FasL Gene Research Articles

Cardiac Left Ventricular miRNA-26a Is Downregulated in Ovariectomized Mice, Upregulated upon 17-Beta Estradiol Replacement, and Inversely Correlated with Collagen Type 1 Gene Expression.

Heart failure with preserved ejection fraction (HFpEF) is more prevalent in post- compared to pre-menopausal women. The underlying mechanisms are not fully understood. Data in humans is confounded by age and co-morbidities. We investigated the effects of ovariectomy and estrogen replacement on the left ventricular (LV) gene expression of pro-inflammatory and pro-fibrotic factors involved in HFpEF and putative regulating miRNAs. Nine-week-old C57BL/6 female mice were subjected to ovariectomy (OVX) or SHAM operation. OVX and SHAM groups were sacrificed 1-, 6-, and 12-weeks post-surgery (T1/SHAM; T1/OVX; T6/SHAM; T6/OVX, T12/SHAM). 17β-estradiol (E2) or vehicle (VEH) was then administered to the OVX groups for 6 weeks (T12/OVX/E2; T12/OVX/VEH). Another SHAM group was sacrificed 12-weeks post-surgery. RNA and miRNAs were extracted from the LV apex. An early 3-fold increase in the gene expression of IL-1α, IL-6, Mmp9, Mmp12, Col1α1, and Col3α1 was observed one-week post-surgery in T1/OVX vs. T1/SHAM, but not at later time points. miRNA-26a was lower in T1/OVX vs. T1/SHAM and was inversely correlated with Col1α1 and Col3α1 expression 1-week post-surgery (r = -0.79 p < 0.001; r = -0.6 p = 0.007). miRNAs-26a, 29b, and 133a were significantly higher, while Col1α1, Col3α1, IL-1α, IL-6, Tnfα, Mmp12, and FasL gene expression was significantly lower in E2- compared to vehicle-treated OVX mice. miRNA-26a was inversely correlated with Col3α1 in T12/OVX/ E2 (r = -0.56 p = 0.02). OVX triggered an early increase in the gene expression of pro-inflammatory and pro-fibrotic factors, highlighting the importance of the early phase post-cessation of ovarian function. E2 replacement therapy, even if it was not immediately initiated after OVX, reversed these unfavorable changes and upregulated cardiac miRNA-26a, previously unknown to be affected by menopausal status.

The role of FASL gene polymorphism (rs: 763110), its serum level and IL21 level with incidence of psoriasis in Iraqi patients

Psoriasis is a chronic, immune-mediated skin disease with systemic pro-inflammatory can defined by keratinocyte hyper proliferation. FASL gene cell surface death receptor which is important in apoptosis mediated by cytotoxic T cells and natural killer cells. The goals of current study is design to investigate genotyping of the FASL gene (Fas ligand gene) -844 T>C (rs:763110), evaluate its serum level and to estimate level of IL-21correlated with incidence of psoriasis in Iraqi patients. 100 blood samples collected from December 2022 to February 2023, blood samples split into two groups first 50 psoriasis patients (30 males and 20 females) with age range (17-66years) and second group 50 Apparently healthy as control group (24 males 26 females) with age range (20-60 years) visit the Al-Yarmouk Teaching Hospital’s Department of Dermatology in Iraq/Baghdad. (HRM–PCR) Technique was use for the investigation of gene polymorphism of the FASL gene (rs763110). While EIISA technique used to estimate serum level of each FASL gene and IL-21 in serum. The result of FASL gene polymorphism revealed that there are three genotype (TT),(TC),(CC). There was no significant difference, between (TC) and (CC) genotype In the FASLG -844 and between the psoriasis and control groups. Moreover there was correlation between genotyping and serum level for FASL (rs763110) gene in that (TC) genotype serum level show significant different from (CC) genotype serum level with p-value (P≤0.05) as well as the FASL serum level in patient which represent high significantly different between psoriasis patients when compared to the healthy controls with p-value (P≤0.01). While result of IL21 serum level in psoriasis patients revealed high significant different with p-value (P≤0.01) vs healthy control with high significant different in sever psoriatic patient vs mild and healthy control with p value (P≤0.01).

A novel Fas ligand plays an important role in cell apoptosis of Crassostrea hongkongensis: molecular cloning, expression profiles and functional identification of ChFasL.

Apoptosis regulates normal development, homeostasis, immune tolerance and response to environmental stress by eliminating unwanted or diseased cells, and plays a key role in non-specific immunity of invertebrates. The exogenous pathway mediated by death receptors and death ligands is a very important pathway for cell apoptosis. Death ligands are mainly members of the tumour necrosis factor (TNF) family, of which FasL is an important member. The deep involvement of FasL in vertebrates cell apoptosis and immunity has been reported many times, but there is limited research on the FasL gene in shellfish, and its functional importance in oyster cell apoptosis and immunity remains unclear. The full length of ChFasL was identified and cloned based on the genome of Crassostrea hongkongensis. Quantitative PCR was used to detect the relative expression of ChFasL in different developmental stages and tissues, as well as the changes of relative expression in hemocytes after bacterial infection. The expression position of ChFasL in HEK293T cells was also located by subcellular localization, and the effect of increased recombinant protein content on the activity of reporter genes p53 and p21 was studied by dual-fluorescence reporter gene. Finally, the changes of apoptosis rate in hemocytes after ChFasL silencing was identified by RNA interference technology. We identified a novel FasL gene from C. hongkongensis and named it ChFasL. We found that ChFasL has potential N-linked glycosylation site, a transmembrane domain and a TNF region, which was a typical characteristics of TNF family. ChFasL was expressed in all developmental stages of larvae and in all tissues of oysters. After stimulation by V. alginolyticus or S. haemolyticus, its relative expression in hemocytes increased significantly, suggesting that ChFasL was deeply engaged in the immune response process of C. hongkongensis to external microbial stimulation. The results of subcellular localization showed that ChFasL was mainly distributed in the cytoplasm of HEK293T cells. With the overexpression of the recombinant protein pcDNA3 1- ChFasL, the activity of p53 and p21 significantly increased, showing a positive regulatory effect. Moreover, after dsRNA successfully reduced the relative expression of ChFasL, the apoptosis rate of hemocytes was significantly lower than that the dsGFP group. These results comprehensively confirmed the important role of ChFasL in the apoptosis process of C. hongkongensis, which provided the basis and premise for the in-depth understanding of the immune function of apoptosis in molluscs, and also contributed to the research on the pathogenic death mechanism and disease resistance breeding of marine bivalves.

Apoptosis and inflammatory genes variants in primary non-response to anti-TNF therapy in Crohn's disease patients.

Anti-TNF therapy has indeed revolutionized the treatment of Crohn's disease, leading to higher rates of response and remission in patients. However, a significant proportion of 20-40% of patients do not respond to the initial therapy, others experience a secondary loss of response with ongoing treatment. Adverse drug reactions also occur in some patients. The effectiveness of anti-TNF treatment may be influenced by genetic variability, including FCGR3A, ADAM17, TNFRSF1A, TNFRSF1B, FAS, FASL, IL1B, CASP9 , and MIF genes. In this article, we provide an overview of the current knowledge and findings in the pharmacogenetics of anti-TNF drugs in CD focusing on the aspect of apoptosis and inflammatory genes variants in primary non-response. Pharmacogenetic investigations have been conducted to identify genetic markers that can predict response to anti-TNF therapy. However, large multi-center validation studies and multi-loci algorithms development are required to effectively prognose the treatment effect. The identification of predictive markers of response to anti-TNF therapy can help clinicians make informed decisions about treatment options and minimize adverse drug reactions in patients.

SARS-CoV-2 Structural Proteins Modulated Blood-Testis Barrier-Related Proteins through Autophagy in the Primary Sertoli Cells.

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) disrupts the blood-testis barrier (BTB), resulting in alterations in spermatogenesis. However, whether BTB-related proteins (such as ZO-1, claudin11, N-cadherin, and CX43) are targeted by SARS-CoV-2 remains to be clarified. BTB is a physical barrier between the blood vessels and the seminiferous tubules of the animal testis, and it is one of the tightest blood-tissue barriers in the mammalian body. In this study, we investigated the effects of viral proteins, via ectopic expression of individual viral proteins, on BTB-related proteins, the secretion of immune factors, and the formation and degradation of autophagosomes in human primary Sertoli cells. Our study demonstrated that ectopic expression of viral E (envelope protein) and M (membrane protein) induced the expressions of ZO-1 and claudin11, promoted the formation of autophagosomes, and inhibited autophagy flux. S (spike protein) reduced the expression of ZO-1, N-cadherin, and CX43, induced the expression of claudin11, and inhibited the formation and degradation of autophagosomes. N (nucleocapsid protein) reduced the expression of ZO-1, claudin11, and N-cadherin. All the structural proteins (SPs) E, M, N, and S increased the expression of the FasL gene, and the E protein promoted the expression and secretion of FasL and TGF-β proteins and the expression of IL-1. Blockage of autophagy by specific inhibitors resulted in the suppression of BTB-related proteins by the SPs. Our results indicated that SARS-CoV-2 SPs (E, M, and S) regulate BTB-related proteins through autophagy.

The potential role of the KFG and KITLG proteins in preventing granulosa cell apoptosis in Bubalus bubalis

BackgroundThe dynamics of mammalian follicular development and atresia is an intricate process involving the cell-cell communication mediated by secreted ovarian factors. These interactions are critical for oocyte development and regulation of follicular atresia which in part are mediated by keratinocyte growth factor (KGF) and kit ligand (KITLG), but their roles in the regulation of apoptosis in buffalo granulosa cells have not yet been defined. During mammalian follicular development, granulosa cell apoptosis triggers the atresia so ~ 1% follicles reach the ovulation stage. In the present study, we used buffalo granulosa cells to examine the effects of KGF and KITLG in apoptosis regulation and investigated potential mechanism on Fas-FasL and Bcl-2 signaling pathways. ResultIsolated buffalo granulosa cells were cultured with KGF and KITLG proteins using different doses (0, 10, 20, and 50 ng/ml) independently or in combination. Expression analysis for both anti-apoptotic (Bcl-2, Bcl-xL, and cFLIP) and pro-apoptotic (Bax, Fas, and FasL) genes at transcriptional levels were carried out by real-time PCR. Upon treatments, expression levels of anti-apoptotic genes were significantly upregulated in a dose-dependent manner, showing an upregulation at 50 ng/ml (independently), and at 10 ng/ml in combination. Additionally, upregulation of growth-promoting factors, bFGF, and α-Inhibin was also observed. ConclusionsOur findings suggest the potential roles of KGF and KITLG in determining granulosa cell growth and regulating apoptosis.

Autoimmune Lymphoproliferative Syndrome (ALPS) Disease and ALPS Phenotype: Are They Two Distinct Entities?

Autoimmune lymphoproliferative syndrome (ALPS) is an inherited disorder of lymphocyte homeostasis classically due to mutation of FAS, FASL, and CASP10 genes (ALPS-FAS/CASP10). Despite recent progress, about one-third of ALPS patients does not carry classical mutations and still remains gene orphan (ALPS-U, undetermined genetic defects). The aims of the present study were to compare the clinical and immunological features of ALPS-FAS/CASP10 versus those of ALPS-U affected subjects and to deepen the genetic characteristics of this latter group. Demographical, anamnestic, biochemical data were retrieved from medical record of 46 ALPS subjects. An enlarged panel of genes (next-generation sequencing) was applied to the ALPS-U group. ALPS-U subjects showed a more complex phenotype if compared to ALPS-FAS/CASP10 group, characterized by multiorgan involvement (P = 0.001) and positivity of autoimmune markers (P = 0.02). Multilineage cytopenia was present in both groups without differences with the exception of lymphocytopenia and autoimmune neutropenia that were more frequent in ALPS-U than in the ALPS-FAS/CASP10 group (P = 0.01 and P = 0.04). First- and second-line treatments were able to control the symptoms in 100% of the ALPS-FAS/CASP10 patients, while 63% of ALPS-U needed >2 lines of treatment and remission in some cases was obtained only after target therapy. In the ALPS-U group, we found in 14 of 28 (50%) patients 19 variants; of these, 4 of 19 (21%) were known as pathogenic and 8 of 19 (42%) as likely pathogenic. A characteristic flow cytometry panel including CD3CD4-CD8-+TCRαβ+, CD3+CD25+/CD3HLADR+, TCR αβ+ B220+, and CD19+CD27+ identified the ALPS-FAS/CASP10 group. ALPS-U seems to represent a distinct entity from ALPS-FAS/CASP10; this is relevant for management and tailored treatments whenever available.

Long-Term Ingestion of Sicilian Black Bee Chestnut Honey and/or D-Limonene Counteracts Brain Damage Induced by High Fat-Diet in Obese Mice

Obesity is linked to neurodegeneration, which is mainly caused by inflammation and oxidative stress. We analyzed whether the long-term intake of honey and/or D-limonene, which are known for their antioxidant and anti-inflammatory actions, when ingested separately or in combination, can counteract the neurodegeneration occurring in high fat diet (HFD)-induced obesity. After 10 weeks of HFD, mice were divided into: HFD-, HFD + honey (HFD-H)-, HFD + D-limonene (HFD-L)-, HFD + honey + D-limonene (HFD-H + L)-fed groups, for another 10 weeks. Another group was fed a standard diet (STD). We analyzed the brain neurodegeneration, inflammation, oxidative stress, and gene expression of Alzheimer's disease (AD) markers. The HFD animals showed higher neuronal apoptosis, upregulation of pro-apoptotic genes Fas-L, Bim P27 and downregulation of anti-apoptotic factors BDNF and BCL2; increased gene expression of the pro-inflammatory IL-1β, IL-6 and TNF-α and elevated oxidative stress markers COX-2, iNOS, ROS and nitrite. The honey and D-limonene intake counteracted these alterations; however, they did so in a stronger manner when in combination. Genes involved in amyloid plaque processing (APP and TAU), synaptic function (Ache) and AD-related hyperphosphorylation were higher in HFD brains, and significantly downregulated in HFD-H, HFD-L and HFD-H + L. These results suggest that honey and limonene ingestion counteract obesity-related neurodegeneration and that joint consumption is more efficacious than a single administration.

Evaluation of the FAS and FASL Gene changes in women with premature ovarian failure: A case-control study.

Premature ovarian failure (POF), is menopause occurring before the age of 40, affecting 1-3% of women worldwide. The risk of POF increases with altered immunological parameters such as FAS and FASL genes, which play a fundamental role in embryogenesis and cellular homeostasis. The study aimed to investigate the potential role of FAS and FASL genes in POF pathogenesis. In this case-control study, the polymorphisms of FAS-670A/G and FASLIVS2nt_124A/G apoptotic genes were analyzed in 51 Iranian women suffering from POF, and 61 healthy controls. Isolation of DNA was done using the salting-out method, and genotypic analysis was performed for all the subjects using the polymerase chain reaction-restriction fragment length polymorphism method. Our results revealed that homozygous FAS-670A/A and G/G, and heterozygous FAS-670A/G are not significantly different between cases and controls (p = 0.99). Also, in different genotyping models of FASIVS2nt_124, polymorphisms were not related to POF risk (p = 0.23). There is no statistical association between these polymorphisms and POF risk in women referred to genetic counseling clinics.

Molecular Genetics of Thrombotic Myeloproliferative Neoplasms: Implications in Precision Oncology.

Classical BCR-ABL-negative myeloproliferative neoplasms (MPN) include polycythaemia vera, essential thrombocythaemia, and primary myelofibrosis. Unlike monogenic disorders, a more complicated series of genetic mutations are believed to be responsible for MPN with various degrees of thromboembolic and bleeding complications. Thrombosis is one of the early manifestations in patients with MPN. To date, the driver genes responsible for MPN include JAK2, CALR, MPL, TET2, ASXL1, and MTHFR. Affords have been done to elucidate these mutations and the incidence of thromboembolic events. Several lines of evidence indicate that mutations in JAK2, MPL, TET2 and ASXL1 gene and polymorphisms in several clotting factors (GPIa, GPIIa, and GPIIIa) are associated with the occurrence and prevalence of thrombosis in MPN patients. Some polymorphisms within XRCC1, FBG, F2, F5, F7, F12, MMP9, HPA5, MTHFR, SDF-1, FAS, FASL, TERT, ACE, and TLR4 genes may also play a role in MPN manifestation. This review aims to provide an insightful overview on the genetic perspective of thrombotic complications in patients with MPN.

Apoptosis as a Potential Target to Arrest and Survival of Hydatid Cyst.

Hydatidosis is a serious and life-threatening disease that may lead to the death of the host if diagnosed and treated improperly. Apoptosis has been investigated as a mechanism of host innate immunity in suppressing parasites and also the survival of cysts in the human body. The present study investigates the process and role of apoptosis caused by a host cell or parasite in hydatid cysts. Survey cytotoxic effect and apoptotic mortality of hydatid-treated lymphocytes were investigated. Also, to determine the mechanism of apoptosis in host and parasite, the mean gene expressions of Bcl-2, Bax, Caspase 3 in hydatid-treated lymphocytes, and Fas-L gene in the laminated-germinal layer of fertile and infertile hydatid cysts were evaluated. The viability of fertile and infertile hydatid fluid-treated lymphocytes was significantly different compared with the control group. Flow cytometry also showed apoptotic cells. Bax mean gene expression was significantly different between fertile and infertile treated lymphocytes. However, there was no significant difference in the mean expression of Caspase 3, and Bcl-2 genes in these two groups. Although the expression of the Fas-L gene in infertile cysts was higher than in fertile cysts, the result was not significant. It seems that hydatid cyst fluid may induce apoptosis in lymphocytes so that, hydatid cysts can escape from the immune system and stay alive. On the other hand, the results represent the possible immune path of host apoptosis against the parasite as one of the important routes in infertility of hydatid cysts.

Plasma Levels of sFas-sFasL and FASL Gene Expression Are Associated with Tuberculosis.

Apoptosis of macrophages infected by Mycobacterium tuberculosis via Fas-FasL is an important immune mechanism against infection. This study investigated the association of tuberculosis (TB) with the presence of the polymorphisms FAS -670A/G and FASL -124A/G, the levels of sFas and sFasL, and the gene expression of FASL and cytokines. Samples of 200 individuals diagnosed with TB and 200 healthy controls were evaluated. Real-time PCR (genotyping and gene expression) and ELISA (dosages of sFas, sFasL, IFN-γ, and IL-10) tests were performed. There was no association of FAS -670A/G and FASL -124A/G polymorphisms with TB. The TB group exhibited high plasma levels of sFas and reduced plasma levels of sFasL (p < 0.05). The correlation analysis between these markers revealed a positive correlation between the levels of sFas and sFasL, sFasL and FASL expression, and between sFas and FASL expression (p < 0.05). In the TB group, there was a positive correlation between FASL expression and IFN-γ levels and higher levels of IL-10 compared to IFN-γ (p < 0.05). High levels of sFas and reduced levels of sFasL and FASL expression may contribute to the inhibition of apoptosis in infected cells and represent a possible bacterial resistance resource to maintain the infection.

Fas cell surface death receptor/Fas ligand genetic variants in gastric cancer patients: A case control study

Background &amp; objectives: Various studies have suggested a correlation between Fas Cell Surface Death Receptor/Fas Ligand (FAS/FASL) variants and multiple types of cancers. The present study aimed to investigate the association between FAS-670A/G and FASL-844C/T and the synergistic effects of both variants on the risk of Gastric Cancer (GC) in the Kurdish population of West of Iran. Methods: This study was conducted by polymerase chain reaction-restriction fragment length polymorphism technique using MvaI and BsrDI restriction enzymes in 98 GC patients and 103 healthy control individuals. Results: According to the obtained results, a significant association (P=0.008) of FASL polymorphism among GC patients and the control group was detected. Furthermore, no significant differences were found in the FAS polymorphism frequencies between GC patients and the control group. Codominant and dominant models in FASL polymorphism showed significant protective effects against GC [odds ratio (OR) =0.307, 95% confidence interval (CI) (0.134-0.705), P=0.005; OR=0.205, 95% CI (0.058-0.718), P=0.013 and OR=0.295, 95% CI (0.129-0.673), P=0.004 for models of codominant CC vs. CT, codominant CC vs. TT and dominant, respectively]. Furthermore, the presence of both FAS-670G and FASL-844T alleles represented a significant protective effect against GC occurrence [OR=0.420, 95% CI (0.181-0.975), P=0.043]. Interpretation &amp; conclusions: So far, we believe this is the first study the results of which suggest that FASL gene variation and its synergistic effects with FAS gene could be associated with the risk of GC in the Kurdish population in the west of Iran.

Effect of valproic acid on extrinsic and intrinsic apoptotic pathways, cell viability and apoptosis in hepatocellular carcinoma PLC/PRF5 cell line.

Inhibitors of histone deacetylase enzymes induce various molecular and extracellular effects that lead to their anticancer role. In this study, the result of valproic acid on the expression of genes of extrinsic pathway and intrinsic pathway of apoptosis, cell viability, and apoptosis in liver cancer PLC/PRF5 cell line was designed. For this purpose, PLC/PRF5 liver cancer cells were cultured, and after the overlapping of the cells reached about 80%, the cells were collected with trypsin and after washing, they were cultured on a plate with a concentration of 3 x 105. After 24 hours, the culture medium was treated with a medium containing valproic acid (the control group received only DMSO). 24, 48, and 72 hours after treatment to determine the cell viability, apoptotic cells, gene expression, MTT, flow cytometry, and Real-time techniques. The results showed that valproic acid significantly inhibited cell growth, induced apoptosis, and decreased the expression of Bcl-2 and Bcl-xL genes. Also, it increased the expression of DR4, DR5, FAS, FAS-L, TRAIL, BAX, BAK, and APAF1 genes. In general, valproic acid seems to play its apoptotic role through intrinsic and extrinsic pathways in liver cancer.

The role of FASL, BCL-2 and BAX polymorphisms in brazilian patients with prostate cancer and benign prostatic hyperplasia.

Prostate cancer (PCA) is one of the leading causes of death among men, being related to several factors, including the aging male population, like benign prostatic hyperplasia (BPH), a histopathological and hyperplastic alteration associated to prostate aging. The FASL, BCL-2 and BAX genes are involved in cell apoptosis regulation and can be related to the development of both cancer and hyperplasia. This study aimed to investigate the association of FASL - 844 (rs763110), BCL-2 -938 (rs2279115) and BAX - 248 (rs4645878) polymorphic variants in Southern Brazilian PCA and BPH patients and healthy controls. 348 samples were analyzed, being 123 from PCA patients, 143 BPH patients and 82 healthy controls, using PCR-RFLP techniques. The results of genotyping analysis were adjusted by age, and compared with PSA levels and prostate volume. The analyzes of genotype frequencies according to PCA, HPB and controls, were performed by logistic regression corrected by age, and showed that the FASL CC genotype can be a risk factor for PCA patients, when compared to controls (p = 0.041). The clinical data investigation indicated higher PSA levels in PCA patients with FASL CC genotype, as compared to TC genotype carriers (p = 0.044), higher PSA levels for healthy individuals with BCL-2 AA genotype, comparing with CC genotype (p = 0.027) and higher PSA levels in BPH group with FASL CC genotype, as compared to TC genotype (p = 0.044). Our data indicate the FASLCC genotype as a risk factor for prostate pathologies, whileBCL-2 CC can act as a protective genotype.

The effect of valproic acid on intrinsic, extrinsic, and JAK/STAT pathways in neuroblastoma and glioblastoma cell lines.

Background and purpose:Epigenetics has been defined as the study of mitotically heritable alterations in gene expression that are not caused by changes in DNA sequence. Epigenetic-mediated silencing of a gene includes genomic imprinting, histone deacetylation, DNA methylation, and RNA-associated silencing. Cell growth and cell proliferation are inhibited by some histone deacetylase and histone inhibitors. This study was designed to investigate the effect of valproic acid (VPA) on extrinsic, intrinsic, and the Janus kinase (JAK)- signal transducer and activator of transcription (STAT) pathways in neuroblastoma and glioblastoma cell lines.Experimental approach:The neuroblastoma and glioblastoma cells were cultured and treated with VPA. MTT assay was done to determine cell viability. Besides, a flow cytometry assay was performed to determine apoptotic cells and finally, the relative gene expression level was evaluated by qRT-PCR.Findings / Results:VPA changed the expression level of the genes of the extrinsic, intrinsic, and JAK/STAT pathways which induced cell apoptosis and inhibited cell growth in the neuroblastoma and glioblastoma cells. In the neuroblastoma cell lines, VPA upregulated the expression level of FAS, FAS-L, DR4, DR5, and TRAIL genes significantly. Additionally, it significantly up-regulated the expression level of Bak, Bax, and Bim genes and down-regulated the expression level of Bcl-xL, Bcl-2, and Mcl-1 genes in both neuroblastoma and glioblastoma cell lines.Conclusion and implications:VPA induced cell apoptosis through extrinsic, intrinsic, and JAK/STAT pathways.

Monogenic Disorder Associated with Autoimmune Lymphoproliferative Syndrome -Like Phenotype: A Systematic Review

Background: Autoimmune lymphoproliferative syndrome (ALPS) is a congenital disorder that results in an apoptosis impairment of lymphocytes, leading to chronic lymphoproliferation and autoimmunity, mainly autoimmune cytopenia. Some of autoreactive T cells cannot become apoptosis in activation-induced cell death (AICD) pathway; therefore, they have accumulation of autoreactive TCRαβ+CD4−CD8− doublenegative T (αβ- DNT) cells, leading to cytopenia, splenomegaly, lymphadenopathy, autoimmune disorders and a greatly increased lifetime risk of lymphoma. FAS, FASL, CASP8 and CASP10 gene defects are often responsible for the disease, the phenotype of which can vary from asymptomatic/mild forms to severe disease. More rarely, defects are associated to other genes involved in ALPS-like phenotype.&#x0D; Methods: A systematic literature search was performed in Web of Science, PubMed and Scopus from the earliest available date to march 2021 with standard keywords to find patients with ALPS-like phenotypes. Demographic, clinical, immunological and molecular data were extracted.&#x0D; Results: In this systematic review we reported 61 patients with genetically determined ALPS-like. Most of ALPS-like cases carry mutations in the STAT3 (n=15), LRBA (n=11) and CARD11 (n=8) genes. The most common presentation was splenomegaly and lymphadenopathy followed by hepatomegaly. The most common autoimmunity was autoimmune hemolytic anemia and immune thrombocytopenic purpura followed by auto immune neutropenia. Elevated serum immunoglobulin was reported especially in IgG, IgM and IgA.&#x0D; Conclusion: In the present study, 61 patients with genetically determined ALPS-like were examined. Our results showed that most of ALPS-like cases carry mutations in the STAT3. We reported that the most common presentations were splenomegaly and lymphadenopathy. Elevated serum immunoglobulin, IL-10, vitamin B12 and increased proportion of DNT cells were reported.

The mechanism of immune related signal pathway Egr2-FasL-Fas in transcription regulation and methylated modification of Paralichthys olivaceus under acute hypoxia stress

Apoptosis genes Egr2, Fas and FasL are related to immune responses. However, the mechanism of these genes inducing apoptosis in fish are still not very clear. An acute hypoxia treatment (1.73 ± 0.06 mg/L) for 24 h was carried out on Japanese flounder (Paralichthys olivaceus). The increasingly dense apoptotic signals at 3 h, 6 h, 12 h by TUNEL in skeletal muscle indicated that hypoxia could quickly affect muscle growth and development. Furthermore, we concluded that the Egr2-FasL-Fas signal pathway, which was located at the upstream of apoptotic executor protein caspases, was related to the apoptosis by quantitative real-time PCR, protein concentration detection in ELISA and double gene in situ hybridization methods. The mechanism of the pathway was researched in transcription regulation and epigenetic modification by dual-luciferase reporter assay and bisulfite modified method, respectively. Egr2, as a transcription factor, could up-regulate the expression of FasL gene. And its binding site was mainly between −479 to −1 of FasL gene promoter. The 5th CpG dinucleotides (−514) methylation levels in FasL gene were significantly affected by hypoxia, and they were negatively correlated with its expressions. These suggested that the −514 site may be a very important site to regulate the FasL gene expression. Above results, we concluded that hypoxia activated the immune related signal pathway Egr2-FasL-Fas to induced skeletal muscle apoptosis to affect growth and development of Japanese flounder. The study revealed the mechanism of hypoxia induced apoptosis, which could provide a reference for fish immunity and aquaculture management.

Fas cell surface death receptor/Fas ligand genetic variants in gastric cancer patients: A case-control study.

Various studies have suggested a correlation between Fas cell surface death receptor/Fas ligand (FAS/FASL) variants and multiple types of cancers. The present study aimed to investigate the association between FAS-670A/G and FASL-844C/T and the synergistic effects of both variants on the risk of gastric cancer (GC) in the Kurdish population of west of Iran. This study was conducted by polymerase chain reaction-restriction fragment length polymorphism technique using MvaI and BsrDI restriction enzymes in 98 GC patients and 103 healthy control individuals. According to the obtained results, a significant association (P=0.008) of FASL polymorphism among GC patients and the control group was detected. Furthermore, no significant differences were found in the FAS polymorphism frequencies between GC patients and the control group. Codominant and dominant models in FASL polymorphism showed significant protective effects against GC [odds ratio (OR)=0.307, 95% confidence interval (CI) (0.134-0.705), P=0.005; OR=0.205, 95% CI (0.058-0.718), P=0.013 and OR=0.295, 95% CI (0.129-0.673), P=0.004 for models of codominant CC vs. CT, codominant CC vs. TT and dominant, respectively]. Furthermore, the presence of both FAS-670G and FASL-844T alleles represented a significant protective effect against GC occurrence [OR=0.420, 95% CI (0.181-0.975), P=0.043]. So far, we believe this is the first study, the results of which suggest that FASL gene variation and its synergistic effects with FAS gene could be associated with the risk of GC in the Kurdish population in the west of Iran.

E2f2 Attenuates Apoptosis of Activated T Lymphocytes and Protects from Immune-Mediated Injury through Repression of Fas and FasL.

Targeted disruption of E2f2 in mice causes T-cell hyperactivation and a disproportionate cell cycle entry upon stimulation. However, E2f2−/− mice do not develop a lymphoproliferative condition. We report that E2f2 plays a Fas-dependent anti-apoptotic function in vitro and in vivo. TCR-stimulated murine E2f2−/− T cells overexpress the proapoptotic genes Fas and FasL and exhibit enhanced apoptosis, which is prevented by treatment with neutralizing anti-FasL antibodies. p53 pathway is activated in TCR-stimulated E2f2−/− lymphocytes, but targeted disruption of p53 in E2f2−/− mice does not abrogate Fas/FasL expression or apoptosis, implying a p53-independent apoptotic mechanism. We show that E2f2 is recruited to Fas and FasL gene promoters to repress their expression. in vivo, E2f2−/− mice are prone to develop immune-mediated liver injury owing to an aberrant lymphoid Fas/FasL activation. Taken together, our results suggest that E2f2-dependent inhibition of Fas/FasL pathway may play a direct role in limiting the development of immune-mediated pathologies.