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.

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.

Orthodontic treatment in adults: Challenges, outcomes, and factors affecting compliance and satisfaction.

BACKGROUND: The demand for orthodontic treatment among adults has witnessed a substantial rise in recent years. This study aims to explore the complexities of adult orthodontics, focusing on challenges faced, treatment outcomes, and the influence of factors such as age, gender, and education on patient compliance and satisfaction. METHODS: A multi-dimensional approach was employed, combining a review of clinical records with structured patient surveys. Descriptive statistics summarized demographic characteristics, treatment duration, and orthodontic problems addressed. Inferential statistics included Pearson correlation, Chi-squared tests, and analysis of variance to examine age compliance, gendersatisfaction, and education-orthodontic problem relationships. Qualitative analysis enriched findings, and statistical software facilitated data processing. RESULTS: The analysis revealed a statistically significant negative correlation between age and compliance (r = -0.28, P < 0.05), indicating that younger participants demonstrated higher compliance rates. Gender emerged as a significant factor influencing patient satisfaction (P = 0.024), with females reporting notably higher levels of satisfaction than males. Furthermore, participants with advanced education levels (Master's/Ph.D.) were significantly more likely to have orthodontic issues related to malocclusion (P = 0.041). CONCLUSION: The study provides an insight into the multi-dimensional aspects of adult orthodontics, recognizing the challenges, compliance, and satisfaction levels. Tailored approaches considering age, gender, and education are essential. This research contributes to a deeper understanding of orthodontic treatment in adults and its potential implications for enhanced patient care.

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.

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.

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.

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.

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.

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.

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.

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.

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.