Curcumin and saroglitazar attenuate diet-induced nonalcoholic steatohepatitis by activating the Nrf2 pathway and suppressing ERK1/2 signaling.

Objectives: Non-alcoholic fatty liver disease (NAFLD) is a chronic steatohepatitis disorder. If left untreated, it can progress to hepatocellular carcinoma. Several studies have shown that saroglitazar, a PPARα/γ dual agonist, and curcumin (the principal constituent of turmeric) may be effective in the treatment of NAFLD. This research aimed to study the pharmacological mechanism of these compounds in rats with NAFLD. Materials and Methods: NAFLD was induced in male Wistar rats (aged 6-8 weeks) by feeding them a high-fat diet (HFD) for 6 weeks. Subsequently, the rats were divided into four groups, with Group 1 continuing on HFD, while groups 2, 3, and 4 received HFD supplemented with saroglitazar, curcumin, and both saroglitazar and curcumin, respectively. We evaluated the expression of Nrf2, ERK1/2, NOX1,2,4, antioxidant enzymes, PPARα, γ, and genes regulating lipid metabolism in the liver. Histopathology of liver tissue was also examined. Furthermore, we analyzed serum levels of lipid profiles and hepatic enzymes. Results: Rats with NAFLD that received treatment involving saroglitazar and curcumin showed a significant decrease in the expression of ERK1/2, SREBP1, PPARγ, pro-inflammatory cytokines, NOXs, and ROS levels. Additionally, the levels of Nrf2, PPARα, and antioxidant enzymes showed a significant increase. The serum levels of lipid profiles and hepatic enzymes also decreased significantly after drug treatment. Conclusion: Our results confirm that both saroglitazar and curcumin ameliorate NAFLD by regulating the Nrf2 and ERK1/2 signaling pathways. These findings suggest that curcumin could serve as a suitable substitute for saroglitazar, although they appear to have a synergistic effect.

The effect of saraglitazar on TGF-ß-induced smad3 phosphorylation and expression of genes related to liver fibrosis in LX2 cell line.

BACKGROUND AND PURPOSE: Liver fibrosis is a reversible liver injury that occurs as a result of many chronic inflammatory diseases and can lead to cirrhosis, which is irreversible and fatal. So, we studied the anti-fibrotic effects of saroglitazar on LX-2 cell lines, as a dual PPARα/γ agonist. METHODS: Cells, after 80% confluence, were treated with TGF-ß (2 ng/mL) for 24 h. Then cells were treated with saroglitazar at different doses (2.5, 5, 10 µM) for 24 h. After same incubation, the cells of control group, TGF-ß group, and TGF-ß + saroglitazar group were harvested for RNA and protein extraction to determine the effects of saroglitazar. RT-PCR and western blot methods were used to express genes related to fibrosis. RESULTS: Our results show that the relative expression of α-SMA, collagen1α, N-cadherin, NOX (1, 2, and 4), and phosphorylated Smad3 protein was significantly higher in TGF-ß-treated cells compared with the normal group, and E-cadherin expression was decreased in TGF-ß-treated cells. After TGF-ß-treated cells were exposed to saroglitazar, the expression of these genes was significantly reversed (P < 0.05). CONCLUSIONS: Our results clearly show the short-term inhibitory role of saroglitazar in the expression of fibrotic factors using the TGF-ß/Smad signaling pathway. These results suggest that saroglitazar can be considered as a suitable therapeutic strategy for fibrotic patients. Although more studies are needed.

Comparison of the anti-inflammatory and antilipidemic activity of diosmin and saroglitazar in a model of nonalcoholic fatty liver induced by a high-fat diet in Wistar rats.

Objectives: Non-alcoholic fatty liver disease (NAFLD) is the most common liver-related metabolic disorder in the world, with a global prevalence of 25%. Compounds with anti-inflammatory, lipid-lowering, and insulin-sensitizing properties can be used for the prevention or treatment of NAFLD. Therefore, this study was conducted to investigate the effect of saroglitazar (a dual PPARα/γ agonist) and diosmin (a flavonoid) on non-alcoholic fatty liver induced by a high-fat diet (HFD) in Wistar rats. Materials and Methods: Forty male Wistar rats (6-8 weeks old) were fed an HFD to induce NAFLD. After 7 weeks, rats were divided into four groups: group1 was fed HFD, and the other groups received HFD+saroglitazar, HFD+diosmin, and HFD+ saroglitazar+diosmin. We examined body and liver weight, histopathology, serum levels of liver enzymes (ALT and AST), and lipid profiles (LDL-C and HDL-C) using the standard protocols. qRT-PCR was also used to examine the expression of PPARα, PPARγ, SREBP1c, FAS, ACC, CPT1α, and pro-inflammatory genes (IL6, TNFα, and TGFß). Results: Rats fed the HFD showed characteristics of NAFLD (pathologically and biochemically). Administration of saroglitazar and diosmin alone caused a significant decrease in the levels of PPARγ, SREBP1c, FAS, ACC, ALT, AST, LDL-C, and pro-inflammatory genes and a significant increase in PPARα, CPT1a, and HDL-C in comparison with the HF group (P<0.05). Their combined effect was more evident. Conclusion: Our results showed that diosmin, like saroglitazar, significantly ameliorated inflammatory and lipid profiles in HFD-induced NAFLD, suggesting that diosmin, as a natural compound, could be a suitable alternative to saroglitazar.

Diabetes and ovarian cancer: risk factors, molecular mechanisms and impact on prognosis.

BACKGROUND AND AIM: Diabetes mellitus has been linked to a lower rate of cancer survival and an increase in the incidence of most malignancies. Investigations showed that diabetes might affect ovarian cancer (OC) prognosis and survival. Based on the current information, this study intends to review the risk factors, molecular pathways, and impact of diabetes on OC. METHODS: The data was derived from online databases, including Web of Science, PubMed, and Scopus. The inclusion criteria were original studies, which included the risk factors, molecular mechanisms, and impact of diabetes on OC. The effect of different antidiabetic drugs was also discussed in this manuscript. All of the clinical, in vivo, and in vitro studies were included in the present study. RESULTS: The diagnosis of diabetes mellitus negatively affects the survival and prognosis in OC cases. The epidemiologic data shows that the risk of OC increases in patients with diabetes mellitus compared to the healthy population. Insulin-like growth factors family was raised in diabetic patients, which target several mechanisms, including targeting oxidative stress, angiogenesis, and tumor markers. Antidiabetic drugs such as metformin, sitagliptin, and rosiglitazone have a promising effect on elongation of survival and enhancement of prognosis in OC patients. CONCLUSIONS: Diabetes mellitus is a significant risk factor for OC in women, and it negatively impacts survival and prognosis. Molecular mechanisms such as IGF family, oxidative stress, and inflammatory cytokines have been identified to explain this relationship. Antidiabetic drugs like metformin, sitagliptin, and rosiglitazone have shown promise in improving survival and prognosis of OC patients.

Liquid biopsy in ovarian cancer: advantages and limitations for prognosis and diagnosis.

Ovarian cancer (OC) is a highly fatal gynecologic malignancy, often diagnosed at an advanced stage which presents significant challenges for disease management. The clinical application of conventional tissue biopsy methods and serological biomarkers has limitations for the diagnosis and prognosis of OC patients. Liquid biopsy is a novel sampling method that involves analyzing distinctive tumor elements secreted into the peripheral blood. Growing evidence suggests that liquid biopsy methods such as circulating tumor cells, cell-free RNA, circulating tumor DNA, exosomes, and tumor-educated platelets may improve early prognosis and diagnosis of OC, leading to enhanced therapeutic management of the disease. This study reviewed the evidence demonstrating the utility of liquid biopsy components in OC prognosis and diagnosis, and evaluated the current advantages and limitations of these methods. Additionally, the existing obstacles and crucial topics for future studies utilizing liquid biopsy in OC patients were discussed.

Examining dyslipidaemia, metabolic syndrome and liver enzyme levels in patients with prediabetes and type 2 diabetes in population from Hoveyzeh cohort study: A case-control study in Iran.

INTRODUCTION: Type 2 diabetes mellitus (T2DM) is among the world's top 10 leading causes of death. Additionally, prediabetes is a major risk factor for diabetes. Identifying diabetes co-occurring disorders can aid in reducing adverse effects and facilitating early detection. In this study, we evaluated dyslipidaemia, metabolic syndrome (MetS), and liver enzyme levels in pre-diabetic and T2DM patients in the Persian cohort compared to a control group. MATERIALS AND METHODS: In this cross-sectional study, 2259 pre-diabetes, 1664 T2DM and 5840 controls (35-70 years) who were selected from the Hoveyzeh cohort centre were examined. Body mass index, blood pressure, fasting blood glucose (FBG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), triglyceride (TG) and liver enzymes: γ-glutamyltransferase (GGT), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were determined using the standard protocols. MetS subjects were also identified based on the National Cholesterol Education Program guidelines. RESULTS: Prediabetes and T2MD were closely correlated with the lipid profile, MetS, and liver enzymes (ALT, GGT, ALT/AST). MetS increases the risk of T2DM by 12.45 [95% CI: 10.88-14.24] fold, while an increase in ALT/AST ratio increases the risk of T2DM by 3.68 [95% CI: 3.159-4.154] fold. ROC curve analysis also revealed the diagnostic roles of GGT, ALT, AST and the ALT/AST ratio among pre-diabetics, diabetics and the control group. The GGT level corresponds to the highest AUCs (0.685) with the highest sensitivity (70.25%). CONCLUSIONS: Our results indicated a significant increase in liver enzymes, lipid profile and MetS status in both pre-diabetic and T2MD subjects, with the differences being more pronounced in diabetic individuals. Consequently, on the one hand, these variables may be considered predictive risk factors for diabetes, and on the other hand, they may be used as diagnostic factors. In order to confirm the clinical applications of these variables, additional research is required.

Evaluation of the gene encoding carnitine transporter (OCTN2/SLC22A5) expression in human breast cancer and its association with clinicopathological characteristics.

BACKGROUND: Fatty acid oxidation (FAO) is a major energy-generating process in the mitochondria and supports proliferation, growth, and survival of cancer cells. L-Carnitine is an essential co-factor for carrying long-chain fatty acids into the mitochondria. The entry of l-carnitine across cell membrane is regulated by OCTN2 (SLC22A5). Thus, it can plays a significant role in the mitochondrial fatty acid oxidation. This study aimed to evaluate the OCTN2 expression and its association with clinicopathological characteristics in breast cancer. METHODS: In this work, OCTN2 was examined in 54 pairs of fresh samples of breast cancer (BC) and adjacent noncancerous tissue using quantitative real-time polymerase chain reaction and immunohistochemistry (IHC). The IHC approach was also used to investigate the expression of additional clinicopathological features. RESULTS: The present research findings revealed that the relative expression of OCTN2 in BC tissues was substantially higher than the adjacent normal tissues. This up-regulation was correlated positively with tumor size and Ki-67 and negatively with the progesterone receptor (PR) status, providing evidence of the opposite effects of OCTN2 and PR on tumor development. CONCLUSION: The study shows that the OCTN2 expression in BC patients may be used as a prognostic biomarker and a tumor oncogene. As a result, it could be considered a possible therapeutic target. Nevertheless, the significance of the findings needs to be confirmed by further studies.

Evaluation of long-chain acyl-coenzyme A synthetase 4 (ACSL4) expression in human breast cancer.

BACKGROUND AND PURPOSE: Breast cancer (BC) is one of the major causes of female cancer-related death. It has recently been demonstrated that metabolic reprogramming including alteration in lipid metabolism is indicated in various types of cancer. The enzymes of the acyl-coenzyme A synthetase long-chain family (ACSLs) are responsible for converting fatty acids to their corresponding fatty acyl-coenzyme A esters which are essential for some lipid metabolism pathways. ACSL4 is one of the isoforms of ACSLs and has a marked preference for arachidonic and eicosapentaenoic acids. The objective of this study was to evaluate ACSL4 expression, its prognostic significance, and its correlation with p53 tumor suppressor in BC patients. EXPERIMENTAL APPROACH: In this study 55 pairs of fresh samples of BC and adjacent non-cancerous tissue were used to analyze ACSL4 expression, using real-time polymerase chain reaction and immunohistochemistry (IHC) staining. The expression of other studied variables was also examined using the IHC technique. FINDINGS / RESULTS: ACSL4 expression was significantly higher in BC tissues compared to the adjacent normal tissue. This upregulation was negatively correlated with Ki-67 and age, and positively correlated with p53 status. The correlation between ACSL4 and p53 may indicate the role of p53 in the regulation of lipid metabolism in cancer cells, in addition to its role in the regulation of ferroptosis cell death. CONCLUSION AND IMPLICATIONS: Our results indicated that the expression of ACSL4 may be considered as a prognostic indicator and potential therapeutic target in BC. However, further studies are needed to confirm the significance of these findings.

Expression and clinicopathological significance of lipin-1 in human breast cancer and its association with p53 tumor suppressor gene.

Breast cancer (BC) is an important cause of female cancer-related death. It has recently been demonstrated that metabolic disorders including lipid metabolism are a hallmark of cancer cells. Lipin-1 is an enzyme that displays phosphatidate phosphatase activity and regulates the rate-limiting step in the pathway of triglycerides and phospholipids synthesis. The objective of this study was to evaluate lipin-1 expression, its prognostic significance, and its correlation with p53 tumor suppressor in patients with BC. In this study, 55 pairs of fresh samples of BC and adjacent noncancerous tissue were used to analyze lipin-1, using quantitative real-time polymerase chain reaction and immunohistochemistry (IHC) staining. The expression of other clinicopathological variables and p53 was also examined using IHC technique. The cell migration was studied in MCF-7 and MDA-MB231 cells following the inhibition of lipin-1 by propranolol. Our results show that the relative expression of lipin-1 messenger RNA was significantly higher in BC tissues compared with the adjacent normal tissue and its inhibition reduced cell migration in cancer cells. This upregulation was negatively correlated with histological grade of tumor and p53 status (p = .001 and p = .034) respectively and positively correlated with the tumor size (p = .006). Our results also seem to indicate that the high lipin-1 expression is related to a good prognosis in patients with BC. The expression of lipin-1 may be considered as a novel independent prognostic factor. The inhibition of lipin-1 may also have therapeutic significance for patients with BC. The correlation between lipin-1 and p53 confirms the role of p53 in the regulation of lipid metabolism in cancer cells.