CN114774302B - Application of lactobacillus plantarum CQPC02 in preparation of product for preventing and/or treating lupus nephritis - Google Patents
Application of lactobacillus plantarum CQPC02 in preparation of product for preventing and/or treating lupus nephritis Download PDFInfo
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- CN114774302B CN114774302B CN202210224353.4A CN202210224353A CN114774302B CN 114774302 B CN114774302 B CN 114774302B CN 202210224353 A CN202210224353 A CN 202210224353A CN 114774302 B CN114774302 B CN 114774302B
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Abstract
The invention discloses application of lactobacillus plantarum CQPC02 in preparing a product for preventing and/or treating lupus nephritis, wherein the lactobacillus plantarum CQPC02 is preserved in China general microbiological culture collection center (CGMCC) with the preservation number of CGMCC No.14491. The intervention effect of lactobacillus plantarum CQPC02 on lupus nephritis is observed by establishing an animal model. The effect of the lactobacillus plantarum CQPC02 on lupus nephritis is truly achieved by detecting relevant indexes and inflammation-related cytokine levels in mouse serum, and further pathological observation and tissue mRNA and protein gene expression detection are adopted to deeply clarify the action mechanism of the lactobacillus plantarum CQPC 02.
Description
Technical Field
The invention relates to the field of microorganisms and biotechnology, in particular to application of lactobacillus plantarum CQPC02 in preparation of products for preventing and/or treating lupus nephritis.
Background
Sichuan pickle is a natural fermented vegetable in Chinese tradition. Its production history has been about two thousand years. The long production and use history makes it a Chinese-style marked food. The area of the pickle which is frequently eaten exceeds 2000 ten thousand hectares. The Sichuan pickle is rich in nutrition and beneficial substances such as vitamins and mineral elements. Besides being used as side dish, it can also be used for making delicious food together with other foods. Due to the geographical environment of the Sichuan basin and the unique living habit of multi-ethnic mixed life, the Sichuan naturally fermented pickle has special quality, and particularly a large number of fermenting microorganisms are generated in the natural fermentation process. Research has shown that microorganisms found in naturally fermented kimchi are useful in the food industry, and they also exhibit various biological activities including intestinal protection, slimming, anti-inflammatory and antioxidant effects. The Chinese Sichuan natural fermented pickle has various microorganism types, has good development and utilization values, and is a potential probiotic resource source.
Lupus nephritis is systemic lupus erythematosus nephritis, which is a complex immune disorder nephritis, and is frequently caused by renal failure, and the symptom of glomerulonephritis is shown after the onset of the disease. Lupus nephritis causes lesions such as immunity decline, lymph node hyperplasia, glomerulonephritis and the like, kidney tissues can generate glomerulosclerosis or diffuse hyperplasia, metabolic and toxin expelling functions of patients are seriously damaged, and finally chronic renal failure is caused, and life is endangered when the chronic renal failure is serious. Most lupus nephritis is followed by excessive activation of B cells and T cells, the T cells differentiate into helper T cells, which play a role in the middle process only in immunization, but more T cells develop into regulatory T cells that can resolve inflammation in the presence of probiotics, directly intervening in nephritis. The self structural components of the probiotics can also directly stimulate and activate an immune system in an antigen mode, and play a role in expelling toxic substances in the body and reducing inflammation. In experimental research, pristane can successfully construct a lupus nephritis model, is widely accepted in scientific research, has been used for detecting the effect of medicines and health-care foods on lupus nephritis, can cause inflammation and strengthen immune response, can cause high activation of T cells, and can greatly increase the reactivity of B cells, so that animals are promoted to produce various autoantibodies, and lupus nephritis occurs.
Disclosure of Invention
The technical problems to be solved by the invention are as follows: there is provided the use of lactobacillus plantarum CQPC02 for the manufacture of a product for the prevention and/or treatment of lupus nephritis.
In order to solve the technical problems, the adopted technical scheme is as follows: use of lactobacillus plantarum CQPC02 for the preparation of a product for the prevention and/or treatment of lupus nephritis, said product being a pharmaceutical product.
The lactobacillus plantarum has the following preservation information:
classification naming: lactobacillus plantarum;
latin name: lactobacillus plantarum;
the units for preserving the biological material sample are all: china general microbiological culture Collection center (China Committee for culture Collection);
address: beijing, chaoyang area, north Chenxi Lu No.1, 3;
preservation date: received by the collection center of 08 and 04 in 2017 and registered in a book; the results were measured by the collection at 2017, 08 and 04: survival;
preservation number: CGMCC No.14491.
The beneficial effects are that: lactobacillus plantarum CQPC02 is a lactobacillus which is separated and identified from Tibetan herd family homemade natural fermentation yogurt collected by Sichuan red original by the research team, has better basically in vitro resistance, has the survival rate of over 90 percent in pH=3.0 artificial gastric juice and has the growth efficiency of nearly 70 percent in 0.3 percent bile salt.
The intervention effect of lactobacillus plantarum CQPC02 on lupus nephritis is observed through establishing an animal model. The effect of the lactobacillus plantarum CQPC02 on lupus nephritis is truly achieved by detecting relevant indexes and inflammation-related cytokine levels in mouse serum, and further pathological observation and tissue mRNA and protein gene expression detection are adopted to deeply clarify the action mechanism of the lactobacillus plantarum CQPC 02.
Drawings
FIG. 1H & E stained sections of mouse kidney tissue;
FIG. 2 mRNA expression in mouse kidney tissue.
Detailed Description
The process of the present invention is further illustrated by the following examples, which are not intended to limit the invention thereto.
A method for separating and purifying lactobacillus plantarum comprises the following steps: respectively taking 1mL of pickle water sample, carrying out 10-time gradient dilution to 10-6 by using sterile normal saline, then taking 100 mu L of bacterial liquid with 10-4, 10-5 and 10-6 and 3 gradients, carrying out flat coating, culturing at 37 ℃ for 24-48h, and observing and recording colony morphology; and (3) picking colonies with different forms on the flat plate for streak separation, culturing at 37 ℃ for 48 hours, and then picking single colonies with different forms on the flat plate again for streak separation, and repeating the steps for 2 to 3 times until pure single colonies with consistent forms are obtained.
1 materials and methods
1.1 materials and reagents
The lactobacillus plantarum CQPC02 separates and identifies the domestic natural fermentation pickle in Chongqing south shore area, and the pickle is preserved in China general microbiological culture Collection center (CGMCC) with the patent preservation number of 14491.
SPF-class six-week-old female C57BL/J6 mice, 23+ -2 g in weight, purchased from Chongqing university laboratory animal center, and produced with license number SCXK (Yu) 2018-0003. The animal experiment in the study is approved by the ethical committee of animal experiments in the functional food collaborative innovation of Chongqing market, and the approval number is 2021050007B.
Pristine Shanghai microphone Biochemical technology Co., ltd; total Protein (TP), serum creatinine (SCr), urea nitrogen (BUN), total Cholesterol (TC), triglycerides (TG), albumin (ALB) assay kit, south-ky, established bioengineering institute; horseradish peroxidase Sigma united states company; IL-6, IL-12, TNF-alpha and IFN-gamma detection kit Shanghai enzyme-linked biotechnology Co., ltd; TRIzol reagent Invitrogen, inc. of America; SYBR Green PCRMaster Mix, qPCR primer, SDS-PAGE prefabricated gel, primary antibody, secondary antibody, american Thermo Fisher Scientific company; protein concentration determination kit Bio-Rad, inc., USA; the rest reagents are all of domestic analytical purity.
1.2 instruments and apparatus
BX43 microscope olympus corporation of japan; varioskan LUX multifunctional microplate reader, stoponLeus quantitative PCR Instrument, iBright imaging System, USA Thermo Fisher Scientific company.
1.3 method
1.3.1 animal experiments
The C57BL/J6 mice are fed in the environment with the temperature of 20+/-1 ℃ and the humidity of 30% -40%, the experimental mice can eat and drink water freely, and the experiment is formally started after the mice are fed for 7d in an adaptive mode. The 50 mice were randomly divided into 5 groups of 10, each of which was a normal group, a model group, a drug positive control group, a LP-CQPC02 low concentration treatment (LP-CQPC 02-L) group and a LP-CQPC02 high concentration treatment (L), respectivelyP-CQPC 02-H). Normal groups of mice were intraperitoneally injected with physiological saline once the first day after the beginning of the experimental formally, and the remaining groups of mice were intraperitoneally injected with 0.5mL pristane. Drug positive control mice were dosed daily with 10mg/kg of prednisone solution, and LP-CQPC02-L and LP-CQPC02-H mice were dosed daily with 10 8 CFU/kg and 10 9 Metering of CFU/kg stomach lavage LP-CQPC02, prednisone and LP-CQPC02 lasted 12 weeks. After 12 weeks, the mice were sacrificed by cervical scission, and heart blood and viscera were dissected from the mice for testing.
1.3.2 urine protein assay
After the start of the experiment, mice were kept in metabolic cages every two weeks, urine output from the mice was collected over 1 day, and the amount of protein in the urine of the mice was measured for 24 hours using a total protein kit (coomassie brilliant blue method).
1.3.3 serum and tissue inflammatory cytokine determination
After taking heart blood and collecting mouse whole blood, centrifugal separation is carried out for 10min at 1500rpm and 4 ℃, and the upper serum is removed for experiment. In addition, 0.1g of kidney tissue was weighed, 0.9mL of physiological saline was added to the kidney tissue, and the kidney tissue was homogenized at 4℃and centrifuged (4000 rpm, 10 min), and the supernatant was collected for the experiment. Finally, the IL-6, IL-12, TNF-alpha and IFN-gamma inflammatory cytokine levels in serum and tissues are determined according to a detection kit method.
1.3.4 serum SCr, BUN, TC, TG and ALB level assay
Mouse serum was collected by 1.3.3 method and assayed for SCr, BUN, TC, TG and ALB levels by the assay kit method.
1.3.5 anti-dsDNA antibody assay
Mouse blood was collected every two weeks after the start of the experiment using orbital bleeds, and then anti-dsDNA antibodies were assayed using a microtiter plate and an indirect immunofluorescence assay after preparing mouse serum according to the 1.3.3 method.
1.3.6 tissue section observations
After dissecting the mice, kidney tissue of the mice was fixed with 10% formalin. After 48H dehydration, the tissue samples were embedded in paraffin, sectioned, and finally stained with hematoxylin-eosin (H & E) fuel and examined for histopathological changes using an optical microscope.
1.3.7qPCR experiment
To 0.1g of kidney tissue of a mouse, 0.9mL of physiological saline was added, and the tissue mixture was homogenized. RNA was then extracted from the kidney tissue of the mice using RNAzol (1.0 mL). Absorbance values of the extracted RNAs were measured at 260nm and 280nm, RNA purity and concentration were calculated, and RNA concentration was adjusted to 1 μg/μl. After reverse transcription to generate cDNA, 1. Mu.L of cDNA, 10. Mu. L SYBR Green PCR Master Mix, 7. Mu.L of sterile distilled water and 1. Mu.L of each of the upstream and downstream primer solutions were mixed to prepare a reaction system solution. Then at 95℃for 60s; continuing at 95 ℃ for 15s, and carrying out 40 cycles; the temperature is 55 ℃ for 30s; the temperature is 72 ℃ for 35s; the temperature is 95 ℃ for 30s; the reaction was carried out at 55℃for 35s and 2 was used -ΔΔCt The related genes were quantitatively analyzed by the method, and GAPDH was used as an internal reference in the experiment (Table 1).
TABLE 1 primer sequences used in this experiment
1.4 statistical analysis
All the indicators were subjected to three replicates after the animal experiment was completed, and the results obtained by the measurement were represented as an average value, while standard deviation (average value.+ -. Standard deviation) was noted. Then, whether each group of index values obtained by adopting the one-factor analysis of variance has significant difference in P <0.05 or not.
2 results and analysis
2.1 amount of protein in urine of mice
During the course of the experiment, the amount of protein in urine of normal group mice did not change significantly, but urine protein of other group mice increased with time. After 2 weeks, 7, 5 and 4 mice developed proteinuria under the action of LP-CQPC02-L, LP-CQPC02-H and prednisone, and all mice in the model group developed proteinuria. After 12 weeks, urine protein content was higher in lupus nephritis mice (model group) than in LP-CQPC02 and prednisone treated mice and normal group mice (table 2). Urine protein output of mice treated with high concentrations of LP-CQPC02 and prednisone was closest to that of normal mice, with the LP-CQPC02-H mice group being only Yu Poni pine group mice.
TABLE 2 urine protein content of mice of each group during the experiment
Note that: different letters indicate significant differences between groups at the P <0.05 level, the same letters indicate no significant differences, and the following is true.
2.2 IL-6, IL-12, TNF-alpha and IFN-gamma cytokine levels in mouse serum and kidney tissue
As shown in tables 3 and 4, the IL-6, IL-12, TNF- α and IFN- γ cytokine levels were significantly lower in the serum and kidney tissues of the normal group mice than in the other groups (P < 0.05). IL-6, IL-12, TNF- α and IFN- γ cytokine levels were significantly down-regulated (P < 0.05) in lupus nephritis mice (model group) and were more able to down-regulate these cytokine levels at high concentrations of LP-CQPC02 (LP-CQPC 02-H) and prednisone after action relative to model group mice.
TABLE 3 mouse serum IL-6, IL-12, TNF-alpha and IFN-gamma levels
TABLE 4 mouse kidney tissue IL-6, IL-12, TNF-alpha and IFN-gamma levels
2.3 mouse serum SCr, BUN, TC, TG, TP and ALB levels
The serum SCr, BUN, TC and TG levels were higher in the model group than in the other groups, while the serum SCr, BUN, TC and TG levels were lowest in the normal mice (P <0.05, table 5). The SCr, BUN, TC and TG levels were also reduced in LP-CQPC02 and prednisone treated mice compared to model group mice, but were higher than in normal mice. LP-CQPC02 allows nephritis mice to have SCr, BUN, TC and TG levels near normal levels. In addition, TP and ALB serum levels were in opposite trend, and each group level was in the order of normal group, prednisone group, LP-CQPC02-H group and control group from high to low.
TABLE 5 mouse serum SCr, BUN, TC, TG, TP and ALB levels
2.4dsDNA Positive Rate
Autoantibodies dsDNA were detected by indirect immunofluorescence at weeks 2, 4, 6, 7, 10 and 12 post-treatment. The results showed that all mice in the model group were positive and that lupus nephritis induction was successful from the end of week 6. The group of LP-CQPC02-L mice detected positive on weekends 8 and the group of LP-CQPC02-H and prednisone mice detected positive on weedinds 10, meaning that LP-CQPC02 and prednisone slowed down the mice to develop lupus nephritis and the effects of LP-CQPC02 and prednisone were similar (Table 6).
TABLE 6 dsDNA Positive Rate of Lupus nephritis mice in each group
2.5 histopathological observations of the kidneys
As shown in FIG. 1, the kidney tissue of the model group mice has serious lesions, a large number of glomeruli are irregular in shape, partial glomeruli are broken, and serious inflammatory cell infiltration occurs between tissues. The glomeruli and the cell structures of the normal mice are complete, and both the LP-CQPC02 and the prednisone can relieve renal tissue lesions caused by lupus nephritis and reduce the damage of the kidney group. Meanwhile, the high-concentration LP-CQPC02 (LP-CQPC 02-H) and prednisone have better effects, and can promote the tissue morphology of kidney tissues to be close to that of normal groups.
2.6 mRNA expression in mouse kidney tissue
As shown in FIG. 2, mRNA expression of NF-. Kappa. B, TGF-. Beta.1, VEGF, ICAM-1 and VCAM-1 was the weakest in kidney tissue of normal mice and the expression of IκB-. Alpha.was the strongest. Whereas the model group I.kappa.B-alpha is the least expressed, NF-. Kappa. B, TGF-. Beta.1, VEGF, ICAM-1 and VCAM-1 are the most expressed. Compared with the model group, the LP-CQPC02 and prednisone can significantly up-regulate the expression of kidney tissue IκB-alpha of the model group, down-regulate the expression of NF- κ B, TGF- β1, VEGF, ICAM-1 and VCAM-1 (P < 0.05), and the effect of high-concentration LP-CQPC02 (LP-CQPC 02-H) and prednisone is stronger than that of low-concentration LP-CQPC02 (LP-CQPC 02-L).
Urine protein plays an important role in the occurrence and development of kidney diseases, a large amount of proteinuria in complex comprehensive kidney diseases is one of main diseases, and the clinical main manifestation of lupus nephritis is the occurrence of proteinuria. The lupus nephritis mice with the modeling result in the study also show proteinuria, and both the LP-CQPC02 and the prednisone can reduce the protein amount in the urine of the lupus nephritis mice, so that the effect of relieving the lupus nephritis is achieved, and the effect of the LP-CQPC02 is increased along with the increase of the concentration. Serum creatinine and urea nitrogen are nitrogen-containing organic compounds that are the end products of protein metabolism. When kidney function is normal, these small molecules are filtered from the glomeruli. When the kidney is damaged, the glomerular filtration capacity decreases and serum creatinine and urea nitrogen levels increase, so that an increase in serum creatinine and urea nitrogen levels can be used as an indicator for clinical diagnosis of kidney damage. Excessive cholesterol and triglycerides are responsible for hyperlipidemia, and when kidney disease deteriorates to some extent, the characteristics of hyperkalemia coexist. Cholesterol and triglycerides can therefore also be regarded as indicators of reduced renal function and kidney damage. Patients with nephrotic syndrome have a significant decrease in total protein in serum due to long-term proteinuria. Albumin is the most common protein in serum and is commonly used in the treatment of severe diseases, including clinically in the treatment of oedema caused by kidney disease, reduction of total protein and albumin content in case of renal dysfunction. It follows that maintaining the serum total protein and albumin levels is an important way to maintain normal renal function. In the study, the LP-CQPC02 and prednisone also show the capability of inhibiting serum creatinine, urea nitrogen, cholesterol and triglyceride increase and total protein and albumin decrease caused by lupus nephritis, and play a role in protecting kidneys by regulating the related indexes of the kidney diseases.
IL-12 plays an important role in the autoimmune response of lupus nephritis, where IL-12 levels are elevated during the onset period. One of the characteristics of lupus nephritis is the presence of a large number of autoantibodies, which IL-12 can promote direct production by cells, and increased IL-12 levels further result in the large production of such autoantibodies, exacerbating the condition. IFN-gamma is taken as an inflammation medium and participates in the whole immune inflammation process of nephritis, and the IFN-gamma level of glomerulonephritis patients is clinically shown to be obviously increased. After nephritis occurs, the cytokines associated with inflammation change, and the content of cytokines associated with inflammation, such as IL-6, IL-12, TNF-alpha and IFN-gamma in blood is also increased significantly. Inflammatory cytokines IL-6, IL-12, TNF- α and IFN- γ were all significantly elevated in lupus nephritis mice in this study, while LP-CQPC02 and prednisone were able to significantly inhibit this change.
The essential process of autoreactive antibodies in lupus nephritis is the conversion to IgG by mutation and class. The massive deposition of IgG anti-dsDNA antibodies and immune complexes in plasma in the glomeruli causes kidney damage and thus inflammatory cell infiltration. In addition, high concentrations of dsDNA antibodies were found to occur almost exclusively in lupus nephritis, and dsDNA antibodies showed specificity for lupus nephritis and thus could be used as an indicator for diagnosing systemic lupus nephritis. The kidney tissue of the clinical lupus nephritis patient mostly has the phenomena of glomerular cell proliferation change, glomerular neutrophil infiltration and the like. The experimental indicators of this study also demonstrate that both LP-CQPC02 and prednisone are indicative of the inhibition of dsDNA antibody appearance and protection of kidney tissue from pathological changes.
NF- κb signaling pathways are involved in a variety of pathological processes, and thus their signaling pathways have become potential targets for drug or bioactive substance intervention. NF-. Kappa.B is an important transcription factor that, upon activation, activates a variety of immune and inflammation-related genes including TNF, IL-1, IL-2, IL-6, IL-8, IL-10, adhesion molecules (ICAM-1, VCAM-1). NF- κB is involved in a variety of physiological and pathological processes and pathogenesis of kidney disease. In nephritis, the body's inflammatory response is too strong, resulting in damage to the kidney's own tissues. In therapy, inhibition of NF- κB activity may reduce inflammatory lesions. NF- κB activity is closely related to IκB- α. When the expression of the IκB-alpha is weakened, NF- κB is separated from the IκB-alpha to play a role in promoting inflammation and damaging cells and tissues; when the expression of IκB-alpha is increased, dissociated NF- κB can be quickly bound to newly synthesized IκB, so that the activity of NF- κB is reduced and the organism is protected. Activation of NF- κB may cause inflammatory growth factors including TGF- β1, and TGF- β1 may activate NF- κB as a regulatory product via a positive feedback pathway. TGF-. Beta.1 is the most important pro-fibrotic factor in the body and is involved in fibrosis of organs including the kidney, in which abnormal expression of TGF-. Beta.1 often occurs. TGF- β1 in the kidney is secreted by podocytes that secrete TGF- β1 through a related action with the endothelial cells and Glomerular Mesangial Cells (GMCs) that secrete TGF- β1 upon stimulation by immunoglobulins (IgA). Glomerular endothelial cells are capable of TGF- β1 secretion by stimulation of VEGF after kidney damage has occurred. Abnormal expression of TGF-beta 1 and VEGF is a typical expression after lupus nephritis, so that the two expressions can be regulated to effectively control the lupus nephritis, and the anti-inflammatory cytokines such as IL-6, IL-12, TNF-alpha, IFN-gamma and the like can be inhibited. NF-. Kappa.B activates into the nucleus and binds to target sequences and regulates transcriptional activity of related genes such as ICAM-1, VCAM-1, TNF-. Alpha., IL-6, etc. Enhancement and initiation of these factor genes comprises the binding site for NF-. Kappa.B. ICAM-1 and VCAM-1 are two adhesion factors, both belonging to the immunoglobulin superfamily. ICAM-1 and VCAM-1 mediate the adhesion of leukocytes to endothelial cells by binding to receptors on the surface of leukocytes and subsequent transfer of leukocytes across endothelial cells. The accumulation of leukocytes can block capillaries, activated leukocytes can release a large amount of toxic substances, and damage neurons and glial cells, thereby aggravating tissue damage and nephritis. In addition, leukocytes also release some inflammatory mediators and cytokines, exacerbating the inflammatory response, attracting more leukocytes into the tissue, forming a vicious circle.
The study observes a novel lactobacillus plantarum LP-CQPC02 discovered from natural fermented pickle, and verifies the intervention effect of the LP-CQPC02 on lupus nephritis through an animal model. Experimental results show that LP-CQPC02 can relieve inflammatory lesions of mouse serum and tissues caused by lupus nephritis, and in particular, LP-CQPC02 can regulate the marker expression TGF-beta 1 of the lupus nephritis. The existing medicine for treating lupus nephritis, which is clinically used at present, has a certain side effect generally, in the study, prednisone is used as a medicine with small side effect and is used as a medicine positive control, and the effect of LP-CQPC02 can be close to that of prednisone through comparison, so that the lupus nephritis can be intervened healthier. Thus, LP-CQPC02 has the effect of acting as a probiotic to interfere with lupus nephritis.
Claims (2)
1. The application of lactobacillus plantarum CQPC02 in preparing a product for preventing and/or treating lupus nephritis is characterized in that lactobacillus plantarum CQPC02 is preserved in China general microbiological culture collection center with the preservation number of CGMCC No.14491.
2. The use according to claim 1, wherein: the product is a medicine.
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