Icaritin (ICA) is a prenylflavonoid natural product extracted from plants of the Epimedium genus. The approval of ICA softgel capsules as a class 1.2 traditional Chinese medicine (TCM) innovative drug represents a major advancement offering a novel therapeutic approach for patients with advanced hepatocellular carcinoma (HCC). Class 1.2 TCM innovative drugs generally denote extracts and formulations derived from single plants, animals, minerals, or other substances. ICA exhibits diverse pharmacological effects, encompassing anti-inflammatory, immune-regulatory, anti-oxidation, anti-osteoporosis, anti-depression, and notably anti-cancer properties. This review presents a comprehensive overview of the molecular mechanisms underlying the anti-cancer properties of ICA, and further highlights recent progress in use of ICA in cancer research, discusses present challenges, and examines potential opportunities for ICA application and further development.
The concept of food and medicine homology (FMH) is deeply embedded in traditional Chinese medicine and carries historical importance. The recent rigorous definition of FMH pertains to substances that exhibit both pharmacological and nutritional functions, and have active ingredients that are fundamentally non-toxic and appropriate for extended consumption. With the progression of modern biotechnology, the application of this concept in treating diseases has markedly expanded, and its intrinsic mechanisms have been examined in detail. The use of FMH substances in cancer therapy, as either a primary treatment or an adjuvant therapy, has paved the way to low-toxicity cancer treatments. This commentary examines the theoretical underpinnings, potential advantages, and practical applications of FMH substances in cancer prevention, treatment, and nutritional support enhancement. Advantages including low toxicity, long-term edibility, minimal adverse effects, and high patient compliance are discussed. Moreover, owing to its multicomponent and multitarget characteristics, FMH may provide novel opportunities for cancer therapy. Given the high lethality of cancer and associated ethical implications, current research should prioritize fundamental studies investigating potential FMH applications in cancer therapy. Concurrently, preliminary preclinical studies would be appropriate to establish a solid foundation for subsequent clinical trials.
Excessive consumption of acetaminophen (APAP) has emerged as the primary culprit behind drug-induced liver injury (DILI), with N-acetylcysteine serving as the principal antidote. However, use of N-acetylcysteine is limited to the early stages of APAP-induced DILI and may cause adverse side effects. Consequently, it is imperative to explore alternative therapeutic approaches to alleviate APAP-induced liver toxicity. In this study the mechanisms underlying the protective role of epigallocatechin gallate (EGCG) in DILI were determined. Our findings revealed that EGCG inhibited NEDD8, thus stabilizing HUWE1, a crucial E3 ubiquitin ligase involved in protein degradation. HUWE1 binds and degrades TFR1, a protein essential for cellular iron uptake and inhibits ferroptosis. By stabilizing HUWE1 and degrading TFR1, EGCG suppressed ferroptosis and ameliorated APAP-induced liver injury. Our results highlight the therapeutic potential of EGCG in mitigating DILI through regulation of HUWE1 and ferroptosis, which offers a promising approach for the treatment of DILI.
The prevalence of depressive-like behavior is significantly higher in patients with cholestatic liver disease, leading to a notable reduction in the quality of life. This situation underscores the urgent need to investigate the mechanisms underlying the association between cholestasis and clinical depression. This review provides a comprehensive examination of how neuroendocrine disorders resulting from cholestasis influence the onset of depression through both direct and indirect mechanisms. First, how the accumulation of bile acids in the central nervous system (CNS) during cholestasis leads to damage to the blood-brain barrier, neuroinflammation, and neurodegeneration is discussed, highlighting the key roles of bile acid receptors, such as FXR and TGR5, in this process. Additionally, the gut-brain axis has been shown to be involved in the development of brain diseases in a variety of ways. Therefore, the indirect indirect effects of bile acids via the gut-brain axis, which affect the composition of the gut microbiota, the integrity of the gut barrier, and the secretion of gut hormones are summarized, thereby regulating the development of depression. However, whether bile acids can directly enter the CNS and which targets are targetable within the gut-brain axis remain pivotal questions. Addressing these issues will open new avenues for developing more effective therapeutic strategies aimed at alleviating depressive symptoms experienced by patients with cholestasis.
Treatment of cancer can be challenging, because of the disease’s intricate and varied nature. Consequently, developing nanomedicines with multimodal therapeutic capabilities for precise tumor therapy holds substantial promise in advancing cancer treatment. Herein, a nanoplatform strategy involving supramolecular photosensitizers (ETSCe6 NPs) and chelated metal ions (Au and Bi) was found to induce a shift in tumor microenvironment responsiveness from photothermal therapy to photodynamic therapy, thus facilitating tumor visualization for precise diagnosis and treatment. Self-assembly of supramolecular photosensitizers enhanced photothermal therapy through aggregation-caused quenching. Moreover, glutathione triggered disulfide bond cleavage, and consequently Ergosterol (ET) and Chlorin e6 release. Therefore, chemotherapy and photodynamic therapy achieved synergistic anticancer effects. Ce6 cavities were also used to chelate high valence Au and Bi metal ions for computed tomography. The ETSCe6@Au, Bi NPs demonstrated remarkable efficacy in vitro and in vivo, achieving complete tumor elimination after treatment. This integrated approach combining imaging, chemotherapy, photodynamic, and photothermal therapies has substantial promise for clinical applications, and may provide an innovative strategy for developing intelligent nanomedicines with promising prospects.
We assessed Cordyceps sinensis mycelium culture extract (Cs4) for alleviating long COVID symptoms. In this randomized trial 110 participants were assigned to receive Cs4 (55 participants) or were waitlisted (55 participants) for 12 weeks. The primary outcome was the change in long COVID symptom severity at 12 weeks, as measured by the modified COVID-19 Yorkshire Rehabilitation Scale. The secondary outcomes included changes in the Brief Fatigue Inventory Form, Insomnia Severity Index, Hospital Anxiety and Depression Scale, St. George’s Respiratory Questionnaire, and the Short Form 12 health survey at 12 weeks. Participants receiving Cs4 showed improvement in long COVID symptoms compared to the waitlist control group (MD, −10.1; 95% CI, −14.1 to −6.1; P < 0.001) at 12 weeks. Cs4 recipients also experienced improvement in fatigue (MD, −8.1; 95% CI, −14.2 to −2.0; P = 0.011), insomnia (MD, −2.9; 95% CI, −4.6 to −1.2; P = 0.001), and respiratory symptoms (MD, −6.3; 95% CI, −11.4 to −1.2; P = 0.018). Cs4 also improved the quality of life (physical component MD, 7.0; 95% CI, 4.2–9.8; P < 0.001; mental component MD, 6.8; 95% CI, 2.9–10.7; P < 0.001). No severe adverse events were reported. Cs4 may be a beneficial treatment for patients with long COVID symptoms.
Monoamine oxidase (MAO) is a useful target in the treatment of neurodegenerative diseases and depressive disorders. Understanding the structure-activity relationship (SAR) and mechanisms underlying MAO inhibitors is crucial but challenging. The coumarin scaffold has been shown to be ideal for MAO inhibitors, yet the SAR for MAO inhibition and selectivity based on coumarin remains unclear. In this study a fluorescence-based high throughput screening method was developed using a MAO fluorescent substrate (MR2). Subsequently, three series of coumarin derivatives, including esculetin, daphnetin and 3-substituted coumarin, were synthesized and the inhibitory effects on MAO were assayed. The SAR study revealed that phenyl substitution had a unique effect on MAO inhibitory activity and selectivity. Specifically, 3-phenyl substitution in coumarin derivatives significantly enhanced MAO-B inhibition and increased selectivity for MAO-A, while 4-phenyl substitution is more effective for MAO-A inhibition. Discovery studios were also utilized to investigate the structural requirements for the effective inhibition of MAO by coumarins. Furthermore, the mechanisms underlying inhibition for five phenyl coumarin derivatives were elucidated through enzymatic kinetics analysis and molecular docking simulations. These findings provide new insights into the interactions between coumarins and MAOs and significantly contribute to the development of coumarin-based MAO inhibitors.
Phagocytosis is a fundamental mechanism used by the body to resist pathogens and restore physiological homeostasis. Herein, to identify small molecules with anti-inflammatory properties via phagocytosis inhibition, we constructed a library of natural products and evaluated their ability to modulate phagocytosis in RAW264.7 macrophages. Berberine (BBR) is the major constituent of traditional Chinese medicine Coptidis Rhizoma that is recorded in Chinese Pharmacopoeia with the effect of clearing heat-toxin, and is used in the therapeutic management of various inflammatory diseases. BBR was found to inhibit phagocytosis and significantly alleviate inflammation via suppressing interleukin-1α (IL-1α), interleukin-1β (IL-1β), inducible nitric oxide synthase (iNOS), and tumor necrosis factor-α (TNF-α), according to real-time quantitative polymerase chain reaction (RT-qPCR) analyses, and phosphorylated-p65 (p-p65), iNOS, and cyclooxygenase-2 (COX-2), according to western blot analyses. BBR inhibited the expression of F-actin, a key protein in phagosome formation. Notably, BBR exerted its phagocytosis effects through targeting phosphoinositide 3-kinase (PI3K), thereby activating the small GTPase-Cdc42 (CDC42), Wiskott-Aldrich syndrome protein (WASP), and actin-related protein 2/3 complex subunit 2 (Arp2/3). BBR attenuated LPS-mediated inflammation through promoting macrophage phagocytosis. We determined that BBR targets the toll-like receptor 4 (TLR4)-PI3K-CDC42 pathway, thereby inhibiting the nuclear factor-kappa B (NF-κB) pathway, and consequently regulating phagocytosis and the inflammatory response. Our findings suggest that BBR might serve as a candidate for the development of phagocytic inhibitors.
Phosphodiesterase-4 (PDE4), a member of the phosphodiesterase superfamily, has highly important roles in cyclic nucleotide signaling pathways and a variety of skin disorders. Blocking PDE4 activity with PDE4 inhibitors increases intracellular cAMP levels and effectively relieves the skin inflammatory phenotype of psoriasis. However, traditional PDE4 inhibitors may cause adverse effects such as gastrointestinal reactions. Natural products typically exhibit safety profiles and structural novelty, which are particularly advantageous for drug discovery. LW, a derivative of the natural product Moracin M, was found to have favorable PDE4 inhibitory activity (PDE4 IC50 = 54 nM). Examination of LW in psoriasis treatment demonstrated good anti-inflammatory effects in cellular models. In an imiquimod-induced mouse model, LW treatment markedly improved psoriatic symptoms, as evidenced by increased PASI scores and ameliorated skin pathology. Moreover, LW significantly downregulated Inflammatory factors in the serum and alleviated spleen damage. Therefore, LW has substantial therapeutic potential, through effectively decreasing inflammatory factor levels and ameliorating psoriatic skin phenotypes. Our findings support LW as a potential candidate compound for developing new psoriasis treatments.
Kawasaki disease (KD) is a form of vasculitis that affects primarily children and can lead to severe cardiovascular complications. Because current treatment options are often ineffective for some patients, new therapeutic strategies are needed. Cryptotanshinone (CTS), a compound derived from Salvia miltiorrhiza Bunge, has shown potential as an anti-inflammatory agent. Herein, in a mouse model of KD induced by Lactobacillus casei cell wall extract (LCWE), CTS was found to significantly decrease inflammation in the aortic root and coronary arteries. This treatment inhibited the activation of macrophages and neutrophils, which are critical contributors to KD. Network pharmacology analysis suggested that CTS modulates the chemokine signaling pathway, thereby inhibiting the recruitment of inflammatory cells and preventing further vasculitis progression. Single-nucleus RNA sequencing (snRNA-seq) revealed that CTS decreased macrophage numbers and chemokine activity, particularly that of Ccl8, and consequently neutrophil recruitment. Our findings suggest that CTS might provide a promising therapeutic option for KD by modulating immune cell interactions and inflammation.