Urolithin B inhibits proliferation and migration and promotes apoptosis and necrosis by inducing G2/M arrest and targeting MMP-2/-9 expression in osteosarcoma cells.

Osteosarcoma (OS) is the most prevalent primary bone cancer, with a high morbidity and mortality rate. Over the past decades, therapeutic approaches have not considerably improved patients' survival rates, and further research is required to find efficient treatments for OS. Data from several studies have shown that urolithin B (UB), the intestinal metabolite of polyphenolic ellagitannins, is emerging as a new class of anticancer compounds, yet its effect on OS cancer cells remains elusive. Herein, we investigated UB's antimetastatic, antiproliferative, and apoptotic effects on the MG-63 OS cell line. Cell viability assay, annexin V/propidium iodide staining, cell cycle arrest analysis, determination of the gene expression of MMP-2, MMP-9, Bax, Bcl-2, and p53 messenger RNA (mRNA), evaluation of reactive oxygen species (ROS) generation and migration, and MMP-2 and MMP-9 protein expression assessments were performed. UB caused late apoptosis, necrosis, G2/M arrest, and ROS generation in MG-63 cells. It increased the mRNA expression of the p53 tumor suppressor and Bax proapoptotic genes. UB also inhibited the migration and metastatic behavior of MG-63 OS cells by downregulating mRNA and MMP-2 and MMP-9 protein expression. In general, although further in vivo investigations are warranted, the current results showed that UB might be utilized as a potential novel natural compound for OS therapy due to its nontoxic, antiproliferative, and antimetastatic nature.

Comparison of the effect of saffron, crocin, and safranal on serum levels of oxidants and antioxidants in diabetic rats: A systematic review and meta-analysis of animal studies.

This study aimed to evaluate the effect of saffron, crocin, and safranal on serum levels of oxidants and antioxidants in diabetic rats. The authors searched the databases with standard keywords until June 8, 2021. The random-effects model was used to pool standardized mean differences (SMD) with 95% confidence intervals to assess the effects of saffron and its active component. To investigate heterogeneity, subgroup analysis and meta-regression were utilized. Begg and Egger's tests were used to measure publication bias. Our results showed that saffron, crocin, and safranal were able to significantly reduce the serum levels of oxidants with strong efficacy so that saffron had the highest effectiveness on serum malondialdehyde (SMD, -2.84 (µmol/L) [95% confidence interval (CI), -4.32 to -1.36]; p < .001, I 2 = 83.5%). In addition, saffron and its effective compounds were highly effective by increasing the serum level of antioxidants. In addition, saffron and its effective compounds were able to significantly increase the serum level of antioxidants with strong efficacy, while saffron had the highest effect on the serum level of total antioxidant capacity (SMD, 3.90 (µmol/L) [95% CI, 0.78-7.03]; p = .014, I 2 = 86.9%). The findings of this study show that treatment with saffron, crocin, and safranal by strengthening the antioxidant defense system and modulating oxidative stress shows antidiabetic effects in the diabetic model of rats, also these findings support the potential effect of saffron and its effective compounds for the management of diabetes and its complications. However, more human studies are needed.

The effect of crocin and losartan on TGF-ß gene expression and histopathology of kidney tissue in a rat model of diabetic nephropathy.

Objective: Diabetic nephropathy is one of the most common microvascular complications of diabetes mellitus that finally leads to complete loss of kidney function. Therefore, this study aimed to evaluate the effect of crocin and losartan on TGF-ß gene expression and histopathology of kidney tissue in a rat model of diabetic nephropathy. Materials and Methods: Forty male Wistar rats were randomly divided into five groups (n=8): Untreated control, Diabetic (D), D + crocin, D + losartan, and D + losartan + crocin. Induction of diabetes was performed using streptozotocin (50 mg/kg/ Intraperitoneal injection). At the end of the eight-week period, the rats were sacrificed. Spectrophotometry measured serum glucose, urea, creatinine, and uric acid levels. Microalbumin and creatinine levels were measured in 24-hour urine. Real-time PCR was used to determine the relative expression of the TGF-ß gene in kidney tissue. Renal tissue histopathology was also examined. Results: The results showed that hyperglycemia increased biochemical factors associated with diabetes, TGF-ß gene expression, and kidney damage. Separate treatment with crocin and losartan led to a decrease in renal function factors and TGF-ß gene expression and improved kidney damage. Conclusion: Our results showed that crocin could improve kidney function in diabetic conditions. In addition, we showed that crocin increases the effectiveness of losartan. Consequently, we suggest that crocin in combination with chemical drugs can be a potential therapeutic agent for diabetes and its complications. Nonetheless, human studies are needed to make firm findings.

The Comparison of the Plasma Levels of the Lead Element in Patients with Gastrointestinal Cancers and Healthy Individuals.

Back ground and Aim: Heavy metals are considered as risk factors in the development of some types of cancers. In this context, the lead (Pb) along with its biological impacts on the human body has raised significant concerns in public health. The aim of this study was to compare the plasma levels of the lead element in patients with gastrointestinal (GI) cancer and healthy subjects to examine whether this element has a role in the susceptibility of cancer. Methods: In a case-control study conducted between March 2016 to February 2017, the plasma levels of the lead were assessed. One-hundred patients with upper and lower GI cancers, as well as one-hundered healthy subjects who were age- and sex-matched participated in our study. A classic flame atomic absorption spectroscopy (FAAS) method was employed for the determination of the lead element in plasma levels of all subjects. Results: The mean age of patients was 53.8±10.6 years old. The patient group consisted of 51 male and 49 female patients. The results showed that the concentrations of Pb were lower than the defined toxic levels. The comparison of the mean levels of Pb between the case and control groups revealed that there was no statistically significant difference even when the gender, age, and history of smoking were included in the statistical analysis. Our findings showed that the concentration of Pb is significantly associated with the type of cancer (p<0.003) and the location of the tumor (whether upper or lower tract was affected) (p<0.003). Conclusion: Lead may contributes to the pathology and progression of GI cancers but we can not conclude that it involved in the causation or susceptibility of healthy individuals to develop GI cancer.

Resveratrol supplementation improves DNA integrity and sperm parameters in streptozotocin-nicotinamide-induced type 2 diabetic rats.

Reproductive dysfunction is one of the diabetes complications. Resveratrol, a polyphenol compound, shows antidiabetic and antioxidant effects. The aim of the present study was to investigate the protective effects of resveratrol on sperm parameters and chromatin quality in experimentally induced type 2 diabetes by streptozotocin and nicotinamide. Forty male adult Wistar rats were grouped into normal control, diabetic control and resveratrol-treated diabetic groups (1, 5 and 10 mg/kg orally treated for 30 days). Type 2 diabetes was induced using a single dose of streptozotocin and nicotinamide by intraperitoneal injection. Then, the different parameters and chromatin condensation of the epididymal extracted spermatozoon were studied using aniline blue (AB), acridine orange (AO) and toluidine blue (TB) staining. The sperm parameters including count, motility and viability had significant reduction in diabetic rats (p < 0.05). Resveratrol increased count, motility and viable spermatozoa relative to the diabetic group (p < 0.05). The mean percentage of AB, AO and TB staining positive spermatozoa was increased in diabetic groups compared to control (p < 0.001) and decreased after treatment with 1 and 5 mg/kg resveratrol (p < 0.001). The results of AO and TB staining showed that resveratrol did not have any beneficial effect on chromatin condensation and denatured DNA at the dose of 10 mg/kg.

Effect of resveratrol on SNARE proteins expression and insulin resistance in skeletal muscle of diabetic rats.

OBJECTIVES: Soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex proteins are involved in membrane trafficking. The expression of isoforms of SNAP-23, syntaxin-4, and VAMP-2 is significantly done in skeletal muscles; they control GLUT4 trafficking. It is believed that type 2 diabetes could be caused by the modifications in the expression of SNARE complex proteins. The purpose of this study was to evaluate the effect of resveratrol on the expression of these proteins in type 2 diabetes. MATERIALS AND METHODS: Forty male Wistar rats were selected. Streptozotocin and nicotinamide were applied for the induction of type 2 diabetes. The animals were divided into five groups. Healthy and diabetic groups were set as control; resveratrol (1, 5, and 10 mg/kg body weight) was applied to treat the three groups of diabetic rats for 30 days. Real-time qRT-PCR was applied to evaluate the expression of SNARE complex proteins. RESULTS: There is a link between diabetes and insulin resistance and up-regulation of SNARE proteins expression. Resveratrol improved hyperglycemia and insulin resistance along with a non-significant reduction in the expression of SNARE proteins. CONCLUSION: Increased expression of SNARE proteins was possibly a compensatory mechanism in response to insulin resistance in the skeletal muscles of diabetic rats. Resveratrol non-significantly reduced the expression of SNARE proteins by enhancing insulin sensitivity, where this effect was dose-dependent. Thus, higher doses of resveratrol and longer intervention periods could probably be more effective. Another molecular mechanism of the anti-diabetic properties of resveratrol was identified with an effect on the expression of SNARE proteins.

Effect of resveratrol on resistin and apelin gene expressions in adipose tissue of diabetic rats.

BACKGROUND/AIM: Adipose tissue plays a major role in glucose homeostasis. Dietary antioxidants such as resveratrol (RSV) may offer some protection against the early stage of diabetes mellitus and the development of complications. The present study investigated the effects of RSV on biochemical parameters and resistin and apelin gene expressions in adipose tissue of rats with type 2 diabetes. MATERIALS AND METHODS: Diabetes was induced using a single dose of streptozotocin + nicotinamide. Three groups of diabetic rats were treated with different doses of RSV (1, 5, and 10 mg/kg body weight per day). Oxidative status, serum biochemical parameters, insulin, and HOMA index were measured. Finally, resistin and apelin gene expressions were determined in rats' adipose tissue using RT- PCR (qRT-PCR). RESULTS: A significant reduction in serum glucose level was observed in rats treated with 5 and 10 mg/kg per day RSV compared with the diabetic control. Resistin expression in adipose tissue was reduced in RSV-treated groups, while no significant changes were observed in apelin expression. CONCLUSION: The results showed that RSV improves insulin sensitivity due to a simultaneous decrease in blood glucose and an increase in insulin. We concluded that RSV has potential hypoglycemic effect, probably by increasing insulin levels and changing the expression of resistin.

Effect of Resveratrol Supplementation on the SNARE Proteins Expression in Adipose Tissue of Stroptozotocin-Nicotinamide Induced Type 2 Diabetic Rats.

BACKGROUND: Glucose uptake by muscles and fat cells is carried out by the GLUT4 system. Isoforms of the SNAP23, syntaxin-4 and VAMP-2 play an important role in regulating GLUT-4 trafficking and fusion in adipocytes. The changes of SNARE proteins levels and thus impaired GLUT-4 displacement can be one of the etiological causes of type 2 diabetes. Due to changes in the expression of these proteins in diabetes, the aim of this study was to investigate the effect of the natural compound resveratrol with anti-diabetic properties on impaired expression of SNARE proteins in type 2 diabetes. METHODS: Forty male Wistar rats were used in this study. Type 2 diabetes was induced by administering a single dose of streptozotocin and nicotinamide. The expression of SNAP-23, syntaxin-4 and VAMP-2 proteins were assessed using real-time qRT-PCR. Also, some biochemical parameters were examined, including fasting blood glucose, insulin levels and insulin resistance. RESULTS: The results of this study showed that, resveratrol supplementation increased blood insulin level, reduced the fasting blood glucose, and improved the insulin resistance. In addition, resveratrol supplementation increased the expression of SNAP-23, syntaxin-4 and VAMP-2 proteins that involved in GLUT-4 transport in adipose tissue of diabetic rats. CONCLUSION: Final results showed that SNARE proteins expression is significantly reduced in diabetic rats and treatment with resveratrol supplementation is associated with the increased expression of these proteins.

Matrix metalloproteinase: investigation from gene to protein as effective factor in myocardial infarction.

Current evidence indicates that extracellular matrix (ECM) remodeling is a component of acute myocardial infarction (AMI) and matrix metalloproteinase (MMP) has a role in early atherosclerosis, plaque rupture and myocardial infarction (MI). The necessity of inhibition of ECM remodeling and subsequent injuries in patients with AMI suggests that MMP might be involved in this task. Therefore, we investigated the activities of MMP-1, -2, -3, and -9 which play an important role in AMI. Plasma and peripheral blood mononuclear cells (PBMCs) of 50 patients with AMI were isolated from peripheral blood after the onset of AMI within 24 h, comparing with 50 control subjects. The active form of MMPs was measured by enzyme linked immunosorbent assay (ELISA); MMP proteins presence and expression by immunoblotting and zymography analysis; and mRNA expression of MMPs by real time reverse transcriptase polymerase chain reaction. Plasma concentrations of MMPs increase in patients rather than control subjects. Gel zymography revealed 43, 66, 45, and 83 kDa molecular weight bands which consistent with active MMP-1, -2, -3, and -9, respectively, exhibiting gelatin-degrading activity in both patient and control subjects. No up-regulation of mRNA expression was found. To our knowledge, it is the first monitoring of MMP gene and protein expression and also circulating active MMPs in Iranian patients with AMI and normal subjects. Up-regulation of MMPs activity is common in the falling myocardium and missing up-regulation of transcription indicates that protein levels of MMPs were regulated at the post transcriptional level.