Search Results (29)

Oral lichen planus (OLP) is a chronic, T cell-mediated inflammatory disorder classified by the World Health Organization as an oral potentially malignant disorder (OPMD). Despite decades of research, its precise etiology remains incompletely understood and involves a complex interplay between genetic predisposition, environmental triggers, and autoimmune-like responses. This review provides a comprehensive update on OLP pathogenesis, emphasizing the role of CD8 positive cytotoxic T lymphocyte-driven basal keratinocyte apoptosis and the skewing of the T-cell receptor (TCR) repertoire. We highlight the significance of the epidermal growth factor receptor (EGFR) signaling pathway as a molecular bridge between chronic inflammation and epithelial proliferation. Furthermore, we discuss a stepwise therapeutic approach that prioritizes the management of the oral microenvironment—specifically Candida colonization and periodontal health—before escalating to immunosuppressive agents. Finally, we explore emerging precision medicine frontiers, including IL-17/IL-23 inhibitors and JAK inhibitors, alongside traditional Japanese Kampo medicine (Hange-shashin-to) and systemic adjuncts like Cepharanthine, offering a contemporary perspective on modern OLP management. This integrative framework redefines OLP not merely as a chronic inflammatory disorder, but as an immunologically sustained, microenvironment-driven, potentially malignant condition. Full article

Severe respiratory inflammation or viral infections can lead to acute lung injury (ALI), a disease characterized by diffuse inflammatory injury of the pulmonary epithelium and endothelium. Cepharanthine (CEP) is reported as a promising drug candidate due to its antiviral properties. However, CEP exhibits poor solubility and low bioavailability. Therefore, we developed a novel liposome, named CEP@LP-M^CCR2, which integrates the advantages of cell membranes and lipid materials, to achieve effective accumulation of CEP in inflamed lungs. It exhibits a 1.73-fold increase in lung accumulation at 24 h in vivo, a 4.56-fold increase in cellular uptake in MLE-12 cells. CEP@LP-M^CCR2 is equipped with a CCR2-overexpressed surface, enabling it to selectively neutralize elevated levels of CCL2, which is related to ALI, thereby reducing macrophage infiltration, thereby reducing the spread of inflammation, such as a reduction in levels of key pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6). CEP@LP-M^CCR2 could suppress M1 macrophage polarization, which led to a marked decrease in iNOS and an increase in Arg1. It upregulated the expression of junctional proteins E-cadherin and Occludin, indicating potential recovery of the pulmonary epithelial barrier. RNA sequencing analysis implied the potential of CEP@LP-M^CCR2 to inactivate the TNF/NF-κB signaling axis. Full article

Equine herpesvirus (EHV) infections represent a significant global veterinary and economic challenge affecting both horses and donkeys across all inhabited continents. This narrative review comprehensively examines the nine distinct EHV species (EHV-1 through EHV-9), their taxonomic classification within Alphaherpesvirinae and Gammaherpesvirinae subfamilies, and their diverse host tropism patterns. The complex molecular pathogenesis involves sophisticated viral glycoproteins (gK, gB, gC, gH, gM, gL, gG, gD, gI, gE) that orchestrate cellular invasion, immune evasion, and intercellular transmission. Clinical manifestations vary considerably, ranging from respiratory diseases and reproductive failures to severe neurological disorders, with EHV-1 demonstrating the most severe presentations including myeloencephalopathy. Global distribution analysis reveals widespread circulation across Europe, Asia, Africa, the Americas, and Oceania, with species-specific clinical patterns. Current therapeutic options remain largely supportive, with experimental compounds like berbamine and cepharanthine, celastrol, blebbistatin, and hyperoside showing promise in preclinical studies. Vaccination programs demonstrate limited effectiveness, failing to prevent transmission at population levels despite inducing individual immune responses. The sophisticated immune evasion strategies employed by EHVs, including the “Trojan horse” mechanism utilizing infected leukocytes, highlight the complexity of host–pathogen interactions and underscore the urgent need for innovative prevention and treatment strategies. Full article

Cervical cancer ranks as a primary contributor to cancer-related deaths in women globally and is the fourth most prevalent malignant neoplasm. Cepharanthine, a naturally occurring biscoclaurine alkaloid extracted from Stephania cepharantha, has demonstrated anticancer and antimetastatic efficacy across multiple cancer types. However, its mechanism of action in cervical cancer remains unexplored. Our results demonstrated that cepharanthine effectively suppressed the proliferation and motility of the CaSki, HeLa, and C33A cell lines. Furthermore, cepharanthine triggered apoptosis through Bcl-2 suppression and increased cleaved-PARP-1, Bax, and cleaved-caspase-3 expression and AMPK/p53 phosphorylation, while inducing G0/G1 phase arrest in CaSki cells and sub-G1 phase arrest in HeLa and C33A cells. Additionally, cepharanthine reduced the mitochondrial membrane potential (∆ψm), compromised mitochondrial functionality, and increased reactive oxygen species (ROS) accumulation, promoting oxidative stress via the modulation of the Nrf2/Keap1 pathway in CaSki, HeLa, and C33A cells, which exhibit an anti-cervical cancer effect. Similarly, cepharanthine markedly reduced tumor progression in C33A BALB/c nude mice, which aligns with the in vitro observations. Collectively, these findings indicate that cepharanthine has potential therapeutic applications in the treatment of cervical cancer and warrants future clinical investigation. Full article

Major histocompatibility complex class I (MHC-I)-mediated antigen presentation plays a pivotal role in anti-tumor immunity by enabling CD8⁺ T cells to recognize and eliminate malignant cells. In melanoma, modulation of this pathway is critical for improving the efficacy of immunotherapies. Our study demonstrates that the natural compound Cepharanthine (CEP) exhibits notable antitumor activity by enhancing MHC-I-mediated antigen presentation. CEP treatment upregulated MHC-I expression (both membrane-bound and total levels) in melanoma cells in a concentration-dependent manner, thereby improving antigen-presenting capacity. Interestingly, when autophagy was pharmacologically blocked using Bafilomycin A1, co-treatment with CEP did not lead to further elevation of MHC-I expression, suggesting that CEP’s effect is mediated through disruption of the autophagic pathway. Mechanistically, CEP induced autophagosome accumulation, as evidenced by an increase in GFP-LC3 puncta. Fluorescence imaging further confirmed that CEP selectively impaired lysosomal acidification without affecting autophagosome–lysosome fusion, thereby inhibiting late-stage autophagic flux. Furthermore, CEP treatment promoted CD8⁺ T cell infiltration into tumor tissues and enhanced the antitumor efficacy of anti-PD-1 therapy, resulting in greater tumor suppression compared to either treatment alone. The study elucidates how CEP’s selective lysosomal inhibition creates a tumor microenvironment more susceptible to immune surveillance, primarily through preserved MHC-I surface expression and subsequent T cell recognition. This work highlights CEP as a promising immunomodulatory agent and provides a potential strategy for improving the outcomes of immune checkpoint blockade therapy. Full article

Nonspecific toxicity to normal and malignant cells restricts the clinical utility of many anticancer drugs. In particular, anemia in cancer patients develops due to drug-induced toxicity to red blood cells (RBCs). The anticancer alkaloid, cepharanthine (CEP), elicits distinct forms of cell death including apoptosis and autophagy, but its cytotoxicity to RBCs has not been investigated. Colorimetric and fluorometric techniques were used to assess eryptosis and hemolysis in control and CEP-treated RBCs. Cells were labeled with Fluo4/AM and annexin-V-FITC to measure Ca²⁺ and phosphatidylserine (PS) exposure, respectively. Forward scatter (FSC) was detected to estimate cell size, and extracellular hemoglobin along with lactate dehydrogenase and aspartate transaminase activities were assayed to quantify hemolysis. Physiological manipulation of the extracellular milieu and various signaling inhibitors were tested to dissect the underlying mechanisms of CEP-induced RBC death. CEP increased PS exposure and hemolysis indices and decreased FSC in a concentration-dependent manner with prominent membrane blebbing. Although no Ca²⁺ elevation was detected, chelation of intracellular Ca²⁺ by BAPTA-AM reduced hemolysis. Whereas SB203580, D4476, acetylsalicylic acid, necrosulfonamide, and melatonin inhibited both PS exposure and hemolysis, staurosporin, L-NAME, ascorbate, caffeine, adenine, and guanosine only prevented hemolysis. Interestingly, sucrose had a unique dual effect by exacerbating PS exposure and reversing hemolysis. Of note, blocking KCl efflux augmented PS exposure while aggravating hemolysis only under Ca²⁺-depleted conditions. CEP activates Ca²⁺-independent pathways to promote eryptosis and hemolysis. The complex cytotoxic profile of CEP can be mitigated by targeting the identified modulatory pathways to potentiate its anticancer efficacy. Full article

Cepharanthine (CEP) is a natural bisbenzylisoquinoline alkaloid known for its antibacterial, antiviral, and anti-inflammatory activities. Its antifungal effect, however, has not been well studied. In this work, we used machine learning-based virtual screening with Random Forest, Neural Network, and Support Vector Machine models to identify potential inhibitors of Fusarium solani. CEP was selected as a candidate and tested experimentally. The results showed that it inhibited the growth of Fusarium solani, Fusarium proliferatum, Fusarium oxysporum, Alternaria alternata, and Botrytis cinerea. It also reduced the sporulation and spore germination of Fusarium solani and disrupted its redox balance. Transcriptome analysis showed changes in gene expression related to basic metabolic pathways. Molecular docking suggested that CEP binds to the FsCFEM1 protein, and molecular dynamics simulations confirmed stable binding, with key roles for residues THR748 and LEU950. These results suggest that CEP is a potential bio-based antifungal agent and provide novel insights into its mechanism against Fusarium solani. Full article

Schistosomiasis is a parasitic disease caused by helminth parasites of the genus Schistosoma, affecting >200 million people worldwide. Current schistosomiasis treatment relies on a single drug, praziquantel, highlighting the urgent need for new therapies. We have identified a non-neuronal tegumental acetylcholinesterase from Schistosoma mansoni (SmTAChE) as a rational and molecularly defined drug target. Molecular modeling reveals significant structural differences between SmTAChE and human AChE, suggesting the potential for identifying parasite-specific inhibitors. Here, we screened recombinant SmTAChE (rSmTAChE) against two chemical libraries: the Broad Institute Drug Repurposing Hub (5440 compounds) and the Diversity-Oriented Synthesis (DOS)-A library (3840 compounds). High-throughput screening identified 116 hits from the Repurposing Hub (2.13% hit rate) and 44 from the DOS-A (1.14% hit rate) library that inhibited rSmTAChE ≥60% at 20 µM. Dose–response assays using both rSmTAChE and recombinant human AChE (rHsAChE) revealed 19 Repurposing Hub compounds (IC₅₀: 0.4–24 µM) and four DOS-A scaffolds (IC₅₀: 13–29 µM), with higher selectivity for rSmTAChE. Selective inhibitors such as cepharanthine, primaquine, mesalazine, and embelin emerged as promising candidates for further evaluation in schistosomiasis treatment. These 23 newly identified selective hits provide a foundation for the further development of novel anti-schistosome therapies. Full article

Background/Objectives: Stephania epigaea is a plant from the Menispermaceae family. Its root is an important traditional folk medicine, which is called Diburong in China. Diburong is rich in benzylisoquinoline alkaloids (BIAs), including cepharanthine, which has been demonstrated to exhibit significant anti-inflammatory, antiviral, antineoplastic, and anti-SARS-CoV-2 activities, as well as raising leukocytes. Cepharanthine is composed of (R)- and (S)-1-benzylisoquinoline alkaloid (1-BIA). (S)-norcoclaurine-6-O-methyltransferase (6OMT) is a rate-limiting enzyme in BIA biosynthesis. However, its role in the cepharanthine biosynthetic pathway, particularly with the (R) stereoisomer substrate, remains largely unexplored. This study aimed to identify Se6OMTs involved in the cepharanthine biosynthetic pathway and elucidate the O-methyltransferases (OMTs) responsible for the production of (R)- and (S)-stereoisomer BIAs. Methods: In this study, three OMTs were cloned from S. epigaea and functionally characterized using nine 1-BIAs of (R)- and (S)-configurations as substrates. Results: Two O-methyltransferases, Se6OMT1 and Se6OMT3, showed efficient catalytic activity at the C6 position of both (R)- and (S)-norcoclaurine. Furthermore, Se6OMT3 demonstrated high catalytic activity at the C7 and C4′ positions of other (R)- and (S)-configuration 1-BIAs, which resulted in the generation of multiple products. Conclusions: This study focused on 6OMT enzymes in S. epigaea, identifying Se6OMTs involved in the cepharanthine biosynthetic pathway, determining the OMTs involved in the production of (R)- and (S)-stereoisomer BIAs. This research provides valuable insights into the substrate promiscuity of Se6OMTs on (R)- and (S)-configured 1-BIAs in S. epigaea and highlights the genetic components necessary for the metabolic engineering and synthetic biology approaches to cepharanthine production. Full article

Equid herpesvirus type 8 (EqHV-8) is known to cause respiratory disease and miscarriage in horses and donkeys, which is a major problem for the equine farming industry. However, there are currently limited vaccines or drugs available to effectively treat EqHV-8 infection. Therefore, it is crucial to develop new antiviral approaches to prevent potential pandemics caused by EqHV-8. This study evaluates the antiviral and antioxidant effects of cepharanthine against EqHV-8 by employing both in vitro assays and in vivo mouse models to assess its therapeutic efficacy. To assess the effectiveness of cepharanthine against EqHV-8, we conducted experiments using NBL-6 and RK-13 cells. Additionally, we developed a mouse model to validate cepharanthine’s effectiveness against EqHV-8. In our in vitro experiments, we assessed the cepharanthine’s ability to inhibit infection caused by EqHV-8 in NBL-6 and RK-13 cells. Our results demonstrated that cepharanthine has a dose-dependent inhibitory effect, indicating that it possesses anti-EqHV-8 properties at the cellular level. Moreover, we investigated the mechanism through which cepharanthine exerts its protective effects. It was observed that cepharanthine effectively reduces the oxidative stress induced by EqHV-8 by activating the AMPK and Nrf2/HO-1 signaling pathways. Furthermore, when administered to EqHV-8 infected mice, cepharanthine significantly improved lung tissue pathology and reduced oxidative stress. The findings presented herein collectively highlight cepharanthine as a promising candidate for combating EqHV-8 infections. Full article

Cepharanthine (CEP), a biscoclaurine alkaloid extracted from Stephania cepharantha Hayata, has been widely used for the treatment of various acute and chronic diseases, including leukopenia, and snake bites. Here, our objective was to investigate the anti-oxidative stress and anti-inflammatory response effects of CEP in lipopolysaccharide (LPS)-induced macrophages as well as dextran sulfate sodium (DSS)-induced colitis mice. Our findings demonstrated that supplementation with CEP effectively mitigates body weight loss and elevation of disease activity index (DAI), reduces the malondialdehyde (MDA) content to 2.45 nM/mL while increasing the reduced glutathione (GSH) content to 35.53 μg/mL, inhibits inflammatory response, and maintains proper intestinal epithelium tight junctions in DSS-induced wild type (WT) mice. However, it failed to provide protective effects in DSS-induced transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) knockout (NRF2^−/−) mice. GSH content decreased to 10.85 μg/10⁶ cells following LPS treatment, whereas supplementation with CEP increased the GSH content to 12.26 μg/10⁶ cells. Moreover, CEP effectively attenuated ROS production in LPS-induced macrophages. Additionally, CEP exhibited inhibitory effects on pro-inflammatory cytokines and mediators in LPS-induced macrophages. Furthermore, we observed that supplementation with CEP promoted the expression of NRF2/heme oxygenase 1 (HO-1)/NADPH quinone oxidoreductase-1 (NQO-1) as well as the phosphorylation of the adenosine monophosphate-activated protein kinase alpha 1 (AMPK-α1)/protein kinase B (AKT)/glycogen synthase kinase-3 beta (GSK-3β) signaling pathway in macrophages while inhibiting the phosphorylation of the extracellular signal-regulated kinase (ERK)/c-Jun N-terminal kinase (JNK), and nuclear factor-kappa B p65 (NF-κB p65) signaling pathway in LPS-induced macrophages. Although CEP did not demonstrate inhibitory effects on oxidative stress or promote the expression of HO-1/NQO-1, it effectively activated the phosphorylation of the AMPK-α1/AKT/GSK-3β signaling pathway which is an upstream regulator of NRF2 in LPS-induced primary peritoneal macrophages from NRF2^−/− mice. In summary, our findings suggest that CEP exerts protective effects against oxidative stress and inflammatory response by activating the AMPK-α1/AKT/GSK-3β/NRF2 signaling pathway while concurrently inhibiting the activation of mitogen activated protein kinases (MAPKs) and the NF-κB p65 signaling pathway. These results not only elucidate the mechanisms underlying CEP’s protective effects on colon oxidative stress and inflammation but also provide evidence supporting NRF2 as a potential therapeutic target for IBD treatment. Full article

Cepharanthine, a natural bisbenzylisoquinoline (BBIQ) alkaloid isolated from the plant Stephania Cephalantha Hayata, is the only bisbenzylisoquinoline alkaloid approved for human use and has been used in the clinic for more than 70 years. Cepharanthine has a variety of medicinal properties, including signaling pathway inhibitory activities, immunomodulatory activities, and antiviral activities. Recently, cepharanthine has been confirmed to greatly inhibit SARS-CoV-2 infection. Therefore, we aimed to describe the pharmacological properties and mechanisms of cepharanthine, mainly including antitumor, anti-inflammatory, anti-pathogen activities, inhibition of bone resorption, treatment of alopecia, treatment of snake bite, and other activities. At the same time, we analyzed and summarized the potential antiviral mechanism of cepharanthine and concluded that one of the most important anti-viral mechanisms of cepharanthine may be the stability of plasma membrane fluidity. Additionally, we explained its safety and bioavailability, which provides evidence for cepharanthine as a potential drug for the treatment of a variety of diseases. Finally, we further discuss the potential new clinical applications of cepharanthine and provide direction for its future development. Full article

Severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) induces a severe cytokine storm that may cause acute lung injury/acute respiratory distress syndrome (ALI/ARDS) with high clinical morbidity and mortality in infected individuals. Cepharanthine (CEP) is a bisbenzylisoquinoline alkaloid isolated and extracted from Stephania cepharantha Hayata. It exhibits various pharmacological effects, including antioxidant, anti-inflammatory, immunomodulatory, anti-tumor, and antiviral activities. The low oral bioavailability of CEP can be attributed to its poor water solubility. In this study, we utilized the freeze-drying method to prepare dry powder inhalers (DPI) for the treatment of acute lung injury (ALI) in rats via pulmonary administration. According to the powder properties study, the aerodynamic median diameter (D_a) of the DPIs was 3.2 μm, and the in vitro lung deposition rate was 30.26; thus, meeting the Chinese Pharmacopoeia standard for pulmonary inhalation administration. We established an ALI rat model by intratracheal injection of hydrochloric acid (1.2 mL/kg, pH = 1.25). At 1 h after the model’s establishment, CEP dry powder inhalers (CEP DPIs) (30 mg/kg) were sprayed into the lungs of rats with ALI via the trachea. Compared with the model group, the treatment group exhibited a reduced pulmonary edema and hemorrhage, and significantly reduced content of inflammatory factors (TNF-α, IL-6 and total protein) in their lungs (p < 0.01), indicating that the main mechanism of CEP underlying the treatment of ALI is anti-inflammation. Overall, the dry powder inhaler can deliver the drug directly to the site of the disease, increasing the intrapulmonary utilization of CEP and improving its efficacy, making it a promising inhalable formulation for the treatment of ALI. Full article

Over the past few years, COVID-19 has caused widespread suffering worldwide. There is great research potential in this domain and it is also necessary. The main objective of this study was to identify potential inhibitors against acid sphingomyelinase (ASM) in order to prevent coronavirus infection. Experimental studies revealed that SARS-CoV-2 causes activation of the acid sphingomyelinase/ceramide pathway, which in turn facilitates the viral entry into the cells. The objective was to inhibit acid sphingomyelinase activity in order to prevent the cells from SARS-CoV-2 infection. Previous studies have reported functional inhibitors against ASM (FIASMAs). These inhibitors can be exploited to block the entry of SARS-CoV-2 into the cells. To achieve our objective, a drug library containing 257 functional inhibitors of ASM was constructed. Computational molecular docking was applied to dock the library against the target protein (PDB: 5I81). The potential binding site of the target protein was identified through structural alignment with the known binding pocket of a protein with a similar function. AutoDock Vina was used to carry out the docking steps. The docking results were analyzed and the inhibitors were screened based on their binding affinity scores and ADME properties. Among the 257 functional inhibitors, Dutasteride, Cepharanthine, and Zafirlukast presented the lowest binding affinity scores of −9.7, −9.6, and −9.5 kcal/mol, respectively. Furthermore, computational ADME analysis of these results revealed Cepharanthine and Zafirlukast to have non-toxic properties. To further validate these findings, the top two inhibitors in complex with the target protein were subjected to molecular dynamic simulations at 100 ns. The molecular interactions and stability of these compounds revealed that these inhibitors could be a promising tool for inhibiting SARS-CoV-2 infection. Full article

Cepharanthine (CEP), a bisbenzylisoquinoline alkaloid from tubers of Stephania, protects against some inflammatory diseases. Aconitate decarboxylase 1 (ACOD1) is also known as immune-responsive gene 1 (IRG1), which plays an important immunometabolism role in inflammatory diseases by mediating the production of itaconic acid. ACOD1 exhibits abnormal expression in ulcerative colitis (UC). However, whether CEP can combat UC by affecting ACOD1 expression remains unanswered. This study was designed to explore the protective effects and mechanisms of CEP in treating colitis through in vitro and in vivo experiments. In vitro assays indicated that CEP inhibited LPS-induced secretion of pro-inflammatory cytokines and ACOD1 expression in RAW264.7 macrophages. Additionally, in the mouse model of DSS-induced colitis, CEP decreased macrophage infiltration and ACOD1 expression in colon tissue. After treatment with antibiotics (Abx), the expression of ACOD1 changed with the composition of gut microbiota. Correlation analysis also revealed that Family-XIII-AD3011-group and Rumini-clostridium-6 were positively correlated with ACOD1 expression level. Additionally, data of the integrative Human Microbiome Project (iHMP) showed that ACOD1 was highly expressed in the colon tissue of UC patients and this expression was positively correlated with the severity of intestinal inflammation. Collectively, CEP can counter UC by modulating gut microbiota and inhibiting the expression of ACOD1. CEP may serve as a potential pharmaceutical candidate in the treatment of UC. Full article