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Diabetes, Metabolic Syndrome and... 2024Non-alcoholic fatty liver disease (NAFLD) is a common disease and has been increasing in recent years. To date, no FDA-approved drug specifically targets NAFLD. (Review)
Review
BACKGROUND
Non-alcoholic fatty liver disease (NAFLD) is a common disease and has been increasing in recent years. To date, no FDA-approved drug specifically targets NAFLD.
METHODS
The terms "Non-alcoholic Fatty Liver Disease" and "NAFLD" were used in a search of ClinicalTrials.gov on August 24, 2023. Two evaluators independently examined the trials using predetermined eligibility criteria. Studies had to be interventional, NAFLD focused, in Phase IV, and completed to be eligible for this review.
RESULTS
The ClinicalTrials.gov database was searched for trials examining pharmacotherapeutics in NAFLD. The search revealed 1364 trials, with 31 meeting the inclusion criteria. Out of these, 19 were finalized for evaluation. The dominant intervention model was Parallel. The most prevalent studies were in Korea (26.3%) and China (21.1%). The most common intervention was metformin (12.1%), with others like Exenatide and Pioglitazone accounting for 9.1%.
CONCLUSION
Therapeutics used to manage NAFLD are limited. However, various medications offer potential benefits. Further investigations are definitely warranted.
PubMed: 38327733
DOI: 10.2147/DMSO.S448476 -
JCEM Case Reports Feb 2024Acquired generalized lipodystrophy (AGL) is a rare condition characterized by the diffuse loss of adipose tissue resulting in hyperglycemia, severe insulin resistance,...
Acquired generalized lipodystrophy (AGL) is a rare condition characterized by the diffuse loss of adipose tissue resulting in hyperglycemia, severe insulin resistance, and sequelae of metabolic disease. Here, we report the case of a 32-year-old woman who developed uncontrolled hyperglycemia and significant weight loss within 2 months postpartum. Upon endocrine evaluation, she was found to have generalized loss of adiposity, hypoleptinemia, and persistent hyperglycemia despite aggressive insulin administration. Glycemic response was obtained with U-500 intramuscular insulin, pioglitazone, and metformin-sitagliptin. At 14 months postpartum, the patient achieved spontaneous remission with normoglycemia off medication and restoration of adipose tissue deposition. Autoimmune workup revealed positive antinuclear antibodies (ANA) and anti-U1-ribonucleoprotein (anti-U1-RNP) titers, suggestive of an autoimmune etiology to her condition. This case of AGL represents the first reported case of spontaneous remission and the first to develop in the postpartum period.
PubMed: 38314238
DOI: 10.1210/jcemcr/luae009 -
Diabetes & Metabolism Journal Feb 2024This study assessed the efficacy and safety of triple therapy with pioglitazone 15 mg add-on versus placebo in patients with type 2 diabetes mellitus (T2DM) inadequately...
Pioglitazone as Add-on THERAPY in Patients with Type 2 Diabetes Mellitus Inadequately Controlled with Dapagliflozin and Metformin: Double-Blind, Randomized, Placebo-Controlled Trial.
BACKGROUND
This study assessed the efficacy and safety of triple therapy with pioglitazone 15 mg add-on versus placebo in patients with type 2 diabetes mellitus (T2DM) inadequately controlled with metformin and dapagliflozin.
METHODS
In this multicenter, double-blind, randomized, phase 3 study, patients with T2DM with an inadequate response to treatment with metformin (≥1,000 mg/day) plus dapagliflozin (10 mg/day) were randomized to receive additional pioglitazone 15 mg/day (n=125) or placebo (n=125) for 24 weeks. The primary endpoint was the change in glycosylated hemoglobin (HbA1c) levels from baseline to week 24 (ClinicalTrials.gov identifier: NCT05101135).
RESULTS
At week 24, the adjusted mean change from baseline in HbA1c level compared with placebo was significantly greater with pioglitazone treatment (-0.47%; 95% confidence interval, -0.61 to -0.33; P<0.0001). A greater proportion of patients achieved HbA1c <7% or <6.5% at week 24 with pioglitazone compared to placebo as add-on to 10 mg dapagliflozin and metformin (56.8% vs. 28% for HbA1c <7%, and 23.2% vs. 9.6% for HbA1c <6.5%; P<0.0001 for all). The addition of pioglitazone also significantly improved triglyceride, highdensity lipoprotein cholesterol levels, and homeostatic model assessment of insulin resistance levels, while placebo did not. The incidence of treatment-emergent adverse events was similar between the groups, and the incidence of fluid retention-related side effects by pioglitazone was low (1.5%).
CONCLUSION
Triple therapy with the addition of 15 mg/day of pioglitazone to dapagliflozin plus metformin was well tolerated and produced significant improvements in HbA1c in patients with T2DM inadequately controlled with dapagliflozin plus metformin.
PubMed: 38310875
DOI: 10.4093/dmj.2023.0314 -
Frontiers in Oncology 2023A series of seven clinical trials on relapsed or refractory (r/r) metastatic neoplasias followed the question: Are networks of ligand-receptor cross-talks that support... (Review)
Review
A series of seven clinical trials on relapsed or refractory (r/r) metastatic neoplasias followed the question: Are networks of ligand-receptor cross-talks that support tumor-specific cancer hallmarks, druggable with tumor tissue editing approaches therapeutically exploiting tumor plasticity? Differential recombinations of pioglitazone, a dual peroxisome-proliferator activated receptor (PPARα/γ) agonist, with transcriptional modulators, i.e., all-trans retinoic acid, interferon-α, or dexamethasone plus metronomic low-dose chemotherapy (MCT) or epigenetic modeling with azacitidine plus/minus cyclooxygenase-2 inhibition initiated tumor-specific reprogramming of cancer hallmarks, as exemplified by inflammation control in r/r melanoma, renal clear cell carcinoma (RCCC), Hodgkin's lymphoma (HL) and multisystem Langerhans cell histiocytosis (mLCH) or differentiation induction in non-promyelocytic acute myeloid leukemia (non-PML AML). Pioglitazone, integrated in differentially designed editing schedules, facilitated induction of tumor cell death as indicated by complete remission (CR) in r/r non-PML AML, continuous CR in r/r RCCC, mLCH, and in HL by addition of everolimus, or long-term disease control in melanoma by efficaciously controlling metastasis, post-therapy cancer repopulation and acquired cell-resistance and genetic/molecular-genetic tumor cell heterogeneity (M-CRAC). PPARα/γ agonists provided tumor-type agnostic biomodulatory efficacy across different histologic neoplasias. Tissue editing techniques disclose that wide-ranging functions of PPARα/γ agonists may be on-topic focused for differentially unlocking tumor phenotypes. Low-dose MCT facilitates targeted reprogramming of cancer hallmarks with transcriptional modulators, induction of tumor cell death, M-CRAC control and editing of non-oncogene addiction. Thus, pioglitazone, integrated in tumor tissue editing protocols, is an important biomodulatory drug for addressing urgent therapeutic problems, such as M-CRAC in relapsed or refractory tumor disease.
PubMed: 38273846
DOI: 10.3389/fonc.2023.1289222 -
Research in Veterinary Science Mar 2024The objective of this experiment was to evaluate the effects of dietary fish oil and pioglitazone as peroxisome proliferators-activated receptor gamma (PPARγ)...
The effect of peroxisome proliferator-activated receptor gamma (PPARγ) as a mediator of dietary fatty acids and thiazolidinedione in pulmonary arterial hypertension induced by cold stress of broilers.
The objective of this experiment was to evaluate the effects of dietary fish oil and pioglitazone as peroxisome proliferators-activated receptor gamma (PPARγ) activating ligands on the reduction of cold-induced ascites in broiler chickens. A total of 480 one-day-old (Ross 308) male chicks were randomly allocated to four treatment groups with eight replicates of 15 birds each. The following treatments were used: 1) ambient temperature (negative control), with basal diet; 2) cold-induced ascites (positive control), with basal diet; 3) cold-induced ascites, with basal diet +10 mg/kg/day pioglitazone and 4) cold-induced ascites, with basal diet +1% of fish oil. When compared with the positive control, body weight gain was higher (P ≤ 0.05) for broilers fed diets containing fish oil and pioglitazone at 28, 42, and 0-42 d. Broilers under cold-induced ascites had the highest blood pressure at 21 and 42 d, while fish oil and pioglitazone treatment reduced the blood pressure (P ≤ 0.05). Red blood cells, white blood cells, hematocrit, erythrocyte osmotic fragility, bursa of Fabricius and spleen weights were improved (P ≤ 0.05) for chickens fed fish oil diets and pioglitazone compared to the cold-induced ascites (positive control). Exposure to cold temperature resulted in an increase in plasma T and T/T ratio and decline in plasma T (P ≤ 0.05). In conclusion, PPARγ agonist pioglitazone and fish oil as source of omega-3 polyunsaturated fatty acid could be used as a strategy to reduce the negative effects of pulmonary arterial hypertension and ascites in broiler chickens.
Topics: Animals; Male; Chickens; PPAR gamma; Pulmonary Arterial Hypertension; Pioglitazone; Ascites; Cold-Shock Response; Diet; Fatty Acids, Omega-3; Fish Oils; Animal Feed; Dietary Supplements
PubMed: 38266350
DOI: 10.1016/j.rvsc.2024.105157 -
Cellular and Molecular Gastroenterology... 2024Changes in phosphatidylcholine levels in the liver have been associated with the development of metabolic dysfunction-associated steatotic liver disease. Here, the...
BACKGROUND & AIMS
Changes in phosphatidylcholine levels in the liver have been associated with the development of metabolic dysfunction-associated steatotic liver disease. Here, the effects of supplementing phosphatidylcholine on the development of early signs of metabolic dysfunction-associated steatohepatitis were assessed.
METHODS
Male and female C57BL/6J mice were fed a liquid control or a fructose-, fat-, and/or cholesterol-rich diet for 7 or 8 weeks. The diets of female mice were fortified ± phosphatidylcholine (12.5 mg/g diet). In liver tissue and portal blood, indices of liver damage, inflammation, and bacterial endotoxemia were measured. J774A.1 cells and human monocytes preincubated with phosphatidylcholine (0.38 mmol/L) were challenged with lipopolysaccharide (50-100 ng/mL) ± the peroxisome proliferator-activated receptor γ (PPARγ) activator pioglitazone (10 μmol/L) or ± a liver receptor homolog 1 (LRH-1) antagonist 1-(3'-[1-(2-[4-morpholinyl]ethyl)-1H-pyrazol-3-yl]-3-biphenylyl)ethanon (1-10 μmol/L).
RESULTS
In fructose-, fat-, and/or cholesterol-rich diet-fed mice the development of fatty liver and the beginning of inflammation were associated with significantly lower hepatic phosphatidylcholine levels when compared with controls. Supplementing phosphatidylcholine significantly attenuated the development of fatty liver and inflammation, being associated with protection against the induction of PPARγ2, and activation of nuclear factor of κ light polypeptide gene enhancer in B-cell inhibitor α whereas Lrh1 expression was unchanged. The protective effects of phosphatidylcholine on the lipopolysaccharide-induced activation of J774A.1 cells and human monocytes were attenuated significantly by the PPARγ activator pioglitazone and the LRH-1 antagonist.
CONCLUSIONS
Our data suggest that phosphatidylcholine levels in the liver are lower in early metabolic dysfunction-associated steatohepatitis in mice and that supplementation of phosphatidylcholine can diminish the development of metabolic dysfunction-associated steatotic liver disease through mechanisms involving LRH-1/PPARγ2/ nuclear factor κ-light-chain enhancer of activated B-cell signaling.
Topics: Male; Female; Humans; Animals; Mice; Non-alcoholic Fatty Liver Disease; PPAR gamma; Pioglitazone; Mice, Inbred C57BL; Lipopolysaccharides; Diet; Inflammation; Dietary Supplements; Cholesterol; Fructose
PubMed: 38262589
DOI: 10.1016/j.jcmgh.2024.01.009 -
Frontiers in Pharmacology 2023Spontaneous subarachnoid hemorrhage (SAH), is a disorder that may be fatal and is primarily caused by a ruptured brain aneurysm. Despite significant leaps forward in...
Spontaneous subarachnoid hemorrhage (SAH), is a disorder that may be fatal and is primarily caused by a ruptured brain aneurysm. Despite significant leaps forward in the methods to produce aneurysms, the long-term outcomes did not much improve. Pioglitazone is a medication that has been authorized by the FDA as an agonist for the peroxisome proliferator-activated receptor-gamma (PPARγ). Pioglitazone or PPARγ has neuroprotective benefits in animal experiments both during and after traumatic brain injury (TBI) and SAH. Nevertheless, the treatment impact of Pioglitazone on humans is still unknown at this time. As a result, we will conduct a randomized, double-blind, placebo-controlled trial to explore the impact of pioglitazone on SAH. This trial will recruit 400 patients with SAH from four Chinese hospitals. These patients will be equally and randomly assigned to Pioglitazone and placebo control groups for up to 30 days. Scores on the modified Rankin scale (mRS) are the primary outcomes. The secondary outcomes are a 30-day all-cause mortality rate, 6 months of Montreal cognitive assessment (Mo-CA), delayed cerebral ischemia, the requirement for intensive care, the incidence of sepsis, . All serious adverse events (SAEs) were recorded during the hospital. Every primary and safety analysis was conducted based on the intention-to-treat technique. The participants were given either a matching placebo or 15 mg of pioglitazone, with dose titrated to a target of 45 mg daily. Data on the therapeutic use of pioglitazone after SAH will be provided as a consequence of the findings of this experiment. In addition, this pilot trial is the first to prospectively investigate the effectiveness and safety of pioglitazone in patients with SAH. Ethics approval was obtained from the Medical Ethics Committee of 904th Hospital of Joint Logistic Support Force of PLA (Wuxi Taihu Hospital, approval No. 20220701). The findings of the trial will be presented at conferences, discussed in relevant patient groups, and published in peer-reviewed journals. clinicaltrials.gov, identifier ChiCTR2200062954.
PubMed: 38249343
DOI: 10.3389/fphar.2023.1323292 -
Diabetology & Metabolic Syndrome Jan 2024Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common liver disease affecting 30% of the world's population and is often associated with... (Review)
Review
2024 UPDATE: the Brazilian Diabetes Society position on the management of metabolic dysfunction-associated steatotic liver disease (MASLD) in people with prediabetes or type 2 diabetes.
BACKGROUND
Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common liver disease affecting 30% of the world's population and is often associated with metabolic disorders such as metabolic syndrome, type 2 diabetes (T2D), and cardiovascular disease. This review is an update of the Brazilian Diabetes Society (Sociedade Brasileira de Diabetes [SBD]) evidence-based guideline for the management of MASLD in clinical practice.
METHODS
The methodology was published previously and was defined by the internal institutional steering committee. The SBD Metabolic Syndrome and Prediabetes Department drafted the manuscript, selecting key clinical questions for a narrative review using MEDLINE via PubMed with the MeSH terms [diabetes] and [fatty liver]. The best available evidence was reviewed, including randomized clinical trials (RCTs), meta-analyses, and high-quality observational studies related to MASLD.
RESULTS AND CONCLUSIONS
The SBD Metabolic Syndrome and Prediabetes Department formulated 9 recommendations for the management of MASLD in people with prediabetes or T2D. Screening for the risk of advanced fibrosis associated with MASLD is recommended in all adults with prediabetes or T2D. Lifestyle modification (LSM) focusing on a reduction in body weight of at least 5% is recommended as the first choice for these patients. In situations where LSMs are insufficient to achieve weight loss, the use of anti-obesity medications is recommended for those with a body mass index (BMI) ≥ 27 kg/m. Pioglitazone and glucagon-like peptide-1 receptor agonists (GLP-1RA) monotherapy are the first-line pharmacological treatments for steatohepatitis in people with T2D, and sodium-glucose cotransporter-2 (SGLT2) inhibitors may be considered in this context. The combination of these agents may be considered in the treatment of steatohepatitis and/or fibrosis, and bariatric surgery should be considered in patients with a BMI ≥ 35 kg/m, in which the combination of LSM and pharmacotherapy has not been shown to be effective in improving MASLD.
PubMed: 38238868
DOI: 10.1186/s13098-024-01259-2 -
Journal of Traditional Chinese Medicine... Feb 2024To explore the mechanism of the Chinese medicine Cigu Xiaozhi prescription (, CGXZ) in the treatment of the non-alcoholic fatty liver disease (NAFLD) by detoxification...
OBJECTIVE
To explore the mechanism of the Chinese medicine Cigu Xiaozhi prescription (, CGXZ) in the treatment of the non-alcoholic fatty liver disease (NAFLD) by detoxification and phlegm-reducing, the effect of CGXZ prescription on ceramide-mediated lipid apoptosis in Hep G2 cells with NAFLD.
METHODS
The experiment was randomly divided into 6 groups: normal control group, model group, CGXZ prescription medicated serum high, medium, and low dose groups, and pioglitazone positive control group. Using 500 μmol/L free fatty acid (FFA) mixture to induce Hep G2 cells to establish NAFLD cell model, respectively, with 2%, 4%, and 6% concentration of CGXZ prescription medicated serum intervention for 24 h. The changes in organelles and lipid droplet accumulation were observed under the electron microscope. Furthermore, TdT-mediated dUTP Nick-End Labeling method was used to assay hepatocyte apoptosis; Biochemical determination of glutamic-pyruvic transaminase, glutamic oxalacetic transaminase, triglycerides, and FFA levels in Hep G2 cells; the content of ceramide was determined by high-performance thin-layer chromatography. Finally, Western Blot and quantitative real-time polymerase chain reaction (qRT-PCR) were used to determine the protein and gene expression levels, such as inducible nitric oxide synthase (iNOS), nuclear factor κB (NF-κB), B cell lymphoma 2 (Bcl-2) and Bcl-2-associated X (Bax).
RESULTS
Under the electron microscope, the cells in the model group showed moderate-to-severe steatosis, and apoptotic bodies could be seen. The model group had greater improvements in the apoptosis rate ( 0.01), and the levels of ceramide C2 and FFA in the cytoplasm ( 0.01) than the normal control group. The protein expressions of NF-κB, iNOS, and Bax were significantly up-regulated ( 0.05), while the Bcl-2 had no significant change ( 0.05). Compared with the model group, the levels of ceramide C2 and FFA ( 0.01), the protein expressions of NF-κB, iNOS, and Bax ( 0.05) in the CGXZ prescription treatment group and pioglitazone positive control group were significantly decreased; Only the Bcl-2 protein was significantly up-regulated in the high-dose Chinese medicine group ( 0.05). The down-regulation of Bax mRNA expression in each Chinese medicine treatment group was significantly better than in the pioglitazone positive control group ( 0.01).
CONCLUSIONS
The CGXZ prescription, formulated with the method of detoxification and phlegm, can inhibit lipoapoptosis in the NAFLD cell model by down-regulating the levels of ceramide C2 and FFA, which may be achieved by regulating ceramide/iNOS/NF-κB signaling pathway.
Topics: Humans; Non-alcoholic Fatty Liver Disease; Liver; NF-kappa B; bcl-2-Associated X Protein; Ceramides; Pioglitazone; Prescriptions
PubMed: 38213240
DOI: 10.19852/j.cnki.jtcm.20231215.002 -
Cancers Dec 2023The concept of post-therapy metastatic spread, cancer repopulation and acquired tumor cell resistance (M-CRAC) rationalizes tumor progression because of tumor cell... (Review)
Review
The concept of post-therapy metastatic spread, cancer repopulation and acquired tumor cell resistance (M-CRAC) rationalizes tumor progression because of tumor cell heterogeneity arising from post-therapy genetic damage and subsequent tissue repair mechanisms. Therapeutic strategies designed to specifically address M-CRAC involve tissue editing approaches, such as low-dose metronomic chemotherapy and the use of transcriptional modulators with or without targeted therapies. Notably, tumor tissue editing holds the potential to treat patients, who are refractory to or relapsing (r/r) after conventional chemotherapy, which is usually based on administering a maximum tolerable dose of a cytostatic drugs. Clinical trials enrolling patients with r/r malignancies, e.g., non-small cell lung cancer, Hodgkin's lymphoma, Langerhans cell histiocytosis and acute myelocytic leukemia, indicate that tissue editing approaches could yield tangible clinical benefit. In contrast to conventional chemotherapy or state-of-the-art precision medicine, tissue editing employs a multi-pronged approach targeting important drivers of M-CRAC across various tumor entities, thereby, simultaneously engaging tumor cell differentiation, immunomodulation, and inflammation control. In this review, we highlight the M-CRAC concept as a major factor in resistance to conventional cancer therapies and discusses tissue editing as a potential treatment.
PubMed: 38201607
DOI: 10.3390/cancers16010180