The chemical name of brown cyanidin is 4', 5,7-trihydroxy-3', 6-dimethoxyflavone. It is a yellow crystalline powder with the molecular formula of c17h14o7 and the relative molecular mass of 330.28. It is a flavonoid with a variety of pharmacological activities mainly found in mugwort leaves and wild horse chase [1-2]. Similar to many flavonoids, brown cyanidin is recognized for its pharmacological properties, including anti-tumor, anti-inflammatory, anti diabetic, antioxidant, antimutagenic, immunosuppressive functions, and has potential application value [3]. .
1 anti tumor
Cancer is due to the disorder of the mechanism regulating cell growth and differentiation, which makes cancer cells proliferate indefinitely. At present, drugs that can be used to treat cancer affect their clinical efficacy due to their adverse reactions. . Brown cyanidin has significant inhibitory effects on a variety of cancer cells (Table 1). The anti-tumor mechanism of brown cyanidin is multifaceted, including inducing tumor apoptosis, inhibiting tumor cell invasion and migration, and inducing tumor cell cycle arrest through a variety of pathways (Fig. 1). In recent years, the anticancer mechanism of brown cyanidin has become a research hotspot, which can be used as a candidate drug for the development of new anticancer drugs.
1.1 induction of tumor apoptosis
Apoptosis is an active, gene directed, evolutionarily conserved process. . Kim et al [5] found that brown cyanidin (100 µ mol/l) induced the apoptosis of human breast epithelial cells (mcf10a RAS) by 40%. The related mechanisms included increasing the accumulation of reactive oxygen species (ROS), upregulating the ratio of Pro apoptotic Bax to anti apoptotic Bcl-2, inducing the cleavage of Caspase-3 and poly (ADP ribose) polymerase (PARP), increasing the expression of p53 and p21, and inhibiting the activation of erk1/2.
In human ovarian cancer cell line CaOV-3, brown cyanidin induces apoptosis through the reduction of mitochondrial membrane potential, the cleavage of PARP and caspase-3/-9, and the release of cytochrome C in a time-dependent manner [11]. Brown cyanidin also has proliferation inhibition and apoptosis induction effects on human renal cancer cells, which leads to the release of cytochrome c through the activation of Bax in a time and dose-dependent manner, and downregulates the expression of Mcl-1 and c-FLIP at the transcriptional level, thereby inducing human renal cancer apoptosis[13]. In addition, brown cyanidin significantly induced apoptosis of breast cancer cell line MCF-7 by regulating ERK and p38 MAPK pathways in a dose-dependent manner [6]. The mechanism of oncogenic apoptosis mediated by phalloidin is complex and diverse, which is an important direction for further study of its anti-tumor effect.
1.2 inhibition of tumor cell invasion and migration
The invasion and migration of tumor is the metastasis of tumor cells from the primary tumor to other parts through lymphatic vessels and blood vessels. Studies have shown that matrix metalloproteinases (MMPs) play an important role in the invasion and migration of tumor cells [19]. Brown cyanidin inhibited the phorbol ester (TPA) - induced upregulation of cyclooxygenase-2 (COX-2) and MMP-9 expression of mcf10a in breast cells in a concentration (10-50 µ mol/l) related manner, while blocking the phosphorylation level of erk1/2, a signaling molecule that regulates COX-2 and MMP, and brown cyanidin inhibited the invasion and migration phenotype of mcf10a cells induced by TPA [20]. . Therefore, targeted inhibition of MMP may be another effective strategy for cancer prevention or treatment.
1.3 induce g2/m arrest of tumor cells
Abnormal cell cycle regulation mechanism is the main reason for unlimited proliferation of tumor cells. Many anticancer drugs arrest the cell cycle at specific checkpoints and induce apoptotic cell death. The g2/m checkpoint blocks cells in the G2 phase when DNA is damaged, allowing cells to repair DNA damage before entering mitosis [21-22]. Brown cyanidin induced g2/m phase arrest and DNA fragmentation in glioma U87 cells is associated with p53/p21 upregulation and cyclin-b1, CDK1 downregulation [16-17]. In hec1a cells, brown cyanidin leads to inactivation of CDC2 cyclin B1 complex by regulating erk/atm/ chk1/2 pathway and induces g2/m arrest of endometrial cancer cells [7]. Therefore, the study of brown cyanidin induced tumor cell cycle arrest and affected the expression of cell cycle related proteins may be another important mechanism of its anti-tumor.
2 anti inflammatory
Inflammation is a physiological response of the human body to stimuli (pathogens, viruses, tissue lesions or allergens), but persistent inflammation can cause a variety of diseases, including diabetes, cancer, cardiovascular disease, arthritis and autoimmune diseases [23]. The anti-inflammatory properties of flavonoids are crucial to reveal this new class of plant derived effective anti-inflammatory drugs. .
In the mouse model of back airbag inflammation, brown cyanidin increased the number and protein level of leukocytes in the secretion of airbag, inhibited the expression of COX-2 and the activation of nuclear factor к B (nf- к b), and significantly reduced the levels of tumor necrosis factor - α (tnf- α), IL-1 β and prostaglandin E2 (PGE2). It also inhibited carrageenan induced hind paw edema in rats [25]. In lipopolysaccharide (LPS) - treated RAW264.7 cells, brown cyanidin has the ability to inhibit nf- κ B activity, nitric oxide (no) formation and nitric oxide synthase (iNOS) expression [26]. Brown cyanidin can reduce the ear tissue edema of mouse ear edema model, inhibit the activity of tPA mediated nf- κ B, and the inhibition rate can reach 77%[27].
In the LPS induced acute lung injury model, Ig Brown cyanidin in mice after 24 h of LPS treatment can significantly reduce the dry and wet lung specific gravity and the protein concentration in bronchoalveolar lavage fluid, while downregulating tnf- α, IL-6 and IL-1 β in bronchoalveolar lavage fluid, upregulating IL-4 and IL-10, and significantly reducing the levels of COX-2 and nf- κ B [28]. Brown cyanidin alleviates cartilage damage in osteoarthritis model mice by blocking nf- κ bsignaling pathway [29]. Brown cyanidin also significantly blocked the edema reaction of mouse feet in the acute test, and inhibited the growth of granuloma in rats stimulated by cotton balls in the chronic test [30].
In addition, the effect of brown cyanidin on central inflammation has also been reported. Microglia are innate immune cells in the central nervous system and play a central role in the occurrence and maintenance of neuroinflammation. Brown cyanidin inhibited BV2 inflammatory activation of microglia in vitro (IC50 = 27 µ mol/l), reduced NO production, and attenuated microglial neurotoxicity in microglia / neuroblastoma cocultures. In an in vivo mouse model of encephalomyelitis, systemic injection of brown cyanidin improved neuroinflammation [31]. Compared with other synthetic compounds, brown cyanidin can fight a variety of neurodegenerative and neuroinflammatory diseases, such as multiple sclerosis, Parkinson's disease and Alzheimer's disease.
At present, only preliminary studies have shown the anti-inflammatory effect of brown cornflower associated with nf- κ B inhibition (Table 2). Therefore, more research is needed to support the potential application of brown cyanidin as a therapeutic drug for inflammatory diseases.
3 antibacterial
. In the reaction of β - lactam antibiotics to methicillin-resistant Staphylococcus aureus isolates and Escherichia coli, brown cyanidin has a moderate antibacterial effect, and the antibacterial effect on most Staphylococcus aureus is the best (the minimum inhibitory concentration value is 16 ～ 32 μ g/ml) [14]. In other studies, brown cyanidin has the highest antibacterial effect on Staphylococcus aureus, with a minimum inhibitory concentration of 128 μ mol/ml[33]. Brown cyanidin showed antibacterial activity against E. coli mutant Δ TolC in liquid culture, and completely inhibited enol reductase (FabI) activity at a concentration of 100 µ mol/l; Brown cyanidin significantly inhibited FabI activity in vitro (IC50 of 75 µ mol/l), but showed no selectivity for this enzyme in vivo [34]. Therefore, further research is recommended to fully understand how Brown cyanidin exerts its antibacterial effect.
4 reduce blood glucose
Diabetes mellitus is a complex metabolic disease characterized by hyperglycemia. With the reduction of glucose utilization and insulin resistance, long-term hyperglycemia will lead to life-threatening complications, such as neuropathy, retinopathy and cardiovascular disease [35]. In the mouse model of type 2 diabetes mellitus, Ig Brown cyanidin can reduce fasting blood glucose levels and insulin resistance. This dietary intervention helps to reduce the accumulation of advanced glycation end products in diabetic kidneys [36].
. Brown cyanidin (2, 4 mg/kg) treated diabetic mice induced by high-fat diet for 14 days. The results showed that brown cyanidin triggered upregulation of sarcoplasmic Ca2 + - ATPase (serca2b) enhanced insulin sensitivity and reduced ER stress, while it could inhibit blood glucose levels, improve glucose tolerance and reduce insulin resistance in diabetic mice [38]. Brown cyanidin exerted hypoglycemic effects in streptozotocin stimulated type 1 diabetic mice [39]. Therefore, brown cyanidin can be used as a potential candidate natural compound for the treatment of obesity, insulin resistance and diabetes related diseases.
5 immunosuppression
Brown cyanidin can be used as an anti allergic agent (IC50 = 4.5 µ mol/l) to protect RBL-2H3 cells from passive skin anaphylaxis and scratching behavior caused by IgE antigen complex. Its mechanism of action is by preventing the release of β - hexosaminidase and inhibiting the activity of nf- κ B, the gene expression of IL-4 and tnf- α [40]. Brown cyanidin significantly inhibited concanavalin A-induced T cell proliferation and activation, and inhibited the secretion of pro-inflammatory cytokines such as IL-2, tnf- α, interferon gamma (ifn- γ) from activated T cells. In vivo, it significantly improved the ear swelling induced by picryl chloride by inhibiting the stat1/t-bet pathway in a dose-dependent manner [41]. . But so far, the number of studies on the immunosuppressive effect of brown cyanidin is limited, and more studies are still needed to fully understand its exact molecular mechanism.
6 others
. In addition, brown cyanidin also exhibits strong DPPH and ONOO radical scavenging properties, with IC50 values of 2.6 and 20.5 µ mol/l, respectively [42]. Brown cyanidin can stimulate the proliferation, migration and angiogenesis of human umbilical vascular endothelial cells through vegfr2/fak/pi3k/akt/nf- к B pathway, which may help to develop angiogenic agents to promote the growth of collateral vessels in ischemic tissues [43].
Another study reported that thrombosis was prevented by inhibiting arachidonic acid triggered platelet aggregation and the formation of serotonin and thromboxane A2, as well as increasing partial prothrombin time (PT) and activated partial thromboplastin time (APTT) [44]. . When treated with TA98 strain of Salmonella typhimurium, brown cyanidin could block 3-amino-1-methyl-5H-The metabolic activities of pyridine [4,3-b] indole (Trp-P-2) and many other heterocyclic amines showed strong antimutagenic effects [45]. In addition, brown cyanidin is also an antagonist of htas2r31 (IC50 of 11.7 µ mol/l) [46].
7 conclusion
Brown cyanidin is a multi-target drug. Its anti-tumor mechanism is complex. At the molecular level, it involves the mitochondrial apoptosis pathway, ERK / Akt, p38 MAPK and other signaling pathways, as well as the regulation of cell cycle related proteins CDK1, cycilin B, ROS, MMPs and so on. Its anti-tumor molecular mechanism still needs further study. . Brown cyanidin can reduce blood glucose and regulate endoplasmic reticulum stress, providing a new direction for the treatment of obesity, insulin resistance, diabetes and other related diseases.
The anti-inflammatory and immune regulation of brown cyanidin have a two-way synergistic effect. On the one hand, it can regulate immune activated macrophages and promote the differentiation and activation of T cells. On the other hand, it can inhibit the inflammatory response by inhibiting the release of inflammatory factors, so as to achieve a two-way anti-inflammatory effect. Therefore, this effect can be well applied to diabetic complications. For its anti-inflammatory and immunomodulatory activities, we can try to combine it with hypoglycemic effect, and then launch the new drug development and clinical rational drug use of brown cyanidin in the treatment of diabetes and its complications.
At present, few studies have reported the neuroprotective effect and anticoagulant function of brown cyanidin, which will help to develop potential drugs for the prevention and treatment of neurodegenerative diseases such as Alzheimer's disease and the improvement of atherosclerosis and thrombosis. In addition, the study on the combined efficacy of brown cyanidin is rarely reported, and its drug combination may achieve better therapeutic effect, or reduce some adverse reactions. Therefore, further in vivo studies and preclinical trials are needed to reveal the pharmacological properties of this bioactive flavone and its related mechanism of action.
References (omitted)
Source: caoxiaodie, Ma Chong, Chen Li. Research progress on pharmacological effects and mechanism of action of brown cyanidin [j]. modern medicine and clinic, 2022, 37 (11): 2653-2658