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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 -
Neurosciences (Riyadh, Saudi Arabia) Jan 2024To explore the barriers preventing pioglitazone use in stroke survivors and primary and secondary stroke care services.
OBJECTIVES
To explore the barriers preventing pioglitazone use in stroke survivors and primary and secondary stroke care services.
METHODS
A qualitative grounded theory approached design was used to assess post-stroke diabetes treatments and to assess clinical applicability of pioglitazone as a preventive treatment to minimize its side effects (SEs) associated. Three focus groups were established with 48 participants from Scotland and Wales health board centers during January 2019 to July 2022.
RESULTS
A qualitative grounded theory approached design was used to assess post-stroke diabetes treatments and to assess clinical applicability of pioglitazone as a preventive treatment to minimize its SEs associated. Three focus groups were established with 48 participants from Scotland and Wales health board centers during January 2019 to July 2022.
CONCLUSION
These strategies might allow greater treatment adherence by stroke survivors and increased confidence of the health care professionals in their practice. The findings suggest that further research will be needed to facilitate wider usage of pioglitazone in treating people with stroke and health education is necessitate when using diabetes drugs post-stroke.
Topics: Humans; Pioglitazone; Comorbidity; Diabetes Mellitus; Stroke; Survivors
PubMed: 38195138
DOI: 10.17712/nsj.2024.1.20230043 -
IScience Jan 2024Idiopathic nephrotic syndrome (NS) is a common glomerular disease. Although glucocorticoids (GC) are the primary treatment, the PPARγ agonist pioglitazone (Pio) also...
Idiopathic nephrotic syndrome (NS) is a common glomerular disease. Although glucocorticoids (GC) are the primary treatment, the PPARγ agonist pioglitazone (Pio) also reduces proteinuria in patients with NS and directly protects podocytes from injury. Because both drugs reduce proteinuria, we hypothesized these effects result from overlapping transcriptional patterns. Systems biology approaches compared glomerular transcriptomes from rats with PAN-induced NS treated with GC vs. Pio and identified 29 commonly regulated genes-of-interest, primarily involved in extracellular matrix (ECM) remodeling. Correlation with clinical idiopathic NS patient datasets confirmed glomerular ECM dysregulation as a potential mechanism of injury. Cellular deconvolution revealed GC- and Pio-induced amelioration of altered genes primarily within podocytes and mesangial cells. While validation studies are indicated, these analyses identified molecular pathways involved in the early stages of NS (prior to scarring), suggesting that targeting glomerular ECM dysregulation may enable a future non-immunosuppressive approach for proteinuria reduction in idiopathic NS.
PubMed: 38188512
DOI: 10.1016/j.isci.2023.108631 -
Cureus Dec 2023Non-alcoholic fatty liver disease (NAFLD), now known as metabolic dysfunction-associated liver disease (MASLD), is a spectrum of liver disease. It can be identified by... (Review)
Review
Non-alcoholic fatty liver disease (NAFLD), now known as metabolic dysfunction-associated liver disease (MASLD), is a spectrum of liver disease. It can be identified by the fact that considerable amount of hepatocytes with minimal or no alcohol use have steatosisBecause of its rising incidence along with increasing rates of obesity, metabolic syndromes, and diabetes mellitus type 2, NAFLD is expected to overtake all other causes of cirrhosis over the next decade, necessitating liver transplantation. Nevertheless, heart disease persists as the most prevalent manifestation of mortality, with only a small percentage experiencing fibrosis and complications associated with the liver. Pathologically, NAFLD is linked to lipid toxicity, oxidative stress, lipid deposits, and endoplasmic reticulum stress. A healthy diet, physical exercise, and a decrease in weight are advised by current international guidelines for the treatment of NAFLD, along with a limited number of medicinal therapies, including vitamin E and pioglitazone. Various natural substances have also been identified as NAFLD in vivo and in vitro regulators. The frequency, complexity of the pathophysiology, lack of authorised medications, and difficulty in interpretation of NAFLD have made it a major problem. This article assesses MASLD's pathophysiology, diagnosis, treatment, and epidemiology. This study also reviews a few natural substances that have been shown to have therapeutic advantages for NAFLD.
PubMed: 38186528
DOI: 10.7759/cureus.50159 -
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 -
Journal of Cachexia, Sarcopenia and... Feb 2024Chronic inflammation and insulin resistance are highly prevalent in patients on maintenance haemodialysis (MHD) and are strongly associated with protein energy wasting.... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Chronic inflammation and insulin resistance are highly prevalent in patients on maintenance haemodialysis (MHD) and are strongly associated with protein energy wasting. We conducted a pilot, randomized, placebo-controlled trial of recombinant human interleukin-1 receptor antagonist (IL-1ra) and pioglitazone to explore the safety, feasibility and efficacy for insulin-mediated protein metabolism in patients undergoing MHD.
METHODS
Twenty-four patients were randomized to receive IL-1ra, pioglitazone or placebo for 12 weeks. Changes in serum inflammatory markers and insulin-mediated protein synthesis, breakdown and net balance in the whole-body and skeletal muscle compartments were assessed using hyperinsulinaemic-hyperaminoacidemic clamp technique at baseline and Week 12.
RESULTS
Among 24 patients, median (interquartile range) age was 51 (40, 61), 79% were African American and 21% had diabetes mellitus. All patients initiated on intervention completed the study, and no serious adverse events were observed. There was a statistically significant decrease in serum high-sensitivity C-reactive protein in the pioglitazone group compared with placebo, but not in the IL-1ra group. No significant differences in the changes of whole-body or skeletal muscle protein synthesis, breakdown and net balance were found between the groups.
CONCLUSIONS
In this pilot study, there were no statistically significant effects of 12 weeks of IL-1ra or pioglitazone on protein metabolism in patients on MHD.
CLINICALTRIALS
gov registration: NCT02278562.
Topics: Humans; Pioglitazone; Interleukin 1 Receptor Antagonist Protein; Pilot Projects; Renal Dialysis; Insulin; Biomarkers
PubMed: 38178557
DOI: 10.1002/jcsm.13395 -
Neurology India 2023Disease-modifying agents like Pioglitazone have shown promising effects on neuroinflammation and homeostasis of amyloid plaques, but there is a lack of research papers... (Meta-Analysis)
Meta-Analysis Review
Drug Repositioning of Pioglitazone in Management and Improving the Cognitive Function among the Patients With Mild to Moderate Alzheimer's Disease: A Systematic Review and Meta-Analysis.
BACKGROUND
Disease-modifying agents like Pioglitazone have shown promising effects on neuroinflammation and homeostasis of amyloid plaques, but there is a lack of research papers providing conclusive evidence.
OBJECTIVES
This study is aimed to determine the safety and efficacy of Pioglitazone in improving cognitive function in patients with mild-moderate Alzheimer's disease (AD).
MATERIALS AND METHODS
Trials published in the last 12 years were identified from PubMed, Scopus, Cochrane Central, and other trial registries. Five hundred twenty-five records were obtained, from which five studies were included for quantitative analysis. Studies comparing Pioglitazone with a suitable placebo or other oral hypoglycemic agent were considered for review. Data was extracted using a pretested form, which was followed by a risk of bias assessment (ROB) with Cochrane's ROB assessment tool.
RESULTS
This meta-analysis included studies where Pioglitazone (15-30 mg) was compared to other oral hypoglycemic agents, placebo, or diabetic diet for a minimum duration of 6 months. Pioglitazone did not show a statistically significant improvement in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) scores [mean difference (MD): -1.16; 95% confidence interval (CI): -4.14-1.81]. By conducting sensitivity analysis with the removal of one study, significant efficacy was obtained [MD: -2.75; 95% CI: -4.84--0.66]. The Wechsler Memory Scale-Revised logical memory I (WMS-R) scores had a significant improvement in the Pioglitazone group [MD: 2.02; 95% CI: 0.09-3.95].
CONCLUSION
Pioglitazone is a safe medication that has a promising effect in slowing the advancement of AD.
Topics: Humans; Alzheimer Disease; Pioglitazone; Drug Repositioning; Cognition
PubMed: 38174446
DOI: 10.4103/0028-3886.391397 -
Heliyon Jan 2024Adipokines and inflammatory cytokines (ADICs) play important roles in type 2 diabetes mellitus (T2DM). This study aimed to compare the changes of ADIC levels (ΔADICs)...
Comparison of changes in adipokine and inflammatory cytokine levels in patients with newly diagnosed type 2 diabetes treated with exenatide, insulin, or pioglitazone: A post-hoc study of the CONFIDENCE trial.
BACKGROUND
Adipokines and inflammatory cytokines (ADICs) play important roles in type 2 diabetes mellitus (T2DM). This study aimed to compare the changes of ADIC levels (ΔADICs) in patients with newly diagnosed T2DM treated with different antihyperglycemic agents, and further investigate the impact of these changes on metabolic indices, β-cell function and insulin resistance (IR).
METHODS
Four hundred and sixteen patients with newly diagnosed T2DM from 25 centers in China randomly received 48-week intervention with exenatide, insulin or pioglitazone. Anthropometric and laboratory data, indices of β-cell function and IR, and levels of AIDCs, including interleukin-1 beta (IL-1β), interferon-gamma (IFN-γ), leptin, and fibroblast growth factor 21 (FGF21) were detected at baseline and the end of the study.
RESULTS
In total, 281 participants (68 % male, age: 50.3 ± 9.4 years) completed the study. After 48- week treatment, IL-1β and IFN-γ were significantly decreased with exenatide treatment ( < 0.001 and = 0.001, respectively), but increased with insulin ( = 0.009 and = 0.026, respectively). However, pioglitazone treatment had no impact on ADICs. No significant change in leptin or FGF21 was detected with any of the treatments. After adjustment for baseline values and changes of body weight, waist and HbA1c, the between-group differences were found in ΔIL-1β (exenatide vs. insulin: = 0.048; and exenatide vs. pioglitazone: = 0.003, respectively) and ΔIFN-γ (exenatide vs. insulin: = 0.049; and exenatide vs. pioglitazone: < 0.001, respectively). Multiple linear regression analysis indicated that Δweight was associated with ΔIL-1β ( = 0.753; 95 % CI, 0.137-1.369; = 0.017). After adjusting for treatment effects, Δweight was also be correlated with ΔFGF21 ( = 1.097; 95%CI, 0.250-1.944; = 0.012); furthermore, ΔHOMA-IR was correlated with Δleptin ( = 0.078; 95%CI, 0.008-0.147; = 0.029) as well. However, ΔHOMA-IR was not significantly associated with ΔIL-1β after adjusting for treatment effects ( = 0.513).
CONCLUSION
Exenatide treatment led to significant changes of inflammatory cytokines levels (IL-1β and IFN-γ), but not adipokines (leptin and FGF21), in newly diagnosed T2DM patients. The exenatide-mediated improvement in weight and IR may be associated with a decrease in inflammatory cytokine levels.
PubMed: 38169889
DOI: 10.1016/j.heliyon.2023.e23309 -
Biomedicines Dec 2023Type 2 diabetes mellitus (T2DM) is a chronic progressive disease due to insulin resistance. Oxidative stress complicates the etiology of T2DM. Saxagliptin is a selective...
BACKGROUND
Type 2 diabetes mellitus (T2DM) is a chronic progressive disease due to insulin resistance. Oxidative stress complicates the etiology of T2DM. Saxagliptin is a selective dipeptidyl peptidase-4 (DPP-4) inhibitor, while Pioglitazone is a thiazolidinedione insulin sensitizer. This study aimed to assess the effect of Saxagliptin and Pioglitazone monotherapy and combination therapy on the biochemical and biological parameters in streptozotocin (STZ)-induced diabetic rats.
METHODS
The study included thirty-five male albino rats. Diabetes mellitus was induced by intraperitoneal STZ injection (35 mg/kg). For a 1-month duration, rats were divided into five groups. Glucose homeostasis traits, lipid profiles, kidney functions, liver enzymes, and oxidative stress markers were measured. Gene expression of miRNA-29a, phosphoenolpyruvate carboxykinase (PEPCK), phosphoinositide-3-kinase (PI3K), and interleukin 1 beta (IL-1β) was assessed using qRT-PCR.
RESULTS
At a 1-month treatment duration, combination therapy improves oxidative stress markers more than either drug alone. The combination therapy had significantly higher levels of SOD, catalase, and GSH and lower levels of MDA compared to the monotherapy. Additionally, the diabetic group showed a significant increase in the expression levels of miRNA-29a, PEPCK, and IL-1β and a significant decrease in PI3K compared to the normal control group. However, combination therapy of Saxagliptin and Pioglitazone was more effective than either Saxagliptin or Pioglitazone alone in reversing these results, especially for PEPCK and IL-1β.
CONCLUSIONS
Our findings revealed that combining Saxagliptin and Pioglitazone improves glycemic control and genetic and epigenetic expression profiles, which play an essential regulatory role in normal metabolism.
PubMed: 38137521
DOI: 10.3390/biomedicines11123300 -
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