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13 pages, 925 KiB  
Article
Effect of Hydroponically Grown Red Panax Ginseng on Perceived Stress Level, Emotional Processing, and Cognitive Functions in Moderately Stressed Adults: A Randomized, Double-Blind, Placebo-Controlled Study
by Valérie Dormal, Lucas Jonniaux, Marine Buchet, Laurent Simar, Sylvie Copine and Louise Deldicque
Nutrients 2025, 17(6), 955; https://doi.org/10.3390/nu17060955 (registering DOI) - 9 Mar 2025
Abstract
Background/objectives: Chronic stress is a pervasive issue affecting individuals worldwide, with profound implications for mental and physical well-being. Panax ginseng, a widely used herbal supplement renowned for its adaptogenic properties, is hypothesized to alleviate some stress effects. This study aims to evaluate the [...] Read more.
Background/objectives: Chronic stress is a pervasive issue affecting individuals worldwide, with profound implications for mental and physical well-being. Panax ginseng, a widely used herbal supplement renowned for its adaptogenic properties, is hypothesized to alleviate some stress effects. This study aims to evaluate the impact of hydroponically grown Red Panax ginseng root powder with a high level of rare ginsenosides supplementation on perceived stress levels, as well as on the emotional and cognitive abilities of moderately stressed participants. Methods: A randomized, double-blind, controlled study was conducted with 149 participants. They were randomly assigned to either the Ginseng supplementation group (N = 72; 200 mg/day, including 24 mg of ginsenosides) or the Placebo group (N = 77). The intervention lasted for 3 weeks. The perceived stress level was measured at baseline (D0) and at the end of the intervention (D21) using a validated scale (PSS) alongside assessments of emotional (BDI and PANAS) and cognitive abilities (CANTAB subtests). Results: Significantly larger decreases in the PSS and negative affect score (PANAS) were observed following intervention in the Ginseng group compared with the Placebo group. Compared to the Placebo group, participants in the Ginseng group showed faster response latencies during a spatial planning task (OTSC subtest). In addition, there was a marginally larger decrease in the BDI score in the Ginseng group. Conclusions: These results confirm the emotional and cognitive benefits of Red Panax ginseng in moderately stressed adults and pave the way for further exploration of its use as a promising approach to improving psychological well-being. Full article
(This article belongs to the Special Issue Dietary Supplements for Human Health and Disease)
15 pages, 727 KiB  
Article
The Impact of Rhodiola Rosea Extract on Strength Performance in Alternative Bench-Press and Bench-Pull Exercises Under Resting and Mental Fatigue Conditions: A Randomized, Triple-Blinded, Placebo-Controlled, Crossover Trial
by Daniel Marcos-Frutos, Žiga Leban, Zhaoqian Li, Xing Zhang, Paula M. Lara, Carlos Alix-Fages, Pablo Jiménez-Martínez, Nadia Zebboudji, Annabelle Caillet, Beatriz Redondo, Jesús Vera, Danica Janicijevic and Amador García-Ramos
Nutrients 2025, 17(6), 940; https://doi.org/10.3390/nu17060940 - 7 Mar 2025
Viewed by 138
Abstract
Objectives: This study aimed to explore the effects of four days of Rhodiola Rosea (RR) supplementation on bench-press and bench-pull exercises under resting or mental fatigue conditions in young healthy individuals. Methods: Eighteen participants (seven women) visited the laboratory on five [...] Read more.
Objectives: This study aimed to explore the effects of four days of Rhodiola Rosea (RR) supplementation on bench-press and bench-pull exercises under resting or mental fatigue conditions in young healthy individuals. Methods: Eighteen participants (seven women) visited the laboratory on five occasions separated by 7 days—one preliminary session and four experimental sessions. In the preliminary session, participants were familiarised with the Stroop and Multiple Object Tracking tests, after which their one-repetition maximum loads for bench presses and bench pulls were determined. The four experimental sessions had the same protocol, differing only in the supplement (RR or placebo) and mental task conditions (Stroop test or control video). Participants were assigned randomly and counterbalanced to each experimental condition: (I) RR and Stroop test, (II) RR and control video, (III) placebo and Stroop test, and (IV) placebo and control video. Results: The main findings indicate that RR supplementation has trivial-to-small effects in terms of mental fatigue, visuo-cognitive processing, or perceived exertion. However, RR was significantly superior to placebo on strength performance in the control video condition during some sets, as it increased the number of repetitions performed in the bench press and the fastest velocity in the bench pull. Out of 52 comparisons, 17 small effect sizes were observed, with 14 favouring RR and 3 favouring placebo, with the remaining differences being trivial. Conclusions: These results suggest that short-term RR supplementation is safe and provides its main ergogenic effects on physical performance rather than in visuo-cognitive or mental outcomes. Full article
(This article belongs to the Special Issue Nutritional Supports for Sport Performance)
85 pages, 24685 KiB  
Review
Adaptogens in Long-Lasting Brain Fatigue: An Insight from Systems Biology and Network Pharmacology
by Alexander Panossian, Terrence Lemerond and Thomas Efferth
Pharmaceuticals 2025, 18(2), 261; https://doi.org/10.3390/ph18020261 - 15 Feb 2025
Viewed by 794
Abstract
Long-lasting brain fatigue is a consequence of stroke or traumatic brain injury associated with emotional, psychological, and physical overload, distress in hypertension, atherosclerosis, viral infection, and aging-related chronic low-grade inflammatory disorders. The pathogenesis of brain fatigue is linked to disrupted neurotransmission, the glutamate-glutamine [...] Read more.
Long-lasting brain fatigue is a consequence of stroke or traumatic brain injury associated with emotional, psychological, and physical overload, distress in hypertension, atherosclerosis, viral infection, and aging-related chronic low-grade inflammatory disorders. The pathogenesis of brain fatigue is linked to disrupted neurotransmission, the glutamate-glutamine cycle imbalance, glucose metabolism, and ATP energy supply, which are associated with multiple molecular targets and signaling pathways in neuroendocrine-immune and blood circulation systems. Regeneration of damaged brain tissue is a long-lasting multistage process, including spontaneously regulating hypothalamus-pituitary (HPA) axis-controlled anabolic–catabolic homeostasis to recover harmonized sympathoadrenal system (SAS)-mediated function, brain energy supply, and deregulated gene expression in rehabilitation. The driving mechanism of spontaneous recovery and regeneration of brain tissue is a cross-talk of mediators of neuronal, microglia, immunocompetent, and endothelial cells collectively involved in neurogenesis and angiogenesis, which plant adaptogens can target. Adaptogens are small molecules of plant origin that increase the adaptability of cells and organisms to stress by interaction with the HPA axis and SAS of the stress system (neuroendocrine-immune and cardiovascular complex), targeting multiple mediators of adaptive GPCR signaling pathways. Two major groups of adaptogens comprise (i) phenolic phenethyl and phenylpropanoid derivatives and (ii) tetracyclic and pentacyclic glycosides, whose chemical structure can be distinguished as related correspondingly to (i) monoamine neurotransmitters of SAS (epinephrine, norepinephrine, and dopamine) and (ii) steroid hormones (cortisol, testosterone, and estradiol). In this narrative review, we discuss (i) the multitarget mechanism of integrated pharmacological activity of botanical adaptogens in stress overload, ischemic stroke, and long-lasting brain fatigue; (ii) the time-dependent dual response of physiological regulatory systems to adaptogens to support homeostasis in chronic stress and overload; and (iii) the dual dose-dependent reversal (hormetic) effect of botanical adaptogens. This narrative review shows that the adaptogenic concept cannot be reduced and rectified to the various effects of adaptogens on selected molecular targets or specific modes of action without estimating their interactions within the networks of mediators of the neuroendocrine-immune complex that, in turn, regulates other pharmacological systems (cardiovascular, gastrointestinal, reproductive systems) due to numerous intra- and extracellular communications and feedback regulations. These interactions result in polyvalent action and the pleiotropic pharmacological activity of adaptogens, which is essential for characterizing adaptogens as distinct types of botanicals. They trigger the defense adaptive stress response that leads to the extension of the limits of resilience to overload, inducing brain fatigue and mental disorders. For the first time, this review justifies the neurogenesis potential of adaptogens, particularly the botanical hybrid preparation (BHP) of Arctic Root and Ashwagandha, providing a rationale for potential use in individuals experiencing long-lasting brain fatigue. The review provided insight into future research on the network pharmacology of adaptogens in preventing and rehabilitating long-lasting brain fatigue following stroke, trauma, and viral infections. Full article
(This article belongs to the Section Natural Products)
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Graphical abstract

Graphical abstract
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<p>Simplified pattern of adaptive stress response over time (blue color dot line) and stress-protective effect of an adaptogen (red color line) increasing resistance and decreasing sensitivity to a conditional stressor, extending the duration of the resistance anabolic phase to fatigue, and preventing the onset of the exhaustion phase (distress), leading to adaptation to stress and increasing the level of homeostasis. AU—an arbitrary unit of an outcome measure of a stress response, e.g., increasing the number of errors over the time detected in Conner’s computerized cognitive performance test for attention and impulsivity, biochemical markers (cortisol, nitric oxide, etc.). It is modified from [<a href="#B31-pharmaceuticals-18-00261" class="html-bibr">31</a>,<a href="#B32-pharmaceuticals-18-00261" class="html-bibr">32</a>,<a href="#B88-pharmaceuticals-18-00261" class="html-bibr">88</a>,<a href="#B89-pharmaceuticals-18-00261" class="html-bibr">89</a>].</p>
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<p>Symbolic representation of three typical scenarios of the degree of brain fatigue over time after a head injury, emotional strain-induced stroke, or viral infection: a—adaptive reversible recovery when the patient returns to work and social life (green line), b—for others, the mental energy does not return as expected, but the person gets on with the job, even if the energy is not quite enough. It works for a while, but after maybe a few months or half a year, the person has run out of energy, and brain fatigue increases (solid blue line); c—irreversible damage if some patients still have severe distressing and long-lasting brain fatigue can make work impossible and daily lifestyle at home be sufficiently exhausting (red line) [<a href="#B5-pharmaceuticals-18-00261" class="html-bibr">5</a>].</p>
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<p>Glutamate–glutamine cycle in nerve cells [<a href="#B156-pharmaceuticals-18-00261" class="html-bibr">156</a>,<a href="#B157-pharmaceuticals-18-00261" class="html-bibr">157</a>,<a href="#B158-pharmaceuticals-18-00261" class="html-bibr">158</a>,<a href="#B159-pharmaceuticals-18-00261" class="html-bibr">159</a>,<a href="#B160-pharmaceuticals-18-00261" class="html-bibr">160</a>]. Neurotransmission between two neurons’ synapses and interactions with a nearby astrocyte, where glutamate is the signal substance between nerve cells. Glutamate is released from the presynaptic terminal, and after exerting its effect on the recipient neuron, the postsynaptic membrane is taken up by the astrocytes’ discharge and converted to glutamine, which is then transported back to the nerve cells to form new glutamate. Glutamate inside the astrocytes also signals that glucose is taken from the blood into the astrocytes and onto the nerve cells as new energy. In distress or brain damage-induced neuroinflammation, see the SOS sign in red; the astrocytes’ capacity to convert glutamate into glutamine is reduced due to a lack of energy supply mediated by reduced ATP. More glutamate accumulates around the nerve cells, and increasing amounts accumulate in the synapse areas, making signaling less specific. If mental activity is high in this situation, there is a risk that nerve cell signaling will fail due to decreased amounts of glucose/energy. The astrocytes take up less glucose, and less energy and glutamate are available in the neurons. Modified from [<a href="#B5-pharmaceuticals-18-00261" class="html-bibr">5</a>,<a href="#B6-pharmaceuticals-18-00261" class="html-bibr">6</a>].</p>
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<p>Simplified overview of the stress system (central nervous system, CNS, and peripheral tissues/organs in the periphery) and reciprocal connections of elements of the neuroendocrine-immune complex to mobilize an adaptive response against the stressor. The brain and spinal cord comprise the CNS, the cerebral cortex—glutamatergic pyramidal and GABA-ergic interneurons, and glial cells, including astrocytes, oligodendrocytes, and microglia. The forebrain includes dorsal glutamatergic neurons, ventral GABAergic interneurons, and locus coeruleus (LC) neurons. The peripheral components of the stress system include the hypothalamic–pituitary–adrenal axis (HPA), the autonomic nervous system (ANS) comprising the sympathetic nervous system (SNS) secreting mainly norepinephrine (NE) and acetylcholine (AcCh), and the sympathy–adrenomedullary (SAM) system, and (ii) the parasympathetic nervous system (PNS) secreting AcCh. Two key end hormones, cortisol and epinephrine, regulate metabolism, circulation, and blood homeostasis. The abbreviations of hormones and neurotransmitters are as follows: Hypothalamic hormones: CRH, corticotropin-releasing hormone; GnRH, gonadotropin-releasing hormone; and dopamine. Pituitary hormones: ACTH, adrenocorticotropic hormone; AVP, arginine vasopressin; FSH, follicle-stimulating hormone; GH, growth hormone; LH, luteinizing hormone; Oxt, oxytocin; PRL, prolactin; and TSH, thyroid-stimulating hormone. Adrenal cortex hormones: steroid hormones—corticosteroids (cortisol), mineralocorticoids, and androgens. Adrenal hormone: E, epinephrine. Pineal gland hormone: melatonin. Other peripheral hormones: testosterone, T; estrogens, Es; thyroxin, T4; triiodothyronine, T3; somatomedins, IGF; angiotensin II; erythropoietin; calcitriol; somatostatin; glucagon; insulin; parathyroid hormone; and calcitonin. Neurotransmitters: Neuropeptide Y; substance P; GABA; serotonin; dopamine; acetylcholine; norepinephrine; and epinephrine.</p>
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<p>This figure presents a hypothetical representation of the adaptogenic effect of adaptogens on adaptive homeostasis. Adaptive homeostasis refers to the transient reversible adjustments of the homeostatic range in response to exposure to challenging signaling molecules or events. Any biological function or measurement oscillates around a mean or median within a homeostatic range considered ’normal’ or physiological. Adaptogens, as shown in the figure, increase the normal homeostatic thresholds (adaptive homeostasis) to a pathological state, thereby enhancing resilience to stress within the adaptive stress system. This system regulates various bodily functions, including the neuroendocrine-immune complex, blood circulatory and digestive systems, organismal development, and aging.</p>
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<p>Adaptive stress response factors, mediators, and effectors and the effect of adaptogens in stress and inflammaging-induced aging-related diseases. The adaptive stress response involves the activation of intracellular and extracellular signaling pathways and increased expression of antiapoptotic proteins, neuropeptides, antioxidant enzymes, and the defense response of an organism, resulting in increased survival. One primary mechanism of adaptogens’ action is that they trigger adaptive cellular stress response pathways in human brain cells, similar to exercise, dietary restriction, and cognitive stimulation, which may exert their health benefits. Each of these environmental factors induces a mild stress response in nerve cells in the brain, increasing the expression of stress resistance proteins such as heat-shock protein 70 (HSP-70), Hsp32, and nerve cell growth factors, preventing the degeneration of neurons during aging, enhancing learning and memory, and exerting beneficial effects on many different organ systems, including the cardiovascular and glucose-regulating systems. These endogenous cellular defense pathways, including NRF2 signaling pathways, integrate adaptive stress responses to prevent neurodegenerative disease.</p>
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<p>Chronic stress-induced symptoms and the effect of adaptogens on key mediators and effectors of adaptive stress response and effectors induce neuroprotection, resulting in increased cognitive function and mental and physical performance. Brain cells respond adaptively by enhancing their ability to function and resist stress, as shown by an update from the authors’ free access publication [<a href="#B25-pharmaceuticals-18-00261" class="html-bibr">25</a>] and authors’ drawings.</p>
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<p>The hypothetic molecular mechanisms and modes of the pharmacological action of adaptogen are updated from the authors’ free access publication [<a href="#B66-pharmaceuticals-18-00261" class="html-bibr">66</a>] and authors’ drawings. Effects of adaptogens on key mediators of neuroendocrine-immune complex, cardiovascular, and detoxifying systems that regulate adaptive stress response to stressors/pathogens in stress and aging-induced diseases and disorders. CRH- and ACTH-induced stimulation of GPCR receptors activates the cAMP-dependent protein kinase (PKA) signaling pathway in the regulation of energy balance and metabolism across multiple systems, including adipose tissue (lipolysis), liver (gluconeogenesis, glucose tolerance), pancreas, gut (insulin exocytosis and sensitivity), etc. The key molecules involved in the PI3K-Akt signaling pathway are receptor tyrosine kinases (RTKs). Activating the PI3K-Akt signaling pathway promotes cell proliferation and growth, stimulates cell cycle vascular remodeling and cell survival, and inhibits cell apoptosis in response to extracellular signals. The nonspecific antiviral action of ginseng is associated with the activation of innate immunity by upregulation of the expression of the pathogen’s pattern recognition receptors, specifically toll-like receptors and TLR-mediated signaling pathways. The protein kinase C (PKC) family of enzymes with isoforms plays an essential cell-type-specific role, particularly in the immune system, through phosphorylation of CARD-CC family proteins and subsequent NF-κB activation. Three stress-activated MAPK signaling pathways playing crucial roles in cell proliferation, differentiation, survival, and death have been implicated in the pathogenesis of many human diseases, including Alzheimer’s disease, Parkinson’s disease, and cancer. (1) The stress factors inducing the activation of the c-Jun N-terminal kinase (JNK)/stress-activated protein kinase (SAPK)-mediated adaptive signaling pathway are heat shock, irradiation, reactive oxygen species, cytotoxic drugs, inflammatory cytokines, hormones, growth factors, and other stresses. Activating the JNK/MAPK10 signaling pathway promotes cell death and apoptosis via the upregulation of proapoptotic genes. (2) The activation of the extracellular-signal-regulated kinase (ERK) pathway is initiated by hormones and stresses to trigger endothelial cell proliferation during angiogenesis, T cell activation, long-term potentiation in hippocampal neurons, phosphorylation of the transcription factor p53, activation of phospholipase A2 in mast cells, followed by activation of biosynthesis leukotrienes and inflammation/allergy, etc. (3) The third major stress-activated p38 signaling pathway contributes to the control of inflammation, the release of cytokines by macrophages and neutrophils, apoptosis, cell differentiation, and cell cycle regulation. Activation is shown in red, while the inhibition is in blue color cycles/ellipses (effect of ginseng/ginsenosides), arrows, and clouds. BDNF, brain-derived neurotrophic factor; cAMP, cyclic adenosine monophosphate; CREB, cAMP-responsive element-binding protein; ERK, extracellular signal-regulated kinase; GSK-3, glycogen synthase kinase-3; JNK, the c-Jun N-terminal kinase (JNK)/stress-activated protein kinase (SAPK MAPK, mitogen-activated protein kinase); NF-κB, nuclear factor-kappa B; Nrf2, nuclear factor E2-related factor 2; PI3K, phosphatidylinositol 3-kinase; PKA, protein kinase A; PKB, protein kinase B; PLC, phospholipase C.</p>
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<p>Effect of <span class="html-italic">Rhodiola</span> extracts on the eicosanoid signaling pathway. Arachidonic acid (AA) was released from membrane phospholipids by phospholipase A2 (PLA2) and then converted to eicosanoids by two types of enzymes: (i) prostaglandin endoperoxide synthases (PTGS), commonly referred to as cyclooxygenases (COX-1 and COX-2), catalyze the key step in the synthesis of prostaglandin H2 (PGH2), which is converted into pro-inflammatory thromboxanes (TXs), prostaglandins (PGE, PGF, and PGD), and prostacyclins (PGI). (ii) The lipoxygenases include ALOX5, ALOX12, and ALOX15. ALOX5 catalyzes the key step in the conversion of AA to pro-inflammatory leukotriene A4, B4, and C4. ALOX12 synthesizes pro-inflammatory 12(S)-HETE [12(S)-hydroxyeicosatetraenoic acid]. ALOX15, in concert with ALOX5, is involved in forming anti-inflammatory lipoxins A4 and B4. Eicosanoid receptors belong to the family of G-protein-coupled receptors. Some of these receptors include BLT-1,-2 CYSLTR1, and CYSLTR2 for pro-inflammatory leukotrienes; PTGERs for prostaglandin E2; PTGFR for pro-inflammatory prostaglandin F2; PTGDR for prostaglandin D2; and TBXA2R for pro-inflammatory thromboxane A2. Eicosanoids transduce signals via their membrane receptors and mediate complex biological processes like inflammation, vascular permeability, allergic reactions, labor induction, and carcinogenesis. Downstream effect analysis reveals predicted pharmacological effects of <span class="html-italic">Rhodiola</span> mediated by eicosanoid signaling pathways [<a href="#B68-pharmaceuticals-18-00261" class="html-bibr">68</a>].</p>
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<p>Simplified hypothetic representation of the hormetic dose–response relationship of toxic hormetins and adaptogens; figures adapted from free access publication [<a href="#B30-pharmaceuticals-18-00261" class="html-bibr">30</a>,<a href="#B220-pharmaceuticals-18-00261" class="html-bibr">220</a>,<a href="#B269-pharmaceuticals-18-00261" class="html-bibr">269</a>].</p>
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<p>(<b>a</b>) The total number of genes deregulated by ginsenoside Rg5 in concentrations ranging from 1 μM to 1 aM; (<b>b</b>) ginsenoside Rg5 concentration-dependent fold change expression of selected differentially regulated genes in the hippocampal neuronal cell line HT22; (<b>c</b>) Venn diagram of genes deregulated by ginsenoside Rg5 at concentrations 1 μM, 1 nM, 1 pM, 1 fM, and 1 aM.</p>
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<p>CRH signaling pathways are differently regulated by <span class="html-italic">Withania somnifera</span> extract at a concentration of 1.5 mg/L (corresponding to the dose of 90 mg in humans), WSL (<b>a</b>), and 5 mg/L (corresponding to the dose of 300 mg in humans), WS (<b>b</b>) in cultivated neuroglial cells. <a href="#pharmaceuticals-18-00261-f012" class="html-fig">Figure 12</a>a shows the inhibition of the CRH receptor-related intracellular signal transduction pathway, while <a href="#pharmaceuticals-18-00261-f012" class="html-fig">Figure 12</a>b shows the predicted activation of this pathway. At a concentration of 5 mg/L, corresponding to a human daily dose of 300 mg, WS extract did not affect the expression of CRH, AP-1 transcription factor subunit (FOS), CACNA1E, CACNG6, or CACNA2D3 encoding calcium voltage-gated channel auxiliary subunits as it did at a lower concentration of 1.6 mg/L. Protein kinase C η and ζ encoding genes. PRKCH and PRKCZ were downregulated, and guanylate cyclase 1 soluble subunit α and β (GUCY1A3, GUCY1B3) and prostaglandin-endoperoxide synthase 2/COX-2 (PTGS2) genes were upregulated [<a href="#B67-pharmaceuticals-18-00261" class="html-bibr">67</a>].</p>
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<p>Glucocorticoid signaling pathways are differently regulated by <span class="html-italic">Withania somnifera</span> extract at a concentration of 1.5 mg/L (corresponding to the dose of 90 mg in humans), WSL (<b>a</b>), and 5 mg/L (corresponding to the dose of 300 mg in humans), WS (<b>b</b>) in cultivated neuroglial cells [<a href="#B67-pharmaceuticals-18-00261" class="html-bibr">67</a>].</p>
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<p>Effect of Withania extracts in two doses on the eicosanoid signaling pathway. The details are the legends of <a href="#pharmaceuticals-18-00261-f005" class="html-fig">Figure 5</a> [<a href="#B67-pharmaceuticals-18-00261" class="html-bibr">67</a>].</p>
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<p>The mediators and interactions between vascular and brain cells in poststroke adult neurogenesis and angiogenesis: BDNF, brain-derived neurotrophic factor; IFN-γ, interferon-gamma; IL-4, interleukin-4; iNOS, inducible nitric oxide synthase; MMP-3, matrix metalloproteinase-3; NGF, nerve growth factor; TGF-β, transforming growth factor-β; TNFα, tumor necrosis factor-alpha; VEGF, vascular endothelial growth factor (Modified from [<a href="#B12-pharmaceuticals-18-00261" class="html-bibr">12</a>]).</p>
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<p>The effects of RR-WS (Adaptra<sup>®</sup>) on gene expression in human T98G neuroglia cells and the predicted activation of the development of neurons. The authors’ drawings were adapted from a free access publication [<a href="#B69-pharmaceuticals-18-00261" class="html-bibr">69</a>]. The synergy effects (red arrows) of hybridization of a combination of Rhodiola with Withania on neurogenesis signaling pathways in isolated neuroglia cells. The intensity of green and red squares indicates fold changes compared to control, where green means down- and red means upregulation. Synergistic or antagonistic effects on gene expression were observed by comparison of the impact of the BHP Adaptra = combination of RR-WS (sample A1) with a lack of the impact of individual extracts RR (<span class="html-italic">R. rosea</span>), WS (<span class="html-italic">Withania somnifera</span>), and WSL <span class="html-italic">Withania somnifera</span> low dose, correspondingly samples A2, A3, and A7) at a significance level of <span class="html-italic">p</span> &lt; 0.05 (log = 1.3) and a z-score &gt; 2. The symbolic interpretation of synergy and antagonism by the image of a hybrid creature from Greek mythology, the Sphinx of Lanuvium, with a human head and a lion’s body-derived wing due to their synergistic and antagonistic (e.g., lack of human legs) interactions. The image of two kinds of hybrid creatures from ancient mythology is a visual analogy of botanical hybrid preparations (BHP) symbolizing synergy, e.g., wings of a sphinx, a mythical hybrid creature with the head of a human, the body of a lion, and the wings derived due to the synergy effect. Sphinx of Lanuvium. Near Rome. Roman, about AD 120–140. British Museum. It was found at Monte Cagnolo, outside Lanuvium, near Rome. Source: [<a href="#B417-pharmaceuticals-18-00261" class="html-bibr">417</a>].</p>
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19 pages, 1108 KiB  
Review
Performance of Mushrooms in Fermented Beverages: A Narrative Review
by Tiziana Di Renzo, Anna Reale, Stefania Nazzaro, Pasquale Marena, Muhamad Hafiz Abd Rahim, Nurul Aqilah Mohd Zaini, Nur ‘Aliah Daud and Wan Abd Al Qadr Imad Wan-Mohtar
Beverages 2025, 11(1), 19; https://doi.org/10.3390/beverages11010019 - 23 Jan 2025
Viewed by 927
Abstract
Mushrooms are indeed gaining attention for their unique therapeutic and nutritional qualities, especially in fermented drinks. This trend builds on their historical use in traditional medicine, especially within Eastern practices, where mushrooms like reishi, chaga, shiitake, oyster, lion’s mane, and cordyceps are known [...] Read more.
Mushrooms are indeed gaining attention for their unique therapeutic and nutritional qualities, especially in fermented drinks. This trend builds on their historical use in traditional medicine, especially within Eastern practices, where mushrooms like reishi, chaga, shiitake, oyster, lion’s mane, and cordyceps are known for their immune-boosting, anti-inflammatory, and adaptogenic properties. This narrative review highlights the growing interest in the use of mushrooms as functional ingredients in fermented beverages, emphasizing their technological and functional advantages. Fermentation significantly enhances the nutritional content and bioavailability of mushrooms, making it an ideal method to maximize the health benefits and sensory appeal of mushroom-based beverages. Microbial activity breaks down complex compounds in mushrooms, making their bioactive components more accessible for absorption; bringing unique flavors, aromas, and textures; and creating a rich-sensory experience while offering potential health benefits. Mushrooms can also improve the stability and shelf life of fermented beverages due to the presence of antimicrobial and antioxidant compounds, adding another valuable benefit to their use in functional beverages. However, despite their potential, further research is needed to fully understand their impact on health and to refine production techniques for optimal quality and consistency. This review provides a comprehensive overview of the current knowledge of mushroom-fermented beverages, highlighting both the known benefits and research gaps that require further investigation. Given the early stage of this field, the review emphasizes the importance of the additional investigation to unlock the full potential of mushrooms in functional beverage applications. Full article
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<p>Critical challenges in fermented mushroom beverages production.</p>
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<p>Future directions in fermentation of mushroom beverages.</p>
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41 pages, 9889 KiB  
Review
Salidroside: An Overview of Its Promising Potential and Diverse Applications
by Keke Liang, Shuhe Ma, Kai Luo, Renjie Wang, Chenrong Xiao, Xianxie Zhang, Yue Gao and Maoxing Li
Pharmaceuticals 2024, 17(12), 1703; https://doi.org/10.3390/ph17121703 - 17 Dec 2024
Cited by 1 | Viewed by 1527
Abstract
Salidroside, a phenolic compound isolated from various Rhodiola plants, is the principal active constituent of Traditional Chinese Medicine known for its adaptogenic properties. Due to the challenging environment of Rhodiola species, such as high altitude, high radiation, drought, and hypoxia, the source of [...] Read more.
Salidroside, a phenolic compound isolated from various Rhodiola plants, is the principal active constituent of Traditional Chinese Medicine known for its adaptogenic properties. Due to the challenging environment of Rhodiola species, such as high altitude, high radiation, drought, and hypoxia, the source of salidroside is scarce. However, numerous studies have shown that salidroside has a range of biological activities, including cardiovascular and central nervous system activity, and anti-hypoxia, anti-inflammatory, and anti-aging activities. Although previous studies have partially summarized the pharmacological effects of salidroside, the overall pharmacological effects have not been analyzed. Hence, this review will systematically summarize the isolation, purification, synthesis, derivatization, pharmacological activity, pharmacokinetics, clinical application, and safety of salidroside. It is expected to provide new insights for the further research and pharmaceutical development of salidroside. Full article
(This article belongs to the Section Natural Products)
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Graphical abstract

Graphical abstract
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<p>Rhodiola plants and herbal slices. (<b>A</b>) Rhodiola plants. (<b>B</b>) Rhodiola herbal slices.</p>
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<p>The structure of salidroside.</p>
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<p>The distribution of Rhodiola (the color of the hexagons represents the number of distribution records in each hexagon) [<a href="#B11-pharmaceuticals-17-01703" class="html-bibr">11</a>].</p>
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<p>The extraction method of salidroside.</p>
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<p>Synthesis of salidroside (A) by reaction of tyrosol (1) with bromotetraacetyl glucose (2).</p>
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<p>Dibenzyl protects salidroside (A) synthesis of the phenol hydroxyl group of tyrosol.</p>
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<p>Synthetic strategy of salidroside (A) from p-bromophenol.</p>
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<p>Synthetic strategy of salidroside (A) [<a href="#B46-pharmaceuticals-17-01703" class="html-bibr">46</a>].</p>
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<p>Synthetic strategies of salidroside (A) [<a href="#B47-pharmaceuticals-17-01703" class="html-bibr">47</a>].</p>
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<p>Synthesis strategy of salidroside (A) [<a href="#B50-pharmaceuticals-17-01703" class="html-bibr">50</a>].</p>
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<p>Biosynthetic pathway of salidroside.</p>
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<p>Proposed biosynthetic pathways of salidroside [<a href="#B56-pharmaceuticals-17-01703" class="html-bibr">56</a>].</p>
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<p>The last reaction of salidroside biosynthesis.</p>
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<p>Structure of salidroside derivatives. Note: Compounds 1-4 are all salidroside derivatives.</p>
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<p>Synthetic route of salidroside derivatization [<a href="#B73-pharmaceuticals-17-01703" class="html-bibr">73</a>]. Note: (<b>A</b>) The dianalogues of salidroside were screened as compounds 5 and 6 according to (<b>B</b>); (<b>B</b>) The synthetic route of salidroside analogues.</p>
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<p>The central nervous system protects the activity of the salidroside.</p>
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<p>The cardiovascular system protection activity of salidroside.</p>
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<p>The anti-inflammatory activity of salidroside.</p>
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<p>The hypoxia activity of salidroside.</p>
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<p>Pharmacological profiles of salidroside. Note: "↑" indicates an increase and "↓" indicates a decrease.</p>
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17 pages, 3525 KiB  
Review
Harnessing the Antibacterial, Anti-Diabetic and Anti-Carcinogenic Properties of Ocimum sanctum Linn (Tulsi)
by Rakesh Arya, Hossain Md. Faruquee, Hemlata Shakya, Sheikh Atikur Rahman, Most Morium Begum, Sudhangshu Kumar Biswas, Md. Aminul Islam Apu, Md. Azizul Islam, Md. Mominul Islam Sheikh and Jong-Joo Kim
Plants 2024, 13(24), 3516; https://doi.org/10.3390/plants13243516 - 16 Dec 2024
Viewed by 2021
Abstract
Ocimum sanctum Linn (O. sanctum L.), commonly known as Holy Basil or Tulsi, is a fragrant herbaceous plant belonging to the Lamiaceae family. This plant is widely cultivated and found in north-central parts of India, several Arab countries, West Africa and tropical [...] Read more.
Ocimum sanctum Linn (O. sanctum L.), commonly known as Holy Basil or Tulsi, is a fragrant herbaceous plant belonging to the Lamiaceae family. This plant is widely cultivated and found in north-central parts of India, several Arab countries, West Africa and tropical regions of the Eastern World. Tulsi is known to be an adaptogen, aiding the body in adapting to stress by harmonizing various bodily systems. Revered in Ayurveda as the “Elixir of Life”, Tulsi is believed to enhance lifespan and foster longevity. Eugenol, the active ingredient present in Tulsi, is a l-hydroxy-2-methoxy-4-allylbenzene compound with diverse therapeutic applications. As concerns over the adverse effects of conventional antibacterial agents continue to grow, alternative therapies have gained prominence. Essential oils (EOs) containing antioxidants have a long history of utilization in traditional medicine and have gained increasing popularity over time. Numerous in vitro, in vivo and clinical studies have provided compelling evidence supporting the safety and efficacy of antioxidant EOs derived from medicinal plants for promoting health. This comprehensive review aims to highlight the scientific knowledge regarding the therapeutic properties of O. sanctum, focusing on its antibacterial, anti-diabetic, anti-carcinogenic, radioprotective, immunomodulatory, anti-inflammatory, cardioprotective, neurogenesis, anti-depressant and other beneficial characteristics. Also, the extracts of O. sanctum L. have the ability to reduce chronic inflammation linked to neurological disorders such as Parkinson’s and Alzheimer’s disease. The information presented in this review shed light on the multifaceted potential of Tulsi and its derivatives in maintaining and promoting health. This knowledge may pave the way for the development of novel therapeutic interventions and natural remedies that harness the immense therapeutic potential of Tulsi in combating various health conditions, while also providing valuable insights for further research and exploration in this field. Full article
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<p><span class="html-italic">O. sanctum</span> L. (Tulsi) plant.</p>
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<p>The schematic diagram illustrates the different medicinal properties of <span class="html-italic">O. sanctum</span> L. (Tulsi). Each of these activities highlights the diverse therapeutic potential of Tulsi, making it a valuable nutraceutical agent in promoting health and managing different diseases. (Figure created with <a href="http://biorender.com" target="_blank">biorender.com</a>).</p>
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15 pages, 3310 KiB  
Article
Levilactobacillus brevis 47f: Bioadaptation to Low Doses of Xenobiotics in Aquaculture
by Diana Reznikova, Nikita Kochetkov, Alexey Vatlin, Dmitry Nikiforov-Nikishin, Olesya Galanova, Anastasia Klimuk, Svetlana Smorodinskaya, Daria Matyushkina, Alexey Kovalenko, Ivan Butenko, Maria Marsova and Valery Danilenko
Biology 2024, 13(11), 925; https://doi.org/10.3390/biology13110925 - 14 Nov 2024
Viewed by 925
Abstract
Agricultural and industrial activities are increasing pollution of water bodies with low doses of xenobiotics that have detrimental effects on aquaculture. The aim of this work was to determine the possibility of using Levilactobacillus brevis 47f culture in fish aquaculture under the influence [...] Read more.
Agricultural and industrial activities are increasing pollution of water bodies with low doses of xenobiotics that have detrimental effects on aquaculture. The aim of this work was to determine the possibility of using Levilactobacillus brevis 47f culture in fish aquaculture under the influence of low doses of xenobiotics as an adaptogen. An increase in the survival of Danio rerio individuals exposed to the xenobiotic bisphenol A solution and fed with the L. brevis 47f was shown compared to control groups and, at the same time, the cytokine profile in the intestinal tissues of Danio rerio was also investigated. Analysis of differential gene expression of the L. brevis 47f grown under the action of high concentrations of bisphenol A showed changes in mRNA levels of a number of genes, including genes of various transport proteins, genes involved in fatty acid synthesis, genes of transcriptional regulators, genes of the arabinose operon, and the oppA gene. The identification of L. brevis 47f proteins from polyacrylamide gel by mass spectrometry revealed L-arabinose isomerase, Clp chaperone subunit, ATP synthase subunits, pentose phosphate pathway and glycolysis enzyme proteins, which are likely part of the L. brevis 47f strain’s anti-stress response, but probably do not affect its adaptogenic activity toward Danio rerio. Full article
(This article belongs to the Section Microbiology)
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<p>(<b>a</b>) Survival dynamics of <span class="html-italic">Danio rerio</span> individuals for 60 days and (<b>b</b>) on day 60 of the experiment to study the survival of individuals when exposed to bisphenol A in the presence/absence of probiotic. CTR—control group, LAC—group received <span class="html-italic">L. brevis</span> 47f with feed and were in a toxicant-free solution, BPA2—group received basic feed and were in a bisphenol A solution at a concentration of 2 mg/L, BPL2—group received <span class="html-italic">L. brevis</span> 47f under consideration with feed and were in a bisphenol A solution at a concentration of 2 mg/L. According to Kruskal–Wallis test, <span class="html-italic">p</span>-value &lt; 0.05. Letters above the columns represent the static significance between the different experimental groups.</p>
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<p>Relative expression level of some cytokines in <span class="html-italic">Danio rerio</span> intestinal tissues in bisphenol A solution with a concentration of 2 mg/L depending on the fact that the <span class="html-italic">Levilactobacillus brevis</span> 47f strain was received.</p>
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<p>Volcano plot showing <span class="html-italic">L. brevis</span> 47f genes whose expression change is statistically significant at a bisphenol A concentration of 50 mg/L (<span class="html-italic">p</span>-value &lt; 0.05, |Fold Change| ≤ 2).</p>
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<p>Electrophoregram of <span class="html-italic">Levilactobacillus brevis</span> 47f cell fraction proteins when treated with different concentrations of bisphenol A (C, 1, 2–0, 2, 50 mg/L, respectively). M marker (120, 85, 50, 35, 25, 20 kDa). The arrow indicates the protein fraction to be analyzed. The original gel can be found in <a href="#app1-biology-13-00925" class="html-app">Supplementary Figure S1</a>.</p>
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21 pages, 3247 KiB  
Review
Matrikines of Sea Cucumbers: Structure, Biological Activity and Mechanisms of Action
by Aleksandr Popov, Emma Kozlovskaya, Tatyana Rutckova, Olga Styshova, Vyacheslav Makhankov, Aleksey Vakhrushev, Dmitry Hushpulian, Irina Gazaryan, Oksana Son and Ludmila Tekutyeva
Int. J. Mol. Sci. 2024, 25(22), 12068; https://doi.org/10.3390/ijms252212068 - 10 Nov 2024
Viewed by 897
Abstract
Matrikines (MKs), the products of enzymatic fragmentation of various extracellular matrix (ECM) proteins, regulate cellular activity by interacting with specific receptors. MKs affect cell growth, proliferation, and migration, can induce apoptosis and autophagy, and are also effectively used in biomedicine and functional nutrition. [...] Read more.
Matrikines (MKs), the products of enzymatic fragmentation of various extracellular matrix (ECM) proteins, regulate cellular activity by interacting with specific receptors. MKs affect cell growth, proliferation, and migration, can induce apoptosis and autophagy, and are also effectively used in biomedicine and functional nutrition. Recently, there has been great interest in the structural features and biological activity of MKs from various sources. This review summarized and analyzed the results of modern research on MKs from sea cucumbers, primarily from trepang (MKT). Particular attention is paid to the analysis of the existing knowledge on the antioxidant, anti-inflammatory and adaptogenic activities of these MKs and the possible mechanisms of their protective action. Full article
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<p>Various types of glycosaminoglycans (GAG) carbohydrate monomers: (<b>a</b>) chondroitin/dermatan sulfate, (<b>b</b>) heparan sulfate/heparin, (<b>c</b>) keratan sulfate, (<b>d</b>) hyaluronic acid. Abbreviations: GlcUA, glucuronic acid; GlcNAc, N-acetylglucosamine; IdoUA, iduronic acid; GalNAc, N-acetylgalactosamine; gal, galactose.</p>
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<p>Proposed protective effect of MKT under the conditions of oxidative stress through the AMPK signaling pathway and associated downstream factors. Adapted from Ref. [<a href="#B35-ijms-25-12068" class="html-bibr">35</a>]. Abbreviations: ROS/RNS, reactive oxygen and nitrogen species; AMP, 5′ adenosine monophosphate; ATP, 5′ adenosine triphosphate; AMPK, 5′ adenosine monophosphate-activated protein kinase; MKT, matrikines <span class="html-italic">A. japonicus</span>; mtDNA, mitochondrial DNA; NRF-1,2, nuclear transcription factors (NRF-1, NRF-2); OXPHOS, oxidative phosphorylation; PGC, 1α-peroxisome proliferator-activated receptor gamma coactivator 1-alpha; TFAM, mitochondrial transcription factor A.</p>
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<p>Possible mechanism of the MKT protective effect on inflammatory processes induced by ROS and inflammatory factors (LPS, NF-κB, TNFα, IL-6 and IL-1β). Adapted from Ref. [<a href="#B39-ijms-25-12068" class="html-bibr">39</a>]. Abbreviations: LPS, lipopolysaccharide; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; IκB, cytosolic inhibitory protein; IKK, IkappaB kinase; IL, 1β-interleukin-1beta; IL-6, interleukin-6; MKT, matrikines <span class="html-italic">A. japonicus</span>; OXPHOS, oxidative phosphorylation; TNFα, tumor necrosis factor.</p>
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<p>MKT may affect classical and non-classical pathways of STAT3 signaling. Adapted from Ref. [<a href="#B42-ijms-25-12068" class="html-bibr">42</a>]. Abbreviations: IL-6, interleukin 6; gp130, glycoprotein 130, expressed signal transducer; STAT3, transducer and activator of transcription family 3; JAK, Janus kinase; MAPK, mitogen-activated protein kinase; GRIM-19, a cell death regulatory protein; HSP22, heat shock protein; MKT, matrikines <span class="html-italic">A. japonicus</span>; Mitostat3, a small pool of Stat3 was found localized in mitochondria.</p>
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<p>Possible ways of protective action of MKs and MKT in signaling and metabolic pathways under oxidative stress and heavy physical exercise. Adapted from Ref. [<a href="#B34-ijms-25-12068" class="html-bibr">34</a>]. Abbreviations: AMP, 5′-adenosine monophosphate; ATP, 5′- adenosine triphosphate; AMPK, 5′-adenosine monophosphate-activated protein kinase; GSK, 3β-glycogen synthase kinase 3β; MKT, matrikines <span class="html-italic">A. japonicus</span>; mTOR, the mammalian target of rapamycin; NRF1, nuclear respiratory factor 1; parkin, ubiquitin ligase; PDH, pyruvate dehydrogenase; PDK4, pyruvate dehydrogenase lipoamide kinase isozyme 4; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator 1-alpha; PI3K, phosphoinositide 3-kinase; PINK1, intimately involved with mitochondrial quality control by identifying damaged mitochondria and targeting specific mitochondria for degradation, PPARα, peroxisome proliferator-activated receptor; SIRT1, deacetylates transcription factors that contribute to cellular regulation (reaction to stressors, longevity).</p>
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<p>Adaptogenic mechanisms of the protective effect of MKs and MKT on the human body during oxidative stress, which causes fatigue and loss of vitality. Abbreviations: MKT, matrikines <span class="html-italic">A. japonicus;</span> SOD, superoxide dismutase.</p>
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<p>A generalized scheme for Hsp70 and Hsp90 chaperone action on protein clients. Adapted from Ref. [<a href="#B53-ijms-25-12068" class="html-bibr">53</a>]. Abbreviations: Hsc70, heat shock cognate 71 kDa; Hsp (Hsp70 and Hsp90), chaperones (heat shock proteins); LAMP2A, lysosome-associated membrane protein type 2A; Tom (Tom20, Tom22, and Tom70), translocases of the outer mitochondrial membrane; TRAP1, tumor necrosis factor receptor-associated protein 1.</p>
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15 pages, 3998 KiB  
Review
Plants with Potential Importance in Supporting the Treatment of Depression: Current Trends, and Research
by Renata Nurzyńska-Wierdak
Pharmaceuticals 2024, 17(11), 1489; https://doi.org/10.3390/ph17111489 - 6 Nov 2024
Viewed by 2004
Abstract
Depression is one of the most common diseases in the world, and it is also the most common mental disorder. Depressive disorders are a real threat not only to individuals, but also to the general population. This disease is a leading cause of [...] Read more.
Depression is one of the most common diseases in the world, and it is also the most common mental disorder. Depressive disorders are a real threat not only to individuals, but also to the general population. This disease is a leading cause of disability and inability to work. Due to the numerous side effects of conventional drugs, attention is increasingly being paid to other solutions, including herbal medicines. Many plant species are known for their traditional uses in the treatment of anxiety, insomnia, and depression. The clinically proven effects of adaptogenic raw materials on depression symptoms are probably related to the positive impact of some secondary metabolites (terpenoids, alkaloids, glucosinolates, phenols). Currently, it is emphasized that in many cases the antioxidant and anti-inflammatory properties of plant substances play a protective role at the neurocellular level. Among the medicinal plants analyzed in clinical trials for the treatment of depression, the following seem to be particularly interesting: saffron (Crocus L.), turmeric (Curcuma L.), ginkgo (Ginkgo L.), St. John’s wort (Hypericum L.), and passionflower (Passiflora L.), which have broad and strong biological activity, well-documented history of action and use, and effectiveness in preventing and/or treating anxiety and depression. These plants are still in the sphere of biochemical and phytopharmaceutical research, the results of which are very promising. Full article
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<p>Structure of hypericin and hyperforin, active substances of SJW.</p>
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14 pages, 2665 KiB  
Article
Isolation of Lessertiosides A and B and Other Metabolites from Lessertia frutescens and Their Neuroprotection Activity
by Kadidiatou O. Ndjoubi, Sylvester I. Omoruyi, Robert C. Luckay and Ahmed A. Hussein
Plants 2024, 13(21), 3076; https://doi.org/10.3390/plants13213076 - 1 Nov 2024
Viewed by 866
Abstract
Lessertia frutescens (synonym Sutherlandia frutescens) is an important South African medicinal plant used traditionally to treat different human pathologies and is considered an adaptogenic plant. This study sought to isolate compounds from the plant and determine their protective potentials using SH-SY5Y cells [...] Read more.
Lessertia frutescens (synonym Sutherlandia frutescens) is an important South African medicinal plant used traditionally to treat different human pathologies and is considered an adaptogenic plant. This study sought to isolate compounds from the plant and determine their protective potentials using SH-SY5Y cells and MPP+ (1-methyl-4-phenylpyridinium) to mimic Parkinson’s disease. The phytochemical analysis of a 70% aqueous methanolic extract of L. frutescens leaves resulted in the isolation and identification of 11 pure compounds (111), among which compounds 1 and 2 were identified as new metabolites. The new compounds were characterised using IR, UV, NMR, and HRESIMS and were given the trivial names lessertiosides A (1) and B (2). Additionally, the flavonoids 8-methoxyvestitol (7) and mucronulatol (8) were isolated for the first time from the plant. The biological actions show that the isolated compounds had negligible toxicity on SH-SY5Y cells and improved cell viability in the cells exposed to MPP+. Furthermore, as a mechanism of action, the compounds could sustain cellular ATP generation and prevent MPP+-induced apoptotic cell death. Our findings provide evidence for the neuroprotective properties of compounds isolated from L. frutescens in MPP+-induced neuronal damage for the first time and create an avenue for these compounds to be further investigated to elucidate their molecular targets. Full article
(This article belongs to the Special Issue Toxicity and Anticancer Activities of Natural Products from Plants)
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<p>Chemical structure of <span class="html-italic">L. frutescens</span> isolated compounds (<b>1</b>–<b>9</b>).</p>
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<p>Chemical structure of <span class="html-italic">L. frutescens</span> isolated compounds (<b>1</b>–<b>9</b>).</p>
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<p>Cytotoxicity of <span class="html-italic">L. frutescens</span> compounds (<b>3</b>–<b>11</b>) on SH-SY5Y cells. SH-SY5Y cells were treated with concentrations of 2, 5, and 10 µg/mL of compounds for 24 h. After treatment, MTT assays were performed. The absorbance values obtained from quadruplicate wells were expressed as a percentage of the control. The bars in the graphs represent the means ± SEM of experiments performed in triplicates.</p>
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<p><span class="html-italic">L. frutescens</span> compounds (<b>3</b>–<b>11</b>) protect SH-SY5Y cells from MPP<sup>+</sup> toxicity. SH-SY5Y cells were treated with 2, 5, and 10 µg/mL concentrations compounds for 2 h before the addition of MPP<sup>+</sup> and cells were incubated for 24 h, followed by MTT assays. Absorbance values obtained from quadruplicate wells were calculated as a percentage of control. Bars represent the means ± SEM of three independent experiments, and the significance of difference indicated with * <span class="html-italic">p</span> &lt; 0.05, ** <span class="html-italic">p</span> &lt; 0.01, *** <span class="html-italic">p</span> &lt; 0.001 and **** <span class="html-italic">p</span> &lt; 0.0001 when cells pre-treated with compounds were compared to MPP<sup>+</sup> and the boxed asterisks represent the comparison between MPP<sup>+</sup> and the control cells.</p>
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<p>Impact of <span class="html-italic">L. frutescens</span> compounds (<b>3</b>–<b>11</b>) on ATP production. SH-SY5Y cells were treated with 2, 5, and 10 µg/mL concentrations compounds for 2 h before the addition of MPP<sup>+</sup> and cells were incubated for 24 h, followed by ATP assays. Luminescence values obtained were expressed as a percentage of the control. Bars represent means ± SEM of three independent experiments, and the significance of difference is indicated with * <span class="html-italic">p</span> &lt; 0.05 and **** <span class="html-italic">p</span> &lt; 0.0001 when cells pre-treated with compounds were compared to MPP<sup>+</sup>, and the boxed asterisks represent the comparison between MPP<sup>+</sup> and the control cells.</p>
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<p>Impact of <span class="html-italic">L. frutescens</span> compounds (<b>3</b>–<b>11</b>) on ATP production. SH-SY5Y cells were treated with 2, 5, and 10 µg/mL concentrations compounds for 2 h before the addition of MPP<sup>+</sup> and cells were incubated for 24 h, followed by caspase 3/7 Glo assays. Luminescence values obtained were represented as fold of control. Bars represent means ± SEM of three independent experiments, and the significance of the difference is indicated with ** <span class="html-italic">p</span> &lt; 0.01, *** <span class="html-italic">p</span> &lt; 0.001, and **** <span class="html-italic">p</span> &lt; 0.0001 when cells pre-treated with compounds were compared to MPP<sup>+</sup>, and the boxed asterisks represent the comparison between MPP<sup>+</sup> and the control cells.</p>
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<p>HMBC correlations of compound <b>1</b> (H→C).</p>
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<p>HMBC correlations of lessertioside B (H→C).</p>
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23 pages, 2073 KiB  
Review
A Comprehensive Review on Deep Eutectic Solvents: Their Current Status and Potential for Extracting Active Compounds from Adaptogenic Plants
by Malgorzata Stanisz, Beata J. Stanisz and Judyta Cielecka-Piontek
Molecules 2024, 29(19), 4767; https://doi.org/10.3390/molecules29194767 - 9 Oct 2024
Cited by 4 | Viewed by 2753
Abstract
Deep eutectic solvents (DESs) have attracted attention from researchers as novel compounds for extracting active substances because of their negligible toxicity, polarity, and ability to be tailored depending on the experiment. In this review, we discuss deep eutectic solvents as a promising medium [...] Read more.
Deep eutectic solvents (DESs) have attracted attention from researchers as novel compounds for extracting active substances because of their negligible toxicity, polarity, and ability to be tailored depending on the experiment. In this review, we discuss deep eutectic solvents as a promising medium for the extraction of adaptogenic compounds. In comparison to traditional methods, extraction with the use of DESs is a great alternative to the excessive usage of harmful organic solvents. It can be conducted in mild conditions, and DESs can be designed with different precursors, enhancing their versatility. Adaptogenic herbs have a long medicinal history, especially in Eastern Asia. They exhibit unique properties through the active compounds in their structures, including saponins, flavonoids, polysaccharides, and alkaloids. Therefore, they demonstrate a wide range of pharmaceutical effects, such as anti-inflammatory, antibacterial, and anticancer abilities. Since ancient times, many different adaptogenic herbs have been discovered and are well known, including Panax ginseng, Scutellaria baicalensis, and Schisandra chinensis. Active compounds can be extracted using standard methods, such as hydrolyzation, maceration, and conventional reflux extraction. However, due to the limitations of classical processing technologies, there has been a need to develop new and eco-friendly methods. We focus on the types of solvents, extraction efficiency, properties, and applications of the obtained active compounds. This review highlights the potential of DESs as eco-friendly alternatives for extracting bioactive compounds. Full article
(This article belongs to the Section Green Chemistry)
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<p>Number of publications related to selected keywords in the timeframes of 2013–2018 and 2019–2024.</p>
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<p>Advantages of DESs.</p>
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<p>Application of DESs [<a href="#B20-molecules-29-04767" class="html-bibr">20</a>,<a href="#B33-molecules-29-04767" class="html-bibr">33</a>,<a href="#B34-molecules-29-04767" class="html-bibr">34</a>,<a href="#B35-molecules-29-04767" class="html-bibr">35</a>,<a href="#B36-molecules-29-04767" class="html-bibr">36</a>,<a href="#B37-molecules-29-04767" class="html-bibr">37</a>].</p>
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<p>Different types of adaptogenic plants.</p>
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<p>Extraction steps of adaptogens using DESs.</p>
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17 pages, 7719 KiB  
Article
UHPLC-DAD/ESI-TOF-MS Phytochemical Characterization and Evaluation of the Impact of Eleutherococcus senticosus Fruit Intractum on Biochemical, Hepatological, and Blood Parameters in Balb/c Mice
by Filip Graczyk, Jakub Gębalski, Dorota Sulejczak, Milena Małkowska, Magdalena Wójciak, Dorota Gawenda-Kempczyńska, Elżbieta Piskorska, Krystian Krolik, Maciej Markiewicz, Aneta Kondrzycka-Dąda, Wiktoria Lepianka, Grzegorz Borowski, Marcin Feldo, Robert Verporte and Daniel Załuski
Int. J. Mol. Sci. 2024, 25(17), 9295; https://doi.org/10.3390/ijms25179295 - 27 Aug 2024
Cited by 1 | Viewed by 1178
Abstract
Eleutherococcus senticosus (Rupr. et Maxim.) Maxim. (ES) has gained popularity for its adaptogenic, immunostimulant, and anti-inflammatory properties. Because of overexploitation of the roots, the species is considered to be endangered and has been put on the Red List in some countries (e.g., the [...] Read more.
Eleutherococcus senticosus (Rupr. et Maxim.) Maxim. (ES) has gained popularity for its adaptogenic, immunostimulant, and anti-inflammatory properties. Because of overexploitation of the roots, the species is considered to be endangered and has been put on the Red List in some countries (e.g., the Republic of Korea). Therefore, the fruits of E. senticosus might be explored as a new sustainable source of compounds with adaptogenic activity. This study aimed to assess the chemical composition and the safety profile (hepatotoxicity, blood morphology, biochemical parameters of blood plasma) of E. senticosus fruit intractum in Balb/c mice after oral administration of 750 and 1500 mg/kg b.w. UHPLC analysis coupled with DAD and MS detectors was used to quantify the metabolites. For the first time, oleanolic and ursolic acids were quantified in the intractum (16.01 ± 1.3 and 2.21 ± 0.17 µg/g of oleanolic and ursolic acids, respectively). Regarding polyphenols, chlorogenic acid (0.92 mg/g of dried extract), caffeic acid (0.43 mg/g), dicaffeoylquinic acids (in total: 1.27 mg/g), and an unidentified caffeic acid ester (0.81 mg/g) were identified. The results in Balb/c mice revealed that the intractum does not cause significant variations in red blood cells parameters. In turn, a significant decrease in the total number of leukocytes was observed (5.8 × 103 µL), with a percentage increase in lymphocytes among the groups (80.2, 81.8, and 82.6). The ability of the intractum to decrease alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels may indicate its anti-inflammatory activity. Our observations justify that the fruits of E. senticosus are safe in the doses used and do not cause significant changes in the activity of the liver enzymes or in blood parameters. Full article
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<p>The chemical structures of eleutheroside B (syringin 4-<span class="html-italic">β</span>-D-glucoside), eleutheroside E ((−)-siringaresinol 4,4”-<span class="html-italic">O</span>-<span class="html-italic">β</span>-D-diglucoside), and eleutheroside E1 ((−)-siringaresinol 4-<span class="html-italic">O</span>-<span class="html-italic">β</span>-D-glucoside).</p>
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<p>Base peak chromatogram (grey line) and the chromatogram registered at λ = 320 nm (red line) of <span class="html-italic">E. senticosus</span> fruit intractum.</p>
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<p>The change in average body weight (g) in groups of mice treated with different doses of intractum (mg/kg b.w.).</p>
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<p>Average weight of individual organs collected from groups of mice; results presented as mean ± SD. Different letters (a, b) indicate statistically significant differences, with <span class="html-italic">p</span> &lt; 0.05.</p>
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<p>H&amp;E staining. Microphotographs of representative liver sections obtained from control mice (<b>A</b>) and animals treated with 750 (<b>B</b>) or 1500 mg/kg b.w. (<b>C</b>) of the intractum.</p>
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<p>Hierarchical cluster analysis of three analyzed groups of mice based on all examined parameters.</p>
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<p>Principal component analysis of analyzed groups of mice based on all examined parameters.</p>
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18 pages, 2427 KiB  
Article
Controlled Cultivation Confers Rhodiola rosea Synergistic Activity on Muscle Cell Homeostasis, Metabolism and Antioxidant Defense in Primary Human Myoblasts
by Fortuna Iannuzzo, Elisabetta Schiano, Arianna Pastore, Fabrizia Guerra, Gian Carlo Tenore, Ettore Novellino and Mariano Stornaiuolo
Antioxidants 2024, 13(8), 1000; https://doi.org/10.3390/antiox13081000 - 18 Aug 2024
Cited by 1 | Viewed by 1574
Abstract
Rhodiola rosea L. is recognized for its adaptogenic properties and ability to promote muscle health, function and recovery from exercise. The plethora of biological effects of this plant is ascribed to the synergism existing among the molecules composing its phytocomplex. In this manuscript, [...] Read more.
Rhodiola rosea L. is recognized for its adaptogenic properties and ability to promote muscle health, function and recovery from exercise. The plethora of biological effects of this plant is ascribed to the synergism existing among the molecules composing its phytocomplex. In this manuscript, we analyze the activity of a bioactive fraction extracted from Rhodiola rosea L. controlled cultivation. Biological assays were performed on human skeletal myoblasts and revealed that the extract is able to modulate in vitro expression of transcription factors, namely Pax7 and myoD, involved in muscle differentiation and recovery. The extract also promotes ROS scavenging, ATP production and mitochondrial respiration. Untargeted metabolomics further reveals that the mechanism underpinning the plant involves the synergistic interconnection between antioxidant enzymes and the folic/acid polyamine pathway. Finally, by examining the phytochemical profiles of the extract, we identify the specific combination of secondary plant metabolites contributing to muscle repair, recovery from stress and regeneration. Full article
(This article belongs to the Special Issue Antioxidant Response in Skeletal Muscle)
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Figure 1
<p>RRcc modulates undifferentiated muscle cells and promotes defense from oxidative stress. Growth (<b>A</b>), qPCR analysis of differentiation-related muscle cell transcription factors (<b>B</b>), antioxidant enzymes (<b>C</b>) and total ROS content (<b>D</b>) in primary muscle myoblasts treated for 48 h in the presence of RRcc (30 μg/mL), RRwh (30 μg/mL), an equal amount of vehicle (veh) or left untreated (untr). Data are shown as mean ± SD of five independent experiments. Statistical analysis was performed by ANOVA test comparing each mean with that of untreated cells. <span class="html-italic">p</span> value = * &lt;0.05, otherwise differences were not statistically significant.</p>
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<p>RRcc promotes ATP production and mitochondrial activity in cultured human myoblasts. Intracellular ATP content (<b>A</b>), <span class="html-italic">Pgc1α</span> mRNA levels (<b>B</b>) and mitochondrial activity(<b>C</b>) in primary muscle myoblasts treated for 48 h in the presence of RRcc (30 μg/mL), RRwh (30 μg/mL), an equal amount of vehicle (veh) or left untreated (untr). Data are shown as mean ± SD of five independent experiments. Statistical analysis was performed by ANOVA test comparing each mean with that of untreated cells. <span class="html-italic">p</span> value = * &lt;0.05, *** &lt; 0.001, otherwise differences were not statistically significant.</p>
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<p>RRcc presents folic acid-cycle and polyamine pathway modulatory activity in human myoblasts. Metabolic profile of primary muscle myoblasts treated for 48 h with RRcc (30 μg/mL), RRwh (30 μg/mL), an equal amount of vehicle (veh) or left untreated (untr). (<b>A</b>) Content (fold variation vs. untr) of the indicated metabolites as measured in the four different experimental conditions; (<b>B</b>) primary component analysis (PCA) score plot showing that the metabolic profiles of RRcc and RRwh are different from veh and untr cells; (<b>C</b>) content (fold variation vs. untr) of the folic acid-cycle and polyamine pathway metabolites as measured in the four different experimental conditions (<span class="html-italic">n</span> = 3 independent experiments); (<b>D</b>) PCA score plot showing the metabolic profile of RRcc being different from RRwh. In A and C, values are represented as mean ± SD. Two-way ANOVA and Bonferroni post-test analysis were performed; * = <span class="html-italic">p</span> &lt; 0.05; ** = <span class="html-italic">p</span> &lt; 0.01; *** = <span class="html-italic">p</span> &lt; 0.001; **** = <span class="html-italic">p</span> &lt; 0.0001; otherwise differences were not statistically significant.</p>
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<p>RRcc activity relies on the synergism between the folic acid pathway and antioxidant activity and on the presence of quercetin-glycosides. (<b>A</b>,<b>B</b>) mRNA levels of muscle cell differentiation markers in primary muscle myoblasts treated for 48 h in the presence of RRcc (30 μg/mL), RRwh (30 μg/mL), an equal amount of vehicle (veh) or left untreated (untr). When indicated, folic acid (FA, 5μM), cystine (Cys2, 1 mM), quercetin (Q, 1 μM), quercetin 3-glycoside (QG, 1 μM), rutin (Q2G, 1 μM) and quercetin 3-rhamnoglucoside 7-glucoside (Q3G, 1 μM) were included in the treatment. Data are shown as mean ± SD of five independent experiments. Statistical analysis was performed by ANOVA test comparing each mean with that of untreated cells. <span class="html-italic">p</span> value = * &lt;0.05, *** &lt;0.001, otherwise differences not statistically significant.</p>
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<p>Overlapped UHPL-HRMS base peak chromatogram of <span class="html-italic">Rhodiola rosea</span> L. wild harvest (RRwh, black chromatogram) and <span class="html-italic">Rhodiola rosea</span> L. controlled cultivation (RRcc, red chromatogram) with peak annotation.</p>
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19 pages, 327 KiB  
Review
Ashwagandha’s Multifaceted Effects on Human Health: Impact on Vascular Endothelium, Inflammation, Lipid Metabolism, and Cardiovascular Outcomes—A Review
by Michał Wiciński, Anna Fajkiel-Madajczyk, Zuzanna Kurant, Sara Liss, Paweł Szyperski, Monika Szambelan, Bartłomiej Gromadzki, Iga Rupniak, Maciej Słupski and Iwona Sadowska-Krawczenko
Nutrients 2024, 16(15), 2481; https://doi.org/10.3390/nu16152481 - 31 Jul 2024
Cited by 4 | Viewed by 13044
Abstract
Withania somnifera, commonly known as Ashwagandha, has been popular for many years. Numerous studies have shown that the extract of this plant, due to its wealth of active substances, can induce anti-inflammatory, neuroprotective, immunomodulatory, hepatoprotective, cardioprotective, anti-diabetic, adaptogenic, anti-arthritic, anti-stress, and antimicrobial [...] Read more.
Withania somnifera, commonly known as Ashwagandha, has been popular for many years. Numerous studies have shown that the extract of this plant, due to its wealth of active substances, can induce anti-inflammatory, neuroprotective, immunomodulatory, hepatoprotective, cardioprotective, anti-diabetic, adaptogenic, anti-arthritic, anti-stress, and antimicrobial effects. This review examines the impact of Ashwagandha extract on the vascular endothelium, inflammation, lipid metabolism, and cardiovascular outcomes. Studies have shown that Ashwagandha extracts exhibit an anti-angiogenic effect by inhibiting vascular endothelial growth factor (VEGF)-induced capillary sprouting and formation by lowering the mean density of microvessels. Furthermore, the results of numerous studies highlight the anti-inflammatory role of Ashwagandha extract, as the action of this plant causes a decrease in the expression of pro-inflammatory cytokines. Interestingly, withanolides, present in Ashwagandha root, have shown the ability to inhibit the differentiation of preadipocytes into adipocytes. Research results have also proved that W. somnifera demonstrates cardioprotective effects due to its antioxidant properties and reduces ischemia/reperfusion-induced apoptosis. It seems that this plant can be successfully used as a potential treatment for several conditions, mainly those with increased inflammation. More research is needed to elucidate the exact mechanisms by which the substances contained in W. somnifera extracts can act in the human body. Full article
(This article belongs to the Special Issue Effects of Plant Extracts on Human Health)
18 pages, 3086 KiB  
Review
Salidroside: A Promising Agent in Bone Metabolism Modulation
by Piotr Wojdasiewicz, Stanisław Brodacki, Ewa Cieślicka, Paweł Turczyn, Łukasz A. Poniatowski, Weronika Ławniczak, Mieszko Olczak, Elżbieta U. Stolarczyk, Edyta Wróbel, Agnieszka Mikulska, Anna Lach-Gruba, Beata Żuk, Katarzyna Romanowska-Próchnicka and Dariusz Szukiewicz
Nutrients 2024, 16(15), 2387; https://doi.org/10.3390/nu16152387 - 23 Jul 2024
Cited by 1 | Viewed by 2686
Abstract
Rhodiola rosea, a long-lived herbaceous plant from the Crassulaceae group, contains the active compound salidroside, recognized as an adaptogen with significant therapeutic potential for bone metabolism. Salidroside promotes osteoblast proliferation and differentiation by activating critical signaling pathways, including bone morphogenetic protein-2 and [...] Read more.
Rhodiola rosea, a long-lived herbaceous plant from the Crassulaceae group, contains the active compound salidroside, recognized as an adaptogen with significant therapeutic potential for bone metabolism. Salidroside promotes osteoblast proliferation and differentiation by activating critical signaling pathways, including bone morphogenetic protein-2 and adenosine monophosphate-activated protein kinase, essential for bone formation and growth. It enhances osteogenic activity by increasing alkaline phosphatase activity and mineralization markers, while upregulating key regulatory proteins including runt-related transcription factor 2 and osterix. Additionally, salidroside facilitates angiogenesis via the hypoxia-inducible factor 1-alpha and vascular endothelial growth factor pathway, crucial for coupling bone development with vascular support. Its antioxidant properties offer protection against bone loss by reducing oxidative stress and promoting osteogenic differentiation through the nuclear factor erythroid 2-related factor 2 pathway. Salidroside has the capability to counteract the negative effects of glucocorticoids on bone cells and prevents steroid-induced osteonecrosis. Additionally, it exhibits multifaceted anti-inflammatory actions, notably through the inhibition of tumor necrosis factor-alpha and interleukin-6 expression, while enhancing the expression of interleukin-10. This publication presents a comprehensive review of the literature on the impact of salidroside on various aspects of bone tissue metabolism, emphasizing its potential role in the prevention and treatment of osteoporosis and other diseases affecting bone physiology. Full article
(This article belongs to the Section Phytochemicals and Human Health)
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<p>The graphical representation of salidroside (C<sub>14</sub>H<sub>20</sub>O<sub>7</sub>) structure. The 2D and 3D structures were accustomed according to the PubChem database (PubChem CID: 159278).</p>
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<p>A schematic illustration of the impact of salidroside (SAL) and hypoxia on the hypoxia-inducible factor 1-alpha (HIF-1α)/vascular endothelial growth factor (VEGF) signaling pathway. SAL and hypoxia inhibit the degradation of HIF-1α (red designation, right side), leading to the accumulation of HIF-1α (green designation, left side) in the cytoplasm. Subsequently, HIF-1α translocates to the nucleus, where it dimerizes with hypoxia-inducible factor 1-beta (HIF-1β) and binds to the hypoxia-responsive element (HRE). This interaction initiates the transcription of the VEGF gene, which in turn stimulates the synthesis of VEGF in the cytoplasm. The newly synthesized VEGF is then secreted out of the cell, where it binds to VEGF receptors (VEGF-R) on the surface of endothelial cells, stimulating their proliferation and leading to the formation of new blood vessels. It is noteworthy that SAL promotes angiogenesis in a manner similar to hypoxia, but potentially offers a more favorable anabolic mechanism, as it does not induce biological stress in the cells.</p>
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<p>Diagram summarizing the effects of salidroside (SAL) on cellular signaling pathways. Stimulatory effects are highlighted with green arrows, whereas inhibitory effect is denoted by red arrow. Nrf2—nuclear factor erythroid 2–related factor 2; BMP-2—bone morphogenetic protein 2; BMP-6—bone morphogenetic protein 6; BMP-7—bone morphogenetic protein 7; PI3K/Akt—phosphoinositide 3-kinase/protein kinase B; AMPK—adenosine monophosphate-activated protein kinase; MAPK/ERK—mitogen-activated protein kinase/extracellular signal-regulated kinase; HIF-1α/VEGF—hypoxia-inducible factor 1-alpha/vascular endothelial growth factor; TGF-β/Smad2/3—transforming growth factor-beta/Smad family member 2/3.</p>
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