CircPVT1 promotes migration and invasion by regulating miR-490-5p/HAVCR2 axis in osteosarcoma cells.

Circular RNAs (circRNAs) play an important role in the progression of osteosarcoma. However, the precise function of circPVT1 in osteosarcoma remains elusive. This study aims to explore the molecular mechanism underlying the involvement of circPVT1 in osteosarcoma cells. We quantified circPVT1 expression using qRT-PCR in both control and osteosarcoma cell lines. To investigate the roles of circPVT1, miR-490-5p and HAVCR2 in vitro, we separately conducted overexpression and inhibition experiments for circPVT1, miR-490-5p and HAVCR2 in HOS and U2OS cells. Cell migration was assessed through wound healing and transwell migration assays, and invasion was measured via the Matrigel invasion assay. To elucidate the regulatory mechanism of circPVT1 in osteosarcoma, a comprehensive approach was employed, including fluorescence in situ hybridization, qRT-PCR, Western blot, bioinformatics, dual-luciferase reporter assay and rescue assay. CircPVT1 expression in osteosarcoma cell lines surpassed that in control cells. The depletion of circPVT1 resulted in a notable reduction in the in vitro migration and invasion of osteosarcoma cells. Mechanism experiments revealed that circPVT1 functioned as a miR-490-5p sequester, and directly targeted HAVCR2. Overexpression of miR-490-5p led to a significant attenuation of migration and invasion of osteosarcoma cells, whereas HAVCR2 overexpression had the opposite effect, promoting these abilities. Additionally, circPVT1 upregulated HAVCR2 expression via sequestering miR-490-5p, thereby orchestrating the migration and invasion in osteosarcoma cells. CircPVT1 orchestrates osteosarcoma migration and invasion by regulating the miR-490-5p/HAVCR2 axis, underscoring its potential as a promising therapeutic target for osteosarcoma.

Variations in the germinal center response revealed by genetically diverse mouse strains.

The humoral response is complex and involves multiple cellular populations and signaling pathways. Bacterial and viral infections, as well as immunization regimens, can trigger this type of response, promoting the formation of microanatomical cellular structures called germinal centers (GCs). GCs formed in secondary lymphoid organs support the differentiation of high-affinity plasma cells and memory B cells. There is growing evidence that the quality of the humoral response is influenced by genetic variants. Using 12 genetically divergent mouse strains, we assessed the impact of genetics on GC cellular traits. At steady state, in the spleen, lymph nodes and Peyer's patches, we quantified GC B cells, plasma cells and follicular helper T cells. These traits were also quantified in the spleen of mice following immunization with a foreign antigen, namely, sheep red blood cells, in addition to the number and size of GCs. We observed both strain- and organ-specific variations in cell type abundance, as well as for GC number and size. Moreover, we find that some of these traits are highly heritable. Importantly, the results of this study inform on the impact of genetic diversity in shaping the GC response and identify the traits that are the most impacted by genetic background.

Measurement of cumulative high-sensitivity C-reactive protein and monocyte to high-density lipoprotein ratio in the risk prediction of type 2 diabetes: a prospective cohort study.

BACKGROUND: Converging data have suggested that monocytic inflammation and C-reactive protein (CRP) are biologically intertwined processes and are involved in diabetogenesis. This study aimed to investigate the association between systemic inflammation assessed by joint cumulative high-sensitivity C-reactive protein (CumCRP) and monocyte to high-density lipoprotein ratio (CumMHR) and incident type 2 diabetes (T2D) and their predictive value for T2D in a general population. METHODS: A total of 40,813 nondiabetic participants from a prospective real-life cohort (Kailuan Study, China) were followed biennially from 2010/2011 until December 31, 2020. Multivariable Cox regression analyses were conducted to evaluate the adjusted hazard ratios (aHRs) of incident diabetes. RESULTS: During a median follow-up of 7.98 (IQR: 5.74-8.87) years, 4848 T2D cases developed. CumMHR and CumCRP were alone or jointly associated with incident T2D after adjusting for potential confounders. Elevated CumMHR levels significantly increased the risk of incident diabetes in each CumCRP strata (P-interaction: 0.0278). Participants with concomitant elevations in CumMHR and CumCRP levels had the highest risk (aHR: 1.71, 95% CI 1.52-1.91) compared to both in the low strata. Notably, the coexposure-associated T2D risk was modified by age, sex, hypertension, dyslipidemia, and prediabetes status. C-statistics increased from 0.7377 to 0.7417 when CumMHR and CumCRP were added into the multivariable-adjusted model, with a net reclassification improvement (%) of 12.39 (9.39-15.37) (P < 0.0001). CONCLUSIONS: Cumulative hsCRP and MHR were both independently and jointly associated with an increased risk of T2D and their addition to established risk factors should improve risk prediction and reclassification of diabetes.

Prevalence and risk factors of obesity among undergraduate student population in Ghana: an evaluation study of body composition indices.

BACKGROUND: Obesity is a classified risk factor for several of the world's leading causes of death. In this study, we combined information contained in body mass index (BMI), total percentage body fat (TPBF) and relative fat mass (RFM) to estimate obesity prevalence and examine the risk factors associated with obesity. METHODS: The study recruited 1027 undergraduate students aged between 16 and 25 years using a cross-sectional study design and two-stage stratified random sampling between January and April 2019 from the Kwame Nkrumah University of Science and Technology, Kumasi, Ghana. Demographic, lifestyle, and family history of chronic disease data, were collected using a structured questionnaire. Bioelectrical impedance, along with height, weight, age, and gender, were used to estimate BMI and TPBF. The RFM was calculated using a published equation. The TPBF and RFM ranges were evaluated based on standard BMI thresholds and an informative combined obesity prevalence estimated in a Bayesian framework. Multiple logistic regression analysis was used to evaluate potential risk factors of overweight/obesity. RESULTS: Concordance between BMI, TPBF and RFM for obesity classification was 84% among female and 82.9% among male students. The Bayesian analysis revealed a combined prevalence means of obesity of 9.4% (95%CI: 6.9-12.2%) among female students and 6.7% (95%CI:4.3-9.5%) among male students. The odds of obesity were increased between 1.8 and 2.5 for females depending on the classification index. A significant increasing trend of obesity was observed with university-level. A family history of obesity was associated with a high estimate of general, central, and high TPBF. CONCLUSION: Using multiple adiposity indicators conjointly in a Bayesian framework offers a greater power to examine obesity prevalence. We have applied this and reported high obesity prevalence, especially among female students. University level and family history of obesity were key determinants for obesity among the student population.

Temporal relationship between atherogenic dyslipidemia and inflammation and their joint cumulative effect on type 2 diabetes onset: a longitudinal cohort study.

BACKGROUND: Concurrent atherogenic dyslipidemia and elevated inflammation are commonly observed in overt hyperglycemia and have long been proposed to contribute to diabetogenesis. However, the temporal relationship between them and the effect of their cumulative co-exposure on future incident type 2 diabetes (T2D) remains unclear. METHODS: Longitudinal analysis of data on 52,224 participants from a real-world, prospective cohort study (Kailuan Study) was performed to address the temporal relationship between high-sensitivity C-reactive protein (hsCRP) and the atherogenic index of plasma (AIP, calculated as triglyceride/high-density lipoprotein) in an approximately 4-year exposure period (2006/2007 to 2010/2011). After excluding 8824 participants with known diabetes, 43,360 nondiabetic participants were included for further analysis of the T2D outcome. Cox regression models were used to examine the adjusted hazard ratios (aHRs) upon the cumulative hsCRP (CumCRP) and AIP (CumAIP) in the exposure period. RESULTS: In temporal analysis, the adjusted standardized correlation coefficient (ß1) of hsCRP_2006/2007 and AIP_2010/2011 was 0.0740 (95% CI, 0.0659 to 0.0820; P < 0.001), whereas the standardized correlation coefficient (ß2) of AIP_2006/2007 and hsCRP_2010/2011 was - 0.0293 (95% CI, - 0.0385 to - 0.0201; P < 0.001), which was significantly less than ß1 (P < 0.001). During a median follow-up of 7.9 years, 5,118 T2D cases occurred. Isolated exposure to CumAIP or CumCRP was dose-dependently associated with T2D risks, independent of traditional risk factors. Significant interactions were observed between the median CumAIP (- 0.0701) and CumCRP thresholds (1, 3 mg/L) (P = 0.0308). Compared to CumAIP < - 0.0701 and CumCRP < 1 mg/L, those in the same CumAIP stratum but with increasing CumCRP levels had an approximately 1.5-fold higher T2D risk; those in higher CumAIP stratum had significantly higher aHRs (95% CIs): 1.64 (1.45-1.86), 1.87 (1.68-2.09), and 2.04 (1.81-2.30), respectively, in the CumCRP < 1, 1 ≤ CumCRP < 3, CumCRP ≥ 3 mg/L strata. Additionally, the T2D risks in the co-exposure were more prominent in nonhypertensive, nondyslipidemic, nonprediabetic, or female participants. CONCLUSIONS: These findings suggest a stronger association between elevated hsCRP and future AIP changes than vice versa and highlight the urgent need for combined assessment and management of chronic inflammation and atherogenic dyslipidemia in primary prevention, particularly for those with subclinical risks of T2D.

Combined effect of adiposity and elevated inflammation on incident type 2 diabetes: a prospective cohort study.

BACKGROUND: Adiposity and elevated inflammation are two hallmarks of hyperglycemia. However, it is unknown whether clustering of elevated inflammation and adiposity interact act on diabetogenesis and lead to a greater risk for incident type 2 diabetes (T2D). METHODS: Adiposity was indicated by body mass index, waist circumference and ultrasonography-measured fatty liver degrees. Elevated inflammation was indicated as high-sensitivity C-reactive protein levels ≥ 2 mg/L. Time-to-event survival analyses were conducted to investigate the joint effect of adiposity and inflammation on incident T2D on both multiplicative and additive scales. RESULTS: Among 82,172 non-diabetic participants from a prospective cohort in China, 14,278 T2D occurred over a median follow-up of 11 years. In the multivariable-adjusted model, elevated inflammation [1.12 (1.08‒1.16)] and adiposity [1.76 (1.69‒1.83) for overweight/obesity, 1.49 (1.44‒1.55) for central obesity, and 2.02 (1.95‒2.09) for fatty liver] were significantly associated with incident diabetes. Higher adiposity-associated risks and incidence rates of diabetes were observed with elevated inflammation. When studying the joint effect, the adjusted HRs were 1.77 (1.69‒1.85) for overweight/obesity, 1.14 (1.06‒1.23) for elevated inflammation, and 2.08 (1.97‒2.19) for their joint effect, with a relative excess risk due to interaction of 0.17 (0.05‒0.28). The attributable proportions were 71.30% for overweight/obesity, 12.96% for elevated inflammation, and 15.74% for their interaction. Similar results were observed when adiposity was assessed as waist circumference or fatty liver. CONCLUSIONS: Adiposity and elevated inflammation synergically lead to greater risks of incident diabetes than addition of each individual exposure. Strategies simultaneously targeting both risks should produce more benefits for diabetes prevention than through initiatives directed at each separate risk.

Supra-additive effect of chronic inflammation and atherogenic dyslipidemia on developing type 2 diabetes among young adults: a prospective cohort study.

BACKGROUND: Both elevated inflammation and atherogenic dyslipidemia are prominent in young-onset diabetes and are increasingly identified as biologically intertwined processes that contribute to diabetogenesis. We aimed to investigate the age-specific risks of type 2 diabetes (T2D) upon concomitant chronic inflammation and atherogenic dyslipidemia. METHODS: Age-stratified Cox regression analysis of the risk of incident diabetes upon co-exposure to time-averaged cumulative high-sensitivity C-reactive protein (CumCRP) and atherogenic index of plasma (CumAIP) among 42,925 nondiabetic participants from a real-world, prospective cohort (Kailuan Study). RESULTS: During a median 6.41 years of follow-up, 3987 T2D developed. Isolated CumAIP and CumCRP were significantly associated with incident T2D in the entire cohort and across all age subgroups. Both CumAIP and CumCRP were jointly associated with an increased risk of diabetes (P-interaction = 0.0126). Compared to CumAIP < -0.0699 and CumCRP < 1 mg/L, co-exposure to CumAIP ≥ - 0.0699 and CumCRP ≥ 3 mg/L had a significant hazard ratio (HR) [2.55 (2.23-2.92)] after adjusting for socio-demographic, life-style factors, family history of diabetes, blood pressure, renal function and medication use. The co-exposure-associated risks varied greatly by age distribution (P-interaction = 0.0193): < 40 years, 6.26 (3.47-11.28); 40-49 years, 2.26 (1.77-2.89); 50-59 years, 2.51 (2.00-3.16); 60-69 years, 2.48 (1.86-3.30); ≥ 70 years, 2.10 (1.29-3.40). In young adults (< 45 years), both exposures had a significant supra-additive effect on diabetogenesis (relative excess risk due to interaction: 0.80, 95% CI 0.10-1.50). CONCLUSIONS: These findings highlight the need for age-specific combined assessment and management of chronic inflammation and dyslipidemia in primary prevention against T2D, particularly for young adults. The clinical benefit derived from dual-target intervention against dyslipidemia and inflammation will exceed the sum of each part alone in young adults.

S-methyl cysteine sulfoxide and its potential role in human health: a scoping review.

Higher intakes of cruciferous and allium vegetables are associated with a lower risk of cardiometabolic-related outcomes in observational studies. Whilst acknowledging the many healthy compounds within these vegetables, animal studies indicate that some of these beneficial effects may be partially mediated by S-methyl cysteine sulfoxide (SMCSO), a sulfur-rich, non-protein, amino acid found almost exclusively within cruciferous and alliums. This scoping review explores evidence for SMCSO, its potential roles in human health and possible mechanistic action. After systematically searching several databases (EMBASE, MEDLINE, SCOPUS, CINAHL Plus Full Text, Agricultural Science), we identified 21 original research articles meeting our inclusion criteria. These were limited primarily to animal and in vitro models, with 14/21 (67%) indicating favorable anti-hyperglycemic, anti-hypercholesterolemic, and antioxidant properties. Potential mechanisms included increased bile acid and sterol excretion, altered glucose- and cholesterol-related enzymes, and improved hepatic and pancreatic ß-cell function. Raising antioxidant defenses may help mitigate the oxidative damage observed in these pathologies. Anticancer and antibacterial effects were also explored, along with one steroidogenic study. SMCSO is frequently overlooked as a potential mediator to the benefits of sulfur-rich vegetables. More research into the health benefits of SMCSO, especially for cardiometabolic and inflammatory-based pathology, is warranted. Human studies are especially needed.

Sulfur compounds: From plants to humans and their role in chronic disease prevention.

Sulfur is essential for the health of plants and is an indispensable dietary component for human health and disease prevention. Its incorporation into our food supply is heavily reliant upon the uptake of sulfur into plant tissue and our subsequent intake. Dietary requirements for sulfur are largely calculated based upon requirements for the sulfur-containing amino acids (SAA), cysteine and methionine, to meet the demands for synthesis of proteins, enzymes, co-enzymes, vitamins, and hormones. SAA are found in abundance in animal sources and are relatively low in plants. However, some plants, particularly cruciferous and allium vegetables, produce many protective sulfur-containing secondary metabolites, such as glucosinolates and cysteine sulfoxides. The variety and quantity of these sulfur-containing metabolites are extensive and their effects on human health are wide-reaching. Many benefits appear to be related to sulfur's role in redox biochemistry, protecting against uncontrolled oxidative stress and inflammation; features consistent within cardiometabolic dysfunction and many chronic metabolic diseases of aging. This narrative explores the origins and importance of sulfur, its incorporation into our food supply and dietary sources. It also explores the overarching potential of sulfur for human health, particularly around the amelioration of oxidative stress and chronic inflammation, and subsequent chronic disease prevention.

Association of cumulative monocyte to high-density lipoprotein ratio with the risk of type 2 diabetes: a prospective cohort study.

BACKGROUND: Recent studies have established that monocyte-derived inflammation plays a central role in the pathogenesis of type 2 diabetes mellitus (T2DM). It is unclear whether chronic metabolic inflammation, reflected by the cumulative monocyte to high-density lipoprotein ratio (CumMHR), predisposes the general population to T2DM. METHODS: This study included 40,813 participants without diabetes from a real-life, community-based cohort (the Kailuan Study) attending a 2-year cycle of health survey since 2006. Cumulative exposure was obtained from 2006/2007 to 2010/2011. Follow-up started at 2010/2011 and through 2020. Multivariable-adjusted Cox regression models were used to calculate the CumMHR-associated risk of incident T2DM. RESULTS: Over a median follow-up period of 7.98 (IQR: 5.74-8.87) years, 4,848 T2DM cases occurred. The CumMHR was positively associated with the risk of incident T2DM after adjusting for age, sex, smoking, drinking habits, physical activities, BMI, triglyceride-glycemia index, log(leukocyte count), log(hsCRP), blood pressure, renal function, and medication uses with adjusted HRs of 1.0 (ref.), 1.18 (1.05‒1.25), 1.17 (1.07‒1.27), 1.38 (1.26‒1.50), respectively, in CumMHR Quartiles 1, 2, 3 and 4. When follow-up ended at 2014/2015, the short-term (4‒year) adjusted T2DM risks in CumMHR Quartiles 2, 3, and 4 were 1.14 (1.01‒1.29), 1.17 (1.04‒1.32), 1.40 (1.25‒1.58), respectively, relative to Quartile 1. A significant interaction between CumMHR and cumulative high-sensitivity C-reactive protein (CumCRP) was observed (P-interaction: 0.0109). The diabetic risk in the highest quartile of CumMHR was higher (1.53 [1.28‒1.84]) when CumCRP < 1 mg/L, attenuated with increasing CumCRP levels (1 ~ 10 mg/L) and disappeared in CumCRP ≥ 10 mg/L. Hypertension, overweight, or smoking habits further modified the CumMHR-associated diabetic risk. CONCLUSIONS: Cumulative MHR may be a promising supplement to hsCRP for more comprehensively assessing the influence of metabolic inflammation on T2DM susceptibility. For primary prevention, targeting high CumMHR, especially in cases at low risk of diabetes defined by traditional risk factors, may further help reduce the diabetic risk.

Common Heritable Immunological Variations Revealed in Genetically Diverse Inbred Mouse Strains of the Collaborative Cross.

Variations in the proportion and number of specific immune cell types among healthy individuals are influenced by both heritable and nonheritable factors. Mouse models, subjected to fewer nonheritable factors than humans, allow the identification of genetic factors that shape the immune system. We characterized immunological trait variability in the Collaborative Cross (CC), a powerful genetic resource of recombinant inbred mouse strains derived from eight diverse founder strains. Of the 18 immunological traits studied in more than 60 CC strains, eight showed genome-wide significant linkage, revealing new genetic loci linked to specific immune traits. We also found that these traits were highly subject to heritable influences. As for humans, mouse immunological traits varied as a continuum rather than as discrete immunophenotypes. The CC thus represents a useful resource to identify factors that determine immunological variations, as well as defining other immune traits likely to be heritable in humans.

Glycosylation Profiling as a Biomarker of Suboptimal Health Status for Chronic Disease Stratification.

WHO defines health as "a state of complete physical, mental, and social well-being and not merely the absence of disease or infirmity." We coined and defined suboptimal health status (SHS) as a subclinical, reversible stage of the pre-chronic disease. SHS is a physical state between health and disease, characterized by health complaints, general weakness, chronic fatigue, and low energy levels. We have developed an instrument to measure SHS, Suboptimal Health Status Questionnaire-25 (SHSQ-25), a self-reported survey assessing five health components that has been validated in various ethnical populations. Our studies suggest that SHS is associated with the major components of cardiovascular health and the early onset of metabolic diseases. Besides subjective measure of health (SHS), glycans are conceived as objective biomarkers of SHS. Glycans are complex and branching carbohydrate moieties attached to proteins, participating in inflammatory regulation and chronic disease pathogenesis. We have been investigating the role of glycans and SHS in multiple cardiometabolic diseases in different ethnical populations (African, Chinese, and Caucasian). Here we present case studies to prove that a combination of subjective health measure (SHS) with objective health measure (glycans) represents a window of opportunity to halt or reverse the progression of chronic diseases.

Genetic characterization of early renal changes in a novel mouse model of diabetic kidney disease.

Genetic factors influence susceptibility to diabetic kidney disease. Here we mapped genes mediating renal hypertrophic changes in response to diabetes. A survey of 15 mouse strains identified variation in diabetic kidney hypertrophy. Strains with greater (FVB/N(FVB)) and lesser (C57BL/6 (B6)) responses were crossed and diabetic F2 progeny were characterized. Kidney weights of diabetic F2 mice were broadly distributed. Quantitative trait locus analyses revealed diabetic mice with kidney weights in the upper quartile shared alleles on chromosomes (chr) 6 and 12; these loci were designated as Diabetic kidney hypertrophy (Dkh)-1 and -2. To confirm these loci, reciprocal congenic mice were generated with defined FVB chromosome segments on the B6 strain background (B6.Dkh1/2f) or vice versa (FVB.Dkh1/2b). Diabetic mice of the B6.Dkh1/2f congenic strain developed diabetic kidney hypertrophy, while the reciprocal FVB.Dkh1/2b congenic strain was protected. The chr6 locus contained the candidate gene; Ark1b3, coding aldose reductase; the FVB allele has a missense mutation in this gene. Microarray analysis identified differentially expressed genes between diabetic B6 and FVB mice. Thus, since the two loci identified by quantitative trait locus mapping are syntenic with regions identified for human diabetic kidney disease, the congenic strains we describe provide a valuable new resource to study diabetic kidney disease and test agents that may prevent it.

Unlocking the Therapeutic Potential of Ellagic Acid for Non-Alcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis.

Obesity is in epidemic proportions in many parts of the world, contributing to increasing rates of non-alcoholic fatty liver disease (NAFLD). NAFLD represents a range of conditions from the initial stage of fatty liver to non-alcoholic steatohepatitis (NASH), which can progress to severe fibrosis, through to hepatocellular carcinoma. There currently exists no treatment for the long-term management of NAFLD/NASH, however, dietary interventions have been investigated for the treatment of NASH, including several polyphenolic compounds. Ellagic acid is one such polyphenolic compound. Nutraceutical food abundant in ellagic acid undergoes initial hydrolysis to free ellagic acid within the stomach and small intestine. The proposed mechanism of action of ellagic acid extends beyond its initial therapeutic potential, as it is further broken down by the gut microbiome into urolithin. Both ellagic acid and urolithin have been found to alleviate oxidative stress, inflammation, and fibrosis, which are associated with NAFLD/NASH. While progress has been made in understanding the pharmacological and biological activity of ellagic acid and its involvement in NAFLD/NASH, it has yet to be fully elucidated. Thus, the aim of this review is to summarise the currently available literature elucidating the therapeutic potential of ellagic acid and its microbial-derived metabolite urolithin in NAFLD/NASH.

The caregiving role influences Suboptimal Health Status and psychological symptoms in unpaid carers.

Background: Suboptimal Health Status (SHS) is the physical state between health and disease. This study aimed to fill in the knowledge gap by investigating the prevalence of SHS and psychological symptoms among unpaid carers and to identify SHS-risk factors from the perspective of predictive, preventive and personalised medicine (PPPM). Methods: A cross-sectional study was conducted among 368 participants who were enrolled from Australia, including 203 unpaid carers as cases and 165 individuals from the general population as controls. SHS scores were measured using SHSQ-25 (Suboptimal Health Status Questionnaire-25), whilst psychological symptoms were measured by DASS-21 (Depression, Anxiety and Stress Scale-21). Chi-square was used to measure SHS and psychological symptom prevalence. Spearman correlation analysis was utilised to identify the relationship between SHSQ-25 and DASS-21 scores. Logistic regression analysis was used for multivariate analysis. Results: The prevalence of SHS in carers was 43.0% (98/203), significantly higher than the prevalence 12.7% (21/165) in the general population (p < 0.001). In addition, suboptimal health prevalence was higher in female carers (50.3%; 95/189) than females in the general population (12.4%; 18/145). Logistic regression showed that the caregiving role influenced SHS, with carers 6.4 times more likely to suffer from SHS than their non-caring counterparts (aOR = 6.400, 95% CI = 3.751-10.919). Conclusions: Unpaid carers in Australia have a significantly higher prevalence of SHS than that in the general population and experience poorer health. The SHSQ-25 is a powerful tool that can be utilised to screen at-risk individuals to predict their risk of chronic disease development, an essential pillar for shifting the paradigm change from reactive medicine to that of predictive, preventive and personalised medicine (PPPM). Supplementary Information: The online version contains supplementary material available at 10.1007/s13167-024-00370-8.

Identification of circRNA biomarkers in osteosarcoma: An updated systematic review and meta-analysis.

Circular RNAs (circRNAs) play a crucial role in cancer development and progression. This study aimed to identify potential circRNA biomarkers for osteosarcoma. Articles published from January 2010 to September 2023 were searched across eight databases to compare circRNA expression profiles in osteosarcoma and control samples (human, animal and cell lines). Meta-analysis was conducted under a random effects model. Subgroup analysis of circRNAs in different samples and tissues was performed. Diagnostic value was evaluated using receiver operator characteristic curves. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis explored functions of circRNA host genes. A circRNA-miRNA-mRNA axis depicted the regulatory mechanism in osteosarcoma. Among 1356 circRNAs with differential expression were identified across 226 original studies, only 74 were reported in at least three published sub-studies. Meta-analysis identified 58 dysregulated circRNAs (52 upregulated and 6 downregulated). Eleven circRNAs consistently showed dysregulation in tissues and cell lines, with hsa_circ_0005721 showing potential as a circulating biomarker in osteosarcoma. Sensitivity analysis demonstrated 97 % consistency. The overall area under the curve was 0.87 (95 % CI, 0.83-0.89). GO and KEGG enrichment analyses revealed host gene involvement in cancer. The circRNA-miRNA-mRNA axis revealed the regulatory axis and interactions within osteosarcoma specifically. This study demonstrates circRNAs as potential diagnostic biomarkers for osteosarcoma. Consistently reported dysregulated circRNAs are potential biomarkers in osteosarcoma pathogenesis, with hsa_circ_0005721 as a potential circulating biomarker for diagnosis and treatment.

Low Remnant Cholesterol and In-Hospital Bleeding Risk After Ischemic Stroke or Transient Ischemic Attack.

BACKGROUND: Bleeding risk brought by intensive lipid-lowering therapy and low low-density lipoprotein cholesterol is concerning, while evidence regarding the relationship between remnant cholesterol and bleeding is frightening. This study aimed to investigate the association between remnant cholesterol at admission and an in-hospital bleeding event after acute ischemic stroke or transient ischemic attack (TIA). METHODS AND RESULTS: A total of 3222 eligible patients admitted to Shanghai Huashan Hospital between 2015 and 2021 with complete lipid data were analyzed. Patients were classified into low (<20.0 mg/dL), moderate (20.0-29.9 mg/dL), and high (≥30 mg/dL) groups by remnant cholesterol. The mean age of patients was 63.0± 13.1 years, including 2301 (71.4%) men and 651 (20.2%) with TIA. The median (interquartile range) of remnant cholesterol was 18.6 (13.5-25.9) mg/dL. After adjustment for confounding variables, patients with low remnant cholesterol had a higher risk of bleeding events (odds ratio, 2.56 [95% CI, 1.12-6.67]) than those with moderate remnant cholesterol. The high remnant cholesterol group was not significantly associated with bleeding risk. Combined assessment of low-density lipoprotein cholesterol and remnant cholesterol further identified patients with the highest risk of bleeding events. CONCLUSIONS: Low remnant cholesterol levels were associated with bleeding events during the acute stage of ischemic stroke and TIA. The assessment of remnant cholesterol could inform the bleeding risk during hospitalization both for patients and physicians in clinical practice.

S-Methyl Cysteine Sulfoxide Does Not Ameliorate Weight Gain or Hyperlipidemia in Mice Fed a High-Fat Diet.

SCOPE: Higher intake of cruciferous and allium vegetables is associated with lower cardiometabolic risk. Little research has investigated the cardiometabolic effects of S-methyl cysteine sulfoxide (SMCSO), found abundant in these vegetables. This study hypothesizes that SMCSO will blunt development of metabolic syndrome features in mice fed high-fat feed. METHODS AND RESULTS: Fifty C57BL/6 male mice are randomly assigned to standard-chow, high-fat, or high-fat supplemented with low-SMCSO (43 mg kg-1 body weight [BW] day-1), medium-SMCSO (153 mg kg-1 BW day-1), or high-SMCSO (256 mg kg-1 BW day-1) for 12-weeks. High-fat with SMCSO did not prevent diet-induced obesity, glucose intolerance, or hypercholesterolemia. Mice fed high-fat with SMCSO has higher hepatic lipids than mice fed standard-chow or high-fat alone. Urinary SMCSO increases at 6- and 12-weeks in the low-SMCSO group, before reducing 46% and 28% in the medium- and high-SMCSO groups, respectively, at 12-weeks, suggesting possible tissue saturation. Interestingly, two SMCSO-fed groups consume significantly more feed, without significant weight gain. Due to limitations in measuring consumed feed, caution should be taken interpreting these results. CONCLUSION: SMCSO (43-256 mg kg-1 BW day-1) does not ameliorate metabolic syndrome features in high-fat fed mice. Substantial knowledge gaps remain. Further studies should administer SMCSO separately (i.e., gavage), with metabolic studies exploring tissue levels to better understand its physiological action.

Intraindividual Discordance Between Remnant Cholesterol and Low-Density Lipoprotein Cholesterol Associated With Incident Stroke: Results From 2 National Cohorts.

BACKGROUND: The atherogenic effect of remnant cholesterol is being increasingly acknowledged. This study aimed to explore the association of discordance between remnant cholesterol and low-density lipoprotein cholesterol with stroke onset using 2 Chinese national cohorts. METHODS AND RESULTS: We studied 11 139 participants from CHARLS (China Health and Retirement Longitudinal Study) and 5993 participants from CHNS (China Health and Nutrition Survey) aged 45 years or older. The discordance between remnant cholesterol and low-density lipoprotein cholesterol was defined using the difference in percentile units (>15 units). There were 988 (8.9%) and 128 (2.1%) stroke events reported during follow-up in the 2 cohorts. Elevated remnant cholesterol was significantly associated with a higher risk of total stroke in 2 cohorts. After adjusting for remnant cholesterol level, the discordantly high remnant cholesterol group was significantly associated with an increased stroke risk (CHARLS: subdistribution hazard ratio [sHR], 1.31 [95 CI, 1.10-1.55]; CHNS: sHR, 1.84 [95 CI, 1.15-3.08]) compared with the discordantly low group. Consistent results were shown even among those with optimal low-density lipoprotein cholesterol level. CONCLUSIONS: The discordance between remnant cholesterol and low-density lipoprotein cholesterol, representing the intraindividual discrepancy, is significantly associated with stroke onset among Chinese adults.

Remnant cholesterol traits and risk of stroke: A multivariable Mendelian randomization study.

Observational epidemiological studies have reported a relationship between remnant cholesterol and stroke. However, the results are inconclusive, and causality remains unclear due to confounding or reverse causality. Our objective in this study was to investigate the causal relevance of remnant cholesterol and the risk of stroke and its subtypes using the Mendelian randomization (MR) approach. Genome-wide association studies (GWASs) including 115,082 European individuals (UK Biobank) were used to identify instruments for remnant cholesterol, including intermediate-density lipoprotein (IDL) cholesterol and very-low-density lipoprotein (VLDL) cholesterol. Summary-level data for total stroke, intracerebral hemorrhage, subarachnoid hemorrhage, ischemic stroke (IS), and IS subtypes were obtained from GWAS meta-analyses conducted by the MEGASTROKE consortium. Univariable and multivariable MR analyses were performed. The GWAS identified multiple single-nucleotide polymorphisms after clumping for remnant cholesterol (n = 52), IDL cholesterol (n = 62), and VLDL cholesterol (n = 67). Assessed individually using MR, remnant cholesterol (weighted median: odds ratio [OR] 1.32 per 1-SD higher trait; 95% CI: 1.04-1.67; P = 0.024) had effect estimates consistent with a higher risk of LAS-IS, driven by IDL cholesterol (OR 1.32; 95% CI: 1.04-1.68; P = 0.022). In multivariable MR, IDL cholesterol (OR 1.46; 95% CI: 1.10-1.93; P = 0.009) retained a robust effect on LAS-IS after controlling for VLDL cholesterol and high-density lipoprotein cholesterol. The MR analysis did not indicate causal associations between remnant cholesterol and other stroke subtypes. This study suggests that remnant cholesterol is causally associated with the risk of LAS-IS driven by IDL cholesterol.