Aim
Cyclosporin A (CsA) is a widely used immunosuppressive drug that causes hypertension and hyperkalemia. Moreover, CsA‐induced stimulation of the thiazide‐sensitive NaCl cotransporter (NCC) in the ...kidney has been shown to be responsible for the development of hyperkalemic hypertension. In this study, we tested whether CsA induces the activation of NCC by stimulating the basolateral Kir4.1/Kir5.1 channel in the distal convoluted tubule (DCT).
Methods
Electrophysiology, immunoblotting, metabolic cages, and radio‐telemetry methods were used to examine the effects of CsA on Kir4.1/Kir5.1 activity in the DCT, NCC function, and blood pressure in wild‐type (WT) and kidney‐specific Kir4.1 knockout (KS‐Kir4.1 KO) mice.
Results
The single‐channel patch clamp experiment demonstrated that CsA stimulated the basolateral 40 pS K+ channel in the DCT. Whole‐cell recording showed that short‐term CsA administration (2 h) not only increased DCT K+ currents but also shifted the K+ current (IK) reversal potential to the negative range (hyperpolarization). Furthermore, CsA administration increased phosphorylated NCC (pNCC) levels and inhibited renal Na+ and K+ excretions in WT mice but not in KS‐Kir4.1 KO mice, suggesting that Kir4.1 is required to mediate CsA effects on NCC function. Finally, long‐term CsA infusion (14 days) increased blood pressure, plasma K+ concentration, and total NCC or pNCC abundance in WT mice, but these effects were blunted in KS‐Kir4.1 KO mice.
Conclusion
We conclude that CsA stimulates basolateral K+ channel activity in the DCT and that Kir4.1 is essential for CsA‐induced NCC activation and hyperkalemic hypertension.
BackgroundPast studies have found a strong relationship between alcohol drinking and human health.MethodsIn this study, we first tested the association of rs671 with alcohol use in 2349 participants ...in southeast China. We then evaluated the causal impact between alcohol use and cardiovascular traits through a Mendelian randomisation (MR) analysis.ResultsWe found strong evidence for the association of rs671 in the ALDH2 gene with alcohol drinking (p=6.08×10-47; ORadj G=4.50, 95% CI 3.67 to 5.52). We found that female G carriers of rs671 had a higher proportion of non-drinkers than male G carriers (88.01% vs 38.70%). In non-drinkers, the female G allele frequency was higher than the male G allele frequency (71.1% vs 55.2%). MR analysis suggested that alcohol use had a causal effect on blood pressure (increasing 9.46 mm Hg for systolic blood pressure (p=9.67×10-4) and 7.50 mm Hg for diastolic blood pressure (p=9.62×10-5)), and on hypertension in men (p=0.011; OR =1.19, 95% CI 1.04 to 1.36) and in pooled samples (p=0.013; OR =1.20, 95% CI 1.04 to 1.39), but not in women. We did not observe a causal effect of alcohol use on body mass index and lipid levels; further studies are needed to clarify the non-causal relationship.ConclusionsCompared to never-drinkers, current and previous alcohol use had a causal effect on blood pressure and hypertension in pooled samples and in men. These results reflect Chinese culture which does not encourage women to drink.
•Precise qualitative and quantitative analysis of phospholipid molecular species.•258 phospholipid molecular species were characterized in 486 human milk samples.•Dynamic changes of classes and sub ...classes of phospholipid over time were analyzed.•Critical change of phospholipid profile between lactation periods were analyzed.
Phospholipids are critical for milk digestion and infant development. But the profile of phospholipid molecular species in human milk and its dynamic changes during the lactation period have never been reported. The present study elucidated precise qualitative and quantitative analysis of 258 phospholipid molecular species in 486 human milk samples. Phosphatidylcholine is the most abundant class, followed by phosphatidylserine, phosphatidylethanolamine and sphingomyelin as the second abundant class in different lactation period. The plasmalogens declined along the lactation period, and the polyunsaturated-phospholipids decreased after 10–15 days. The decrease of phosphatidylcholines and phosphatidylglycerols, and the increase of lysophosphatidylethanolamines and lysophosphatidylcholines are critical changes from 0 to 5 days to 10–15 days; increase of phosphatidylinositols, phosphatidylserines, lysophosphatidylethanolamines and lysophosphatidylcholines is the key changes from 10–15 days to 40–45 days; the decrease of most phospholipid molecular species is the characteristic change from 40–45 days to 200–240 days; and the phospholipid profile achieved stability after 200 days.
The recombination of electron–hole pairs severely detracts from the efficiency of photocatalysts. This issue could be addressed in metal–organic frameworks (MOFs) through optimization of the ...charge-transfer kinetics via rational design of structures at atomic level. Herein, a pyrazolyl porphyrinic Ni-MOF (PCN-601), integrating light harvesters, active catalytic sites, and high surface areas, has been demonstrated as a superior and durable photocatalyst for visible-light-driven overall CO2 reduction with H2O vapor at room temperature. Kinetic studies reveal that the robust coordination spheres of pyrazolyl groups and Ni-oxo clusters endow PCN-601 with proper energy band alignment and ultrafast ligand-to-node electron transfer. Consequently, the CO2-to-CH4 production rate of PCN-601 far exceeds those of the analogous MOFs based on carboxylate porphyrin and the classic Pt/CdS photocatalyst by more than 3- and 20-fold, respectively. The reaction avoids the use of hole scavengers and proceeds in a gaseous phase which can take full advantage of the high gas uptake of MOFs. This work demonstrates that the rational design of coordination spheres in MOF structures not only reconciles the contradiction between reactivity and stability but also greatly promotes the interfacial charge transfer to achieve optimized kinetics, providing guidance for the design of highly efficient MOF photocatalysts.
Pure organic materials with intrinsic room‐temperature phosphorescence typically rely on heavy atoms or heteroatoms. Two different strategies towards constructing organic room‐temperature ...phosphorescence (RTP) species based upon the through‐space charge transfer (TSCT) unit of 2.2paracyclophane (PCP) were demonstrated. Materials with bromine atoms, PCP‐BrCz and PPCP‐BrCz, exhibit RTP lifetime of around 100 ms. Modulating the PCP core with non‐halogen‐containing electron‐withdrawing units, PCP‐TNTCz and PCP‐PyCNCz, successfully elongate the RTP lifetime to 313.59 and 528.00 ms, respectively, the afterglow of which is visible for several seconds under ambient conditions. The PCP‐TNTCz and PCP‐PyCNCz enantiomers display excellent circular polarized luminescence with dissymmetry factors as high as −1.2×10−2 in toluene solutions, and decent RTP lifetime of around 300 ms for PCP‐TNTCz enantiomers in crystalline state.
A series of organic phosphors based on paracyclophanes (PCPs) exhibit both strong room‐temperature phosphorescence (RTP) and excellent circularly polarized luminescence. Modulating the PCP core with non‐halogen‐containing electron‐withdrawing units elongates the RTP lifetime to 313.59 and 528.00 ms. The afterglow is visible for several seconds under ambient conditions.
Endometrial cancer (EC) is the most common malignancy affecting women in developed countries. Recently, the EC disease burden has changed; therefore, the Global Burden of Disease (GBD) 2017 was used ...to comprehensively analyze the global, regional, and national burden of EC between 1990 and 2017. General GBD cancer estimation methods were used with the data input from vital registration systems and cancer registries. Annual percent changes were calculated to quantify the trends of EC burden estimates during the study period. Furthermore, the sociodemographic index (SDI) was used to assess the relationship between the EC burden estimates and development level. From 1990 to 2017, the age-standardized incidence and prevalence rate of EC increased globally by 0.58 and 0.89% per year, respectively. In contrast, the age-standardized death rate and disability-adjusted-life years (DALYs) decreased by 1.19 and 1.21% per year, respectively. Increasing trends in both the incidence and prevalence were observed in all SDI quintiles, except for the low SDI quintiles, whereas decreasing trends were observed in all SDI quintiles for mortality and DALYs. Additionally, a non-linear association existed for the level of mortality rate, DALYs, and SDI. Of note, there was a strong positive association between a high body mass index and DALYs across all SDI quintiles. In conclusion, EC incidence and prevalence rates are growing globally, whereas the death rate and DALYs decreased between 1990 and 2017. Greater efforts, particularly detailed prevention strategies for reducing obesity, should be performed to reverse this phenomenon.
Neonatal hypoxic-ischemic encephalopathy (HIE) represents as a major cause of neonatal morbidity and mortality. However, the underlying molecular mechanisms in brain damage are still not fully ...elucidated. This study was conducted to determine the specific potential molecular mechanism in the hypoxic-ischemic induced cerebral injury.
Here, hypoxic-ischemic (HI) animal models were established and primary cortical neurons were subjected to oxygen-glucose deprivation (OGD) to mimic HIE model in vivo and in vitro. The HI-induced neurological injury was evaluated by Zea-longa scores, Triphenyte-trazoliumchloride (TTC) staining the Terminal Deoxynucleotidyl Transferased Utp Nick End Labeling (TUNEL) and immunofluorescent staining. Then the expression of Cytochrome c oxidase subunit 5a (COX5A) was determined by immunohistochemistry, western blotting (WB) and quantitative real time Polymerase Chain Reaction (qRT-PCR) techniques. Moreover, HSV-mediated COX5A over-expression virus was transducted into OGD neurons to explore the role of COX5A in vitro, and the underlying mechanism was predicted by GeneMANIA, then verified by WB and qRT-PCR.
HI induced a severe neurological dysfunction, brain infarction, and cell apoptosis as well as obvious neuron loss in neonatal rats, in corresponding to the decrease on the expression of COX5A in both sides of the brain. What's more, COX5A over-expression significantly promoted the neuronal survival, reduced the apoptosis rate, and markedly increased the neurites length after OGD. Moreover, Triosephosephate isomerase (TPI) was predicted as physical interactions with COX5A, and COX5A over-expression largely increased the expressional level of TPI.
The present findings suggest that COX5A plays an important role in promoting neurological recovery after HI, and this process is related to TPI up-regulation.
The adaption of brain region is fundamental to the development and maintenance of nervous system disorders. The prelimbic cortex (PrL) participates in the affective components of the pain sensation. ...However, whether and how the adaptation of PrL contributes to the comorbidity of neuropathic pain and depression are unknown.
Using resting-state functional magnetic resonance imaging (rs-fMRI), genetic knockdown or overexpression, we systematically investigated the activity of PrL region in the pathogenesis of neuropathic pain/depression comorbid using the combined approaches of immunohistochemistry, electrophysiology, and behavior.
The activity of PrL and the excitability of pyramidal neurons were decreased, and the osteoclastic tartrate-resistant acid phosphatase 5 (Acp5) expression in PrL neurons was upregulated following the acquisition of spared nerve injury (SNI)-induced comorbidity. Genetic knockdown of Acp5 in pyramidal neurons, but not parvalbumin (PV) neurons or somatostatin (SST) neurons, attenuated the decrease of spike number, depression-like behavior and mechanical allodynia in comorbidity rats. Overexpression of Acp5 in PrL pyramidal neurons decreased the spike number and induced the comorbid-like behavior in naïve rats. Moreover, the expression of interleukin-6 (IL-6), phosphorylated STAT3 (p-STAT3) and acetylated histone H3 (Ac-H3) were significantly increased following the acquisition of comorbidity in rats. Increased binding of STAT3 to the Acp5 gene promoter and the interaction between STAT3 and p300 enhanced acetylation of histone H3 and facilitated the transcription of Acp5 in PrL in the modeled rodents. Inhibition of IL-6/STAT3 pathway prevented the Acp5 upregulation and attenuated the comorbid-like behaviors in rats.
These data suggest that the adaptation of PrL mediated by IL-6/STAT3/Acp5 pathway contributed to the comorbidity of neuropathic pain/depression induced by SNI.
Resident microbiota activate regulatory cells that modulate intestinal inflammation and promote and maintain intestinal homeostasis. IL-10 is a key mediator of immune regulatory function. Our studies ...described the functional importance and mechanisms by which gut microbiota and specific microbial components influenced the development of intestinal IL-10-producing B cells. We used fecal transplant to germ-free (GF) Il10+/EGFP reporter and Il10-/- mice to demonstrate that microbiota from specific pathogen-free mice primarily stimulated IL-10-producing colon-specific B cells and T regulatory-1 cells in ex-GF mice. IL-10 in turn down-regulated microbiota-activated mucosal inflammatory cytokines. TLR2/9 ligands and enteric bacterial lysates preferentially induced IL-10 production and regulatory capacity of intestinal B cells. Analysis of Il10+/EGFP mice crossed with additional gene-deficient strains and B cell co-transfer studies demonstrated that microbiota-induced IL-10-producing intestinal B cells ameliorated chronic T cell-mediated colitis in a TLR2, MyD88 and PI3K-dependent fashion. In vitro studies implicated PI3Kp110δ and AKT downstream signaling. These studies demonstrated that resident enteric bacteria activated intestinal IL-10-producing B cells through TLR2, MyD88 and PI3K pathways. These B cells reduced colonic T cell activation and maintained mucosal homeostasis in response to intestinal microbiota.
Autoimmune factor was regarded as one of the risk factors in the pathogenesis of chronic pancreatitis (CP), especially for autoimmune pancreatitis (AIP). However, whether autoimmune factor plays a ...role in non-AIP CP or not was unknown.
Hospitalized patients with non-AIP CP from January 2010 to October 2016 were detected for 22 autoantibodies at the time of hospital admission. Autoantibodies with frequency > 0.5% were enrolled to calculate the frequency in historial healthy controls through literature search in PubMed. Differentially expressed autoantibodies were determined between patients and historial healthy controls, and related factors were identified by multivariate logistic regression analysis.
In a total of 557 patients, 113 cases were detected with 19 kinds of positive autoantibodies, among them anti-β2-glycoprotein I (β2-GPI) antibody was most frequent (9.16%). Compared with historial healthy controls, the frequencies of serum β2-GPI and anti SS-B antibody in patients were significantly higher, while frequencies of anti-smooth muscle antibody and anticardiolipin antibody were significantly lower (all P < 0.05). Multivariate logistic regression analysis result showed that diabetes mellitus (OR = 2.515) and common bile duct stricture (OR = 2.844) were the risk factors of positive β2-GPI antibody in patients while diabetes mellitus in first-/second-/third-degree relatives (OR = 0.266) was the protective factor. There were no related factors for other three differentially expressed autoantibodies.
Four autoantibodies were expressed differentially between patients with non-AIP CP and historial healthy controls. Due to limited significance for diagnosis and treatment of chronic pancreatitis, autoantibodies detection is not recommended conventionally unless suspected of AIP.
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