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.

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.

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.

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.

Flavonoids are promising safe therapy against COVID-19.

Flavonoids are a class of phenolic natural products, well-identified in traditional and modern medicines in the treatment of several diseases including viral infection. Flavonoids showed potential inhibitory activity against coronaviruses including the current pandemic outbreak caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and designated as COVID-19. Here, we have collected all data related to the potential inhibitory mechanisms of flavonoids against SARS-CoV-2 infection and their significant immunomodulatory activities. The data were mapped and compared to elect major flavonoids with a promising role in the current pandemic. Further, we have linked the global existence of flavonoids in medicinal plants and their role in protection against COVID-19. Computational analysis predicted that flavonoids can exhibit potential inhibitory activity against SARS-CoV-2 by binding to essential viral targets required in virus entry and/ or replication. Flavonoids also showed excellent immunomodulatory and anti-inflammatory activities including the inhibition of various inflammatory cytokines. Further, flavonoids showed significant ability to reduce the exacerbation of COVID-19 in the case of obesity via promoting lipids metabolism. Moreover, flavonoids exhibit a high safety profile, suitable bioavailability, and no significant adverse effects. For instance, plants rich in flavonoids are globally distributed and can offer great protection from COVID-19. The data described in this study strongly highlighted that flavonoids particularly quercetin and luteolin can exhibit promising multi-target activity against SARS-CoV-2, which promote their use in the current and expected future outbreaks. Therefore, a regimen of flavonoid-rich plants can be recommended to supplement a sufficient amount of flavonoids for the protection and treatment from SARS-CoV-2 infection.

Obesity and COVID-19: What are the Consequences?

Obesity is an increasing health problem all over the world. In combination with the current COVID-19 pandemic, this has turned into a massive challenge as individuals with overweight and obesity at all ages show a significant increase in their risk of getting severe COVID-19. Around 20% of all patients that were hospitalized for COVID-19 suffered from obesity alone, whereas obesity in combination with other metabolic comorbidities, such as type 2 diabetes and hypertension, account for up to 60% of all hospitalizations in relation to COVID-19. Therefore, it is of immense importance to put the spotlight on the high incidence of obesity present already in childhood both by changing the individual minds and by encouraging politicians and the whole society to commence preventive interventions for achieving a better nutrition for all social classes all over the world. In the current review, we aim to explain the different pathways and mechanisms that are responsible for the increased risk of severe COVID-19 in people with overweight and obesity. Furthermore, we discuss how the pandemic has led to weight gains in many people during lockdown. At the end, we discuss the importance of preventing such an interface between a non-communicable disease like obesity and a communicable disease like COVID-19 in the future.

Lipid-based therapies against SARS-CoV-2 infection.

Viruses have evolved to manipulate host lipid metabolism to benefit their replication cycle. Enveloped viruses, including coronaviruses, use host lipids in various stages of the viral life cycle, particularly in the formation of replication compartments and envelopes. Host lipids are utilised by the virus in receptor binding, viral fusion and entry, as well as viral replication. Association of dyslipidaemia with the pathological development of Covid-19 raises the possibility that exploitation of host lipid metabolism might have therapeutic benefit against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this review, promising host lipid targets are discussed along with potential inhibitors. In addition, specific host lipids are involved in the inflammatory responses due to viral infection, so lipid supplementation represents another potential strategy to counteract the severity of viral infection. Furthermore, switching the lipid metabolism through a ketogenic diet is another potential way of limiting the effects of viral infection. Taken together, restricting the access of host lipids to the virus, either by using lipid inhibitors or supplementation with exogenous lipids, might significantly limit SARS-CoV-2 infection and/or severity.

Comparative evaluation of flavonoids reveals the superiority and promising inhibition activity of silibinin against SARS-CoV-2.

Flavonoids are phenolic compounds naturally found in plants and commonly consumed in diets. Herein, flavonoids were sequentially evaluated by a comparative in silico study associated with systematic literature search. This was followed by an in vitro study and enzyme inhibition assays against vital SARS-CoV-2 proteins including spike (S) protein, main protease (Mpro ), RNA-dependent RNA-polymerase (RdRp), and human transmembrane serine protease (TMPRSS2). The results obtained revealed 10 flavonoids with potential antiviral activity. Out of them, silibinin showed promising selectivity index against SARS-CoV-2 in vitro. Screening against S protein discloses the highest inhibition activity of silibinin. Mapping the activity of silibinin indicated its excellent binding inhibition activity against SARS-CoV-2 S protein, Mpro and RdRP at IC50 0.029, 0.021, and 0.042 µM, respectively, while it showed no inhibition activity against TMPRSS2 at its IC50(SARS-CoV-2) . Silibinin was tested safe on human mammalian cells at >7-fold its IC50(SARS-CoV-2) . Additionally, silibinin exhibited >90% virucidal activity at 0.031 µM. Comparative molecular docking (MD) showed that silibinin possesses the highest binding affinity to S protein and RdRP at -7.78 and -7.15 kcal/mol, respectively. MDs showed that silibinin exhibited stable interaction with key amino acids of SARS-CoV-2 targets. Collectively, silibinin, an FDA-approved drug, can significantly interfere with SARS-CoV-2 entry and replication through multi-targeting activity.

COVID-19 Vaccines, Effectiveness, and Immune Responses.

The COVID-19 pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has captivated the globe's attention since its emergence in 2019. This highly infectious, spreadable, and dangerous pathogen has caused health, social, and economic crises. Therefore, a worldwide collaborative effort was made to find an efficient strategy to overcome and develop vaccines. The new vaccines provide an effective immune response that safeguards the community from the virus' severity. WHO has approved nine vaccines for emergency use based on safety and efficacy data collected from various conducted clinical trials. Herein, we review the safety and effectiveness of the WHO-approved COVID-19 vaccines and associated immune responses, and their impact on improving the public's health. Several immunological studies have demonstrated that vaccination dramatically enhances the immune response and reduces the likelihood of future infections in previously infected individuals. However, the type of vaccination and individual health status can significantly affect immune responses. Exposure of healthy individuals to adenovirus vectors or mRNA vaccines causes the early production of antibodies from B and T cells. On the other hand, unhealthy individuals were more likely to experience harmful events due to relapses in their existing conditions. Taken together, aligning with the proper vaccination to a patient's case can result in better outcomes.

Multi-Omics Analysis Revealed a Significant Alteration of Critical Metabolic Pathways Due to Sorafenib-Resistance in Hep3B Cell Lines.

Hepatocellular carcinoma (HCC) is the second prominent cause of cancer-associated death worldwide. Usually, HCC is diagnosed in advanced stages, wherein sorafenib, a multiple target tyrosine kinase inhibitor, is used as the first line of treatment. Unfortunately, resistance to sorafenib is usually encountered within six months of treatment. Therefore, there is a critical need to identify the underlying reasons for drug resistance. In the present study, we investigated the proteomic and metabolomics alterations accompanying sorafenib resistance in hepatocellular carcinoma Hep3B cells by employing ultra-high-performance liquid chromatography quadrupole time of flight mass spectrometry (UHPLC-QTOF-MS). The Bruker Human Metabolome Database (HMDB) library was used to identify the differentially abundant metabolites through MetaboScape 4.0 software (Bruker). For protein annotation and identification, the Uniprot proteome for Homo sapiens (Human) database was utilized through MaxQuant. The results revealed that 27 metabolites and 18 proteins were significantly dysregulated due to sorafenib resistance in Hep3B cells compared to the parental phenotype. D-alanine, L-proline, o-tyrosine, succinic acid and phosphatidylcholine (PC, 16:0/16:0) were among the significantly altered metabolites. Ubiquitin carboxyl-terminal hydrolase isozyme L1, mitochondrial superoxide dismutase, UDP-glucose-6-dehydrogenase, sorbitol dehydrogenase and calpain small subunit 1 were among the significantly altered proteins. The findings revealed that resistant Hep3B cells demonstrated significant alterations in amino acid and nucleotide metabolic pathways, energy production pathways and other pathways related to cancer aggressiveness, such as migration, proliferation and drug-resistance. Joint pathway enrichment analysis unveiled unique pathways, including the antifolate resistance pathway and other important pathways that maintain cancer cells' survival, growth, and proliferation. Collectively, the results identified potential biomarkers for sorafenib-resistant HCC and gave insights into their role in chemotherapeutic drug resistance, cancer initiation, progression and aggressiveness, which may contribute to better prognosis and chemotherapeutic outcomes.

Caspofungin-resistance in Candida auris is cell wall-dependent phenotype and potential prevention by zinc oxide nanoparticles.

Candida auris is an emergent nosocomial multi-drug-resistant yeast that represents a global health threat. Recently, C. auris clinical isolates with caspofungin resistance were identified. Mutation in FKS1 gene was determined as a mechanism of resistance. However, the ability of C. auris to develop acquired and cross-resistance has never been investigated. Herein, this resistance ability due to caspofungin and associate mechanisms were investigated. C. auris clinical isolate was successively cultured for ten generations in the presence of caspofungin compared to fluconazole-treatment and untreated controls. This was followed by the analysis of target gene expression and phenotypic changes. The obtained results showed that caspofungin-treated C. auris exhibited elevated MIC50(caspofungin), slower growth, elevated chitin content, overexpression of caspofungin target genes, and cross-resistance to fluconazole. Interestingly, caspofungin exposure induced cell-cell adhesion and biofilm formation. C. auris gradually lost caspofungin resistance after removal of antifungal pressure, while keeping the overexpression of fungal cell wall-related genes including ALS5. We propose that C. auris ageing in the presence of caspofungin caused the development of persistent phenotypic changes in the fungal cell wall, leading to acquired and physical cross-resistance mechanisms. Surprisingly, formulation of caspofungin in zinc oxide nanoparticles prevented the aforementioned behavioral changes regardless of the pathogen generations. LAY SUMMARY: Candida auris developed resistance against caspofungin. Our data indicated that this resistance mechanism is unique because of changes in the genes related to cell wall adhesions. Formulation of caspofungin in ZnO nanoparticles was able to overcome these phenotypic changes.

De novo transcriptome sequencing, assembly, and gene expression profiling of a salt-stressed halophyte (Salsola drummondii) from a saline habitat.

Salsola drummondii is a perennial habitat-indifferent halophyte growing in saline and nonsaline habitats of the Arabian hyperarid deserts. It offers an invaluable opportunity to examine the molecular mechanisms of salt tolerance. The present study was conducted to elucidate these mechanisms through transcriptome profiling of seedlings grown from seeds collected in a saline habitat. The Illumina Hiseq 2500 platform was employed to sequence cDNA libraries prepared from shoots and roots of nonsaline-treated plants (controls) and plants treated with 1200 mM NaCl. Transcriptomic comparison between salt-treated and control samples resulted in 17,363 differentially expressed genes (DEGs), including 12,000 upregulated genes (7870 in roots, 4130 in shoots) and 5363 downregulated genes (4258 in roots and 1105 in shoots). The majority of identified DEGs are known to be involved in transcription regulation (79), signal transduction (82), defense metabolism (101), transportation (410), cell wall metabolism (27), regulatory processes (392), respiration (85), chaperoning (9), and ubiquitination (98) during salt tolerance. This study identified potential genes associated with the salt tolerance of S. drummondii and demonstrated that this tolerance may depend on the induction of certain genes in shoot and root tissues. These gene expressions were validated using reverse-transcription quantitative PCR, the results of which were consistent with transcriptomics results. To the best of our knowledge, this is the first study providing genetic information on salt tolerance mechanisms in S. drummondii.

SARS-CoV-2 spike protein: pathogenesis, vaccines, and potential therapies.

PURPOSE: COVID-19 pandemic has emerged as a result of infection by the deadly pathogenic severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), causing enormous threats to humans. Coronaviruses are distinguished by a clove-like spike (S) protein, which plays a key role in viral pathogenesis, evolutions, and transmission. The objectives of this study are to investigate the distinctive structural features of SARS-CoV-2 S protein, its essential role in pathogenesis, and its use in the development of potential therapies and vaccines. METHODOLOGY: A literature review was conducted to summarize, analyze, and interpret the available scientific data related to SARS-CoV-2 S protein in terms of characteristics, vaccines development and potential therapies. RESULTS: The data indicate that S protein subunits and their variable conformational states significantly affect the virus pathogenesis, infectivity, and evolutionary mutation. A considerable number of potential natural and synthetic therapies were proposed based on S protein. Additionally, neutralizing antibodies were recently approved for emergency use. Furthermore, several vaccines utilizing the S protein were developed. CONCLUSION: A better understanding of S protein features, structure and mutations facilitate the recognition of the importance of SARS-CoV-2 S protein in viral infection, as well as the development of therapies and vaccines. The efficacy and safety of these therapeutic compounds and vaccines are still controversial. However, they may potentially reduce or prevent SARS-CoV-2 infection, leading to a significant reduction of the global health burden of this pandemic.

Selective inhibition of Rhizopus eumelanin biosynthesis by novel natural product scaffold-based designs caused significant inhibition of fungal pathogenesis.

Melanin is a dark color pigment biosynthesized naturally in most living organisms. Fungal melanin is a major putative virulence factor of Mucorales fungi that allows intracellular persistence by inducing phagosome maturation arrest. Recently, it has been shown that the black pigments of Rhizopus delemar is of eumelanin type, that requires the involvement of tyrosinase (a copper-dependent enzyme) in its biosynthesis. Herein, we have developed a series of compounds (UOSC-1-14) to selectively target Rhizopus melanin and explored this mechanism therapeutically. The compounds were designed based on the scaffold of the natural product, cuminaldehyde, identified from plant sources and has been shown to develop non-selective inhibition of melanin production. While all synthesized compounds showed significant inhibition of Rhizopus melanin production and limited toxicity to mammalian cells, only four compounds (UOSC-1, 2, 13, and 14) were selected as promising candidates based on their selective inhibition to fungal melanin. The activity of compound UOSC-2 was comparable to the positive control kojic acid. The selected candidates showed significant inhibition of Rhizopus melanin but not human melanin by targeting the fungal tyrosinase, and with an IC50 that are 9 times lower than the reference standard, kojic acid. Furthermore, the produced white spores were phagocytized easily and cleared faster from the lungs of infected immunocompetent mice and from the human macrophages when compared with wild-type spores. Collectively, the results suggested that the newly designed derivatives, particularly UOSC-2 can serve as promising candidate to overcome persistence mechanisms of fungal melanin production and hence make them accessible to host defenses.

Potential targeting of Hep3B liver cancer cells by lupeol isolated from Avicennia marina.

Medicinal plants are valuable sources of different active constituents that are known to have important pharmacological activities including anticancer effects. Lupeol, a pentacyclic triterpenoid, present in many medicinal plants, has a wide range of biological activities. Although the anticancer activity of lupeol was reported, the published data are inconsistent and the clear mechanism of action has never been assigned. The current study aims at investigating the anticancer specificity and mechanism of lupeol isolated from Avicennia marina, which grows in the desert of the United Arab Emirates. The compound was purified by chromatography and identified by spectroscopy. Compared with a negative control, lupeol caused significant (p < .001) growth inhibitory activity on MCF-7 and Hep3B parental and resistant cells by 45%, 46%, 72%, and 35%, respectively. The mechanism of action of lupeol was further explored by measuring its effect on key players in cancer development and progression, BCL-2 anti-apoptotic and BAX pro-apoptotic proteins. Lupeol significantly (p < .01) downregulated BCL-2 gene expression in parental and resistant Hep3B cells by 33 and 3.5 times, respectively, contributing to the induction of apoptosis in Hep3B cells, whereas it caused no effect on BAX. Furthermore, the immunoblotting analysis revealed that lupeol cleaved the executioner caspase-3 into its active form. Interestingly, lupeol showed no significant effect on the proliferation of monocytes, whereas it caused an increase in the sub-G1 population and a reduction in the apoptosis rates of monocytes at 48 and 72 h, indicative of no immuno-inflammatory responses. Collectively, lupeol can be considered as promising effective and safe anticancer agent, particularly against Hep3B cancer cells.

New Bioactive Fused Triazolothiadiazoles as Bcl-2-Targeted Anticancer Agents.

A series of 3-(6-substituted phenyl-[1,2,4]-triazolo[3,4-b]-[1,3,4]-thiadiazol-3-yl)-1H-indoles (5a-l) were designed, synthesized and evaluated for anti-apoptotic Bcl-2-inhibitory activity. Synthesis of the target compounds was readily accomplished through a reaction of acyl hydrazide (1) with carbon disulfide in the presence of alcoholic potassium hydroxide to afford the corresponding intermediate potassium thiocarbamate salt (2), which underwent cyclization reaction in the presence of excess hydrazine hydrate to the corresponding triazole thiol (3). Further cyclisation reaction with substituted benzoyl chloride derivatives in the presence of phosphorous oxychloride afforded the final 6-phenyl-indol-3-yl [1,2,4]-triazolo[3,4-b]-[1,3,4]-thiadiazole compounds (5a-l). The novel series showed selective sub-micromolar IC50 growth-inhibitory activity against Bcl-2-expressing human cancer cell lines. The most potent 6-(2,4-dimethoxyphenyl) substituted analogue (5k) showed selective IC50 values of 0.31-0.7 µM against Bcl-2-expressing cell lines without inhibiting the Bcl-2-negative cell line (Jurkat). ELISA binding affinity assay (interruption of Bcl-2-Bim interaction) showed potent binding affinity for (5k) with an IC50 value of 0.32 µM. Moreover, it fulfils drug likeness criteria as a promising drug candidate.

Estimating the viral loads of SARS-CoV-2 in the oral cavity when complicated with periapical lesions.

BACKGROUND: The oral cavity represents a main entrance of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Angiotensin-converting enzyme 2 (ACE-2), neuropilin-1 (NRP-1), and transmembrane serine protease 2 (TMPRSS2) are essential for the entry of SARS-CoV-2 to the host cells. Both ACE-2 and NRP-1 receptors and TMPRSS2 have been identified in the oral cavity. However, there is limited knowledge about the impact of periapical lesions and their metabolites on the expression of these critical genes. This study aims to measure the impact of periapical lesions and their unique fatty acids (FAs) metabolites on the expression of the aforementioned genes, in addition to interleukin 6 (IL-6) gene and hence SARS-CoV-2 infection loads can be estimated. METHODS: Gene expression of ACE-2, NRP-1, TMPRSS2, and IL-6 was performed in periapical lesions in comparison to healthy oral cavity. Since FAs are important immunomodulators required for the lipid synthesis essential for receptors synthesis and viral replication, comparative FAs profiling was determined in oral lesions and healthy pulp tissues using gas chromatography-mass spectrometry (GC-MS). The effect of major identified and unique FAs was tested on mammalian cells known to express ACE-2, NRP-1, and TMPRSS2 genes. RESULTS: Gene expression analysis indicated that ACE-2, NRP-1, and TMPRSS2 were significantly upregulated in healthy clinical samples compared to oral lesions, while the reverse was true with IL-6 gene expression. Saturated and monounsaturated FAs were the major identified shared and unique FAs, respectively. Major shared FAs included palmitic, stearic and myristic acids with the highest percentage in the healthy oral cavity, while unique FAs included 17-octadecynoic acid in periapical abscess, petroselinic acid and L-lactic acid in periapical granuloma, and 1-nonadecene in the radicular cyst. Computational prediction showed that the binding affinity of identified FAs to ACE-2, TMPRSS2 and S protein were insignificant. Further, FA-treated mammalian cells showed significant overexpression of ACE-2, NRP-1 and TMPRSS2 genes except with L-lactic acid and oleic acid caused downregulation of NRP-1 gene, while 17-octadecynoic acid caused insignificant effect. CONCLUSION: Collectively, a healthy oral cavity is more susceptible to viral infection when compared to that complicated with periapical lesions. FAs play important role in viral infection and their balance can affect the viral loads. Shifting the balance towards higher levels of palmitic, stearic and 1-nonadecene caused significant upregulation of the aforementioned genes and hence higher viral loads. On the other hand, there is a reverse correlation between inflammation and expression of SARS-CoV-2 receptors. Therefore, a mouth preparation that can reduce the levels of palmitic, stearic and 1-nonadecene, while maintaining an immunomodulatory effect can be employed as a future protection strategy against viral infection.

Design, synthesis, and computational validation of novel compounds selectively targeting HER2-expressing breast cancer.

Human epidermal growth factor receptor (HER) is a family of multidomain proteins that plays important role in the regulation of several biological functions. HER2 is a member of HER that is highly presented in breast cancer cells. Here, we designed and synthesized a series of diaryl urea/thiourea compounds. The compounds were tested on HER2+ breast cancer cells including MCF-7 and SkBr3, compared to HER2- breast cancer cells including MDA-MB-231 and BT-549. Only compounds 12-14 at 10 µM showed selective anti-proliferative activity against MCF-7 and SkBr3 by 65-79%. Compounds 12-14 showed >80% inhibition of the intracellular kinase domain of HER2. The results obtained indicated that compounds 12-14 are selectively targeting HER2+ cells. The IC50 of compound 13 against MCF-7 and SkBR3 were 1.3 ± 0.009 and 0.73 ± 0.03 µM, respectively. Molecular docking and MD simulations (50 ns) were carried out, and their binding free energies were calculated. Compounds 12-14 formed strong hydrogen bond and pi-pi stacking interactions with the key residues Thr862 and Phe864. 3DQSAR model confirmed the role of 3-bromo substituent of pyridine ring and 4-chloro substituent of phenyl ring in the activity of the compounds. In conclusion, novel compounds, particularly 13 were developed selectively against HER2-expressing/overexpressing breast cancer cells including MCF7 and SkBr3.

Essential Oil-Based Design and Development of Novel Anti-Candida Azoles Formulation.

Candida is the most common fungal class, causing both superficial and invasive diseases in humans. Although Candida albicans is the most common cause of fungal infections in humans, C. auris is a new emergent serious pathogen causing complications similar to those of C. albicans. Both C. albicans and C. auris are associated with high mortality rates, mainly because of their multidrug-resistance patterns against most available antifungal drugs. Although several compounds were designed against C. albicans, very few or none were tested on C. auris. Therefore, it is urgent to develop novel effective antifungal drugs that can accommodate not only C. albicans, but also other Candida spp., particularly newly emergent one, including C. auris. Inspired by the significant broad-spectrum antifungal activities of the essential oil cuminaldehyde and the reported wide incorporation of azoles in the antifungal drugs, a series of compounds (UoST1-11) was designed and developed. The new compounds were designed to overcome the toxicity of the aldehyde group of cuminaldehyde and benefit from the antifungal selectivity of azoles. The new developed UoST compounds showed significant anti-Candida activities against both Candida species. The best candidate compound, UoST5, was further formulated into polymeric nanoparticles (NPs). The new formula, UoST5-NPs, showed similar activities to the nanoparticles-free drug, while providing only 25% release after 24 h, maintainng prolonged activity up to 48 h and affording no toxicity. In conclusion, new azole formulations with significantly enhanced activities against C. albicans and C. auris, while maintaining prolonged action and no toxicities at lower concentrations, were developed.

Metabolic Profiling of Candida auris, a Newly-Emerging Multi-Drug Resistant Candida Species, by GC-MS.

Candida auris, a newly-emerging Candida species, is a serious global health threat due to its multi-drug resistant pattern, difficulty to diagnose, and the high mortality associated with its invasive and bloodstream infections. Unlike C. albicans, and C. dubliniensis which can form true hyphae, C. auris grows as yeast or pseudohyphae and is capable of developing biofilms. The reasons for the inability of C. auris to form true hyphae are currently unknown. Metabolites secreted by microorganisms, including Candida, are known as important factors in controlling morphogenesis and pathogenesis. Metabolic profiling of C. auris and C. albicans cultures was performed using gas chromatography⁻mass spectrometry (GC⁻MS). Compared to C. albicans, C. auris secreted several hyphae-inhibiting metabolites, including phenylethyl, benzyl and isoamyl alcohols. Furthermore, a biofilm-forming metabolite-tyrosol-was identified. On the other hand, several other biomarkers identified from C. auris but not from C. albicans cultures may be produced by the organism to overcome the host immune system or control fungal adaptations, and hence ease its invasion and infections. The results from this study are considered as the first identification of C. auris metabolic activities as a step forward to understand its virulence mechanisms.