Application of traditional Chinese medicine composition in preparation of medicine for relieving side effects of oxaliplatin chemotherapy

Abstract

The invention discloses application of a traditional Chinese medicine composition in preparation of a medicine for relieving side effects of oxaliplatin chemotherapy. The traditional Chinese medicine composition composed of radix paeoniae alba and liquorice is used for relieving various side reactions caused by oxaliplatin, wherein the side reactions comprise peripheral neurotoxicity, hematological toxicity and systemic reaction. The traditional Chinese medicine composition plays a role in relieving peripheral neurotoxicity caused by oxaliplatin through multiple ways, on one hand, neuroinflammatory response in dorsal root ganglions is inhibited, the dorsal root ganglions are responsible for receiving and conducting sensory nerve impulse, the injury is mainly represented as sensory disorders such as numbness of hands and feet, stabbing pain and delayed feeling, and on the other hand, the neuroinflammatory response in the dorsal root ganglions is inhibited; therefore, OIPN can be relieved by inhibiting the inflammatory reaction; on the other hand, the blood flow of microvessels is promoted, and the circulation disorder of the microvessels at the tail ends of the limbs is improved to relieve OIPN. Moreover, the traditional Chinese medicine composition does not influence the anti-tumor effect of oxaliplatin, is good in safety, and does not damage important organs such as heart, liver, spleen, lung and kidney.

Description

Technical Field

[0001] The present invention relates to the use of a traditional Chinese medicine composition in the preparation of a drug for relieving the side effects of oxaliplatin chemotherapy, and belongs to the technical field of pharmacy. Background Art

[0002] The chemotherapy drug oxaliplatin is currently a first-line chemotherapy drug in clinical practice and is widely used in various solid tumors such as colorectal cancer and gastric cancer. However, while oxaliplatin exerts its anti-tumor effect, it can cause a variety of side effects, including peripheral neurotoxicity, hematological toxicity, fatigue, weight loss, etc. These side effects cause varying degrees of distress to patients and, in severe cases, chemotherapy medication has to be stopped, thus affecting the therapeutic effect of chemotherapy drugs.

[0003] The incidence of oxaliplatin-induced peripheral neurotoxicity (OIPN) is relatively high. Current clinical data show that 85% - 95% of patients develop acute neurotoxicity 24 - 48 hours after oxaliplatin administration, characterized by cold sensitivity and paresthesia in the extremities. When the chemotherapy cycle is prolonged and the dose of oxaliplatin gradually accumulates, chronic neurotoxicity is likely to occur, manifested as peripheral nerve paresthesia, and there may also be manifestations such as motor dysfunction and reduced fine resolution. The occurrence of these adverse reactions may lead to the delay or cessation of chemotherapy treatment in patients, accelerate tumor progression, and seriously affect the quality of life of patients at the same time.

[0004] The pathogenesis of OIPN is complex and not fully understood. Currently, it is believed that multiple factors are involved in its occurrence. The possible pathogenesis includes: (1) Chemotherapy drugs act on the sensory cell bodies and axons of dorsal root ganglia, release pro-inflammatory cytokines, activate the apoptotic signal transduction cascade, change the excitability of central and peripheral neurons, and lead to the shedding of the perineurium; (2) Ion channel dysregulation; (3) Microtubule disruption and axonal transport disorders; (4) Mitochondrial dysfunction and oxidative stress; (5) Triggering multiple abnormalities in the immune system, including abnormal cytokine secretion and abnormal immune cell function, etc., leading to the development of neuroinflammation and sensitization of the sensory nervous system; (6) Axonal degeneration; (7) Damage to dorsal root ganglion sensory neurons.

[0005] Currently, the treatment methods for OIPN have limited effects. The American Society of Clinical Oncology has issued new prevention and treatment guidelines for chemotherapy-induced peripheral neurotoxicity, indicating that there is still a lack of preventive and therapeutic medications. No drug is recommended for prevention, and only duloxetine is moderately recommended for treatment, but it has gastrointestinal and central adverse reactions. And past studies have not paid attention to whether these drugs will have an impact on tumor progression.

[0006] Oxaliplatin can also cause hematological toxicity, mainly including thrombocytopenia and leukopenia. The possible reasons are that oxaliplatin has a toxic effect on rapidly dividing cells. (1) It interferes with the proliferation and differentiation of megakaryocytes in the bone marrow, and platelets are produced by megakaryocytes in the bone marrow, thus reducing platelet production; (2) It damages hematopoietic stem cells in the bone marrow, and these stem cells are the precursor cells for the production of white blood cells, thus reducing white blood cell production. Oxaliplatin may also cause systemic side effects, such as feeling fatigued, loss of appetite, weight loss, etc. Therefore, a traditional Chinese medicine composition that can relieve the side effects of the chemotherapy drug oxaliplatin, does not affect the efficacy of the chemotherapy drug, and has good safety is needed. Summary of the Invention

[0007] To solve the deficiencies of the prior art, the present invention provides an application of a traditional Chinese medicine composition in the preparation of a drug for relieving the side effects of the chemotherapy drug oxaliplatin. The traditional Chinese medicine composition is specifically composed of white peony root and licorice root. This traditional Chinese medicine composition not only has a significant relieving effect on various side effects caused by oxaliplatin, such as peripheral neurotoxicity, hematological toxicity (thrombocytopenia and leukopenia), and systemic reactions (feeling fatigued, loss of appetite, weight loss), but also does not affect the anti-tumor effect of oxaliplatin and has good safety.

[0008] The present invention is achieved through the following technical solutions:

[0009] The first object of the present invention is to provide an application of a traditional Chinese medicine composition in the preparation of a drug for relieving the side effects of oxaliplatin chemotherapy. The traditional Chinese medicine composition includes, by weight parts: 1 - 3 parts of white peony root and 1 - 3 parts of licorice root.

[0010] In an embodiment of the present invention, the active ingredients of the traditional Chinese medicine composition include albiflorin and glycyrrhizic acid, or include one or more of gallic acid, oxypaeoniflorin, paeoniflorin, liquiritin, benzoic acid, isoliquiritin, quercetin, benzoylpaeoniflorin, naringenin, paeonol.

[0011] In an embodiment of the present invention, when the traditional Chinese medicine composition is used, it is prepared into Shaoyao Gancao Decoction for administration.

[0012] In an embodiment of the present invention, the Shaoyao Gancao Decoction is obtained by decocting white peony root and licorice root.

[0013] In an embodiment of the present invention, the Shaoyao Gancao Decoction is specifically prepared by the following method:

[0014] Mix white peony root and licorice root in proportion, add 8 - 12 times the amount of water and decoct for 0.5 - 2 h, then filter. Add 6 - 10 times the amount of water to the medicinal residues and decoct for 0.5 - 2 h, then filter. Combine the two filtrates and concentrate to obtain the Shaoyao Gancao Decoction.

[0015] In one embodiment of the present invention, the traditional Chinese medicine composition is administered before the administration of oxaliplatin, simultaneously with oxaliplatin, or after the administration of oxaliplatin.

[0016] In one embodiment of the present invention, the side effects of oxaliplatin chemotherapy include abnormal mechanical pain threshold and / or abnormal cold sensitivity.

[0017] In one embodiment of the present invention, the side effects of oxaliplatin chemotherapy include pathological damage to the dorsal root ganglion (DRG).

[0018] In one embodiment of the present invention, the side effects of oxaliplatin chemotherapy include neuroinflammation.

[0019] In one embodiment of the present invention, the side effects of oxaliplatin chemotherapy include microvascular circulatory disorders at the extremities of the limbs.

[0020] In one embodiment of the present invention, the side effects of oxaliplatin chemotherapy include thrombocytopenia and / or leukopenia.

[0021] Advantages of the present invention:

[0022] In the present invention, a traditional Chinese medicine composition composed of Paeonia lactiflora Pall. and Glycyrrhiza uralensis Fisch. is used to alleviate various side effects caused by oxaliplatin, including peripheral neurotoxicity, hematological toxicity, and systemic reactions. The traditional Chinese medicine composition alleviates the peripheral neurotoxicity caused by oxaliplatin through multiple pathways. On the one hand, it inhibits the neuroinflammatory reaction in the dorsal root ganglion. The dorsal root ganglion is responsible for receiving and conducting sensory nerve impulses, and its damage is mainly manifested as sensory disorders, such as numbness, tingling, and dullness in the hands and feet. Therefore, inhibiting its inflammatory reaction will alleviate OIPN. On the other hand, it promotes microvascular blood flow, and improving microvascular circulatory disorders at the extremities of the limbs can alleviate OIPN. And this traditional Chinese medicine composition does not affect the antitumor effect of oxaliplatin, has good safety, and does not damage important organs such as the heart, liver, spleen, lungs, and kidneys. Description of the drawings

[0023] In order to more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the following will briefly introduce the drawings required for the description of the embodiments or the prior art. Obviously, the following drawings are only some embodiments of the present invention. For those of ordinary skill in the art, without creative efforts, other drawings can also be obtained based on these drawings.

[0024] Figure 1 are the components contained in Shaoyao Gancao Decoction;

[0025] Figure 2 Shaoyao Gancao Decoction can alleviate the abnormal mechanical pain threshold and cold sensitivity caused by oxaliplatin;

[0026] Figure 3 The Shaoyao Gancao Decoction can relieve the pathological damage of dorsal root ganglia caused by oxaliplatin;

[0027] Figure 4 The Shaoyao Gancao Decoction inhibits the upregulation of macrophage HK2 transcription in dorsal root ganglia induced by oxaliplatin, reduces its glycolytic activity, decreases the proportion of M1 macrophages, alleviates neuroinflammation, and ultimately relieves OIPN;

[0028] Figure 5 The Shaoyao Gancao Decoction relieves OIPN by inhibiting the formation of NETs at the extremities induced by oxaliplatin and improving microcirculation disorders;

[0029] Figure 6 The effective components of the Shaoyao Gancao Decoction for relieving OIPN are paeoniflorin and glycyrrhizic acid;

[0030] Figure 7 The Shaoyao Gancao Decoction can increase the thrombocytopenia and leukopenia caused by oxaliplatin;

[0031] Figure 8 The Shaoyao Gancao Decoction can relieve the sensory fatigue, decreased appetite, and weight loss caused by oxaliplatin;

[0032] Figure 9 The Shaoyao Gancao Decoction does not affect the antitumor effect of oxaliplatin;

[0033] Figure 10 The combination of the Shaoyao Gancao Decoction and oxaliplatin has good safety. Detailed implementation manners

[0034] The following combines specific examples to further elaborate on this invention patent. These implementation cases are only used to illustrate the present invention and not to limit the scope of the present invention. In addition, after reading the content taught by the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of this application.

[0035] Source of raw materials

[0036] White peony root: Purchased from Shaanxi Xingshengde Pharmaceutical Co., Ltd., produced in Bozhou, Anhui, and is the dried root of the peony plant Paeonia lactiflora Pall. of the Ranunculaceae family.

[0037] Prepared licorice root: Purchased from Shaanxi Xingshengde Pharmaceutical Co., Ltd., produced in Jiuquan, Gansu, and is the processed product of the dried root and rhizome of the licorice plant Glycyrrhiza uralensis Fisch. of the Leguminosae family.

[0038] The formula of the traditional Chinese medicine composition provided by the present invention: white peony root and licorice root. From the perspective of traditional Chinese medicine, white peony root is a blood-tonifying herb. As recorded in "Compendium of Materia Medica Prepared for Use", it has the effects of "tonifying blood, benefiting the spleen, and astringing liver yin", and is used to nourish yin and blood in cases of yin deficiency. Licorice root is a qi-tonifying herb. As recorded in "Supplementary Records of the Divine Husbandman's Materia Medica", it has the effects of "warming the middle and descending qi... quenching thirst, dredging meridians, and regulating qi and blood", and is good at replenishing qi and tonifying the middle. When the two herbs are combined, they have the wonderful effect of promoting the mutual generation of qi and blood, and can play a synergistic effect when combined, replenishing qi and nourishing blood.

[0039] Currently, most chemotherapy-induced peripheral neuropathy models are based on tumor-free models, ignoring the impact of tumor occurrence and development on OIPN. Therefore, according to the clinical medication principle, in this study, an orthotopic colorectal cancer tumor model was first established, and then the treatment effect was studied.

[0040] Construction of the OIPN model: Three days after inoculating mouse colorectal cancer cells, the mice were randomly divided into 5 groups, with 6 mice in each group. (1) CRC group: colorectal cancer; (2) OXA group: CRC + oxaliplatin (3 mg / kg); (3) OSGDL group: OXA + low-dose Shaoyao Gancao Decoction (9 g / kg); (4) OSGDH group: OXA + high-dose Shaoyao Gancao Decoction (18 g / kg); (5) SGDH group: high-dose Shaoyao Gancao Decoction (18 g / kg). Oxaliplatin was administered continuously for 5 days, with a 5-day rest as one cycle, and a total of two cycles were administered. Shaoyao Gancao Decoction was continuously administered by gavage for 20 days. On the 21st day, the mice were sacrificed according to ethical requirements.

[0041] The following combines specific examples to elaborate in detail on the technical solution of the present invention. In the following examples, unless otherwise specified, the reagents, materials, and equipment used can be obtained from commercial sources, or prepared by conventional methods, or are commonly used in this industry.

[0042] Example 1: Preparation of Shaoyao Gancao Decoction

[0043] A preparation method of Shaoyao Gancao Decoction is as follows: 62.5 g each of white peony root and roasted licorice root. Add 10 times the amount of pure water and boil for 1 h, then filter. Add 8 times the amount of pure water to the medicinal residues and boil for 1 h. Combine the two filtrates and concentrate to 1.5 g / mL for the following experiments.

[0044] As Figure 1 shown, the main components contained in Shaoyao Gancao Decoction are as follows. By using high-performance liquid chromatography to analyze Shaoyao Gancao Decoction and comparing it with reference substances, it is found that it mainly contains the following components: gallic acid, oxypaeoniflorin, albiflorin, paeoniflorin, liquiritin, benzoic acid, isoliquiritin, quercetin, benzoylpaeoniflorin, naringenin, paeonol, and glycyrrhizic acid.

[0045] Example 2:

[0046] As Figure 2 shown, Shaoyao Gancao Decoction can relieve the abnormal mechanical pain threshold and abnormal cold sensitivity caused by oxaliplatin.

[0047] The diagnosis of OIPN mainly relies on the combination of physical signs, clinical manifestations, and quantitative sensory testing. The von Frey filament test is an objective tool for measuring the mechanical pain threshold of the skin and can be used for clinical evaluation of pain sensitivity. In this study, the establishment of the OIPN model and the effect of Shaoyao Gancao Decoction on OIPN were detected by von Frey filaments. Before administering oxaliplatin and Shaoyao Gancao Decoction, the baseline responses of the mechanical withdrawal reflex threshold of each group of mice were basically the same. On the 3rd day after administering oxaliplatin, the mechanical withdrawal reflex threshold of the OXA group was significantly lower than that of the CRC group, and as the number of days of oxaliplatin administration increased, the mechanical withdrawal reflex threshold remained at a low level, with an obvious mechanical pain threshold, indicating that the OIPN model induced by oxaliplatin was successfully constructed. After continuously administering different doses of Shaoyao Gancao Decoction daily, the mechanical pain threshold reduction caused by oxaliplatin could be reversed to varying degrees. The OSGDL group could significantly callback the mechanical withdrawal reflex threshold on the 11th day of administration and callback to the same level as the CRC group on the 19th day of administration. The OSGDH group could significantly callback the mechanical withdrawal reflex threshold on the 7th day of administration and callback to the CRC group level on the 11th day of administration ( Figure 2 in A). It shows that Shaoyao Gancao Decoction has a dose-dependent alleviating effect on the mechanical pain threshold caused by OIPN.

[0048] In addition to abnormal mechanical pain threshold, the main manifestations of OIPN also include cold-sensitive sensory abnormalities, usually manifested as an aggravated OIPN response when contacting cold objects. The acetone-induced foot withdrawal response is a cold stimulus caused by the absorption of heat during the volatilization of acetone, which induces the mouse to have a foot withdrawal response and can directly reflect the analgesic effect of the test drug. Before administering oxaliplatin and Shaoyao Gancao Decoction, the number of foot withdrawal responses was basically the same. On the 3rd day after administering oxaliplatin, the number of foot withdrawals in the OXA group was significantly higher than that in the CRC group. As the number of days of oxaliplatin administration increased, the number of foot withdrawals remained at a high level, with abnormal cold sensitivity, indicating that the OIPN model induced by oxaliplatin was successfully constructed. After administering Shaoyao Gancao Decoction, the abnormal cold sensitivity caused by oxaliplatin could be reduced. The OSGDL group could significantly reduce the increase in the number of foot withdrawals caused by oxaliplatin on the 11th day of administration and callback to the same level as the CRC group on the 19th day of administration. The OSGDH group could significantly reduce the increase in the number of foot withdrawals caused by oxaliplatin on the 11th day of administration and callback to the CRC group level on the 15th day of administration ( Figure 2 in B). It shows that Shaoyao Gancao Decoction has a good alleviating effect on the cold-sensitive abnormalities caused by OIPN, and the results of the OSGDH group are better than those of the OSGDL group.

[0049] Example 3:

[0050] As Figure 3 shown, Shaoyao Gancao Decoction can relieve the pathological damage of the dorsal root ganglion (DRG) caused by oxaliplatin.

[0051] The DRG is a relay station for peripheral sensory signals to enter the central nervous system. DRG neurons receive the afferent of peripheral primary sensory information and then transmit it to the center. The neuronal damage and functional changes caused by the accumulation of oxaliplatin in the DRG are considered to be one of the causes of OIPN. Therefore, in this study, pathological observation of the DRG of mice was performed by H&E staining. Compared with the CRC group, the DRG neurons in the OXA group showed obvious vacuolization and impaired neuronal function. The OSGDH group had an obvious inhibitory effect on the vacuolization of DRG neurons caused by OIPN and alleviated neuronal damage ( Figure 3 in A). Nissl bodies are important evaluation indicators of neuronal function. By staining the Nissl bodies in the DRG of mice, it was found that the nerve cell structure in the CRC group was intact, the cell nuclei were mostly round, the nucleoli were clear, the cytoplasm was darkly stained, and the number of Nissl bodies was large; the nerve cell morphology in the OXA group was mostly vacuolated, the nucleoli were not obvious, the number of Nissl bodies was reduced, and the function of neurons was impaired; the nerve cell structure in the OSGDH group was basically the same as that in the CRC group ( Figure 3 in B), which confirmed that Shaoyao Gancao Decoction had a significant protective effect on oxaliplatin-induced nerve injury.

[0052] Example 4:

[0053] As Figure 4 shown, Shaoyao Gancao Decoction inhibited the upregulation of hexokinase 2 (HK2) transcription in macrophages in the DRG induced by oxaliplatin, reduced its glycolytic activity, decreased the proportion of M1 macrophages, alleviated neuroinflammation, and finally alleviated OIPN.

[0054] This study found that Shaoyao Gancao Decoction could inhibit the upregulation of HK2 in the DRG induced by oxaliplatin, and HK2 was mainly expressed in macrophages in the DRG tissue. Immunofluorescence staining confirmed the above expression changes and expression distribution patterns ( Figure 4 in A - B). It is known that HK2 can promote the glycolysis process. A significant increase in glycolysis was observed in the DRG tissue of mice receiving oxaliplatin, while in the DRG tissue of mice receiving the combination of Shaoyao Gancao Decoction and oxaliplatin, the abnormally activated glycolysis was rebalanced. Glycolysis is crucial for the polarization of pro-inflammatory M1 macrophages. Consistent with the expression of HK2, the M1 macrophages in the DRG of the OXA group increased significantly, manifested as an increase in the fluorescence intensity and proportion of its marker CD86 ( Figure 4In (C), however, in the OSGDH group, this phenomenon was attenuated, indicating that Shaoyao Gancao Decoction inhibits M1 macrophage polarization by regulating oxaliplatin-induced glycolysis. In addition, M1 macrophages use glycolysis as the main ATP source and secrete high levels of pro-inflammatory cytokines. The levels of pro-inflammatory cytokines IL-1β and TNF-α in the DRG and plasma of the OXA group were significantly increased; however, with the decrease in the number of pro-inflammatory macrophages in the DRG of the OSGDH group, these pro-inflammatory cytokine levels returned to levels comparable to those in the CRC group ( Figure 4 In (D). Neuroinflammation was also observed in the DRG of the OXA group, manifested as enhanced HGBM1 staining intensity; meanwhile, consistent with the decrease in the number of M1 macrophages and the accompanying reduction in the release of pro-inflammatory factors, enhanced HGBM1 staining intensity was no longer observed in the OSGDH group ( Figure 4 In (E). Next, we set out to clarify the role of HK2 in oxaliplatin-induced macrophage polarization. HK2 was knocked down in THP1 cells ( Figure 4 In (F), oxaliplatin treatment effectively induced M1 polarization in the control group, but there was no similar change in HK2-silenced cells ( Figure 4 In (G). Similarly, in HK2-deficient cells, oxaliplatin treatment failed to induce the production of pro-inflammatory cytokines TNF-α and IL-1β ( Figure 4 In (H). These findings emphasize that HK2 upregulation is crucial for oxaliplatin-induced M1 polarization. In summary, as Figure 4 shown in (I), we conclude that Shaoyao Gancao Decoction inhibits M1 polarization and subsequent neuroinflammation by inhibiting the transcriptional activation of macrophage HK2 in the DRG induced by oxaliplatin, reducing the overactivation of glycolysis, and thus alleviating OIPN.

[0055] Example 5:

[0056] As Figure 5 shown, Shaoyao Gancao Decoction improves microcirculation disorders and alleviates OIPN by inhibiting the formation of NETs induced by oxaliplatin at the extremities.

[0057] Previous studies have shown that microcirculation disorders induced by neutrophil extracellular traps (NETs) are one of the important causes of OIPN. This study attempted to determine whether Shaoyao Gancao Decoction could alleviate OIPN by inhibiting the formation of NETs. OIPN is mainly manifested as sensory abnormalities at the extremities. To reveal the role of NETs in the development of OIPN mechanistically, laser Doppler perfusion imaging was used to detect the dynamic changes in blood flow in the lower limbs of mice. The pseudo-color imaging of blood flow in the lower limbs of mice showed that compared with the CRC group, the blood perfusion volume in the OXA group was significantly reduced, and OSGDH could significantly improve the blood flow in the lower limbs of mice.Figure 5 In (A - B), it indicates that Shaoyao Gancao Decoction has a relieving effect on the lower limb blood microcirculation disorder in OIPN mice. The plantar skin of mice, as the primary neurons that sense, receive, and transmit peripheral signals, transmits through nerve fibers into the DRG and spinal cord, and then uploads to the sensory cortex of the brain, finally generating pain sensation. Therefore, observing the formation of NETs in the plantar skin of mice for its impact on OIPN, MPO, as one of the main markers of NETs, was found through fluorescence co - localization that oxaliplatin can cause a significant increase in the expression of MPO around blood vessels ( Figure 5 in (C), thus leading to blood microcirculation disorder. It shows that Shaoyao Gancao Decoction relieves microcirculation disorder and improves OIPN by inhibiting the formation of NETs in the plantar skin.

[0058] Example 6:

[0059] As Figure 6 shown, albiflorin and glycyrrhizic acid are the effective components of Shaoyao Gancao Decoction in relieving OIPN

[0060] Given that Shaoyao Gancao Decoction can reverse the up - regulation of HK2 transcription induced by OXA, through target prediction of the compounds in Shaoyao Gancao Decoction ( Figure 6 in (A), it was found that glycyrrhizic acid can directly bind to the transcription factor of HK2 - signal transducer and activator of transcription 3 (STAT3). First, it was explored whether OXA activates HK2 transcription through STAT3. The results showed that OXA treatment could not up - regulate the expression of HK2 in cells with STAT3 knockdown ( Figure 6 in (B), and STAT3 knockdown could reverse OXA - induced M1 - type polarization of macrophages and the release of pro - inflammatory cytokines ( Figure 6 in (C - D); suggesting that OXA activates HK2 transcription through STAT3, thereby promoting M1 - type polarization of macrophages and the release of inflammatory factors. These findings indicate that OXA activates HK2 transcription through STAT3, thereby promoting the M1 polarization of macrophages and the release of inflammatory cytokines ( Figure 6 in (E). To clarify the mechanism by which glycyrrhizic acid reverses the activation effect of OXA on STAT3, a cellular thermal shift assay was performed, which confirmed that glycyrrhizic acid can directly bind to STAT3 ( Figure 6 in (F). Further through molecular docking, it was found that glycyrrhizic acid specifically binds to the GLY - 253 site of STAT3 ( Figure 6 in (G), and this site is crucial for the phosphorylation and activation of the STAT3 Y705 site and its subsequent nuclear translocation. Western blot analysis showed that glycyrrhizic acid can reverse OXA - induced phosphorylation of the STAT3 Y705 site ( Figure 6In addition, recombinant cells expressing wild-type and constitutively phosphorylated STAT3 (Y705D) were constructed. The results showed that in cells with constitutive phosphorylation and activation of STAT3, OXA could not further induce an increase in HK2 expression; and glycyrrhizic acid could not downregulate HK2 expression either. Figure 6 In Figure I). The above confirmed that glycyrrhizic acid blocked the induction of OXA phosphorylation by directly binding to the STAT3 GLY-253 site, thereby disrupting the transcriptional activation of HK2 by STAT3. Figure 6 Inspired by the multi-component and multi-target characteristics of traditional Chinese medicine, we next explored whether there were other components in SGD responsible for regulating HK2. Through cellular thermal shift assay, albiflorin could directly bind to HK2. Figure 6 In Figure K); molecular docking further revealed that albiflorin specifically bound to the ASP209 site of HK2. Figure 6 In Figure L), this site is crucial for HK2 to bind glucose and subsequent enzymatic reactions. By evaluating the indicators of HK2 catalytic activity, it was found that albiflorin inhibited the enzymatic activity of HK2 in a dose-dependent manner. Figure 6 In Figure M). It was confirmed that albiflorin bound to the ASP209 site of HK2, thereby effectively inhibiting the enzymatic activity of HK2. Figure 6 In Figure N). The above results indicated that albiflorin and glycyrrhizic acid were the effective components of Shaoyao Gancao Decoction in relieving OIPN.

[0061] Example 7:

[0062] As Figure 7 shown, Shaoyao Gancao Decoction could increase the thrombocytopenia and leukopenia caused by oxaliplatin.

[0063] Since Shaoyao Gancao Decoction contains multiple components, its alleviation of the side effects of oxaliplatin may not be limited to peripheral neurotoxicity. Therefore, we also explored whether Shaoyao Gancao Decoction could relieve the hematological toxicity caused by oxaliplatin. The results showed that the platelet count in the OXA group was significantly lower than that in the CRC group, and the platelet counts in the OSGDL group and the OSGDH group were significantly higher than those in the OXA group. Figure 7 In Figure A); the white blood cell count in the OXA group was significantly lower than that in the CRC group, and the white blood cell counts in the OSGDL group and the OSGDH group were significantly higher than those in the OXA group. Figure 7 In Figure B). It indicated that Shaoyao Gancao Decoction could increase the platelets and white blood cells decreased by oxaliplatin, and had the effect of relieving the hematological toxicity caused by oxaliplatin.

[0064] Example 8:

[0065] As Figure 8 shown, Shaoyao Gancao Decoction could relieve the sensory fatigue, decreased appetite, and weight loss caused by oxaliplatin.

[0066] In addition, we also explored whether Shaoyao Gancao Decoction could alleviate the systemic reactions caused by oxaliplatin, such as feeling fatigued, decreased appetite, and weight loss. The rod rotation fatigue test was used to evaluate the degree of fatigue in mice. The latency period was the duration from when the mouse was placed on the rotating rod until it fell off. The shorter the latency period, the higher the degree of fatigue; the number of falls was the number of times the mouse fell off the rotating rod within a specified time. The more times it fell, the higher the degree of fatigue. The results showed that the degree of fatigue in the OXA group was significantly higher than that in the CRC group, and the degrees of fatigue in the OSGDL group and the OSGDH group were significantly lower than that in the OXA group ( Figure 8 as shown in A - B). In addition, the food intake in the OXA group was lower than that in the CRC group, and the food intakes in the OSGDL group and the OSGDH group were higher than that in the OXA group ( Figure 8 as shown in C). The body weight in the OXA group was lower than that in the CRC group, and the food intakes in the OSGDL group and the OSGDH group were slightly higher than that in the OXA group ( Figure 8 as shown in D). It was shown that Shaoyao Gancao Decoction could alleviate the systemic reactions caused by oxaliplatin.

[0067] Example 9:

[0068] As Figure 9 shown, while Shaoyao Gancao Decoction alleviates the side effects of oxaliplatin chemotherapy, it does not affect the anti - tumor effect of oxaliplatin.

[0069] Based on the orthotopic tumor model of colorectal cancer, this study evaluated the effect of Shaoyao Gancao Decoction on the anti - tumor effect of oxaliplatin. Small animal PET - CT can ensure the observation of the biological behavior of simulated diseases in vivo, non - invasively reflect the biological characteristics of tumor cells, and detect the progression of tumor diseases. 18F - FDG was injected into the tail vein of mice for PET - CT imaging observation. The results showed that there was a high uptake of 18F - FDG in the tumor sites of the CRC group, and no obvious 18F - FDG uptake was observed in the OXA group, the OSGDL group, and the OSGDH group ( Figure 9 as shown in A), indicating that oxaliplatin administration could significantly inhibit the growth of tumors in mice, and Shaoyao Gancao Decoction did not affect the anti - tumor effect of oxaliplatin. After the administration, the tumors were photographed, the volumes were calculated, and H&E staining ( Figure 9 as shown in B - 9D) found that the tumor volumes in the intestinal segments of mice in the CRC group were significantly larger than those in the OXA group, the OSGDL group, and the OSGDH group, indicating that oxaliplatin had an obvious anti - tumor effect, and Shaoyao Gancao Decoction did not affect the anti - tumor effect of oxaliplatin.

[0070] Example 10:

[0071] As Figure 10 shown, the combination of Shaoyao Gancao Decoction and oxaliplatin has good safety.

[0072] By performing pathological observations on the major organs, namely the heart, liver, spleen, lungs, and kidneys, no obvious organic lesions were found. During the treatment period, no observable abnormal behaviors were exhibited by the mice either. This indicates that the combined use of Shaoyao Gancao Decoction and oxaliplatin is safe and effective.

[0073] The embodiments provided above are not intended to limit the scope covered by the present invention, nor are the described steps intended to limit the order of their execution. Obvious improvements made by those skilled in the art to the present invention in combination with the existing well-known common knowledge also fall within the protection scope defined by the claims of the present invention.

Claims

1. Use of a Chinese medicine composition in the preparation of a drug for alleviating the side effects of oxaliplatin chemotherapy, characterized in that: The traditional Chinese medicine composition comprises, by weight: 1-3 parts of white peony root and 1-3 parts of liquorice.

2. The use according to claim 1, characterized in that: The active ingredients of the traditional Chinese medicine composition include paeoniflorin and glycyrrhizic acid, or include one or more of gallic acid, oxidized paeoniflorin, paeoniflorin, liquiritin, benzoic acid, isoliquiritigenin, quercetin, benzoylpeoniflorin, naringenin, and paeonol.

3. The use according to claim 1, characterized in that: When the Chinese medicine composition is used, it is prepared into Shaoyao Gancao Decoction for administration.

4. The use according to claim 3, characterized in that: The Shaoyao Gancao decoction is obtained by decocting white peony root and liquorice.

5. The use according to claim 3 or 4, characterized in that: The Shaoyaogancao decoction is specifically prepared by the following method: White peony root and licorice are mixed in proportion, 8 to 12 times of water are added, the mixture is boiled for 0.5 to 2 hours and then filtered, 6 to 10 times of water are added to the residue, the mixture is boiled for 0.5 to 2 hours and then filtered, the two filtrates are combined and concentrated to obtain the Peony and Licorice Decoction.

6. The use according to claim 1, characterized in that: The side effects of oxaliplatin chemotherapy include abnormal mechanical pain threshold and / or abnormal cold sensitivity.

7. The use according to claim 1, characterized in that: The side effects of oxaliplatin chemotherapy include pathological damage to the dorsal root ganglia.

8. The use according to claim 1, characterized in that: The side effects of oxaliplatin chemotherapy include neuroinflammation.

9. The use according to claim 1, characterized in that: The side effects of oxaliplatin chemotherapy include microvascular circulation disorders in the extremities.

10. The use according to claim 1, characterized in that: The side effects of oxaliplatin chemotherapy include thrombocytopenia and / or leukopenia.

Images