Anti-Neuroinflammatory Effects of Adaptogens: A Mini-Review.

Introduction: Adaptogens are a group of plants that exhibit complex, nonspecific effects on the human body, increasing its ability to adapt, develop resilience, and survive in stress conditions. They are found in many traditional medicinal systems and play a key role in restoring the body's strength and stamina. Research in recent years has attempted to elucidate the mechanisms behind their pharmacological effects, but it appears that these effects are difficult to define precisely and involve multiple molecular pathways. Neuroinflammation: In recent years, chronic inflammation has been recognized as one of the common features of many central nervous system disorders (dementia and other neurodegenerative diseases, depression, anxiety, ischemic stroke, and infections). Because of the specific nature of the brain, this process is called neuroinflammation, and its suppression can result in an improvement of patients' condition and may promote their recovery. Adaptogens as anti-inflammatory agents: As has been discovered, adaptogens display anti-inflammatory effects, which suggests that their application may be broader than previously thought. They regulate gene expression of anti- and proinflammatory cytokines (prostaglandins, leukotriens) and can modulate signaling pathways (e.g., NF-κB). Aim: This mini-review aims to present the anti-neuroinflammatory potential of the most important plants classified as adaptogens: Schisandra chinensis, Eleutherococcus senticosus, Rhodiola rosea and Withania somnifera.

The Genus Cuphea P. Browne as a Source of Biologically Active Phytochemicals for Pharmaceutical Application and Beyond-A Review.

Cuphea P. Browne (Lythraceae) is a monophyletic taxon comprising some 240-260 species that grow wild in the warm, temperate, and tropical regions of South and Central America and the southern part of North America. They have been valued as traditional medicinal remedies for numerous indications, including treating wounds, parasitic infections, hypertension, digestive disorders, cough, rheumatism, and pain. Modern pharmacological research provides data that support many of these traditional uses. Such a wide array of medicinal applications may be due to the exceptionally rich phytochemical profile of these plants, which includes bioactive compounds classified into various metabolite groups, such as polyphenols, triterpenes, alkaloids, and coumarins. Furthermore, Cuphea seed oils, containing medium-chain fatty acids, are of increasing interest in various industries as potential substitutes for coconut and palm oils. This review aims to summarize the results of phytochemical and pharmacological studies on Cuphea plants, with a particular focus on the therapeutic potential and molecular mechanisms of the action of polyphenolic compounds (especially flavonoids and tannins), which have been the subject of many recently published articles.

Progress in Antimelanoma Research of Natural Triterpenoids and Their Derivatives: Mechanisms of Action, Bioavailability Enhancement and Structure Modifications.

Melanoma is one of the most dangerous forms of skin cancer, characterized by early metastasis and rapid development. In search for effective treatment options, much attention is given to triterpenoids of plant origin, which are considered promising drug candidates due to their well described anticancer properties and relatively low toxicity. This paper comprehensively summarizes the antimelanoma potential of natural triterpenoids, that are also used as scaffolds for the development of more effective derivatives. These include betulin, betulinic acid, ursolic acid, maslinic acid, oleanolic acid, celastrol and lupeol. Some lesser-known triterpenoids that deserve attention in this context are 22ß-hydroxytingenone, cucurbitacins, geoditin A and ganoderic acids. Recently described mechanisms of action are presented, together with the results of preclinical in vitro and in vivo studies, as well as the use of drug delivery systems and pharmaceutical technologies to improve the bioavailability of triterpenoids. This paper also reviews the most promising structural modifications, based on structure-activity observations. In conclusion, triterpenoids of plant origin and some of their semi-synthetic derivatives exert significant cytotoxic, antiproliferative and chemopreventive effects that can be beneficial for melanoma treatment. Recent data indicate that their poor solubility in water, and thus low bioavailability, can be overcome by complexing with cyclodextrins, or the use of nanoparticles and ethosomes, thus making these compounds promising antimelanoma drug candidates for further development.

Antihyaluronidase and Antioxidant Potential of Atriplex sagittata Borkh. in Relation to Phenolic Compounds and Triterpene Saponins.

The genus Atriplex provides species that are used as food and natural remedies. In this work, the levels of soluble phenolic acids (free and conjugated) and flavonoids in extracts from roots, stems, leaves and flowers of the unexplored Atriplex sagittata Borkh were investigated by LC-ESI-MS/MS, together with their antioxidant and antihyaluronidase activity. Phenolic acids were present in all parts of A. sagittata; and were most abundant in the leaves (225.24 µg/g dw.), whereas the highest content of flavonoids were found in the flowers (242.71 µg/g dw.). The most common phenolics were 4-hydroxybenzoic and salicylic acids, kaempferol-3-glucoside-7-rhamnoside, kaempferol-3-rutinoside and the rare narcissoside, which was present in almost all morphotic parts. The stem extract had the highest antioxidant activity and total phenolic content (611.86 mg/100 g dw.), whereas flower extract exerted the most potent antihyaluronidase effect (IC50 = 84.67 µg/mL; control-quercetin: IC50 = 514.28 µg/mL). Phytochemical analysis of the flower extract led to the isolation of two triterpene saponins that were shown to be strong hyaluronidase inhibitors (IC50 = 33.77 and 168.15 µg/mL; control-escin: IC50 = 307.38 µg/mL). This is the first report on the presence of phenolics and saponins in A. sagittata. The results suggest that both groups of metabolites may contribute to the overall activity of this plant species.

Antimelanoma Potential of Cladonia mitis Acetone Extracts - Comparative in Vitro Studies in Relation to Usnic Acid Content.

In this study, the cytotoxic activity of acetone extracts of Cladonia mitis was assessed with respect to the content of usnic acid, a secondary metabolite commonly present in this species. Following quantitative HPLC analysis of the extracts, usnic acid was isolated by preparative chromatography. The study of cytotoxic activity was performed using the MTT test on three melanoma cell lines - HTB140, A375 and WM793. The selectivity of action was also assessed by comparing the effect towards normal human keratinocytes HaCaT. The results showed a dose-dependent cytotoxic activity of the extracts tested and usnic acid itself, but no relationship was found between the content of usnic acid and the activity of the extracts. Furthermore, the extracts showed varied, but rather low anti-tyrosinase activity. Other in vitro and in vivo studies are necessary to demonstrate that C. mitis extracts may be useful in the adjuvant external treatment of skin melanoma.

Optimization of Extraction Conditions and Cytotoxic Activity of Rapanone in Comparison to Its Homologue, Embelin.

Rapanone is a plant-derived simple alkyl-dihydroxybenzoquinone structurally close to embelin, a well-known cytotoxic agent. The pharmacological characterization of rapanone is still incomplete, and to fill the data gap, a good source for its acquisition is required to conduct further research. This study aimed to optimize the conditions for the extraction of rapanone from the leaves of white-berried Ardisia crenata Sims. For this purpose, three methods were employed: heat reflux (HRE), shaking (SE), and ultrasound-assisted extraction (UAE), and such parameters as the extraction time, solvent, and the number of extractions from the same sample were set as experimental variables. Furthermore, cytotoxic activity toward prostate cancer, thyroid cancer, and colorectal carcinoma cell lines was investigated and compared with doxorubicin and embelin. The most effective and economical method for the extraction of rapanone was shown to be 20 min UAE with ethyl acetate or chloroform. Rapanone exhibited high cytotoxic activity against PC3 (IC50 = 6.50 µg/mL), Du145 (IC50 = 7.68 µg/mL), FTC133 (IC50 = 6.01 µg/mL), 8505C (IC50 = 7.84 µg/mL), and Caco-2 (IC50 = 8.79 µg/mL) cell lines after 24 h and against the HT29 cell line after 48 h (IC50 = 11.67 µg/mL). Furthermore, it revealed a more favorable safety profile than either its homologue, embelin, or doxorubicin. The set of optimal extraction parameters obtained may be utilized for scientific and industrial purposes to achieve the best rapanone yield. Moreover, this benzoquinone revealed a high cytotoxic activity with good selectivity.

Simultaneous Quantification of Ursolic and Oleanolic Acids in Glechoma hederacea and Glechoma hirsuta by UPLC/MS/MS.

The content of ursolic acid and oleanolic acid was determined in different plant parts of two Glechoma species, G. hederacea and G. hirsuta. To achieve optimal extraction conditions of ursolic acid and oleanolic acid from plant material, several methods including maceration, heat reflux, Soxhlet, and ultrasonic extraction, as well as various solvents (methanol, dichloromethane, ethyl acetate), were investigated and compared.For the simultaneous quantification of pentacyclic triterpenes in extracts from Glechoma sp., an UPLC-MS/MS was developed and validated. The method exhibited good linearity, precision, and recovery, and it also was simple, specific, and fast. We developed the method for future application in the quality control of plant materials and botanical extracts containing ursolic acid and oleanolic acid. With regard to the triterpene constituents, both G. hederacea and G. hirsuta can be used equally, and the aboveground parts of both species, but the leaves especially, are abundant sources of ursolic acid (7.1 - 7.5 mg/g dry weight [DW]). Dichloromethane as an extractant provided the best extraction efficiency as well as selectivity to obtain Glechoma extracts rich in triterpenes as compared to methanol and ethyl acetate, regardless of the particular extraction technique. Dry dichloromethane extracts from aerial parts of Glechoma sp. obtained by the heat reflux method resulted in products with a high content of UA (17 - 25% w/w) are considered to be convenient and rich sources of this compound.

Relationship between Maturity Stage, Triterpenoid Content and Cytotoxicity of Sorbus intermedia (EHRH.) PERS. Fruits - A Chemometric Approach.

In this study, two ursane-type triterpenes, i. e., ursolic acid (UA) and 3-O-ß-acetoxyursolic acid (AUA), were isolated and quantified in Sorbus intermedia (EHRH.) PERS. fruits. UA and AUA levels differed slightly throughout fruit maturation, and both triterpenes showed similar dynamics of accumulation with the highest levels found in ripe fruits (up to 6.33±0.56 and 1.17±0.18 mg/g dw. of UA and AUA, respectively). The extracts derived from unripe fruits displayed significant cytotoxic effects against WM793, DU-145, PC3, 8505C, Caco2 and A549 cells, but no correlation between UA and AUA levels and cytotoxicity was found. On the other hand, extracts from mature fruits were not active towards almost all of the tested cell lines. The chemometric approach showed that the extracts derived from fruits harvested earlier clustered to form a clearly distanced group from extracts prepared from more-mature fruits. The extracts at higher concentrations formed separate groups, which indicated the concentration-dependent effect of these extracts on the cells.

Comparative Quantitative Study of Ardisiacrispin A in Extracts from Ardisia crenata Sims Varieties and Their Cytotoxic Activities.

Ardisia crenata Sims (Primulaceae) occurs in natural habitats in two varieties, bearing red or white fruits. While roots of the red-berried ardisia are valued as a medicinal product, the pharmacological activity of which is attributed to triterpene saponins, including ardisiacrispin A, data on the white-berried variety are scarce. A TLC-densitometric method was developed and validated to estimate the levels of saponins, calculated as ardisiacrispin A, in different plant parts in both varieties. Their content amounted to 22.17±4.75 and 25.72±1.46 mg/g d.w. in roots, and 2.64±0.74 and 3.43±0.70 mg/g d.w. in fruits of red-berried and white-berried ardisia, respectively. Assessment of cytotoxicity of ardisiacrispin A and A. crenata extracts on a panel of human cancer cell lines revealed a similar effect of root extracts from both varieties, with the highest potency against melanoma WM793 and colon cancer Caco2. Thus, roots of the white-berried variety may be treated as a substitute for red-berried ardisia and serve as an alternative source for the acquisition of plant material rich in bioactive saponins.

Cannabis sativa L. as a Natural Drug Meeting the Criteria of a Multitarget Approach to Treatment.

Cannabis sativa L. turned out to be a valuable source of chemical compounds of various structures, showing pharmacological activity. The most important groups of compounds include phytocannabinoids and terpenes. The pharmacological activity of Cannabis (in epilepsy, sclerosis multiplex (SM), vomiting and nausea, pain, appetite loss, inflammatory bowel diseases (IBDs), Parkinson's disease, Tourette's syndrome, schizophrenia, glaucoma, and coronavirus disease 2019 (COVID-19)), which has been proven so far, results from the affinity of these compounds predominantly for the receptors of the endocannabinoid system (the cannabinoid receptor type 1 (CB1), type two (CB2), and the G protein-coupled receptor 55 (GPR55)) but, also, for peroxisome proliferator-activated receptor (PPAR), glycine receptors, serotonin receptors (5-HT), transient receptor potential channels (TRP), and GPR, opioid receptors. The synergism of action of phytochemicals present in Cannabis sp. raw material is also expressed in their increased bioavailability and penetration through the blood-brain barrier. This review provides an overview of phytochemistry and pharmacology of compounds present in Cannabis extracts in the context of the current knowledge about their synergistic actions and the implications of clinical use in the treatment of selected diseases.

Serjanic Acid Glycosides from Chenopodium hybridum L. with Good Cytotoxicity and Selectivity Profile against Several Panels of Human Cancer Cell Lines.

Two triterpene saponins, including a novel serjanic acid derivative, were isolated from Chenopodium hybridum L. (Amaranthaceae) aerial parts. Their structures were elucidated by a combination of spectroscopic methods (MS, 1D and 2D NMR). Both compounds were evaluated for cytotoxicity and selectivity on skin, prostate, gastrointestinal, thyroid and lung cancer cells. Their effect was dose and time-dependent with varied potency, the highest against prostate PC3 and melanoma WM793, where IC50 was lower than the reference drug doxorubicin. Structure-activity relationship is briefly discussed.

(+)-Usnic Acid as a Promising Candidate for a Safe and Stable Topical Photoprotective Agent.

The study aimed to examine whether usnic acid-a lichen compound with UV-absorbing properties-can be considered as a prospective photoprotective agent in cosmetic products. Moreover, a comparison of two usnic acid enantiomers was performed to preselect the more effective compound. To meet this aim, an in vitro model was created, comprising the determination of skin-penetrating properties via skin-PAMPA assay, safety assessment to normal human skin cells (keratinocytes, melanocytes, fibroblasts), and examination of photostability and photoprotective properties. Both enantiomers revealed comparable good skin-penetrating properties. Left-handed usnic acid was slightly more toxic to keratinocytes (IC50 80.82 and 40.12 µg/mL, after 48 and 72 h, respectively) than its right-handed counterpart. The latter enantiomer, in a cosmetic formulation, was characterized by good photoprotective properties and photostability, comparable to the UV filter octocrylene. Perhaps most interestingly, (+)-usnic acid combined with octocrylene in one formulation revealed enhanced photoprotection and photostability. Thus, the strategy can be considered for the potential use of (+)-usnic acid as a UV filter in cosmetic products. Moreover, the proposed model may be useful for the evaluation of candidates for UV filters.

Saponins as chemosensitizing substances that improve effectiveness and selectivity of anticancer drug-Minireview of in vitro studies.

Triterpene saponins (saponosides) are found in higher plants and display a wide range of biological and pharmacological activities. The antitumor effects of saponins have been proved by their cytotoxic, cytostatic, proapoptotic, and anti-invasive effects in many cellular models. Saponins hold great potential for being developed into chemopreventive and chemotherapeutic drugs. A promising way of reducing the adverse effects of chemotherapy without attenuating its efficiency is provided by the combined application of chemotherapeutic agents and saponosides in subtoxic concentrations. Until recently, saponosides were primarily used as adjuvants that enhance the effect of vaccines. In cancer therapy, saponins are applied in combination with immunotoxins because they increase the selectivity of given immunotoxins against cancer cells and therefore inure normal cells to the cytotoxic effects of immunotoxins. Significantly, certain saponins have been identified that drastically enhance the efficacy of many chemotherapeutic agents, including cisplatin, paclitaxel, doxorubicin, docetaxel, mitoxantrone, and cyclophosphamide. Moreover, saponins used in combination therapy enhance the sensitivity of chemoresistant tumor cells to clinically used chemotherapeutic agents. This review sheds light on the molecular mechanisms underlying cancer co-treatment with saponins and chemotherapy, with a particular focus on modulation of the cell signaling pathways associated with the promotion and progression of cancer cell proliferation, apoptosis, and metastasis.

Steroidal saponins from the genus Allium.

Steroidal saponins are widely distributed among monocots, including the Amaryllidaceae family to which the Allium genus is currently classified. Apart from sulfur compounds, these are important biologically active molecules that are considered to be responsible for the observed activity of Allium species, including antifungal, cytotoxic, enzyme-inhibitory, and other. In this paper, literature data concerning chemistry and biological activity of steroidal saponins from the Allium genus has been reviewed.

Synergistic Cytotoxic and Anti-invasive Effects of Mitoxantrone and Triterpene Saponins from Lysimachia ciliata on Human Prostate Cancer Cells.

Triterpene saponins are secondary metabolites typical for higher plants. They possess a wide range of pharmaceutical and biological activities. These include anti-inflammatory, vasoprotective, expectorant, and antitumor properties. In particular, the ability of saponins to enhance the cytotoxicity of chemotherapeutic drugs has opened new perspectives for their application in combined cancer chemotherapy. In this study, the biological activity of the saponin fraction isolated from Lysimachia ciliata (denoted as CIL-1/2) was evaluated to assess its chemosensitizing activity in prostate cancer cell lines (DU-145, PC-3). No cytotoxic or cytostatic effect of the CIL-1/2 fraction administered at the concentration of 0.5 µg/mL was observed. In contrast, cocktails of CIL-1/2 and mitoxantrone (a drug commonly used in prostate cancer therapy) exerted synergistic cytostatic and proapoptotic effects. Furthermore, the synergy of proapoptotic activities of the analyzed cocktails is accompanied by their synergistic effects on prostate cancer cell movement and invasiveness. The significantly weaker impact of this cocktail on normal prostate cells additionally adds to the significance of our data and confirms that the CIL-1/2 fraction might be considered a potent adjuvant for prostate cancer chemotherapy.

Allium ursinum: botanical, phytochemical and pharmacological overview.

Ramson-Allium ursinum L. is a medicinal and dietary plant species with a long tradition of use. This mini-review summarizes the current knowledge on the phytochemistry and pharmacological properties of this valuable plant, with special emphasis on antimicrobial, cytotoxic, antioxidant, and cardio-protective effects.

Comparative Analysis of Polyphenolic Profile and Chemopreventive Potential of Hemp Sprouts, Leaves, and Flowers of the Sofia Variety.

This study investigates the phytochemical composition and biological activities of hemp (Cannabis sativa L.) leaves, flowers' methanolic extracts from the Sofia variety, and its sprouts cultivated under different light conditions (natural light, darkness, blue, and white LED light for 5, 7, and 9 days). Phytochemical analysis using HPLC identified four key polyphenolic compounds in sprouts' extracts: chlorogenic, caffeic, and gallic acids, and myricetin, with a predomination of the chlorogenic acid. In contrast, leaves and flowers' extracts contained cannflavins A and B and chlorogenic, p-coumaric, and ferulic acids, with a significant presence of isochlorogenic acid. Antioxidant capacity, assessed by FRAP method, revealed higher antioxidant potential in leaves compared to flowers and sprouts, with sprouts grown under blue and white LED lights exhibiting the highest activity. Cytotoxic activity was evaluated on human colon cancer cell lines (HT29, HCT116, DLD-1) and normal colon epithelial cells (CCD 841 CoN). Results demonstrated significant and selective cytotoxicity against cancer cell lines, with leaves showing more pronounced effects than flowers, and sprouts only moderate activity. All samples revealed an anti-inflammatory effect in vitro. To conclude, sprouts, leaves, and flowers of the Sofia hemp may be considered promising products for chemoprevention in the future.

Critical Assessment of the Anti-Inflammatory Potential of Usnic Acid and Its Derivatives-A Review.

Inflammation is a response of the organism to an external factor that disrupts its natural homeostasis, and it helps to eliminate the cause of tissue injury. However, sometimes the body's response is highly inadequate and the inflammation may become chronic. Thus, the search for novel anti-inflammatory agents is still needed. One of the groups of natural compounds that attract interest in this context is lichen metabolites, with usnic acid (UA) as the most promising candidate. The compound reveals a broad spectrum of pharmacological properties, among which anti-inflammatory properties have been studied both in vitro and in vivo. The aim of this review was to gather and critically evaluate the results of the so-far published data on the anti-inflammatory properties of UA. Despite some limitations and shortcomings of the studies included in this review, it can be concluded that UA has interesting anti-inflammatory potential. Further research should be directed at the (i) elucidation of the molecular mechanism of UA; (ii) verification of its safety; (iii) comparison of the efficacy and toxicity of UA enantiomers; (iv) design of UA derivatives with improved physicochemical properties and pharmacological activity; and (v) use of certain forms or delivery carriers of UA, especially in its topical application.

Multidirectional Effects of Terpenoids from Sorbus intermedia (EHRH.) PERS Fruits in Cellular Model of Benign Prostate Hyperplasia.

Benign prostatic hyperplasia (BPH) is a common urological disease affecting aging men. Its pathogenesis is regarded as complex and multifactorial, with sex hormones and inflammation as key contributory factors. In the current study, we investigated the anti-BPH potential of terpenoids present in the fruits of Sorbus intermedia (EHRH.) PERS. Not only the effects on testosterone-stimulated normal prostate epithelial PNT2 cells, namely suppression of 5-α-reductase activity, PSA secretion, and cell proliferation, were determined but also the inhibitory activity on heat-induced protein denaturation, hyaluronidase, as well as IL-6, TNF-α, and NO release in LPS-treated macrophages. Sorbus terpenoids significantly inhibited 5-α-reductase activity and reduced PSA secretion in PNT2 cells, reversing the stimulatory effect of testosterone. PNT2 cell proliferation was also found to be attenuated. Subsequently, all compounds reduced the release of pro-inflammatory mediators in RAW 264.7 cells. In addition, ursolic acid (UA) and its aldehyde (UAL) were the most potent hyaluronidase inhibitors of all compounds, with IC50 values of 225.75 µg/mL and 369.77 µg/mL, respectively. For better understanding and interpretation of the overall effect of Sorbus terpenoids on different aspects of BPH pathogenesis and development, cluster analysis was applied.

Effect of Methyl Jasmonate Elicitation on Triterpene Production and Evaluation of Cytotoxic Activity of Mycelial Culture Extracts of Ganoderma applanatum (Pers.) Pat.

Abiotic elicitation, a well-known strategy in mushroom biotechnology, promotes increased accumulation of secondary metabolites in mycelial cultures. The study aimed the effects of methyl jasmonate (MeJA) on the production of triterpenes in submerged cultures of Ganoderma applanatum. Further, the study evaluated the cytotoxic activity of the extract corresponding to the optimal elicitation variant in selected human cancer cell lines as well as the selectivity against normal cells. MeJA was added on days 1, 4, 6, and 8 in the 10-day growth cycle at concentrations of 10, 50, 100, 150, and 200 µM MeJA. The HPLC-DAD was used to analyze the triterpenes. The cytotoxic activity was tested using the MTTFc assay in grouped panels of skin, prostate, and gastrointestinal cancer cells. The results of the quantitative analyses confirmed the stimulating effect of MeJA on the production of ganoderic acid A and ganoderic acid C. The greatest increase in total triterpenes was found on day 6 of the culture cycle compared to the control group-with the concentration of MeJA-150 µM. Compared to the control samples, mycelial culture extract after the most productive elicitation variant showed significant cytotoxic activity against prostate cancer cells and moderate effects on melanoma cells. Ganoderma applanatum mycelial cultures can be proposed as a model to study the dynamics of the accumulation of compounds with therapeutic values through abiotic elicitation.