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.

Uniqueness of Candida auris cell wall in morphogenesis, virulence, resistance, and immune evasion.

Candida auris has drawn global attention due to its alarming multidrug resistance and the emergence of pan resistant strains. C. auris poses a significant risk in nosocomial candidemia especially among immunocompromised patients. C. auris showed unique virulence characteristics associated with cell wall including cell polymorphism, adaptation, endurance on inanimate surfaces, tolerance to external conditions, and immune evasion. Notably, it possesses a distinctive cell wall composition, with an outer mannan layer shielding the inner 1,3-ß glucan from immune recognition, thereby enabling immune evasion and drug resistance. This review aimed to comprehend the association between unique characteristics of C. auris's cell wall and virulence, resistance mechanisms, and immune evasion. This is particularly relevant since the fungal cell wall has no human homology, providing a potential therapeutic target. Understanding the complex interactions between the cell wall and the host immune system is essential for devising effective treatment strategies, such as the use of repurposed medications, novel therapeutic agents, and immunotherapy like monoclonal antibodies. This therapeutic targeting strategy of C. auris holds promise for effective eradication of this resilient pathogen.

Azole-based compounds as potential anti-Acanthamoeba agents.

Acanthamoeba castellanii is an opportunistic pathogen with public health implications, largely due to its invasive nature and non-specific symptoms. Our study focuses on the potential of azole compounds, particularly those with triazole scaffolds, as anti-amoebic agents. Out of 10 compounds, compounds T1 and T8 exhibited effective anti-Acanthamoeba activity with MIC50 values of 125.37 and 143.92 µg mL-1, respectively. Interestingly, compounds T1, T4, T5 and T8 revealed profound anti-excystation activity with MIC50 at 32.01, 85.53, 19.54 and 80.57 µg mL-1, respectively, alongside limited cytotoxicity to human cells. The study underscores the potential of T1, T4, T5, and T8, thiazole-based compounds, as anti-Acanthamoeba agents by both eliminating amoeba viability and preventing excystation, via preserving the amoeba in its latent cyst form, exposing them to elimination by the immune system. Notably, compounds T1, T4, T5, and T8 showed optimal molecular properties, moderate oral bioavailability, and stable complex formation with Acanthamoeba CYP51. They also display superior binding interactions. Further research is needed to understand their mechanisms and optimize their efficacy against Acanthamoeba infections.

Structure-based drug design of DNA minor groove binders and evaluation of their antibacterial and anticancer properties.

Antimicrobial and chemotherapy resistance are escalating medical problem of paramount importance. Yet, research for novel antimicrobial and anticancer agents remains lagging behind. With their reported medical applications, DNA minor groove binders (MGBs) are worthy of exploration. In this study, the approach of structure-based drug design was implemented to generate 11 MGB compounds including a novel class of bioactive alkyne-linked MGBs. The NCI screening protocol was utilized to evaluate the antitumor activity of the target MGBs. Furthermore, a variety of bactericidal, cytopathogenicity, MIC90, and cytotoxicity assays were carried out using these MGBs against 6 medically relevant bacteria: Salmonella enterica, Escherichia coli, Serratia marcescens, Bacillus cereus, Streptococcus pneumoniae and Streptococcus pyogenes. Moreover, molecular docking, molecular dynamic simulations, DNA melting, and isothermal titration calorimetry (ITC) analyses were utilized to explore the binding mode and interactions between the most potent MGBs and the DNA duplex d(CGACTAGTCG)2. NCI results showed that alkyne-linked MGBs (26 & 28) displayed the most significant growth inhibition among the NCI-60 panel. In addition, compounds MGB3, MGB4, MGB28, and MGB32 showed significant bactericidal effects, inhibited B. cereus and S. enterica-mediated cytopathogenicity, and exhibited low cytotoxicity. MGB28 and MGB32 demonstrated significant inhibition of S. pyogenes, whereas MGB28 notably inhibited S. marcescens and all four minor groove binders significantly inhibited B. cereus. The ability of these compounds to bind with DNA and distort its groove dimensions provides the molecular basis for the allosteric perturbation of proteins-DNA interactions by MGBs. This study shed light on the mechanism of action of MGBs and revealed the important structural features for their antitumor and antibacterial activities, which are important to guide future development of MGB derivatives as novel antibacterial and anticancer agents.

1H-NMR metabolomics analysis identifies hypoxanthine as a novel metastasis-associated metabolite in breast cancer.

Breast cancer is one of the leading causes of death in females, mainly because of metastasis. Oncometabolites, produced via metabolic reprogramming, can influence metastatic signaling cascades. Accordingly, and based on our previous results, we propose that metabolites from highly metastatic breast cancer cells behave differently from less-metastatic cells and may play a significant role in metastasis. For instance, we aim to identify these metabolites and their role in breast cancer metastasis. Less metastatic cells (MCF-7) were treated with metabolites secreted from highly metastatic cells (MDA-MB-231) and the gene expression of three epithelial-to-mesenchymal transition (EMT) markers including E-cadherin, N-cadherin and vimentin were examined. Some metabolites secreted from MDA-MB-231 cells significantly induced EMT activity. Specifically, hypoxanthine demonstrated a significant EMT effect and increased the migration and invasion effects of MCF-7 cells through a hypoxia-associated mechanism. Hypoxanthine exhibited pro-angiogenic effects via increasing the VEGF and PDGF gene expression and affected lipid metabolism by increasing the gene expression of PCSK-9. Notably, knockdown of purine nucleoside phosphorylase, a gene encoding for an important enzyme in the biosynthesis of hypoxanthine, and inhibition of hypoxanthine uptake caused a significant decrease in hypoxanthine-associated EMT effects. Collectively for the first time, hypoxanthine was identified as a novel metastasis-associated metabolite in breast cancer cells and represents a promising target for diagnosis and therapy.

Incidence and risk factors of prostate cancer among the Northern and Eastern parts of the United Arab Emirates population.

BACKGROUND: Prostate cancer (PCa) is a prevalent disease worldwide. However, the incidence and patient-specific risk factors of PCa in the Middle East, specifically in the United Arab Emirates, have not been previously reported. METHODS: We conducted a retrospective cohort study on 2377 men diagnosed with either benign prostatic hyperplasia (BPH) or PCa in the Northern and Eastern regions of the United Arab Emirates, excluding the Western part, which includes Abu Dhabi. The study spanned from January 2012 and December 2021. To calculate the PCa incidence rate, we utilized the world age-standardized incidence rates (W-ASIR) categorized by age groups. Patient-specific risk factors of PCa were identified through a multivariate logistic regression analysis of clinical data. RESULTS: A total of 247 cases of PCa and 2130 cases of BPH were included in the study. In our cohort, the W-ASIR for PCa was 21.3 per 100,000 men. The incidence of PCa showed an increasing trend with age, with the highest incidence observed among men aged 70 years and older. Accordingly, multivariate analysis revealed that age over 70 was associated with an increased risk of PCa (OR: 2.546, 95% confidence interval [CI]: 1.892-3.425, p < 0.01). On the other hand, preexisting conditions such as hypertension and diabetes mellitus were found to lower the risk of PCa (OR: 0.222, 95% CI: 0.163-0.302, p < 0.001) and (OR: 0.364, 95% CI: 0.205-0.648, p < 0.001), respectively. Additionally, metformin intake was associated with a reduced risk of PCa (OR: 0.385, 95% CI: 0.190-0.782, p = 0.008); while insulin usage increased the risk of PCa (OR: 2.586, 95% CI: 1.539-4.344, p < 0.001). Anti-BPH medications such as phosphodiesterase inhibitors (OR: 0.223, 95% CI: 0.069-0.723, p = 0.012) or 5-α reductase (OR: 0.206, 95% CI: 0.110-0.389, p < 0.000), were found to lower the risk of PCa. CONCLUSION: The findings underscore the high incidence of PCa in the United Arab Emirates, with age being a significant factor. Furthermore, the study highlights the influence of certain comorbidities and medications on the risk of developing PCa within the United Arab Emirates population.

Design, Synthesis, and Potent Anticancer Activity of Novel Indole-Based Bcl-2 Inhibitors.

The Bcl-2 family plays a crucial role in regulating cell apoptosis, making it an attractive target for cancer therapy. In this study, a series of indole-based compounds, U1-6, were designed, synthesized, and evaluated for their anticancer activity against Bcl-2-expressing cancer cell lines. The binding affinity, safety profile, cell cycle arrest, and apoptosis effects of the compounds were tested. The designed compounds exhibited potent inhibitory activity at sub-micromolar IC50 concentrations against MCF-7, MDA-MB-231, and A549 cell lines. Notably, U2 and U3 demonstrated the highest activity, particularly against MCF-7 cells. Respectively, both U2 and U3 showed potential BCL-2 inhibition activity with IC50 values of 1.2 ± 0.02 and 11.10 ± 0.07 µM using an ELISA binding assay compared with 0.62 ± 0.01 µM for gossypol, employed as a positive control. Molecular docking analysis suggested stable interactions of compound U2 at the Bcl-2 binding site through hydrogen bonding, pi-pi stacking, and hydrophobic interactions. Furthermore, U2 demonstrated significant induction of apoptosis and cell cycle arrest at the G1/S phase. Importantly, U2 displayed a favourable safety profile on HDF human dermal normal fibroblast cells at 10-fold greater IC50 values compared with MDA-MB-231 cells. These findings underscore the therapeutic potential of compound U2 as a Bcl-2 inhibitor and provide insights into its molecular mechanisms of action.

Biosynthesized Silver Nanoparticles from Cyperus Conglomeratus Root Extract Inhibit Osteogenic Differentiation of Immortalized Mesenchymal Stromal Cells.

BACKGROUND: Silver nanoparticles (AgNPs) are a focus of huge interest in biological research, including stem cell research. AgNPs synthesized using Cyperus conglomeratus root extract have been previously reported but their effects on mesenchymal stromal cells have yet to be investigated. OBJECTIVES: The aim of this study is to investigate the effects of C. conglomeratus-derived AgNPs on adipogenesis and osteogenesis of mesenchymal stromal cells. METHODS: AgNPs were synthesized using C. conglomeratus root extract, and the phytochemicals involved in AgNPs synthesis were analyzed using gas chromatography-mass spectrometry (GC-MS). The cytotoxicity of the AgNPs was tested on telomerase-transformed immortalized human bone marrow-derived MSCs-hTERT (iMSC3) and human osteosarcoma cell line (MG-63) using MTT and apoptosis assays. The uptake of AgNPs by both cells was confirmed using inductively coupled plasma-optical emission spectrometry (ICP-OES). Furthermore, the effect of AgNPs on iMSC3 adipogenesis and osteogenesis was analyzed using stain quantification and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). RESULTS: The phytochemicals predominately identified in both the AgNPs and C. conglomeratus root extract were carbohydrates. The AgNP concentrations tested using MTT and apoptosis assays (0.5-64 µg/ml and 1,4 and 32 µg/ml, respectively) showed no significant cytotoxicity on iMSC3 and MG-63. The AgNPs were internalized in a concentration-dependent manner in both cell types. Additionally, the AgNPs exhibited a significant negative effect on osteogenesis but not on adipogenesis. CONCLUSION: C. conglomeratus-derived AgNPs had an impact on the differentiation capacity of iMSC3. Our results indicated that C. conglomeratus AgNPs and the associated phytochemicals could exhibit potential medical applications.

Intra-clade Heterogeneity in Candida auris: Risk of Management.

Candida auris has emerged as a significant nosocomial fungal pathogen with a high risk of pathogenicity. Since the initial detection of C. auris in 2009, it gained lots of attention with a recent alert by the Centers for Disease Control and Prevention (CDC) due to its high infectivity and drug resistance. Several studies showed the capability of C. auris to secrete lytic enzymes, germinate, and form a biofilm that eventually results in interactions with the host cells, leading to serious infections. Other studies demonstrated a decrease in susceptibility of C. auris strains to available antifungals, which may be caused by mutations within the target genes, or the drug efflux pumps. However, the contribution of C. auris heterogeneity in pathogenicity and drug resistance is not well studied. Here, we shed light on the factors contributing to the development of heterogeneity in C. auris. These include phenotypic changes, biofilm formation, mechanisms of drug resistance, host invasion, mode of transmission, and expression of virulence factors. C. auris exhibits different phenotypes, particularly aggregative, and non-aggregative forms that play an important role in fungal heterogeneity, which significantly affects drug resistance and pathogenicity. Collectively, heterogeneity in C. auris significantly contributes to ineffective treatment, which in turn affects the fungal pathogenicity and drug resistance. Therefore, understanding the underlying reasons for C. auris heterogeneity and applying effective antifungal stewardship could play a major role in controlling this pathogen.

Molecular pathogenicity of 1-nonadecene and L-lactic acid, unique metabolites in radicular cysts and periapical granulomas.

Recently, 1-nonadecene and L-lactic acid were identified as unique metabolites in radicular cysts and periapical granuloma, respectively. However, the biological roles of these metabolites were unknown. Therefore, we aimed to investigate the inflammatory and mesenchymal-epithelial transition (MET) effects of 1-nonadecene, and the inflammatory and collagen precipitation effects of L-lactic acid on both periodontal ligament fibroblasts (PdLFs) and peripheral blood mononuclear cells (PBMCs). PdLFs and PBMCs were treated with 1-nonadecene and L-lactic acid. Cytokines' expression was measured using quantitative real-time polymerase chain reaction (qRT-PCR). E-cadherin, N-cadherin, and macrophage polarization markers were measured using flow cytometry. The collagen, matrix metalloproteinase (MMP)-1, and released cytokines were measured using collagen assay, western blot, and Luminex assay, respectively. In PdLFs, 1-nonadecene enhances inflammation through the upregulation of some inflammatory cytokines including IL-1ß, IL-6, IL-12A, monocyte chemoattractant protein (MCP)-1, and platelet-derived growth factor (PDGF) α. 1-Nonadecene also induced MET through the upregulation of E-cadherin and the downregulation of N-cadherin in PdLFs. 1-Nonadecene polarized macrophages to a pro-inflammatory phenotype and suppressed their cytokines' release. L-lactic acid exerted a differential impact on the inflammation and proliferation markers. Intriguingly, L-lactic acid induced fibrosis-like effects by enhancing collagen synthesis, while inhibiting MMP-1 release in PdLFs. These results provide a deeper understanding of 1-nonadecene and L-lactic acid's roles in modulating the microenvironment of the periapical area. Consequently, further clinical investigation can be employed for target therapy.

Risks of prostate cancer and mortality in the city of Sharjah, United Arab Emirates.

Background: Prostatic hyperplasia (BPH) and prostate cancer (PCa) are common age-related diseases in men. According to World Health Organization (WHO), PCa is the second most common cancer among Emirati men. This study aimed to identify the risk factors associated with PCa and mortality in a cohort diagnosed with PCa between 2012 and 2021 in Sharjah, United Arab Emirates (UAE). Methods: The data collected in this retrospective case-control study included patient demographics and comorbidities, as well as PCa markers such as prostate-specific antigen (PSA), prostate volume, prostate-specific antigen density (PSAD), and Gleason scores. Risk factors for PCa were assessed using multivariate logistic regression analysis, and factors associated with all-cause mortality in PCa patients were evaluated using Cox-proportional hazard analysis. Results: Of the 192 cases analyzed in this study, 88 were diagnosed with PCa and 104 were diagnosed with BPH. Regarding risk factors for PCa, a higher risk of PCa was associated with age 65 or older (OR=2.76, 95% confidence interval (CI): 1.04-7.30; P=0.038) and serum PSAD greater than 0.1 ng/mL2 (OR=3.48, 95% CI:1.66-7.32; P=0.001), whereas being of UAE nationals (OR=0.40, 95% CI:0.18-0.88; P=0.029) were associated with lower risk of PCa, after adjusting for patient demographics and comorbidities. Moreover, regarding cancer markers, higher serum PSA level (P=0.003) and smaller prostate volume (P=0.028) were associated with a higher risk of PCa, after adjusting with patients' age and BMI. Additionally, a high-grade Gleason score was associated with an increased risk of all-cause mortality after adjusting for patient's age and BMI (hazard ratio, aHR= 2.3, 95% CI:1.3-4.1; P= 0.016). Conclusion: This study found that age 65 or older and serum PSAD greater than 0.1 ng/mL2 are risk factors for PCa, while UAE nationality is associated with a lower risk. PSAD may be a better screening marker for PCa compared to traditional markers such as PSA and prostate volume.

Evolutionary relevance of metabolite production in relation to marine sponge bacteria symbiont.

Sponges are habitats for a diverse community of microorganisms. Sponges provide shelter, whereas microbes provide a complementary defensive mechanism. Here, a symbiotic bacterium, identified as Bacillus spp., was isolated from a marine sponge following culture enrichment. Fermentation-assisted metabolomics using thin-layer chromatography (TLC) and gas chromatography-mass spectrometry (GC-MS) indicated that marine simulated nutrition and temperature was the optimum in metabolite production represented by the highest number of metabolites and the diverse chemical classes when compared to other culture media. Following large-scale culture in potato dextrose broth (PDB) and dereplication, compound M1 was isolated and identified as octadecyl-1-(2',6'-di-tert-butyl-1'-hydroxyphenyl) propionate. M1, at screening concentrations up to 10 mg/ml, showed no activity against prokaryotic bacteria including Staphylococcus aureus and Escherichia coli, while 1 mg/ml of M1 was sufficient to cause a significant killing effect on eukaryotic cells including Candida albicans, Candida auris, and Rhizopus delemar fungi and different mammalian cells. M1 exhibited MIC50 0.97 ± 0.006 and 7.667 ± 0.079 mg/ml against C. albicans and C. auris, respectively. Like fatty acid esters, we hypothesize that M1 is stored in a less harmful form and upon pathogenic attack is hydrolyzed to a more active form as a defensive metabolite. Subsequently, [3-(3,5-di-tert-butyl-4-hydroxyphenyl)-propionic acid] (DTBPA), the hydrolysis product of M1, exhibited ~ 8-fold and 18-fold more antifungal activity than M1 against C. albicans and C. auris, respectively. These findings indicated the selectivity of that compound as a defensive metabolite towards the eukaryotic cells particularly the fungi, a major infectious agent to sponges. Metabolomic-assisted fermentation can provide a significant understanding of a triple marine-evolved interaction. KEY POINTS: • Bacillus species, closely related to uncultured Bacillus, is isolated from Gulf marine sponge • Metabolomic-assisted fermentations showed diverse metabolites • An ester with a killing effect against eukaryotes but not prokaryotes is isolated.

Changes in the gut microbiota of NOD mice in response to an oral Salmonella-based vaccine against type 1 diabetes.

We developed an oral Salmonella-based vaccine that prevents and reverses diabetes in non-obese diabetic (NOD) mice. Related to this, the gastrointestinal tract harbors a complex dynamic population of microorganisms, the gut microbiome, that influences host homeostasis and metabolism. Changes in the gut microbiome are associated with insulin dysfunction and type 1 diabetes (T1D). Oral administration of diabetic autoantigens as a vaccine can restore immune balance. However, it was not known if a Salmonella-based vaccine would impact the gut microbiome. We administered a Salmonella-based vaccine to prediabetic NOD mice. Changes in the gut microbiota and associated metabolome were assessed using next-generation sequencing and gas chromatography-mass spectrometry (GC-MS). The Salmonella-based vaccine did not cause significant changes in the gut microbiota composition immediately after vaccination although at 30 days post-vaccination changes were seen. Additionally, no changes were noted in the fecal mycobiome between vaccine- and control/vehicle-treated mice. Significant changes in metabolic pathways related to inflammation and proliferation were found after vaccine administration. The results from this study suggest that an oral Salmonella-based vaccine alters the gut microbiome and metabolome towards a more tolerant composition. These results support the use of orally administered Salmonella-based vaccines that induced tolerance after administration.

Bilateral keratouveitis associated with COVID-19 multisystem inflammatory syndrome in children.

We report the case of a 16-year-old girl admitted to hospital with multisystem inflammatory syndrome in children (MIS-C) secondary to COVID-19. Conjunctivitis-like symptoms prompted ocular examination, which demonstrated peripheral confluent corneal opacities and anterior uveitis. Uveitis laboratory investigations were negative, and with topical steroid treatment her signs and symptoms resolved completely. These features may be overlooked in the setting of MIS-C, where patients are systemically unwell and are typically examined at the bedside.

Peptide-functionalized zinc oxide nanoparticles for the selective targeting of breast cancer expressing placenta-specific protein 1.

Functionalized metal oxide nanoparticles (NPs) have demonstrated specific binding affinity to antigens or receptors presented on the cancer cell surface, favouring selective targeting and minimizing side effects during the chemotherapy. Placenta-specific protein 1 (PLAC-1) is a small cell surface protein overexpressed in certain types of breast cancer (BC); therefore, it can be used as a therapeutic target. The objective of this study is to develop NPs that can bind PLAC-1 and hence can inhibit the progression and metastatic potential of BC cells. Zinc oxide (ZnO) NPs were coated with a peptide (GILGFVFTL), which possesses a strong binding ability to PLAC-1. The physical attachment of the peptide to ZnO NPs was verified through various physicochemical and morphological characterization techniques. The selective cytotoxicity of the designed NPs was investigated using PLAC-1-bearing MDA-MB 231 human BC cell line and compared to LS-180 cells that do not express PLAC-1. The anti-metastatic and pro-apoptotic effects of the functionalized NPs on MDA-MB 231 cells were examined. Confocal microscopy was used to investigate the mechanism of NPs uptake by MDA-MB 231 cells. Compared to non-functionalized NPs, peptide functionalization significantly improved the targeting and uptake of the designed NPs by PLAC-1-expressing cancer cells with significant pro-apoptotic and anti-metastatic effects. The uptake of peptide functionalized ZnO NPs (ZnO-P NPs) occurred via peptide-PLAC1 interaction-assisted clathrin-mediated endocytosis. These findings highlight the potential targeted therapy of ZnO-P NPs against PLAC-1-expressing breast cancer cells.

Nano-combination for Reviving the Activity of Fluconazole against Rhizopus delemar.

BACKGROUND: Rhizopus delemar, the main causative pathogen for the lethal mucormycosis and a severe threat during the COVID-19 pandemic, is resistant to most antifungals, including fluconazole, a known selective antifungal drug. On the other hand, antifungals are known to enhance fungal melanin synthesis. Rhizopus melanin plays an important role in fungal pathogenesis and in escaping the human defense mechanism, thus complicating the use of current antifungal drugs and fungal eradication. Because of drug resistance and the slow discovery of effective antifungals, sensitizing the activity of older ones seems a more promising strategy. METHODS: In this study, a strategy was employed to revive the use and enhance the effectiveness of fluconazole against R. delemar. UOSC-13, a compound synthesized in-house to target the Rhizopus melanin, was combined with fluconazole either as is or after encapsulation in poly (lactic-coglycolic acid) nanoparticles (PLG-NPs). Both combinations were tested for the growth of R. delemar, and the MIC50 values were calculated and compared. RESULTS: The activity of fluconazole was found to be enhanced several folds following the use of both combined treatment and nanoencapsulation. The combination of fluconazole with UOSC-13 caused a 5-fold reduction in the MIC50 value of fluconazole. Furthermore, encapsulating UOSC-13 in PLG-NPs enhanced the activity of fluconazole by an additional 10 folds while providing a wide safety profile. CONCLUSION: Consistent with previous reports, the encapsulation of fluconazole without sensitization showed no significant difference in activity. Collectively, sensitization of fluconazole represents a promising strategy to revive the use of outdated antifungal drugs back in the market.

SARS-CoV-2-free residual proteins mediated phenotypic and metabolic changes in peripheral blood monocytic-derived macrophages in support of viral pathogenesis.

The large-scale dissemination of coronavirus disease-2019 (COVID-19) and its serious complications have pledged the scientific research communities to uncover the pathogenesis mechanisms of its etiologic agent, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Methods of unveiling such mechanisms are rooted in understanding the viral agent's interactions with the immune system, including its ability to activate macrophages, due to their suggested role in prolonged inflammatory phases and adverse immune responses. The objective of this study is to test the effect of SARS-CoV-2-free proteins on the metabolic and immune responses of macrophages. We hypothesized that SARS-CoV-2 proteins shed during the infection cycle may dynamically induce metabolic and immunologic alterations with an inflammatory impact on the infected host cells. It is imperative to delineate such alterations in the context of macrophages to gain insight into the pathogenesis of these highly infectious viruses and their associated complications and thus, expedite the vaccine and drug therapy advent in combat of viral infections. Human monocyte-derived macrophages were treated with SARS-CoV-2-free proteins at different concentrations. The phenotypic and metabolic alterations in macrophages were investigated and the subsequent metabolic pathways were analyzed. The obtained results indicated that SARS-CoV-2-free proteins induced concentration-dependent alterations in the metabolic and phenotypic profiles of macrophages. Several metabolic pathways were enriched following treatment, including vitamin K, propanoate, and the Warburg effect. These results indicate significant adverse effects driven by residual viral proteins that may hence be considered determinants of viral pathogenesis. These findings provide important insight as to the impact of SARS-CoV-2-free residual proteins on the host cells and suggest a potential new method of management during the infection and prior to vaccination.

Alpha to Omicron (Variants of Concern): Mutation Journey, Vaccines, and Therapy.

Coronavirus disease 2019 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) initially emerged in December 2019 and has subsequently expanded globally, leading to the ongoing pandemic. The extensive spread of various SARS-CoV-2 variants possesses a serious public health threat. An extensive literature search along with deep analysis was performed to describe and evaluate the characteristics of SARS-CoV-2 variants of concern in relation to the effectiveness of the current vaccines and therapeutics. The obtained results showed that several significant mutations have evolved during the COVID-19 pandemic. The developed variants and their various structural mutations can compromise the effectiveness of several vaccines, escape the neutralizing antibodies, and limit the efficiency of available therapeutics. Furthermore, deep analysis of the available data enables the prediction of the future impact of virus mutations on the ongoing pandemic along with the selection of appropriate vaccines and therapeutics.

The Essential Role of 17-Octadecynoic Acid in the Pathogenesis of Periapical Abscesses.

INTRODUCTION: Periapical abscesses are 1 of the most frequent pathologic lesions in the alveolar bone. Recently, we have identified 17-octadecynoic acid (17-ODYA) as the highest unique metabolite in periapical abscesses. Therefore, the aim of this study was to investigate the immunologic and pathophysiological roles of this metabolite in the initiation and development of periapical abscesses. METHODS: Periodontal ligament fibroblasts and peripheral blood mononuclear cells were treated with 17-ODYA. Gene expression analysis and interleukin (IL)-8 release were determined using quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay. Macrophage polarization and cytokine release were also determined using flow cytometry and Luminex bioassay (R&D Systems, Minneapolis, MN), respectively. RESULTS: In periodontal ligament fibroblasts, 17-ODYA caused significant (P < .0001) up-regulation of IL-1α, IL-1ß, IL-6, matrix metalloproteinase-1, and monocyte chemoattractant protein-1 at 10 µmol/L after 6 days of treatment and up-regulation of platelet-derived growth factor alpha and vascular endothelial growth factor alpha at all tested concentrations after 2 days of treatment. In peripheral blood mononuclear cells, 17-ODYA significantly increased the expression of IL-1α, IL-1ß, IL-6, matrix metalloproteinase-1, and monocyte chemoattractant protein-1 at 10 µmol/L (P < .0001) and vascular endothelial growth factor alpha and platelet-derived growth factor alpha at 1 µmol/L 17-ODYA (P < .0001). 17-ODYA polarized macrophages toward a proinflammatory phenotype (M1) and suppressed the release of pro- and anti-inflammatory cytokines. 17-ODYA significantly enhanced the release of IL-8. CONCLUSIONS: This study was the first to identify the pathologic role of 17-ODYA in the development of periapical abscesses. The results of this study are important in shedding light on the pathogenesis of periapical abscesses in relation to microbial metabolites.