Isobavachalcone: A redox antifungal agent impairs the mitochondria protein of Cryptococcus neoformans.

Isobavachalcone (IBC) is a natural small molecule with various biological activities; however, its inhibitory effects on Cryptococcus neoformans remain unclear. In our study, IBC showed a good antifungal effect. Through in vitro experiments, its minimum inhibitory concentration was 0.5-1 µg/mL. It exhibited the same antifungal effect as Amphotericin B in brain and lung infections in in vivo experiments. IBC also showed a synergistic antifungal effect with emodin with lower toxicity, and C. neoformans did not develop drug resistance to IBC. In the mechanistic study, significantly damaged mitochondria of C. neoformans, a significant reduction in mitochondrial membrane potential and adenosine triphosphate production, and an increase in hydrogen peroxide (H2O2) caused by IBC were observed using transmission electron microscopy. Through drug affinity-responsive target stability combined with phenotype detection, riboflavin synthases of aconitase and succinate dehydrogenase were screened. Molecular docking, quantitative polymerase chain reaction experiments, target inhibitor and agonist intervention, molecular interaction measurements, and minimum inhibitory concentration detection of the constructed expression strains revealed that IBC targeted the activity of these two enzymes, interfered by the tricarboxylic acid cycle, inhibited the production of adenosine triphosphate, blocked electron transport, reduced mitochondrial membrane potential, and induced antioxidation imbalance and reactive oxygen species accumulation, thus producing an antifungal effect. Therefore, IBC is a promising lead drug and redox antifungal agent for C. neoformans.

Association between coffee and caffeine intake and risk of COPD: Findings based on NHANES 2007-2012.

BACKGROUND: The association between coffee and caffeine intake and the risk of COPD and lung function has not been thoroughly discussed in Americans, with subgroup and threshold effects remaining unclear. OBJECTIVES: This study investigated the association between coffee and caffeine consumption and the risk of chronic obstructive pulmonary disease (COPD) as well as lung function utilizing data from the NHANES 2007-2012. METHODS: We assessed the associations of coffee and caffeine consumption with the risk of COPD and lung function parameters, including FEV1 and FVC, adjusting for common demographic and disease characteristics in a cross-sectional analysis of NHANES data. RESULTS: A total of 9763 participants were included in the study, and 592 were diagnosed with COPD. Multivariate regression models revealed positive associations between coffee and caffeine consumption and the risk of COPD and lung function. Subgroup analyses stratified by sex, DM, hypertension status, and smoking habits identified potential effect modifiers as well as inflection points from threshold effect examinations. CONCLUSIONS: The results of this cross-sectional study indicated significant positive correlations between coffee and caffeine consumption and the risk of COPD. Additionally, positive correlations between exposure variables and FEV1 and FVC were detected. Among the stratification factors, smoking status exhibited the most potential for modifying effects. Future practices and research are needed to validate the results and explore the underlying mechanisms.

Age-specific differences in the association between prediabetes and cardiovascular diseases in China: A national cross-sectional study.

BACKGROUND: Cardiovascular disease (CVD) is a leading cause of morbidity and mortality worldwide, the global burden of which is rising. It is still unclear the extent to which prediabetes contributes to the risk of CVD in various age brackets among adults. To develop a focused screening plan and treatment for Chinese adults with prediabetes, it is crucial to identify variations in the connection between prediabetes and the risk of CVD based on age. AIM: To examine the clinical features of prediabetes and identify risk factors for CVD in different age groups in China. METHODS: The cross-sectional study involved a total of 46239 participants from June 2007 through May 2008. A thorough evaluation was conducted. Individuals with prediabetes were categorized into two groups based on age. Chinese atherosclerotic CVD risk prediction model was employed to evaluate the risk of developing CVD over 10 years. Random forest was established in both age groups. SHapley Additive exPlanation method prioritized the importance of features from the perspective of assessment contribution. RESULTS: In total, 6948 people were diagnosed with prediabetes in this study. In pre-diabetes, prevalences of CVD were 5 (0.29%) in the younger group and 148 (2.85%) in the older group. Overall, 11.11% of the younger group and 29.59% of the older group were intermediate/high-risk of CVD for prediabetes without CVD based on the Prediction for ASCVD Risk in China equation in ten years. In the younger age group, the 10-year risk of CVD was found to be more closely linked to family history of CVD rather than lifestyle, whereas in the older age group, resident status was more closely linked. CONCLUSION: The susceptibility to CVD is age-specific in newly diagnosed prediabetes. It is necessary to develop targeted approaches for the prevention and management of CVD in adults across various age brackets.

Cardiovascular disease risk in early-onset vs late-onset type 2 diabetes in China: A population-based cross-sectional study.

BACKGROUND: This study investigated the effects of early-onset type 2 diabetes (EOD) vs late-onset type 2 diabetes (LOD) on nonfatal cardiovascular diseases (CVD) in China. METHODS: We conducted a cross-sectional survey of 46 239 participants from 14 provinces in China from 2007 to 2008, selecting 4949 participants with type 2 diabetes for analysis. Participants were categorized as EOD (<40 years) or LOD (≥40 years) based on age at diabetes diagnosis. Sociodemographic and nonfatal CVD information was collected through an interviewer-assisted questionnaire and clinical examination. Logistic regression analysis was used to investigate the nonfatal CVD risk. RESULTS: Out of 4949 participants with type 2 diabetes, 390 (7.88%) had nonfatal CVD. Participants with EOD had a higher age-standardized prevalence of nonfatal CVD than those with LOD (11.4% vs 4.4%). Compared to LOD patients, EOD patients tended to be males and had a higher family history of diabetes, unhealthy lifestyle behaviors, and lower blood pressure levels. After adjustment for age and sex, EOD patients had a higher risk of nonfatal CVD than LOD patients (odds ratio [OR] 2.3, 95% CI 1.5-3.5). After further adjustment for diabetes duration, use of drugs, and other risk factors, the OR of nonfatal CVD was reduced but significant (OR 1.8, 95% CI 1.1-2.9). Sensitivity analysis revealed that EOD patients with metabolic syndrome had an increased nonfatal CVD risk compared to LOD patients (OR 2.0, 95% CI 1.2-3.5). CONCLUSIONS: EOD patients are at increased risk of nonfatal CVD. Individualized intervention and management measures for EOD patients are necessary.

Coffee consumption and periodontitis: a Mendelian Randomization study.

BACKGROUND: Coffee is one of the most consumed beverages in the world, coffee consumption has been growing in the United States over the past 20 years. Periodontitis is defined by the pathologic loss of the periodontal ligament and destruction of the connective tissue attachment and alveolar bone loss and is related to different systemic diseases and conditions. However, the causality has remained unclarified, thus we regarded discovering the causal relationship between coffee consumption and the liability to periodontitis as the objective of the study. METHODS: Coffee consumption was subdivided into binary coffee consumption and continuous coffee consumption to refine the study design. Genetic instruments were stretched from the MRC-IEU's (MRC Integrative Epidemiology Unit) output from the GWAS pipeline using phesant-derived variables based on the UK Biobank, the Gene-Lifestyle Interactions in Dental Endpoints (GLIDE) project, and the joint meta-analysis of a recent GWAS. The IVW (Inverse Variance Weighted) was regarded as the primary method to estimate the causality, a scatter plot revealed the intuitive result, and tests for stability were also carried out. RESULTS: An effect of continuous coffee consumption on the risk of periodontitis was found, with per SD of coffee consumed increases, the risk of periodontitis rises by 1.04% (Odds Ratio of IVW is 1.0104), while the effect of binary coffee consumption on periodontitis did not meet the requirement of indicating a strong causal association, neither were the reverse causality analyses. CONCLUSIONS: The study indicated the causality of continuous coffee consumption to the risk of periodontitis with a relatively small scale of effect estimate and no strong evidence for an effect of binary coffee-consuming behavior on periodontitis. There was also no intensive evidence suggesting reverse causality.

Mitochondrial UQCC3 controls embryonic and tumor angiogenesis by regulating VEGF expression.

Mitochondria play important roles in angiogenesis. However, the mechanisms remain elusive. In this study, we found that mitochondrial ubiquinol-cytochrome c reductase complex assembly factor 3 (UQCC3) is a key regulator of angiogenesis. TALEN-mediated knockout of Uqcc3 in mice caused embryonic lethality at 9.5-10.5 days postcoitum, and vessel density was dramatically reduced. Similarly, knockout of uqcc3 in zebrafish induced lethality post-fertilization and impaired vascular development. Knockout of UQCC3 resulted in slower tumor growth and angiogenesis. Mechanistically, UQCC3 was upregulated under hypoxia, promoted reactive oxygen species (ROS) generation, enhanced HIF-1α stability and increased VEGF expression. Finally, higher expression of UQCC3 was associated with poor prognosis in multiple types tumors, implying a role for UQCC3 in tumor progression. In conclusion, our findings highlight the important contribution of UQCC3 to angiogenesis under both physiological and pathological conditions, indicating the potential of UQCC3 as a therapeutic target for cancer.

Therapeutic effect of demethylated hydroxylated phillygenin derivative on Helicobacter pylori infection.

Modifying and transforming natural antibacterial products is a novel idea for developing new efficacious compounds. Phillygenin has an inhibitory effect on H. pylori. The aim of the present study was to prepare a phillygenin derivative (PHI-Der) through demethylation and hydroxylation. The minimum inhibitory concentration of 18 strains of H. pylori from different sources was 8-32 µg/mL in vitro, and the activity increased 2-8 times than that of phillygenin. PHI-Der could significantly inhibit the colonization of H. pylori in vivo, reduce the inflammatory response, and promote the repair of inflammatory damage. Further, we used SwissTargetPrediction to predict that its main targets are ALOX5, MCL1, and SLC6A4, and find that it can inhibit bacterial biofilm formation and reduce bacterial infection of cells. It can enhance the intracellular oxidative capacity of H. pylori to inhibit H. pylori growth. Further, it could prevent the oxidation of H. pylori-infected cells and reduce the inflammatory response, which plays a role in protection. In conclusion, compared to phillygenin, PHI-Der had better antibacterial activity and was more effective in treating H. pylori infection. It has characteristics of high safety, specificity, resistance to drug resistance and better antibacterial activity than phillygenin, it's a good antioxidant for host cells.

Development of models to predict 10-30-year cardiovascular disease risk using the Da Qing IGT and diabetes study.

BACKGROUND: This study aimed to develop cardiovascular disease (CVD) risk equations for Chinese patients with newly diagnosed type 2 diabetes (T2D) to predict 10-, 20-, and 30-year of risk. METHODS: Risk equations for forecasting the occurrence of CVD were developed using data from 601 patients with newly diagnosed T2D from the Da Qing IGT and Diabetes Study with a 30-year follow-up. The data were randomly assigned to a training and test data set. In the training data set, Cox proportional hazard regression was used to develop risk equations to predict CVD. Calibration was assessed by the slope and intercept of the line between predicted and observed probabilities of outcomes by quintile of risk, and discrimination was examined using Harrell's C statistic in the test data set. Using the Sankey flow diagram to describe the change of CVD risk over time. RESULTS: Over the 30-year follow-up, corresponding to a 10,395 person-year follow-up time, 355 of 601 (59%) patients developed incident CVD; the incidence of CVD in the participants was 34.2 per 1,000 person-years. Age, sex, smoking status, 2-h plasma glucose level of oral glucose tolerance test, and systolic blood pressure were independent predictors. The C statistics of discrimination for the risk equations were 0.748 (95%CI, 0.710-0.782), 0.696 (95%CI, 0.655-0.704), and 0.687 (95%CI, 0.651-0.694) for 10-, 20-, and 30- year CVDs, respectively. The calibration statistics for the CVD risk equations of slope were 0.88 (P = 0.002), 0.89 (P = 0.027), and 0.94 (P = 0.039) for 10-, 20-, and 30-year CVDs, respectively. CONCLUSIONS: The risk equations forecast the long-term risk of CVD in patients with newly diagnosed T2D using variables readily available in routine clinical practice. By identifying patients at high risk for long-term CVD, clinicians were able to take the required primary prevention measures.

Impact of UHT processing on volatile components and chemical composition of sea buckthorn (Hippophae rhamnoides) pulp: A prediction of the biochemical pathway underlying aroma compound formation.

The effects of ultrahigh-temperature sterilization (UHT) on the volatile components and chemical composition of sea buckthorn pulp (SBP) were evaluated firstly. UHT had significant effects on the volatiles of SBP (mainly occurring at 140 °C for 2 s and 4 s), in which 140 °C for 2 s resulted in a decrease of 3.48% and 14.60% in total volatiles and esters, and an increase of 6.73% in alcohols, while alcohols contents sharply decreased by 6.90% at 140 °C for 4 s. Moreover, 140 °C for 2 s and 4 s decreased the amino acid content by 35.39% and 29.75%, respectively, while UHT significantly promoted the increase of fatty acids, but only a small increase at 140 °C for 4 s. The speculation is that a large number of volatiles were formed during the 140 °C for 2 s and 4 s, mainly from amino acid reactions and lipid oxidation.

Qualitative Analyses of the Reasons Why Patients Do Not Attend Scheduled Inpatient Appointments in a Hospital in Guangzhou, China.

PURPOSE: Exploration of the reasons why people miss scheduled inpatient appointments from the perspectives of patients. METHODS: Semi-structured interviews via telephone were conducted with patients who missed their inpatient appointments. Data were analyzed based on Colaizzi's seven-step method. RESULTS: Twenty-five patients and five dependents were enrolled. Three themes were identified: practical barriers, lack of knowledge about the disease, and negative emotional responses. Personal social obligations, state of illness, financial issues and long waiting times were the main practical barriers preventing patients from attending their inpatient appointment. Patients' perceptions of feasible self-solving symptoms, readily believing people around them, and a blindly optimistic attitude towards disease contributed to their insufficient knowledge about the disease. Negative emotional responses (eg, sense of fear and lack of trust in physicians) had a detrimental effect on inpatient attendance. CONCLUSION: Three main factors contributed to non-attendance of inpatient appointments: practical barriers, lack of knowledge about disease, and negative emotional response. Our study provides new, valuable evidence on non-attendance of inpatient appointments in China. Our findings could offer meaningful insights into developing effective strategies to reduce non-attendance of inpatient appointments in other countries.

Mechanism of SEMA3G knockdown-mediated attenuation of high-fat diet-induced obesity.

Obesity is a worldwide health problem. Semaphorins are involved in axonal guidance; however, the role of secretory semaphorin 3G (SEMA3G) in regulating adipocyte differentiation remains unclear. Microarray analysis showed that the SEMA3G gene was upregulated in an in vitro model of adipogenesis. In this study, SEMA3G was highly expressed in the white adipose tissue and liver. Analysis of 3T3-L1 cell and primary mouse preadipocyte differentiation showed that SEMA3G mRNA and protein levels were increased during the middle stage of cell development. In vitro experiments also showed that adipocyte differentiation was promoted by SEMA3G; however, SEMA3G inhibition using a recombinant lentiviral vector expressing a specific shRNA showed the opposite results. Mice were fed a chow or high-fat diet (HFD); knockdown of SEMA3G was found to inhibit weight gain, reduce fat mass in the tissues, prevent lipogenesis in the liver tissue, reduce insulin resistance and ameliorate glucose tolerance in HFD mice. Additionally, the effect of SEMA3G on HFD-induced obesity was activated through PI3K/Akt/GSK3ß signaling in the adipose tissue and the AMPK/SREBP-1c pathway in the liver. Moreover, the plasma concentrations of SEMA3G and leptin were measured in 20 obese and 20 non-obese human subjects. Both proteins were increased in obese subjects, who also exhibited a lower level of adiponectin and presented with insulin resistance. In summary, we demonstrated that SEMA3G is an adipokine essential for adipogenesis, lipogenesis, and insulin resistance and is associated with obesity. SEMA3G inhibition may, therefore, be useful for treating diet-induced obesity and its complications.

Persistence and outcomes of non-vitamin K antagonist oral anticoagulants versus warfarin in patients with non-valvular atrial fibrillation.

AIMS AND OBJECTIVES: To compare persistence and outcomes of non-vitamin K antagonist oral anticoagulants (NOACs) versus warfarin in Chinese patients with non-valvular atrial fibrillation (AF). BACKGROUND: Given the unpredictable warfarin response and the costliness of NOACs, more research is needed to clarify which drug enjoys better persistence and outcomes, helping to provide personalised care for patients. DESIGN: A prospective cohort study. METHODS: Chinese patients taking NOACs or warfarin from March 2016-April 2018 were followed up by telephone or outpatient visit at 3, 6 months and half a year thereafter. Anticoagulant persistence and outcomes including stroke and bleeding were collected. We used Cox regression to analyse data. This study was reported according to the STROBE guideline. RESULTS: A total of 344 patients were enrolled; 146 patients received NOACs including dabigatran and rivaroxaban, and 198 patients received warfarin. Persistence with anticoagulants was low and dropped sharply at the third month. Patients on NOACs had worse persistence at 3, 6 and 12 months than those on warfarin. There was no difference in the incidence of ischaemic stroke and bleeding between groups, although ischaemic stroke and major bleeding occurred less frequently in the NOACs group. Paroxysmal AF, no heart failure and no stroke were predictors of NOACs non-persistence. Prior catheter ablation and no diabetes were associated with poor persistence of warfarin. The main reason for anticoagulant cessation was patient preference. CONCLUSIONS: Chinese patients taking NOACs had lower persistence, similar rate of ischaemic stroke and bleeding compared with those on warfarin. Further inventions are needed to improve persistence in Chinese patients on NOACs. RELEVANCE TO CLINICAL PRACTICE: Anticoagulation should highlight both persistence and outcomes emphasising personalised care of different drugs. Further interventions to improve persistence should be developed based on causes and risk factors and carried out in the third month of therapy.

[Surgical treatment of fracture-dislocation of connect of cervical vertebrae and thoracic vertebrae].

OBJECTIVE: To discuss the value of anterior operation in fracture-dislocation of connect of cervical vertebrae and thoracic vertebrae. METHODS: From 1997, 21 patients with fracture-dislocation of connect of cervical vertebra and thoracic vertebrae were operated on. The interval between injury and operation was within 24 hours in 4 cases, 2-7 days in 9 cases, 8-14 days in 3 cases and within 4 weeks in 5 cases. The locations were C6,7 in 7 cases, C7 in 9 cases and T1 in 5 cases. The nerves function of spinal of all the cases have different degrees of injury. Classification of Frankel were the following: 3 cases of grade A, 6 cases of grade B, 9 cases of grade C, and 3 cases of grade D. The operative procedure included the following: anterior operation of cervical vertebrae; incision of most fracture vertebral body to decompress; transplantation of ilium bone grafting fusion; and internal fixation of anterior cervical vertebrae with locking-steel. RESULTS: In 21 patients, 1 died of accompanying by pulmonary infection; 20 were followed up 8 months to 3 years with an average of 21 months. All transplanted ilium had fused. The nerve function of spinal cord had recovered in different degrees(2 cases of grade A, 1 case of grade C, 9 cases of grade D and 8 cases of grade E); the turn of vertebral column was normal. No internal fixation failed. CONCLUSION: Anterior operation is a better way to treat fracture-dislocation of connect of cervical vertebrae and thoracic vertebrae with easy operation, less complications, satisfactory reduction of fracture and good stability.