Genome-wide association and polygenic risk score estimation of type 2 diabetes mellitus in Kinh Vietnamese-A pilot study.

A genome-wide association study (GWAS) is a powerful tool in investigating genetic contribution, which is a crucial factor in the development of complex multifactorial diseases, such as type 2 diabetes mellitus. Type 2 diabetes mellitus is a major healthcare burden in the Western Pacific region; however, there is limited availability of genetic-associated data for type 2 diabetes in Southeast Asia, especially among the Kinh Vietnamese population. This lack of information exacerbates global healthcare disparities. In this study, 997 Kinh Vietnamese individuals (503 with type 2 diabetes and 494 controls) were prospectively recruited and their clinical and paraclinical information was recorded. DNA samples were collected and whole genome genotyping was performed. Standard quality control and genetic imputation using the 1000 Genomes database were executed. A polygenic risk score for type 2 diabetes was generated in different models using East Asian, European, and mix ancestry GWAS summary statistics as training datasets. After quality control and genetic imputation, 107 polymorphisms reached suggestive statistical significance for GWAS (≤5 × 10-6) and rs11079784 was one of the potential markers strongly associated with type 2 diabetes in the studied population. The best polygenic risk score model predicting type 2 diabetes mellitus had AUC = 0.70 (95% confidence interval = 0.62-0.77) based on a mix of ancestral GWAS summary statistics. These data show promising results for genetic association with a polygenic risk score estimation in the Kinh Vietnamese population; the results also highlight the essential role of population diversity in a GWAS of type 2 diabetes mellitus.

Modifiable predictors of mental health literacy in the educational context: a systematic review and meta-analysis.

Mental health literacy is vital for well-being in educational settings, extending beyond academics to include social and emotional development. It empowers individuals, allowing them to recognize and address their mental health needs and provide essential support to their peers. Despite the acknowledged importance of modifiable factors, there is a noticeable research gap in those amenable to change through educational interventions. Thus, this systematic review aims to identify potentially modifiable predictors of mental health literacy in the educational context. A systematic search was conducted for quantitative studies published between 2019 and October 2023 using several databases following PRISMA guidelines. Studies needed to focus on potentially modifiable predictors of mental health literacy in the educational context. Study quality was assessed using the Appraisal tool for Cross-Sectional Studies (AXIS tool). In total, 3747 titles and abstracts were screened, 60 articles were assessed in full-text screening, and 21 were included in the review. Significant correlations between mental health literacy and modifiable predictors, including stigma toward professional help, self-efficacy, attitudes toward help-seeking, social support, positive psychological states, receiving mental health training, and psychological distress, were identified. By addressing these factors, educational institutions can cultivate community's adept in mental health, fostering an environment marked by empathy, understanding, and proactive engagement in addressing mental health issues. The implications serve as a foundation for future research, policy development, and implementing of practical strategies to enhance mental health literacy in diverse educational settings.

Internet analytics of an innovative digital educational resource of type 1 diabetes HelloType1 in local languages for people living with diabetes families and healthcare professionals in Southeast Asia.

BACKGROUND: There is minimal data of health outcomes for Type 1 Diabetes (T1D) in Southeast Asia (SEA) where government funding of insulin and blood glucose monitoring either do not exist or is limited. The full impact of Covid-19 pandemic on the national economies of SEA remain unknown. In the midst of the pandemic, in 2021, HelloType1 was developed by Action4Diabetes (A4D), a non-government organisation charity in collaboration with Southeast Asia local healthcare professionals as an innovative digital educational resource platform of T1D in local languages. HelloType1 was launched in Cambodia, Vietnam, Thailand and Malaysia in 2021 to 2022 with Memorandums of Understandings (MOUs) signed between A4D and each country. Internet data analytics were undertaken between the 1st of January 2022 to 31st of December 2022. AIMS: The aims of this study were to explore the usability and internet data analytics of the HelloType1 online educational platform within each country. METHODS: The data analytics were extracted Google analytics that tracks data from the website hellotype1.com and Facebook analytics associated with the website. RESULTS: There was a 147% increase in the number of HelloType1 users between the first 6 months versus the latter 6 months in 2022 and a 15% increase in the number of pages visited were noted. The majority of traffic source were coming from organic searches with a significant increase of 80% growth in 2022. CONCLUSIONS: The results of the analytics provide important insights on how an innovative diabetes digital educational resource in local languages may be optimally delivered in low-middle income countries with limited resources.

Clinical and genetic analysis of Vietnamese patients diagnosed with early-onset Parkinson's disease.

BACKGROUND: Genetic factors play a crucial role in the pathogenesis of Parkinson's disease (PD). However, no comprehensive study has described genetic alterations in Vietnamese patients diagnosed with PD. This study aimed to identify genetic causes and their association with clinical phenotypes in a Vietnamese PD cohort. METHODS: A total of 83 patients with early-onset PD (disease onset before the age of 50) were recruited for genetic analysis using a combination of multiplex ligation-dependent probe amplification and next-generation sequencing for a panel of 20 PD-associated genes. RESULTS: It was found that 37 out of 83 patients carried genetic alterations, with 24 pathogenic/likely pathogenic/risk variants and 25 variants of uncertain significance. The pathogenic/likely pathogenic/risk variants were mostly detected in LRRK2, PRKN, and GBA, while the variants of uncertain significance were identified in 12 different genes that were studied. The most common genetic alteration was LRRK2 c.4883G>C (p.Arg1628Pro), and patients with PD carrying this variant were found to have a distinct phenotype. Participants carrying pathogenic/likely pathogenic/risk variants had a significantly higher rate of a family history of PD. CONCLUSION: These results provide a further understanding of genetic alterations associated with PD in a South-East Asian population.

Association of KCNJ11 and ABCC8 single-nucleotide polymorphisms with type 2 diabetes mellitus in a Kinh Vietnamese population.

Type 2 diabetes mellitus (T2DM) is a genetically influenced disease, but few studies have been performed to investigate the genetic basis of T2DM in Vietnamese subjects. Thus, the potential associations of KCNJ11 and ABCC8 single nucleotide polymorphisms (SNPs) with T2DM were investigated in a Kinh Vietnamese population. A cross-sectional study consisting of 404 subjects including 202 T2DM cases and 202 non-T2DM controls was designed to examine the potential associations of 4 KCNJ11 and ABCC8 SNPs (rs5219, rs2285676, rs1799859, and rs757110) with T2DM. Genotypes were identified based on restriction fragment length polymorphism and tetra-primer amplification refractory mutation system polymerase chain reaction. After statistically adjusting for age, sex, and BMI, rs5219 was found to be associated with an increased risk of T2DM under 2 inheritance models: codominant (OR = 2.15, 95% confidence intervals [CI] = 1.09-4.22) and recessive (OR = 2.08, 95%CI = 1.09-3.94). On the other hand, rs2285676, rs1799859, and rs757110 were not associated with an increased risk of T2DM. Haplotype analysis elucidated a strong linkage disequilibrium between the 3 SNPs, rs5219, rs2285676, and rs757110. The haplotype rs5219(A)/rs2285676(T)/rs757110(G) was associated with an increased risk of T2DM (OR = 1.42, 95%CI = 1.01-1.99). The results show that rs5219 is a lead candidate SNP associated with an increased risk of developing T2DM in the Kinh Vietnamese population. Further functional characterization is needed to uncover the mechanism underlying the potential genotype-phenotype associations.

Oreocharisphuongii (Gesneriaceae), a new species from central Vietnam.

Oreocharisphuongii, a new species of Gesneriaceae from central Vietnam, is described and illustrated here. The new species is most similar to O.longifolia by sharing peduncles up to 22 cm long, bracts 2, zygomorphic, yellow flowers with tubular corolla, stamens 4 with two pairs of coherent anthers and capsules up to 6 cm long. It mainly differs from the latter by the combination of some morphological characters of leaves (shape, base, apex and margin), size of calyx lobes, indumentum of corolla tube and inner surface of three lower corolla lobes. Detailed morphological description together with colour illustration, information on phenology, distribution, ecology, preliminarily conservation status of the new species and comparison with its similar species are also presented.

Molecular characteristics of young-onset colorectal cancer in Vietnamese patients.

BACKGROUND: Colorectal cancer (CRC) is one of the most common cancer globally. Understanding the genetic characteristics of CRC is essential for appropriate treatment and genetic counseling. METHODS: The genetic profile of CRC tumor tissues was identified using next-generation sequencing of 17 target genes (MLH1, MSH2, MSH6, PMS2, EPCAM, APC, SMAD4, BMPR1A, MUTYH, STK11, PTEN, TP53, ATM, CDH1, CHEK2, POLE, and POLD1) in a cohort of 101 Vietnamese patients diagnosed with young-onset CRC. Corresponding germline genetic alterations of determined somatic mutations were subsequently confirmed from patients' blood samples. RESULTS: Somatic mutations were determined in 96 out of 101 CRC patients. Two-thirds of the tumors harbored more than two mutations, and the most prevalent mutated genes were TP53 and APC. Among confirmed germline mutations, 10 pathogenic mutations and 11 variants of unknown significance were identified. CONCLUSIONS: Given the burden of CRC and the gradually reducing cost of genetic testing, multigene panel screening can benefit young-onset CRC patients as well as their relatives.

Asymptomatic Infant With Atypical SCID and Novel Hypomorphic RAG Variant Identified by Newborn Screening: A Diagnostic and Treatment Dilemma.

The T-cell receptor excision circle (TREC) assay detects T-cell lymphopenia (TCL) in newborns and is especially important to identify severe combined immunodeficiency (SCID). A spectrum of SCID variants and non-SCID conditions that present with TCL are being discovered with increasing frequency by newborn screening (NBS). Recombination-activating gene (RAG) deficiency is one the most common causes of classical and atypical SCID and other conditions with immune dysregulation. We present the case of an asymptomatic male with undetectable TRECs on NBS at 1 week of age. The asymptomatic newborn was found to have severe TCL, but normal B cell quantities and lymphocyte proliferation upon mitogen stimulation. Next generation sequencing revealed compound heterozygous hypomorphic RAG variants, one of which was novel. The moderately decreased recombinase activity of the RAG variants (16 and 40%) resulted in abnormal T and B-cell receptor repertoires, decreased fraction of CD3+ TCRVα7.2+ T cells and an immune phenotype consistent with the RAG hypomorphic variants. The patient underwent successful treatment with hematopoietic stem cell transplantation (HSCT) at 5 months of age. This case illustrates how after identification of a novel RAG variant, in vitro studies are important to confirm the pathogenicity of the variant. This confirmation allows the clinician to expedite definitive treatment with HSCT in an asymptomatic phase, mitigating the risk of serious infectious and non-infectious complications.

Anti-Atherosclerotic Properties of Wild Rice in Low-Density Lipoprotein Receptor Knockout Mice: The Gut Microbiome, Cytokines, and Metabolomics Study.

BACKGROUND AND AIM: We previously reported the anti-atherogenic properties of wild rice in low-density lipoprotein receptor knockout (LDL-r-KO) mice. The present study aimed to discover the mechanism of action for such effects. MATERIALS: Fecal and plasma samples from the wild rice treated and control mice were used. Fecal bacterial population was estimated while using 16S rDNA technology. The plasma samples were used to estimate the levels of 35 inflammatory markers and metabolomics, while using Meso Scale multiplex assay and liquid chromatography-mass spectrometry (LC-MS/MS) techniques. RESULTS: Many bacteria, particularly Anaeroplasma sp., Acetatifactor sp., and Prophyromonadaceae sp., were found in higher quantities in the feces of wild rice fed mice as compared to the controls. Cytokine profiles were significantly different between the plasma of treated and control mice. Among them, an increase in the level of IL-10 and erythropoietin (EPO) could explain the anti-atherogenic properties of wild rice. Among many metabolites tested in plasma of these animals, surprisingly, we found an approximately 60% increase in the levels of glucose in the wild rice fed mice as compared to that in the control mice. CONCLUSION: Additional studies warrant further investigation of the interplay among gut microbiome, inflammatory status, and macronutrient metabolism.

Chronic oral application of a periodontal pathogen results in brain inflammation, neurodegeneration and amyloid beta production in wild type mice.

BACKGROUND: The results from cross sectional and longitudinal studies show that periodontitis is closely associated with cognitive impairment (CI) and Alzhemer's Disease (AD). Further, studies using animal model of periodontitis and human post-mortem brain tissues from subjects with AD strongly suggest that a gram-negative periodontal pathogen, Porphyromonas gingivalis (Pg) and/or its product gingipain is/are translocated to the brain. However, neuropathology resulting from Pg oral application is not known. In this work, we tested the hypothesis that repeated exposure of wild type C57BL/6 mice to orally administered Pg results in neuroinflammation, neurodegeneration, microgliosis, astrogliosis and formation of intra- and extracellular amyloid plaque and neurofibrillary tangles (NFTs) which are pathognomonic signs of AD. METHODS: Experimental chronic periodontitis was induced in ten wild type 8-week old C57BL/6 WT mice by repeated oral application (MWF/week) of Pg/gingipain for 22 weeks (experimental group). Another 10 wild type 8-week old C57BL/6 mice received vehicle alone (control group) MWF per week for 22 weeks. Brain tissues were collected and the presence of Pg/gingipain was determined by immunofluorescence (IF) microscopy, confocal microscopy, and quantitative PCR (qPCR). The hippocampi were examined for the signs of neuropathology related to AD: TNFα, IL1ß, and IL6 expression (neuroinflammation), NeuN and Fluoro Jade C staining (neurodegeneration) and amyloid beta1-42 (Aß42) production and phosphorylation of tau protein at Ser396 were assessed by IF and confocal microscopy. Further, gene expression of amyloid precursor protein (APP), beta-site APP cleaving enzyme 1 (BACE1), a disintegrin and metalloproteinase domain-containing protein10 (ADAM10) for α-secretase and presenilin1 (PSEN1) for É£-secretase, and NeuN (rbFox3) were determined by RT-qPCR. Microgliosis and astrogliosis were also determined by IF microscopy. RESULTS: Pg/gingipain was detected in the hippocampi of mice in the experimental group by immunohistochemistry, confocal microscopy, and qPCR confirming the translocation of orally applied Pg to the brain. Pg/gingipain was localized intra-nuclearly and peri-nuclearly in microglia (Iba1+), astrocytes (GFAP+), neurons (NeuN+) and was evident extracellularly. Significantly greater levels of expression of IL6, TNFα and IL1ß were evident in experimental as compared to control group (p<0.01, p<0.00001, p<0.00001 respectively). In addition, microgliosis and astrogliosis were evident in the experimental but not in control group (p <0.01, p<0.0001 respectively). Neurodegeneration was evident in the experimental group based on a fewer number of intact neuronal cells assessed by NeuN positivity and rbFOX3 gene expression, and there was a greater number of degenerating neurons in the hippocampi of experimental mice assessed by Fluoro Jade C positivity. APP and BACE1 gene expression were increased in experimental group compared with control group (p<0.05, p<0.001 respectively). PSEN1 gene expression was higher in experimental than control group but the difference was not statistically significant (p = 0.07). ADAM10 gene expression was significantly decreased in experimental group compared with control group (p<0.01). Extracellular Aß42 was detected in the parenchyma in the experimental but not in the control group (p< 0.00001). Finally, phospho-Tau (Ser396) protein was detected and NFTs were evident in experimental but not in the control group (p<0.00001). CONCLUSIONS: This study is the first to show neurodegeneration and the formation of extracellular Aß42 in young adult WT mice after repeated oral application of Pg. The neuropathological features observed in this study strongly suggest that low grade chronic periodontal pathogen infection can result in the development of neuropathology that is consistent with that of AD.

Germinated Brown Rice Attenuates Atherosclerosis and Vascular Inflammation in Low-Density Lipoprotein Receptor-Knockout Mice.

The present study investigates the impact of germinated brown rice (GBR) on atherosclerosis and the underlying mechanism in low-density lipoprotein receptor-knockout (LDLr-KO) mice. The intensity of atherosclerosis in aortas of LDLr-KO mice receiving diet supplemented with 60% GBR (weight/weight) was significantly less than that in mice fed with 60% white rice (WR) or control diet ( p < 0.05); all diets contained 0.06% cholesterol. WR or GBR diet did not significantly alter plasma total or LDL-cholesterol, fecal sterols, or glucose, or the activities of antioxidant enzymes, compared to the control diet. The adhesion of monocytes to aortas from LDLr-KO mice fed with WR diet was significantly more than that from mice receiving the control diet ( p < 0.01). GBR diet decreased monocyte adhesion to aortas compared to WR diet ( p < 0.01). GBR diet also reduced the levels of plasminogen activator inhibitor-1 (PAI-1), monocyte chemotactic protein-1 (MCP-1), and tumor necrosis factor-α (TNF-α) in plasma, and the abundances of MCP-1, PAI-1, TNF-α, intracellular cell adhesion molecule-1, toll-like receptor-4, PAI-1, LDLr-like protein, and urokinase plasminogen activator and its receptor in aortas or hearts from LDLr-KO mice in comparison to the WR diet ( p < 0.05, 0.01, respectively). The findings suggest that GBR administration attenuated atherosclerosis and vascular inflammation in LDLr-KO mice compared to WR. The anti-atherosclerotic effect of GBR in LDLr-KO mice at least in part results from its anti-inflammatory activity.

Maternal hypercholesterolemia enhances oxysterol concentration in mothers and newly weaned offspring but is attenuated by maternal phytosterol supplementation.

In hypercholesterolemic pregnancies, the maternal environment is characterized by excessive levels of atherogenic lipids that may increase cardiovascular disease risk in mothers and their offspring. We examined the influence of maternal hypercholesterolemia and phytosterol (PS) intervention on the concentration and metabolism of oxysterols, bioactive oxygenated cholesterol derivatives that regulate arterial health and lesion progression, in mothers and their newly weaned offspring. Twenty-one female apoE-/- mice were randomly assigned to three different diets throughout gestation and lactation: (1) chow, (2) high cholesterol (CH; 0.15%) and (3) CH with added PS (2%, CH/PS). At the end of the lactation period, mothers and pups were euthanized for serum and hepatic oxysterol analyses, hepatic transcriptional profiling of hepatic sterol regulatory targets and atherosclerosis. Hypercholesterolemic dams and their pups demonstrated increased (P˂.05) serum oxysterols [including 24 hydroxycholesterol (HC), 25HC, 27HC, 7αHC, 7ßHC and 7 ketocholesterol)] compared with the chow group that were normalized by maternal PS supplementation. Hepatic oxysterol concentrations followed a similar pattern of response in mothers but were not altered in newly weaned pups. Hepatic mRNA expression suggested a pattern of enhanced abca1/g1 high-density-lipoprotein-mediated efflux but a reduction in biliary abcg5/g8 export in both dams and their pups. Although arterial lesions were not apparent in newly weaned pups, CH dams demonstrated enhanced atherosclerosis that was reduced upon PS intervention. These results demonstrate that offspring from hypercholesterolemic pregnancies have enhanced circulating oxysterol concentrations and highlight the potential utility of PS as a lipid-lowering option during hypercholesterolemic pregnancies for which there are currently limited options.

Inhibitory Effects of North American Wild Rice on Monocyte Adhesion and Inflammatory Modulators in Low-Density Lipoprotein Receptor-Knockout Mice.

The present study examined the effects of wild rice on monocyte adhesion, inflammatory and fibrinolytic mediators in low-density lipoprotein receptor-knockout (LDLr-KO) mice. Male LDLr-KO mice received a cholesterol (0.06%, w/w)-supplemented diet with or without white or wild rice (60%, w/w) for 20 weeks. White rice significantly increased monocyte adhesion and abundances of monocyte chemoattractant protein-1, tissue necrosis factor-α, intracellular cell adhesion molecule-1, plasminogen activator inhibitor-1, urokinase plasminogen activator (uPA), and uPA receptor in aortae and hearts of LDLr-KO mice compared to the control diet. Wild rice inhibited monocyte adhesion to the aorta, atherosclerosis, and abundances of the inflammatory and fibrinolytic regulators in the cardiovascular tissue of LDLr-KO mice compared to white rice. White or wild rice did not significantly alter the levels of cholesterol, triglycerides, or antioxidant enzymes in plasma. The anti-atherosclerotic effect of wild rice may result from its inhibition on monocyte adhesion and inflammatory modulators in LDLr-KO mice.

Reduced monocyte adhesion to aortae of diabetic plasminogen activator inhibitor-1 knockout mice.

OBJECTIVE AND DESIGN: To determine the requirement of plasminogen activator inhibitor-1-knockout (PAI-1) for monocyte adhesion in animals and cells under diabetic conditions. METHODS AND SUBJECTS: Monocyte adhesion assay, enzyme-linked immunosorbent assay, and Western blotting were used in analyzing samples from PAI-1-knockout (PAI-1-KO) mice or cultured human umbilical vein endothelial cells (HUVEC). TREATMENTS: Diabetes in PAI-1-KO and wild-type mice was induced by intraperitoneal injection of streptozotocin (STZ). HUVEC was transfected with short interference RNA (siRNA) against PAI-1, tumor necrosis factor-α (TNFα), or toll-like receptor (TLR4), and then was treated with glycated low-density lipoproteins (glyLDL). RESULTS: The adhesion of monocytes to aortic intima was reduced in PAI-1-KO mice, which was associated with decreased levels of TNFα and monocyte chemotactic protein-1 (MCP-1) in plasma and cardiovascular tissue, and increased abundances of urokinase plasminogen activator (uPA) and uPA receptor (uPAR) in cardiovascular tissue compared to wild-type mice. Significant reductions in monocyte adhesion, inflammatory, and fibrinolytic regulators were detected in cardiovascular tissue or plasma in diabetic PAI-1-KO mice compared to wild-type diabetic mice. Transfection of PAI-1, TNFα or TLR4 siRNA to HUVEC inhibited glyLDL-induced monocyte adhesion to EC. PAI-1 siRNA inhibited the abundances of TLR4 and TNFα in EC. CONCLUSION: The findings suggest that PAI-1 is required for diabetes-induced monocyte adhesion via interactions with uPA/uPAR, and it also regulates TLR4 and TNFα expression in vascular EC. Inhibition of PAI-1 potentially reduces vascular inflammation under diabetic condition.

Dietary corn fractions reduce atherogenesis in low-density lipoprotein receptor knockout mice.

Accumulating evidence has suggested that intake of whole grains is a protective factor against pathogenesis of coronary artery disease. The exact mechanisms, however, are still not clearly understood. In this study, we hypothesized that adequate intake of corn fractions (aleurone, endosperm and germ) can modify lipid profiles in relation to atherosclerotic lesion development in low-density lipoprotein receptor knockout (LDLr-KO) mice. The purpose of the present study was to investigate the potential cardiovascular benefits of corn fractions in LDLr-KO mice through a number of biomarkers including lipid profile, and morphologic and morphometrical analysis of atherosclerotic lesions in aortic root. Four groups of male LDLr-KO mice were fed with the experimental diets supplemented with (3 treated) or without (control) 5% (wt/wt) of each of corn fractions for 10 weeks. All diets were supplemented with 0.06% (wt/wt) cholesterol. Compared with mice in the control group, atherosclerotic lesions in the aortic roots were significantly reduced (P=.003) in the mice that were fed diet supplemented with aleurone and germ fractions. This effect was associated with significant reductions in plasma total (P=.02) and LDL (P=.03) cholesterol levels, and an increase in fecal cholesterol excretion (P=.04). Furthermore, abdominal fat mass was significantly reduced by consumption of aleurone (P=.03). In summary, the consumption of aleurone and germ may help attenuate atherosclerosis by reducing plasma total and LDL cholesterol levels.

Combination effects of wild rice and phytosterols on prevention of atherosclerosis in LDL receptor knockout mice.

Dietary modifications including healthy eating constitute one of the first line strategies for prevention and treatment of atherosclerotic cardiovascular diseases (CVD), including atherosclerosis. In this study, we assessed anti-atherogenic effects of a combination of wild rice and phytosterols in low-density lipoprotein receptor knockout (LDL-r-KO) mice. Male LDL-r-KO mice were divided into four groups and fed with: (1) control diet; (2) the control diet containing 60% (w/w) wild rice; (3) the control diet containing 2% (w/w) phytosterols; or (4) the control diet containing both wild rice and phytosterols for 20weeks. All diets were supplemented with 0.06% (w/w) dietary cholesterol. Blood samples, hearts, and feces were collected and used for biochemical and histological examination. Consumption of 60% (w/w) wild rice in combination with 2% (w/w) phytosterols significantly reduced the size and severity of atherosclerotic lesions in the aortic roots as compared to those in the control group. This effect was associated with significant reductions in plasma total, LDL and VLDL cholesterol concentrations as well as an increase in fecal cholesterol excretion. In conclusion, the dietary combination of wild rice and phytosterols prevents atherogenesis in this animal model. Further investigations are needed to understand mechanisms of action and potential clinical outcome of such dietary intervention.

Endoplasmic reticulum stress in diabetic mouse or glycated LDL-treated endothelial cells: protective effect of Saskatoon berry powder and cyanidin glycans.

Endoplasmic reticulum (ER) stress is associated with insulin resistance and diabetic cardiovascular complications, and mechanism or remedy for ER stress remains to be determined. The results of the present study demonstrated that the levels of ER stress or unfolded protein response (UPR) markers, the intensity of thioflavin T (ThT) fluorescence and the abundances of GRP78/94, XBP-1 and CHOP proteins were elevated in cardiovascular tissue of diabetic leptin receptor-deficient (db/db) mice. Cyanidin-3-glucoside (C3G) and cyanidin-3-galactoside (C3Ga) are major anthocyanins in Saskatoon berry (SB) powder. The administration of 5% SB powder for 4 weeks attenuated ThT fluorescence and the UPR markers in hearts and aortae of wild-type and db/db mice. Treatment with glycated low-density lipoprotein (gLDL) increased ThT intensity in human umbilical vein endothelial cells (ECs). Elevated UPR markers were detected in gLDL-treated EC compared to control cultures. The involvement of ER stress in gLDL-treated EC was supported by that the addition of 4-phenyl butyrate acid (a known ER stress antagonist) inhibited gLDL-induced increases in ER stress or UPR markers. C3G at 30 µM or C3Ga at 100 µM reached their maximal inhibition on gLDL-induced increases in ThT, GRP78/94, XBP-1 and CHOP in EC. The results demonstrated that ER stress was enhanced in cardiovascular tissue of db/db mice or gLDL-treated EC. SB powder or cyanidin glycans prevented the abnormal increases in ER stress and UPR markers in cardiovascular tissue of diabetic db/db mice or gLDL-treated EC.

Effects of Saskatoon berry powder on monocyte adhesion to vascular wall of leptin receptor-deficient diabetic mice.

HYPOTHESIS: Atherosclerotic cardiovascular complications are the leading cause of death in diabetic patients. Monocyte adhesion is an early event for atherogenesis. Previous studies demonstrated that dark-skin berries had cardiovascular protective effects. We hypothesize that Saskatoon berry (SB) powder may reduce monocyte adhesion in leptin receptor-deficient (db/db) diabetic mice. METHODS: Wild-type and db/db mice were fed with chow or supplemented with SB powder. Anthocyanins in SB powder were identified using mass spectrometry. Mouse monocytes were incubated with mouse aorta. Monocyte adhesion was counted under microscopy. Inflammatory or metabolic markers in blood or tissue were analyzed using immunological or biochemical methods. RESULTS: SB powder significantly reduced monocyte adhesion to aorta from diabetic db/db mice compared to regular chow. The increased monocyte adhesion to aorta was normalized in db/db mice treated with ≥5% of SB powder for 4 weeks. Increased contents of Nicotinamide adenine dinucleotide phosphate oxidase (NADPH) oxidase-4, heat shock factor-1, monocyte chemotactic protein (MCP)-1, intracellular adhesion molecule (ICAM)-1, P-selectin, tumor necrosis factor-α, plasminogen activator inhibitor (PAI)-1 and urokinase plasminogen activator in aorta or heart apex, elevated plasma PAI-1 and MCP-1 were detected in db/db mice on chow compared to wild-type mice on the same diet; 5% SB powder inhibited the increases of inflammatory, fibrinolytic or stress regulators in aorta or heart apex of db/db mice. Monocyte adhesion positively correlated with blood glucose, cholesterol, body weight, heart MCP-1, PAI-1 or ICAM-1. CONCLUSION: The findings suggest that SB powder attenuated monocyte adhesion to aorta of db/db mice, which was potentially mediated through inhibiting the inflammatory, stress and/or fibrinolyic regulators.

The effects of fish oil consumption on cardiovascular remodeling in ApoE deficient mice.

Owing to their spontaneous development of atherosclerosis, apolipoprotein E knockout mice (ApoE(KO)) are one of the best studied animal models for this disease. Little is known about the utility of various omega-3 fatty acid regimens, in particular fish oils, in preventing cardiac disease in ApoE(KO) mice. The purpose of this study was to determine the cardiovascular effects of omega-3 fatty acid supplementation with either safflower oil (control), fish oil, flaxseed oil, or designed oil in ApoE(KO) mice fed a high-fat diet for a total of 16 weeks. In-vivo cardiac function was assessed weekly using murine echocardiography. Blood pressure, plasma lipid levels, and brain natriuretic peptide (BNP) were serially measured. The results show that ApoE(KO) mice fed fish oil demonstrated an increase in left ventricular wall thickness as a result of increased afterload. Despite chronic treatment with fish oil over 16 weeks, blood pressure increased in ApoE(KO) mice by 20% compared with the baseline. Both echocardiographic evidence of left ventricular hypertrophy and biochemical increase in BNP levels confirmed diastolic dysfunction in ApoE(KO) mice fed fish oil. This suggests that high-fat diet supplemented with fish oil may lead to adverse cardiovascular effects in ApoE deficient mice.

Wild rice (Zizania palustris L.) prevents atherogenesis in LDL receptor knockout mice.

OBJECTIVES: Dietary modifications including healthy eating constitute one of the first line strategies for prevention and treatment of cardiovascular disease (CVD) risk factors including high cholesterol and atherosclerosis. The purpose of the present study was to investigate the potential cardiovascular benefits of wild rice in male and female LDL-receptor-deficient (LDLr-KO) mice. METHODS: Wild rice was used to create a semi-synthetic diet containing approximately 60% of total energy from carbohydrate. Two other experimental diets were similar in macronutrient composition, but containing either white rice or commercial carbohydrate sources. All diets were supplemented with 0.06% (w/w) dietary cholesterol. The mice were divided into six experimental groups and fed with these diets over 24 weeks. RESULTS: Consumption of wild rice significantly reduced the size and severity of atherosclerotic lesions in the aortic roots of male and female mice by 71 and 61% respectively, compared to the control group of the same gender. This effect was associated with significant reductions of plasma cholesterol levels by 15 and 40%, low density lipoprotein (LDL) levels by 12 and 42%, and very low density lipoprotein (VLDL) levels by 35 and 75% respectively, in male and female mice compared to the control group of the same gender. Increased fecal cholesterol excretion of up to 34% was also noted, compared to the control group of the same gender. However, the antiatherogenic effect of wild rice was not associated with increased superoxide dismutase (SOD) and catalase (CAT) activities. CONCLUSION: Current data suggest that cholesterol-lowering effects of wild rice may be the main factor for the prevention of atherogenesis in LDLr-KO mice. Additional studies are needed to understand the mechanism of action.