Impact of the ketogenic diet as a dietary approach on cardiovascular disease risk factors: a meta-analysis of randomized clinical trials.

BACKGROUND: Cardiovascular diseases (CVD) remain the leading cause of mortality globally, and the scarcity of scientific evidence regarding the impact of ketogenic diets on CVD risk factors necessitates urgent attention and redress. OBJECTIVES: This meta-analysis evaluates the impact of the ketogenic diet on CVD risk factors compared with control diets through randomized controlled trials (RCTs). METHODS: The study was registered in advance in the PROSPERO database (CRD42023491853). A systematic search was conducted across PubMed, Web of Science, EMBASE, and Cochrane Library to identify relevant RCTs. Fixed and random effects were employed to calculate the mean differences and 95% confidence intervals (CIs) for changes in CVD risk factors pre- and postketogenic diet intervention. RESULTS: A total of 27 RCTs with 1278 participants were analyzed. The ketogenic diet intervention presented increase in total cholesterol (mean differences: 0.36 mmol/L; 95% CI: 0.15, 0.57; I2: 85.1%), low-density lipoprotein cholesterol (mean differences: 0.35 mmol/L; 95% CI: 0.20, 0.50; I2: 73.9%) and high-density lipoprotein cholesterol (mean differences: 0.16 mmol/L; 95% CI: 0.09, 0.23; I2: 86.7%) concentrations. Reductions were observed in the triglyceride (mean differences: -0.20 mmol/L; 95% CI: -0.29, -0.11; I2: 72.2%), blood glucose (mean differences: -0.18 mmol/L; 95% CI: -0.33, -0.02; I2: 76.4%), blood insulin (mean differences: -8.32 pmol/L; 95% CI: -14.52, -2.12; I2: 81.5%), diastolic blood pressure (mean differences: -1.41 mmHg; 95% CI: -2.57, -0.26; I2: 49.1%), weight (mean differences: -2.59 kg; 95% CI: -3.90, -1.28; I2: 87.4%), and body mass index (mean differences: -1.59 kg/m2; 95% CI: -2.32, -0.86; I2: 84.5%) concentrations after implementing ketogenic diets. CONCLUSIONS: Although the ketogenic diet demonstrates benefits in terms of triglyceride, blood pressure, weight, and glycemic control, its impact on CVD risk factors, especially the elevated total cholesterol and low-density lipoprotein cholesterol concentrations, warrants a cautious approach.

MLXIPL associated with tumor-infiltrating CD8+ T cells is involved in poor prostate cancer prognosis.

Introduction: Within tumor microenvironment, the presence of preexisting antitumor CD8+ T Q7 cells have been shown to be associated with a favorable prognosis in most solid cancers. However, in the case of prostate cancer (PCa), they have been linked to a negative impact on prognosis. Methods: To gain a deeper understanding of the contribution of infiltrating CD8+ T cells to poor prognosis in PCa, the infiltration levelsof CD8+ T cells were estimated using the TCGA PRAD (The Cancer Genome Atlas Prostate Adenocarcinoma dataset) and MSKCC (Memorial Sloan Kettering Cancer Center) cohorts. Results: Bioinformatic analyses revealed that CD8+ T cells likely influence PCa prognosis through increased expression of immune checkpoint molecules and enhanced recruitment of regulatory T cells. The MLXIPL was identified as the gene expressed in response to CD8+ T cell infiltration and was found to be associated with PCa prognosis. The prognostic role of MLXIPL was examined in two cohorts: TCGA PRAD (p = 2.3E-02) and the MSKCC cohort (p = 1.6E-02). Subsequently, MLXIPL was confirmed to be associated with an unfavorable prognosis in PCa, as evidenced by an independent cohort study (hazard ratio [HR] = 2.57, 95% CI: 1.42- 4.65, p = 1.76E-03). Discussion: In summary, the findings suggested that MLXIPL related to tumor-infiltrating CD8+ T cells facilitated a poor prognosis in PCa.

HCMMD: systematic evaluation of metabolites in body fluids as liquid biopsy biomarker for human cancers.

Metabolomics is a rapidly expanding field in systems biology used to measure alterations of metabolites and identify metabolic biomarkers in response to disease processes. The discovery of metabolic biomarkers can improve early diagnosis, prognostic prediction, and therapeutic intervention for cancers. However, there are currently no databases that provide a comprehensive evaluation of the relationship between metabolites and cancer processes. In this review, we summarize reported metabolites in body fluids across pan-cancers and characterize their clinical applications in liquid biopsy. We conducted a search for metabolic biomarkers using the keywords ("metabolomics" OR "metabolite") AND "cancer" in PubMed. Of the 22,254 articles retrieved, 792 were deemed potentially relevant for further review. Ultimately, we included data from 573,300 samples and 17,083 metabolic biomarkers. We collected information on cancer types, sample size, the human metabolome database (HMDB) ID, metabolic pathway, area under the curve (AUC), sensitivity and specificity of metabolites, sample source, detection method, and clinical features were collected. Finally, we developed a user-friendly online database, the Human Cancer Metabolic Markers Database (HCMMD), which allows users to query, browse, and download metabolite information. In conclusion, HCMMD provides an important resource to assist researchers in reviewing metabolic biomarkers for diagnosis and progression of cancers.

Inhibiting G6PD by quercetin promotes degradation of EGFR T790M mutation.

EGFRT790M mutation causes resistance to the first-generation tyrosine kinase inhibitors (TKIs) in patients with non-small cell lung cancer (NSCLC). However, the therapeutic options for sensitizing first TKIs and delaying the emergence of EGFRT790M mutant are limited. In this study, we show that quercetin directly binds with glucose-6-phosphate dehydrogenase (G6PD) and inhibits its enzymatic activity through competitively abrogating NADP+ binding in the catalytic domain. This inhibition subsequently reduces intracellular NADPH levels, resulting in insufficient substrate for methionine reductase A (MsrA) to reduce M790 oxidization of EGFRT790M and inducing the degradation of EGFRT790M. Quercetin synergistically enhances the therapeutic effect of gefitinib on EGFRT790M-harboring NSCLCs and delays the acquisition of the EGFRT790M mutation. Notably, high levels of G6PD expression are correlated with poor prognosis and the emerging time of EGFRT790M mutation in patients with NSCLC. These findings highlight the potential implication of quercetin in overcoming EGFRT790M-driven TKI resistance by directly targeting G6PD.

Silver nanoparticles-decorated extracellular matrix graft: fabrication and tendon reconstruction performance.

BACKGROUND: The reconstruction of tendons with large defects requires grafts with high mechanical strength and is often hindered by complications such as infection and adhesion. Hence, grafts combining the advantages of mechanical resilience and antibacterial/antiadhesion activity are highly sought after. METHODS: The silver nanoparticles (GA-Ag NPs) synthesized from gallic acid and silver nitrate were attached to a decellularized extracellular matrix (Decellularized Tendon crosslinking GA-AgNPs, DT-Ag). We examined the histological structure, mechanical property, morphology, Zeta potential, cytotoxicity, antibacterial properties, antioxidant and anti-inflammatory properties, and ability of the DT-Ag to treat tendon defects in animals. RESULTS: Approximately 108.57 ± 0.94 µg GA-Ag NPs loaded per 50 mg DT, the cross-linked part of GA-Ag NPs was 65.47 ± 0.57%, which provided DT-Ag with long-lasting antibacterial activity. Meanwhile, GA endowed DT-Ag with good antioxidant and anti-inflammatory activities. Additionally, The DT-Ag facilitated M2 macrophage polarization, and suppressed fibrin deposition by hindering fibroblast adhesion. Mormore, the main advantages of DT-Ag, namely its long-lasting antibacterial activity (tested using Escherichia coli and Staphylococcus aureus as models) and the ability to prevent tissue adhesion were confirmed in vivo. CONCLUSION: The fabricated multifunctional tendon graft was highly hydrophilic, biocompatible, and mechanically resilient, and concluded to be well suited for dealing with the main complications of surgical tendon reconstruction and has bright application prospects.

The Interaction Between Measurement and Individual Difference in Ego Depletion: Task Type, Trait Self-Control and Action Orientation.

Previous research found that performing an initial self-control task impairs subsequent self-control performance, which is referred to as ego depletion. However, recent meta-analyses and replication studies have led to controversies over whether the ego depletion effect is as reliable as previously assumed. The present study aimed to shed more light on these controversies by combining depletion measurement task type and personality as moderators. Study 1 investigated trait self-control and action orientation's moderation role for depletion effects on stop-signal task (inhibitory control). Study 2 examined the trait self-control and action orientation's moderation role for depletion effects on a majority congruent Stroop task (goal maintenance). Results showed that trait self-control moderated the ego depletion effect on stop-signal reaction time (SSRT). High trait self-control people were less vulnerable to the ego depletion effect on the reactive inhibitory control task, whereas the moderating role of trait self-control for ego depletion was not found in the goal maintenance task. More particularly, high action-oriented people were less susceptible to the ego depletion effect on the goal maintenance task, but there was no moderation effect of action orientation for ego depletion in the stop-signal task. We discuss types of task for depletion measurement and individual differences in ego depletion, and we suggest possible avenues for future research.

Comparison of prognosis between coronary computed tomography angiography versus invasive coronary angiography for stable coronary artery disease: a systematic review and meta-analysis.

Background: The impact of using invasive coronary angiography (ICA) or coronary computed tomography angiography (CCTA) as an initial examination on the incidence of major adverse cardiovascular events (MACEs) in patients with stable coronary artery disease and the occurrence of major operation-related complications is uncertain. Objective: This study aimed to explore the effects of ICA vs. CCTA on MACEs, all-cause death, and major operation-related complications. Methods: A systematic search of electronic databases (PubMed and Embase) was conducted for randomized controlled trials and observational studies comparing MACEs between ICA and CCTA from January 2012 to May 2022. The primary outcome measure was analyzed using a random-effects model as a pooled odds ratio (OR). The main observations were MACEs, all-cause death, and major operation-related complications. Results: A total of six studies, comprising 26,548 patients, met the inclusion criteria (ICA n = 8,472; CCTA n = 18,076). There were statistically significant differences between ICA and CCTA for MACE [OR 1.37; 95% confidence interval (CI), 1.06-1.77; p = 0.02], all-cause death (OR 1.56; 95% CI, 1.38-1.78; p < 0.00001), and major operation-related complications (OR 2.10; 95% CI, 1.23-3.61; p = 0.007) among patients with stable coronary artery disease. Subgroup analysis demonstrated statistically significant results in the impact of ICA or CCTA on MACEs according to the length of follow-up. Compared to CCTA, ICA was related to a higher incidence of MACEs in the subgroup with a short follow-up (≤3 years) (OR 1.74; 95% CI, 1.54-1.96; p < 0.00001). Conclusions: Among patients with stable coronary artery disease, an initial examination with ICA was significantly associated with the risk of MACEs, all-cause death, and major procedure-related complications compared to CCTA in this meta-analysis.

The Role of Gynostemma pentaphyllum in Regulating Hyperlipidemia.

Developing effective and safe lipid-lowering drugs is highly urgent. This study aims to investigate the effectiveness and underlying mechanisms of Gynostemma pentaphyllum (GP) in the treatment of hyperlipidemia. First, a meta-analysis was performed to determine the lipid-lowering effects of GP. Thereafter, hyperlipidemia was induced in mice using a high-fat diet (HFD) and was subsequently treated with Gynostemma pentaphyllum extract (GPE) by daily gavage for 12 weeks. The body weight, tissue weight, blood lipid level, and liver lipid level were determined. Additionally, mouse serum samples were subjected to metabolomic profiling and feces were collected at different time points for metagenomic analysis via 16S rDNA sequencing. A total of 15 out of 1520 studies were retrieved from six databases. The pooled results of the meta-analysis showed that GP effectively reduced triglyceride levels and increased high-density lipoprotein cholesterol (both [Formula: see text]). Animal experiments revealed that GPE administration significantly reduced body weight, ameliorated high blood lipid levels, limited lipid deposition, and improved insulin resistance. Furthermore, GPE treatment markedly changed the intestinal microbiota structure and constitution of tryptophan metabolites. In conclusion, our results confirm the lipid-lowering effect of GP, which may be partly attributable to regulation of the intestinal microbiota and tryptophan metabolism.

Neuraminidase 1 promotes renal fibrosis development in male mice.

The functions of the influenza virus neuraminidase has been well documented but those of the mammalian neuraminidases remain less explored. Here, we characterize the role of neuraminidase 1 (NEU1) in unilateral ureteral obstruction (UUO) and folic acid (FA)-induced renal fibrosis mouse models. We find that NEU1 is significantly upregulated in the fibrotic kidneys of patients and mice. Functionally, tubular epithelial cell-specific NEU1 knockout inhibits epithelial-to-mesenchymal transition, inflammatory cytokines production, and collagen deposition in mice. Conversely, NEU1 overexpression exacerbates progressive renal fibrosis. Mechanistically, NEU1 interacts with TGFß type I receptor ALK5 at the 160-200aa region and stabilizes ALK5 leading to SMAD2/3 activation. Salvianolic acid B, a component of Salvia miltiorrhiza, is found to strongly bind to NEU1 and effectively protect mice from renal fibrosis in a NEU1-dependent manner. Collectively, this study characterizes a promotor role for NEU1 in renal fibrosis and suggests a potential avenue of targeting NEU1 to treat kidney diseases.

Diagnostic role of plasma ORM2 in differentiating prostate cancer from benign prostatic hyperplasia.

PURPOSE: Markers are needed to increase the diagnostic accuracy of prostate-specific antigen (PSA) in prostate cancer (PCa) screening. Mounting evidence has shown that plasma proteins can be hopeful biomarkers for cancer diagnosis. METHODS: Tandem mass tag (TMT)-based proteomics and parallel reaction monitoring (PRM) analysis were used to screen the differential proteins and further validated in other independent studies (n = 539). Receiver-operating characteristic (ROC), decision curves and nomograms were applied to assess the diagnostic accuracy of biomarkers. RESULTS: Three candidate proteins (DBP, LCAT and ORM2) were preliminarily screened. Subsequent validation studies revealed significant upregulation of ORM2 in PCa patients across other independent cohorts. ORM2 yielded excellent discriminative power for PCa from benign prostatic hyperplasia (BPH) patients (AUC = 0.861 and 0.814 in validation phases 2a and 2b, respectively). Importantly, the combination of ORM2 and PSA gave better predictive accuracy than PSA alone. We incorporated age, PSA and ORM2 into a nomogram, which yielded C-index of 0.883 in validation phase 2a. A similar C-index of 0.879 was obtained in external validation phase 2b. CONCLUSIONS: In summary, our study suggests that ORM2 could be treated as a complementary biomarker for PSA in distinguishing PCa from BPH.

Variability of body mass index and risks of prostate, lung, colon, and ovarian cancers.

Objective: We investigated the association between cancer incidence and body mass index (BMI) variability calculated from the recall of weight at decades of age by participants in the USA Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. Methods: A total of 89,822 individuals' BMI were recorded as recalled the participant's aged 30, 40, 50, 60, 70 years, and baseline. BMI variability was assessed using four indices: SD, coefficient of variation (CV), variability independent of the mean (VIM), and average real variability (ARV). The multivariate Cox regression analysis was performed to calculate hazard ratios (HRs) of these measures for incident cancers and corresponding 95% CIs. Results: During the median follow-up of 11.8 years, there were newly diagnosed 5,012 cases of prostate cancer, 792 cases of lung cancer, 994 cases of colon cancer, and 132 cases of ovarian cancer. Compared with the lowest quartile (Q1) group, the highest quartile (Q4) group of BMI variability indices was associated with increased lung cancer risk, including BMI_SD (HR, 1.58; 95% CI, 1.17-2.12), BMI_CV (HR, 1.46; 95% CI, 1.10-1.94), BMI_VIM (HR, 1.73; 95% CI, 1.33-2.25), and BMI_ARV (HR, 2.17; 95% CI, 1.62-2.91). Associations between BMI variability and prostate, colon, and ovarian cancer incidences were of limited significance. Conclusion: The findings imply that maintaining a stable weight across adulthood is associated with a decreased incidence of lung cancer.

Antihypertensive Drug Use and the Risk of Depression: A Systematic Review and Network Meta-analysis.

Background: Although numerous cohort studies have reported an association between antihypertensives use and depression, the exact effect of antihypertensives on depression remains unclear. Objective: To clarify the association between antihypertensives use and risk of depression. Methods: We retrieved relevant literature using PubMed database until August 30, 2021. Four main classes of antihypertensives, thus, angiotensin antagonists, beta blockers, calcium channel blockers and diuretics were studied. The incidence of depression was pooled based on a single drug category. Network meta-analyses were conducted to comprehensively assess the effects of the four classes of antihypertensives on the risk of depression. Results: A total of nine out of 9,557 studies involving 414,873 subjects were retrieved. The pooled results showed a positive association between the use of calcium channel blockers and symptoms of depression [odds ratio (OR): 1.09, 95% confidence interval (CI):1.06-1.13], while use of the angiotensin antagonists, beta blockers and diuretics was not associated with risk of depression. Subgroup analysis suggested a significant relationship between beta blockers usage and risk of depression in cohort studies (OR:1.21, 95% CI: 1.16-1.26). The results of network meta-analysis indicated that all other three classes of drugs increased the risk of depression: angiotensin antagonists (OR: 1.30, 95% CI: 1.04-1.63), beta blockers (OR: 1.53, 95% CI: 1.22-1.91), and calcium channel blockers (OR: 1.40, 95% CI: 1.12-1.75), compared with diuretics. Conclusion: In conclusion, our results indicate that the use of angiotensin antagonists, beta blockers and calcium channel blockers are potential risk factors of depression.

The Use of Oseltamivir as Adjunctive Therapy for the Treatment of Hand-Food-and-Mouth Disease: A Meta-Analysis of Randomized Clinical Trials.

Background: Hand-foot-and-mouth disease (HFMD) is a common childhood illness caused by enteroviruses. Oseltamivir (OS), a neuraminidase inhibitor, has been frequently used as an adjunctive therapy for the treatment of HFMD. Solid evidence, however, is lacking regarding the efficacy of such adjunctive therapy. This work is to conduct a meta-analysis of randomized clinical trials (RCTs) to assess the efficacy of oseltamivir for HFMD in children. Methods: Eligible studies from inception to October 10, 2020 were identified by searching six databases (PubMed, Embase, CENTRAL, CNKI, Wanfang, and VIP database). Quality of evidence was assessed using the Cochrane Collaboration tool. Results: Of a total of 91 entries, 11 RCTs involving 977 HFMD children were included in the final analysis. The results showed that the therapy combined with oseltamivir was more effective, with higher effective rate (RR, 0.84; 95% CI, 0.80 to 0.87; p < 0.01), shorter fever clearance time (days) (SMD, -0.74; 95% CI, -1.12 to -0.35; p < 0.01), shorter rash regression time (days) (MD, -0.89; 95% CI, -1.05 to -0.72; p < 0.01) and shorter clinical cure time (SMD, -1.08; 95% CI, -1.55 to -0.61; p < 0.01). No significant difference was observed in the risk of adverse reactions between the groups with and without oseltamivir. Conclusion: The use of oseltamivir as adjunctive therapy shows effectiveness and no increased risk of adverse reactions for the treatment of HFMD in children.

Prognostic comparison between radical prostatectomy and radiotherapy in prostate cancer patients at different stages and ages.

Radical prostatectomy (RP) and radiotherapy (RT) are both evidence-based nonconservative treatments for prostate cancer (PCa). However, which treatment is better remains controversial. This study aimed to compare the prognostic difference between radical prostatectomy (RP) and radiotherapy (RT) in PCa patients at different stages and ages. Two independent PCa cohorts (the Surveillance, Epidemiology, and End Results, SEER; and the Prostate, Lung, Colorectal, and Ovarian, PLCO) were employed. Cox regression was used to calculate the hazard ratios (HRs) and the corresponding 95% confidence intervals (CIs). In both cohorts, patients who received RT exhibited a worse prognostic outcome than those who underwent RP. When stratified analysis was performed by tumor node metastasis (TNM) stage and age at diagnosis in the SEER cohort, the HR of RT versus RP for overall survival increased with TNM stage but decreased with age. Specifically, PCa patients in stage I in the age range of 55-84 years, stage IIA at 70-85+ years, and stage IIB at 75-85+ years had better survival with RT than RP patients (p < 0.05). In contrast, patients in stages IIA, IIB, III and IV with respective age ranges of 55-64 years; 50-74 years; 55-59, 65-74 years; and 45-74 years showed worse survival with RT compared with RP (p < 0.05). These findings were partially validated in the PLCO dataset. Our results indicated that the choice between RT and RP should be guided by TNM stage and age. These findings may facilitate counseling regarding the prognostic effect of RT and RP for PCa patients.

Neuraminidase 1 is a driver of experimental cardiac hypertrophy.

AIMS: Despite considerable therapeutic advances, there is still a dearth of evidence on the molecular determinants of cardiac hypertrophy that culminate in heart failure. Neuraminidases are a family of enzymes that catalyze the cleavage of terminal sialic acids from glycoproteins or glycolipids. This study sought to characterize the role of neuraminidases in pathological cardiac hypertrophy and identify pharmacological inhibitors targeting mammalian neuraminidases. METHODS AND RESULTS: Neuraminidase 1 (NEU1) was highly expressed in hypertrophic hearts of mice and rats, and this elevation was confirmed in patients with hypertrophic cardiomyopathy (n = 7) compared with healthy controls (n = 7). The increased NEU1 was mainly localized in cardiomyocytes by co-localization with cardiac troponin T. Cardiomyocyte-specific NEU1 deficiency alleviated hypertrophic phenotypes in response to transverse aortic constriction or isoproterenol hydrochloride infusion, while NEU1 overexpression exacerbated the development of cardiac hypertrophy. Mechanistically, co-immunoprecipitation coupled with mass spectrometry, chromatin immunoprecipitation, and luciferase assays demonstrated that NEU1 translocated into the nucleus and interacted with GATA4, leading to Foetal gene (Nppa and Nppb) expression. Virtual screening and experimental validation identified a novel compound C-09 from millions of compounds that showed favourable binding affinity to human NEU1 (KD = 0.38 µM) and effectively prevented the development of cardiac remodelling in cellular and animal models. Interestingly, anti-influenza drugs zanamivir and oseltamivir effectively inhibited mammalian NEU1 and showed new indications of cardio-protection. CONCLUSIONS: This work identifies NEU1 as a critical driver of cardiac hypertrophy and inhibition of NEU1 opens up an entirely new field of treatment for cardiovascular diseases.

Serum-Urine Matched Metabolomics for Predicting Progression of Henoch-Schonlein Purpura Nephritis.

Henoch-Schonlein purpura nephritis (HSPN) is a common glomerulonephritis secondary to Henoch-Schonlein purpura (HSP) that affects systemic metabolism. Currently, there is a rarity of biomarkers to predict the progression of HSPN. This work sought to screen metabolic markers to predict the progression of HSPN via serum-urine matched metabolomics. A total of 90 HSPN patients were enrolled, including 46 HSPN (+) patients with severe kidney damage (persistent proteinuria >0.3 g/day) and 44 HSPN (-) patients without obvious symptoms (proteinuria < 0.3 g/day). Untargeted metabolomics was determined by liquid chromatography-quadrupole time-of-flight mass spectrometry (LC-Q/TOF-MS). A total of 38 and 50 differential metabolites were, respectively, identified in serum and urine from the comparison between HSPN (+) and HSPN (-) patients. Altered metabolic pathways in HSPN (+) mainly included glycerophospholipid metabolism, pyruvate metabolism, and citrate cycle. A panel of choline and cis-vaccenic acid gave areas under the curve of 92.69% in serum and 72.43% in urine for differential diagnosis between HSPN (+) and HSPN (-). In addition, the two metabolites showed a significant association with clinical indices of HSPN. These results suggest that serum-urine matched metabolomics comprehensively characterized the metabolic differences between HSPN (+) and HSPN (-), and choline and cis-vaccenic acid could serve as biomarkers to predict HSPN progression.

Genetic variants in N6-methyladenosine are associated with bladder cancer risk in the Chinese population.

Recently N6-Methyladenosine (m6A) has been identified to guide the interaction of RNA-binding protein hnRNP C and their target RNAs, which is termed as m6A-switches. We systematically investigated the association between genetic variants in m6A-switches and bladder cancer risk. A two-stage case-control study was performed to systematically calculate the association of single nucleotide polymorphisms (SNPs) in 2798 m6A-switches with bladder cancer risk in 3,997 subjects. A logistic regression model was used to assess the effects of SNPs on bladder cancer risk. A series of experiments were adopted to explore the role of genetic variants of m6A-switches. We identified that rs5746136 (G > A) of SOD2 in m6A-switches was significantly associated with the reduced risk of bladder cancer (additive model in discovery stage: OR = 0.80, 95% CI 0.69-0.93, P = 3.6 × 10-3; validation stage: adjusted OR = 0.88, 95% CI 0.79-0.99, P = 3.0 × 10-2; combined analysis: adjusted OR = 0.85, 95% CI 0.78-0.93, P = 4.0 × 10-4). The mRNA level of SOD2 was remarkably lower in bladder cancer tissues than the paired adjacent samples. SNP rs5746136 may affect m6A modification and regulate SOD2 expression by guiding the binding of hnRNP C to SOD2, which played a critical tumor suppressor role in bladder cancer cells by promoting cell apoptosis and inhibiting proliferation, migration and invasion. In conclusion, our findings suggest the important role of genetic variants in m6A modification. SOD2 polymorphisms may influence the expression of SOD2 via an m6A-hnRNP C-dependent mechanism and be promising predictors of bladder cancer risk.

Metabolomic and transcriptomic analyses of the anti-rheumatoid arthritis potential of xylopic acid in a bioinspired lipoprotein nanoformulation.

Xylopic acid (XA), a diterpene kaurene and the major active ingredient of the African spice Xylopia aethiopica (Annonaceae), is reported to possess anti-inflammatory and analgesic properties. Here, we investigated the therapeutic potential of XA for rheumatoid arthritis (RA), a debilitating autoimmune inflammatory disease characterized by joint damage, in the complete Freund's adjuvant (CFA)-induced arthritis model in rats. We synthesized bioinspired reconstituted high-density lipoprotein (rHDL) nanoparticles loaded with purified XA crystals (rHDL/XA) that passively accumulate in inflamed joints of CFA-induced arthritic rats. Treatment with rHDL/XA minimized mononuclear cell infiltration of CFA-induced arthritic sites and ameliorated disease burden. Metabolomic and transcriptomic analyses revealed that the major molecular pathways perturbed following CFA-induced arthritis correlated with amino acid and lipid metabolism, which were restored to normal states by rHDL/XA treatment. This work demonstrates the anti-RA potential of XA in a nanoformulation and uncovers its underlying therapeutic mechanisms at the transcript and metabolite levels.

Metabolomics identifying biomarkers of PM2.5 exposure for vulnerable population: based on a prospective cohort study.

Long-term exposure to particular matter (PM), especially fine PM (< 2.5 µm in the aerodynamic diameter, PM2.5), is associated with increased risk of cardiovascular disorders. This study aimed to evaluate the association between long-term exposure to PM2.5/PM10 and the metabolic change in the plasma. Specifically, using metabolomics, we sought to identify the biomarkers for the vulnerable subgroup to PM2.5 exposure. A total of 78 college student volunteers were recruited into this prospective cohort study. All participants received 8 rounds of physical examinations at twice quarterly. Air purifiers were placed in 40 of 78 participants' dormitories for 14 days. Before and after intervention, physical examinations were performed and the peripheral blood was collected. Plasma metabolomics was determined by ultra-performance liquid chromatography-mass spectrometry. During the follow-up, the average concentrations of PM2.5 and PM10 were 53 µg/m3 and 93 µg/m3, respectively. Totally, 42 and 120 differential metabolic features were detected for PM10 and PM2.5 exposure, respectively. In total, 25 differential metabolites were identified for PM2.5 exposure, most of which were phospholipids. No distinctive metabolites were found for PM10 exposure. A total of 6 differential metabolites (lysoPC (P-20:0), lysoPC (P-18:1(9z)), lysoPC (20:1), lysoPC (O-16:0), choline, and found 1,3-diphenylprop-2-en-1-one) were characterized and confirmed for sensitive individuals. Importantly, we found LysoPC (P-20:0) and LysoPC (P-18:1(9z)) changed significantly before and after air purifier intervention. Our results indicated that the phospholipid catabolism was involved in long-term PM2.5 exposure. LysoPC (P-20:0) and LysoPC (P-18:1(9z)) may be the biomarkers of PM2.5 exposure.

Melatonin as an inducer of arecoline and their coordinated roles in anti-oxidative activity and immune responses.

Arecoline is one of the main medicinal constituents in areca. Melatonin is an amine molecule with multiple functions in plants and animals. However, the interaction between arecoline and melatonin remains unknown. Herein, metabolomics analysis showed that multiple metabolites including arecoline were induced in areca by exogenous melatonin. In vitro assay demonstrated that the induced arecoline had strong antioxidant capacities, being similar to the traditional function of melatonin. Both arecoline and melatonin could significantly improve plant disease resistance against Colletotrichum kahawae and delay post-harvest physiological deterioration (PPD) of areca fruits, through modulation of the levels of jasmonic acid (JA), salicylic acid (SA), ethylene (ETH) and abscisic acid (ABA), reactive oxygen species (ROS) level as well as glycolytic activity. In addition, animal and cell assays indicated that arecoline and melatonin could commonly enhance anti-inflammatory effects through regulating ROS and hypoxia inducible factor-1α (HIF-1α). Taken together, melatonin could serve as an inducer of arecoline and they show coordinated roles in antioxidative activity and immune responses in areca and animals. This study greatly extends the knowledge of the action of melatonin in areca and animals.