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The interaction between human serum albumin (HSA) and hispidin, a polyketide abundantly present in both edible and therapeutic mushrooms, was explored through multispectral methods, hydrophobic probe assays, location competition trials, and molecular docking simulations. The results of fluorescence quenching analysis showed that hispidin quenched the fluorescence of HSA by binding to it via a static mechanism. The binding of hispidin and HSA was validated further by synchronous fluorescence, three-dimensional fluorescence, and UV/vis spectroscopy analysis. The apparent binding constant (Ka) at different temperatures, the binding site number (n), the quenching constants (Ksv), the dimolecular quenching rate constants (Kq), and the thermodynamic parameters (∆G, ∆H, and ∆S) were calculated. Among these parameters, ∆H and ∆S were determined to be 98.75 kJ/mol and 426.29 J/(mol·K), respectively, both exhibiting positive values. This observation suggested a predominant contribution of hydrophobic forces in the interaction between hispidin and HSA. By employing detergents (SDS and urea) and hydrophobic probes (ANS), it became feasible to quantify alterations in Ka and surface hydrophobicity, respectively. These measurements confirmed the pivotal role of hydrophobic forces in steering the interaction between hispidin and HSA. Site competition experiments showed that there was an interaction between hispidin and HSA molecules at site I, which situates the IIA domains of HSA, which was further confirmed by the molecular docking simulation.

Androgen deprivation therapy (ADT) is the primary treatment for advanced prostate cancer (PCa). However, prolonged ADT inevitably results in therapy resistance with the emergence of the castration-resistant PCa phenotype (CRPC). Hence, there is an urgent need to explore new treatment options capable of delaying PCa progression. Hispidin (HPD) is a natural polyketide primarily derived from plants and fungi. HPD has been shown to have a diverse pharmacological profile, exhibiting anti-inflammatory, antiviral, cardiovascular and neuro-protective activities. However, there is currently no research regarding its properties in the context of PCa treatment. This research article seeks to evaluate the anti-cancer effect of HPD and determine the underlying molecular basis in both androgen-sensitive PCa and CRPC cells. Cell growth, migration, and invasion assays were performed via the MTS method, a wound healing assay and the transwell method. To investigate if HPD affected the expression of proteins, Western blot analysis was conducted. Furthermore, apoptosis was assessed by Annexin V-FITC/PI staining and Western blot analyses. HPD exhibited a favorable pharmaceutical profile to inhibit cell growth; disrupt the cell cycle; attenuate wound healing, migration and invasion; and induce apoptosis in PCa cells in vitro. The mechanistic results demonstrated that HPD reduced AR, MMP-2 and MMP-9 expression and activated the caspase-related pathway, leading to programmed cell death in PCa cells. We showed the anti-cancer effect of HPD on PCa cells and confirmed its feasibility as a novel therapeutic agent. This study provides significant insights into the delineation of the molecular mechanism of HPD in PCa cells and the development of an effective and safe therapy using HPD to eliminate PCa progression.

Hispidin is a polyketide found in plants and fungi. In bioluminescent fungi, hispidin serves as a precursor of luciferin and is produced by hispidin synthases. Previous studies revealed that hispidin synthases differ in orthologous polyketide synthases from non-bioluminescent fungi by the absence of two domains with predicted ketoreductase and dehydratase activities. Here, we investigated the hypothesis that the loss of these domains in evolution led to the production of hispidin and the emergence of bioluminescence. We cloned three orthologous polyketide synthases from non-bioluminescent fungi, as well as their truncated variants, and assessed their ability to produce hispidin in a bioluminescence assay in yeast. Interestingly, expression of the full-length enzyme hsPKS resulted in dim luminescence, indicating that small amounts of hispidin are likely being produced as side products of the main reaction. Deletion of the ketoreductase and dehydratase domains resulted in no luminescence. Thus, domain truncation by itself does not appear to be a sufficient step for the emergence of efficient hispidin synthases from orthologous polyketide synthases. At the same time, the production of small amounts of hispidin or related compounds by full-length enzymes suggests that ancestral fungal species were well-positioned for the evolution of bioluminescence.

Degenerative diseases of the brain include Parkinson’s disease (PD), which is associated with moveable signs and is still incurable. Hispidin belongs to polyphenol and originates primarily from the medicinal fungi Inonotus and Phellinus, with distinct biological effects. In the study, MES23.5 cells were induced by 1-methyl-4-phenylpyridinium (MPP+) to build a cell model of PD in order to detect the protective effect of hispdin and to specify the underlying mechanism. Pretreatment of MES23.5 cells with 1 h of hispdin at appropriate concentrations, followed by incubation of 24 h with 2 μmol/L MPP+ to induce cell damage. MPP+ resulted in reactive oxygen species production that diminished cell viability and dopamine content. Mitochondrial dysfunction in MS23.5 cells exposed to MPP+ was observed, indicated by inhibition of activity in the mitochondrial respiratory chain complex I, the collapse of potential in mitochondrial transmembrane, and the liberation of mitochondrial cytochrome c. Enabling C-Jun N-terminal kinase (JNK), reducing Bcl-2/Bax, and enhancing caspase-9/caspase-3/PARP cleavage were also seen by MPP+ induction associated with increased DNA fragmentation. All of the events mentioned above associated with MPP+-mediated mitochondrial-dependent caspases cascades were attenuated under cells pretreatment with hispidin (20 µmol/L); similar results were obtained during cell pretreatment with pan-JNK inhibitor JNK-IN-8 (1 µmol/L) or JNK3 inhibitor SR3576 (25 µmol/L). The findings show that hispidin has neuroprotection against MPP+-induced mitochondrial dysfunction and cellular apoptosis and suggest that hispidin can be seen as an assist in preventing PD.

Natural products extracted from plants can be potent for developing pharmaceutical products. Hispidin, a polyphenolic compound mainly derived from the medicinal mushroom Phellinus linteus, has been shown to have a therapeutic potential against cancer cells. Pancreatic cancer is one of the most aggressive solid malignancies with high resistance to existing drugs. Cancer stem cells (CSCs) are responsible for chemoresistance. The present study aimed to evaluate the anticancer effects of hispidin on pancreatic CSCs. The cytotoxic effects of hispidin on BxPC-3 and AsPC-1 pancreatic cancer cells and BxPC-3 CD44 CSCs and the synergistic effects of gemcitabine and hispidin on CSCs were evaluated by a series of in vitro experiments including the 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT), fluorescence-activated cell sorting, colony forming, Transwell assay, immunocytochemistry, sphere-forming, and western blot assays. Hispidin exerted antitumor effects against both BxPC-3 pancreatic cancer cells and CSCs. Furthermore, it was found that hispidin sensitized pancreatic CSCs to gemcitabine and promoted the therapeutic efficacy of gemcitabine. Hispidin might be a novel chemosensitizer for gemcitabine and a potential synergistic agent for increasing the therapeutic index of gemcitabine as a treatment for pancreatic cancer.

Background Hispidin (HIP) and its derivatives, a class of natural fungal metabolites, possess complex chemical structures with extensive pharmacological activities. Phellinus igniarius , the most common source of HIP, can be used as both medicine and food. However, the biosynthetic pathway of HIP in P. igniarius remains unclear and we have a limited understanding of the regulatory mechanisms related to HIP. In this work, we sought to illustrate a biosynthesis system for hispidin and its derivatives at the protein level. Results We found that tricetolatone (TL) is a key biosynthetic precursor in the biosynthetic pathway of hispidin and that its addition led to increased production of hispidin and various hispidin derivatives. Based on the changes in the concentrations of precursors and intermediates, key timepoints in the biosynthetic process were identified. We used isobaric tags for relative and absolute quantification (iTRAQ) to study dynamic changes of related proteins in vitro. The 270 differentially expressed proteins were determined by GO enrichment analysis to be primarily related to energy metabolism, oxidative phosphorylation, and environmental stress responses after TL supplementation. The differentially expressed proteins were related to ATP synthase, NAD binding protein, oxidoreductase, and other elements associated with electron transfer and dehydrogenation reactions during the biosynthesis of hispidin and its derivatives. Multiple reaction monitoring (MRM) technology was used to selectively verify the iTRAQ results, leading us to screen 11 proteins that were predicted to be related to the biosynthesis pathways. Conclution These findings help to clarify the molecular mechanism of biosynthesis of hispidin and its derivatives and may serve as a foundation for future strategies to identify new hispidin derivatives.

Background: Hispidin, a polyphenol component mainly derived from the medicinal mushroom species Phellinus and Inonotus, shows promise for biomedical applications, yet its potential in wound healing remains largely unexplored. This research investigates the wound healing effects of hispidin through in vitro and in vivo experiments, while also evaluating its antimicrobial properties and safety profile. Methods: In vitro scratch assays were conducted to evaluate the impact of hispidin on the migration of NIH-3T3 cells. The wound healing potential of hispidin was assessed in rats using excision wounds, dead space wounds, and linear incisions, treated with various topical ointments including a simple ointment, 2.5% (w/w) and a 5% (w/w) hispidin ointment, and a 0.2% (w/w) nitrofurazone ointment, administered at 0.2 g daily for 14 days. Results: Hispidin demonstrated antimicrobial properties and was particularly effective against Staphylococcus epidermidis. Hispidin enhanced NIH-3T3 cell viability, and promoted wound closure in scratch assays, correlating with increased levels of FGF21, TGF-β1, EGF, and VEGF. In excision wound models, the 5% (w/w) hispidin ointment improved wound contraction, epithelialization, tissue regeneration, fibroblast activity, and angiogenesis. In the granulation tissue from dead space wound models, hispidin reduced pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) and lipid peroxidation, while increasing anti-inflammatory cytokines (IL-10) and antioxidant activities (SOD, GPx, CAT), along with connective tissue markers like hydroxyproline, hexosamine, and hexuronic acid. Hispidin also enhanced wound breaking strength in incision models. Acute dermal toxicity studies indicated no adverse effects at 2000 mg/kg. Conclusions: These findings highlight hispidin’s potential in wound care, demonstrating its antimicrobial, regenerative, and safety properties.

Hispidin (1) is a polyphenolic compound with a wide range of pharmacological activities that is distributed in both plants and fungi. In addition to natural extraction, hispidin can be obtained by chemical or enzymatic synthesis. In this study, the identification and characterization of an undescribed enzyme, PheG, from Phellinus igniarius (P. igniarius), which catalyzes the construction of a key C─C bond in the enzymatic synthesis of hispidin are reported. It is demonstrated in vitro that PheG generates hispidin by catalyzing C─C bond formation in the aldol condensation reaction. Based on these results, a plausible pathway for hispidin biosynthesis is proposed by utilizing the primary triacetic acid lactone (TAL, 2) and 3,4‐dihydroxybenzaldehyde (3). The mechanisms for the aldol condensation reaction of PheG are investigated using molecular dynamics (MD) simulations, molecular mechanics/generalized Born surface area (MM/GBSA) binding free energy calculations, density functional theory, and site‐specific mutations. The locations of the key amino acid residues that catalyze the conversion of substrates 2 and 3 to hispidin at the active site of PheG‐1 are identified. This study provides a new method for preparing hispidin with high efficiency and low cost. Hispidin is a polyphenolic compound with a variety of biological activities. Herein, a new aldol condensase PheG from Phellinus igniarius (P. igniarius) can catalyze tricetolatone and 3, 4‐dihydroxybenzaldehyde to hispidin. The catalytic mechanism of nucleophilic addition of PheG is determined by MM/GBSA, density functional theory calculation, and site‐directed mutation.

Hispidin oligomers are styrylpyrone pigments isolated from the medicinal fungi Inonotus xeranticus and Phellinus linteus. They exhibit diverse biological activities and strong free radical scavenging activity. To rationalize the antioxidant activity of a series of four hispidin oligomers and determine the favored mechanism involved in free radical scavenging, DFT calculations were carried out at the B3P86/6-31+G (d, p) level of theory in gas and solvent. The results showed that bond dissociation enthalpies of OH groups of hispidin oligomers (ArOH) and spin density delocalization of related radicals (ArO•) are the appropriate parameters to clarify the differences between the observed antioxidant activities for the four oligomers. The effect of the number of hydroxyl groups and presence of a catechol moiety conjugated to a double bond on the antioxidant activity were determined. Thermodynamic and kinetic studies showed that the PC-ET mechanism is the main mechanism involved in free radical scavenging. The spin density distribution over phenoxyl radicals allows a better understanding of the hispidin oligomers formation.

There is a large number of bioactive polyketides well-known for their anticancer, antibiotic, cholesterol-lowering, and other therapeutic functions, and hispidin is among them. It is a highly abundant secondary plant and fungal metabolite, which is investigated in research devoted to cancer, metabolic syndrome, cardiovascular, neurodegenerative, and viral diseases. This review summarizes over 20 years of hispidin studies of its antioxidant, anti-inflammatory, anti-apoptotic, antiviral, and anti-cancer cell activity.