Sesuvium Portulacastrum Potentiates Anticancer Activity by Facilitating the Expression of IRS-1/AKT Signalling: An In vitro Study.

Sesuvium portulacastrum, a coastal medicinal plant with traditional uses has shown promising biological activities including anti-inflammatory, antioxidant and antimicrobial properties. However, the mechanisms of action active ingredients of this plant have not been studied. Aim of the current study is to investigate the anticancer activity of Sesuvium portulacastrum using in vitro and in silico analysis. The in vitro assays included NO radical scavenging activity, total phenolic and flavonoid content determination. The data were analysed by one-way-ANOVA and p<0.05 was considered as statistically significant. The phytochemical analysis showed the presence of tannins, steroids, terpenoids and phenols. Antioxidant activity of S. portulacastrum showed the dose dependent effect of nitric oxide radical scavenging activity. In silico analysis showed a better binding affinity with IR, IRS1 and Akt molecules which demonstrated the action of bioactive compound of S. portulacastrum against IRS-1/AKT signalling pathway.

Heavy Metal Exposure-Induced Cardiovascular Diseases: Molecular Mechanisms and Therapeutic Role of Antioxidants.

Globally, cardiovascular diseases (CVDs) are the main cause of mortality every year worldwide. CVD health is influenced by various health factors, such as blood pressure, cholesterol levels, and glucose control. The main risk factors include smoking, physical activity, food intake, and body mass index. Around 90% of CVDs could be prevented by controlling these risk factors. Heavy metals are indigenous to the environment of the earth. However, modern lifestyles have led to the exploitation of our environment by unconstrained use of heavy metals. Though heavy metals are essential components, they are hazardous to humans and living systems due to their persistent and non-degradable nature. The mainpurpose of this study is to provide a literature review on the mechanisms of heavy metals, particularly arsenic, lead, and cadmium, that cause cardiovascular diseases. The major mechanism by which heavy metals result in various modalities of cardiovascular disease is the generation of reactive species and the depletionof the antioxidant reserves inside the biological system. The generation of reactive species gradually leads to the activation of various signaling pathways, resulting in either apoptosis or unrestricted cell growth. These unfavorable conditions result in a state when there is an imbalance between reactive species generation and antioxidant activity. Both endogenously present antioxidants and dietary antioxidants are very much essential in regulating the redox potential of the body. They help in the detoxification and excretion of heavy metals and their metabolites in the biological system. Therefore, recognizing the role of heavy metals in cardiovascular health is crucial for developing preventive strategies and interventions aimed at mitigating their adverse effects on human health.

Longitudinal study on salivary IL-6 trajectories in postoperative OSCC patients after chemotherapy and radiotherapy.

BACKGROUND: Oral squamous cell carcinoma (OSCC) poses a significant healthcare challenge globally, necessitating precise biomarkers for effective management. Interleukin-6 (IL-6) in saliva has emerged as a potential biomarker, yet its dynamics post-chemotherapy and radiotherapy remain underexplored. AIM: The aim of our study is to investigate the longitudinal dynamics of salivary interleukin-6 (IL-6) expression in postoperative OSCC patients over a one-year follow-up period after chemotherapy and radiotherapy. METHODS: This longitudinal study enrolled 60 participants, including postoperative OSCC patients and controls, collecting saliva samples over one year. RT-PCR and ELISA techniques measured IL-6 expression. Statistical analyses, including repeated measures ANOVA and univariate tests, evaluated IL-6 dynamics. RESULTS: Pre-treatment, OSCC patients exhibited elevated IL-6 levels compared to controls. Post-therapy, IL-6 levels decreased significantly with p < .0001, indicating treatment response and further result to baseline normalizing at 6-month follow-up. Significant differences were observed across treatment stages, supporting IL-6 as a diagnostic and prognostic marker for OSCC. RT-PCR and ELISA results showed the statistical significance of IL-6's role as a predictive marker. CONCLUSION: Salivary IL-6 emerges as a promising biomarker in OSCC management, necessitating further research to harness its diagnostic and therapeutic potential. By understanding IL-6 dynamics, personalized treatment approaches can be developed to improve patient outcomes. Longitudinal studies with larger cohorts and multi-omics approaches are warranted to validate findings and identify novel therapeutic targets.

Blueberry extract and its bioactive compounds mitigate oxidative stress and suppress human lung cancer cell (A549) growth by modulating the expression of p53/EGFR/STAT3/IL6-mediated signaling molecules.

Bioactive phytocompounds are crucial components in all plants. Since the time of traditional medicine, the utilization of plants has been grounded in the potential of these bioactive compounds to treat or manage specific illnesses. These natural bioactive compounds have sparked growing interest in employing medicinal plants for addressing various conditions, such as inflammatory diseases, diabetes, and cancer. This study focuses on assessing the qualitative phytochemical composition, antioxidant potential, and cytotoxic effects of blueberry (Vaccinium sect. Cyanococcus) extract using three different solvents, namely water, ethanol, and methanol. The extract exhibited notable antioxidant activities, as evidenced by DPPH and H2O2 free radical scavenging assays. The cell viability assay also demonstrated cell growth inhibition in A549 cells. Furthermore, nine specific phytocompounds sourced from existing literature were selected for molecular docking studies against CDK6 and, AMPK key protein kinases which enhance the cancer progression. The molecular docking results also revealed favorable binding scores, with a high score of -9.5 kcal/mol in CDK6 protein and a maximum score of AMPK with targets of -8.8 kcal/mol. The selected phytocompounds' pharmacodynamic properties such as ADMET also supported the study. Furthermore, rutin stated that pre-dominantly present in blueberry plants shows a potent cytotoxicity effect in A549 cells. Functional annotations by bioinformatic analysis for rutin also revealed the strong enrichment in the involvement of PI3K/AKT1/STAT, and p53 signaling pathways. Based on this analysis, the identified rutin and other compounds hold a promising anticancer activity. Overall, the comprehensive evaluation of both in vitro and in silico data suggests that the Vaccinium sect. Cyanococcus extract could serve as a valuable source of pharmaceutical agents and may prove effective in future therapeutic applications.

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.

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.

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.

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.

Effect of different drugs for controlling post-operative swelling after implant surgery among Indians.

Pain and swelling are common complications associated with dental implant surgery. Forty five patients were included in this study (Group 1: Paracetamol+ amoxicillin (n=15), Group 2: Paracetamol+ Cold packs (n=15), Group 3: Paracetamol (n=15)). Post op drugs were given based on the group, and Pre and post-operative photographs were evaluated with Adobe photoshop software. The photographs were evaluated with Adobe Photoshop for Statistical analysis was done by repeated measures ANOVA. The first day post-surgery, there was increased swelling in group 1 with mean surface area of swelling of 47.6±2.1 mm2 and considerable decrease in group 2, 42.1±3.5 mm2. The surface area of swelling in this group was maintained in the same range till Day 7.

Molecular docking analysis of cetuximab with NOTCH signalling pathway targets for oral cancer.

Notch signaling is an evolutionarily ancient mechanism which intricated in cell-cell communication and it plays a crucial role in various developments in malignancies. Inactivating mutations of NOTCH targets are present in about 10 % of cases of squamous cell carcinoma of the skin, oral cavity, and esophagus that rendering it one of the most frequently mutated genes in oral squamous cell carcinoma. Therefore, it is of interest to document the molecular docking analysis of cetuximab with the NOTCH signaling targets such as NOTCH1, NICD, and HES1. These results suggest that targeting the NOTCH signaling with cetuximab might leads to the better outcome for suppression of invasion and metastasis in oral carcinoma.

Molecular docking analysis of proflavin with the Wnt pathway targets for OSCC.

Wnt signaling pathway plays a critical role in tumor progression and metastasis of various cancer types. Therefore, it is of interest to document the molecular docking analysis of proflavin with the Wnt pathway targets (GSK3ß, ß-catenin, and VIM) for oral squamous cell carcinoma (OSCC). These results suggest that targeting the wnt signaling downstream targets with proflavine might leads to the better outcome for therapeutic outcome for the inhibition of invasion and metastasis in oral squamous cell carcinoma.