In Vitro and In Silico Anti-Glioblastoma Activity of Hydroalcoholic Extracts of Artemisia annua L. and Artemisia vulgaris L.

Glioblastoma, the most aggressive and challenging brain tumor, is a key focus in neuro-oncology due to its rapid growth and poor prognosis. The C6 glioma cell line is often used as a glioblastoma model due to its close simulation of human glioma characteristics, including rapid expansion and invasiveness. Alongside, herbal medicine, particularly Artemisia spp., is gaining attention for its anticancer potential, offering mechanisms like apoptosis induction, cell cycle arrest, and the inhibition of angiogenesis. In this study, we optimized extraction conditions of polyphenols from Artemisia annua L. and Artemisia vulgaris L. herbs and investigated their anticancer effects in silico and in vitro. Molecular docking of the main phenolic compounds of A. annua and A. vulgaris and potential target proteins, including programmed cell death (apoptosis) pathway proteins proapoptotic Bax (PDB ID 6EB6), anti-apoptotic Bcl-2 (PDB ID G5M), and the necroptosis pathway protein (PDB ID 7MON), mixed lineage kinase domain-like protein (MLKL), in complex with receptor-interacting serine/threonine-protein kinase 3 (RIPK3), revealed the high probability of their interactions, highlighting the possible influence of chlorogenic acid in modulating necroptosis processes. The cell viability of rat C6 glioma cell line was assessed using a nuclear fluorescent double-staining assay with Hoechst 33342 and propidium iodide. The extracts from A. annua and A. vulgaris have demonstrated anticancer activity in the glioblastoma model, with the synergistic effects of their combined compounds surpassing the efficacy of any single compound. Our results suggest the potential of these extracts as a basis for developing more effective glioblastoma treatments, emphasizing the importance of further research into their mechanisms of action and therapeutic applications.

Anti-Cancer Properties of Resveratrol: A Focus on Its Impact on Mitochondrial Functions.

Cancer is one of the most serious public health issues worldwide, demanding ongoing efforts to find novel therapeutic agents and approaches. Amid growing interest in the oncological applications of phytochemicals, particularly polyphenols, resveratrol-a naturally occurring polyphenolic stilbene derivative-has emerged as a candidate of interest. This review analyzes the pleiotropic anti-cancer effects of resveratrol, including its modulation of apoptotic pathways, cell cycle regulation, inflammation, angiogenesis, and metastasis, its interaction with cancer stem cells and the tumor microenvironment. The effects of resveratrol on mitochondrial functions, which are crucial to cancer development, are also discussed. Future research directions are identified, including the elucidation of specific molecular targets, to facilitate the clinical translation of resveratrol in cancer prevention and therapy.

Phenolic Compounds of Rhodiola rosea L. as the Potential Alternative Therapy in the Treatment of Chronic Diseases.

The roots and rhizomes of Rhodiola rosea L. (Crassulaceae), which is widely growing in Northern Europe, North America, and Siberia, have been used since ancient times to alleviate stress, fatigue, and mental and physical disorders. Phenolic compounds: phenylpropanoids rosavin, rosarin, and rosin, tyrosol glucoside salidroside, and tyrosol, are responsible for the biological action of R. rosea, exerting antioxidant, immunomodulatory, anti-aging, anti-fatigue activities. R. rosea extract formulations are used as alternative remedies to enhance mental and cognitive functions and protect the central nervous system and heart during stress. Recent studies indicate that R. rosea may be used to treat diabetes, cancer, and a variety of cardiovascular and neurological disorders such as Alzheimer's and Parkinson's diseases. This paper reviews the beneficial effects of the extract of R. rosea, its key active components, and their possible use in the treatment of chronic diseases. R. rosea represents an excellent natural remedy to address situations involving decreased performance, such as fatigue and a sense of weakness, particularly in the context of chronic diseases. Given the significance of mitochondria in cellular energy metabolism and their vulnerability to reactive oxygen species, future research should prioritize investigating the potential effects of R. rosea main bioactive phenolic compounds on mitochondria, thus targeting cellular energy supply and countering oxidative stress-related effects.

Naringin and Naringenin: Their Mechanisms of Action and the Potential Anticancer Activities.

Naringin and naringenin are the main bioactive polyphenols in citrus fruits, the consumption of which is beneficial for human health and has been practiced since ancient times. Numerous studies have reported these substances' antioxidant and antiandrogenic properties, as well as their ability to protect from inflammation and cancer, in various in vitro and in vivo experimental models in animals and humans. Naringin and naringenin can suppress cancer development in various body parts, alleviating the conditions of cancer patients by acting as effective alternative supplementary remedies. Their anticancer activities are pleiotropic, and they can modulate different cellular signaling pathways, suppress cytokine and growth factor production and arrest the cell cycle. In this narrative review, we discuss the effects of naringin and naringenin on inflammation, apoptosis, proliferation, angiogenesis, metastasis and invasion processes and their potential to become innovative and safe anticancer drugs.

An updated review on the versatile role of chrysin in neurological diseases: Chemistry, pharmacology, and drug delivery approaches.

Neurological diseases are responsible for a large number of morbidities and mortalities in the world. Flavonoids are phytochemicals that possess various health-promoting impacts. Chrysin, a natural flavonoid isolated from diverse fruits, vegetables, and even mushrooms, has several pharmacological activities comprising antioxidant, anti-inflammatory, antiapoptotic, anticancer, and neuroprotective effects. The current study was designed to review the relationship between chrysin administration and neurological complications by discussing the feasible mechanism and signaling pathways. Herein, we mentioned the sources, pharmacological properties, chemistry, and drug delivery systems associated with chrysin pharmacotherapy. The role of chrysin was discussed in depression, anxiety, neuroinflammation, Alzheimer's disease, Parkinson's disease, Huntington's disease, epilepsy, cerebral ischemia, spinal cord injury, neuropathy, Multiple Sclerosis, and Guillain-Barré Syndrome. The findings indicate that chrysin has protective effects against neurological conditions by modulating oxidative stress, inflammation, and apoptosis in animal models. However, more studies should be done to clear the neuroprotective effects of chrysin.

Antioxidant Effects of Schisandra chinensis Fruits and Their Active Constituents.

Schisandra chinensis Turcz. (Baill.) fruits, their extracts, and bioactive compounds are used in alternative medicine as adaptogens and ergogens protecting against numerous neurological, cardiovascular, gastrointestinal, liver, and skin disorders. S. chinensis fruit extracts and their active compounds are potent antioxidants and mitoprotectors exerting anti-inflammatory, antiviral, anticancer, and anti-aging effects. S. chinensis polyphenolic compounds-flavonoids, phenolic acids and the major constituents dibenzocyclooctadiene lignans are responsible for the S. chinensis antioxidant activities. This review will focus on the direct and indirect antioxidant effects of S. chinensis fruit extract and its bioactive compounds in the cells during normal and pathological conditions.

Emerging cellular and molecular mechanisms underlying anticancer indications of chrysin.

Chrysin has been shown to exert several beneficial pharmacological activities. Chrysin has anti-cancer, anti-viral, anti-diabetic, neuroprotective, cardioprotective, hepatoprotective, and renoprotective as well as gastrointestinal, respiratory, reproductive, ocular, and skin protective effects through modulating signaling pathway involved in apoptosis, oxidative stress, and inflammation. In the current review, we discussed the emerging cellular and molecular mechanisms underlying therapeutic indications of chrysin in various cancers. Online databases comprising Scopus, PubMed, Embase, ProQuest, Science Direct, Web of Science, and the search engine Google Scholar were searched for available and eligible research articles. The search was conducted by using MeSH terms and keywords in title, abstract, and keywords. In conclusion, experimental studies indicated that chrysin could ameliorate cancers of the breast, gastrointestinal tract, liver and hepatocytes, bladder, male and female reproductive systems, choroid, respiratory tract, thyroid, skin, eye, brain, blood cells, leukemia, osteoblast, and lymph. However, more studies are needed to enhance the bioavailability of chrysin and evaluate this agent in clinical trial studies.

Molecular Mechanisms of Melatonin-Mediated Cell Protection and Signaling in Health and Disease.

Melatonin, an endogenously synthesized indolamine, is a powerful antioxidant exerting beneficial action in many pathological conditions. Melatonin protects from oxidative stress in ischemic/reperfusion injury, neurodegenerative diseases, and aging, decreases inflammation, modulates the immune system, inhibits proliferation, counteracts the Warburg effect, and promotes apoptosis in various cancer models. Melatonin stimulates antioxidant enzymes in the cells, protects mitochondrial membrane phospholipids, especially cardiolipin, from oxidation thus preserving integrity of the membranes, affects mitochondrial membrane potential, stimulates activity of respiratory chain enzymes, and decreases the opening of mitochondrial permeability transition pore and cytochrome c release. This review will focus on the molecular mechanisms of melatonin effects in the cells during normal and pathological conditions and possible melatonin clinical applications.

Fatty Acid Oxidation and Mitochondrial Morphology Changes as Key Modulators of the Affinity for ADP in Rat Heart Mitochondria.

Fatty acids are the main respiratory substrates important for cardiac function, and their oxidation is altered during various chronic disorders. We investigated the mechanism of fatty acid-oxidation-induced changes and their relations with mitochondrial morphology and ADP/ATP carrier conformation on the kinetics of the regulation of mitochondrial respiration in rat skinned cardiac fibers. Saturated and unsaturated, activated and not activated, long and medium chain, fatty acids similarly decreased the apparent KmADP. Addition of 5% dextran T-70 to mimic the oncotic pressure of the cellular cytoplasm markedly increased the low apparent KmADP value of mitochondria in cardiac fibers respiring on palmitoyl-l-carnitine or octanoyl-l-carnitine, but did not affect the high apparent KmADP of mitochondria respiring on pyruvate and malate. Electron microscopy revealed that palmitoyl-l-carnitine oxidation-induced changes in the mitochondrial ultrastructure (preventable by dextran) are similar to those induced by carboxyatractyloside. Our data suggest that a fatty acid oxidation-induced conformational change of the adenosine diphosphate (ADP)/adenosine triphosphate (ATP) carrier (M-state to C-state, condensed to orthodox mitochondria) may affect the oxidative phosphorylation affinity for ADP.

Flavonoids as Anticancer Agents.

Flavonoids are polyphenolic compounds subdivided into 6 groups: isoflavonoids, flavanones, flavanols, flavonols, flavones and anthocyanidins found in a variety of plants. Fruits, vegetables, plant-derived beverages such as green tea, wine and cocoa-based products are the main dietary sources of flavonoids. Flavonoids have been shown to possess a wide variety of anticancer effects: they modulate reactive oxygen species (ROS)-scavenging enzyme activities, participate in arresting the cell cycle, induce apoptosis, autophagy, and suppress cancer cell proliferation and invasiveness. Flavonoids have dual action regarding ROS homeostasis-they act as antioxidants under normal conditions and are potent pro-oxidants in cancer cells triggering the apoptotic pathways and downregulating pro-inflammatory signaling pathways. This article reviews the biochemical properties and bioavailability of flavonoids, their anticancer activity and its mechanisms of action.

The Essential Oil and Hydrolats from Myristica fragrans Seeds with Magnesium Aluminometasilicate as Excipient: Antioxidant, Antibacterial, and Anti-inflammatory Activity.

Nutmeg (Myristica fragrans) essential oil has antimicrobial, antiseptic, antiparasitic, anti-inflammatory, and antioxidant properties. We have recently demonstrated that hydrodistillation of nutmeg essential oil by applying magnesium aluminometasilicate as an excipient significantly increases both the content and amount of bioactive substances in the oil and hydrolats. In this study, we aimed to compare the antioxidant, antimicrobial, and anti-inflammatory activity of hydrolats and essential oil obtained by hydrodistillation in the presence and absence of magnesium aluminometasilicate as an excipient. The 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging method revealed that magnesium aluminometasilicate did not significantly improved antioxidant activity of both essential oil and hydrolat. Antibacterial efficiency was evaluated by monitoring growth of 15 bacterial strains treated by a range of dilutions of the essential oil and the hydrolats. Essential oil with an excipient completely inhibited the growth of E. faecalis, S. mutans (referent), and P. multocida, whereas the pure oil was only efficient against the latter strain. Finally, the anti-inflammatory properties of the substances were assessed in a fibroblast cell culture treated with viral dsRNR mimetic Poly I:C. The essential oil with an excipient protected cells against Poly I:C-induced necrosis more efficiently compared to pure essential oil. Also, both the oil and the hydrolats with aluminometasilicate were more efficient in preventing IL-6 release in the presence of Poly I:C. Our results show that the use of magnesium aluminometasilicate as an excipient might change and in some cases improve the biological activities of nutmeg essential oil and hydrolats.

Direct effects of (-)-epicatechin and procyanidin B2 on the respiration of rat heart mitochondria.

Flavonol (-)-epicatechin and its derived dimer procyanidin B2, present in high amounts in cocoa products, have been shown to exert beneficial effects on the heart and cardiovascular system; however, their mechanism of action has not been fully elucidated. We studied effects of (-)-epicatechin and procyanidin B2 on the oxidative phosphorylation of isolated rat heart mitochondria. (-)-Epicatechin and procyanidin B2 had stimulating effect (up to 30% compared to control) on substrate-driven (State 2) mitochondrial respiration. Their effect was dependent on the respiratory substrates used. (-)-Epicatechin at higher concentrations (from 0.27 µg/mL) significantly decreased (up to 15%) substrate- and ADP-driven (State 3) mitochondrial respiration in case of pyruvate and malate oxidation only. Procyanidin B2 (0.7-17.9 ng/mL) inhibited State 3 respiration rate up to 19%, the most profound effect being expressed with succinate as the substrate. (-)-Epicatechin at concentrations of 0.23 µg/mL and 0.46 µg/mL prevented loss of the cytochrome c from mitochondria when substrate was succinate, supporting the evidence of membrane stabilizing properties of this flavonol. Thus, both (-)-epicatechin and procyanidin B2 directly influenced mitochondrial functions and the observed effects could help to explain cardiometabolic risk reduction ascribed to the consumption of modest amounts of cocoa products.

The effect of Leonurus cardiaca herb extract and some of its flavonoids on mitochondrial oxidative phosphorylation in the heart.

Motherwort (Leonurus cardiaca) possesses antibacterial, antioxidant, anti-inflammatory, and analgesic activities, and is used as a complementary remedy to improve heart function and blood circulation. Since cardiovascular diseases are often associated with an alteration of mitochondria, the main producers of ATP in cardiac muscle cells, the aim of our work was to determine bioactive constituents present in motherwort aerial parts extract in ethanol and investigate their effects on the functions of cardiac mitochondria. Quantitative determination of polyphenols in L. cardiaca herb extract was performed by HPLC. Mitochondrial respiration rates were evaluated using a Clark-type oxygen electrode. Mitochondrial ROS generation was determined fluorimetrically with Amplex Red and horseradish peroxidase. The results showed that constituents (chlorogenic acid, orientin, quercetin, hyperoside, and rutin) of L. cardiaca herb extract uncouple (by 20-90 %) mitochondrial oxidation from phosphorylation, partially inhibit (by ~ 40 %) the mitochondrial respiratory chain in cases of pyruvate and malate as well as succinate oxidation, and effectively attenuate the generation of free radicals in mitochondria. Since partial uncoupling of mitochondria, respiratory inhibition, and decreased ROS production are proposed as possible mechanisms of cardioprotection, our results imply that L. cardiaca herb extract could be a useful remedy to protect cardiac muscles from the effects of pathogenic processes.