| Diabetes mellitus is a chronic metabolic disease,of which more than 90%of patients are type 2 diabetes mellitus(T2DM)patients.T2DM can cause a variety of complications,which is the main reason for the high mortality of patients with diabetes.Diabetic nephropathy(DN)is one of the common progressive complications of type 2 diabetes mellitus(T2DM),and patients with T2DM complicated with DN account for 20%to 40%of all T2DM patients.The pathogenesis of T2DM and DN is complex,and there is no unified theory to clarify their occurrence and development process.Poor control of blood glucose,blood lipid and blood pressure levels are potential factors for the pathogenesis of T2DM and DN.At present,there is no specific drug that can cure T2DM and DN.The development of natural drugs with less side effects is an important research direction for the treatment of these diseases.Cordyceps militaris,as a medicinal and edible fungus,has been proved to have hypoglycemic,antioxidant and immune-enhancing effects.Recent studies have found that Cordyceps militaris affects host glucose and lipid metabolism by regulating intestinal microbes,but the mechanism of Cordyceps militaris on T2DM and DN is still unclear.Therefore,this thesis takes this direction as the starting point for the preliminary exploration of the mechanism.1.Intestinal flora is dysregulated in T2DM mice,and Cordyceps militaris can alleviate T2DM by regulating intestinal flora.In this study,Kunming mice were induced by STZ(streptozotocin)and HFD(high fat diet model group)to establish a T2DM mouse model.The normal control group,model group,metformin group,cordycepin intervention group(high and low dose of cordycepin group,high and low dose of cordycepin water extract group)were set up.Gut microbiome sequencing results showed that the composition and abundance of intestinal microbiota in T2DM mice were significantly changed,and the abundance of some intestinal probiotics and their metabolites was up-regulated after Cordyceps militaris intervention.The results of fecal untargeted metabolomics showed that compared with the model group,the differential metabolites in the Cordyceps militaris intervention group mainly included amino acids,fatty acids,carboxylic acids and their derivatives,which were involved in PI3K/Akt/FOXO signaling pathway,TCA cycle,tryptophan metabolism pathway,etc.Spearman correlation analysis showed that Alistipes and Lachnospiraceae_NK4A136_group were significantly correlated with TCA cycle intermediates in the Cordyceps militaris intervention group compared with the model group.Therefore,Cordyceps militaris can exert anti-T2DM effects by regulating intestinal flora and its metabolites.2.Cordyceps militaris can protect the kidney of DN mice by regulating TLR4/NFκB and Nrf2/HO-1 pathways.In this study,on the basis of the establishment of T2DM model,the DN model was successfully constructed by prolonging the induction period of high-sugar and high-fat diet.Renal tubular epithelial cells were desquamated,mesangial matrix was proliferating and renal interstitial inflammatory cells were infiltrated in DN mice.Cordyceps militaris treatment could improve renal pathological damage.Cordyceps militaris intervention can reduce blood glucose and blood lipid content,down-regulate insulin resistance index,and make the physiological and biochemical indicators of DN mice close to normal levels.At the same time,Cordyceps militaris can reduce the contents of creatinine,blood urea nitrogen,cystatin-c and UA,increase the content of uric acid,and enhance the renal function of DN mice.In addition,Cordyceps militaris can up-regulate the relative expression levels of Nrf2 and HO-1 mRNA in the kidney,down-regulate the relative expression levels of TLR4 and NF-κB mRNA,and enhance the antioxidant and anti-inflammatory ability of mice by participating in TLR4/NF-κB signaling pathway and Nrf2/HO-1 signaling pathway.3.The energy metabolism of DN mice is disordered,and Cordyceps militaris can improve DN by regulating glucose metabolism.The results of renal targeted metabolomics showed that compared with the normal control group,the metabolites of the model group were significantly different,and 20 potential biomarkers were identified,mainly including glucose,fructose-6-phosphate,glyceraldehyde-3phosphate,involving glycolysis and gluconeogenesis pathway,TCA cycle,lysosomal biogenesis pathway,pentose phosphate pathway and other metabolic pathways.The glucose level in the DN group increased,the glucose metabolism flux changed,and the metabolic flow of glucose into the glycolytic pathway,pentose phosphate pathway,and polyol pathway increased significantly,resulting in product accumulation and kidney damage.The treatment group of Cordyceps militaris improved DN kidney damage by regulating glucose metabolism pathways,alleviating glucose metabolism disorders,reducing the accumulation of some differential metabolites,and activating autophagy.In conclusion,Cordyceps militaris can intervene or alleviate T2DM and its complication of DN by increasing the diversity and changing the structure of intestinal flora,and regulating TLR4/NF-κB pathway and Nrf2/HO-1 pathway.At the same time,the results of targeted metabolomics showed that energy metabolism was reprogrammed in the kidney of DN mice,which provided a theoretical basis for further exploring the pathogenesis and therapeutic targets of T2DM and DN. |
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