug has been reported to offer potential advantages in regulating body weight and reducing heart failure,hypoglycemia,and stroke risk in patients with type 2 diabetes.Some in vitro and animal experiments also show that this drug has good effects on cancer treatment.However,some case reports and experiments also show the side effect of CANA,such as amputation,fracture,and pancreatitis,while the mechanism is still unknown.Overall,CANA has a good effect on the management of type 2 diabetes by reducing the risk of kidney failure,cardiovascular diseases,and stroke.However,as a new drug,more clinical trials and experiments of CANA should be carried out in the future.展开更多
This study examined the effects of various levels of dietary nonphytate phosphorus on laying performance and the expression patterns of phosphorus metabolism related genes in Dwarf pink-shell Jaying hens. A total of 4...This study examined the effects of various levels of dietary nonphytate phosphorus on laying performance and the expression patterns of phosphorus metabolism related genes in Dwarf pink-shell Jaying hens. A total of 405 28-week-old Dwarf pink-shell laying hens were fed the same corn-soybean basal meals but containing 0.20%, 0.25%, 0.30%, 0.35% or 0.40% nonphytate phosphorus. The results showed that feed intake, egg production, and average egg weights were quadratically correlated with dietary nonphytate phosphorus content （P 〈 0.05）, and the highest egg production, feed intake and average egg weights were achieved when dietary nonphytate phosphorus was at 0.3% （P 〈 0.05）. mRNA expression of intestinal sodium phosphorus co-transporter linearly decreased when dietary nonphytate phosphorus increased, mRNA and protein expression of intestinal calbindin and vitamin D receptor correlated quadratically with dietary nonphytate phosphorus, and the highest expression was found when dietary available phosphorus was at 0.2,5% to 0.3%. In conclusion, the ideal phosphorus requirement for Dwarf pink-shell layer hens is estimated to be 0.3% in a corn-soybean diet. With this level of phosphorus supplementation, calbindin and vitamin D receptor reached their highest expression.展开更多
The distribution of the Na-K-2Cl co-transporter （NKCCl） in the cochlear K^＋ cycling pathway in cochlea and cochlear histological changes in the NKCCl knockout mice were investigated. By using immunohistochemistry a...The distribution of the Na-K-2Cl co-transporter （NKCCl） in the cochlear K^＋ cycling pathway in cochlea and cochlear histological changes in the NKCCl knockout mice were investigated. By using immunohistochemistry and toluidine blue staining, the localization of NKCCl in cochlea of the C57BL/6J mice and the cochlear histological changes in the NKCCl knockout mice were observed. It was found that the NKCCl was expressed mainly in the stria marginal cells and the fibrocytes in the inferior portion of the spiral ligament in the adult C57BL/6J mice. Subpopulation of the fibrocytes in the suprastrial region and the limbus was also moderately immunoreactive. While in the cochlea of the NKCCl knockout mice, Reissner＇s membrane was collapsed and scala media disappeared, accompanied with the loss of inner hair cells, outer hair cells and the support cells. The tunnel of Corti was often absent. All the findings suggested the localization of NKCCl in the cochlea was closely correlated with cochlear K^＋ cycling. Loss of NKCCl led to the destruction of the cochlear structures, and subsequently influenced the physiological function of cochlea.展开更多
A common challenge in managing kidney transplant recipients(KTR)is posttransplant diabetes mellitus(PTDM)or diabetes mellitus(DM)newly diagnosed after transplantation,in addition to known pre-existing DM.PTDM is an im...A common challenge in managing kidney transplant recipients(KTR)is posttransplant diabetes mellitus(PTDM)or diabetes mellitus(DM)newly diagnosed after transplantation,in addition to known pre-existing DM.PTDM is an important risk factor for post-transplant cardiovascular(CV)disease,which adversely affects patient survival and quality of life.CV disease in KTR may manifest as ischemic heart disease,heart failure,and/or left ventricular hypertrophy.Available therapies for PTDM include most agents currently used to treat type 2 diabetes.More recently,the use of sodium glucose co-transporter 2 inhibitors(SGLT2i),glucagon-like peptide-1 receptor agonists(GLP-1 RA),and dipeptidyl peptidase 4 inhibitors(DPP4i)has cautiously extended to KTR with PTDM,even though KTR are typically excluded from large general population clinical trials.Initial evidence from observational studies seems to indicate that SGLT2i,GLP-1 RA,and DPP4i may be safe and effective for glycemic control in KTR,but their benefit in reducing CV events in this otherwise high-risk population remains unproven.These newer drugs must still be used with care due to the increased propensity of KTR for intravascular volume depletion and acute kidney injury due to diarrhea and their single-kidney status,pre-existing burden of peripheral vascular disease,urinary tract infections due to immunosuppression and a surgically altered urinary tract,erythrocytosis from calcineurin inhibitors,and reduced kidney function from acute or chronic rejection.展开更多
Objective To assess the efficiency and safety of a novel sodium-glucose co-transporter 2(SGLT2) inhibitor—SGLT2 inhibitors,in combination with insulin for type 1 diabetes mellitus(T1DM). Methods We searched Medline,E...Objective To assess the efficiency and safety of a novel sodium-glucose co-transporter 2(SGLT2) inhibitor—SGLT2 inhibitors,in combination with insulin for type 1 diabetes mellitus(T1DM). Methods We searched Medline,Embase,and the Cochrane Collaboration Library to identify the eligible studies published between January 2010 and July 2016 without restriction of language. The Food and Drug Administration(FDA) data and Clinical Trials(http://www.clinicaltrials.gov) were also searched. The included studies met the following criteria:randomized controlled trials; T1DM patients aged between 18 and 65 years old; patients were treated with insulin plus SGLT2 inhibitors for more than 2 weeks; patients' glycosylated hemoglobin(HbA1c) levels were between 7% and 12%. The SGLT2 inhibitors group was treated with SGLT2 inhibitors plus insulin,and the placebo group received placebo plus insulin treatment. The outcomes should include one of the following items:fasting blood glucose,HbA1c,glycosuria,or adverse effects. Data were analyzed by two physicians independently. The risk of bias was evaluated by using the Cochrane Collaboration's Risk of Bias tool and heterogeneity among studies was assessed using Chi-square test. Random effect model was used to analyze the treatment effects with Revman 5.3. Results Three trials including 178 patients were enrolled. As compared to the placebo group,SGLT2 inhibitor absolutely decreased fasting blood glucose [mean differences(MD)-2.47 mmol/L,95% confidence interval(CI)-3.65 to-1.28,P<0.001] and insulin dosage(standardized MD-0.75 U,95%CI-1.17 to-0.33,P<0.001). SGLT2 inhibitors could also increase the excretion of urine glucose(MD 131.09 g/24 h,95%CI 91.79 to 170.39,P<0.001). There were no significant differences in the incidences of hyperglycemia [odds ratio(OR) 1.82,95%CI 0.63 to 5.29,P=0.27],urinary tract infection(OR 0.95,95%CI 0.19 to 4.85,P=0.95),genital tract infection(OR 0.27,95%CI 0.01 to 7.19,P=0.43),and diabetic ketoacidosis(OR 6.03,95%CI 0.27 to 135.99,P=0.26) between the two groups. Conclusion SGLT2 inhibitors combined with insulin might be an efficient and safe treatment modality for T1DM patients.展开更多
Type 2 diabetes mellitus is a metabolic disorder of deranged fat, protein and carbohydrate metabolism resulting in hyperglycemia as a result of insulin resistance and inadequate insulin secretion. Although a wide vari...Type 2 diabetes mellitus is a metabolic disorder of deranged fat, protein and carbohydrate metabolism resulting in hyperglycemia as a result of insulin resistance and inadequate insulin secretion. Although a wide variety of diabetes therapies is available, yet limited efficacy, adverse effects, cost, contraindications, renal dosage adjustments, inflexible dosing schedules and weight gain significantly limit their use. In addition, many patients in the United States fail to meet the therapeutic HbA1c goal of 【 7% set by the American Diabetes Association. As such new and emerging diabetes therapies with different mechanisms of action hope to address some of these drawbacks to improve the patient with type 2 diabetes. This article reviews new and emerging classes, including the sodium-glucosecotransporter-2 inhibitors, 11β-Hydroxysteroid dehydrogenase type 1 inhibitors, glycogen phosphorylase inhibitors; protein tyrosine phosphatase 1B inhibitors, G Protein-Coupled receptor agonists and glucokinase activators. These emerging diabetes agents hold the promise of providing benefit of glucose lowering, weight reduction, low hypoglycemia risk, improve insulin sensitivity, pancreatic β cell preservation, and oral formulation availability. However, further studies are needed to evaluate their safety profile, cardiovascular effects, and efficacy durability in order to determine their role in type 2 diabetes management.展开更多
Canagliflozin(CFZ) is a member of new class of glucose lowering agents, sodium-glucose co-transporter(SGLT) inhibitors, which got approval by food and drug administration. It has insulin independent action by blocking...Canagliflozin(CFZ) is a member of new class of glucose lowering agents, sodium-glucose co-transporter(SGLT) inhibitors, which got approval by food and drug administration. It has insulin independent action by blocking the transporter protein SGLT2 in the kidneys, resulting in urinary glucose excretion and reduction in blood glucose levels. In clinical trials, CFZ significantly decreased HbA1c level when administered either as monotherapy or as combined therapy with other anti-diabetic drugs. Intriguingly, it showed additional benefits like weight reduction and lowering of blood pressure. The commonly observed side effects were urinary and genital infections. It has exhibited favorable pharmacokinetic and pharmacodynamic profiles even in patients with renal and hepatic damage. Hence, this review purports to outline CFZ as a newer beneficial drug for type 2 diabetes mellitus.展开更多
A convenient approach for the preparation of （2S,3R,4R,5S,6R）-2-（3-（4-ethylbenzyl）-4-chlorophenyl）-6-（hydroxymethyl）- tetrahydro-2H-pyran-3,4,5-triol I is developed. The target compound via four steps is synth...A convenient approach for the preparation of （2S,3R,4R,5S,6R）-2-（3-（4-ethylbenzyl）-4-chlorophenyl）-6-（hydroxymethyl）- tetrahydro-2H-pyran-3,4,5-triol I is developed. The target compound via four steps is synthesized from 4-bromo-2-（bromomethyl）- 1-chlorobenzene and the isomers of undesired ortho-products were avoided during the preparation.展开更多
According to a genome-wide association study,intronic SNPs within the human sterile 20/SPS1-related proline/alanine-rich kinase(SPAK) gene was linked to 20% of the general population and may be associated with elevate...According to a genome-wide association study,intronic SNPs within the human sterile 20/SPS1-related proline/alanine-rich kinase(SPAK) gene was linked to 20% of the general population and may be associated with elevated blood pressure. As cell volume changes,mammalian SPAK kinases respond to phosphorylate and regulate cation-coupled chloride co-transporter activity. To our knowledge,phosphorylation of upstream with-no-lysine(K)(WNK) kinases would activate SPAK kinases. The activation of WNK-OSR1/SPAK cascade on the kidneys and aortic tissue is related to the development of hypertension. Several regulators of the WNK pathway such as the Kelch kinase protein 3-Cullin 3 E3 ligase,hyperinsulinemia,and low potassium intake to mediate hypertension have been identified. In addition,the SPAK kinases may affect the action of renin-angiotensin-aldosterone system on blood pressure as well. In 2010,two SPAK knock-in and knock-out mouse models have clarified the pathogenesis of lowering blood pressure by influencing the receptors on the kidneys and aortic smooth muscle. More recently,two novel SPAK inhibitors for mice,Stock 1S-14279 and Closantel were discovered in 2014. Targeting of SPAK seems to be promising for future antihypertensive therapy. Therefore we raised some viewpoints for the issue for the antihypertensive therapy on the SPAK(gene or kinase).展开更多
AIM： To quantify changes in urinary excretion of aquaporin2 water channels （u-AQP2）, the sodium-potassium-chloride co-transporter （u-NKCC2） and the epithelial sodium channels （u-ENaC） during treatment with bend...AIM： To quantify changes in urinary excretion of aquaporin2 water channels （u-AQP2）, the sodium-potassium-chloride co-transporter （u-NKCC2） and the epithelial sodium channels （u-ENaC） during treatment with bendrofumethiazide （BFTZ）, amiloride and placebo.METHODS： In a randomized, double-blinded, placebo-controlled, 3-way crossover study we examined 23 healthy subjects on a standardized diet and fuid intake. The subjects were treated with amiloride 5 mg, BFTZ 1.25 mg or placebo twice a day for 4.5 d before each examination day. On the examination day, glomerular filtration rate was measured by the constant infusion clearance technique with 51Cr-EDTA as reference substance. To estimate the changes in water transport via AQP2 and sodium transport via NKCC2 and ENaC, u-NKCC2, the gamma fraction of ENaC （u-ENaCγ）, and u-AQP2 were measured at baseline and after infusion with 3% hypertonic saline. U-NKCC2, u-ENaCγ, u-AQP2 and plasma concentrations of vasopressin （p-AVP）, renin （PRC）, angiotensin Ⅱ （p-ANG Ⅱ） and aldosterone （p-Aldo） were measured, by radioimmunoassay. Central blood pressure was estimated by applanation tonometry and body fuid volumes were estimated by bio-impedance spectroscopy. General linear model with repeated measures or related samples Friedman’s two-way analysis was used to compare differences. Post hoc Bonferroni correction was used for multiple comparisons of post infusion periods to baseline within each treatment group.RESULTS： At baseline there were no differences in u-NKCC2, u-ENaCγ and u-AQP2. PRC, p-Ang Ⅱ and p-Aldo were increased during active treatments （P 〈 0.001）. After hypertonic saline, u-NKCC2 increased during amiloride （6% ± 34%; P = 0.081） and increased significantly during placebo （17% ± 24%; P = 0.010）. U-AQP2 increased signifcantly during amiloride （31% ± 22%; P 〈 0.001） and placebo （34% ± 27%; P 〈 0.001）, while u-NKCC2 and u-AQP2 did not change signifcantly during BFTZ （-7% ± 28%; P = 0.257 and 5% ± 16%; P = 0.261）. U- ENaCγ increased in all three groups （ P 〈 0.050）. PRC, AngⅡ and p-Aldo decreased to the same extent, while AVP increased, but to a smaller degree during BFTZ （ P = 0.048）. cDBP decreased significantly during BFTZ （P 〈 0.001）, but not during amiloride or placebo. There were no significant differences in body fuid volumes.CONCLUSION： After hypertonic saline, u-NKCC2 and u-AQP2 increased during amiloride, but not during BFTZ. Lower p-AVP during BFTZ potentially caused less stimulation of NKCC2 and AQP2 and subsequent lower reabsorption of water and sodium.展开更多
Background: Sodium glucose co-transporter 2 (SGLT2) inhibitors are a new class that approved by FDA for patient with type 2 DM. Dapagliflozin alone or in combination therapy with metformin provided effective glycemic ...Background: Sodium glucose co-transporter 2 (SGLT2) inhibitors are a new class that approved by FDA for patient with type 2 DM. Dapagliflozin alone or in combination therapy with metformin provided effective glycemic control and HbA<sub>1c</sub> reduction, with minimal hypoglycemia and hypotension adverse effects. Objective: To evaluate the safety and efficacy of the combination therapy of dapagliflozin and metformin in type 2 diabetes mellitus patients. Methods: Research was conducted through MEDLINE and Embase databases in search of randomized controlled studies including dapagliflozin, sodium glucose co-transporter 2, metformin, and efficacy. Results: Forty seven articles were spotted, 3 randomized controlled studies were involved in this review. Dapagliflozin and metformin combination was found beneficial in HbA<sub>1c</sub> reduction equal to 20.7% - 31.5% from the baseline compared to patients on metformin alone. 40.6% of patients on combination therapy achieved the ADA recommended reduction in HbA<sub>1c</sub> to less than 7%. Moreover fasting plasma glucose level was reduced by 23.4 mg/dl from the baseline in the combination therapy compared to 5.9 mg/dl in metformin group. Body weight reduction was statistically significant (P Conclusion: The combination therapy of dapagliflozin and metformin found to be safe and effective in type 2 diabetes mellitus management with minimal adverse effects.展开更多
Background: After years of predictable outcomes with limited tools to combat the ravages of proteinuric chronic kidney disease (CKD) associated with or without diabetes, exciting new options are available to slow the ...Background: After years of predictable outcomes with limited tools to combat the ravages of proteinuric chronic kidney disease (CKD) associated with or without diabetes, exciting new options are available to slow the progression of CKD. Purpose: Focusing on sodium-glucose co-transporter 2 inhibitors (SGLT2), angiotensin receptor blockers (ARB), angiotensin converting enzyme inhibitors (ACE I), and new mineralocorticoid antagonists (MRA), this review examines how these agents compliment the standard of care in an attempt to educate and stimulate broader use of these agents. Methods: Using the search terms “mineralocorticoid antagonist, sodium glucose co-transporter 2 inhibitors, proteinuria, albuminuria, and diabetic kidney disease,” five randomized controlled clinical trials were identified and then analyzed in the context of the results found from the Irbesartan Diabetic Nephropathy Trial (IDNT). Two trials using SGLT2 and 2 using MRA were reviewed. Results: In the 2 SGLT2 trials renal outcomes were reduced by 30% - 39% among patients with estimated GFR ranging from roughly 25 - 90 mL/min. In the 2 MRA trials, renal outcomes fell by 13% - 18% among patients with estimated GFR ranging from 25 - 90 mL/min. In the IDNT, renal outcomes fell by 19%. Trial duration ranged from 28 - 41 months, and in all trials, the IDNT, Ace inhibitors (ACE I) and ARBs use was uniform. There is small overlap in the 5 trials in which both MRA and SGLT2 agents were used. Conclusions: Over a wide range of renal function, both MRA and SGLT2 inhibitors demonstrate outstanding efficacy in diabetic and non-diabetic (SGLT2) proteinuric kidney disease. Compared to the prior standard of care, these agents dramatically improve outcomes.展开更多
AIM To determine the variability/conservation of the domain of hepatitis B virus(HBV) pre S1 region that interacts with sodium-taurocholate cotransporting polypeptide(hereafter, NTCP-interacting domain) and the preval...AIM To determine the variability/conservation of the domain of hepatitis B virus(HBV) pre S1 region that interacts with sodium-taurocholate cotransporting polypeptide(hereafter, NTCP-interacting domain) and the prevalence of the rs2296651 polymorphism(S267 F, NTCP variant) in a Spanish population. METHODS Serum samples from 246 individuals were included and divided into 3 groups: patients with chronic HBV infection(CHB)(n = 41, 73% Caucasians), patients with resolved HBV infection(n = 100, 100% Caucasians) and an HBV-uninfected control group(n = 105, 100% Caucasians). Variability/conservation of the amino acid(aa) sequences of the NTCPinteracting domain,(aa 2-48 in viral genotype D) and a highly conserved pre S1 domain associated with virion morphogenesis(aa 92-103 in viral genotype D) were analyzed by next-generation sequencing and compared in 18 CHB patients with viremia > 4 log IU/mL. The rs2296651 polymorphism was determined in all individuals in all 3 groups using an in-house real-time PCR melting curve analysis.RESULTS The HBV pre S1 NTCP-interacting domain showed a high degree of conservation among the examined viral genomes especially between aa 9 and 21(in the genotype D consensus sequence). As compared with the virion morphogenesis domain, the NTCPinteracting domain had a smaller proportion of HBV genotype-unrelated changes comprising > 1% of the quasispecies(25.5% vs 31.8%), but a larger proportion of genotype-associated viral polymorphisms(34% vs 27.3%), according to consensus sequences from Gen Bank patterns of HBV genotypes A to H. Variation/conservation in both domains depended on viral genotype, with genotype C being the most highly conserved and genotype E the most variable(limited finding, only 2 genotype E included). Of note, proline residues were highly conserved in both domains, and serine residues showed changes only to threonine or tyrosine in the virion morphogenesis domain. The rs2296651 polymorphism was not detected in any participant.CONCLUSION In our CHB population, the NTCP-interacting domain was highly conserved, particularly the proline residues and essential amino acids related with the NTCP interaction, and the prevalence of rs2296651 was low/null.展开更多
The transport of colloids and radionuclides is sophisticated because of the variety of charge properties between colloidal particles and host subsurface media, which causes great difficulty in establishing a reliable ...The transport of colloids and radionuclides is sophisticated because of the variety of charge properties between colloidal particles and host subsurface media, which causes great difficulty in establishing a reliable model of radionuclides migration by taking the colloid phase into consideration. In this work,the co-transport of illite colloids(IC) and Eu(Ⅲ) in the quartz sand and iron-coated sand porous media was investigated by column experiments to address the predominant mechanism of charge properties on co-transport. Results showed that Eu(Ⅲ) transport was driven by the illite colloids and electrostatic interaction was critical in governing the co-transport patterns. The promotion of Eu(Ⅲ) transport by IC was attenuated in the iron-coated sand systems;more IC-Eu(Ⅲ) complexes were retained uniformly in the column. The pore throat shrinkage caused by electrostatic attachment between aggregated IC and iron oxides exacerbated the physical straining and size exclusion effect of IC-Eu(Ⅲ) complexes. An aggravated irreversible retention of IC-Eu(Ⅲ) was detected in iron-coated sand column due to the electrostatic attraction of IC-Eu(Ⅲ) to host media. The findings are essential for improving the understanding on the potential transport, retention and release risk of colloids associated radionuclides, and imply that the positively charged permeable reactive barrier is an effective strategy to reduce the transport risk of colloid associated radionuclides.展开更多
基金Supported by the Royal Perth Hospital Medical Research Foundation,No.VMMRF2018。
文摘BACKGROUND Type 1 diabetes(T1D) is associated with major chronic microvascular complications which contribute significantly to diabetes associated morbidity.The protein primarily responsible for glucose reabsorption in the kidney is sodium glucose co-transporter 2(SGLT2). Presently, SGLT2 inhibitors are widely used in diabetic patients to improve blood glucose levels and prevent cardiovascular and renal complications. Given the broad therapeutic application of SGLT2 inhibitors, we hypothesised that SGLT2 inhibition may exert its protective effects via alterations of the gut microbiome and tested this in a type 1 diabetic mouse model of diabetic retinopathy.AIM To determine whether the treatment with two independent SGLT2 inhibitors affects gut health in a type 1 diabetic mouse model.METHODS The SGLT2 inhibitors empagliflozin or dapagliflozin(25 mg/kg/d) or vehicle dimethylsulfoxide(DMSO) were administered to C57 BL/6 J, Akita, Kimba and Akimba mice at 10 wk of age for 8 wk via their drinking water. Serum samples were collected and the concentration of succinate and the short chain fatty acid(SCFA) butyric acid was measured using gas chromatography-mass spectrometry. Enzyme-linked immunosorbent assay(ELISA) was performed to determine the concentration of insulin and leptin. Furthermore, the norepinephrine content in kidney tissue was determined using ELISA. Pancreatic tissue was collected and stained with haematoxylin and eosin and analysed using brightfield microscopy.RESULTS Due to the presence of the Akita allele, both Akita and Akimba mice showed a reduction in insulin production compared to C57 BL/6 J and Kimba mice.Furthermore, Akita mice also showed the presence of apoptotic bodies within the pancreatic islets. The acinar cells of Akita and Akimba mice showed swelling which is indicative of acute injury or pancreatitis. After 8 wk of SGLT2 inhibition with dapagliflozin, the intermediate metabolite of gut metabolism known as succinate was significantly reduced in Akimba mice when compared to DMSO treated mice. In addition, empagliflozin resulted in suppression of succinate levels in Akimba mice. The beneficial SCFA known as butyric acid was significantly increased in Akita mice after treatment with dapagliflozin when compared to vehicle treated mice. The norepinephrine content in the kidney was significantly reduced with both dapagliflozin and empagliflozin therapy in Akita mice and was significantly reduced in Akimba mice treated with empagliflozin.In non-diabetic C57 BL/6 J and Kimba mice, serum leptin levels were significantly reduced after dapagliflozin therapy.CONCLUSION The inhibition of SGLT2 reduces the intermediate metabolite succinate, increases SCFA butyric acid levels and reduces norepinephrine content in mouse models of T1 D. Collectively, these improvements may represent an important mechanism underlying the potential benefits of SGLT2 inhibition in T1 D and its complications.
基金supported by a grant from Guangzhou Medical University,No.2008C24
文摘Accumulating evidence has demonstrated that the sodium-potassium-chloride co-transporter 1 and potassium-chloride co-transporter 2 have a role in the modulation of pain transmission at the spinal level through chloride regulation in the pain pathway and by effecting neuronal excitability and pain sensitization. The present study aimed to investigate the analgesic effect of the speciifc sodium-potassium-chloride co-transporter 1 inhibitor bumetanide, and the change in spinal sodium-potassium-chloride co-transporter 1 and potassium-chloride co-transporter 2 expression in a rat model of incisional pain. Results showed that intrathecal bumetanide could decrease cumulative pain scores, and could increase thermal and mechanical pain thresholds in a rat model of incisional pain. Sodium-potassium-chloride co-transporter 1 expression in-creased in neurons from dorsal root ganglion and the deep laminae of the ipsilateral dorsal horn following incision. By contrast, potassium-chloride co-transporter 2 expression decreased in neurons of the deep laminae from the ipsilateral dorsal horn. These ifndings suggest that spinal sodium-potassium-chloride co-transporter 1 expression was up-regulated and spinal potassi-um-chloride co-transporter 2 expression was down-regulated following incision. Intrathecal bumetanide has analgesic effects on incisional pain through inhibition of sodium-potassi-um-chloride co-transporter 1.
文摘Euglycemic diabetic ketoacidosis(EDKA)is a well-known complication of sodium-glucose co-transporter 2 inhibitors,and many cases with variable onset following the initiation of these agents are reported before,with a median onset of approximately 2 wk.This letter discusses a 45-year-old lady who initially presented with ischemic stroke but developed EDKA 4 d after starting empagliflozin,a rare occurrence.The patient had severe metabolic acidosis that necessitated admission into the intensive care unit.Prompt discontinuation of empagliflozin and DKA management resulted in clinical recovery.
文摘Sodium-glucose co-transporter 2(SGLT2)inhibitors are an insulin-independent class of oral antihyperglycemic medication and from recently established therapy in chronic heart failure patients.A rare,but potentially life-threatening complication of SGLT2 inhibitor use is euglycemic diabetic ketoacidosis.We described a case of a middle-aged male patient with type 2 diabetes who developed metabolic ketoacidosis after a few days of empagliflozin administration.SGLT2 inhibitor related ketoacidosis presents with euglycemia or only modestly elevated glucose blood concentrations,which causes delayed detection and treatment of ketoacidosis.There are multiple possible risk factors and mechanism that might contribute to the pathogenesis of ketoacidosis.It is implied that SGLT2 inhibitor use and prescription by non-diabetologists(cardiologists,nephrologists,family physicians,etc.)will continue to grow in the future.It is important to inform the general cardiac public about this rare but serious side effect of SGLT2 inhibitors.
基金supported by the National Key Research and Development Project of Chinathe National Natural Science Fund of China (Grant number 2018YFC1800403, 41571226)。
文摘The rapid development and widespread use of ZnO nanoparticles(nZnO) in various industries have raised concerns about their potential environmental impact.Therefore,understanding the fate and role of nZnO in the natural environment is crucial for mitigating their hazardous effects on the environment and human safety.The purpose of the present study was to provide scientific support for understanding and eliminating the joint risk of nanoparticle and heavy metal pollution in the soil environment by revealing the co-transport characteristics of Cd(Ⅱ) and ZnO nanoparticles(nZnO) in soil under different ionic strength(IS) and pH.The impacts of different IS and pH on the co-transport of Cd(Ⅱ) and nZnO in a20 cm long with an inner diameter of 2.5 cm acrylic column packed with 10 cm high soil samples were investigated in the present study.In the above system,a500 μg L^(-1) Cd(Ⅱ) loaded nZnO suspension pulse with varying IS or pH was introduced into the soil column for leaching over 5 PVs,followed up by 5 PVs background solutions without nZnO.The IS was 1,10,or 50 mM NaCl,with pH6,or the pH was 6,7 or 8 with 1 mM NaCl.Meanwhile,Sedimentation experiments for nZnO,adsorption of Cd(Ⅱ) on soil,and nZnO,DLVO theory calculation for the same background condition were conducted.The presence of nZnO significantly increased the mobility of Cd(Ⅱ) as a result of its strong adsorption capacity for nZnO-associated Cd(Ⅱ).However,with the increase of IS,the co-transport of nZnO and Cd(Ⅱ) was decreased and the retention of nZnO in the soil column due to more nZnO attended to aggregate and sediment during the transport and the decrease in the adsorption capacity of nZnO for Cd(Ⅱ) by competition of Na^(+).When pH was 6,7,and 8,the co-transport of nZnO and Cd(Ⅱ) increased with higher pH due to the lower electrostatic attraction between nZnO and soil under higher pH.Meanwhile,the DLVO theory was fitted to describe the above co-transport process of nZnO and Cd(Ⅱ).More attention should be paid to the presence of nZnO on the migration of Cd(Ⅱ) in the natural soil to control the potential risk of nanoparticles and heavy metals to the environment.The risk of co-transport of nZnO and Cd(Ⅱ) might be controlled by adjusting IS and pH in the soil solution.
文摘Three novel gem-dimethyl C-glucosides were designed as sodium-glucose co-transporter 2 （SGLT2） inhibitors, and their syntheses started from D-glucose and three 2-substituted-5-bromobenzoic acids were achieved via a facile 8-step protocol, with the key step being anhydrous aluminum chloride-catalyzed Friedel-Crafts alkylation of tertiary alcohols and phenetol. These three SGLT2 inhibitors were evaluated in vivo with a mice oral glucose tolerance test （OGTT）, and the anti-hyperglycemic activities of all these three compounds were comparable with that of the positive control Dapagliflozin.
基金Beijing Excellent Talents Training Assistance(Grant No.2017000082595G244)the Health and Research Bureau of Tongzhou District(Grant No.TWKY-2016-QN-01-58)。
文摘Canagliflozin(CANA)is a sodium-glucose co-transporter 2 inhibitor.One of the important mechanisms of CANA is the inhibitory effect on the glucose uptake in the proximal tubule of the nephron,and the other mechanism can be the reduction of inflammatory cytokine expression monocytes and macrophages.It is proved by FDA for the management of type 2 diabetes.In the present work,we summarized the publication and clinical evidence of the CANA on healthy individuals and those with related metabolic diseases,such as type 1 and 2 diabetes,obesity,or cardiovascular and kidney diseases.This drug has been reported to offer potential advantages in regulating body weight and reducing heart failure,hypoglycemia,and stroke risk in patients with type 2 diabetes.Some in vitro and animal experiments also show that this drug has good effects on cancer treatment.However,some case reports and experiments also show the side effect of CANA,such as amputation,fracture,and pancreatitis,while the mechanism is still unknown.Overall,CANA has a good effect on the management of type 2 diabetes by reducing the risk of kidney failure,cardiovascular diseases,and stroke.However,as a new drug,more clinical trials and experiments of CANA should be carried out in the future.
基金financially supported by the Chinese Universities Scientific Fund
文摘This study examined the effects of various levels of dietary nonphytate phosphorus on laying performance and the expression patterns of phosphorus metabolism related genes in Dwarf pink-shell Jaying hens. A total of 405 28-week-old Dwarf pink-shell laying hens were fed the same corn-soybean basal meals but containing 0.20%, 0.25%, 0.30%, 0.35% or 0.40% nonphytate phosphorus. The results showed that feed intake, egg production, and average egg weights were quadratically correlated with dietary nonphytate phosphorus content （P 〈 0.05）, and the highest egg production, feed intake and average egg weights were achieved when dietary nonphytate phosphorus was at 0.3% （P 〈 0.05）. mRNA expression of intestinal sodium phosphorus co-transporter linearly decreased when dietary nonphytate phosphorus increased, mRNA and protein expression of intestinal calbindin and vitamin D receptor correlated quadratically with dietary nonphytate phosphorus, and the highest expression was found when dietary available phosphorus was at 0.2,5% to 0.3%. In conclusion, the ideal phosphorus requirement for Dwarf pink-shell layer hens is estimated to be 0.3% in a corn-soybean diet. With this level of phosphorus supplementation, calbindin and vitamin D receptor reached their highest expression.
文摘The distribution of the Na-K-2Cl co-transporter （NKCCl） in the cochlear K^＋ cycling pathway in cochlea and cochlear histological changes in the NKCCl knockout mice were investigated. By using immunohistochemistry and toluidine blue staining, the localization of NKCCl in cochlea of the C57BL/6J mice and the cochlear histological changes in the NKCCl knockout mice were observed. It was found that the NKCCl was expressed mainly in the stria marginal cells and the fibrocytes in the inferior portion of the spiral ligament in the adult C57BL/6J mice. Subpopulation of the fibrocytes in the suprastrial region and the limbus was also moderately immunoreactive. While in the cochlea of the NKCCl knockout mice, Reissner＇s membrane was collapsed and scala media disappeared, accompanied with the loss of inner hair cells, outer hair cells and the support cells. The tunnel of Corti was often absent. All the findings suggested the localization of NKCCl in the cochlea was closely correlated with cochlear K^＋ cycling. Loss of NKCCl led to the destruction of the cochlear structures, and subsequently influenced the physiological function of cochlea.
文摘A common challenge in managing kidney transplant recipients(KTR)is posttransplant diabetes mellitus(PTDM)or diabetes mellitus(DM)newly diagnosed after transplantation,in addition to known pre-existing DM.PTDM is an important risk factor for post-transplant cardiovascular(CV)disease,which adversely affects patient survival and quality of life.CV disease in KTR may manifest as ischemic heart disease,heart failure,and/or left ventricular hypertrophy.Available therapies for PTDM include most agents currently used to treat type 2 diabetes.More recently,the use of sodium glucose co-transporter 2 inhibitors(SGLT2i),glucagon-like peptide-1 receptor agonists(GLP-1 RA),and dipeptidyl peptidase 4 inhibitors(DPP4i)has cautiously extended to KTR with PTDM,even though KTR are typically excluded from large general population clinical trials.Initial evidence from observational studies seems to indicate that SGLT2i,GLP-1 RA,and DPP4i may be safe and effective for glycemic control in KTR,but their benefit in reducing CV events in this otherwise high-risk population remains unproven.These newer drugs must still be used with care due to the increased propensity of KTR for intravascular volume depletion and acute kidney injury due to diarrhea and their single-kidney status,pre-existing burden of peripheral vascular disease,urinary tract infections due to immunosuppression and a surgically altered urinary tract,erythrocytosis from calcineurin inhibitors,and reduced kidney function from acute or chronic rejection.
文摘Objective To assess the efficiency and safety of a novel sodium-glucose co-transporter 2(SGLT2) inhibitor—SGLT2 inhibitors,in combination with insulin for type 1 diabetes mellitus(T1DM). Methods We searched Medline,Embase,and the Cochrane Collaboration Library to identify the eligible studies published between January 2010 and July 2016 without restriction of language. The Food and Drug Administration(FDA) data and Clinical Trials(http://www.clinicaltrials.gov) were also searched. The included studies met the following criteria:randomized controlled trials; T1DM patients aged between 18 and 65 years old; patients were treated with insulin plus SGLT2 inhibitors for more than 2 weeks; patients' glycosylated hemoglobin(HbA1c) levels were between 7% and 12%. The SGLT2 inhibitors group was treated with SGLT2 inhibitors plus insulin,and the placebo group received placebo plus insulin treatment. The outcomes should include one of the following items:fasting blood glucose,HbA1c,glycosuria,or adverse effects. Data were analyzed by two physicians independently. The risk of bias was evaluated by using the Cochrane Collaboration's Risk of Bias tool and heterogeneity among studies was assessed using Chi-square test. Random effect model was used to analyze the treatment effects with Revman 5.3. Results Three trials including 178 patients were enrolled. As compared to the placebo group,SGLT2 inhibitor absolutely decreased fasting blood glucose [mean differences(MD)-2.47 mmol/L,95% confidence interval(CI)-3.65 to-1.28,P<0.001] and insulin dosage(standardized MD-0.75 U,95%CI-1.17 to-0.33,P<0.001). SGLT2 inhibitors could also increase the excretion of urine glucose(MD 131.09 g/24 h,95%CI 91.79 to 170.39,P<0.001). There were no significant differences in the incidences of hyperglycemia [odds ratio(OR) 1.82,95%CI 0.63 to 5.29,P=0.27],urinary tract infection(OR 0.95,95%CI 0.19 to 4.85,P=0.95),genital tract infection(OR 0.27,95%CI 0.01 to 7.19,P=0.43),and diabetic ketoacidosis(OR 6.03,95%CI 0.27 to 135.99,P=0.26) between the two groups. Conclusion SGLT2 inhibitors combined with insulin might be an efficient and safe treatment modality for T1DM patients.
文摘Type 2 diabetes mellitus is a metabolic disorder of deranged fat, protein and carbohydrate metabolism resulting in hyperglycemia as a result of insulin resistance and inadequate insulin secretion. Although a wide variety of diabetes therapies is available, yet limited efficacy, adverse effects, cost, contraindications, renal dosage adjustments, inflexible dosing schedules and weight gain significantly limit their use. In addition, many patients in the United States fail to meet the therapeutic HbA1c goal of 【 7% set by the American Diabetes Association. As such new and emerging diabetes therapies with different mechanisms of action hope to address some of these drawbacks to improve the patient with type 2 diabetes. This article reviews new and emerging classes, including the sodium-glucosecotransporter-2 inhibitors, 11β-Hydroxysteroid dehydrogenase type 1 inhibitors, glycogen phosphorylase inhibitors; protein tyrosine phosphatase 1B inhibitors, G Protein-Coupled receptor agonists and glucokinase activators. These emerging diabetes agents hold the promise of providing benefit of glucose lowering, weight reduction, low hypoglycemia risk, improve insulin sensitivity, pancreatic β cell preservation, and oral formulation availability. However, further studies are needed to evaluate their safety profile, cardiovascular effects, and efficacy durability in order to determine their role in type 2 diabetes management.
文摘Canagliflozin(CFZ) is a member of new class of glucose lowering agents, sodium-glucose co-transporter(SGLT) inhibitors, which got approval by food and drug administration. It has insulin independent action by blocking the transporter protein SGLT2 in the kidneys, resulting in urinary glucose excretion and reduction in blood glucose levels. In clinical trials, CFZ significantly decreased HbA1c level when administered either as monotherapy or as combined therapy with other anti-diabetic drugs. Intriguingly, it showed additional benefits like weight reduction and lowering of blood pressure. The commonly observed side effects were urinary and genital infections. It has exhibited favorable pharmacokinetic and pharmacodynamic profiles even in patients with renal and hepatic damage. Hence, this review purports to outline CFZ as a newer beneficial drug for type 2 diabetes mellitus.
文摘A convenient approach for the preparation of （2S,3R,4R,5S,6R）-2-（3-（4-ethylbenzyl）-4-chlorophenyl）-6-（hydroxymethyl）- tetrahydro-2H-pyran-3,4,5-triol I is developed. The target compound via four steps is synthesized from 4-bromo-2-（bromomethyl）- 1-chlorobenzene and the isomers of undesired ortho-products were avoided during the preparation.
文摘According to a genome-wide association study,intronic SNPs within the human sterile 20/SPS1-related proline/alanine-rich kinase(SPAK) gene was linked to 20% of the general population and may be associated with elevated blood pressure. As cell volume changes,mammalian SPAK kinases respond to phosphorylate and regulate cation-coupled chloride co-transporter activity. To our knowledge,phosphorylation of upstream with-no-lysine(K)(WNK) kinases would activate SPAK kinases. The activation of WNK-OSR1/SPAK cascade on the kidneys and aortic tissue is related to the development of hypertension. Several regulators of the WNK pathway such as the Kelch kinase protein 3-Cullin 3 E3 ligase,hyperinsulinemia,and low potassium intake to mediate hypertension have been identified. In addition,the SPAK kinases may affect the action of renin-angiotensin-aldosterone system on blood pressure as well. In 2010,two SPAK knock-in and knock-out mouse models have clarified the pathogenesis of lowering blood pressure by influencing the receptors on the kidneys and aortic smooth muscle. More recently,two novel SPAK inhibitors for mice,Stock 1S-14279 and Closantel were discovered in 2014. Targeting of SPAK seems to be promising for future antihypertensive therapy. Therefore we raised some viewpoints for the issue for the antihypertensive therapy on the SPAK(gene or kinase).
基金Supported by Grants from The Lundbeck FoundationAase and Ejnar Danielsens Foundation+1 种基金Helen and Ejnar Bjoernows FoundationRegion Midjutlands Research Fund
文摘AIM： To quantify changes in urinary excretion of aquaporin2 water channels （u-AQP2）, the sodium-potassium-chloride co-transporter （u-NKCC2） and the epithelial sodium channels （u-ENaC） during treatment with bendrofumethiazide （BFTZ）, amiloride and placebo.METHODS： In a randomized, double-blinded, placebo-controlled, 3-way crossover study we examined 23 healthy subjects on a standardized diet and fuid intake. The subjects were treated with amiloride 5 mg, BFTZ 1.25 mg or placebo twice a day for 4.5 d before each examination day. On the examination day, glomerular filtration rate was measured by the constant infusion clearance technique with 51Cr-EDTA as reference substance. To estimate the changes in water transport via AQP2 and sodium transport via NKCC2 and ENaC, u-NKCC2, the gamma fraction of ENaC （u-ENaCγ）, and u-AQP2 were measured at baseline and after infusion with 3% hypertonic saline. U-NKCC2, u-ENaCγ, u-AQP2 and plasma concentrations of vasopressin （p-AVP）, renin （PRC）, angiotensin Ⅱ （p-ANG Ⅱ） and aldosterone （p-Aldo） were measured, by radioimmunoassay. Central blood pressure was estimated by applanation tonometry and body fuid volumes were estimated by bio-impedance spectroscopy. General linear model with repeated measures or related samples Friedman’s two-way analysis was used to compare differences. Post hoc Bonferroni correction was used for multiple comparisons of post infusion periods to baseline within each treatment group.RESULTS： At baseline there were no differences in u-NKCC2, u-ENaCγ and u-AQP2. PRC, p-Ang Ⅱ and p-Aldo were increased during active treatments （P 〈 0.001）. After hypertonic saline, u-NKCC2 increased during amiloride （6% ± 34%; P = 0.081） and increased significantly during placebo （17% ± 24%; P = 0.010）. U-AQP2 increased signifcantly during amiloride （31% ± 22%; P 〈 0.001） and placebo （34% ± 27%; P 〈 0.001）, while u-NKCC2 and u-AQP2 did not change signifcantly during BFTZ （-7% ± 28%; P = 0.257 and 5% ± 16%; P = 0.261）. U- ENaCγ increased in all three groups （ P 〈 0.050）. PRC, AngⅡ and p-Aldo decreased to the same extent, while AVP increased, but to a smaller degree during BFTZ （ P = 0.048）. cDBP decreased significantly during BFTZ （P 〈 0.001）, but not during amiloride or placebo. There were no significant differences in body fuid volumes.CONCLUSION： After hypertonic saline, u-NKCC2 and u-AQP2 increased during amiloride, but not during BFTZ. Lower p-AVP during BFTZ potentially caused less stimulation of NKCC2 and AQP2 and subsequent lower reabsorption of water and sodium.
文摘Background: Sodium glucose co-transporter 2 (SGLT2) inhibitors are a new class that approved by FDA for patient with type 2 DM. Dapagliflozin alone or in combination therapy with metformin provided effective glycemic control and HbA<sub>1c</sub> reduction, with minimal hypoglycemia and hypotension adverse effects. Objective: To evaluate the safety and efficacy of the combination therapy of dapagliflozin and metformin in type 2 diabetes mellitus patients. Methods: Research was conducted through MEDLINE and Embase databases in search of randomized controlled studies including dapagliflozin, sodium glucose co-transporter 2, metformin, and efficacy. Results: Forty seven articles were spotted, 3 randomized controlled studies were involved in this review. Dapagliflozin and metformin combination was found beneficial in HbA<sub>1c</sub> reduction equal to 20.7% - 31.5% from the baseline compared to patients on metformin alone. 40.6% of patients on combination therapy achieved the ADA recommended reduction in HbA<sub>1c</sub> to less than 7%. Moreover fasting plasma glucose level was reduced by 23.4 mg/dl from the baseline in the combination therapy compared to 5.9 mg/dl in metformin group. Body weight reduction was statistically significant (P Conclusion: The combination therapy of dapagliflozin and metformin found to be safe and effective in type 2 diabetes mellitus management with minimal adverse effects.
文摘Background: After years of predictable outcomes with limited tools to combat the ravages of proteinuric chronic kidney disease (CKD) associated with or without diabetes, exciting new options are available to slow the progression of CKD. Purpose: Focusing on sodium-glucose co-transporter 2 inhibitors (SGLT2), angiotensin receptor blockers (ARB), angiotensin converting enzyme inhibitors (ACE I), and new mineralocorticoid antagonists (MRA), this review examines how these agents compliment the standard of care in an attempt to educate and stimulate broader use of these agents. Methods: Using the search terms “mineralocorticoid antagonist, sodium glucose co-transporter 2 inhibitors, proteinuria, albuminuria, and diabetic kidney disease,” five randomized controlled clinical trials were identified and then analyzed in the context of the results found from the Irbesartan Diabetic Nephropathy Trial (IDNT). Two trials using SGLT2 and 2 using MRA were reviewed. Results: In the 2 SGLT2 trials renal outcomes were reduced by 30% - 39% among patients with estimated GFR ranging from roughly 25 - 90 mL/min. In the 2 MRA trials, renal outcomes fell by 13% - 18% among patients with estimated GFR ranging from 25 - 90 mL/min. In the IDNT, renal outcomes fell by 19%. Trial duration ranged from 28 - 41 months, and in all trials, the IDNT, Ace inhibitors (ACE I) and ARBs use was uniform. There is small overlap in the 5 trials in which both MRA and SGLT2 agents were used. Conclusions: Over a wide range of renal function, both MRA and SGLT2 inhibitors demonstrate outstanding efficacy in diabetic and non-diabetic (SGLT2) proteinuric kidney disease. Compared to the prior standard of care, these agents dramatically improve outcomes.
基金Supported by Instituto de Salud Carlos Ⅲ,No.PI14/01416 and No.PI15/00856cofinanced by the European Regional Development Fund(ERDF)the Gilead Fellowship Program,No.GLD14-00296
文摘AIM To determine the variability/conservation of the domain of hepatitis B virus(HBV) pre S1 region that interacts with sodium-taurocholate cotransporting polypeptide(hereafter, NTCP-interacting domain) and the prevalence of the rs2296651 polymorphism(S267 F, NTCP variant) in a Spanish population. METHODS Serum samples from 246 individuals were included and divided into 3 groups: patients with chronic HBV infection(CHB)(n = 41, 73% Caucasians), patients with resolved HBV infection(n = 100, 100% Caucasians) and an HBV-uninfected control group(n = 105, 100% Caucasians). Variability/conservation of the amino acid(aa) sequences of the NTCPinteracting domain,(aa 2-48 in viral genotype D) and a highly conserved pre S1 domain associated with virion morphogenesis(aa 92-103 in viral genotype D) were analyzed by next-generation sequencing and compared in 18 CHB patients with viremia > 4 log IU/mL. The rs2296651 polymorphism was determined in all individuals in all 3 groups using an in-house real-time PCR melting curve analysis.RESULTS The HBV pre S1 NTCP-interacting domain showed a high degree of conservation among the examined viral genomes especially between aa 9 and 21(in the genotype D consensus sequence). As compared with the virion morphogenesis domain, the NTCPinteracting domain had a smaller proportion of HBV genotype-unrelated changes comprising > 1% of the quasispecies(25.5% vs 31.8%), but a larger proportion of genotype-associated viral polymorphisms(34% vs 27.3%), according to consensus sequences from Gen Bank patterns of HBV genotypes A to H. Variation/conservation in both domains depended on viral genotype, with genotype C being the most highly conserved and genotype E the most variable(limited finding, only 2 genotype E included). Of note, proline residues were highly conserved in both domains, and serine residues showed changes only to threonine or tyrosine in the virion morphogenesis domain. The rs2296651 polymorphism was not detected in any participant.CONCLUSION In our CHB population, the NTCP-interacting domain was highly conserved, particularly the proline residues and essential amino acids related with the NTCP interaction, and the prevalence of rs2296651 was low/null.
基金supported by the National Natural Science Foundation of China(Nos.22176077,22006060)the Fundamental Research Funds for the Central Universities(No.lzujbky-2022-sp04)Science and Technology Program of Gansu Province,China(No.20JR10RA615).
文摘The transport of colloids and radionuclides is sophisticated because of the variety of charge properties between colloidal particles and host subsurface media, which causes great difficulty in establishing a reliable model of radionuclides migration by taking the colloid phase into consideration. In this work,the co-transport of illite colloids(IC) and Eu(Ⅲ) in the quartz sand and iron-coated sand porous media was investigated by column experiments to address the predominant mechanism of charge properties on co-transport. Results showed that Eu(Ⅲ) transport was driven by the illite colloids and electrostatic interaction was critical in governing the co-transport patterns. The promotion of Eu(Ⅲ) transport by IC was attenuated in the iron-coated sand systems;more IC-Eu(Ⅲ) complexes were retained uniformly in the column. The pore throat shrinkage caused by electrostatic attachment between aggregated IC and iron oxides exacerbated the physical straining and size exclusion effect of IC-Eu(Ⅲ) complexes. An aggravated irreversible retention of IC-Eu(Ⅲ) was detected in iron-coated sand column due to the electrostatic attraction of IC-Eu(Ⅲ) to host media. The findings are essential for improving the understanding on the potential transport, retention and release risk of colloids associated radionuclides, and imply that the positively charged permeable reactive barrier is an effective strategy to reduce the transport risk of colloid associated radionuclides.
