Determination of trace chelating carboxylic acids in rice by green extraction combined with liquid chromatography-mass spectrometry analysis and its application in the evaluation of old and new rice.

RATIONALE: Accurate identification of old rice samples from new ones benefits their market circulation and consumers. However, the current detection methods are still not satisfactory because of their insufficient accuracy or (and) time-consuming process. METHODS: Chelating carboxylic acids (CCAs) were selectively extracted from rice, by stirring with chelating resin and a dilute Na2CO3 solution. The green analytical chemistry guidelines for sample preparation were investigated by using the green chemistry calculator AGREE prep. The extractant was determined by liquid chromatography-mass spectrometry (LC/MS), and statistical analysis of the analytical data was carried out to evaluate the significance of the difference by ChiPlot. RESULTS: The limit of quantitation for the CCAs is in the range of 1 to 50 ng/mL, with a reasonable reproducibility. The CCAs in 23 rice samples were determined within a wide concentration range from 0.03 to 1174 µg/g. Intriguingly, the content of citric acid, malonic acid, α-ketoglutaric acid and cis-aconite acid in new rice was each found to be distinctively higher than that in old rice by several times. Even mixtures of old and new rice were found to show much difference in the concentration of citric acid and malic acid. CONCLUSION: A green analytical method has been developed for the simultaneous determination of CCAs by LC/MS analysis, and the identification of old rice samples from new ones was easily carried out according to their CCA content for the first time. The results indicated that the described method has powerful potential for the accurate identification of old rice samples from new ones.

Efficacy, Safety, and Treatment Burden of Aflibercept 2 mg and Ranibizumab in Retinal Vein Occlusion: A Systematic Review and Meta-analysis.

INTRODUCTION: This systematic review and meta-analysis aimed to provide an updated evidence base for clinical decision-making by comparing the efficacy and safety of aflibercept 2 mg and ranibizumab in treating retinal vein occlusion (RVO). METHODS: A systematic search was conducted using eight databases up to December 2021. Randomized controlled trials (RCTs) and real-world studies (RWSs) comparing aflibercept and ranibizumab in patients with RVO were evaluated. The primary outcomes assessed were efficacy, number of injections administered, and adverse events. RESULTS: Three RCTs (424 patients) and 11 RWSs (1415 patients) were included. For central RVO (CRVO), RCTs demonstrated a comparable efficacy, whereas RWSs showed that mean changes from baseline in best-corrected visual acuity (BCVA) and central retinal thickness (CRT) were significantly greater with aflibercept compared to ranibizumab; the number of injections of aflibercept was fewer than that of ranibizumab in RCTs, but similar in RWSs. For branch RVO (BRVO), no statistically significant difference in efficacy between the two drugs in RCTs/RWSs was observed, with fewer injections of aflibercept at 12 months in RWSs. The safety profiles of both drugs were similar for both CRVO and BRVO. CONCLUSIONS: For CRVO, aflibercept had similar efficacy and safety profile but with fewer injections versus ranibizumab in RCTs; RWSs showed greater BCVA improvement and CRT reduction with aflibercept than ranibizumab. For BRVO, RCTs showed similar in efficacy, safety, and injection numbers for both drugs, while RWSs demonstrated that aflibercept required fewer injections at 12 months of follow-up. Overall, this study provides updated evidence for clinical decision-making in the treatment of RVO.

Identification of a shared gene signature and biological mechanism between diabetic foot ulcers and cutaneous lupus erythemnatosus by transcriptomic analysis.

Diabetic foot ulcers (DFU) and cutaneous lupus erythematosus (CLE) are both diseases that can seriously affect a patient's quality of life and generate economic pressure in society. Symptomatically, both DLU and CLE exhibit delayed healing and excessive inflammation; however, there is little evidence to support a molecular and cellular connection between these two diseases. In this study, we investigated potential common characteristics between DFU and CLE at the molecular level to provide new insights into skin diseases and regeneration, and identify potential targets for the development of new therapies. The gene expression profiles of DFU and CLE were obtained from the Gene Expression Omnibus (GEO) database and used for analysis. A total of 41 common differentially expressed genes (DEGs), 16 upregulated genes and 25 downregulated genes, were identified between DFU and CLE. GO and KEGG analysis showed that abnormalities in epidermal cells and the activation of inflammatory factors were both involved in the occurrence and development of DFU and CLE. Protein-protein interaction network (PPI) and sub-module analysis identified enrichment in seven common key genes which is KRT16, S100A7, KRT77, OASL, S100A9, EPGN and SAMD9. Based on these seven key genes, we further identified five miRNAs(has-mir-532-5p, has-mir-324-3p,has-mir-106a-5p,has-mir-20a-5p,has-mir-93-5p) and7 transcription factors including CEBPA, CEBPB, GLI1, EP30D, JUN,SP1, NFE2L2 as potential upstream molecules. Functional immune infiltration assays showed that these genes were related to immune cells. The CIBERSORT algorithm and Pearson method were used to determine the correlations between key genes and immune cells, and reverse key gene-immune cell correlations were found between DFU and CLE. Finally, the DGIbd database demonstrated that Paquinimod and Tasquinimod could be used to target S100A9 and Ribavirin could be used to target OASL. Our findings highlight common gene expression characteristics and signaling pathways between DFU and CLE, indicating a close association between these two diseases. This provides guidance for the development of targeted therapies and mutual interactions.

Hypoxia-activated ADCC-enhanced humanized anti-CD147 antibody for liver cancer imaging and targeted therapy with improved selectivity.

Therapeutic antibodies (Abs) improve the clinical outcome of cancer patients. However, on-target off-tumor toxicity limits Ab-based therapeutics. Cluster of differentiation 147 (CD147) is a tumor-associated membrane antigen overexpressed in cancer cells. Ab-based drugs targeting CD147 have achieved inadequate clinical benefits for liver cancer due to side effects. Here, by using glycoengineering and hypoxia-activation strategies, we developed a conditional Ab-dependent cellular cytotoxicity (ADCC)-enhanced humanized anti-CD147 Ab, HcHAb18-azo-PEG5000 (HAP18). Afucosylated ADCC-enhanced HcHAb18 Ab was produced by a fed-batch cell culture system. Azobenzene (Azo)-linked PEG5000 conjugation endowed HAP18 Ab with features of hypoxia-responsive delivery and selective targeting. HAP18 Ab potently inhibits the migration, invasion, and matrix metalloproteinase secretion, triggers the cytotoxicity and apoptosis of cancer cells, and induces ADCC, complement-dependent cytotoxicity, and Ab-dependent cellular phagocytosis under hypoxia. In xenograft mouse models, HAP18 Ab selectively targets hypoxic liver cancer tissues but not normal organs or tissues, and has potent tumor-inhibiting effects. HAP18 Ab caused negligible side effects and exhibited superior pharmacokinetics compared to those of parent HcHAb18 Ab. The hypoxia-activated ADCC-enhanced humanized HAP18 Ab safely confers therapeutic efficacy against liver cancer with improved selectivity. This study highlights that hypoxia activation is a promising strategy for improving the tumor targeting potential of anti-CD147 Ab drugs.

Correlative factors of poor prognosis and abnormal cellular immune function in patients with Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is a serious disease causing human dementia and social problems. The quality of life and prognosis of AD patients have attracted much attention. The role of chronic immune inflammation in the pathogenesis of AD is becoming more and more important. AIM: To study the relationship among cognitive dysfunction, abnormal cellular immune function, neuroimaging results and poor prognostic factors in patients. METHODS: A retrospective analysis of 62 hospitalized patients clinical diagnosed with AD who were admitted to our hospital from November 2015 to November 2020. Collect cognitive dysfunction performance characteristics, laboratory test data and neuroimaging data from medical records within 24 h of admission, including Mini Mental State Examination Scale score, drawing clock test, blood T lymphocyte subsets, and neutrophils and lymphocyte ratio (NLR), disturbance of consciousness, extrapyramidal symptoms, electroencephalogram (EEG) and head nucleus magnetic spectroscopy (MRS) and other data. Multivariate logistic regression analysis was used to determine independent prognostic factors. the modified Rankin scale (mRS) was used to determine whether the prognosis was good. The correlation between drug treatment and prognostic mRS score was tested by the rank sum test. RESULTS: Univariate analysis showed that abnormal cellular immune function, extrapyramidal symptoms, obvious disturbance of consciousness, abnormal EEG, increased NLR, abnormal MRS, and complicated pneumonia were related to the poor prognosis of AD patients. Multivariate logistic regression analysis showed that the decrease in the proportion of T lymphocytes in the blood after abnormal cellular immune function (odd ratio: 2.078, 95% confidence interval: 1.156-3.986, P < 0.05) was an independent risk factor for predicting the poor prognosis of AD. The number of days of donepezil treatment to improve cognitive function was negatively correlated with mRS score (r = 0.578, P < 0.05). CONCLUSION: The decrease in the proportion of T lymphocytes may have predictive value for the poor prognosis of AD. It is recommended that the proportion of T lymphocytes < 55% is used as the cut-off threshold for predicting the poor prognosis of AD. The early and continuous drug treatment is associated with a good prognosis.

Inhibitory effect of benzocaine from Schisandra chinensis on Alternaria alternata.

The clinical effects of Schisandra chinensis against human disease are well-documented; however, studies on its application in controlling plant pathogens are limited. Here, we investigated its inhibitory effect on the growth of Alternaria alternata, a fungus which causes significant post-harvest losses on apples, known as black spot disease. S. chinensis fruit extract exhibited strong inhibitory effects on the growth of A. alternata with an EC50 of 1882.00 mg/L. There were 157 compounds identified in the extract by high performance liquid chromatography-mass spectrometry, where benzocaine constituted 14.19% of the extract. Antifungal experiments showed that the inhibitory activity of benzocaine on A. alternata was 43.77-fold higher than the crude extract. The application of benzocaine before and after A. alternata inoculation on apples prevented the pathogen infection and led to mycelial distortion according to scanning electron microscopy. Transcriptome analysis revealed that there were 4226 genes differentially expressed between treated and untreated A. alternata-infected apples with benzocaine. Metabolomics analysis led to the identification of 155 metabolites. Correlation analysis between the transcriptome and metabolome revealed that benzocaine may inhibit A. alternata growth via the beta-alanine metabolic pathway. Overall, S. chinensis extract and benzocaine are environmentally friendly plant-based fungicides with potential to control A. alternata.

An activatable fluorescent-photoacoustic dual-modal probe for highly sensitive imaging of nitroxyl in vivo.

Nitroxyl (HNO) plays a vital role in various biological functions and pharmacological activities, so the development of an excellent near-infrared fluorescent (NIRF) and photoacoustic (PA) dual-modality probe is crucial for understanding HNO-related physiological and pathological progression. Herein, we proposed and synthesized a novel NIRF/PA dual probe (QL-HNO) by substituting an indole with quinolinium in hemicyanine for the sensitive detection of exogenous and endogenous HNO in vivo. The designed probe showed the highest sensitivity in NIRF mode and a desirable PA signal-to-noise ratio for HNO detection in vitro and was further applied for NIRF/PA dual-modal imaging of HNO with high contrast in living cells and tumor-bearing animals. Based on the excellent performance of QL-HNO, we believe that this study provides a promising molecular tool for further understanding of HNO-related physiological and pathological progression.

Hypoxia-activated selectivity-improved anti-PKM2 antibody combined with prodrug TH-302 for potentiated targeting therapy in hepatocellular carcinoma.

Background: Hypoxia induces hepatocellular carcinoma (HCC) malignancies; yet it also offers treatment opportunities, exemplified by developing hypoxia-activated prodrugs (HAPs). Although HAP TH-302 combined with therapeutic antibody (Ab) has synergistic effects, the clinical benefits are limited by the on-target off-tumor toxicity of Ab. Here, we sought to develop a hypoxia-activated anti-M2 splice isoform of pyruvate kinase (PKM2) Ab combined with TH-302 for potentiated targeting therapy. Methods: Codon-optimized and hypoxia-activation strategies were used to develop H103 Ab-azo-PEG5k (HAP103) Ab. Hypoxia-activated HAP103 Ab was characterized, and hypoxia-dependent antitumor and immune activities were evaluated. Selective imaging and targeting therapy with HAP103 Ab were assessed in HCC-xenografted mouse models. Targeting selectivity, systemic toxicity, and synergistic therapeutic efficacy of HAP103 Ab with TH-302 were evaluated. Results: Human full-length H103 Ab was produced in a large-scale bioreactor. Azobenzene (azo)-linked PEG5k conjugation endowed HAP103 Ab with hypoxia-activated targeting features. Conditional HAP103 Ab effectively inhibited HCC cell growth, enhanced apoptosis, and induced antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) functions. Analysis of HCC-xenografted mouse models showed that HAP103 Ab selectively targeted hypoxic HCC tissues and induced potent tumor-inhibitory activity either alone or in combination with TH-302. Besides the synergistic effects, HAP103 Ab had negligible side effects when compared to parent H103 Ab. Conclusion: The hypoxia-activated anti-PKM2 Ab safely confers a strong inhibitory effect on HCC with improved selectivity. This provides a promising strategy to overcome the on-target off-tumor toxicity of Ab therapeutics; and highlights an advanced approach to precisely kill HCC in combination with HAP TH-302.

Lead-associated mortality in the US 1999-2020: a time-stratified analysis of a national cohort.

OBJECTIVES: We undertook time-stratified analyses of the National Health and Nutrition Examination Survey in the US to assess time trends (1999-2020) in the associations of blood lead (BL) with blood pressure, mortality, the BL-associated population attributable fraction (PAF). METHODS: Vital status of participants, 20-79 years old at enrolment, was ascertained via the National Death Index. Regressions, mediation analyses and PAF were multivariable adjusted and standardized to 2020 US Census data. RESULTS: In time-stratified analyses, BL decreased from 1.76 µg/dl in 1999-2004 to 0.93 µg/dl in 2017-2020, while the proportion of individuals with BL < 1 µg/dl increased from 19.2% to 63.0%. Total mortality was unrelated to BL (hazard ratio (HR) for a fourfold BL increment: 1.05 [95% confidence interval, CI: 0.93-1.17]). The HR for cardiovascular death was 1.44 (1.01-2.07) in the 1999-2000 cycle, but lost significance thereafter. BL was directly related to cardiovascular mortality, whereas the indirect BL pathway via BP was not significant. Low socioeconomic status (SES) was directly related to BL and cardiovascular mortality, but the indirect SES pathway via BL lost significance in 2007-2010. From 1999-2004 to 2017-2020, cardiovascular PAF decreased (P < 0.001) from 7.80% (0.17-14.4%) to 2.50% (0.05-4.68%) and number of lead-attributable cardiovascular deaths from 53 878 (1167-99 253) to 7539 (160-14 108). CONCLUSION: Due to implementation of strict environmental policies, lead exposure is no longer associated with total mortality, and the mildly increased cardiovascular mortality is not associated with blood lead via blood pressure in the United States.

OSTEO18, a novel urinary proteomic signature, associated with osteoporosis in heart transplant recipients.

Background: Immunosuppressive treatment in heart transplant (HTx) recipient causes osteoporosis. The urinary proteomic profile (UPP) includes peptide fragments derived from the bone extracellular matrix. Study aims were to develop and validate a multidimensional UPP biomarker for osteoporosis in HTx patients from single sequenced urinary peptides identifying the parent proteins. Methods: A single-center HTx cohort was analyzed. Urine samples were measured by capillary electrophoresis coupled with mass spectrometry. Cases with osteoporosis and matching controls were randomly selected from all available 389 patients. In derivation case-control dataset, 1576 sequenced peptides detectable in ≥30 % of patients. Applying statistical analysis on these, an 18-peptide multidimensional osteoporosis UPP biomarker (OSTEO18) was generated by support vector modeling. The 2 replication datasets included 118 and 94 patients. For further validation, the whole cohort was analyzed. Statistical methods included logistic regression and receiver operating characteristic curve (ROC) analysis. Results: In derivation dataset, the AUC, sensitivity and specificity of OSTEO18 were 0.83 (95 % CI: 0.76-0.90), 74.3 % and 87.1 %, respectively. In replication datasets, results were confirmatory. In the whole cohort (154 osteoporotic patients [39.6 %]), the ORs for osteoporosis increased (p < 0.0001) across OSTEO18 quartiles from 0.39 (95 % CI: 0.25-0.61) to 3.14 (2.08-4.75). With full adjustment for known osteoporosis risk factors, OSTEO18 improved AUC from 0.708 to 0.786 (p = 0.0003) for OSTEO18 categorized (optimized threshold: 0.095) and to 0.784 (p = 0.0004) for OSTEO18 as continuously distributed classifier. Conclusion: OSTEO18 is a clinically meaningful novel biomarker indicative of osteoporosis in HTx recipients and is being certified as in-vitro diagnostic.

The metabolic profiles and body composition of non-obese metabolic associated fatty liver disease.

Background/purpose: Metabolic-associated fatty liver disease (MAFLD) is a major cause of chronic liver disease worldwide and is generally thought to be closely related to obesity and diabetes. However, it also affects non-obese individuals, particularly in Asian cultures. Methods: Healthy physical examination subjects and MAFLD patients were included in the endocrinology department of Jiangsu Provincial Hospital of Traditional Chinese Medicine. MAFLD was defined as fatty liver in imaging without virus infection, drug, alcohol, or other known causes of chronic liver disease. Non-obese MAFLD was defined as MAFLD in non-obese subjects (BMI<25 kg/m2). Results: The final analysis comprised 1047 participants in total. Of 946 MAFLD patients, 162 (17.12%) were diagnosed with non-obese MAFLD. Non-obese MAFLD patients were older, had lower alanine aminotransferase (ALT), triglyceride, and waist circumference, but had higher high density lipoprotein cholesterol (HDL-c) than obese MAFLD patients. Compared with non-obese healthy controls, non-obese MAFLD patients had higher BMI, ALT, gamma-glutamyl transferase (GGT), uric acid (UA), triglycerides (TG), and low density lipoprotein cholesterol (LDL-c). In terms of body composition, body fat mass (BFM), waist-hip ratio (WHR), percent body fat (PBF), visceral fat area (VFA), and fat mass index (FMI) were lower in non-obese healthy controls than non-obese MAFLD patients. A binary logistic regression analysis revealed that non-obese MAFLD was linked with lower GGT and higher HDL-c. Conclusion: In this study cohort, non-obese MAFLD was present at a prevalence of 13.90%. In contrast to non-obese healthy controls, non-obese MAFLD patients exhibited different metabolic profiles, but they also had different body compositions.

Acute pulpitis promotes purinergic signaling to induce pain in rats via P38MAPK/NF-κB signaling pathway.

Toothache is one of the most common types of pain, but the mechanisms underlying pulpitis-induced pain remain unknown. The ionotropic purinergic receptor family (P2X) is reported to mediate nociception in the nervous system. This study aims to investigate the involvement of P2X3 in the sensitisation of the trigeminal ganglion (TG) and the inflammation caused by acute pulpitis. An acute tooth inflammation model was established by applying LPS to the pulp of SD rats. We found that the increased expression of P2X3 was induced by acute pulpitis. A selective P2X3 inhibitor (A-317491) reduced pain-like behavior in the maxillofacial region of rats and depressed the activation of neurons in the trigeminal ganglion induced by pulpitis. The upregulated MAPK signaling (p-p38, p-ERK1/2) expression in the ipsilateral TG induced by pulpitis could also be depressed by the application of the P2X3 inhibitor. Furthermore, the expression of markers of inflammatory processes, such as NF-κB, TNF-α and IL-1ß, could be induced by acute pulpitis and deduced by the intraperitoneal injection of P2X3 antagonists. Our findings demonstrate that purinergic P2X3 receptor signaling in TG neurons contributes to pulpitis-induced pain in rats and that P2X3 signaling may be a potential therapeutic target for tooth pain.

New Type Annihilator of π-Expanded Diketopyrrolopyrrole for Robust Photostable NIR-Excitable Triplet-Triplet Annihilation Upconversion.

Near-infrared light excitable triplet-triplet annihilation upconversion (NIR TTA-UC) materials have attracted interest in a variety of emerging applications such as photoredox catalysis, optogenetics, and stereoscopic 3D printing. Currently, the practical application of NIR TTA-UC materials requires substantial improvement in photostability. Here, we found that the new annihilator of π-expanded diketopyrrolopyrrole (π-DPP) cannot activate oxygen to generate superoxide anion via photoinduced electron transfer, and its electron-deficient characteristics prevent the singlet oxygen-mediated [2 + 2] cycloaddition reaction; thus, π-DPP exhibited superior resistance to photobleaching. In conjunction with the NIR photosensitizer PdTNP, the upconversion efficiency of π-DPP is as high as 8.9%, which is eight times of the previously reported PdPc/Furan-DPP. Importantly, after polystyrene film encapsulation, less than 10% photobleaching was observed for this PdTNP/π-DPP-based NIR TTA-UC material after four hours of intensive NIR light exposure. These findings provide a type of annihilator with extraordinary photostability, facilitating the development of NIR TTA-UC materials for practical photonics.

Seasonal variation in ambulatory blood pressure control in patients on clinic blood pressure-guided antihypertensive treatment.

BACKGROUND: We investigated seasonal variation in ambulatory blood pressure control in hypertensive patients on clinic blood pressure-guided antihypertensive treatment. METHODS: The study participants were hypertensive patients enrolled in an 8-week therapeutic study. Antihypertensive treatment was initiated with long-acting dihydropyridine calcium channel blockers amlodipine 5 mg/day or the gastrointestinal therapeutic system (GITS) formulation of nifedipine 30 mg/day, with the possible up-titration to amlodipine 10 mg/day or nifedipine-GITS 60 mg/day at 4 weeks of follow-up. RESULTS: The proportion of up-titration to higher dosages of antihypertensive drugs at 4 weeks of follow-up was higher in patients who commenced treatment in autumn/winter ( n  = 302) than those who commenced treatment in spring/summer ( n  = 199, 24.5 vs. 12.0%, P  < 0.001). The control rate of clinic blood pressure, however, was lower in autumn/winter than in spring/summer at 4 (56.7 vs. 70.7%, P  = 0.003) and 8 weeks of follow-up (52.5 vs. 74.9%, P  < 0.001). At 8 weeks, patients who commenced treatment in autumn/winter, compared with those who commenced treatment in spring/summer, had a significantly ( P ≤0.03) smaller daytime (mean between-season difference -3.2/-2.8 mmHg) but greater nighttime SBP/DBP reduction (3.6/1.6 mmHg). Accordingly, at 8 weeks, the prevalence of nondippers was significantly ( P  < 0.001) higher in spring/summer than in autumn/winter for both SBP (54.8 vs. 30.0%) and DBP (53.4 vs. 28.8%). CONCLUSION: Clinic blood pressure-guided antihypertensive treatment requires a higher dosage of medication in cold than warm seasons, which may have led to over- and under-treatment of nighttime blood pressure, respectively.

Comparison of two single-pill dual combination antihypertensive therapies in Chinese patients: a randomized, controlled trial.

BACKGROUND: Current hypertension guidelines recommend combination of an angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker with a calcium-channel blocker or thiazide diuretic as initial antihypertensive therapy in patients with monotherapy uncontrolled hypertension. However, to what extent these two different combinations are comparable in blood pressure (BP)-lowering efficacy and safety remains under investigation, especially in the Chinese population. We investigated the BP-lowering efficacy and safety of the amlodipine/benazepril and benazepril/hydrochlorothiazide dual therapies in Chinese patients. METHODS: In a multi-center, randomized, actively controlled, parallel-group trial, we enrolled patients with stage 1 or 2 hypertension from July 2018 to June 2021 in 20 hospitals and community health centers across China. Of the 894 screened patients, 560 eligible patients were randomly assigned to amlodipine/benazepril 5/10 mg (n = 282) or benazepril/hydrochlorothiazide 10/12.5 mg (n = 278), with 213 and 212 patients, respectively, who completed the study and had a valid repeat ambulatory BP recording during follow-up and were included in the efficacy analysis. The primary outcome was the change from baseline to 24 weeks of treatment in 24-h ambulatory systolic BP. Adverse events including symptoms and clinically significant changes in physical examinations and laboratory findings were recorded for safety analysis. RESULTS: In the efficacy analysis (n = 425), the primary outcome, 24-h ambulatory systolic BP reduction, was - 13.8 ± 1.2 mmHg in the amlodipine/benazepril group and - 12.3 ± 1.2 mmHg in the benazepril/hydrochlorothiazide group, with a between-group difference of - 1.51 (p = 0.36) mmHg. The between-group differences for major secondary outcomes were - 1.47 (p = 0.18) in 24-h diastolic BP, - 2.86 (p = 0.13) and - 2.74 (p = 0.03) in daytime systolic and diastolic BP, and - 0.45 (p = 0.82) and - 0.93 (p = 0.44) in nighttime systolic and diastolic BP. In the safety analysis (n = 560), the incidence rate of dry cough was significantly lower in the amlodipine/benazepril group than in the benazepril/hydrochlorothiazide group (5.3% vs 10.1%, p = 0.04). CONCLUSIONS: The amlodipine/benazepril and benazepril/hydrochlorothiazide dual therapies were comparable in ambulatory systolic BP lowering. The former combination, compared with the latter, had a greater BP-lowering effect in the daytime and a lower incidence rate of dry cough. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03682692. Registered on 18 September 2018.

The mixed effect of Endocrine-Disrupting chemicals on biological age Acceleration: Unveiling the mechanism and potential intervention target.

INTRODUCTION: Although previous studies investigated the potential adverse effects of endocrine-disrupting chemicals (EDCs) on biological age acceleration and aging-related diseases, the mixed effect of multiple types of EDCs on biological age acceleration, including its potential underlying mechanism, remains unclear. METHODS: Data from the National Health and Nutrition Examination Survey (NHANES) were used to analyze biological age measures, including Klemera-Doubal method biological age (KDM-BA), phenotypic age, and homeostatic dysregulation (HD). Weight quantile sum (WQS) regression was performed to screen biological age-related EDCs (BA-EDCs) and assess the mixed effect of BA-EDCs on biological age acceleration and aging-related disease. Targets of BA-EDCs were obtained from three databases, while heart aging-related genes were obtained from the Aging Anno database. Protein-protein interaction (PPI) network and MCODE algorithm were applied to identify potential interactions between BA-EDC targets and heart aging-related genes. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were performed to identify related pathways. RESULTS: This cross-sectional study included 1,439 participants. A decile increase in BA-EDCs co-exposure was associated with 0.31 years and 0.17 years of KDM-BA and phenotypic age acceleration, respectively. The mixed effect of BA-EDCs was associated with an increased prevalence of atherosclerotic cardiovascular disease (ASCVD). Vitamins C and E demonstrated a significant interaction effect on the association between BA-EDCs and KDM-BA acceleration. PPI network and functional enrichment analysis indicated that the AGE-RAGE signaling pathway in diabetic complications was significantly enriched. CONCLUSION: Our results showed that the co-exposure effect of BA-EDCs was associated with biological age acceleration and ASCVD, with the AGE-RAGE signaling pathway being the underlying mechanism. Vitamins C and E may also be an actionable target for preventing EDC-induced biological aging.

Alcohol Consumption and Antihypertensive Treatment Effect in Male Patients With Hypertension.

BACKGROUND: Alcohol consumption is a proven risk factor of hypertension. In the present analysis, we investigated the use of antihypertensive medications and blood pressure control in male alcohol drinkers and non-drinkers with hypertension (systolic/diastolic blood pressure 160-199/100-119 mm Hg). METHODS: The study participants were patients enrolled in a 12-week therapeutic study and treated with the irbesartan/hydrochlorothiazide combination 150/12.5 mg once daily, with the possible up-titration to 300/12.5 mg/day and 300/25 mg/day at 4 and 8 weeks of follow-up, respectively, for blood pressure control of <140/90 mm Hg or <130/80 mm Hg in patients with diabetes mellitus. Alcohol consumption was classified as non-drinkers and drinkers. RESULTS: The 68 alcohol drinkers and 168 non-drinkers had similar systolic/diastolic blood pressure at baseline (160.8 ±â€…12.1/99.8 ±â€…8.6 vs. 161.8 ±â€…11.0/99.2 ±â€…8.6, P ≥ 0.55) and other characteristics except for current smoking (80.9% vs. 47.6%, P < 0.0001). In patients who completed the 12-week follow-up (n = 215), the use of higher dosages of antihypertensive drugs was similar at 4 weeks of follow-up in drinkers and non-drinkers (10.6% vs. 12.4%, P = 0.70), but increased to a significantly higher proportion in drinkers than non-drinkers at 12 weeks of follow-up (54.7% vs. 36.6%, P = 0.01). The control rate of hypertension tended to be lower in alcohol drinkers, compared with non-drinkers, at 4 weeks of follow-up (45.6% vs. 58.9%, P = 0.06), but became similar at 12 weeks of follow-up (51.5% vs. 54.8%, P = 0.65). CONCLUSION: Alcohol drinkers compared with non-drinkers required a higher dosage of antihypertensive drug treatment to achieve similar blood pressure control. CLINICAL TRIAL REGISTRY NUMBER: NCT00670566 at www.clinicaltrials.gov.

The protein kinase A signaling pathway mediates the effect of electroacupuncture on excessive contraction of the bladder detrusor in a rat model of neurogenic bladder.

BACKGROUND: Neurogenic bladder (NB) is a form of neurological bladder dysfunction characterized by excessive contraction of the bladder detrusor. Protein kinase A (PKA) signaling is involved in the contraction of the detrusor muscle. AIMS: To investigate whether PKA signaling mediates the effect of electroacupuncture (EA) on the excessive contraction of the bladder detrusor in NB. METHODS: Sixty rats were randomly divided into control, sham, NB, NB + EA, and NB + EA + H89 (a PKA receptor antagonist) groups. The modified Hassan Shaker spinal cord transection method was used to generate a NB model. After EA intervention for one week, urodynamic tests were used to evaluate bladder function, hematoxylin and eosin staining was conducted to assess morphological changes, enzyme-linked immunosorbent assay (ELISA) was performed to measure the concentration of PKA, and Western blotting was conducted to measure the protein levels of phosphorylated myosin light chain kinase (p-MLCK)/p-MLC. RESULTS: The results showed that NB resulted in morphological disruption, impairment of urodynamics, and decreases in the concentration of PKA and the protein levels of p-MLCK/p-MLC. EA reversed the changes induced by NB dysfunction. However, the improvement in urodynamics and the increases in the concentration of PKA and the protein levels of p-MLCK/p-MLC were inhibited by H89. CONCLUSION: Our findings indicate that the PKA signaling pathway mediates the beneficial effect of EA on excessive contraction of the bladder detrusor in a rat model of NB.

microRNAs: critical targets for treating rheumatoid arthritis angiogenesis.

Vascular neogenesis, an early event in the development of rheumatoid arthritis (RA) inflammation, is critical for the formation of synovial vascular networks and plays a key role in the progression and persistence of chronic RA inflammation. microRNAs (miRNAs), a class of single-stranded, non-coding RNAs with approximately 21-23 nucleotides in length, regulate gene expression by binding to the 3' untranslated region (3'-UTR) of specific mRNAs. Increasing evidence suggests that miRNAs are differently expressed in diseases associated with vascular neogenesis and play a crucial role in disease-related vascular neogenesis. However, current studies are not sufficient and further experimental studies are needed to validate and establish the relationship between miRNAs and diseases associated with vascular neogenesis, and to determine the specific role of miRNAs in vascular development pathways. To better treat vascular neogenesis in diseases such as RA, we need additional studies on the role of miRNAs and their target genes in vascular development, and to provide more strategic references. In addition, future studies can use modern biotechnological methods such as proteomics and transcriptomics to investigate the expression and regulatory mechanisms of miRNAs, providing a more comprehensive and in-depth research basis for the treatment of related diseases such as RA.

Is Cr(III) re-oxidation occurring in Cr-contaminated soils after remediation: Meta-analysis and machine learning prediction.

Whether Cr(III) in Cr(III)-containing sites formed after Cr(VI) reduction and stabilization remediation are re-oxidized and pose toxicity risks again has been a growing concern. In this study, 1030 data were collected to perform a meta-analysis to clarify the effects of various factors (oxidant type, soil and Cr(III) solid compound properties, aging conditions, and testing methods) on Cr(III) oxidation. We observed that the soil properties of clay, pH ≥ 8, the lower CEC capacity, easily reducible Mn content, and Cr(III) content, and the higher Eh value and Fe content can promote the re-oxidation of Cr(III). Publication bias and sensitivity analyses confirmed the stability and reliability of the meta-analysis. Subsequently, we used five machine learning algorithms to construct and optimize the models. The prediction results of the RF model (RMSE <1.36, R2 >0.71) with good algorithm performance showed that after ten years of remediation, the extractable Cr(VI) concentration in the soil was 0.0087 mg/L, indicating a negligible secondary pollution risk of Cr(III) re-oxidation. This study provides theoretical support for subsequent risk management and control after Cr(VI) soil remediation and provides a solution for the quantitative prediction of Cr(III) re-oxidation.