Application of morinda citrifolia in preparation of medicine for inhibiting gastric cancer cells
By inducing ferroptosis in gastric cancer cells through specific components in noni fermentation juice, the problem of insufficient efficacy of noni juice in inhibiting gastric cancer in existing technologies has been solved, achieving effective inhibition of gastric cancer cells and control of tumor growth.
Patent Information
- Application Number
- CN202510887495.2
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-06-30
- Publication Date
- 2025-10-17
AI Technical Summary
Current technologies lack effective methods to further enhance the efficacy of noni juice in inhibiting gastric cancer cells, especially in patients with advanced gastric cancer.
A drug to inhibit gastric cancer cells was prepared by using apigenin-7-O-glucuronide, genistein, naringenin-7-O-glucuronide, and curcumin alcohol in noni fermentation juice to induce ferroptosis in gastric cancer cells through the GPX4/HO-1 signaling pathway.
Noni fermented juice can effectively inhibit the growth of gastric cancer cells. By inducing ferroptosis, it promotes apoptosis and the loss of damage repair capacity, thereby controlling the growth of gastric cancer tumors and providing a simple and safe treatment option.
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Abstract
Description
TECHNICAL FIELD
[0001] The present application relates to the technical field of biological medicine, in particular to the application of Morinda citrifolia in preparation of gastric cancer cell inhibiting drugs. BACKGROUND
[0002] The treatment of gastric carcinoma (GC) is a major challenge to global health, with the fifth highest incidence rate, and more than 700,000 people died of gastric cancer in 2018. At present, surgical resection is the best treatment for GC, and great progress has been made in targeted therapy and immunotherapy, but a large part of the population finds that the gastric cancer is in the advanced stage, and the efficacy for patients with advanced GC is limited. The mechanism of GC progression is complex. In the development process of tumor cells, it is particularly important to induce programmed cell death, including pyroptosis and ferroptosis, which plays an important role in the progression of GC. Therefore, it is imperative to study the signal pathways related to GC cell death and precise targeted therapy.
[0003] In the Hainan Chengmai gastric cancer research survey of centenarians, it was found that Morinda citrifolia drug ingredients are often used to treat gastric ulcer, gastritis, Helicobacter pylori, and regulate blood glucose and blood lipids. Hainan is located in the tropical region, and natural Morinda citrifolia (Noni), whose scientific name is Morinda citrifolia L., is a plant of the Rubiaceae Morinda L. family. Noni is widely used in traditional medicine in tropical regions. Noni is usually obtained by natural fermentation to obtain Noni Juice, and its tumor growth inhibition is mainly due to flavonoids, anthraquinones, polyphenols, and terpenoids. Scholars have found that the alcohol precipitate extract of Noni enhances the activity of macrophages, activates nitric oxide effect, tumor necrosis factor, interferon, and interleukin, and indirectly inhibits tumor growth and metastasis by improving immune function.
[0004] Noni Juice has been reported to treat tumors. It can inhibit the proliferation of hepatocellular carcinoma Bel7402 cells and promote apoptosis, inhibit the proliferation and migration of breast cancer MCF7 cells, and affect the mTOR signaling pathway. Its active ingredients can inhibit the proliferation of intestinal cancer and affect the growth of lung cancer A549. It also has good effects in terms of glucose metabolism, lipid metabolism, inflammation, and antioxidant stress. At present, there is a lack of reports on the further efficacy of Noni Juice on gastric cancer. SUMMARY
[0005] In view of this, the purpose of the present application is to propose the application of Morinda citrifolia in the preparation of gastric cancer cell inhibiting drugs.
[0006] The technical solution of the present application is as follows:
[0007] Application of Morinda citrifolia fermentation juice in preparation of an iron death inducer for inhibiting gastric cancer cells, wherein the blood entering components of the Morinda citrifolia fermentation juice include apigenin-7-O-glucuronide, genistein, naringenin-7-O-glucuronide and turmerone.
[0008] Further, the content of apigenin-7-O-glucuronide in the Morinda citrifolia fermentation juice is at least 0.90 ng / mL.
[0009] Further, the Morinda citrifolia fermentation juice induces gastric cancer cell iron death through the GPX4 / HO-1 signaling pathway.
[0010] Further, the gastric cancer cells include SNU216 cells and MKN45 cells.
[0011] Further, the Morinda citrifolia is Morinda citrifolia juice, and the preparation method of the Morinda citrifolia fermentation juice includes picking fresh Morinda citrifolia, washing, airing, not adding any moisture, directly sealing and storing for fermentation for 14 months, and then filtering, homogenizing and sterilizing for standby.
[0012] Further, the concentration of the Morinda citrifolia fermentation juice is at least 10% v / v.
[0013] Further, the concentration of the Morinda citrifolia fermentation juice is at least 15% v / v.
[0014] The application provides a medicine for inhibiting gastric cancer cells, which comprises the Morinda citrifolia fermentation juice as an iron death inducer for promoting gastric cancer cells to undergo iron death.
[0015] Further, the blood entering components of the Morinda citrifolia fermentation juice include apigenin-7-O-glucuronide, genistein, naringenin-7-O-glucuronide and turmerone.
[0016] Further, the medicine further comprises a pharmaceutically acceptable carrier and / or adjuvant.
[0017] Compared with the prior art, the application has the following beneficial effects:
[0018] The application provides application of Morinda citrifolia in preparation of a medicine for inhibiting gastric cancer cells.
[0019] Through the C-NKG mouse in situ gastric cancer model, it is known that the active ingredients of Noni raw juice can control the growth of gastric cancer tumors, can intervene in the growth of gastric cancer cells, and promote the occurrence of ferroptosis of gastric cancer cells, indicating that Noni can be used for preparing a drug for preventing and treating gastric cancer, which is simple and safe.
[0020] The present application uses MKN-45 and SNU-216 cells to study the mechanism of Noni Juice in promoting ferroptosis by cell culture technology, molecular biology means, in vitro inhibition of cell proliferation, lipid oxidation, transcription level expression, and mitochondrial morphology. Through experimental zoology research on in situ gastric cancer model in vivo, the efficacy and mechanism of Noni Juice are evaluated, and UPLC-Q Exactive MS method is used for blood component analysis to determine the effective components of Noni Juice in inducing ferroptosis of gastric cancer cells, and to provide a new direction for natural drug treatment of gastric cancer. BRIEF DESCRIPTION OF DRAWINGS
[0021] Figure 1 For in vitro research on the effect of Noni juice on gastric cancer cell death, wherein A is a curve graph of the effect of different concentrations of Noni juice on the growth of MKN45 cells and SNU216 cells, B is a plate growth graph of the effect of different concentrations of Noni juice on MKN45 cell and SNU216 cell clones, and C is a scratch test graph of different concentrations of Noni juice.
[0022] Figure 2 For the results of Noni juice affecting gastric cancer cell migration and invasion, wherein A is a data graph of gastric cancer cell migration intervened by Noni, and B is a data graph of gastric cancer cell invasion intervened by Noni.
[0023] Figure 3 For the effect of Noni juice on gastric cancer cell apoptosis and cycle, wherein A is a data graph of apoptosis intervention experiment of gastric cancer cells, and B is a data graph of cycle experiment of gastric cancer cells intervened.
[0024] Figure 4 For transcriptome analysis of gastric cancer cells intervened by Noni juice, the graph is a KEGG pathway enrichment graph of differential genes.
[0025] Figure 5 For ferroptosis of gastric cancer cells intervened by Noni juice, wherein A is a data graph of GSH and MDA determination, B is a data graph of ROS of SNU216 gastric cancer cells intervened by Noni, and C is a data graph of mitochondrial membrane potential of SNU216 gastric cancer cells intervened by Noni.
[0026] Figure 6 For detecting the expression data graph of ferroptosis protein of gastric cancer cells intervened by Noni.
[0027] Figure 7 For the data graph affecting mitochondrial function, it is a mitochondrial electron microscope graph of SNU216 gastric cancer cells intervened by Noni.
[0028] Figure 8 Figure A is a diagram of the Noni intervention in gastric cancer animal experiment, Figure B is a diagram of the Noni intervention in gastric cancer animal experiment, Figure C is a diagram of the Noni intervention in gastric cancer experiment, Figure D is a diagram of the intervention experiment gastric volume analysis, and Figure E is a diagram of the Noni intervention in gastric cancer animal experiment.
[0029] Figure 9 Figure A is a diagram of the Noni intervention in gastric cancer animal experiment, Figure B is a diagram of the Noni intervention in gastric cancer animal experiment, Figure C is a diagram of the Noni intervention in gastric cancer experiment, Figure D is a diagram of the intervention experiment gastric volume analysis, and Figure E is a diagram of the Noni intervention in gastric cancer animal experiment.
[0030] Figure 10 Figure A is a diagram of the Noni intervention in gastric cancer animal experiment, Figure B is a diagram of the Noni intervention in gastric cancer animal experiment, Figure C is a diagram of the Noni intervention in gastric cancer experiment, Figure D is a diagram of the intervention experiment gastric volume analysis, and Figure E is a diagram of the Noni intervention in gastric cancer animal experiment.
[0031] Figure 11 Figure A is a diagram of the Noni intervention in gastric cancer animal experiment, Figure B is a diagram of the Noni intervention in gastric cancer animal experiment, Figure C is a diagram of the Noni intervention in gastric cancer experiment, Figure D is a diagram of the intervention experiment gastric volume analysis, and Figure E is a diagram of the Noni intervention in gastric cancer animal experiment.
[0032] Figure 12 Figure A is a diagram of the Noni intervention in gastric cancer animal experiment, Figure B is a diagram of the Noni intervention in gastric cancer animal experiment, Figure C is a diagram of the Noni intervention in gastric cancer experiment, Figure D is a diagram of the intervention experiment gastric volume analysis, and Figure E is a diagram of the Noni intervention in gastric cancer animal experiment.
[0033] Figure 13 Figure A is a diagram of the Noni intervention in gastric cancer animal experiment, Figure B is a diagram of the Noni intervention in gastric cancer animal experiment, Figure C is a diagram of the Noni intervention in gastric cancer experiment, Figure D is a diagram of the intervention experiment gastric volume analysis, and Figure E is a diagram of the Noni intervention in gastric cancer animal experiment.
[0034] Figure 14 Figure A is a diagram of the Noni intervention in gastric cancer animal experiment, Figure B is a diagram of the Noni intervention in gastric cancer animal experiment, Figure C is a diagram of the Noni intervention in gastric cancer experiment, Figure D is a diagram of the intervention experiment gastric volume analysis, and Figure E is a diagram of the Noni intervention in gastric cancer animal experiment. DETAILED DESCRIPTION
[0035] In order to make the purpose, technical scheme and advantages of the present application clearer, the present application will be further described in detail below with examples. It should be understood that the specific examples described herein are only used to explain the present application and are not used to limit the present application.
[0036] The experimental methods used in the examples of the present application are all conventional methods unless otherwise specified.
[0037] The materials, reagents and the like used in the embodiments of the present application can be obtained from commercial channels if no special description is made.
[0038] Fetal Bovine Serum (FBS), Penicillin-Streptomycin (PS), phosphate buffered solution (PBS)
[0039] Example 1
[0040] The Noni fruit naturally grown in Chengmai, Hainan, a longevity hometown, is picked, pretreated, fermented, filtered, homogenized, sterilized and the like. The preparation method of the Noni fruit juice is as follows: fresh Noni fruit is picked, washed, dried, without any moisture, directly sealed and stored for fermentation for 14 months, and then filtered, homogenized and sterilized for standby. The production process is carried out in the production base of Hainan Fengshi Tree Noni Co., Ltd., and relevant quality inspection is carried out. In the research process, the configuration of the cell intervention medium is mainly to filter and sterilize the Noni original juice, and the medium ratio is as follows: 0% Noni intervention medium (containing 10% FBS, 1% PS, 15% PBS and 74% RPMI-1640), 5% Noni intervention medium (containing 10% FBS, 1% PS, 5% Noni, 10% PBS and 74% RPMI-1640), 10% Noni intervention medium (containing 10% FBS, 1% PS, 10% Noni, 5% PBS and 74% RPMI-1640), and 15% Noni intervention medium (containing 10% FBS, 1% PS, 15% Noni and 74% RPMI-1640). The Noni original juice used in the experiment is the same batch of fermentation liquor.
[0041] Example 2
[0042] The Noni Juice is used for cell function experiment, and the results are shown in Figure 1 As shown in Figure 1 A, when the gastric cancer cells are treated with 15% Noni Juice for 24h, the survival rate of MKN45 cells is 53.99%, and the survival rate of SNU216 cells is 61.91%; when the gastric cancer cells are treated with 15% Noni Juice for 48h, the survival rate of MKN45 cells is 28.41%, and the survival rate of SNU216 cells is 49.3%. Within 20% Noni Juice, the cell activity is dose-dependent, and when the concentration exceeds 20%, the cells are basically completely inactive. Figure 1The number of cell clones was studied by a method of colony formation experiment. It was found from the plates that the number of clones gradually decreased with the increase of Noni Juice content. When 10% Noni Juice was added, basically no clone grew, thus it was determined that it could inhibit the proliferation of gastric cancer cells at a low dose. Figure 1 C The scratch experiment was performed using 10% Noni Juice. The experimental results showed that after intervention, the cells basically had no damage repair. Different concentrations of Noni Juice affected the degree of gastric cancer cell scratch damage repair and the migration rate.
[0043] The Transwell method was used to study the effect of Noni on the migration and invasion of gastric cancer cells. It was found from Figure 2 A and B showed that the migration and invasion ability of MKN45 and SNU216 cells decreased sharply with the increase of Noni content, and the results had statistical significance. It was found from the results that the migration ability of SNU216 cells was stronger than that of MKN45 cells.
[0044] SNU216 cells were treated with 0% Noni and 15% Noni for 48h to obtain PBS control group and Noni treatment group cells. The apoptosis of the solvent control group cells and the treatment group cells was detected by Annexin FITC and PI double staining method to study the effect of Noni on the apoptosis of SNU216 cells, and the results are shown in Figure 3 A. The 15% Noni treatment group had statistical significance in cell apoptosis compared with the PBS control group, and the apoptosis rate was higher. SNU-216 cells were treated with 0% Noni and 15% Noni for 48h to obtain PBS control group and Noni treatment group cells. PI staining method was used, and the changes of cell cycle of each group were detected by flow cytometry to study the effect of Noni on the cell cycle of SNU-216 cells. In Figure 3 B results, in SNU-216 cells, the 15% Noni treatment group had statistical difference compared with the PBS control group in G0 / G1 and S phase (p<0.001, p<0.001, p<0.001), respectively, decreased by 25.66%, increased by 76.57%, which could significantly reduce the number of G0 / G1 cells, increase the number of S phase cells, affect the synthesis of DNA, and promote apoptosis.
[0045] Example 3
[0046] To further investigate the effect of Noni Juice on SNU216 cells, SNU216 cells were treated with 15% Noni medium for 48h (3 replicates), and the control group was treated with 0% Noni medium for 48h (3 replicates). The treated and control cells were collected for transcriptome sequencing. RNA-seq analysis showed that, to further explore the mechanism of Noni Juice, transcriptome sequencing analysis was performed on the treated and control SNU216 cells (n=3), of which 634 genes were up-regulated and 550 genes were down-regulated. Further analysis showed that iron death-related genes (SAT1, HMOX1, SAT2, MAP1LC3B2) were significantly up-regulated. KEGG pathway enrichment analysis Figure 4 ) showed that the pyruvate metabolism and oxidative phosphorylation pathways were significantly down-regulated, while the MAPK signaling pathway was significantly up-regulated. Oxidative phosphorylation is a key pathway for mitochondrial energy metabolism, leading to metabolic reprogramming, and its functional changes can affect the growth and metastasis of tumor cells. These findings suggest that Noni Juice may exert an anti-tumor effect by regulating iron death-related pathways.
[0047] Example 4
[0048] SNU216 cells and MKN-45 cells were treated with 15% Noni Juice for 48h, and PBS was used as a control. The glutathione (GSH) content and malonic dialdehyde (MDA) content were studied, as shown in Figure 5 A, the GSH content in the cells decreased, and the MDA content increased, which was statistically significant; Figure 5 B The use of fluorescent probe DCFH-DA to detect the production of reactive oxygen species (ROS) showed that, compared with the Control group, the ROS level in the Noni group was significantly increased, and the results were statistically significant; Figure 5 C The use of fluorescent probe JC-1 to evaluate the mitochondrial membrane potential showed that, compared with the Control group, the mitochondrial membrane potential level in the Noni group was significantly increased, affecting mitochondrial function. Western blot was used to study the expression of related proteins, as shown in Figure 6 The Western blot results showed that, compared with the Control group, the expression of the related proteins in the Noni group was significantly increased. JuiceThe expression of iron death-related proteins changed significantly after treatment. Specifically, HO-1 expression was up-regulated, accompanied by decreased GPX4 expression and increased MDA content. Further research found that Noni induced the dissociation of Keap1 from Nrf2, leading to the degradation of Keap1, while Nrf2 translocated into the nucleus. The accumulated Nrf2 in the nucleus inhibited the cystine transport mediated by System Xc-, thereby reducing GSH synthesis, further exacerbating the imbalance of cellular iron homeostasis, and ultimately inducing ferroptosis.
[0049] And by taking TEM of SNU-216 cells before and after treatment with Noni, it was found that Figure 7 The control group (PBS) SNU-216 cells had regular morphology, irregular oval-shaped nuclei (N) with clear nucleoli, short rod-shaped or oval-shaped mitochondria (M) in the cytoplasm with complete and clear cristae, and normal endoplasmic reticulum (ER) structure. The 15% (v / v) Noni juice treatment group showed typical ferroptosis morphological characteristics: irregular cell morphology, reduced nuclear volume, and peripheral aggregation of heterochromatin; swollen mitochondria, oval-shaped, with indistinct cristae, and some mitochondria showing abnormal morphology; multiple autophagic bodies (AP) were visible in the cytoplasm. These ultrastructural changes, combined with the accumulation of ROS, increased MDA content, and other biochemical indicators, further confirmed that Noni juice can induce ferroptosis in gastric cancer cells.
[0050] Example 5
[0051] By culturing gastric cancer cells, in situ gastric cancer modeling was performed on C-NKG mice and treatment studies were conducted, 20 μL of cell suspension (resuspended in PBS and Matrigel) containing 1 × 10 6 cells were injected into each C-NKG mouse, and the cells were inoculated on the gastric serosa layer. The fluorescence value was observed on the 3rd day after the operation. In vivo imaging was used to study the in situ gastric cancer modeling, as shown in Figure 8 The C-NKG mouse stomach was successfully modeled, and the control group was treated with PBS and the treatment group was treated with Noni juice. 500 μL of each was administered intragastrically for intervention, starting from Figure 8 As can be seen in A-E, Noni juice did not suppress tumor growth at day 10, but at day 20, imaging data showed that Noni juice suppressed the growth of gastric cancer cells, and the ROI value decreased significantly. At day 30, compared with the control group, the ROI value decreased more obviously, Figure 8 C is a body weight chart, and the increase in body weight in the later stage is due to the increase in ascites in mice, Figure 8 D-E are gastric cancer dissection weight data and dissection chart, and it is found that the gastric cancer in the treatment group is significantly clearer than that in the control group. It can be concluded that the active ingredients of Noni juice can control the growth of gastric cancer tumors.
[0052] By HE staining, it was found that Figure 9A shows: HE staining of gastric cancer tumor tissue in control group (PBS) mice can be seen in the part, gastric cancer tumor tissue in mice treated with PBS control group, cancer cells grow in single infiltration, promote the growth of surrounding fibrous tissue. Noni group of mice gastric cancer tumor tissue HE staining can be seen in the part, after 30 days of Noni gavage treatment, the difference of this HE staining is the largest, the upper part of the gastric cancer tissue is completely necrotic, and the lower part is the live gastric cancer tumor cells with obvious nucleolus. It is proved that after the intervention of Noni, the mouse gastric cancer tumor tissue appears necrosis, and the surrounding cancer cells also appear apoptosis. It is proved that Noni active ingredients promote the death of gastric cancer cells.
[0053] By immunohistochemical analysis of gastric cancer tissue, the positive rate of HO-1, GPX4 and Ki67 antibody cell expression is different. Immunohistochemical analysis shows that there is a significant difference between the cancer tissues of Noni treatment group and control group Figure 9 B). Quantitative analysis results show that the positive expression rate of HO-1 in Noni treatment group is significantly higher than that in control group, and the positive expression rate of GPX4 and Ki67 in Noni treatment group is significantly lower than that in control group (p<0.05). These results are consistent with the molecular changes observed in vitro experiments, further confirming the mechanism of Noni in inhibiting the growth of gastric cancer cells and inducing ferroptosis by regulating the GPX4 / HO-1 signaling pathway.
[0054] UPLC-Q Exactive MS method was used to analyze the blood components of Noni Juice. LC-MS analysis results show that 362 chemical components are identified, of which 45 are prototype blood components (see Table 1 for details, including retention time (RT), predicted molecular formula, mass spectrum mode, accurate mass-to-charge ratio and identification score). Based on chemical classification, these blood components mainly include carboxylic acids and their derivatives (13.81%), fatty acyls (13.33%), pulcherrimic acid lipids (11.43%) and oxygen-containing organic compounds (10%). The total ion chromatogram of Noni Juice-containing serum in positive and negative ion modes is shown in Figure 10 Literature research shows that these compounds have significant anti-tumor activity. From the analysis of the main blood components (Table 1), it can be seen that the main potential anti-tumor active compounds are flavonoids, including Apigenin 7-O-glucuronide (AGL), Genistein, Naringenin-7-O-beta-D-glucuronide and Curcumol, etc.
[0055] The AGL content in Noni Juice was quantitatively analyzed by using a Waters ACQUITY UPLC I-CLASS ultra-high performance liquid chromatography system. Figure 12 A-C respectively show the total ion chromatogram of the sample, the total ion chromatogram of the standard solution, and the standard curve of AGL. The TargetLynx software was used for quantitative analysis, the chromatographic retention time allowed deviation range was ± 15 s, and the AGL content in Noni Juice was calculated by external standard method to be 0.9643 ng / mL.
[0056] Table 1 Summary of main blood components
[0057]
[0058]
[0059]
[0060] Example 6
[0061] Based on the analysis results of blood component metabolites, combined with the gastric cancer (GC) related genes with scores higher than the average value in the GeneCards database (https: / / www.genecards.org / ) and the ferroptosis related targets in the FerrDB database (https: / / www.zhounan.org / ferrdb / ), a total of 71 GC related target genes were screened out (A). Figure 12 Further analysis determined 11 core targets that played a key role in the process of ferroptosis in gastric cancer (B). Figure 12
[0062] GO and KEGG enrichment analysis was performed on the 11 core targets. A total of 3038 entries were obtained by GO enrichment analysis, of which 2458 entries were statistically significant (P < 0.05). In the biological process (GO-BP) analysis, 2201 of the 2636 entries were significantly enriched; the molecular function (GO-MF) analysis showed that 171 of the 218 entries were significantly enriched; and the cell component (GO-CC) analysis found that 86 of the 184 entries were significantly enriched. KEGG pathway enrichment analysis identified a total of 179 signaling pathways, of which 132 were statistically significant (P < 0.05). After screening out the disease related pathways, the STAT3 / HIF-1α pathway was finally determined as the key regulatory pathway.
[0063] To elucidate the association mechanism between Noni Juice, ferroptosis, and gastric cancer, a Chinese medicine-compound-target-pathway interaction network was constructed. Cytoscape 3.7.2 software was used to visualize the three signaling pathways with the most significant P values and their corresponding targets, resulting in a network diagram containing 39 nodes and 116 edges. Furthermore, a Sankey diagram ( Figure 12 C and 12D).
[0064] Molecular docking analysis showed that the binding energies of the active ingredients in Noni Juice (Apigenin 7-O-glucuronide, Genistein, Naringenin-7-O-beta-D-glucuronide and Curcumol) with core proteins (EGFR, MAPK3) were as follows: Figure 13 Among them, Apigenin 7-O-glucuronide and Naringenin-7-O-beta-D-glucuronide showed higher binding stability.
[0065] Further studies have found that the HIF-1 signaling pathway plays an important role in the process of ferroptosis. To verify the reliability of the prediction results of network pharmacology, Western blot experiments ( Figure 12 E) Expression changes of key targets after Noni Juice treatment were examined. Results showed that Noni Juice treatment significantly reduced the expression levels of STAT3 and HIF1α, an effect partially reversed by the ferroptosis inhibitor Fer-1. Mechanistic studies suggest that decreased HIF1α expression leads to suppressed glycolysis. Simultaneously, inhibition of the STAT3 / HIF-1α signaling pathway reduces energy metabolism and inflammatory cytokine secretion in gastric cancer cells, ultimately inducing irreversible oxidative stress and promoting ferroptosis.
[0066] Based on the research results, the following mechanism of action is proposed ( Figure 14 ): After entering the cells, Noni's active ingredients first cause mitochondrial dysfunction and promote the dissociation of the Keap1-Nrf2 complex. Free Nrf2 then translocates to the nucleus and upregulates HO-1 expression. HO-1 activation leads to enhanced intracellular oxidative stress, promoting ROS production, which in turn causes MDA accumulation and GPX4 depletion. At the same time, Noni intervention also inhibits the expression of STAT3 and HIF-1α, further exacerbating mitochondrial dysfunction and glycolysis obstruction. These changes collectively lead to oxidative phosphorylation disorders and impaired autophagy, ultimately inducing ferroptosis in gastric cancer cells.
[0067] The above is the preferred embodiment of the present application, it should be pointed out that, for those skilled in the art, without departing from the principles of the present application, can also make a number of improvements and refinements, these improvements and refinements are also considered to be within the scope of the present application.
Claims
1. The application of Noni fermented juice is characterized by: The noni fermented juice is used in the preparation of an iron-dependent death inducer for inhibiting gastric cancer cells. The main blood-entering components of the noni fermented juice include apigenin-7-O-glucuronide, genistein, naringenin-7-O-glucuronide and curcuminol.
2. The use according to claim 1, characterized in that The content of apigenin-7-O-glucuronide in the fermented noni juice is at least 0.90 ng / mL.
3. The use according to claim 1, characterized in that The noni fermented juice induces ferroptosis of gastric cancer cells through the GPX4 / HO-1 signaling pathway.
4. The use according to claim 3, characterized in that The gastric cancer cells include SNU216 cells and MKN45 cells.
5. The use according to any one of claims 1 to 4, characterized in that: The preparation method of the noni fermented juice comprises the following steps: picking fresh noni fruits, washing, drying, and fermenting them in a sealed cellar for at least 14 months, and then filtering, homogenizing, and sterilizing to obtain the noni fermented juice.
6. The use according to claim 5, characterized in that The concentration of the Noni fermented juice is at least 10% v / v.
7. The use according to claim 6, characterized in that The concentration of the Noni fermented juice is at least 15% v / v.
8. A drug for inhibiting gastric cancer cells, characterized in that: The noni fermented juice according to claim 4 is used as a ferroptosis inducer to promote ferroptosis of gastric cancer cells.
9. The drug according to claim 8, characterized in that The components of the noni fermented juice that enter the blood include apigenin-7-O-glucuronide, genistein, naringenin-7-O-glucuronide and curcuminol.
10. The drug according to claim 8, characterized in that It also includes pharmaceutically acceptable carriers and / or excipients.