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1.
Proc Natl Acad Sci U S A ; 120(23): e2219419120, 2023 06 06.
Article in English | MEDLINE | ID: mdl-37252972

ABSTRACT

Prolyl hydroxylase domain (PHD) enzymes change HIF activity according to oxygen signal; whether it is regulated by other physiological conditions remains largely unknown. Here, we report that PHD3 is induced by fasting and regulates hepatic gluconeogenesis through interaction and hydroxylation of CRTC2. Pro129 and Pro615 hydroxylation of CRTC2 following PHD3 activation is necessary for its association with cAMP-response element binding protein (CREB) and nuclear translocation, and enhanced binding to promoters of gluconeogenic genes by fasting or forskolin. CRTC2 hydroxylation-stimulated gluconeogenic gene expression is independent of SIK-mediated phosphorylation of CRTC2. Liver-specific knockout of PHD3 (PHD3 LKO) or prolyl hydroxylase-deficient knockin mice (PHD3 KI) show attenuated fasting gluconeogenic genes, glycemia, and hepatic capacity to produce glucose during fasting or fed with high-fat, high-sucrose diet. Importantly, Pro615 hydroxylation of CRTC2 by PHD3 is increased in livers of fasted mice, diet-induced insulin resistance or genetically obese ob/ob mice, and humans with diabetes. These findings increase our understanding of molecular mechanisms linking protein hydroxylation to gluconeogenesis and may offer therapeutic potential for treating excessive gluconeogenesis, hyperglycemia, and type 2 diabetes.


Subject(s)
Diabetes Mellitus, Type 2 , Glucose , Humans , Mice , Animals , Glucose/metabolism , Proline/metabolism , Hydroxylation , Diabetes Mellitus, Type 2/metabolism , Liver/metabolism , Cyclic AMP Response Element-Binding Protein/genetics , Cyclic AMP Response Element-Binding Protein/metabolism , Gluconeogenesis/physiology , Prolyl Hydroxylases/metabolism , Hepatocytes/metabolism , Mice, Inbred C57BL
2.
Ecotoxicol Environ Saf ; 270: 115877, 2024 Jan 15.
Article in English | MEDLINE | ID: mdl-38150747

ABSTRACT

Epigenetics, specifically histone post-translational modification (HPTM) induced by environmental factors, plays a crucial role in the development of diabetes. Sodium benzoate (NAB) is a widely used additive, however, its potential contribution to diabetes has been largely overlooked. In 2018, a novel HPTM called benzoylation (Kbz) induced by NAB was discovered. This modification can be catalyzed by ACSS2 (acyl-CoA synthetase short-chain member 2) and acyltransferase P300/CBP, and can be reversed by erase enzymes SIRT2. Studies have indicated that Kbz may regulate insulin secretion, although the exact molecular mechanism remains unclear. In our study, C57BL/6J mice were divided into two groups: the NC group and the 1g/kg NAB water feeding group. In vivo experiments were conducted using ß-TC-6 cells, with 6 mM NAB or 100 µM benzoyl-CoA as stimuli, and 10 µM A485 (P300 inhibitor), 5 µM ACSS2 inhibitor (inhibiting benzoyl-CoA synthesis), or 5 µM AGK2 (SIRT2 inhibitor) as intervention factors. Our study found that, although the experimental concentration of NAB is below the maximum allowable concentration in food, it still damaged the insulin secretion function of C57BL/6J mice and induced inflammation and apoptosis of islet ß cells. We observed significant differences in serum benzoyl-CoA levels between healthy individuals and patients with type 2 diabetes. Furthermore, NAB concentration-dependently increases benzoyl-CoA and Kbz levels. When Kbz is down-regulated using A485 and ACSS2 inhibitor, we observed a reduction in ß cell inflammation, apoptosis, and insulin secretion damage. Conversely, up-regulating Kbz using AGK2 resulted in increased levels of ß cell inflammation and apoptosis. In conclusion, our data suggest that NAB, despite being within the safe dose range, may be an overlooked environmental risk factor contributing to the pathogenesis of diabetes through its impact on Kbz.


Subject(s)
Diabetes Mellitus, Type 2 , Sodium Benzoate , Humans , Mice , Animals , Sodium Benzoate/toxicity , Sodium Benzoate/metabolism , Sirtuin 2/metabolism , Diabetes Mellitus, Type 2/chemically induced , Mice, Inbred C57BL , Histones , Inflammation/chemically induced , Apoptosis
3.
BMC Endocr Disord ; 22(1): 174, 2022 Jul 08.
Article in English | MEDLINE | ID: mdl-35804355

ABSTRACT

BACKGROUND: Tumor-related osteomalacia (TIO) is a rare paraneoplastic syndrome characterized by severe hypophosphatemia and osteomalacia. The diagnosis of TIO can be very difficult because of its nonspecific nature of clinical manifestations. Here we reported a case of young TIO patient with "painful knee joint with difficulty in moving" to improve the clinical diagnosis and treatment levels. CASE PRESENTATION: The patient's clinical features were consistent with TIO. A tumor was successfully located in left tibial by 68Ga-DOTATATE PET/CT, and then was surgically resected. Upon pathologic assessment, the tumor was diagnosed as phosphaturia stromal tumor (PMT) with positive Vim staining. After the surgery, serum phosphate level rapidly recovered and symptoms significantly improved. CONCLUSION: TIO should be considered in patients with chronically hypophosphorus osteomalacia in the setting of no family history. Early removal of the responsible tumors is clinically essential for the treatment, and imaging examination is of great significance for tumor localization.


Subject(s)
Osteomalacia , Paraneoplastic Syndromes , Humans , Knee Joint/diagnostic imaging , Knee Joint/pathology , Knee Joint/surgery , Osteomalacia/etiology , Osteomalacia/surgery , Paraneoplastic Syndromes/etiology , Positron Emission Tomography Computed Tomography , Positron-Emission Tomography , Radionuclide Imaging
4.
Mediators Inflamm ; 2022: 7643322, 2022.
Article in English | MEDLINE | ID: mdl-35909658

ABSTRACT

Inflammation and fibrosis are the important pathophysiologic processes in diabetic kidney disease (DKD), which is induced by epigenetics, especially histone posttranslational modification (HPTMs). Recent reports highlighted that butyrate, one of the short-chain fatty acids (SCFAs) primarily originated from the fermentation of dietary fiber in the gut, attenuates inflammation and fibrosis in the prevention and treatment of DKD; however, the molecular mechanisms are still unclear. Histone lysine butyrylation (Kbu), a novel histone modification marker induced by butyrate, has been found to be involved in the regulation of pathophysiological processes. To reveal the mechanisms of butyrate-induced histone (Kbu), in the prevention and treatment of DKD, both DKD models in vivo and in vitro were treated with sodium butyrate (NaB). Our results confirmed that exogenous NaB improved the disorder of glucose and lipid metabolism, prevented proteinuria and renal failure, and inhibited renal inflammation and fibrosis. Meanwhile, NaB also induced histone Kbu and H3K9 butyrylation (H3K9bu) in vivo and in vitro; however, inhibition of histone Kbu with the histone modification enzyme p300 inhibitor A485 reversed the anti-inflammatory and anti-fibrosis effects of NaB. In conclusion, our data reveal that NaB antagonizes renal inflammatory and fibrosis injury and attenuates DKD possibly via histone Kbu, suggesting that butyrate-induced histone Kbu or H3K9bu may be an important molecular mechanism in the pathogenesis and treatment of DKD.


Subject(s)
Diabetes Mellitus , Diabetic Nephropathies , Butyric Acid/pharmacology , Butyric Acid/therapeutic use , Diabetic Nephropathies/drug therapy , Diabetic Nephropathies/metabolism , Histones/metabolism , Humans , Inflammation/drug therapy , Protein Processing, Post-Translational
5.
Nutr Cancer ; 73(1): 31-44, 2021.
Article in English | MEDLINE | ID: mdl-32202158

ABSTRACT

Non-digestible carbohydrate (NDC) is a fiber that can be fermented into short chain fatty acids (SCFAs) in gut, represented by resistant starch (RS) and inulin. Colorectal cancer (CRC) is one of the most common malignant cancer. Pre-clinical studies have reported that NDC can produce SCFAs to protect the gut epithelium, which is associated with prevention of CRC, but this role in clinical trails is controversial. In this review, we discusses whether RS and inulin should be offered to cancer/precancerous patients or healthy subjects to decrease their risk of CRC. A multiple database search was conducted for studies published on RS/inulin supplementation as a chemopreventive method from 1989 to 2019. The meta-analysis showed the total SCFAs and butyrate concentrations (P = 0.84; P = 0.79), and excretions (P = 0.55; P = 0.63) in feces did not increase significantly after RS/inulin supplementation. Only two studies reported that RS/inulin inhibit the proliferation of large bowel epithelial, whereas 15 studies showed that it does not decrease the risk of neoplasia. RS/inulin restored the promotion of tumor risk factors in two studies and did not in four studies. Notably, the other four studies showed that RS increases pro-tumorigenesis mechanisms. The clinical evidences consistently show that RS/inulin is ineffective for preventing colorectal neoplasia.


Subject(s)
Carbohydrates , Colorectal Neoplasms , Fatty Acids, Volatile , Inulin , Butyrates , Colorectal Neoplasms/prevention & control , Feces , Humans , Starch
6.
Mediators Inflamm ; 2020: 9389720, 2020.
Article in English | MEDLINE | ID: mdl-33149724

ABSTRACT

AIMS: Omentin-1, a newly identified adipokine, has been demonstrated to be associated with bone metabolism, but the results have been inconsistent. Moreover, the potential relationship of circulating omentin-1 with diabetic osteoporosis has never been reported. This study is intended for studying the association between circulating omentin-1, bone mineral density (BMD), prior fragility fractures, and other bone metabolic-related parameters. METHODS: Circulating omentin-1 levels were measured in 172 patients with type 2 diabetes mellitus (T2DM), and participants were divided into the normal BMD group (n = 52), the osteopenia group (n = 66), and the osteoporosis group (n = 54). The relationship between circulating omentin-1 and diabetic osteoporosis and other parameters was analyzed. RESULTS: Circulating omentin-1 was significantly higher in the osteoporosis group than in the normal group and in the osteopenia group (both P < 0.05). Circulating omentin-1 levels were correlated significantly and positively with sex; high-density lipoprotein cholesterol; apolipoprotein A; and prevalence of prior fragility fractures, diabetic nephropathy, and retinopathy; they were correlated negatively with diastolic blood pressure, triglyceride, hemoglobin, atherogenic index of plasma, osteoporosis self-assessment tool for Asians, BMD at different skeletal sites, and corresponding T scores, irrespective of age, sex, and body mass index (P < 0.01 or P < 0.05). Moreover, circulating omentin-1 was an independent decisive factor for the presence of osteoporosis only in women after multivariate adjustment (odds ratio: 1.069; 95% confidence interval: 1.003-1.139; P < 0.05). Lastly, the analysis of receiver operating characteristic curves revealed that the best cutoff value for circulating omentin-1 to predict diabetic osteoporosis was 15.37 ng/mL (sensitivity: 71.7%; specificity: 58.5%) in female subjects. CONCLUSIONS: High levels of circulating omentin-1 may be associated with the development of osteoporosis in female diabetic subjects and may be a potential biomarker for diabetic osteoporosis in women.


Subject(s)
Cytokines/blood , Diabetes Mellitus, Type 2/blood , Lectins/blood , Osteoporosis/blood , Absorptiometry, Photon , Aged , Aged, 80 and over , Anthropometry , Asian People , Biomarkers/blood , Bone Density , Bone Diseases, Metabolic , Bone and Bones/metabolism , China/epidemiology , Cross-Sectional Studies , Diabetes Mellitus, Type 2/complications , Female , GPI-Linked Proteins/blood , Humans , Inflammation , Linear Models , Male , Middle Aged , Multivariate Analysis , Osteoporosis/complications , ROC Curve , Tartrate-Resistant Acid Phosphatase/metabolism
7.
Cytokine ; 113: 356-364, 2019 01.
Article in English | MEDLINE | ID: mdl-30322810

ABSTRACT

Neuregulin-4 (Nrg4) is a novel adipokine associated with obesity, hyperglycemia, insulin resistance, dislipidemia, inflammation, and oxidative stress in mice and humans. However, no report has demonstrated the relationship of circulating Nrg4 with diabetic peripheral neuropathy (DPN). The objective of our study was to investigate the relationship between circulating Nrg4 and DPN in a cross-sectional study. Circulating Nrg4 levels were determined with an enzyme-linked immunosorbent assays kit in 132 newly diagnosed type 2 diabetes mellitus (nT2DM) patients and 41 normal controls (NC group). The associations of circulating Nrg4 with other parameters were also analyzed. Circulating Nrg4 levels were significantly lower in nT2DM patients with no DPN than in NC subjects, and were further markedly decreased in nT2DM patients with DPN (P < 0.01 or P < 0.05). Circulating Nrg4 levels were progressively decreased with an increasing number of abnormal DPN screening (P for trend < 0.01). Circulating Nrg4 levels correlated negatively with 8-iso-prostaglandin F2α (8-iso-PGF2α), high-sensitivity C-reactive protein (hs-CRP) and vibration perception threshold (VPT) (all P < 0.01), and 8-iso-PGF2α, hs-CRP, glycated hemoglobin A1c and VPT were independently related factors to circulating Nrg4 in nT2DM patients (P < 0.01 or P < 0.05). Moreover, circulating Nrg4 was significantly associated with the development of DPN even after controlling for anthropometric, biochemical and clinical parameters. Additionally, the analysis of receiver operating characteristic curves revealed that the best cutoff value for circulating Nrg4 to predict DPN was 1.58 ng/mL (sensitivity 90.91%, specificity 54.55%, and area under the curve 0.716). These findings together suggested that circulating Nrg4 levels were reduced in DPN patients and Nrg4 may be a novel adipokine associated with inflammation, oxidative stress, and long-term glycemic control in nT2DM patients.


Subject(s)
Diabetes Mellitus, Type 2/blood , Diabetic Neuropathies/blood , Neuregulins/blood , Peripheral Nervous System Diseases/blood , Adult , Aged , Aged, 80 and over , Asian People , China , Cross-Sectional Studies , Diabetes Mellitus, Type 2/diagnosis , Diabetic Neuropathies/diagnosis , Female , Humans , Male , Middle Aged , Peripheral Nervous System Diseases/diagnosis
8.
Lipids Health Dis ; 18(1): 205, 2019 Nov 24.
Article in English | MEDLINE | ID: mdl-31760943

ABSTRACT

BACKGROUND: Resistant starch (RS) is a starch that can be fermented by the microbial flora within gut lumen. Insulin resistance (IR) is a pathophysiological condition related to diabetes and obesity. RS could reduce blood glucose and ameliorate IR in animals, but its effect in human population is controversial. OBJECTIVE: The authors conducted a systematic literature review to evaluate the effect of RS diet supplement on ameliorating IR in patients with T2DM and simple obesity. METHODS: Databases that supplemented with RS in ameliorating IR in T2DM and simple obesity were queried for studies on or before August 15, 2018. Parameters including fasting insulin, fasting glucose, body mass index (BMI), homeostatic model assessment (HOMA) etc. were extracted from studies to systemically evaluate effects of RS. RESULTS: The database search yielded 14 parallel or crossover studies that met the inclusion criteria. The results indicated that there was no significant difference in the amelioration of BMI, HOMA-%S and HOMA-%B in T2DM patients between RS and the non-RS supplementation. However, the fasting blood glucose, fasting insulin and HOMA-IR in T2DM with obesity who supplemented RS were lower than control group, and the subgroup analysis according to the dose of RS supplementation was inconsistency. There was no significant difference between RS and non-RS supplements in patients with simple obesity. CONCLUSION: RS supplementation can ameliorate IR in T2DM, especially for the patients of T2DM with obesity, but not in simple obesity.


Subject(s)
Blood Glucose/metabolism , Diabetes Mellitus, Type 2/diet therapy , Dietary Supplements , Insulin Resistance , Obesity/diet therapy , Starch/administration & dosage , Adult , Biotransformation , Body Mass Index , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/complications , Fasting/blood , Female , Humans , Insulin/blood , Intestinal Mucosa/drug effects , Intestinal Mucosa/metabolism , Male , Middle Aged , Obesity/blood , Obesity/complications , Starch/blood
9.
Mediators Inflamm ; 2019: 6207563, 2019.
Article in English | MEDLINE | ID: mdl-31485193

ABSTRACT

BACKGROUND: Hyperglycemia plays a vital role in diabetic nephropathy (DN); autophagy and its potential upregulator receptor-interacting protein kinase 2 (RIPK2) are associated with ROS, which play a potential role in regulating NLRP3, and may be involved in inflammation in DN. AIM: In this study, we aimed to explore the mechanisms mediated by RIPK2 in autophagy and the relationship with ROS-NLRP3 of DN, by investigating the levels of RIPK2 and autophagy in glomerular mesangial cells (GMCs) stimulated with high glucose. MATERIAL AND METHODS: GMCs were divided into the following groups: normal group (NC), high glucose group (HG), and RIPK2 siRNA group. RIPK2, LC3, caspase1, and IL-1ß levels were measured by western blotting and RT-PCR. Autophagosomes were measured by GFP-RFP-LC3; ROS were detected by DCFH-DA. RESULTS: High glucose upregulated RIPK2 and LC3 in GMCs during short periods (0-12 h) (p < 0.01), while RIPK2 and LC3 were significantly downregulated in the long term (12-72 h) (p < 0.01); these changes were positively correlated with glucose concentration (p < 0.01). In addition, levels of ROS, caspase1, and IL-1ß increased in a time- and dose-dependent manner in the high glucose group, even with an increased expression of LC3 (p < 0.01). However, LC3 expression decreased in the siRIPK2 group, while levels of ROS, caspase1, and IL-1ß increased (p < 0.01). CONCLUSIONS: Autophagy was activated by high glucose at short time periods but was inhibited in the long term, demonstrating a dual role for high glucose in autophagy of GMCs. RIPK2 regulates ROS-NLRP3 inflammasome signaling through autophagy and may be involved in the pathogenesis of DN.


Subject(s)
Glucose/pharmacology , Inflammasomes/metabolism , Mesangial Cells/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Reactive Oxygen Species/metabolism , Animals , Blotting, Western , Cells, Cultured , Enzyme-Linked Immunosorbent Assay , Mesangial Cells/drug effects , Mice , Real-Time Polymerase Chain Reaction , Signal Transduction
10.
Diabetes Obes Metab ; 20(8): 1977-1982, 2018 08.
Article in English | MEDLINE | ID: mdl-29573118

ABSTRACT

The effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on risk of stroke have not been conclusively established. Therefore, we conducted a meta-analysis to evaluate the effects of SGLT2 inhibitors on stroke risk in patients with type 2 diabetes mellitus (T2DM) by searching available randomized trials in PubMed, Embase, CENTRAL, Web of Science, Scopus and ClinicalTrials.gov databases. We identified 32 eligible trials involving 75 540 participants. The incidence of stroke in groups receiving SGLT2 inhibitor monotherapy or combination therapy did not differ significantly from that in control groups, with a relative risk (RR) of 1.01 and 1.0, respectively. Three SGLT2 inhibitors were tested, with similar RR values (canagliflozin [RR, 0.91], dapagliflozin [RR, 0.99] and empagliflozin [RR, 1.03]). Subgroup analyses showed that RR values were not affected by gender, age, diabetes duration, BMI or HbA1C levels, but Black patients had a lower incidence of stroke than White or Asian patients. This meta-analysis indicated that SGLT2 inhibitor therapy did not increase stroke incidence, and no significant differences in stroke risk were observed among 3 SGLT2 inhibitors (class effect). However, the small racial disparity requires further study and confirmation.


Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Diabetic Angiopathies/prevention & control , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use , Stroke/prevention & control , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/ethnology , Diabetic Angiopathies/chemically induced , Diabetic Angiopathies/complications , Diabetic Angiopathies/epidemiology , Drug Monitoring , Drug Therapy, Combination/adverse effects , Health Status Disparities , Humans , Incidence , Randomized Controlled Trials as Topic , Risk , Sodium-Glucose Transporter 2 Inhibitors/adverse effects , Stroke/chemically induced , Stroke/epidemiology , Stroke/ethnology
11.
Mediators Inflamm ; 2017: 2438247, 2017.
Article in English | MEDLINE | ID: mdl-28182085

ABSTRACT

Background. Inflammation and fibrosis are the important pathophysiologic processes in diabetic nephropathy (DN). Maresin 1 is a potential anti-inflammatory lipid mediator, which has displayed powerful proresolving activities. Aim. We determine whether maresin 1 has protective effect on mouse glomerular mesangial cells (GMCs) induced by high glucose. Methods. We cultured GMCs stimulated by high glucose and categorized as follows: normal glucose group (5.6 mmol/L), high glucose group (30 mmol/L), mannitol group, maresin 1 intervention group (1, 10, and 100 nmol/L), maresin 1 and normal glucose group, and the N-acetylcysteine (NAC) intervention group (10 µmol/L NAC). After 24 h, the expression of ROS, NLRP3, caspase-1, procaspase-1, IL-1ß, and pro-IL-1ß was detected by western-blot, RT-PCR, and immunofluorescence. After 48 h, the expression of TGF-ß1 and FN was detected by RT-PCR and ELISA. Results. Compared with normal glucose group, the expression of ROS, NLRP3, caspase-1, IL-1ß, TGF-ß1, and FN increased in high glucose group (P < 0.05), but it decreased after the treatment of maresin 1 in different concentrations. On the contrary, the expression of procaspase-1 and pro-IL-1ß protein was restrained by high glucose and enhanced by maresin 1 in a dose-dependent manner (P < 0.05). Conclusion. Maresin 1 can inhibit NLRP3 inflammasome, TGF-ß1, and FN in GMCs; it may have protective effect on DN by mitigating the inflammation and early fibrosis.


Subject(s)
Docosahexaenoic Acids/pharmacology , Fibrosis/immunology , Glucose/toxicity , Inflammation/immunology , Mesangial Cells/drug effects , Mesangial Cells/immunology , Animals , Anti-Inflammatory Agents/pharmacology , Caspase 1/metabolism , Cells, Cultured , Enzyme-Linked Immunosorbent Assay , Fibrosis/metabolism , Inflammation/metabolism , Interleukin-1beta/metabolism , Mesangial Cells/metabolism , Mice , Reactive Oxygen Species/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction/drug effects
12.
Mediators Inflamm ; 2017: 1685194, 2017.
Article in English | MEDLINE | ID: mdl-29038616

ABSTRACT

BACKGROUND: Sumoylation is extensively involved in the regulation of NF-κB signaling. PIASy, as a SUMO E3 ligase, has been proved to mediate sumoylation of IκB kinase γ (IKKγ) and contribute to the activation of NF-κB under genotoxic agent stimulation. However, the association of PIASy and NF-κB signaling in the pathogenesis of diabetic nephropathy (DN) has not been defined. METHODS: Rat glomerular mesangial cells (GMCs) were stimulated by high glucose; siRNA was constructed to silence the expression of PIASy; the expression of PIASy, SUMO isoforms (SUMO1, SUMO2/3), and NF-κB signaling components was analyzed by Western blot; the interaction between IKKγ and SUMO proteins was detected by coimmunoprecipitation; and the release of inflammatory cytokines MCP-1 and IL-6 was assayed by ELISA. RESULTS: High glucose significantly upregulated the expression of PIASy, SUMO1, and SUMO2/3 in a dose- and time-dependent manner (P < 0.05), induced the phosphorylation and sumoylation of IKKγ (P < 0.05), and then triggered NF-κB signaling whereas MCP-1 and IL-6 were released from GMCs (P < 0.05). Moreover, these high glucose-induced effects were observably reversed by siRNA-mediated knockdown of PIASy (P < 0.05). CONCLUSION: The SUMO E3 ligase PIASy mediates high glucose-induced activation of NF-κB inflammatory signaling, suggesting that PIASy may be a potential therapeutic target of DN.


Subject(s)
Glucose/pharmacology , Mesangial Cells/metabolism , NF-kappa B/metabolism , Ubiquitin-Protein Ligases/metabolism , Animals , Blotting, Western , Chemokine CCL2/metabolism , Diabetic Nephropathies/metabolism , Enzyme-Linked Immunosorbent Assay , Fluorescent Antibody Technique , Immunoprecipitation , Interleukin-6/metabolism , Phosphorylation/drug effects , RNA, Small Interfering , Rats , SUMO-1 Protein/genetics , SUMO-1 Protein/metabolism , Signal Transduction/drug effects
13.
Diabetes Metab Syndr Obes ; 17: 2997-3007, 2024.
Article in English | MEDLINE | ID: mdl-39145286

ABSTRACT

Purpose: This manuscript performed a meta-analysis to compare the effects of a low-fat diet (LFD) and a low-carbohydrate diet (LCD) on body weight and lipid levels in adolescents with overweight and obesity. Patients and Methods: PubMed and other databases were searched for the full-text literature comparing LFD and LCD up to November 2023 using a subject plus free word strategy, with search terms such as "low-fat diet", "low-carbohydrate diet", "obesity", "weight", "adolescents", "RCT", and so on. Two independent reviewers selected promising candidate trials, collected the data, and assessed the quality of the trials. RevMan 5.3 software was utilized to conduct a meta-analysis of the randomized controlled trials (RCTs) that were included. Results: 5 RCTs with 192 participants were included in this meta-analysis. Weight (mean difference -2.81; 95% CI -5.38 to -0.25), Body Mass Index (BMI) (-1.13; 95% CI -2.14 to -0.11) and Triglyceride (TG) (-0.36; 95% CI -0.46 to -0.27) of the LCD were significantly lower than that of the LFD. At the same time, the high-density lipoprotein cholesterol (HDL) levels of the LCD were significantly higher than those of the LFD (0.08; 95% CI 0.04 to 0.12) (P < 0.05). However, there was no significant difference in the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR), percent body fat, total cholesterol (TC), and low-density lipoprotein cholesterol (LDL) between the two groups (P>0.05). Conclusion: According to this study, LCD is more helpful in improving weight loss, HDL and TG. Thus, LCD may serve as an effective intervention for weight management in adolescents with overweight and obesity, although further research is needed to determine its long-term effects.

14.
Inflammation ; 2024 Jun 01.
Article in English | MEDLINE | ID: mdl-38822951

ABSTRACT

Diabetic kidney disease (DKD) is a common microvascular complication of diabetes, inflammation and fibrosis play an important role in its progression. Histone lysine crotonylation (Kcr) was first identified as a new type of post-translational modification in 2011. In recent years, prominent progress has been made in the study of sodium crotonate (NaCr) and histone Kcr in kidney diseases. However, the effects of NaCr and NaCr-induced Kcr on DKD remain unclear. In this study, db/db mice and high glucose-induced human tubular epithelial cells (HK-2) were used respectively, and exogenous NaCr and crotonoyl-coenzyme A (Cr-CoA) as intervention reagents, histone Kcr and DKD-related indicators were detected. The results confirmed that NaCr had an antidiabetic effect and decreased blood glucose and serum lipid levels and alleviated renal function and DKD-related inflammatory and fibrotic damage. NaCr also induced histone Kcr and histone H3K18 crotonylation (H3K18cr). However, NaCr and Cr-CoA-induced histone Kcr and protective effects were reversed by inhibiting the activity of Acyl-CoA synthetase short-chain family member 2 (ACSS2) or histone acyltransferase P300 in vitro. In summary, our data reveal that NaCr may mitigate DKD via an antidiabetic effect as well as through ACSS2 and P300-induced histone Kcr, suggesting that Kcr may be the potential molecular mechanism and prevention target of DKD.

15.
Biochem Biophys Res Commun ; 438(3): 568-74, 2013 Aug 30.
Article in English | MEDLINE | ID: mdl-23911785

ABSTRACT

The posttranslational modification of proteins by small ubiquitin-like modifiers (SUMOs) has emerged as an important regulatory mechanism for the alteration of protein activity, stability, and cellular localization. The latest research demonstrates that sumoylation is extensively involved in the regulation of the nuclear factor κB (NF-κB) pathway, which plays a critical role in the regulation of inflammation and contributes to fibrosis in diabetic nephropathy (DN). However, the role of sumoylation in the regulation of NF-κB signaling in DN is still unclear. In the present study, we cultured rat glomerular mesangial cells (GMCs) stimulated by high glucose and divided GMCs into six groups: normal glucose group (5.6mmol/L), high glucose groups (10, 20, and 30mmol/L), mannitol group (i.e., osmotic control group), and MG132 intervention group (30mmol/L glucose with MG132, a proteasome inhibitor). The expression of SUMO1, SUMO2/3, IκBα, NF-κBp65, and monocyte chemotactic protein 1 (MCP-1) was measured by Western blot, reverse-transcription polymerase chain reaction, and indirect immunofluorescence laser scanning confocal microscopy. The interaction between SUMO1, SUMO2/3, and IκBα was observed by co-immunoprecipitation. The results showed that the expression of SUMO1 and SUMO2/3 was dose- and time-dependently enhanced by high glucose (p<0.05). However, the expression of IκBα sumoylation in high glucose was significantly decreased compared with the normal glucose group (p<0.05). The expression of IκBα was dose- and time-dependently decreased, and NF-κBp65 and MCP-1 were increased under high glucose conditions, which could be mostly reversed by adding MG132 (p<0.05). The present results support the hypothesis that high glucose may activate NF-κB inflammatory signaling through IκBα sumoylation and ubiquitination.


Subject(s)
Glucose/administration & dosage , I-kappa B Proteins/metabolism , Mesangial Cells/metabolism , NF-kappa B/physiology , Animals , Chemokine CCL2/biosynthesis , Diabetic Nephropathies/etiology , Glucose/pharmacology , NF-KappaB Inhibitor alpha , Rats , SUMO-1 Protein/metabolism , Signal Transduction/drug effects , Sumoylation/drug effects , Transcription Factor RelA/biosynthesis
16.
Aging (Albany NY) ; 15(22): 13384-13410, 2023 11 27.
Article in English | MEDLINE | ID: mdl-38015723

ABSTRACT

A ketogenic diet (KD) and ß-hydroxybutyrate (ßOHB) have been widely reported as effective therapies for metabolic diseases. ß-Hydroxybutyrate dehydrogenase 1 (BDH1) is the rate-limiting enzyme in ketone metabolism. In this study, we examined the BDH1-mediated ßOHB metabolic pathway in the pathogenesis of diabetic kidney disease (DKD). We found that BDH1 is downregulated in the kidneys in DKD mouse models, patients with diabetes, and high glucose- or palmitic acid-induced human renal tubular epithelial (HK-2) cells. BDH1 overexpression or ßOHB treatment protects HK-2 cells from glucotoxicity and lipotoxicity by inhibiting reactive oxygen species overproduction. Mechanistically, BDH1-mediated ßOHB metabolism activates NRF2 by enhancing the metabolic flux of ßOHB-acetoacetate-succinate-fumarate. Moreover, in vivo studies showed that adeno-associated virus 9-mediated BDH1 renal expression successfully reverses fibrosis, inflammation, and apoptosis in the kidneys of C57 BKS db/db mice. Either ßOHB supplementation or KD feeding could elevate the renal expression of BDH1 and reverse the progression of DKD. Our results revealed a BDH1-mediated molecular mechanism in the pathogenesis of DKD and identified BDH1 as a potential therapeutic target for DKD.


Subject(s)
Diabetes Mellitus , Diabetic Nephropathies , Animals , Humans , Mice , 3-Hydroxybutyric Acid/pharmacology , Antioxidants/therapeutic use , Diabetic Nephropathies/metabolism , Kidney/pathology , NF-E2-Related Factor 2/genetics , Hydroxybutyrate Dehydrogenase/metabolism
17.
J Diabetes Res ; 2022: 1861009, 2022.
Article in English | MEDLINE | ID: mdl-35899018

ABSTRACT

Background: Chronic kidney disease (CKD) is a main health problem associated with increased risk of cardiovascular disease, morbidity, and mortality. Recent studies shown that the progression of CKD may be related to the change of intestinal flora. Resistant starch (RS) is a type of dietary fiber that can act as a substrate for microbial fermentation. Some studies have found that the supplementation of RS can improve the intestinal flora disorder in CKD patients. However, the specific effect of RS on CKD patients remains controversial. Objective: We designed this meta-analysis to identify and assess the effects of RS on patients with CKD. Methods: A comprehensive search of MEDLINE, Embase, Web of Science, and Cochrane systematic review databases was conducted in January 2020, and all new trials were updated in August 2021. Randomized trials were collected to assess the effects of RS on patients with CKD. The weighted average effect size of the net change was calculated by using the random-effects model. Results: The meta-analysis included 8 studies involving 301 participants. RS intake significantly reduced serum indolephenol sulfate (IS), blood phosphorus, IL-6, and uric acid levels in dialysis patients. The mean difference (MD) of serum IS (P = 0.0002) in the dialysis subgroup was -12.57 µmol/L (95% CI: -19.28, -5.86 µmol/L). The MD of blood phosphorus (P = 0.03) was -0.39 mg/dl (95% CI: -0.78, -0.01 mg/dl). The MD of serum uric acid (P = 0.004) between the dialysis subgroup and the nondialysis subgroup was -31.58 mmol/L (95% CI: -52.99, -10.17 mmol/L). The mean difference (MD) of IL-6 (P = 0.02) in the dialysis subgroup was -1.16 µmol/L (95% CI: -2.16, -0.16 µmol/L). However, there was no significant change of RS on hs-CRP, serum creatinine, blood urea nitrogen (BUN), blood paracresol sulfate, and blood lipid. Conclusions: The intake of RS reduced the serum IS, serum phosphorus, IL-6, and uric acid levels significantly in dialysis patients, while hs-CRP, serum creatinine, BUN, serum paracresol sulfate, and blood lipid showed no significant changes.


Subject(s)
Renal Insufficiency, Chronic , Resistant Starch , C-Reactive Protein , Creatinine , Humans , Interleukin-6 , Phosphorus , Sulfates , Uric Acid
18.
J Matern Fetal Neonatal Med ; 35(16): 3135-3142, 2022 Aug.
Article in English | MEDLINE | ID: mdl-32967476

ABSTRACT

INTRODUCTION: Omega-3 fatty acids plus vitamin (e.g. vitamin D and E) may be beneficial to treat gestational diabetes mellitus (GDM), and we aimed to study the influence of omega-3 fatty acids plus vitamin versus placebo on the treatment efficacy of GDM. METHODS: We searched the databases including PubMed, Embase, and the Cochrane Central Register of Controlled Trials, and randomized controlled trials (RCTs) assessing the influence of omega-3 fatty acids and vitamins combination supplementation versus placebo on metabolic status of GDM were included. RESULTS: Five RCTs were included in the meta-analysis. Compared with control intervention for women with GDM or prediabetes, omega-3 fatty acids plus vitamin substantially reduced fasting plasma glucose (FPG, mean difference [MD] = -11.25; 95% confidence intervals [CI] = -13.73 to -8.77; p < .00001), insulin (MD=-6.16; 95% CI=-7.92 to -4.39; p < .00001), homeostasis model of assessment-insulin resistance (HOMA-IR, MD = 173.51; 95% CI = 164.72 to 182.30; p < .00001) and triglycerides (MD = 173.51; 95% CI = 164.72 to 182.30; p < .00001), as well as increased total antioxidant capacity (TAC, MD = 173.51; 95% CI = 164.72 to 182.30; p < .00001), but revealed no significant impact on total cholesterol (MD = 173.51; 95% CI = 164.72 to 182.30; p < .00001), low­density lipoprotein cholesterol (LDL-C, MD = 173.51; 95% CI = 164.72 to 182.30; p < .00001), preterm delivery (OR = 173.51; 95% CI = 164.72 to 182.30; p < .00001) or macrosomia > 4000 g (OR = 173.51; 95% CI = 164.72 to 182.30; p < .00001). CONCLUSIONS: The supplementation of omega-3 fatty acids in combination with vitamin D or E can improve glycemic control, alleviate oxidative stress, and reduce triglycerides, but had no effects on total cholesterol, preterm delivery or macrosomia > 4000 g in women with GDM or prediabetes.


Subject(s)
Diabetes, Gestational , Fatty Acids, Omega-3 , Prediabetic State , Premature Birth , Blood Glucose/metabolism , Cholesterol, LDL , Diabetes, Gestational/drug therapy , Dietary Supplements , Fatty Acids, Omega-3/therapeutic use , Female , Fetal Macrosomia , Humans , Infant, Newborn , Prediabetic State/drug therapy , Pregnancy , Premature Birth/drug therapy , Triglycerides , Vitamin D/therapeutic use , Vitamin E/therapeutic use , Vitamins/therapeutic use
19.
Front Endocrinol (Lausanne) ; 12: 693144, 2021.
Article in English | MEDLINE | ID: mdl-34456864

ABSTRACT

The relationship between dietary inflammatory index (DII) scores and the risk of diabetes mellitus (DM) is unclear; therefore, a systematic review and meta-analysis of the current published literature was conducted. Relevant studies published online (PubMed, Embase, and Web of Science) until February 1, 2021 were identified for review. The initial search yielded 13 reports, and after perusing their titles, abstracts, and full texts, 5 studies were deemed appropriate for inclusion in the systematic review and meta-analysis. Individuals with higher DII scores (representing a more proinflammatory diet) had a higher risk of DM (pooled odds ratio 1.32, 95% confidence interval 1.01-1.72, I2 58.6%, p < 0.05). Although the current meta-analysis indicated a trend toward a positive association between DII and DM, further evidence-especially from larger prospective studies in different countries-is needed to clarify this association.


Subject(s)
Diabetes Mellitus/epidemiology , Diet , Inflammation/epidemiology , Animals , Body Mass Index , Humans , Risk Factors
20.
Ann Transl Med ; 9(10): 873, 2021 May.
Article in English | MEDLINE | ID: mdl-34164507

ABSTRACT

BACKGROUND: Alcoholic fatty liver disease (AFLD) is characterized by hepatic steatosis and carries an elevated risk of cirrhosis and hepatocellular carcinoma. However, the mechanism of AFLD has not been elucidated thoroughly, and there are still no efficient therapies in clinic. Notably, butyrate, one kind of short-chain fatty acids produced by gut microbiota, has been shown to improve methionine-choline-deficient diet-induced non-alcoholic steatohepatitis. And our previous study found that butyrate ameliorated endotoxemia in db/db mice. In this study, we aimed to explore the role of butyrate in the development of AFLD. METHODS: C57BL/6 mice were treated with saline (normal control), alcohol with or without butyrate by gavage for 6 months. AFLD was evaluated by the levels of serum alcohol, aspartate aminotransferase (AST), alanine transaminase (ALT), triglyceride (TG) and intrahepatic TG. And the histology and inflammation in liver and colon were analyzed using hematoxylin-eosin (H&E) staining, immunohistochemistry and western blot. In addition, gut microbiota composition was analyzed using the V3-V4 regions of the bacterial 16S ribosomal RNA gene by sequence. Furthermore, we performed in vitro experiment to verify the role of butyrate in hepatocyte by western blot and transmission electron microscopy. RESULTS: We found that butyrate ameliorated alcohol-induced hepatic steatosis and inflammation. Furthermore, chronic alcohol feeding induced dysbiosis and dysfunction of the gut microbiota, disrupted the intestinal barrier, and increased serum endotoxin levels. Meanwhile, butyrate improved the intestinal barrier disruption and endotoxemia induced by alcohol, but did not significantly alleviate the microbiome dysfunction. Mechanistically, butyrate ameliorated AFLD by inhibiting gasdermin D (GSDMD)-mediated pyroptosis. CONCLUSIONS: In summary, we found butyrate ameliorated alcoholic fatty liver by down-regulating GSDMD-mediated pyroptosis. We speculate that butyrate improves AFLD mainly by maintaining intestinal barrier function and alleviating gut leakage. These findings suggest that butyrate may have the potential to serve as a novel treatment for AFLD.

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