Search

Abstract Background The American Heart Association recently introduced a novel cardiovascular health (CVH) metric, Life's Essential 8 (LE8), for health promotion. However, the relationship between LE8 and cancer mortality risk remains uncertain. Methods We investigated 17,076 participants from US National Health and Nutrition Examination Survey (US NHANES) and 272,727 participants from UK Biobank, all free of cancer at baseline. The CVH score, based on LE8 metrics, incorporates four health behaviors (diet, physical activity, smoking, and sleep) and four health factors (body mass index, lipid, blood glucose, and blood pressure). Self-reported questionnaires assessed health behaviors. Primary outcomes were mortality rates for total cancer and its subtypes. The association between CVH score (continuous and categorical variable) and outcomes was examined using Cox model with adjustments. Cancer subtypes-related polygenic risk score (PRS) was constructed to evaluate its interactions with CVH on cancer death risk. Results Over 141,526 person-years in US NHANES, 424 cancer-related deaths occurred, and in UK Biobank, 8,872 cancer deaths were documented during 3,690,893 person-years. High CVH was associated with reduced overall cancer mortality compared to low CVH (HR 0.58, 95% CI 0.37–0.91 in US NHANES; 0.51, 0.46–0.57 in UK Biobank). Each one-standard deviation increase in CVH score was linked to a 19% decrease in cancer mortality (HR: 0.81; 95% CI: 0.73–0.91) in US NHANES and a 19% decrease (HR: 0.81; 95% CI: 0.79–0.83) in UK Biobank. Adhering to ideal CVH was linearly associated with decreased risks of death from lung, bladder, liver, kidney, esophageal, breast, colorectal, pancreatic, and gastric cancers in UK Biobank. Furthermore, integrating genetic data revealed individuals with low PRS and high CVH exhibited the lowest mortality from eight cancers (HRs ranged from 0.36 to 0.57) compared to those with high PRS and low CVH. No significant modification of the association between CVH and mortality risk for eight cancers by genetic predisposition was observed. Subgroup analyses showed a more pronounced protective association for overall cancer mortality among younger participants and those with lower socio-economic status. Conclusions Maintaining optimal CVH is associated with a substantial reduction in the risk of overall cancer mortality. Adherence to ideal CVH correlates linearly with decreased mortality risk across multiple cancer subtypes. Individuals with both ideal CVH and high genetic predisposition demonstrated significant health benefits. These findings support adopting ideal CVH as an intervention strategy to mitigate cancer mortality risk and promote healthy aging.

Abstract Background Artificial sweeteners are widely popular worldwide as substitutes for sugar or caloric sweeteners, but there are still several important unknowns and controversies regarding their associations with cardiovascular disease (CVD). We aimed to extensively assess the association and subgroup variability between artificial sweeteners and CVD and CVD mortality in the UK Biobank cohort, and further investigate the modification effects of genetic susceptibility and the mediation role of type 2 diabetes mellitus (T2DM). Methods This study included 133,285 participants in the UK Biobank who were free of CVD and diabetes at recruitment. Artificial sweetener intake was obtained from repeated 24-hour diet recalls. Cox proportional hazard models were used to estimate HRs. Genetic predisposition was estimated using the polygenic risk score (PRS). Furthermore, time-dependent mediation was performed. Results In our study, artificial sweetener intake (each teaspoon increase) was significantly associated with an increased risk of incident overall CVD (HR1.012, 95%CI: 1.008,1.017), coronary artery disease (CAD) (HR: 1.018, 95%CI: 1.001,1.035), peripheral arterial disease (PAD) (HR: 1.035, 95%CI: 1.010,1.061), and marginally significantly associated with heart failure (HF) risk (HR: 1.018, 95%CI: 0.999,1.038). In stratified analyses, non-whites were at greater risk of incident overall CVD from artificial sweetener. People with no obesity (BMI

Summary: Sleep deprivation (SD) has been reported to induce intestinal damage by several mechanisms, yet its role in modulating epithelial repair remains unclear. In this study, we find that chronic SD leads to colonic damage through continuous hypoxia. However, HIF1α, which generally responds to hypoxia to modulate barrier integrity, was paradoxically dysregulated in the colon. Further investigation revealed that a metabolic disruption during SD causes accumulation of α-ketoglutarate in the colon. The excessive α-ketoglutarate degrades HIF1α protein through PHD2 (prolyl hydroxylase 2) to abolish the intestinal repair functions of HIF1α. Collectively, these findings provide insights into how SD can exacerbate intestinal damage by fine-tuning metabolism to abolish HIF1α-mediated repair.

Abstract Pathological cardiac hypertrophy is one of the major risk factors of heart failure and other cardiovascular diseases. However, the mechanisms underlying pathological cardiac hypertrophy remain largely unknown. Here, we identified the first evidence that TNFAIP3 interacting protein 3 (TNIP3) was a negative regulator of pathological cardiac hypertrophy. We observed a significant upregulation of TNIP3 in mouse hearts subjected to transverse aortic constriction (TAC) surgery and in primary neonatal rat cardiomyocytes stimulated by phenylephrine (PE). In Tnip3-deficient mice, cardiac hypertrophy was aggravated after TAC surgery. Conversely, cardiac-specific Tnip3 transgenic (TG) mice showed a notable reversal of the same phenotype. Accordingly, TNIP3 alleviated PE-induced cardiomyocyte enlargement in vitro. Mechanistically, RNA-sequencing and interactome analysis were combined to identify the signal transducer and activator of transcription 1 (STAT1) as a potential target to clarify the molecular mechanism of TNIP3 in pathological cardiac hypertrophy. Via immunoprecipitation and Glutathione S-transferase assay, we found that TNIP3 could interact with STAT1 directly and suppress its degradation by suppressing K48-type ubiquitination in response to hypertrophic stimulation. Remarkably, preservation effect of TNIP3 on cardiac hypertrophy was blocked by STAT1 inhibitor Fludaradbine or STAT1 knockdown. Our study found that TNIP3 serves as a novel suppressor of pathological cardiac hypertrophy by promoting STAT1 stability, which suggests that TNIP3 could be a promising therapeutic target of pathological cardiac hypertrophy and heart failure.

Abstract Background Fibrosis has important pathoetiological and prognostic roles in chronic liver disease. This study evaluates the role of radiomics in staging liver fibrosis. Method After literature search in electronic databases (Embase, Ovid, Science Direct, Springer, and Web of Science), studies were selected by following precise eligibility criteria. The quality of included studies was assessed, and meta-analyses were performed to achieve pooled estimates of area under receiver-operator curve (AUROC), accuracy, sensitivity, and specificity of radiomics in staging liver fibrosis compared to histopathology. Results Fifteen studies (3718 patients; age 47 years [95% confidence interval (CI): 42, 53]; 69% [95% CI: 65, 73] males) were included. AUROC values of radiomics for detecting significant fibrosis (F2-4), advanced fibrosis (F3-4), and cirrhosis (F4) were 0.91 [95%CI: 0.89, 0.94], 0.92 [95%CI: 0.90, 0.95], and 0.94 [95%CI: 0.93, 0.96] in training cohorts and 0.89 [95%CI: 0.83, 0.91], 0.89 [95%CI: 0.83, 0.94], and 0.93 [95%CI: 0.91, 0.95] in validation cohorts, respectively. For diagnosing significant fibrosis, advanced fibrosis, and cirrhosis the sensitivity of radiomics was 84.0% [95%CI: 76.1, 91.9], 86.9% [95%CI: 76.8, 97.0], and 92.7% [95%CI: 89.7, 95.7] in training cohorts, and 75.6% [95%CI: 67.7, 83.5], 80.0% [95%CI: 70.7, 89.3], and 92.0% [95%CI: 87.8, 96.1] in validation cohorts, respectively. Respective specificity was 88.6% [95% CI: 83.0, 94.2], 88.4% [95% CI: 81.9, 94.8], and 91.1% [95% CI: 86.8, 95.5] in training cohorts, and 86.8% [95% CI: 83.3, 90.3], 94.0% [95% CI: 89.5, 98.4], and 88.3% [95% CI: 84.4, 92.2] in validation cohorts. Limitations included use of several methods for feature selection and classification, less availability of studies evaluating a particular radiological modality, lack of a direct comparison between radiology and radiomics, and lack of external validation. Conclusion Although radiomics offers good diagnostic accuracy in detecting liver fibrosis, its role in clinical practice is not as clear at present due to comparability and validation constraints.

Abstract Background and purpose Whether symptomatic unruptured intracranial aneurysms (UIAs) lead to change in circulating inflammation remains unclear. This study aims to evaluate the role of hematological inflammatory indicators in predicting symptomatic UIA. Methods Adult patients diagnosed with saccular intracranial aneurysm from March 2019 to September 2023 were recruited retrospectively. Clinical and laboratory data, including the white blood cells (WBC), neutral counts (NEUT), lymphocyte counts (LYM), and monocyte counts (MONO) of each patient, were collected. The neutrophil-to-lymphocyte ratio (NLR) and lymphocyte-to-monocyte ratio (LMR) were calculated as NLR = NEUT/LYM, LMR = LYM/MONO, SII = PLT*NEUT/LYM. The hematological inflammatory indicators were compared in symptomatic saccular and asymptomatic UIA patients. Multivariable logistic regression analyses were performed to explore the factors predicting symptomatic UIA. Results One hundred and fifty UIA patients with a mean age of 58.5 ± 12.4 were included, of which 68% were females. The NLR and LMR were significantly associated with symptomatic UIA, and the association remained in small UIAs (

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can trigger autoimmune inflammation in the liver, leading to acute autoimmune hepatitis (AIH). We herein report a case involving a 39-year-old woman with a 23-day history of yellow skin and urine. Using the revised original scoring system of the International AIH Group, we definitively diagnosed the patient with acute severe AIH (AS-AIH). She began treatment with 80 mg/day intravenous methylprednisolone, which was gradually reduced and followed by eventual transition to oral methylprednisolone. The patient finally achieved a biochemical response after 30 days of therapy, and liver transplantation was avoided. Clinicians should be aware that the onset of AS-AIH after SARS-CoV-2 infection differs from the onset of conventional AIH with respect to its clinical and pathological features. Early diagnosis and timely glucocorticoid treatment are crucial in improving outcomes.

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease without specific Food and Drug Administration-approved drugs. Recent advances suggest that chromatin remodeling and epigenetic alteration contribute to the development of NAFLD. The functions of the corresponding molecular modulator in NAFLD, however, are still elusive. KDM1A, commonly known as lysine-specific histone demethylase 1, has been reported to increase glucose uptake in hepatocellular carcinoma. In addition, a recent study suggests that inhibition of KDM1A reduces lipid accumulation in primary brown adipocytes. We here investigated the role of KDM1A, one of the most important histone demethylases, in NAFLD. In this study, we observed a significant upregulation of KDM1A in NAFLD mice, monkeys, and humans compared to the control group. Based on these results, we further found that the KDM1A can exacerbate lipid accumulation and inflammation in hepatocytes and mice. Mechanistically, KDM1A exerted its effects by elevating chromatin accessibility, subsequently promoting the development of NAFLD. Furthermore, the mutation of KDM1A blunted its capability to promote the development of NAFLD. In summary, our study discovered that KDM1A exacerbates hepatic steatosis and inflammation in NAFLD via increasing chromatin accessibility, further indicating the importance of harnessing chromatin remodeling and epigenetic alteration in combating NAFLD. KDM1A might be considered as a potential therapeutic target in this regard.

Abstract Objective: The relationship of a diet low in fibre with mortality has not been evaluated. This study aims to assess the burden of non-communicable chronic diseases (NCD) attributable to a diet low in fibre globally from 1990 to 2019. Design: All data were from the Global Burden of Disease (GBD) Study 2019, in which the mortality, disability-adjusted life-years (DALY) and years lived with disability (YLD) were estimated with Bayesian geospatial regression using data at global, regional and country level acquired from an extensively systematic review. Setting: All data sourced from the GBD Study 2019. Participants: All age groups for both sexes. Results: The age-standardised mortality rates (ASMR) declined in most GBD regions; however, in Southern sub-Saharan Africa, the ASMR increased from 4·07 (95 % uncertainty interval (UI) (2·08, 6·34)) to 4·60 (95 % UI (2·59, 6·90)), and in Central sub-Saharan Africa, the ASMR increased from 7·46 (95 % UI (3·64, 11·90)) to 9·34 (95 % UI (4·69, 15·25)). Uptrends were observed in the age-standardised YLD rates attributable to a diet low in fibre in a number of GBD regions. The burden caused by diabetes mellitus increased in Central Asia, Southern sub-Saharan Africa and Eastern Europe. Conclusions: The burdens of disease attributable to a diet low in fibre in Southern sub-Saharan Africa and Central sub-Saharan Africa and the age-standardised YLD rates in a number of GBD regions increased from 1990 to 2019. Therefore, greater efforts are needed to reduce the disease burden caused by a diet low in fibre.

In this study, 21 new honokiol derivatives were synthesised, and their anti-cancer properties were investigated. Among these, compound 1g exhibited the most potent cytotoxic activity against human nasopharyngeal carcinoma CNE-2Z cells, human gastric cancer SGC7901 cells, human breast cancer MCF-7 cells, and mouse leydig testicular cancer I-10 lines with IC50 values of 6.04, 7.17, 6.83, and 5.30 μM, respectively. Compared to the parental compound, 1g displayed up to 5.18-fold enhancement of the cytotoxic effect on CNE-2Z cells. We further demonstrated that 1g inhibited cell growth, suppressed migration and invasion, and induced apoptosis of CNE-2Z cells by down-regulating HIF-1α, MMP-2, MMP-9, Bcl-2, Akt and up-regulating Bax protein levels. Transfection of CNE-2Z cells with HIF-1α siRNA reduced cell migration and invasion. In addition, in vivo experiments confirmed that 1g inhibited tumour growth in CNE-2Z cell-xenografted nude mice with low toxicity. Thus, our data suggested that 1g was a potent and safe lead compound for nasopharyngeal carcinoma therapy.

Abstract Background Non-alcoholic fatty liver (NAFLD) and its related metabolic syndrome have become major threats to human health, but there is still a need for effective and safe drugs to treat these conditions. Here we aimed to identify potential drug candidates for NAFLD and the underlying molecular mechanisms. Methods A drug repositioning strategy was used to screen an FDA-approved drug library with approximately 3000 compounds in an in vitro hepatocyte model of lipid accumulation, with honokiol identified as an effective anti-NAFLD candidate. We systematically examined the therapeutic effect of honokiol in NAFLD and metabolic syndrome in multiple in vitro and in vivo models. Transcriptomic examination and biotin-streptavidin binding assays were used to explore the underlying molecular mechanisms, confirmed by rescue experiments. Results Honokiol significantly inhibited metabolic syndrome and NAFLD progression as evidenced by improved hepatic steatosis, liver fibrosis, adipose inflammation, and insulin resistance. Mechanistically, the beneficial effects of honokiol were largely through AMPK activation. Rather than acting on the classical upstream regulators of AMPK, honokiol directly bound to the AMPKγ1 subunit to robustly activate AMPK signaling. Mutation of honokiol-binding sites of AMPKγ1 largely abolished the protective capacity of honokiol against NAFLD. Conclusion These findings clearly demonstrate the beneficial effects of honokiol in multiple models and reveal a previously unappreciated signaling mechanism of honokiol in NAFLD and metabolic syndrome. This study also provides new insights into metabolic disease treatment by targeting AMPKγ1 subunit-mediated signaling activation.

Rationale Aortic aneurysm (AA) is a serious condition that largely increases the risk of aortic dissection and sudden death. Exploring the global burden of disease and changes in risk factors for AA is essential for public health policy development. Objective To project the death burden from AA and its attributable risk factors in the following decade based on the epidemiological data over the past 30 years. Methods and Results We analysed the death burden of AA and trends of four risk factors from 1990–2019 using the updated 2019 Global Burden of Disease study database by Joinpoint regression analysis. Furthermore, we project the AA-related death burden for the next decade using the Bayesian age-period-cohort model. This study discovered that the global burden of death attributable to AA began to increase after decreasing for two decades. This upward trend will continue in the subsequent decade (average annual percent change: 0.318%, 95% CI: 0.288 to 0.348). Meanwhile, the disease burdens in all economic regions except high-middle socio-demographic index (SDI) regions will continuously increase in the next decade, with the fastest acceleration in the low-middle SDI region (average annual percent change: 1.183%, 95% CI: 1.166 to 1.200). Notably, high systolic blood pressure will surpass the contribution of smoking to become the most important risk factor for mortality due to AA. Conclusion This study discovered a rebounding trend in the aortic aneurysm-related death burden globally. High systolic blood pressure will be the top risk factor attributed to death from AA. Therefore, it should be considered as the first-degree risk factor in the guidance of AA management and criteria for population-based screening programs.Key messages The death burden of aortic aneurysms is beginning to rebound globally, and the trend will continue for the next decade. High systolic blood pressure will replace smoking as the most important risk factor associated with aortic aneurysm death.

We conducted a study on the confinement properties of non-neutral proton plasma in an asymmetric magnetic mirror using the three-dimensional (3D) particle-in-cell simulation method. Our findings indicate a close relationship between the ability of the magnetic mirror to confine protons and the incidence orientation of the proton beam. This relationship can only be accurately assessed through 3D simulation, as opposed to two-dimensional simulation. In addition, we observed that a higher velocity parallel to the magnetic field direction results in a shorter confinement time. The electric field at and near the central point of the mirror exhibits quasi-periodic vibrations, attributed to the electrostatic oscillation of the proton and the cyclotron motion. Furthermore, we discovered a drift motion of the confined proton plasma in the direction of the magnetic field gradient. These findings hold implications for the design of magnetic mirrors capable of effectively confining charged particle beams.

Skin aging is a complex process involving intricate genetic and environmental factors. In this study, we performed a comprehensive analysis of the transcriptional regulatory landscape of skin aging in canines. Weighted Gene Co-expression Network Analysis (WGCNA) was employed to identify aging-related gene modules. We subsequently validated the expression changes of these module genes in single-cell RNA sequencing (scRNA-seq) data of human aging skin. Notably, basal cell (BC), spinous cell (SC), mitotic cell (MC), and fibroblast (FB) were identified as the cell types with the most significant gene expression changes during aging. By integrating GENIE3 and RcisTarget, we constructed gene regulation networks (GRNs) for aging-related modules and identified core transcription factors (TFs) by intersecting significantly enriched TFs within the GRNs with hub TFs from WGCNA analysis, revealing key regulators of skin aging. Furthermore, we demonstrated the conserved role of CTCF and RAD21 in skin aging using an H2O2-stimulated cell aging model in HaCaT cells. Our findings provide new insights into the transcriptional regulatory landscape of skin aging and unveil potential targets for future intervention strategies against age-related skin disorders in both canines and humans.

Nonalcoholic fatty liver disease (NAFLD) has become the most prevalent chronic liver disease worldwide, without any Food and Drug Administration-approved pharmacological intervention in clinic. Trim38, as an important member of the TRIM (tripartite motif-containing) family, was largely reported to be involved in the regulation of innate immune and inflammatory responses. However, the functional roles of TRIM38 in NAFLD remain largely unknown. Here, the expression of TRIM38 was first detected in liver samples of both NAFLD mice model and patients diagnosed with NAFLD. We found that TRIM38 expression was downregulated in NAFLD liver tissues compared with normal liver tissues. Genetic Trim38-KO in vivo showed that TRIM38 depletion deteriorated the high-fat diet and high fat and high cholesterol diet-induced hepatic steatosis and high fat and high cholesterol diet-induced liver inflammation and fibrosis. In particular, we found that the effects of hepatocellular lipid accumulation and inflammation induced by palmitic acid and oleic acid were aggravated by TRIM38 depletion but mitigated by TRIM38 overexpression in vitro. Mechanically, RNA-Seq analysis demonstrated that TRIM38 ameliorated nonalcoholic steatohepatitis progression by attenuating the activation of MAPK signaling pathway. We further found that TRIM38 interacted with transforming growth factor-β-activated kinase 1 binding protein 2 and promoted its protein degradation, thus inhibiting the transforming growth factor-β-activated kinase 1-MAPK signal cascades. In summary, our study revealed that TRIM38 could suppress hepatic steatosis, inflammatory, and fibrosis in NAFLD via promoting transforming growth factor-β-activated kinase 1 binding protein 2 degradation. TRIM38 could be a potential target for NAFLD treatment.

ObjectiveThe aim of the study was to depict the global death burden of atrial fibrillation and/or flutter (AFF) between 1990 and 2019 and predict this burden in the next decade.MethodsWe retrieved annual death data on cases and rates of AFF between 1990 and 2019 from the Global Burden of Disease (GBD) Study 2019 and projected the trends for 2020–2029 by developing the Bayesian age-period-cohort model.ResultsThe global number of deaths from AFF increased from 117,038.00 in 1990 to 315,336.80 in 2019. This number is projected to reach 404,593.40 by 2029. The age-standardized mortality rates (ASMRs) of AFF have increased significantly in low- to middle-sociodemographic index (SDI) regions, which will surpass that in high SDI regions and reach above 4.60 per 100,000 by 2029. Globally, women have a higher ASMR than men, which is largely attributed to disproportionately higher mortality in women than men in lower SDI regions. Notably, AFF-related premature mortality continues to worsen worldwide. A pandemic of high systolic blood pressure and high body mass index (BMI) largely contributes to AFF-associated death. In particular, low- to middle-SDI regions and younger populations are increasingly affected by the rapidly growing current and future risk of high BMI.ConclusionThe global death burden of AFF in low-income countries and younger generations have not been sufficiently controlled in the past and will continue growing in the future, which is largely attributed to metabolic risks, particularly for high BMI. There is an urgent need to implement effective measures to control AFF-related mortality.

BackgroundAtrial fibrillation (AF) is the most prevalent cardiac arrhythmia, which poses huge disease burdens in China. A study was conducted to systematically analyze the recent prevalence trend of AF and age-related disparities in AF risk among the nationwide healthy check-up population.MethodWe conducted a nationwide cross-sectional study involving 3,049,178 individuals ≥35 years from health check-up centers to explore the prevalence and trend of AF by age, sex, and region from 2012 to 2017. Additionally, we analyzed risk factors associated with AF among the overall population and different age groups via the Boruta algorithm, the LASSO regression, and the Logistic regression.ResultThe age-, sex-. and regional-standardized prevalence of AF kept stable between 0.4%–0.45% among national physical examination individuals from 2012 to 2017. However, the prevalence of AF showed an undesirable upward trend in the 35–44-year age group (annual percentage changes (APC): 15.16 [95%CI: 6.42,24.62]). With increasing age, the risk of AF associated with the overweight or obesity gradually exceeds that associated with diabetes and hypertension. In addition to traditional leading risk factors such as age≥65 and coronary heart disease, elevated uric acid and impaired renal function were tightly correlated with AF in the population.ConclusionThe significant rise in the prevalence of AF in the 35–44 age group reminds us that in addition to the elderly (the high-risk group), younger people seem to be in more urgent need of attention. Age-related disparities in AF risk also exist. This updated information may provide references for the national prevention and control of AF.

Background and aimsMetabolic dysfunction-associated fatty liver disease (MAFLD) was proposed to substitute NAFLD in 2020. This new term highlights the systematic metabolic disturbances that accompany fatty liver. We evaluated the correlations between MAFLD and subclinical carotid atherosclerosis (SCA) based on a nationwide health examination population in China.MethodsWe performed a nationwide cross-sectional population and a Beijing retrospective cohort from 2009 to 2017. SCA was defined as elevated carotid intima-media thickness. The multivariable logistic and Cox models were used to analyze the association between MAFLD and SCA.Results153,482 participants were included in the cross-sectional study. MAFLD was significantly associated with SCA in fully adjusted models, with an odds ratio of 1.66; 95% confidence interval (CI): 1.62-1.70. This association was consistent in the cohort, with a hazard ratio (HR) of 1.31. The association between baseline MAFLD and incident SCA increased with hepatic steatosis severity. Subgroup analysis showed an interaction between age and MAFLD, with a higher risk in younger groups (HR:1.67, 95% CI: 1.17-2.40).ConclusionIn this large cross-section and cohort study, MAFLD was significantly associated with the presence and development of SCA. Further, the risk was higher among MAFLD individuals with high hepatic steatosis index and young adults.

Abstract Background Global distributions and trends of the risk-attributable burdens of chronic obstructive pulmonary disease (COPD) have rarely been systematically explored. To guide the formulation of targeted and accurate strategies for the management of COPD, we analyzed COPD burdens attributable to known risk factors. Methods Using detailed COPD data from the Global Burden of Disease study 2019, we analyzed disability-adjusted life years (DALYs), years lived with disability (YLDs), years of life lost (YLLs), and deaths attributable to each risk factor from 1990 to 2019. Additionally, we calculated estimated annual percentage changes (EAPCs) during the study period. The population attributable fraction (PAF) and summary exposure value (SEV) of each risk factor are also presented. Results From 1990 to 2019, the age-standardized DALY and death rates of COPD attributable to smoking and household air pollution, occupational particles, secondhand smoke, and low temperature presented consistently declining trends in almost all socio-demographic index (SDI) regions. However, the decline in YLD was not as dramatic as that of the death rate. In contrast, the COPD burden attributable to ambient particulate matter, ozone, and high temperature exposure showed undesirable increasing trends in the low- and low-middle-SDI regions. In addition, the age-standardized DALY and death rates attributable to each risk factor except household air pollution and low temperature were the highest in the low-middle-SDI region. In 2019, the COPD burden attributable to smoking ambient particulate matter, ozone, occupational particles, low and high temperature was obviously greater in males than in females. Meanwhile, the most important risk factors for female varied across regions (low- and low-middle-SDI regions: household air pollution; middle-SDI region: ambient particles; high-middle- and high-SDI region: smoking). Conclusions Increasing trends of COPD burden attributable to ambient particulate matter, ozone, and high temperature exposure in the low-middle- and low-SDI regions call for an urgent need to implement specific and effective measures. Moreover, considering the gender differences in COPD burdens attributable to some risk factors such as ambient particulate matter and ozone with similar SEV, further research on biological differences between sexes in COPD and relevant policy-making of disease prevention are required.

Background: Coronavirus disease 2019 (COVID-19) pandemic continues to escalate intensively worldwide. Massive studies on general populations with SARS-CoV-2 infection have revealed that pre-existing comorbidities were a major risk factor for the poor prognosis of COVID-19. Notably, 49–75% of COVID-19 patients had no comorbidities, but this cohort would also progress to severe COVID-19 or even death. However, risk factors contributing to disease progression and death in patients without chronic comorbidities are largely unknown; thus, specific clinical interventions for those patients are challenging. Methods: A multicenter, retrospective study based on 4806 COVID-19 patients without chronic comorbidities was performed to identify potential risk factors contributing to COVID-19 progression and death using LASSO and a stepwise logistic regression model. Results: Among 4806 patients without pre-existing comorbidities, the proportions with severe progression and mortality were 34.29% and 2.10%, respectively. The median age was 47.00 years [interquartile range, 36.00–56.00], and 2162 (44.99%) were men. Among 51 clinical parameters on admission, age ≥ 47, oxygen saturation < 95%, increased lactate dehydrogenase, neutrophil count, direct bilirubin, creatine phosphokinase, blood urea nitrogen levels, dyspnea, increased blood glucose and prothrombin time levels were associated with COVID-19 mortality in the entire cohort. Of the 3647 patients diagnosed with non-severe COVID-19 on admission, 489(13.41%) progressed to severe disease. The risk factors associated with COVID-19 progression from non-severe to severe illness were increased procalcitonin levels, SpO2 < 95%, age ≥ 47, increased LDH, activated partial thromboplastin time levels, decreased high-density lipoprotein cholesterol levels, dyspnea and increased D-dimer levels. Conclusions: COVID-19 patients without pre-existing chronic comorbidities have specific traits and disease patterns. COVID-19 accompanied by severe bacterial infections, as indicated by increased procalcitonin levels, was highly associated with disease progression from non-severe to severe. Aging, impaired respiratory function, coagulation dysfunction, tissue injury, and lipid metabolism dysregulation were also associated with disease progression. Once factors for multi-organ damage were elevated and glucose increased at admission, these findings indicated a higher risk for mortality. This study provides information that helps to predict COVID-19 prognosis specifically in patients without chronic comorbidities.

BackgroundPathological cardiac hypertrophy is commonly resulted from sustained pressure overload and/or metabolic disorder and eventually leads to heart failure, lacking specific drugs in clinic. Here, we aimed to identify promising anti-hypertrophic drug(s) for heart failure and related metabolic disorders by using a luciferase reporter-based high-throughput screening.MethodsA screen of the FDA-approved compounds based on luciferase reporter was performed, with identified luteolin as a promising anti-hypertrophic drug. We systematically examined the therapeutic efficacy of luteolin on cardiac hypertrophy and heart failure in vitro and in vivo models. Transcriptome examination was performed to probe the molecular mechanisms of luteolin.ResultsAmong 2,570 compounds in the library, luteolin emerged as the most robust candidate against cardiomyocyte hypertrophy. Luteolin dose-dependently blocked phenylephrine-induced cardiomyocyte hypertrophy and showed extensive cardioprotective roles in cardiomyocytes as evidenced by transcriptomics. More importantly, gastric administration of luteolin effectively ameliorated pathological cardiac hypertrophy, fibrosis, metabolic disorder, and heart failure in mice. Cross analysis of large-scale transcriptomics and drug-target interacting investigations indicated that peroxisome proliferator activated receptor γ (PPARγ) was the direct target of luteolin in the setting of pathological cardiac hypertrophy and metabolic disorders. Luteolin can directly interact with PPARγ to inhibit its ubiquitination and subsequent proteasomal degradation. Furthermore, PPARγ inhibitor and PPARγ knockdown both prevented the protective effect of luteolin against phenylephrine-induced cardiomyocyte hypertrophy in vitro.ConclusionOur data clearly supported that luteolin is a promising therapeutic compound for pathological cardiac hypertrophy and heart failure by directly targeting ubiquitin-proteasomal degradation of PPARγ and the related metabolic homeostasis.

The heart is the main organ of the circulatory system and requires fatty acids to maintain its activity. Stress is a contributor to aggravating cardiovascular diseases and even death, and exacerbates the abnormal lipid metabolism. The cardiac metabolism may be disturbed by stress. Cholecystokinin (CCK), which is a classical peptide hormone, and its receptor (CCKR) are expressed in myocardial cells and affect cardiovascular function. Nevertheless, under stress, the exact role of CCKR on cardiac function and cardiac metabolism is unknown and the mechanism is worth exploring. After unpredictable stress, a common stress-inducing model that induces the development of mood disorders such as anxiety and reduces motivated behavior, we found that the abnormal contraction and diastole of the heart, myocardial injury, oxidative stress and inflammation of mice were aggravated. Cholecystokinin A receptor and cholecystokinin B receptor knockout (CCK1R2R-/-) significantly reversed these changes. Mechanistically, fatty acid metabolism was found to be altered in CCK1R2R-/- mice. Differential metabolites, especially L-tryptophan, L-aspartic acid, cholesterol, taurocholic acid, ADP, oxoglutaric acid, arachidonic acid and 17-Hydroxyprogesterone, influenced cardiac function after CCK1R2R knockout and unpredictable stress. We conclude that CCK1R2R-/- ameliorated myocardial damage caused by unpredictable stress via altering fatty acid metabolism.

In the past few decades, non-alcoholic fatty liver disease (NAFLD) and heart failure with preserved ejection fraction (HFpEF) have become the most common chronic liver disease and the main form of heart failure (HF), respectively. NAFLD is closely associated with HFpEF by sharing common risk factors and/or by boosting systemic inflammation, releasing other secretory factors, and having an expansion of epicardial adipose tissue (EAT). Therefore, the treatments of NAFLD may also affect the development and prognosis of HFpEF. However, no specific drugs for NAFLD have been approved by the Food and Drug Administration (FDA) and some non-specific treatments for NAFLD are applied in the clinic. Currently, the treatments of NAFLD can be divided into non-pharmacological and pharmacological treatments. Non-pharmacological treatments mainly include dietary intervention, weight loss by exercise, caloric restriction, and bariatric surgery. Pharmacological treatments mainly include administering statins, thiazolidinediones, glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter 2 inhibitors, and metformin. This review will mainly focus on analyzing how these treatments may affect the development and prognosis of HFpEF.

Background and aimsThe metabolomic profile of a biofluid can be affected by age, and thus provides detailed information about the metabolic alterations in biological processes and reflects the in trinsic rule regulating the growth and developmental processes.MethodsTo systemically investigate the characteristics of multiple metabolic profiles associated with canine growth, we analyzed the metabolomics in the plasma and urine samples from 15 young and 15 adult beagle dogs via UHPLC-Q-TOFMS-based metabolomics. Blood routine and serum biochemical analyses were also performed on fasting blood samples.ResultsThe metabolomics results showed remarkable differences in metabolite fingerprints both in plasma and urine between the young and adult groups. The most obvious age-related metabolite alterations include decreased serumlevels of oxoglutaric acid and essential amino acids and derivatives but increased levels of urine levels of O-acetylserine. These changes primarily involved in amino acid metabolism and bile secretion pathways. We also found that the levels of glutamine were consistently higher in both serum and urine of adults, while N-acetylhistamine and uracil concentrations were much lower in the adult group compared to younger ones.ConclusionOur study provides a whole metabolic profile of serum and urine characteristics of young and adult canines, identifying several metabolites that were significantly associated with age change, which provides theoretical support for the nutrition-related research and age-related homeostasis maintenance in dogs.

Background and aimsThe epidemiological characteristics of MAFLD and its relationship with atrial fibrillation (AF) are limited in China. Therefore, we explored the epidemiological characteristics of MAFLD from adults along with the association of MAFLD and 12-ECG diagnosed AF in a nationwide population from health check-up centers.MethodsThis observational study used cross-sectional and longitudinal studies with 2,083,984 subjects from 2009 to 2017. Age-, sex-, and regional-standardized prevalence of MAFLD was estimated. Latent class analysis (LCA) was used to identify subclusters of MAFLD. Multivariable logistic regression and mixed-effects Cox regression models were used to analyze the relationship between MAFLD and AF.ResultsThe prevalence of MAFLD increased from 22.75% to 35.58% during the study period, with higher rates in males and populations with high BMI or resided in northern regions. The MAFLD population was clustered into three classes with different metabolic features by LCA. Notably, a high proportion of MAFLD patients in all clusters had overweight and prediabetes or diabetes. The MAFLD was significantly associated with a higher risk of AF in the cross-sectional study and in the longitudinal study. In addition, the coexistence of prediabetes or diabetes had the largest impact on subsequent AF.ConclusionOur findings suggested a high prevalence of MAFLD and a high prevalence of other metabolic diseases in the MAFLD population, particularly overweight and glucose dysregulation. Moreover, MAFLD was associated with a significantly higher risk for existing and subsequent subclinical AF in the Chinese population.

The increased burden of nonalcoholic fatty liver disease (NAFLD) parallels the increased incidence of overweight and metabolic syndrome worldwide. Because of the close relationship between metabolic disorders and fatty liver disease, a new term, metabolic-related fatty liver disease (MAFLD), was proposed by a group of experts to more precisely describe fatty liver disease resulting from metabolic disorders. According to the definitions, MAFLD and NAFLD populations have considerable discrepancies, but overlap does exist. This new definition has a nonnegligible impact on clinical practices, including diagnoses, interventions, and the risk of comorbidities. Emerging evidence has suggested that patients with MAFLD have more metabolic comorbidities and an increased risk of all-cause mortality, particularly cardiovascular mortality than patients with NAFLD. In this review, we systemically summarized and compared the risk and underlying mechanisms of cardiovascular disease (CVD) in patients with NAFLD or MAFLD.

Background:Gut microbiota has been identified as an imbalance in patients with irritable bowel syndrome (IBS). Fecal microbiota transplantation (FMT) is a novel method to restore microbiota and treat IBS patients.ObjectiveTo conduct a meta-analysis and estimate the efficacy and safety of FMT for the treatment of IBS patients with subgroup analyses to explore the most effective way of FMT for IBS.MethodsAll eligible studies were searched from PubMed, Embase, Web of Science, and the Cochrane Library through multiple search strategies. Data were extracted from studies comprising the following criteria: double-blind, randomized controlled trials (RCTs) that compared the efficacy of FMT with placebo for adult patients (≥18 years old) with IBS. A meta-analysis was performed to evaluate the summary relative risk (RR) and 95% confidence intervals (CIs).ResultsA total of seven RCTs comprising 489 subjects were eligible for this meta-analysis. Pooled data showed no significant improvement of global IBS symptoms in patients with FMT compared with placebo (RR = 1.34; 95% CI 0.75–2.41, p = 0.32). A significant heterogeneity was observed among the studies (I2 = 83%, p < 0.00001). There was no significant evidence of funnel plot asymmetry (Egger's test, p = 0.719; Begg's test, p = 1.000), indicating no existence of publication bias. Subgroup analyses revealed that FMT operated by invasive routes, including gastroscope, colonoscope, and nasojejunal tube, significantly improved global IBS symptoms (RR = 1.96; 95% CI 1.23–3.11, p = 0.004) with heterogeneity (I2 = 57%, p = 0.06) and an NNT of 3 (95% CI 2–14). However, FMT delivered via oral capsules showed a negative impact on patients with IBS (RR = 0.56; 95% CI 0.33–0.96, p = 0.03) with a low heterogeneity (I2 = 39%, p = 0.2) and an NNH of 3 (95% CI 2–37).ConclusionThe current evidence from RCTs with all routes of FMT does not show significant global improvement in patients with IBS. However, FMT operated by invasive routes significantly improved global IBS symptoms.

Canine models are increasingly being used in metabolic studies due to their physiological similarity with humans. The present study aimed to identify changes in metabolic pathways and biomarkers with potential clinical utility in a canine model of obesity and metabolic disorders induced by a high-fat diet (HFD). Eighteen male beagles were included in this study, 9 of which were fed a HFD for 24 weeks, and the remaining 9 were fed normal chow (NC) during the same period. Plasma and urine samples were collected at weeks 12 and 24 for untargeted metabolomic analysis. Dogs fed a HFD showed a gradual body weight increase during the feeding period and had hyperlipidemia, increased leukocyte counts, and impaired insulin sensitivity at week 24. Plasma and urine metabonomics analysis displayed clear separations between the HFD-fed and NC-fed dogs. A total of 263 plasma metabolites varied between the two groups, including stearidonic acid, linolenic acid, carnitine, long-chain ceramide, 3-methylxanthine, and theophylline, which are mainly engaged in fatty acid metabolism, sphingolipid metabolism, and caffeine metabolism. A total of 132 urine metabolites related to HFD-induced obesity and metabolic disorders were identified, including 3-methylxanthine, theophylline, pyridoxal 5’-phosphate, and harmine, which participate in pathways such as caffeine metabolism and vitamin digestion and absorption. Eight metabolites with increased abundance (e.g., 3-methylxanthine, theophylline, and harmine) and 4 metabolites with decreased abundance (e.g., trigonelline) in both the plasma and urine of the HFD-fed dogs were identified. In conclusion, the metabolomic analysis revealed molecular events underlying a canine HFD model and identified several metabolites as potential targets for the prevention and treatment of obesity-related metabolic disorders.

Drought is one of the most important abiotic stresses affecting maize growth and development and therefore resulting in yield loss. Thus it is essential to understand molecular mechanisms of drought stress responses in maize for drought tolerance improvement. The root plays a critical role in plants sensing water deficit. In the present study, two maize inbred lines, H082183, a drought-tolerant line, and Lv28, a drought-sensitive line, were grown in the field and treated with different water conditions (moderate drought, severe drought, and well-watered conditions) during vegetative stage. The transcriptomes of their roots were investigated by RNA sequencing. There were 1 428 and 512 drought-responsive genes (DRGs) in Lv28, 688 and 3 363 DRGs in H082183 under moderate drought and severe drought, respectively. A total of 31 Gene Ontology (GO) terms were significantly over-represented in the two lines, 13 of which were enriched only in the DRGs of H082183. Based on results of Kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis, “plant hormone signal transduction” and “starch and sucrose metabolism” were enriched in both of the two lines, while “phenylpropanoid biosynthesis” was only enriched in H082183. Further analysis revealed the different expression patterns of genes related to abscisic acid (ABA) signal pathway, trehalose biosynthesis, reactive oxygen scavenging, and transcription factors might contribute to drought tolerance in maize. Our results contribute to illustrating drought-responsive molecular mechanisms and providing gene resources for maize drought improvement.

Orchids constitute approximately 10% of flowering plant species. However, only about 10 orchid genomes have been published. Metabolites are the main way through which orchids respond to their environment. Dendrobium nobile, belonging to Dendrobium, the second largest genus in Orchidaceae, has high ornamental, medicinal, and ecological value. D. nobile is the source of many popular horticultural varieties. Among the Dendrobium species, D. nobile has the highest amount of dendrobine, which is regarded as one of the criteria for evaluating medicinal quality. Due to lack of data and analysis at the genomic level, the biosynthesis pathways of dendrobine and other related medicinal ingredients in D. nobile are unknown. In this paper, we report a chromosome-scale reference genome of D. nobile to facilitate the investigation of its genomic characteristics for comparison with other Dendrobium species. The assembled genome size of D. nobile was 1.19 Gb. Of the sequences, 99.45% were anchored to 19 chromosomes. Furthermore, we identified differences in gene number and gene expression patterns compared with two other Dendrobium species by integrating whole-genome sequencing and transcriptomic analysis [e.g., genes in the polysaccharide biosynthesis pathway and upstream of the alkaloid (dendrobine) biosynthesis pathway]. Differences in the TPS and CYP450 gene families were also found among orchid species. All the above differences might contribute to the species-specific medicinal ingredient biosynthesis pathways. The metabolic pathway-related analysis will provide further insight into orchid responses to the environment. Additionally, the reference genome will provide important insights for further molecular elucidation of the medicinal active ingredients of Dendrobium and enhance the understanding of orchid evolution.

BackgroundEmerging evidence suggests an association between remnant cholesterol (RC) and vascular damage and hypertension. However, this association has not been explored in a large-scale population in China, and a temporal relationship between RC and hypertension also needs to be investigated.MethodsWe conducted a retrospective cross-sectional study in 2,199,366 individuals and a longitudinal study in 24,252 individuals with repeated measurements of lipid profile and blood pressure in at least a 3-year follow-up. The logistic model was used to explore the association between lipid components and hypertension in the cross-sectional analysis. The Cox model was used to analyze the association between high RC (HRC) at baseline and the subsequent incidence of hypertension or the association between hypertension at baseline and incidence of HRC. The cross-lagged panel model was applied to analyze the temporal relationship between RC and hypertension.ResultsRC level as a continuous variable had the highest correlation with hypertension among lipid profiles, including RC, low-density lipoprotein cholesterol, total cholesterol, non-high-density lipoprotein cholesterol, and triglycerides, with an odds ratio of 1.59 (95% confidence interval: 1.58–1.59). In the longitudinal cohort, HRC at baseline was associated with incident hypertension. We further explored the temporal relationship between RC and hypertension using the cross-lagged analysis, and the results showed that RC increase preceded the development of hypertension, rather than vice versa.ConclusionsRC had an unexpected high correlation with the prevalence and incidence of hypertension. Moreover, RC increase might precede the development of hypertension, suggesting the potential role of RC in the development of hypertension.

Objective: High systolic blood pressure (HSBP) remains the leading risk factor for mortality worldwide; however, limited data have revealed all-cause and cause-specific burdens attributed to HSBP at global and regional levels. This study aimed to estimate the global burden and priority diseases attributable to HSBP by region, sex, and age.Methods: Based on data and evaluation methods from the Global Burden of Diseases, Injuries, and Risk Factors Study 2019, we estimated trends of age-standardized mortality rate (ASMR), the age-standardized rate of disability-adjusted life years (ASDRs), and the age-standardized rate of years lived with disability (ASYRs) attributable to HSBP during 1990-2019. Further, we analyzed cause-specific burdens attributable to HSBP by sex, age, year, and region.Results: Globally, a significant downtrend was found in the ASMR attributed to HSBP while ASYRs did not change substantially during 1990-2019. The majority of HSBP burden has shifted from high-middle sociodemographic index (SDI) regions to lower SDI regions. All-cause and most cause-specific burdens related to HSBP were improved in high SDI regions but the downtrends have stagnated in recent years. Although many cause-specific deaths associated with HSBP declined, chronic kidney disease (CKD) and endocarditis associated deaths were aggravated globally and ischemic heart disease (IHD), atrial fibrillation and flutter, aortic aneurysm (AA), and peripheral artery disease (PAD) associated deaths were on the rise in low/low-middle/middle SDI regions. Additionally, males had higher disease burdens than females. Middle-aged people with CVDs composed the major subgroup affected by HSBP while older people had the highest ASMRs associated with HSBP.Conclusions: This study revealed the global burden and priority diseases attributable to HSBP with wide variation by region, sex, and age, calling for effective and targeted strategies to reduce the prevalence and mortality of HSBP, especially in low/low-middle/middle SDI regions.

The newly emerged tigecycline-inactivating enzymes Tet(X3) and Tet(X4), which are associated with high-level tigecycline resistance, demonstrated significantly higher activities in comparison to that of the prototypical Tet(X) enzyme, threatening the clinical efficacy of tigecycline as a last-resort antibiotic to treat multidrug-resistant (MDR) Gram-negative bacterial infections. However, the molecular mechanisms leading to high-level tigecycline resistance remain elusive.

Objective: We aimed to identify and represent factors associated with thrombocytopenia in intensive care unit, especially the pathogens and drugs related to severe and extremely thrombocytopenia. Then, we aim to compare the mortality of platelet transfusion and non-transfusion in patients with different degrees of thrombocytopenia. Methods: We identified all thrombocytopenic patients in intensive care unit by using platelet-specific values and then extracted electronic health records from our Hospital Information System. Data were statistically analyzed with t test, chi-square test, and logistic regression. Results: We found that infections (32.7%) were the most frequent cause associated with thrombocytopenia, followed by sepsis shock (3.93%) and blood loss (2.99%). Meanwhile, antifungals ( p = 0.002) and bacterial infection ( p = 0.037) were associated with severe and extremely severe thrombocytopenia. Finally, we found that the mortality of platelet transfusion and non-transfusion in patients was statistically significant for patients with platelet counts between 30 and 49/nL (χ 2 = 9.719, p = 0.002). Conclusion: Infection and sepsis emerged as two primary factors associated with thrombocytopenia in intensive care unit. Meanwhile, antifungals and bacterial infection were associated with platelet counts less than 49/nL. Finally, platelet transfusion may be associated with reduced mortality in patients with platelet counts between 30 and 49/nL.

Interferon-inducible protein (IFI204) (p204, the murine homolog of human IFI16) is known as a cytosolic DNA sensor to recognize DNA viruses and intracellular bacteria. However, little is known about its role during extracellular bacterial infection. Here we show that IFI204 is required for host defense against the infection of Staphylococcus aureus, an extracellular bacterial pathogen. IFI204 deficiency results in decreased survival, increased bacterial loads, severe organs damage, and decreased recruitment of neutrophils and macrophages. Production of several inflammatory cytokines/chemokines including IFN-β and KC is markedly decreased, as well as the related STING-IRF3 and NF-κB pathways are impaired. However, exogenous administration of recombinant KC or IFN-β is unable to rescue the susceptibility of IFI204-deficient mice, suggesting that other mechanisms rather than KC and IFN-β account for IFI204-mediated host defense. IFI204 deficiency leads to a defect in extracellular bacterial killing in macrophages and neutrophils, although bacterial engulf, and intracellular killing activity are normal. Moreover, the defect of bactericidal activity is mediated by decreased extracellular trap formation in the absence of IFI204. Adoptively transferred WT bone marrow cells significantly protect WT and IFI204-deficient recipients against Staphylococcus infection compared with transferred IFI204-deficient bone marrow cells. Hence, this study suggests that IFI204 is essential for the host defense against Staphylococcus infection.

TRAF6 is a ubiquitin E3 ligase regulating a number of biological processes. Here the authors show that ROS, generated during pathological cardiac stress, induces TRAF6 auto-ubiquitination and activation, promoting its interaction with and ubiquitination of TAK1 that contributes to development of cardiac hypertrophy.

Abstract Although pathological cardiac hypertrophy represents a leading cause of morbidity and mortality worldwide, our understanding of the molecular mechanisms underlying this disease is still poor. Here, we demonstrate that suppressor of IKKɛ (SIKE), a negative regulator of the interferon pathway, attenuates pathological cardiac hypertrophy in rodents and non-human primates in a TANK-binding kinase 1 (TBK1)/AKT-dependent manner. Sike-deficient mice develop cardiac hypertrophy and heart failure, whereas Sike-overexpressing transgenic (Sike-TG) mice are protected from hypertrophic stimuli. Mechanistically, SIKE directly interacts with TBK1 to inhibit the TBK1-AKT signalling pathway, thereby achieving its anti-hypertrophic action. The suppression of cardiac remodelling by SIKE is further validated in rats and monkeys. Collectively, these findings identify SIKE as a negative regulator of cardiac remodelling in multiple animal species due to its inhibitory regulation of the TBK1/AKT axis, suggesting that SIKE may represent a therapeutic target for the treatment of cardiac hypertrophy and heart failure.

The effects of α-linolenic acid (ALA)-rich flaxseed oil (FDO) against ethanol-induced liver injury and the probable molecular mechanisms in a mouse model of chronic-plus-single-binge ethanol feeding were evaluated. Mice were fed Lieber-DeCarli ethanol or control liquid diets with corn oil (CNO) or flaxseed oil for 10 days. On day 11, mice are gavaged with a single dose of ethanol or maltose dextrin. Ethanol exposure with CNO caused severe liver injury, inflammation and oxidative stress in liver, which were remarkably ameliorated by FDO. FDO supplementation decreased the elevation of plasma endotoxin level, which might be attributed to ameliorating ethanol-induced intestinal barrier dysfunction via upregulating the expressions of tight junction proteins. Additionally, FDO supplementation suppressed endotoxin-triggered inflammation via blocking TLR4/MyD88/NF-κB cascades in liver. These findings suggest that ALA-rich flaxseed oil may have potential to be developed as an effective agent for ethanol-induced liver injury.

TRAF family proteins regulate immune signalling cascades. Here, the authors show that TRAF3 is upregulated in the liver in non-alcoholic fatty liver disease, promoting insulin resistance, inflammation and hepatic steatosis via its interaction with the kinase TAK1.

Effects of saponins from leaves of Panax notoginseng (LPNS) against alcoholic liver injury were evaluated, and their probable molecular mechanisms were further elucidated in a mouse model of chronic-plus-single-binge ethanol feeding. Alcohol exposure dramatically increased plasma levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), triacylglycerol (TG) and endotoxin; these elevations were attenuated by treatment with LPNS at a dose of 100 or 300 mg/kg. LPNS was also found to suppress thiobarbituric acid reactive substances (TBARS) production, enhance glutathione (GSH) level and superoxide dismutase (SOD) activity in liver. The protective of LPNS against oxidative stress was associated with down-regulation of hepatic cytochrome P450 2E1 (CYP2E1), and upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and haem oxygenase-1 (HO-1). Additionally, LPNS ameliorated gut leakiness via upregulating the expressions of tight junction proteins, and suppressed endotoxin-mediated inflammation via down-regulating toll-like receptor-4 (TLR-4), CD14 and p-NF-κB p65. These results demonstrate that treatment with LPNS effectively protects against alcoholic liver injury through reducing ethanol-induced oxidative stress and ameliorating gut-derived endotoxin-mediated inflammation.

Hepatic ischemia/reperfusion (I/R), characterized by severe inflammation and cell death, causes significant liver damage, and there are no effective approaches to prevent this pathological condition. We evaluated the potentially protective functions of ginsenoside Rg1 in hepatic I/R injury and the underlying mechanisms. A mouse hepatic I/R model was established by 60 min of induced ischemia followed by 0, 6, 12 or 24 h of reperfusion. Ginsenoside Rg1 (20 mg/kg/day) significantly promoted hepatic function and suppressed liver necrosis and inflammatory responses. Mechanistically, the JNK/MAPK signaling was dramatically diminished by ginsenoside Rg1. Furthermore, we unexpectedly found that only the cytotoxicity induced by inflammation, rather than oxidative stress, was significantly inhibited by ginsenoside Rg1 in vitro, and this inhibition was almost completely abolished by treatment with a specific JNK activator, anisomycin. Thus, ginsenoside Rg1 exerts protective effects against hepatic I/R in a JNK signaling-dependent manner.

BackgroundDickkopf‐3 (DKK3) is a negative regulator of the Wnt/β‐catenin signaling pathway, which is involved in inflammation. However, little is known about the relationship between DKK3 expression and the progression of atherosclerosis. The aim of the present study was to define the role of DKK3 and its potential mechanism in the development of atherosclerosis. Methods and ResultsImmunofluorescence analysis showed that DKK3 was strongly expressed in macrophages of atherosclerotic plaques from patients with coronary heart disease and in hyperlipidemic mice. The expression level was significantly increased in atherogenesis. DKK3−/−ApoE−/− mice exhibited a significant decrease in atherosclerotic lesions in the entire aorta, aortic sinus, and brachiocephalic arteries. Transplantation of bone marrow from DKK3−/−ApoE−/− mice into lethally irradiated ApoE−/− recipients resulted in a reduction of atherosclerotic lesions, compared with the lesions in recipients transplanted with ApoE−/− donor cells, suggesting that the effect of DKK3 deficiency was largely mediated by bone marrow–derived cells. A reduction in the necrotic core size, accompanied by increased collagen content and smooth muscle cells and decreased accumulation of macrophages and lipids, contributed to the stability of plaques in DKK3−/−ApoE−/− mice. Furthermore, multiple proinflammatory cytokines exhibited marked decreases in DKK3−/−ApoE−/− mice. Finally, we observed that DKK3 ablation increased β‐catenin expression in the nuclei of macrophages both in vivo and in vitro. ConclusionsDKK3 expression in macrophages is involved in the pathogenesis of atherosclerosis through modulation of inflammation and inactivation of the Wnt/β‐catenin pathway.

Multi-origin Chinese herbal medicines, with herbs originating from more than one species of plants, is a common phenomenon but an important issue in Traditional Chinese Medicines (TCMs). In the present study, a gas chromatography-mass spectrometry (GC-MS)—based fatty acid profiling approach to rapidly discriminate multi-origin Chinese medicines in terms of species and medicinal parts was proposed and validated using tuberous roots (Curcumae Radix) and rhizomes (Curcumae Rhizoma and Curcumae Longae Rhizoma) derived from four Curcuma species (e.g., C. wenyujin, C. kwangsiensis, C. phaeocaulis and C. longa) as models. Both type and content of fatty acids varied among different species of either tuberous roots or rhizomes, indicating each species has its own fatty acid pattern. Orthogonal partial least squares discriminant analysis (OPLS-DA) and hierarchical clustering analysis (HCA) based on dataset of global fatty acid profiling showed that either tuberous roots or rhizomes samples could be clearly classified into four clusters according to their species. Furthermore, those tested samples could also be discriminated in terms of their medicinal parts (e.g., tuberous root and rhizome). Our findings suggest that the proposed GC-MS-based fatty acid profiling followed by multivariate statistical analysis provides a reliable platform to discriminate multi-origin Chinese herbal medicines according to species and medicinal parts, which will be helpful for ensuring their quality, safety and efficacy.