Interactions between Fkh1 monomers stabilize its binding to DNA replication origins.

Eukaryotic DNA replication is initiated from multiple genomic origins, which can be broadly categorized as firing early or late in the S phase. Several factors can influence the temporal usage of origins to determine the timing of their firing. In budding yeast, the Forkhead family proteins Fkh1 and Fkh2 bind to a subset of replication origins and activate them at the beginning of the S phase. In these origins, the Fkh1/2 binding sites are arranged in a strict configuration, suggesting that Forkhead factors must bind the origins in a specific manner. To explore these binding mechanisms in more detail, we mapped the domains of Fkh1 that were required for its role in DNA replication regulation. We found that a short region of Fkh1 near its DNA binding domain was essential for the protein to bind and activate replication origins. Analysis of purified Fkh1 proteins revealed that this region mediates dimerization of Fkh1, suggesting that intramolecular contacts of Fkh1 are required for efficient binding and regulation of DNA replication origins. We also show that the Sld3-Sld7-Cdc45 complex is recruited to Forkhead-regulated origins already in the G1 phase and that Fkh1 is constantly required to keep these factors bound on origins before the onset of the S phase. Together, our results suggest that dimerization-mediated stabilization of DNA binding by Fkh1 is crucial for its ability to activate DNA replication origins.

Genome-wide aggregated trans-effects on risk of type 1 diabetes: A test of the "omnigenic" sparse effector hypothesis of complex trait genetics.

The "omnigenic" hypothesis postulates that the polygenic effects of common SNPs on a typical complex trait are mediated through trans-effects on expression of a relatively sparse set of effector ("core") genes. We tested this hypothesis in a study of 4,964 cases of type 1 diabetes (T1D) and 7,497 controls by using summary statistics to calculate aggregated (excluding the HLA region) trans-scores for gene expression in blood. From associations of T1D with aggregated trans-scores, nine putative core genes were identified, of which three-STAT1, CTLA4 and FOXP3-are genes in which variants cause monogenic forms of autoimmune diabetes. Seven of these genes affect the activity of regulatory T cells, and two are involved in immune responses to microbial lipids. Four T1D-associated genomic regions could be identified as master regulators via trans-effects on gene expression. These results support the sparse effector hypothesis and reshape our understanding of the genetic architecture of T1D.

Association study to evaluate Foxo1 and Foxo3 gene polymorphisms in polycystic ovary syndrome: a preliminary case-control study and in silico analysis.

BACKGROUND: Polycystic ovary syndrome (PCOS) is known as a multifactorial and multi-gene-mediated endocrine disorder among women of reproductive age. FoxO1 and FoxO3 are members of the forkhead transcriptional factors family that play a pivotal role in the function of ovaries. The current work is aimed at investigating the association between gene variants of FoxO1 and FoxO3 and the risk of PCOS in a sample of the Iranian population. METHODS AND RESULTS: We recruited 200 women diagnosed with PCOS and 200 healthy women. Both polymerase PCR-RFLP and ARMS-PCR methods were used for genotyping. Sanger sequencing was recruited to confirm the genotyping results. The T allele of rs17592236 and the C allele of rs12585277 decreased PCOS risk by 29 and 28%, respectively. In contrast, the C allele of rs2253310 and G allele of rs2802292 increased the risk of PCOS by 1.39 and 1.63 folds, correspondingly. Bioinformatics results showed that some genes, including matrix metallopeptidase 9 (MMP-9), phosphoinositide-3-Kinase Regulatory Subunit 224 1 (PIK3R1), peroxisome proliferator-activated receptor Gamma (PPARG), and glycogen synthase 225 kinase-3 beta (GSK-3 beta) have significant interactions with FoxO1, suggesting that FoxO1 might have crucial roles in regulating different signaling pathways in ovarian cells. CONCLUSION: We found that FoxO1 rs17592236C > T and rs12585277C > T had a protective role against PCOS, while FoxO3 rs2253310C > G and rs2802292G > T  enhanced the risk of this metabolic disorder in our population. Additional studies on larger populations with varying races are needed to confirm these findings.

Efficacy of active ingredients in Qingdai on ulcerative colitis: a network pharmacology-based evaluation.

OBJECTIVE: To elucidate the protective effect of Qingdai (, QD) on ulcerative colitis (UC) by means of and approaches. METHODS: A systems pharmacology analysis was per-formed to predict the active components of QD whereas the putative biological targets of QD against UC were obtained through target fishing, network cons-truction and enrichment analyses. Meanwhile, we examined the ameliorative effect of QD in a mouse model of dextran sulfate sodium (DSS)-induced colitis. During the 10-day experiment, the control and diseased mice were given with oral gavages of QD (1.3 g raw herbs·kg·d) or 5-aminosalicylic acid (5-ASA, 100 mg·kg·d) every day. The underlying pharma-cological mechanisms of QD in UC were determined using polymerase chain reaction tests, histological staining, enzyme-linked immunoassays, and Western blotting analysis. RESULTS: Searching from various network pharmacology databases, 29 compounds were identified in QD. According to the screening criteria suggested by TCMSP (i.e. OB ≥ 30% and DL ≥ 0.18), nine of them were considered the active ingredients that contribute to the ameliorative effects of QD on different mouse models of colitis. Most importantly, the protective effect of QD on DSS-induced colitis was significantly associated with modulations of the expression levels of glycogen synthase kinase 3-ß (Gsk3-ß) and forkhead box p3 (Foxp3), which are widely considered as important regulators of excessive inflammatory responses. CONCLUSIONS: The results of this study provide solid scientific evidence for the use of QD or its core active components in the clinical management of UC.

Wenshen Yangxue decoction promotes follicular development in aged female mice stimulation of the silent information regulator 3/forkhead transcription factor O1 3a pathway.

OBJECTIVE: To primarily explore the effect and mechanism of Wenshen Yangxue decoction in promoting follicular development in elderly female mice. METHODS: Fifty Institute of Cancer Research mice were randomly divided into blank, controlled ovarian hyperstimulation (COH), low-dose Wenshen Yangxue decoction, medium-dose Wenshen Yangxue decoction, and high-dose Wenshen Yangxue decoction groups, with 10 mice in each group. The number of ovulations, number of fertilizations, mitochondrial adenosine triphosphate (ATP) level, and mitochondrial DNA (mtDNA) of oocytes in each group were compared. Reverse transcription-polymerase chain reaction and Western blotting were used to detect the mRNA and protein expression levels of silent information regulator 3 (Sirt3) and forkhead transcription factor O1 3a (FOXO3a). RESULTS: Wenshen Yangxue decoction significantly increased the number of ovulations in mice (P < 0.05) and promoted the formation of fertilized eggs. The ATP level and mtDNA copy number of mice oocytes in the high-dose groups were significantly higher than those in the COH group (P < 0.05). Wenshen Yangxue decoction significantly increased the mRNA and protein levels of Sirt3 and FOXO3a in mouse oocytes. CONCLUSION: Wenshen Yangxue decoction promoted the development of follicles in elderly female mice, increased the number of ovulations and improved fertility. Its mechanism may be related to increased mitochondrial energy metabolism and regulation of the Sirt3/FOXO3a pathway.

Unveiling Forkhead-mediated regulation of yeast cell cycle and metabolic networks.

Transcription factors are regulators of the cell's genomic landscape. By switching single genes or entire molecular pathways on or off, transcription factors modulate the precise timing of their activation. The Forkhead (Fkh) transcription factors are evolutionarily conserved to regulate organismal physiology and cell division. In addition to molecular biology and biochemical efforts, genome-wide studies have been conducted to characterize the genomic landscape potentially regulated by Forkheads in eukaryotes. Here, we discuss and interpret findings reported in six genome-wide Chromatin ImmunoPrecipitation (ChIP) studies, with a particular focus on ChIP-chip and ChIP-exo. We highlight their power and challenges to address Forkhead-mediated regulation of the cellular landscape in budding yeast. Expression changes of the targets identified in the binding assays are investigated by taking expression data for Forkhead deletion and overexpression into account. Forkheads are revealed as regulators of the metabolic network through which cell cycle dynamics may be temporally coordinated further, in addition to their well-known role as regulators of the gene cluster responsible for cell division.

Regulation of mitochondrial function by forkhead transcription factors.

Mitochondria play a central role in several important cellular processes such as energy production, apoptosis, fatty acid catabolism, calcium regulation, and cellular stress response. Multiple nuclear transcription factors have been reported for their role in the regulation of mitochondrial gene expression. More recently, the role of the forkhead family of transcription factors in various mitochondrial pathways has been reported. Among them, FOXO1, FOXO3a, FOXG1, and FOXM1 have been reported to localize to the mitochondria, of which the first two have been observed to bind to the mitochondrial D-loop. This suggests an important role for forkhead transcription factors in the direct regulation of the mitochondrial genome and function. Forkheads such as FOXO3a, FOXO1, and FOXM1 are involved in the cellular response to oxidative stress, hypoxia, and nutrient limitation. Several members of the forkhead family of transcription factors are also involved in the regulation of nuclear-encoded genes associated with the mitochondrial pathway of apoptosis, respiration, mitochondrial dynamics, and homeostasis.

Resveratrol protects against interleukin-1β-induced chondrocyte injury by regulating the silent information regulator 1/frame transcription factor O1 pathway / 中华风湿病学杂志

Objective:To study the effect of resveratrol (RES) on interleukin-1β (IL-1β)-induced chondrocytes and its pathways of action.Methods:Wistar mammary rat chondrocytes were extracted and divided into 5 groups: control group, IL-1β group, RES+IL-1β group, RES+IL-1β+EX-527 [silent information regulator 1 (SIRT1) inhibitor] group and RES+IL-1β+AS [frame transcription factor O1 (FOXO1) inhibitor] group. Quantitative real time polymerase chain reaction (qRT-PCR) was used to detect SIRT1, forkhead FOXO1 and matrix metalloproteinase 3 (MMP-3) mRNA expression. Protein expression of chondrocyte type Ⅱ collagen (Col-Ⅱ) detected by immunofluorescence, and the expression of chondrocyte SIRT1 and p-FOXO1/FOXO1 was measured by Western blot. The expression of chondrocyte inflammatory factors IL-6 and TNF-α was measured by enzyme-linked immunosorbent assay. One-way analysis of variance (ANOVA) was performed and two-way comparisons between groups were made using the least significant difference (LSD) method. P< 0.001 was statistically significant. Results:Compared to normal chondrocytes, the mRNA and protein expressions of Col-Ⅱ, SIRT1, FOXO1 and p-FOXO1/FOXO1 in chondrocytes induced by IL-1β was significantly decreased ( P<0.001). The secretion of tumor necrosis factor (TNF)-α [(24.70±2.84), t=19.24, P<0.001] and IL-6 [(3.35±0.28), t=12.97, P<0.001] was significantly increased, and the mRNA expression of MMP-3 [(2.46± 0.23), t=12.61, P<0.001] was significantly increased. The mRNA and protein expressions of Col-Ⅱ, SIRT1, FOXO1 and p-FOXO1/FOXO1 were significantly increased. The secretion of TNF-α [(12.60±1.05), t=10.14, P<0.001] and IL-6 [(2.00±0.15), t=9.89, P<0.001] was significantly reduced by RES treated IL-1β-induced chondrocytes. mRNA expression of MMP-3 [(1.30±0.14), t=10.460, P<0.001] was decreased. After adding SIRT1 inhibitor EX-527 or FOXO1 inhibitor AS, RES significantly reduced the mRNA and protein expression of Col-Ⅱ, SIRT1, FOXO1 and p-FOXO1/FOXO1 in IL-1β-induced chondrocytes ( P<0.001). The secretion of TNFα and IL-6 was significantly decreased ( P<0.001), and the mRNA expression of MMP-3 was significantly decreased ( P<0.001). Conclusion:RES significantly ameliorates IL-1β-induced cartilage extracellular matrix egradation and inflammatory responses via the SIRT1/FOXO1 pathway.

Effects of long non-coding RNA FAM224A on the proliferation and migration of ovarian cancer cells by regulating the expression of miRNA-590-3p / 肿瘤研究与临床

Objective:To explore the effects of long non-coding RNA (lncRNA) FAM224A on the proliferation and migration of ovarian cancer cells by regulating the expression of miRNA-590-3p (miR-590-3p).Methods:Human ovarian cancer cell lines OC3, SKOV-3, HO-8910, A2780 and human normal ovarian epithelial cell line IOSE80 were selected, and the relative expression of FAM224A in each cell line was detected by real-time quantitative polymerase chain reaction (qRT-PCR). The cell line with the lowest relative expression level of FAM224A was screened for follow-up experiment. The cells were divided into FAM224A group (transfected with FAM224A mimic gene) and control group (transfected with control mimic gene). CCK-8 method and cell scratch test were used to detect the cell proliferation and migration ability of the two groups. The bioinformatics website LncBase v.2 predicted that the target gene that FAM224A might complementarily bind to was miR-590-3p. qRT-PCR was used to detect the relative expression levels of miR-590-3p and forkhead box protein A2 (FOXA2) mRNA, and the expressions of related proteins were detected by Western blot.Results:The relative expression levels of FAM224A in ovarian cancer cell lines OC3, SKOV-3, HO-8910, A2780 and normal ovarian epithelial cell line IOSE80 were 0.23±0.04, 0.65±0.05, 0.45±0.03, 0.63±0.08 and 1.02±0.11, respectively, and the difference was statistically significant ( F = 14.78, P < 0.01), and the cell line with the lowest relative expression level of FAM224A was OC3. The results of CCK-8 method showed that the proliferation ability of OC3 cells in the FAM224A group was lower than that in the control group on the 2nd, 3rd, 4th and 5th day of culture (all P < 0.05). The scratch healing rates of OC3 cells in the FAM224A group and the control group were (18.6±2.3)% and (71.7±7.2)%, respectively, and the difference was statistically significant ( t = 6.99, P < 0.01). The relative expression levels of FAM224A in OC3 cells in the FAM224A group and the control group was 12.36±1.45 and 1.14±0.24, respectively ( t = 13.08, P < 0.01); the relative expression levels of miR-590-3p were 0.19±0.06 and 1.04±0.20, respectively ( t = 4.01, P < 0.01); the relative expression levels of FOXA2 mRNA were 6.37±1.37 and 1.05±0.08, respectively ( t = 3.86, P < 0.01). Compared with the control group, the expression of FOXA2 protein in OC3 cells in the FAM224A group was increased, the expressions of cell proliferation protein cyclin-dependent kinase 2 (CDK2) and cyclin D3 were decreased, and the expression of cell migration protein Snail was decreased. Conclusions:FAM224A is low expressed in ovarian cancer cell lines. FAM224A reduces the proliferation and migration ability of ovarian cancer OC3 cells by inhibiting the expression of miR-590-3p.

Role of the Forkhead Transcription Factors Fd4 and Fd5 During Drosophila Leg Development.

Appendage development requires the coordinated function of signaling pathways and transcription factors to pattern the leg along the three main axes: the antero-posterior (AP), proximo-distal (PD), and dorso-ventral (DV). The Drosophila leg DV axis is organized by two morphogens, Decapentaplegic (Dpp), and Wingless (Wg), which direct dorsal and ventral cell fates, respectively. However, how these signals regulate the differential expression of its target genes is mostly unknown. In this work, we found that two members of the Drosophila forkhead family of transcription factors, Fd4 and Fd5 (also known as fd96Ca and fd96Cb), are identically expressed in the ventro-lateral domain of the leg imaginal disc in response to Dpp signaling. Here, we analyze the expression regulation and function of these genes during leg development. We have generated specific mutant alleles for each gene and a double fd4/fd5 mutant chromosome to study their function during development. We highlight the redundant role of the fd4/fd5 genes during the formation of the sex comb, a male specific structure that appears in the ventro-lateral domain of the prothoracic leg.

Nicotinamide as a Foundation for Treating Neurodegenerative Disease and Metabolic Disorders.

Neurodegenerative disorders impact more than one billion individuals worldwide and are intimately tied to metabolic disease that can affect another nine hundred individuals throughout the globe. Nicotinamide is a critical agent that may offer fruitful prospects for neurodegenerative diseases and metabolic disorders, such as diabetes mellitus. Nicotinamide protects against multiple toxic environments that include reactive oxygen species exposure, anoxia, excitotoxicity, ethanolinduced neuronal injury, amyloid (Aß) toxicity, age-related vascular disease, mitochondrial dysfunction, insulin resistance, excess lactate production, and loss of glucose homeostasis with pancreatic ß-cell dysfunction. However, nicotinamide offers cellular protection in a specific concentration range, with dosing outside of this range leading to detrimental effects. The underlying biological pathways of nicotinamide that involve the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), the mechanistic target of rapamycin (mTOR), AMP activated protein kinase (AMPK), and mammalian forkhead transcription factors (FoxOs) may offer insight for the clinical translation of nicotinamide into a safe and efficacious therapy through the modulation of oxidative stress, apoptosis, and autophagy. Nicotinamide is a highly promising target for the development of innovative strategies for neurodegenerative disorders and metabolic disease, but the benefits of this foundation depend greatly on gaining a further understanding of nicotinamide's complex biology.

Forkhead Transcription Factors in Health and Disease.

Forkhead box (FOX) proteins belong to an evolutionarily conserved family of transcription factors that has evolved by gene/genome duplication. FOX family members have undergone sequence and regulatory diversification. However, they have retained some degree of functional redundancy, in addition to playing specific roles, both during development and in the adult. Genetic alterations or misregulation of FOX genes underlie human genetic diseases, cancer, and/or aging. In this review, we provide an updated overview of the main characteristics of the members of this family, in terms of breadth of expression, protein domain composition, evolution, and function.

miR-142-5p target regulation of forkhead transcription protein O subfamily 3 mediateing helper T cell 17 cell inflammation reaction promotes the development of autoimmune uveitis / 中华眼底病杂志

Objective:To observe the expression of miR-142-5p and forkhead transcription protein O subgroup 3 (FOXO3) in CD4 + T cells of experimental autoimmune uveitis (EAU) model rats, and preliminarily explore the targeting relationship between the two and the effect on EAU impact. Methods:Ten Lewis rats were randomly divided into model group and control group. Rats in the model group wree induced an EAU animal model by adoptive immunization. Twenty days after immunization, CD4 + T cells were extracted from the eyeballs and draining lymph nodes of rats in the control group and model group, and divided into control group, model group, mimic-negative control (NC) group, miR-142-5p-mimic group, and small interference (si)-NC group, si-FOXO3 group for in vitro experiments. The miR-142-5p-mimic group and si-FOXO3 group were transfected with miR-142-5p-mimic and si-FOXO3, respectively. Twenty-five Lewis rats were randomly divided into model group, mimic-NC transfected group, miR-142-5p-mimic transfected group, si-NC transfected group, and si-FOXO3 transfected group. The above-mentioned in vitro experimental groups were injected with cells respectively. Slit lamp microscopy and EAU score were performed on 4, 8, 12, 16, 20 days after immunization; on 20 days after immunization, hematoxylin-eosin staining was performed for histopathological grading. Real-time fluorescence quantitative polymerase chain reaction was used to detect the relative expression of miR-142- 5p and FOXO3 mRNA in CD4 + T cells and eye tissues of rats in each group, and helper T cell 17 (Th17) marker interleukin (IL)-17, IL-22, retinoic acid-related orphan receptor gamma (ROR gamma) relative expression level in the supernatant. Bioinformatics website and dual luciferase was used to predict the targeting relationship between miR-142-5p and FOXO3. One-way analysis of variance or t test was used for comparison between groups. Results:All rats in the model group showed symptoms of EAU to varying degrees, and the symptoms became worse with time. Compared with the control group, the relative expression of miR-142-5p mRNA in CD4 + T cells of the model group increased, and the relative expression of FOXO3 mRNA decreased. The differences were statistically significant ( t=7.374, 10.423; P=0.002, 0.001). Compared with the mimic-NC group, the relative expression of miR-142-5p mRNA in the CD4 + T cells of the miR-142-5p-mimic group increased, and the difference was statistically significant ( t=6.540, P=0.003). Compared with the model group, mimic-NC group, and si-NC group, the relative expression of IL-17, IL-22, and RORγ mRNA in CD4 + T cells in the miR- 142-5p-mimic group and si-FOCO3 group increased significantly. The difference was statistically significant ( F=26.110, 6.292, 5.269, 55.660, 10.490, 11.430; P<0.05). Compared with the mimic-NC transfected group, the relative expression of miR-142-5p mRNA in the ocular tissues of the miR-142-5p-mimic transfected rats increased significantly, and the difference was statistically significant ( t=6.690, P<0.05). Compared with the transfected si-NC group, the relative expression of FOXO3 mRNA in the eye tissue of the transfected si-FOXO3 group was significantly decreased, and the difference was statistically significant ( t=17.751, P<0.05). Rats in the mimic-NC transfected group, miR-142-5p-mimic transfected group, si-NC transfected group, and si-FOXO3 transfected group prolonged with time after immunization, and the EAU scores showed an upward trend. The EAU score and histopathological grade of rats in the miR-142-5p-mimic transfected group were higher than those in the mimic-NC transfected group, and the difference was statistically significant ( t=5.633, 6.286; P<0.05). The EAU score and histopathological grade of the rats in the transfected si-FOXO3 group were higher than those in the transfected si-NC group, and the difference was statistically significant ( t=6.852, 6.635; P<0.05). FOXO3 has a targeting relationship with miR-142-5p. Conclusions:In EAU rat CD4 + T cells, the expression of miR-142-5p is up-regulated, while the expression of FOXO3 is down-regulated. miR-142-5p targets the expression of FOXO3 to promote the development of Th17 cell-related inflammatory factors.

Expression and clinical significance of forkhead transcription factor O1 in diffuse large B-cell lymphoma / 白血病·淋巴瘤

Objective:To investigate the correlation of the expression of forkhead transcription factor O1 (FOXO1) with clinicopathological features and the prognosis in patients with diffuse large B-cell lymphoma (DLBCL).Methods:The data of 42 patients newly diagnosed with DLBCL in Hebei General Hospital admitted from June 2012 to January 2020 were collected. The expressions of FOXO1, phosphorylated FOXO1 (p-FOXO1) in DLBCL tissues were detected by using immunohistochemistry. The association of FOXO1 expression with clinicopathological features and the prognosis in DLBCL patients was retrospectively analyzed.Results:The positive rate of FOXO1 was 42.9% (18/42) and the positive rate of p-FOXO1 was 28.6% (12/42) in DLBCL tissues. There were no statistically significant differences in the positive rates of FOXO1 and p-FOXO1 among patients stratified by gender, age, Ann Arbor staging, immunophenotype, Eastern Cooperative Oncology Group score, lactate dehydrogenase, international prognostic index, β 2-microglobulin (β 2-MG) and primary sites (all P > 0.05). The positive rate of FOXO1 in patients with non-B symptoms was higher than that in those with B symptoms [53.6% (15/28) vs. 21.4% (3/14), χ2=3.938, P=0.047], and there was no statistically significant difference in the positive rate of p-FOXO1 among patients with or without B symptoms ( P > 0.05). The 2-year overall survival (OS) rate in FOXO1 positive group was higher than that in FOXO1 negative group (90.9% vs. 66.7%), the 2-year OS rate in p-FOXO1 positive group was lower than that in p-FOXO1 negative group (50.0% vs. 85.0%), and the differences were not statistically significant (all P > 0.05). Among patients without B symptoms, the 2-year OS rate in FOXO1 positive group was higher than that in FOXO1 negative group (100.0% vs. 50.0%, χ2=5.486, P=0.019). Among patients with primary lymph node, elevated β 2-MG and non-B symptoms, the 2-year OS rate in p-FOXO1 negative expression group was higher than that in p-FOXO1 positive group (100.0% vs. 50.0%, 100.0% vs. 25.0%, 91.7% vs. 33.3%), and the differences were statistically significant (all P < 0.05). Conclusions:FOXO1 may be involved in the development and progression of DLBCL, and FOXO1 positive expression may indicate the good prognosis of patients. These results suggest that p-FOXO1 positive expression may be related with poor prognosis.

Expression and clinical significance of forkhead box A2 and forkhead box J2 in hepatocellular carcinoma / 临床肝胆病杂志

ObjectiveTo investigate the expression levels of forkhead box A2 (FOXA2) and forkhead box J2 (FOXJ2) in hepatocellular carcinoma (HCC) tissue and the association of FOXA2 and FOXJ2 with HCC. MethodsClinical data and pathological tissue samples were collected from 54 patients with pathologically confirmed HCC in The First Affiliated Hospital of Henan University of Traditional Chinese Medicine from January 2014 to July 2019. The immunohistochemical SP method was used to measure the protein expression levels of FOXA2 and FOXJ2 in HCC tissue, and their association with HCC-related clinicopathological features and patient prognosis was analyzed. The chi-square test and the adjusted chi-square test were used for comparison of categorical data; a Spearman correlation analysis was performed to investigate the correlation between the expression of FOXA2 and FOXJ2; the Kaplan-Meier method was used for survival analysis; Image-Pro Plus was used to perform the semi-quantitative analysis of the expression of FOXA2 and FOXJ2; the Wilcoxon rank-sum test was used for comparison between groups. ResultsThe positive rates of the protein expression of FOXA2 and FOXJ2 in HCC tissue were 70.37% (38/54) and 75.92% (41/54), respectively, and there was a significant positive correlation between the expression levels of FOXA2 and FOXJ2 (rs=0.648, P＜0.001). In both negative and positive groups, the expression level of FOXA2 was associated with tumor diameter, degree of tumor differentiation, number of tumors, and alpha-fetoprotein (χ2=5.440, 4.113, 4.352, and 3.865, P=0.020, 0.043, 0037, and 0.049), and the expression level of FOXJ2 was associated with the degree of tumor differentiation (χ2=9.267, P=0.002). The group with positive expression of FOXA2 and FOXJ2 had a significantly higher cumulative survival rate than the group with negative expression of FOXA2 and FOXJ2 (P＜0.01). ConclusionThe expression levels of FOXA2 and FOXJ2 are associated with the development, progression, and prognosis of HCC, and they have a synergistic effect in the development and progression of HCC.

Mechanism of action of forkhead box transcription factors in hepatocellular carcinoma and their prospects as treatment targets / 临床肝胆病杂志

Hepatocellular carcinoma (HCC) is one of the most common malignant cancers and has high incidence and mortality rates and poor prognosis. Forkhead box (FOX) transcription factor family can regulate cell growth, differentiation, and tissue development and plays an important role in tumor. This article reviews the association of the molecular expression of the FOX family with the development, progression, and prognosis of HCC and analyzes the mechanism of action of FOX in the progression of HCC. It is pointed out that FOX family is expected to become a new target for HCC treatment.

CD25+ FOXP3+ and CD4+ CD25+ cells distribution in decidual departments of women with severe and mild pre-eclampsia: Comparison with healthy pregnancies.

PROBLEM: The aim of this study was to quantify and compare the distribution of regulatory CD25+ FOXP3+ and activated CD4+ CD25+ T cells in decidua basalis and parietalis of severe and mild pre-eclampsia (PE) to normal healthy pregnancies. METHOD OF STUDY: Decidual tissue (decidua basalis and parietalis) of 13 women with mild PE, 15 women with severe PE, and 19 women with healthy term pregnancies were analyzed by immunohistochemistry and double immunofluorescence. RESULTS: The total number of CD25+ FOXP3+ cells/mm2 in decidua basalis was decreased in the severe and mild PE versus normal pregnancy group. The total number of CD4+ CD25+ cells/mm2 in decidua basalis was decreased in the severe PE versus normal pregnancy group. The number of CD25+ FOXP3+ and CD4+ CD25+ cells in decidua parietalis was decreased in both PE groups. CONCLUSION: Our data suggest that immunological changes of PE reflect on decidua basalis and parietalis and emphasize the importance of characterizing T cells in both decidual departments.

Prospects and Perspectives for WISP1 (CCN4) in Diabetes Mellitus.

The prevalence of diabetes mellitus (DM) continues to increase throughout the world. In the United States (US) alone, approximately ten percent of the population is diagnosed with DM and another thirty-five percent of the population is considered to have prediabetes. Yet, current treatments for DM are limited and can fail to block the progression of multi-organ failure over time. Wnt1 inducible signaling pathway protein 1 (WISP1), also known as CCN4, is a matricellular protein that offers exceptional promise to address underlying disease progression and develop innovative therapies for DM. WISP1 holds an intricate relationship with other primary pathways of metabolism that include protein kinase B (Akt), mechanistic target of rapamycin (mTOR), AMP activated protein kinase (AMPK), silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), and mammalian forkhead transcription factors (FoxOs). WISP1 is an exciting prospect to foster vascular as well as neuronal cellular protection and regeneration, control cellular senescence, block oxidative stress injury, and maintain glucose homeostasis. However, under some scenarios WISP1 can promote tumorigenesis, lead to obesity progression with adipocyte hyperplasia, foster fibrotic hepatic disease, and lead to dysregulated inflammation with the progression of DM. Given these considerations, it is imperative to further elucidate the complex relationship WISP1 holds with other vital metabolic pathways to successfully develop WISP1 as a clinically effective target for DM and metabolic disorders.

Macrophage-Derived Exosomal Mir-155 Regulating Cardiomyocyte Pyroptosis and Hypertrophy in Uremic Cardiomyopathy.

miR-155 was synthesized and loaded into exosomes in increased infiltration of macrophages in a uremic heart. The released exosomal fusion with the plasma membrane leads to the release of miR-155 into the cytosol and translational repression of forkhead transcription factors of the O class (FoxO3a) in cardiomyocytes. Finally, macrophage-derived miR-155-containing exosomes promoted cardiomyocyte pyroptosis and uremic cardiomyopathy changes (cardiac hypertrophy and fibrosis) by directly targeting FoxO3a in uremic mice.

High expression of forkhead box M1 (FOXM1) is a poor prognostic biomarker in lung adenocarcinoma.

BACKGROUND: Forkhead box M1 (FOXM1) is closely related to the formation and development of cancer. Because of differences in cellular origin, lung adenocarcinoma (ADC) and lung squamous cell carcinoma (SCC) usually exhibit different signatures. Therefore, it is essential to investigate the abnormalities of FOXM1 in the two subtypes separately. METHODS: Through the Oncomine and TCGA databases, we investigated the expression of FOXM1 mRNA, its prognostic value and possible mechanisms leading to its dysregulation. Furthermore, networks involving FOXM1 and its significantly altered neighboring genes were identified using the cBioPortal database. GO and KEGG enrichment analyses were performed using DAVID. RESULTS: Expression of FOXM1 mRNA was higher in lung tumor tissues than in normal tissues, and higher in SCC tissues than in ADC tissues. FOXM1 mRNA expression was correlated with N stage, TNM stage, age, sex and smoking history in ADC, but only correlated with N stage, age and sex in SCC. Survival analysis indicated that high expression of FOXM1 mRNA resulted to poor overall survival (OS) for ADC patients, but not for SCC patients. Cox regression analysis confirmed that FOXM1 mRNA expression was an independent prognostic indicator for ADC patients, and regression analysis identified a moderately positive correlation between FOXM1 mRNA levels and copy number alterations (CNAs), but a weakly negative association with DNA methylation. FOXM1 was mainly involved in cell cycle regulation, G2/M transition, G1/S transition and p53, PI3K-Akt and TGF-beta signaling pathway. CONCLUSIONS: High expression of FOXM1 mRNA might be an independent biomarker of poor OS in ADC patients.