Showing papers on "Brucine published in 2021"

ATF3 contributes to brucine-triggered glioma cell ferroptosis via promotion of hydrogen peroxide and iron

Abstract: Ferroptotic cell death is characterized by iron-dependent lipid peroxidation that is initiated by ferrous iron and H2O2 via Fenton reaction, in which the role of activating transcription factor 3 (ATF3) remains elusive. Brucine is a weak alkaline indole alkaloid extracted from the seeds of Strychnos nux-vomica, which has shown potent antitumor activity against various tumors, including glioma. In this study, we showed that brucine inhibited glioma cell growth in vitro and in vivo, which was paralleled by nuclear translocation of ATF3, lipid peroxidation, and increases of iron and H2O2. Furthermore, brucine-induced lipid peroxidation was inhibited or exacerbated when intracellular iron was chelated by deferoxamine (500 μM) or improved by ferric ammonium citrate (500 μM). Suppression of lipid peroxidation with lipophilic antioxidants ferrostatin-1 (50 μM) or liproxstatin-1 (30 μM) rescued brucine-induced glioma cell death. Moreover, knockdown of ATF3 prevented brucine-induced accumulation of iron and H2O2 and glioma cell death. We revealed that brucine induced ATF3 upregulation and translocation into nuclei via activation of ER stress. ATF3 promoted brucine-induced H2O2 accumulation via upregulating NOX4 and SOD1 to generate H2O2 on one hand, and downregulating catalase and xCT to prevent H2O2 degradation on the other hand. H2O2 then contributed to brucine-triggered iron increase and transferrin receptor upregulation, as well as lipid peroxidation. This was further verified by treating glioma cells with exogenous H2O2 alone. Moreover, H2O2 reversely exacerbated brucine-induced ER stress. Taken together, ATF3 contributes to brucine-induced glioma cell ferroptosis via increasing H2O2 and iron.

Quality by Design for Optimizing a Novel Liposomal Jojoba Oil-Based Emulgel to Ameliorate the Anti-Inflammatory Effect of Brucine.

Abstract: One of the recent advancements in research is the application of natural products in developing newly effective formulations that have few drawbacks and that boost therapeutic effects. The goal of the current exploration is to investigate the effect of jojoba oil in augmenting the anti-inflammatory effect of Brucine natural alkaloid. This is first development of a formulation that applies Brucine and jojoba oil int a PEGylated liposomal emulgel proposed for topical application. Initially, various PEGylated Brucine liposomal formulations were fabricated using a thin-film hydration method. (22) Factorial design was assembled using two factors (egg Phosphatidylcholine and cholesterol concentrations) and three responses (particle size, encapsulation efficiency and in vitro release). The optimized formula was incorporated within jojoba oil emulgel. The PEGylated liposomal emulgel was inspected for its characteristics, in vitro, ex vivo and anti-inflammatory behaviors. Liposomal emulgel showed a pH of 6.63, a spreadability of 48.8 mm and a viscosity of 9310 cP. As much as 40.57% of Brucine was released after 6 h, and drug permeability exhibited a flux of 0.47 µg/cm2·h. Lastly, % of inflammation was lowered to 47.7, which was significant effect compared to other formulations. In conclusion, the anti-inflammatory influence of jojoba oil and Brucine was confirmed, supporting their integration into liposomal emulgel as a potential nanocarrier.

Brucine-loaded transliposomes nanogel for topical delivery in skin cancer: statistical optimization, in vitro and dermatokinetic evaluation.

Abstract: The aim of the present study was to develop, optimize brucine-loaded transliposomes (BRC-TL) formulation for dermal delivery of brucine for skin cancer. The BRC-TL formulations were evaluated for vesicle size, entrapment efficiency, and in vitro drug release. The optimized formulation was further evaluated for skin penetration by confocal laser microscopy and dermatokinetic study. The optimized BRC-TL formulation presented sealed lamellar shaped vesicles, with vesicles size, polydispersity index, entrapment efficiency, and in vitro drug release of 136.20 ± 2.87 nm, 0.354 ± 0.02, 86.01 ± 1.27%, and 83.09 ± 2.07%, respectively. Ex vivo permeation study showed that, developed BRC-TL formulation had a 2.4-fold increment in permeation as compared to BRC suspension. Texture analysis showed that the BRC-TL gel presented firmness of 158.91 g, consistency of 615.03 g/s, cohesiveness of − 115.26 g and a viscosity index of − 472.05 g/s. The confocal images of rat skin clearly showed the deeper penetration of rhodamine B-loaded TL formulation as compared to the Rhodamine B-hydro alcoholic solution. The optimized BRC-TL formulation demonstrated significantly higher cytotoxicity than placebo liposome and BRC suspension (P < 0.05). Further, the BRC-TL nanogel treated rat skin showed a substantial increase in CSkin max and AUC0–8 in comparison to rat skin treated with BRC conventional gel (P < 0.05). The data revealed that the developed TLs formulation could be a promising drug nanocarrier for brucine dermal delivery in the treatment of skin cancer.

Chronotoxicity of Semen Strychni is associated with circadian metabolism and transport in mice.

Abstract: Objectives We aimed to determine the circadian responses of mice to Semen Strychni and to investigate the role of pharmacokinetics in generating chronotoxicity. Methods Total extract of Semen Strychni was administered by oral gavage to wild-type (WT) and Bmal1-/- (a circadian clock-deficient model) mice at different circadian time points for toxicity (including survival) and pharmacokinetic characterization. Nephrotoxicity and neurotoxicity were evaluated by measuring plasma creatinine and creatine kinase BB (CK-BB), respectively. Drug metabolism and transport assays were performed using liver/intestine microsomes and everted gut sacs, respectively. Key findings Semen Strychni nephrotoxicity and neurotoxicity as well as animal survival displayed significant circadian rhythms (the highest level of toxicity was observed at ZT18 and the lowest level at ZT2 to ZT6). According to pharmacokinetic experiments, herb dosing at ZT18 generated higher plasma concentrations (and systemic exposure) of strychnine and brucine (two toxic constituents) compared with ZT6 dosing. This was accompanied by reduced formation of both dihydroxystrychnine and strychnine glucuronide (two strychnine metabolites) at ZT18. Bmal1 ablation sensitized mice to Semen Strychni-induced toxicity (with increased levels of plasma creatinine and CK-BB) and abolished the time dependency of toxicity. Metabolism of Semen Strychni (strychnine and brucine) in the liver and intestine microsomes of WT mice was more extensive at ZT6 than at ZT18. These time differences in hepatic and intestinal metabolism were lost in Bmal1-/- mice. Additionally, the intestinal efflux transport of Semen Strychni (strychnine and brucine) was more extensive at ZT6 than ZT18 in WT mice. However, the time-varying transport difference was abolished in Bmal1-/- mice. Conclusions Circadian responses of mice to Semen Strychni are associated with time-varying efflux transport and metabolism regulated by the circadian clock (Bmal1). Our findings may have implications for optimizing phytotherapy with Semen Strychni via timed delivery.

Brucine inhibits proliferation of glioblastoma cells by targeting the G-quadruplexes in the c-Myb promoter.

Abstract: The proto-oncogene c-Myb plays an important role in cell proliferation, and its upregulation affects the development of glioblastomas. G-quadruplexes are secondary DNA or RNA structures that usually form in the promoter region of oncogenes, including c-Myb, and regulate the expression of these genes. The traditional Chinese medicine, brucine, is a ligand of the G-quadruplexes located in the promoter region of c-Myb. The present study investigated the therapeutic effects and mechanism of action of brucine in U87, LN18, and LN229 cells in vitro and in vivo. Our results showed that brucine suppressed the growth of these cells in vitro by arresting the cell cycle and reducing c-Myb expression. Dual-luciferase reporter assays showed that brucine inhibited c-Myb expression by targeting the guanine-rich sequence that forms G-quadruplexes in the c-Myb promoter. Moreover, U87 tumors were suppressed by brucine in a tumor xenograft nude mouse model. Therefore, brucine is potentially effective for treating glioblastomas.

Pharmacokinetic, acute toxicity, and pharmacodynamic studies of semen strychni total alkaloid microcapsules

Abstract: Purpose: To investigate the safety and effectiveness of semen strychni total alkaloid microcapsules (SSTAM), compared with semen strychni total alkaloids (SSTA). Methods: Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was employed to assess pharmacokinetics of brucine and strychnine in rats. Acute toxicity was investigated in pre-test and formal experiments in mice. The pharmacodynamics of SSTAM and SSTA were evaluated by their analgesic and anti-inflammatory activities. Results: With respect to brucine, the half-life of SSTA group (1.6 mg/kg), low-dose SSTAM group (6 mg/kg) and high-dose SSTAM group (10 mg/kg) was 5.723, 9.321 and 9.025 h, respectively. With respect to strychnine, the half-life of SSTA group, low-dose SSTAM group and high-dose SSTAM group was 4.065, 8.819 and 8.654 h, respectively. The LD50 values of SSTAM group and SSTA group were 236.59 and 30.27 mg/kg, respectively. The pain inhibition rates of SSTAM groups (25 and 50 mg/kg) were higher than that of SSTA group (p < 0.05) while the pain threshold values of the SSTAM groups (25 and 50 mg/kg) were higher than that of blank control (p < 0.01) and SSTA groups (p < 0.01) at 60 min and 120 min. The inhibition rates of the SSTAM groups (25 and 50 mg/kg) were higher than that of SSTA group based on ear swelling and cotton ball granulation tests. Compared with blank control and SSTA groups, the absorbance values of SSTAM groups (25 and 50 mg/kg) were lower (p < 0.01). Conclusion: SSTAM increases the dosage of administration but reducea the toxicity of the alkaloids in rats, and is thus a potentially safe and effective drug delivery system.

Brucine Diol-Catalyzed Enantioselective Morita-Baylis-Hillman Reaction in the Presence of Brucine N-Oxide

Abstract: Brucine diol (BD) catalyzed asymmetric Morita–Baylis–Hillman (MBH) reaction is observed for the first time. Brucine N-oxide (BNO) was found to not have an effective chiral catalyst. Faster reaction rate was obtained using unsaturated ester or aromatic aldehydes in the presence of BNO. 4-Nitrobenzaldehyde and α,β-unsaturated ketone/ester were converted to the MBH adduct in moderate yields (up to 74%) with 70% ee value by this catalytic system. The mechanism of BD catalysis is probably initiated by conjugating the vicinal diol of BD to the carbonyl group of the aromatic aldehyde through hydrogen bonding. The tertiary amine of BD acts as a nucleophile to activate vinyl ketone for coupling with the carbonyl of aldehyde through an intramolecular carbonylated reaction. Finally, the breakdown of the complex caused the formation of the MBH adduct (a benzyl-allyl alcohol). The chirality of the benzyl-allyl alcohol is likely affected by the interaction of the bulky asymmetric plane of BD.

Brucine promotes apoptosis in cervical cancer cells (ME-180) via suppression of inflammation and cell proliferation by regulating PI3K/AKT/mTOR signaling pathway.

Abstract: Brucine are the main constituents of Strychnos nux-vomica Earlier reports have determined brucine shows anti-inflammatory, analgesic and excellent anti-tumor drug Even though its anticervical cancer cells remains not clearly evaluated So that, we hypothesized the anti-cervical cancer activity of brucine against the cervical (ME-180) cells Brucine inhibited the inflammation, cell proliferation and promoted rate of apoptotic cell death ad reduced the mitochondrial potential, which is evidenced by respective (AO/EB, Rh-123, and PI) staining Furthermore ELISA and real time PCR reaction determined that brucine were down regulated inflammatory (TNF-α, NF-kB, IL-6 & COX-2) cell proliferation (Cyclin D1) and apoptotic marker Bax, caspase-3, PI3K (phosphoinosital 3 kinase), AKT, mTOR (mammalian target of rapamycin) and over expression Bcl-2, associated death promoter These findings were confirmed and finally suggested that brucine inhibited inflammation, cell proliferation and promoted the apoptosis through the down-regulation of PI3K/AKT/mTOR pathway Taken together, these data were exhibited brucine as a good therapeutic agents for the prevention of anticancer cervical cancer drugs

Brucine gel formulation and preparation method therefor

Abstract: A brucine gel formulation, a preparation method therefor and use thereof. Said gel formulation comprises 0.5% - 1% of brucine, 0.5% - 3% of a gel matrix and 10% - 30% of a co-solvent. Said brucine hydrogel does not contain a transdermal enhancer, but has an excellent transdermal effect, is easy to coat, has good biosolubility, good skin absorption and good drug film adhesion, and is non-irritating to the skin and mucosa.