PPARγ activation by pioglitazone enhances the anti-proliferative effects of doxorubicin on pro-monocytic THP-1 leukemia cells via inducing apoptosis and G2/M cell cycle arrest.

PURPOSE: Doxorubicin (DOX) is a common chemotherapeutic agent, with toxic side effects, and chemoresistance. Combination chemotherapy is a successful approach to overcome these limitations. Here, we investigated the effects of pioglitazone (PGZ), a PPARγ agonist, and/or DOX on the viability, cell cycle, apoptosis on THP-1 cells and normal human monocytes (NHMs). METHODS: MTT assay was used to evaluate the cytotoxicity of DOX and/or PGZ. Cell cycle progression and apoptosis induction were examined by PI or Annexin V-PI double staining, and analyzed by flow cytometry. Quantitative RT-PCR was used to evaluate the changes in the mRNA expression of cell cycle progression or apoptosis-associated genes including P27, P21, CDK2, P53, BCL2 and FasR. RESULTS: DOX, PGZ and DOX + PGZ exerted their cytotoxic effects in a dose- and time-dependent manner with low toxicity on NHMs. The cell growth inhibitory effects of DOX were in association with G2/M arrest, while PGZ executed S phase arrest. PGZ treatment enhanced G2/M among DOX-treated combinations with moderate elevation in the S phase. DOX, PGZ and combined treatments induced apoptosis (mostly late phase) in a dose-dependent manner. All treatments resulted in the significant overexpression of p21, p27, p53 and FasR genes and downregulation of CDK2. DOX + PGZ combined treatments exhibited the most significant changes in mRNA expression. CONCLUSION: We demonstrated that the antiproliferative, cell cycle regulation and apoptosis-inducing capacity of DOX was enhanced by PGZ in THP-1 leukemia cells in a dose-dependent manner. Therefore, the combination of DOX + PGZ could be used as a novel combination to target AML.

The lower expression of circulating miR-210 and elevated serum levels of HIF-1α in ischemic stroke; Possible markers for diagnosis and disease prediction.

BACKGROUND: Stroke, either due to ischemia or hemorrhage, causes acute neurological damages to the brain. There is shortage of reliable biomarkers for ischemic stroke (IS), and we therefore investigated the serum concentrations of microRNA-210 (miR-210) and hypoxia inducible factor-1α (HIF-1α), as possible diagnostic and/or prognostic markers for IS. METHODS: Serum samples were acquired from 52 IS patients and their healthy counterparts at five time points: upon admission, 24 and 48 h after admission, upon discharge and 3 months later. Serum levels of miR-210 and HIF-1α were respectively analyzed using real time RT-PCR and ELISA. Diagnostic and prognostic accuracy tests were performed to assess the value of suggested biomarkers. RESULTS: IS patients demonstrated higher levels of serum HIF-1α and lower miR-210 in comparison to the healthy subjects. MiR-210 was suggested to be a weak diagnostic biomarker at the time of admission (AUC = 0.61; p = 0.05), while HIF-1α was an acceptable diagnostic marker for IS (AUC = 0.73; p < 0.0001). The higher expression of miR-210 and lower levels of HIF-1α were associated with better survivals in IS patients. CONCLUSIONS: Serum miR-210 is a weak diagnostic marker of IS. Serum HIF-1α is a better biomarker in diagnosing IS patients but further work in larger groups, including those with hemorrhagic stroke is necessary to confirm its diagnostic utility. Similarly, the prognostic potentiality of miR-210 and HIF-1α was acceptable but needs bigger sample size and longer follow-up to be statistically confirmed.

The elevation of S100B and downregulation of circulating miR-602 in the sera of ischemic stroke (IS) patients: the emergence of novel diagnostic and prognostic markers.

Ischemic stroke (IS) is a major cause of mortality and disability. However, no reliable prognostic or diagnostic biomarker has been utilized to date. Here, we have evaluated the serum S100B concentration and miR-602 expression as potential biomarkers for IS. Fifty-two IS patients and 52 age- and sex-matched healthy volunteers were enrolled. Blood samples were collected from all patients at the time of admission, 24 and 48 h later, at the time of discharge, and 3 months later. Real-time (RT) PCR was used to measure the serum level of miR602. We also measured the serum concentration of S100B using ELISA. As compared with healthy subjects, IS patients had a higher level of serum S100B and lower serum miR-602. ROC curve analyses revealed that miR-602 (AUC = 0.8168; P < 0.0001) and S100B (AUC = 0.8699; P < 0.0001) had acceptable ability to differentiate between IS patients from healthy subjects. Furthermore, serum S100B was a reliable predictor of the survival outcome at 3 months (P = 0.021). The expression of miR-602 was significantly higher in patients with bigger NIHSS scores. The lower levels of miR-602 and higher concentration of S100B in the sera of IS patients could be associated with clinically significant diagnostic utilities. S100B could be also introduced as a reliable prognostic marker for stroke and implemented in future research.

Aryl hydrocarbon receptor dynamics in esophageal squamous cell carcinoma: From immune modulation to therapeutic opportunities.

Esophageal squamous cell carcinoma (ESCC) is a substantial global health burden. Immune escape mechanisms are important in ESCC progression, enabling cancer cells to escape the surveillance of the host immune system. One key player in this process is the Aryl Hydrocarbon Receptor (AhR), which influences multiple cellular processes, including proliferation, differentiation, metabolism, and immune regulation. Dysregulated AhR signaling participates in ESCC development by stimulating carcinogenesis, epithelial-mesenchymal transition, and immune escape. Targeting AhR signaling is a potential therapeutic approach for ESCC, with AhR ligands showing efficacy in preclinical studies. Additionally, modification of AhR ligands and combination therapies present new opportunities for therapeutic intervention. This review aims to address the knowledge gap related to the role of AhR signaling in ESCC pathogenesis and immune escape.

Pioglitazone as a potential modulator in autoimmune diseases: a review on its effects in systemic lupus erythematosus, psoriasis, inflammatory bowel disease, and multiple sclerosis.

INTRODUCTION: Current medications for autoimmune disorders often induce broad-ranging side effects, prompting a growing interest in therapies with more specific immune system modulation. Pioglitazone, known for its anti-diabetic properties, is increasingly recognized for significant immunomodulatory potential. Beyond its traditional use in diabetes management, pioglitazone emerges as a promising therapeutic candidate for autoimmune disorders. AREAS COVERED: This comprehensive review explores pioglitazone's impact on four prominent autoimmune conditions: systemic lupus erythematosus, psoriasis, inflammatory bowel disease, and multiple sclerosis. We focus on pioglitazone's diverse effects on immune cells and cytokines in these diseases, highlighting its potential as a valuable therapeutic option for autoimmune diseases. Here we have reviewed the latest and most current research literature available on PubMed, based on research published in the last 15 years. EXPERT OPINION: Pioglitazone as an immunomodulatory agent can regulate T cell differentiation, inhibit inflammatory cytokines, and promote anti-inflammatory macrophages. While further clinical studies are needed to fully understand its mechanisms and optimize treatment strategies, pioglitazone represents a potential therapeutic approach to improve outcomes for patients with these challenging autoimmune conditions. The future of autoimmune disease research may involve personalized treatment approaches, and collaborative efforts to improve patient quality of life.

This article explores the potential use of pioglitazone, a medication commonly used to treat diabetes, for autoimmune disorders treatment. The focus of the review centers around the effects of pioglitazone on systemic lupus erythematosus, psoriasis, inflammatory bowel disease, and multiple sclerosis. In the case of systemic lupus erythematosus, pioglitazone appears to induce a shift in specific immune cells, leading to a reduction in systemic inflammation and damage to organs. In psoriasis, the medication shows promise in suppressing immune responses, thereby alleviating skin inflammation. For individuals with inflammatory bowel disease, pioglitazone seems to safeguard a protein with anti-inflammatory properties, aiding in the repair of bowel tissue. Regarding multiple sclerosis, pioglitazone appears to influence the behavior of immune cells and promote the restoration of nerve tissue. These diverse effects of pioglitazone on the immune system suggest its potential as a valuable treatment option for autoimmune diseases. However, it is important to note that further research is necessary to fully comprehend the mechanisms by which pioglitazone operates and to determine the optimal approaches for its utilization in clinical studies.

Tumor Necrosis Factor Alpha (TNFα) Gene Promoter Polymorphisms and Haplotypes are Associated with the Febrile Seizure (FS) and TNFα Serum Levels.

Objectives: Febrile seizure (FS) is a neuroinflammatory disease involving fever-induced seizures affecting children in the early stages of life. TNFα is a pro-inflammatory cytokine reported to be elevated in FS. Specific promoter variants of TNFα could be associated with its elevated cytokine expression and susceptibility to FS. The present study analyzed the association of specific TNFα variants, including TNFα -238 G/A (rs361525), TNFα -308 G/A (rs1800629), and TNFα -376 G/A (rs1800750) promoter polymorphisms, with FS susceptibility, and TNFα serum levels in an Iranian population. Materials & Methods: Sixty-eight FS patients and 136 controls were enrolled. The SSP-PCR method was utilized to analyze TNFα promoter genotypes. This research also confirmed the genotyping results by sequencing samples of ten patients and normal controls. Results: The GG genotype of -238 SNP was associated with the increased risk of FS [OR = 12.65, 95% CI (2.83-56.60), P-value = 0.0012]. The AA genotype in the-308 region was increased in patients with FS and associated with the disease [OR = 4.62, 95% CI (1.46-14.56), P-value = 0.028]. The increased occurrence of heterozygous AG in the -376 SNP among control groups has been linked to a decreased risk of FS [OR = 0.22, 95% CI (0.11-0.43), P-value = 0.0001]. This study revealed that AGA (-238/ -308/ -376) haplotype with the highest frequency in controls was associated with a decreased risk of FS, while GAA (-238/ -308/ -376) carriers were more susceptible to FS. Conclusion: The current study suggested that TNFα gene promoter variants at rs361525, rs1800629, and rs1800750 could be associated with the susceptibility to FS and altered serum levels of TNFα.

Association between Pro-oxidant-Antioxidant balance and high-sensitivity C-reactive protein in type 2 diabetes mellitus: A Study on Postmenopausal Women.

INTRODUCTION: Oxidative stress known as a predictive marker for cardiovascular and metabolic diseases could be measured through pro-oxidant antioxidant balance (PAB). The present study aimed to evaluate PAB and its association with high-sensitivity C-reactive protein (hs-CRP) in the serum of postmenopausal women with diabetes mellitus. METHODS: In this case-control study, 99 diabetic and 100 healthy postmenopausal women without diabetes mellitus were recruited. Serum PAB values, hs-CRP, lipid profile, insulin, and vitamin D levels were measured. Moreover, insulin resistance (HOMA-IR, HOMA-ß and QUICKI), waist circumference (WC), waist-to-hip ratio (WHR), waist-to-height ratio (WHtR), and body mass index (BMI) were calculated. RESULTS: Serum PAB, hs-CRP, insulin resistance, HOMA-ß, QUICKI, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) levels were significantly higher in the postmenopausal women with diabetes mellitus, while there was no significant difference in the total cholesterol (TC), serum insulin, WC, WHR, WHtR and vitamin D levels between the groups. Pearson correlation coefficient showed that HDL-C and insulin levels were directly correlated with serum PAB. Also, there was a significant direct relationship between LDL-C and insulin levels and hs-CRP. There was no meaningful relationship between serum insulin and vitamin D levels and other assessed parameters. Backward logistic regression showed a positive relationship between diabetes mellitus and serum PAB and an inverse relationship with serum HDL levels. CONCLUSIONS: Serum PAB, hs-CRP concentration, and lipid profile were significantly different between postmenopausal women with and without diabetes mellitus. These differences may contribute to the development of coronary complications.