PMID: 

Eur J Pharmacol. 2019 Aug 5 ;856:172352. Epub 2019 Apr 17. PMID: 31004603

Abstract Title: 

Isoliquiritigenin suppresses the proliferation and induced apoptosis via miR-32/LATS2/Wnt in nasopharyngeal carcinoma.

Abstract: 

Nasopharyngeal Carcinoma is limited by the various severe side-effects and surgery is rarely performed. Iosliquiritigenin has a series of biological activities, such as antiviral, anti-free radical and antitumor. However, the role and underlying mechanism of isoliquiritigenin in nasopharyngeal carcinoma have not been understood yet. Herein, the results revealed that isoliquiritigenin could inhibit cell proliferation in nasopharyngeal carcinoma cell lines, including C666-1 and CNE2, in both Cell Counting Kit-8 (CCK-8) and 5-Ethynyl-2'-deoxyuridine (EdU) assay. In addition, isoliquiritigenin promoted nasopharyngeal carcinoma cell apoptosis, with the up-regulations of Bax, Caspase-3 and Caspase-9 and the down-regulation of Bcl-2. Meanwhile, isoliquiritigenin suppressed nasopharyngeal carcinoma cells migration and invasion with the down-regulation of matrix metalloproteinases (MMP)-2 and MMP-9. Furthermore, the expression of miR-32 was up-regulated in the nasopharyngeal carcinoma tissues, while isoliquiritigenin could significantly down-regulate the expression of miR-32. And over-expression of miR-32 promoted the nasopharyngeal carcinoma cells growth, migration and invasion, and suppressed apoptosis. However, isoliquiritigenin treatment dramatically inhibited the effect of miR-32. Besides, luciferase reporter assay confirmed that large tumor suppressor 2 (LATS2) was a direct target of miR-32. And isoliquiritigenin increased the expression of LATS2, while silencing of LATS2 promoted the nasopharyngeal carcinoma cells growth. Moreover, western blotting discovered that isoliquiritigenin inhibited nasopharyngeal carcinoma cells growth via Wnt signaling pathway. Finally, CNE2 cells transplanted xenografts tumor model in nude mice were performed and it suggested that isoliquiritigenin could inhibit the development of xenografts nude mice, along with the decrease of tumor volume and the expression of miR-32 and LATS2. Overall, isoliquiritigenin was confirmed to be a potent anti-nasopharyngeal carcinoma compound both in vitro and in vivo, and accomplished by regulation of miR-32/LATS2/Wnt.

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PMID: 

Biosci Rep. 2019 May 31 ;39(5). Epub 2019 May 2. PMID: 30910851

Abstract Title: 

Harmine suppresses bladder tumor growth by suppressing vascular endothelial growth factor receptor 2-mediated angiogenesis.

Abstract: 

Angiogenesis is a vital step during the process of oncogenesis of a lot of tumors, with no exception in bladder cancer. One of the useful strategies for the development of new drugs against cancer is targeting angiogenesis. In the present study, we found that a small-molecule natural product, which belonged to theβ-carboline alkaloid, named harmine, could strongly inhibit tumor angiogenesis thus exhibiting its ideal treatment efficacy in bladder cancer.study verified that harmine had the effect of inhibition on human bladder tumor xenograft growth. The inhibitory effect of harmine to bladder cancer growth was coordinated by the effects shown on angiogenesis. To further explore the pharmacological activities of harmine, we tested harmine's influence on blood vessel formation and found that harmine effectively blocked the microvessel sprouting in rat aortic ring assay when stimulated by vascular endothelial growth factor (VEGF). Furthermore, harmine inhibited human umbilical vein endothelial cell (HUVEC) proliferation as well as chemotactic motility, and when we treated HUVEC cell with harmine, the formation of capillary-like structures was also restrained. Moreover, harmine induced bladder cancer cell apoptosis through triggering the caspase-dependent apoptotic pathway and the downstream vascular endothelial growth factor receptor 2 (VEGFR2) kinase pathway was down-regulated, thus suppressing tumor development signals. Herein, our study demonstrated that natural product harmine might have potential in curing human bladder tumor because of its pharmacological function on tumor angiogenesis, trigged by VEGFR2 signaling pathways.

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PMID: 

Phytomedicine. 2019 Aug ;61:152842. Epub 2019 Jan 30. PMID: 31048127

Abstract Title: 

Natural alkaloid harmine promotes degradation of alpha-synuclein via PKA-mediated ubiquitin-proteasome system activation.

Abstract: 

BACKGROUND: Parkinson's disease (PD) is an age-dependent progressive movement disorder characterized by a profound and selective loss of nigrostriatal dopaminergic neurons. Accumulation of-synuclein (-syn) positive protein aggregates in the substantia nigra is a pathological hallmark of PD, indicating that protein turnover defect is implicated in PD pathogenesis.PURPOSE: This study aims to identify neuroprotective compounds which can alleviate the accumulation of-syn in neuronal cells and dissect the underlying mechanisms.METHODS: High throughput screening was performed by dot blot assay. The degradation of different forms of-syn by candidate compounds were assessed by western blot. The autophagy lysosome pathway and ubiquitin-proteasome system were examined to dissect the degradation pathway. The UPS activity was assessed by cellular UPS substrates degradation assay and biochemical proteasome activity assay. Q-PCR was performed to test the mRNA level of different proteasome subunits. Furthermore, Neuroprotective effect of candidate compound was tested by LDH assay and PI staining.RESULTS: Through the high throughput screening, harmine was identified as a potent-syn lowering compound. The time-dependent and dose-dependent effects of harmine on the degradation of different forms of-syn were further confirmed. Harmine could dramatically promote the degradation of UPS substrates GFP-CL1, Ub-R-GFP and Ub-G76V-GFP, and activate cellular proteasome activity. Mechanistically, harmine dramatically enhanced PKA phosphorylation to enhance proteasome subunit PSMD1 expression. PKA inhibitor blocked the effects of harmine in activating UPS, up regulating PSMD1 and promoting-syn degradation, indicating that harmine enhances UPS function via PKA activation. Moreover, harmine efficiently rescued cell death induced by over-expression of-syn, via UPS-dependent manner.CONCLUSION: Harmine, as a new proteasome enhancer, may have potential to be developed into therapeutic agent against neurodegenerative diseases associated with UPS dysfunction and aberrant proteins accumulation.

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PMID: 

Histol Histopathol. 2019 May 3:18122. Epub 2019 May 3. PMID: 31049922

Abstract Title: 

Harmine shows therapeutic activity on Nicotine-induced liver failure in mice.

Abstract: 

This experiment evaluated the effects of harmine against nicotine-induced damage to the liver of mice. Nicotine is a major toxic component of cigarette smoke and a major risk factor for functional disorders in the liver, because it induces oxidative stress. Harmine is a harmal-derived alkaloid with therapeutic and antioxidant properties. In this study, 80 male mice were randomly assigned to 10 groups: the normal control and nicotine control groups (2.5 mg/kg); the harmine groups (5, 10, 15, and 20 mg/kg), and the nicotine + harmine groups (5, 10, 15 and 20 mg/kg mg/kg). Treatments were administered intraperitoneally daily for 28 days. Nitric oxide (NO) level, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) concentrations were determined. In addition, thiobarbituric acid reactive species, antioxidant capacity, and the diameters of the hepatocytes and central hepatic vein (CHV) were investigated. Nicotine administration significantly improved liver MDA and NO levels, CHV and hepatocyte diameters, and liver enzymes, and it decreased tissue FRAP levels compared to the normal control group (p

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PMID: 

Fitoterapia. 2019 Sep ;137:104196. Epub 2019 Jun 6. PMID: 31175948

Abstract Title: 

Pre-clinical investigations ofβ-carboline alkaloids as antidepressant agents: A systematic review.

Abstract: 

Depressive disorders remain a current public health problem whose prevalence has increased in the past decades. In the constant search for new therapeutic alternatives,β-carboline alkaloids have been identified as good candidates for new antidepressant drugs. In this systematic review, we summarized all pre-clinical investigations involving the use of natural or semisynthetic β-carboline in depression models. A literature search was conducted in August 2018, using PubMed, Scopus and Science Direct databases. All reports were carefully analyzed, and data extraction was conducted through standardized forms. Methodological quality assessment of in vivo studies was also performed. The entire systematic review was performed according to PRISMA statement. From atotal of 373 articles, 26 met all inclusion criteria. In vitro and in vivo studies have evaluated a wide variety of β-carbolines through enzymatic and binding assays, and acute or chronic animal models. Most of the in vivo and in vitro studies is concentrated on two molecules: harman and harmine.They have been investigated in several animal models and some mechanisms of action have been proposed for their antidepressant activity. In general, β-carbolines modulate 5-HT and GABA systems, promote neurogenesis, induce neuroendocrine response and restore astrocytic function, being effective when administrated acutely or chronically in different animal models, including chronic mild stress protocols. In short, β-carbolines are multi-target antidepressant compounds and may be useful in the treatment of depressive disorders.

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PMID: 

Sci Total Environ. 2016 Dec 1 ;572:554-569. Epub 2016 Aug 24. PMID: 27552133

Abstract Title: 

Radiofrequency radiation injures trees around mobile phone base stations.

Abstract: 

In the last two decades, the deployment of phone masts around the world has taken place and, for many years, there has been a discussion in the scientific community about the possible environmental impact from mobile phone base stations. Trees have several advantages over animals as experimental subjects and the aim of this study was to verify whether there is a connection between unusual (generally unilateral) tree damage and radiofrequency exposure. To achieve this, a detailed long-term (2006-2015) field monitoring study was performed in the cities of Bamberg and Hallstadt (Germany). During monitoring, observations and photographic recordings of unusual or unexplainable tree damage were taken, alongside the measurement of electromagnetic radiation. In 2015 measurements of RF-EMF (Radiofrequency Electromagnetic Fields) were carried out. A polygon spanning both cities was chosen as the study site, where 144 measurements of the radiofrequency of electromagnetic fields were taken at a height of 1.5m in streets and parks at different locations. By interpolation of the 144 measurement points, we were able to compile an electromagnetic map of the power flux density in Bamberg and Hallstadt. We selected 60 damaged trees, in addition to 30 randomly selected trees and 30 trees in low radiation areas (n=120) in this polygon. The measurements of all trees revealed significant differences between the damaged side facing a phone mast and the opposite side, as well as differences between the exposed side of damaged trees and all other groups of trees in both sides. Thus, we found that side differences in measured values of power flux density corresponded to side differences in damage. The 30 selected trees in low radiation areas (no visual contact to any phone mast and power flux density under 50μW/m) showed no damage. Statistical analysis demonstrated that electromagnetic radiation from mobile phone masts is harmful for trees. These results are consistent with the fact that damage afflicted on trees by mobile phone towers usually start on one side, extending to the whole tree over time.

PMID: 

Cancer Cell Int. 2019 ;19:159. Epub 2019 Jun 11. PMID: 31198408

Abstract Title: 

Harmine suppresses hyper-activated Ras-MAPK pathway by selectively targeting oncogenic mutated Ras/Raf in.

Abstract: 

Background: Mutationally activated Ras proteins are closely linked to a wide variety of human cancers. Hence, there has been an intensive search for anti-Ras therapies for cancer treatment. The sole Ras gene, which encodes LET-60, inregulates vulval development. While the loss of-function leads to failure of vulva formation, the-() allele, which contains a missense mutation mimicking a Ras codon 13 mutation found in human cancers, results in extra vulval tissue, a phenotype named Muv (multiple vulvas).Methods: By taking advantage of the easy-to-score Muv phenotype of-(), we used a step-by-step screening approach (from crude extract to active fraction to active natural compound) to search for inhibitors of oncogenic Ras. Mutants of other key components in the Ras-mitogen-activated protein kinase (MAPK) pathway were used to identify other candidate targets.Results: The natural compound harmine, isolated from the plant, was found to suppress the Muv phenotype of-(). In addition, harmine targets the hyper-activation of the Ras/MAPK pathway specifically caused by overexpression or mutated forms of LET-60/Ras and its immediate downstream molecule LIN-45/Raf. Finally, harmine can be absorbed into the worm body and probably functions in its native form, rather than requiring metabolic activation.Conclusion: In sum, we have revealed for the first time the anti-Ras activity of harmine in amodel system. Our results revealed the potential anti-cancer mechanism of harmine, which may be useful for the treatment of specific human cancers that are associated with oncogenic Ras mutations.

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PMID: 

Onco Targets Ther. 2019 ;12:4585-4593. Epub 2019 Jun 12. PMID: 31354292

Abstract Title: 

Harmine suppresses the proliferation of pancreatic cancer cells and sensitizes pancreatic cancer to gemcitabine treatment.

Abstract: 

Purpose: Pancreatic carcinoma is one of the most deadliest types of cancer, and relatively insensitive to the currently available chemotherapy. Thus, the discovery of novel therapeutic agents to prolong the survival times of patients with pancreatic cancer is urgently required.Methods: Cell proliferation was assessed using the sulforhodamine B and cell clone formation assay, apoptosis was analyzed through Annexin V/PI staining, analysis of cell cycle distribution was determined by PI staining, and the expression of proteins was detected via Western blotting.Results: Our data showed that harmine exerted an anti-proliferative effect and cell cycle arrest at G2/M in pancreatic cancer cells. Meanwhile, harmine plus gemcitabine showed strong synergy in inhibiting the proliferation of pancreatic cancer cells. Furthermore, harmine induced apoptosis and enhanced the gemcitabine-induced apoptosis in pancreatic cancer cells. The AKT/mTOR pathway is involved in mechanisms of gemcitabine resistance in pancreatic cancer cells, our data demonstrated that harmine plus gemcitabine significantly suppressed the AKT/mTOR signaling pathway.Conclusion: Harmine may be a potential candidate for the treatment of pancreatic cancer. Morever, the combination of harmine with gemcitabine appears to be an attractive option for the treatment of patients with pancreatic cancer.

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PMID: 

Int J Prev Med. 2019 ;10:97. Epub 2019 Jun 7. PMID: 31360344

Abstract Title: 

Effect of Harmine on Nicotine-Induced Kidney Dysfunction in Male Mice.

Abstract: 

Background: The nicotine content of cigarettes plays a key role in the pathogenesis of kidney disease. Harmine is a harmal-derived alkaloid with antioxidant properties. This study was designed to evaluate the effects of harmine against nicotine-induced damage to the kidneys of mice.Methods: In this study, 64 male mice were randomly assigned to eight groups: saline and nicotine-treated groups (2.5 mg/kg), harmine groups (5, 10, and 15 mg/kg), and nicotine (2.5 mg/kg) + harmine-treated groups (5, 10, and 15 mg/kg). Treatments were administered intraperitoneally daily for 28 days. The weights of the mice and their kidneys, kidney index, glomeruli characteristics, thiobarbituric acid reactive species, antioxidant capacity, kidney function indicators, and serum nitrite oxide levels were investigated.Results: Nicotine administration significantly improved kidney malondialdehyde (MDA) level, blood urea nitrogen (BUN), creatinine, and nitrite oxide levels and decreased glomeruli number and tissue ferric reducing/antioxidant power (FRAP) level compared to the saline group (

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PMID: 

Int J Oncol. 2019 Jun ;54(6):1995-2004. Epub 2019 Apr 9. PMID: 31081045

Abstract Title: 

Harmine induces anticancer activity in breast cancer cells via targeting TAZ.

Abstract: 

Harmine (HM) is aβ‑carboline alkaloid found in multiple medicinal plants. It has been used in folk medicine for anticancer therapy; however, the molecular mechanism of HM on human breast cancer remains unclear. Transcriptional co‑activator with PDZ‑binding motif (TAZ), also known as WW domain‑containing transcription regulator 1, serves an important role in the carcinogenesis and progression of breast cancer. The aim of the present study was to elucidate the potential anticancer activity and mechanism of HM in breast cancer, in vitro and in vivo. Cell proliferation was measured using a CCK‑8 assay, apoptotic activity was detected by flow cytometry and DAPI staining, and cell migration was examined using a wound healing assay. The expression of proteins, including extracellular signal‑regulate kinase (Erk), phosphorylated (p‑) Erk, protein kinase B (Akt), p‑Akt, B‑cell lymphoma 2 (Bcl‑2) and Bcl‑2‑associated X protein (Bax), were determined by western blotting. The mRNA expression of TAZ was detected using reverse transcription‑quantitative polymerase chain reaction analysis. The expression of proteins in mouse tumor tissues were examined by immunohistochemistry. HM significantly suppressed cellular proliferation and migration, promoted apoptosis in vitro and inhibited tumor growth in vivo. In addition, HM significantly decreased the expression of TAZ, p‑Erk, p‑Akt and Bcl‑2, but increased that of Bax. The overexpression of TAZ in breast cancer cells inhibited the antitumor effect of HM. In conclusion, HM was found to induce apoptosis and prevent the proliferation and migration of human breast cancer cell lines, possibly via the downregulation of TAZ.

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