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PMID: Curr Clin Pharmacol. 2020 Jun 28. Epub 2020 Jun 28. PMID: 32598269 Abstract Title: Berberine nanoencapsulation attenuates hallmarks of scoplomine induced Alzheimer's-like disease in rats. Abstract: BACKGROUND: Berberine (BBR), an isoquinoline alkaloid, acts as a multipotent active pharmaceutical ingredient to counteract several types of dementia based on its numerous pharmacological actions including antioxidant, antiinflammatory, cholesterol-lowering effect, and inhibition of Aβ production and AChE. However, BBR suffers from poor absorption, bioavailability and brain drug uptake. The present study is directed for the formulation and characterization of Chitosan BBR-nanoparticles (BBR-NPs) as well as the estimation of its neuroprotective effects against scopolamine induced cognitive impairments.METHODS: BBR-NPs were formulated using ionic gelation method and tripolyphosphate was chosen as a cross linker. Nanoparticles size, zeta potential, encapsulation efficiency and releasing profile were estimated. To investigate the neuroprotective effects, adult fifty six Wistar male rats were randomly distributed into: three control groups, received saline, polyethylene glycol or chitosan- NPs respectively; induced group, received scopolamine (2 mg/ kg, i.p.) and three treated groups were orally administrated BBR (50 mg/ kg), BBR- NP (7 mg/ kg) and donepezil (2.25 mg/ kg, as positive control) followed by scopolamine injection after 40 min, daily for 4 weeks. Morris water maze test, oxidative stress parameters, cholinergic and amyloid-β processing intermediates as well as neuroplasticity markers and histopathological examination were assessed.RESULTS: Our results showed that BBR- NPs were better than BBR and donepezil as BBR- NPs were powerful inhibitory ligands toward AChE and Aβ42 formation and significantly down regulated Tau, iNOS and BACE gene expression in rats' hippocampus. BBR-NPs administration, at 1/6 of BBR therapeutic recommended dose, significantly improved learning and memory function. This could be accredited to the diminution of oxidative stress and amyloid-β toxicity in addition to the improvement of the neuroplasticity markers.CONCLUSIONS: The enhancing effect of BBR- NPs could be related to the enhancing of its bioavailability, absorption and brain drug uptake which need more investigation in future work.
PMID: Drug Des Devel Ther. 2020 ;14:2449-2460. Epub 2020 Jun 23. PMID: 32606611 Abstract Title: Berberine Attenuates Arterial Plaque Formation in Atherosclerotic Rats with Damp-Heat Syndrome via Regulating Autophagy. Abstract: Purpose: Berberine (BBR) is an effective component of Huanglian and has shown to attenuate atherosclerosis (AS); however, the detailed mechanism of BBR-mediated protective actions against AS remains elusive. This study was undertaken to examine the effects of BBR on aortic atherosclerotic plaque stability and the expression of autophagy-related proteins in AS rats with damp-heat syndrome or yang deficiency.Methods: Thirty SD rats were randomly divided into (1) control (CON); (2) damp-heat syndrome atherosclerosis (AS + DH); (3) yang deficiency syndrome atherosclerosis (AS + YX); (4) damp-heat syndrome atherosclerosis + BBR (AS + DH + BBR); (5) yang deficiency syndrome, atherosclerosis + BBR (AS + YX + BBR); and (6) damp-heat syndrome, atherosclerosis + BBR + 3-methyladenine (AS + DH + BBR + 3-MA) (n = 5/group) groups. Pathological morphology, macrophage plaque infiltration, inflammation, and LC3-II and P62 expression were assessed.Results: Compared with the CON group, the AS + DH and AS + YX groups had an increased plaque area in the aortic tissue with substantial foam cell and macrophage infiltration, and increased levels of IL-1β and TNF-α (P
PMID: Onco Targets Ther. 2020 ;13:5223-5230. Epub 2020 Jun 9. PMID: 32606742 Abstract Title: Berberine Inhibits the Apoptosis-Induced Metastasis by Suppressing the iPLA2/LOX-5/LTB4 Pathway in Hepatocellular Carcinoma. Abstract: Purpose: Hepatocellular carcinoma (HCC) is one of the most malignant cancers around the world. HCC is less sensitive to conventional cytotoxic agents and easily develops into systemic metastases. However, the molecular mechanisms of the metastasis of HCC are poorly understood and need elucidation.Materials and Methods: Transwell system of the chemotherapy-challenged and unchallenged HepG2 cells was established. Adhesion assay and scratch-wound assay were utilized to analyze the adhesion and migration of HepG2 cells. iPLA2 and LOX-5 expression were analyzed by Western blot. LTB4 level was analyzed by ELISA.Results: Chemotherapeutics are traditionally regarded as a way of killing tumor cells; on the other hand, we proved that the chemotherapeutics-induced tumor cell apoptosis can also change the tumor microenvironment by activating the LOX pathway and subsequently release inflammatory factors such as LTB4 which can stimulate the adhesion and migration of the small number of surviving cells. Berberine can reverse the adhesion and migration of HepG2 cells by inhibiting the expression of LOX-5 and reducing the LTB4 production in the tumor microenvironment.Conclusion: Our study sheds light on a novel anti-metastasis strategy that the combination of Berberine and chemotherapy may prevent the chemotherapy-induced metastasis in HCC.
PMID: Cancer Chemother Pharmacol. 2020 Jul ;86(1):151-161. Epub 2020 Jun 30. PMID: 32607786 Abstract Title: Berberine chloride suppresses non-small cell lung cancer by deregulating Sin3A/TOP2B pathway in vitro and in vivo. Abstract: PURPOSE: Berberine chloride (BBC) is a well-known plant isoquinoline alkaloid derived from Berberis aristata. In this study, we aim to explore the effect of BBC on non-small cell lung cancer (NSCLC), and further expound the underlying mechanism of BBC induces NSCLC cell death in vitro and in vivo.METHODS: CCK-8 assay and colony formation assay were used to test the viability and colony formation ability of NSCLC cells. Apoptosis analysis was used to analyze the apoptotic cells. siRNAs were utilized to disturb the expression of Sin3A. qPCR and Western blot analysis were employed to determine mRNA and protein levels of related genes and proteins. Tumor xenografts model was used for in vivo detection.RESULTS: BBC inhibited the proliferation and colony formation of human NSCLC cells in a dose- and time-dependent manner. In addition, BBC induced DNA double-stranded breaks (DSBs) through downregulating TOP2B level, leading to apoptosis in human NSCLC cells. The Chip-seq data of A549 cells obtained from the ENCODE consortium indicate that Sin3A binds on the promoters of TOP2B. Knockdown of Sin3A led to downregulation of TOP2B in human NSCLC cells. Furthermore, BBC decreased Sin3A expression and shortened the half-life of Sin3A, results in downregulation of TOP2B in human NSCLC cells.CONCLUSION: In this study, we demonstrated a new mechanism that BBC suppresses human NSCLC by deregulating Sin3A/TOP2B pathway, leading to DNA damage and apoptosis in human NSCLC in vitro and in vivo.
PMID: Med Sci Monit. 2020 Jul 5 ;26:e921831. Epub 2020 Jul 5. PMID: 32623439 Abstract Title: Therapeutic Effect of Berberine on Insomnia Rats by ErbB Signaling Pathway. Abstract: BACKGROUND Insomnia seriously affects people's health and quality of life. Short-term use of Western drugs may also be harmful. Traditional Chinese medicine has been widely used to treat diseases in world. Therefore, this paper aims to study the therapeutic effect of berberine based on the insomnious rat model. MATERIAL AND METHODS The insomnia rat model was established by intragastric administration of caffeine and parachlorophenylalanine (PCPA). Berberine and diazepam were used to treat the established insomnia rats. Then, the pathological changes of insomnia rats were detected. In addition, transcriptome sequencing and data analysis were carried out using rat hippocampus. The expression of key genes was verified by quantitative polymerase chain reaction and western blot. RESULTS After 7 days of intragastric administration of berberine, the body weight, memory, and sleep quality of insomnia rats were significantly improved. The key roles of Erbb4, Erbb2, Ar, and Grin2a in berberine treatment were identified. Through the analysis of biological functions and signaling pathways, berberine was shown to play a salutary role through nervous system development and ErbB signaling pathway. Gene-set enrichment analysis (GSEA) results showed that berberine treatment affected more metabolic pathways. Compared with diazepam, berberine can play a faster role, and also improve the overall health level of insomnia rats. CONCLUSIONS These results suggest that berberine can alleviate insomnia in rats through a neuroprotective effect and improved metabolic level. Berberine has great potential in treatment of insomnia and might have better clinical significance.
Current study reveals that berberine has inhibitory effect in pro-inflammatory cytokine-activated BEAS-2B cells.
PMID: Int J Med Sci. 2020 ;17(10):1464-1473. Epub 2020 Jun 8. PMID: 32624703 Abstract Title: Berberine Inhibits Pro-inflammatory Cytokine-induced IL-6 and CCL11 Production via Modulation of STAT6 Pathway in Human Bronchial Epithelial Cells. Abstract: Berberine is an isoquinoline alkaloid isolated from various Chinese herbs that has potential of anti-inflammatory, anti-lipidemic, anti-neoplastic, and anti-diabetic activity. In this study, we evaluated the anti-inflammatory efficacy of berberine on allergic airway inflammation by targeting epithelial cells. Allergic airway inflammation driven by T helper 2 (Th2)-type immunity is characterized by airway hyperresponsiveness, elevated IgE production, and eosinophilic infiltration. For eosinophil recruitment, major chemoattractant CCL11 (eotaxin-1) was secreted by lung epithelial cells. BEAS-2B cells, a human bronchial epithelial cell line, were pre-treated with berberine and then activated by IL-4 plus TNF-α. The viability of BEAS-2B cells was assessed. Expression levels of IL-6 and CCL11 were determined using ELISA and real-time PCR. The signaling pathways of MAP kinases, NF-κB, and STAT6 were analyzed by western blot. Berberine treatment (≤1 μM) didn't significantly affect the viability of BEAS-2B cells with or without IL-4 plus TNF-stimulation. Berberine significantly inhibited the secretion of IL-6 and CCL11 from pro-inflammatory cytokine-activated BEAS-2B cells. NF-κB and MAP kinase pathways were seemingly unaffected in BEAS-2B cells with berberine treatment. Significant reduction ofnuclear STAT6 protein expression in activated BEAS-2B cells with berberine treatment was observed. Current study reveals that berberine has inhibitory effect in pro-inflammatory cytokine-activated BEAS-2B cells through reducing IL-6 and CCL11 production, which is possibly modulated by suppressing STAT6 signaling pathway.
Sulforaphane inhibits autophagy and induces exosome-mediated paracrine senescence via regulating mTOR/TFE3.
PMID: Mol Nutr Food Res. 2020 Jun 1:e1901231. Epub 2020 Jun 1. PMID: 32476238 Abstract Title: Sulforaphane Inhibits Autophagy and Induces Exosome-Mediated Paracrine Senescence via Regulating mTOR/TFE3. Abstract: SCOPE: The development of novel compounds that trigger non-apoptotic cell death may represent alternative therapeutic strategies for esophageal squamous cell carcinoma (ESCC) treatment. Cellular senescence suppresses tumorigenesis by halting the proliferation of tumor cells, implying the induction of senescence as a promising anticancer strategy, especially when combined with senolytic agents that specially kill senescent cells. This study is designed to screen novel anti-ESCC compounds from a natural product resource and identify its mechanism-of-action.METHODS AND RESULTS: Identified are the significant anti-cancer effect and underlying mechanism of SFN, an isothiocyanate derived from cruciferous vegetables, through RNA sequencing, western blot, and immunofluorescent assays. It is found that SFN inhibits proliferation of ESCC cells through inducing senescence. Mechanistically, SFN induces reactive oxygen species (ROS) via disrupting the balance between glutathione and oxidized glutathione, leading to DNA damage. In addition, ROS deregulates autophagy and promotes lysosome abnormal biogenesis through regulating mTOR/TFE3 axis. Finally, the inhibited autophagic flux facilitates exosome production, resulting in exosome-mediated paracrine senescence.CONCLUSIONS: This study suggests the important roles of autophagy and exosome-mediated paracrine senescence in cancer therapy and highlights SFN as a potent anti-ESCC drug candidate.
PMID: Phytomedicine. 2020 Aug 15 ;75:153238. Epub 2020 May 20. PMID: 32507349 Abstract Title: Inhibitory effects of phytochemicals on NLRP3 inflammasome activation: A review. Abstract: BACKGROUND: The NLRP3 inflammasome formation and following cytokine secretion is a crucial step in innate immune responses. Internal and external factors may trigger inflammasome activation and result in inflammatory cytokine secretion. Inflammasome formation and activity play critical roles in several disease pathologies such as cardiovascular, metabolic, renal, digestive, and CNS diseases. Underlying pathways are not yet clear, but phytochemicals as alternative therapies have been extensively used for suppression of inflammatory responses.PURPOSE: In this review, we aimed to summarize in vivo and in vitro effects on NLRP3 inflammasome activation of selected phytochemicals.METHOD: Three phytochemicals; Sulforaphane, Curcumin, and Resveratrol were selected, and studies were reviewed to clarify their intracellular signaling mechanism in NLRP3 inflammasome activity. PubMed and Scopus databases are used for the search. For sulforaphane, 8 articles, for curcumin, 25 articles, and for resveratrol, 41 articles were included in the review.CONCLUSION: In vitro and in vivo studies pointed out that the selected phytochemicals have inhibitory properties on NLRP3 inflammasome activity. However, neither the mechanism is clear, nor the study designs and doses are standardized.
Sulforaphane may hold potential for treating bladder carcinoma in patients with resistance to an mTOR inhibitor.
PMID: Int J Mol Sci. 2020 Jun 4 ;21(11). Epub 2020 Jun 4. PMID: 32512849 Abstract Title: Chronic Sulforaphane Administration Inhibits Resistance to the mTOR-Inhibitor Everolimus in Bladder Cancer Cells. Abstract: Progressive bladder cancer growth is associated with abnormal activation of the mammalian target of the rapamycin (mTOR) pathway, but treatment with an mTOR inhibitor has not been as effective as expected. Rather, resistance develops under chronic drug use, prompting many patients to lower their relapse risk by turning to natural, plant-derived products. The present study was designed to evaluate whether the natural compound, sulforaphane (SFN), combined with the mTOR inhibitor everolimus, could block the growth and proliferation of bladder cancer cells in the short- and long-term. The bladder cancer cell lines RT112, UMUC3, and TCCSUP were exposed short- (24 h) or long-term (8 weeks) to everolimus (0.5 nM) or SFN (2.5µM) alone or in combination. Cell growth, proliferation, apoptosis, cell cycle progression, and cell cycle regulating proteins were evaluated. siRNA blockade was used to investigate the functional impact of the proteins. Short-term application of SFN and/or everolimus resulted in significant tumorgrowth suppression, with additive inhibition on clonogenic tumor growth. Long-term everolimus treatment resulted in resistance development characterized by continued growth, and was associated with elevated Akt-mTOR signaling and cyclin-dependent kinase (CDK)1 phosphorylation and down-regulation ofp19 and p27. In contrast, SFN alone or SFN+everolimus reduced cell growth and proliferation. Akt and Rictor signaling remained low, and p19 and p27 expressions were high under combined drug treatment. Long-term exposure to SFN+everolimus also induced acetylation of the H3 and H4 histones. Phosphorylation of CDK1 was diminished, whereby down-regulation of CDK1 and its binding partner, Cyclin B, inhibited tumor growth. In conclusion, the addition of SFN to the long-term everolimus application inhibits resistance development in bladder cancer cells in vitro. Therefore, sulforaphane may hold potential for treating bladder carcinoma in patients with resistance to an mTOR inhibitor.
PMID: J BUON. 2020 Mar-Apr;25(2):959-964. PMID: 32521892 Abstract Title: Sulforaphane exerts anticancer effects on human liver cancer cells via induction of apoptosis and inhibition of migration and invasion by targeting MAPK7 signalling pathway. Abstract: PURPOSE: This study was undertaken to investigate the anticancer effects of Sulforaphane against liver cancer and to elucidate the underlying molecular mechanisms.METHODS: WST-1 assay was used to monitor the proliferation rate. DAPI and annexin V/propidium iodide (PI) staining was used for apoptosis. Flow cytometry was used for cell cycle analysis. Wound heal and transwell assays were used to monitor cell migration and invasion. The protein expression was determined by western blot analysis.RESULTS: It was found that Sulforaphane decreased the viability of the liver cancer HepG2 cells and exhibited an IC50 of 9µM. Nonetheless, Sulforaphane (µM) exerted very low toxic effects on the normal AML12 hepatocytes and exhibited an IC50 of 100 µM. Flow cytometery analysis showed that Sulforaphane triggered G2/M arrest of the liver HepG2 cancer cells. DAPI staining revealed that Sulforaphane triggered the apoptotic cell death of HepG2 cells which was accompanied with activation of caspases 3 and 9, upregulation of Bax and downregulation of Bcl-2. Transwell assays showed that Sulforaphane inhibited the migration and invasion of the HepG2 liver cancer cells in a dose dependent manner. The effects of Sulforaphane were also investigated on the MAPK7 signalling pathway and it was found that Sulforaphane could block this pathway in HepG2 cells.CONCLUSION: Taken together, Sulforaphane may prove essential in the development of chemotherapy for liver cancers.
Sulforaphane alter the microbiota and mitigate colitis severity on mice ulcerative colitis induced by DSS.
PMID: AMB Express. 2020 Jul 3 ;10(1):119. Epub 2020 Jul 3. PMID: 32621086 Abstract Title: Sulforaphane alter the microbiota and mitigate colitis severity on mice ulcerative colitis induced by DSS. Abstract: Sulforaphane (SFN) is a kind of natural isothiocyanate, which exists in cruciferous plants. Only few studies were about the anti-inflammatory effects of sulforaphane in ulcerative colitis. In this study, our purpose is to explore the effects of sulforaphane on the intestinal microbial community of UC mice. The severity of mice colitis were measured by colon length, survial rate, body weight and disease activity index (DAI) score. Histological and morphological evaluation of colon tissues were performed by HE. 16S rRNA gene amplicon pyrosequencing was used to analyza the changes of mouse flora. The variety of flora expression were explored using quantitative PCR. Sulforaphane treated mice had larger body weight and longer colon length than DSS-induced mice. The colon tissues of DSS group showed congestion and edema. Meanwhile, treatment with sulforaphane effectively reducted the damage scores and MPO activity. Sulforaphane reversed DSS-induced gut dysbiosis. Sulforaphane would shift the balance to Butyricicoccus on inflammation. The possible anti-inflammatory mechanism of sulforaphane is to coordinate with the probiotics such as Butyricicoccus. In summary, these findings proved that sulforaphane might be a useful content and serve as a potential therapy in the treatment of UC.
PMID: Int J Mol Med. 2020 Apr ;45(4):1261-1269. Epub 2020 Feb 14. PMID: 32124952 Abstract Title: Cordyceps sinensis attenuates HBx‑induced cell apoptosis in HK‑2 cells through suppressing the PI3K/Akt pathway. Abstract: The authors' previous studies demonstrated that the major renal damage from hepatitis B virus infection is HBx‑induced apoptosis of renal tubular epithelial cells. Cordyceps sinensis is one of the most valuable of traditional Chinese medicines and is extensively used to treat chronic renal diseases. However, there is no research on the potential renal protective effect of C. sinensis on HBx‑induced apoptosis of renal tubular cells. The protective effect and underlying mechanism of C. sinensis were examined using a renal tubular epithelial cell line stably overexpressing HBx. HK‑2 cells were stably transfected with pCMV‑HBx to establish HBx‑overexpression in an in vitro cell model and HK‑2 cells transfected with an empty vector were generated as a control. The effect of C. sinensis on cell proliferation and apoptosis, the phosphatidylinositol‑3‑kinase (PI3K)/protein kinase B (Akt) signaling pathway, and the enzyme activity of caspase‑3 and caspase‑9 was measured. The present study demonstrated that HBx transfection inhibited cell proliferation; increased apoptosis, caspase‑3 and caspase‑9 activity; and increased the activity of the PI3K/Akt pathway. Treatment with C. sinensis attenuated all of these HBx‑induced responses. HBx triggered apoptosis and activated the PI3K/Akt signaling pathway in HK‑2 cells. C. sinensis treatment significantly attenuated the effect of HBx, at least in part by suppressing the PI3K/Akt signaling pathway.
PMID: Neurochem Res. 2020 Jun 17. Epub 2020 Jun 17. PMID: 32556929 Abstract Title: Polyphenols from Toona sinensiss Seeds Alleviate Neuroinflammation Induced by 6-Hydroxydopamine Through Suppressing p38 MAPK Signaling Pathway in a Rat Model of Parkinson's Disease. Abstract: Polyphenols from Toona sinensis seeds (PTSS) have demonstrated anti-inflammatory effects in various diseases, while the anti-neuroinflammatory effects still remain to be investigated. We aimed to investigate the effects of PTSS on Parkinson's disease and underlying mechanisms using a rat model. We employed 6-hydroxydopamine (6-OHDA) to male Sprague Dawley (SD) rats and PC12 cells to construct the in vivo and vitro models of PD and dopaminergic (DA) neuron injury, respectively. Cell viability was detected by cell counting kit-8 (CCK-8) assay and protein levels of inflammatory mediators and some p38 MAPK pathway molecules were investigated by immunohistochemistry and Western blot analyses. The results showed that 6-OHDA significantly increased protein levels of inflammatory mediators, such as cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and tumor necrosis factorα (TNF-α), which could be reversed by PTSS through suppressing the p38 MAPK pathway. The anti-inflammatory effects of PTSS were significantly enhanced by the specific p38 inhibitor of SB203580 in vitro. The present work suggests that PTSS can exert anti-inflammatory effects on PD models, which maybe attributed to the suppression of p38 MAPK signaling pathway.
Toona sinensis modulates autophagy and cytokines in lipopolysaccharide-induced RAW 264.7 macrophages.
PMID: Biomed Pharmacother. 2020 Jun 18 ;129:110386. Epub 2020 Jun 18. PMID: 32563986 Abstract Title: Toona sinensis modulates autophagy and cytokines in lipopolysaccharide-induced RAW 264.7 macrophages. Abstract: Toona sinensis (TS) is a medicinal herb possessing anti-apoptotic, anti-oxidant, and anti-inflammatory properties and is used to treat diabetes, cancer, and inflammatory diseases. In traditional Chinese medicine theory, TS clears dampness and heat, strengthens the stomach function, and regulates vital energy flow. TS is also used as an astringent and a pesticide. In this study, we aimed to evaluate how TS influences autophagy and cytokines during the inflammatory process in RAW 264.7 macrophages. The treatment groups were pre-supplemented with TS leaf extract; rapamycin was used to enhance autophagy and lipopolysaccharide (LPS) was used to induce inflammation. The expression of autophagy-related proteins was analyzed by western blotting. The survival rate of, and chemokine expression and oxidative stress in the cells were also assessed. TS leaf extract inhibited mammalian target of rapamycin (mTOR) phosphorylation at site S2448 in the macrophages. At relatively higher concentrations (50 and 75 μg/mL), TS elevated the expression of light chain 3 II (LC3-II), which further modulated autophagy. Pre-supplementation with TS leaf extract elevated the total glutathione (GSH) level and GSH/oxidized GSH (GSSG) ratio, but it decreased the GSSG, total nitric oxide, nitrate, nitrite, malondialdehyde, and superoxide anion levels. TS reversed the effects of LPS-induced cytokines, including interleukin (IL)-6 and IL-10. TS did not induce significant toxicity at the studied concentrations. In conclusion, TS leaf extract may modulate autophagy during inflammation. Furthermore, it may prevent cell damage via anti-inflammation and anti-oxidation. Thus, this study supports the ethnomedical use of TS in the prevention of inflammation-related diseases.
Hesperidin, a polyphenolic compound extracted from citrus fruits and known for its anti-inflammatory properties, may have beneficial effects on cardiovascular and neurodegenerative diseases
PMID: Front Pharmacol. 2018 ;9:1449. Epub 2018 Dec 17. PMID: 30618745 Abstract Title: Mycelia Exert Anti-liver Cancer Effects and Inhibit STAT3 Signalingand. Abstract: Hepatocellular carcinoma (HCC), the major form of primary liver cancer, is a common cause of cancer-related death worldwide. Signal transducer and activator of transcription 3 (STAT3) signaling is constantly activated in HCC and has been proposed as a chemotherapeutic target for HCC.(AC), a medicinal mushroom unique to Taiwan, is traditionally used for treating HCC. Whereas natural AC is scarce, cultured AC mycelia are becoming alternatives. In this study, we investigated the anti-HCC effects of the ethyl acetate fraction of an ethanolic extract of AC mycelia (EEAC), particularly exploring the involvement of STAT3 signaling in these effects. We found that EEAC reduced cell viability, induced apoptosis, and retarded migration and invasion in cultured HepG2 and SMMC-7721 cells. Immunoblotting results showed that EEAC downregulated protein levels of phosphorylated and total STAT3 and JAK2 (an upstream kinase of STAT3) in HCC cells. Real-time PCR analyses showed that STAT3, but not JAK2, mRNA levels were decreased by EEAC. EEAC also lowered the protein level of nuclear STAT3, decreased the transcriptional activity of STAT3, and downregulated protein levels of STAT3-targeted molecules, including anti-apoptotic proteins Bcl-xL and Bcl-2, and invasion-related proteins MMP-2 and MMP-9. Over-activation of STAT3 in HCC cells diminished the cytotoxic effects of EEAC. In SMMC-7721 cell-bearing mice, EEAC (100 mg/kg, i.g. for 18 days) significantly inhibited tumor growth. Consistent with ourdata, EEAC induced apoptosis and suppressed JAK2/STAT3 activation/phosphorylation in the tumors. Taken together, EEAC exerts anti-HCC effects bothand; and inhibition of STAT3 signaling is, at least in part, responsible for these effects. We did not observe significant toxicity of EEAC in normal human liver-derived cells, nude mice and rats. Our results provide a pharmacological basis for developing EEAC as a safe and effective agent for HCC management.
Study on Antrodia camphorata polysaccharide in alleviating the neuroethology of Parkinson's disease.
PMID: Phytother Res. 2019 Sep ;33(9):2288-2297. Epub 2019 Jul 29. PMID: 31359520 Abstract Title: Study on antrodia camphorata polysaccharide in alleviating the neuroethology of PD mice by decreasing the expression of NLRP3 inflammasome. Abstract: Parkinson's disease (PD) is a neurodegenerative disease, and the role of neuroinflammation in the pathogenesis and progression of PD has been confirmed. The polysaccharides and triterpenoids of antrodia camphorata (a polyporous fungus) harbor diverse and powerful pharmacological effects. In this study, 6-hydroxydopamine was used to construct a PD mouse model. After antrodia camphorata polysaccharide (ACP) intervention, neurobehavioral changes were detected, neurotransmitter changes in striatum were determined by high-performance liquid chromatography, the alterations of striatal NOD-like receptor pyrin domain containing three (NLRP3) were examined by immunohistochemistry, and the expression of NLRP3, IL-1β, Caspase-1, and proCaspase-1 were detected by western blot. To be specific, the items of neurobehavioral test included open field activity, rotary test, pole test, gait analysis, and swimming test. As a result, 6-hydroxydopamine could lead to PD-like lesions, including tremor, stiffness, attenuated spontaneous activity, and bradykinesia in mice, and the expression of tyrosine hydroxylase in the striatum was decreased. After ACP intervention, the neuroethology of mice was significantly improved, as demonstrated by the elevated levels of dopamine in the striatum and the decreased expression of dopamine in the striatum in NLRP3 inflammasome. NLRP3 inflammasome played an important role in neuroinflammation in PD mice. ACP could reduce the activation of NLRP3 and expression of related inflammatory factors.
PMID: J Food Biochem. 2019 08 ;43(8):e12936. Epub 2019 Jun 4. PMID: 31368557 Abstract Title: Antrodia cinnamomea-An updated minireview of its bioactive components and biological activity. Abstract: Antrodia cinnamomea or Antrodia camphorata is a distinctive mushroom of Taiwan, which is being used as a traditional medicine to treat various health-related conditions. More than 78 compounds have been identified in A. cinnamomea. Large numbers of phytochemical studies have been carried out in A. cinnamomea due to the high amount of terpenoids. Besides that, the extracts and active components of A. cinnamomea were reported to have various biological activities including hepatoprotective, antihypertensive, antihyperlipidemic, anti-inflammatory, antioxidant, antitumor, and immunomodulatory activities. In this review article, we have summarized the recent findings of A. cinnamomea and its molecular mechanisms of action in various disease models. PRACTICAL APPLICATIONS: A. cinnamomea, medicinal fungus used in traditional medicine in Taiwan also possess high market value. Aim of the present review is to highlight the compounds present in A. cinnamomea and their different pharmacological activities in preventing/cure various diseases/disorders. A. cinnamomea can be potentially developed into health foods or drugs.
PMID: Int J Mol Sci. 2019 Oct 2 ;20(19). Epub 2019 Oct 2. PMID: 31581697 Abstract Title: Antidiabetic and Antihyperlipidemic Effects of Sulphurenic Acid, a Triterpenoid Compound from, in Streptozotocin-Induced Diabetic Mice. Abstract: The present study was designed to evaluate the protective effect of sulphurenic acid (SA), a pure compound from, on diabetes and hyperlipidemia in an animal model study and to clarify the underlying molecular mechanism. Diabetes was induced by daily 55 mg/kg intraperitoneal injections of streptozotocin (STZ) solution over five days. Diabetic mice were randomly divided into six groups and orally gavaged with SA (at three dosages) or glibenclamide (Glib), fenofibrate (Feno) or vehicle for 3 weeks. Our findings showed that STZ-induced diabetic mice had significantly increased fasting blood glucose, glycated hemoglobin (HbA1), plasma triglyceride (TG), and total cholesterol (TC) levels (
PMID: J Ethnopharmacol. 2020 May 15 ;260:112969. Epub 2020 May 15. PMID: 32422358 Abstract Title: Extracts of Cordyceps sinensis inhibit breast cancer growth through promoting M1 macrophage polarization via NF-κB pathway activation. Abstract: ETHNOPHARMACOLOGICAL RELEVANCE: Cordyceps sinensis is a traditional Chinese medicine. It is widely reported that Cordyceps sinensis has inhibitory effect on tumor growth and immunoregulation effect on macrophages. However, the exact mechanism of Cordyceps sinensis on macrophage polarization in tumor progression is not known.AIM OF STUDY: We aimed to investigate the role of extracts of Cordyceps sinensis on macrophage polarization and its underlying mechanism in antitumor activity.MATERIALS AND METHODS: The 4T1 orthotopic xenograft mouse model and immunohistochemical staining were used to investigate the effect of Cordyceps sinensis on breast tumor and the change of the macrophages phenotype in the tumor, respectively. A 3D co-culture assay was used to confirm the activity in vitro. Measurement of cytokines and NO, quantitative real-time PCR and flow cytometry assays were used to investigate the effect of Cordyceps sinensis on the macrophage polarization in vitro. The mechanism of the effect of Cordyceps sinensis on macrophages was investigated by using western blot assays.RESULTS: In the orthotopic mouse tumor model, Cordyceps sinensis inhibited the 4T1 tumor growth in a dose dependent manner, and the immunohistochemical staining analysis showed that there is a positive correlation between tumor growth inhibition and macrophage M1-like polarized phenotype. The cytokines and NO measurement, quantitative real-time PCR assay and flow cytometry assays confirmed that Cordyceps sinensis could promote macrophage differentiation toward the M1 phenotype. The 3D co-culture assay and western blot assay showed that Cordyceps sinensis could inhibit tumor growth by promoting macrophage polarization and enhance its activity by activating the NF-κB signaling pathway.CONCLUSION: These findings suggest that Cordyceps sinensis could potently suppress TNBC progression by promoting M1 phenotypic differentiation of macrophages via activation NF-κB signaling pathway in tumor microenvironment.
PMID: J Pharmacol Exp Ther. 2020 May ;373(2):279-289. Epub 2020 Feb 26. PMID: 32102917 Abstract Title: Cordycepin Inhibits Cancer Cell Proliferation and Angiogenesis through a DEK Interaction via ERK Signaling in Cholangiocarcinoma. Abstract: Cholangiocarcinoma (CCA) is a malignant tumor that arises from the epithelial cells of the bile duct and is notorious for its poor prognosis. The clinical outcome remains disappointing, and thus more effective therapeutic options are urgently required. Cordycepin, a traditional Chinese medicine, provides multiple pharmacological strategies in antitumors, but its mechanisms have not been fully elucidated. In this study, we reported that cordycepin inhibited the viability and proliferation capacity of CCA cells in a time- and dose-dependent manner determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and colony formation assay. Flow cytometry and Hoechst dye showed that cordycepin induced cancer cell apoptosis via extracellular signal-regulated kinase (ERK) 1/2 deactivation. Moreover, cordycepin significantly reduced the angiogenetic capabilities of CCA in vitro as examined by tube formation assay. We also discovered that cordycepin inhibited DEK expression by using Western blot assay. DEK serves as an oncogenic protein that is overexpressed in various gastrointestinal tumors. DEK silencing inhibited CCA cell viability and angiogenesis but not apoptosis induction determined by Western blot and flow cytometry. Furthermore, cordycepin significantly inhibited tumor growth and angiogenic capacities in a xenograft model by downregulating the expression of DEK, phosphorylated ERK1/2 CD31 and von Willebrand factor (vWF). Taken together, we demonstrated that cordycepin inhibited CCA cell proliferation and angiogenesis with a DEK interaction via downregulation in ERK signaling. These data indicate that cordycepin may serve as a novel agent for CCA clinical treatment and prognosis improvement. SIGNIFICANCE STATEMENT: Cordycepin provides multiple strategies in antitumors, but its mechanisms are not fully elucidated, especially on cholangiocarcinoma (CCA). We reported that cordycepin inhibited the viability of CCA cells, induced apoptosis via extracellular signal-regulated kinase 1/2 deactivation and DEK inhibition, and reduced the angiogenetic capabilities of CCA both in vivo and in vitro.
Cordycepin exhibits a suppressive effect on T cells through inhibiting TCR signalling cascade in CFA-induced inflammation Mice model.
PMID: Immunopharmacol Immunotoxicol. 2020 Apr ;42(2):119-127. Epub 2020 Feb 27. PMID: 32105161 Abstract Title: Cordycepin exhibits a suppressive effect on T cells through inhibiting TCR signaling cascade in CFA-induced inflammation mice model. Abstract: Cordycepin has been shown to exhibit multiple pharmacological activities, such as antitumor, antifungi, antivirus, and immune-regulation activities, and is involved in the regulation of T cells. However, cordycepin that affects T cell activity is still not clear, and the molecular mechanism of cordycepin in regulation of TCR signaling has not yet been elucidated. In this study, the potential effect of cordycepin on T cells was observed in CFA-induced inflammation mice model, and the function of cordycepin in regulating TCR signaling cascade was investigated.A CFA-induced inflammation mice model was established for observing the effect of cordycepin on the thymus and spleen swellings, and T cell infiltration in paw tissue was detected by immunohistochemistry. The protein expression or phosphorilation was detected by western blotting, and the NFAT1 nuclear translocation was determined by fluorescence imaging. The cell proliferation, apoptosis, and IL-2 production were analyzed by CCK-8 method, flow cytometry, and ELISA.In the mice model, the thymus and spleen swellings were suppressed and the T cell infiltration in paw tissue was inhibited by cordycepin at a concentration of 10 mg/kg. Although the expressions of ZAP70 and PLCγ1 were not significantly changed in the human T cell line Jurkat with cordycepin pretreatment, the CD3-antibody-induced phosphorylations of ZAP70 and PLCγ1 were markedly blocked. The protein level of p85 decreased when Jurkat cells were pretreated with cordycepin, and cordycepin blocked TCR downstream molecule Erk phosphorylation and NFAT1 nuclear translocation. Further investigation revealed that cordycepin inhibited T cell proliferation, reduced IL-2 production, and induced T cell apoptosis.These findings suggest that cordycepin regulates TCR signaling to inhibit excessive T cell activation in inflammation. Thus, cordycepin may be a potential therapeutic application in inflammation-associated diseases.
PMID: Int J Mol Sci. 2020 Mar 2 ;21(5). Epub 2020 Mar 2. PMID: 32131547 Abstract Title: Cordycepin Resensitizes T24R2 Cisplatin-Resistant Human Bladder Cancer Cells to Cisplatin by Inactivating Ets-1 Dependent MDR1 Transcription. Abstract: Tumor cell resistance to anti-cancer drugs is a major obstacle in tumor therapy. In this study, we investigated the mechanism of cordycepin-mediated resensitization to cisplatin in T24R2 cells, a T24-derived cell line. Treatment with cordycepin or cisplatin (2μg/mL) alone failed to induce cell death in T24R2 cells, but combination treatment with these drugs significantly induced apoptosis through mitochondrial pathways, including depolarization of mitochondrial membranes, decrease in anti-apoptotic proteins Bcl-2, Bcl-xL, and Mcl-1, and increase in pro-apoptotic proteins Bak and Bax. High expression levels of MDR1 were the cause of cisplatin resistance in T24R2 cells, and cordycepin significantly reduced MDR1 expression through inhibition of MDR1 promoter activity. MDR1 promoter activity was dependent on transcription factor Ets-1 in T24R2 cells.Although correlation exists between MDR1 and Ets-1 expression in bladder cancer patients, active Ets-1, Thr38 phosphorylated form (pThr38), was critical to induce MDR1 expression. Cordycepin decreased pThr-38 Ets-1 levels and reduced MDR1 transcription, probably through its effects on PI3K signaling, inducing the resensitization of T24R2 cells to cisplatin. The results suggest that cordycepin effectively resensitizes cisplatin-resistant bladder cancer cells to cisplatin, thus serving as a potential strategy for treatment of cancer in patients with resistance to anti-cancer drugs.
PMID: Food Funct. 2020 Mar 26 ;11(3):2107-2116. PMID: 32163051 Abstract Title: Natural cordycepin induces apoptosis and suppresses metastasis in breast cancer cells by inhibiting the Hedgehog pathway. Abstract: In the study, we investigated the role of the hedgehog (Hh) pathway in cordycepin's effects on human breast cancer cells, with respect to cell growth, apoptosis and metastasis. We found cordycepin to have low toxicity but significant anticancer effects. Cordycepin-induced apoptosis led to increased PUMA, CYTO-C, FAS, DR4/5, and cleaved caspase-3; and decreased BCL-2, XIAP and PDGFR-α. Cordycepin inhibited metastasis, which was associated with up-regulated E-cadherin, and down-regulated N-cadherin, SNAIL, SLUG and ZEB1. Cordycepin also inhibited expression of Hh pathway components and GLI transcriptional activity. Inversely, knockout of GLI blocked cordycepin-mediated effectson the apoptotic, epithelial-mesenchymal transition (EMT) and Notch pathways, which indicates that GLI is crucial for cordycepin's effects against breast cancer. Inhibition of GLI enhanced cordycepin's effect on breast cancer cell growth. To our knowledge, this is the first study of cordycepin's effect on the Hh pathway in breast cancer, and provides preliminary data for the in vivo study, and possible therapeutic use, of cordycepin.
PMID: Life Sci. 2020 Jun 15 ;251:117645. Epub 2020 Apr 5. PMID: 32268154 Abstract Title: Cordycepin protects against acute pancreatitis by modulating NF-κB and NLRP3 inflammasome activation via AMPK. Abstract: Acute pancreatitis (AP) is a noninfectious inflammatory disease with high morbidity and mortality, which is characterized by severe inflammation and tissue necrosis. Cordycepin (CRD), derived from Cordyceps militaris, possesses anti-inflammatory effects and immunomodulation properties. Here, we investigated the protective effects of CRD on pancreatic injury and clarified potential mechanisms in AP model. There were established caerulein-induced AP and CRD pretreatment models in vivo and in vitro, as showed by serum enzymes, histopathological alterations and pro-inflammatory cytokines. Pretreatment with CRD notably downregulated the serum amylase and lipase levels and apparently reduced pancreatic histopathological alterations in AP mice. Meanwhile, the MPO staining confirmed that CRD pretreatment modulated the infiltration of neutrophils in AP mice. Furthermore, CRD markedly decreased the levels of pro-inflammatory factors (IL-6, IL-1β, and TNF-α) though inhibiting the activation of nuclear factor-κB (NF-κB) and NLR family pyrin domain-containing protein 3 (NLRP3) inflammasome in AP mice. In pancreatic acinar cancer cell 266-6, CRD pretreatment decreased cholecystokinin(CCK)-induced inflammatory response was consistent withthose in vivo. Mechanistically, CRD was also revealed to activate activated protein kinase (AMPK) and attenuated inflammation both in vivo and in vitro. On the whole, this study indicated that CRD protects mice from pancreatic inflammatory process and damage by suppressed NF-κB and NLRP3 inflammasome activation via AMPK, which probably contributed to the potential therapy for AP.
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Hesperidin, a polyphenolic compound extracted from citrus fruits and known for its anti-inflammatory properties, may have beneficial effects in the prevention of cardiovascular and neurodegenerative diseases. Further study indicates that hesperidin may prevent varicose vein formation and be useful in the treatment of hemorrhoids and diabetes, yet many have yet to hear about this powerful flavonoid
PMID: Chin J Nat Med. 2020 May ;18(5):345-355. PMID: 32451092 Abstract Title: Cordycepin inhibits pancreatic cancer cell growth in vitro and in vivo via targeting FGFR2 and blocking ERK signaling. Abstract: Cordycepin (3'-deoxyadenosine) from Cordyceps militaris has been reported to have anti-tumor effects. However, the molecular target and mechanism underlying cordycepin impeding pancreatic cancer cell growth in vitro and in vivo remain vague. In this study, we reported functional target molecule of cordycepin which inhibited pancreatic cancer cells growth in vitro and in vivo. Cordycepin was confirmed to induce apoptosis by activating caspase-3, caspase-9 and cytochrome c. Further studies suggested that MAPK pathway was blocked by cordycepin via inhibiting the expression of Ras and the phosphorylation of Erk. Moreover, cordycepin caused S-phase arrest and DNA damage associated with activating Chk2 (checkpoint kinase 2) pathway and downregulating cyclin A2 and CDK2 phosphorylation. Very interestingly, we showed that cordycepin could bind to FGFR2 (K= 7.77× 10) very potently to inhibit pancreatic cancer cells growth by blocking Ras/ErK pathway. These results suggest that cordycepin could potentially be a leading compound which targeted FGFR2 to inhibit pancreatic cells growth by inducing cell apoptosis and causing cell cycle arrest via blocking FGFR/Ras/ERK signaling for anti-pancreatic cancer new drug development.
PMID: Integr Cancer Ther. 2020 Jan-Dec;19:1534735420923756. PMID: 32456485 Abstract Title: Exerts Anticancer Effect on Non-Small Cell Lung Cancer by Inhibiting Hedgehog Signaling via Suppression of TCTN3. Abstract: This study aimed to investigate the effect ofextract on the proliferation and apoptosis of non-small cell lung cancer (NSCLC) cells and determine the underlying mechanisms. We performed a CCK-8 assay to detect cell proliferation, detection of morphological changes through transmission electron microscopy (TEM), annexin V-FITC/PI double staining to analyze apoptosis, and immunoblotting to measure the protein expression of apoptosis and hedgehog signaling-related proteins, withtreated NSCLC cells. In this study, we first found thatreduced the viability and induced morphological disruption in NSCLC cells. The gene expression profiles indicated a reprogramming pattern of genes and transcription factors associated with the action of TCTN3 on NSCLC cells. We also confirmed that the-induced inhibition of TCTN3 expression affected the hedgehog signaling pathway. Immunoblotting indicated that-mediated TCTN3 downregulation induced apoptosis in NSCLC cells, involved in the serial activation of caspases. Moreover, we demonstrated that thenegatively modulated GLI1 transcriptional activity by suppressing SMO/PTCH1 signaling, which affects the intrinsic apoptotic pathway. When hedgehog binds to the PTCH1, SMO dissociates from PTCH1 inhibition at cilia. As a result, the active GLI1 translocates to the nucleus.clearly suppressed GLI1 nuclear translocation, leading to Bcl-2 and Bcl-xL down-regulation. These results suggested thatinduced NSCLC cell apoptosis, possibly through the downregulation of SMO/PTCH1 signaling and GLI1 activation via inhibition of TCTN3. Taken together, our findings provide new insights into the treatment of NSCLC using.
PMID: Integr Cancer Ther. 2020 Jan-Dec;19:1534735420932635. PMID: 32571104 Abstract Title: Efficacy of Ethyl Acetate Fraction offor Cancer-Related Fatigue in Blood Biochemical andH-Nuclear Magnetic Resonance Metabolomic Analyses. Abstract: This study investigated the adjuvant effects for anticancer and antifatigue of the combination ofextract with sorafenib. The 5 extracts ofwere obtained through hexane, chloroform, ethyl acetate, butanol, and water and were evaluated for anticancer growth activity. Among these extracts, ethyl acetate extract ofshowed the best tumor growth inhibitory activity and the adjuvant effects in combination with sorafenib. As a result of biochemical analysis with serum, the combination of ethyl acetate extract ofwith sorafenib showed the adjuvant effects both improving hepatic function and relieving cancer-related fatigue. In addition,H-nuclear magnetic resonance-based metabolic profiling in liver tissues showed that the change of metabolism by ethyl acetate extract ofwith sorafenib was related with serum fatigue biomarkers. Therefore, the combination strategy such as ethyl acetate extraction ofwith sorafenib constitutes a promising therapeutic strategy in hepatocellular carcinoma, via the inhibition of cancer growth, the enhancement of liver function, as well as the alleviation of cancer-related fatigue.