Protective effects of baicalin against phenylarsine oxide-induced cytotoxicity in human skin keratinocytes.

Phenylarsine oxide (PAO) is a known environmental pollutant and skin keratinocytes are most seriously affected. Baicalin (BCN) was reported to have antioxidant and anti-inflammatory effects, but its protective effect against PAO toxicity is unknown. This study aimed at exploring whether baicalin can reverse the toxicity of human epidermal keratinocytes that are subjected to PAO exposure and underlying mechanisms. In silico analysis from a publicly accessible HaCaT cell transcriptome dataset exposed to chronic Arsenic showed significant differential expression of several genes, including the genes related to DNA replication. Later, we performed in vitro experiments, in which HaCaT cells were exposed to PAO (500 nM) in the existence of BCN (10-50 µM). Treatment of PAO alone induces the JNK, p38 and caspase-3 activation, which were engaged in the apoptosis induction, while the activity of AKT was significantly inhibited, which was engaged in the suppression of apoptosis. PAO suppressed SIRT3 expression and induced intracellular reactive oxygen species (ROS), causing a marked reduce in cell viability and apoptosis. However, BCN treatment restored the PAO-induced suppression of SIRT3 and AKT expression, reduced intracellular ROS generation, and markedly suppressed both caspase-3 activation and apoptosis induction. However, the protective effect of BCN was significantly attenuated after pretreatment with nicotinamide, an inhibitor of SIRT3. These findings indicate that BCN protects against cell death induced by PAO via inhibiting excessive intracellular ROS generation via restoring SIRT3 activity and reactivating downstream AKT pathway. In this study, we firstly shown that BCN is an efficient drug to prevent PAO-induced skin cytotoxicity, and these findings need to be confirmed by in vivo and clinical investigations.

Assessment of Helicobacter pylori cytotoxin-associated Gene A (Cag A) protein and its association with ferritin and vitamin B12 deficiencies among adult healthy asymptomatic residents in Sharjah, United Arab Emirates.

The United Arab Emirates (UAE) serves as an effective epidemiological site for assessing Helicobacter pylori (H. pylori) infection due to its diverse population. However, comprehensive studies on the prevalence of H. pylori in the UAE are notably scarce. In depth prevalence studies are needed as a preventive measure against gastric cancer and other emerging extra gastric diseases associated with H. pylori infection. Aim: This study aimed to assess H. pylori infection and its virulent oncoprotein, the Cytotoxin-Associated Gene (Cag A) and its association with ferritin and vitamin B12 deficiencies. Methods: The study was conducted on 1094 healthy asymptomatic volunteers residents in the Sharjah Emirate, UAE. Enzyme-linked immunosorbent assay (ELISA) was performed to assess H. pylori infection using H. pylori antibodies (IgG), and detection of CagA protein using Cag A antibody (IgG) in the human serum. Ferritin and vitamin B12 serum levels were assessed and correlated to H. pylori infection. Results: This study focuses mainly on the assessment of H. pylori and its virulent factor CagA, in relation to vitamin B12 and ferritin deficiencies. Remarkably, 49.6 % of the participants were detected positive for H. pylori, with over half of these cases involving CagA positive strains. Notably, among Emirati participants, 76.11 % of those with H. pylori infection were CagA positive. Statistical analysis revealed a significant correlation between H. pylori, CagA level, and ferritin/vitamin B12 deficiencies. Conclusion: These findings emphasize the importance of timely detection and eradication of H. pylori not only as a preventive strategy against gastric cancer but also as an effective strategy to rescue the adverse effects from ferritin and vitamin B12 deficiencies, thereby improving the overall health outcomes of individuals affected by H. pylori infection.

Prevalence of Imposter Syndrome and Its Risk Factors Among University of Sharjah Medical Students.

Background Imposter syndrome describes an internal experience of intellectual fraud, where individuals attribute their academic or occupational endeavors and achievements primarily to luck rather than to their diligent efforts. Additionally, the stringent standards and prerequisites set by medical institutions create an environment conducive to impostorism among medical students. This study aimed to evaluate the prevalence and severity of imposter syndrome among medical students at the University of Sharjah. Methodology This research was designed as a descriptive cross-sectional study. A total of 400 participants enrolled in the study using non-probability convenience sampling, but 399 participants, 49.4% (197) from colleges of medicine and 50.6% (202) from dentistry, successfully completed the questionnaire. Participants completed a questionnaire containing the Clance Imposter Phenomenon Scale. Statistical associations between variables were tested using the chi-square test. Individuals with chronic medical conditions or those using medications with known psychiatric side effects were excluded. Results The analyzed sample comprised 399 students, with 64.7% females and 35.3% males. Most respondents were from year 2 (21.3%, 85), while the fewest were from year 5 (18.3%, 73). The majority of students fell into the categories of moderate (46.4%, 185) and frequent (35.8%, 143) imposter experiences. Among all investigated characteristics, pure academic factors such as field of study (p = 0.001), study phases (p = 0.032), advisor's attitude (p = 0.029), and comparison with peers' performance and grades (p = 0.024 and <0.001, respectively) exhibited the highest significant association with the severity of imposter syndrome. Conclusions This study revealed a high prevalence of imposter syndrome among medical students, emphasizing the need for comprehensive strategies and interventions targeting academically associated risk factors to alleviate the burden of imposter syndrome.

Inhibition of PRMT5-mediated regulation of DKK1 sensitizes colorectal cancer cells to chemotherapy.

The Dickkopf family proteins (DKKs) are strong Wnt signaling antagonists that play a significant role in colorectal cancer (CRC) development and progression. Recent work has shown that DKKs, mainly DKK1, are associated with the induction of chemoresistance in CRC and that DKK1 expression in cancer cells correlates with that of protein arginine N-methyltransferase 5 (PRMT5). This points to the presence of a regulatory loop between DKK1 and PRMT5. Herein, we addressed the question of whether PRMT5 contributes to DKK1 expression in CRC and hence CRC chemoresistance. Both in silico and in vitro approaches were used to explore the relationship between PRMT5 and different DKK members. Our data demonstrated that DKK1 expression is significantly upregulated in CRC clinical samples, KRAS-mutated CRC in particular and that the levels of DKK1 positively correlate with PRMT5 activation. Chromatin immunoprecipitation (ChIP) data indicated a possible epigenetic role of PRMT5 in regulating DKK1, possibly through the symmetric dimethylation of H3R8. Knockdown of DKK1 or treatment with the PRMT5 inhibitor CMP5 in combination with doxorubicin yielded a synergistic anti-tumor effect in KRAS mutant, but not KRAS wild-type, CRC cells. These findings suggest that PRMT5 regulates DKK1 expression in CRC and that inhibition of PRMT5 modulates DKK1 expression in such a way that reduces CRC cell growth.

PRMT5 Mediated HIF1α Signaling and Ras-Related Nuclear Protein as Promising Biomarker in Hepatocellular Carcinoma.

Protein arginine N-methyltransferase 5 (PRMT5) has been identified as a potential therapeutic target for various cancer types. However, its role in regulating the hepatocellular carcinoma (HCC) transcriptome remains poorly understood. In this study, publicly available databases were employed to investigate PRMT5 expression, its correlation with overall survival, targeted pathways, and genes of interest in HCC. Additionally, we utilized in-house generated NGS data to explore PRMT5 expression in dysplastic nodules compared to hepatocellular carcinoma. Our findings revealed that PRMT5 is significantly overexpressed in HCC compared to normal liver, and elevated expression correlates with poor overall survival. To gain insights into the mechanism driving PRMT5 overexpression in HCC, we analyzed promoter CpG islands and methylation status in HCC compared to normal tissues. Pathway analysis of PRMT5 knockdown in the HCC cells revealed a connection between PRMT5 expression and genes related to the HIF1α pathway. Additionally, by filtering PRMT5-correlated genes within the HIF1α pathway and selecting up/downregulated genes in HCC patients, we identified Ras-related nuclear protein (RAN) as a target associated with overall survival. For the first time, we report that PRMT5 is implicated in the regulation of HIF1A and RAN genes, suggesting the potential prognostic utility of PRMT5 in HCC.

Evaluation of Antiproliferative Properties of CoMnZn-Fe2O4 Ferrite Nanoparticles in Colorectal Cancer Cells.

The PEG-coated ferrite nanoparticles Co0.2Mn0.6Zn0.2Fe2O4 (X1), Co0.4Mn0.4Zn0.2Fe2O4 (X2), and Co0.6Mn0.2Zn0.2Fe2O4 (X3) were synthesized by the coprecipitation method. The nanoparticles were characterized by XRD, Raman, VSM, XPS, and TEM. The magnetic hyperthermia efficiency (MH) was determined for PEG-coated nanoparticles using an alternating magnetic field (AMF). X2 nanoparticles displayed the highest saturation magnetization and specific absorption rate (SAR) value of 245.2 W/g for 2 mg/mL in a water medium. Based on these properties, X2 nanoparticles were further evaluated for antiproliferative activity against HCT116 cells at an AMF of 495.25 kHz frequency and 350 G strength, using MTT, colony formation, wound healing assays, and flow cytometry analysis for determining the cell viability, clonogenic property, cell migration ability, and cell death of HCT116 cells upon AMF treatment in HCT116 cells, respectively. We observed a significant inhibition of cell viability (2% for untreated control vs. 50% for AMF), colony-forming ability (530 cells/colony for untreated control vs. 220 cells/colony for AMF), abrogation of cell migration (100% wound closure for untreated control vs. 5% wound closure for AMF), and induction of apoptosis-mediated cell death (7.5% for untreated control vs. 24.7% for AMF) of HCT116 cells with respect to untreated control cells after AMF treatment. Collectively, these results demonstrated that the PEG-coated (CoMnZn-Fe2O4) mixed ferrite nanoparticles upon treatment with AMF induced a significant antiproliferative effect on HCT116 cells compared with the untreated cells, indicating the promising antiproliferative potential of the Co0.4Mn0.4Zn0.2Fe2O4 nanoparticles for targeting colorectal cancer cells. Additionally, these results provide appealing evidence that ferrite-based nanoparticles using MH could act as potential anticancer agents and need further evaluation in preclinical models in future studies against colorectal and other cancers.

DNA methylation-mediated epigenetic regulation of oncogenic RPS2 as a novel therapeutic target and biomarker in hepatocellular carcinoma.

Ribosomal Protein S2 (RPS2) has emerged as a potential prognostic biomarker due to its involvement in key cellular processes and its altered expression pattern in certain types of cancer. However, its role in hepatocellular carcinoma (HCC) has yet to be investigated. Herein, we analyzed RPS2 mRNA expression and promoter methylation in HCC patient samples and HepG2 cells. Subsequently, loss-of-function experiments were conducted to determine the function of RPS2 in HCC cells in vitro. Our results revealed that RPS2 mRNA expression is significantly elevated, and its promoter is hypomethylated in HCC patient samples compared to controls. In addition, 5-Azacytidine treatment in HepG2 cells decreased RPS2 promoter methylation level and increased its mRNA expression. RPS2 knockdown in HepG2 cells suppressed cell proliferation and promoted apoptosis. Functional pathway analysis of genes positively and negatively associated with RPS2 expression in HCC showed enrichment in ribosomal biogenesis, translation machinery, cell cycle regulation, and DNA processing. Furthermore, utilizing drug-protein 3D docking, we found that doxorubicin, sorafenib, and 5-Fluorouracil, showed high affinity to the active sites of RPS2, and in vitro treatment with these drugs reduced RPS2 expression. For the first time, we report on DNA methylation-mediated epigenetic regulation of RPS2 and its oncogenic role in HCC. Our findings suggest that RPS2 plays a significant role in the development and progression of HCC, hence its potential prognostic and therapeutic utility. Moreover, as epigenetic changes happen early in cancer development, RPS2 may serve as a potential biomarker for tumor progression.

Sclareol induces cell cycle arrest and ROS-mediated apoptosis and ferroptosis in lung adenocarcinoma cells.

Sclareol (SC) has shown significant anticancer activity against breast and colon cancers among others. However, its ability to precipitate similar anticancer effects in lung cancer has yet to be investigated. To address this issue, SC-treated lung adenocarcinoma cells (A549) were assessed for viability and functional competence as well as the expression of genes related to apoptosis and cell cycling. Our results demonstrated that SC treatment inhibited A549 cell clonogenic features and reduced their migration and invasion potential in a dose-dependent manner. Mechanistically, SC treatment downregulated the expression of cyclin D1 and survivin and upregulated that of p21 and p16, which was associated with a significant increase in the percentage of SubG0 cells. SC treatment is also associated with the induction of both the extrinsic and intrinsic apoptotic pathways, as evidenced by the increased expression and splitting of PARP1 and procaspases 3 and 9 and the reduced expression of antiapoptotic proteins Bcl-2 and Bcl-xL. Increased cell death in SC-treated cells is likely to have resulted from the induction of ferroptosis as suggested by the reduced expression of FPN and the inhibition of the anti-ferroptosis regulator GPX4. In conclusion, the data presented here suggest that SC can reduce lung carcinoma cell growth and metastasis and promote cell death.

Comprehensive In silico analysis of chaperones identifies CRYAB and P4HA2 as potential therapeutic targets and their small-molecule inhibitors for the treatment of cholangiocarcinoma.

Cholangiocarcinoma (CCA) is a subtype of liver cancer with increasing incidence, poor prognosis, and limited treatment modalities. It is, therefore, imperative to identify novel therapeutic targets for better management of the disease. Chaperones are known to be significant regulators of carcinogenesis, however, their role in CCA remains unclear. This study aims to screen chaperones involved in CCA pathogenesis and identify drugs targeting key chaperones to improve the therapeutic response to the disease. To achieve this, first we mined the literature to create an atlas of human chaperone proteins. Next, their expression in CCA was determined by publicly available datasets of patients at mRNA and protein levels. In addition, our analysis involving protein-protein interaction and pathway analysis of eight key dysregulated chaperones revealed that they control crucial cancer-related pathways. Furthermore, topology analysis of the CCA network identified crystallin alpha-B protein (CRYAB) and prolyl-4-hydroxylase subunit 2 (P4HA2) as novel therapeutic targets for the disease. Finally, drug repurposing of 286 clinically approved anti-cancer drugs against these two chaperones performed by molecular docking and molecular dynamics simulations showed that tucatinib and regorafenib had a modulatory effect on them and could be potential inhibitors of CRYAB and P4HA2, respectively. Overall, our study, for the first time, provides insights into the pan-chaperone expression in CCA and explains the pathways that might drive CCA pathogenesis. Further, our identification of potential therapeutic targets and their inhibitors could provide new and complementary approaches to CCA treatment.

Plasma metabolomics profiling identifies new predictive biomarkers for disease severity in COVID-19 patients.

Recently, numerous studies have reported on different predictive models of disease severity in COVID-19 patients. Herein, we propose a highly predictive model of disease severity by integrating routine laboratory findings and plasma metabolites including cytosine as a potential biomarker of COVID-19 disease severity. One model was developed and internally validated on the basis of ROC-AUC values. The predictive accuracy of the model was 0.996 (95% CI: 0.989 to 1.000) with an optimal cut-off risk score of 3 from among 6 biomarkers including five lab findings (D-dimer, ferritin, neutrophil counts, Hp, and sTfR) and one metabolite (cytosine). The model is of high predictive power, needs a small number of variables that can be acquired at minimal cost and effort, and can be applied independent of non-empirical clinical data. The metabolomics profiling data and the modeling work stemming from it, as presented here, could further explain the cause of COVID-19 disease prognosis and patient management.

Can Acanthamoeba Harbor Monkeypox Virus?

Acanthamoeba is well known to host a variety of microorganisms such as viruses, bacteria, protozoa, and yeast. Given the recent number of cases of monkeypox infection, we speculate that amoebae may be aiding viral transmission to the susceptible hosts. Although there is no confirmatory evidence to suggest that Acanthamoeba is a host to monkeypox (a double-stranded DNA virus), the recent discovery of mimivirus (another double-stranded DNA virus) from Acanthamoeba, suggests that amoebae may shelter monkeypox virus. Furthermore, given the possible spread of monkeypox virus from animals to humans during an earlier outbreak, which came about after patients came in contact with prairie dogs, it is likely that animals may also act as mixing vessel between ubiquitously distributed Acanthamoeba and monkeypox virus, in addition to the environmental habitat that acts as an interface in complex interactions between diverse microorganisms and the host.

JAK/STAT signaling and cellular iron metabolism in hepatocellular carcinoma: therapeutic implications.

Iron metabolism plays a crucial role in the development and progression of hepatocellular carcinoma (HCC), the most common type of primary liver cancer. Iron is an essential micronutrient that is involved in many physiological processes, including oxygen transport, DNA synthesis, and cellular growth and differentiation. However, excessive iron accumulation in the liver has been linked to oxidative stress, inflammation, and DNA damage, which can increase the risk of HCC. Studies have shown that iron overload is common in patients with HCC and that it is associated with a poor prognosis and reduced survival rates. Various iron metabolism-related proteins and signaling pathways such as the JAK/STAT pathway are dysregulated in HCC. Moreover, reduced hepcidin expression was reported to promote HCC in a JAK/STAT pathway-dependent manner. Therefore, it is important to understand the crosstalk between iron metabolism and the JAK/STAT pathway to prevent or treat iron overload in HCC. Iron chelators can bind to iron and remove it from the body, but its effect on JAK/STAT pathway is unclear. Also, HCC can be targeted by using the JAK/STAT pathway inhibitors, but their effect on hepatic iron metabolism is not known. In this review, for the first time, we focus on the role of the JAK/STAT signaling pathway in regulating cellular iron metabolism and its association with the development of HCC. We also discuss novel pharmacological agents and their therapeutic potential in manipulating iron metabolism and JAK/STAT signaling in HCC.

Monkeypox virus-induced upregulation of interleukin-10 signaling: could epigenetics be involved in long-term viral persistence?

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DNA Methylation-Mediated Overexpression of CXCL1 in Helicobacter pylori-Induced Gastric Cancer: In Silico- and In Vitro-Based Identification of a Potential Biomarker for Carcinogenesis.

Given the high global prevalence and mortality associated with gastric cancer, and its known causal link with Helicobacter pylori infection, it is important to have a biomarker to identify malignant transformation at early stages. Previously, we, and others, have reported that H. pylori-induced epigenetic changes could mediate carcinogenic transformation of the gastric cells. Also, CXCL1 secreted by gastric cancer cells was reported as a key diagnostic and prognostic biomarker for the pathogenic progression of gastric cancer. In this study, for the first time, we aimed to investigate the role of H. pylori-induced DNA methylation-based epigenetic regulation of CXCL1. In silico analysis of publicly available datasets and in vitro experiments were performed. Our results showed that CXCL1 is highly expressed in both gastric cancer tissues and gastric cancer cells infected with H. pylori. Further, we showed and confirmed that H. pylori-mediated overexpression of CXCL1 is due to hypomethylation of its promoter region. Since epigenetic events such as DNA methylation happen early in the sequence; H. pylori-induced CXCL1 hypomethylation could likely be detected at an early stage of gastric cancer development. Epigenetic modifications, such as CXCL1 hypomethylation, are reversible and could potentially be a therapeutic target using demethylation drugs.

SCAMP3 promotes breast cancer progression through the c-MYC-ß-Catenin-SQSTM1 growth and stemness axis.

The cellular trafficking protein secretory-carrier-membrane-protein 3 (SCAMP3) has been previously shown to promote hepatocellular carcinoma, melanoma, glioma and pancreatic adenocarcinoma. Moreover, previous work has shown that SCAMP3 regulates the epidermal growth factor receptor (EGFR) in triple negative breast cancer (TNBC). However, the oncogenic role of SCAMP3 in different molecular subtypes of breast cancer (BRCA) remains largely unknown. In this study, the role of SCAMP3 in different molecular subtypes of BRCA was investigated using in silico, in vitro and in vivo approaches. In silico analysis of BRCA patient samples showed that SCAMP3 is highly overexpressed in different BRCA molecular subtypes, advanced disease grades and lymph node metastatic stages. Depletion of SCAMP3 inhibited BRCA cell growth, stemness, clonogenic potential and migration and promoted autophagy and cellular senescence. The expression of stemness markers CD44 and OCT4A was reduced in SCAMP3-silenced MDA-MB-231 cells. SCAMP3 overexpression promoted cell proliferation, clonogenicity, tumor spheroid formation and migration in vitro and tumor growth in vivo. SCAMP3 promoted epithelial-mesenchymal-transition (EMT) by regulating E-cadherin expression. SCAMP3 enhanced in vivo tumor growth in MDA-MB-231 tumor xenograft mouse model. Mechanistically, SCAMP3 depletion inhibited ß-Catenin, c-MYC and SQSTM1 expression, while its overexpression increased the expression of the same oncogenic proteins. Increased SCAMP3 expression associated with increased chemoresistance in BRCA cells while its depletion associated with increased sensitivity to chemotherapy. BRCA patients with high SCAMP3 expression showed poor prognosis, decreased overall survival and relapse free survival relative to counterparts with reduced SCAMP3 expression. These findings suggest that SCAMP3 exerts a wide range of oncogenic effects in different molecular subtypes of BRCA by modulating the c-MYC-ß-Catenin-SQSTM1 axis that targets tumor growth, metastasis, stemness and chemoresistance.

Colonic TRPV4 overexpression is related to constipation severity.

BACKGROUND: Chronic constipation is prevalent and involves both colon sensitivity and various changes in intestinal bacteria, particularly mucosa-associated microflora. Here we examined regulatory mechanisms of TRPV4 expression by co-culturing colon epithelial cell lines with intestinal bacteria and their derivatives. We also investigated TRPV4 expression in colon epithelium from patients with constipation. METHODS: Colon epithelial cell lines were co-cultured with various enterobacteria (bacterial components and supernatant), folate, LPS, or short chain fatty acids. TRPV4 expression levels and promoter DNA methylation were assessed using pyrosequencing, and microarray network analysis. For human samples, correlation coefficients were calculated and multiple regression analyses were used to examine the association between clinical background, rectal TRPV4 expression level and mucosa-associated microbiota. RESULTS: Co-culture of CCD841 cells with P. acnes, C. perfringens, or S. aureus transiently decreased TRPV4 expression but did not induce methylation. Co-culture with clinical isolates and standard strains of K. oxytoca, E. faecalis, or E. coli increased TRPV4 expression in CCD841 cells, and TRPV4 and TNF-alpha expression were increased by E. coli culture supernatants but not bacterial components. Although folate, LPS, IL-6, TNF-alpha, or SCFAs alone did not alter TRPV4 expression, TRPV4 expression following exposure to E. coli culture supernatants was inhibited by butyrate or TNF-alphaR1 inhibitor and increased by p38 inhibitor. Microarray network analysis showed activation of TNF-alpha, cytokines, and NOD signaling. TRPV4 expression was higher in constipated patients from the terminal ileum to the colorectum, and multiple regression analyses showed that low stool frequency, frequency of defecation aids, and duration were associated with TRPV4 expression. Meanwhile, incomplete defecation, time required to defecate, and number of defecation failures per 24 h were associated with increased E. faecalis frequency. CONCLUSIONS: Colon epithelium cells had increased TRPV4 expression upon co-culture with K. oxytoca, E. faecalis, or E. coli supernatants, as well as TNFα-stimulated TNFαR1 expression via a pathway other than p38. Butyrate treatment suppressed this increase. Epithelial TRPV4 expression was increased in constipated patients, suggesting that TRPV4 together with increased frequency of E. faecalis may be involved in the pathogenesis of various constipation symptoms.

Association of the BB genotype of the ABO gene with the risk of acute myocardial infarction in hospital-based study.

Objectives: The ABO gene locus has been identified to be associated with myocardial infarction in patients with coronary heart disease. The primary focus of this hospital-based study was to explore the relationship of ABO blood groups and ABO genotypes with acute myocardial infarction (AMI) in Karachi, Pakistan. Methods: In a comparative cross-sectional study, an equal number of adult AMI patients and healthy controls (n=275 in each group; age range 30-70 years, both males and females) were recruited from the Aga Khan University and NICVD, Karachi, with informed consent. The blood samples were analyzed for ABO blood groups and other biomarkers. PCR followed by RFLP techniques were employed for determining the ABO genotypes. Multinomial regression was used to evaluate the association of genotypes with the risk of AMI. Results: Thirteen different combinations of ABO genotypes were observed while the O2O2 and A2A2 genotypes were not detected. No significant association based on the distribution of blood groups A, B, O and AB among AMI patients and healthy individuals was observed. The odds of AMI were 3.32 times in subjects with BB genotype as compared to subjects with OO genotypes after adjustment of age, gender, body mass index, heart rate, total cholesterol, and waist circumference [AOR (95% CI) =3.32 (1.36-8.08), p-value =0.008]. Conclusion: Our hospital-based study indicates that ABO genotype BB was significantly associated with the risk of AMI. This harmful effect of the BB genotype could have a possible relationship with AMI's development in the Pakistani population.

SARS-CoV-2-induced hypomethylation of the ferritin heavy chain (FTH1) gene underlies serum hyperferritinemia in severe COVID-19 patients.

High serum ferritin (hyperferritinemia), a reliable hallmark of severe COVID-19 often associates with a moderate decrease in serum iron (hypoferremia) and a moderate increase in serum hepcidin. This suggests that hyperferritinemia in severe COVID-19 is reflective of inflammation rather than iron overload. To test this possibility, the expression status of ferritin heavy chain (FTH1), transferrin receptor 1 (TFRC), hepcidin (HAMP), and ferroportin (SLC40A1) genes and promoter methylation status of FTH1 and TFRC genes were examined in blood samples obtained from COVID-19 patients showing no, mild or severe symptoms and in healthy-donor monocytes stimulated with SARS-CoV-2-derived peptides. Severe COVID-19 samples showed a significant increase in FTH1 expression and hypomethylation relative to mild or asymptomatic COVID-19 samples. S-peptide treated monocytes also showed a significant increase in FTH1 expression and hypomethylation relative to that in controls; treatment with ECD or NP did not change FTH1 expression nor its methylation status. In silico and in vitro analysis showed a significant increase in the expression of the TET3 demethylase in S peptide-treated monocytes. Findings presented here suggest that S peptide-driven hypomethylation of the FTH1 gene promoter underlies hyperferritinemia in severe COVID-19 disease.