Effect of dual residual risk of cholesterol and inflammation on all-cause mortality in patients with cardiovascular disease.

BACKGROUND: Randomized controlled trials confirm that risks of residual cholesterol and residual inflammation remains in patients with cardiovascular disease (CVD) even after lipid-lowering therapy. This study aims to investigate the association between dual residual risk of cholesterol and inflammation and all-cause mortality in a real-world population with CVD. METHODS: Patients with a CVD history who first took statins between 1 January 2010 and 31 December 2017 in the Kailuan Study were selected as study participants. According to low-density lipoprotein cholesterol (LDL-C) and hypersensitive C-reactive protein levels, patients were divided into those with no residual risk, residual inflammatory risk (RIR), residual cholesterol risk (RCR), and residual cholesterol and inflammatory risk (RCIR). Cox proportional hazard model was conducted to determine hazard ratio (HR) of all-cause mortality for RIR, RCR, and RCIR. Stratified analysis was conducted according to good medication adherence and 75% of the percentage LDL-C decline, high SMART 2 risk score, and blood pressure and blood glucose at standard levels. RESULTS: After 6.10 years of follow-up, 377 all-cause deaths occurred in 3509 participants (mean age 63.69 ± 8.41 years, 86.78% men). After adjusting for related risk factors, the HR and (95% confidence interval [CI]) of all-cause mortality in the RIR, RCR, and RCIR was 1.63 (1.05, 2.52), 1.37 (0.98, 1.90), and 1.75 (1.25, 2.46), compared with no residual risk. Similar associations were observed in participants with moderate or low statin compliance, a lower percentage of LDL-C decline, high SMART 2 risk score, uncontrolled blood pressure, and uncontrolled blood glucose, in the RCIR had a 1.66-fold, 2.08-fold, 1.69-fold, 2.04-fold, and 2.05-fold higher risk of all-cause mortality, respectively, than the reference. CONCLUSION: Risks of residual cholesterol and residual inflammation remain in patients with CVD after receiving statins, and their combined effect significantly increases the risk of all-cause mortality. Here, this increased risk was dependent on statin compliance, LDL-C reduction, SMART 2 risk score, and blood pressure and blood glucose control.

Relationship between magnetic resonance imaging findings and prognosis of intracranial tuberculosis.

BACKGROUND: Intracranial tuberculosis (TB) is an intracranial infection caused by Mycobacterium tuberculosis. Magnetic resonance imaging (MRI), in particular enhanced MRI scan, has the ability to detect characteristic lesions of tuberculous meningitis or cerebral parenchymal TB. PURPOSE: To analyze the relationship between MRI findings and prognosis of patients with intracranial TB. MATERIAL AND METHODS: In this retrospective study, a total of 60 patients were confirmed with intracranial TB in the hospital from May 2019 to December 2020. All enrolled patients underwent TB-related laboratory examinations, cranial MRI, and contrast-enhanced MRI. Laboratory tests were analyzed and the relationship between clinical prognosis and cranial MRI features was evaluated. RESULTS: Of the 60 patients, 28 (46.67%) had disseminated TB complications, 20 (36.67%) had secondary TB complications, and the remaining 10 (16.66%) had lymphatic TB or spinal TB complications. Of the patients, 25 had good short-term prognosis and 35 had poor short-term prognosis; 44 patients had good long-term prognosis and 16 had poor long-term prognosis. The incidence of cerebral parenchymal tuberculomas on enhanced MRI was significantly higher in the group with good prognosis compared to that in the group with poor prognosis (P < 0.05). Logistic analysis suggested that hydrocephalus (odds ratio [OR] = 0.057, 95% confidence interval [CI] = 0.003-0.444; P = 0.018) and cistern involvement (OR = 0.100, 95% CI = 0.011-0.581; P = 0.017) were independent risk factors for poor short-term prognosis. CONCLUSION: MRI can display the pathological changes of intracranial TB in detail; hydrocephalus and cistern involvement were independent risk factors for poor short-term prognosis.

Advances in research on ACE2 as a receptor for 2019-nCoV.

Currently, a novel coronavirus (SARS-CoV-2, also called 2019-nCoV) has triggered pandemic Coronavirus Disease 2019 (COVID-19), an acute infectious respiratory disease that first became epidemic in Wuhan (China) and is now spreading worldwide. Although 2019-nCoV and SARS-CoV are very similar viruses genomically and structurally, the huge number of severe cases and deaths now being caused by 2019-nCoV infections has understandably prompted intense research on the receptor used by it to enter human cells. Angiotensin converting enzyme 2 (ACE2), a functional receptor for SARS-CoV, now appears likely to mediate 2019-nCoV entry into human cells. In this review, we describe the roles performed by ACE2 as an enzymatic catalyst and as a receptor for this novel coronavirus. We also summarize the latest research pertaining to the changes noted in ACE2 expression after viral binding, and the relationships relating to virus transmission and population susceptibility to it. Lastly, we speculate on the pathogenesis of COVID-19 and provide a useful reference for drug development against this aggressive virus.

Subacute dermal toxicity study of bensulfuron-methyl in Sprague-Dawley rats.

Background: Bensulfuron-methyl has recently attracted attention given its widespread use as an herbicide in crops, especially its transdermal safety. However, no dermal toxicity study of this pesticide to mammals has been reported. The present study aims to investigate subacute dermal toxicity of bensulfuron-methyl following repeated doses exposure.Methods: Forty-eight Sprague-Dawley rats were randomly divided into four groups: a normal control group and bensulfuron-methyl groups of different concentrations (250, 500, 1000 mg/kg.bw/day). The rats were topically applied with the substance dermally for 6 h per day for 28 days. At the end of the experiment, all rats were monitored for any changes in their hematological, biochemical parameters, and pathological and histological sections.Results: There were no statistically significant differences (P ≥ 0.05) in the hematological parameters and biochemical parameters. The pathological histological results of rats in the control and the highest concentration group showed no significant abnormalities. The NOAEL of subacute dermal toxicity study was found to be 1000 mg/kg.bw/day in both female and male rats.Conclusion: The result indicated that bensulfuron-methyl is probably safe for humans as a pesticide.

[ACE2 agonist DIZE alleviates lung injury induced by limb ischemia-reperfusion in mice].

This study was aimed to explore the effect of angiotensin converting enzyme 2 (ACE2) agonist diminazene aceturate (DIZE) on acute lung injury (ALI) induced by limb ischemia-reperfusion (LIR) in mice. Male 8-week-old wild-type and hACE2 transgenic ICR mice were randomly divided into 6 groups (6 in each group), including wild-type control (W), wild-type model (WL), wild-type model with DIZE administration (WLD), transgenic control (T), transgenic model (TL), and transgenic model with DIZE administration (TLD) groups. LIR model was established by 4 h reperfusion following 2 h ischemia of bilateral hindlimbs with rubber bands in mice. The WLD and TLD groups were pretreated with DIZE (15 mg/kg, i.p.) for 4 weeks before LIR. At the end of LIR, the mice were sacrificed and lung tissues were sampled. Indexes for evaluating lung injury include organ coefficient and wet/dry weight ratio (W/D), cell count and protein concentration of bronchoalveolar lavage fluid (BALF), as well as morphological change and pathological score were detected. Angiotensin II (Ang II) and Ang (1-7) levels in lung tissue were determined by using ELISA commercial kits. And the protein expressions of angiotensin II type 1 receptor (AT1) and Mas receptor protein in lung tissue were detected by Western blot. The results were as follows: (1) There was obvious lung injury in both the WL and TL groups. The lung injury in the TL group was lighter than that in the WL group. DIZE could attenuate the lung injury in both the two groups. (2) The WL group showed increased Ang II and decreased Ang (1-7) levels, whereas the TL group did not exhibit any changes of these two proteins. DIZE decreased the level of Ang II in both the WL and TL groups, and increased the level of Ang (1-7) in the WL group. (3) In the WL and TL groups, AT1 and Mas receptor protein expressions were up-regulated. DIZE reversed the change of AT1 protein expression, whereas further increased Mas receptor expression in both the two groups. These results suggest that DIZE may improve the renin-angiotensin system homeostasis by regulating ACE2-Ang (1-7)-Mas axis in local lung tissue and play a protective role in LIR-induced ALI in mice.

Oxidative stress promotes myocardial fibrosis by upregulating KCa3.1 channel expression in AGT-REN double transgenic hypertensive mice.

The intermediate-conductance Ca2+-activated K+ (KCa3.1) channels play a pivotal role in the cardiac fibroblast proliferation and inflammatory reaction during the progression of myocardial fibrosis. However, the relationship between KCa3.1 expression and oxidative stress, the important factor of promoting fibrosis, has not been clearly established. This study was designed to investigate whether the role of oxidative stress in promoting myocardial fibrosis is related to KCa3.1 channel by using biochemical approaches. It was found that mean blood pressure, plasma Ang II level, and myocardium malondialdehyde (MDA) content of angiotensinogen-renin (AGT-REN) double transgenic hypertension (dTH) mice were higher than those in wild-type (WT) mice of the same age (4, 8 and 12 months) and were significantly increased with age. However, plasma Ang (1-7) level and myocardium superoxide dismutase (SOD) activity showed a downward trend and were lower than those of the same-aged WT mice (4, 8 and 12 months). In addition, protein expression of myocardium KCa3.1 channel in 4-, 8-, and 12-month-old dTH mice were significantly higher than that of the same-aged WT mice and gradually increased with age. TRAM-34, a blocker of KCa3.1 channel, and losartan mitigated the myocardial structural and functional damage by inhibiting collagen deposition and decreasing the expression of ß-MHC. After intervention of ROS scavenger N-acetyl cysteine (NAC) and NADPH inhibitor apocynin (Apo) in 6-month-old dTH mice for 4 weeks, myocardial oxidative stress level was reduced and KCa3.1 channel protein expression was decreased. Meanwhile, Apo inhibited the myocardium p-ERK1/2/T-ERK protein expression in dTH mice, and after blockage of ERK1/2 pathway with PD98059, the KCa3.1 protein expression was reduced. These results demonstrate for the first time that KCa3.1 channel is likely to be a critical target on the oxidative stress for its promoting role in myocardial fibrosis, and the ERK1/2 pathway may be involved in the regulation of oxidative stress to KCa3.1.

Protective role of ACE2-Ang-(1-7)-Mas in myocardial fibrosis by downregulating KCa3.1 channel via ERK1/2 pathway.

The intermediate-conductance Ca2+-activated K+ (KCa3.1) channel plays a vital role in myocardial fibrosis induced by angiotensin (Ang) II. However, as the antagonists of Ang II, the effect of angiotensin-converting enzyme 2 (ACE2)-angiotensin-(1-7)-Mas axis on KCa3.1 channel during myocardial fibrosis remains unknown. This study was designed to explore the function of KCa3.1 channel in the cardioprotective role of ACE2-Ang-(1-7)-Mas. Wild-type (WT) mice, hACE2 transgenic mice (Tg), and ACE2 deficiency mice (ACE2-/-) were administrated with Ang II by osmotic mini-pumps. As the activator of ACE2, diminazene aceturate (DIZE) inhibited increase of blood pressure, collagen deposition, and KCa3.1 protein expression in myocardium of WT mice induced by Ang II. In Tg and ACE2-/- mice, besides the elevation of blood pressure, Ang II induced transformation of cardiac fibroblast into myofibroblast and resulted in augmentation of hydroxyproline concentration and collagen deposition, as well as KCa3.1 protein expression, but the changes in ACE2-/- mice were more obvious than those in Tg mice. Mas antagonist A779 reduced blood pressure, myocardium fibrosis, and myocardium KCa3.1 protein expression by Ang II in Tg mice, but activation of KCa3.1 with SKA-31 in Tg mice promoted the pro-fibrogenic effects of Ang II. Respectively, in ACE2-/- mice, TRAM-34, the KCa3.1 blocker, and Ang-(1-7) inhibited increase of blood pressure, collagen deposition, and KCa3.1 protein expression by Ang II. Moreover, DIZE and Ang-(1-7) depressed p-ERK1/2/t-ERK increases by Ang II in WT mice, and after blockage of ERK1/2 pathway with PD98059, the KCa3.1 protein expression was reduced in WT mice. In conclusion, the present study demonstrates that ACE2-Ang-(1-7)-Mas protects the myocardium from hypertension-induced injury, which is related to its inhibiting effect on KCa3.1 channels through ERK1/2 pathway. Our results reveal that KCa3.1 channel is likely to be a critical target on the ACE2-Ang-(1-7)-Mas axis for its protective role in myocardial fibrosis and changes of KCa3.1 induced by homeostasis of ACE-Ang II-AT1 axis and ACE2-Ang-(1-7)-Mas axis may be a new therapeutic target in myocardial fibrosis.

Comparison Between Sequential Therapy and Modified Bismuth-Included Quadruple Therapy for Helicobacter pylori Eradication in Chinese Patients.

To compare the efficacy and safety of sequential therapy and modified bismuth-included quadruple therapy as a first-line Helicobacter pylori eradication in China. The patients were randomized to receive sequential therapy [n = 90; rabeprazole (20 mg twice daily) and amoxicillin (1 g twice daily) for 5 days, followed by rabeprazole (20 mg twice daily), tinidazole (500 mg twice daily) plus clarithromycin (500 mg twice daily) for another 5 days] or modified bismuth-included quadruple therapy [n = 109; rabeprazole (20 mg twice daily), levofloxacin hydrochloride (400 mg twice daily), clarithromycin (500 mg twice daily), and colloidal bismuth pectin (200 mg 3 times a day) for 7 days]. A follow-up urea breath test was applied 4 weeks later. A total of 199 patients were diagnosed with H. pylori infection. The intention-to-treat and per-protocol (PP) eradication rates were 91.7% and 92.6%, respectively, in the modified bismuth-included quadruple therapy group, and 74.4% and 76.1%, respectively, in the sequential therapy group. The eradication rates were significantly higher in the modified bismuth-included quadruple therapy group, compared with the sequential therapy group (P = 0.001 for intention to treat and P = 0.001 for PP). Adverse effects were reported by patients from both groups, but the difference did not reach significant level (P = 0.280). The modified bismuth-included quadruple therapy seemed to be superior to the sequential therapy as the first-line regimen for H. pylori eradication in Chinese patients.

Erythropoietin Decreases the Occurrence of Myocardial Fibrosis by Inhibiting the NADPH-ERK-NF-x03BA;B Pathway.

OBJECTIVES: The aim of this study was to investigate the protective role of erythropoietin (EPO) against myocardial fibrosis (MF). METHODS: Pressure-overloaded rats were established by abdominal aortic constriction, the rats were randomly divided in a double-blind manner into 3 groups (n = 12 for each group): sham-operated rats (sham), operated rats receiving physiological saline (vehicle) and operated rats receiving 4,000 U/kg rhEPO (EPO group). The vehicle and drugs were administered to rats by intraperitoneal injection. In addition, cultured adult rat cardiac fibroblasts (CFs) were utilized to investigate the role of EPO in CF proliferation and collagen secretion. RESULTS: After 4 weeks, besides an increase in blood pressure, myocardial hypertrophy, collagen deposition in the myocardium and decreased cardiac function were observed in the pressure-overloaded rats. The expression of NADPH oxidase (Nox2 and Nox4) and inflammatory cytokines (CD45, F4/80 and MCP-1) was also significantly increased. All these alterations were prevented by EPO. TGF-ß promoted CF proliferation, collagen secretion, ROS production and Nox2/Nox4 expression, which was inhibited by EPO. In addition, the TGF-ß-induced increase of ERK1/2 phosphorylation and NF-x03BA;B expression were attenuated by EPO. CONCLUSION: EPO inhibited rat MF induced by pressure overload and improved myocardial function by decreasing CF proliferation and differentiation via inhibition of the NADPH-ERK-NF-x03BA;B pathway.

[In vivo study of the renoprotective effects of EGCG in diabetic db/db mice].

OBJECTIVE: To explore the renoprotective effects of (-)-epigallocatechin-3-gallate (EGCG) and its potential mechanism in type 2 diabetic db/db mice. METHODS: 8-week-old db/db mice (6 h fasting plasma glucose >16.7 mmol/L) were allocated randomly into Control group (non-intervention group, n=8), EGCG A group (50 mg·kg(-1)·d(-1,)n=8), EGCG B group (100 mg·kg(-1)·d(-1,)n=8). Before the study and after the intervention (in the 4(th)and 8(th)week), the body weight, the level of fasting plasma glucose, oral glucose tolerance test (OGTT) were measured and 24 h urine samples were collected. 24 h proteinuria was measured by routine chemical method. The levels of angiotensin Ⅱ(AngⅡ), fasting plasma insulin and urinary 8-OHdG were measured with enzyme-linked immunosorbent assay (ELISA). The protein expression levels of angiotensin Ⅱ type 1 receptor (AT-1R), nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit P22-phox, NADPH oxidase subunit P47-phox, phospho-extracellular regulated protein kinases (p-Erk1/2), phospho-P38 mitogen-activated protein kinase (p-P38MAPK), phospho -phosphatidylinositol 3-hydroxy kinase (p-PI3K) and phospho-protein kinase B (p-AKT) were determined by Western blot. The renal pathological changes were examined by the method of PAS (periodic acid-Schiff stain). RESULTS: After 8 weeks of treatment with EGCG, the level of fasting plasma glucose decreased[(14.4±1.0) mmol/L, (14.2±0.7) mmol/L vs. (17.2±0.8) mmol/L]; the level of fasting plasma insulin increased[(13.2±1.2)mU/L, (13.4±1.3) mU/L vs. (9.9±1.0) mU/L]; the area under the curve (AUC) of OGTT decreased[(49.3±1.8) mmol·L(-1)·h(-1,)(44.8±0.7) mmol·L(-1)·h(-1)vs. (60.0±0.8) mmol·L(-1)·h(-1)]; the level of 24 h proteinuria[(8.8±1.0) mg, (8.6±1.1) mg vs. (11.7±1.3) mg]and urinary 8-OHdG[(90±5) ng/d, (78±5) ng/d vs. (118±10) ng/d]decreased; the level of serum Ang-Ⅱ[(498±23) ng/L, (511±19) ng/L vs. (688±17) ng/L]and renal cortex AngⅡ[(367±5) ng/L, (384±10) ng/L vs. (406±7) ng/L]decreased; the expression levels of AT-1R, P22-phox, P47-phox, p-Erk1/2, p-P38MAPK downregulated obviously and the expression levels of p-PI3K, p-AKT increased significantly (P<0.05), and renal pathology improved as compared with the control group. After 8 weeks of treatment with EGCG, the level of urinary 8-OHdG decreased (P=0.007) and the AUC of OGTT also decreased (P=0.01) in EGCG B group when compared with the EGCG A group. CONCLUSION: EGCG protects the kidney in diabetic db/db mice via anti-oxidative stress pathway, as well as inhibiting Erk1/2-P38MAPK pathway and improving PI3K-AKT signaling transduction pathway.

Biosorption mechanisms involved in immobilization of soil Pb by Bacillus subtilis DBM in a multi-metal-contaminated soil.

Mechanisms of soil Pb immobilization by Bacillus subtilis DBM, a bacterial strain isolated from a heavy-metal-contaminated soil, were investigated. Adsorption and desorption experiments with living bacterial cells as well as dead cells revealed that both extracellular adsorption and intracellular accumulation were involved in the Pb(2+) removal from the liquid phase. Of the sequestered Pb(II), 8.5% was held by physical entrapment within the cell wall, 43.3% was held by ion-exchange, 9.7% was complexed with cell surface functional groups or precipitated on the cell surface, and 38.5% was intracellularly accumulated. Complexation of Pb(2+) with carboxyl, hydroxyl, carbonyl, amido, and phosphate groups was demonstrated by Fourier transform infrared spectroscopic analysis. Precipitates of Pb5(PO4)3OH, Pb5(PO4)3Cl and Pb10(PO4)6(OH)2 that formed on the cell surface during the biosorption process were identified by X-ray diffraction analysis. Transmission electron microscopy-energy dispersive spectroscopic analysis confirmed the presence of the Pb(II) precipitates and that Pb(II) could be sequestered both extracellularly and intracellularly. Incubation with B. subtilis DBM significantly decreased the amount of the weak-acid-soluble Pb fraction in a heavy-metal-contaminated soil, resulting in a reduction in Pb bioavailability, but increased the amount of its organic-matter-bound fraction by 71%. The ability of B. subtilis DBM to reduce the bioavailability of soil Pb makes it potentially useful for bacteria-assisted phytostabilization of multi-heavy-metal-contaminated soil.

MECHANISM OF MICRORNA-218-5P IN MITOCHONDRIAL BIOGENESIS OF SEPSIS-INDUCED ACUTE KIDNEY INJURY BY THE REGULATION OF PGC-1Α.

ABSTRACT: Background: Sepsis-induced acute kidney injury (SI-AKI) is a kind of kidney dysfunction, which brings a lot of suffering. This study aimed to figure out the role of the miR-218-5p/PGC-1α axis in SI-AKI. Methods: AKI mouse model was established through cecal ligation and puncture. PGC-1α expression was activated using an activator ZLN005 before the serum and tissue samples were collected. Next, pathological structure and apoptosis of kidney tissues were observed. Levels of blood urea nitrogen, serum creatinine, and indicators of inflammation and oxidative stress were assessed. Moreover, reactive oxygen species and mitochondrial membrane potential levels, adenosine 5'-triphosphate content, and mitochondrial ultrastructure of kidney tissues were observed. HK2 cells were treated by lipopolysaccharide (LPS) to mimic sepsis in vitro , followed by evaluation of cell survival and apoptosis, inflammation, and oxidative stress. Subsequently, the binding relation between PGC-1α and miR-218-5p was predicted and validated. Then expression of PGC-1α and miR-218-5p was detected. PGC-1α and miR-218-5p expression were intervened to detect their influences in mitochondrial biogenesis. At last, miR-218-5p was overexpressed in ZLN005 (PGC-1α activating agent) pretreated SI-AKI mice to validate the mechanism. Results: PGC-1α is poorly expressed in SI-AKI, but overexpression of PGC-1α using ZLN005 alleviated SI-AKI injury and promoted mitochondrial biogenesis in AKI mice, and relieved LPS-induced cell injury. PGC-1α is a target of miR-218-5p. Downregulation of miR-218-5p expression in HK2 cells attenuated mitochondrial biogenesis disorder. Inhibition of PGC-1α annulled the role of miR-218-5p silencing in cells. In vivo , miR-218-5p overexpression partly reversed the protective role of ZLN005 in SI-AKI mice. Conclusion: miR-218-5p targeted PGC-1α to disrupt mitochondrial biogenesis, thereby exacerbating SI-AKI.

The clinical effectiveness of sivelestat in treating sepsis patients with both acute respiratory distress syndrome and septic cardiomyopathy.

BACKGROUND: We aimed to assess the efficacy of the neutrophil elastase inhibitor, sivelestat, in the treatment of sepsis-induced acute respiratory distress syndrome (ARDS) and septic cardiomyopathy (SCM). METHODS: Between January 2019 and December 2021, we conducted a randomized trial on patients who had been diagnosed with sepsis-induced acute respiratory distress syndrome (ARDS) and septic cardiomyopathy (SCM) at Wuhan Union Hospital. The patients were divided into two groups by random envelop method, the Sivelestat group and the Control group. We measured the serum concentrations of Interleukin (IL)-6, IL-8, Tumor necrosis factor-α (TNF-α), and High-mobility group box 1 (HMGB1) at five time points, which were the baseline, 12 h, 24 h, 48 h, and 72 h after admission to the ICU. We evaluated the cardiac function by sonography and the heart rate variability (HRV) with 24-hour Holter recording between the time of admission to the intensive care unit (ICU) and 72 h after Sivelestat treatment. RESULTS: From January 2019 to December 2021, a total of 70 patients were included in this study. The levels of IL-6, IL-8, and TNF-α were significantly lower in the Sivelestat group at different time points (12 h, 24 h, 48 h, and 72 h). HMGB1 levels were significantly lower at 72 h after Sivelestat treatment (19.46 ± 2.63pg/mL vs. 21.20 ± 2.03pg/mL, P = 0.003). The stroke volume (SV), tricuspid annular plane systolic excursion (TAPSE), early to late diastolic transmitral flow velocity (E/A), early (e') and late (a') diastoles were significantly low in the Control group compared with the Sivelestat group. Tei index was high in the Control group compared with the Sivelestat group (0.60 ± 0.08 vs. 0.56 ± 0.07, P = 0.029). The result of HRV showed significant differences in standard deviation of normal-to-normal intervals (SDNN), low frequency (LF), and LF/HF (high frequency) between the two groups. CONCLUSIONS: Sivelestat can significantly reduce the levels of serum inflammatory factors, improve cardiac function, and reduce heart rate variability in patients with Sepsis-induced ARDS and SCM.

Association between the High-Sensitivity C-Reactive Protein/Albumin Ratio and New-Onset Chronic Kidney Disease in Chinese Individuals.

INTRODUCTION: Inflammation is associated with development of chronic kidney disease (CKD). However, the association of the high-sensitivity C-reactive protein (hs-CRP)/albumin ratio (CAR) on the risk of CKD in the general population is unknown. This study explored the relationship between the CAR and CKD and the ability of this ratio to predict CKD in the general population. METHODS: A total of 47,472 participants in the Kailuan study who met the inclusion criteria in 2010 were selected and grouped using the quartile method. A Cox proportional hazard regression model was used to evaluate the association of the CAR on the risk of CKD. The C-index, net reclassification index (NRI), and overall identification index (IDI) were calculated to evaluate the ability of the CAR to predict CKD. RESULTS: During a follow-up of 378,383 person-years, CKD events occurred in 6,249 study participants (13.16%). The Cox proportional hazard regression model showed that the hazard ratio (95% confidence interval) for CKD events was 1.18 (1.10-1.28) in the Q3 group and 1.42 (1.32-1.53) in the Q4 group when compared with the Q1 group. Compared with the single index, the C-index, NRI, and IDI values were significantly improved when the CAR was added for prediction of risk of CKD. CONCLUSIONS: A higher CAR was an independent risk factor for CKD. The ability of the CAR to predict CKD was better than that of hs-CRP or albumin. The CAR provides an important reference index for predicting the risk of CKD.

Detection and Genomic Characterization of Torque Teno Virus in Pneumoconiosis Patients in China.

Pneumoconiosis is a common occupational disease that can worsen with accompanying infection. Torque teno virus (TTV) is a prevalent human virus with multiple genotypes that can chronically and persistently infect individuals. However, the prevalence of TTV in pneumoconiosis patients is still unclear. This research aims to detect the presence and prevalence of TTV in the alveolar lavage fluid of pneumoconiosis patients in the Hunan Province of China using PCR. As a result, a 65.5% positive rate (19 out of 29) of TTV was detected. The TTV detection rate varies among different stages of silicosis and different pneumoconiosis patient ages. Nine novel TTV genomes ranging in size from 3719 to 3908 nt, named TTV HNPP1, HNPP2, HNPP3, HNPP4, HNPP5, HNPP6-1, HNPP6-2, HNPP7-1 and HNPP7-2, were identified. A genomic comparison and phylogenetic analysis indicated that these nine TTVs represent five different species with high genetic diversity which belong to the genus Alphatorquevirus. HNPP6-1 and HNPP6-2 belong to TTV3, HNPP5 belongs to TTV13, HNPP1 belongs to TTV24, HNPP4 belongs to TTV20, and the others belong to TTV19. The genomes of TTV HNPP1, HNPP6-1, and HNPP6-2 contain three putative open reading frames (ORFs) coding for proteins, ORF1, ORF2, and ORF3, while the other six TTV genomes contain two ORFs coding for proteins, ORF1 and ORF2. These results provide the first description of TTV epidemiology in pneumoconiosis patients in China. The newly identified TTV genome sequences reveal the high genetic diversity of TTV in pneumoconiosis patients and could contribute to a deeper understanding of TTV retention and infection in humans.

Effect of NADPH oxidase inhibitor apocynin on the expression of hypoxia-induced factor-1α and endothelin-1 in rat carotid body exposed to chronic intermittent hypoxia.

The effects of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor apocynin on the enhanced hypoxia induced factor-1α (HIF-1α) and endothelin-1 (ET-1) expression, elevated systolic blood pressure under chronic intermittent hypoxia (CIH) condition and its action mechanism were investigated. Thirty healthy 8-week old Sprague-Dawley (SD) male rats were randomly divided into three groups (n=10 each): sham group, CIH group, and apocynin-treated CIH group. Tail artery systolic blood pressure was measured by tail-cuff method. Real-time fluorescence quantitative polymerase chain reaction (PCR) was used to detect the mRNA expression of HIF-1α and ET-1 in the carotid body, and the HIF-1α protein expression was examined by using Western blotting. The levels of malondialdehyde (MDA) and superoxide dismutase (SOD) were determined by using colorimetric method. In addition, the plasma ET-1 and HIF-1α levels were measured by using enzyme-linked immunosorbent assay. It was found that CIH exposure was associated with increased MDA levels, and apocynin-treated CIH animals showed reduction in MDA levels. Apocynin treatment prevented CIH-induced hypertension as well as CIH-induced decrease in SOD. The increases of HIF-1α and ET-1 mRNA along with HIF-1α protein expression in the carotid body, and elevated circulating HIF-1α and ET-1 levels were observed in CIH-exposed animals. Treatment with apocynin significantly decreased the ET-1 mRNA, HIF-1α protein expression and circulating HIF-1α level in CIH-exposed animals, and there was no statistically significant difference in the HIF-1α mRNA expression between CIH group and apocynin-treated group. These results indicated that apocynin alleviated CIH-induced hypertension by inhibiting NADPH oxidase, further leading to the reduced vasoconstrictor ET-1 level and oxidative stress. HIF-1α/ET-1 system signal pathway may interact with CIH-induced NADPH oxidase-dependent oxidative stress. Inhibition of NADPH oxidase activity may hopefully serve as a useful strategy for prevention and treatment of obstructive sleep apnea hypopnea syndrome-induced hypertension.

[Correlation between the serum level of advanced oxidation protein products and the cognitive function in patients with obstructive sleep apnea hypopnea syndrome].

OBJECTIVE: To observe the change of the cognitive function and the serum level of advanced oxidation protein products (AOPP) in patients with obstructive sleep apnea hypopnea syndrome (OSAHS), and then to investigate the correlation between them. METHODS: Sixty seven patients with OSAHS, 20 healthy controls with matched age, BMI, and education, 15 patients with OSAHS after effective treatment of continuous positive airway pressure (CPAP) with matched age, BMI, and education were enrolled. Polysomnography (PSG), Epworth sleepiness scale (ESS), mini-mental state examination (MMSE), and clock drawing test (CDT) were performed in these groups. The serum level of AOPP, superoxide dismutase (SOD), and malondialdehyde (MDA) were measured. RESULTS: The MMSE and CDT scores of patients with OSAHS were decreased compared to those in healthy controls [(4.73 ± 0.81) vs (2.69 ± 1.38), (2.85 ± 0.61) vs (1.92 ± 0.62)], but the scores improved after effective CPAP treatment. The serum levels of AOPP [(78 ± 20) vs (117 ± 20) µmol/L] and MDA [(2.9 ± 1.0) vs (6.1 ± 3.0) µmol/L] in patients with OSAHS were increased compared to those in healthy controls, but the levels decreased after effective CPAP treatment. The serum SOD level in patients with OSAHS was decreased compared to that in healthy controls [(89 ± 8) vs (57 ± 9) U/ml], but it was increased after effective CPAP treatment. The MMSE and CDT scores of all the subjects including the 2 groups (the OSAHS group and the effective CPAP-treatment group) were correlated with the results of PSG (baseline SaO2, lowest SaO2, AHI, LA/HT, SLT90%). The serum levels of AOPP, MDA and SOD of all the subjects were also correlated with the results of PSG (lowest SaO2, AHI, LA/HT, SLT90%). The serum levels of AOPP, MDA and SOD of all the subjects were correlated with the MMSE and CDT scores. The serum level of AOPP of all the subjects was also correlated with the serum levels of MDA and SOD. CONCLUSIONS: Cognitive impairment in patients with OSAHS is correlated with the severity of the disease. AOPP is a useful marker for oxidative stress and protein injury, and closely correlated with the cognitive impairment in patients with OSAHS.

Upregulated microRNA-450b-5p represses the development of acute liver failure via modulation of liver function, inflammatory response, and hepatocyte apoptosis.

OBJECTIVE: It has been evidenced that microRNAs (miRs) exert crucial effects on acute liver failure (ALF), while the detailed function of miR-450b-5p in ALF progression remained obscure. The purpose of this research was to unravel the regulatory mechanism of miR-450b-5p in ALF via modulating Mouse Double Minute 2 protein (MDM2). METHODS: ALF was induced in mice by intraperitoneal injection of d-galactosamine ( d-GalN) and lipopolysaccharide (LPS). Adenoviruses containing overexpressed miR-450b-5p, MDM2 shRNA, and overexpressed MDM2 sequences were utilized to manipulate miR-450b-5p and MDM2 expression in the liver before the mice were treated with d-GalN/LPS-induced ALF. Subsequently, miR-450b-5p and MDM2 expression levels in liver tissues of ALF mice were examined. Serum biochemical parameters of liver function were tested, serum inflammatory factors were assessed, and the histopathological changes and hepatocyte apoptosis in liver tissues were observed. The relation between miR-450b-5p and MDM2 was verified. RESULTS: In ALF mice, miR-450b-5p was low-expressed while MDM2 was high-expressed. The upregulation of miR-450b-5p or downregulation of MDM2 could alleviate liver function, mitigate the serum inflammatory response and pathological changes in liver tissues, as well as inhibit the apoptosis of hepatocytes. MiR-450b-5p targeted MDM2. MDM2 overexpression reversed the repressive effects of elevated miR-450b-5p on ALF. CONCLUSION: The upregulated miR-450b-5p blocks the progression of ALF via targeting MDM2. This study contributes to affording novel therapeutic targets for ALF treatment.

Obesity and Cardiac Conduction Block Disease in China.

Importance: Although a high body mass index (BMI) has been found to be associated with increased risk of cardiac conduction block (CCB) in older adults, no further studies have investigated the association between obesity and CCB in the general population. Objective: To investigate the association between obesity and CCB, including its subtypes. Design, Setting, and Participants: This cohort study used data from participants in the Kailuan Study in China (2006-2018) who had completed a physical examination in 2006 (baseline) and had not experienced CCB before baseline. Data analysis was conducted from March to September 2023. Exposures: Obesity status was defined by BMI in 3 groups: normal weight (18.5 to <24), overweight (24 to <28), and obesity (≥28). Main Outcome and Measures: The primary outcome was CCB, which was diagnosed from standard 12-lead electrocardiography. The primary end point included high-grade atrioventricular block (HAVB), complete right bundle branch block, complete left bundle branch block, left anterior fascicular block (LAFB), and left posterior fascicular block. First-degree atrioventricular block (FAVB), second-degree type 1 AVB, HAVB, complete and incomplete right and left bundle branch block, LAFB, and left posterior fascicular block were considered separately as secondary end points. Results: Among 86 635 participants (mean [SD] age, 50.8 [11.9] years; 68 205 males [78.7%]), there were 33 259 individuals with normal weight (38.4%), 37 069 individuals with overweight (42.8%), and 16 307 individuals with obesity (18.8%). The mean (SD) follow-up was 10.6 (3.07) years. In the multivariable Cox proportional hazards regression analysis, obesity was associated with an increased risk of incident CCB (hazard ratio [HR], 1.21; 95% CI, 1.04-1.42) vs normal BMI. In secondary analysis, obesity was associated with an increased risk of FAVB (HR, 1.44; 95% CI, 1.21-1.73), HAVB (HR, 1.99; 95% CI, 1.03-3.82), and LAFB (HR, 1.29; 95% CI, 1.03-1.62) vs normal BMI. There was no association between obesity and other CCB subtypes. Obesity was associated with a greater increase in risk of CCB vs normal BMI in older (aged ≥65 years; HR, 1.44; 95% CI, 1.05-1.96) vs younger (aged <65 years; HR, 1.13; 95% CI, 0.96-1.34) participants (P for interaction < .001) and those with diabetes (HR, 2.16; 95% CI, 1.24-3.76) vs without diabetes (HR, 1.19; 95% CI, 1.02-1.39) (P for interaction = .02). Conclusions and Relevance: This study found that obesity was associated with an increased risk of CCB, with greater increases in risk for FAVB, HAVB, and LAFB. Individuals who were older and those who had diabetes had larger increases in risk.

Association between cumulative uric acid to high-density lipoprotein cholesterol ratio and the incidence and progression of chronic kidney disease.

Objective: The ratio of uric acid to high-density lipoprotein cholesterol (UHR) was related to the risk of chronic kidney disease (CKD), we aimed to investigate the association of cumulative UHR (cumUHR) with incidence and progression of CKD. Methods: Our study included a total of 49,913 participants (mean age 52.57 years, 77% males) from the Kailuan Study conducted between 2006 and 2018. Participants who completed three consecutive physical examinations were included. Cumulative UHR (cumUHR) was computed as the summed average UHR between two consecutive physical examinations, multiplied by the time between the two examinations. Participants were then categorized into four groups based on cumUHR quartiles. Subsequently, participants were further divided into a CKD group and a non-CKD group. The associations between cumUHR and CKD and it's progression were assessed by Cox proportional hazards regression models. The cumulative incidence of endpoint events was compared between the cumUHR groups using the log-rank test. The C-index, net reclassification improvement (NRI) and integrated discrimination improvement (IDI) were calculated to assess the predictive performance of cumUHR. Results: After a mean follow-up of 8.0 ± 1.7 years, there were 4843 cases of new-onset CKD, 2504 of low eGFR, and 2617 of proteinuria in the non-CKD group. Within the CKD group, there were 1952 cases of decline in eGFR category, 1465 of >30% decline in eGFR, and 2100 of increased proteinuria. In the non-CKD group, the adjusted hazard ratios (HRs) and confidence intervals (CIs) in the fourth quartile were 1.484 (1.362-1.617), 1.643 (1.457-1.852), and 1.324 (1.179-1.486) for new-onset CKD, low eGFR, and proteinuria, respectively. In the CKD group, the adjusted HRs in the fourth quartile were 1.337 (1.164-1.534), 1.428 (1.216-1.677), and 1.446 (1.267-1.651) for decline in eGFR category, >30% decline in eGFR, and increase in proteinuria, respectively. In addition, we separately added a single UHR measurement and cumUHR to the CKD base prediction model and the CKD progression base prediction model, and found that the models added cumUHR had the highest predictive value. Conclusion: High cumUHR exposure was an independent risk factor for the incidence and progression of CKD, and it was a better predictor than a single UHR measurement.