Palmatine Research Articles

Discovery and development of palmatine analogues as anti-NASH agents by activating farnesoid X receptor (FXR)

Sixty-one palmatine (PMT) derivatives, of which twenty-eight were new, were synthesized and evaluated for their anti-fibrogenic activities via collagen type I α 1 (COL1A1)-promoter based luciferase model in LX-2 cells, taking 2,3,10-trimethoxy-9-p-isopropyloxyprotopalmatine bromide (1) as the lead. Among them, compound 3a exerted the highest potency with the IC50 value of 8.19 μmol/L and SI value of 8.59, and reduced the expressions of multiple fibrogenic biomarkers, including COL1A1, TGF-β1, α-SMA and TIMP1 in a dose-dependent manner. In addition, it significantly reduced liver steatosis and inflammation, and especially attenuated the degree of liver fibrosis in choline-deficient, l-amino acid-defined, high-fat diet (CDAHFD)-induced NASH mice model in vivo. Mechanism study indicated that it significantly ameliorated liver injury by activating farnesoid X receptor (FXR). BDL-induced fibrosis rats model further verified its liver-protective and anti-fibrosis activities. Therefore, PMT derivatives constituted a new family of non-steroidal FXR agonists as anti-NASH candidates, with the advantage of good safety profile, and are worthy for further investigation.

A Cucurbit[6]uril-Based Supramolecular Assembly as a Multifunctional Material for the Detection and Removal of Organic Explosives and Antibiotics

Abstract A novel cucurbit[6]uril-based (CB[6]) supramolecular assembly H2NDS·CB[6] (1) (CB[6] = cucurbit[6]uril, H2NDS = 1,6-naphthalenedisulfonic acid) was successfully synthesized using H2NDS as the “structure inducer”. The fluorescence results showed that 1 could be used as a fluorescence sensor for the detection of organic explosives 4-nitrophenol (4-NP) and 2,4,6-trinitrophenol (TNP), and isoquinoline antibiotics berberine (BER) and palmatine (PAL) in aqueous solution by fluorescence quenching at parts per billion (ppb) levels. Even more exciting, BER exhibits aggregation induced effect (AIE) functionality with 1 in aqueous solution through noncovalent interaction. We have successfully utilized this phenomenon to detect BER, and the limit of detection (LOD) was lower than the fluorescence quenching detection method by 1. This result suggests that we can use the AIE phenomenon of BER to further distinguish 4-NP and TNP from BER. Simultaneously, 1 also displays high adsorption abilities towards BER. As far as we known, there is no report of CB[6]-based supramolecular assembly for both detection and removal of antibiotics. This method is also applied to reliably and accurately detect these analyte concentrations in actual sample water and calf serum.

Palmatine attenuates hepatocyte injury by promoting autophagy via the AMPK/mTOR pathway after alcoholic liver disease.

Alcoholic liver disease is one of the diseases with the highest fatality rate worldwide. The cellular process of autophagy which recycles damaged organelles to maintain protein and organelle homeostasis is found to positively influence survival during hepatic insufficiency, although the mechanism is poorly understood. Palmatine (PLT) has a variety of biological functions, such as broad-spectrum antibacterial action, neuroprotective, antioxidant stress, and antiviral and anti-inflammatory activities. However, it is not known whether PLT has a protective effect against alcoholic liver injury. Here, we investigated the protective effect of PLT in a cellular model of alcohol-induced acute liver injury and further explored its mechanism of action. In this study, we show for the first time that PLT attenuates alcohol-induced hepatocyte injury by promoting autophagy to play an essential protective role. As PLT treatment induced a brief increase in LC3-II conversion and p62 degradation, it also upregulated the expression of ATG5 and ATG7. The expression levels of the proapoptotic proteins Bax, Caspase 3, and Caspase 9 significantly decreased, while the antiapoptotic protein levels of Bcl-2 upregulated after treatment with PLT. However, in presence of the autophagy inhibitor, 3-methyladenine, the effect of PLT in inhibiting ethanol-induced hepatocyte injury reversed significantly. Mechanistically, the protective effects of PLT may be mediated by promoting the activation of the AMP-activated protein kinase/mammalian target of rapamycinsignaling pathway. Therefore, we believe that the development of alcoholic liver injuries may be controlled by PLT by inhibiting hepatocyte apoptosis through the autophagy pathway. The study lays a solid theoretical and practical basis for future animal models and clinical studies of PLT.

The Hypoglycemic Effect of JinQi Jiangtang Tablets Is Partially Dependent on the Palmatine-Induced Activation of the Fibroblast Growth Factor Receptor 1 Signaling Pathway.

JinQi Jiangtang tablet (JQJTT) is a Chinese patent medicine that has been shown to be beneficial for patients with diabetes both preclinically and clinically; however, the molecular mechanism underlying the effects of JQJTT remains unclear. In this study, surface plasmon resonance fishing was employed to identify JQJTT constituent molecules that can specifically bind to fibroblast growth factor receptor 1 (FGFR1), leading to the retrieval of palmatine (PAL), a key active ingredient of JQJTT. In vivo and in vitro experiments demonstrated that PAL can significantly stimulate FGFR1 phosphorylation and upregulate glucose transporter type 1 (GLUT-1) expression, thereby facilitating glucose uptake in insulin resistance (IR) HepG2 cells as well as alleviating hyperglycemia in diabetic mice. Our results revealed that PAL functions as an FGFR1 activator and that the hypoglycemic effect of JQJTT is partially dependent on the PAL-induced activation of the FGFR1 pathway. In addition, this study contributed to the understanding the pharmacodynamic basis and mechanism of action of JQJTT and provided a novel concept for future research on PAL.

Palmatine Protects Against MSU-Induced Gouty Arthritis via Regulating the NF-κB/NLRP3 and Nrf2 Pathways.

PurposeGouty arthritis could be triggered by the deposition of monosodium uric acid (MSU) crystals. Palmatine (PAL), a protoberberine alkaloid, has been proven to possess compelling health-beneficial activities. In this study, we aimed to explore the effect of PAL on LPS plus MSU crystal-stimulated gouty arthritis in vitro and in vivo.MethodsPMA-differentiated THP-1 macrophages were primed with LPS and then stimulated with MSU crystal in the presence or absence of PAL. The expression of pro-inflammatory cytokines and oxidative stress-related biomarkers and signal pathway key targets were determined by ELISA kit, Western blot, immunohistochemistry and qRT-PCR, respectively. In addition, the anti-inflammatory and antioxidant activities of PAL on MSU-induced arthritis mice were also evaluated.ResultsThe results indicated that PAL (20, 40 and 80 μM) dose-dependently decreased the mRNA expression and levels of pro-inflammatory cytokines (interleukin-1beta (IL-1β), IL-6, IL-18 and tumor necrosis factor alpha (TNF-α)). The levels of superoxide dismutase (SOD) and glutathione (GSH) were remarkably enhanced, while the level of malondialdehyde (MDA) was reduced. Western blot analysis revealed that PAL appreciably inhibited NF-κB/NLRP3 signaling pathways through inhibiting the phosphorylation of p-65 and IκBα, blocking the expression of NLRP3, ASC, IL-1β and Caspase-1, as well as enhancing the antioxidant protein expression of Nrf2 and HO-1. In vivo, PAL attenuated MSU-induced inflammation in gouty arthritis, as evidenced by mitigating the joint swelling, and decreasing the productions of IL-1β, IL-6, IL-18, TNF-α and MDA, while enhancing the levels of SOD and GSH. Moreover, PAL further attenuated the infiltration of neutrophils into joint synovitis.ConclusionPAL protected against MSU-induced inflammation and oxidative stress via regulating the NF-κB/NLRP3 and Nrf2 pathways. PAL may represent a potential candidate for the treatment of gouty arthritis.

8-Oxypalmatine, a novel oxidative metabolite of palmatine, exhibits superior anti-colitis effect via regulating Nrf2 and NLRP3 inflammasome

Palmatine (PAL) is an isoquinoline alkaloid derived from Fibraureae caulis Pierre that has been used to relieve inflammatory diseases like ulcerative colitis (UC). The metabolites of PAL were believed to contribute significantly to its outstanding biological activities. 8-Oxypalmatine (OPAL), a liver-mediated oxidative metabolite of PAL, has been firstly identified in the present work. We aimed to comparatively investigate the potential effect and mechanism of OPAL and PAL on dextran sodium sulfate (DSS)-induced colitis in Balb/c mice. Results indicated that OPAL and PAL effectively mitigated clinical manifestations, DAI scores and pathological damage compared with the model group. Moreover, treatment with OPAL and PAL effectively mitigated oxidative stress markers and inflammatory mediators in colon. Additionally, OPAL and PAL significantly activated the Nrf2 pathway, while substantially suppressed the activation of NLRP3 inflammasome. Furthermore, OPAL showed superior anti-colitis effect to PAL, which was similar to the positive drug mesalazine with much smaller dosage. These findings suggested that OPAL exerted appreciable protective effect on DSS-induced colitis, at least in part, via activating Nrf2 pathway and inhibiting NLRP3 inflammasome. OPAL might have the potential to be further developed into a promising candidate for the treatment of UC.

Palmatine Derivatives as Potential Antiplatelet Aggregation Agents via Protein Kinase G/Vasodilator-Stimulated Phosphoprotein and Phosphatidylinositol 3-Kinase/Akt Phosphorylation.

Sixty palmatine (PMT) derivatives were synthesized and evaluated for antiplatelet aggregation taking berberine as the lead, and the structure-activity relationship was first systematically described. Among them, compound 2v showed the best potency in reducing adenosine diphosphate (ADP)-induced platelet aggregation in a dose-dependent manner. It greatly suppressed ADP-induced platelet aggregation, activation, and Akt phosphorylation in vitro and ex vivo after oral administration to mice. It also effectively inhibited carrageenan-induced thrombus formation in the mouse tail and lung, as well as reduced the serum P-selectin level. Compound 2v might simultaneously bind to protein kinase G to improve vasodilator-stimulated phosphoprotein phosphorylation and bind to phosphatidylinositol 3-kinase to inhibit Akt phosphorylation, which synergically reduced platelet aggregation, thereby achieving antithrombotic efficacy. Therefore, PMT derivatives constituted a novel family of antiplatelet aggregation agents with the advantage of a good safety profile, worthy of further investigation.

Palmatine attenuates the doxorubicin-induced inflammatory response, oxidative damage and cardiomyocyte apoptosis

BackgroundAs a natural isoquinoline alkaloid, palmatine (PLT) has been proven to play a protective role against a variety of cardiovascular diseases. However, little research on the effects of PLT on doxorubicin (DOX)-induced cardiotoxicity has been carried out. Thus, we investigated the potential functions of PLT in DOX-induced cardiotoxicity. In the present study, a single intraperitoneal injection of DOX (15 mg/kg) in mice was used to establish an acute cardiotoxicity model. Our study shows that PLT administration could reduce myocardial injury and improve cardiac dysfunction in DOX-treated mice. Further experiments showed that PLT administration suppressed the DOX-induced inflammatory response, oxidative damage and cardiomyocyte apoptosis in mice. Moreover, we found that the protective effect of PLT treatment was counteracted by sirtuin1 (Sirt1) knockdown. In summary, our study shows that PLT treatment can exert a protective effect against DOX-induced cardiotoxicity.

Improving hygroscopic stability of palmatine by replacing Clˉ and preparing single crystal of palmatine-salicylic acid

In order to improve the hygroscopic stability of palmatine (PMT), an unreported single crystal of palmatine-salicylic acid (PMT-SA, [C21H22NO4]C7H5O3) was designed and synthesized by replacing Clˉ of PMTCl, and the hygroscopic stability of PMT was remarkably improved. The crystal structures and intermolecular interactions were characterized by single crystal X-ray diffraction, elemental analysis, NMR (1H and 13C), FT-IR, PXRD, TGA-DSC and Hirshfeld surface analysis, and its properties were studied. Single crystal X-ray diffraction analysis revealed that asymmetric unit of PMT-SA contains one PMT and one SA, and adjacent asymmetric unit are connected via hydrogen bond C6-H6A…O6 to form an annular synthon R44(22). Adjacent synthons form 1D chain by intermolecular hydrogen bond C25-H25…O5 and π…π packing, as if PMT+ are sandwiched between SAˉ chains. Furthermore, 1D chains are interwoven through C27-H27…O5 of SAˉ chains on the both sides to fabricate 2D layers, then 2D layers overlaps into a fascinating 3D framework. Comprehensive structural analysis and Hirshfeld surface analysis reveal that the weak interaction force of hydrogen bonds formed between H atom of aromatic ring in PMT and carboxylic acid group of SA can promote stable crystal structure. Hygroscopic stability and DVS experiments show that hygroscopic stability of PMT-SA is tremendously enhanced, which might attribute to the replacement of Clˉ by SAˉ and the preparation of PMT-SA with a stable crystal structure. This successful work implies that a new approach to design protoberberines pharmaceutical salt with good hygroscopic stability by replacing anions, and provides inspiration for improving physicochemical properties of active pharmaceutical ingredients. Further to this, antibacterial activities of PMT-SA resist Staphylococcus aureus, Staphylococcus albus, and Escherichia coli are higher than PMTCl in vitro at gradient concentrations.

A cucurbit[6]uril based supramolecular assembly for the detection and removal of dyes and antibiotics from water.

A cucurbit[6]uril (CB[6]) based supramolecular assembly CB[6]-[NDS]2- (1, NDS = 2,6-naphthalenedisulfonic acid anion) was used to detect dyes such as reactive blue 19 (RB19), rhodamine B (RB), methyl orange (MO), methyl red (MR), and methyl violet (MV), and isoquinoline antibiotics such as berberine (BER) and palmatine (PAL) with detection limits of 143, 128, 374, 193, 305, 27 and 34 ppb, respectively. Simultaneously, 1 also displayed high adsorption abilities towards these organic molecules. These results indicate that 1 is a favorable material for the simultaneous selective detection and removal of specific dyes and antibiotics from water, being potentially useful in monitoring water quality and treating wastewater. The possible mechanisms of the detection and adsorption are also proposed.

A nano-phytochemical ophthalmic solution for marked improvement of corneal wound healing in healthy ordiabetic mice.

Aim: To formulate a novel nano-phytochemical ophthalmic solution to promote corneal wound healing. Methods: Dipotassium glycyrrhizinate (DG) and palmatine (PAL) were used to formulate this formulation marked as DG-PAL, and its efficacy and mechanisms for promoting corneal wound healing were evaluated in mice. Results: DG-PAL was easily fabricated with excellent physical profiles. In in vivo efficiency evaluations, DG-PAL demonstrated an excellent promoting effect on corneal epithelial/nerve wound healing in both healthy and diabetic mice. These effects were involved in the DG-PAL-induced decreased expression levels of HMGB1 and its signaling-related factors in the corneas and trigeminal neurons of the healthy or diabetic mice. Conclusion: DG-PAL possibly represents a promising ophthalmic solution for promoting corneal wound healing.

Palmatine, a Bioactive Protoberberine Alkaloid Isolated from Berberis cretica, Inhibits the Growth of Human Estrogen Receptor-Positive Breast Cancer Cells and Acts Synergistically and Additively with Doxorubicin.

Palmatine (PLT) is a natural isoquinoline alkaloid that belongs to the class of protoberberines and exhibits a wide spectrum of pharmacological and biological properties, including anti-cancer activity. The aim of our study was to isolate PLT from the roots of Berberis cretica and investigate its cytotoxic and anti-proliferative effects in vitro alone and in combination with doxorubicine (DOX) using human ER+/HER2− breast cancer cell lines. The alkaloid was purified by column chromatography filled with silica gel NP and Sephadex LH-20 resin developed in the mixture of methanol: water (50:50 v/v) that provided high-purity alkaloid for bioactivity studies. The purity of the alkaloid was confirmed by high resolution mass measurement and MS/MS fragmentation analysis in the HPLC-ESI-QTOF-MS/MS-based analysis. It was found that PLT treatment inhibited the viability and proliferation of breast cancer cells in a dose-dependent manner as demonstrated by MTT and BrdU assays. PLT showed a quite similar growth inhibition on breast cancer cells with IC50 values ranging from 5.126 to 5.805 µg/mL. In contrast, growth of normal human breast epithelial cells was not affected by PLT. The growth inhibitory activity of PLT was related to the induction of apoptosis, as determined by Annexin V/PI staining. Moreover, PLT sensitized breast cancer cells to DOX. Isobolographic analysis revealed synergistic and additive interactions between studied agents. Our studies suggest that PLT can be a potential candidate agent for preventing and treating breast cancer.

Cucurbituril-mediated AIE: An unconventional indicator displacement assay for ketamine detection

Typical AIE luminogens with extensive π-electron conjugation are limited in use on account of their complex synthesis, high cost and environmental concerns. To this end, we report here a novel host-guest inclusion complex that is assembled from nonemissive ligands, and surprisingly exhibits notable AIE features in aqueous solution while maintaining good sensitivity for ketamine (KET) detection. Isothermal titration studies confirm that palmatine (PAL) binds to cucurbit[8]uril (Q8) in a 2:1 ratio with an equilibrium association constant of 1.75 × 1011 M−2, suggesting that the unconventional AIE effects can be attributed to the stacking of two PAL moieties inside a single Q8 cavity. Geometric constraints of the macrocycle result in dimeric coupling of PAL in the ground state with significant bathochromic shifts in absorption and emission, which can be readily excited to exhibit enhanced photoluminescence. The unusual upfield perturbation and broadening of Q8 signals in the 1H NMR spectrum upon binding with PAL convey decisive information that Q8 not only serves as a molecular container, but also participates in the electron delocalization during the AIE events. Upon addition of KET, fluorescence was switched off through guest exchange to generate KET@Q8 as well as free PAL. The significant AIE characteristics of 2*PAL@Q8 in combination with its specific molecular recognition towards KET gives rise to 5.0 ng/mL limit of detection with linear range from 16.8 to 500 ng/mL, and a pronounced selectivity over possible interfering substances in biological matrices. We demonstrate the first example of Q8-mediated AIE effects, where the photoluminescence of virtually nonemissive or feebly emissive ligands is remarkably intensified through clustering inside a macrocyclic host molecule, therefore offering great promise for further development into dedicated AIE-based sensors.

Palmatine Protects against Cerebral Ischemia/Reperfusion Injury by Activation of the AMPK/Nrf2 Pathway.

Palmatine (PAL), a natural isoquinoline alkaloid, possesses extensive biological and pharmaceutical activities, including antioxidative stress, anti-inflammatory, antitumor, neuroprotective, and gastroprotective activities. However, it is unknown whether PAL has a protective effect against ischemic stroke and cerebral ischemia/reperfusion (I/R) injury. In the present study, a transient middle cerebral artery occlusion (MCAO) mouse model was used to mimic ischemic stroke and cerebral I/R injury in mice. Our study demonstrated that PAL treatment ameliorated cerebral I/R injury by decreasing infarct volume, neurological scores, and brain water content. PAL administration attenuated oxidative stress, the inflammatory response, and neuronal apoptosis in mice after cerebral I/R injury. In addition, PAL treatment also decreases hypoxia and reperfusion- (H/R-) induced neuronal injury by reducing oxidative stress, the inflammatory response, and neuronal apoptosis. Moreover, the neuroprotective effects of PAL were associated with the activation of the AMP-activated protein kinase (AMPK)/nuclear factor E2-related factor 2 (Nrf2) pathway, and Nrf2 knockdown offsets PAL-mediated antioxidative stress and anti-inflammatory effects. Therefore, our results suggest that PAL may be a novel treatment strategy for ischemic stroke and cerebral I/R injury.

Palmatine ameliorates high fat diet induced impaired glucose tolerance

BackgroundThe impaired glucose tolerance (IGT) is a representative prediabetes characterized by defective glucose homeostasis, and palmatine (PAL) is a natural isoquinoline alkaloid with multiple pharmacological effects. Our study aims to investigate the therapeutic effect of PAL on the impaired glucose tolerance.MethodsMale Sprague–Dawley rats were used to establish an IGT model with high fat diet (HFD). Oral glucose tolerance test (OGTT) and further biochemical analysis were conducted to determine the effect of PAL on glucose intolerance in vivo. Molecular details were clarified in a cellular model of IGT induced by Palmitate (PA) on INS-1 cells.ResultsOur study demonstrated a relief of IGT with improved insulin resistance in HFD induced rats after PAL treatment. Besides, promoted pancreas islets function was validated with significantly increased β cell mass after the treatment of PAL. We further found out that PAL could alleviate the β cell apoptosis that accounts for β cell mass loss in IGT model. Moreover, MAPK signaling was investigated in vivo and vitro with the discovery that PAL regulated the MAPK signaling by restricting the ERK and JNK cascades. The insulin secretion assay indicated that PAL significantly promoted the defective insulin secretion in PA-induced INS-1 cells via JNK rather than ERK signaling. Furthermore, PAL treatment was determined to significantly suppress β cell apoptosis in PA-induced cells. We thus thought that PAL promoted the PA-induced impaired insulin release by inhibiting the β cell apoptosis and JNK signaling in vitro.ConclusionIn summary, PAL ameliorates HFD-induced IGT with novel mechanisms.

Novel biocompatible AIEgen from natural resources: Palmatine and its bioimaging application

In recent years, aggregation-induced emission luminogens (AIEgens) have been widely used in bioimaging, organic optoelectronics, chemical/biosensors and other fields. However, some shortcomings of AIEgens greatly limit their practical application, including complex synthesis, high cost, environmentally unfriendly and difficult to degrade. In this work, a good natural AIE material of palmatine (PA) was found, which is a total alkaloid extracted from the stems and roots of the plant Fibraurea recisa Pierre. According to its fluorescence characteristics through fluorescence spectrum and UV–Vis absorption spectrum analyses, indicating that it is an unconventional rotor-free AIEgen with good water-solubility and excellent solide-state emission characteristics. Moreover, PA has little cytotoxicity and has potential biological imaging ability. The results indicated that PA was a potential of natural material as promising AIE probes.

Palmatine antioxidant and anti-acetylcholinesterase activities: A pre-clinical assessment

There is evidence that palmatine (PA), an alkaloid isolated from the Guatteria friesiana plant, has some important biological activities, including anti-inflammatory and antidepressant effects. In this study, the antioxidant and anti-acetylcholinesterase (AChE) effects of PA were assessed. The antioxidant capacity was evaluated in vitro and in vivo through 7 distinct assays, and the anti-AChE activity was determined in vitro. The standards, trolox and ascorbic acid were used for the in vitro antioxidant test, while hydrogen peroxide was selected as a stressor for the Saccharomyces cerevisiae test. Additionally, PA was also combined with trolox and ascorbic acid to determine the likelihood of synergistic effects occurrence to what concerns to antioxidant potential. PA exhibited a potent and concentration-dependent antioxidant potential, although a stronger antioxidant activity was stated using the PA + trolox combination. PA was also found to inhibit AChE activity when compared to the negative control. Thus, PA may be viewed as a promissory phytotherapeutic agent to manage oxidative stress-mediated neurological diseases, especially the Alzheimer's and Parkinson's diseases.

Characterization of Burkholderia sp. strain CJ1, a newly isolated berberine-degrading bacterium from rhizosphere of Coptis japonica

Burkholderia sp. strain CJ1 was newly isolated as berberine (BBR) degrading bacteria from rhizosphere of Coptis japonica. CJ1 had the ability to utilize BBR as the sole carbon source and revealed that BBR metabolism via 11-hydroxylation and demethylenation pathway. It was also revealed that the 11-hydroxylation ability of BBR and palmatine (PAL) has induced by BBR.

The Influence of Palmatine Isolated from Berberis sibiricaRadix on Pentylenetetrazole-Induced Seizures in Zebrafish.

Palmatine (PALM) and berberine (BERB) are widely identified isoquinoline alkaloids among the representatives of the Berberidaceae botanical family. The antiseizure activity of BERB was shown previously in experimental epilepsy models. We assessed the effect of PALM in a pentylenetetrazole (PTZ)-induced seizure assay in zebrafish, with BERB as an active reference compound. Both alkaloids were isolated from the methanolic root extract of Berberis sibirica by counter-current chromatography, and their ability to cross the blood–brain barrier was determined via quantitative structure–activity relationship assay. PALM exerted antiseizure activity, as confirmed by electroencephalographic analysis, and decreased c-fos and bdnf levels in PTZ-treated larvae. In a behavioral assay, PALM dose-dependently decreased PTZ-induced hyperlocomotion. The combination of PALM and BERB in ED16 doses revealed hyperadditive activity towards PTZ-induced hyperlocomotion. Notably, we have indicated that both alkaloids may exert their anticonvulsant activity through different mechanisms of action. Additionally, the combination of both alkaloids in a 1:2.17 ratio (PALM: BERB) mimicked the activity of the pure extract, which indicates that these two active compounds are responsible for its anticonvulsive activity. In conclusion, our study reveals for the first time the anticonvulsant activity of PALM and suggests the combination of PALM and BERB may have higher therapeutic value than separate usage of these compounds.

Palmatine induces G2/M phase arrest and mitochondrial-associated pathway apoptosis in colon cancer cells by targeting AURKA

Studies have shown that palmatine (PAL) has anti-cancer effects. However, the activity and potential mechanisms of PAL against colorectal cancer remain elusive. The results showed that PAL significantly inhibited the proliferation of colon cancer cells in vitro and in vivo without significant effect on non-tumorigenic colon cells. Target prediction and clinical sample database analysis suggested that PAL may contribute to colon cancer cells phase arrest and apoptosis by targeting aurora kinase A (AURKA). Inhibition and overexpression of AURKA proved that PAL induces G2/M phase arrest and apoptosis in colon cancer cells by targeting AURKA. Moreover, PAL promoted intracellular Reactive oxygen species (ROS) production and decreased mitochondrial membrane potential (ΔΨm). PAL reduced the levels of AURKA, Bcl-xl and Bcl2 proteins, and promoted the expression of pro-apoptotic proteins P53, P73, Caspase3 and Caspase9, as well as the increase of cytochrome c (cyt. c) in cell lysates in vitro and in vivo. Together, our study confirmed that PAL induced G2/M phase arrest and mitochondrial-associated pathway apoptosis in colon cancer cells by targeting AURKA. PAL may provide a novel solution for the treatment of colon cancer by serving as a new AURKA inhibitor.