Search Results (136)

Constant light (LL) exposure is an established environmental risk factor for metabolic diseases, in which the whitening of brown adipose tissue (BAT) plays a critical role. This study aimed to elucidate the molecular mechanisms through which cordycepin counteracts LL-induced BAT whitening and improves metabolic function. We established an LL-exposed mouse model and employed an integrative approach combining pharmacological, metabolic, molecular, and computational (docking) assays to define cordycepin’s effects and targets. Cordycepin treatment significantly improved cold tolerance and attenuated BAT whitening in LL mice. Mechanistically, cordycepin directly bound to and enhanced the activity of the NAD⁺-dependent deacetylase SIRT1. This activation mitigated LL-induced impairments in mitochondrial biogenesis, dynamics, and autophagy. Furthermore, SIRT1 activation rebalanced fatty acid metabolism by downregulating CD36 and upregulating CPT1, thereby restoring the coupling of fatty acid uptake to oxidation. All beneficial effects of cordycepin were abolished by the selective SIRT1 inhibitor EX-527. In summary, our work provides strong evidence that cordycepin directly interacts with SIRT1 and enhances its deacetylase activity, thereby restoring mitochondrial function and fatty acid oxidative homeostasis in BAT to counteract constant LL-induced metabolic dysfunction. These findings position cordycepin as a promising natural compound targeting the SIRT1 pathway for metabolic disorders. Full article

This narrative review proposes the ‘Brain Health Triad’ as a novel integrative framework for neurorehabilitation and cognitive enhancement, built upon three interdependent biological pillars: neurostimulation, neurotrophy, and neuroprotection. We illustrate how the synergistic interplay between a ‘core triad’ composed of Hericium erinaceus, Bacopa monnieri, and L-Theanine targets these pillars with high specificity. Hericium erinaceus fosters neurotrophy by inducing Nerve Growth Factor (NGF) and Brain-derived neurotrophic factor (BDNF) synthesis through erinacines and hericenones; Bacopa monnieri complements this by enhancing neurostimulation and synaptic plasticity via bacosides; and L-Theanine regulates neurotransmitter balance and alpha-wave activity to stabilize the neural signaling environment. This core architecture is further reinforced by adjunctive nootropic clusters—including withanolides, ginkgolides, citicoline, cordycepin, macamides, and fulvic acid—which provide essential support for mitochondrial resilience and the mitigation of amyloid-β and tau toxicities. By synthesizing molecular evidence from the BDNF/TrkB/CREB signaling axis and the Nrf2/NF-κB homeostatic switch, we demonstrate that this multi-target strategy offers a more robust path to neuronal resilience than traditional single-target approaches. We conclude that this integrated model provides a solid framework for future clinical applications in the management of age-related cognitive decline and neurodegenerative diseases. Full article

Oral squamous cell carcinoma (OSCC) remains a major clinical challenge, highlighting the need for novel therapeutic strategies. Natural bioactive compounds such as curcumin (Cu) and cordycepin (Co) have shown anticancer potential; however, their effects on cancer cell morphology and behavior remain incompletely characterized. This study assessed the individual and combined effects of Cu and Co on oral squamous cell carcinoma cells (OECM-1) and normal human gingival epithelial cells (HGEpiC) over 24 and 48 h. Metabolic activity, membrane integrity, oxidative stress, apoptosis, and inflammatory responses were evaluated using MTT, LDH, ROS-H₂O₂, caspase 3/7, and NO assays. Label-free digital holographic microscopy enabled real-time monitoring of morphology, motility, and proliferation. Both compounds induced ROS-mediated cytotoxicity, but responses were notably more pronounced in OECM-1 than in HGEpiC cells. Real-time morphological profiling revealed distinct response patterns: Co primarily exerted cytostatic effects, whereas Cu induced cell shrinkage, impaired motility, and inhibited cell division. The combination treatment (CC) largely reflected Cu-driven morphological and functional changes, with Co coexisting without counteracting Cu’s effects. Taken together, these findings reveal compound-specific mechanisms of action for Cu and Co in OSCC therapy. Full article

The growth–specialized metabolism trade-off limits fungal natural product production. Here, we investigated cordycepin overproduction in Cordyceps militaris high-yield GYS60 and low-yield GYS80 via comparative proteomics, Post-Translational Modification (PTM) mapping, and metabolomics. We identified an acetyl-CoA-gated checkpoint centered on O-methyltransferase CCM_06472, whose activity is modulated by Lys123 acetylation and Ser34 phosphorylation in a manner consistent with activation and inhibition. GYS60 hyperactivates the tricarboxylic acid (TCA) cycle and β-oxidation to generate a 4.1-fold acetyl-CoA surplus, 62% of which is channeled into cordycepin synthesis. A single K123Q acetylation-mimetic mutation boosted cordycepin titers by >4-fold in wild-type strains. This acetyl-CoA checkpoint reveals PTM-gated flux allocation as a key regulatory mechanism, providing a minimal-intervention strategy for engineering fungal cell factories. Full article

Given the therapeutic potential of bioactive cordycepin in medical and healthcare products, precision fermentation using an engineered strain of Aspergillus oryzae was performed to enhance cordycepin production. To understand and predict the dynamics of cell growth and cordycepin production in this fungal strain, mathematical modeling of submerged fermentation was applied. The effects of different nitrogen sources (yeast extract, peptone, (NH₄)₂SO₄, NH₄Cl, NaNO₃, and KNO₃) and carbon sources (glucose and cassava starch hydrolysate, CSH) on cell growth and cordycepin production were evaluated under submerged fermentation conditions. The results showed that organic nitrogen sources significantly enhanced biomass formation and cordycepin production compared with inorganic nitrogen sources. Among them, yeast extract provided the best performance, yielding the highest biomass (13.63–15.99 g/L) and cordycepin titer (1.24–1.72 g/L). In contrast, nitrate-based nitrogen sources supported cell growth but resulted in negligible cordycepin production. Under optimized conditions in a bioreactor, both glucose and CSH supported fungal growth, although CSH promoted higher biomass formation while glucose favored cordycepin biosynthesis. The kinetic model demonstrated that the growth of engineered A. oryzae was well described by the logistic growth model (R² > 0.88). The cordycepin production profiles were well fitted by the Luedeking–Piret model (R² > 0.99), indicating a mixed growth-associated product with kinetic constants α and β representing growth-associated and non-growth-associated production, respectively. Overall, the developed kinetic model provides a quantitative framework for describing cell growth, substrate utilization, and cordycepin formation, offering guidance for process optimization and scale-up of cordycepin production in engineered fungal systems. Full article

Background/Objectives: The medical mushroom Ophiocordyceps sinensis (Caterpillar Fungus), known for its ability to enhance “vitality,” is one of the most popular medicines in Asian traditional medical systems. According to the Chinese Pharmacopeia, O. sinensis is standardized for its adenosine content, the precursor of ATP, which mediates numerous physiological and pathological processes in many diseases. The related fungus of order Hypocreales, Cordyceps militaris, and its major bioactive constituents, 3′-deoxyadenosine (cordycepin), also exhibit pleiotropic biological activities. This review aims to provide a rationale for the adaptogenic and resilience-supporting effects of these medicinal fungi and to align food and drug regulation in Western countries. Methods: In this narrative review, we integrated results from chemical, pharmacokinetic, network pharmacology, preclinical, and clinical studies of O. sinensis, C. militaris, and cordycepin using network pharmacology and bioinformatics tools. Results: Across studies, recurrent mechanistic hubs included PI3K–Akt, AMPK–mTOR, MAPK, NF-κB, apoptosis, and adaptive stress-response signaling pathways, linking immune regulation and metabolic homeostasis. Experimental studies confirmed modulation of cytokine production, kinase signaling, and mitochondrial regulators. Clinical meta-analyses demonstrate consistent adjunctive benefits in renal and pulmonary disorders, although heterogeneity in preparation and methodological limitations remains significant. The review reveals controversy regarding the bioavailability of cordycepin in vivo and its concentration in vitro studies, raising the hypothesis that cordycepin may act as a driver, triggering the organism’s adaptive stress response in stress-induced and aging-related diseases. Pharmacokinetic data indicate that systemic cordycepin concentrations after oral administration remain in the nanomolar range, suggesting that some predicted molecular interactions may occur indirectly or through systems-level mechanisms. The review, for the first time, suggests establishing a regulatory category for resilience-supporting physiological modulators to align food and drug regulation in the EU with contemporary systems biology, thereby complementing the work of EFSA, EMA, FDA, and Asian authorities. Conclusions:O. sinensis, C. militaris, and 3-deoxyadenosine share a common adaptogenic mechanism for maintaining homeostasis of cellular and integrated biological system functions. The systems-level network analysis and reductionistic molecular ligand preceptor pharmacology provide complementary approaches for understanding the multi-target bioactivity of these fungi. This review clarifies conceptual and regulatory barriers to recognizing resilience-supporting interventions and informs future regulatory innovation. Full article

Edible mushrooms have long been valued as functional foods and traditional remedies, yet a significant developmental gap hinders their transition from nutraceuticals to standardized pharmaceutical ingredients. This narrative review provides a comprehensive and integrative analysis of edible mushroom-derived bioactive compounds as emerging candidates for pharmaceutical development. It examines major chemical classes, including polysaccharides (e.g., β-glucans), proteins (e.g., lectins, FIPs), triterpenoids (e.g., ganoderic acids), nucleosides (e.g., adenosine and cordycepin), and phenolic compounds, which underpin immunomodulatory, anticancer, antioxidant, anti-inflammatory, and metabolic activities. Beyond bioactivity, the review critically examines the downstream processing pipeline required for translation into pharmaceutical ingredients, encompassing controlled biomass production, pre-extraction processing, extraction technologies, isolation and purification strategies, and structural elucidation techniques. Key bottlenecks are identified, including bioavailability limitations of β-glucans (2–5%), lack of standardization, limited human clinical evidence, and regulatory constraints, explaining why robust preclinical evidence has not consistently translated into clinical success. Emerging solutions are also highlighted, including application of multi-omics tools, nano-encapsulation strategies, and synthetic biology approaches to improve scalability and reproducibility. By synthesizing research on natural product chemistry, biotechnology, and pharmacology, this study maps the journey of edible mushrooms from traditional dietary components to pharmaceutical-grade ingredients, providing a focused resource for researchers and industry stakeholders aiming to navigate mushroom-based drug development. Full article

WIB-801CE, a standardized Cordyceps militaris extract containing 7.0% cordycepin, suppresses platelet activation induced by thrombin, collagen, and adenosine diphosphate (ADP). As these agonists generate thromboxane A₂ (TXA₂), which amplifies platelet activation via a self-propagating feedback loop, blockade of TXA₂-mediated signaling offers strong antithrombotic potential. TXA₂-antagonistic effects were evaluated using U46619, a stable TXA₂ analog. Platelet activation was assessed by fibrinogen binding to integrin αIIbβ₃, aggregation, and phosphorylation of platelet-activating proteins—PI3K (Tyr458), Akt (Ser473), p38 MAPK (Thr180/Tyr182), ERK1 (Thr202/Tyr204), JNK1 (Thr183/Tyr185)—and inhibitory proteins—VASP (Ser157) and IP₃RI (Ser1756)—via immunoblotting. Thrombin-induced fibrin clot retraction, cytotoxicity, coagulation parameters, and antioxidant capacity were also examined. WIB-801CE significantly inhibited U46619-induced fibrinogen binding to integrin αIIbβ₃ and platelet aggregation, without inducing cytotoxicity or impairing hemostatic function. It also significantly downregulated the phosphorylation of platelet-activating proteins and upregulated the phosphorylation of platelet-inhibiting proteins. Additionally, WIB-801CE abolished thrombin-induced fibrin clot retraction and demonstrated antioxidant capacity. WIB-801CE disrupts TXA₂-driven platelet activation and thrombus stabilization by selectively modulating phosphorylation of key signaling proteins at defined regulatory sites. These properties highlight its promise as a therapeutic candidate for thrombotic disorders with platelet hyperreactivity. Full article

Cordyceps militaris is an entomopathogenic fungus traditionally used in Asian ethnomedicine and increasingly investigated for its potential health-promoting properties, including immunomodulatory and anti-inflammatory activities. In recent years, it has gained attention as a dietary supplement with possible applications in sports nutrition. This narrative review summarizes and critically evaluates the current human evidence regarding the ergogenic and post-exercise recovery effects of C. militaris supplementation in healthy individuals. A structured database search was conducted using predefined eligibility criteria, and the methodological quality of included studies was appraised through domain-based risk-of-bias assessment. Five intervention studies published between 2017 and 2024, comprising 321 participants aged 16–35 years, were identified. Supplementation protocols ranged from 1 to 16 weeks, with daily doses of 1–12 g administered either as isolated fungal material or as a part of multi-ingredient formulations. Assessed outcomes included indices of aerobic performance and exercise capacity, such as maximal or peak oxygen uptake (VO₂max/VO₂peak), time to exhaustion, power output, running performance, and maintenance of peripheral oxygen saturation during high-intensity exercise. Several studies also evaluated biochemical markers related to muscle damage and inflammatory responses, including creatine kinase, blood urea nitrogen, and white blood cell counts. Although some studies reported improvements in selected performance and recovery parameters, the findings were inconsistent. The certainty of the evidence is limited by small sample sizes, heterogeneity of participants and exercise protocols, insufficient reporting of randomization, lack of trial registration in most studies, absence of standardized preparations with quantified bioactive constituents, and the use of multi-ingredient supplements. Well-designed randomized controlled trials using chemically characterized preparations and homogeneous athletic populations are required to clarify the efficacy and practical relevance of C. militaris in sports nutrition. Full article

Cordyceps militaris is an important medicinal and edible fungus that contains a wide range of bioactive ingredients, including cordycepin, polysaccharides, ergosterol, mannitol, proteins, and carotenoids, which collectively confer tonic, anti-fatigue, immunopotentiating, antioxidant, anti-inflammatory, and metabolic-regulating properties. Notably, the culture residue of C. militaris, which remains rich in bioactive compounds, is mostly discarded during production, resulting in resource waste and potential environmental pollution. In this study, C. militaris culture residue extract (CME) was prepared by ultrasonic extraction, and its antiviral activity was evaluated using Nicotiana benthamiana via foliar spraying. The results showed that CME treatment significantly upregulated the expression of defense-related genes PR1, PR2, and ICS1, with PR1 showing the most pronounced induction (13.20-fold before and 11.89-fold after TMV inoculation), thereby conferring strong antiviral activity. In addition, root irrigation with 10 mg/mL CME significantly increased plant height, stem diameter, dry weight, fresh weight, chlorophyll content, and carotenoid content in tomato plants. Taken together, these findings indicate that CME functions as a plant immune inducer capable of effectively suppressing tobacco viral diseases while promoting plant growth. This study not only provides a new strategy for the value-added reutilization of C. militaris culture residues but also offers a scientific basis for the green control of tobacco mosaic disease. Full article

Cordycepin is a key active component of Cordyceps militaris, but the molecular mechanism underlying temperature-regulated biosynthesis remains unclear. In this study, Cordyceps militaris strain KN-1 was used as experimental material, with low-temperature (15 °C), control (20 °C), and high-temperature (25 °C) treatments applied during the fruiting body stage. Transcriptomics, untargeted metabolomics, weighted gene co-expression network analysis (WGCNA), and Reverse Transcription quantitative PCR (RT-qPCR) validation were integrated to elucidate the molecular mechanism of temperature-mediated cordycepin biosynthesis. The results showed that 25 °C increased fruiting body cordycepin content by 84%, while 15 °C reduced it. Transcriptomic analysis identified differentially expressed genes (DEGs) enriched in transmembrane transport and fatty acid metabolism, and untargeted metabolomics revealed differential metabolites (DAMs) enriched in lipids and organic acids, indicating that temperature primarily affects Cordyceps militaris membrane function. WGCNA showed that the MEblue module was positively correlated with cordycepin (r = 0.93), with Major Facilitator Superfamily (MFS) members accounting for the highest proportion (47.1%) that may affect cordycepin transmembrane transport. Multi-omics analysis indicated that high temperature promotes cordycepin accumulation through the synergistic regulation of multiple pathways: upregulating genes in the pentose phosphate pathway, purine metabolism, and cordycepin biosynthetic gene cluster (Cns1–Cns3), increasing protective agent pentostatin content, downregulating cordycepin-degrading genes, and enhancing cordycepin transmembrane transport. This study clarifies the molecular mechanism of temperature-mediated cordycepin accumulation, providing a theoretical basis for improving cordycepin production via temperature regulation, optimizing Cordyceps militaris strain quality, and facilitating efficient industrial production. Full article

The genus Isaria is a group of abundant and widely distributed entomopathogenic fungi that plays an important role in the history of traditional Chinese medicine. Entomopathogenic fungi with medicinal value were collected from the field, and optimal temperature and growth media compositions were investigated to establish a theoretical foundation for the future development of these strains. A strain of Isaria cateniobliqua, designated ICF, was isolated from soil in the Hualongshan National Nature Reserve in southern Shaanxi. The optimal cultivation temperature and nutrient solution were screened, and the effects of subcultivation on mycelium production, metabolite production, and hydroxyl radical scavenging activity of strain ICF were investigated. The optimal growth temperature for strain ICF was determined to be 21 °C, with the ideal culture medium consisting of glucose and tussah silkworm pupa powder supplemented with KH₂PO₄ and MgSO₄. Mycelium production and cordycepin content peaked in the fourth generation (G4), whereas peak metabolite production and cordycepic acid production occurred in the fifth generation (G5). Polysaccharide content was highest in the first generation (G1), and hydroxyl radical scavenging activity was optimal in G4. Exploring the optimal culture conditions of the strain provides a theoretical basis for its development, utilization, and industrial production for medicinal applications. Full article

Activation of hepatic stellate cells (HSCs) featuring upregulated expression of α-smooth muscle actin (α-SMA) is recognized as a key driver for hepatic fibrosis, which provides a promising strategy for seeking anti-liver fibrogenic agents via suppressing the activation event. In this study, we designed and synthesized twenty-eight cordycepin derivatives through structural modifications at the C2 position and the C6-NH₂ group of the purine moiety. These compounds were screened for their inhibitory effects on HSC activation by detecting the mRNA expression of α-SMA using quantitative real-time polymerase chain reaction (qPCR) in the LX-2 cell model. Most compounds displayed inhibitory activity comparable to cordycepin, with compound 3a bearing a C2-chloro and a N6-methyl-N6-(2-chlorobenzyl) substituent, demonstrating enhanced in vitro anti-fibrotic effect. This compound was able to dose-dependently downregulate α-SMA and collagen-I at both mRNA and protein levels, inhibited LX-2 cell migration, and exhibited improved metabolic stability in liver microsomes. The Western blotting result also indicated that 3a could activate the AMPK signaling pathway. Overall, these results suggest 3a may serve as a lead compound for further investigation. Full article

Cordycepin (3′-deoxyadenosine, 3′-dA), the flagship nucleoside antibiotic from Cordyceps militaris, exerts potent anti-inflammatory, antimicrobial, and antitumor activity but is rapidly inactivated by human adenosine deaminase (ADA). While prodrugs, ADA inhibitors, and nanocarriers have been pursued to prolong its half-life, the influence of solid form on delivery performance remains unexplored. Here, three polymorphs—anhydrate-I (flake-like), anhydrate-II (rod-like), and a previously unreported monohydrate (fibrillar)—were prepared, characterized (PXRD, TG-DSC, FTIR), and subjected to equilibrium solubility, slurry-conversion, and humidity-sorption mapping. The monohydrate dehydrates at 144 °C and sequentially transforms to anhydrate-I → anhydrate-II (ΔH = −127.5 J g⁻¹), establishing a monotropic relationship between the two anhydrous forms. Solubility displays a bell-shaped profile versus water activity: the monohydrate is stable above aw 0.8, whereas anhydrate-II predominates below aw 0.2. In model immediate-release tablets, anhydrate-II achieves complete dissolution within 10 min, whereas the monohydrate sustains release for 30 min. Hygroscopicity tests show the monohydrate absorbs <6% water up to 75% RH without structural change, whereas anhydrate-I converts to the monohydrate above 63% RH. The quantitative humidity–crystal form–performance correlations provide a rational platform for crystal form selection and the design of stable, efficacious cordycepin solid dosage forms. Full article

Cordyceps militaris (C. militaris) is a medicinal fungus renowned for its diverse therapeutic properties, largely attributed to bioactive compounds such as cordycepin, polysaccharides, adenosine, D-mannitol, carotenoids, and ergosterol. However, the production and composition of these metabolites are highly influenced by cultivation conditions, highlighting the need for systematic optimization strategies. This review synthesizes current findings on how nutritional factors—including carbon and nitrogen sources, their ratios, and trace elements—and environmental parameters such as oxygen availability, pH, temperature, and light regulate C. militaris metabolite biosynthesis. The impacts of solid-state fermentation (using grains, insects, and agro-industrial residues) and liquid state fermentation (submerged and surface cultures) are compared, with attention to their roles in mycelial growth, fruiting body formation, and secondary metabolite production. Special emphasis is placed on mixed grain–insect substrates and light regulation, which have emerged as promising methods to enhance cordycepin accumulation. Beyond summarizing advances, this review also identifies key knowledge gaps that must be addressed: (i) the incomplete understanding of metabolite regulatory networks, (ii) the absence of standardized cultivation protocols, and (iii) unresolved challenges in scale-up, including oxygen transfer, foam control, and downstream processing. We propose that future research should integrate multi-omics approaches with bioprocess engineering to overcome these limitations. Collectively, this review highlights both current progress and remaining challenges, providing a roadmap for advancing the sustainable, scalable, and application-driven production of bioactive compounds from C. militaris. Full article