Identification, prioritization, and evaluation of RlpA protein as a target against multidrug-resistant Pseudomonas aeruginosa.

According to the World Health Organization, infectious diseases, particularly those caused by multidrug-resistant bacteria (MDR), are projected to claim the lives of 15 million people by 2050. Septicemia carries a higher morbidity and mortality rate than infections caused by susceptible Pseudomonas aeruginosa, and MDR-mediated ocular infections can lead to impaired vision and blindness. To identify and develop a potential drug against MDR P. aeruginosa, we employed in silico reverse genetics-based target mining, drug prioritization, and evaluation. Rare Lipoprotein A (RlpA) was selected as the target protein, and its crystal structure was geometrically optimized. Molecular docking and virtual screening analyses revealed that RlpA exhibits strong binding affinity with 11 compounds. Among these, 3-chlorophthalic acid was evaluated, and subsequent in vitro assays demonstrated significant anti-Pseudomonas activity with negligible cytotoxicity. The compound was further evaluated against both drug-susceptible and MDR P. aeruginosa strains in vitro, with cytotoxicity assessed using an MTT assay. The study demonstrated that 3-chlorophthalic acid exhibits potent anti-Pseudomonas activity with minimal toxicity to host cells. Consequently, this compound emerges as a promising candidate against MDR P. aeruginosa, warranting further investigation.

Nimbolide: promising agent for prevention and treatment of chronic diseases (recent update).

Background: Nimbolide, a bioactive compound derived from the neem tree, has garnered attention as a potential breakthrough in the prevention and treatment of chronic diseases. Recent updates in research highlight its multifaceted pharmacological properties, demonstrating anti-inflammatory, antioxidant, and anticancer effects. With a rich history in traditional medicine, nimbolide efficacy in addressing the molecular complexities of conditions such as cardiovascular diseases, diabetes, and cancer positions it as a promising candidate for further exploration. As studies progress, the recent update underscores the growing optimism surrounding nimbolide as a valuable tool in the ongoing pursuit of innovative therapeutic strategies for chronic diseases. Methods: The comprehensive search of the literature was done until September 2020 on the MEDLINE, Embase, Scopus and Web of Knowledge databases. Results: Most studies have shown the Nimbolide is one of the most potent limonoids derived from the flowers and leaves of neem (Azadirachta indica), which is widely used to treat a variety of human diseases. In chronic diseases, nimbolide reported to modulate the key signaling pathways, such as Mitogen-activated protein kinases (MAPKs), Wingless-related integration site-ß (Wnt-ß)/catenin, NF-κB, PI3K/AKT, and signaling molecules, such as transforming growth factor (TGF-ß), Matrix metalloproteinases (MMPs), Vascular Endothelial Growth Factor (VEGF), inflammatory cytokines, and epithelial-mesenchymal transition (EMT) proteins. Nimbolide has anti-inflammatory, anti-microbial, and anti-cancer properties, which make it an intriguing compound for research. Nimbolide demonstrated therapeutic potential for osteoarthritis, rheumatoid arthritis, cardiovascular, inflammation and cancer. Conclusion: The current review mainly focused on understanding the molecular mechanisms underlying the therapecutic effects of nimbolide in chronic diseases.

Correction: Ben Ammar et al. Anti-Inflammatory Activity of Geraniol Isolated from Lemon Grass on Ox-LDL-Stimulated Endothelial Cells by Upregulation of Heme Oxygenase-1 via PI3K/Akt and Nrf-2 Signaling Pathways. Nutrients 2022, 14, 4817.

In the original publication [...].

Geraniol attenuates oxidative stress and neuroinflammation-mediated cognitive impairment in D galactose-induced mouse aging model.

D-galactose (D-gal) administration was proven to induce cognitive impairment and aging in rodents' models. Geraniol (GNL) belongs to the acyclic isoprenoid monoterpenes. GNL reduces inflammation by changing important signaling pathways and cytokines, and thus it is plausible to be used as a medicine for treating disorders linked to inflammation. Herein, we examined the therapeutic effects of GNL on D-gal-induced oxidative stress and neuroinflammation-mediated memory loss in mice. The study was conducted using six groups of mice (6 mice per group). The first group received normal saline, then D-gal (150 mg/wt) dissolved in normal saline solution (0.9%, w/v) was given orally for 9 weeks to the second group. In the III group, from the second week until the 10th week, mice were treated orally (without anesthesia) with D-gal (150 mg/kg body wt) and GNL weekly twice (40 mg/kg body wt) four hours later. Mice in Group IV were treated with GNL from the second week up until the end of the experiment. For comparison of young versus elderly mice, 4 month old (Group V) and 16-month-old (Group VI) control mice were used. We evaluated the changes in antioxidant levels, PI3K/Akt levels, and Nrf2 levels. We also examined how D-gal and GNL treated pathological aging changes. Administration of GNL induced a significant increase in spatial learning and memory with spontaneously altered behavior. Enhancing anti-oxidant and anti-inflammatory effects and activating PI3K/Akt were the mechanisms that mediated this effect. Further, GNL treatment upregulated Nrf2 and HO-1 to reduce oxidative stress and apoptosis. This was confirmed using 99mTc-HMPAO brain flow gamma bioassays. Thus, our data suggested GNL as a promising agent for treating neuroinflammation-induced cognitive impairment.

Molecular analysis to identify novel potential biomarkers as drug targets in colorectal cancer therapy: an integrated bioinformatics analysis.

Colorectal cancer (CRC) is a heterogeneous disease that requires new diagnostic and prognostic markers. Integrated bioinformatics approach to identify novel therapeutic targets associated with CRC. Using GEO2R identified DEGs in CRC, and Funrich software facilitated the visualization of DEGs through Venn diagrams. From a total of 114 enhanced DEGs, potential hub genes were further filtered based on their nodal strength and edges using STRING database. To gain insights into the functional roles of these hub genes, gene ontology and pathway enrichment were conducted thorough g: profiler web server. Subsequently, overall survival plots from GEPIA and oncogenic predictive functions like mRNA expressions for stages and nodal metastasis were employed to identify hub genes in CRC patient samples. Additionally, the cBioPortal and HPA databases also revealed genetic alterations and expression levels in these hub genes in CRC patients, further supporting their involvement in colorectal cancer. Gene expression by RT-PCR shows upregulation of hub genes in HT-29 cells. Finally, our integrated bioinformatic analysis revealed that ABCE1, AURKA, HSPD1, PHKA1, CDK4, and YWHAE as hub genes with potential oncogenic roles in CRC. These genes hold promise as diagnostic and prognostic markers for colorectal tumorigenesis, providing insights into targeted therapies for improved patient outcomes.

Hesperidin Inhibits Oral Cancer Cell Growth via Apoptosis and Inflammatory Signaling-Mediated Mechanisms: Evidence From In Vitro and In Silico Analyses.

Background Oral carcinoma presents a significant health challenge, prompting the need for innovative therapeutic approaches. Elevation of inflammatory mediators, including tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), has promoted cellular proliferation, inhibited apoptosis, and fostered oral cancer progression through complex signaling pathways. Hesperidin, a flavanone glycoside found in citrus fruits, is of keen interest in this study as it has been proven to have multiple health benefits through in vivo and in vitro studies. However, the mechanism behind the anticancer activity of hesperidin in oral carcinoma remains obscure. Aim The study aimed to explore the anticancer potential of hesperidin on human oral cancer cells (KB cells) by modulating pro-inflammatory and apoptotic signaling mechanisms. Methods Cancer cell growth inhibitory activity was assessed using the MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide) assay. Gene expression analysis was performed using real-time RT-PCR analysis. In addition, in silico docking analysis was conducted to confirm the binding affinity of hesperidin with pro-inflammatory and apoptosis signaling molecules. The data were analyzed using one-way ANOVA and the "t" test. Results Utilizing the MTT assay, a dose-dependent cytotoxic effect of hesperidin was unveiled, with a remarkable IC50 value indicative of its potent inhibition of cell proliferation. Complementing these findings (p<0.05), qRT-PCR analysis demonstrated hesperidin's regulatory influence on key molecular targets within the KB cell line. Hesperidin treatment resulted in a noteworthy reduction in TNF-α, interleukin-1 beta (IL-1-ß), IL-6, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and B-cell lymphoma 2 (Bcl-2) mRNA expression levels (p<0.05), highlighting its inhibitory role in cell proliferation, migration, and inflammation processes. Simultaneously, hesperidin promoted the expression of BAX mRNA (p<0.05), indicating an enhancement in cell death. Molecular docking simulations further revealed robust binding affinities between hesperidin and target proteins, suggesting its potential to disrupt cellular functions and inflammatory signaling pathways in oral cancer cells. Conclusion The cytotoxic effects on the KB cell line and its anti-inflammatory properties position hesperidin as a compelling candidate for further exploration in the quest for effective oral carcinoma treatments. These findings shed light on the intricate molecular mechanisms underlying hesperidin's promise as a therapeutic agent against oral carcinoma.

Studies on the Effect of Piperine on Hepatocyte Nuclear Factor 1 Alpha (HNF-1α) and Sterol Regulatory Element-Binding Protein 1c (SREBP-1c) Levels in High-Fat-Diet and Sucrose-Induced Type 2 Diabetes Mellitus Rats.

BACKGROUND: Piperine, a naturally occurring compound in black pepper (Piper nigrum), is known for its potential health benefits, including its reported enhancement of insulin sensitivity. However, the precise impact of piperine on hepatocyte nuclear factor 1 alpha (HNF-1α) and sterol regulatory element-binding protein 1c (SREBP-1c), transcription factors for insulin signaling and glucose metabolism in hepatocytes, remains unclear. OBJECTIVE: This study aims to investigate the effect of piperine, compared to metformin, on blood glucose and insulin levels by modifying the expression of hepatic HNF-1α and SREBP-1c in high-fat-diet (HFD) and sucrose-induced type 2 diabetes mellitus (T2DM) rats and in human Chang liver cells. METHODS: Adult male albino rats were categorized into four groups: group 1 as the control, group 2 as T2DM, group 3 as T2DM rats treated with piperine (40 mg), and group 4 as T2DM rats treated with metformin (50 mg). Fasting blood glucose (FBG) and serum insulin levels were measured using enzyme-linked immunosorbent assay (ELISA), while real-time polymerase chain reaction (RT-PCR) analysis was conducted to assess the mRNA expression of HNF-1α and SREBP-1c. Further, piperine was treated with normal and high glucose-induced Chang liver cells, and gene expression was analysed. Data analysis was performed using one-way analysis of variance (ANOVA), with a significance set at p<0.05. RESULTS: Treatment with piperine led to a notable decrease in blood glucose levels and circulating insulin when compared with T2DM rats (group 2). Additionally, piperine administration resulted in the upregulation of HNF-1α mRNA expression and downregulation of SREBP-1c mRNA levels whose effects were found to be near that of the control and standard drug metformin's effects. In vitro study also confirmed that piperine improved the HNF-1α expression and reduced the expression of SREBP-1c in Chang liver cells. CONCLUSION: Our findings suggest that piperine treatment effectively regulates hyperglycemic and hyperinsulinemic insulin resistance in the liver by modulating the expression of HNF-1α and SREBP-1c. Consequently, piperine emerges as a promising candidate for therapeutic intervention in managing T2DM.

Interplay between dental caries pathogens, periodontal pathogens, and sugar molecules: approaches for prevention and treatment.

Globally, oral diseases affect nearly 3.5 billion people, accounting for 4.6% of the healthcare expenditure. Common oral diseases include dental caries and periodontal disease, associated with biofilms formed by cariogenic pathogens. Epidemiological studies associate carbohydrates with these diseases due to  the sugars metabolized by cariogenic pathogens. This review focuses on dental caries and periodontal pathogens, quorum sensing, lectin-carbohydrate interactions, and various sugar molecules. Cariogenic sugars significantly influence biofilms by enhancing pathogen adhesion, viability, and gene expressions associated with biofilm formation. Moreover, lectin-carbohydrate interactions contribute to biofilm stability. Disrupting these interactions is a potential strategy for oral disease prevention. The use of nanoparticles, such as quantum dots, provides novel insights into lectin-sugar interactions and the development of inhibitors. Additionally, nanomaterials like calcium phosphate nanoparticles neutralize acids and inhibit microbial growth. This overview emphasizes understanding the relationships between oral diseases, microbial communities, and sugars to devise preventive and therapeutic strategies against oral diseases.

Facile Microwave-Assisted Hydrothermal Synthesis of Copper Oxide Nanoneedle Arrays for Practical Biomedical Applications.

INTRODUCTION: Copper oxide nanoneedle arrays (CuO NAs) have been widely used as antibacterial agents and in therapeutic applications because of their unique physicochemical features, low cytotoxicity, low cost, exceptional antibacterial action, and significant interest in biomedicine. Various analytical techniques were used to assess the related phase constitution, optical characteristics, elemental content, and surface morphology. The X-ray diffraction (XRD) patterns and field-emission scanning electron microscopy (FE-SEM) micrographs revealed that the CuO NAs had a monoclinic phase with a nanoneedle-like shape. Our findings may cover the progress of innovative and effective anti-bacterial capabilities based on CuO NAs, which have been shown to be effective against various pathogens, making them ideal options for fighting bacterial infections.  Objective: This research aimed to synthesize CuO NAs using microwave-solvothermal (MW-ST) technology, explore their effectiveness, and assess their biological activity. METHODS: The CuO NAs were synthesized using the MW-ST process, and their properties were assessed using X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), field emission scanning electron microscopy (FE-SEM), energy dispersive analysis (EDS), field emission transmission microscopy (FE-TEM), and ultraviolet-visible (UV-Vis) techniques. The biocompatibility of CuO NAs was determined through hemolytic assays, and their bioactivities like antioxidant and anti-inflammatory assays were also determined. RESULTS: The CuO NAs were successfully developed, and various analytical tools were used to characterize and validate their morphology, size, crystallinity, and elemental compositions. It has been shown in in-vitro investigations that a strong anti-inflammatory impact is demonstrated by the inhibition of protein denaturation with low hemolytic potential. As a result, CuO NAs have the potential to be an excellent choice for anti-inflammatory solicitations. CONCLUSION: CuO NAs were synthesized and characterized with various advanced techniques, revealing the formation of nanoneedles-like morphology. Based on the experimental findings, CuO NAs have the potential for anti-microbial, anti-oxidant, anti-inflammatory, and anti-hemolytic activities. However, additional in-vivo testing is essential to properly evaluate their efficiency and safety.

Exploring the therapeutic potential of curcumin in oral squamous cell carcinoma (HSC-3 cells): Molecular insights into hypoxia-mediated angiogenesis.

BACKGROUND: Oral cancer represents a substantial global health burden, often associate with hypoxia-induced angiogenesis as a critical factor in its progression. Curcumin, a naturally occurring bioactive compounds, has gained increasing attention for its potential anticancer properties. OBJECTIVE: To assess the impact of curcumin on oral cancer, particularly its role in modulating HIF-1α-mediated angiogenesis in HSC-3 cells. METHODS: Our investigation involved multiple experimental approaches, including MTT assay, aerobic glycolysis by metabolic kit, cell cycle, and apoptosis assessment via flow cytometry. Furthermore, we employed molecular docking techniques to examine the interactions between curcumin and key angiogenesis related proteins, including HIF-1α, VEGF-B, MMP-3, and STAT3. RESULTS: Our results demonstrate that curcumin exerts significant effects on the cell survivability, cell cycle regulation, and apoptosis induction in oral cancer cells. These effects were particularly pronounced under the conditions of HIF-1α mediated angiogenesis. Computational binding analysis revealed strong binding interactions with curcumin and the selected proteins, implying a plausible mechanism through which curcumin may modulate the angiogenic pathways in oral cancer. CONCLUSION: Our research sheds light on the diverse effects of curcumin on oral cancer cells, emphasizing its potential as a promising therapeutic tool for addressing hypoxia-induced angiogenesis. However, further investigation is essential to comprehensively understand the molecular mechanisms underlying these effects in in vitro models. This deeper comprehension is crucial for translating these findings into clinical applications aimed at improving oral cancer treatment.

Identification of Novel Marine Bioactive Compound as Potential Multiple Inhibitors in Triple-negative Breast Cancer - An in silico Approach.

BACKGROUND: Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer lacking specific receptors, with dysregulated and overactivated Hedgehog (Hh) and mTOR/PI3K/AKT signaling pathways as potential therapeutic targets. OBJECTIVE: This study aimed to identify potential inhibitors among 53 alkaloids derived from 9 marine bryozoans using in silico approaches. It sought to analyze their impact on key signaling targets and their potential for future experimental validation. METHODS: In this research, selected targets were evaluated for protein-protein interactions, coexpression survival, and expression profiles. The protein expression was validated through the Human Protein Atlas (HPA) database and druggability through DGIdb. Online web servers were employed to assess drug-likeness, physiochemical properties, pharmacokinetics, and toxicological characteristics of the compounds. Molecular docking and dynamic simulations were carried out for ligand-protein interactions. Common Pharmacophore features, bioavailability, bioactivity, and biological activity spectrum (BAS) were also analyzed. RESULTS: Out of the 13 compounds studied, 10 displayed strong binding affinity with binding energies ranging from >-6.5 to <-8 Kcal/mol across all targets. Molecular dynamics simulations provided insights into Amathamide E's stability and conformational changes. Pharmacophore modeling revealed common features in 14 compounds potentially responsible for their biological activity. CONCLUSION: Our findings indicate the potential of marine-derived compounds as TNBC inhibitors. Further in vitro and in vivo validation is necessary to establish their effectiveness and explore their role as novel anti-TNBC agents.

Unlocking the potential of beta sitosterol: Augmenting the suppression of oral cancer cells through extrinsic and intrinsic signalling mechanisms.

The global increase in the prevalence of oral neoplasms and related deaths can be attributed to social development and lifestyle factors, leading to poor prognosis and a lack of early clinical detection. Oral cancer ranks ranked sixth mostly diagnosed cancer and is a leading cause of cancer-related deaths. In light of these circumstances, our objective was to assess the potential of ß-sitosterol, a naturally occurring herbal compound, as an anticancer agent against KB cells, a representative cell line for oral cancer. Our study primarily focused on evaluating the cytotoxic effect and mRNA expression of apoptotic proteins by ß-sitosterol on KB cells. The results demonstrated a remarkable cytotoxic effect, leading to cell death. Further investigation using flow cytometric analysis revealed that this cell death was mediated through the initiation of the apoptotic signalling by ß-sitosterol. The use of the bioinformatic tool, STITCH, supported our study by predicting drug-protein interactions and suggesting that ß-sitosterol may play a significant role in targeting apoptotic pathways. Additionally, docking results were employed to validate the findings demonstrating high binding affinity of ß-sitosterol with apoptotic-mediated signalling targets. To gain deeper insights into the molecular insights, we measured mRNA levels for BAX, BCL-2, MCL-1, P53, P21, MDM2, caspase3, and caspase9. Based on our comprehensive findings, our study concludes that ß-sitosterol holds significant therapeutic potential against oral cancer cells. These results strongly suggest that this herbal compound should be further explored as a potential treatment option for oral cancer for clinical trial.

Identification of molecular targets of Trigonelline for treating breast cancer through network pharmacology and bioinformatics-based prediction.

Breast cancer, a highly prevalent and fatal cancer that affects the female population worldwide, stands as a significant health challenge. Despite the abundance of chemotherapy drugs, the adverse side effects associated with them have initiated an investigation into natural plant-based compounds. Trigonelline, an alkaloid found in Trigonella foenum-graecum, was previously reported for its anticancer properties by the researchers. In this present study, we have identified the molecular targets of Trigonelline in breast cancer and predicted its drug-like properties and toxicity. By analyzing breast cancer targets from databases including TTD, TCGA, Gene cards, and Trigonelline targets obtained from CTD, we identified 14 specific targets of Trigonelline in the context of breast cancer. The protein-protein interaction (PPI) network of the 14 Trigonelline targets provided insights into the complex relationships between different genes and targets. Heatmap analysis demonstrated the expression patterns of these 14 genes at the protein and RNA levels in breast cancer cells and breast tissues. Notably, four genes, namely EGF, BAX, EGFR, and MTOR, were enriched in the breast cancer pathway. At the same time, PARP1, DDIT3, BAX, and TNF were associated with the apoptosis pathway according to KEGG pathway enrichment analyses. Molecular docking studies between Trigonelline and target proteins from the Protein Data Bank (PDB) revealed favorable binding affinity. Furthermore, mutation analysis of target genes within a dataset of 1918 samples from cBioPortal revealed the absence of mutations. Remarkably, Trigonelline also exhibited binding affinity towards two mutant proteins, and based on these findings, we predicted that Trigonelline could be utilized to target breast cancer genes and their mutants through network pharmacology. Additionally, this was supported by molecular dynamic simulation studies. As our study is preliminary, further validation through in vitro and in vivo studies is essential to confirm the efficacy of Trigonelline in breast cancer treatment.

Identification of Potential Phytochemical Inhibitors From Conium maculatum Targeting the Epidermal Growth Factor Receptor in Metastatic Colorectal Cancer via Molecular Docking Analysis.

Background Metastatic colorectal cancer (mCRC) continues to rank as the second deadliest cancer on the global scale. CRC diagnosed at metastatic (stage IV) makes treatment strategies more challenging. Even though there are numerous therapeutic options available, the side effects of these treatments threaten the human health. Therefore, we are in the phase of searching new molecules that are less harmful and cost-effective. The common source of many pharmaceutical medications is plants. This study focuses on virtually screening phytochemicals from Conium maculatum as potential inhibitors of the epidermal growth factor receptor (EGFR), a crucial target in cancer therapy. Methods and materials C. maculatum was selected due to its phytochemicals and prior indications of its anticancer properties. In silico investigations encompass druglikeness screening, pharmacokinetics assessment, molecular docking, toxicity prediction, molecular target screening, and molecular dynamics simulations. A comprehensive analysis led to the identification of promising lead compounds. Results A total of 25 compounds exhibited favorable pharmacokinetic and drug-like characteristics. Among them, 12 compounds displayed a high affinity for EGFR as determined by molecular docking experiments. Further safety assessment using ProTox-II revealed that seven compounds had no anticipated toxicity, affirming their safety profiles.  Conclusion These findings collectively predicted the efficacy of seven phytochemicals from C. maculatum as EGFR inhibitors in mCRC. Further experimental investigations and optimization of the identified leads were needed to validate the efficacy and safety of identified lead compounds and explore their therapeutic potential in CRC.

Efficacy of mucolytics and steam therapy in the management of sinusitis among Indians

It is of interest to compare the treatment modalities of sinus membrane thickening, by analyzing the difference in pre and post-intervention radiographic measurement of sinus membrane thickness. Results showed that combination therapy of steam and mucolytics decreased the sinus thickening in a statistically significant manner compared to mucolytics alone. Thus, there is a correlation between maxillary sinus membrane thickening and patency of maxillary ostium radiographically.

Influence of antagonist tooth on mandibular implant positioning during surgery among Indians

A retrospective radiographic analysis of cone beam computed tomographic radiographs of 42 patients who had undergone dental implant therapy at the department of implantology, Saveetha Dental College Hospitals, India. The mean angular deviation was 3.17 ° in the anterior, 1.6° in the premolar and 0.81° in the molar region. Data shows that free hand placement could be done with minimal deviation taking the opposing dentition as a guide.