Annona Muricata L. extract restores renal function, oxidative stress, immunohistochemical structure, and gene expression of TNF-α, IL-ß1, and CYP2E1 in the kidney of DMBA-intoxicated rats.

Introduction: 7,12-dimethylbenz (a) anthracene (DMBA) is a harmful polycyclic aromatic hydrocarbon derivative known for its cytotoxic, carcinogenic, and mutagenic effects in mammals and other species. Annona muricata, L. (Graviola; GRV) is a tropical fruit tree traditionally well-documented for its various medicinal benefits. This investigation is the first report on the potential antioxidant and antinfammatory reno-protective impact of GRV against DMBA-induced nephrotoxicity in rats. Methods: Forty male albino rats were allocated into four equal groups (n = 10). The 1st group served as the control, the 2nd group (GRV) was gastro-gavaged with GRV (200 mg/kg b.wt), the 3rd group (DMBA) was treated with a single dose of DMBA (15 mg/kg body weight), and the 4th group (DMBA + GRV) was gastro-gavaged with a single dose of DMBA, followed by GRV (200 mg/kg b.wt). The GRV administration was continued for 8 weeks. Results and Discussion: Results revealed a significant improvement in renal function, represented by a decrease in urea, creatinine, and uric acid (UA) in the DMBA + GRV group. The antioxidant potential of GRV was confirmed in the DMBA + GRV group by a significant decline in malondialdehyde (MDA) and a significant increase in catalase (CAT), superoxide dismutase (SOD), glutathione S transferase (GST), and reduced glutathione (GSH) compared to DMBA-intoxicated rats; however, it was not identical to the control. Additionally, the antiinflammatory role of GRV was suggested by a significant decline in mRNA expression of cytochrome P450, family 2, subfamily e, polypeptide 1 (CYP2E1), tumor necrosis factor-alpha (TNF-α), and interleukin 1 beta (IL-1ß) in the DMBA + GRV group. Moreover, GRV improved the histopathologic and immunohistochemical expression of TNF-α, CYP450, and IL1ß in DMBA-intoxicated kidney tissue. Conclusively, GRV is a natural medicinal product that can alleviate the renal injury resulting from environmental exposure to DMBA. The reno-protective effects of GRV may involve its anti-inflammatory and/or antioxidant properties, which are based on the presence of phytochemical compounds such as acetogenins, alkaloids, and flavonoids.

Structural Exploration of the PfBLM Helicase-ATP Binding Domain and Its Implications in the Quest for Antimalarial Therapies.

BACKGROUND OBJECTIVES: The battle against malaria has witnessed remarkable progress in recent years, characterized by increased funding, the development of life-saving tools, and a significant reduction in disease prevalence. Yet, the formidable challenge of drug resistance persists, threatening to undo these gains. METHODS: To tackle this issue, it is imperative to identify new effective drug candidates against the malaria parasite and exhibit minimal toxicity. This study focuses on discovering such candidates by targeting PfRecQ1, also known as PfBLM, a vital protein within the malaria parasite. PfRecQ1 plays a crucial role in the parasite's life cycle and DNA repair processes, making it an attractive drug development target. The research employs advanced computational techniques, including molecular modeling, structure-based virtual screening (SBVS), ADMET profiling, molecular docking, and dynamic simulations. RESULTS: The study sources ligand molecules from the extensive MCULE database and utilizes strict filters to ensure the compounds meet essential criteria. Through these techniques, the research identifies MCULE-3763806507-0-9 as a promising anti-malarial drug candidate, surpassing the binding affinity of potential antimalarial drugs. However, it is essential to underscore that the drug-like properties are primarily based on in silico experiments, and wet lab experiments are necessary to validate these candidates' therapeutic potential. INTERPRETATION CONCLUSION: This study represents a critical step in addressing the challenge of drug resistance in the fight against malaria.

Using CADD tools to inhibit the overexpressed genes FAP, FN1, and MMP1 by repurposing ginsenoside C and Rg1 as a treatment for oral cancer.

Oral cancer is one of the most common cancer types. Many factors can express certain genes that cause the proliferation of oral tissues. Overexpressed genes were detected in oral cancer patients; three were highly impacted. FAP, FN1, and MMP1 were the targeted genes that showed inhibition results in silico by ginsenoside C and Rg1. Approved drugs were retrieved from the DrugBank database. The docking scores show an excellent interaction between the ligands and the targeted macromolecules. Further molecular dynamics simulations showed the binding stability of the proposed natural products. This work recommends repurposing ginsenoside C and Rg1 as potential binders for the selected targets and endorses future experimental validation for the treatment of oral cancer.

Increased NOTCH1 expression is associated with low survival in moderate/ poor differentiated human oral squamous cell carcinoma patients.

Notch deregulation has been reported in various types of cancers, including Oral squamous cell carcinomas (OSCCs). The role of Notch1 signaling in oral squamous cell carcinoma (OSCC) remains poorly understood. In this study, NOTCH1 was aberrantly expressed in human oral cancer tissues compared with that in normal marginal tissues and was associated with poor prognosis. The positive Notch 1 expression was significantly associated with poor tumor differentiation status. Kaplan-Meier survival curves revealed that elevated cytoplasmic NOTCH1 expression levels in OSCC patients were associated with poor overall survival. Moreover, multivariate COX proportional hazard models revealed that T N status, AJCC stage histological grade were independent prognostic factors for survival. Our result clearly demonstrates the oncogenic role of Notch1 in oral cancer and Notch1 may be a useful biomarker to target oral cancer patients.

Effects of Repeated in-vitro Exposure to Saudi Honey on Bacterial Resistance to Antibiotics and Biofilm Formation.

Introduction: Although Sumra and Sidr Saudi honey is widely used in traditional medicine due to its potent activity, it is unknown whether its prolonged usage has impact upon bacterial virulence or leading to reduced antibiotic sensitivity. Thus, the study aims to investigate the effect of prolonged (repeated) in-vitro exposure to Saudi honey on the antibiotic susceptibility profiles and biofilm formation of pathogenic bacteria. Methods: Several bacteria, including Staphylococcus aureus, Escherichia coli, and Acinetobacter baumannii, were in-vitro exposed ten times [passaged (P10)]to Sumra and Sider honey individually to introduce adapted bacteria (P10). Antibiotic susceptibility profiles of untreated (P0) and adapted (P10) bacteria were assessed using disc diffusion and microdilution assays. The tendency regarding biofilm formation following in-vitro exposure to honey (P10) was assessed using the Crystal violet staining method. Results: Adapted (P10) bacteria to both Sumra and Sidr honey showed an increased sensitivity to gentamicin, ceftazidime, ampicillin, amoxycillin/clavulanic acid, and ceftriaxone, when compared with the parent strains (P0). In addition, A. baumannii (P10) that was adapted to Sidr honey displayed a 4-fold increase in the minimal inhibitory concentration of the same honey following in-vitro exposure. 3-fold reduction in the tendency toward biofilm formation was observed for the Sumra-adapted (P10) methicillin resistant S. aureus strain, although there was a lower rate of reduction (1.5-fold) in biofilm formation by both the Sumra- and Sidr-adapted A. baumannii (P10) strains. Conclusion: The data highlight the positive impact of prolonged in-vitro exposure to Saudi honey (Sumra and Sider) for wound-associated bacteria since they displayed a significant increase in their sensitivity profiles to the tested antibiotic and a reduction in their ability to form biofilm. The increased bacterial sensitivity to antibiotics and a limited tendency toward biofilm formation would suggest the great potential therapeutic use of this Saudi honey (Sumra and Sidr) to treat wound infections.

Preclinical efficacy of oncolytic VSV-IFNß in treating cancer: A systematic review.

Background: Cancer incidence and mortality are increasing rapidly worldwide, necessitating further investigation into developing and optimizing emergent cancer therapies. Oncolytic viruses such as vesicular stomatitis virus encoding interferon ß (VSV-IFNß) have attracted considerable attention, as they offer great efficacy and safety profiles. This systematic review aimed to determine and compare the efficacy profile between VSV-IFNß and non-treatment controls in preclinical cancer models. Methodology: The Embase and Medline databases were systematically searched for relevant studies using related key terms and Medical Subject Headings (MeSH). Titles, abstracts, and full texts were screened, and data from eligible articles were extracted by two groups independently and in duplicate (two reviewers per group). Disagreements were resolved by a fifth independent reviewer. The included articles were all preclinical (translational) in vivo English studies that investigated and compared the efficacy profile between VSV-IFNß and non-treatment controls in animal models. The risk of bias among the studies was assessed by two reviewers independently and in duplicate using SYRCLE's risk-of-bias tool for animal studies; disparities were addressed by a third independent reviewer. Results: After employing relevant MeSH and key terms, we identified 1598 articles. A total of 87 articles were either duplicates or conference proceedings and were thus excluded. Following title and abstract screening, 37 articles were included in the full-text assessment. Finally, 14 studies met the eligibility criteria. Forty-two experiments from the included studies examined the potential efficacy of VSV-IFNß through different routes of administration, including intratumoral, intraperitoneal, and intravenous routes. Thirty-seven experiments reported positive outcomes. Meanwhile, five experiments reported negative outcomes, three and two of which examined intratumoral and intravenous VSV-IFNß administration, respectively. Conclusion: Although the majority of the included studies support the promising potential of VSV-IFNß as an oncolytic virus, further research is necessary to ensure a safe and efficacious profile to translate its application into clinical trials. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022335418.

Dihydropyrimidone Derivatives as Thymidine Phosphorylase Inhibitors: Inhibition Kinetics, Cytotoxicity, and Molecular Docking.

Overexpression of the thymidine phosphorylase (TP) enzyme induces angiogenesis, which eventually leads to metastasis and tumor growth. The crucial role of TP in cancer development makes it an important target for anticancer drug discovery. Currently, there is only one US-FDA-approved drug, i.e., Lonsurf, a combination of trifluridine and tipiracil, for the treatment of metastatic colorectal cancer. Unfortunately, numerous adverse effects are associated with its use, such as myelosuppression, anemia, and neutropenia. Since the last few decades, the discovery of new, safe, and effective TP inhibitory agents has been rigorously pursued. In the present study, we evaluated a series of previously synthesized dihydropyrimidone derivatives 1-40 for their TP inhibitory potential. Compounds 1, 12, and 33 showed a good activity with IC50 = 314.0 ± 0.90, 303.5 ± 0.40, and 322.6 ± 1.60 µM, respectively. The results of mechanistic studies revealed that compounds 1, 12, and 33 were the non-competitive inhibitors. These compounds were also evaluated for cytotoxicity against 3T3 (mouse fibroblast) cells and were found to be non-cytotoxic. Finally, the molecular docking suggested the plausible mechanism of non-competitive inhibition of TP. The current study thus identifies some dihydropyrimidone derivatives as potential inhibitors of TP, which can be further optimized as leads for cancer treatment.

SARS-CoV-2 RBD protein enhances the oncolytic activity of the vesicular stomatitis virus.

Despite recent advances in the research on oncolytic viruses (OVs), a better understanding of how to enhance their replication is key to improving their therapeutic index. Understanding viral replication is important to improve treatment outcomes based on enhanced viral spreading within the tumor milieu. The VSV-Δ51 oncolytic virus has been widely used as an anticancer agent with a high selectivity profile. In this study, we examined the role of the SARS-CoV-2 spike protein receptor-binding domain (RBD) in enhancing VSV-Δ51 viral production and oncolytic activity. To test this hypothesis, we first generated a novel VSV-Δ51 mutant that encoded the SARS-COV-2 RBD and compared viral spreading and viral yield between VSV-Δ51-RBD and VSV-Δ51 in vitro. Using the viral plaque assay, we demonstrated that the presence of the SARS-CoV-2 RBD in the VSV-Δ51 genome is associated with a significantly larger viral plaque surface area and significantly higher virus titers. Subsequently, using an ATP release-based assay, we demonstrated that the SARS-CoV-2 RBD could enhance VSV-Δ51 oncolytic activity in vitro. This observation was further supported using the B16F10 tumor model. These findings highlighted a novel use of the SARS-CoV-2 RBD as an anticancer agent.

Current Insights into Diagnosis, Prevention Strategies, Treatment, Therapeutic Targets, and Challenges of Monkeypox (Mpox) Infections in Human Populations.

In the wake of the emergence and worldwide respread of a viral infection called Monkeypox (Mpox), there is a serious threat to the health and safety of the global population. This viral infection was endemic to the western and central parts of Africa, but has recently spread out of this endemic area to various countries, including the United Kingdom (UK), Portugal, Spain, the United States of America (USA), Canada, Sweden, Belgium, Italy, Australia, Germany, France, the Netherlands, Israel, and Mexico. This is a timely review focusing on recent findings and developments in the epidemiology, clinical features, therapeutic targets, diagnosis, prevention mechanisms, research challenges and possible treatment for Mpox. To date (29 November 2022), there have been around 81,225 reported cases of Mpox. In most cases, this illness is mild; however, there is a fatality rate ranging from 1 to 10%, which might be increased due to associated complications and/or secondary infections. There is a real challenge in the diagnosis of Mpox, since its symptoms are very similar to those of other infections, including smallpox and chickenpox. Generally, to prevent/limit the risk and transmission of Mpox, the detection and isolation of infected individuals, as well as hand hygiene and cleanliness, are essential and effective approaches to control/combat this viral infection. Nevertheless, updated information about Mpox from different angles is lacking. Thus, this review provides updated and comprehensive information about the Mpox illness, which should highlight the global burden, pathogenicity, symptoms, diagnosis, prevention measures and possible treatment of this emerging disease.

The Protective and Therapeutic Anti-Alzheimer Potential of Olea europaea L. cv. Picual: An In Silico and In Vivo Study.

LC-HRESIMS metabolomic profiling of Olea europaea L. cv. Picual (OEP) (Saudi Arabian olive cultivar, F. Oleacea) revealed 18 compounds. Using pharmacology networking to specify the targets of the identified compounds with a relationship to Alzheimer's disease, it was possible to identify the VEGFA, AChE, and DRD2 genes as the top correlated genes to Alzheimer's disease with 8, 8, and 6 interactions in the same order. The mechanism of action on cellular components, biological processes, and molecular functions was determined by gene enrichment analysis. A biological pathway comparison revealed 13 shared pathways between the identified genes and Alzheimer protein genes (beta-amyloid band tau proteins). The suggested extract's anti-Alzheimer potential in silico screening was confirmed through in vivo investigation in regressing the neurodegenerative features of Alzheimer's dementia in an aluminum-intoxicated rat model (protective and therapeutic effects, 100 mg/kg b.w.). In vivo results suggested that OEP extract significantly improved Alzheimer's rats, which was indicated by the crude extract's ability to improve T-maze performance; lower elevated serum levels of AChE, AB peptide, and Ph/T ratio; and normalize the reduced level of TAC during the study. The results presented in this study may provide potential dietary supplements for the management of Alzheimer's disease.

Clinical Implications of Krüpple-like Transcription Factor KLF-14 and Certain Micro-RNA (miR-27a, miR-196a2, miR-423) Gene Variations as a Risk Factor in the Genetic Predisposition to PCOS.

Polycystic ovary syndrome (PCOS) is a disorder with a symptomatic manifestation of an array of metabolic and endocrine impairments. PCOS has a relatively high prevalence rate among young women of reproductive age and is a risk factor for some severe metabolic diseases such as T2DM, insulin insensitivity, and obesity, while the most dominant endocrine malfunction is an excess of testosterone showing hyperandrogenism and hirsutism. MicroRNAs have been implicated as mediators of metabolic diseases including obesity and insulin resistance, as these can regulate multiple cellular pathways such as insulin signaling and adipogenesis. Genome-wide association studies during the last few years have also linked the Krüpple-like family of transcription factors such as KLF14, which contribute in mechanisms of mammalian gene regulation, with certain altered metabolic traits and risk of atherosclerosis and type-2 DM. This study has characterized the biochemical and endocrine parameters in PCOS patients with a comprehensive serum profiling in comparison to healthy controls and further examined the influence of allelic variations for miRNAs 27a (rs895819 A > G), 196a2 (rs11614913 C > T), 423 (rs6505162C > A), and transcription factor KLF14 (rs972283 A > G) gene polymorphism on the risk and susceptibility to PCOS. The experimental protocol included amplification refractory mutation-specific (ARMS)-PCR to detect and determine the presence of these polymorphic variants in the study subjects. The results in this case−control study showed that most of the serum biomarkers, both biochemical and endocrine, that were analyzed in the study demonstrated statistically significant alterations in PCOS patients, including lipids (LDL, HDL, cholesterol), T2DM markers (fasting glucose, free insulin, HOMA-IR), and hormones (FSH, LH, testosterone, and progesterone). The distribution of Krüppel-like factor 14 rs972283 G > A, miR-27a rs895819 A > G, and miR-196a-2 rs11614913 C > T genotypes analyzed within PCOS patients and healthy controls in the considered population was significant (p < 0.05), except for miR-423 rs6505162 C > A genotypes (p > 0.05). The study found that in the codominant model, KLF14-AA was strongly associated with greater PCOS susceptibility (OR 2.35, 95% CI = 1.128 to 4.893, p < 0.022), miR-27a-GA was linked to an enhanced PCOS susceptibility (OR 2.06, 95% CI = 1.165 to 3.650, p < 0.012), and miR-196a-CT was associated with higher PCOS susceptibility (OR 2.06, 95% CI = 1.191 to 3.58, p < 0.009). Moreover, allele A of KLF-14 and allele T of miR-196a2 were strongly associated with PCOS susceptibility in the considered population.

Biochemical Characterization and Molecular Determination of Estrogen Receptor-α (ESR1 PvuII-rs2234693 T>C) and MiRNA-146a (rs2910164 C>G) Polymorphic Gene Variations and Their Association with the Risk of Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) is regarded as one of the most frequently encountered endocrine disorders and affects millions of young women worldwide, resulting in an array of complex metabolic alterations and reproductive failure. PCOS is a risk factor for diabetes mellitus, obstructive sleep apnea, obesity and depression in patients. Estrogen receptors (ESRs) are significant candidates in endocrine function and ovarian response in women. Moreover, microRNAs and long non-coding RNAs are emerging as principal mediators of gene expression and epigenetic pathways in various disease states. This study has characterized the clinical parameters in PCOS patients with comprehensive biochemical profiling compared to healthy controls and further examined the influence of allelic variations for estrogen receptor-α (ESR1 PvuII-rs2234693 T>C) and miRNA-146a (rs2910164 C>G) gene polymorphism on the risk of and susceptibility to PCOS. In this case-control study, we have used amplification refractory mutation specific (ARMS)-PCR to detect and determine the presence of these polymorphic variants in the study subjects. Our results demonstrated that most of the biochemical markers, which were analyzed in the study, show statistically significant alterations in PCOS patients, including fasting glucose, free insulin, HOMA-IR, LDL, HDL, cholesterol and hormones such as FSH, LH, testosterone and progesterone, which correlate with the established biochemical alterations in the disorder. Further, it is reported that for estrogen receptor-α (ESR1 PvuII-rs2234693 T>C), the frequency of the T allele (fT) was significantly higher among patients (0.64 vs. 0.44) compared to controls, while the frequency of the C allele (fC) was lower in patients (0.36 vs. 0.56) compared to controls. However, it was found that there was no association of an increased risk of PCOS with the ESR1 PvuII-rs2234693 C>T gene polymorphism. On the contrary, the study found strong association of miRNA-146a (rs2910164 C>G) gene polymorphism with an enhanced risk of PCOS. The frequency of the C allele (fC) was significantly higher among patients (0.52 vs. 0.36) compared to controls. The frequency of the G allele (fG) was found to be lower in patients (0.48 vs. 0.64) compared to controls. The codominant, dominant and recessive models display a statistically significant association of polymorphic variations with PCOS. Moreover, the G allele was associated strongly with PCOS susceptibility with an OR = 1.92 (95%) CI = (1.300−2.859), RR = 1.38 (1.130−1.691) p-value < 0.001.

Laboratory Biomarkers Associated with Severity and Mortality of COVID-19.

BACKGROUND: Corona Virus Disease 2019 (COVID-19) emerged late 2019 and has become a global pandemic. There is an urgent need for identification of biomarkers to predict severity of the disease for early treatment and to avoid mortality especially in high-risk population. Therefore, the aim of this study is to investigate laboratory results in COVID-19 patients in Saudi Arabia to identify potential biomarkers correlated with disease severity. METHODS: Clinical records of 200 patients diagnosed with COVID-19 from July to August 2020 at Jeddah East Hospital were retrospectively analyzed. Laboratory tests including coagulation parameters, D-dimer, kidney, cardiac, and liver enzymes were statistically investigated in patients admitted to wards and intensive care units (ICU). RESULTS: The majority of patients admitted to ward (156/200) were young (mean 47 years old) compared to those admitted to ICU (mean 60 years old), 14/44 passed away in the ICU. Magnesium was significantly (p < 0.05) elevated in the ICU group while blood urea nitrogen and creatinine level was significantly higher in deceased patients (p < 0.05). Lactate dehydrogenase results were high among all groups, compared to normal range, although its level significantly increased (p > 0.05) in ICU and death groups. CONCLUSIONS: Elevated lactate dehydrogenase, blood urea nitrogen and creatinine levels may increase the risk of ICU admission and death from COVID-19, which can be used as potential biomarkers for disease severity. Using these markers could help physicians choose the optimal therapeutical option and provide patients with better treatment.

Molecular determination of progesterone receptor's PROGINS allele (Alu insertion) and its association with the predisposition and susceptibility to polycystic ovary syndrome (PCOS).

Polycystic ovary syndrome, previously known as Stein-Leventhal syndrome, is associated with altered reproductive endocrinology, predisposing a young woman towards the risk of PCOS. It has a prevalence of 6-20% among the reproductive-age women. Progesterone is a key hormone in the pathophysiology of PCOS and patients show diminished response (progesterone resistance), implicating the role of progesterone receptor (PR) as a factor in the disease etiology and prognosis. In this case-control study, we have used mutation-specific PCR (confirmed by Sanger sequencing) to detect the presence of a pathologically significant PR polymorphic variant called as PROGINS. The variant has an Alu insertion in intron G and has two SNPs in exon 4 and exon 5, with all the three aberrations in complete disequilibrium. Our results demonstrated a statistically significant difference in the frequencies of PROGINS between the PCOS patients and healthy controls (p = 0.047). The frequencies of the genotypes CC (A1/A1), CT (A1/A2), and TT (A2/A2) in patients were 74.50%, 20.58%, and 4.90%, and in healthy controls they were 87.28%, 11%, and 1.69%, respectively. Our results put forward two determining factors with regard to PCOS: (i) the frequency of PROGINS allele was significantly higher among PCOS patients compared to the healthy matched controls (0.15 vs 0.07) in the studied population, (ii) the PROGIN allele was significantly associated with the lower levels of serum progesterone in PCOS patients (p < 0.003). The findings are conspicuous as these relate the PROGINS variant to the increased susceptibility of PCOS and might explain the progesterone resistance in patients.