-
Frontiers in Bioscience (Landmark... Apr 2024Ovarian cancer is a highly lethal gynecologic malignancy. ARHGAP10, a member of Rho GTPase-activating proteins, is a potential tumor suppressor in ovarian cancer....
BACKGROUND
Ovarian cancer is a highly lethal gynecologic malignancy. ARHGAP10, a member of Rho GTPase-activating proteins, is a potential tumor suppressor in ovarian cancer. However, its role and the involved mechanism need further examination. Here, we investigated whether ARHGAP10 is also associated with ferroptosis.
METHODS
Lentivirus infection was used for gene overexpression or silencing. Real-time polymerase chain reaction (RT-PCR) and Western blot were used to assess mRNA and protein levels, respectively. Cell viability was assessed by Cell Counting Kit-8 (CCK-8) assay. Lipid reactive oxygen species level was measured by flow cytometry. A tumorigenicity assay was performed to evaluate tumor growth , and sections of mouse tumor tissues were examined by immunofluorescence microscopy. Chromatin Immunoprecipitation (ChIP) assay was used to assess the binding of H3K9ac to the promoter region of ARHGAP10.
RESULTS
ARHGAP10 overexpression promoted ferroptosis in ovarian cancer cells, resulting in decreased cell viability, and increased lipid reactive oxygen species (ROS) level. Further, it decreased and increased GPX4 and PTGS2 expression, respectively, and also induced suppression of tumor growth in mice. Fer-1, a potent inhibitor of ferroptosis, suppressed the above effects of ARHGAP10. Contrarily, ARHGAP10 silencing alleviated ferroptosis in ovarian cancer cells, which was reversed by RSL3, a ferroptosis-inducing agent. Lastly, sodium butyrate (SB) was found to transcriptionally regulate ARHGAP10, thereby also contributing to the ferroptosis of ovarian cancer cells.
CONCLUSIONS
Our results suggest that SB/ARHGAP10/GPX4 is a new signaling axis involved in inducing ferroptosis in ovarian cancer cells and suppressing tumor growth, which has potential clinical significance.
Topics: Ferroptosis; Female; Ovarian Neoplasms; Humans; Animals; GTPase-Activating Proteins; Cell Line, Tumor; Reactive Oxygen Species; Butyric Acid; Gene Expression Regulation, Neoplastic; Mice; Mice, Nude; Cell Survival; Phospholipid Hydroperoxide Glutathione Peroxidase
PubMed: 38812318
DOI: 10.31083/j.fbl2905167 -
Proceedings of the National Academy of... Jun 2024The phylum (kingdom , realm ) is a broad assemblage of diverse viruses with comparatively short double-stranded DNA genomes (<50 kbp) that produce icosahedral capsids...
The phylum (kingdom , realm ) is a broad assemblage of diverse viruses with comparatively short double-stranded DNA genomes (<50 kbp) that produce icosahedral capsids built from double jelly-roll major capsid proteins. Preplasmiviricots infect hosts from all cellular domains, testifying to their ancient origin, and, in particular, are associated with six of the seven supergroups of eukaryotes. Preplasmiviricots comprise four major groups of viruses, namely, polintons, polinton-like viruses (PLVs), virophages, and adenovirids. We used protein structure modeling and analysis to show that protein-primed DNA polymerases (pPolBs) of polintons, virophages, and cytoplasmic linear plasmids encompass an N-terminal domain homologous to the terminal proteins (TPs) of prokaryotic PRD1-like tectivirids and eukaryotic adenovirids that are involved in protein-primed replication initiation, followed by a viral ovarian tumor-like cysteine deubiquitinylase (vOTU) domain. The vOTU domain is likely responsible for the cleavage of the TP from the large pPolB polypeptide and is inactivated in adenovirids, in which TP is a separate protein. Many PLVs and transpovirons encode a distinct derivative of polinton-like pPolB that retains the TP, vOTU, and pPolB polymerization palm domains but lacks the exonuclease domain and instead contains a superfamily 1 helicase domain. Analysis of the presence/absence and inactivation of the vOTU domains and replacement of pPolB with other DNA polymerases in eukaryotic preplasmiviricots enabled us to outline a complete scenario for their origin and evolution.
Topics: Capsid Proteins; DNA Viruses; Eukaryota; DNA-Directed DNA Polymerase; Models, Molecular; Phylogeny
PubMed: 38805295
DOI: 10.1073/pnas.2405771121 -
Viruses May 2024Duck Tembusu Virus (DTMUV) is a pathogen of the Flaviviridae family that causes infections in poultry, leading to significant economic losses in the duck farming... (Review)
Review
Duck Tembusu Virus (DTMUV) is a pathogen of the Flaviviridae family that causes infections in poultry, leading to significant economic losses in the duck farming industry in recent years. Ducks infected with this virus exhibit clinical symptoms such as decreased egg production and neurological disorders, along with serious consequences such as ovarian hemorrhage, organ enlargement, and necrosis. Variations in morbidity and mortality rates exist across different age groups of ducks. It is worth noting that DTMUV is not limited to ducks alone; it can also spread to other poultry such as chickens and geese, and antibodies related to DTMUV have even been found in duck farm workers, suggesting a potential risk of zoonotic transmission. This article provides a detailed overview of DTMUV research, delving into its genomic characteristics, vaccines, and the interplay with host immune responses. These in-depth research findings contribute to a more comprehensive understanding of the virus's transmission mechanism and pathogenic process, offering crucial scientific support for epidemic prevention and control.
Topics: Animals; Ducks; Flavivirus; Flavivirus Infections; Genome, Viral; Poultry Diseases; Viral Vaccines; Farmers; Antibodies, Viral; Humans
PubMed: 38793692
DOI: 10.3390/v16050811 -
Antioxidants (Basel, Switzerland) May 2024Ascorbate (vitamin C) is an essential vitamin for the human body and participates in various physiological processes as an important coenzyme and antioxidant.... (Review)
Review
Ascorbate (vitamin C) is an essential vitamin for the human body and participates in various physiological processes as an important coenzyme and antioxidant. Furthermore, the role of ascorbate in the prevention and treatment of cancer including gynecological cancer has gained much more interest recently. The bioavailability and certain biological functions of ascorbate are distinct in males versus females due to differences in lean body mass, sex hormones, and lifestyle factors. Despite epidemiological evidence that ascorbate-rich foods and ascorbate plasma concentrations are inversely related to cancer risk, ascorbate has not demonstrated a significant protective effect in patients with gynecological cancers. Adequate ascorbate intake may have the potential to reduce the risk of human papillomavirus (HPV) infection and high-risk HPV persistence status. High-dose ascorbate exerts antitumor activity and synergizes with chemotherapeutic agents in preclinical cancer models of gynecological cancer. In this review, we provide evidence for the biological activity of ascorbate in females and discuss the potential role of ascorbate in the prevention and treatment of ovarian, endometrial, and cervical cancers.
PubMed: 38790722
DOI: 10.3390/antiox13050617 -
Genes Apr 2024P53 overexpression plays a critical role in cancer pathogenesis by disrupting the intricate regulation of cellular proliferation. Despite its firmly established function...
P53 overexpression plays a critical role in cancer pathogenesis by disrupting the intricate regulation of cellular proliferation. Despite its firmly established function as a tumor suppressor, elevated p53 levels can paradoxically contribute to tumorigenesis, influenced by factors such as exposure to carcinogens, genetic mutations, and viral infections. This phenomenon is observed across a spectrum of cancer types, including bladder (BLCA), ovarian (OV), cervical (CESC), cholangiocarcinoma (CHOL), colon adenocarcinoma (COAD), diffuse large B-cell lymphoma (DLBC), esophageal carcinoma (ESCA), head and neck squamous cell carcinoma (HNSC), kidney chromophobe (KICH), kidney renal clear cell carcinoma (KIRC), liver hepatocellular carcinoma (LIHC), lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), and uterine corpus endometrial carcinoma (UCEC). This broad spectrum of cancers is often associated with increased aggressiveness and recurrence risk. Effective therapeutic strategies targeting tumors with p53 overexpression require a comprehensive approach, integrating targeted interventions aimed at the p53 gene with conventional modalities such as chemotherapy, radiation therapy, and targeted drugs. In this extensive study, we present a detailed analysis shedding light on the multifaceted role of TP53 across various cancers, with a specific emphasis on its impact on disease-free survival (DFS). Leveraging data from the TCGA database and the GTEx dataset, along with GEPIA, UALCAN, and STRING, we identify TP53 overexpression as a significant prognostic indicator, notably pronounced in prostate adenocarcinoma (PRAD). Supported by compelling statistical significance ( < 0.05), our analysis reveals the distinct influence of TP53 overexpression on DFS outcomes in PRAD. Additionally, graphical representations of overall survival (OS) underscore the notable disparity in OS duration between tumors exhibiting elevated TP53 expression (depicted by the red line) and those with lower TP53 levels (indicated by the blue line). The hazard ratio (HR) further emphasizes the profound impact of TP53 on overall survival. Moreover, our investigation delves into the intricate TP53 protein network, unveiling genes exhibiting robust positive correlations with TP53 expression across 13 out of 27 cancers. Remarkably, negative correlations emerge with pivotal tumor suppressor genes. This network analysis elucidates critical proteins, including SIRT1, CBP, p300, ATM, DAXX, HSP 90-alpha, Mdm2, RPA70, 14-3-3 protein sigma, p53, and ASPP2, pivotal in regulating cell cycle dynamics, DNA damage response, and transcriptional regulation. Our study underscores the paramount importance of deciphering TP53 dynamics in cancer, providing invaluable insights into tumor behavior, disease-free survival, and potential therapeutic avenues.
Topics: Humans; Tumor Suppressor Protein p53; Neoplasms; Computational Biology; Gene Expression Regulation, Neoplastic; Biomarkers, Tumor
PubMed: 38790205
DOI: 10.3390/genes15050577 -
Genes Apr 2024germline monoallelic variants have been detected in a number of patients affected by breast/ovarian cancer or endometrial cancer, suggesting a potential susceptibility...
BACKGROUND
germline monoallelic variants have been detected in a number of patients affected by breast/ovarian cancer or endometrial cancer, suggesting a potential susceptibility role, though their significance remains elusive since the disease mechanism is normally recessive. Hence, the aim of this research was to explore the hypothesis that a second hit could have arisen in the other allele in the tumor tissue.
METHODS
we used Sanger sequencing and immunohistochemistry to search for a second variant in the tumoral DNA and to assess protein expression, respectively.
RESULTS
we detected one variant of unknown significance, one variant with conflicting interpretation of pathogenicity and three benign/likely benign variants; the protein was not detected in the tumor tissue of half of the patients, and in others, its expression was reduced.
CONCLUSIONS
our results fail to demonstrate that germinal monoallelic variants increase cancer risk through a LOH (loss of heterozygosity) mechanism in the somatic tissue; however, the absence or partial loss of the protein in many tumors suggests its dysregulation regardless of genetic status.
Topics: Humans; DNA Glycosylases; Female; Endometrial Neoplasms; Ovarian Neoplasms; Breast Neoplasms; Middle Aged; Loss of Heterozygosity; Genetic Predisposition to Disease; Aged; Adult
PubMed: 38790183
DOI: 10.3390/genes15050554 -
Journal of Dairy Science May 2024An economic simulation was carried out over 183 milk-producing countries to estimate the global economic impacts of 12 dairy cattle diseases and health conditions:...
An economic simulation was carried out over 183 milk-producing countries to estimate the global economic impacts of 12 dairy cattle diseases and health conditions: mastitis (subclinical and clinical), lameness, paratuberculosis (Johne's disease), displaced abomasum, dystocia, metritis, milk fever, ovarian cysts, retained placenta, and ketosis (subclinical and clinical). Estimates of disease impacts on milk yield, fertility, and culling were collected from the literature, standardized, meta-analyzed using a variety of methods ranging from simple averaging to random-effects models, and adjusted for comorbidities to prevent overestimation. These comorbidity-adjusted disease impacts were then combined with a set of country-level lactational incidence and/or prevalence estimates, herd characteristics, and price estimates within a series of Monte Carlo simulations that estimated and valued the economic losses due to these diseases. It was estimated that total annual global losses are USD 65 billion (B). Subclinical ketosis, clinical mastitis, and subclinical mastitis were the costliest diseases modeled, resulting in mean annual global losses of approximately USD 18B, USD 13B, and USD 9B, respectively. Estimated global annual losses due to clinical ketosis, displaced abomasum, dystocia, lameness, metritis, milk fever, ovarian cysts, paratuberculosis, and retained placenta were estimated to be USD 0.2B, 0.6B, 0.6B, 6B, 5B, 0.6B, 4B, 4B, and 3B, respectively. Without adjustment for comorbidities, when statistical associations between diseases were disregarded, mean aggregate global losses would have been overestimated by 45%. Although annual losses were greatest in India (USD 12B), the USA (USD 8B), and China (USD 5B), depending on the measure of losses used (losses as a percent of GDP, losses per capita, losses as a percent of gross milk revenue), the relative economic burden of these dairy cattle diseases across countries varied markedly.
PubMed: 38788837
DOI: 10.3168/jds.2023-24626 -
Toxins Apr 2024Recent discoveries establish DNA and RNA as bona fide substrates for ADP-ribosylation. NADAR ("NAD- and ADP-ribose"-associated) enzymes reverse guanine ADP-ribosylation...
Recent discoveries establish DNA and RNA as bona fide substrates for ADP-ribosylation. NADAR ("NAD- and ADP-ribose"-associated) enzymes reverse guanine ADP-ribosylation and serve as antitoxins in the DarT-NADAR operon. Although NADARs are widespread across prokaryotes, eukaryotes, and viruses, their specificity and broader physiological roles remain poorly understood. Using phylogenetic and biochemical analyses, we further explore de-ADP-ribosylation activity and antitoxin functions of NADAR domains. We demonstrate that different subfamilies of NADAR proteins from representative strains and an -infecting phage retain biochemical activity while displaying specificity in providing protection from toxic guanine ADP-ribosylation in cells. Furthermore, we identify a myxobacterial enzyme within the YbiA subfamily that functions as an antitoxin for its associated DarT-unrelated ART toxin, which we termed YarT, thus presenting a hitherto uncharacterised ART-YbiA toxin-antitoxin pair. Our studies contribute to the burgeoning field of DNA ADP-ribosylation, supporting its physiological relevance within and beyond bacterial toxin-antitoxin systems. Notably, the specificity and confinement of NADARs to non-mammals infer their potential as highly specific targets for antimicrobial drugs with minimal off-target effects.
Topics: ADP-Ribosylation; Escherichia coli; Escherichia coli Proteins; Bacterial Toxins; Adenosine Diphosphate Ribose; Phylogeny; Toxin-Antitoxin Systems; DNA, Bacterial; DNA
PubMed: 38787060
DOI: 10.3390/toxins16050208 -
Ethiopian Journal of Health Sciences Sep 2023In the female population, pelvic organ prolapse is a common problem that lowers people's quality of life in terms of their health. Depending on the severity of the...
BACKGROUND
In the female population, pelvic organ prolapse is a common problem that lowers people's quality of life in terms of their health. Depending on the severity of the prolapse and the symptoms, there are many treatment options. Simple observation, vaginal pessaries, or surgical management are all possible treatments. Reconstructive pelvic surgery with or without mesh augmentation and obliterative surgery are two surgical treatments that are available. Due to the contentious concerns surrounding the use of mesh and the rising demand for uterine preservation, surgical practices are currently shifting.
METHODS
Just two cases are included in this study due to the rarity of this condition. In this study, I introduce a new technique to the literature (Mostafa Maged sling technique) which will be challenging. This technique depends on round ligaments and ovarian ligament to hitch up the whole uterus.
RESULTS
There were no difficulties following the procedure. None of the patients required blood transfusions, and there were no signs of dehiscence or incision infection. Non-steroidal antiinflammatory medications were administered to both patients as analgesia. On the first postoperative day, the foley catheters were removed from both patients.
CONCLUSION
A simple and new manueuver is applied in the literature to treat the uterine prolapse. It is easy to learn and easy to perform. We need further studies to compare different techniques including Mostafa Maged sling operation to manage uterine prolapse.
Topics: Humans; Female; Uterine Prolapse; Middle Aged; Suburethral Slings; Uterus; Gynecologic Surgical Procedures; Pelvic Organ Prolapse; Surgical Mesh
PubMed: 38784517
DOI: 10.4314/ejhs.v33i5.22 -
JAMA Network Open May 2024
Topics: Humans; COVID-19; Neoplasms; Male; Female; Middle Aged; SARS-CoV-2; Aged; Adult; Antineoplastic Agents; Withholding Treatment
PubMed: 38780944
DOI: 10.1001/jamanetworkopen.2024.11859