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Brazilian Journal of Medical and... 2024The imbalance between pro-inflammatory M1 and anti-inflammatory M2 macrophages plays a critical role in the pathogenesis of sepsis-induced acute lung injury (ALI)....
The imbalance between pro-inflammatory M1 and anti-inflammatory M2 macrophages plays a critical role in the pathogenesis of sepsis-induced acute lung injury (ALI). Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) may modulate macrophage polarization toward the M2 phenotype by altering mitochondrial activity. This study aimed to investigate the role of the PGC-1α agonist pioglitazone (PGZ) in modulating sepsis-induced ALI. A mouse model of sepsis-induced ALI was established using cecal ligation and puncture (CLP). An in vitro model was created by stimulating MH-S cells with lipopolysaccharide (LPS). qRT-PCR was used to measure mRNA levels of M1 markers iNOS and MHC-II and M2 markers Arg1 and CD206 to evaluate macrophage polarization. Western blotting detected expression of peroxisome proliferator-activated receptor gamma (PPARγ) PGC-1α, and mitochondrial biogenesis proteins NRF1, NRF2, and mtTFA. To assess mitochondrial content and function, reactive oxygen species levels were detected by dihydroethidium staining, and mitochondrial DNA copy number was measured by qRT-PCR. In the CLP-induced ALI mouse model, lung tissues exhibited reduced PGC-1α expression. PGZ treatment rescued PGC-1α expression and alleviated lung injury, as evidenced by decreased lung wet-to-dry weight ratio, pro-inflammatory cytokine secretion (tumor necrosis factor-α, interleukin-1β, interleukin-6), and enhanced M2 macrophage polarization. Mechanistic investigations revealed that PGZ activated the PPARγ/PGC-1α/mitochondrial protection pathway to prevent sepsis-induced ALI by inhibiting M1 macrophage polarization. These results may provide new insights and evidence for developing PGZ as a potential ALI therapy.
Topics: Mice; Animals; Pioglitazone; Up-Regulation; PPAR gamma; Acute Lung Injury; Sepsis; Lipopolysaccharides; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
PubMed: 38511769
DOI: 10.1590/1414-431X2024e13235 -
Journal of Pharmacological Sciences Apr 202411β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) plays an important role in regulating the expression of glucocorticoid actions in target tissues. Overexpression of...
11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) plays an important role in regulating the expression of glucocorticoid actions in target tissues. Overexpression of 11β-HSD1 in mouse adipose tissue causes a metabolic syndrome-like phenotype, leading to hypertension. Although, many 11β-HSD1 inhibitors have been studied, few have shown a clear ameliorative effect against hypertension. We investigated whether JTT-654, a novel 11β-HSD1 inhibitor, ameliorated hypertension and elucidated the underlying mechanisms. JTT-654 showed inhibitory effects on angiotensinogen production in cortisone-treated 3T3-L1 adipocytes and in a rat model. JTT-654 improved hypertension not only in cortisone-treated rats and spontaneously hypertensive rats (SHR), but also in SHR/NDmcr-cp rats. In the SHR study, JTT-654 and losartan showed the same degree of antihypertensive efficacy. In addition, JTT-654 ameliorated diabetic nephropathy by suppressing renal angiotensinogen production in SHR/NDmcr-cp rats. These effects of JTT-654 were independent of its insulin-sensitizing effects, and similar effects were not observed for pioglitazone, an insulin sensitizer. Moreover, JTT-654 did not affect normotension or hypothalamus-pituitary-adrenal (HPA) axis function in normal Sprague-Dawley rats. Our results indicate that JTT-654 ameliorates hypertension and diabetic nephropathy by inhibiting 11β-HSD1 in the adipose tissue, liver, and kidney.
Topics: Mice; Rats; Animals; 11-beta-Hydroxysteroid Dehydrogenase Type 1; Diabetic Nephropathies; Cortisone; Angiotensinogen; Rats, Sprague-Dawley; Insulin; Kidney; Hypertension; Diabetes Mellitus
PubMed: 38485342
DOI: 10.1016/j.jphs.2024.02.001 -
Frontiers in Oncology 2024
PubMed: 38482207
DOI: 10.3389/fonc.2024.1385766 -
Journal of Traditional and... Mar 2024The purpose of the study was to investigate the anti-hyperglycemic effect of extra virgin sacha inchi oil (EVSIO) and its possible mechanisms and actions against...
BACKGROUND AND AIM
The purpose of the study was to investigate the anti-hyperglycemic effect of extra virgin sacha inchi oil (EVSIO) and its possible mechanisms and actions against pancreatic β-cell death and dysfunction in type 2 diabetic (T2D) rats.
EXPERIMENTAL PROCEDURE
T2D rats were induced with a high-fat diet and low-dose of streptozotocin. The rats were then treated for 5 weeks with EVSIO (0.5, 1, and 2 ml/kg), or pioglitazone. Biochemical and histopathological studies, oxidative and inflammatory markers, and expression of apoptotic-related proteins were then evaluated.
RESULTS
EVSIO treatment exhibited a dose-dependent reduction of fasting blood glucose, area under the curve of glucose, total cholesterol, and triglyceride levels in the diabetic rats, while improved pancreatic β-function was demonstrated by increasing pancreatic and serum insulin levels. EVSIO treatment effectively lowered atrophic pancreatic islets and reduced the level of serum and pancreatic MDA in the diabetic rats. In addition to serum and pancreatic GPx activities in the diabetic rats, EVSIO also augmented serum SOD. Increased levels of NF-κB, TNF-α and IL-6 present in the diabetic rats were greatly reduced by EVSIO treatment. Furthermore, EVSIO revealed an anti-apoptotic effect on the diabetic rat pancreas by upregulating Bcl-2, and downregulating Bax and cleaved caspase-3 protein expression.
CONCLUSION
The overall study results demonstrated the potential anti-hyperglycemic effect of EVSIO in the diabetic rats. The beneficial effects of EVSIO may be attributed to its ability to improve pancreatic β-cell function and ameliorate β-cell apoptosis by inhibiting oxidative stress and inflammatory cytokines.
PubMed: 38481551
DOI: 10.1016/j.jtcme.2023.08.005 -
Oncology Letters Apr 2024Hypoxia is a hallmark of solid tumors. Hypoxic cancer cells adjust their metabolic characteristics to regulate the production of cellular reactive oxygen species (ROS)...
Pioglitazone, a peroxisome proliferator‑activated receptor γ agonist, induces cell death and inhibits the proliferation of hypoxic HepG2 cells by promoting excessive production of reactive oxygen species.
Hypoxia is a hallmark of solid tumors. Hypoxic cancer cells adjust their metabolic characteristics to regulate the production of cellular reactive oxygen species (ROS) and facilitate ROS-mediated metastasis. Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor that regulates the transcription of fatty acid metabolism-related genes that have a key role in the survival and proliferation function of hypoxic cancer cells. In the present study, mRNA expression in HepG2 cells under chemically induced hypoxia was assessed. The protein expression levels of hypoxia-inducible factor 1α (HIF-1α) were measured using western blotting. Following treatment with the PPARγ agonist pioglitazone, cell viability was assessed using a Cell Counting Kit-8 assay, whilst cell proliferation and death were determined using 5-ethynyl-2'-deoxyuridine incorporation staining, and calcein-acetoxymethyl ester and propidium iodide staining, respectively. Cellular ROS production was assessed using dihydroethidium staining. Cobalt chloride was used to induce hypoxia in HepG2 cells, which was evaluated using HIF-1α expression. The results revealed that the mRNA expression of PPARγ, CD36, acetyl-co-enzyme A dehydrogenase (ACAD) medium chain (ACADM) and ACAD short-chain (ACADS) was downregulated in hypoxic HepG2 cells. The PPARγ agonist pioglitazone decreased the cell viability of hypoxic HepG2 cells by inhibiting cell proliferation and inducing cell death. Following treatment with the PPARγ agonist pioglitazone, hypoxic HepG2 cells produced excessive ROS. ROS-mediated cell death induced by the PPARγ agonist pioglitazone was rescued with the antioxidant N-acetyl-L-cysteine. The downregulated mRNA expression of PPARγ, CD36, ACADM and ACADS was not reverted by a PPARγ agonist in hypoxic HepG2 cells. By contrast, the PPARγ agonist suppressed the mRNA expression of BCL2, which was upregulated in hypoxic HepG2 cells. In summary, the PPARγ agonist stimulated excessive ROS production to inhibit cell proliferation and increase the death of hypoxic HepG2 cells by decreasing BCL2 mRNA expression, suggesting a negative association between PPARγ and BCL2 in the regulation of ROS production in hypoxic HepG2 cells.
PubMed: 38449795
DOI: 10.3892/ol.2024.14294 -
Frontiers in Pharmacology 2024Targeted chemotherapy and immune checkpoint inhibitors (ICPi) have expanded the spectrum of therapies for patients with relapsed/refractory (r/r) Hodgkin's disease and...
Targeted chemotherapy and immune checkpoint inhibitors (ICPi) have expanded the spectrum of therapies for patients with relapsed/refractory (r/r) Hodgkin's disease and significantly improved the proportion of patients with long-term disease control. However, there is no standardized therapeutic option in case of further progression. Recently, we demonstrated that therapy with MEPED (metronomic chemotherapy, everolimus, pioglitazone, etoricoxib, dexamethasone) is highly effective in patients with r/r Hodgkin's disease. The benefit after pre-treatment with ICPi has not been studied, yet. Here, we report a patient with progressive Hodgkin's disease on Pembrolizumab for the first time who achieved sustained complete remission (CR) after initiation of MEPED therapy. A 57-year-old patient was pre-treated with brentuximab vedotin for relapsed advanced Hodgkin's disease and had received Pembrolizumab for progression from November 2020 to July 2022. Due to further progression, MEPED therapy was started in August 2022 and continued until May 2023. It consisted of a strictly oral daily (28-day cycle) application of low-dose treosulfan 250 mg, everolimus 15 mg, pioglitazone 45 mg, etoricoxib 60 mg, and dexamethasone 0.5 mg. Treatment response was evaluated by F-18 FDG-PET/CT (PET/CT). CR was defined by a negative Deauville score (DS) of 1-3. Already 3 months after starting MEPED, a CR (DS: 3) was confirmed by PET/CT in November 2022. The next follow-up in May 2023 continued to show CR (DS: 3). The therapy was very well tolerated. No hematological or other organ toxicity was observed. However, in May 2023 the patient presented with leg edema and weight gain, most likely due to pioglitazone and the PET/CT revealed suspected everolimus-induced pneumonitis, so MEPED was discontinued and diuretic therapy and treatment with prednisolone was started with gradual dose reduction. This resulted in a rapid complete resolution of the symptoms. The next PET-CT in July 2023 continued to show CR (DS: 3) without evidence of pneumonitis. Currently, therapy with MEPED has not been resumed. In conclusion, we demonstrate for the first time that MEPED therapy is highly effective in a patient with Hodgkin's disease who has been refractory to ICPi. Sustained CR was achieved over 11 months after initiation of MEPED therapy. Further studies on a larger patient cohort should be performed.
PubMed: 38444946
DOI: 10.3389/fphar.2024.1334233 -
Metabolomics : Official Journal of the... Feb 2024Thiazolidinediones (TZDs), represented by pioglitazone and rosiglitazone, are a class of cost-effective oral antidiabetic agents posing a marginal hypoglycaemia risk....
INTRODUCTION
Thiazolidinediones (TZDs), represented by pioglitazone and rosiglitazone, are a class of cost-effective oral antidiabetic agents posing a marginal hypoglycaemia risk. Nevertheless, observations of heart failure have hindered the clinical use of both therapies.
OBJECTIVE
Since the mechanism of TZD-induced heart failure remains largely uncharacterised, this study aimed to explore the as-yet-unidentified mechanisms underpinning TZD cardiotoxicity using a toxicometabolomics approach.
METHODS
The present investigation included an untargeted liquid chromatography-mass spectrometry-based toxicometabolomics pipeline, followed by multivariate statistics and pathway analyses to elucidate the mechanism(s)of TZD-induced cardiotoxicity using AC16 human cardiomyocytes as a model, and to identify the prognostic features associated with such effects.
RESULTS
Acute administration of either TZD agent resulted in a significant modulation in carnitine content, reflecting potential disruption of the mitochondrial carnitine shuttle. Furthermore, perturbations were noted in purine metabolism and amino acid fingerprints, strongly conveying aberrations in cardiac energetics associated with TZD usage. Analysis of our findings also highlighted alterations in polyamine (spermine and spermidine) and amino acid (L-tyrosine and valine) metabolism, known modulators of cardiac hypertrophy, suggesting a potential link to TZD cardiotoxicity that necessitates further research. In addition, this comprehensive study identified two groupings - (i) valine and creatine, and (ii) L-tryptophan and L-methionine - that were significantly enriched in the above-mentioned mechanisms, emerging as potential fingerprint biomarkers for pioglitazone and rosiglitazone cardiotoxicity, respectively.
CONCLUSION
These findings demonstrate the utility of toxicometabolomics in elaborating on mechanisms of drug toxicity and identifying potential biomarkers, thus encouraging its application in the toxicological sciences. (245 words).
Topics: Humans; Rosiglitazone; Pioglitazone; Myocytes, Cardiac; Cardiotoxicity; Diabetes Mellitus, Type 2; Metabolomics; Thiazolidinediones; Heart Failure; Amino Acids; Biomarkers; Carnitine; Valine
PubMed: 38393619
DOI: 10.1007/s11306-024-02097-z -
Journal of Advanced Pharmaceutical... 2024Type 2 diabetes is common globally. Pioglitazone (PGZ) is an oral TZD antidiabetic, whereas chromium-picolinate (Cr-PL) and Cr-glucose tolerance factor (Cr-GTF) are...
Type 2 diabetes is common globally. Pioglitazone (PGZ) is an oral TZD antidiabetic, whereas chromium-picolinate (Cr-PL) and Cr-glucose tolerance factor (Cr-GTF) are useful type 2 diabetes mellitus (T2DM) supplements. Cr-PL/GTF antioxidants cure T2DM. They may fail in diabetes with or without insulin-sensitizing medications. It examined how Cr-PL, Cr-GTF, PGZ, and their combination affected glucose, glycosylated hemoglobin, insulin, and HOMA-IR. Sixty-three adult Sprague-Dawley rats (220-300 g) were selected, and nine rats were randomly assigned to a normal nondiabetic group. In contrast, 54 rats were randomly split into 9 rats per each of the 6 major groups and injected intraperitoneally with 40 mg/kg STZ to induce T2DM. Rats were administered PGZ = 0.65 mg/kg (rat weight)/day, Cr-PL = 1 mg/kg, Cr-GTF = 1 mg/kg, and their combinations (PGZ + Cr-PL and Cr-GTF) daily for 6 weeks per intervention. The PGZ + Cr-PL and PGZ + Cr-GTF groups had substantially lower insulin levels than the PGZ group (13.38 ± 0.06, 12.98 ± 0.19 vs. 14.11 ± 0.02, respectively), with the PGZ + Cr-GTF group having the lowest insulin levels (12.98 ± 0.19 vs. 14.11 ± 0.02, 13.38±0.06, respectively). Intervention substantially reduced HOMA-IR in the PZ + Cr-PL and PZ + Cr-GTF groups compared to PGZ (7.49 ± 0.04, 6.69 ± 0.11 vs. 8.37 ± 0.04, respectively). This research found that combining PGZ with Cr-GTF resulted in considerably lower HOMA-IR levels than the PGZ and Cr-PL groups (6.69 ± 0.11 vs. 8.37 ± 0.04, 7.49 ± 0.04, respectively). Both Cr-PL and Cr-GTF may control T2DM. Both Cr complexes improved T2DM biomarkers more than the control diabetic group without medication. PGZ alone and PGZ + Cr-PL had less pharmacological synergy than Cr-GTF and PGZ in altering insulin and HOMA-IR blood levels. These encouraging discoveries need more study.
PubMed: 38389974
DOI: 10.4103/JAPTR.JAPTR_343_23 -
Diabetes Spectrum : a Publication of... 2024Insulin resistance is implicated in both the pathogenesis of nonalcoholic fatty liver disease (NAFLD) and its progression from steatosis to steatohepatitis, cirrhosis,...
Insulin resistance is implicated in both the pathogenesis of nonalcoholic fatty liver disease (NAFLD) and its progression from steatosis to steatohepatitis, cirrhosis, and even hepatocellular carcinoma, which is known to be more common in people with type 2 diabetes. This article reviews the role of insulin resistance in the metabolic dysfunction observed in obesity, type 2 diabetes, atherogenic dyslipidemia, and hypertension and how it is a driver of the natural history of NAFLD by promoting glucotoxicity and lipotoxicity. The authors also review the genetic and environmental factors that stimulate steatohepatitis and fibrosis progression and their relationship with cardiovascular disease and summarize guidelines supporting the treatment of NAFLD with diabetes medications that reduce insulin resistance, such as pioglitazone or glucagon-like peptide 1 receptor agonists.
PubMed: 38385099
DOI: 10.2337/dsi23-0013 -
Diabetes Spectrum : a Publication of... 2024Nonalcoholic fatty liver disease (NAFLD) and its more severe form, nonalcoholic steatohepatitis (NASH), can promote the development of cirrhosis, hepatocellular...
Nonalcoholic fatty liver disease (NAFLD) and its more severe form, nonalcoholic steatohepatitis (NASH), can promote the development of cirrhosis, hepatocellular carcinoma, cardiovascular disease, and type 2 diabetes. Similarly, type 2 diabetes confers the greatest risk for the development of NASH, especially when associated with obesity. Although lifestyle changes are critical to success, early implementation of pharmacological treatments for obesity and type 2 diabetes are essential to treat NASH and avoid disease progression. This article reviews current guidance regarding the use of pharmacological agents such as pioglitazone, glucagon-like peptide 1 receptor agonists, and sodium-glucose cotransporter 2 inhibitors in the setting of NAFLD and NASH. It also reviews the latest information on new drugs currently being investigated for the treatment of NASH.
PubMed: 38385098
DOI: 10.2337/dsi23-0012