Relationship of dietary intake of food folate and synthetic folic acid intake from fortified foods with all-cause mortality in individuals with chronic kidney disease.

OBJECTIVE: To evaluate the association of the dietary intake of food folate (natural folate) and synthetic folic acid intake from fortified foods with the risk of all-cause mortality and end-stage kidney disease (ESKD) among the chronic kidney disease (CKD) population in regions with folic acid fortification. METHODS: 4028 individuals with established CKD in Chronic Renal Insufficiency Cohort (CRIC) were included. Diet was assessed using a validated diet history questionnaire at the baseline, year 2, and year 4, and nutrient intake, including food folate and folic acid from fortified foods, was estimated using the National Nutrient Database. The outcomes were all-cause mortality and ESKD. The results for all-cause mortality were further validated using the data from National Health and Nutrition Examination Surveys (NHANES). RESULTS: During a median follow-up of 11.1 years, 1155 deaths and 938 ESKD cases occurred. Compared with the first quartile of food folate intake, the third (HR: 0.74; 95% CI: 0.62, 0.90) and fourth (HR: 0.79; 95% CI: 0.63, 0.98) quartiles had a lower risk of all-cause mortality. Nevertheless, there was no significant association of synthetic folic acid intake from fortified foods with all-cause mortality. Similar results were observed for ESKD. Consistently, in NHANES, food folate intake and serum 5-methyltetrahydrofolate, but not folic acid intake, were inversely associated with all-cause mortality, while serum unmetabolized folic acid was positively associated with all-cause mortality in CKD participants. CONCLUSIONS: Higher intake of dietary natural folate, but not synthetic folic acid intake from fortified foods, was associated with lower risks of all-cause mortality and ESKD among CKD participants.

Association of unsweetened and sweetened tea consumption with the risk of new-onset chronic kidney disease: Findings from UK Biobank and Coronary Artery Risk Development in Young Adults (CARDIA) study.

Background: The association between tea consumption and chronic kidney disease (CKD) remained inconsistent. We aimed to evaluate the association of tea consumption with new-onset CKD and examine the effects of common additives (milk and sweeteners) and genetic variations in caffeine metabolism on the association. Methods: 176 038 and 3104 participants free of CKD at baseline in the United Kingdom Biobank (UK Biobank) and Coronary Artery Risk Development in Young Adults (CARDIA) study were included, respectively. Dietary information was collected using 24-hour dietary recall questionnaires. The study outcome was new-onset CKD. Results: In the UK Biobank, during a median follow-up of 12.13 years, 3535 (2.01%) participants developed CKD. Compared with tea non-consumers, the risk of new-onset CKD was significantly lower in unsweetened tea consumers (hazard ratio (HR) = 0.84, 95% confidence interval (CI) = 0.76-0.93), but not in sweetened tea consumers (HR = 0.96, 95% CI = 0.85-1.08), regardless of whether milk was added to tea. Accordingly, relative to tea non-consumers, the adjusted HRs (95% CIs) of new-onset CKD for participants who reported drinking unsweetened tea 1.5 or fewer, >1.5 to 2.5, >2.5 to 3.5, >3.5 to 4.5, and >4.5 drinks/d were HR = 0.86, 95% CI = 0.75-0.99; HR = 0.88, 95% CI = 0.78-1.00; HR = 0.83, 95% CI = 0.73-0.94; HR = 0.83, 95% CI = 0.72-0.95; and HR = 0.86, 95% CI = 0.75-0.99. Moreover, the association of unsweetened tea consumption with new-onset CKD was stronger among those with faster genetically predicted caffeine metabolism levels, although the interaction was insignificant (P-value interaction = 0.768). Consistently, in the CARDIA study, compared with tea non-consumers, a significantly lower risk of new-onset CKD was found in unsweetened tea consumers (HR = 0.80, 95% CI = 0.65-0.98) but not in sweetened tea consumers (HR = 0.97, 95% CI = 0.70-1.34). Conclusions: Compared with tea non-consumers, consumption of unsweetened tea, but not sweetened tea, was significantly associated with a lower risk of new-onset CKD, regardless of whether milk was added.

Habitual glucosamine use, APOE genotypes, and risk of incident cause-specific dementia in the older population.

BACKGROUND: The relationship of glucosamine use with incident dementia in the older population remains uncertain. We aimed to evaluate the longitudinal association between habitual glucosamine supplement and the risk of cause-specific dementia and examine the possible effect modifiers on this association. METHODS: The study included 214,945 participants over the age of 60 who had available information on glucosamine use and did not have dementia at baseline in the UK Biobank. The APOE genotypes were determined by a combination variant of rs429358 and rs7412. The primary outcome was incident vascular dementia, incident Alzheimer's disease, and incident frontotemporal dementia, respectively. RESULTS: Over a median follow-up duration of 12 years, 1039, 1774, and 122 participants developed vascular dementia, Alzheimer's disease, and frontotemporal dementia, respectively. Overall, habitual glucosamine use was significantly associated with a lower risk of incident vascular dementia (adjusted HR, 0.82; 95%CI, 0.70-0.96), but not significantly associated with incident Alzheimer's disease (adjusted HR, 1.02; 95%CI, 0.92-1.14) and incident frontotemporal dementia (adjusted HR, 0.95; 95%CI, 0.63-1.43). Moreover, the inverse association between habitual glucosamine use and incident vascular dementia was more pronounced in participants with concomitant supplement of calcium (P-interaction = 0.011), and those without concomitant supplement of zinc (P-interaction = 0.018). However, APOE ε4 dosage and baseline cognitive function did not significantly modify the relationships of glucosamine use with incident vascular dementia or Alzheimer's disease (All P-interactions > 0.05). CONCLUSIONS: Regardless of APOE genotypes and baseline cognitive function, habitual glucosamine use was significantly inversely associated with incident vascular dementia in the older population.

Tea Consumption and New-Onset Acute Kidney Injury: The Effects of Milk or Sweeteners Addition and Caffeine/Coffee.

Aims: To explore the relationship between tea consumption and the risk of incident acute kidney injury (AKI) and examine the effects of coffee consumption, genetic variation in caffeine metabolism, and the use of tea additives (milk and sweeteners) on this association. Methods: Using data from the UK Biobank, 498,621 participants who were free of AKI and had information on tea intake were included. Black tea is the main type consumed in this population. Dietary information was collected from standardized and validated Food-Frequency Questionnaire (FFQ). Outcome was incident AKI, determined via primary care data, hospital inpatient data, death register records, or self-reported data at follow-up visits. Results: After a median follow-up period of 12.0 years, 21,202 participants occurred AKI. Overall, there was a reversed J-shaped relation between tea consumption and incident AKI, with an inflection point at 3.5 cup/d (p for nonlinearity < 0.001). The relation was similar among participants with different genetically predicted caffeine metabolism (p-interaction = 0.684), while a more obvious positive association was found between heavy tea consumption and AKI when more coffee was consumed (p-interaction < 0.001). Meanwhile, there was a reversed J-shaped relationship for drinking tea with neither milk nor sweeteners, and a L-shaped association for drinking tea with milk (with or without sweeteners) with incident AKI. However, no significant association was found between drinking tea with sweeteners only and incident AKI. Conclusions: There was a reversed J-shaped relation between tea consumption and incident AKI, suggesting that light to moderate tea consumption, especially adding milk, can be part of a healthy diet.

Associations between Serum 25-hydroxyvitamin D, Sun Exposure Time, Dietary Vitamin D Intake, and New-Onset Acute Kidney Injury among 413,169 UK Adults.

BACKGROUND: The prospective associations of serum 25(OH)D, sun exposure time, and dietary vitamin D with risk of acute kidney injury (AKI) are unclear. OBJECTIVES: We aimed to evaluate the relations of serum 25(OH)D, sun exposure time, and dietary vitamin D intake with new-onset AKI and examine whether genetic susceptibility modified such associations. METHODS: A total of 413,169 participants (mean age was 56.4 y, 47.2% were male) from UK Biobank without prior AKI were included. Sun exposure time was expressed as time spent outdoors. Genetic risk scores were calculated by 263 single nucleotide polymorphisms, which showed significant associations with the estimated glomerular filtration rate. The primary outcome was new-onset AKI. Cox proportional hazards models were used to estimate the HRs and (95% CIs). RESULTS: During a median follow-up duration of 12 y, 16,938 (4.1%) participates developed new-onset AKI. Compared with those with serum 25(OH)D <25 nmol/L, significantly lower risks of new-onset AKI were found between participants with 25(OH)D 25 to <50 nmol/L (adjusted HR: 0.76; 95% CI: 0.73, 0.80), and ≥50 nmol/L (adjusted HR: 0.69; 95% CI: 0.65, 0.72). Moreover, in summer, participants who spent ≥4 h outdoors per day (tertile 3) had a significantly lower risk of new-onset AKI (adjusted HR: 0.90; 95% CI: 0.86, 0.95) than those who spent <2 h outdoors per day (tertile 1). Similar results were found for time spent outdoors in winter. In addition, those in quintile 5 of dietary vitamin D intake showed a lower risk of new-onset AKI (≥4.2 µg/d, adjusted HR: 0.90; 95% CI: 0.82, 0.98) than those in quintile 1 (<1.0 µg/d). Genetic risks of kidney diseases did not significantly modify all the 3 above associations (all P-interactions >0.05). CONCLUSIONS: Serum 25(OH)D concentrations, time spent outdoors, and dietary vitamin D intake were all inversely associated with new-onset AKI, independent of genetic risks for kidney diseases.

Simiao pill attenuates collagen-induced arthritis and bleomycin-induced pulmonary fibrosis in mice by suppressing the JAK2/STAT3 and TGF-ß/Smad2/3 signalling pathway.

ETHNOPHAMACOLOGICAL RELEVANCE: Simiao Pill (SM) as a classic prescription of traditional Chinese medicine treatment of damp-heat arthralgia, the earliest from 'Cheng Fan Bian Du ', written by the Qing Dynasty doctor Zhang Bingcheng. Previous studies have shown that SM has obvious curative effect on rheumatoid arthritis, which provides a basis for the application of SM in rheumatoid arthritis related complications. AIM OF THE STUDY: Interstitial lung disease (ILD), as the most severe complication of rheumatoid arthritis (RA), lacks effective clinical treatments and a corresponding animal model. Simiao pill (SM) is a traditional Chinese medicine prescription extensively used as a complementary and alternative treatment for RA. However, the effect and mechanism of SM on RA-ILD have not yet been reported. This study aimed to investigate an appropriate animal model that can simulate RA-ILD, and the efficacy, safety, and mechanism of SM on RA-ILD. METHODS: Collagen-induced arthritis (CIA) and bleomycin-induced pulmonary fibrosis model were combined to construct the CIA-BLM model. After the intervention of SM, the protective effects of SM on RA-ILD were determined by detecting the CIA mouse arthritis index (AI), Spleen index, and the extent of pulmonary fibrosis. The joint inflammation and pulmonary fibrosis were detected by immunohistochemistry, H&E staining, safranin- O fast green Sirius red staining, trap staining, and Masson staining. Finally, the mechanism was verified by Western blot and immunohistochemistry. RESULTS: Our work showed that SM significantly reduced joint swelling, arthritis index, pulmonary fibrosis score, and spleen index in CIA mice. The pathological examination results indicated Si-Miao Pill suppressed inflammation, pulmonary fibrosis, bone erosion, and cartilage degradation of the ankle joint. Besides, SM up-regulated expressions of E-cadherin, whereas down-regulated expressions of α-SMA. Further studies confirmed that SM regulated JAK2/STAT3 and TGF-ß/SMAD2/3. CONCLUSION: SM can not only effectively improve joint inflammation by JAK2/STAT3 Pathway but also inhibit pulmonary fibrosis by TGF-ß/SMAD2/3. The fibrosis induced by CIA-BLM model was more stable and obvious than that induced by CIA model alone.

Associations of habitual glucosamine supplementation with incident gout: a large population based cohort study.

OBJECTIVES: The association between habitual glucosamine use and incident gout has not been examined in previous studies. We aimed to evaluate the association of habitual use of glucosamine with the risk of gout in general population. METHODS: A total of 436,594 participants (55.4% female) without prior gout at baseline who completed a questionnaire on supplementation use, which included glucosamine, in the UK Biobank were enrolled. Incident gout was recorded from self-report, death register, primary care, and hospital admission data. RESULTS: At baseline, 53,433 (22.1%) females and 30,685 (15.8%) males reported habitual glucosamine use. During a median follow-up period of 12.1 years, 1718 (0.7%) females and 5685 (2.9%) males developed gout. After multivariable adjustment for major risk factors, glucosamine use was associated with a significantly lower risk of incident gout in females (hazard ratio [HR], 0.81, 95% confidence interval [CI], 0.71-0.92), but not in males (HR, 1.05, 95% CI, 0.97-1.13), compared with non-use (P-interaction < 0.001). Among females, the inverse association between glucosamine use and gout was stronger in participants with diuretics use (HR, 0.64, 95% CI, 0.50-0.81) than those without diuretics use (HR, 0.89, 95% CI, 0.77-1.03) (P-interaction = 0.015). Moreover, gout genetic risk scores did not significantly modify the association between glucosamine use and the risk of incident gout in males (P-interaction = 0.548) or females (P-interaction = 0.183). CONCLUSIONS: Habitual glucosamine use to relieve osteoarthritis pain was related to lower risk of gout in females, but not in males.

Habitual Fish Oil Supplementation and Incident Chronic Kidney Disease in the UK Biobank.

BACKGROUND: To explore the relation of habitual fish oil use with the risk of chronic kidney diseases (CKD). METHODS: 408,023 participants (54.2% female) without prior CKD and with completed information regarding their consumption of major food groups and fish oil in the UK Biobank were enrolled. Fish oil use and dietary intakes were assessed by touch screen questionnaire and food frequency questionnaire, respectively. Incident CKD was recorded from hospital inpatient records. RESULTS: At baseline, 128,843 (31.6%) participants reported taking fish oil supplements. During a median follow-up period of 12.0 years, a total of 10,782 (2.6%) participants developed CKD. With adjustments for important confounders, habitual fish oil use was associated with a significantly lower hazard of incident CKD (hazard ratio [HR], 0.90; 95% confidence interval [CI], 0.87-0.95), compared with non-use. Consistently, participants reporting ≥2 servings/week of oily fish (HR, 0.86; 95% CI, 0.79-0.94) and nonoily fish (HR, 0.86; 95% CI, 0.77-0.97) consumption had a lower hazard of incident CKD compared to those reporting no consumption ever. Additionally, among the 97,914 participants with data on plasma fatty acid, there were significant inverse relationships of plasma omega-3 polyunsaturated fatty acid (PUFA) (per SD increment, HR, 0.89, 95% CI, 0.84-0.94) and eicosatetraenoic acid (per SD increment, HR, 0.91, 95% CI, 0.87-0.96) with incident CKD. CONCLUSIONS: Habitual fish oil use was associated with a lower hazard of CKD, which was further confirmed by the consistent inverse relations between fish consumption and circulating omega-3 PUFA concentration with incident CKD.

Berberine Modulates LPA Function to Inhibit the Proliferation and Inflammation of FLS-RA via p38/ERK MAPK Pathway Mediated by LPA1.

OBJECTIVE: This study aimed to investigate whether berberine exerted anti-inflammatory and antiproliferative effects on the fibroblast-like synoviocytes of rheumatoid arthritis (FLS-RA) through regulating the lysophosphatidic acid (LPA) function. METHODS: Firstly, the expression levels of LPA and lysophosphatidic acid receptor 1 (LPA1) in RA patients, osteoarthritis (OA) patients, and healthy controls were detected. Moreover, molecular docking was employed to characterize the binding sites of berberine in the predicted protein targets. Later, FLS-RA were stimulated using berberine, LPA, and the specific inhibitor (Ki16425) of LPA1, thereafter, the effects on the proliferation, apoptosis, the release of inflammatory mediators of FLS-RA, and the MAPK pathway were observed. RESULTS: Compared with healthy controls (n = 25), the plasma LPA level (n = 28) and synovial fluid (n = 10) were markedly higher in RA patients. LPA1 was highly expressed in RA patients (n = 4) relative to that in OA patients (n = 4). Berberine remarkably inhibited the proliferation and the excessive production of IL-6 and TNF-α in FLS-RA, whereas suppressing the expression of K-ras, c-Raf, and p-38/ERK-phosphorylation. In addition, berberine inhibited the LPA-induced p-38/ERK-phosphorylation through binding to LPA1. CONCLUSIONS: LPA plays a certain role in promoting the proliferation and inflammation of FLS-RA. Berberine potentially modulates LPA function to suppress the proliferation and inflammation of FLS-RA through blocking the p38/ERK MAPK pathway mediated by LPA1. These findings suggest that, berberine possesses potential lipid-regulating, antiarthritis, and synovial hyperplasia inhibition activities against RA, which may provide a promising therapeutic target for the clinical drug development for RA patients with dyslipidemia and high CVD risk.

Dihydromyricetin improves type 2 diabetes-induced cognitive impairment via suppressing oxidative stress and enhancing brain-derived neurotrophic factor-mediated neuroprotection in mice.

Type 2 diabetes mellitus (T2DM) leads to cognitive impairment (CI), but there have been no effective pharmacotherapies or drugs for cognitive dysfunction in T2DM. Dihydromyricetin (DHM) is a natural flavonoid compound extracted from the leaves of Ampelopsis grossedentata and has various pharmacological effects including anti-oxidant and anti-diabetes. Thus, we investigated the effects of DHM on CI in T2DM mouse model and its possible mechanism. To induce T2DM, mice were fed with high-sugar and high-fat diet for 8 weeks, followed by a low dose streptozotocin (STZ) administration. After the successful induction of T2DM mouse model, mice were treated respectively with equal volume of saline (T2DM group), 125 mg/kg/d DHM (L-DHM group), or 250 mg/kg/d DHM (H-DHM group). After 16 weeks of DHM administration, the body weight (BW), fasting blood glucose, blood lipids, intraperitoneal glucose tolerance (IPGT), and cognitive function were determined. Then, alterations in the expressions of oxidative stress markers and brain-derived neurotrophic factor (BDNF) in the hippocampus were investigated. Our findings demonstrated that DHM could significantly ameliorate CI and reverse aberrant glucose and lipid metabolism in T2DM mice, likely through the suppression of oxidative stress and enhancement of BDNF-mediated neuroprotection. In conclusion, our results suggest that DHM is a promising candidate for the treatment of T2DM-induced cognitive dysfunction.

Multifunctional Bi@PPy-PEG Core-Shell Nanohybrids for Dual-Modal Imaging and Photothermal Therapy.

High-performance theranostic nanoagents, which integrate multimodal imaging and photothermal therapy for clinical anticancer treatment, are highly desired. Herein, we report the synthesis and bioapplication of a multifunctional theranostic nanoagent based on polyethylene glycol (PEG)-modified polypyrrole (PPy)-coated bismuth (Bi) nanohybrids (referred to as Bi@PPy-PEG NHs) for X-ray computed tomography/photoacoustic (CT/PA) dual-modal imaging and photothermal therapy (PTT). The obtained Bi@PPy-PEG NHs have a distinct core-shell structure with the metallic Bi nanoparticle as the inner core and the PPy-PEG layer as the shell. The Bi@PPy-PEG NHs show excellent physiological stability and compatibility, without noticeable cytotoxicity. Importantly, the NHs exhibit strong NIR absorbance and remarkable photothermal conversion capability and conversion stability, with the photothermal conversion efficiency as high as ∼46.3%. Thanks to the strong PTT effect, highly effective photothermal ablation on cancer cells has been achieved both in vitro and in vivo. Furthermore, a high-contrast in vitro and in vivo CT/PA dual-modal imaging has been realized, showing great potential to provide comprehensive diagnosis information for antitumor treatment. In particular, the CT enhancement efficiency of the NHs is of ∼14.4 HU mM-1, which is ∼3.7-fold that of clinically used iohexol. Therefore, our work highlights the potential of using such core-shell Bi@PPy-PEG NHs as a versatile theranostic nanoplatform for cancer imaging and therapy.

[Ameliorative effects and the mechanism of lyceum barbarum polysaccharide on insulin resistance of HepG2 cell].

OBJECTIVE: To observe the effects of lyceum barbarum polysaccharide (LBP) on insulin resistance of HepG2 cells and investigate its possible mechanism. METHODS: IR-HepG2 cell model was induced with high glucose and high insulin in combination for 24 hours,with 104/vaccination in the 96-well plates, hole density after adherent cells (30 µg/ml、100 µg/ml、300 µg/ml) LBP cultivate 48 h, 200 µl/hole, each all had four holes. The effects of LBP at different concentrations on HepG2 cell activity and insulin resistance were tested. Intracellular malondialdehyde (MDA) content and superoxide dismutase (SOD) activity were detected. The expressions of related proteins in insulin signal transduction pathways such as insulin receptor substrate-2(IRS-2), phosphatidylinositol-3-kinase(PI3-K), protein kinase B(Akt) and glucose transport-2(GLUT2) were determined. RESULTS: Compared with normal control group, the content of MDA was increased significantly and the activity of SOD and the expression levels of IRS-2,PI-3K,Akt and GLUT2 were decreased significantly in the IR model group. Compared with IR model group, medium and high concentrations of LBP decreased the content of MDA and increased the activity of SOD and the expression levels of IRS-2, PI-3K, Akt and GLUT2 in insulin-resistant HepG2 cells. MTT showed that at the same time, the OD value gradually decreased with the increase of LBP's concentration; under the same concentration of LBP, the OD value also gradually decreased with the extension of time, which indicated that LBP inhibited the proliferation of HepG2 cells with time and concentration-dependent manner. Glucose consumption experiment indicated that medium and high concentration of LBP could increase the glucose consumption of insulin-resistant HepG2 cells significantly, but low concentration of LBP had no significant impacted on glucose consumption of insulin-resistant HepG2 cells. CONCLUSIONS: Medium and high concentration of LBP can improve insulin resistance of HepG2 cell, its mechanisns may be associated with decreasing the level of oxidative stress and increasing the protein expressions of insulin signaling pathway.

Berberine ameliorates collagen-induced arthritis in rats associated with anti-inflammatory and anti-angiogenic effects.

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by inflammation and joint destruction. In this study, we explored the effect of berberine on rats with bovine type II collagen-induced arthritis (CIA), an animal model for RA. Following treatment, berberine attenuates arthritic scores and suppresses collagen-specific immune responses in CIA rats. Compared with the un-treated CIA group, berberine reversed pathological changes, which showed a significant improvement in synovial hyperplasia and inflammatory infiltration. The expression levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, IL-17 and vascular endothelial growth factor (VEGF) were obviously reduced in the sera of berberine-treated rats (all P<0.05). Moreover, berberine showed marked inhibition of the expression of VEGF and CD34 (all P<0.05). Interestingly, berberine significantly suppresses p-ERK, p-p38 and p-JNK activation (all P<0.05), which may partially explain the anti-RA activity of berberine. These results suggest that berberine ameliorates CIA in rats associated with anti-inflammatory and anti-angiogenic effects, which might be of great therapeutic value for RA.