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Abstract The purpose of the current study was to analyze and validate the existing gap in knowledge, by conducting a differential expression analysis and validation of NEK6, NEK7, and NEK9 in breast, cervical, and glioblastoma cancer and targeting these proteins through development of novel site specific inhibitor with favorable pharmacokinetic and safety profile, using open-source databases. The analysis revealed that the targeted kinases were overexpressed in all three types of cancer. Their expression was significantly linked to overall survival rates, which suggests that they play a major role in the development and progression of these cancers. After, having the prognostic importance of These findings provided a rationale for synthesizing novel compound i.e., dimethyl 2,2’-((methylenebis(2-(2H-benzo[d][1,2,3]triazol-2-yl)-4-(2,4,4-trimethylpentan-2-yl)-6,1phenylene))bis(oxy))diacetate (TAJ4)), capable of effectively targeting these proteins using in-vitro cytotoxicity assays and comprehensive computational approaches. Then the inhibitory potential of TAJ4 was evaluated against cell lines of the respective cancers (HeLa cells, MCF-7 cells, and Vero cells). The growth inhibitory values (GI50) suggested that TAJ4 exhibited strong inhibitory potential towards MCF-7 cells (GI50 = 3.18 ± 0.11 µM) in comparison to the HeLa cell line (GI50 = 8.12 ± 0.43 µM), surpassing that of standard drugs. Furthermore, in-silico investigations, including density functional theory (DFT) calculations and molecular docking studies, revealed a substantial reactivity profile of TAJ4, with promising molecular interactions against NEK7, NEK9, TP53, NF-KAPPA-B, and caspase-3 proteins. Further investigation using in-vitro and in-vivo approaches is recommended to fully establish the therapeutic efficacy and safety profile of TAJ4.

Abstract Oropharyngeal cancer, a subset of head and neck cancer, is increasingly recognized as a unique clinical entity primarily influenced by high-risk human papillomavirus (HPV) infections, particularly HPV-16. This review delves into the viral life cycle of HPV-16 and its interactions with host cells, with a specific focus on the crucial roles played by the viral oncoproteins E6 and E7. These oncoproteins drive cellular proliferation by targeting critical tumor suppressor proteins like p53 and Rb, resulting in uncontrolled cell growth and genomic instability. Furthermore, the significance of epigenetic modifications induced by HPV-16 and their implications is important for cancer progression. This comprehensive review provides valuable insights into the intricate molecular landscape of HPV-induced oropharyngeal cancer, shedding light on the development of targeted therapies and preventive strategies for this emerging global health concern. Video Abstract

Breast cancer is one of the most common diseases of the modern age. Although many methods for its treatment have been reported so far, the report and synthesis of new compounds based on new technologies, especially nanotechnology, is important. One of the laboratory methods for evaluating the anticancer properties of compounds is the in vitro MTT method (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide). In this study, the in vitro anti-breast cancer activity of the newly synthesized (Titanium Metal-Organic Framework) Ti-MOF cross-linked oxidized pectin and chitosan hydrogel, which uses biopolymers in its synthesis and structure, was investigated. The anticancer activity results showed that the synthetic nanopolymer had cell proliferation and viability of 27% more than the control and (the half maximal inhibitory concentration) IC50 of 111 μg/mL against breast cancer cells. Before the anticancer evaluation, the structure of the synthesized Ti-MOF cross-linked oxidized pectin, and chitosan hydrogel was confirmed by (X-Ray Diffraction) XRD pattern (Fourier Transform Infrared) FT-IR spectrum (Energy-dispersive X-ray) EDAX spectroscopy, N2 adsorption/desorption isotherm and (Scanning Electron Microscope) Scanning Electron Microscope images. The results of identification and characterization showed that the synthetic nanopolymer was in the range of nanoparticles. The peaks of the expected functional groups and reactant elements were observed in the FT-IR spectrum and energy-dispersive X-ray spectroscopy of the final product. High physicochemical capabilities such as the uniform morphology, crystallization of particles, and high specific surface area from synthesized Ti-MOF cross-linked oxidized pectin, and chitosan hydrogel were observed. The unique properties of the synthesized Ti-MOF cross-linked oxidized pectin and chitosan hydrogel can be attributed to the appropriate method of its synthesis that was carried out in this study.

Lycopene, the potential antioxidant naturally occurring in red carotenoid pigment is found in many fruits and vegetables. In this work, antioxidant power and antimicrobial potentials of lycopene against the multidrug-resistant (MDR) Streptococcus agalactiae (S. agalactiae) and Streptococcus pyogenes (S. pyogenes) were studied when added to ethanolic leaf extracts of Helianthus annuus (H. annuus). Supplementation of the lycopene along with ethanolic leaf extract of H. annuus indicates a 30 % enhancement in the antioxidant activity by 2, 2-Diphenyl-1-Picrylhydrazyl (DPPH) assay and reduction of 24 % reactive oxygen species (ROS) in human fibroblast cells under calcium stress compared to leaf extract alone. The antibacterial activity of the leaf extract + lycopene showed improved bacterial inhibition as low as 40 and 70 μg of the leaf extract compared with extract alone against S. pyogenes and S. agalactiae respectively. Taken together, the observations show that the natural anti-oxidant, lycopene, when added to the extract enhanced the antibacterial activity at lower concentrations which could possibly reduce the larger dose as observed in alternative or complementary medical practices.

Poly [adenosine diphosphate (ADP)-ribose] polymerases (PARPs) are members of a family of 17 enzymes that performs several fundamental cellular processes. Aberrant activity (mutation) in PARP12 has been linked to various diseases including inflammation, cardiovascular disease, and cancer. Herein, a large library of compounds (ZINC-FDA database) has been screened virtually to identify potential PARP12 inhibitor(s). The best compounds were selected on the basis of binding affinity scores and poses. Molecular dynamics (MD) simulation and binding free energy calculation (MMGBSA) were carried out to delineate the stability and dynamics of the resulting complexes. To this end, root means deviations, relative fluctuation, atomic gyration, compactness, covariance, residue-residue contact map, and free energy landscapes were studied. These studies have revealed that compounds ZINC03830332, ZINC03830554, and ZINC03831186 are promising agents against mutated PARP12.

Adenium obesum commonly known as “desert rose” belongs to the family Apopcynaceae and has previously been reported for its anti-influenza, antimicrobial, and cytotoxic efficacies and well-known for their ethno-medicinal applications. In the present study, ethanolic extracts of A. obesum (AOE) were analyzed by gas chromatography-mass spectrometry (GC–MS) to identify the important phytochemical compounds. The GC–MS analysis of AOE detected the presence of 26 phytochemical compounds. This plant is traditionally used for the treatment of various diseases. In this report, the antioxidant, anti-inflammatory, and anticancer activities of ethanolic leaf extract from A. obesum (AOE) were studied. The antioxidant potential of ethanolic extract of AOE was examined by different antioxidant assays, such as antioxidant capacity by the DPPH, ABTS, superoxide, hydroxyl radical scavenging, and lipid peroxidation inhibition assays. The antioxidant activities of various reaction mixtures of AOE were compared with a reference or standard antioxidant (ascorbic acid). In addition, we also evaluated the anticancer activity of AOE, and it was observed that AOE was found to be cytotoxic against A549 lung cancer cells. It was found that AOE inhibited the viability of A549 lung cancer cells by inducing nuclear condensation and fragmentation. Furthermore, ethanolic AOE demonstrated the anti-inflammatory potential of AOE in murine alveolar macrophages (J774A.1) as an in vitro model system. AOE showed its potential in reducing the levels of inflammatory mediators including the proinflammatory cytokines and TNF-α. The results obtained in the present investigation established the antioxidant, anticancer, and anti-inflammatory potency of AOE, which may account for subsequent studies in the formulation of herbal-based medicine.

Abstract Background Pneumocystis pneumonia (PCP) is a fatal infectious disease caused by Pneumocystis jirovecii (PJP). The major factor relevant to morbidity and mortality seems to be the host inflammatory reaction. The objective of this study was to evaluate the role of IL-2, IL-4, IL-10, and IL-13 cytokine mRNA expression among suspected P. jirovecii infection. Methods This was a cross-sectional analytical study undertaken in Aseer region, Saudi Arabia. One hundred suspected PCP cases and 100 healthy controls were included in the study. Basic clinical manifestations, radiological findings, microbiological and immunological findings were extracted from the hospital records from January 2019 to August 2019, Pneumocystis detection was done by immune-fluorescent staining (IFAT, Gomorimethanamine silver staining (GMSS), Giemsa staining, Toluidine blue O (TBO), and Pneumocystis RT-PCR. Results Increased more than 5 fold, 3 fold, 4 fold, and 7 fold of IL-2, IL-4, IL-10, and IL-13 mRNA expression were observed in PCP cases compared to controls. Higher expression of IL-2 mRNA was connected with crept, wheezing and chest X-ray findings like central perihilar infiltrate, patchy infiltrate, consolidation, hilar lymphadenopathy, pneumothorax, pleural effusion which showed higher expression compared to counterpart (p

Inflammation is pivotal to the pathogenesis of diabetes mellitus (DM), but pathological alterations of the neutrophil–lymphocyte ratio (NLR), an emerging inflammatory index in DM management, remains understudied. The aim of this study is to examine the relationship between NLR and glycemic control in the Saudi population. Gender, age, WBC count, and fasting blood glucose (FBG) were obtained from Al-Borg Medical Laboratories for 14,205 subjects. Means, prevalence, risk measures, and the diagnostic accuracy of elevated NLR and hyperglycemia (HG) were evaluated. Subjects with elevated NLR (>3) had significantly higher FBG (105.10 ± 0.33 vs. 114.0 ± 2.81) and NLR was significantly elevated in impaired fasting glycemia (IFG; 1.21 ± 0.01 vs. 1.25 ± 0.01) and HG (1.21 ± 0.01 vs. 1.39 ± 0.02). Elevations of NLR in HG but not in IFG persisted across all age groups except young males and elderly females. The prevalence of elevated NLR in hyperglycemic subjects was 4.12% compared to 2.16% in subjects with normal FBG. HG was more prevalent in subjects with elevated NLR (17.33% vs. 12.46%) who had a relative risk (RR) of 1.68 (95% CI = 1.38–2.06, p < 0.0001) and an odds ratio (OR) of 1.94 (95% CI = 1.48–2.56, p < 0.0001) to be hyperglycemic. Nevertheless, NLR failed to discriminate individuals with normal FBG from those with HG based on ROC curve analysis. Pathological fluctuations in NLR may serve as supportive evidence in DM management.

Antibiotic resistance (AR) is the resistance mechanism pattern in bacteria that evolves over some time, thus protecting the bacteria against antibiotics. AR is due to bacterial evolution to make itself fit to changing environmental conditions in a quest for survival of the fittest. AR has emerged due to the misuse and overuse of antimicrobial drugs, and few antibiotics are now left to deal with these superbug infections. To combat AR, vaccination is an effective method, used either therapeutically or prophylactically. In the current study, an in silico approach was applied for the design of multi-epitope-based vaccines against Providencia rettgeri, a major cause of traveler’s diarrhea. A total of six proteins: fimbrial protein, flagellar hook protein (FlgE), flagellar basal body L-ring protein (FlgH), flagellar hook-basal body complex protein (FliE), flagellar basal body P-ring formation protein (FlgA), and Gram-negative pili assembly chaperone domain proteins, were considered as vaccine targets and were utilized for B- and T-cell epitope prediction. The predicted epitopes were assessed for allergenicity, antigenicity, virulence, toxicity, and solubility. Moreover, filtered epitopes were utilized in multi-epitope vaccine construction. The predicted epitopes were joined with each other through specific GPGPG linkers and were joined with cholera toxin B subunit adjuvant via another EAAAK linker in order to enhance the efficacy of the designed vaccine. Docking studies of the designed vaccine construct were performed with MHC-I (PDB ID: 1I1Y), MHC-II (1KG0), and TLR-4 (4G8A). Findings of the docking study were validated through molecular dynamic simulations, which confirmed that the designed vaccine showed strong interactions with the immune receptors, and that the epitopes were exposed to the host immune system for proper recognition and processing. Additionally, binding free energies were estimated, which highlighted both electrostatic energy and van der Waals forces to make the complexes stable. Briefly, findings of the current study are promising and may help experimental vaccinologists to formulate a novel multi-epitope vaccine against P. rettgeri.