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Theranostics 2021Peroxisome proliferator-activated receptor gamma (PPARγ) has the ability to counter Th17 responses, but the full mechanisms remain elusive. Herein, we aimed to...
Peroxisome proliferator-activated receptor gamma (PPARγ) has the ability to counter Th17 responses, but the full mechanisms remain elusive. Herein, we aimed to elucidate this process in view of cellular metabolism, especially glutaminolysis. MTT, CCK-8, Annexin V-FITC/PI staining or trypan blue exclusion assays were used to analyze cytotoxicity. Flow cytometry and Q-PCR assays were applied to determine Th17 responses. The detection of metabolite levels using commercial kits and rate-limiting enzyme expression using western blotting assays was performed to illustrate the metabolic activity. ChIP assays were used to examine H3K4me3 modifications. Mouse models of dextran sulfate sodium (DSS)-induced colitis and house dust mite (HDM)/lipopolysaccharide (LPS)-induced asthma were established to confirm the mechanisms studied . The PPARγ agonists rosiglitazone and pioglitazone blocked glutaminolysis but not glycolysis under Th17-skewing conditions, as indicated by the detection of intracellular lactate and α-KG and the fluorescence ratios of BCECF-AM. The PPARγ agonists prevented the utilization of glutamine and thus directly limited Th17 responses even when Foxp3 was deficient. The mechanisms were ascribed to restricted conversion of glutamine to glutamate by reducing the expression of the rate-limiting enzyme GLS1, which was confirmed by GLS1 overexpression. Replenishment of α-KG and 2-HG but not succinate weakened the effects of PPARγ agonists, and α-KG-promoted Th17 responses were dampened by siIDH1/2. Inhibition of KDM5 but not KDM4/6 restrained the inhibitory effect of PPARγ agonists on IL-17A expression, and the H3K4me3 level in the promoter and CNS2 region of the gene locus down-regulated by PPARγ agonists was rescued by 2-HG and GLS1 overexpression. However, the limitation of PPARγ agonists on the mRNA expression of RORγt was unable to be stopped by 2-HG but was attributed to GSH/ROS signals subsequent to GLS1. The exact role of PPARγ was proved by GW9662 or PPARγ knockout, and the mechanisms for PPARγ-inhibited Th17 responses were further confirmed by GLS1 overexpression . PPARγ agonists repressed Th17 responses by counteracting GLS1-mediated glutaminolysis/2-HG/H3K4me3 and GSH/ROS signals, which is beneficial for Th17 cell-related immune dysregulation.
Topics: Animals; Colitis; Disease Models, Animal; Female; Glutamic Acid; Glutaminase; Glutamine; Glutathione; Glycolysis; Histones; Interleukin-17; Mice; Mice, Inbred C57BL; PPAR gamma; Pioglitazone; RNA, Messenger; Reactive Oxygen Species; Rosiglitazone; Th17 Cells
PubMed: 33754076
DOI: 10.7150/thno.54803 -
World Journal of Gastroenterology Sep 2019Non-alcoholic fatty liver disease (NAFLD) has become a major cause of chronic liver disease. The Chinese herbal medicine (CHM) Dachaihu decoction (DCHD) has been proved...
BACKGROUND
Non-alcoholic fatty liver disease (NAFLD) has become a major cause of chronic liver disease. The Chinese herbal medicine (CHM) Dachaihu decoction (DCHD) has been proved to treat NAFLD with good efficacy in previous studies. Based on the TCM principle of formula formation, we divided DCHD into soothing liver part, invigorating spleen part, and dredging intestine part. Marshall officially proposed the concept of "intestinal-hepatic axis", which systematically explains the interactions between the intestine and liver. We hypothesized that the effect of CHM on NAFLD is achieved by regulating the liver and intestine. Thus, we aimed to investigate the possible effect of a CHM formula on NAFLD in a rat model.
AIM
To investigate the effects of a CHM formula (a decoction of Chinese thorowax root, scutellaria root, and white peony root) on NAFLD and its regulatory effect on the "intestinal-liver" axis.
METHODS
Sixty rats were randomly divided into control, model, pioglitazone hydrochloride (PH), and CHM (a decoction of Chinese thorowax root, scutellaria root, and white peony root) groups. An NAFLD rat model was established using a high-fat high-fructose diet for 16 wk. From the 13th week, rats were administered with PH or a decoction of Chinese thorowax, scutellaria, and white peony root (CHM group) for 4 wk. Rats in the control group and model group were administered with an equal volume of distilled water. At the end of the study, blood was collected the abdominal aorta. Liver tissues were harvested and any morphological changes were observed by hematoxylin-eosin (HE) staining, Oil red O staining, and Masson staining. In addition, blood lipids, liver function markers, and triglyceride (TG) in liver tissues were analyzed. The levels of transforming growth factor-β1 (TGF-β1), tumor necrosis factor-α (TNF-α), Toll-like receptor-4 (TLR4), and nuclear factor-kappa B (NF-кB) in liver tissues and secreted immunoglobulin A (sIgA) in intestinal tissues were analyzed by ELISA, and protein and mRNA expression of occludin and zonula occludens-1 (ZO-1) in the intestine were measured using Western blot and reverse transcription-quantitative polymerase chain reaction, respectively. The endotoxin level in plasma was detected by endpoint chromogenic assay.
RESULTS
Compared to the normal control group, the liver coefficient, serum TG, total cholesterol (TC), low density lipoprotein (LDL), aspartate aminotransferase (AST), and alanine aminotransferase (ALT), blood glucose, plasma endotoxin, and the levels of TG, TNF-α, TGF-β, NF-kB, and TLR4 in liver tissues increased significantly in the model group, while serum high density lipoprotein (HDL), intestinal sIgA, and protein and mRNA expression of occludin and ZO-1 decreased significantly in the model group ( < 0.01). PH and CHM attenuated the elevated liver coefficient, serum TG, TC, LDL, AST, and ALT, blood glucose, plasma endotoxin, and the levels of TG, TNF-α, TGF-β, NF-kB, and TLR4 in liver tissues and increased serum HDL levels compared to the model group ( < 0.01). Intestinal sIgA and the protein and mRNA expression of intestinal occludin and ZO-1 were significantly increased in the PH group compared to the model and CHM groups ( < 0.01).
CONCLUSION
The decoction of Chinese thorowax root, scutellaria root, and white peony root is beneficial in regulating lipid metabolism and liver function, which indicates that it has a good effect on the liver. To a certain extent, this CHM formula can affect both the liver and intestine, while its effect on the liver is superior to that on the intestine.
Topics: Animals; Bupleurum; Diet, High-Fat; Disease Models, Animal; Drugs, Chinese Herbal; Fructose; Humans; Intestinal Mucosa; Lipid Metabolism; Liver; Liver Function Tests; Male; Non-alcoholic Fatty Liver Disease; Paeonia; Pioglitazone; Plant Roots; Rats; Rats, Sprague-Dawley; Scutellaria
PubMed: 31558860
DOI: 10.3748/wjg.v25.i34.5105 -
Metabolites Mar 2023Psoriasis is a chronic, systematic, inflammatory disease in which multiple metabolic and immunologic disturbances lead to lipid abnormalities, impaired glucose... (Review)
Review
Psoriasis is a chronic, systematic, inflammatory disease in which multiple metabolic and immunologic disturbances lead to lipid abnormalities, impaired glucose tolerance, metabolic syndrome, diabetes mellitus, atherosclerosis, hypertension, ischemic heart disease, and numerous metabolic disorders. In clinical practice, the most commonly used drugs in the treatment of lipid abnormalities are statins and fibrates. Statins are characterized by pleiotropic effects such as antioxidant, anti-inflammatory, anticoagulant, and antiproliferative. They work by reducing the concentrations of low-density lipoprotein (LDL), total cholesterol, and triglycerides and stabilizing atherosclerotic plaque. Fibrates are medications, which help to lower triglycerides, LDL, very low-density lipoprotein (VLDL) levels and increase lower high-density lipoprotein (HDL). In recent years, many new drugs were found to normalize the lipid profile in patients with psoriasis: glitazones (pioglitazone, troglitazone), and glucagon-like peptide-1 (GLP-1) receptor agonists. Pioglitazone improves the lipid profile, including the decrease of triglycerides, fatty acids, and LDL, as well as the increase of HDL. Glucagon-like peptide 1 (GLP-1) analogs decrease modestly low-density lipoprotein cholesterol (LDL-C), total cholesterol, and triglycerides. The purpose of this study is to assess the current state of knowledge on the effect of different hypolipidemic treatments on the course of psoriasis. The study includes literature from medical databases PubMed and Google Scholar. We were browsing PubMed and Google Scholar until the beginning of December. The systematic review includes 41 eligible original articles.
PubMed: 37110152
DOI: 10.3390/metabo13040493 -
Cureus Dec 2023Lobeglitazone is a newer oral hypoglycemic agent that has been tested in type 2 diabetes mellitus (T2DM). We aim to conduct a narrative review to find out the... (Review)
Review
Lobeglitazone is a newer oral hypoglycemic agent that has been tested in type 2 diabetes mellitus (T2DM). We aim to conduct a narrative review to find out the therapeutic benefits of lobeglitazone in patients with T2DM. We scientifically searched the electronic database of PubMed from inception until September 12, 2023, using Medical Subject Heading (MeSH) keywords. Additionally, we searched for pre-clinical trials related to lobeglitazone. We retrieved all available results of phase 1 to phase 3 studies of lobeglitazone in T2DM. Subsequently, we reviewed the results narratively. Three double-blind, randomized, placebo-controlled studies and a phase 3 trial of lobeglitazone showed that 0.5 mg daily dose exhibits effective therapeutic activity in glycemic, lipid, and hepatic control, and is also used as a secondary treatment in non-alcoholic fatty liver disease. Lobeglitazone exhibits as much antidiabetic activity as other thiazolidinediones such as pioglitazone and rosiglitazone. Side effects of lobeglitazone included peripheral edema, weight gain, and bone mineral density, which did not require hospitalization for these effects. This article highlights the pharmacological, pre-clinical, clinical, and safety pharmacology of novel thiazolidinedione lobeglitazone.
PubMed: 38186506
DOI: 10.7759/cureus.50085 -
F1000Research 2020Since a 2017 update, there have been important advances in stroke prevention. These include new evidence about nutrition, antiplatelet therapy, anticoagulation,... (Review)
Review
Since a 2017 update, there have been important advances in stroke prevention. These include new evidence about nutrition, antiplatelet therapy, anticoagulation, lipid-lowering therapy, hypertension control, pioglitazone, and carotid endarterectomy and stenting. Evidence regarding toxic metabolites produced by the intestinal microbiome from egg yolk and red meat has important dietary implications, particularly for patients with impaired renal function, including the elderly. They should avoid egg yolk and red meat and limit the intake of animal flesh. Higher doses of folic acid may be needed for patients with the T allele of MTHFR, so it may not be sufficient to give vitamin B12 (methylcobalamin) alone, even in countries with folate fortification. There is now good evidence that lipid-lowering therapy is even more beneficial in the elderly than in younger patients; we should be using lipid-lowering therapy more intensively, often/usually combining statins with ezetimibe. There is new evidence that lower systolic blood pressure targets are better for most patients, but a subgroup with stiff arteries, a wide pulse pressure, and a diastolic pressure of <60 would be more likely to be harmed than helped by aiming for a systolic target of <120 mmHg. There is a better understanding of how the pharmacological properties of direct-acting oral anticoagulants and the metabolism of antiplatelet agents should inform decisions about the use of these agents. Pioglitazone markedly reduces the risk of stroke, both in diabetics and prediabetics; it should be used more widely. It is now clear that carotid endarterectomy is safer than stenting and that the difference is strongly affected by age. Most patients, and in particular older patients, would be better served by endarterectomy than stenting.
Topics: Aged; Blood Pressure; Diet; Endarterectomy, Carotid; Humans; Hypertension; Pioglitazone; Recurrence; Secondary Prevention; Stroke
PubMed: 32864099
DOI: 10.12688/f1000research.23199.1 -
JAMA Network Open Dec 2023Diabetic nephropathy and diabetic retinopathy share many similarities in pathophysiological processes. Preclinical studies have shown that sodium-glucose cotransporter 2...
IMPORTANCE
Diabetic nephropathy and diabetic retinopathy share many similarities in pathophysiological processes. Preclinical studies have shown that sodium-glucose cotransporter 2 inhibitors (SGLT2is) have a protective role in the risk of diabetic retinopathy.
OBJECTIVE
To compare the risk of sight-threatening retinopathy associated with SGLT2is and other second-line glucose-lowering medications (including pioglitazone, sulfonylureas, and dipeptidyl peptidase-4 inhibitors [DPP-4is]) in patients with type 2 diabetes (T2D).
DESIGN, SETTING, AND PARTICIPANTS
This cohort study in Taiwan applied a new-user and active-comparator design. Patient demographic and clinical data were obtained from the National Health Insurance Research Database. Adult patients with newly diagnosed T2D from January 1, 2009, to December 31, 2019, were recruited and followed up until December 31, 2020. Propensity score matching was used to identify pairs of patients treated with SGLT2i vs DPP-4i, SGLT2i vs pioglitazone, and SGLT2i vs sulfonylurea from January 1, 2016, to December 31, 2019. Data were analyzed between August 18, 2022, and May 5, 2023.
EXPOSURES
Treatment with SGLT2i, DPP-4i, pioglitazone, and sulfonylureas starting on January 1, 2016.
MAIN OUTCOMES AND MEASURES
The main outcome was sight-threatening retinopathy in participants. Cox proportional hazards regression models were used to assess relative hazards of sight-threatening retinopathy between the matched case and control groups.
RESULTS
A total of 3 544 383 patients with newly diagnosed T2D were identified. After 1:1 propensity score matching, 65 930 pairs of patients treated with SGLT2i vs DPP-4i, 93 760 pairs treated with SGLT2i vs pioglitazone, and 42 121 pairs treated with SGLT2i vs sulfonylurea were identified. These matched patients included 236 574 males (58.6%), with a mean (SD) age of 56.9 (11.8) years. In the matched cohorts, SGLT2i had a significantly lower risk of sight-threatening retinopathy than DPP-4i (adjusted hazard ratio [AHR], 0.57; 95% CI, 0.51-0.63), pioglitazone (AHR, 0.75; 95% CI, 0.69-0.81), and sulfonylureas (AHR, 0.62; 95% CI, 0.53-0.71). The Kaplan-Meier curves showed that SGLT2i was associated with a significantly lower cumulative incidence of sight-threatening retinopathy than DPP-4i (3.52 vs 6.13; P < .001), pioglitazone (4.32 vs 5.76; P < .001), and sulfonylureas (2.94 vs 4.67; P < .001).
CONCLUSIONS AND RELEVANCE
This cohort study found that SGLT2i was associated with a lower risk of sight-threatening retinopathy compared with DPP-4i, pioglitazone, and sulfonylureas. This finding suggests that SGLT2i may play a role not only in reduced risk of diabetic nephropathy but also in the slow progression of diabetic retinopathy in patients with T2D.
Topics: Adult; Humans; Male; Middle Aged; Cohort Studies; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Pioglitazone; Retinal Diseases; Sulfonylurea Compounds; Sodium-Glucose Transporter 2 Inhibitors; Aged; Female
PubMed: 38117497
DOI: 10.1001/jamanetworkopen.2023.48431 -
Frontiers in Neuroscience 2021Alzheimer's disease is a quintessential 'unmet medical need', accounting for ∼65% of progressive cognitive impairment among the elderly, and 700,000 deaths in the... (Review)
Review
Alzheimer's disease is a quintessential 'unmet medical need', accounting for ∼65% of progressive cognitive impairment among the elderly, and 700,000 deaths in the United States in 2020. In 2019, the cost of caring for Alzheimer's sufferers was $244B, not including the emotional and physical toll on caregivers. In spite of this dismal reality, no treatments are available that reduce the risk of developing AD or that offer prolonged mitiagation of its most devestating symptoms. This review summarizes key aspects of the biology and genetics of Alzheimer's disease, and we describe how pioglitazone improves many of the patholophysiological determinants of AD. We also summarize the results of pre-clinical experiments, longitudinal observational studies, and clinical trials. The results of animal testing suggest that pioglitazone can be corrective as well as protective, and that its efficacy is enhanced in a time- and dose-dependent manner, but the dose-effect relations are not monotonic or sigmoid. Longitudinal cohort studies suggests that it delays the onset of dementia in individuals with pre-existing type 2 diabetes mellitus, which small scale, unblinded pilot studies seem to confirm. However, the results of placebo-controlled, blinded clinical trials have not borne this out, and we discuss possible explanations for these discrepancies.
PubMed: 34220427
DOI: 10.3389/fnins.2021.666958 -
Biomolecules Jul 2023Despite the increasing prevalence rate of nonalcoholic fatty liver disease (NAFLD) worldwide, efficient pharmacotherapeutic regimens against NAFLD still need to be...
BACKGROUND
Despite the increasing prevalence rate of nonalcoholic fatty liver disease (NAFLD) worldwide, efficient pharmacotherapeutic regimens against NAFLD still need to be explored. Previous studies found that pioglitazone and metformin therapy could partly ameliorate NAFLD, but their combination therapy effects have not been researched. In the present study, we assessed the protective effects of metformin and pioglitazone combination therapy on liver lipid metabolism in high-fat diet (HFD)-fed mice and investigated the molecular mechanism.
METHODS
Male C57BL/6 mice were divided into five groups: normal control; HFD control; metformin monotherapy; pioglitazone monotherapy and combined therapy. After 8 weeks of pharmacological intervention, glucose and lipid metabolism characteristics, hepatic histology, lipidomics profiling and RNA-seq analysis were performed.
RESULTS
The combination of pioglitazone and metformin significantly ameliorated HFD-induced metabolic disturbance and the hepatic oil red O area. A lipidomics analysis showed that combined therapy could significantly reduce the high levels of free fatty acids (FFA), diacylglycerol and triglycerides, while a set of glycerophospholipids and sphingolipids were increased in the combined therapy group. Consistently, an RNA-seq analysis also showed a remarkable reduction in genes associated with FFA uptake and de novo lipogenesis, including , , , , , and in the combined therapy group.
CONCLUSIONS
Pioglitazone and metformin might have a synergistic protective effect on NAFLD by improving hepatic lipid profiles in HFD-induced mice. Further studies are needed to verify the clinical effects.
Topics: Male; Animals; Mice; Mice, Inbred C57BL; Lipid Metabolism; Mice, Obese; Pioglitazone; Non-alcoholic Fatty Liver Disease
PubMed: 37627267
DOI: 10.3390/biom13081199 -
Frontiers in Physiology 2021The insulin-sensitizer pioglitazone exerts its cardiometabolic benefits in type 2 diabetes (T2D) through a redistribution of body fat, from ectopic and visceral areas to...
The insulin-sensitizer pioglitazone exerts its cardiometabolic benefits in type 2 diabetes (T2D) through a redistribution of body fat, from ectopic and visceral areas to subcutaneous adipose depots. Whereas excessive weight gain and lipid storage in obesity promotes insulin resistance and chronic inflammation, the expansion of subcutaneous adipose by pioglitazone is associated with a reversal of these immunometabolic deficits. The precise events driving this beneficial remodeling of adipose tissue with pioglitazone remain unclear, and whether insulin-sensitizers alter the lipidomic composition of human adipose has not previously been investigated. Using shotgun lipidomics, we explored the molecular lipid responses in subcutaneous adipose tissue following 6months of pioglitazone treatment (45mg/day) in obese humans with T2D. Despite an expected increase in body weight following pioglitazone treatment, no robust effects were observed on the composition of storage lipids (i.e., triglycerides) or the content of lipotoxic lipid species (e.g., ceramides and diacylglycerides) in adipose tissue. Instead, pioglitazone caused a selective remodeling of the glycerophospholipid pool, characterized by a decrease in lipids enriched for arachidonic acid, such as plasmanylethanolamines and phosphatidylinositols. This contributed to a greater overall saturation and shortened chain length of fatty acyl groups within cell membrane lipids, changes that are consistent with the purported induction of adipogenesis by pioglitazone. The mechanism through which pioglitazone lowered adipose tissue arachidonic acid, a major modulator of inflammatory pathways, did not involve alterations in phospholipase gene expression but was associated with a reduction in its precursor linoleic acid, an effect that was also observed in skeletal muscle samples from the same subjects. These findings offer important insights into the biological mechanisms through which pioglitazone protects the immunometabolic health of adipocytes in the face of increased lipid storage.
PubMed: 34925073
DOI: 10.3389/fphys.2021.784391 -
Scientific Reports Nov 2023The antidiabetic drug pioglitazone ameliorates insulin resistance by activating the transcription factor PPARγ. In addition to its blood glucose-lowering action,...
The antidiabetic drug pioglitazone ameliorates insulin resistance by activating the transcription factor PPARγ. In addition to its blood glucose-lowering action, pioglitazone exerts pleiotropic effects including amelioration of nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH). The mechanism by which pioglitazone achieves this latter effect has remained unclear, however. We here show that pioglitazone administration increases the amount of linoleic acid (LA) metabolites in adipose tissue of KK-Ay mice. These metabolites are produced by lactic acid bacteria in the gut, and pioglitazone also increased the fraction of Lactobacillus in the gut microbiota. Administration of the LA metabolite HYA (10-hydroxy-cis-12-octadecenoic acid) to C57BL/6 J mice fed a high-fat diet improved liver histology including steatosis, inflammatory cell infiltration, and fibrosis. Gene ontology analysis of RNA-sequencing data for the liver revealed that the top category for genes downregulated by HYA treatment was related to extracellular matrix, and the expression of individual genes related to fibrosis was confirmed to be attenuated by HYA treatment. Mechanistically, HYA suppressed TGF-β-induced Smad3 phosphorylation and fibrosis-related gene expression in human hepatic stellate cells (LX-2). Our results implicate LA metabolites in the mechanism by which pioglitazone ameliorates liver fibrosis, and they suggest that HYA is a potential therapeutic for NAFLD/NASH.
Topics: Mice; Humans; Animals; Non-alcoholic Fatty Liver Disease; Pioglitazone; Linoleic Acid; Hepatic Stellate Cells; Gastrointestinal Microbiome; Mice, Inbred C57BL; Liver; Liver Cirrhosis; Fibrosis; Diet, High-Fat; Transforming Growth Factor beta
PubMed: 37923895
DOI: 10.1038/s41598-023-46404-5