NLRP13 inflammasome complex is hypermethylated in familial Mediterranean fever and global methylation correlates with the disease severity.

Familial Mediterranean fever (FMF) is an autoinflammatory disease caused by variations in the MEFV gene, which encodes the pyrin protein, a member of the inflammasomes. Despite the complex pathogenesis of FMF, epigenetic changes also play roles in the disease progression. In our previous study, we observed a relationship between NLRP13, which is one of the members of the inflammasome complex and has a pyrin domain in its structure, and the MEFV gene using the STRING database. In this study, we examined NLRP13 expression and methylation status in 40 patients with FMF attack and 20 healthy individuals. We then investigated the global DNA methylation status of patients with FMF in the attack period and control groups. We further examined the relationship between the clinical manifestation and global methylation as well as NLRP13 gene expression of patients with FMF and healthy individuals. As a result, we showed that hypomethylation in patients with FMF leads to different clinical outcomes in terms of disease severity. In addition, the data indicated that NLRP13 inflammasome is epigenetically controlled in patients with FMF and the presence of amyloidosis may affect the hypermethylation of this gene. Moreover, NLRP13 was silenced because of the hypermethylation of the promoter. The increase of methylation level at the promoter region participated in the inactivation of NLRP13. In the current study, we not only found a new gene that plays a role in the pathogenesis of FMF disease, but also new evidence for the epigenetic regulation of the disease.

Combination treatment of bortezomib and epirubicin increases the expression of TNFRSF10 A/B, and induces TRAIL-mediated cell death in colorectal cancer cells.

Colorectal cancer is one of the most common cancers worldwide, affecting the colon and rectum. A major problem in the treatment of colorectal cancer is acquired chemoresistance, including resistance against death receptor-induced apoptosis. Therefore, investigating new biomarkers for the treatment of the disease and sensitization strategies against TRAIL might be of high clinical importance. TNFRSF10A/B are known as death receptors for TRAIL-induced apoptotic cell death. In this study, we used multiple bioinformatic tools and experimental analyses to investigate the role of TRAIL receptors TNFRSF10A and TNFRSF10B in colorectal cancer. We also identified the potential effect of bortezomib and epirubicin in the induction of TRAIL-mediated apoptotic cell death. Here, we showed that TNFRSF10 A/B expressions are upregulated in various tumor types, including COAD, and its high expression is decreased with the different clinicopathological parameters in COAD. We also found an association between TNFRSF10 A/B expression and tumor molecular subtypes. We further detected the association between the expression of TNFRSF10 A/B and immune cell tumor infiltration, including B cells, CD8+ T cells, neutrophils and dendritic cells. In addition, we showed that combining bortezomib and epirubicin treatment leads to the upregulation of TNFRSF10 A/B in colorectal cancer cells in vitro. The increase in the expression of death receptors was correlated with higher active caspase-3 levels following the incubation of cells with recombinant TRAIL protein, which is a ligand for TNFRSF10 A/B receptors. Our results suggest that TNFRSF10 A/B may be a marker to differentiate tumor molecular subtypes in colorectal cancer. The expression of TNFRSF10 A/B may be associated with the recruitment of immune cells into tumors and the development of tumor suppression. The combination of bortezomib and epirubicin treatment might sensitize colorectal cancer cells to TRAIL-induced apoptosis via the upregulation of death receptor.

The expression of O-linked glycosyltransferase GALNT7 in breast cancer is dependent on estrogen-, progesterone-, and HER2-receptor status, with prognostic implications.

GALNT7 is a glycosyltransferase enzyme transferring N-acetylgalactosamine to initiate O-linked glycosylation in the Golgi apparatus. Breast cancer is the most common cancer in women globally. Estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2; ERBB2) are important biomarkers in the prognosis and molecular subtyping of breast cancer. Here, we showed that ER-positive, PR-positive or HER2-positive breast tumors have higher expression of GALNT7 compared to ER-negative, PR-negative or HER2-negative breast tumors, respectively. We found that CpG-aggregated methylation of GALNT7 gene is decreased, and in parallel, its transcript levels are increased in breast cancer compared to healthy breast tissue. We observed that the difference in the expression of GALNT7 between negative and positive status of the receptors is the highest for HER2, followed by ER and PR, pointing that HER2 might be relatively more influential than ER and PR on the expression of GALNT7 in breast cancer. We reported that basal-like breast tumors have decreased expression of GALNT7 compared to non-basal-like tumors, and that high GALNT7 expression is associated with favorable relapse-free and distant metastasis-free survival in HER2 status-dependent manner in breast cancer patients. Moreover, we showed that GALNT7 expression in breast cancer is cell type- (epithelial vs stromal cells), tumor grade- and ethnicity-dependent. Combined, we propose that GALNT7 might contribute to different clinical outcomes depending on the receptor status in breast cancer, and that a better understanding of GALNT7 and its function in the context of breast cancer is needed.

Promoter Hypomethylation Upregulates ANXA2 Expression in Pancreatic Cancer and is Associated with Poor Prognosis.

Pancreatic cancer (PC) is one of the world's most aggressive and deadly cancers, owing to non-specific early clinical symptoms, late-stage diagnosis, and poor survival. Therefore, it is critical to identify specific biomarkers for its early diagnosis. Annexin A2 (ANXA2) is a calcium-dependent phospholipid-binding protein that has been reported to be upregulated in several cancer types, making it an emerging biomarker and potential cancer therapeutic target. However, the mechanism underlying the regulation of ANXA2 overexpression is still unclear. It is well established that genetic and epigenetic alterations may lead to widespread dysregulation of gene expression. Hence, in this study, we focused on exploring the regulatory mechanism of ANXA2 by investigating the transcriptional profile, methylation pattern, somatic mutation, and prognostic value of ANXA2 in PC using several bioinformatics databases. Our results revealed that the expression levels of ANXA2 were remarkably increased in PC tissues comparing to normal tissues. Furthermore, the high expression of ANXA2 was significantly related to the poor prognosis of PC patients. More importantly, we demonstrated for the first time that the ANXA2 promoter is hypomethylated in PC tissues compared to normal tissues which may result in ANXA2 overexpression in PC. However, more experimental research is required to corroborate our findings.

The influence of the host sex on parasitemia of parasite lineages belonging to Haemoproteus majoris in a natural bird community.

Immunological capability shows a sexual dimorphism in diverse animal species. Females are generally more immunocompetent than males, leading to the higher susceptibility of males to infection compared to females and thus greater infection-related pathology in males. These sex-differences in immunity remain understudied in birds. Here, we compared the percentage of parasitemia of three different parasite lineages belonging to the morphological species Haemoproteus majoris (namely, PARUS1, PHSIB1 and WW2) in terms of the sex of birds living in a natural community. We found that parasitemia (percentage of erythrocytes infected with parasites) of WW2 lineage, but not of the other two lineages of H. majoris, is higher in male birds compared to female birds. Similarly, we showed that the total parasitemia of these three H. majoris lineages is higher in male birds compared to female birds. Our study points out that male birds at the community level may be more susceptible to infection by certain parasites than female birds. We propose that sexual dimorphism in parasitemia of certain parasites in host birds might be more common than previously thought, similar to what is observed in other species, influencing host population dynamics in a sex-specific manner. Therefore, it can be speculated that infection by certain parasites might differentially affect male and female birds, possibly resulting in a bias in survival rates between sexes due to infections, in certain contexts.

Copy number and expression of CEP89, a protein required for ciliogenesis, are increased and predict poor prognosis in patients with ovarian cancer.

CEP89 (centrosomal protein 89) is required for ciliogenesis and mitochondrial metabolism, but its role in cancer has yet to be clarified. We report that CEP89 is overexpressed in ovarian cancer (OC) compared to normal ovaries. Likewise, its expression is higher in malignant ovarian tumors than in borderline ovarian tumors with low malignant potential. More than a quarter of patients with OC have copy number gains in the CEP89 gene, and patients with high expression have more than a year shorter overall survival compared to those with low expression. Moreover, we found that CEP89 can be considered as a prognostic marker for poor overall survival in patients with OC, after adjusting for tumor stage and residual tumor. Nine out of the top 10 protein interactors of CEP89 have the highest percentage of total copy number variation (CNV) events in OC among all other cancer types. Furthermore, CEP89 messenger RNA (mRNA) levels are higher in OC patients with disease recurrence compared to those with no recurrence. We also analyzed CEP89 levels in OC cell lines in terms of CNV, mRNA, and protein levels; and observed that the FUOV-1 cell line has the highest levels among cell lines that originated from primary sites. Our study suggests that CEP89 may be a valuable prognostic predictor for the overall survival of patients with OC, and it could also be a novel therapeutic target in this malignancy.

Involvement of ATMIN-DYNLL1-MRN axis in the progression and aggressiveness of serous ovarian cancer.

The loss of DYNLL1 contributes to chemoresistance in ovarian cancer. DYNLL1 binds to MRE11, a component of MRN complex (MRE11-RAD50-NBS1), and limits its function in homologous recombination (HR) repair in BRCA1-mutant cells. Decreased activity of MRE11 results in less HR-repair events and thus leads to higher sensitivity against DNA-damaging agents such as cisplatin. Therefore, a better understanding of the cellular changes in DYNLL1-MRN axis in ovarian cancer is needed. Here, we showed that DYNLL1 overexpression leads to decreased chemoresistance even in BRCA-proficient ovarian cancer cells. ATMIN, a transcriptional activator of DYNLL1, showed decreased expression; however, two components of MRN complex, MRE11 and NBS1 (NBN), showed increased expression in high grade compared to low grade serous ovarian cancer. We found that the components of MRN complex (MRE11-RAD50-NBS1) have higher protein levels in sites of omental metastasis and serous tubal intraepithelial carcinoma (STIC) compared to surrounding non-malignant stromal cells in patients with high grade serous ovarian cancer. We showed that the percentage of copy number variation (CNV) events in genes encoding ATMIN, DYNLL1, MRE11 and NBN are the highest in ovarian cancer among other cancer types. ATMIN and DYNLL1 genes are mostly characterized by copy number losses; however, CNV events in MRN complex components are mostly copy number gains. This study highlights the importance of ATMIN-DYNLL1-MRN axis in the development, progression and therapy response of ovarian cancer. MRN levels in ovarian cancer that differ from adjacent, non-malignant tissues may represent actionable therapeutic vulnerabilities.

Analysis of longevity in Chordata identifies species with exceptional longevity among taxa and points to the evolution of longer lifespans.

Animals have a considerable variation in their longevity. This fundamental life-history trait is shaped by both intrinsic and extrinsic mortality pressures, influenced by multiple parameters including ecological variables and mode-of-life traits. Here, we examined the distribution of maximum age at multiple taxonomic ranks (class, order and family) in Chordata, and identified species with exceptional longevity within various taxa. We used a curated dataset of maximum longevity of animals from AnAge database, containing a total of 2542 chordates following our filtering criteria. We determined shapes of maximum age distributions at class, order and family taxonomic ranks, and calculated skewness values for each distribution, in R programming environment. We identified species with exceptional longevity compared to other species belonging to the same taxa, based on our definition of outliers. We collected data on ecological variables and mode-of-life traits which might possibly contribute, at least in part, to the exceptional lifespans of certain chordates. We found that 23, 12 and 4 species have exceptional longevity when we grouped chordates by their class, order and family, respectively. Almost all distributions of maximum age among taxa were positively skewed (towards increased longevity), possibly showing the emergence of longer lifespans in contrast to shorter lifespans, through the course of evolution. However, potential biases in the collection of data should be taken into account. Most of the identified species in the current study have not been previously studied in the context of animal longevity. Our analyses point that certain chordates may have evolved to have longer lifespans compared to other species belonging to the same taxa, and that among taxa, outliers in terms of maximum age have always longer lifespans, not shorter. Future research is required to understand how and why increased longevity have arose in certain species.

A collective analysis of lifespan-extending compounds in diverse model organisms, and of species whose lifespan can be extended the most by the application of compounds.

Research on aging and lifespan-extending compounds has been carried out using diverse model organisms, including yeast, worms, flies and mice. Many studies reported the identification of novel lifespan-extending compounds in different species, some of which may have the potential to translate to the clinic. However, studies collectively and comparatively analyzing all the data available in these studies are highly limited. Here, by using data from the DrugAge database, we first identified top compounds in terms of their effects on percent change in average lifespan of diverse organisms, collectively (n = 1728). We found that, when data from all organisms studied were combined for each compound, aspirin resulted in the highest percent increase in average lifespan (52.01%), followed by minocycline (27.30%), N-acetyl cysteine (17.93%), nordihydroguaiaretic acid (17.65%) and rapamycin (15.66%), in average. We showed that minocycline led to the highest percent increase in average lifespan among other compounds, in both Drosophila melanogaster (28.09%) and Caenorhabditis elegans (26.67%), followed by curcumin (11.29%) and gluconic acid (5.51%) for D. melanogaster and by metformin (26.56%), resveratrol (15.82%) and quercetin (9.58%) for C. elegans. Moreover, we found that top 5 species whose lifespan can be extended the most by compounds with lifespan-extending properties are Philodina acuticornis, Acheta domesticus, Aeolosoma viride, Mytilina brevispina and Saccharomyces cerevisiae (211.80%, 76%, 70.26%, 55.18% and 45.71% in average, respectively). This study provides novel insights on lifespan extension in model organisms, and highlights the importance of databases with high quality content curated by researchers from multiple resources, in aging research.

Expression profiles of Natural Killer Group 2D Ligands (NGK2DLs) in colorectal carcinoma and changes in response to chemotherapeutic agents.

Colorectal cancer (CRC) is one of the most common cancers worldwide. Natural Killer Group 2D Receptor (NKG2D) and their ligands (NKG2DLs) play crucial roles in natural killer (NK) cell-mediated cytotoxicity. Tumorigeneses cause increased NKG2DLs expression on tumor cell surfaces, thereby these cells individually eliminated by NK cells. However, CRC cells can reduce their NKG2DL expression to escape from NK-mediated immune surveillance which is associated with poor prognosis. Therefore, previous studies suggest that up-regulation of NKG2DLs can contribute to promising NK cell-mediated immunotherapy strategies. We aimed to analyze NKG2DLs expression profiles in response to chemotherapeutic drugs and increased MHC class I polypeptide-related sequence A (MICA) expression, which is related to favorable prognosis in CRC, using low doses of bortezomib and epirubicin combination without causing direct cytotoxicity. Results showed that MICA expression  sligthly increased following drug treatment in the CRC cells but not for the normal cells. Also, we enriched our study with Gene Expression Omnibus (GEO) datasets including expression profiles of various NKG2DLs using in silico analyses. Accordingly, NKG2DL expression in CRC was screened in proportion to other cancers, histologic subtypes, TNM stages and metastatic samples to compare with our data. Overall, the analyzed data showed that NKG2DLs demonstrate different expression profiles in response to chemotherapeutic agents and a combination of low-dose bortezomib and epirubicin slightly increased MICA mRNA expression in CRC cell lines. However, performing further analysis of the combination therapy for MICA protein expression and studying its interaction with NK cells will make the results more meaningful.

A broad analysis in clinical and in vitro models on regulator of G-protein signalling 10 regulation that is associated with ovarian cancer progression and chemoresistance.

Ovarian cancer is one of the deadliest types of gynaecological cancers and more than half of the patients die within 5 years after diagnosis. Recurrence in advanced staged patients after chemotherapy is associated with increased chemoresistance, which results in poor prognosis. Regulator of G-protein signalling 10 (RGS10) negatively regulates cell proliferation, migration and survival by attenuating G-protein coupled-receptors mediated signalling pathways. Recent studies have shown that loss of RGS10 expression is significantly associated with proliferation and cisplatin resistance in ovarian cancer cells. SIGNIFICANCE OF THE STUDY: In this study, we analysed differential RGS10 expression levels using public microarray datasets from clinical and in vitro ovarian cancer samples. We validated that cancer progression and chemotherapy exposure change RGS10 expression. We enriched our study to evaluate the relationship between chemoresistance and differential RGS10 expression against ovarian cancer potential chemotherapeutic agent, palbociclib. Results showed that palbociclib treatment reduced cell viability, despite significantly decreased RGS10 expression in chemoresistant cells. Overall, the results confirmed that cancer progression and chemoresistance are significantly associated with the down-regulation of RGS10 while some chemotherapeutics seem to be beneficial in decreasing chemoresistance in ovarian cancer.

In silico analysis of DYNLL1 expression in ovarian cancer chemoresistance.

Ovarian cancer (OC) is the most lethal gynecological cancer and chemoresistance is responsible for the treatment failure and unfavorable clinical outcome in this disease. The deletion of DYNLL1 was reported to result in increased chemoresistance in BRCA1-mutant high-grade serous ovarian carcinoma cells. Considering its role in chemoresistance, a better understanding of DYNLL1 expression is needed to develop novel strategies in the treatment of OC. In the current study, we aimed to investigate the differential expression of DYNLL1 in OC with respect to cell types, chemosensitivity profiles, certain drug treatments, and cancer progression. DYNLL1 levels were analyzed using expression profiling data sets from Gene Expression Omnibus and quantitative reverse-transcription polymerase chain reaction in R. We found that the level of DYNLL1 was higher in OC histotypes compared with normal ovarian cells. DYNLL1 expression is decreased in OC cells of epithelial type; but, it is increased in OC cells of stromal type, compared with matched control cells. Chemoresistant OC cells were shown to have lower DYNLL1 expression than chemosensitive OC cells. Carboplatin and NSC319726 treatments resulted in slightly decreased DYNLL1 expression and DYNLL1 levels were decreased in the course of cancer progression in OC epithelial cells. The results suggest that changes in DYNLL1 expression in OC might be cell-type dependent and lower DYNLL1 levels may be associated with increased chemoresistance in OC. Although further studies are needed, certain drugs and cancer progression may lead to lower DYNLL1 levels, possibly resulting in increased chemoresistance. Therefore, it can be stated that DYNLL1 might be an important player in OC progression and chemoresistance.

DYNLL1 is hypomethylated and upregulated in a tumor stage- and grade-dependent manner and associated with increased mortality in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and cellular mechanisms regulating HCC pathogenesis and progression are not completely understood. DYNLL1 is essential for the development and expansion of MYC-driven B cell lymphoma, and also regulates genomic stability and responses to DNA-damaging chemotherapy in BRCA1-deficient tumors. However, the role and regulation of DYNLL1 has not been previously studied in the context of HCC. Here we report that DYNLL1 gene is hypomethylated and its expression is upregulated in HCC patients compared to healthy controls. The expression of DYNLL1 changes in a tumor grade- and stage-dependent manner in HCC. In this study, we further show that high DYNLL1 expression results in shorter overall and progression-free survival in hepatocellular carcinoma patients. Similar to DYNLL1, one of its protein interactors, RACK1, also shows decreased CpG-aggregated methylation and increased expression in HCC. RACK1 expression increases from early to late stage and from low to high grade in HCC. We found that high RACK1 expression is significantly associated with increased mortality of HCC patients. The present study shows that the epigenetic regulation of DYNLL1 and its consequent upregulation might be contributing to cancer development and progression in HCC. Its higher expression in late stage or high grade HCC may favor more aggressive disease as pointed by the increased mortality in high expression cohort. A better mechanistic understanding of the role of DYNLL1 in HCC will be needed to develop targeted treatment strategies in the future.

Regulator of G Protein Signaling 10 (Rgs10) Expression Is Transcriptionally Silenced in Activated Microglia by Histone Deacetylase Activity.

RGS10 has emerged as a key regulator of proinflammatory cytokine production in microglia, functioning as an important neuroprotective factor. Although RGS10 is normally expressed in microglia at high levels, expression is silenced in vitro following activation of TLR4 receptor. Given the ability of RGS10 to regulate inflammatory signaling, dynamic regulation of RGS10 levels in microglia may be an important mechanism to tune inflammatory responses. The goals of the current study were to confirm that RGS10 is suppressed in an in vivo inflammatory model of microglial activation and to determine the mechanism for activation-dependent silencing of Rgs10 expression in microglia. We demonstrate that endogenous RGS10 is present in spinal cord microglia, and RGS10 protein levels are suppressed in the spinal cord in a nerve injury-induced neuropathic pain mouse model. We show that the histone deacetylase (HDAC) enzyme inhibitor trichostatin A blocks the ability of lipopolysaccharide (LPS) to suppress Rgs10 transcription in BV-2 and primary microglia, demonstrating that HDAC enzymes are required for LPS silencing of Rgs10 Furthermore, we used chromatin immunoprecipitation to demonstrate that H3 histones at the Rgs10 proximal promoter are deacetylated in BV-2 microglia following LPS activation, and HDAC1 association at the Rgs10 promoter is enhanced following LPS stimulation. Finally, we have shown that sphingosine 1-phosphate, an endogenous microglial signaling mediator that inhibits HDAC activity, enhances basal Rgs10 expression in BV-2 microglia, suggesting that Rgs10 expression is dynamically regulated in microglia in response to multiple signals.

Epigenetic-mediated immune suppression of positive co-stimulatory molecules in chemoresistant ovarian cancer cells.

The immunological response against cancer is a critical balance between immune-activating and immune-suppressing mechanisms. Ovarian cancer creates a suppressive microenvironment to escape immune elimination; however, the molecular mechanisms are poorly understood, and it is unclear whether chemotherapeutic drugs exert an immunoreactive or immunosuppressive effect on the tumor microenvironment. 4-1BB ligand (4-1BBL/CD157) and OX-40 ligand (OX-40L/CD252) are important regulators of effector cytotoxic T-cells activity. This study demonstrates that expression of positive co-stimulatory molecules, OX-40L and 4-1BBL, is suppressed while expression of immunosuppressive molecule programmed death ligand-1 (PD-L1/CD274) is enhanced in chemoresistant cells compared to parental chemosensitive ovarian cancer cells. Here, the molecular mechanisms of silencing of OX-40L and 4-1BBL expression were investigated in chemoresistant A2780-AD ovarian cancer cells. The suppression of OX-40L and 4-1BBL are due to DNA hypermethylation and histone deacetylation, two important mechanisms that contribute to gene silencing during cancer progression. We identify important epigenetic regulators, histone deacetylase 1/3 (HDAC1/HDAC3) and DNA methyltransferase 1 (DNMT1), that exhibit aberrant association with OX-40L and 4-1BBL promoters in chemoresistant ovarian cancer cells. Knockdown of HDAC1 or DNMT1 expression, and pharmacological inhibition of DNMT or HDAC enzymatic activity, significantly increase OX-40L and 4-1BBL expression in chemoresistant cells. This study suggests that loss of histone acetylation and accumulation of DNA methylation correlates with suppressed expression of OX-40L and 4-1BBL in chemoresistant ovarian cancer cells. This study marks the first report of the regulation of these two molecules by histone deacetylation and DNA methylation in chemoresistant ovarian cancer cells.

Combination Treatment with Sublethal Ionizing Radiation and the Proteasome Inhibitor, Bortezomib, Enhances Death-Receptor Mediated Apoptosis and Anti-Tumor Immune Attack.

Sub-lethal doses of radiation can modulate gene expression, making tumor cells more susceptible to T-cell-mediated immune attack. Proteasome inhibitors demonstrate broad anti-tumor activity in clinical and pre-clinical cancer models. Here, we use a combination treatment of proteasome inhibition and irradiation to further induce immunomodulation of tumor cells that could enhance tumor-specific immune responses. We investigate the effects of the 26S proteasome inhibitor, bortezomib, alone or in combination with radiotherapy, on the expression of immunogenic genes in normal colon and colorectal cancer cell lines. We examined cells for changes in the expression of several death receptors (DR4, DR5 and Fas) commonly used by T cells for killing of target cells. Our results indicate that the combination treatment resulted in increased cell surface expression of death receptors by increasing their transcript levels. The combination treatment further increases the sensitivity of carcinoma cells to apoptosis through FAS and TRAIL receptors but does not change the sensitivity of normal non-malignant epithelial cells. Furthermore, the combination treatment significantly enhances tumor cell killing by tumor specific CD8⁺ T cells. This study suggests that combining radiotherapy and proteasome inhibition may simultaneously enhance tumor immunogenicity and the induction of antitumor immunity by enhancing tumor-specific T-cell activity.

Half of most frequently mutated genes in breast cancer are expressed differentially between premenopausal and postmenopausal breast cancer patients.

Breast cancer has distinct causes and molecular characteristics at premenopausal and postmenopausal ages. The age-standardized incidence rate for postmenopausal breast cancer is more than 10 times higher than in premenopausal breast cancer. Here, we showed that the expression of 10 out of 20 most frequently mutated genes in breast cancer (namely, PIK3CA, CDH1, MUC16, PTEN, FAT3, FAT1, SPEN, ARID1A, LRP1B and RUNX1) is higher in premenopausal women with breast cancer than in postmenopausal women with breast cancer. The most significant differences in the expression in terms of menopause status were observed for RUNX1 and FAT1. Furthermore, we found that the majority of these 10 genes also show ER (estrogen receptor) or PR (progesterone receptor) status-dependent expression in both premenopausal and postmenopausal breast cancer patients. Unlike what we observed in the case of ER or PR status, the expression of most of these genes does not change depending on HER2 (human epidermal growth factor receptor 2) status in both premenopausal and postmenopausal breast cancer patients. Combined, our analysis suggests that menopause status might influence the expression of most frequently mutated genes in breast cancer, and that the most of these genes whose expression differ between pre- and post-menopausal women with breast cancer also show ER or PR status-dependent expression in women with breast cancer.

Epigenetic insights into Familial Mediterranean Fever: Increased RGS10 expression and histone modifications accompanies inflammation in familial Mediterranean fever disease.

BACKGROUND: Familial Mediterranean fever (FMF) is an autosomal recessive autoinflammatory disease characterized by recurring fever, erythema, joint pain, and abdominal discomfort during acute episodes. While FMF patients typically share MEFV gene mutations, they display varying clinical manifestations, suggesting the involvement of modifying genes, epigenetic mechanisms, or environmental factors. G protein regulator signal 10 (RGS10), a member of the RGS protein family, exhibits anti-inflammatory effects in autoinflammatory diseases. There are no studies on the role of plays in FMF pathogenesis or histone modification in FMF. AIMS: This study aimed to shed light on the epigenetic regulation of FMF from several perspectives. The relationship between RGS10 DNA hypermethylation in FMF clinical parameters and the regulation of 22 histone modifications were examined in FMF attack patients and the control group. METHODS: Sixty FMF (remission/attack) and thirty healthy individuals were included in the study. First, RNA was isolated from the blood of patients/controls, and the expression of RGS10 was examined. Then, DNA was isolated from the patients, and gene-specific hypermethylation was investigated using the bisulfite conversion method. Finally, histone extraction was performed for FMF patients and controls and 22 histone H3 modifications were determined. In addition, using ADEX bioinformatics tools, RGS10 expression and methylation profiles were detected in different autoinflammatory diseases. RESULTS: This study indicate that RGS10 expression decreased in attack-free/attack patients than control, attributed to DNA methylation. In addition, there were a positive correlation between FMF patients and attack, WBC, neutrophil, MCHC and MPV. Moreover, higher H3K4 me3, H3K9 me2, and H3K14ac levels were observed in patients with FMF attacks. This research also showed a consistent decrease in RGS10 expression in patients with SjS, SSc, and T1D compared with controls. I also obtained five prognosis-related CpGs (cg17527393, cg19653161, cg20445950, cg18938673 and cg13975098) of RGS10 in patients with SjS, RA, SSc, SLE and T1D. CONCLUSION: The present study provides insights into the complex relationship between RGS10, epigenetic modifications, and immune responses in FMF. While RGS10 may initially enhance immune responses, genetic mutations and epigenetic changes associated with FMF acute episode may override this regulatory effect, resulting in increased inflammation and clinical symptoms. Moreover, our study revealed elevated levels of specific histone modifications in the context of FMF, suggesting significant epigenetic changes that could contribute to the disease pathogenesis. Understanding these associations opens new avenues for research and potential therapeutic interventions, potentially involving epigenetic therapies targeting histone modifications.

Phytochemical profiling, cytotoxic, anti-migration, and anti-angiogenic potential of phenolic-rich fraction from Peganum harmala: in vitro and in ovo studies.

Peganum harmala has been extensively employed in Algerian traditional medicine practices. This study aimed to explore the impact of n-butanol (n-BuOH) extract sourced from Peganum harmala seeds on cell proliferation, cell migration, and angiogenesis inhibition. Cytotoxic potential of n-BuOH extract was evaluated using MTT (3-(4,5-dimethylthiazol-2-yl) 2,5 diphenyltetrazolium bromide) assay against human breast adenocarcinoma MCF-7 cells, cell migration was determined using scratch assay, and anti-angiogenic effect was evaluated through macroscopic and histological examinations conducted on chick embryo chorioallantoic membrane. Additionally, this research estimated the phytochemical profile of n-BuOH extract. Fifteen phenolic compounds were identified using Ultra-performance liquid chromatography UPLC-ESI-MS-MS analysis. In addition, the n-BuOH extract of P. harmala exhibited potent antioxidant and free radical scavenging properties. The n-BuOH extract showed potent cytotoxicity against MCF-7 cell with an IC50 value of 8.68 ± 1.58 µg/mL. Furthermore, n-BuOH extract significantly reduced migration. A strong anti-angiogenic activity was observed in the groups treated with n-BuOH extract in comparison to the negative control. Histological analysis confirmed the anti-angiogenic effect of the n-BuOH extract. This activity is probably a result of the synergistic effects produced by different polyphenolic classes.

Interchanging functionality among homologous elongation factors using signatures of heterotachy.

Numerous models of molecular evolution have been formulated to describe the forces that shape sequence divergence among homologous proteins. These models have greatly enhanced our understanding of evolutionary processes. Rarely are such models empirically tested in the laboratory, and even more rare, are such models exploited to generate novel molecules useful for synthetic biology. Here, we experimentally demonstrate that the heterotachy model of evolution captures signatures of functional divergence among homologous elongation factors (EFs) between bacterial EF-Tu and eukaryotic eEF1A. These EFs are GTPases that participate in protein translation by presenting aminoacylated-tRNAs to the ribosome. Upon release from the ribosome, the EFs are recharged by nucleotide exchange factors EF-Ts in bacteria or eEF1B in eukaryotes. The two nucleotide exchange factors perform analogous functions despite not being homologous proteins. The heterotachy model was used to identify a set of sites in eEF1A/EF-Tu associated with eEF1B binding in eukaryotes and another reciprocal set associated with EF-Ts binding in bacteria. Introduction of bacterial EF-Tu residues at these sites into eEF1A protein efficiently disrupted binding of cognate eEF1B as well as endowed eEF1A with the novel ability to bind bacterial EF-Ts. We further demonstrate that eEF1A variants, unlike yeast wild-type, can function in a reconstituted in vitro bacterial translation system.