An Intraperitoneal Injection Technique in Adult Zebrafish that Minimizes Body Damage and Associated Mortality.

The adult zebrafish (Danio rerio), which is genetically accessible, is being employed as a valuable vertebrate model to study human disorders such as cardiomyopathy. Intraperitoneal (IP) injection is an important method that delivers compounds to the body for either testing therapeutic effects or generating disease models such as doxorubicin-induced cardiomyopathy (DIC). Currently, there are two methods of IP injection. Both methods have limitations when handling toxic compounds such as doxorubicin, which result in side effects manifesting as severe damage to the body shape and fish death. While these shortcomings could be overcome by extensive investigator training, a new IP injection method that has minimal side effects is desirable. Here, a unique IP injection method that is able to handle toxic compounds is reported. Consistently reduced cardiac function can result without incurring significant fish death. The technique can be easily mastered by researchers who have minimal experience with adult zebrafish.

Targeting host calcium channels and viroporins: a promising strategy for SARS-CoV-2 therapy.

Despite passing the pandemic phase of the COVID-19, researchers are still investigating various drugs. Previous evidence suggests that blocking the calcium channels may be a suitable treatment option. Ca2+ is required to enhance the fusion process of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Also, some important inflammatory factors during SARS-CoV-2 infection are dependent on Ca2+ level. On the other hand, viroporins have emerged as attractive targets for antiviral therapy due to their essential role in viral replication and pathogenesis. By inhibiting the host calcium channels and viroporins, it is possible to limit the spread of infection. Therefore, calcium channel blockers (CCBs) and drugs targeting Viroporins can be considered an effective option in the fight against SARS-CoV-2.

The effects of statins on the function and differentiation of blood cells.

Statins are inhibitors of ß-hydroxy ß-methylglutaryl-CoA (HMG-CoA) reductase (HMGCR). They are used in patients with cardiovascular risk and/or suffering with cardiovascular disease. In addition to their efficient lipid-lowering effects, statins exhibit independent so called pleiotropic effects potentially affecting several immune response properties including immune cell activation, migration, cytokine generation, immune metabolism, and survival. Statins also regulate innate and acquired immunity. The focus of this review is to highlight the role of statins in modulating the function and differentiation of various blood cells. Given the proposed wider application of these medicines and their potentially important advantages in treatment of inflammatory and autoimmune disorders, more studies are needed with special focus on the molecular targets of statins included in regulating the immune response.

Immunomodulatory actions of vitamin D in various immune-related disorders: a comprehensive review.

For many years, vitamin D has been acknowledged for its role in maintaining calcium and phosphate balance. However, in recent years, research has assessed its immunomodulatory role and come up with conflicting conclusions. Because the vitamin D receptor is expressed in a variety of immune cell types, study into the precise role of this molecule in diseases, notably autoimmune disorders, has been made possible. The physiologically activated version of vitamin D also promotes a tolerogenic immunological condition in addition to modulating innate and acquired immune cell responses. According to a number of recent studies, this important micronutrient plays a complex role in numerous biochemical pathways in the immune system and disorders that are associated with them. Research in this field is still relatively new, and some studies claim that patients with severe autoimmune illnesses frequently have vitamin D deficiencies or insufficiencies. This review seeks to clarify the most recent research on vitamin D's immune system-related roles, including the pathophysiology of major disorders.

Molecular mechanisms of anthracycline induced cardiotoxicity: Zebrafish come into play.

Anthracyclines are among the most potent chemotherapeutics; however, cardiotoxicity significantly restricts their use. Indeed, anthracycline-induced cardiotoxicity (AIC) fares among the worst types of cardiomyopathy, and may only slowly and partially respond to standard heart failure therapies including ß-blockers and ACE inhibitors. No therapy specifically designed to treat anthracycline cardiomyopathy at present, and neither is it known if any such strategy could be developed. To address this gap and to elucidate the molecular basis of AIC with a therapeutic goal in mind, zebrafish has been introduced as an in vivo vertebrate model about a decade ago. Here, we first review our current understanding of the basic molecular and biochemical mechanisms of AIC, and then the contribution of zebrafish to the AIC field. We summarize the generation of embryonic zebrafish AIC models (eAIC) and their use for chemical screening and assessment of genetic modifiers, and then the generation of adult zebrafish AIC models (aAIC) and their use for discovering genetic modifiers via forward mutagenesis screening, deciphering spatial-temporal-specific mechanisms of modifier genes, and prioritizing therapeutic compounds via chemical genetic tools. Several therapeutic target genes and related therapies have emerged, including a retinoic acid (RA)-based therapy for the early phase of AIC and an autophagy-based therapy that, for the first time, is able to reverse cardiac dysfunction in the late phase of AIC. We conclude that zebrafish is becoming an important in vivo model that would accelerate both mechanistic studies and therapeutic development of AIC.

Modulatory properties of curcumin in cancer: A narrative review on the role of interferons.

The immune network is an effective network of cell types and chemical compounds established to maintain the body's homeostasis from foreign threats and to prevent the risk of a wide range of diseases; hence, its proper functioning and balance are essential. A dysfunctional immune system can contribute to various disorders, including cancer. Therefore, there has been considerable interest in molecules that can modulate the immune network. Curcumin, the active ingredient of turmeric, is one of these herbal remedies with many beneficial effects, including modulation of immunity. Curcumin is beneficial in managing various chronic inflammatory conditions, improving brain function, lowering cardiovascular disease risk, prevention and management of dementia, and prevention of aging. Several clinical studies have supported this evidence, suggesting curcumin to have an immunomodulatory and anti-inflammatory function; nevertheless, its mechanism of action is still not clear. In the current review, we aim to explore the modulatory function of curcumin through interferons in cancers.

Molecular Function of cGAS-STING in SARS-CoV-2: A Novel Approach to COVID-19 Treatment.

Coronavirus illness 2019 is a significant worldwide health danger that began with severe acute respiratory syndrome coronavirus two infections. It is the largest pandemic of our lifetime to date, affecting millions of people and crippling economies globally. There is currently no viable therapy for this devastating condition. The fast spread of SARS-CoV-2 underlines the critical need for favorable treatments to prevent SARS-CoV-2 infection and dissemination. Regulating the upstream cytokine release might be a possible method for COVID-19 therapy. We propose that more consideration be paid to the dysregulated IFN-I release in COVID-19 and that cGAS and STING be considered therapeutic targets for avoiding cytokine storms and as critical components in host antiviral defense mechanisms.

Identification of Potential Prognostic Markers and Key Therapeutic Targets in Hepatocellular Carcinoma Using Weighted Gene Co-Expression Network Analysis: A Systems Biology Approach.

Background: As the most prevalent form of liver cancer, hepatocellular carcinoma (HCC) ranks the fifth highest cause of cancer-related death worldwide. Despite recent advancements in diagnostic and therapeutic techniques, the prognosis for HCC is still unknown. Objectives: This study aimed to identify potential genes contributing to HCC pathogenicity. Materials and Methods: To this end, we examined the GSE39791 microarray dataset, which included 72 HCC samples and 72 normal samples. An investigation of co-expression networks using WGCNA found a highly conserved blue module with 665 genes that were strongly linked to HCC. Results: APOF, NAT2, LCAT, TTC36, IGFALS, ASPDH, and VIPR1 were the blue module's top 7 hub genes. According to the results of hub gene enrichment, the most related issues in the biological process and KEGG were peroxisome organization and metabolic pathways, respectively. In addition, using the drug-target network, we discovered 19 FDA-approved medication candidates for different reasons that might potentially be employed to treat HCC patients through the modulation of 3 hub genes of the co-expression network (LCAT, NAT2, and VIPR1). Our findings also demonstrated that the 3 scientifically validated miRNAs regulated the co-expression network by the VIPR1 hub gene. Conclusion: We found co-expressed gene modules and hub genes linked with HCC advancement, offering insights into the mechanisms underlying HCC progression as well as some potential HCC treatments.

Association between interleukin-1 receptor antagonist (IL-1ra) VNTR, gene polymorphism and breast cancer susceptibility in Iranian population: Experimental and web-based analysis.

Breast cancer is one of the leading causes of cancer mortality. Growing evidence indicates that interleukins and its polymorphisms are involved in the pathogenesis of breast cancer. Variable number of tandem repeat (VNTR) polymorphism can affect transcription rate, mRNA stability and also the resulting protein expression and activity. Hence, present study aimed to assess the possible association between interleukin-1 receptor antagonist (IL-1Ra) VNTR polymorphism, and breast cancer susceptibility in Iranian population. A total of 300 Iranian individuals, 150 breast cancer patients and 150 age-matched healthy women, were included in this study. DNA extracted by salting out method and genotyping was done using the polymerase chain reaction. The frequency of the allele 2(5% vs. 22%) and the 2/2 genotype (22% vs. 46%) of IL-1Ra VNTR polymorphism was significantly higher in healthy control compared to breast cancer patient: therefore, A2 allele may play a protective role against breast cancer and its progression (p = .0001 and OR = 0.105, 95% CI: [0.044-0.248]). The allele 2 and 2/2 genotype of the IL-Ra VNTR polymorphism can be a protective factor against breast cancer susceptibility.

Immunomodulatory effects of curcumin in systemic autoimmune diseases.

Systemic autoimmune diseases like rheumatoid arthritis, multiple sclerosis, and systemic lupus erythematosus represent various autoimmune conditions identified by immune system dysregulation. The activation of immune cells, auto-antigen outbreak, inflammation, and multi-organ impairment is observed in these disorders. The immune system is an essential complex network of cells and chemical mediators which defends the organism's integrity against foreign microorganisms, and its precise operation and stability are compulsory to avoid a wide range of medical complications. Curcumin is a phenolic ingredient extracted from turmeric and belongs to the Zingiberaceae, or ginger family. Curcumin has multiple functions, such as inhibiting inflammation, oxidative stress, tumor cell proliferation, cell death, and infection. Nevertheless, the immunomodulatory influence of curcumin on immunological reactions/processes remains mostly unknown. In the present narrative review, we sought to provide current information concerning the preclinical and clinical uses of curcumin in systemic autoimmune diseases.

Evaluating the HLA-G (rs1063320) genetic variant and risk of human papillomavirus infection: a meta-analysis of 953 cases and 877 controls.

Human leukocyte antigen-G (HLA-G) has immune-modulatory functions. Although the role of genetic variant HLA-G (rs1063320) in susceptibility to human papillomavirus (HPV) infection has been widely considered, it is still a matter of discussion. In order to shed light on the issue, we, therefore, conducted a meta-analysis to evaluate the common impact of the HLA-G (rs1063320) variant on susceptibility to HPV infection. Subsequently, the distribution of genotypes, genotyping techniques and ethnicity groups was collected, and general analyses were performed. A total number of five studies with 953 cases and 877 controls were found to meet our criteria. The polymorphism of HLA-G (rs1063320) was evaluated. This is the first meta-analysis to explore the connection between the HLA-G 3' UTR + 3142C/G (rs1063320) genetic variant and the risk of HPV infection. Our results showed no association between the variant of HLA-G 3' UTR + 3142C/G (rs1063320) and susceptibility to HPV infection in studied target populations.Impact StatementWhat is already known on this subject? Human papillomavirus (HPV) is the most widespread sexually transmitted infection in both men and women all over the world. It is correlated with prominent load of diseases and malignancies, including anogenital warts and anogenital and oropharyngeal cancers. In recent years, several studies manifested that different SNPs located on special genes seems to influence HPV infection risk.What the results of this study add? Our findings disclosed no relation between the variant of HLA-G 3' UTR + 3142C/G (rs1063320) and vulnerability to HPV infection in the target individuals.What are the implications of these findings for clinical practice and/or further research? The findings in current survey may offer a basis for further study on HLA-G variant in future investigation.

From diabetes to renal aging: the therapeutic potential of adiponectin.

Nowadays, the complications related to diabetes, such as nephropathy, cardiovascular problems, and aging, are highly being considered. Renal cell aging is affected by various mechanisms of inflammation, oxidative stress, and basement membrane thickening, which are significant causes of renal dysfunction in diabetes. Due to recent studies, adiponectin plays a key role in diabetes-related kidney diseases as a fat-derived hormone. In diabetes, reduced adiponectin levels are associated to renal cell aging. Oxidative stress and related signaling pathways are the main routes in which adiponectin may be effective to decline diabetes-associated aging. Therefore, adiponectin signaling in target tissues becomes one of the research areas of interest in metabolism and clinical medicine. Studies on adiponectin signaling will increase our understanding of adiponectin role in diabetes-linked diseases as well as shortening life span conditions which may guide the design of antidiabetic and anti-aging drugs.

The Polymorphism of miR-146a (rs2910164) and Breast Cancer Risk: A Meta-Analysis of 17 Studies.

BACKGROUND: Single-Nucleotide Polymorphisms (SNPs) in genes responsible for coding microRNAs (miRNAs) are shown to be crucial in progression of Breast Cancer (BC). OBJECTIVE: The purpose of this meta-analysis is to obtain more definitive and reliable results due to the ambiguity and inconsistency of the previous findings in this regard. This study aimed at clarifying the association of mir14a polymorphisms with breast cancer. METHODS: We searched PubMed, EMBASE, Web of Science and Google Scholar databases for papers published before August 10, 2019. Afterward, genotypes' distribution, genotyping methods and ethnicity groups were extracted and Overall analyses were conducted. A total number of seventeen researches on 7676 subjects and 7476 controls were found to meet our criteria in this meta-analysis. RESULTS: Our observations confirmed the increased risk in breast cancer with rs 2910164 polymorphism in three genetic models: allele contrast fixed genetic model, Recessive fixed genetic model and CC vs. GG genetic model (P value 0.0109, 0.0404 and 0.0019, respectively). CONCLUSION: The rs2910164 polymorphism is associated with increased breast cancer risk. We suggest that more multicenter studies with larger samples investigate this matter to further clarify the association and verify our findings.

Antioxidant Properties of Saffron Stigma and Petals: A Potential Therapeutic Approach for Insulin Resistance through an Insulin-Sensitizing Adipocytokine in High-Calorie Diet Rats.

BACKGROUND: Oxidative stress and alteration of lipid profile due to obesity and overweight is a major risk factor for atherosclerotic plaque or coronary artery disease. Because of antioxidant and lipid lowering potential of saffron, this study investigated weight alteration, lipid profiles, and insulin resistance index in high-calorie diet rats treated with aqueous extract of saffron stigma and petal. METHODS: Forty Sprague-Dawley male rats were randomly divided into 8 groups including healthy control, high-fat diet control, nicotinic acid treated, Anethum graveolens treated, and saffron stigma and petal treated groups. Rats received a high-calorie diet for 16 weeks. For treatment, aqueous extract of saffron stigma (40 and 80 mg/kg) and petal (50 and 100 mg/kg) was used once daily for 4 weeks. Afterward, lipid profile, oxidative stress status, and insulin and adiponectin levels were measured using desired kits. RESULTS: There was a significant decrease in the mean weight of the groups receiving saffron stigma and petal compared to control group (P < 0.05). The increased level of insulin hormone in obese group was improved in treated groups especially in the case of saffron stigma. Also, the decreased level of adiponectin was recovered in treated groups. An improvement was seen in oxidative stress markers and lipid profiles in treated groups compared to obesity pair. CONCLUSIONS: In this study, a remarkable antioxidant and lipid lowering potential was detected for saffron stigma, which could improve insulin resistance in obese rats. Therapeutic and protective effect of saffron is mainly related to its richness in phenolic compounds. Saffron stigma compared with petal had more notable effect, which could and should be mentioned in pharmaceutical studies.

The regulatory effect of saffron stigma on the gene expression of the glucose metabolism key enzymes and stress proteins in streptozotocin-induced diabetic rats.

Oxidative stress plays a crucial role in the pathogenesis of hyperglycemia mediated complications. Since a great number of researches have reported antioxidant features of saffron, this study investigated the antioxidant effect of saffron stigma extract (SSE) in streptozotocin-induced diabetic rats. Twenty eight diabetic male Wistar rats were divided in four groups containing: two diabetic groups receiving 25 and 100 mg/kg SSE respectively, one diabetic group receiving glibenclamide (0.6 mg/kg) and one diabetic control group receiving normal saline. Seven healthy adult male Wistar rats were also used as normal control group. After treatment (21 days), fasting blood glucose, insulin, oxidative stress markers, and pancreatic regeneration were assessed. The gene expression level of heat shock factor1, heat shock protein 27, and heat shock protein 70, also glucokinase (GK), and glucose 6-phosphatase (G6Pase) were determined using real-time polymerase chain reaction (RT-PCR). SSE in high dose (100 mg/kg) reduced fasting blood glucose (8.3 ± 0.4 mmol/L) compared with diabetic control (24.6 ± 1.2 mmol/L) (P < 0.05). Furthermore, SSE in high dose increased insulin level compared with diabetic control group (12.7 ± 0.6 vs 7.1 ± 0.3 µU/mL). RT-PCR analysis revealed decline in mRNA levels of stress proteins and G6Pase and increase in mRNA level of GK in treatment diabetic groups compared with diabetic control group. Data showed antioxidant and antidiabetic effects of SSE through altering insulin release and glucose metabolism pathways. Hypoglycemic potential of SSE may be due to change in GK and G6Pase enzymes expression. These findings provide a basis for the therapeutic potential of saffron in treatment of diabetes.

NLRP3 inflammasome as a treatment target in atherosclerosis: A focus on statin therapy.

Activation of NOD-like receptor (NLR) family and pyrin domain containing 3 (NLRP3) inflammasome contributes to inflammation and may lead to atherosclerosis. The NLRP3 inflammasome as a molecular platform regulates the activation of ATP signaling, K+ efflux, cathepsin-B activity, lysosomal function and pro-inflammatory cytokines (i.e. IL-1ß and IL-18). Statins has been widely prescribed for the treatment of hyperlipidemia and cardiovascular diseases. In addition to lipid-lowering effect, statins have immunomodulatory, anti-inflammatory, antioxidant and antiapoptotic functions. An increasing number of studies indicated NLRP3 inflammasome and their downstream mediators as important targets for statin drugs in inflammatory diseases. In this review, we discussed different aspect of the NLRP3 inflammasome signaling pathways and focused on the effect of statin drugs on NLRP3 inflammasomes in association to atherosclerosis in order to elucidate possible targets for future research and clinical settings.

Positive correlation between vitamin D receptor gene TaqI variant and gastric cancer predisposition in a sample of Iranian population.

Gastric cancer is the second cause of cancer-related mortality and the fourth most common cancers worldwide. Owing to the immune modulatory effect of vitamin D in the body, the role of vitamin D receptor gene in vitamin D regulation receives a great deal of research interest. The aim of the current study was to highlight the association between two variants of TaqI and FokI in the vitamin D receptor gene and gastric cancer predisposition in a sample of South Khorasan population. The present investigation consisted of 69 patients affected with gastric cancer and 100 healthy individuals. The genomic DNA was extracted by salting out the protocol from peripheral venous blood. Genotyping of TaqI and FokI variants were performed by PCR-RFLP method. Our findings manifested that TC genotype of TaqI polymorphism was statistically significant between the case and the control groups (p = 0.002). Moreover, the frequency of TC + CC genotypes was statistically significant between the two groups (p = 0.009). Furthermore, we could not find any meaningful association between FokI variant and the participant groups. The present results declared that, in our population, TC genotype of TaqI polymorphism has an association with gastric cancer susceptibility. In addition, more investigation with greater sample sizes is needed to confirm our results.

Association between polymorphisms of VKORC1 and CYP2C9 genes with warfarin maintenance dose in a group of warfarin users in Birjand city, Iran.

Warfarin is the cardinal anticoagulant drug prescribed around the world. Due to stochastic bleeding in patients, it is essential to adjust the dose for every individual. The aim of the present study was to evaluate the frequency of CYP2C9 and VKORC1 gene polymorphisms and their association with warfarin maintenance dose in a sample of cardiovascular patients in Birjand, South-Khorasan province of Iran. Patients with a history of cardiovascular disorders who take warfarin daily were selected. CYP2C9 and VKORC1 gene polymorphisms were detected by polymerase chain reaction-restriction fragment length polymorphism in all participants. A total of 114 patients (mean age: 52.7 ± 14.9 years, M/F ratio: 0.76) participated in this study. Regarding CYP2C9 gene polymorphisms, the most frequent genotype was 1*/1* (80.4% in females and 62.5% in males). The frequency of 1*/2* and 2*/2* variants was 13% and 6.5% in females and 25% and 12.5% in males, respectively. The frequency of VKORC1 gene (1639 G > A), was 31.5%, 39.5%, and 29% for GG, GA, and AA in males, respectively. Besides, the mentioned genotype frequencies for females were 50%, 40.5%, and 9.5%, respectively. Moreover, there was a statistically significant correlation between VKORC1 gene -1639 G > A variant and warfarin maintenance dose (P < 0.001) but not for CYP2C9 variants. The results of the current study confirmed that the mutant variants of CYP2C9 are not frequent and do not have any impact on warfarin dose. In the case of VKORC1, the mutant allele (A) showed a positive correlation with warfarin dose adjustment.

Positive correlation between interleukin-1 receptor antagonist gene 86bp VNTR polymorphism and colorectal cancer susceptibility: a case-control study.

Colorectal cancer (CRC) is one of the most common malignancies worldwide. Genetic variations in cytokine genes and their receptors lead to the severity of the disease. The interleukin-1 receptor antagonist (IL1RN) is a cytokine that inhibits interleukin-1 (IL-1) activity by binding to IL-1 receptors. Also, interleukin-4 (IL-4) is an anti-inflammatory cytokine that can play an important role in several cancers. The present case-control study was aimed to evaluate the association of IL-4 and IL1RN VNTR polymorphisms with the susceptibility to CRC in a sample of Iranian population provided by the Research Center for Gastroenterology and Liver Disease at Taleghani Hospital, Tehran. A total of 123 patients diagnosed with CRC and 152 healthy controls were recruited in the present study. Genomic DNA was extracted by salting out method from whole blood and genotyping of IL1RN and IL-4 VNTR polymorphisms were determined by PCR-based technology. Our study manifested the frequency of 1/2 and 2/4 genotypes of IL1RN 68bp VNTR polymorphism are significantly different between both groups (p = 0.0001 and p = 0.01 respectively). However, we could not find any correlation between IL-4 VNTR polymorphism and CRC cancer. It seems that 1/2 and 2/4 genotypes of IL1RN are correlated with CRC susceptibility in our population, although, more studies are needed to confirm our results.

Role of the NLRP3 inflammasome in cancer.

Inflammasomes are large intracellular multi-protein signalling complexes that are formed in the cytosolic compartment as an inflammatory immune response to endogenous danger signals. The formation of the inflammasome enables activation of an inflammatory protease caspase-1, pyroptosis initiation with the subsequent cleaving of the pro-inflammatory cytokines interleukin (IL)-1ß and proIL-18 to produce active forms. The inflammasome complex consists of a Nod-like receptor (NLR), the adapter apoptosis-associated speck-like (ASC) protein, and Caspase-1. Dysregulation of NLRP3 inflammasome activation is involved tumor pathogenesis, although its role in cancer development and progression remains controversial due to the inconsistent findings described. In this review, we summarize the current knowledge on the contribution of the NLRP3 inflammasome on potential cancer promotion and therapy.