Circadian-clock-controlled endocrine and cytokine signals regulate multipotential innate lymphoid cell progenitors in the bone marrow.

Innate lymphoid cells (ILCs), strategically positioned throughout the body, undergo population declines over time. A solution to counteract this problem is timely mobilization of multipotential progenitors from the bone marrow. It remains unknown what triggers the mobilization of bone marrow ILC progenitors (ILCPs). We report that ILCPs are regulated by the circadian clock to emigrate and generate mature ILCs in the periphery. We found that circadian-clock-defective ILCPs fail to normally emigrate and generate ILCs. We identified circadian-clock-controlled endocrine and cytokine cues that, respectively, regulate the retention and emigration of ILCPs at distinct times of each day. Activation of the stress-hormone-sensing glucocorticoid receptor upregulates CXCR4 on ILCPs for their retention in the bone marrow, while the interleukin-18 (IL-18) and RORα signals upregulate S1PR1 on ILCPs for their mobilization to the periphery. Our findings establish important roles of circadian signals for the homeostatic efflux of bone marrow ILCPs.

Imperative connotation of SODs in cancer: Emerging targets and multifactorial role of action.

Superoxide dismutase (SOD) is a crucial enzyme responsible for the redox homeostasis inside the cell. As a part of the antioxidant defense system, it plays a pivotal role in the dismutation of the superoxide radicals ( O 2 - $$ {{\mathrm{O}}_2}^{-} $$ ) generated mainly by the oxidative phosphorylation, which would otherwise bring out the redox dysregulation, leading to higher reactive oxygen species (ROS) generation and, ultimately, cell transformation, and malignancy. Several studies have shown the involvement of ROS in a wide range of human cancers. As SOD is the key enzyme in regulating ROS, any change, such as a transcriptional change, epigenetic remodeling, functional alteration, and so forth, either activates the proto-oncogenes or aberrant signaling cascades, which results in cancer. Interestingly, in some cases, SODs act as tumor promoters instead of suppressors. Furthermore, SODs have also been known to switch their role during tumor progression. In this review, we have tried to give a comprehensive account of SODs multifactorial role in various human cancers so that SODs-based therapeutic strategies could be made to thwart cancers.

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.

Assessment of Broad-Spectrum Antimicrobial, Antibiofilm, and Anticancer Potential of Lactoferrin Extracted from Camel Milk.

Lactoferrin is a multifunctional glycoprotein present in mammalian milk. It possesses antimicrobial, antioxidant, immunomodulatory, and several biological functions. Owing to the current trend of increasing antibiotic resistance, our study was designed to purify lactoferrin from camel milk colostrum using cation exchange chromatography on the SP-Sepharose high-performance column. The purity and molecular weight of lactoferrin were checked by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). The chromatogram of the purification procedure illustrated a single peak corresponding to lactoferrin, while the SDS-PAGE revealed 78 kDa molecular weight protein. Furthermore, lactoferrin protein and its hydrolysate form were assessed for its antimicrobial potential. The highest inhibitory effect of whole lactoferrin at the concentration (4 mg/ml) was observed against methicillin-resistant S. aureus (MRSA) and S. aureus, while 10 mg/ml concentration was effective against K. pneumonia, and 27 mg/ml was potent against multidrug-resistant (MDR) bacteria, P. aeruginosa. Likewise, MRSA was more sensitive toward iron-free lactoferrin (2 mg/ml) and hydrolyzed lactoferrin (6 mg/ml). The tested lactoferrin forms showed variability in minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) among tested bacteria. The scanning electron microscopy (SEM) analysis images revealed distortions of the bacterial cells exposed to lactoferrin. The antibiofilm effect differed depending on the concentration and the type of the bacteria; biofilm inhibition ranged from 12.5 to 91.3% in the tested pathogenic bacteria. Moreover, the anticancer activity of lactoferrin forms exhibited a dose-dependent cytotoxicity against human lung cancer cell line (A549).

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.

Effect of Nk-lysin peptides on bacterial growth, MIC, antimicrobial resistance, and viral activities.

NK-lysins from chicken, bovine and human are used as antiviral and antibacterial agents. Gram-negative and gram-positive microorganisms, including Streptococcus pyogenes, Streptococcus mutans, Escherichia coli, Pseudomonas aeruginosa, Klebsiella oxytoca, Shigella sonnei, Klebsiella pneumoniae and Salmonella typhimurium, are susceptible to NK-lysin treatment. The presence of dominant TEM-1 gene was noted in all untreated and treated bacteria, while TOHO-1 gene was absent in all bacteria. Importantly, ß-lactamase genes CTX-M-1, CTX-M-8, and CTX-M-9 genes were detected in untreated bacterial strains; however, none of these were found in any bacterial strains following treatment with NK-lysin peptides. NK-lysin peptides are also used to test for inhibition of infectivity, which ranged from 50 to 90% depending on NK-lysin species. Chicken, bo vine and human NK-lysin peptides are demonstrated herein to have antibacterial activity and antiviral activity against Rotavirus (strain SA-11). On the basis of the comparison between these peptides, potent antiviral activity of bovine NK-lysin against Rotavirus (strain SA-11) is particularly evident, inhibiting infection by up to 90%. However, growth was also significantly inhibited by chicken and human NK-lysin peptides, restricted by 80 and 50%, respectively. This study provided a novel treatment using NK-lysin peptides to inhibit expression of ß-lactamase genes in ß-lactam antibiotic-resistant bacterial infections.

Synthesis and computational insights of flavone derivatives as potential estrogen receptor alpha (ER-α) antagonist.

Hormone-related breast cancer is mostly caused by interactions with estrogen receptor alpha (ER-α), which functions as a transcription factor to control the transcription of numerous genes. Flavones are considered a good substrate for the estrogen receptor. Substitution of the N-heterocyclic ring on the flavon structure may potentiate its anticancer effect. A series of flavon derivatives with an N-heteroaryl ring at the 4' position of the B ring of flavon were designed, prepared and evaluated for in vitro breast cancer activity. Binding interactions of the PzFL, PzF, PiFL, PiF and IFL compounds with ER-α were studied by molecular docking. Molecular dynamics simulation studies were carried out in order to determine the stability and convergence of protein-ligand complexes. The compounds were produced by cyclizing chalcones and chalcones were produced by Claisen-Schmidt condensation of substituted aldehydes and 2-hydroxy acetophenone. Breast cancer activity was evaluated by the MTT assay on MCF-7 cell lines. Also, compounds were studied for their estrogen receptor binding potential on the same cell lines. Molecular docking of compounds showed a good docking score. The molecular dynamics of these compounds expressed stable root mean square deviation, stable radius of gyration and low binding energy, suggesting that ligand bound to protein is quite stable in the complex. MTT assay on MCF-7 cell lines reported PzF and IFL were the most active compounds with lower IC50 values. ER-α binding assay of these compounds revealed the presence of binding interactions with receptors. This study offers a viable reference point for the design of flavon-incorporated N-heterocyclic ring derivatives as breast cancer compounds.Communicated by Ramaswamy H. Sarma.

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.

Phenolic Acids-Mediated Regulation of Molecular Targets in Ovarian Cancer: Current Understanding and Future Perspectives.

Cancer is a global health concern with a dynamic rise in occurrence and one of the leading causes of mortality worldwide. Among different types of cancer, ovarian cancer (OC) is the seventh most diagnosed malignant tumor, while among the gynecological malignancies, it ranks third after cervical and uterine cancer and sadly bears the highest mortality and worst prognosis. First-line treatments have included a variety of cytotoxic and synthetic chemotherapeutic medicines, but they have not been particularly effective in extending OC patients' lives and are associated with side effects, recurrence risk, and drug resistance. Hence, a shift from synthetic to phytochemical-based agents is gaining popularity, and researchers are looking into alternative, cost-effective, and safer chemotherapeutic strategies. Lately, studies on the effectiveness of phenolic acids in ovarian cancer have sparked the scientific community's interest because of their high bioavailability, safety profile, lesser side effects, and cost-effectiveness. Yet this is a road less explored and critically analyzed and lacks the credibility of the novel findings. Phenolic acids are a significant class of phytochemicals usually considered in the nonflavonoid category. The current review focused on the anticancer potential of phenolic acids with a special emphasis on chemoprevention and treatment of OC. We tried to summarize results from experimental, epidemiological, and clinical studies unraveling the benefits of various phenolic acids (hydroxybenzoic acid and hydroxycinnamic acid) in chemoprevention and as anticancer agents of clinical significance.

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.

Interlinking of diabetes mellitus and cancer: An overview.

Cancer and diabetes mellitus (DM) are among the leading causes of mortality and morbidity in the global arena. Lately, several studies demonstrated that DM could promote cancer. However, the exact mechanism(s) highlighting this association are largely untouched and require comprehensive detailing. In the present review, we aimed to explore and decipher the possible mechanism of DM an cancer association. Hyperglycemia could be a subordinate plausible explanation of carcinogenesis in the diabatic patient. It is well known that high glucose levels may help in cancer proliferation. In addition, chronic inflammation, the other well-known factor of diabetes, could also play a role in carcinogenesis. Moreover, the numerous medicines to treat diabetes either increase or reduce cancer risk. Insulin is one of the potent growth factors that promotes cell propagation and induces cancer directly or via insulin like growth factor-1. On the other hand, hyperinsulinemia leads to an increased activity of growth factor-1 by inhibiting growth factor binding protein-1. To improve cancer prognosis, individuals with diabetes should be screened to discover cancer at an early stage and treated appropriately.

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.

Prioritization of bioactive compounds envisaging yohimbine as a multi targeted anticancer agent: insight from molecular docking and molecular dynamics simulation.

Recently, multi-targeted drugs have attracted much attention in cancer therapy where several therapeutic proteins are targeted by a single agent. Using the published scientific literature, we selected sixteen well-known anticancer targets and seven potential phytobioactive chemicals to find a multitargeted compound by screening through molecular docking. The feasible protein-ligand interaction was further predicted by protein-ligand interaction analysis and molecular dynamic simulation. The phytochemical yohimbine exhibited the lowest docking score in the range of -8.3 to -10.0 kcal/mol over other ligands with all the studied protein targets. Molecular interaction data also revealed the feasible binding of yohimbine with all targets. Moreover, the molecular simulation data also confirmed the stability of protein-ligand complexes with three most scored targets viz. ERK2, PARP1 and PIK3α. Based on our results, yohimbine seems to be the most potent compound out of those selected compounds and can be considered as effective lead molecule against the studied target proteins.Communicated by Ramaswamy H. Sarma.

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.