A review of the anticancer properties of bee products and their molecular mechanisms: An overview on lung cancer

Lung cancer is one of the most common types of cancer in the world, and it represents a significant percentage of all diagnosed cancers. Despite better clinical outcomes associated with current drugs, lung cancer has a worse survival rate than any of the other commonly occurring malignancies. Evidence suggests that natural products offer promising potential for improving the current treatment approaches and/or developing novel treatment strategies. Bee products such as honey, propolis, and venom have been reported to exert anti-cancer effects on a variety of human cancer cell lines, thereby paving the way for a wide range of treatment possibilities. The current review focuses on the cytotoxic effects of bee bioactive compounds on all types of cancer, and the molecular pathways by which they might reduce tumor cell growth or trigger apoptosis of cancer cells, with particular reference to lung cancer. This strategy could potentially improve the efficacy of current remedies, reduce the doses of chemotherapy drugs, and decrease adverse effects of chemotherapy drugs. Furthermore, in vitro studies on anti-cancer properties of bee products are carefully reviewed. The results reveal that bee products have the potential to become effective treatment agents against many forms of cancer in the future

Observation of the impact of reactive oxygen species-inducers on the metabolomes of pulmonary artery smooth muscle cells and retinal pigment epithelial cells

Background: Endogenous and exogenous reactive oxygen species (ROS) inducers cause intracellular metabolic modifications leading eventually to serious diseases.Overproduction of ROS is associated with many diseases including diabetes, diabetic retinopathy and cardiovascular diseases (CVD). Exposing of different cell types to oxidative agents impair the cell redox status by primarily inducing the excessive generation of superoxide that is enzymatically converted to other forms of oxidative agents causing cell damage. The hyperglycaemia that occurs due to diabetes mellitus causes high ROS production. Identification of reliable markers that indicate metabolic alteration due to oxidative stress could enable a better understanding of many diseases in terms of diagnosis and treatment with therapeutic targets.Aim: To identify the main metabolic markers that are influenced by ROS in pulmonary artery smooth muscle cells (PASMCs) and retinal pigment epithelial cells(RPE) in-vitro. To investigate the impact of anti-oxidant agents in attenuating the modifications that may appear due to the high production of ROS. Study design and methodology: biological cell samples were prepared and collected for each of the four included studies based on the intervention of each study whether it is the impact of hyperglycaemia with or without vitamin as antioxidants and the impact of TSPO protein deletion. In the first study, PASMCs were exposed to diabetic-like conditions and either supplemented or not supplemented by anti-oxidant agents. In the following study, PASMCs were also examined under hyperglycaemia in normoxic or hypoxic conditions. In the two other following studies, we investigated the impact of oxidised low density lipoprotein (OxLDL) and hyperglycaemia on the TSPO knockout and wildtype RPE cells. All studies were carried out utilizing high-performance liquid chromatography-mass spectrometry. We used untargeted metabolic profiling to detect comprehensive metabolic alterations that occurred intracellularly due to our interventions. MzMatch software was used to identify the metabolites present;multivariate and univariate analyses were employed to determine the most reliable metabolites as biomarkers for oxidative stress.;Results: The outcomes established that high glucose influences cell proliferation and enhances oxidative stress. The general metabolomics results show the induction of carbohydrate metabolism accompanied by activation of the pentose phosphate pathway (PPP) to boost the generation of NADPH as an antioxidant product. Amino acids were also disturbed while some of them were up-regulated and some others were down-regulated. Lipids were frequently the most influenced pathway suggesting that the cell membrane was damaged by ROS induction.Purines and pyrimidines, in addition, were influenced consequently due to the changes occurring in PPP metabolism.Conclusion: These hypothesis-free metabolomics profiling studies have identified intracellular metabolites in PASMCs, and RPE cells which are differentially sensitiveto the hyperglycaemia or oxidative stress inducers and may be useful to initiate hypothesises about markers that can help to prevent or cure diseases where oxidative stress plays a role.Background: Endogenous and exogenous reactive oxygen species (ROS) inducers cause intracellular metabolic modifications leading eventually to serious diseases.Overproduction of ROS is associated with many diseases including diabetes, diabetic retinopathy and cardiovascular diseases (CVD). Exposing of different cell types to oxidative agents impair the cell redox status by primarily inducing the excessive generation of superoxide that is enzymatically converted to other forms of oxidative agents causing cell damage. The hyperglycaemia that occurs due to diabetes mellitus causes high ROS production. Identification of reliable markers that indicate metabolic alteration due to oxidative stress could enable a better understanding of many diseases in terms of diagnosis and treatment with therapeutic targets.Aim: To identify the main metabolic markers that are influenced by ROS in pulmonary artery smooth muscle cells (PASMCs) and retinal pigment epithelial cells(RPE) in-vitro. To investigate the impact of anti-oxidant agents in attenuating the modifications that may appear due to the high production of ROS. Study design and methodology: biological cell samples were prepared and collected for each of the four included studies based on the intervention of each study whether it is the impact of hyperglycaemia with or without vitamin as antioxidants and the impact of TSPO protein deletion. In the first study, PASMCs were exposed to diabetic-like conditions and either supplemented or not supplemented by anti-oxidant agents. In the following study, PASMCs were also examined under hyperglycaemia in normoxic or hypoxic conditions. In the two other following studies, we investigated the impact of oxidised low density lipoprotein (OxLDL) and hyperglycaemia on the TSPO knockout and wildtype RPE cells. All studies were carried out utilizing high-performance liquid chromatography-mass spectrometry. We used untargeted metabolic profiling to detect comprehensive metabolic alterations that occurred intracellularly due to our interventions. MzMatch software was used to identify the metabolites present;multivariate and univariate analyses were employed to determine the most reliable metabolites as biomarkers for oxidative stress.;Results: The outcomes established that high glucose influences cell proliferation and enhances oxidative stress. The general metabolomics results show the induction of carbohydrate metabolism accompanied by activation of the pentose phosphate pathway (PPP) to boost the generation of NADPH as an antioxidant product. Amino acids were also disturbed while some of them were up-regulated and some others were down-regulated. Lipids were frequently the most influenced pathway suggesting that the cell membrane was damaged by ROS induction.Purines and pyrimidines, in addition, were influenced consequently due to the changes occurring in PPP metabolism.Conclusion: These hypothesis-free metabolomics profiling studies have identified intracellular metabolites in PASMCs, and RPE cells which are differentially sensitiveto the hyperglycaemia or oxidative stress inducers and may be useful to initiate hypothesises about markers that can help to prevent or cure diseases where oxidative stress plays a role

Deletion of TSPO resulted in change of metabolomic profile in retinal pigment epithelial cells

Age-related macular degeneration is the main cause of vision loss in the aged population worldwide. Drusen, extracellular lesions formed underneath the retinal pigment epithelial (RPE) cells, are a clinical feature of AMD and associated with AMD progression. RPE cells support photoreceptor function by providing nutrition, phagocytosing outer segments and removing metabolic waste. Dysfunction and death of RPE cells are early features of AMD. The translocator protein, TSPO, plays an important role in RPE cholesterol efflux and loss of TSPO results in increased intracellular lipid accumulation and reactive oxygen species (ROS) production. This study aimed to investigate the impact of TSPO knockout on RPE cellular metabolism by identifying the metabolic differences between wildtype and knockout RPE cells, with or without treatment with oxidized low density lipoprotein (oxLDL). Using liquid chromatography mass spectrometry (LC/MS), we differentiated several metabolic pathways among wildtype and knockout cells. Lipids amongst other intracellular metabolites were the most influenced by loss of TSPO and/or oxLDL treatment. Glucose, amino acid and nucleotide metabolism was also affected. TSPO deletion led to up-regulation of fatty acids and glycerophospholipids, which in turn possibly affected the cell membrane fluidity and stability. Higher levels of glutathione disulphide (GSSG) were found in TSPO knockout RPE cells, suggesting TSPO regulates mitochondrial-mediated oxidative stress. These data provide biochemical insights into TSPO-associated function in RPE cells and may shed light on disease mechanisms in AMD

Untargeted metabolic profiling cell-based approach of pulmonary artery smooth muscle cells in response to high glucose and the effect of the antioxidant vitamins D and E

Pulmonary arterial hypertension (PAH) is a multi-factorial disease characterized by the hyperproliferation of pulmonary artery smooth muscle cells (PASMCs). Excessive reactive oxygen species (ROS) formation resulted in alterations of the structure and function of pulmonary arterial walls, leading to right ventricular failure and death. Diabetes mellitus has not yet been implicated in pulmonary hypertension. However, recently, variable studies have shown that diabetes is correlated with pulmonary hypertension pathobiology, which could participate in the modification of pulmonary artery muscles. The metabolomic changes in PASMCs were studied in response to 25 mM of D-glucose (high glucose, or HG) in order to establish a diabetic-like condition in an in vitro setting, and compared to five mM of D-glucose (normal glucose, or LG). The effect of co-culturing these cells with an ideal blood serum concentration of cholecalciferol-D3 and tocopherol was also examined. The current study aimed to examine the role of hyperglycemia in pulmonary arterial hypertension by the quantification and detection of the metabolomic alteration of smooth muscle cells in high-glucose conditions. Untargeted metabolomics was carried out using hydrophilic interaction liquid chromatography and high-resolution mass spectrometry. Cell proliferation was assessed by cell viability and the [³H] thymidine incorporation assay, and the redox state within the cells was examined by measuring reactive oxygen species (ROS) generation. The results demonstrated that PASMCs in high glucose (HG) grew, proliferated faster, and generated higher levels of superoxide anion (O₂·-) and hydrogen peroxide (H₂O₂). The metabolomics of cells cultured in HG showed that the carbohydrate pathway, especially that of the upper glycolytic pathway metabolites, was influenced by the activation of the oxidation pathway: the pentose phosphate pathway (PPP). The amount of amino acids such as aspartate and glutathione reduced via HG, while glutathione disulfide, N6-Acetyl-L-lysine, glutamate, and 5-aminopentanoate increased. Lipids either as fatty acids or glycerophospholipids were downregulated in most of the metabolites, with the exception of docosatetraenoic acid and PG (16:0/16:1(9Z)). Purine and pyrimidine were influenced by hyperglycaemia following PPP oxidation. The results in addition showed that cells exposed to 25 mM of glucose were oxidatively stressed comparing to those cultured in five mM of glucose. Cholecalciferol (D3, or vitamin D) and tocopherol (vitamin E) were shown to restore the redox status of many metabolic pathways

Cluster Identification of Diabetic Risk Factors among Saudi Population

Aims: The aim of the study was to estimate the prevalence and risk factors of diabetes mellitus among adult population of Albaha region, Saudi Arabia and to identify the diabetic risk clusters among Saudi population using various cluster analysis techniques. Study Design: Cross-sectional observation and Hierarchal cluster analyses. Place and Duration of Study: The study was conducted in three different cities of the Albaha region, Saudi Arabia including Albaha, AlAqiq and Baljurashi among Saudi adults 15 years of age or above. The study was carried out from April 2019 to May 2019. Methodology: The first part of the research was a random cross-sectional observational diabetic risk factors screening using a structured questionnaire among adult volunteers of the Albaha region. The second part constituted a multiple cluster analysis technique performed to identify the diabetic risk factors from 13 regions of Saudi Arabia, clustered into five main regions, using NCSS software. Results: In the first part, the risk factors identified among non-diabetic participants showed a significant association with the development of diabetes mellitus, particularly physical inactivity (49.12%), hypertension (41.15%), and high body mass index (19.03%). Likewise, in 11.54% of diabetic patients, elevated body mass index (30.51%), hypertension (27.12%) and physical inactivity (55.93%), which could be associated with diabetic complications. In the second part, the three forms of cluster analyses (the agglomerate hierarchical cluster, clustered heat map and K means clustering analysis) identified physical inactivity and high body mass index as key risk factors which are connected to all other risk factors among the total of 213591 volunteers. Conclusion: Increased prevalence of diabetes and risk of developing diabetes mellitus in the Kingdom require substantial education and training programs to counsel volunteers on all aspects of self-care. Our data provides a robust evidence to establish diabetic counseling through regular diabetes awareness program that can reduce the risk of developing diabetes mellitus

Synthesis, molecular docking, and dynamic simulation targeting main protease (Mpro) of new, Thiazole clubbed pyridine scaffolds as potential COVID-19 inhibitors

Many biological activities of pyridine and thiazole derivatives have been reported, including antiviral activity and, more recently, as COVID-19 inhibitors. Thus, in this paper, we designed, synthesized, and characterized a novel series of N-aminothiazole-hydrazineethyl-pyridines, beginning with a N′-(1-(pyridine-3-yl)ethylidene)hydrazinecarbothiohydrazide derivative and various hydrazonoyl chlorides and phenacyl bromides. Their Schiff bases were prepared from the condensation of N-aminothiazole derivatives with 4-methoxybenzaldehyde. FTIR, MS, NMR, and elemental studies were used to identify new products. The binding energy for non-bonding interactions between the ligand (studied compounds) and receptor was determined using molecular docking against the SARS-CoV-2 main protease (PDB code: 6LU7). Finally, the best docked pose with highest binding energy (8a = −8.6 kcal/mol) was selected for further molecular dynamics (MD) simulation studies to verify the outcomes and comprehend the thermodynamic properties of the binding. Through additional in vitro and in vivo research on the newly synthesized chemicals, it is envisaged that the achieved results will represent a significant advancement in the fight against COVID-19

Farnesiferol C Exerts Antiproliferative Effects on Hepatocellular Carcinoma HepG2 Cells by Instigating ROS-Dependent Apoptotic Pathway

Farnesiferol C (Far-C) is a coumarin commonly extracted from Ferula asafetida and is popularly used as a traditional source of natural remedy. Liver cancer or hepatocellular carcinoma (HCC) has emerged as a major cause behind cancer burden, and limited therapeutic interventions have further aggravated the clinical management of HCC. In the present study, the authors tested the hypothesis that Far-C-instigated oxidative stress resulted in anti-proliferation and apoptosis instigation within human liver cancer HepG2 cells. The observations reported herewith indicated that Far-C exerted considerable cytotoxic effects on HepG2 cells by reducing the cell viability (p p p Bax, Bad, and Bcl2) along with genes exerting regulatory effects on cell cycle (cyclinD1) and its progression (p21Cip1 and CDK4). The evidence thus clearly shows the preclinical efficacy of Far-C against HepG2 cells. However, further mechanistic investigations deciphering the alteration of different pathways post-Far-C exposure will be highly beneficial

Prostate Apoptotic Induction and NFκB Suppression by Dammarolic Acid: Mechanistic Insight into Onco-Therapeutic Action of an Aglycone Asiaticoside

Prostate cancer (PCa) is addressed as the second most common form of onco-threat worldwide and is usually considered as the major cause of mortality in men. Recent times have seen a surge in exploration of plant-derived components for alternative therapeutical interventions against different oncological malignancies. Dammarolic acid or Asiatic acid (AsA) is an aglycone asiaticoside that has been reported for its efficacy in several ailments including cancer. The current study aimed to investigate the anti-proliferative potency of AsA against human prostate cancer PC-3 cells. Purified AsA was diluted and PC-3 cells were exposed to 20, 40, and 80 µM concentration and incubated for 24 h. Post-exposure, PC-3 cells showcased a substantial loss of their viability at 20 µM (p < 0.05), moreover, this reduction in cell viability escalated proportionally with an increase in AsA at concentrations of 40 and 80 µM (p < 0.01; p < 0.001) respectively. AsA-impelled loss of cellular viability was also evident from the acridine orange-stained photomicrographs, which was also used to quantify the viable and apoptotic cells using Image J software. Additionally, quantification of ROS within PC-3 cells also exhibited an increase in DCF-DA-mediated fluorescence intensity post-exposure to AsA in a dose-dependent manner. AsA-induced apoptosis in PC-3 cells was shown to be associated with augmented activity of caspase-3 proportionally to the AsA concentrations. Thus, initially, this exploratory study explicated that AsA treatment leads to anti-proliferative effects in PC-3 cells by enhancing oxidative stress and inciting apoptosis en route to onset of nuclear fragmentation

Antidepressant Effect of Crocin in Mice with Chronic Mild Stress

This study aimed to investigate the antidepressant property of crocin (Crocetin digentiobiose ester) using a chronic mild stress (CMS)-induced depression model in experimental mice. The tail suspension test (TST) and the sucrose preference test were used to evaluate the antidepressant effect on albino mice of either sex after three weeks of CMS. The period of immobility in the TST and percentage preference for sucrose solution were recorded. By monitoring brain malondialdehyde (MDA) level, catalase (CAT) activity, and reduced glutathione (GSH) level, the antioxidant potential was assessed. Three dosages of crocin (4.84, 9.69, and 19.38 mg/kg) were evaluated. When compared to controls, animals that received crocin administration during three periods of CMS had considerably shorter immobility times during the TST. Crocin treatment also raised the percentage preference for sucrose solution in a dose-dependent manner, bringing it to parity with the conventional antidepressant, imipramine. Animals that received a high dose of crocin had a much greater spontaneous locomotor activity. Furthermore, a high dose of crocin remarkably lowered plasma corticosterone and nitrite levels brought on by CMS. Additionally, high doses of crocin given during CMS greatly enhanced reduced glutathione levels while considerably reducing the brain’s MDA and catalase activities. In conclusion, high doses of crocin may have an antidepressant effect in an animal model through several mechanisms. However, further studies should be carried out to explore the role of neurotransmitters for their antidepressant property

Can natural products targeting EMT serve as the future anticancer therapeutics?

Cancer is the leading cause of death and has remained a big challenge for the scientific community. Because of the growing concerns, new therapeutic regimens are highly demanded to decrease the global burden. Despite advancements in chemotherapy, drug resistance is still a major hurdle to successful treatment. The primary challenge should be identifying and developing appropriate therapeutics for cancer patients to improve their survival. Multiple pathways are dysregulated in cancers, including disturbance in cellular metabolism, cell cycle, apoptosis, or epigenetic alterations. Over the last two decades, natural products have been a major research interest due to their therapeutic potential in various ailments. Natural compounds seem to be an alternative option for cancer management. Natural substances derived from plants and marine sources have been shown to have anti-cancer activity in preclinical settings. They might be proved as a sword to kill cancerous cells. The present review attempted to consolidate the available information on natural compounds derived from plants and marine sources and their anti-cancer potential underlying EMT mechanisms