Low-density lipoprotein cholesterol in oldest old with acute myocardial infarction: Is lower the better?

BACKGROUND: the relationship between low-density lipoprotein cholesterol (LDL-C) and adverse outcomes among the older people remains controversial. OBJECTIVE: to further clarify the association between admission LDL-C levels and cardiovascular mortality (CVM) among oldest old individuals (≥80 years) with acute myocardial infarction (AMI). DESIGN: a prospective cohort study. SETTING: two-centre. SUBJECTS: a consecutive sample of 1,224 oldest old individuals with AMI admitted to Beijing FuWai and Shenzhen FuWai hospitals. METHODS: all individuals were subdivided according to baseline LDL-C levels (<1.8, 1.8-2.6 and ≥ 2.6 mmol/l) and further stratified by high-sensitivity C-reactive protein (hsCRP) concentrations (<10 and ≥10 mg/l). The primary outcome was CVM. The time from admission to the occurrence of CVM or the last follow-up was analysed in Kaplan-Meier and Cox analyses. RESULTS: the median age of the overall population was 82 years. During an average of 24.5 months' follow-up, 299 cardiovascular deaths occurred. Kaplan-Meier analysis showed that LDL-C < 1.8 mmol/l group had the highest CVM among oldest old individuals with AMI. Multivariate Cox regression analysis further revealed that compared with those with LDL-C levels <1.8 mmol/l, subjects with LDL-C levels ≥2.6 mmol/l (hazard ratio: 0.67, 95% confidence interval: 0.46-0.98) had significantly lower risk of CVM, especially in those with high hsCRP levels. Moreover, when categorising according to LDL-C and hsCRP together, data showed that individuals with low LDL-C and high hsCRP levels had the highest CVM. CONCLUSIONS: LDL-C < 1.8 mmol/l was associated with a high CVM after AMI in oldest old individuals, especially when combined with high hsCRP levels, which may need to be confirmed by randomised controlled trials.

Prognostic impacts of ß-blockers in acute coronary syndrome patients without heart failure treated by percutaneous coronary intervention.

BACKGROUND: The use of ß-blockers for acute coronary syndrome (ACS) patients without heart failure (HF) is controversial, and lacks of evidence in the era of reperfusion and intensive secondary preventions. This study aimed to investigate the prognostic impacts of ß-blockers on patients with ACS but no HF treated by percutaneous coronary intervention (PCI). METHODS: A total of 2397 consecutive patients with ACS but no HF treated by PCI were retrospectively recruited from January 2010 to June 2017. Univariable Cox regression was used to assess the prognostic impacts of ß-blockers, followed by adjusted analysis, one-to-one propensity score matching (PSM), and inverse probability treatment weighting (IPTW) analysis, in order to control for systemic between-group differences. The primary outcome was all-cause death. RESULTS: Among the included patients, 2060 (85.9%) were prescribed with ß-blockers at discharge. The median follow-up time was 727 (433-2016) days, with 55 (2.3%) cases of all-cause death. Unadjusted analysis showed that the use of ß-blockers was associated with lower risk of death (hazard ratio [HR]: 0.42, 95% confidence interval [CI]: 0.23-0.76, P = 0.004), which was sustained in adjusted analysis (HR: 0.53, 95% CI: 0.29-0.98, P = 0.044), PSM analysis (HR: 0.44, 95% CI: 0.20-0.96, P = 0.039) and IPTW analysis (HR: 0.49. 95% CI: 0.35-0.70, P < 0.001). Risk reduction was also seen in ß-blocker users for cardiac death, but not for major adverse cardiovascular events. CONCLUSIONS: The use of ß-blockers was associated with reduced long-term mortality for ACS-PCI patients without HF.

Mean Platelet Volume/Platelet Count Ratio and Culprit Plaque Morphologies: An Optical Coherence Tomography Study in Patients with ST Segment Elevation Myocardial Infarction.

This study aimed to investigate the predictive value of mean platelet volume/platelet count ratio (MPR) for coronary plaque features in patients with ST segment elevation myocardial infarction (STEMI). A total of 275 STEMI patients undergoing preintervention optical coherence tomography examination were included, with 142 categorized as plaque rupture (PR) and 133 as plaque erosion (PE). Multivariable logistic regression showed higher MPR was an independent predictor of PR (tertile 3 vs tertile 1, odds ratio: 6.257, 95% confidence interval: 1.586-24.686, P = 0.009). MPR showed better diagnostic performance than other platelet indices. The optimal MPR threshold for diagnosing PR was 0.0473 (sensitivity: 0.721, specificity: 0.647). When added to models of established risk factors, MPR significantly improved the predictive accuracy of PR (area under the curve: 0.767 vs 0.722, P difference = 0.004). In conclusion, for STEMI patients, MPR was an independent predictor of PR and improved diagnostic performance for PR.

The variation of serum uric acid levels among patients with myocardial infarction treated with ticagrelor and the association between serum uric acid and platelet reactivity / 中华心血管病杂志

Objectives: To compare the impact of ticagrelor or clopidogrel on serum uric acid levels among patients with ST-segment elevation myocardial infarction (STEMI) who underwent primary percutaneous coronary intervention (PCI) and further evaluate the effects of variation of serum uric acid levels on platelet reactivity. Methods: STEMI patients who admitted to Fuwai Hospital from April 2017 to January 2020, and underwent primary PCI and discharged alive with aspirin and ticagrelor or clopidogrel were included in this study. Patients were divided into ticagrelor group and clopidogrel group. The baseline clinical data were collected. Serum uric acid and creatinine levels at baseline and 30 days post-PCI were measured. Light transmittance aggregometry was used to assess maximum aggregation rate induced by adenosine diphosphate and arachidonic acid. The changes of serum uric acid and creatinine were compared between the two groups. Multivariate logistic regression was performed to evaluate independent related factors for rise in the uric acid levels, and the effect of variation of serum uric acid level on platelet reactivity was analyzed. Results: A total of 967 patients were included, the age was (59.4±12.1) years, and 163 case were female. There were 550 cases in ticagrelor group (56.9%) and 417 cases in clopidogrel group (43.1%). Baseline serum uric acid and creatinine levels were similar between the 2 groups. At 30 days, the serum uric acid level [(347.2±96.5) mmol/L vs. (341.2±105.3) mmol/L, P=0.009] and absolute [46.4 (-2.4, 88.1) mmol/L vs. 25.0 (-21.9, 73.0) mmol/L, P=0.001] and percentage [13.2 (-0.01, 29.0) % vs. 7.9 (-5.7, 25.0) %, P=0.007] increase in the serum uric acid levels were significantly higher in ticagrelor group than in clopidogrel group. The level of serum creatinine at 30 days was significantly lower in ticagrelor group than in clopidogrel group [(89.7±21.3) μmol/L vs. (94.4±43.9) μmol/L, P<0.05], whereas there were no differences in absolute [8.0 (-1.4, 16.6) μmol/L vs. 7.8 (-2.0, 16.6) μmol/L] and percentage [10.5 (-1.7%, 22.6%) vs. 9.8 (-2.4%, 22.1%)] change in the serum creatinine between the 2 groups (all P>0.05). Logistic regression analysis showed that, after adjusting for confounding factors, ticagrelor therapy was an independent related factor of serum uric acid elevation (OR=1.582, 95% CI:1.023-2.447, P=0.039). The variation of the serum uric acid levels did not affect platelet aggregation and the percentage of high platelet reactivity in both groups. Conclusions: Ticagrelor use is related to a significant increase in the serum uric acid levels at 30 days post-PCI in this patient cohort. The variations in the uric acid levels do not increase the percentage of high platelet reactivity in STEMI patients treated with ticagrelor or clopidogrel.

Stem cell therapy for COVID-19 and other respiratory diseases: Global trends of clinical trials.

Respiratory diseases, including coronavirus disease 2019 and chronic obstructive pulmonary disease (COPD), are leading causes of global fatality. There are no effective and curative treatments, but supportive care only. Cell therapy is a promising therapeutic strategy for refractory and unmanageable pulmonary illnesses, as proved by accumulating preclinical studies. Stem cells consist of totipotent, pluripotent, multipotent, and unipotent cells with the potential to differentiate into cell types requested for repair. Mesenchymal stromal cells, endothelial progenitor cells, peripheral blood stem cells, and lung progenitor cells have been applied to clinical trials. To date, the safety and feasibility of stem cell and extracellular vesicles administration have been confirmed by numerous phase I/II trials in patients with COPD, acute respiratory distress syndrome, bronchial dysplasia, idiopathic pulmonary fibrosis, pulmonary artery hypertension, and silicosis. Five routes and a series of doses have been tested for tolerance and advantages of different regimes. In this review, we systematically summarize the global trends for the cell therapy of common airway and lung diseases registered for clinical trials. The future directions for both new clinical trials and preclinical studies are discussed.

Associations between postprocedural D-dimer, hs-CRP, LDL-C levels and prognosis of acute myocardial infarction patients treated by percutaneous coronary intervention / 中华心血管病杂志

Objective: To investigate the association between postprocedural D-dimer, high sensitivity C-reactive protein(hs-CRP) and low-density lipoprotein-cholesterol(LDL-C) and outcomes of acute myocardial infarction (AMI) patients treated by percutaneous coronary intervention(PCI), in order to clarify the impacts of thrombotic, inflammatory and cholesterol risks on long-term prognosis. Methods: Patients with AMI who underwent emergency PCI from January 2010 to June 2017 in Fuwai Hospital with complete baseline data were enrolled. Patients were stratified into four groups according to quartiles of D-dimer, hs-CRP and LCL-C. Cox regression was used to analyze the relationship between these biomarkers and prognosis. Restricted cubic spline (RCS) was used to characterize the continuous association between risk of all-cause death and biomarkers. The primary outcome was all-cause death. Results: A total of 3 614 patients were included in the analysis. The age was (59.2±12.0) years old, and 2 845 (78.7%) were male and 3 161 (87.5%) patients were diagnosed as ST-segment elevation myocardial infarction. The follow-up time was 652 (414, 1 880) days. Survival analysis showed that postprocedural D-dimer and hs-CRP were significantly associated with all-cause mortality (all P<0.05). Cox regression with multiple adjustments showed that patients with D-dimer≥580 μg/L presented higher risk of all-cause death (HR=2.03, 95%CI 1.22-3.38, P=0.006), compared to patients with D-dimer<220 μg/L. RCS analysis showed that risk of all-cause death was stably high when D-dimer reached 500 μg/L. Multivariable Cox regression also showed that patients with hs-CRP<2.74 mg/L (HR=1.86, 95%CI 1.10-3.15, P=0.020)or hs-CRP≥11.99 mg/L (HR=2.14, 95%CI 1.35-3.40, P=0.001) presented higher mortality compared to patients whose hs-CRP was 2.74-7.18 mg/L. RCS analysis indicated a J-shaped relation between hs-CRP and mortality, as greater risk of death was observed when hs-CRP was lower than 2 mg/L or higher than 10 mg/L. LDL-C was not associated with outcomes (all P>0.05). Conclusions: Postprocedural D-dimer is significantly associated with long-term prognosis of AMI patients treated by PCI. Patients with extremely high or low levels of hs-CRP presents worse outcomes. Intensive and tailored antithrombotic or anti-inflammatory therapies should be considered for patients with increased thrombotic risk and those with extremely high or low inflammatory risk.

Comparison of six-month follow-up results of primary percutaneous coronary intervention guided by optical coherence tomography or coronary angiography / 中华心血管病杂志

Objective: To compare the 6-month follow-up results of primary percutaneous coronary intervention (PPCI) guided by optical coherence tomography (OCT) or coronary angiography (CAG) alone in a larger ST-segment elevation myocardial infarction (STEMI) cohort. Methods: We enrolled 275 STEMI patients undergoing OCT-guided PPCI from March 2017 through December 2018. Two hundred and seventy-five propensity score matched STEMI patients undergoing CAG-guided PPCI served as control group. The 6-month clinical follow-up results were compared between the two groups. The demographic data, complications, coronary angiography and OCT characteristics were evaluated. Results: OCT evaluation showed that there were 151 patients (54.9%) with plaque prolapse and 113 patients (41.1%) with stent malposition. Proximal and/or distal dissection of stents occurred in 38 patients (13.8%), of which 3 patients (1.1%) had both proximal and distal dissection. Of the 38 patients, 2 patients received rescue stent implantation. Results of clinical follow-up at 6 months showed that there was no significant difference in cardiovascular death, repeat myocardial infarction, target vessel revascularization, stroke and hemorrhage endpoint events between OCT-guided PPCI patients and CAG-guided PPCI patients (P=0.682). Conclusion: Clinical events at 6 months are similar between OCT-guided PPCI and CAG-guided PPCI for STEMI patients.

Effects of short-term fasting on the resistance of Nile tilapia (Oreochromis niloticus) to Streptococcus agalactiae infection.

Short-term feed deprivation or fasting is commonly experienced by aquaculture fish species and may be caused by seasonal variations, production strategies, or diseases. To assess the effects of fasting on the resistance of Nile tilapia to Streptococcus agalactiae infection, vaccinated and unvaccinated fish were fasted for zero, one, three, and seven days prior to infection. The cortisol levels of both vaccinated and unvaccinated fish first decreased and then increased significantly as fasting time increased. Liver glycogen, triglycerides, and total cholesterol decreased significantly after seven days of fasting, but glucose content did not vary significantly between fish fasted for three and seven days. Hexokinase (HK) and pyruvate kinase (PK) activity levels were lowest after seven days of fasting, while phosphoenolpyruvate carboxykinase (PEPCK) activity levels varied in opposition to those of HK and PK. Serum superoxide dismutase (SOD) and catalase (CAT) activity levels first increased and then decreased as fasting time increased; SOD activity was highest after three days of fasting. Interleukin-1beta (IL-1ß) and IL-6 mRNA expression levels first increased and then decreased significantly, peaking after three days of fasting. However, suppressor of cytokine signaling-1 (SOCS-1) mRNA expression levels were in opposition to those of IL-1ß and IL-6. Specific antibody levels did not vary significantly among unvaccinated fish fasted for different periods. Although specific antibody level first increased and then decreased in the vaccinated fish as fasting duration increased, there were no significant differences in the survival rates of fasted vaccinated fish after challenge with S. agalactiae. The final survival rates of vaccinated fish fasted for zero, one, three, and seven days were 86.67 ±â€¯5.44%, 80.00 ±â€¯3.14%, 88.89 ±â€¯6.28%, and 84.44 ±â€¯8.32%, respectively. Among the unvaccinated fish, the survival rate was highest (35.56 ±â€¯3.14%) in the fish fasted for three days and lowest (6.67 ±â€¯3.14%) in the fish fasted for seven days. Therefore, our results indicated that short-term fasting (three days) prior to an infection might increase the resistance of unvaccinated Nile tilapia to S. agalactiae.

Vaccine-induced antibody level as the parameter of the influence of environmental salinity on vaccine efficacy in Nile tilapia.

To effectively increase production and improve economic returns, the co-culture of Nile tilapia (Oreochromis niloticus) and marine shrimp has been adopted in many countries, including China. Although O. niloticus is an euryhaline fish that can tolerate elevated salinities and even full-strength seawater, fluctuations in salinity levels can undoubtedly induce stress and affect the immune response of this fish. Therefore, this study assessed the impact of salinity on vaccine efficacy in Nile tilapia, which used serum antibody level as a surrogate marker to detect vaccine efficacy. Nile tilapia were acclimatized to 0, 10, 20, or 30 ppt salinity, and then immunized with a formalin-inactivated Streptococcus agalactiae vaccine. Significantly lower levels of antibody in vaccinated fish were found at 20 and 30 ppt salinity compared to 0 and 10 ppt salinity. White blood cell counts, absolute blood lymphocyte counts, and serum bactericidal activity levels were all significantly lower in vaccinated fish at 20 and 30 ppt salinity. Elevated cortisol levels were detected in all of the fish exposure to salinity. Concentrations of serum electrolytes (Na+ and Cl-) were significantly higher in fish at 30 ppt salinity, as compared to fish at lower salinities. Furthermore, the mRNA transcription levels of three of the immune-related genes analyzed (IgM, IL-1ß, and IFN-γ, but not Hsp70) were significantly inhibited in the vaccinated fish at 20 and 30 ppt salinity. A suppressed immune response and decreased vaccine efficacy were also indicated by the lower survival rate of vaccinated fish at 20 ppt salinity when challenged with S. agalactiae. Therefore, salinities ≥20 ppt negatively affected antibody production in Nile tilapia, ultimately affecting vaccine efficacy.

Characteristics of Balance and Surface Electromyography of Trunk Flexor and Extensor for Stroke Patients / 中国康复理论与实践

Objective To study balance function and surface electromyography (sEMG) activity of erector spinae (ES) and rectus ab-dominis(RA)in stroke patients.Methods From April,2015 to December,2016,17 stroke patients(test group)and 13 healthy subjects(con-trol group)were tested with balance platform:sitting with eyes open/close,with the platform swing of 10°,with trunk flexion and extension in maximum.The root mean square(RMS)of sEMG was recorded on both sides of ES and RA synchronously.The swing length and area of center of mass,the center of pressure on X and Y axes were also recorded as sitting with eyes open/close.Results For the test group,RMS of bilateral ES was significantly different as sitting with eyes open/close and with trunk flexion and extension in maximum (t>2.173, P<0.05).Compared with the control group,RMS of ES and RA in unaffected side increased as sitting with eyes open/close(t>2.175,P<0.05), as well as the swing length and area of center of mass(t>2.760,P<0.05).Conclusion The strength imbalance is found in ES in stroke pa-tients,which may associate with the balance function impairment,and need to be improved in rehabilitation.

Epithelial Sodium Channels in Pulmonary Epithelial Progenitor and Stem Cells.

Regeneration of the epithelium of mammalian lungs is essential for restoring normal function following injury, and various cells and mechanisms contribute to this regeneration and repair. Club cells, bronchioalveolar stem cells (BASCs), and alveolar type II epithelial cells (ATII) are dominant stem/progenitor cells for maintaining epithelial turnover and repair. Epithelial Na(+) channels (ENaC), a critical pathway for transapical salt and fluid transport, are expressed in lung epithelial progenitors, including club and ATII cells. Since ENaC activity and expression are development- and differentiation-dependent, apically located ENaC activity has therefore been used as a functional biomarker of lung injury repair. ENaC activity may be involved in the migration and differentiation of local and circulating stem/progenitor cells with diverse functions, eventually benefiting stem cells spreading to re-epithelialize injured lungs. This review summarizes the potential roles of ENaC expressed in native progenitor and stem cells in the development and regeneration of the respiratory epithelium.

Major surfome and secretome profile of Streptococcus agalactiae from Nile tilapia (Oreochromis niloticus): Insight into vaccine development.

Streptococcus agalactiae is a major piscine pathogen that is responsible for huge economic losses to the aquaculture industry. Safe recombinant vaccines, based on a small number of antigenic proteins, are emerging as the most attractive, cost-effective solution against S. agalactiae. The proteins of S. agalactiae exposed to the environment, including surface proteins and secretory proteins, are important targets for the immune system and they are likely to be good vaccine candidates. To obtain a precise profile of its surface proteins, S. agalactiae strain THN0901, which was isolated from tilapia (Oreochromis niloticus), was treated with proteinase K to cleave surface-exposed proteins, which were identified by liquid chromatography-tandem spectrometry (LC-MS/MS). Forty surface-associated proteins were identified, including ten proteins containing cell wall-anchoring motifs, eight lipoproteins, eleven membrane proteins, seven secretory proteins, three cytoplasmic proteins, and one unknown protein. In addition, culture supernatant proteins of S. agalactiae were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and all of the Coomassie-stained bands were subsequently identified by LC-MS/MS. A total of twenty-six extracellular proteins were identified, including eleven secretory proteins, seven cell wall proteins, three membrane proteins, two cytoplasmic proteins and three unknown proteins. Of these, six highly expressed surface-associated and secretory proteins are putative to be vaccine candidate of piscine S. agalactiae. Moreover, immunogenic secreted protein, a highly expressed protein screened from the secretome in the present study, was demonstrated to induce high antibody titer in tilapia, and it conferred protection against S. agalactiae, as evidenced by the relative percent survival (RPS) 48.61± 8.45%. The data reported here narrow the scope of screening protective antigens, and provide guidance in the development of a novel vaccine against piscine S. agalactiae.

Ferric Phosphate Hydroxide Microstructures Affect Their Magnetic Properties.

Uniformly sized and shape-controlled nanoparticles are important due to their applications in catalysis, electrochemistry, ion exchange, molecular adsorption, and electronics. Several ferric phosphate hydroxide (Fe4(OH)3(PO4)3) microstructures were successfully prepared under hydrothermal conditions. Using controlled variations in the reaction conditions, such as reaction time, temperature, and amount of hexadecyltrimethylammonium bromide (CTAB), the crystals can be grown as almost perfect hyperbranched microcrystals at 180 °C (without CTAB) or relatively monodisperse particles at 220 °C (with CTAB). The large hyperbranched structure of Fe4(OH)3(PO4)3 with a size of ∼19 µm forms with the "fractal growth rule" and shows many branches. More importantly, the magnetic properties of these materials are directly correlated to their size and micro/nanostructure morphology. Interestingly, the blocking temperature (T B) shows a dependence on size and shape, and a smaller size resulted in a lower T B. These crystals are good examples that prove that physical and chemical properties of nano/microstructured materials are related to their structures, and the precise control of the morphology of such functional materials could allow for the control of their performance.

Genes Regulating Epithelial Polarity Are Critical Suppressors of Esophageal Oncogenesis.

Esophageal cancer is an aggressive disease featured by early lymphatic and hematogenous dissemination, and is the sixth leading cause of cancer-related deaths worldwide. The proper formation of apicobasal polarity is essential for normal epithelium physiology and tissue homeostasis, while loss of polarity is a hallmark of cancer development including esophageal oncogenesis. In this review, we summarized the stages of esophageal cancer development associated with the loss or deregulation of epithelial cell apicobasal polarity. Loss of epithelial apicobasal polarity exerts an indispensable role in the initiation of esophageal oncogenesis, tumor progression, and the advancement of tumors from benign to malignant. In particular, we reviewed the involvement of several critical genes, including Lkb1, claudin-4, claudin-7, Par3, Lgl1, E-cadherin, and the Scnn1 gene family. Understanding the role of apicobasal regulators may lead to new paradigms for treatment of esophageal tumors, including improvement of prognostication, early diagnosis, and individually tailored therapeutic interventions in esophageal oncology.

Ultrathin cerium orthovanadate nanobelts for high-performance flexible all-solid-state asymmetric supercapacitors.

Ultrathin CeVO4 nanobelts were successfully synthesized by a hydrothermal method. The thickness of a single nanobelt is about 2.4 nm, which can effectively shorten the ion diffusion and fasten the charge pathway. More importantly, ultrathin CeVO4 nanobelts and graphene are easily assembled as a flexible all-solid-state asymmetric device, which shows a highly flexible property and achieves a maximum energy density of 0.78 mW h cm(-3) and a high life cycle of >6000 cycles.

Microporous Ni11(HPO3)8(OH)6 nanocrystals for high-performance flexible asymmetric all solid-state supercapacitors.

Microporous nickel phosphite [Ni11(HPO3)8(OH)6] nanocrystals were prepared using a hydrothermal method, and were successfully applied as a positive electrode in a flexible all solid-state asymmetric supercapacitor. Because of the specific micro/nanostructure, the flexible solid-state asymmetric supercapacitor can achieve a maximum energy density of 0.45 mW h cm(-3), which is higher than most reported supercapacitors. More importantly, the device performance remains efficient for 10,000 cycles.

Determination of fungicides in fruit juice by ultrasound-assisted dispersive liquid-liquid microextraction based on solidification of floating organic solvent droplets followed by high performance liquid chromatography.

Ultrasound-assisted dispersive liquid-liquid microextraction (UA-DLLME) based on solidification of the floating organic solvent droplets (SFO) combined with HPLC was used for determination of five fungicides in fruit juice samples. 1-Dodecanol, which has a low density and low toxicity, was used as the extraction solvent in UA-DLLME. The solidification of floating organic droplets facilitates the transfer of analytes from the aqueous phase to the organic phase. This method was easy, quick, inexpensive, precise, and linear over a wide range. Under the optimized conditions, the enrichment factors for a 5 mL fruit juice sample were 25 to 56, and the LODs for the five fungicides ranged from 5 to 50 microg/L. The average recoveries ranged from 71.8 to 118.2% with RSDs of 0.9 to 13.9%. Application of the DLLME-SFO technique allows successful separation and preconcentration of the fungicides at a low concentration level in fruit juice samples.

δ ENaC: a novel divergent amiloride-inhibitable sodium channel.

The fourth subunit of the epithelial sodium channel, termed delta subunit (δ ENaC), was cloned in human and monkey. Increasing evidence shows that this unique subunit and its splice variants exhibit biophysical and pharmacological properties that are divergent from those of α ENaC channels. The widespread distribution of epithelial sodium channels in both epithelial and nonepithelial tissues implies a range of physiological functions. The altered expression of SCNN1D is associated with numerous pathological conditions. Genetic studies link SCNN1D deficiency with rare genetic diseases with developmental and functional disorders in the brain, heart, and respiratory systems. Here, we review the progress of research on δ ENaC in genomics, biophysics, proteomics, physiology, pharmacology, and clinical medicine.

Characterization of a novel splice variant of δ ENaC subunit in human lungs.

Salt absorption via apical epithelial sodium channels (ENaC) is a critical rate-limiting process in maintaining airway and lung lining fluid at the physiological level. δ ENaC (termed δ1 in this article) has been detected in human lung epithelial cells in addition to α, ß, and γ subunits (Ji HL, Su XF, Kedar S, Li J, Barbry P, Smith PR, Matalon S, Benos DJ. J Biol Chem 281: 8233-8241, 2006; Nie HG, Chen L, Han DY, Li J, Song WF, Wei SP, Fang XH, Gu X, Matalon S, Ji HL, J Physiol 587: 2663-2676, 2009) and may contribute to the differences in the biophysical properties of amiloride-inhibitable cation channels in pulmonary epithelial cells. Here we cloned a splicing variant of the δ1 ENaC, namely, δ2 ENaC in human bronchoalveolar epithelial cells (16HBEo). δ2 ENaC possesses 66 extra amino acids attached to the distal amino terminal tail of the δ1 ENaC. δ2 ENaC was expressed in both alveolar type I and II cells of human lungs as revealed by in situ hybridization and real-time RT-PCR. To characterize the biophysical and pharmacological features of the splicing variant, we injected Xenopus oocytes with human ENaC cRNAs and measured whole cell and single channel currents of δ1ßγ, δ2ßγ, and αßγ channels. Oocytes injected with δ2ßγ cRNAs exhibited whole cell currents significantly greater than those expressing δ1ßγ and αßγ channels. Single channel activity, unitary conductance, and open probability of δ2ßγ channels were significantly greater compared with δ1ßγ and αßγ channels. In addition, δ2ßγ and δ1ßγ channels displayed significant differences in apparent Na(+) affinity, dissociation constant for amiloride (K(i)(amil)), the EC(50) for capsazepine activation, and gating kinetics by protons. Channels comprising of this novel splice variant may contribute to the diversities of native epithelial Na(+) channels.

8-(4-chlorophenylthio)-guanosine-3',5'-cyclic monophosphate-Na stimulates human alveolar fluid clearance by releasing external Na+ self-inhibition of epithelial Na+ channels.

Salt absorption via alveolar epithelial Na(+) channels (ENaC) is a critical step for maintaining an airspace free of flooding. Previously, we found that 8-(4-chlorophenylthio)-guanosine-3',5'-cyclic monophosphate-Na (CPT-cGMP) activated native and heterologous ENaC. To investigate the potential pharmacological relevance, we applied this compound intratracheally to human lungs and found that ex vivo alveolar fluid clearance was increased significantly. Furthermore, this compound eliminated self-inhibition in human lung H441 cells and in oocytes expressing human αßγ but not δßγ channels. To further elucidate this novel mechanism, we constructed mutants abolishing (ß(ΔV348) and γ(H233R)) or augmenting (α(Y458A) and γ(M432G)) self-inhibition. The mutants eliminating self-inhibition lost their responses to CPT-cGMP, whereas those enhancing self-inhibition facilitated the stimulatory effects of this compound. CPT-cGMP was unable to activate a high P(o) mutant (ß(S520C)) and plasmin proteolytically cleaved channels. Our data suggest that elimination of self-inhibition of αßγ ENaC may be a novel mechanism for CPT-cGMP to stimulate salt reabsorption in human lungs.