Natural bioactive compounds and FOXO3a in cancer therapeutics: An update.

Forkhead box protein 3a (FOXO3a) is a transcription factor that regulates various downstream targets upon its activation, leading to the upregulation of tumor suppressor and apoptotic pathways. Hence, targeting FOXO3a is an emerging strategy for cancer prevention and treatment. Recently, Natural Bioactive Compounds (NBCs) have been used in drug discovery for treating various disorders including cancer. Notably, several NBCs have been shown as potent FOXO3a activators. NBCs upregulate FOXO3a expressions through PI3K/Akt, MEK/ERK, AMPK, and IκB signaling pathways. FOXO3a promotes its anticancer effects by upregulating the levels of its downstream targets, including Bim, FasL, and Bax, leading to apoptosis. This review focuses on the dysregulation of FOXO3a in carcinogenesis and explores the potent FOXO3a activating NBCs for cancer prevention and treatment. Additionally, the review evaluates the safety and efficacy of NBCs. Looking ahead, NBCs are anticipated to become a cost-effective, potent, and safer therapeutic option for cancer, making them a focal point of research in the field of cancer prevention and treatment.

Natural bioactive compounds and STAT3 against hepatocellular carcinoma: An update.

Hepatocellular carcinoma (HCC) is a challenging and very fatal liver cancer. The signal transducer and activator of transcription 3 (STAT3) pathway is a crucial regulator of tumor development and are ubiquitously active in HCC. Therefore, targeting STAT3 has emerged as a promising approach for preventing and treating HCC. Various natural bioactive compounds (NBCs) have been proven to target STAT3 and have the potential to prevent and treat HCC as STAT3 inhibitors. Numerous kinds of STAT3 inhibitors have been identified, including small molecule inhibitors, peptide inhibitors, and oligonucleotide inhibitors. Due to the undesirable side effects of the conventional therapeutic drugs against HCC, the focus is shifted to NBCs derived from plants and other natural sources. NBCs can be broadly classified into the categories of terpenes, alkaloids, carotenoids, and phenols. Most of the compounds belong to the family of terpenes, which prevent tumorigenesis by inhibiting STAT3 nuclear translocation. Further, through STAT3 inhibition, terpenes downregulate matrix metalloprotease 2 (MMP2), matrix metalloprotease 9 (MMP9) and vascular endothelial growth factor (VEGF), modulating metastasis. Terpenes also suppress the anti-apoptotic proteins and cell cycle markers. This review provides comprehensive information related to STAT3 abrogation by NBCs in HCC with in vitro and in vivo evidences.

Fluoride Binding Potential of Selected Phytochemicals: A Pilot Study.

Fluoride (F-) contamination in drinking water is a major global concern. According to several studies, India and China are the most affected by the presence of excess F-. Long-time exposure to F- concentrations above 1.5 ppm can lead to hard and soft tissue fluorosis (F- toxicity). There are no effective cure or treatment for fluorosis and the condition is almost irreversible. Considering water to be the prime media through which F- reaches humans, maintaining optimal F- levels in water remains the only possible remedy. F- endemic areas have adapted several conventional defluoridation techniques to resolve the issue. Among these, adsorption with plant compounds is widely used for F- removal. Studies have shown that plant metabolites can ameliorate the toxic effects of F-. Based on this, we attempt to elucidate the potential binding and electrochemical bio-sensing properties of selected phytochemicals towards F-. The focus of the present work is to evaluate the interactions of phytochemicals with F-; for which, the binding studies of phytochemicals with F- have been elaborated by UV-visible spectroscopy and emission techniques. Benesi-Hildebrand's (BH) plot was used to calculate the binding constant (CUR - 34.9 × 103 (M-1), QUER - 13 × 103 (M-1), ESC -6.3 × 103 (M-1), FIS - 5.36 × 103 (M-1) and PCA -1.5 × 103 (M-1), and detection limit (CUR - 1.54 × 10-7 M, QUER - 0.156 × 10-6 M, ESC - 0.221 × 10-6 M, FIS - 0.175 × 10-6 M, and PCA - 5.8 × 10-6 M) for the F-:phytochemical mixtures. Further, the binding characteristics were confirmed using 1H-NMR titration experiments. Our findings highlight the potential of phytochemicals as effective binding agents for F-, thereby reducing its bioavailability.

Virtual screening of FOXO3a activators from natural product-like compound library.

FOXO3a is an inevitable transcription factor, which is involved in the regulation of biological processes such as proliferation, DNA damage repair, cell cycle arrest and cell death. Previous studies confirmed that FOXO3a is an excellent tumor suppressor and in cancer cells, it gets phosphorylated followed by proteasomal degradation. FOXO3a is found to be inactivated in cancer cells, whereas in normal cells it gets activated and upregulates its downstream targets, which induces apoptotic pathways. Hence, activation of FOXO3a can be implicated in cancer prevention and treatment. A variety of commercially available FOXO3a activators such as doxorubicin and metformin possess undesirable adverse effects to normal cells and tissues, which are their major limitations. Natural bioactive compounds, eliminating the limitations of such compounds, become an excellent choice for the treatment and prevention of cancer. In this study, a library of natural product-like compounds was screened for their FOXO3a activation potential through in silico approach, which included the use of several bioinformatics tools and processes. Other molecular interaction studies as well as binding and specificity studies were carried out with the help of molecular dynamics simulation. Virtual screening of 7700 small molecules from the Natural Products-like Compound Library revealed the top three FOXO3a activators F3385-6269, F2183-0033 and F3351-0330. Further validation studies are warranted to confirm these findings.

MAO inhibiting phytochemicals from the roots of Glycyrrhiza glabra L.

Glycyrrhizin, a natural compound that is substantially present in Glycyrrhiza glabra L. (Gg) root. Monoamine oxidase B (MAOB) inhibitor is used for the treatment of several important neuropsychological diseases like Parkinson's disease. Gg is known to possess psychoactive properties which relates to its MAO inhibitory potential. This study sought to determine the MAO inhibition property of glycyrrhizin from Gg root extract. The Aqueous extract containing glycyrrhizin was isolated from the root of Gg and characterized using TLC, HPLC, and LC-MS techniques. In silico docking was conducted using Extra precision Glide 2018, Schrödinger docking suite. In addition, the pharmacokinetic properties of the compounds were predicted using SwissADME. The binding energies of the glycyrrhizin correlated well with their in vitro MAO inhibitory potential. Glycyrrhizin exhibited potent inhibitory activity towards MAOB whereas, an aqueous extract of Gg root inhibits both A and B forms of MAO enzyme. Further, molecular docking and molecular dynamics simulation showed that liquiritigenin and methoxyglabridin showed higher stability than other inhibitor compounds from the Gg root extract. These observations suggest that the phytochemicals from the Gg root extract have potent MAO inhibition properties, which can be exploited for the treatment of neurodegenerative disorders.Communicated by Ramaswamy H. Sarma.

Potent FOXO3a Activators from Biologically Active Compound Library for Cancer Therapeutics: An in silico Approach.

The forkhead transcription factor FOXO3a is a member of the FOXO subfamily, which controls a number of cellular processes including apoptosis, proliferation, cell cycle progression, DNA damage, and carcinogenesis. In addition, it reacts to a number of biological stressors such as oxidative stress and UV radiation. FOXO3a has been predominantly associated with many diseases including cancer. Recent research suggests that FOXO3a suppresses tumor growth in cancer. By cytoplasmic sequestration of the FOXO3a protein or mutation of the FOXO3a gene, FOXO3a is commonly rendered inactive in cancer cells. Furthermore, the onset and development of cancer are linked to its inactivation. In order to reduce and prevent tumorigenesis, FOXO3a needs to be activated. So, it is critical to develop new strategies to enhance FOXO3a expression for cancer therapy. Hence, the present study has been aimed to screen small molecules targeting FOXO3a using bioinformatics tools. Molecular docking and molecular dynamic simulation studies reveal the potent FOXO3a activating small molecules such as F3385-2463, F0856-0033, and F3139-0724. These top three compounds will be subjected to further wet experiments. The findings of this study will lead us to explore the potent FOXO3a activating small molecules for cancer therapeutics.

Garcinia gummi-gutta: Phytochemicals and pharmacological applications.

Garcinia gummi-gutta, also known as Garcinia cambogia, is a member of the Guttiferae family. Garcinia is a polygamous genus consisting 200 species of trees and shrubs. It is found in different zones of the planet including Asia's tropical regions. In India alone, around 30 species have been discovered. They are widely used as a flavoring agent to garnish fish curry in southern India, particularly in Kerala and Karnataka. The fruit rind of G. gummi-gutta has traditionally been used to treat gastrointestinal problems, diarrhea, and ulcers. South Indian people have been utilizing it traditionally as evidenced by its ethnobotanical properties. In vivo and in vitro effects of the crude fruit extract showed anti-inflammatory, anti-cancer, anthelmintic, anti-microbial, and antioxidant activities. G. gummi-gutta fruit rind is medicinally significant and is frequently used in ayurvedic and traditional medicine for many diseases. Various secondary metabolites such as organic acids-hydroxycitric acid (HCA), flavonoids, terpenes, polysaccharides and polyisoprenylated benzophenones-garcinol, xanthochymol, guttiferone, benzophenone, xanthone, biflavonoids, alkaloids, tannins, phenols, and saponins isolated from the G. gummi-gutta have diverse pharmacological activities. This review provides a summary of G. gummi-gutta, including its biological activities, phytochemistry, and ethnobotanical applications.

Screening of potent STAT3-SH2 domain inhibitors from JAK/STAT compound library through molecular dynamics simulation.

The Signal Transducer and Activator of Transcription 3 (STAT3) protein is activated consistently in the tumor cells and thus studied as a potent target for cancer prevention. The TYR705-phosphorylated (pTyr) STAT3 forms a homo-dimer by binding to its recognition site in the Src Homology 2 (SH2) domain of another STAT3 monomer, causing cellular survival, proliferation, inflammation, and tumor invasion. Many inhibitors of STAT3-SH2 have recently been identified using both computational and experimental approaches. In this study, we used molecular docking, Absorption, Distribution, Metabolism, and Excretion/Toxicological (ADME/tox) and molecular dynamics modeling to examine binding affinities and specificities of 191 inhibitor drugs from the SELLECKCHEM database. The binding free energies of the inhibitors were calculated by Induced Fit Docking (IFD) prime energy. The binding hotspots of STAT3-SH2 were evaluated via binding energy decomposition and hydrogen bond distribution analysis, and the inhibitor compound's stability was assessed through MD simulation. (-)-Epigallocatechin gallate, Kaempferol-3-O-rutinoside, Picroside I, Saikosaponin D, and Ginsenoside Rk1 were found to be the top hit inhibitor compounds. They exhibited an exceptional docking score, a low binding free energy, interacted with the key amino acid residue, and showed significant ADME/tox moderation. These compounds were further proved to be favorable by their stability in an MD simulation run for 100 ns using GROMACS software. The inhibitors (-)-Epigallocatechin gallate, Kaempferol-3-O-rutinoside, and Saikosaponin D show improved stability in molecular dynamic modeling and are expected to have a significant STAT3-SH2 inhibitory effect against cancer.

Fluoride Induced Neurobehavioral Impairments in Experimental Animals: a Brief Review.

Fluoride is one of the major toxicants in the environment and is often found in drinking water at higher concentrations. Living organisms including humans exposed to high fluoride levels are found to develop mild-to-severe detrimental pathological conditions called fluorosis. Fluoride can cross the hematoencephalic barrier and settle in various brain regions. This accumulation affects the structure and function of both the central and peripheral nervous systems. The neural ultrastructure damages are reflected in metabolic and cognitive activities. Hindrances in synaptic plasticity and signal transmission, early neuronal apoptosis, functional alterations of the intercellular signaling pathway components, improper protein synthesis, dyshomeostasis of the transcriptional and neurotrophic factors, oxidative stress, and inflammatory responses are accounted for the fluoride neurotoxicity. Fluoride causes a decline in brain functions that directly influence the overall quality of life in both humans and animals. Animal studies are widely used to explore the etiology of fluoride-induced neurotoxicity. A good number of these studies support a positive correlation between fluoride intake and toxicity phenotypes closely associated with neurotoxicity. However, the experimental dosages highly surpass the normal environmental concentrations and are difficult to compare with human exposures. The treatment procedures are highly dependent on the dosage, duration of exposure, sex, and age of specimens among other factors which make it difficult to arrive at general conclusions. Our review aims to explore fluoride-induced neuronal damage along with associated histopathological, behavioral, and cognitive effects in experimental models. Furthermore, the correlation of various molecular mechanisms upon fluoride intoxication and associated neurobehavioral deficits has been discussed. Since there is no well-established mechanism to prevent fluorosis, phytochemical-based alleviation of its characteristic indications has been proposed as a possible remedial measure.

Acute Hypobaric Hypoxia Exposure Causes Neurobehavioral Impairments in Rats: Role of Brain Catecholamines and Tetrahydrobiopterin Alterations.

Hypoxia is a state in which the body or a specific part of the body is deprived of adequate oxygen supply at the tissue level. Sojourners involved in different activities at high altitudes (> 2500 m) face hypobaric hypoxia (HH) due to low oxygen in the atmosphere. HH is an example of generalized hypoxia, where the homeostasis of the entire body of an organism is affected and results in neurochemical changes. It is known that lower O2 levels affect catecholamines (CA), severely impairing cognitive and locomotor behavior. However, there is less evidence on the effect of HH-mediated alteration in brain Tetrahydrobiopterin (BH4) levels and its role in neurobehavioral impairments. Hence, this study aimed to shed light on the effect of acute HH on CA and BH4 levels with its neurobehavioral impact on Wistar rat models. After HH exposure, significant alteration of the CA levels in the discrete brain regions, viz., frontal cortex, hippocampus, midbrain, and cerebellum was observed. HH exposure significantly reduced spontaneous motor activity, motor coordination, and spatial memory. The present study suggests that the HH-induced behavioral changes might be related to the alteration of the expression pattern of CA and BH4-related genes and proteins in different rat brain regions. Overall, this study provides novel insights into the role of BH4 and CA in HH-induced neurobehavioral impairments.

Chemotherapeutic Potential of Saikosaponin D: Experimental Evidence.

Saikosaponin D (SSD), an active compound derived from the traditional plant Radix bupleuri, showcases potential in disease management owing to its antioxidant, antipyretic, and anti-inflammatory properties. The toxicological effects of SSD mainly include hepatotoxicity, neurotoxicity, hemolysis, and cardiotoxicity. SSD exhibits antitumor effects on multiple targets and has been witnessed in diverse cancer types by articulating various cell signaling pathways. As a result, carcinogenic processes such as proliferation, invasion, metastasis, and angiogenesis are inhibited, whereas apoptosis, autophagy, and differentiation are induced in several cancer cells. Since it reduces side effects and strengthens anti-cancerous benefits, SSD has been shown to have an additive or synergistic impact with chemo-preventive medicines. Regardless of its efficacy and benefits, the considerations of SSD in cancer prevention are absolutely under-researched due to its penurious bioavailability. Diverse studies have overcome the impediments of inadequate bioavailability using nanotechnology-based methods such as nanoparticle encapsulation, liposomes, and several other formulations. In this review, we emphasize the association of SSD in cancer therapeutics and the discussion of the mechanisms of action with the significance of experimental evidence.

Potential role of Marine Bioactive Compounds in cancer signaling pathways: A review.

Cancer is characterized by alterations that cause the over-proliferation of cells and hyperactivation of signaling pathways. Alterations of signaling molecules dysregulate physiological functions like cell growth, proliferation, metastasis, and cell death. Hence, the potential anticancer compounds primarily target signaling networks for therapeutic interventions in cancer. In the past few years, cancer therapy directed its focus on bioactive compounds that originated from marine sources considering their diverse and untapped nature. These Marine Bioactive Compounds (MBCs) are broadly classified into distinct categories such as alkaloids, carbohydrates, fatty acids, peptides, phenols, quinones, terpenes, and saponins. Bioactive compounds from each class initiate cell death via different signaling pathways. The primary objective of this review is to provide comprehensive information about the pathways that are predominantly targeted by every class of MBCs and integrating data from several marine anticancer research. Here, we studied the role of MBCs in signaling networks that inhibit various cancer types. As a result, we concluded that PI3K/AKT, ROS, and p53 are the three prime signaling pathways targeted by the MBCs to induce apoptosis in cancer cells. Carbohydrates, peptides, and terpenes are the major MBCs classes that regulate signaling pathways in cancer. Hence it is concluded that future anticancer research can be primarily focused on the MBCs derived from the scrutinized classes that adhere to pathways like PI3K/AKT, ROS, and p53 to achieve par excellence results.

Role of oxidative stress-mediated cell death and signaling pathways in experimental fluorosis.

Free radicals and other oxidants have enticed the interest of researchers in the fields of biology and medicine, owing to their role in several pathophysiological conditions, including fluorosis (Fluoride toxicity). Radical species affect cellular biomolecules such as nucleic acids, proteins, and lipids, resulting in oxidative stress. Reactive oxygen species-mediated oxidative stress is a common denominator in fluoride toxicity. Fluorosis is a global health concern caused by excessive fluoride consumption over time. Fluoride alters the cellular redox homeostasis, and its toxicity leads to the activation of cell death mechanisms like apoptosis, autophagy, and necroptosis. Even though a surfeit of signaling pathways is involved in fluorosis, their toxicity mechanisms are not fully understood. Thus, this review aims to understand the role of reactive species in fluoride toxicity with an outlook on the effects of fluoride in vitro and in vivo models. Also, we emphasized the signal transduction pathways and the mechanism of cell death implicated in fluoride-induced oxidative stress.