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Although there have been significant advances in cancer treatment, the urgent need to inhibit breast cancer metastasis remained unmet. Bruceine A (BA) is a natural compound extracted from Bruceae Fructus and has long been recognized to have antitumor effects with high safety and biocompatibility. However, the mechanisms and/or targets of BA for metastatic breast cancer treatment are still not fully elucidated. In this study, we systematically investigated the effects of BA on inhibition of breast cancer metastasis and its underlying mechanisms. We found that, in addition to its cytotoxic effects, BA significantly inhibited the invasion and migration capabilities of two types of breast cancer cell lines (MDA‐MB‐231 and MCF‐7) while concurrently promoting apoptosis in these cells. Further mechanistic studies revealed that, by targeting the canonical PI3K‐AKT signaling pathway, BA initiated autophagy of both types of breast cancer cell lines in vitro. In vivo results further confirmed the in vitro findings, manifested by shrinkage of size and weight of breast tumor as well as initiation of autophagy (indicated by upregulation of LC3I/II) through targeting PI3K‐AKT pathway on mice model. These data collectively demonstrated the potential of BA in antimetastasis of breast cancer cells, suggesting its future clinical transformation in metastatic breast cancer therapy. [ABSTRACT FROM AUTHOR]

Pancreatic cancer remains one of the cancers with the poorest prognosis bearing an overall 5-year survival rate of about 5%. Efficient new chemotherapic drugs are still highly desired. Here, bruceine A, a quassinoid identified from the dried fruits of Brucea javanica (L.) Merr., displayed the most potent anti-proliferation activity against pancreatic cancer in vitro and in vivo. Phosphoproteomic analysis revealed p38α MAPK phosphorylation was involved in bruceine A’s action in MIA PaCa-2 cells. Utilizing fortebio octet system and microscale thermophoresis, we found p38α MAPK had high affinity for bruceine A. Molecular docking and molecular dynamic simulations showed that bruceine A widely bound to residues (Leu171, Ala172, Met179, Thr180, Val183) in P-loop of p38α MAPK. Key determinants of bruceine A binding with P-loop of p38α MAPK were 19-CO, 22-CH3, 32-CH3, and 34-CH3. Taken together, our findings demonstrate that bruceine A binds directly to p38α MAPK, which can be used to probe the role of p38α MAPK phosphorylation in pancreatic cancer progression, and as a novel lead compound for pancreatic cancer therapy.

• Bruceine A (BA) has a protective effect against alcoholic liver disease (ALD) in vivo and in vitro. • FXR overexpression alleviates steatosis and inflammation caused by ethanol. • FXR overexpression inhibits ethanol-induced AIM2 inflammasome activation in vivo and in vitro. • BA alleviates ALD by inhibiting AIM2 inflammasome activation via activating FXR. Alcoholic liver disease (ALD), a public health challenge worldwide caused by long-term persistent drinking, is life-threatening with minimal approved therapies. Hepatic steatosis accompanied by inflammation is an initial and inevitable stage in the complex progression of simple alcoholic liver injury to more severe liver diseases such as hepatitis, liver fibrosis, cirrhosis and liver cancer. We aimed to identify the therapeutic role of Bruceine A (BA) in ALD whilst attempting to explore whether its protective effects depend specifically on the farnesoid X receptor (FXR). Autodock was applied to detect the affinity between BA and FXR. Lieber-DeCarli liquid diet with 5 % ethanol (v/v) was adopted to establish the mouse ALD model. The lentivirus mediating FXR (LV-FXR) was injected into mice via the tail vein to establish FXR-overexpressed mice. FXR silencing or overexpression plasmids were transfected into AML-12 cells prior to ethanol stimulation. Quantitative real-time PCR, Western blotting and immunofluorescence assays were employed to determine the expression of related genes. We subjected liver sections to H&E and Oil Red O staining to evaluate the liver histological injury and the deposition of lipid droplets. BA significantly reduced body weight and liver-to-body weight ratios as well as biochemical indexes in mice. Ethanol-induced liver damage and lipid accumulation could be alleviated by BA treatment. BA bound to FXR by two hydrogen bonds. There was a positive correlation between BA administration and FXR expression. BA inhibited the expression of lipid synthesis genes and enhanced the expression of lipid metabolism genes by activating FXR, thus alleviating steatosis in ALD. Moreover, BA exerted an ameliorative effect against inflammation by inhibiting the activation of absent in melanoma 2 (AIM2) inflammasome by activating FXR. FXR overexpression possessed the ability to counter the accumulation of lipid and the activation of AIM2 inflammasome caused by ethanol. FXR deficiency exacerbated ethanol-induced liver steatosis and inflammation. The hepatoprotective effect of BA could be disrupted by FXR antagonist guggulsterone (GS) in vivo and FXR siRNA in vitro. BA alleviated alcoholic liver disease by inhibiting AIM2 inflammasome activation through an FXR-dependent mechanism. This study may potentially represent a new therapeutic approach for ALD. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC), as the most aggressive subtype of breast cancer, presents a scarcity of miraculous drugs in suppressing its proliferation and metastasis. Bruceine A (BA) is a functional group-rich quassin compound with extensive and distinctive pharmacological activities. Within the present study, we investigated the capabilities of BA in suppressing TNBC proliferation and metastasis as well as its potential mechanisms. The results displayed that BA dramatically repressed the proliferation of MDA-MB-231 and 4T1 cells with corresponding IC 50 values of 78.4 nM and 524.6 nM, respectively. Concurrently, BA arrested cells in G1 phase by downregulating cycle-related proteins Cyclin D1 and CDK4. Furthermore, BA distinctly induced mitochondrial dysfunction as manifested by diminished mitochondrial membrane potential, elevated reactive oxygen species generation, minimized ATP production, and Caspase-dependent activation of the mitochondrial apoptosis pathway. Additionally, BA restrained the invasion and metastasis of TNBC cells by repressing MMP9 and MMP2 expression. Intriguingly, after pretreatment with MEK activator C16-PAF, the inhibitory effect of BA on MEK/ERK pathway was notably diminished, while the proliferation suppression and metastasis repression exerted by BA were all strikingly curtailed. Molecular docking illustrated that BA potently combined with residues on the MEK1 protein with the presence of diverse intermolecular interactions. Ultimately, BA effectively suppressed tumor growth in the 4T1 xenograft tumor model with no detectable visceral toxicity in the high-dose group and, astonishingly, repressed tumor metastasis in the 4T1-luc lung metastasis model. Collectively, our study demonstrates that BA is a promising chemotherapeutic agent for treating TNBC and suppressing lung metastasis. [Display omitted] • The mechanism of action of BA in inhibiting TNBC was first explored. • BA can suppress the MEK/ERK pathway in vitro. • BA can activate the mitochondrial apoptosis pathway in vitro. • BA showed a strong affinity with MEK1. • BA inhibited tumor growth and metastasis in vivo and showed no tissue toxicity. [ABSTRACT FROM AUTHOR]

Bruceine A is a natural quassinoid compound extracted from the fruit of the Traditional Chinese Medicine Brucea javanica (L.) Merr. that has various types of various biological activities. However, whether the compound has a protective effect on diabetic kidney disease remains unknown. Galectin-1 is actively involved in a variety of chronic inflammation-relevant human diseases including diabetic kidney disease. Here, we identified Bruceine A as a kidney protective molecule against a model of diabetic kidney disease in db/db mice with potent anti-inflammatory activity both in vitro and in vivo. Mechanistically, by selectively binding to the conserved carbohydrate-recognition domain of galectin-1 and disrupting the interaction between galectin-1 and the receptor for activated protein C kinase 1, Bruceine A was found to inhibit galectin-1-mediated inflammatory signal transduction under high glucose stress in rat mesangial HBZY-1 cells. Thus, our findings reveal Bruceine A as an unidentified galectin-1 inhibitor affording significant protection against diabetic kidney disease and may provide novel pharmacological therapeutics for the disease., (Copyright © 2022 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Abstract: The present study was designated to ascertain the anthelmintic activity of the dried fruits of Brucea javanica and to isolate and characterise the active constituents. The methanol extract from the fruits of B. javanica showed significant anthelmintic activity against Dactylogyrus intermedius (EC50 (median effective concentration) value=49.96mgl−1). Based on this finding, the methanol extract was fractionated on silica gel column chromatography in a bioassay-guided fractionation affording two known quassinoids showing potent activity, bruceine A and bruceine D. Both bruceine A and D exhibited significant activity against D. intermedius with EC50 values of 0.49mgl−1 and 0.57mgl−1, respectively, which were more effective than the positive control, mebendazole (EC50 value=1.25mgl−1). In addition, the 48-h median lethal concentration (LC50) for bruceine A and D against the host (Carassius auratus) was 10.6-fold and 9.7-fold higher than the EC50 for D. intermedius. These results provide evidence that the isolated compounds might be potential sources of new anti-parasitic drugs for the control of Dactylogyrus. This is the first report on an in vivo anthelmintic investigation for B. javanica against D. intermedius. [Copyright &y& Elsevier]

The article presents a research on the efficacy of bruciene A, a natural quassinoid compound extracted from dried fruits of Brucea javanica, in treating canine babesiosis, a tick-borne disease caused by intraerythrocytic apicomplexan parasites Babesia gibsoni and Babesia canis. Babesia gibsoni infection is diagnosed through the causation of anemia, fever, thrombocytopenia, splenomegaly, lymphadenopathy and lethargy. Results of a clinical investigation show that bruciene A is a potential treatment for canine babesiosis.

Pancreatic cancer is one of the most aggressive cancers with a poor prognosis and 5-year low survival rate. In the present study, we report that bruceine A, a quassinoid found in Brucea javanica (L.) Merr. has a strong antitumor activity against human pancreatic cancer cells both in vitro and in vivo. Human proteome microarray reveals that 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4) is the candidate target of bruceine A and both fluorescence measurement and microscale thermophoresis suggest bruceine A binds to PFKFB4. Bruceine A suppresses glycolysis by inhibiting PFKFB4, leading to cell cycle arrest and apoptosis in MIA PaCa-2 cells. Furthermore, glycogen synthase kinase-3 β (GSK3β) is identified as a downstream target of PFKFB4 and an PFKFB4-interacting protein. Moreover, bruceine A induces cell growth inhibition and apoptosis through GSK3β, which is dysregulated in pancreatic cancer and closely related to the prognosis. In all, these findings suggest that bruceine A inhibits human pancreatic cancer cell growth via PFKFB4/GSK3β-mediated glycolysis, and it may serve as a potent agent for curing human pancreatic cancer. [Display omitted] • Bruceine A has a strong anti-pancreatic cancer activity both in vitro and in vivo. • PFKFB4 is a target of bruceine A. • GSK3β is a downstream signal and interacting protein of PFKFB4. • Bruceine A inhibits pancreatic cancer cell growth via PFKFB4/GSK3β signaling. [ABSTRACT FROM AUTHOR]