Application of Berninamycin D in preparation of anti-inflammatory drugs

Abstract

The invention discloses an application of Berninamycin D in preparation of an anti-inflammatory drug, and relates to the technical field of inflammation inhibition. According to the present invention, the anti-inflammatory activity test results show that the Berninamycin D has good anti-tumor cell inflammatory reaction activity, and does not have cytotoxicity under high concentration, such that the Berninamycin D has good anti-inflammatory drug effect, and can be used for preparing the anti-inflammatory drug.

Description

Technical Field

[0001] The present invention relates to the technical field of inhibiting inflammation, and in particular to the use of Berninamycin D in the preparation of anti-inflammatory drugs. Background Art

[0002] Tumor development and progression are closely linked to inflammation. Long-term chronic inflammation can promote tumorigenesis, and inflammatory responses within the tumor microenvironment can also influence tumor progression and metastasis. Currently, inflammatory diseases are commonly treated with nonsteroidal anti-inflammatory drugs (NSAIDs), steroids, and immunosuppressants. These drugs alleviate inflammatory responses by inhibiting the synthesis or release of inflammatory mediators. For example, aspirin may reduce the risk of certain cancers and potentially slow the progression of existing cancers. In recent years, studies have reported on the anti-inflammatory effects of RiPPs (ribosomal peptide natural products) on lung cancer cells. The main technical challenges faced by RiPPs in anti-inflammatory lung cancer cell research include low natural product content and difficulties in extraction and purification, which limit the efficiency of activity screening; the mechanism of anti-inflammatory action remains unclear, resulting in a lack of in-depth signaling pathway research; complex structures, making synthesis and modification difficult, which limits structural optimization and efficacy enhancement; and insufficient in vivo efficacy and safety evaluation, which hinders preclinical research needs. Furthermore, complex biosynthetic pathways and low heterologous expression efficiency also restrict their large-scale production and further development.

[0003] Long-term or high-dose use of NSAIDs may cause side effects such as gastrointestinal damage and increased cardiovascular risk. Long-term use of steroid drugs may lead to immunosuppression and osteoporosis.

[0004] In view of this, the present invention is proposed. Summary of the Invention

[0005] The purpose of the present invention is to provide the use of Berninamycin D in the preparation of anti-inflammatory drugs, thereby providing a new drug option for inhibiting inflammation, especially inhibiting the inflammatory response in the tumor microenvironment.

[0006] The present invention is achieved in that: In a first aspect, the present invention provides use of Berninamycin D in the preparation of anti-inflammatory drugs.

[0007] In a second aspect, the present invention further provides the use of Berninamycin D and an anti-inflammatory drug in the preparation of a drug for the combined treatment of inflammation, wherein the inflammation is tracheitis, enteritis, gastritis, pneumonia, hepatitis or tumor cell inflammation.

[0008] The present invention has the following beneficial effects: Anti-inflammatory activity tests conducted in the present invention revealed that Berninamycin D exhibits excellent anti-inflammatory activity against tumor cell inflammatory responses and is non-cytotoxic at high concentrations. Therefore, Berninamycin D exhibits excellent anti-inflammatory efficacy and can be used to prepare anti-inflammatory drugs. In addition to inhibiting or eliminating tumor cell inflammation, Berninamycin D also exhibits efficacy against inflammatory conditions such as pneumonia and hepatitis, demonstrating promising application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0009] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the following briefly introduces the drawings required for use in the embodiments. It should be understood that the following drawings only illustrate certain embodiments of the present invention and therefore should not be regarded as limiting the scope. For ordinary technicians in this field, other relevant drawings can be obtained based on these drawings without paying any creative work.

[0010] Figure 1 The figure shows the results of the cytotoxicity assay of Berninamycin D on A549 cells. The green signal indicates living cells, and the red signal indicates dead cells. Figure 2 This is the liquid chromatogram during compound preparation; Figure 3 This is the result of liquid chromatography purity test analysis of the 12.5 min effluent collected; Figure 4 is the mass spectrum of Berninamycin D; Figure 5 Berninamycin D NMR 1 H spectrum detection result diagram; Figure 6 Figure 2 is the statistical result of IL-6 ELISA on the anti-inflammatory activity of Berninamycin D in A549 cells (Note: NT represents the blank treatment group without IL-1β induction); Figure 7 The figure shows the results of nitric oxide concentration detection in RAW264.7 cells after treatment with Berninamycin D (Note: NT represents the blank treatment group without LPS induction); Figure 8 The figure shows the results of IL-6 concentration detection in RAW264.7 cells after treatment with Berninamycin D (Note: NT represents the blank treatment group without LPS induction); Figure 9 The figure shows the results of TNFα concentration detection after RAW264.7 cells were treated with Berninamycin D (Note: NT represents the blank treatment group without LPS induction). DETAILED DESCRIPTION

[0011] To make the purpose, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention are described clearly and completely below. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer are used. Where the manufacturer of the reagents or instruments is not specified, all are conventional products that can be purchased commercially.

[0012] In a first aspect, the present invention provides use of Berninamycin D in the preparation of anti-inflammatory drugs.

[0013] The inventors found that Berninamycin D has good anti-inflammatory activity and has good application prospects in the anti-inflammatory field.

[0014] The structural formula of Berninamycin D is shown below:

[0015] In a preferred embodiment of the present invention, the anti-inflammatory drug is used for at least one of the following diseases: Tracheitis, enteritis, gastritis, pneumonia, hepatitis, or tumor cell inflammation induced by inflammatory factors.

[0016] Anti-inflammatory experiments on mouse RAW264.7 cells have shown that Berninamycin D can inhibit the release of inflammatory factors in RAW cells. Inflammatory factors are highly expressed in the tumor microenvironment, and suppressing their release by Berninamycin D may help improve the tumor microenvironment. Inflammatory conditions such as pneumonia and hepatitis are often accompanied by elevated levels of inflammatory factors, and suppressing their release may help alleviate symptoms. In other embodiments, Berninamycin D may also be used to inhibit tracheitis, enteritis, and gastritis, and is expected to have some anti-inflammatory effects.

[0017] In a preferred embodiment of the present invention, the tumor cells are selected from non-small cell lung cancer, breast cancer, melanoma, colon cancer, renal cancer, lymphoma, mast cell tumor, liver cancer, pituitary tumor, myeloma, brain neuroma, testicular Leydig cell tumor, gastric cancer, prostate cancer or pancreatic cancer.

[0018] Berninamycin D has a particularly good inhibitory activity against the inflammatory response of non-small cell lung cancer cells, showing inhibitory activity at 12.5 μM-25 μM.

[0019] Cytotoxicity experiments have shown that Berninamycin D has no obvious toxicity to tumor cells, indicating that Berninamycin D has lower cytotoxicity and may have lower side effects such as gastrointestinal damage and increased cardiovascular risk.

[0020] In a preferred embodiment of the present invention, the inflammatory factor is selected from interleukin (IL), interferon (IFN) or tumor necrosis factor (TNF).

[0021] In a preferred embodiment of the present invention, the interleukin is selected from at least one of IL-1α, IL-1β, IL-4, IL10, IL11 and IL12A; the interferon is selected from at least one of IFNA1, IFNA2, IFNA3, IFNA4, IFNB and IFN-γ; and the tumor necrosis factor is selected from at least one of TNF, TNFα and TNFβ.

[0022] In a second aspect, the present invention also provides the use of Berninamycin D and an anti-inflammatory drug in the preparation of a drug for the combined treatment of inflammation, such as tracheitis, enteritis, gastritis, pneumonia, hepatitis, or tumor cell inflammation induced by inflammatory factors. Combining Berninamycin D with other anti-inflammatory drugs can enhance the therapeutic effect of inflammation.

[0023] In a preferred embodiment of the present invention, the anti-inflammatory drug is selected from non-steroidal anti-inflammatory drugs, immunosuppressants, adrenocortical hormone drugs and adrenocorticotropic hormone drugs and their salts or esters.

[0024] In a preferred embodiment of the present invention, the nonsteroidal anti-inflammatory drug is selected from ibuprofen, indomethacin, naproxen, aspirin, loxoprofen, ketoprofen, pranoprofen, diclofenac, tiaprofenic acid, butibufen, chlorophenylacetic acid, omiprofen, anfenic acid, naphthalene acid, nabuprofen, cyclohexanebutic acid, bufenol, carbazole ibuprofen, cilcoprofen, epoxy indole, clothiobuprofen, clofenamic acid, nicotinic acid, clofenamic acid, clofenamic acid, diclofenamic acid, cyclohexane chlorophenylacetic acid, fenclorac, phenylindole salicylic acid, fenoprofen, fluphenazine, flufenamic acid, phenobarbital, flufenamic acid, norbuprofen, indoprofen, mefenamic acid, minoprofen, nitrofen, chlorfenamic acid ... acylpyrrolidone, indolexamethasone, phenothiazine propionic acid, sulindac, tiabuprofen, meclofenamic acid, monoclofenamic acid, pirflufenamic acid, triflumidate, cloxoprofen, amiloride, etodolac, phenpromazine, aceclofenac, flunixin, methamphetamine, flufenamic acid, flunoprofen, flurbiprofen, pimeprofen, trifenac, aminoprofen, buclofenac, sulindac, toluidine, zomepirac, tiopinic acid, zidometacin, acemetacin, fentiazac, clidanac, mefenamic acid, meclofenamic acid, tolfenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, piroketaprofen, alminoprofen, ketorolac, rifodronate, thiodanac, alclofenac, chlornaprofen, fluprofen, or thibuprofen.

[0025] In a preferred embodiment of the present invention, the adrenocortical hormone drug and the adrenocorticotropic hormone drug and the salt or ester thereof are selected from cortisone, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, prednisone, prednisolone, methylprednisolone, triamcinolone, triamcinolone, triamcinolone hydrochloride, triamcinolone prednisolone, dexamethasone, betamethasone, clobetasone butyrate, clobetasol propionate, beclomethasone, triamcinolone acetonide, flumethasone pivalate, mometasone furoate, detamethasone valerate, betamethasone dipropionate, fluocinolone acetonide, clofluocinolone, halometasone, beclomethasone dipropionate, budesonide or fluticasone; The immunosuppressant is selected from mycophenolate mofetil (MMF), anti-human thymocyte immunoglobulin (ATG), infliximab, alemtuzumab, abatacept or intravenous immunoglobulin (IVIG).

[0026] In a preferred embodiment of the present invention, the above-mentioned medicine further comprises a pharmaceutically acceptable carrier.

[0027] The drug also includes pharmaceutically acceptable carriers, including but not limited to fillers, lubricants, disintegrants, binders, glidants, etc.

[0028] In the preferred technical solution of the present invention, the pharmaceutically acceptable carrier includes but is not limited to one or a combination of polyvinyl pyrrolidone and its derivatives, polyvinyl alcohol and its derivatives, methyl cellulose and its derivatives, ethyl cellulose and its derivatives, hydroxypropyl cellulose and its derivatives, starch and its derivatives, polyethylene glycol and its derivatives, lactose, sucrose, mannitol, trehalose, sorbitol, dextrin, microcrystalline cellulose, acrylic resin, calcium hydrogen phosphate, calcium stearate, sodium stearyl fumarate, silicon dioxide, titanium dioxide, talc, and indigo.

[0029] The features and performance of the present invention are further described in detail below with reference to the embodiments.

[0030] Example 1 The strain PS-15 of Streptomyces oliveri was isolated from soil of the Qinghai-Tibet Plateau and deposited in the Guangdong Provincial Microbiological Culture Collection Center with the deposit number: GDMCC No: 65939. The deposit date is February 26, 2025. The name of the submitted biological material is: Streptomyces atroolivaceus PS-15, classified as: Streptomyces atroolivaceus The strain was identified as viable. Through fermentation, separation of the fermentation products, and analysis of the extracts, it was discovered that one of the metabolites of the strain was Berninamycin D.

[0031] 1. Isolation of Berninamycin D 1. Strain fermentation, extraction and column chromatography steps: (1) The PS-15 strain preserved above was inoculated into TSB medium and cultured with shaking until the liquid became turbid and no large mycelial clumps were found, which could be used as seed liquid.

[0032] (2) Take 200 μL of seeds and spread them on ISP2 solid medium. After the surface is dried, place it in a 28°C incubator for about 10 days. Ferment a total of 30 L of ISP2 solid medium.

[0033] (3) The fermented culture medium was ground in a meat grinder, and the ground sludge was placed in a 2 L glass bottle. 1.5 L of ethyl acetate was added and fully dissolved. An ultrasonic cleaner was used to remove bubbles for 2 min to promote dissolution, and extraction was performed three times.

[0034] (4) Filter the extract and use a rotary evaporator to dry it to obtain a crude extract.

[0035] (5) The crude extract was mixed with a small amount of 200-300 mesh normal phase silica gel (weight ratio = 1:0.8), dissolved in a small amount of ethyl acetate, and then evaporated to dryness using a rotary evaporator.

[0036] (6) Pour in about 400 g of silica gel powder, dissolve it in ethyl acetate, stir it, and pour it into the column to allow the silica gel to settle (the chromatographic medium in the silica gel column is silica gel and ethyl acetate; the eluent is ethyl acetate and methanol).

[0037] (7) Add the evaporated powder sample to the upper layer of silica gel. After flowing for about 10 seconds, add a small amount of dry silica gel to the upper layer of the sample. Add ethyl acetate to dissolve the upper layer of silica gel and plug it with a small amount of cotton.

[0038] (8) Continue to pour in ethyl acetate to rinse the sample.

[0039] (9) When the colored layer is seen flowing to the middle of the column, start collecting fractions. When the fractions collected reach 1 L, start mixing methanol (5%, 10%, 20%, 40%) into the mobile phase. Rinse the last bottle with 100% methanol, and collect 150 mL in each bottle.

[0040] (10) The collected product was evaporated to dryness using a rotary evaporator and transferred to a vial for compound preparation.

[0041] 2. Preparation of compounds: Liquid chromatography is performed on the isolated extract of step 1 to obtain a high-purity compound: Liquid chromatography conditions for compound preparation were as follows: column temperature: 23°C, preparative column: 150 × 10 mm, Gemini 5 μm NX-C18 (Phenomenex). Mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile (0.1% formic acid), gradient from 35% to 60% mobile phase B over 20 min, flow rate: 2.5 mL / min.

[0042] Preliminary experiments revealed that sharp peaks appeared at 12.5 and 15 min, respectively, and the target compound had high absorption peaks at 250 nm and 280 nm through full wavelength scanning.

[0043] Therefore, the program was set to collect the product at 12.5 and 15 min, and the signal at 250 nm and 280 nm was detected under the UV detector. The liquid chromatogram results at 250 nm were referenced to Figure 2 shown.

[0044] The product collected at 12.5 min was loaded onto the liquid chromatography column again, and the signal at 250 nm was detected under a UV detector to determine the purity of the separated product. The signal at 250 nm was referenced to Figure 3 As shown, a sharp peak appeared when the effluent was collected for 8 minutes.

[0045] The product collected at 12.5 min of the effluent was dried, and the yield of the main metabolite per liter of fermentation medium after fermentation in ISP2 medium was approximately 1.07 mg (for subsequent mass spectrometry and nuclear magnetic resonance detection).

[0046] 3. The product with the sharp peak at 12.5 min in the above-mentioned liquid chromatography separation (compound preparation stage) was subjected to high performance liquid chromatography-mass spectrometry and nuclear magnetic resonance identification. The HPLC analysis conditions were as follows: Column temperature: 23°C. Preparative column: 100 × 2.1 mm, Gemini 1.7 μm NX-C18 (Phenomenex). Mobile phase A was water containing 0.1% formic acid, and mobile phase B was acetonitrile containing 0.1% formic acid. The elution gradient was: initial 20% B, increasing linearly to 100% B over 12 minutes, returning to 20% B at 14 minutes. The flow rate was 0.3 mL / min, and the injection volume was 5 μL.

[0047] Mass spectrometry detection conditions are as follows: Column temperature: 23°C. Preparative column: 100 × 2.1 mm, Gemini 1.7 μm NX-C18 (Phenomenex). Mobile phase A was water containing 0.1% formic acid, and mobile phase B was acetonitrile containing 0.1% formic acid. The elution gradient was: initial 20% B, increasing linearly to 100% B over 12 minutes, and returning to 20% B at 14 minutes. The flow rate was 0.3 mL / min, and the injection volume was 5 μL. Detection was in positive ion mode.

[0048] The mass spectrometry results of the product with a sharp peak at 12.5 min separated by liquid chromatography refer to Figure 4 As shown, nuclear magnetic 1 H spectrum Figure 5 The results show that the product with a sharp peak at 12.5 min of the chromatographic separation is Berninamycin D. That is, the liquid chromatography peak time of Berninamycin D during the preparation in step 2 is 12.5 min.

[0049] Example 2 The cytotoxicity assay of Berninamycin D isolated and obtained in Example 1 was performed as follows: 1. A549 cells were seeded at a density of 5000 cells / well in a 96-well plate. 100 μL of F12K medium containing 10% fetal bovine serum (FBS) was added and cultured overnight.

[0050] 2. After 48 h of starvation treatment, discard the blank culture medium.

[0051] 3. Add 200 μL of F12K medium containing Berninamycin D. Use cisplatin as a positive control. Use methanol as a solvent control.

[0052] 4. After 3 days of incubation, remove the supernatant.

[0053] 5. Add 50 μL of calcein / PI staining solution and place in the dark for 30 min.

[0054] 6. Use a fluorescence microscope to take photos and observe.

[0055] Results reference Figure 1 As shown in the figure, at a concentration of 100 μM, Berninamycin D had no significant cytotoxicity against non-small cell lung cancer cells.

[0056] Example 3 Berninamycin D anti-inflammatory activity testing.

[0057] 1. A549 cells were seeded at a density of 15,000 cells / well in a 96-well plate. 100 μL of F12K medium containing 10% FBS was added and cultured overnight.

[0058] 2. After 48 h of starvation treatment, discard the blank culture medium.

[0059] 3. Add 200 μL of F12K medium containing Berninamycin D.

[0060] 4. After treating the cells with the compounds for 30 min, 1 ng / mL of the pro-inflammatory cytokine IL-1β was added.

[0061] 5. Incubate for 48 hours.

[0062] 6. Detection was performed using an IL-6 ELISA kit (BD OptEIA, 555220).

[0063] IL-6 ELISA Assay Steps: 1. Coating Antibody: Dissolve the capture antibody in coating bufffer at a ratio of 1:250. Add 50 μL to a 96-well ELISA plate and cover the plate with tin foil. Coating should proceed overnight at 4°C.

[0064] 2. Washing: Remove the overnight coated 96-well plate, shake off the liquid, and tap to remove any remaining liquid. Add 300 μL of wash buffer to each well, let it sit for 1 minute, shake off the liquid, and tap to remove any remaining liquid. Repeat this step three times.

[0065] 3. Blocking: Add 300 μL of assay diluent solution to each well and block at room temperature for 1 h.

[0066] 4. Wash: Wash the plate three times with wash buffer.

[0067] 5. Combine primary antibody (add samples and standards): Thaw the standards and samples 15 min in advance, add 50 μL to each well, and incubate at room temperature for 2 h.

[0068] Standard dilution: Dissolve 4.5 μL of IL-6 standard in 595 μL of assay diluent. Perform serial two-fold dilutions to the seventh concentration.

[0069] Sample dilution: Dilute the sample according to actual conditions.

[0070] 6. Wash: Wash the plate three times with wash buffer (same steps as step 3).

[0071] 7. Bind the secondary antibody: Dilute the detection Ab into the assay diluent solution at a ratio of 1:250 and add an equal volume of enzyme reagent (HRP) to prepare a worker detector (use within 15 minutes). Add 50 μL of the worker detector to each well. Incubate at room temperature, protected from light, for 1 hour.

[0072] 8. Wash: Wash the plate three times with wash buffer (same steps as step 3).

[0073] 9. Color development: Place the substrate solution (TMB) at room temperature 30-60 minutes in advance. 15 minutes before use, mix Solution A and Solution B in a 1:1 ratio. Add 50 μL of the substrate solution to each well and incubate at room temperature for 10 minutes in the dark.

[0074] 10. Stop the reaction: Add 25 μL of stop solution to each well.

[0075] 11. Detection: Detect the absorbance at 450 nm and 570 nm within 30 minutes.

[0076] 12. Calculate the secretion of IL-6.

[0077] Results reference Figure 6 The results showed that Berninamycin D could inhibit the inflammatory response induced by IL-1β in non-small cell lung cancer cells. The inhibitory activity was observed at 12.5 μM to 25 μM.

[0078] Example 4 Anti-inflammatory activity test of Berninamycin D on RAW264.7 cells (macrophages) Experimental steps: 1. RAW264.7 cells were seeded at a density of 10,000 cells / well in a 96-well plate. 100 μL of DMEM medium containing 10% FBS was added and cultured for 48 h.

[0079] 2. After 48 h of culture, discard the blank culture medium.

[0080] 3. Add 200 μL of DMEM (with 5% FBS) culture medium containing different concentrations of Berninamycin D, and methanol as a solvent control.

[0081] 4. Add 1 μg / mL of the pro-inflammatory cytokine LPS 1 h after treating the cells with the compound.

[0082] Incubate at 37°C for 48 h.

[0083] 6. Transfer the culture supernatant to a 1.5 mL EP tube and centrifuge at 1000 rpm for 20 min at 4°C. Collect the supernatant for assays of NO content (Solarbo S0021 Nitric Oxide Detection Kit), IL-6 secretion (Xinbosheng EMC004, Mouse IL-6 ELISA Kit), and TNFα secretion (Xinbosheng EMC102, Mouse TNFα ELISA Kit).

[0084] The steps for nitric oxide testing are as follows: 1. Remove Griess Reagent I (hereinafter referred to as "Reagent I") and Griess Reagent II (hereinafter referred to as "Reagent II") and return them to room temperature.

[0085] 2. Dilute the standard to concentrations of 3.125, 6.25, 12.5, and 25 µM in complete culture medium (DMEM + 10% FBS).

[0086] 3. Add standards and samples to a 96-well plate at a volume of 50 µL per well.

[0087] 4. Add 50 µL / well of room temperature Reagent I to each well.

[0088] 5. Add room temperature Reagent II to each well at 50 µL / well.

[0089] 6. Measure the absorbance at 540 nm using a microplate reader.

[0090] 7. Calculate the concentration of nitric oxide in the sample based on the standard curve.

[0091] The IL-6 and TNFα detection steps were referred to the kit instructions.

[0092] Figure 7 、 Figure 8 and Figure 9 The results showed that Berninamycin D treatment could significantly reduce the secretion of nitric oxide, IL-6, and TNFα in RAW264.7 cells induced by LPS.

[0093] In summary, Berninamycin D can inhibit the release of inflammatory factors in RAW cells. Inflammatory factors are highly expressed in the tumor microenvironment, and inhibiting their release by Berninamycin D may help improve the tumor microenvironment. Inflammatory conditions such as pneumonia and hepatitis are often accompanied by elevated levels of inflammatory factors, and inhibiting their release may help alleviate symptoms.

[0094] The foregoing description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Those skilled in the art will readily appreciate that various modifications and variations of the present invention are possible. Any modifications, equivalent substitutions, or improvements made within the spirit and principles of the present invention are intended to be within the scope of protection of the present invention.

Claims

1. Application of Berninamycin D in the preparation of anti-inflammatory drugs.

2. The use according to claim 1, characterized in that The anti-inflammatory drug is used for at least one of the following diseases: Tracheitis, enteritis, gastritis, pneumonia, hepatitis, or tumor cell inflammation.

3. The use according to claim 2, characterized in that The tumor cells are selected from non-small cell lung cancer, breast cancer, melanoma, colon cancer, kidney cancer, lymphoma, mast cell tumor, liver cancer, pituitary tumor, myeloma, brain neuroma, testicular Leydig cell tumor, gastric cancer, prostate cancer or pancreatic cancer.

4. The use according to claim 2, characterized in that The tumor cell inflammation is induced by inflammatory factors, and the inflammatory factors are selected from interleukin (IL), interferon (IFN) or tumor necrosis factor (TNF).

5. The use according to claim 4, characterized in that The interleukin is selected from at least one of IL-1α, IL-1β, IL-4, IL10, IL11 and IL12A; the interferon is selected from at least one of IFNA1, IFNA2, IFNA3, IFNA4, IFNB and IFN-γ; the tumor necrosis factor is selected from at least one of TNF, TNFα and TNFβ.

6. Use of Berninamycin D and an anti-inflammatory drug in the preparation of a drug for combined treatment of inflammation, characterized in that: The inflammation is tracheitis, enteritis, gastritis, pneumonia, hepatitis or tumor cell inflammation.

7. The use according to claim 6, characterized in that The anti-inflammatory drug is selected from non-steroidal anti-inflammatory drugs, immunosuppressants, adrenocortical hormone drugs and adrenocorticotropic hormone drugs and their salts or esters.

8. The use according to any one of claims 1 to 5 or any one of claims 6 to 7, characterized in that: The drug further includes a pharmaceutically acceptable carrier.

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