Corrigendum: The role of peroxisome proliferator-activated receptors in the modulation of hyperinflammation induced by SARS-CoV-2 infection: A perspective for COVID-19 therapy.

[This corrects the article DOI: 10.3389/fimmu.2023.1127358.].

CXC chemokine receptor 4 (CXCR4) blockade in cancer treatment.

CXC chemokine receptor type 4 (CXCR4) is a member of the G protein-coupled receptors (GPCRs) superfamily and is specific for CXC chemokine ligand 12 (CXCL12, also known as SDF-1), which makes CXCL12/CXCR4 axis. CXCR4 interacts with its ligand, triggering downstream signaling pathways that influence cell proliferation chemotaxis, migration, and gene expression. The interaction also regulates physiological processes, including hematopoiesis, organogenesis, and tissue repair. Multiple evidence revealed that CXCL12/CXCR4 axis is implicated in several pathways involved in carcinogenesis and plays a key role in tumor growth, survival, angiogenesis, metastasis, and therapeutic resistance. Several CXCR4-targeting compounds have been discovered and used for preclinical and clinical cancer therapy, most of which have shown promising anti-tumor activity. In this review, we summarized the physiological signaling of the CXCL12/CXCR4 axis and described the role of this axis in tumor progression, and focused on the potential therapeutic options and strategies to block CXCR4.

The role of peroxisome proliferator-activated receptors in the modulation of hyperinflammation induced by SARS-CoV-2 infection: A perspective for COVID-19 therapy.

Coronavirus disease 2019 (COVID-19) is a severe respiratory disease caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that affects the lower and upper respiratory tract in humans. SARS-CoV-2 infection is associated with the induction of a cascade of uncontrolled inflammatory responses in the host, ultimately leading to hyperinflammation or cytokine storm. Indeed, cytokine storm is a hallmark of SARS-CoV-2 immunopathogenesis, directly related to the severity of the disease and mortality in COVID-19 patients. Considering the lack of any definitive treatment for COVID-19, targeting key inflammatory factors to regulate the inflammatory response in COVID-19 patients could be a fundamental step to developing effective therapeutic strategies against SARS-CoV-2 infection. Currently, in addition to well-defined metabolic actions, especially lipid metabolism and glucose utilization, there is growing evidence of a central role of the ligand-dependent nuclear receptors and peroxisome proliferator-activated receptors (PPARs) including PPARα, PPARß/δ, and PPARγ in the control of inflammatory signals in various human inflammatory diseases. This makes them attractive targets for developing therapeutic approaches to control/suppress the hyperinflammatory response in patients with severe COVID-19. In this review, we (1) investigate the anti-inflammatory mechanisms mediated by PPARs and their ligands during SARS-CoV-2 infection, and (2) on the basis of the recent literature, highlight the importance of PPAR subtypes for the development of promising therapeutic approaches against the cytokine storm in severe COVID-19 patients.

Allelic and Genotype Frequencies of CYP2B6∗2 (64C > T) and CYP2B6∗3 (777C > A) in Three Dominant Ethnicities of the Iranian Population.

Background: Cytochrome P450 complex plays a key role in drug metabolism. CYP2B6 has an essential part in Cytochrome P450 complex metabolism. This study aims to determine the allelic distribution of CYP2B6∗2 and CYP2B6∗3 in three main Iranian ethnicities: Fars, Turk, and Kurd. Methods: The study was conducted on 174 unrelated healthy volunteers from three main Iranian ethnicities. After DNA extraction from peripheral blood samples, genotyping of CYP2B6∗2 and ∗3 was performed using tetra ARMS and ARMS PCR, respectively. Results: The average age of 174 cases was 40.69 ± 11.87 (mean ± SD) and 39.06 ± 11.63 (mean ± SD) for males and females. In the CYP2B6∗2 variant, the genotyping frequency of wild type (C/C), heterozygous (C/T), and homozygous mutant (T/T) was 8.7%, 86%, and 5.2%, respectively. The CYP2B6∗2 (c.64C > T) allele frequency was 48.2% (95% CI: (37.8-58.6)). In the CYP2B6∗3 variant, the frequency of wild type (C/C), heterozygous (C/T), and homozygous mutant (T/T) was 75.3%, 11%, and 13.6%, respectively. The CYP2B6∗3 (c.777C > A) allelic frequency was 19.1% (95% CI: (17.5-20.7)). Conclusion: Allelic distribution in three main Iranian ethnicities, i.e., Turk, Kurd, and Fars, is remarkably higher than that in other populations, even that in Southern Iran. High frequencies of CYP2B6∗2 and ∗3 in the Iranian population highly affect drug responsiveness. Understanding such variability could help to increase drug efficacy and reduce its toxicity.

Frequency of CYP2B6 Alleles in Major Iranian Ethnicities, Affecting Response to Efavirenz.

Introduction: Efavirenz is an antihuman immunodeficiency virus (HIV) drug metabolized by cytochrome P450 2B6 (CYP2B6) enzyme. Cytochrome P450 2B6 is an enzyme that in humans is encoded by the CYP2B6 gene. Polymorphisms of this gene play a crucial role in the metabolism of drugs such as Efavirenz. This study aims to evaluate the frequency of three clinically significant CYP2B6 polymorphisms (CYP2B6 ∗ 6 (516G > T), CYP2B6 ∗ 4 (785A > G), and CYP2B6 ∗ 5 (1459C > T)) in three major Iranian ethnicities. Methods: One hundred forty-seven participants from three main Iranian ethnicities were included in this study. After DNA extraction, CYP2B6 ∗ 6 (516G > T), CYP2B6 ∗ 4 (785A > G), and CYP2B6 ∗ 5 (1459C > T) were genotyped using tetra-primer amplification refractory mutation system polymerase chain reaction (ARMS-PCR). Results: The frequency of the mutated allele in the Iranian population for CYP2B6 ∗ 6 (516G > T) was 41.50 (95% CI: 35.81, 47.36), which was significantly lower than in Kurds (59.62, 95% CI: 45.10, 72.99). Similarly, Kurds had a higher frequency of mutated allele of CYP2B6 ∗ 5 (1459C > T) (46.15%, 95% CI: 32.23, 60.53) than in Iranians (24.49%, 95% CI: 19.68, 29.82). The frequency of A and G alleles of CYP2B6 ∗ 4 (785A > G) was 62.59% (95% CI: 56.78, 68.13) and 37.41 (95% CI: 31.87, 43.22), respectively. Conclusion: Kurds are at higher risk of adverse drug reactions (ADRs) and insufficient anti-HIV response compared to other Iranians.

Recent advances in atezolizumab-based programmed death-ligand 1 (PD-L1) blockade therapy for breast cancer.

Breast cancer, the most common cancer in women worldwide, is curable in âˆ¼ 70-80 % of patients with early-stage, non-metastatic disorder. However, advanced breast cancer with distant organ metastases is incurable with available therapeutics. Thus, scientists have sought emerging strategies for treating metastatic breast cancers., Immune checkpoint inhibitors (ICIs) have represented a significant development in breast cancer immunotherapy. Now, targeting immune checkpoint molecules (e.g., programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1)) have attracted increasing attention in the context of breast cancer therapy, chiefly triple-negative breast cancer (TNBC). Atezolizumab, a humanized IgG1 monoclonal antibody (mAb), has been designed to interfere with the binding of the PD-L1 ligand to its receptor. Targeting PD-L1 using atezolizumab potentiates T-cell responses to the tumor and consequently boosts tumor responses. The results of the IMpassion130 trial have recently led to the approval of the combination of atezolizumab and nab-paclitaxel to treat unresectable locally advanced or metastatic patients with PD-L1-positive TNBC. Herein, we summarize the clinical efficacy of atezolizumab in treating breast cancer and briefly discuss the possible immune-related adverse events (irAEs).

Vaginal and oral probiotics effect in the prevention of preterm delivery in patients visiting Kamali Hospital, Karaj, Iran in 2020.

Introduction: The prevalence of preterm labor (PTL) is growing, and annually one in ten babies is born prematurely. Various studies have examined the effect of oral or vaginal probiotics on the prevention of preterm labor, which has yielded contrasting results. This study aimed to compare the impact of vaginal and oral probiotics on the prevention of preterm delivery. Methods: This clinical trial was performed among 185 pregnant women with a gestational age greater than or equal to 25 weeks visiting Kamali Hospital, Karaj, Iran in 2020. The participants were divided into three groups; intervention group 1 receiving Oral probiotic pill once a day until 37 weeks of pregnancy, intervention group 2 receiving probiotic vaginal suppository once a day until 37 weeks of pregnancy, and control group not receiving any intervention. Patients were then followed up until the end of pregnancy. Results: Demographic characteristics and gestational age at the time of intervention were not significantly different among the three groups. Overall, 26.7 % in the control group, 30 % in intervention group 1 %, and 22.5 % in intervention group 2 had deliveries less than 37 weeks. There was no significant difference in the frequency of preterm labor and the duration of pregnancy among the groups (all p > 0.05). Conclusion: Probiotics use does not increase the rate of preterm delivery or reduce the duration of pregnancy, but the rate of preterm delivery was lower in the oral probiotic group. Further clinical studies on the impact of probiotics on PTL can yield valuable results.

Quality of Life and Related Paraclinical Factors in Iranian Patients with Transfusion-Dependent Thalassemia.

Background: Thalassemia is one of the most common genetic hematologic disorders in the world. Despite outstanding achievements in prenatal diagnosis and a decrease in the number of patients, thalassemia is still a significant issue in most parts of the world, especially in the Mediterranean countries. Understanding the factors associated with this condition is crucial to help clinicians and policymakers provides social and medical support for patients to facilitate their lives. This study aims to appraise the quality of life (QoL) and its related paraclinical factors in Iranian transfusion-dependent thalassemia patients. Methods and Materials: This study is a cross-sectional study performed in the thalassemia clinic of Imam-Ali Hospital, Karaj, Iran. The demographic, clinical, and laboratory data of 100 patients with transfusion-dependent thalassemia were recorded. The patients' QoL was measured by the World Health Organization Quality of Life Instruments Brief (WHOQOL-BREF) version questionnaire. The results were analyzed using SPSS software. Results: This study demonstrated that all four features of life are influenced in transfusion-dependent thalassemia patients. Also, higher educational status and lower serum ferritin levels were associated with better scores in assessing the QoL. On the other hand, an elevated level of AST (aspartate transaminase), ALT (alanine transaminase), and FBS (fasting blood sugar) are associated with lower scores. Conclusion: All features of QoL are correlated to the patients' laboratory findings. Our data suggest that managing patients' laboratory indices is attributed to their higher QoL. We also suggest regular screening of patients' QoL to manage disease complications more efficiently.

Alpha-lipoic acid supplementation effects on serum values of some oxidative stress biomarkers in women with gestational diabetes.

AIMS: Alpha-lipoic acid (ALA) is a unique antioxidant that can eradicate different kinds of free radicals. The current trial was designed to investigate the effects of ALA supplementation on some oxidative stress biomarkers in women with GDM. MATERIALS AND METHODS: Sixty women with GDM at 24-28 weeks of pregnancy were selected and then they were divided into the drug (n = 30) received ALA 300 mg/day for 8 weeks and the placebo (n = 30) groups. Serum values of fasting blood sugar (FBS), thiol groups, glutathione, catalase, total antioxidant capacity (TAC), total oxidant status (TOS) and malondialdehyde (MDA) were measured. Values of the oxidative stress index (OSI), the MDA/TAC ratio and total antioxidant gap (TAG) were calculated. RESULTS: After the intervention values of FBS (p = .001), TAC (p < .001), OSI (p = .003), TAG (p = .001) and catalase (p < .001) were improved significantly in the drug group. Values of TOS (p = .070) and glutathione (p = .088) were improved marginally in the drug group. CONCLUSIONS: The current study showed that ALA supplementation at a dosage of 300 mg/day in women with GDM had improving effects on maternal circulating values of FBS, TAC, OSI, TAG, TOS, glutathione and catalase.

Role of oxytocin and c-Myc pathway in cardiac remodeling in neonatal rats undergoing cardiac apical resection.

Oxytocin (OT) is a nonapeptide hormone that can improve cardiomyocyte proliferation, suggesting a potential heart regeneration function. Here, we investigated the role of oxytocin and the c-Myc pathway in cardiac remodeling in neonatal rats undergoing cardiac apical resection. We have utilized a knockout of oxytocin receptor (OTR) with OTR-shRNA. A neonatal rat model of cardiac resection (≈10%-15%) was first established. The protein levels of OTR and c-Myc and the expression of cyclin d1 and c-Myc genes were then evaluated in the cardiac tissues at 1, 7, and 21 days after cardiac resection. We also analyzed the proliferation of cardiomyocytes through α-actinin, BrdU, and ki-67 markers. At last, the hemodynamic and electrophysiologic functions were evaluated eight weeks after cardiac resection. At 21 days, the regeneration of cardiomyocytes was repaired among rats in the control and resection groups, while OTR-shRNA groups were failed to improve. Inhibition of OTR failed cardiac regeneration and reduced the number of proliferating cardiomyocytes. The c-Myc protein was significantly reduced in the OTR-shRNA injection hearts. Moreover, we have severely found a depressed heart function in the OTR-shRNA injection animals. These observations revealed that the OT must improve cardiac remodeling in neonatal rat hearts by regulating the c-Myc pathway.

Effects of probiotic, cinnamon, and synbiotic supplementation on glycemic control and antioxidant status in people with type 2 diabetes; a randomized, double-blind, placebo-controlled study.

PURPOSE: The aim of this study was to investigate the effect of probiotic bacteria of Lactobacillus acidophilus, cinnamon powder and their combinations on the glycemic and antioxidant indices in patients with type 2 diabetes. METHODS: A total of 136 patients randomized with type 2 diabetes entered the study and were randomly divided into four groups who were matched for age and gender. Thereafter, alongside their routine pharmacotherapy, each group followed one of the following diets: Group A: Lactobacillus acidophilus 108 cfu and 0.5 g of powdered cinnamon (synbiotic). Group B: Lactobacillus acidophilus (probiotic), Group C: powdered cinnamon. Group D: rice flour powder as placebo. At the beginning and end of the intervention, fasting blood sugar (FBS), HbA1c, advance glycation end products (AGE), aspartate aminotransferase (AST), alanine aminotransferase (ALT) and antioxidant enzymes of superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT) were measured. RESULTS: Following 3 months of treatment, the mean FBS level was decreased significantly in probiotic, cinnamon, and synbiotic supplementation groups compared with control (P < 0.01). FBS levels in probiotic, cinnamon, and synbiotic groups were significantly decreased compared with the control group (P = 0.001, P = 0.063 and P = 0.001, respectively). The mean HbA1C in probiotic, cinnamon, and synbiotic groups were also decreased (P = 0.001, P = 0.001 and P = 0.04, respectively). The mean AGE in synbiotic group was significantly decreased (P = 0.037). Probiotic, cinnamon and synbiotic all could improve antioxidant enzyme activity modestly. However, the most significant effect was seen in probiotic group. CONCLUSIONS: According to the current results, the use of probiotic supplements (individually or in combination with cinnamon) leads to a reduction in blood glucose and an increase in antioxidant enzymes in people with type 2 diabetes.

A Randomized Clinical Trial Study: Anti-Oxidant, Anti-hyperglycemic and Anti-Hyperlipidemic Effects of Olibanum Gum in Type 2 Diabetic Patients.

Diabetes is a common metabolic disease in the world that has many adverse effects. Olibanum gum resin (from trees of the genus Boswellia) has traditionally been used in the treatment of various diseases such as diabetes. The aim of this study was the comparison of Olibanum gum resin effect with placebo on the treatment of type 2 diabetes. Inclusion criteria was diabetic patients with fasting blood sugar (FBS) =140-200 mg/dL. This study has been designed as double-blined clinical trial on 71 patients with type 2 diabetes and the patients randomly were divided to interventional and placebo groups. The patients on standard anti-diabetic therapy (metformin) treated with Olibanum gum resin (400 mg caps) and placebo tow times per day for 12 weeks, respectively. At the end of the twelfth week, the FBS, HbA1c, Insulin, total Cholesterol (Chol), LDL, Triglyceride (TG), HDL and other parameters were measured. The Olibanum gum resin lowered the FBS, HbA1c, Insulin, Chol, LDL and TG levels significantly (p < 0.001, p < 0.001, p <0.001, p = 0.003, p < 0.001 and p < 0.001, respectively) without any significant effects on the other blood lipid levels and liver/kidney function tests (p > 0.05) compared with the placebo at the endpoint. Moreover, this plant showed anti-oxidant effect and also no adverse effects were reported. The results suggest that Olibanum gum resin could be used as a safe anti-oxidant, anti-hyperglycemic and anti-hyperlipidemic agent for type 2 diabetic patients.

Neuroprotective effects of mebudipine and dibudipine on cerebral oxygen-glucose deprivation/reperfusion injury.

In the present study, we investigated the effects of mebudipine and dibudipine, two new Ca(2+) channel blockers, on primary murine cortical neurons exposed to oxygen-glucose deprivation/reperfusion. The experiments were performed on cells after 11-16 days of culture. To initiate oxygen-glucose deprivation /reperfusion, the culture medium was replaced by glucose-free medium, and the cells were transferred to a humidified incubation chamber in a mixture of 95% N(2) and 5% CO(2) at 37 degrees C for 30 min. The cultures were pretreated with mebudipine and dibudipine 3 h prior to oxygen-glucose deprivation/reperfusion, in order to explore their effects on neurons under oxygen-glucose deprivation conditions. Cell viability and nitric oxide (NO) production were assessed by MTT assay and the modified Griess method, respectively. Exposure of murine cortical neuronal cells to 30 min oxygen-glucose deprivation significantly decreased cell viability and increased NO production. Pretreatment of the cultures with mebudipine and dibudipine significantly increased cell viability and decreased NO generation in a dose-dependent manner. However, the drugs had no protective effect in cells subjected to oxygen-glucose deprivation for 60 min. Pretreatment of cultures with MK-801 (10 microM), a non-competitive NMDA antagonist, decreased neuronal death after 30-min oxygen-glucose deprivation, while application of NBQX (30 microM), a selective AMPA-kainate receptor antagonist, partially attenuated the cell injury. oxygen-glucose deprivation -induced cytotoxicity and NO production were also inhibited by N-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor and MK-801. We conclude that mebudipine and dibudipine could protect cortical neurons against oxygen-glucose deprivation /reperfusion-induced cell injury in a dose-dependent manner, and that this could be mediated partially by decreased NO production.

Mebudipine and dibudipine protect PC12 cells against oxygen-glucose deprivation and glutamate-induced cell death.

The protective effect of two new L-type calcium-channel blockers, mebudipine and dibudipine on neurotoxic effects induced by glutamate and oxygen-glucose deprivation (OGD) in PC12 cells was investigated. PC12 cells were intoxicated with two different methods. First, the cells were incubated with glutamate (10muM/L), glutamate and mebudipine (10muM/L), dibudipine (10muM/L) or nimodipine (10muM/L), on three different treatment schedules (concurrently, pre-3h and pre-24h). In the second method PC12 cells were exposed to in vitro oxygen-glucose deprivation for 30min and 60min alone or with the drugs in the same time schedules described above. Cellular viability was assessed by MTT assay. Glutamate-induced cell death and OGD-induced cell injury were attenuated significantly by mebudipine, dibudipine in comparison with nimodipine in all three different treatment schedules. Application of MK801 (10muM/L), an antagonist of NMDA glutamate receptors inhibited PC12 cell death in both methods. Our study suggests that mebudipine and dibudipine, like nimodipine, may have protective effects against glutamate and oxygen-glucose deprivation-induced neurotoxicity.