Decoding dynamic interactions between EGFR-TKD and DAC through computational and experimental approaches: A novel breakthrough in lung melanoma treatment.

In the quest for effective lung cancer treatments, the potential of 3,6-diaminoacridine-9-carbonitrile (DAC) has emerged as a game changer. While DAC's efficacy against glioblastoma is well documented, its role in combating lung cancer has remained largely untapped. This study focuses on CTX-1, exploring its interaction with the pivotal EGFR-TKD protein, a crucial target in lung cancer therapeutics. A meticulous molecular docking analysis revealed that CTX-1 exhibits a noteworthy binding affinity of -7.9 kcal/mol, challenging Erlotinib, a conventional lung cancer medication, which displayed a binding affinity of -7.3 kcal/mol. For a deeper understanding of CTX-1's molecular mechanics, this study employed rigorous 100-ns molecular dynamics simulations, demonstrating CTX-1's remarkable stability in comparison with erlotinib. The Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) method further corroborated these results, with CTX-1 showing a free binding energy of -105.976 ± 1.916 kJ/mol. The true prowess of CTX-1 was tested against diverse lung cancer cell lines, including A549, Hop-62 and H-1299. CTX-1 not only significantly outperformed erlotinib in anticancer activity but also exhibited a spectrum of therapeutic effects. It effectively diminished cancer cell viability, induced DNA damage, halted cell cycle progression, generated reactive oxygen species (ROS), impaired mitochondrial transmembrane potential, instigated apoptosis and successfully inhibited EGFR-TKD. This study not only underscores the potential of CTX-1 a formidable contender in lung cancer treatment but also marks a paradigm shift in oncological therapeutics, offering new horizons in the fight against this formidable disease.

Interplay of precision therapeutics and MD study: Calocybe indica's potentials against cervical cancer and its interaction with VEGF via octadecanoic acid.

The evolving landscape of personalized medicine necessitates a shift from traditional therapeutic interventions towards precision-driven approaches. Embracing this paradigm, our research probes the therapeutic efficacy of the aqueous crude extract (ACE) of Calocybe indica in cervical cancer treatment, merging botanical insights with advanced molecular research. We observed that ACE exerts significant influences on nuclear morphology and cell cycle modulation, further inducing early apoptosis and showcasing prebiotic attributes. Characterization of ACE have identified several phytochemicals including significant presence of octadeconoic acid. Simultaneously, utilizing advanced Molecular Dynamics (MD) simulations, we deciphered the intricate molecular interactions between Vascular Endothelial Growth Factor (VEGF) and Octadecanoic acid to establish C.indica's role as an anticancer agent. Our study delineates Octadecanoic acid's potential as a robust binding partner for VEGF, with comprehensive analyses from RMSD and RMSF profiles highlighting the stability and adaptability of the protein-ligand interactions. Further in-depth thermodynamic explorations via MM-GBSA calculations reveal the binding landscape of the VEGF-Octadecanoic acid complex. Emerging therapeutic innovations, encompassing proteolysis-targeting chimeras (PROTACs) and avant-garde nanocarriers, are discussed in the context of their synergy with compounds like Calocybe indica P&C. This convergence underscores the profound therapeutic potential awaiting clinical exploration. This study offers a holistic perspective on the promising therapeutic avenues facilitated by C. indica against cervical cancer, intricately woven with advanced molecular interactions and the prospective integration of precision therapeutics in modern oncology.

Curcumin, its derivatives, and their nanoformulations: Revolutionizing cancer treatment.

Curcumin is a natural compound derived from turmeric and can target malignant tumor molecules involved in cancer propagation. It has potent antioxidant activity, but its effectiveness is limited due to poor absorption and rapid elimination from the body. Various curcumin derivatives have also shown anticancer potential in in-vitro and in-vivo models. Curcumin can target multiple signaling pathways involved in cancer development/progression or induce cancer cell death through apoptosis. In addition, curcumin and its derivatives could also enhance the effectiveness of conventional chemotherapy, radiation therapy and reduce their associated side effects. Lately, nanoparticle-based delivery systems are being developed/explored to overcome the challenges associated with curcumin's delivery, increasing its overall efficacy. The use of an imaging system to track these formulations could also give beneficial information about the bioavailability and distribution of the nano-curcumin complex. In conclusion, curcumin holds significant promise in the fight against cancer, especially in its nanoform, and could provide precise delivery to cancer cells without affecting normal healthy cells.

Evaluation of biogenically synthesized MgO NPs anticancer activity against breast cancer cells.

Background: Magnesium is recognized to have pharmacological potential, and its nanoformulation is anticipated to offer significant therapeutic effects, particularly against cancer. In this study, we analyzed the anticancer effect of biogenically synthesized magnesium oxide nanoparticles (MgO NPs) against breast cancer cells (MDA-MB-231). Methods: Different biological evaluations, such as cytotoxicity, cellular morphology, induction of apoptosis, generation of ROS, cell adhesion and cellular migration were estimated using well established methodology. Results: The biogenic MgO NPs exhibited increased cytotoxicity, induced apoptosis, enhanced formation of ROS, promoted cell adhesion and inhibited cellular migration in a dose-dependent manner, showing its therapeutic potential against MDA-MB-231 cells. Conclusion: The current study observed strong anticancer activity of MgO NPs against studied cancer cell lines. However, our study must be validated in an appropriate animal/xenograft model to authenticate the effectiveness of MgO NPs against breast cancer.

Synergistic inhibition of glioblastoma multiforme through an in-silico analysis of luteolin and ferulic acid derived from Angelica sinensis and Cannabis sativa: Advancements in computational therapeutics.

The primary objective of this study is to uncover novel therapeutic agents for the treatment of Glioblastoma Multiforme (GBM), a highly aggressive form of brain cancer, and Alzheimer's Disease (AD). Given the complexity and resistance associated with both conditions, the study underscores the imperative need for therapeutic alternatives that can traverse the biological intricacies inherent in both neuro-oncological and neurodegenerative disorders. To achieve this, a meticulous, target-based virtual screening was employed on an ensemble of 50 flavonoids and polyphenol derivatives primarily derived from plant sources. The screening focused predominantly on molecular targets pertinent to GBM but also evaluated the potential overlap with neural pathways involved in AD. The study utilized molecular docking and Molecular Dynamic (MD) simulation techniques to analyze the interaction of these compounds with a key biological target, protein tyrosine phosphatase receptor-type Z (PTPRZ). Out of the 50 compounds examined, 10 met our stringent criteria for binding affinity and specificity. Subsequently, the highest value of binding energy was observed for the synergistic binding of luteolin and ferulic acid with the value of -10.5 kcal/mol. Both compounds exhibited inherent neuroprotective properties and demonstrated significant potential as pathway inhibitors in GBM as well as molecular modulators in AD. Drawing upon advanced in-silico cytotoxicity predictions and sophisticated molecular modeling techniques, this study casts a spotlight on the therapeutic capabilities of polyphenols against GBM. Furthermore, our findings suggest that leveraging these compounds could catalyze a much-needed paradigm shift towards more integrative therapeutic approaches that span the breadth of both neuro-oncology and neurodegenerative diseases. The identification of cross-therapeutic potential in flavonoids and polyphenols could drastically broaden the scope of treatment modalities against both fatal diseases.

Analysis of some flavonoids for inhibitory mechanism against cancer target phosphatidylinositol 3-kinase (PI3K) using computational tool.

Cancer has been one of the leading causes of mortality worldwide over the past few years. Some progress has been made in the development of more effective cancer therapeutics, resulting in improved survival rates. However, the desired outcome in the form of successful treatment is yet to be achieved. There is high demand for the development of innovative, inexpensive, and effective anticancer treatments using natural resources. Natural compounds have been increasingly discovered and used for cancer therapy owing to their high molecular diversity, novel biofunctionality, and minimal side effects. These compounds can be utilized as chemopreventive agents because they can efficiently inhibit cell growth, control cell cycle progression, and block several tumor-promoting signaling pathways. PI3K is an important upstream protein of the PI3K-Akt-mTOR pathway and a well-established cancer therapeutic target. This study aimed to explore the small molecules, natural flavonoids, viz. quercetin, luteolin, kaempferol, genistein, wogonin, daidzein, and flavopiridol for PI3Kγ kinase activity inhibition. In this study, the binding pose, interacting residues, molecular interactions, binding energies, and dissociation constants were investigated. Our results showed that these flavonoids bound well with PI3Kγ with adequate binding strength scores and binding energy ranging from (-8.19 to -8.97 Kcal/mol). Among the explored ligands, flavopiridol showed the highest binding energy of -8.97 Kcal/mol, dock score (-44.40), and dissociation constant term, pKd of 6.58 against PI3Kγ. Based on the above results, the stability of the most promising ligand, flavopiridol, against PI3Kγ was evaluated by molecular dynamics simulations for 200 ns, confirming the stable flavopiridol and PI3Kγ complex. Our study suggests that among the selected flavonoids specifically flavopiridol may act as potential inhibitors of PI3Kγ and could be a therapeutic alternative to inhibit the PI3Kγ pathway, providing new insights into rational drug discovery research for cancer therapy.

Screening of Cu4 O3 NPs efficacy and its anticancer potential against cervical cancer.

Cu4 O3 is the least explored copper oxide, and its nanoformulation is anticipated to have important therapeutic potential especially against cancer. The current study aimed to biosynthesize Cu4 O3 nanoparticles (NPs) using an aqueous extract of pumpkin seeds and evaluate its antiproliferative efficacy against cervical cells after screening on different cancer cell lines. The obtained NPs were characterized by different spectroscopic analyses, such as UV-vis, thermogravimetric, energy dispersive X-ray, and Fourier-transform infrared spectroscopy (FTIR). In addition, high-resolution transmission electron microscopes (HR-TEM) were used to observe the morphology of the biosynthesized NPs. The UV-vis spectra showed a peak at around 332 nm, confirming the formation of Cu4 O3 NPs. Moreover, FTIR and TAG analyses identified the presence of various bioactive phytoconstituents that might have worked as capping and stabilization agents and comparative stable NPs at very high temperatures, respectively. The HR-TEM data showed the spherical shape of Cu4 O3 NPs in the range of 100 nm. The Cu4 O3 NPs was screened on three different cancer cell lines viz., Hela, MDA-MB-231, and HCT-116 using cytotoxicity (MTT) reduction assay. In addition, Vero was taken as a normal epithelial (control) cell. The high responsive cell line in terms of least IC50 was further assessed for its anticancer potential using a battery of biological tests, including morphological alterations, induction of apoptosis/ROS generation, regulation of mitochondrial membrane potential (MMP), and suppression of cell adhesion/migration. Vero cells (control) showed a slight decline in % cell viability even at the highest tested Cu4 O3 NPs concentration. However, all the studied cancer cells viz., MDA-MB-231, HCT 116, and HeLa cells showed a dose-dependent decline in cell viability after the treatment with Cu4 O3 NPs with a calculated IC50 value of 10, 11, and 7.2 µg/mL, respectively. Based on the above data, Hela cells were chosen for further studies, that showed induction of apoptosis from 3.5 to 9-folds by three different staining techniques acridine orange/ethidium bromide (AO/EB), 4',6-diamidino-2-phenylindole (DAPI), and propidium iodide (PI). The enhanced production of reactive oxygen species (>3.5-fold), modulation in MMP, and suppression of cell adhesion/migration were observed in the cells treated with Cu4 O3 NPs. The current study obtained the significant antiproliferative potential of Cu4 O3 NPs against the cervical cancer cell line, which needs to be confirmed further in a suitable in vivo model. Based on our results, we also recommend the green-based, eco-friendly, and cost-effective alternative method for synthesizing novel nanoformulation.

Mirtazapine attenuated cadmium-induced neuronal intoxication by regulating Nrf2 and NF-κB/TLR4 signals.

Cadmium (Cd) is one of the most hazardous metals to the environment and human health. Neurotoxicity is of the most serious hazards caused by Cd. Mirtazapine (MZP) is a central presynaptic α2 receptor antagonist used effectively in treating several neurological disorders. This study investigated the anti-inflammatory and antioxidant activity of MZP against Cd-induced neurotoxicity. In this study, rats were randomly divided into five groups: control, MZP (30 mg/kg), Cd (6.5 mg/kg/day; i.p), Cd + MZP (15 mg/kg), and Cd + MZP (30 mg/kg). Histopathological examination, oxidative stress biomarkers, inflammatory cytokines, and the impact of Nrf2 and NF-κB/TLR4 signals were assessed in our study. Compared to Cd control rats, MZP attenuated histological abrasions in the cerebral cortex and CA1 and CA3 regions of the hippocampus as well as the dentate gyrus. MZP attenuated oxidative injury by upregulating Nrf2. In addition, MZP suppressed the inflammatory response by decreasing TNF-α, IL-1ß, and IL-6 mediated by downregulating TLR4 and NF-κB. It is noteworthy that MZP's neuroprotective actions were dose-dependent. Collectively, MZP is a promising therapeutic strategy for attenuating Cd-induced neurotoxicity by regulating Nrf2, and NF-κB/TLR4 signals, pending further study in clinical settings.

Metabolomics Analysis as a Tool to Measure Cobalt Neurotoxicity: An In Vitro Validation.

In this study, cobalt neurotoxicity was investigated in human astrocytoma and neuroblastoma (SH-SY5Y) cells using proliferation assays coupled with LC-MS-based metabolomics and transcriptomics techniques. Cells were treated with a range of cobalt concentrations between 0 and 200 µM. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay revealed cobalt cytotoxicity and decreased cell metabolism in a dose and time-dependent manner was observed by metabolomics analysis, in both cell lines. Metabolomic analysis also revealed several altered metabolites particularly those related to DNA deamination and methylation pathways. One of the increased metabolites was uracil which can be generated from DNA deamination or fragmentation of RNA. To investigate the origin of uracil, genomic DNA was isolated and analyzed by LC-MS. Interestingly, the source of uracil, which is uridine, increased significantly in the DNA of both cell lines. Additionally, the results of the qRT-PCR showed an increase in the expression of five genes Mlh1, Sirt2, MeCP2, UNG, and TDG in both cell lines. These genes are related to DNA strand breakage, hypoxia, methylation, and base excision repair. Overall, metabolomic analysis helped reveal the changes induced by cobalt in human neuronal-derived cell lines. These findings could unravel the effect of cobalt on the human brain.

Curcumin and Plumbagin Synergistically Target the PI3K/Akt/mTOR Pathway: A Prospective Role in Cancer Treatment.

Cancer development is associated with the deregulation of various cell signaling pathways brought on by certain genetic and epigenetic alterations. Therefore, novel therapeutic strategies have been developed to target those pathways. The phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) (PI3K/Akt/mTOR) pathway is one major deregulated pathway in various types of cancer. Several anticancer drug candidates are currently being investigated in preclinical and/or clinical studies to target this pathway. Natural bioactive compounds provide an excellent source for anticancer drug development. Curcumin and plumbagin are two potential anticancer compounds that have been shown to target the PI3K/Akt/mTOR pathway individually. However, their combinatorial effect on cancer cells is still unknown. This study aims to investigate the synergistic effect of these two compounds on the PI3K/Akt/mTOR pathway by employing a sequential molecular docking and molecular dynamics (MD) analysis. An increase in binding affinity and a decrease in inhibition constant have been observed when curcumin and plumbagin were subjected to sequential docking against the key proteins PI3K, Akt, and mTOR. The MD simulations and molecular mechanics combined with generalized Born surface area (MM-GBSA) analyses validated the target proteins' more stable conformation when interacting with the curcumin and plumbagin combination. This indicates the synergistic role of curcumin and plumbagin against cancer cells and the possible dose advantage when used in combination. The findings of this study pave the way for further investigation of their combinatorial effect on cancer cells in vitro and in vivo models.

Biogenic Synthesis of Cu-Mn Bimetallic Nanoparticles Using Pumpkin Seeds Extract and Their Characterization and Anticancer Efficacy.

BACKGROUND: Cancer is a chronic, heterogeneous illness that progresses through a spectrum of devastating clinical manifestations and remains the 2nd leading contributor to global mortality. Current cancer therapeutics display various drawbacks that result in inefficient management. The present study is intended to evaluate the anticancer potential of Cu-Mn bimetallic NPs (CMBNPs) synthesized from pumpkin seed extract against colon adenocarcinoma cancer cell line (HT-29). METHODS: The CMBNPs were biosynthesized by continuously stirring an aqueous solution of pumpkin seed extract with CuSO4 and manganese (II) acetate tetrahydrate until a dark green solution was obtained. The characteristic features of biogenic CMBNPs were assessed by UV-visible spectrophotometry (UV-vis), X-ray powder diffraction (XRD), energy-dispersive X-ray (EDX), scanning electron microscopy (SEM), and transmission electron microscopy (TEM). A battery of biological assays, viz. neutral red uptake (NRU) assay, in vitro scratch assay, and comet assay, were performed for anticancer efficacy evaluation. RESULTS: The formation of spherical monodispersed bimetallic nanoparticles with an average size of 50 nm was recorded using TEM. We observed dose-dependent cytotoxicity of CMBNPs in the HT-29 cell line with an IC50 dose of 115.2 µg/mL. On the other hand, CMBNPs did not show significant cytotoxicity against normal cell lines (Vero cells). Furthermore, the treatment of CMBNPs inhibited the migration of cancer cells and caused DNA damage with a significant increase in comet tail length. CONCLUSIONS: The results showed substantial anticancer efficacy of CMBNPs against the studied cancer cell line. However, it is advocated that the current work be expanded to different in vitro cancer models so that an in vivo validation could be carried out in the most appropriate cancer model.

A literature perspective on the pharmacological applications of yohimbine.

Introduction: Phytochemicals have garnered much attention because they are useful in managing several human diseases. Yohimbine is one such phytochemical with significant pharmacological potential and could be exploited for research by medicinal chemists. It is an indole alkaloid obtained from various natural/synthetic sources.Aims and Results: The research on yohimbine started early, and its use as a stimulant and aphrodisiac by humans has been reported for a long time. The pharmacological activity of yohimbine is mediated by the combined action of the central and peripheral nervous systems. It selectively blocks the pre and postsynaptic α2-adrenergic receptors and has a moderate affinity for α1 and α2 subtypes. Yohimbine also binds to other behaviourally relevant monoaminergic receptors in the following order: α-2 NE > 5HT-1A>, 5HT-1B > 1-D > D3 > D2 receptors.Conclusion: The current review highlights some significant findings that contribute to developing yohimbine-based drugs. It also highlights the therapeutic potential of yohimbine against selected human diseases. However, further research is recommended on the pharmacokinetics, molecular mechanisms, and drug safety requirements using well-designed randomized clinical trials to produce yohimbine as a pharmaceutical agent for human use.Key MessagesYohimbine is a natural indole alkaloid with significant pharmacological potential.Humans have used it as a stimulant and aphrodisiac from a relatively early time.It blocks the pre- and postsynaptic α2-adrenergic receptors that could be exploited for managing erectile dysfunction, myocardial dysfunction, inflammatory disorders, and cancer.

An Insight into Molecular Targets of Breast Cancer Brain Metastasis.

Brain metastasis is one of the major reasons of death in breast cancer (BC) patients, significantly affecting the quality of life, physical activity, and interdependence on several individuals. There is no clear evidence in scientific literature that depicts an exact mechanism relating to brain metastasis in BC patients. The tendency to develop breast cancer brain metastases (BCBMs) differs by the BC subtype, varying from almost half with triple-negative breast cancer (TNBC) (HER2- ER- PR-), one-third with HER2+ (human epidermal growth factor receptor 2-positive, and around one-tenth with luminal subclass (ER+ (estrogen positive) or PR+ (progesterone positive)) breast cancer. This review focuses on the molecular pathways as possible therapeutic targets of BCBMs and their potent drugs under different stages of clinical trial. In view of increased numbers of clinical trials and systemic studies, the scientific community is hopeful of unraveling the underlying mechanisms of BCBMs that will help in designing an effective treatment regimen with multiple molecular targets.

Investigating the anticancer efficacy of biogenic synthesized MgONPs: An in vitro analysis.

The biogenic approach of synthesizing metal nanoparticles is an exciting and interesting research area with a wide range of applications. The present study reports a simple, convenient, low-cost method for synthesizing magnesium oxide nanoparticles (MgONPs) from pumpkin seed extracts and their anticancer efficacy against ovarian teratocarcinoma cell line (PA-1). The characteristic features of biogenic MgONPs were assessed by UV-visible spectrophotometry (UV-vis), X-ray powder diffraction (XRD), scanning electron microscopy (SEM), and transmission electron microscopy (TEM). The formation of spherical NPs with an average size of 100 nm was observed by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Moreover, MgONPs exhibit considerable cytotoxicity with an IC50 dose of 12.5 µg/ml. A dose-dependent rise in the induction of apoptosis, ROS formation, and inhibition in the migration of PA-1 cells was observed up to 15 µg/ml concentration, reflecting their significant anticancer potential against ovarian teratocarcinoma cell line. However, additional work, especially in different in vitro and in vivo models, is recommended to find out their real potential before this environment-friendly and cost-effective nanoformulation could be exploited for the benefit of humankind.

Targeting Glutaminase by Natural Compounds: Structure-Based Virtual Screening and Molecular Dynamics Simulation Approach to Suppress Cancer Progression.

Cancer cells change their glucose and glutamine (GLU) metabolism to obtain the energy required to continue growing. Glutaminase (GLS) plays a crucial role in promoting cell metabolism for cancer cell growth; targeting GLU metabolism by inhibiting GLS has attracted interest as a potential cancer management strategy. Herein, we employed a sequential screening of traditional Chinese medicine (TCM) database followed by drug-likeness and molecular dynamics simulations against the active site of GLS. We report 12 potent compounds after screening the TCM database against GLS, followed by a drug-likeness filter with Lipinski and Veber rule criteria. Among them, ZINC03978829 and ZINC32296657 were found to have higher binding energy (BE) values than the control compound 6-Diazo-5-Oxo-L-Norleucine, with BEs of -9.3 and -9.7 kcal/mol, respectively, compared to the BE of 6-Diazo-5-Oxo-L-Norleucine (-4.7 kcal/mol) with GLS. Molecular dynamics simulations were used to evaluate the results further, and a 100 ns MD simulation revealed that the hits form stable complexes with GLS and formed 2-5 hydrogen bond interactions. This study indicates that these hits might be employed as GLS inhibitors in the battle against cancer. However, more laboratory tests are a prerequisite to optimize them as GLS inhibitors.

The Role of Natural Products and Their Multitargeted Approach to Treat Solid Cancer.

Natural products play a critical role in the discovery and development of numerous drugs for the treatment of various types of cancer. These phytochemicals have demonstrated anti-carcinogenic properties by interfering with the initiation, development, and progression of cancer through altering various mechanisms such as cellular proliferation, differentiation, apoptosis, angiogenesis, and metastasis. Treating multifactorial diseases, such as cancer with agents targeting a single target, might lead to limited success and, in many cases, unsatisfactory outcomes. Various epidemiological studies have shown that the steady consumption of fruits and vegetables is intensely associated with a reduced risk of cancer. Since ancient period, plants, herbs, and other natural products have been used as healing agents. Likewise, most of the medicinal ingredients accessible today are originated from the natural resources. Regardless of achievements, developing bioactive compounds and drugs from natural products has remained challenging, in part because of the problem associated with large-scale sequestration and mechanistic understanding. With significant progress in the landscape of cancer therapy and the rising use of cutting-edge technologies, we may have come to a crossroads to review approaches to identify the potential natural products and investigate their therapeutic efficacy. In the present review, we summarize the recent developments in natural products-based cancer research and its application in generating novel systemic strategies with a focus on underlying molecular mechanisms in solid cancer.

Sugiol Suppresses the Proliferation of Human U87 Glioma Cells via Induction of Apoptosis and Cell Cycle Arrest.

The diterpenoid, sugiol, has been reported to exert anticancer effects against a number of human cancers. However, the anticancer effects of sugiol have not been evaluated against the human glioma cells. The present study was designed to examine the effects of sugiol on the proliferation of human U87 glioma cells. The results showed that sugiol significantly (P < 0.05) suppressed the viability of the U87 cells in a concentration dependent manner and exhibited an IC50 value of 15 µM. On the other hand, the growth inhibitory effects of sugiol were minimal on the normal human astrocytes. Acridine orange and ethidium bromide staining (AO/EB) staining revealed that sugiol induces apoptosis which was further confirmed by Western blot analysis, wherein upregulation of Bax and downregulation of Bcl-2 were observed in U87 cells. Flow cytometry showed that sugiol causes cell cycle arrest at the G 0/G 1 stage. The relative percentage of G1 phase was found to be increased from 26.58% at 0 µM to 70.96% at 30 µM sugiol. Taken together, the results suggest sugiol inhibits the growth of glioma cells and may prove to be a lead molecule in the management of human glioma.

Advancement of cancer immunotherapy using nanoparticles-based nanomedicine.

Cancer has complex pathophysiology and is one of the primary causes of death and morbidity across the world. Chemotherapy, targeted therapy, radiation therapy, and immunotherapy are examples of traditional cancer treatments. However, these conventional treatment regimens have many drawbacks, such as lack of selectivity, non-targeted cytotoxicity, insufficient drug delivery at tumor sites, and multi-drug resistance, leading to less potent/ineffective cancer treatment. Due to its immanent biophysical property and ability to change in numerous ways, nano-technology has completely transformed how cancer is identified and treated in recent years. Furthermore, nanotechnology providing solutions to these restrictions and boosting cancer therapy. Nanoparticles are widely used nanomedicine platform in cancer immunotherapy due to their excellent physicochemical properties that include size, shape, and surface features, resulting into desirable biological interactions and have been categorized into several types. Nanoparticles can also be potentially be up taken by antigen-presenting cells that promote the cytosolic delivery of encapsulated antigens and adjuvants. Furthermore, nanoparticles can be fine-tuned and functionalized with specific moieties to promote their efficacy in targeting and delivering cargo materials to specific locations. In this review, we summarized and discussed nanoparticles and potential features to be used as carriers in cancer immunotherapy, the current status of different types of nanoparticles, and the importance of their functionalization. Furthermore, we have also discussed nanoparticles-based nanomedicine in targeted delivery of encapsulated cancer immunotherapeutic and their involvement in the modulation of the tumor microenvironment, promoting cancer immunotherapy.

Exploring the Natural Compounds in Flavonoids for Their Potential Inhibition of Cancer Therapeutic Target MEK1 Using Computational Methods.

The Mitogen-Activated Protein Kinase (MAPK) signaling pathway plays an important role in cancer cell proliferation and survival. MAPKs' protein kinases MEK1/2 serve as important targets in drug designing against cancer. The natural compounds' flavonoids are known for their anticancer activity. This study aims to explore flavonoids for their inhibition ability, targeting MEK1 using virtual screening, molecular docking, ADMET prediction, and molecular dynamics (MD) simulations. Flavonoids (n = 1289) were virtually screened using molecular docking and have revealed possible inhibitors of MEK1. The top five scoring flavonoids based on binding affinity (highest score for MEK1 is -10.8 kcal/mol) have been selected for further protein-ligand interaction analysis. Lipinski's rule (drug-likeness) and absorption, distribution, metabolism, excretion, and toxicity predictions were followed to find a good balance of potency. The selected flavonoids of MEK1 have been refined with 30 (ns) molecular dynamics (MD) simulation. The five selected flavonoids are strongly suggested to be promising potent inhibitors for drug development as anticancer therapeutics of the therapeutic target MEK1.

Association of IL-6 promoter polymorphism hotspots (- 174G/C and - 572G/C) with cardiovascular disease risk factors.

BACKGROUND: Cardiovascular disease (CVD) is the leading cause of death globally, despite the recent advancements in clinical research. Early diagnosis of CVD and prevention of future complications are important for the management of CVD. In the present study, we determined the genotypic linkage of interleukin-6 (IL-6) promoters with the clinical, biochemical, and inflammatory markers of CVD in the Saudi population. MATERIALS AND METHODS: The study consisted of 89 patients (male and female) with CVD who were admitted at the King Abdulaziz university hospital, Jeddah, Saudi Arabia. The biochemical parameters were evaluated using an automated chemistry analyzer, and inflammatory markers were measured using specific enzyme-linked immunosorbent assay (ELISA) kits. For genotypic analysis, Sanger sequencing was performed. We observed a statistically significant association (p < 0.05) between GG (66.29%), GC (30.34%), and CC (3.37%) genotypes at the - 174G/C (rs1800795) hotspot and neopterin levels. However, the genotypes at the - 572G/C (rs1800796) hotspot did not show any association with age, gender, obesity, diabetes, hypertension, dyslipidemia, smoking, and coronary artery status. In addition, no significant association was observed with biochemical and inflammatory markers, namely fasting blood sugar, glycated hemoglobin A1c, creatinine, total cholesterol, triglycerides, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol, IL-6, and C-reactive protein. The comparison between different possible genotypic groups and CVD risk factors showed a statistically significant (p < 0.05) association between the male gender and HDL with GG, rs1800795 group vs. GC, rs1800796 group. Similarly, neopterin level was also found to be significantly (p < 0.05) associated with the genotypes GC, rs1800795, and GG, rs1800796. Additionally, the male gender (p < 0.01), age (p < 0.05), serum creatinine (p < 0.001), and neopterin (p < 0.05) were found to be significantly associated with GG, rs1800795 + GG, rs1800796, GC, rs1800795 + GC, and rs1800796 GC. CONCLUSION: The direct association of neopterin level with IL-6 promoter polymorphism at - 174G/C (rs1800795) hotspot indicated the role of inflammation in CVD pathogenesis in the Saudi population.