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Current Diabetes Reports Nov 2019Thiazolidinediones (TZDs) are the only pharmacologic agents that specifically treat insulin resistance. The beneficial effects of TZDs on the cardiovascular risk factors... (Review)
Review
PURPOSE OF REVIEW
Thiazolidinediones (TZDs) are the only pharmacologic agents that specifically treat insulin resistance. The beneficial effects of TZDs on the cardiovascular risk factors associated with insulin resistance have been well documented. TZD use has been limited because of concern about safety issues and side effects.
RECENT FINDINGS
Recent studies indicate that cardiovascular toxicity with rosiglitazone and increase in bladder cancer with pioglitazone are no longer significant issues. There are new data which show that pioglitazone treatment reduces myocardial infarctions and ischemic strokes. New data concerning TZD-mediated edema, congestive heart failure, and bone fractures improves the clinician's ability to select patients that will have minimal significant side effects. Thiazolidinediones are now generic and less costly than pharmaceutical company-promoted therapies. Better understanding of the side effects coupled with clear benefits on the components of the insulin resistance syndrome should promote TZD use in treating patients with type 2 diabetes.
Topics: Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Insulin Resistance; Pioglitazone; Rosiglitazone; Thiazolidinediones
PubMed: 31776781
DOI: 10.1007/s11892-019-1270-y -
Advanced Materials (Deerfield Beach,... Sep 2023The treatment of reperfusion injury after ischemic stroke remains unsatisfactory since the blood-brain barrier (BBB) prevents most neuroprotective agents from entering...
The treatment of reperfusion injury after ischemic stroke remains unsatisfactory since the blood-brain barrier (BBB) prevents most neuroprotective agents from entering the brain. Here, a strategy is proposed based on bacteria-derived outer-membrane vesicle (OMV) hitchhiking on the neutrophils for enhanced brain delivery of pioglitazone (PGZ) to treat ischemic stroke. By encapsulating PGZ into OMV, the resulting OMV@PGZ nanoparticles inherit the functions associated with the bacterial outer membrane, making them ideal decoys for neutrophil uptake. The results show that OMV@PGZ simultaneously inhibits the activation of nucleotide oligomerization-like receptor protein 3 (NLRP3) inflammasomes and ferroptosis and reduces the reperfusion injury to exert a neuroprotective effect. Notably, the transcription factors Pou2f1 and Nrf1 of oligodendrocytes are identified for the first time to be involved in this process and promoted neural repair by single-nucleus RNA sequencing (snRNA-seq).
Topics: Humans; Ischemic Stroke; Neutrophils; Extracellular Vesicles; Pioglitazone; Reperfusion Injury; Bacteria
PubMed: 37358255
DOI: 10.1002/adma.202301779 -
International Journal of Molecular... Sep 2021Peroxisome proliferator-activated receptor gamma (PPARγ) is a type II nuclear receptor, initially recognized in adipose tissue for its role in fatty acid storage and... (Review)
Review
Peroxisome proliferator-activated receptor gamma (PPARγ) is a type II nuclear receptor, initially recognized in adipose tissue for its role in fatty acid storage and glucose metabolism. It promotes lipid uptake and adipogenesis by increasing insulin sensitivity and adiponectin release. Later, PPARγ was implicated in cardiac development and in critical conditions such as pulmonary arterial hypertension (PAH) and kidney failure. Recently, a cluster of different papers linked PPARγ signaling with another superfamily, the transforming growth factor beta (TGFβ), and its receptors, all of which play a major role in PAH and kidney failure. TGFβ is a multifunctional cytokine that drives inflammation, fibrosis, and cell differentiation while PPARγ activation reverses these adverse events in many models. Such opposite biological effects emphasize the delicate balance and complex crosstalk between PPARγ and TGFβ. Based on solid experimental and clinical evidence, the present review summarizes connections and their implications for PAH and kidney failure, highlighting the similarities and differences between lung and kidney mechanisms as well as discussing the therapeutic potential of PPARγ agonist pioglitazone.
Topics: Animals; Humans; Kidney; Lung; PPAR gamma; Pioglitazone; Pulmonary Arterial Hypertension; Pulmonary Fibrosis; Renal Insufficiency; Signal Transduction; Transforming Growth Factor beta
PubMed: 34638771
DOI: 10.3390/ijms221910431 -
Metabolism: Clinical and Experimental Oct 2023Nonalcoholic fatty liver disease (NAFLD), sarcopenia and sarcopenic obesity (SO) are highly prevalent conditions that may coexist, especially in the aging population,... (Review)
Review
Nonalcoholic fatty liver disease (NAFLD), sarcopenia and sarcopenic obesity (SO) are highly prevalent conditions that may coexist, especially in the aging population, without any approved pharmacologic treatment for all of them. There are multiple pathophysiologic mechanisms suggested to explain an association between NAFLD and sarcopenia or SO, including alterations in the adipokines, cytokines, hepatokines and myokines, which may interplay with other factors, such as aging, diet and physical inactivity. In clinical terms, most observational studies support an association between NAFLD and sarcopenia or SO; importantly, there are few cohort studies indicating higher mortality in patients with NAFLD and sarcopenia. Their association also bears some treatment considerations: for example, pioglitazone or vitamin E, suggested as off label treatment for selected patients with nonalcoholic steatohepatitis, may be recommended in the coexistence of sarcopenia or SO, since limited evidence did not show adverse effects of them on sarcopenia and abdominal obesity. In this review, evidence linking sarcopenia and SO with NAFLD is summarized, with a special focus on clinical data. A synopsis of the major pathophysiological links between NAFLD and sarcopenia/SO is initially presented, followed by selected clinical studies and, finally, treatment considerations in patients with NAFLD and sarcopenia or SO are discussed.
Topics: Humans; Aged; Non-alcoholic Fatty Liver Disease; Sarcopenia; Obesity; Diet; Pioglitazone
PubMed: 37544590
DOI: 10.1016/j.metabol.2023.155676 -
Microbiome Jun 2019Western-style diets arouse neuroinflammation and impair emotional and cognitive behavior in humans and animals. Our previous study showed that a high-fructose diet...
BACKGROUND
Western-style diets arouse neuroinflammation and impair emotional and cognitive behavior in humans and animals. Our previous study showed that a high-fructose diet caused the hippocampal neuroinflammatory response and neuronal loss in animals, but the underlying mechanisms remained elusive. Here, alterations in the gut microbiota and intestinal epithelial barrier were investigated as the causes of hippocampal neuroinflammation induced by high-fructose diet.
RESULTS
A high-fructose diet caused the hippocampal neuroinflammatory response, reactive gliosis, and neuronal loss in C57BL/6N mice. Depletion of the gut microbiota using broad-spectrum antibiotics suppressed the hippocampal neuroinflammatory response in fructose-fed mice, but these animals still exhibited neuronal loss. Gut microbiota compositional alteration, short-chain fatty acids (SCFAs) reduction, intestinal epithelial barrier impairment, NOD-like receptor family pyrin domain-containing 6 (NLRP6) inflammasome dysfunction, high levels of serum endotoxin, and FITC-dextran were observed in fructose-fed mice. Of note, SCFAs, as well as pioglitazone (a selective peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist), shaped the gut microbiota and ameliorated intestinal epithelial barrier impairment and NLRP6 inflammasome dysfunction in fructose-fed mice. Moreover, SCFAs-mediated NLRP6 inflammasome activation was inhibited by histamine (a bacterial metabolite) in ex vivo colonic explants and suppressed in murine CT26 colon carcinoma cells transfected with NLRP6 siRNA. However, pioglitazone and GW9662 (a PPAR-γ antagonist) exerted no impact on SCFAs-mediated NLRP6 inflammasome activation in ex vivo colonic explants, suggesting that SCFAs may stimulate NLRP6 inflammasome independently of PPAR-γ activation. SCFAs and pioglitazone prevented fructose-induced hippocampal neuroinflammatory response and neuronal loss in mice. Additionally, SCFAs activated colonic NLRP6 inflammasome and increased DCX newborn neurons in the hippocampal DG of control mice.
CONCLUSIONS
Our findings reveal that gut dysbiosis is a critical factor for a high-fructose diet-induced hippocampal neuroinflammation in C57BL/6N mice possibly mediated by impairing intestinal epithelial barrier. Mechanistically, the defective colonic NLRP6 inflammasome is responsible for intestinal epithelial barrier impairment. SCFAs can stimulate NLRP6 inflammasome and ameliorate the impairment of intestinal epithelial barrier, resulting in the protection against a high-fructose diet-induced hippocampal neuroinflammation and neuronal loss. This study addresses a gap in the understanding of neuronal injury associated with Western-style diets. A new intervention strategy for reducing the risk of neurodegenerative diseases through SCFAs supplementation or dietary fiber consumption is emphasized.
Topics: Animals; Doublecortin Protein; Dysbiosis; Fatty Acids, Volatile; Fructose; Gastrointestinal Microbiome; Hippocampus; Inflammasomes; Inflammation; Intestinal Mucosa; Male; Mice; Mice, Inbred C57BL; Neuroimmunomodulation; Pioglitazone
PubMed: 31255176
DOI: 10.1186/s40168-019-0713-7 -
Journal of Nanobiotechnology May 2021Enhanced angiogenesis can promote diabetic wound healing. Mesenchymal stem cells (MSCs)-derived exosomes, which are cell-free therapeutics, are promising candidates for...
BACKGROUND
Enhanced angiogenesis can promote diabetic wound healing. Mesenchymal stem cells (MSCs)-derived exosomes, which are cell-free therapeutics, are promising candidates for the treatment of diabetic wound healing. The present study aimed to investigate the effect of exosomes derived from MSCs pretreated with pioglitazone (PGZ-Exos) on diabetic wound healing.
RESULTS
We isolated PGZ-Exos from the supernatants of pioglitazone-treated BMSCs and found that PGZ-Exos significantly promote the cell viability and proliferation of Human Umbilical Vein Vascular Endothelial Cells (HUVECs) injured by high glucose (HG). PGZ-Exos enhanced the biological functions of HUVECs, including migration, tube formation, wound repair and VEGF expression in vitro. In addition, PGZ-Exos promoted the protein expression of p-AKT, p-PI3K and p-eNOS and suppressed that of PTEN. LY294002 inhibited the biological function of HUVECs through inhibition of the PI3K/AKT/eNOS pathway. In vivo modeling in diabetic rat wounds showed that pioglitazone pretreatment enhanced the therapeutic efficacy of MSCs-derived exosomes and accelerated diabetic wound healing via enhanced angiogenesis. In addition, PGZ-Exos promoted collagen deposition, ECM remodeling and VEGF and CD31 expression, indicating adequate angiogenesis in diabetic wound healing.
CONCLUSIONS
PGZ-Exos accelerated diabetic wound healing by promoting the angiogenic function of HUVECs through activation of the PI3K/AKT/eNOS pathway. This offers a promising novel cell-free therapy for treating diabetic wound healing.
Topics: Angiogenesis Inducing Agents; Animals; Cell Movement; Cell Proliferation; Cell Survival; Collagen; Diabetes Mellitus; Diabetes Mellitus, Experimental; Exosomes; Human Umbilical Vein Endothelial Cells; Humans; Male; Mesenchymal Stem Cells; Phosphatidylinositol 3-Kinases; Pioglitazone; Rats; Rats, Sprague-Dawley; Skin; Wound Healing
PubMed: 34020670
DOI: 10.1186/s12951-021-00894-5 -
Vnitrni Lekarstvi 2020Pioglitazone belongs to the drugs primarily reducing insulin resistance. Currently, it is the only insulin sensitizer available. In addition to hypoglycaemic action, it... (Review)
Review
Pioglitazone belongs to the drugs primarily reducing insulin resistance. Currently, it is the only insulin sensitizer available. In addition to hypoglycaemic action, it has a number of other metabolically beneficial effects that are responsible for its positive effect on the vascular wall. The paper provides an overview of cardiovascular clinical trials with pioglitazone, its safety profile and practical recommendations for its administration.
Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Pioglitazone; Thiazolidinediones
PubMed: 32942898
DOI: No ID Found -
Nature Communications Sep 2022Valvular inflammation triggered by hyperlipidemia has been considered as an important initial process of aortic valve disease; however, cellular and molecular evidence...
Valvular inflammation triggered by hyperlipidemia has been considered as an important initial process of aortic valve disease; however, cellular and molecular evidence remains unclear. Here, we assess the relationship between plasma lipids and valvular inflammation, and identify association of low-density lipoprotein with increased valvular lipid and macrophage accumulation. Single-cell RNA sequencing analysis reveals the cellular heterogeneity of leukocytes, valvular interstitial cells, and valvular endothelial cells, and their phenotypic changes during hyperlipidemia leading to recruitment of monocyte-derived MHC-II macrophages. Interestingly, we find activated PPARγ pathway in Cd36 valvular endothelial cells increased in hyperlipidemic mice, and the conservation of PPARγ activation in non-calcified human aortic valves. While the PPARγ inhibition promotes inflammation, PPARγ activation using pioglitazone reduces valvular inflammation in hyperlipidemic mice. These results show that low-density lipoprotein is the main lipoprotein accumulated in the aortic valve during hyperlipidemia, leading to early-stage aortic valve disease, and PPARγ activation protects the aortic valve against inflammation.
Topics: Animals; Aortic Valve; Aortic Valve Stenosis; Calcinosis; Cells, Cultured; Endothelial Cells; Humans; Hyperlipidemias; Immunomodulation; Inflammation; Lipoproteins, LDL; Mice; PPAR gamma; Pioglitazone; Transcriptome
PubMed: 36115863
DOI: 10.1038/s41467-022-33202-2 -
Kidney International Aug 2019
Topics: Humans; Kidney Calculi; Nephrolithiasis; Pioglitazone; Uric Acid
PubMed: 31331471
DOI: 10.1016/j.kint.2019.04.015 -
Orvosi Hetilap Jul 2023In the past decade and a half, clinical diabetology has undergone enormous development. New drug classes have appeared in everyday practice (GLP1 receptor agonists,...
In the past decade and a half, clinical diabetology has undergone enormous development. New drug classes have appeared in everyday practice (GLP1 receptor agonists, SGLT2 inhibitors), which are able to improve the outcome of cardiovascular (macrovascular) complications in diabetes within a few years or even a few months, in contrast to the drugs used in previous large, prospective studies (UKPDS, VADT). The use of thiazolidinediones (including pioglitazone) unfortunately and significantly has declined in recent years, both internationally and domestically, although tested in a randomized, controlled setting (PROactive, 2005), this drug was the first, one might say 'ahead of its time', that significantly reduced the composite clinical endpoint of cardiovascular death, nonfatal myocardial infarction and nonfatal stroke, which became later well-known and took center stage as the 3-point MACE. In this paper, we summarize the most important evidence that accumulated with pioglitazone over the past years. We briefly overview the molecular, cellular and pathophysiological changes it causes, and then, in addition to discussing the cardiovascular, metabolic and other benefits, mention the previously suspected and now confirmed possible side effects. It is our belief that pioglitazone could be successfully used today as part of a combined treatment in properly selected patients, with due care, in the personalized treatment of type 2 diabetes. Orv Hetil. 2023; 164(26): 1012-1019.
Topics: Humans; Pioglitazone; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Prospective Studies; Thiazolidinediones; Cardiovascular Diseases
PubMed: 37393546
DOI: 10.1556/650.2023.32783