Reply to Letter to the editor regarding "The effect of pistachio supplementation on metabolic syndrome and its components in adults: a systematic review and meta-analysis of randomized controlled trials".

Two researchers (F.B and S.K.F.-P.) reviewed the abstracts and titles of all of the acknowledged research to determine whether it was eligible for inclusion in the present meta-analysis according to the inclusion criteria. The authors included all of the relevant available data from 17 articles on interventional studies. Regarding the objection raised about the effect size calculation, the inclusion of the various effect sizes from 1 study is a routine approach used in numerous meta-analyses, and their inclusion in the study did not impair the accuracy of the findings. The included studies were homogeneous in terms of intervention, outcomes, and participants, and the high rate of heterogeneity between the included studies for the majority of the study outcomes may have derived from the different characteristics of the participant populations, especially differences in their health status. As no study included in the review reported the correlation coefficient between the placebo conditions and the experimental conditions, the authors reanalyzed the data by inputting a moderate correlation coefficient of 0.5. Our study showed that pistachio consumption has a positive effect in terms of reducing the components of metabolic syndrome. In conclusion, this study reanalyzed the data and justified the methods used for showing the positive effect of pistachio consumption on metabolic syndrome components, and the potential for further research to identify the underlying mechanisms and the effects on various populations. The study's protocol was registered, and Comprehensive Meta-Analysis software was used in the statistical analyses. The authors recommend further research to investigate the potential effect of the consumption of pistachios. Systematic Review Registration: PROSPERO registration no. CRD42021285424.

In vitro and Pharmacoinformatics-based phytochemical screening for anticancer impacts of pistachio hull essential oil on AGS, PLC/PRF/5, and CACO2 cell lines.

BACKGROUND: The essential oil of pistacia vera (cv. Ohadi) hull (PHEO) was checked using gas chromatography mass spectrometry (GC/MS) analysis. It was studied the genes of the wnt pathway with a certain concentration of PHEO on Human gastric cancer (AGS), human hepatocellular carcinoma (PLC/PRF/5), and human colon cancer (CACO2) cell lines. METHODS AND RESULTS: After evaluating the survival rate of cancer cells by MTT test and determining IC50, pistachio hull essential oil (PHEO) was used for 24-hours to treat the cells. After RNA extraction, the expression of wnt pathway genes was evaluated by Real-Time PCR. Considering the crucial role of ß-catenin accumulation and its effect on the progression of gastrointestinal cancers, Western blot analysis was also used to determine the effect of PHEO in protein expression of ß-catenin inhibition. Also, an in silico analysis was carried out to investigate the effect of PHEO extracted compounds on protein expression of ß-catenin and FZD7 inhibition. According to the results, wnt pathway genes were changed in samples treated using PHEO. The results showed the up-regulation of GSK-3ß and down-regulation of Wnt-1, LEF-1, TCF1, and CTNNB1 genes compared to the control. CONCLUSION: We showed inhibition of ß-catenin protein in cancer cell lines. Four compounds of PHEO were suggested to have an inhibition effect on ß-catenin and FZD7. These compounds can be useful in the treatment of gastrointestinal cancers. Altogether, the inhibitory role of ß-catenin protein can be very effective and can be considered one of the therapeutic goals in the treatment of gastrointestinal cancers.

The effect of pistachio supplementation on metabolic syndrome and its components in adults: a systematic review and meta-analysis of randomized controlled trials.

CONTEXT: Several observational and experimental studies have been conducted to evaluate the effects of pistachio intake on metabolic syndrome (MetS); however, the results are inconsistent. OBJECTIVE: This systematic review and meta-analysis were performed on data from randomized controlled trials (RCTs) to determine the effect of pistachio consumption on MetS components. DATA SOURCES: The PubMed, Scopus, Google Scholar and Web of Science databases were searched from 1986 to 2021. STUDY SELECTION: English-language RCTs on pistachio intake were included that provided outcomes on hypertension, hyperglycemia, hypertriglyceridemia, and high-density lipoprotein (HDL). DATA EXTRACTION: Results are presented as pooled mean differences (MDs) between intervention and control groups with 95%CI reported for each of the components. RESULTS: Seventeen RCTs including 940 adults met the inclusion criteria for this systematic review and meta-analysis. Pistachio supplementation significantly reduced systolic blood pressure (BP; MD, -2.89 mmHg, 95%CI: -4.11 to -1.67; P < 0.001), triglycerides (MD, -16.76 mg/dL, 95%CI: -16.89 to -16.64; P < 0.001), fasting blood glucose (MD, -3.62 mg/dL, 95%CI: -6.45 to -0.8; P < 0.001,) and increased HDL (MD, 1.43 mg/dL, 95%CI: 1.39 to 1.47; P < 0.001) levels. However, there were not observed considerable changes in waist circumference, diastolic BP, and body mass index. CONCLUSION: The results of this research show that pistachio consumption could improve some MetS components, including systolic blood pressure, triglyceride, fasting blood glucose, and HDL levels, without affecting anthropometric indices and diastolic BP.

The Effect of Phytosterols and Fatty Acids of Pistachio (Pistacia vera) Oil on Spermatogenesis and Histological Testis Changes in Wistar Adult Male Rats.

PURPOSE: Oilseeds and their related products are known to have various bioactive and health-promoting ingredients. In this research, we investigated the effects of phytosterols and fatty acids of Pistacia vera on spermatogenesis process and testis histological changes in Wistar male rats for the first time. MATERIALS AND METHODS: A total number of 64 adult male Wistar rats were divided randomly into eight groups including one control group, and seven test groups. Test groups received phytosterols, fatty acids, and pistachio oil orally for 30 days. Then, LH, FSH, and serum testosterone levels were determined. Also, the spermatogenesis process and changes in testicular tissue in rats were investigated. RESULTS: The results of this research suggest that phytosterols in doses of 10 and 50 mg/kg reduce the spermatogenesis process. Fatty acid in a low dose of 10 mg/kg increases spermatogenesis, but when a high dose of 50 mg/kg was used, it harmed the spermatogenesis process. When low levels of phytosterols and fatty acids are used simultaneously in dose 5 mg/kg, improvement in spermatogenesis process is observed but when these were used together in the dose of 25 mg/kg, the spermatogenesis process was disrupted. Using pistachio oil alone also improved spermatogenesis process. CONCLUSION: It seems that phytosterols reduce spermatogenesis at high and low doses, while fatty acids increase spermatogenesis when used in low doses and reduce this process when used in high doses. The use of fatty acids extracted from pistachios to treat infertility in men seems hopeful.

Development of a novel liposomal nanoparticle formulation of cisplatin to breast cancer therapy.

Cisplatin is one of the conventional drugs used in chemotherapy which has a potent antitumor function. However, due to the dangerous side effects, including the damage to DNA of the normal cells, its clinical use is limited. The aim of this study was to prepare and characterize nanoliposome containing cisplatin. We optimized liposome formulations through the modification of the proportion of SPC80 (soybeanphospholipids with 75% phosphatidylcholine) and cholesterol content. Then, novel PEGylated liposomal formulations containing SPC80: cholesterol: DSPE-mPEG (at ratios of 85:10:5) were designed and developed to serve as a therapy to achieve more improved pharmaceutical efficiency. Zeta Sizer showed that PEGylated nanoliposomes had a mean diameter of 119.7 ± 2.1 nm, a zeta potential of -26.03 ± 1.34 mV, and entrapment efficiency of 96.65 ± 3%. The optimum formulations represented sustained, thermo-sensitive release, and augmented cellular uptake. The cytotoxic effect of the liposomal drug was higher than the free medication drug that confirmed the efficiency of cellular uptake. This study suggests that nanoliposome-loaded cisplatin plays a vital role in improving drug efficacy and the reduction of dosage.

The effects of transplanted mesenchymal stem cells treated with 17-b estradiol on experimental autoimmune encephalomyelitis.

The present study was conducted aimed at exploring the modulatory effects of 17-b estradiol (17-bED) on mesenchymal stem cells (MSCs) in the EAE (experimental autoimmune encephalomyelitis) animal model of multiple sclerosis (MS). Following the isolation of bone marrow-derived MSCs from the bilateral femurs and tibias of the male Wistar rats, the cells were harvested and cultured in the presence of 100 nM 17-bED for 24 h. EAE was induced in male Wistar rats (8-12 weeks old) using guinea pig spinal cord homogenate, in combination with the complete Freund's adjuvant. The MSC therapy was triggered when all of the animals obtained a disability score. The symptoms were monitored on a daily basis throughout the study until the rats were euthanized. The mRNA expression of cytokines, including IL-17, IFN-γ, TNF-α, IL-10, IL-4, and TGF-ß together with MMP8 and MMP9 as the family members of matrix metalloproteinases (MMPs) in the brain and spinal cord tissues were examined using real-time PCR. The levels of splenocytes-originated IL-10 and IFN-γ cytokines were also measured by ELISA. The MTT-based research findings showed that the infiltration of lymphocytes into the spleen decreased considerably. It was also observed that the mRNA expression of proinflammatory cytokines decreased significantly, while the mRNA levels of anti-inflammatory cytokines increased remarkably. It was also found that the mRNA levels of the examined matrix metalloproteinases (MMP8 and MMP9) were downregulated significantly. The findings of the present study indicated that the administration of 17-bED enhanced the efficacy of MSCs transplantation and modulated immune responses relatively in the EAE model, via the regulation of either pro- or anti-inflammatory cytokines and matrix metalloproteinases.

A novel copper (II) complex activated both extrinsic and intrinsic apoptotic pathways in liver cancerous cells.

Recent advances have put fundamental focus on the application of copper (II) (Cu [II]) complexes as agents for fighting against cancer. To determine whether [Cu(L)(2imi)] complex as a novel Cu complex can induce apoptosis in HepG2 as cancerous cells and L929 as normal cells via extrinsic or intrinsic apoptotic pathways, both cell lines were treated for 24 and 48 hours at IC50 concentrations of [Cu(L)(2imi)] complex. Then, the expression of some apoptosis-related genes including p53, caspase-8, bcl-2, and bax were assayed by real-time polymerase chain reaction. The [Cu(L)(2imi)] complex seems to inhibit the expression of bcl-2 in complex-treated HepG2 cancerous cells following the 24- and 48-hour treatment. The complex upregulated the p53, bax, and caspase-8 genes, therefore treatment of HepG2 cancerous cells with [Cu(L)(2imi)] complex induces programmed cell death via the upregulation of relative bax/bcl-2 ratio. Finally, this copper complex triggered apoptosis in HepG2 cells via both intrinsic and extrinsic pathway, whereas treatment of normal L929 cells with this complex induce apoptosis only via intrinsic pathway with the upregulation of relative bax/bcl-2 ratio and does not affect the expression level of caspase-8 gene and does not trigger the extrinsic pathway. Finally, these results obtained from present study confirm the role of a novel Cu complex on the induction of apoptosis process in HepG2 and L929 cells by overexpression of bax, inhibition of bcl-2 and increase of the relative bax/bcl-2 ratio. These results support that the [Cu(L)(2imi)] complex is able to induce apoptosis in cancerous cells, therefore, it has a potential for development as a novel anticancer drug.

Evaluating of Induction of Apoptosis by Cornus mass L. Extract in the Gastric Carcinoma Cell Line (AGS)

Aim and objectives: Natural products and derivatives of medicinal vegetation can play an important role to the cure tumor. The Present study was focused to determine the effect of Cornus mass L. extract on the induction of apoptosis in AGS gastric carcinoma cell line in compared to L929 cells. Methods: In this experimental study, AGS and L929 cells were cultured and treated with different concentrations (0­10 mg/ml) of Cornus mass L. extract for 48 and 72 hours. Cell proliferation was assessed by MTT assay. The optical density of the colored solution was quantified at 570 nm wavelengths by an ELISA Reader. Making use of the apoptosis detection kit of Annexin V-FITC, PI and double staining with Annexin V-FITC were carried out for flow cytometry investigations. Data were analyzed by ANOVA. Variations with a P-value less than 0.05 were considered significant. Results: shows a noticeable deviation among various concentrations of extract when cells were treated for 48, 72 h declined cell viability in AGS cell line in comparison L929 cell lines in a dose and time-dependent manner (P < 0.05). This extract also displayed approximately several-fold increased anti-cancer potency in AGS compared to L929 cells. The IC50 value in AGS cells (evaluated after 48,72h) of the extract against AGS cells was 5/44, 2/44 mg/ml (p≤0.05). The analysis results of flow cytometry indicated that apoptosis was induced by the extract in AGS cells treated, compared with L929 cells. Conclusion: Each of our results implicates the reality that Cornus mass L. extract acts as a novel, potent inhibitor of cancer proliferation in in vitro. This may result in developing a promising therapeutic agent for the treatment of indole-sensitive cancers.

Effect of a Copper (II) Complex on The Induction of Apoptosis in Human Hepatocellular Carcinoma Cells

Objectives: In the present study, we aimed to identify the anti-proliferative potential of [Cu(L)(2imi)] complex [L = 2-(((5-chloro-2-oxyphenyl)imino)methyl)phenolato) and 2imi = 2-methyl imidazole] against HepG2 cells as an in vitro model of human hepatocellular carcinoma and normal mouse fibroblast L929 cells. Methods: The cytotoxic and apoptotic effects of [Cu(L)(2imi)] complex on HepG2 cells and normal fibroblasts (L929) were examined by MTT assay and flow cytometry, respectively. Results: Cytotoxicity induced by [Cu(L)(2imi)] complex was time dependent. Also, there was a positive correlation between cytotoxicity and an increase in Cu complex concentration. For HepG2 cells, the cell viability percentage was 50% at 58 µg/mL after 24 h treatment, whereas in the same concentration and conditions, the viability percentage was surprisingly higher (about 100%) for L929 cells. Also, after 48 h treatment, the viability percentage of HepG2 cells at 55 µg/mL concentration was 50% in contrast with 89.3% for L929 cells in the same conditions. Flow cytometry findings suggest that [Cu(L)(2imi)] complex is capable of decreasing cancer cell viability through apoptosis and did not efficiently activate the necrosis process. Conclusions: Finally, we found that [Cu(L)(2imi)] complex possess the potential for development as an anti-cancer drug for human hepatocellular carcinoma.

Vanadium complex: an appropriate candidate for killing hepatocellular carcinoma cancerous cells.

Hepatocellular carcinoma (HCC) is a prevalent human malignancy which its drug resistance is increasing world-wide. This project was designed to assess the anti-cancer effects of 4-bromo-2-(((5-chloro-2-hydroxyphenyl) imino) methyl) phenol ([IV(L)] complex) on the HepG2 cell line and also L929 cells, as normal cells. HepG2 and L929 cells were cultured in RPMI culture medium and the survival rates of the cells were determined after 24 and 48 h using MTT assay to find IC50 concentration of vanadium m, [IV(L)] complex. The early apoptosis and necrosis/late apoptosis were determined by means of annexin V/PI apoptosis detection kit. The results revealed that vanadium m, [IV(L)] complex induce early apoptosis higher in HepG2 cell line than L929 cells. The rates of necrosis/late apoptosis were also induced in HepG2 cells more than L929 cells. Based on the results, vanadium m, [IV(L)] complex might be considered as a safe new drug for treatment of HCC with low side effects on control liver cells.

Nisin Induces Cytotoxicity and Apoptosis in Human Asterocytoma Cell Line (SW1088)

Background: Nisin is a member of the group of anti-microbial peptides which are considered as bacteriocins, but it possesses a vast range of activities. Astrocytoma is among the most prevalent types of brain tumor globally. Considering all facts about this peptide, the aim of the present study was the evaluation of any impact of nisin on proliferation and apoptosis of an astrocytoma cell line (SW1088). Methods: The SW1088 cell line was purchased from the Pasteur Institute of Iran and treated with various concentrations of Nisin. Nisin-induced cell toxicity and apoptosis were detected by both MTT assay and annexin V-FITC /propidium iodide (PI) staining. Result: In current study we observed that the cell death and apoptosis were significantly increased following nisin treatment, as compared to the control group. Conclusion: These results open a new window for establishment promising approaches with the concept of anti-cancer therapy by nisin in the future.

Expression of Inhibitor of Apoptosis Gene Family Members in Bladder Cancer Tissues and the 5637 Tumor Cell Line

Background: Apoptosis is suppressed in cancer tissues and tumor cell lines because anti-apoptosis genes are overexpressed. The inhibitor of apoptosis proteins (IAP) gene family contributes to control of apoptosis. The expression profile of eight genes of the IAP family in biopsies from patients with a history of bladder cancer and normal bladder tissues, as well as a bladder tumor cell line (5637), was assessed in the present study. Methods: Cancer tissue samples were obtained at surgery and the 5637 tumor cell line was cultured in RPMI1640 medium. Beyond tumor margins were selected as normal tissue. Expressional profile of interested genes was obtained by using specific primers and the real-time PCR method. Results: The results showed that expression of seven of the studied genes was up-regulated in cancer tissues and the cell line whereas BIRC4 (XIAP) was down-regulated in both. Conclusions: The results showed that these genes were expressed to a greater extent in cancer tissue and cancer cells than in normal tissues. The data suggested that over-expression of anti-apoptotic genes such as IAP family members, can trigger cells to escape from apoptosis.

A New Indole Derivative Decreased SALL4 Gene Expression in Acute Promyelocytic Leukemia Cell Line (NB4)

Background: Acute myeloblastic leukemia (AML) is a clonal disorder due to bone marrow failure and uncontrolled proliferation of myeloid lineage. Acute promyelocytic leukemia (APL) is a subtype of AML. Heterocyclic compounds, such as indole, are considered as attractive candidates for cancer therapy, due to their abundance in nature and known biological activity. Sal-like protein (SALL4) is a zinc finger transcription factor involving in the multi-potency of stem cells, in the NB4 cell line. This study was aimed to evaluate the effects of basal indole and its new derivative, 2-(1-((2, 4-Aril)imino)-2,2,2-trifluoroethyl) phenyl-1H Indole-3- carbaldehyde (TFPHC), on the expression of SALL4. Methods: Cells were cultured and treated with different concentrations (75, 150, and 300 µg/mL) of the new indole derivative and DMSO, as a vehicle control, for 24 and 48 hours. Cell proliferation was evaluated by using Trypan blue exclusion and MTT assays. The percentage of apoptotic cells was determined by flowcytometry analysis using the Annexin V/PI apoptosis detection kit; mRNA expression of SALL4 was studied using absolute quantitative RT-PCR. Data were analyzed by student's t-test. P<0.05 were considered statistically significant. Results: Our findings demonstrated the effects of new indole derivatives on SALL4 mRNA expression. Expression of SALL4 mRNA was significantly decreased at 75, 150, and 300 µg/mL concentrations. Conclusion: SALL4 plays a role in the survival of APL cells. SALL4 expression could be suppressed by the novel indole derivative. Additionally, SALL4 gene suppression can serve as a target in APL therapy.

Serum CXCL10 and CXCL12 chemokine levels are associated with the severity of coronary artery disease and coronary artery occlusion.

BACKGROUND: Cardiovascular disease constitutes a major cause of death worldwide. Inflammation plays an important role in atherosclerosis formation, coronary artery disease progression, acute coronary thrombosis and occlusion. Chemokines are inflammatory mediators disposing several bio-functions, as leukocyte migration towards inflammatory signals and vascular injuries. The present study was designed to evaluate the potential correlation between serum levels of chemokines CXCL-10 and CXCL-12 and the degree of coronary artery occlusion. METHODS: Eighty eight patient candidates for coronary angiography with coronary artery disease symptoms and potentially high risk of coronary artery occlusion were recruited. Chemokine serum levels were measured with the ELISA method and patients underwent coronary angiography. All patients with coronary artery disease (CAD) were divided into four groups according to the Gensini score. Data were presented as mean±SD. All P values <0.05 were considered significant. RESULTS: Our demographic data showed that of the 88 patients, 46 were male and 42 female. The mean age of patients was 57.95±11.13. Following increased coronary artery occlusion the serum levels of chemokines were significantly increased (CXCL-10 and CXCL-12; P<0.0001 and P<0.0001, respectively). CONCLUSION: In this novel study, a significant correlation between the serum levels of CXCL-10 and CXCL-12 and the severity of coronary artery occlusion was found. This could be attributed to the role of these chemokines in the processes of angiogenesis and angiostasis, a biological phenomenon that can play key role in the development of collateral circulation.

Significant Role(s) of CXCL12 and the SDF-1 3'A Genetic Variant in the Pathogenesis of Multiple Sclerosis.

Both cellular and molecular components of the immune system are among the substantial factors involved in the pathogenesis of multiple sclerosis (MS). Accumulating evidence confirms that chemokines, as the main members of the immune system, play key roles in the regulation of immune responses. Immune system genetic parameters are believed to influence the onset of immune system-related diseases. Regarding the significant role of the CXCR4/CXCL12 axis in cell differentiation and survival and homing of hematopoietic progenitors to the bone marrow and regulation of neuronal progenitor cell migration in the central nervous system (CNS), genetic factors can cause an increased expression of CXCL12 and induce a vigorous immune response against CNS antigens in MS patients. Previous studies have indicated that the expression of CXCL12 could be affected by its polymorphisms at position +801 at the region of the CXCL12 3'A genetic variation. Finally, CXCL12 seems to be involved in the cellular part of the events that take place in the CNS, and therefore it could be considered as a target in MS therapies. Thus, this review was aimed to describe the recent progress in understanding the role of CXCL12 in MS, with an emphasis on CXCL12 serum concentrations and its gene polymorphism at position +801.