Search

Introduction: 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.

Abstract 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.

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.

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.

Colorectal Cancer (CRC) with Microsatellite instability (MSI) and mutLhomolog-1 (MLH1) gene deficiency are less aggressive than MLH1 proficient cancers. MLH1 is involved in several cellular processes, but its connection with the autophagy-dependent cellular response towards anticancer drugs remains unclear. In this study, we aimed to investigate the interaction between MLH1 and the autophagy marker LC3, which facilitated nucleophagy induction, and its potential role in determining sensitivity to 5-Fluorouracil (5-FU) induced cell death. To examine the role of MLH1 in DNA-damage-induced nucleophagy in CRC cells, we utilized a panel of MLH1 deficient and MLH1 proficient CRC cell lines. We included a parental HCT116 cell line (MLH1−/−) and its isogenic cell line HCT116 MLH1+/− in which a single allele of the MLH1 gene was introduced using CRISPR-Cas9 gene editing. We observed that MLH1 proficient cells were less sensitive to the 5-FU-induced cytotoxic effect. The 5-FU induced DNA damage led to LC3 up-regulation, which was dependent on MLH1 overexpression. Moreover, immunofluorescence and immunoprecipitation data showed LC3 and MLH1 were colocalized in CRC cells. Consequently, MLH1 dependent 5-FU-induced DNA damage contributed to the formation of micronuclei. These micronuclei colocalize with autolysosome, indicating a cytoprotective role of MLH1 dependent nucleophagy. Interestingly, siRNA knockdown of MLH1 in HCT116 MLH1+/− prevented LC3 upregulation and micronuclei formation. These novel data are the first to show an essential role of MLH1 in mediating the chemoresistance and survival of cancer cells by increasing the LC3 expression and inducing nucleophagy in 5-FU treated CRC cells.

Background: Acanthamoeba castellanii genotype T4 is the causative agent of the progressively increasing sight-threatening Acanthamoeba keratitis and central nervous system infections. Because of the increased prevalence and the ineffectiveness of the current antiamoebic drugs, we synthesized miltefosine poly(lactic-co-glycolic acid) nanoparticles (miltefosine PLGA NP) as a potential potent and biocompatible antiamoebic drug. The advantage to use PLGA NP is to preserve the cells from the toxic effect of miltefosine drug. In particular, miltefosine PLGA nanoformulation offers a better cellular uptake and a sustained drug release compared with the free drug that presents potent cytotoxicity at high concentrations against human colon cancer cell lines. Methods: The miltefosine NP were synthesized using a double emulsion-solvent evaporation method, characterized, and then assessed for their antiamoebic activity against A. castellanii belonging to the T4 genotype. Blank PLGA NP and miltefosine were used as controls. Results: Amoebicidal assays revealed that at 25 and 50 µM, unmodified miltefosine eradicated 83% and 93% of amoebae, respectively. At these same concentrations of 25 and 50 µM, the amount of miltefosine released form PLGA NP formulation was limited to 22.6%. However, it killed 36% and 56% of the protozoa, respectively. Thus, the efficacy of PLGA NP formulation was similar to that of the unmodified miltefosine. Both miltefosine and its PLGA NP significantly inhibited the pretreated amoebae (minimum inhibitory concentration 50% = 37.23 and 55.26 µM, respectively, compared with 147.2 µM of the blank NP; P < 0.05) and reduced amoebae-mediated host cell death. The blank NP and miltefosine NP exhibited minimal cytotoxicity against colon epithelial cell lines. In contrast, the unmodified miltefosine caused 37%, 71%, and 88% of cytotoxicity at 10, 25, and 50 µM, respectively. Conclusion: Overall, these findings suggest that controlling the release of miltefosine from PLGA NP for a short time was almost as effective as miltefosine alone against A. castellanii genotype T4 while reducing host cell toxicity. Hence, this study demonstrates the feasibility of using PLGA NP for the treatment of Acanthamoebic infections.

Overexpression of ferritin heavy chain (FTH1) often associates with good prognosis in breast cancer (BCa), particularly in the triple‐negative subtype (triple‐negative breast cancer). However, the mechanism by which FTH1 exerts its possible tumor suppressor effects in BCa is not known. Here, we examined the bearing of FTH1 silencing or overexpression on several aspects of BCa cell growth in vitro. FTH1 silencing promoted cell growth and mammosphere formation, increased c‐MYC expression, and reduced cell sensitivity to chemotherapy. In contrast, FTH1 overexpression inhibited cell growth, decreased c‐MYC expression, and sensitized cancer cells to chemotherapy; silencing of c‐MYC recapitulated the effects of FTH1 overexpression. These findings show for the first time that FTH1 suppresses tumor growth by inhibiting the expression of key oncogenes, such as c‐MYC.

Colorectal cancer (CRC) is among the topmost malignancies for both genders. Despite the high incidence rate and advances in diagnostic tools, treatment in many cases is still ineffective. Most cancerous lesions in CRC begin as benign, followed by the development of invasive forms and metastases. The development of CRC has been linked to defects in autophagy, which plays both a pro-and anti-tumor role and is mainly context-dependent. Autophagy suppression could enhance apoptosis via p53 activation, or autophagy also promotes tumor progression by maintaining tumor growth and increasing resistance to chemotherapy. Autophagy promotes the invasion and metastasis of CRC cells via increased epithelial-mesenchymal transition (EMT). Moreover, dysbiosis of gut microbiota upregulated autophagy and metastasis markers. Autophagy responses may also modulate the tumor microenvironment (TME) via regulating the differentiation process of several innate immune cells. Treatments that promote tumor cell death by stimulating or inhibiting autophagy could be beneficial if used as an adjunct treatment, but the precise role of various autophagy-modulating drugs in CRC patients is needed to be explored. In this article, we present an overview of the autophagy process and its role in the pathogenesis and therapeutic resistance of CRC. Also, we focused on the current understanding of the role of the EMT and TME, including its relation to gut microbiota and immune cells, in autophagic manipulation of CRC. We believe that there is a potential link between autophagy, TME, EMT, and drug resistance, suggesting that further studies are needed to explore this aspect.

Increased expression of Yes-associated protein-1 (YAP1) was shown to correlate with reduced survival in breast cancer (BC) patients. However, the exact mechanism of YAP1 regulation in BC cells remains ambiguous. Genomic sequence search showed that the promoter region of the YAP1 gene contains CpG Islands, hence the likelihood of epigenetic regulation by DNA methylation. To address this possibility, the effect of estrogen (17β estradiol; E2) on YAP1 gene expression and YAP1 promoter methylation status was evaluated in BC cells. The functional consequences of E2 treatment in control and YAP1-silenced BC cells were also investigated. Our data showed that E2 modulates YAP1 expression by hypomethylation of its promoter region via downregulation of DNA methyltransferase 3B (DNMT3B); an effect that seems to facilitate tumor progression in BC cells. Although the effect of E2 on YAP1 expression was estrogen receptor (ER) dependent, E2 treatment also upregulated YAP1 expression in MDA-MB231 and SKBR3 cells, which are known ER-negative BC cell lines but expresses ERα. Functionally, E2 treatment resulted in increased cell proliferation, decreased apoptosis, cell cycle arrest, and autophagic flux in MCF7 cells. The knockdown of the YAP1 gene reversed these carcinogenic effects of E2 and inhibited E2-induced autophagy. Lastly, we showed that YAP1 is highly expressed and hypomethylated in human BC tissues and that increased YAP1 expression correlates negatively with DNMT3B expression but strongly associated with ER expression. Our data provide the basis for considering screening of YAP1 expression and its promoter methylation status in the diagnosis and prognosis of BC.

BackgroundNumerous clinical and experimental observations have alluded to the substantial anti-neoplastic role of vitamin D in breast cancer (BC), primarily by inducing apoptosis and affecting metastasis. Tumor progression and resistance to chemotherapy have been linked to vasculogenic mimicry (VM), which represents the endothelial-independent formation of microvascular channels by cancer cells. However, the effect of vitamin D on VM formation in BC has not been thoroughly investigated. This study examined the impact of 1α,25-dihydroxyvitamin D3 (calcitriol), the active form of vitamin D, on the expression of major factors involved in BC migration, invasion, and VM formation.Experimental MethodsPublicly available transcriptomic datasets were used to profile the expression status of the key VM markers in vitamin D-treated BC cells. The in silico data were validated by examining the expression and activity of the key factors that are involved in tumor progression and MV formation in hormone-positive MCF-7 and aggressive triple‐negative MDA-MB-231 BC cells after treatment with calcitriol.Results and DiscussionsThe bioinformatics analysis showed that tumor VM formation-enriched pathways were differentially downregulated in vitamin D-treated cells when compared with control counterparts. Treatment of BC cells with calcitriol resulted in increased expression of tissue inhibitors of metalloproteinases (TIMPs 1 and 2) and decreased content and gelatinolytic activity of matrix metalloproteinases (MMPs 2 and 9). Furthermore, calcitriol treatment reduced the expression of several pro-MV formation regulators including vascular endothelial growth factor (VEGF), tumor growth factor (TGF-β1), and amphiregulin. Eventually, this process resulted in a profound reduction in cell migration and invasion following the treatment of BC cells with calcitriol when compared to the controls. Finally, the formation of VM was diminished in the aggressive triple‐negative MDA-MB-231 cancer cell line after calcitriol treatment.ConclusionOur findings demonstrate that vitamin D mediates its antitumor effects in BC cells by inhibiting and curtailing their potential for VM formation.

Estrogen (E2) regulates hundreds of genes involved in cell metabolism and disrupts iron homoeostasis in various cell types. Herein, we addressed whether E2-induced epigenetic modifications are involved in modulating the expression of iron-regulatory genes. Epigenetic status of FTH1 and TFRC genes was assessed in E2-treated cancer cells. E2-induced DNA methylation was associated with decreased FTH1 and TFRC expression in Hep-G2 and Huh7 cells, but not in AGS or MCF7 cells. Demethylation with 5-Aza-2-deoxycytidine upregulated the expression of both these genes in Hep-G2 cells. The expression of DNMT3B, PRMT5, and H4R3me2s increased in E2-treated cells. Chromatin immunoprecipitation showed that E2 treatment recruited PRMT5 and H4R3me2s on FTH1 but not on TFRC. Knockdown of PRMT5, DNMT3B, and Estrogen-receptor alpha rescued FTH1 from E2-induced silencing. However, knockdown of DNMT3B alone blocked the inhibitory effects of E2 on TFRC. Analysis of human liver tissues in publicly available datasets showed that FTH1 and TFRC are highly expressed in primary liver tumours, but a lower expression is associated with better survival. Interestingly, we showed that the silencing of FTH1 and/or TFRC inhibited carcinogenesis in Hep-G2 cells. For the first time, our findings uncovered the novel signalling pathway involved in the protective effects of E2 against liver cancer.

Cancer is the second leading cause of fatalities at the global level, and the involvement of microbes in several diseases, including cancer is well known. The gut microbiome is known to have an essential role in the regulation of the host's health and physiology. The gut microbiota and their metabolites may induce immunological and cellular pathways to eliminate invading pathogens and trigger an immune response to prevent cancer. Gut microbiota can even affect the efficiency of chemotherapeutic drugs. While, the commensal microbiota activates inflammasomes that keep the host's cellular and gut integrity, dysbiosis in the gut may lead to tumorigenesis and is associated with approximately 20% of all cancers. Herein, we discuss the role of gut microflora in both cancer-genesis as well as the prevention of cancer. We discuss specific microbes that may contribute to cancer development. It is speculated that several bacteria with probiotic characteristics may be used as bio-therapeutic agents to re-establish the microbial population and induce a strong immune response to eliminate cancers, and this should be the subject of future research.

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.

Background: Vitamin D deficiency associates with high risk of breast cancer (BRCA) and increased cellular iron. Vitamin D exerts some of its anti-cancer effects by regulating the expression of key iron regulatory genes (IRGs). The association between vitamin D and cellular iron content in BRCA remains ambiguous. Herein, we addressed whether vitamin D signaling exerts a role in cellular iron homeostasis thereby affecting survival of breast cancer cells.Methods: Expression profile of IRGs in vitamin D-treated breast cancer cells was analyzed using publicly available transcriptomic datasets. After treatment of BRCA cell lines MCF-7 and MDA-MB-231 with the active form of vitamin D, labile iron content, IRGs protein levels, oxidative stress, and cell survival were evaluated.Results: Bioinformatics analysis revealed several IRGs as well as cellular stress relates genes were differentially expressed in BRCA cells. Vitamin D treatment resulted in cellular iron depletion and differentially affected the expression of key IRGs protein levels. Vitamin D treatment exerted oxidative stress induction and alteration in the cellular redox balance by increasing the synthesis of key stress-related markers. Collectively, these effects resulted in a significant decrease in BRCA cell survival.Conclusion: These findings suggest that vitamin D disrupts cellular iron homeostasis leading to oxidative stress induction and cell death.

Homeobox proteins, encoded by HOX genes, are transcriptional factors playing a crucial role in the master regulatory pathway in the cells. Any mutations in HOX genes will affect the expression of its allied proteins. Such mutations were correlated to the development of different cancer types. In this study, we found 15 HOX genes with a potential target to miRNA, which regulates the translation of the protein by binding to its mRNA through the 3′UTR region. Single nucleotide polymorphisms (SNPs) in this binding region could drastically affect the protein expression by affecting the number and the stability of miRNA-mRNA complexes. We found 77 miRNAs in 15 genes which were found to have altered binding efficiency because of 26 SNPs. After which, we tried to evaluate the impact of each of these SNPs on related HOX genes. Some SNPs such as SNP 15689 on the HOXB7 gene will decrease gene expression by creating or enhancing new binding sites for miRNA to mRNA, while other SNPs such as SNP 872760 on the HOXB5 gene will overexpress the gene by breaking or decreasing existing binding sites from miRNA to mRNA. Then we conducted an expression analysis to compare the mRNA expression profiles in normal and cancer tissue. Subsequently, we did an enrichment analysis followed by a network analysis to shed light on the metabolic function of the gene that could be affected by mutation and whether these mutations may affect other genes. For the first time, this study delivers information on the possible epigenetic regulation of HOX genes via the 77 miRNAs that have predicted target binding sites on HOX mRNAs, and SNPs may regulate those. Furthermore, we show that the HOX gene misregulation may influence other HOX and non-HOX genes, based on network analysis.

Objective: Biliary tract cancers are among the most fatal subtypes of gastrointestinal cancer. The pathogenesis of these tumors involves several molecular alterations in the genes. This review article focuses mainly on the role of K-Ras (a proto-oncogene) and p53 (a tumor-suppressor gene) which are among the most commonly mutated genes, with K-Ras activation being detected in 50% to 75% and P53 inactivation in 30% to 40% of biliary tract carcinomas. Methods: PubMed and Google Scholar were searched using the terms TP53, KRAS, mutation, biliary tract carcinoma, cholangiocarcinoma, murine model. In total, 72 articles were reviewed of which 26 articles from the 21st Century were included in this review. The articles excluded were mere repetitions, duplicates or were irrelevant. No data was retrieved from posters, presentations, cell lines and symposiums. Moreover, experiments involving bile aspirations were not included in this review article. Results: Three studies conducted in China, Japan and Taiwan reported a positive correlation between K-Ras mutation and biliary tract carcinoma. Only one study conducted in China showed the sole correlation between p53 inactivation and biliary tract carcinoma. Among the studies conducted in China, Japan and Europe, only four showed a positive association between both K-Ras mutation and p53 inactivation and biliary tract carcinoma. Conclusion: K-Ras and p53 mutation both contribute to biliary tract carcinoma. K-Ras mutation, however, has a much higher frequency as compared to p53 inactivation in these cancers. Keywords: p53, K-Ras, mutation, biliary tract carcinoma, cholangiocarcinoma, murine models. Continuous..

Numerous researches have focused on the genetic variations affecting SARS-CoV-2 infection, whereas the epigenetic effects are inadequately described. In this report, for the first time, we have identified potential candidate genes that might be regulated via SARS-CoV-2 induced DNA methylation changes in COVID-19 infection. At first, in silico transcriptomic data of COVID-19 lung autopsies were used to identify the top differentially expressed genes containing CpG Islands in their promoter region. Similar gene regulations were also observed in an in vitro model of SARS-CoV-2 infected lung epithelial cells (NHBE and A549). SARS-CoV-2 infection significantly decreased the levels of DNA methyltransferases (DNMT1, DNMT3A, and DNMT3B) in lung epithelial cells. Out of 14 candidate genes identified, the expression of 12 genes was upregulated suggesting promoter hypomethylation, while only two genes were downregulated suggesting promoter hypermethylation in COVID-19. Among those 12 upregulated genes, only HSPA1L and ULBP2 were found to be upregulated in AZA-treated lung epithelial cells and immune cells, suggesting their epigenetic regulation. To confirm the hypomethylation of these two genes during SARS-CoV-2 infection, their promoter methylation and mRNA expression levels were determined in the genomic DNA/RNA obtained from whole blood samples of asymptomatic, severe COVID-19 patients and equally matched healthy controls. The methylation level of HSPA1L was significantly decreased and the mRNA expression was increased in both asymptomatic and severe COVID-19 blood samples suggesting its epigenetic regulation by SARS-CoV-2 infection. Functionally, HSPA1L is known to facilitate host viral replication and has been proposed as a potential target for antiviral prophylaxis and treatment.

Cadmium (Cd) is a heavy metal and a highly toxic pollutant that is released into the environment as a byproduct of most modern factories and industries. Cd enters our body in significant quantities from contaminated water, cigarette smoke, or food product to many detrimental health hazards. Based on causal association all the Cd-related or derived compounds have been classified as carcinogens. In this study, we present an overview of the published literature to understand the molecular mechanisms for Cd-induced carcinogenesis and its prevention. In acute Cd poisoning production of reactive oxygen species is a key factor. However, chronic Cd exposure can transform cells to become more resistant to oxidative stress. Also, as an epigenetic mechanism Cd acts indirectly on DNA repair mechanisms via alteration of reactions upstream. Those transformed cells acquire resistance to apoptosis and deregulation of calcium homeostasis. Leading to uncontrolled carcinogenic cell proliferation and inherent DNA lesions. Flavonoids commonly found in plant foods have been shown to have a protective effect against Cd-induced carcinogenicity. A wide variety of tumorigenic mechanisms involved in chronic Cd exposure and the beneficial effects of flavonoids against Cd-induced carcinogenicity necessitate further investigations.

Since the discovery of antibiotics, humans have been benefiting from them by decreasing the morbidity and mortality associated with bacterial infections. However, in the past few decades, misuse of antibiotics has led to the emergence of bacterial infections resistant to multiple drugs, a significant health concern. Bacteria exposed to inappropriate levels of antibiotics lead to several genetic changes, enabling them to survive in the host and become more resistant. Despite the understanding and targeting of genetic-based biochemical changes in the bacteria, the increasing levels of antibiotic resistance are not under control. Many reports hint at the role of epigenetic modifications in the bacterial genome and host epigenetic reprogramming due to interaction with resistant pathogens. Epigenetic changes, such as the DNA-methylation-based regulation of bacterial mutation rates or bacteria-induced histone modification in human epithelial cells, facilitate its long-term survival. In this review article, epigenetic changes leading to the development of antibiotic resistance in clinically relevant bacteria are discussed. Additionally, recent lines of evidence focusing on human host epigenetic changes due to the human–pathogen interactions are presented. As genetic mechanisms cannot explain the transient nature of antimicrobial resistance, we believe that epigenetics may provide new frontiers in antimicrobial discovery.

We have previously found that sera from Crocodylus porosus contain anticancer agents and the treatment of MCF7 cells with this serum resulted in the differential expression of 51 genes. The purpose of this study was to use in silico analysis to identify genes that might be epigenetically modulated in cells treated with crocodile serum and to understand the role of potential genes as novel candidates with epigenetic therapeutic potential. The findings report five proto-oncogenes (TUBA1B, SLC2A1, PGK1, CCND1, and NCAPD2) and two tumor suppressor genes (RPLP2, RPL37) as novel therapeutic targets. Furthermore, we present a comprehensive overview of relevant studies on epigenetic regulation of these genes along with an insight into their clinical implications. Therefore, elucidating the molecules present in the serum and gut bacteria of reptiles such as crocodiles may offer insights into the role of these genes on longevity, health, disease, and life expectancy.

Objective: Aims of this study was to investigate the relationship of 3 common polymorphisms in the HFE gene (C282Y, H63D and S65C) with high body iron status in a population of Pakistani patients with type 2 diabetes mellitus (DM) and to explore if there is any novel mutation in HFE gene in a sample of Pakistani subjects with type 2 DM. Methods: In a case-control design, 200 healthy controls and 200 consecutive adult subjects with type 2 DM (both gender; age range of 30-70 years) were enrolled with informed consent. Their serum samples were analyzed for body iron status (ratio of concentration of soluble transferrin receptor to ferritin concentration). DNA from blood was screened for HFE gene polymorphisms via polymerase chain reaction, followed by restriction fragment length polymorphism or via Sanger sequencing to identify any novel mutation(s) in HFE gene. Results: We found that there was lack of any association between HFE polymorphism and body iron status in Pakistani subjects with type 2 DM and healthy controls. H63D was the most common polymorphism found in this population. Single base substitution of G nucleotide instead of C at the codon position 187 in the HFE gene exon 2 was discovered in one subject with DM. There was also a lack of association between D allele (variant allele of H63D) and type 2 DM. A significant relationship was found between CG genotype and abnormal albuminuria in subjects with type 2 DM (p = 0.036). Continuous...

Recent research suggests that melatonin (Mel), an endogenous hormone and natural supplement, possesses anti-proliferative effects and can sensitise cells to anti-cancer therapies. Although shikonin (SHK) also possesses potential anti-cancer properties, the poor solubility and severe systemic toxicity of this compound hinders its clinical usage. In this study, we combined Mel and SHK, a potentially promising chemotherapeutic drug combination, with the aim of reducing the toxicity of SHK and enhancing the overall anti-cancer effects. We demonstrate for the first time that Mel potentiates the cytotoxic effects of SHK on cancer cells by inducing oxidative stress via inhibition of the SIRT3/SOD2-AKT pathway. Particularly, Mel-SHK treatment induced oxidative stress, increased mitochondrial calcium accumulation and reduced the mitochondrial membrane potential in various cancer cells, leading to apoptosis. This drug combination also promoted endoplasmic reticulum (ER) stress, leading to AKT dephosphorylation. In HeLa cells, Mel-SHK treatment reduced SIRT3/SOD2 expression and SOD2 activity, while SIRT3 overexpression dramatically reduced Mel-SHK-induced oxidative stress, ER stress, mitochondrial dysfunction and apoptosis. Hence, we propose the combination of Mel and SHK as a novel candidate chemotherapeutic regimen that targets the SIRT3/SOD2-AKT pathway in cancer.

الملخص: أهداف البحث: لالتهاب الفقرات والمفاصل أنماط مختلفة في مناطق مختلفة من العالم. وتعتبر معرفة النمط الإقليمي مهمة للتشخيص الصحيح. تهدف هذه الدراسة لتقييم الأعراض والنمط السريري لالتهاب الفقرات والمفاصل بين شريحة المجتمع المنخفضة اقتصاديا واجتماعيا في الباكستان. طرق البحث: خلال الفترة من يوليو ٢٠١٦ إلى يونيو ٢٠١٧، تم إجراء دراسة ملاحظة سريرية في مستشفى تعليمي جامعي للرعاية الثالثة. وكانت العينة التي تم الاختيار منها ٥٠٠٠ شخص في البداية من عيادة الروماتيزم. وتم اختيار ١١٤ شخص وإدراجهم في هذه الدراسة على النحو المحدد في معايير الاشتمال. كما تم تسجيل جميع المتغيرات الديموغرافية وعمل الفحوصات السريرية الأساسية. وتم تجميع معلومات المريض بناء على المشاهدات الدارجة لالتهاب الفقرات والمفاصل. واستخدمت معايير تشخيص مجموعة الدراسة الأوروبية لالتهاب الفقرات والمفاصل لتشخيص وتصنيف المشاركين بالدراسة. النتائج: من بين ١١٤ حالة تم تشخيصها في هذه الدراسة، ضمت الدراسة ٣٦٪ (٤١) من الإناث و٦٤٪ (٧٣) من الذكور. وكان متوسط العمر للمرضى بين ٢٥-٦٥ عاما. وكان الذكور أكثر تضررا بمرتين تقريبا عن الإناث بمعدل ٢: ١.٤. وكان الذكور في العمر ٣٠-٦٠ عاما الأكثر ضررا. وكانت الأنواع الفرعية الأكثر تشخيصا في كثير من الأحيان التهاب الفقار اللاصق، والتهاب المفاصل التفاعلي والتهاب المفاصل الصدفي. وكانت أكثر الأعراض انتشارا هي التهاب المفصل العجزي الحرقفي، وألم التهاب العمود الفقري والتهاب المفصل الزليلي. الاستنتاجات: وجدت الدراسة الهيمنة الذكورية لالتهاب الفقرات والمفاصل، ومن بين جميع المرضى الذين شملتهم هذه الدراسة؛ تم تشخيص التهاب الفقار اللاصق، والتهاب المفاصل الصدفي والتهاب المفاصل التفاعلي مع الأنواع الفرعية السائدة -لالتهاب الفقرات والمفاصل. Abstract: Objectives: The patterns of spondyloarthropathies (SpA) differ across regions globally, and an understanding of these patterns is important for the correct diagnosis of this condition. The aim of this study was to evaluate the presenting symptoms and clinical patterns of SpA in a community of low socioeconomic status in Pakistan. Methods: This clinical observational study was conducted in a tertiary care teaching hospital from July 2016 to June 2017. Five thousand patients were initially recruited in the rheumatology clinic. A total of 114 patients were finally selected and enrolled in this study, as defined by the inclusion criteria. All demographic variables were recorded and baseline clinical investigations were performed. The European Spondyloarthropathy Study Group (ESSG) diagnostic criteria were used to diagnose the condition and classify the study participants. Results: Of the 114 patients, 64% (73 patients) were men and 36% (41 patients) were women. The mean age of the patients ranged 25–65 years. The men were affected twice as much as women with a ratio of 2:1.4. Men in the age group of 30–60 years constituted a large proportion of the study population. The most frequently diagnosed subtypes were ankylosing spondylitis, reactive arthritis, and psoriatic arthritis. The most common presenting symptoms were sacroiliitis, inflammatory spinal pain, and synovitis. Conclusion: Males had a higher prevalence of SpA. Ankylosing spondylitis, psoriatic arthritis, and reactive arthritis were the most commonly diagnosed subtypes. الكلمات المفتاحية: التهاب الفقرات والمفاصل, التهاب المفاصل الروماتويدي, التهاب المفاصل الصدفي, التهاب الفقار اللاصق, التهاب المفاصل التفاعلي, Keywords: Ankylosing spondylitis, Psoriatic arthritis, Reactive arthritis, Rheumatoid arthritis, Spondyloarthropathies

Cancer cells can reprogram their metabolic activities and undergo uncontrolled proliferation by utilizing the power of heat shock proteins (HSPs). HSPs are highly conserved chaperones that facilitate the folding of intracellular proteins under stress. Constitutively, HSPs are expressed at low levels, but their expression upregulates in response to a wide variety of insults, including anticancer drugs, allowing cancer cells to develop chemoresistance. In recent years, several researchers have reported that HSPs could be an important therapeutic target in difficult-to-treat cancers such as colorectal carcinoma (CRC). Worldwide, CRC is the second most common type of cancer and the second leading cause of cancer-related deaths. The molecular complexity of CRC and the coexisting inflammatory conditions present a significant obstacle to developing effective treatment. Recently, considerable progress has been made in enhancing our understanding of the role of HSPs in CRC pathogenesis. Moreover, novel therapeutic strategies targeting HSPs, either alone or in combination with other anticancer agents, have been reported. Herein, we present an overview of the functional mechanisms and the diagnostic and prognostic potential of HSPs in CRC. We also discuss emerging anti-CRC strategies based on targeting HSPs.

Colorectal cancer (CRC) development is a gradual process defined by the accumulation of numerous genetic mutations and epigenetic alterations leading to the adenoma-carcinoma sequence. Despite significant advances in the diagnosis and treatment of CRC, it continues to be a leading cause of cancer-related deaths worldwide. Even in the presence of oxygen, CRC cells bypass oxidative phosphorylation to produce metabolites that enable them to proliferate and survive—a phenomenon known as the “Warburg effect”. Understanding the complex glucose metabolism in CRC cells may support the development of new diagnostic and therapeutic approaches. Here we discuss the most recent findings on genetic mutations and epigenetic modulations that may positively or negatively regulate the Warburg effect in CRC cells. We focus on the non-coding RNA (ncRNA)-based epigenetics, and we present a perspective on the therapeutic relevance of critical molecules and ncRNAs mediating the Warburg effect in CRC cells. All the relevant studies were identified and assessed according to the genes and enzymes mediating the Warburg effect. The findings summarized in this review should provide a better understanding of the relevance of genetic mutations and the ncRNA-based epigenetic alterations to CRC pathogenesis to help overcome chemoresistance.

Helicobacter pylori (H. pylori) infection occurs among half of the general population worldwide, with high geographic variability. Even though H. pylori is the leading cause of several gastric diseases, ranging from gastritis and peptic ulcers to gastric malignancies, such as gastric cancer and mucosa-associated lymphoid tissue lymphoma, most of the infections remain asymptomatic. Early detection and eradication of H. pylori can definitely prevent severe long-term gastric diseases associated with H. pylori. In Lebanon, the prevalence of H. pylori is not well documented, especially in healthy subjects. The aim of this study is to assess H. pylori infections and the associated risk factors in Tripoli, North Lebanon. A cross-sectional study was conducted on 300 healthy Lebanese volunteers, including both children and adults. The H. pylori stool antigens were detected using the Premier Platinum HpSA test. The socio-demographic data, lifestyle characteristics, and gastrointestinal characteristics of all participants were analyzed. Out of the 300 tested volunteer subjects, 31% were found to be positive for H. pylori. A multivariate binary logistic regression analysis for factors associated with H. pylori infection revealed a significant association between H. pylori infection and gastrointestinal disturbances, the crowding index, and occupation. A significant statistical correlation was found between sheesha smoking (p = 0.001) and H. pylori infection. These findings highlight the need for the development of preventive approaches and strategic indications for the appropriate treatment of H. pylori infections in Tripoli, North Lebanon.

Gastric cancer is among the most common malignancies worldwide. Due to limited availability of therapeutic options, there is a constant need to find new therapies that could target advanced, recurrent, and metastatic gastric cancer. Carnosic acid is a naturally occurring polyphenolic abietane diterpene derived from Rosmarinus officinalis and reported to have numerous pharmacological effects. In this study, the cytotoxicity assay, Annexin V-FITC/PI, caspases 3, 8, and 9, cell cycle analysis, and Western blotting were used to assess the effect of carnosic acid on the growth and survival of human gastric cancer cell lines (AGS and MKN-45). Our findings showed that carnosic acid inhibited human gastric cancer cell proliferation and survival in a dose-dependent manner. Additionally, carnosic acid is found to inhibit the phosphorylation/activation of Akt and mTOR. Moreover, carnosic acid enhanced the cleavage of PARP and downregulated survivin expression, both being known markers of apoptosis. In conclusion, carnosic acid exhibits antitumor activity against human gastric cancer cells via modulating the Akt-mTOR signaling pathway that plays a crucial role in gastric cancer cell proliferation and survival.

Introduction: World Health Organization (WHO) introduced hypertension as an epidemic in developing countries. However, hypertension is adequately controlled in only 12.5% of patients. The aim of this study was to evaluate the relationship between Ramadan fasting and mean arterial pressure (MAP). Methods: This clinical, observational study was carried out at Medical O.P.D of Jinnah Medical College Hospital (JMCH), Korangi, Karachi, Pakistan. A total of 150 hypertensive patients (120 males and 30 females) and 150 healthy adults (75 males and 75 females) were evaluated during the month of Ramadan (from August to September 2010). Blood pressure was measured in patients’ right arm in the sitting position. The measurements were taken a week before Ramadan and during each week of this month. The average of measurements was calculated, and the results were analyzed by SPSS version 17. Results: A reduction was observed in the MAP of hypertensive patients (from 117.3±4.2 in the first week to 108.3±4.2 in the fourth week). In the control group, the MAP was 93.1±0.6 in the first week and 92.4±0.6 in the fourth week. Conclusion: This study showed that MAP reduces during Ramadan fasting. This effect of fasting may help control blood pressure in hypertensive patients.

The United Arab Emirates (UAE) has been under continuous populational influences from Asia, Europe, and Africa, making it an ideal site for epidemiological studies on Helicobacter pylori. However, there has been a paucity of well-designed prevalence studies on H. pylori from UAE. The aim of this study was to determine the prevalence of H. pylori and its associated risk factors in the UAE. A prospective cross-sectional study was conducted on healthy asymptomatic residents of UAE. Socio-demographic, lifestyle, and gastrointestinal characteristics of participants were obtained through a questionnaire in parallel within the stool sample collection. A total of 350 participants were included in this study and were tested for H. pylori using the stool antigen test (Premier Platinum HpSAT). Out of the total tested study participants, 41% were found to be H. pylori-infected. Logistic regression analysis has shown a significant association between H. pylori infection and gender, age, ethnicity, profession, domestic overcrowding, source of drinking water, and gastrointestinal characteristics of participants. Based on the results from this study, we suggest that preventive measures against H. pylori infection should be considered worthy by public health authorities.

Gastric cancer is ranked fifth in cancer list and has the third highest mortality rate. Helicobacter pylori is a class I carcinogen and a predominant etiological factor of gastric cancer. H. pylori infection may induce carcinogenesis via epigenetic alterations in the promoter region of various genes. H. pylori is known to induce hypermethylation-silencing of several tumor suppressor genes in H. pylori-infected cancerous and H. pylori-infected non-cancerous gastric mucosae. This article presents a review of the published literature mainly from the last year 15 years. The topic focuses on H. pylori-induced DNA methylation linked to gastric cancer development. The authors have used MeSH terms “Helicobacter pylori„ with “epigenetic,„ “DNA methylation,„ in combination with “gastric inflammation„, gastritis„ and “gastric cancer„ to search SCOPUS, PubMed, Ovid, and Web of Science databases. The success of epigenetic drugs such as de-methylating agents in the treatment of certain cancers has led towards new prospects that similar approaches could also be applied against gastric cancer. However, it is very important to understand the role of all the genes that have already been linked to H. pylori-induced DNA methylation in order to in order to evaluate the potential benefits of epigenetic drugs.