PMID: 

Naunyn Schmiedebergs Arch Pharmacol. 2020 Feb 6. Epub 2020 Feb 6. PMID: 32025757

Abstract Title: 

Lupeol inhibits migration and invasion of colorectal cancer cells by suppressing RhoA-ROCK1 signaling pathway.

Abstract: 

Metastasis is the main cause of death in colorectal cancer (CRC) patients. However, current treatment options for CRC metastasis are very limited. Lupeol, a triterpene that is widely found in vegetables and fruits, has been reported to possess the cancer-preventive and anti-inflammatory functions. However, the roles of Lupeol in the migration and invasion of colorectal cancer remain unclear. Here, we evaluated the effect of Lupeol treatment on colorectal cancer cell lines, HCT116 and SW620, and delineated its underlying mechanisms. Our results showed that Lupeol induced a dose-dependent inhibition of HCT116 and SW620 cells viability, measured by CCK8 assay. Wound healing and Transwell migration and invasion assays revealed that Lupeol significantly suppressed the migration and invasion of CRC cells. Using laser confocal microscope, we observed that the pseudopods and protrusions of HCT116 and SW620 cells decreased and disrupted after treatment with Lupeol. In addition, the quantitative real-time PCR and Western blotting results showed that Lupeol downregulated the expression of RhoA and RhoC, and their downstream effectors ROCK1, Cofilin, p-MLC, and the associated regulatory protein Cyclin A2. Interestingly, the migration and invasion capacity of CRC cells was reduced after RhoA knockdown. And there were no additional changes in CRC cells with RhoA knockdown to treat with Lupeol. These findings demonstrate that Lupeol can suppress the migration and invasion of colorectal cancer cells by remodeling the actin cytoskeleton via RhoA-ROCK1 pathway inhibition, which may provide an effective anti-metastatic agent for CRC patients.

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PMID: 

Biomed Res Int. 2019 ;2019:5601734. Epub 2019 Dec 2. PMID: 31886227

Abstract Title: 

Ligustrazine Prevents Intervertebral Disc Degeneration via Suppression of Aberrant TGFActivation in Nucleus Pulposus Cells.

Abstract: 

Objectives: Aberrant transforming growth factor(TGF) activation is detrimental to both nucleus pulposus (NP) cells and cartilage endplates (CEPs), which can lead to intervertebral disc degeneration (IDD). Ligustrazine (LIG) reduces the expression of inflammatory factors and TGF1 in hypertrophic CEP to prevent IDD. In this study, we investigate the effects of LIG on NP cells and the TGFsignaling.Design: LIG was injected to the lumbar spinal instability (LSI) mouse model. The effect of LIG was evaluated by intervertebral disc (IVD) score in the LSI mouse model. The expression of activated TGFwas examined using immunostaining with pSmad2/3 antibody. The upright posture (UP) rat model was also treated and evaluated in the same manner to assess the effect of LIG. Instudy, IVDs from four-week old mice were isolated and treated with 10, 10, and 10 M of LIG. We used western blot to detect activated TGFexpression. TGF-treated human nucleus pulposus cells (HNPCs) were cotreated with optimized dose of LIG. Immunofluorescence staining was performed to determine pSmad2/3, connective tissue growth factor (CCN2), and aggrecan (ACAN) expression levels.Results: IVD score and the percentage of pSmad2/3+ NP cells were low in LIG-treated LSI mice in comparison with LSI mice, but close to the levels in the Sham group. Similarly, LIG reduced the overexpression of TGF1 in NP cells. The inhibitory effect of LIG was dose dependent. A dose of 10 M LIG not only strongly attenuated Smad2/3 phosphorylation in TGF-treated IVDbut also suppressed pSmad2/3, CCN2, and ACAN expression in TGF-treated NP cells.Conclusions: LIG prevents IDD via suppression of TGFoveractivation in NP cells.

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PMID: 

Int J Mol Med. 2020 Jan 10. Epub 2020 Jan 10. PMID: 31985025

Abstract Title: 

Ligustrazine ameliorates acute kidney injury through downregulation of NOD2‑mediated inflammation.

Abstract: 

Ligustrazine has been used to alleviate clinical acute kidney injury (AKI); however, the underlying molecular mechanisms are poorly understood. In order to further elucidate the molecular mechanism underlying its occurrence, the role of nucleotide‑binding oligomerization domain‑containing 2 (NOD2) in AKI was investigated in the present study, and the results indicated that ligustrazine exerts an important protective effect against AKI in vivo by inhibiting the upregulation of NOD2 expression and reducing apoptosis of kidney cells following ischemia/reperfusion injury in rat models. Furthermore, the inhibitory role of ligustrazine on the upregulation of NOD2 and apoptosis of kidney cells induced by CoCl2 and oxygen and glucose deprivation followed by reoxygenation was investigated in in vitro experiments. The effect of ligustrazine on NOD2 downregulation was partially blocked by inhibiting autophagy. To the best of our knowledge, the results of the present study are the first to provide evidence that ligustrazine can inhibit NOD2‑mediated inflammation to protect against renal injury, which may be in part attributed to theinduction of autophagy. These findings may help design and develop new approaches and therapeutic strategies for AKI to prevent the deterioration of renal function.

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PMID: 

Acta Cir Bras. 2019 Mar 18 ;34(3):e201900305. Epub 2019 Mar 18. PMID: 30892391

Abstract Title: 

Effect of ethyl acetate extract of usnea longissima on esophagogastric adenocarcinoma in rats1.

Abstract: 

PURPOSE: To investigate the effects of the EtOAc extract of U. longissima which is uninvestigated previously on esophagogastric cancer induced in rats with N-methyl-N-nitro-N-nitrosoguanidin (MNNG).METHODS: The anticancer activity of EtOAc extract of U. longissima was examined in the esophagogastric adenocarcinoma models induced in rats with MNNG. EtOAc extract of U. longissima, 50 and 100 mg/kg oral doses were administered once daily for six months. MNNG induced differentiated and undifferentiated type adenocarcinomas in the esophageal and gastric tissues of rats.RESULTS: EtOAc extract of U. longissima obtained from U. longissima prevented gastric and esophageal cancerogenesis induced in rats with MNNG. EtOAc extract of U. longissima did not have a lethal effect at doses of 500, 1000 and 2000 mg/kg. The prominent anticarcinogenic activity of EtOAc extract of U. longissima 50 and 100 mg/kg suggests that it is not toxic and it is selective to the cancer tissue.CONCLUSION: This information may shed light on clinical implementation of EtOAc extract of U. longissima in future.

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PMID: 

Microb Pathog. 2019 Dec 17 ;140:103933. Epub 2019 Dec 17. PMID: 31862392

Abstract Title: 

Endolichenic fungus, Aspergillus quandricinctus of Usnea longissima inhibits quorum sensing and biofilm formation of Pseudomonas aeruginosa PAO1.

Abstract: 

Lichens are composite organisms, comprising of a fungus (mycobiont) and a blue-green alga (photobiont). Along with the mycobiont, numerous non-obligate microfungi live in lichen thalli. These microfungi are called endolichenic fungi (ELF). In recent years, the ELF are emerging as promising natural sources because of their capability to exert unique drug molecules. The current study aimed to isolate the ELF from the lichen, Usnea longissima Ach., to control of biofilm formation and quorum sensing phenomenon in Pseudomonas aeruginosa PAO1, an opportunistic multidrug resistance pathogen that uses quorum sensing network to produce an array of pathogenic agents. Therefore, inhibiting quorum sensing to manage the infection caused by PAO1 could be the paramount alternative approach to conventional antibiotics. The isolated ELF was identified by amplifying the long subunit region of the fungal genome. The extracted metabolites of ELF (MELE) using the acetone solvent was further investigated for anti-quorum sensing activity using the biomarker strain Chromobacterium violaceum 12472 which exerts violacein pigment via the AHL mediated quorum sensing signalling. Moreover, the effect of MELE was also evaluated on the production of virulence factors and biofilm formation of P. aeruginosa PAO1. The molecular identification revealed that ELF (accession number MN171299) exhibited 100% similarity with Aspergillus quandricinctus strain CBS 135.52. The MELE showed significant anti-quorum sensing activity at the concentration of 4 mg/mL without affecting the bacterial cell viability of P. aeruginosa PAO1. The MELE diminished the production of virulence factors, including pyocyanin, protease, elastase, rhamnolipids, and extracellular polysaccharides of P. aeruginosa PAO1 in a concentration-dependent manner. The MELE also disturbed biofilm formation of P. aeruginosa PAO1. The 3-D analysis of biofilm architecture showed that the thickness and surface area covered by microcolonies was decreased as the concentration of MELE was increased. The GC-MS analysis of MELE exhibited that organic acids and fatty acids are major constituents of the MELE. The present study reports first time that the ELF, A. quandricinctus possesses potential to inhibit quorum sensing and biofilm formation of P. aeruginosa and can be further exploited for hospital and healthcare facilities.

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PMID: 

An Acad Bras Cienc. 2019 ;91(3):e20180994. Epub 2019 Oct 7. PMID: 31596391

Abstract Title: 

Inhibition of growth of U87MG human glioblastoma cells by Usnea longissima Ach.

Abstract: 

Herbal medicines are efficient to reduce side effects in the fight against glioblastoma, which plays a critical role within brain cancer species. The recent studies designated for testing the effects of lichens that have shown numerous anticancer activities on glioblastoma so far. In the present study, different concentrations of water extract obtained from Usnea longissima Ach. were used in order to determine cytotoxic (via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and lactate dehydrogenase tests), antioxidant (via total antioxidant capacity test), pro-oxidant (via total oxidant status test) and genotoxic (via 8-hydroxy-2'-deoxyguanosine test) effects of them on human U87MG-glioblastoma cancer cell lines. Primary mixed glial-neuronal non-cancerous cells from Sprague-Dawley rats were also utilized to measure the effects of treatments on non-cancerous cells. Based on median inhibitory concentration values, the data belonged to non-cancerous cells (2486.71 mg/L) showed distinct towering compared to U87MG (80.93 mg/L) cells. The viability of non-cancerous and U87MG cells exposed to extract is decreased in a dose dependent manner. It was also showed that low concentrations of extract notably increased total antioxidant capacity on non-cancerous cells. In addition, various phenolic compounds in extract were detected through high-performance liquid chromatography. The recent results encourage that extract will be able to have therapeutic potential against glioblastoma.

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PMID: 

Biomolecules. 2019 Nov 28 ;9(12). Epub 2019 Nov 28. PMID: 31795147

Abstract Title: 

Lichen Secondary Metabolite Physciosporin Decreases the Stemness Potential of Colorectal Cancer Cells.

Abstract: 

Secondary metabolites of lichens are promising bioresources for candidate anti-cancer drugs. Accordingly, several approaches have been proposed for screening these molecules for novel anti-cancer lead compounds. In this study, we found that a non-toxic concentration of physciosporin, a compound isolated from Pseudocyphellaria granulata, significantly decreased colony formation on soft agar and spheroid formation by CSC221 cancer stem-like cells. Physciosporin also decreased spheroid formation in other colorectal cancer cell lines, including DLD1, Caco2, and HT29. Aldehyde dehydrogenase-1 (ALDH1), the most important cancer stem marker, was sharply downregulated at both the protein and mRNA level following treatment with physciosporin. Physciosporin also decreased the transcriptional activity of the glioma-associated oncogene homolog zinc finger protein (Gli), as well as the Hes1 and CSL promoters, in reporter assays. Moreover, the drug significantly suppressed spheroid formation in CSC221 cells overexpressing Gli1/2 orEN1 (an S2-cleaved but membrane-tethered form of human Notch1) but did not suppress spheroid formation in cells overexpressing both Gli1/2 and ∆EN1, suggesting that physciosporin suppresses colon cancer cell stemness through the Sonic hedgehog and Notch signaling pathways. Together, these results demonstrate for the first time that physciosporin is a potent inhibitor of colorectal cancer cell stemness.

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PMID: 

Biomolecules. 2020 Jan 5 ;10(1). Epub 2020 Jan 5. PMID: 31948092

Abstract Title: 

Anticancer Potential of Lichens' Secondary Metabolites.

Abstract: 

Lichens produce different classes of phenolic compounds, including anthraquinones, xanthones, dibenzofuranes, depsides and depsidones. Many of them have revealed effective biological activities such as antioxidant, antiviral, antibiotics, antifungal, and anticancer. Although no clinical study has been conducted yet, there are number of in vitro and in vivo studies demonstrating anticancer effects of lichen metabolites. The main goal of our work was to review most recent published papers dealing with anticancer activities of secondary metabolites of lichens and point out to their perspective clinical use in cancer management.

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PMID: 

J Exp Clin Cancer Res. 2018 Oct 29 ;37(1):260. Epub 2018 Oct 29. PMID: 30373628

Abstract Title: 

Lentinan inhibits tumor angiogenesis via interferonγ and in a T cell independent manner.

Abstract: 

BACKGROUND: Antiangiogenic agents are commonly used in lung and colon cancer treatments, however, rapid development of drug resistance limits their efficacy.METHODS: Lentinan (LNT) is a biologically active compound extracted from Lentinus edodes. The effects of LNT on tumor angiogenesis were evaluated by immunohistochemistry in murine LAP0297 lung and CT26 colorectal tumor models. The impacts of LNT on immune cells and gene expression in tumor tissues were determined by flow cytometry, qPCR, and ELISA. Nude mice and IFNγ blockade were used to investigate the mechanism of LNT affecting on tumor angiogenesis. The data sets were compared using two-tailed student's t tests or ANOVA.RESULTS: We found that LNT inhibited tumor angiogenesis and the growth of lung and colon cancers. LNT treatments elevated the expression of angiostatic factors such as IFNγ and also increased tumor infiltration of IFNγ-expressing T cells and myeloid cells. Interestingly, IFNγ blockade, but not T cell deficiency, reversed the effects of LNT treatments on tumor blood vessels. Moreover, long-lasting LNT administration persistently suppressed tumor angiogenesis and inhibited tumor growth.CONCLUSIONS: LNT inhibits tumor angiogenesis by increasing IFNγ production and in a T cell-independent manner. Our findings suggest that LNT could be developed as a new antiangiogenic agent for long-term treatment of lung and colon cancers.

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PMID: 

Pathol Oncol Res. 2018 Nov 20. Epub 2018 Nov 20. PMID: 30460541

Abstract Title: 

Immunomodulatory Effect of Lentinan on Aberrant T Subsets and Cytokines Profile in Non-small Cell Lung Cancer Patients.

Abstract: 

As a purified active component from traditional Chinese medicine, lentinan administration can be applied as beneficial chemo-immunotherapy for anti-tumor. In this study, the immunomodulatory effects of lentinan on aberrant T subsets and cytokines profile were evaluated for non-small cell lung cancer (NSCLC). Of all NSCLC patients treated with NP chemotherapeutic protocol (combination of vinorelbin and cisplatin), 73 cases were recruited in this retrospective cohort trial study, of which 38 cases received additional lentinan. The changes of aberrant T subsets and cytokines profile were compared between two groups (chemotherapy in combination with lentinan vs. conserved single chemotherapy) by flow cytometry and molecular biology. Higher subset ratio of CD3CD8cytotoxic T cells was confirmed in the peripheral blood of NSCLC patients. Chemo-immunotherapy of lentinan resulted in a significant increase of CD3 + CD56+ NKT cells (15.7 ± 3.1%), compared with 8.6 ± 1.4% of NKT cells in single chemotherapy group, and up-regulated CD3CD8and CD3CD4subsets as well, but caused the decrease of CD4CD25Tregs induction, accompanied by significant alleviation of IL-10 and TGF-β1, and elevation of IFN-γ, TNF-α, and IL-12 (P 

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