Honokiol suppress the PD-L1 expression to improve anti-tumor immunity in lung cancer.

Lung cancer is a serious health issue globally, and current treatments have proven to be inadequate. Therefore, immune checkpoint inhibitors (ICIs) that target the PD-1/PD-L1 pathway have become a viable treatment option in lun cancer. Honokiol, a lignan derived from Magnolia officinalis, has been found to possess anti-inflammatory, antioxidant, and antitumor properties. Our research found that honokiol can effectively regulate PD-L1 through network pharmacology and transcriptome analysis. Cell experiments showed that honokiol can significantly reduce PD-L1 expression in cells with high PD-L1 expression. Molecular docking, cellular thermal shift assay (CETSA) and Bio-Layer Interferometry (BLI)indicated that Honokiol can bind to PD-L1. Co-culture experiments on lung cancer cells and T cells demonstrated that honokiol mediates PD-L1 degradation, stimulates T cell activation, and facilitates T cell killing of tumor cells. Moreover, honokiol activates CD4 + and CD8 + T cell infiltration in vivo, thus suppressing tumor growth in C57BL/6 mice. In conclusion, this study has demonstrated that honokiol can inhibit the growth of lung cancer by targeting tumor cell PD-L1, suppressing PD-L1 expression, blocking the PD-1/PD-L1 pathway, and enhancing anti-tumor immunity.

Sesamin ameliorates nonalcoholic hepatic steatosis by inhibiting CD36-mediated hepatocyte lipid accumulation in vitro and in vivo.

Hepatic steatosis is a critical factor in the development of nonalcoholic steatohepatitis (NASH). Sesamin (Ses), a functional lignan isolated from Sesamum indicum, possesses hypolipidemic, liver-protective, anti-hypertensive, and anti-tumor properties. Ses has been found to improve hepatic steatosis, but the exact mechanisms through which Ses achieves this are not well understood. In this study, we observed the anti-hepatic steatosis effects of Ses in palmitate/oleate (PA/OA)-incubated primary mouse hepatocytes, AML12 hepatocytes, and HepG2 cells, as well as in high-fat, high-cholesterol diet-induced NASH mice. RNA sequencing analysis revealed that cluster of differentiation 36 (CD36), a free fatty acid (FA) transport protein, was involved in the Ses-mediated inhibition of hepatic fat accumulation. Moreover, the overexpression of CD36 significantly increased hepatic steatosis in both Ses-treated PA/OA-incubated HepG2 cells and NASH mice. Furthermore, Ses treatment suppressed insulin-induced de novo lipogenesis in HepG2 cells, which was reversed by CD36 overexpression. Mechanistically, we found that Ses ameliorated NASH by inhibiting CD36-mediated FA uptake and upregulation of lipogenic genes, including FA synthase, stearoyl-CoA desaturase 1, and sterol regulatory element-binding protein 1. The findings of our study provide novel insights into the potential therapeutic applications of Ses in the treatment of NASH.

Identification of Dihydrobenzofuran Neolignans as Novel PDE4 Inhibitors and Evaluation of Antiatopic Dermatitis Efficacy in DNCB-Induced Mice Model.

Atopic dermatitis is a chronic relapsing skin disease characterized by recurrent, pruritic, localized eczema, while PDE4 inhibitors have been reported to be effective as antiatopic dermatitis agents. 3',4-O-dimethylcedrusin (DCN) is a natural dihydrobenzofuran neolignan isolated from Magnolia biondii with moderate potency against PDE4 (IC50 = 3.26 ± 0.28 µM) and a binding mode similar to that of apremilast, an approved PDE4 inhibitor for the treatment of psoriasis. The structure-based optimization of DCN led to the identification of 7b-1 that showed high inhibitory potency on PDE4 (IC50 = 0.17 ± 0.02 µM), good anti-TNF-α activity (EC50 = 0.19 ± 0.10 µM), remarkable selectivity profile, and good skin permeability. The topical treatment of 7b-1 resulted in the significant benefits of pharmacological intervention in a DNCB-induced atopic dermatitis-like mice model, demonstrating its potential for the development of novel antiatopic dermatitis agents.

The therapeutic effect of Loranthus parasiticus lignan derivatives on collagen-induced arthritis in rats through the SHBG/NFκB pathway.

Lignan-rich beans, nuts, and various seeds are the main foods with antioxidative and hormone-modulating activities. Although the role of lignans in mediating hormone-dependent cancers and cardiovascular diseases is well characterized, the function of lignans in anti-arthritic activity and its underlying mechanisms remain unknown. Three new lignan derivatives, (-)-nortrachelogenin, trachelogenin, and matairesinol, were extracted from Loranthus parasiticus. After establishing the collagen-induced arthritis (CIA) model by intradermal injection of collagen, rats were treated with three new lignan derivatives ((-)-nortrachelogenin: 37%; trachelogenin: 27%; matairesinol: 25.7%) at a concentration of 50 mg/kg and 100 mg/kg, or methotrexate at 0.3 mg/kg. Mixed lignan derivatives significantly attenuated the immune responses in the joints of CIA rats, leading to lower levels of proinflammatory cytokines (IL-6 and TNF-α) and higher levels of free androgen in the serum compared to the CIA model. The results of molecular docking using AutoDock Vina showed that the lignan derivative (-)-nortrachelogenin was the most effective compound for binding to sex hormone-binding globulin (SHBG), thus inhibiting the activity of NFκB in LPS-stimulated macrophages. In this study, (-)-nortrachelogenin was identified as a novel natural lignan derivative with previously unrecognized anti-inflammatory activity. Its molecular mechanism appears related to the regulation of the NFκB/SHBG pathway. Our findings suggest that further application of sex hormone-like compounds in the treatment of rheumatoid arthritis and the potential clinical applications of (-)-nortrachelogenin are promising.

(-)-Syringaresinol attenuates ulcerative colitis by improving intestinal epithelial barrier function and inhibiting inflammatory responses.

BACKGROUND: (-)-Syringaresinol (SYR), a natural lignan with significant antioxidant and anti-inflammatory activities, possesses various pharmacological benefits including cardio-protective, antibacterial, anticancer, and anti-aging effects. It was shown that the effectiveness of (+)-syringaresinol diglucoside on the ulcerative colitis (UC) was attributed to the active metabolite (+)-syringaresinol (the enantiomor of SYR). However, the efficacy of SYR against UC remains unclear, and the associated molecular mechanism has not been revealed yet PURPOSE: This study aimed to assess the protective effect of SYR in UC and its underlying mechanism STUDY DESIGN AND METHODS: We examined SYR's protective impact on the intestinal epithelial barrier and its ability to inhibit inflammatory responses in both a lipopolysaccharide (LPS)-induced Caco-2 cell model and a dextran sodium sulfate (DSS)-induced UC mouse model. We also explored the potential signaling pathways regulated by SYR using transcriptome analysis and western blot assay RESULTS: In Caco-2 cells, SYR significantly increased trans-epithelial electrical resistance, reduced tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interferon-γ (IFN-γ), and cyclooxygenase-2 (COX-2) levels, and enhanced cellular tight junction protein expression and distribution. In mice with UC, oral treatment with SYR (10, 20, 40 mg·kg-1) dose-dependently increased body weight, colon length, and expression of tight junction proteins, decreased disease activity index score, spleen coefficient, cytokine serum levels, bacterial translocation, and intestinal damage, and also preserved the ultrastructure of colonic mucosal cells. Transcriptomics indicated that the anti-UC effect of SYR is mediated via the PI3K-Akt/MAPK/Wnt signaling pathway. CONCLUSION: In summary, SYR effectively mitigated the development of UC by enhancing the intestinal epithelial barrier function and attenuating the inflammatory response. The plant-derived product SYR might be a potentially effective therapeutical agent against UC.

Enhanced Chemoprevention of Prostate Cancer by Combining Arctigenin with Green Tea and Quercetin in Prostate-Specific Phosphatase and Tensin Homolog Knockout Mice.

The low bioavailability of most phytochemicals limits their anticancer effects in humans. The present study was designed to test whether combining arctigenin (Arc), a lignan mainly from the seed of Arctium lappa, with green tea (GT) and quercetin (Q) enhances the chemopreventive effect on prostate cancer. We performed in vitro proliferation studies on different cell lines. We observed a strong synergistic anti-proliferative effect of GT+Q+Arc in exposing androgen-sensitive human prostate cancer LNCaP cells. The pre-malignant WPE1-NA22 cell line was more sensitive to this combination. No cytotoxicity was observed in normal prostate epithelial PrEC cells. For an in vivo study, 3-week-old, prostate-specific PTEN (phosphatase and tensin homolog) knockout mice were treated with GT+Q, Arc, GT+Q+Arc, or the control daily until 16 weeks of age. In vivo imaging using prostate-specific membrane antigen (PSMA) probes demonstrated that the prostate tumorigenesis was significantly inhibited by 40% (GT+Q), 60% (Arc at 30 mg/kg bw), and 90% (GT+Q+Arc) compared to the control. A pathological examination showed that all control mice developed invasive prostate adenocarcinoma. In contrast, the primary lesion in the GT+Q and Arc alone groups was high-grade prostatic intraepithelial neoplasia (PIN), with low-grade PIN in the GT+Q+Arc group. The combined effect of GT+Q+Arc was associated with an increased inhibition of the androgen receptor, the PI3K/Akt pathway, Ki67 expression, and angiogenesis. This study demonstrates that combining Arc with GT and Q was highly effective in prostate cancer chemoprevention. These results warrant clinical trials to confirm the efficacy of this combination in humans.

Honokiol Attenuates Choroidal Neovascularization by Inhibiting the Hypoxia-Inducible Factor-α/Vascular Endothelial Growth Factor Axis via Nuclear Transcription Factor-Kappa B Activation.

PURPOSE: Honokiol is a lignan isolated from Magnolia officinalis and exhibits anti-angiogenic properties. This study was conducted to investigate the role of honokiol in choroidal neovascularization. METHODS: C57BL/6 mice were treated with honokiol at 10-20 mg/kg by daily intraperitoneal injection from day 1 to 6 after laser photocoagulation. ARPE-19 cells were cultured under hypoxic conditions with or without the presence of honokiol. After laser photocoagulation and honokiol treatment, hematoxylin and eosin staining, immunofluorescence and fundus fluorescein angiography were used to analyze the effect of honokiol on choroidal neovascularization formation. Quantitative real-time PCR, western blot, enzyme-linked immunosorbent assay, immunofluorescence, luciferase assay, and chromatin immunoprecipitation were performed to explore the mechanism of honokiol in the pathological process of choroidal neovascularization. Finally, the role of honokiol on the human choroidal vascular endothelial cells was detected by using 5-ethynyl-20-deoxyuridine assay, Transwell and Tube formation assays. RESULTS: The results of hematoxylin and eosin staining and immunofluorescence suggested that honokiol reduced the thickness, length, and area of choroidal neovascularization lesions in laser-induced choroidal neovascularization mouse model. Fundus fluorescein angiography showed that choroidal neovascularization leakage was reduced in honokiol group and the concentration of 20 mg/kg showed better effects. Mechanism studies have shown that honokiol exerted inhibitory effects on choroidal neovascularization by inactivating hypoxia-inducible factor-1α/vascular endothelial growth factor axis through the nuclear transcription factor-kappa B signaling pathway. The same results were obtained in ARPE-19 cells under hypoxic conditions. Furthermore, the conditional medium of retinal pigmented epithelial cells promoted the proliferation, migration, and tube formation of human choroidal vascular endothelial cells, while honokiol reversed these. CONCLUSION: We demonstrated that honokiol attenuated choroidal neovascularization formation by inactivating the hypoxia-inducible factor-1α/vascular endothelial growth factor axis through nuclear transcription factor-kappa B signaling pathway.

Galgravin Isolated from Piper kadsura Ameliorates Lipopolysaccharide (LPS)-Induced Endotoxemia in Mice.

Sepsis results from uncontrolled inflammation, characterized by cytokine storm and immunoparalysis. To assess whether galgravin, a natural lignan isolated from Piper kadsura, can be used to treat sepsis, models of bacterial lipopolysaccharide (LPS)-activated macrophages and LPS-induced endotoxemia mice were used. Galgravin suppressed NF-κB activation in LPS-activated RAW 264.7 macrophages without causing significant cytotoxicity, in which proinflammatory molecules like TNF-α, IL-6, iNOS, and COX-2 were downregulated. In addition, the expression of TNF-α and IL-6 was also suppressed by galgravin in LPS-activated murine bone marrow-derived macrophages. Moreover, galgravin significantly downregulated the mRNA expression of TNF-α, IL-6, and iNOS in the lungs and decreased TNF-α and IL-6 in the serum and IL-6 in the bronchoalveolar lavage fluid of LPS-challenged mice. The COX-2 expression in tissues, including the lung, liver, and kidney, as well as the lung alveolar hemorrhage, was also reduced by galgravin. The present study reveals the anti-inflammatory effects of galgravin in mouse models and implies its potential application in inflammation diseases.

Sesamin: A Promising Therapeutic Agent for Ameliorating Symptoms of Diabetes.

Diabetes is a chronic metabolic disease characterized by improperly regulating proteins, carbohydrates, and lipids due to insulin deficiency or resistance. The increasing prevalence of diabetes poses a tremendous socioeconomic burden worldwide, resulting in the rise of many studies on Chinese herbal medicines to discover the most effective cure for diabetes. Sesame seeds are among these Chinese herbal medicines that were found to contain various pharmacological activities, including antioxidant and anti-inflammatory properties, lowering cholesterol, improving liver function, blood pressure and sugar lowering, regulating lipid synthesis, and anticancer activities. These medicinal benefits are attributed to sesamin, which is the main lignan found in sesame seeds and oil. In this study, Wistar rat models were induced with type 2 diabetes using streptozotocin (STZ) and nicotinamide, and the effect of sesamin on the changes in body weight, blood sugar level, glycosylated hemoglobin (HbA1c), insulin levels, and the states of the pancreas and liver of the rats were evaluated. The results indicate a reduced blood glucose level, HbA1c, TG, and ALT and AST enzymes after sesamin treatment, while increased insulin level, SOD, CAT, and GPx activities were also observed. These findings prove sesamin's efficacy in ameliorating the symptoms of diabetes through its potent pharmacological activities.

Unveiling nature's potential weapon: Magnolol's role in combating bladder cancer by upregulating the miR-124 and inactivating PKC-δ/ERK axis.

BACKGROUND: Bladder cancer (BC) is a challenging disease to manage. Researchers have been investigating the potential of magnolol, a compound derived from Magnolia officinalis, as an anti-cancer agent. However, the exact regulatory mechanism of magnolol and its impact on the NF-κB signaling pathway in BC remain unclear. MATERIALS: To comprehensively evaluate its therapeutic potential, the researchers conducted a series of experiments using BC cell lines (TSGH8301, T24, and MB49) and in vivo animal models. RESULTS: The results of the study demonstrated that magnolol exhibits cytotoxic effects on BC cells by activating both the extrinsic and intrinsic apoptosis signaling pathways. Additionally, the expression of anti-apoptotic genes was downregulated by magnolol treatment. The researchers also uncovered the regulatory role of PKCδ/ERK and miR-124-3p in the NF-κB pathway, which may be influenced by magnolol. Treatment with magnolol led to the inactivation of PKCδ/ERK and an increase in miR-124-3p expression, effectively inhibiting NF-κB-mediated progression of BC. Importantly, the administration of magnolol did not result in significant toxicity in normal tissues, highlighting its potential as a safe adjunctive therapy with minimal adverse effects. CONCLUSION: These findings position magnolol as a promising therapeutic agent for the treatment of BC. By activating apoptosis signaling pathways and inhibiting NF-κB pathway through the upregulation of miR-124-3p and downregulation of PKCδ/ERK activation, magnolol holds promise for suppressing tumor progression and improving patient outcomes in BC. Further research and clinical trials are warranted to explore the full potential of magnolol in the future.

Effect of arctigenin on neurological diseases: A review.

ETHNOPHARMACOLOGICAL RELEVANCE: Arctium lappa L. is a common specie of Asteraceae. Its main active ingredient, Arctigenin (AG), in mature seeds exerts pharmacological effects on the Central Nervous System (CNS). AIM OF THE STUDY: To review studies on the specific effects of the AG mechanism on various CNS diseases and elucidate signal transduction mechanisms and their pharmacological actions. MATERIALS AND METHODS: This investigation reviewed the essential role of AG in treating neurological disorders. Basic information on Arctium lappa L. was retrieved from the Pharmacopoeia of the People's Republic of China. The related articles from 1981 to 2022 on the network database (including CNKI, PubMed, and Wan Fang and so on) were reviewed using AG and CNS diseases-related terms such as Arctigenin and Epilepsy. RESULTS: It was confirmed that AG has a therapeutic effect on Alzheimer's disease, Glioma, infectious CNS diseases (such as Toxoplasma and Japanese Encephalitis Virus), Parkinson's disease, Epilepsy, etc. In these diseases, related experiments such as a Western blot analysis revealed that AG could alter the content of some key factors (such as the reduction of Aß in Alzheimer's disease). However, in-vivo AG's metabolic process and possible metabolites are still undetermined. CONCLUSION: Based on this review, the existing pharmacological research has indeed made objective progress to elucidate how AG prevents and treats CNS diseases, especially senile degenerative disease such as Alzheimer's diseases. It was revealed that AG could be used as a potential nervous system drug as it has a wide range of effects in theory with markedly high application value, especially in the elder group. However, the existing studies are limited to in-vitro experiments; therefore, little is known about how AG metabolizes and functions in-vivo, limiting its clinical application and requiring further research.

Lariciresinol protects rats from complete Freund's adjuvant induced arthritis in rats via modulation of transforming growth factor-ß and nuclear factor kappa B pathway: An in vivo and in silico study.

Rheumatoid arthritis (RA) is a severe inflammatory auto-immune disorder affecting millions of people across the globe. The current therapeutic options are not adequate to address the complications of RA. Therefore, the present study was conducted to elucidate the protective effect of lariciresinol, a lignan, against Complete Freund's adjuvant (CFA)-induced arthritis in rats. The results of the study showed that lariciresinol improves paw swelling and arthritic scores in rats as compared to CFA rats. Lariciresinol also showed a significant reduction in rheumatoid factor, C-reactive protein, tumor necrosis factor-α, interleukin (IL)-17, and tissue inhibitor of metalloproteinases-3 level with a simultaneous increase in IL-4 level. The burden of oxidative stress was also reduced in CFA rats, as shown by reduced MDA levels and increased SOD and GPx after the administration of lariciresinol. In a Western blot analysis, lariciresinol showed a significant reduction of transforming growth factor-ß and nuclear factor-κB (NF-κB) protein levels in CFA rats. To understand the binding characteristic of lariciresinol with NF-κB, molecular docking analysis was conducted, which showed Larciresinol interacted with the active site of NF-κB. Our study demonstrated the significant protective effect of lariciresinol against RA via multi-target action.

Syringaresinol attenuates osteoarthritis via regulating the NF-κB pathway.

Osteoarthritis (OA) is a now regarded as a worldwide whole joint disease with synovial inflammation, cartilage degeneration, and subchondral sclerosis. Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used drugs for OA treatment which only relieve the symptoms and restrain the progression of OA. However, various severe adverse effects often occur in patients with long-term NSAIDs use, which heavily burdens the healthcare system and impacts the quality of life. Therefore, it is much imperative to identify alternative drugs with increased efficacy. Syringaresinol (Syr), a naturally occurring phytochemical which belonging to the lignan group of polyphenols, shows anti-tumor and anti-oxidant activities, which to benefit human health. Studies has shown Syr can regulate the inflammatory response by modulating the secretion and expression level of cytokines IL-6, IL-8, and tumor necrosis factor (TNF)-α. it also shows the inhibitory effect on NF-κB pathway in mouse cells. In the present study, we aimed to demonstrate the anti-inflammatory effects of Syr in OA. In vitro Syr treatment in IL-1ß-activated mouse chondrocytes significantly restrained the expression of NO, PGE2, IL-6, TNF-α, INOS, COX-2 and MMP-13. Moreover, it considerably ameliorated the degradation of aggrecan and collagen II. Furthermore, the phosphorylation of the NF-kB signaling pathway was significantly suppressed by Syr. Moreover, in vivo, the cartilage degeneration was attenuated and the increased Osteoarthritis Research Society International (OARSI) scores were reversed in the DMM + Syr group, comprared to those in the DMM group. In sum, our study demonstrated that Syr can attenuate the inflammation in vitro and further verified its effect on OA in vivo. Thus, Syr might be a potent therapeautic alternative for OA treatment.

Evaluating the Magnolol Anticancer Potential in MKN-45 Gastric Cancer Cells.

Background and Objectives: Combination therapy improves the effect of chemotherapy on tumor cells. Magnolol, used in treating gastrointestinal disorders, has been shown to have anti-cancer properties. We investigated the synergistic effect of cisplatin and magnolol on the viability and maintenance of MKN-45 gastric cancer cells. Materials and Methods: The toxicity of magnolol and/or cisplatin was determined using the MTT technique. The trypan blue method was used to test magnolol and/or cisplatin's effect on MKN-45 cell growth. Crystal violet staining was used to assess the treated cells' tendency for colony formation. The expression of genes linked to apoptosis, cell cycle arrest, and cell migration was examined using the qPCR method. Results: According to MTT data, using magnolol and/or cisplatin significantly reduced cell viability. The ability of the treated cells to proliferate and form colonies was also reduced considerably. Magnolol and/or cisplatin treatment resulted in a considerable elevation in Bax expression. However, the level of Bcl2 expression was dramatically reduced. p21 and p53 expression levels were significantly increased in the treated cells, while MMP-9 expression was significantly reduced. Conclusions: These findings show that magnolol has a remarkable anti-tumor effect on MKN-45 cells. In combination with cisplatin, magnolol may be utilized to overcome cisplatin resistance in gastric cancer cells.

Cytotoxic effects of neolignans from Saururus cernuus (Saururaceae) against prostate cancer cells.

In this study, five neolignans were isolated from Saururus cernuus-threo-dihydroguaiaretic acid (1), threo-austrobailignan-6 (2), threo-austrobailignan-5 (3), verrucosin (4), and saucernetin (5)-and have their cytotoxic effects evaluated in prostate cancer cell lines (PC3 and DU145). Initially, using an in silico approach, tested compounds were predicted to be absorbed by the gastrointestinal tract, be able to permeate the blood-brain barrier and did not show any alert in PAINS (pan-assay structures interference). In vitro assays showed that compounds 2, 4, and 5 reduced cell viability of DU145 cell line at 100 µmol/L after 48 h while compounds 1 and 3 showed to be inactive at the same conditions. Furthermore, compounds 4 and 5 reduced cell number as early as in 24 h at 50 µmol/L and compound 2 showed effects at 100 µmol/L in 24 h against both cancer cell lines PC3 and DU145. Studies using flow cytometry were conducted and indicated that compound 4 induced strong necrosis and apoptosis whereas compound 5 induced strong necrosis. Otherwise, less active compound 2 did not show evidence of induction of apoptosis or necrosis, suggesting that its mechanism of action involves inhibition of cell proliferation. In conclusion, compounds 4 and 5 have been shown to be promising cytotoxic agents against prostate cancer cell lines and can be used as a starting point for the development of new drugs for the treatment of prostate cancer.

Magnolol induces cytotoxic autophagy in glioma by inhibiting PI3K/AKT/mTOR signaling.

Glioma is difficult-to-treat because of its infiltrative nature and the presence of the blood-brain barrier. Temozolomide is the only FDA-approved drug for its management. Therefore, finding a novel chemotherapeutic agent for glioma is of utmost importance. Magnolol, a neolignan, has been known for its apoptotic role in glioma. In this work, we have explored a novel anti-glioma mechanism of Magnolol associated with its role in autophagy modulation. We found increased expression levels of Beclin-1, Atg5-Atg12, and LC3-II and lower p62 expression in Magnolol-treated glioma cells. PI3K/AKT/mTOR pathway proteins were also downregulated in Magnolol-treated glioma cells. Next, we treated the glioma cells with Insulin, a stimulator of PI3K/AKT/mTOR signaling, to confirm that Magnolol induced autophagy by inhibiting this pathway. Insulin reversed the effect on Magnolol-mediated autophagy induction. We also established the same in in vivo glioma model where Magnolol showed an anti-glioma effect by inducing autophagy. To confirm the cytotoxic effect of Magnolol-induced autophagy, we used Chloroquine, a late-stage autophagy inhibitor. Chloroquine efficiently reversed the anti-glioma effects of Magnolol both in vitro and in vivo. Our study revealed the cytotoxic effect of Magnolol-induced autophagy in glioma, which was not previously reported. Additionally, Magnolol showed no toxicity in non-cancerous cell lines as well as rat organs. Thus, we concluded that Magnolol is an excellent candidate for developing new therapeutic strategies for glioma management.

The therapeutic potential of arctigenin against multiple human diseases: A mechanistic review.

BACKGROUND: Arctigenin (ATG), a dibenzyl butyrolactone lignan compound, is one of the major bioactive components from the medicinal plant Arctium lappa. ATG possesses remarkable therapeutic potential against a wide range of human diseases, such as cancers, immune disorders and chronical diseases. The molecular mechanisms behind the biological effects of ATG have been intensively studied. PURPOSE: This review aims to systematically summarize the updated knowledge of the proteins and signaling pathways behind the curative property of ATG, and further analyze the potential connections between them. METHOD: SciFinder, Pubmed, Web of Science and Cochrane Library databases were queried for publications reporting the therapeutic properties of ATG. "Arctigenin", "disease", "cancer", "inflammation", "organ damage", "infection", "toxicity" and "pharmacokinetics" were used as the searching titles. RESULT: 625 publications were identified and 95 met the inclusion criteria and exclusion criteria. 42 studies described the molecular mechanisms implicated in ATG treatments. Several proteins including phosphodiesterase subtype 4D (PDE4D), estrogen receptor (ER) ß, protein phosphatase 2A (PP2A), phosphoinositide 3-kinase (PI3K) and transmembrane protein 16A (TMEM16A) are targeted by ATG in different settings. The frequently described signaling pathways are TLR4/NF-κB, PI3K/AKT/mTOR, AMP-activated protein kinase (AMPK) and nuclear factor erythroid 2-related factor 2 (Nrf-2) signalings. CONCLUSION: Inhibition of PI3K/AKT pathway and activation of AMPK signaling play the pivotal roles in the therapeutic effects of ATG. PI3K/AKT and AMPK signaling widely link to other signaling pathways, modulating various biological processes such as anti-inflammation, anti-oxidative stress, anti-fibrosis, anti-ER stress, anti-steatosis and pro-apoptosis, which constitute the curative mechanisms of ATG against multiple human diseases.

NF-κB Inhibitor Myrislignan Induces Ferroptosis of Glioblastoma Cells via Regulating Epithelial-Mesenchymal Transformation in a Slug-Dependent Manner.

Glioblastoma (GBM) is the most common malignant tumor of the adult central nervous system. Aberrant regulation of cell death is an important feature of GBM, and investigating the regulatory mechanisms of cell death in GBM may provide insights into development of new therapeutic strategies. We demonstrated that myrislignan has ferroptosis-promoting activity. Myrislignan is a lignan isolated from Myristica fragrans Houtt and an inhibitor of NF-κB signaling pathway. Ferroptosis is an iron-dependent form of programmed cell death characterized by the accumulation of intracellular lipid peroxidation products. Interestingly, ferroptosis was associated with other biological processes in tumor cells such as autophagy and necroptosis. Recently, the crosstalk between epithelial-mesenchymal transition (EMT) and ferroptosis has also been reported, but the mechanisms underlying the crosstalk have not been identified. Our results indicated that myrislignan suppressed growth of GBM through EMT-mediated ferroptosis in a Slug-dependent manner. Myrislignan inhibited the activation of NF-κB signaling by blocking the phosphorylation of p65 protein and induced ferroptosis through the Slug-SLC7A11 signaling pathway in GBM cells. In addition, myrislignan suppressed the progression of GBM in xenograft mouse model. Hence, our findings contribute to the understanding of EMT-induced ferroptosis and provide targets for the development of targeted therapy against GBM.

Podophyllotoxin and its derivatives: Potential anticancer agents of natural origin in cancer chemotherapy.

The use of plant secondary metabolites has gained considerable attention among clinicians in the prevention and treatment of cancer. A secondary metabolite isolated mainly from the roots and rhizomes of Podophyllum species (Berberidaceae) is aryltetralin lignan - podophyllotoxin (PTOX). The purpose of this review is to discuss the therapeutic properties of PTOX as an important anticancer compound of natural origin. The relevant information regarding the antitumor mechanisms of podophyllotoxin and its derivatives were collected and analyzed from scientific databases. The results of the analysis showed PTOX exhibits potent cytotoxic activity; however, it cannot be used in its pure form due to its toxicity and generation of many side effects. Therefore, it practically remains clinically unusable. Currently, high effort is focused on attempts to synthesize analogs of PTOX that have better properties for therapeutic use e.g. etoposide (VP-16), teniposide, etopophos. PTOX derivatives are used as anticancer drugs which are showing additional immunosuppressive, antiviral, antioxidant, hypolipemic, and anti-inflammatory effects. In this review, attention is paid to the high potential of the usefulness of in vitro cultures of P. peltatum which can be a valuable source of lignans, including PTOX. In conclusion, the preclinical pharmacological studies in vitro and in vivo confirm the anticancer and chemotherapeutic potential of PTOX and its derivatives. In the future, clinical studies on human subjects are needed to certify the antitumor effects and the anticancer mechanisms to be certified and analyzed in more detail and to validate the experimental pharmacological preclinical studies.