Multisystem health comorbidity networks of metabolic dysfunction-associated steatotic liver disease.

BACKGROUND: The global burden of metabolic dysfunction-associated steatotic liver disease (MASLD) is growing, but its subsequent health consequences have not been thoroughly examined. METHODS: A phenome-wide association study was conducted to map the associations of MASLD with 948 unique clinical outcomes among 361,021 Europeans in the UK Biobank. Disease trajectory and comorbidity analyses were applied to visualize the sequential patterns of multiple comorbidities related to the occurrence of MASLD. The associations jointly verified by observational and polygenic phenome-wide analyses were further replicated by two-sample Mendelian randomization analysis using data from the FinnGen study and international consortia. FINDINGS: The observational and polygenic phenome-wide association study revealed the associations of MASLD with 96 intrahepatic and extrahepatic diseases, including circulatory, metabolic, genitourinary, neurological, gastrointestinal, and hematologic diseases. Sequential patterns of MASLD-related extrahepatic comorbidities were primarily found in circulatory, metabolic, and inflammatory diseases. Mendelian randomization analyses supported the causal associations between MASLD and the risk of several intrahepatic disorders, metabolic diseases, cardio-cerebrovascular disease, and ascites but found no associations with neurological diseases. CONCLUSIONS: This study elucidated multisystem comorbidities and health consequences of MASLD, contributing to the development of combination interventions targeting distinct pathways for health promotion among patients with MASLD. FUNDING: X.L. was funded by the Natural Science Fund for Distinguished Young Scholars of Zhejiang Province (LR22H260001) and the National Nature Science Foundation of China (82204019) and Y.D. was funded by the Key Project of Traditional Chinese Medicine Science and Technology Plan of Zhejiang Province (GZY-ZJ-KJ-24077) and the National Natural Science Foundation of China (82001673 and 82272860).

Serum S-adenosylhomocysteine, rather than homocysteine, is associated with hepatocellular carcinoma survival: a prospective cohort study.

BACKGROUND: Emerging evidence suggested that S-adenosylhomocysteine (SAH) may be a better serum biomarker for cardiovascular disease than homocysteine (Hcy). However, the role of SAH in hepatocellular carcinoma (HCC) prognosis remains unclear. OBJECTIVES: We aimed to prospectively explore the relationships between serum SAH and related metabolites [Hcy, S-adenosylmethionine (SAM)] with HCC survival, and to evaluate the effect modifications by gene polymorphisms in one-carbon metabolism key enzymes. METHODS: We included 1080 newly diagnosed patients with HCC from the Guangdong Liver Cancer Cohort. Serum SAH, Hcy, and SAM were measured utilizing high-performance liquid chromatography-tandem mass spectrometry. Gene polymorphisms in one-carbon metabolism key enzymes were identified using kompetitive allele-specific polymerase chain reaction. Primary outcomes were liver cancer-specific survival (LCSS) and overall survival (OS). Hazard ratios (HRs) and 95% confidence intervals (CIs) were computed using multivariate Cox proportional hazards models. RESULTS: After a median follow-up of 3.6 y, 601 deaths occurred, with 552 (92%) attributed to HCC. Multivariable analysis revealed that patients in the highest quartile of serum SAH concentrations were significantly associated with worse survival compared with those in the lowest quartile, with HRs of 1.58 (95% CI: 1.19, 2.10; P-trend = 0.002) for LCSS and 1.54 (95% CI: 1.18, 2.02; P-trend = 0.001) for OS. There were no significant interactions between serum SAH concentrations and genetic variants of one-carbon metabolism key enzymes. No significant associations were found between serum Hcy, SAM concentrations, and SAM/SAH ratio with LCSS or OS. CONCLUSIONS: Higher serum SAH concentrations, rather than Hcy, were independently associated with worse survival in patients with HCC, regardless of the genetic variants of one-carbon metabolism key enzymes. These findings suggest that SAH may be a novel metabolism-related prognostic biomarker for HCC.

Correlation between serum trimethylamine-N-oxide and body fat distribution in middle-aged and older adults: a prospective cohort study.

BACKGROUND: Trimethylamine-N-oxide (TMAO) is linked with obesity, while limited evidence on its relationship with body fat distribution. Herein, we investigated the associations between serum TMAO and longitudinal change of fat distribution in this prospective cohort study. METHODS: Data of 1964 participants (40-75y old) from Guangzhou Nutrition and Health Study (GNHS) during 2008-2014 was analyzed. Serum TMAO concentration was quantified by HPLC-MS/MS at baseline. The body composition was assessed by dual-energy X-ray absorptiometry at each 3-y follow-up. Fat distribution parameters were fat-to-lean mass ratio (FLR) and trunk-to-leg fat ratio (TLR). Fat distribution changes were derived from the coefficient of linear regression between their parameters and follow-up duration. RESULTS: After an average of 6.2-y follow-up, analysis of covariance (ANCOVA) and linear regression displayed women with higher serum TMAO level had greater increments in trunk FLR (mean ± SD: 1.47 ± 4.39, P-trend = 0.006) and TLR (mean ± SD: 0.06 ± 0.24, P-trend = 0.011). Meanwhile, for women in the highest TMAO tertile, linear mixed-effects model (LMEM) analysis demonstrated the annual estimated increments (95% CI) were 0.03 (95% CI: 0.003 - 0.06, P = 0.032) in trunk FLR and 1.28 (95% CI: -0.17 - 2.73, P = 0.083) in TLR, respectively. In men, there were no similar significant observations. Sensitivity analysis yielded consistent results. CONCLUSION: Serum TMAO displayed a more profound correlation with increment of FLR and TLR in middle-aged and older community-dwelling women in current study. More and further studies are still warranted in the future. TRIAL REGISTRATION: NCT03179657.

Vitamin D receptor gene polymorphisms, bioavailable 25-hydroxyvitamin D, and hepatocellular carcinoma survival.

BACKGROUND: Little is known about the role of vitamin D receptor polymorphisms and their interaction with vitamin D status in hepatocellular carcinoma (HCC) prognosis. METHODS: We evaluated the association of TaqI, BsmI, Cdx-2, and ApaI polymorphisms, individually and in combination, with liver cancer-specific (LCSS) and overall survival (OS) among 967 patients with newly diagnosed HCC. Subsequently, we examined whether these polymorphisms modified the association between serum bioavailable 25-hydroxyvitamin D (25OHD) concentrations and survival. Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: During a median follow-up of 1017 days, 393 deaths occurred, with 360 attributed to HCC. Having TaqI G allele (HRper allele = 1.30, 95% CI = 1.08 to 1.57) or BsmI T allele (HRper allele = 1.41, 95% CI = 1.01 to 1.99) was associated with worse LCSS. Carrying increasing numbers of protective alleles was associated with superior LCSS (HR6-8 vs 0-3 = 0.52, 95% CI = 0.34 to 0.80). The inverse association of bioavailable 25OHD with LCSS was only significant in patients with TaqI AA (HRQuartile 4 vs Quartile 1 = 0.63, 95% CI = 0.44 to 0.92), BsmI CC (HRQuartile 4 vs Quartile 1 = 0.62, 95% CI = 0.44 to 0.88), and 6 to 8 protective alleles (HRQuartile 4 vs Quartile 1 = 0.45, 95% CI = 0.23 to 0.87). Similar associations were observed for OS. CONCLUSIONS: Patients carrying wild-type TaqI, BsmI, or more protective alleles had improved survival and might benefit from optimizing bioavailable 25OHD status.

Choline suppresses hepatocellular carcinoma progression by attenuating AMPK/mTOR-mediated autophagy via choline transporter SLC5A7 activation.

Background: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-associated death. Emerging evidence suggests that autophagy plays a critical role in HCC tumorigenesis, metastasis, and prognosis. Choline is an essential nutrient related to prolonged survival and reduced risk of HCC. However, it remains unclear whether this phenomenon is mediated by autophagy. Methods: Two HCC cell lines (HUH-7 and Hep3B) were used in the present study. Cell growth was evaluated by cell counting kit 8 (CCK-8), colony formation, and in vivo mouse xenografts assays. Cell motility was calculated by wound healing and transwell assays. Autophagosomes were measured by transmission electron microscope (TEM), and autophagy flux was detected by mRFP-GFP-labeled LC3 protein. The mRNA level of genes was measured by quantitative real-time polymerase chain reaction (qRT-PCR). The protein levels were detected by Western blotting (WB). Results: We found that choline inhibited the proliferation, migration, and invasion of HCC cells by downregulating autophagy in vitro and in vivo. Upregulated expression of the solute carrier family 5 member 7 (SLC5A7), a specific choline transporter, correlated with better HCC prognosis. We further discovered that choline could promote SLC5A7 expression, upregulate cytoplasm p53 expression to impair the AMPK/mTOR pathway, and attenuate autophagy. Finally, we found that choline acted synergistically with sorafenib to attenuate HCC development in vitro and in vivo. Conclusions: Our findings provide novel insights into choline-mediated autophagy in HCC, providing the foothold for its future application in HCC treatment.

Alcohol and colorectal cancer risk, subclassified by mutational signatures of DNA mismatch repair deficiency.

BACKGROUND: We examined whether the association between alcohol consumption and colorectal cancer (CRC) incidence was stronger for tumors with higher contributions of defective mismatch repair (dMMR)-related tumor mutational signatures. METHODS: We used data from 227 916 men and women who participated in the Nurses' Health Study (1980-2016), the Nurses' Health Study II (1991-2017), and the Health Professionals Follow-Up Study (1986-2016). Dietary data were collected every 4 years through validated food frequency questionnaires. Relative contributions of 2 defective mismatch repair-related tumor mutational signatures with single-based substitutions (c-dMMRa/SBS15 and c-dMMRb/SBS26) were quantified using whole-exome sequencing data in a subset of incident CRC patients. Duplication-method Cox proportional hazards regression models were used to assess the association between alcohol consumption and the risk of CRC subtypes according to different contributions of the tumor mutational signatures. All statistical tests were 2-sided. RESULTS: We documented 825 incident CRC patients with available tumor mutational signature data over 26 to 36 years of follow-up. The association between alcohol consumption and CRC incidence was stronger for tumors with higher contributions of c-dMMRb/SBS26 (Ptrend = .02 for heterogeneity) compared with tumors with lower contributions of this tumor mutational signature. Compared with nondrinkers, drinkers who imbibed 15 g/d or more of alcohol had a high risk of c-dMMRb/SBS26-high CRC (multivariable-adjusted hazard ratio = 2.43, 95% confidence interval = 1.55 to 3.82) but not c-dMMRb/SBS26-low CRC (multivariable-adjusted hazard ratio = 0.86, 95% confidence interval = 0.57 to 1.28) or c-dMMRb/SBS26-moderate CRC (multivariable-adjusted hazard ratio = 1.14, 95% confidence interval = 0.76 to 1.71). No significant differential associations were observed for c-dMMRa/SBS15 (Ptrend = .41 for heterogeneity). CONCLUSIONS: High alcohol consumption was associated with an increased incidence of CRC containing higher contributions of c-dMMRb/SBS26, suggesting that alcohol consumption may be involved in colorectal carcinogenesis through the DNA mismatch repair pathway.

The emerging therapies are reshaping the first-line treatment for advanced hepatocellular carcinoma: a systematic review and network meta-analysis.

Background: Given the superior performance of various therapies over sorafenib in advanced hepatocellular carcinoma (HCC) and the absence of direct comparisons, it is crucial to explore the efficacy of these treatments in phase III randomized clinical trials. Objectives: The goal is to identify which patients are most likely to benefit significantly from these emerging therapies, contributing to more personalized and informed clinical decision-making. Design: Systematic review and network meta-analysis. Data sources and methods: PubMed, Embase, ClinicalTrials.gov, and international conference databases have been searched from 1 January 2010 to 1 December 2023. Results: After screening, 17 phase III trials encompassing 18 treatments were included. In the whole-population network meta-analysis, the newly first-line tremelimumab plus durvalumab (Tre + Du) was found to be comparable with atezolizumab plus bevacizumab (Atezo + Beva) in providing the best overall survival (OS) benefit [hazard ratio (HR) 1.35, 95% confidence interval (CI): 0.93-1.92]. Concerning OS benefits, sintilimab plus bevacizumab biosimilar (Sint + Beva), camrelizumab plus rivoceranib (Camre + Rivo), and lenvatinib plus pembrolizumab (Lenva + Pemb) appear to exhibit similar effects to Tre + Du and Atezo + Beva. In the context of progression-free survival, Atezo + Beva seemed to outperform Tre + Du (HR: 0.66 CI: 0.49-0.87), while the effects are comparable to Sint + Beva, Camre + Rivo, and Lenva + Pemb. Upon comparison between Asia-Pacific and non-Asia-Pacific cohorts, as well as between hepatitis B virus (HBV)-infected and non-HBV-infected populations, immune checkpoint inhibitor (ICI)-based treatments seemed to exhibit heightened efficacy in the Asia-Pacific group and among individuals with HBV infection. However, combined ICI-based therapies did not show more effectiveness than molecular-targeted drugs in patients without macrovascular invasion and/or extrahepatic spread. As for grades 3-5 adverse events, combined therapies showed comparable safety to sorafenib and lenvatinib. Conclusion: Compared with sorafenib and lenvatinib, combination therapies based on ICIs significantly improved the prognosis of advanced HCC and demonstrated similar safety. At the same time, the optimal treatment approach should be tailored to individual patient characteristics, such as etiology, tumor staging, and serum alpha-fetoprotein levels. With lower incidence rates of treatment-related adverse events and non-inferior efficacy compared to sorafenib, ICI monotherapies should be prioritized as a first-line treatment approach for patients who are not suitable candidates for ICI-combined therapies. Trial registration: PROSPERO, CRD42022288172.

Lay summary/Key points The efficiency of various systemic therapies in advanced HCC patients with specific characteristics remains to be explored. This study revealed that the efficacy of ICI combined therapies is influenced by factors such as tumor staging, etiology, patient demographics, and more. Additionally, ICI monotherapies should be prioritized as a first-line treatment approach for patients who are not suitable candidates for ICI combined therapies. Complementing to recent guidelines, this study indicated that several critical factors needed to be took into consideration for patients with advanced HCC.

Vitamin D and human health: evidence from Mendelian randomization studies.

We summarized the current evidence on vitamin D and major health outcomes from Mendelian randomization (MR) studies. PubMed and Embase were searched for original MR studies on vitamin D in relation to any health outcome from inception to September 1, 2022. Nonlinear MR findings were excluded due to concerns about the validity of the statistical methods used. A meta-analysis was preformed to synthesize study-specific estimates after excluding overlapping samples, where applicable. The methodological quality of the included studies was evaluated according to the STROBE-MR checklist. A total of 133 MR publications were eligible for inclusion in the analyses. The causal association between vitamin D status and 275 individual outcomes was examined. Linear MR analyses showed genetically high 25-hydroxyvitamin D (25(OH)D) concentrations were associated with reduced risk of multiple sclerosis incidence and relapse, non-infectious uveitis and scleritis, psoriasis, femur fracture, leg fracture, amyotrophic lateral sclerosis, anorexia nervosa, delirium, heart failure, ovarian cancer, non-alcoholic fatty liver disease, dyslipidemia, and bacterial pneumonia, but increased risk of Behçet's disease, Graves' disease, kidney stone disease, fracture of radium/ulna, basal cell carcinoma, and overall cataracts. Stratified analyses showed that the inverse association between genetically predisposed 25(OH)D concentrations and multiple sclerosis risk was significant and consistent regardless of the genetic instruments GIs selected. However, the associations with most of the other outcomes were only pronounced when using genetic variants not limited to those in the vitamin D pathway as GIs. The methodological quality of the included MR studies was substantially heterogeneous. Current evidence from linear MR studies strongly supports a causal role of vitamin D in the development of multiple sclerosis. Suggestive support for a number of other health conditions could help prioritize conditions where vitamin D may be beneficial or harmful.

Dietary intake and serum levels of copper and zinc and risk of hepatocellular carcinoma: A matched case-control study.

BACKGROUND: Copper and zinc are involved in the development of multiple malignancies; yet, epidemiological evidence on hepatocellular carcinoma (HCC) is limited. This study aimed to investigate the association between dietary intake and serum levels of copper and zinc with the risk of HCC. METHODS: A total of 434 case-control pairs matched for sex and age (±1 year) were included in this study. Cases with newly diagnosed HCC were from the Guangdong Liver Cancer Cohort (GLCC) study, and healthy controls were from the Guangzhou Nutrition and Health Study (GNHS). A semi-quantitative 79-item food frequency questionnaire (FFQ) was used to assess habitual dietary intakes of copper and zinc. Serum levels of copper and zinc were measured by using inductively coupled plasma mass spectrometry. The copper (Cu)/ zinc (Zn) ratio was computed by dividing copper levels by zinc levels. Conditional logistic regression models were performed to calculate the odds ratio (OR) and 95% confidence intervals (CI) for per 1 standard deviation increase (per-SD increase) in copper and zinc levels. RESULTS: Higher dietary intake (OR per-SD increase = 0.65, 95% CI: 0.44, 0.96, Ptrend = 0.029) and serum levels of zinc (OR per-SD increase = 0.11, 95% CI: 0.04, 0.30, Ptrend <0.001) were both associated with a lower risk of HCC. Subgroup analyses showed that the inverse association was only pronounced in men but not in women ( Pinteraction = 0.041 for dietary zinc intake and 0.010 for serum zinc levels). Serum copper levels (OR per-SD increase = 2.05, 95% CI: 1.39, 3.03, Ptrend = 0.020) and serum Cu/Zn ratio (OR per-SD increase = 6.53, 95% CI: 2.52, 16.92, Ptrend <0.001) were positively associated with HCC risk, while dietary copper intake and dietary Cu/Zn ratio were not associated with HCC risk. CONCLUSION: Zinc may be a protective factor for HCC, especially among men, but the effects of copper on HCC risk are not clear.

Pan-cancer analysis of the prognostic significance of ACKR2 expression and the related genetic/epigenetic dysregulations.

OBJECTIVE: ACKR2 is a scavenger for most inflammation-related CC chemokines. This study aimed to assess the pan-cancer prognostic significance of ACKR2 and the genetic and epigenetic mechanisms underlying its dysregulation. METHODS: Pan-cancer data from The Cancer Genome Atlas (TCGA), Therapeutically Applicable Research to Generate Effective Treatments (TARGET) and The Genotype-Tissue Expression (GTEx) were integrated and analyzed. RESULTS: ACKR2 is consistently associated with favorable progression-free interval (PFI) and overall survival (OS) in TCGA-uveal melanoma (UVM) and TCGA-liver hepatocellular carcinoma (LIHC). ACKR2 is negatively correlated with the expression of CCL1, CCL4, CCL5, CXCL8, CCL17, and CCL20 in TCGA-UVM and TCGA-LIHC. The group with gene copy gain had significantly higher ACKR2 expression than those with loss. The lower ACKR2 expression groups were associated with a significantly higher ratio of BAP1 mutations. In addition, ACKR2 was negatively corrected with DNMT1 expression but was positively corrected with ZC3H13, an m6A writer gene and NSUN3, an RNA m5C writer gene. CONCLUSIONS: ACKR2 expression was associated with favorable prognosis in patients with uveal melanoma and hepatocellular carcinoma. ACKR2 dysregulation might be an accumulated result of gene copy number alterations, transcriptional disruption, and RNA modifications.

Dietary protein intake and changes in muscle mass measurements in community-dwelling middle-aged and older adults: A prospective cohort study.

BACKGROUND & AIMS: Increasing dietary protein intake can be an efficient strategy to prevent sarcopenia. Nevertheless, due to the discrepancy in the population and their dietary pattern, evidence suggested the effects of dietary protein amount or source on sarcopenia prevention varies. This prospective cohort study investigated the correlation between dietary protein intakes or sources and changes in muscle mass measurements. Additionally, the study explored the link between dietary protein and the prevalence of sarcopenia. METHODS: Participants aged 40 to 75 were from Guangzhou Nutrition and Health Study (GNHS) 2011-2013 and returned in 2014-2017. Validated 79-item food frequency questionnaires were applied to calculate the amount of total, animal, and plant protein intakes and animal-to-plant protein ratio (APR). The body composition was examined by dual-energy x-ray absorptiometry (DXA) to calculate the appendicular lean mass (ALM) and its index (ASMI). Sarcopenia was diagnosed based on the 2019 Asia Working Group of Sarcopenia's criteria. ANCOVA was utilized to compare the differences of Δ ALM and Δ ASMI across the quartiles of the dietary protein, and linear regression was employed to examine dose-response associations. Multilinear mixed-effect models were employed to evaluate whether protein intake relates to annual changes in ALM and ASMI. Multivariable logistic regressions were performed to analyze the associations between dietary protein and sarcopenia. RESULTS: In total, 2709 participants during the 3.2-year follow-up period were considered eligible for analysis. Higher dietary protein intakes (total, animal, plant) in both sexes could preserve more ALM and ASMI in a dose-response manner (all P-trend < 0.05). The annual estimated preservations of ASMI were greater in the highest dietary protein intakes (total, animal, plant) quartile than the lowest (0.05-0.13 kg/m2/y, all P < 0.05). In women, the risk of sarcopenia was reduced by 35%-50 % in the highest protein intake (total, animal, plant) quartile than the lowest. The APR did not display any significant associations. CONCLUSIONS: Higher dietary protein intake, regardless of animal or plant sources, is associated with less muscle loss and a lower prevalence of sarcopenia in middle-aged and older Chinese, particularly women. GOV IDENTIFIER: NCT03179657.

Dietary intakes of total, nonheme, and heme iron and hypertension risk: a longitudinal study from the China Health and Nutrition Survey.

AIMS: Evidence is limited regarding the long-term impact of dietary iron intake on the development of hypertension. We investigated the association between dietary intakes of total, nonheme, and heme iron and hypertension risk in a large prospective cohort of Chinese populations over 26 years. METHODS: A total of 16,122 adults (7810 men and 8312 women) who participated in the China Health and Nutrition Survey (1989-2015) were included. Dietary intake was repeatedly assessed by combining three consecutive 24­h individual dietary recalls with household food inventory weighing at each survey round. Incident hypertension was defined as systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg, diagnosis by physicians, or current use of anti-hypertensive drugs. RESULTS: During a median follow­up of 11.1 years, 2863 men and 2532 women developed hypertension. After adjustment for non-dietary and dietary factors, a lower risk of hypertension was found in men and women with higher intakes of total, nonheme, or heme iron. The adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for the highest vs. lowest quartiles were 0.76 (0.67, 0.87) in men and 0.85 (0.74, 0.97) in women for total iron intake, 0.77 (0.67, 0.87) in men and 0.85 (0.74, 0.98) in women for nonheme iron intake, and 0.73 (0.62, 0.87) in men and 0.69 (0.58, 0.82) in women for heme iron intake. Dose-response analyses further revealed a U-shaped association of total and nonheme iron intake and an L-shaped association of heme iron intake with hypertension risk in both men and women (all P for non-linearity < 0.001). CONCLUSIONS: Our findings emphasize the importance of maintaining moderate iron intake in the prevention of hypertension. Both insufficient and excess intake of iron might increase the risk of hypertension.

Long-term dietary iron intake and risk of non-fatal cardiovascular diseases in the China Health and Nutrition Survey.

AIMS: We aimed to investigate the association of long-term dietary iron intake with the risk of non-fatal cardiovascular diseases (CVDs), myocardial infarction (MI), and stroke in Chinese populations with predominantly plant-based diets by sex. METHODS AND RESULTS: A total of 17 107 participants (8569 men and 8538 women) aged 18-80 years in the China Health and Nutrition Survey (CHNS) 1989-2015 were included. Dietary intake was assessed repeatedly by three consecutive 24-h dietary recalls. Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). During a median follow-up of 11.1 years, the adjusted HRs (95% CIs) for non-fatal CVDs risk across quintiles of total iron intake in men were 1.00, 0.65 (0.46-0.93), 0.54 (0.37-0.78), 0.66 (0.46-0.94), 0.69 (0.47-1.03), but no significant association in women. Similar associations were found for stroke risk, but not for MI risk. The dose-response curves for the association of total iron and non-heme iron intake with the risk of non-fatal CVDs and stroke followed a reverse J-shape only in men and similar reverse J-shaped association of heme iron intake with non-fatal CVDs and stroke risk in both men and women (P-non-linearity <0.05). CONCLUSION: Moderate dietary iron intake may protect against non-fatal CVDs and stroke, especially in Chinese men consuming plant-based diets. Both quantity and quality of dietary iron intake should be considered in the prevention of non-fatal CVDs due to differences in dietary patterns among diverse populations.

This prospective cohort study, using data from 8569 men and 8538 women who participated in the China Health and Nutrition Survey (CHNS) 1989­2015, suggests that moderate intake of dietary iron may protect against non-fatal cardiovascular diseases (CVDs) and stroke, especially in men consuming predominantly plant-based diets. Key findings In men, the association of dietary intake of total iron, heme iron, and non-heme iron with the risk of non-fatal CVDs and stroke followed a reverse J-shape, with the lowest risk at ∼26 mg/d of total iron intake, ∼2 mg/d of heme iron intake, and ∼24 mg/d of non-heme iron intake. In women, a J-shaped association between dietary heme iron intake and the risk of non-fatal CVDs and stroke were observed, with the lowest risk at ∼1.8 mg/d of heme iron intake; while higher dietary intakes of total iron and non-heme iron tended to be associated with a lower risk of non-fatal stroke.

Cheese consumption and multiple health outcomes: an umbrella review and updated meta-analysis of prospective studies.

This umbrella review aims to provide a systematic and comprehensive overview of current evidence from prospective studies on the diverse health effects of cheese consumption. We searched PubMed, Embase, and Cochrane Library to identify meta-analyses/pooled analyses of prospective studies examining the association between cheese consumption and major health outcomes from inception to August 31, 2022. We reanalyzed and updated previous meta-analyses and performed de novo meta-analyses with recently published prospective studies, where appropriate. We calculated the summary effect size, 95% prediction confidence intervals, between-study heterogeneity, small-study effects, and excess significance bias for each health outcome. We identified 54 eligible articles of meta-analyses/pooled analyses. After adding newly published original articles, we performed 35 updated meta-analyses and 4 de novo meta-analyses. Together with 8 previous meta-analyses, we finally included 47 unique health outcomes. Cheese consumption was inversely associated with all-cause mortality (highest compared with lowest category: RR = 0.95; 95% CI: 0.92, 0.99), cardiovascular mortality (RR = 0.93; 95% CI: 0.88, 0.99), incident cardiovascular disease (CVD) (RR = 0.92; 95% CI: 0.89, 0.96), coronary heart disease (CHD) (RR = 0.92; 95% CI: 0.86, 0.98), stroke (RR = 0.93; 95% CI: 0.89, 0.98), estrogen receptor-negative (ER-) breast cancer (RR = 0.89; 95% CI: 0.82, 0.97), type 2 diabetes (RR = 0.93; 95% CI: 0.88, 0.98), total fracture (RR = 0.90; 95% CI: 0.86, 0.95), and dementia (RR = 0.81; 95% CI: 0.66, 0.99). Null associations were found for other outcomes. According to the NutriGrade scoring system, moderate quality of evidence was observed for inverse associations of cheese consumption with all-cause and cardiovascular mortality, incident CVD, CHD, and stroke, and for null associations with cancer mortality, incident hypertension, and prostate cancer. Our findings suggest that cheese consumption has neutral to moderate benefits for human health.

Associations of serum betaine with blood pressure and hypertension incidence in middle-aged and older adults: a prospective cohort study.

The impact of betaine on the development of hypertension remains unclear, and prospective data are sparse. We aimed to investigate the association of serum betaine with repeated measurements of blood pressure (BP) and hypertension incidence. This study was based on the Guangzhou Nutrition and Health Study (GNHS), a community-based prospective cohort study in China. Baseline serum betaine was measured by high-performance liquid chromatography-tandem mass spectrometry. BP and hypertension status were assessed at the baseline and 3-year intervals. Linear mixed-effects models (LMEMs) were used to analyze the longitudinal association of serum betaine with BP (n = 1996). Cox proportional hazard models were used to evaluate the association of baseline serum betaine with hypertension incidence (n = 1339). LMEMs showed that compared with the lowest quartile group, the higher quartile groups had lower systolic blood pressure (SBP), diastolic blood pressure (DBP) and pulse pressure (all P-trend < 0.05). Each standard deviation (16.3 µmol L-1) increase in serum betaine was associated with -0.92 (-1.52, -0.32) mmHg of SBP, -0.49 (-0.84, -0.13) mmHg of DBP and -0.43 (-0.81, -0.05) mmHg of pulse pressure. During a median follow-up of 9.2 years, 371 incident cases of hypertension were identified. Serum betaine was associated with lower risk of hypertension only when comparing the third quartile level with the lowest quartile (HR, 0.74; 95% CI, 0.56-0.99). A nonlinear association between serum betaine and the risk of hypertension was found (P-nonlinear = 0.040). A higher serum betaine level was associated with lower risk of hypertension below 54.5 µmol L-1. Our findings suggested that higher serum betaine was associated with favorable blood pressure in middle-aged and older Chinese adults. Higher concentrations of serum betaine were related to lower hypertension risk in people with relatively low serum betaine concentrations.

A cascade-responsive nanoplatform with tumor cell-specific drug burst release for chemotherapy.

Most of the nanomedicines can reduce the side effects of anti-tumor chemical drugs but do not have good enough therapeutic efficacy, largely due to the sustained drug release profile. It might be a promising alternative strategy to develop a cascade-responsive nanoplatform against tumor with the burst release of chemotherapeutics based on the highly efficient tumor cell targeting delivery. In this work, we constructed innovative nanoparticles (PMP/WPH-NPs) consisting of two functional polymers. PMP contained the MMP-2 enzyme sensitive linker and disulfide bond, which could respond to the tumor-overexpressing enzyme MMP-2 and high-level glutathione. While WPH promoted tumor penetration and acid-responsive drug release by modifying cellular penetrating peptides and polymerizing L-histidine. PMP/WPH-NPs exhibited outstanding features including longer blood circulation time, promoted tumor-specific accumulation, enhanced tumor penetration and efficient escape from lysosomes. Subsequently, the model drug paclitaxel (PTX), widely used in the tumor chemotherapy, was encapsulated into PMP/WPH-NPs via an emulsion solvent evaporation method. Within a short period of time, PTX-PMP/WPH-NP in simulated tumor cellular microenvironment could release 8 times more PTX than that in the physiological environment, demonstrating a good potential in tumor cell-specific burst drug release. In addition, PTX-PMP/WPH-NPs exhibited stronger anti-tumor activity than PTX in vitro and in vivo, which also had good biocompatibility according to the hemolysis assay and H&E staining. In summary, our work has succeeded in designing an original polymeric nanoplatform for programmed burst drug release based on the tailored tumor targeting delivery system. This new approach would facilitate the clinical translation of more anti-tumor nanomedicines. STATEMENT OF SIGNIFICANCE: Biomaterials responsive to the tumor-specific stimulus has conventionally used in the targeted-delivery of anti-tumor drugs. However, the levels of common stimulus are not uniformly distributed and not high enough to effectively trigger drug release. In an effort to achieve a better specific drug release and promote the chemotherapeutic efficacy, we constructed a cascade responsive nanoplatform with tumor cell-specific drug burst release profile. The tailored biomaterial could overcome the bio-barriers in vivo and succeeded in the programmed burst drug release based on the tumor cell-specific delivery of chemotherapeutics.

P T symmetry in a superconducting hybrid quantum system with longitudinal coupling.

We propose a scheme consisting of coupled nanomechanical cantilever resonators and superconducting flux qubits to engineer a parity-time- (P T-) symmetric phononic system formed by active and passive modes. The effective gain (loss) of the phonon mode is achieved by the longitudinal coupling of the resonator and the fast dissipative superconducting qubit with a blue-sideband driving (red-sideband driving). A P T-symmetric to broken-P T-symmetric phase transition can be observed in both balanced gain-to-loss and unbalanced gain-to-loss cases. Applying a resonant weak probe field to the dissipative resonator, we find that (i) for balanced gain and loss, the acoustic signal absorption to amplification can be tuned by changing the coupling strength between resonators; (ii) for unbalanced gain and loss, both acoustically induced transparency and anomalous dispersion can be observed around Δ = 0, where the maximum group delay is also located at this point. Our work provides an experimentally feasible scheme to design P T-symmetric phononic systems and a powerful platform for controllable acoustic signal transmission in a hybrid quantum system.

Effects of low-dose B vitamins plus betaine supplementation on lowering homocysteine concentrations among Chinese adults with hyperhomocysteinemia: a randomized, double-blind, controlled preliminary clinical trial.

PURPOSE: To test the hypothesis that daily supplementation with low-dose B vitamins plus betaine could significantly reduce plasma homocysteine concentrations in Chinese adults with hyperhomocysteinemia and free from background mandatory folic acid fortification. METHODS: One hundred apparently healthy adults aged 18-65 years with hyperhomocysteinemia were recruited in South China from July 2019 to June 2021. They were randomly assigned to either the supplement group (daily supplementation: 400 µg folic acid, 8 mg vitamin B6, 6.4 µg vitamin B12 and 1 g betaine) or the placebo group for 12 weeks. Fasting venous blood was collected at baseline, week 4 and week 12 to determine the concentrations of homocysteine, folate, vitamin B12 and betaine. Generalized estimation equations were used for statistical analysis. RESULTS: Statistically significant increments in blood concentrations of folate, vitamin B12 and betaine after the intervention in the supplement group indicated good participant compliance. At baseline, there were no significant differences in plasma homocysteine concentration between the two groups (P = 0.265). After 12-week supplementation, compared with the placebo group, there was a significant reduction in plasma homocysteine concentrations in the supplement group (mean group difference - 3.87; covariate-adjusted P = 0.012; reduction rate 10.1%; covariate-adjusted P < 0.001). In the supplement group, the decreased concentration of plasma homocysteine was associated with increments of blood concentrations of both folate (ß = -1.680, P = 0.004) and betaine (ß = -1.421, P = 0.020) after 12 weeks of supplementation. CONCLUSIONS: Daily supplementation with low-dose B vitamins plus betaine for 12 weeks effectively decreased plasma homocysteine concentrations in Chinese adults with hyperhomocysteinemia. TRIAL REGISTRATION: This trial was registered at clinicaltrials.gov as NCT03720249 on October 25, 2018. Website: https://clinicaltrials.gov/ct2/show/NCT03720249 .

Effects and mechanisms of natural products on Alzheimer's disease.

Alzheimer's disease (AD) is the most common form of dementia in elderly people with a high incidence rate and complicated pathogenesis, and causes progressive cognitive deficit and memory impairment. Some natural products and bioactive compounds from natural sources show great potential in the prevention and treatment of AD, such as apple, blueberries, grapes, chili pepper, Monsonia angustifolia, cruciferous vegetables, Herba epimedii, Angelica tenuissima, Embelia ribes, sea cucumber, Cucumaria frondosa, green tea, Puer tea, Amanita caesarea and Inonotus obliquus, via reducing amyloid beta (Aß) deposition, decreasing Tau hyperphosphorylation, regulating cholinergic system, reducing oxidative stress, inhibiting apoptosis and ameliorating inflammation. This review mainly summarizes the effects of some natural products and their bioactive compounds on AD with the potential molecular mechanisms.