| Background: Chronic kidney disease(CKD)is a common disease,and its incidence rate is as high as 10.8%,and 21% of CKD patients will develop secondary renal anemia.The incidence of renal anemia in dialysis patients is as high as 50%-60%,and the prognosis is poor.In recent years,roxadustat has been a popular drug in the treatment of renal anemia as a hypoxia inducible factor prolyl hydroxylase inhibitors(HIF-PHIs),with good efficacy,but it can also cause some safety issues.Traditional Chinese medicine(TCM)has a good therapeutic effect in treating renal anemia with minimal adverse reactions,and the combination of roxadustat for renal anemia may have the effect of reducing toxicity and increasing efficacy.At present,the combination of TCM and Western medicine has also attracted widespread attention.What is the efficacy and safety of roxadustat? What are the most commonly used TCM and herbal formulas in treating renal anemia? How can the combination of roxadustat and the most commonly used TCM exert therapeutic effects? This paper conducts research on the above issues.Objectives:(1)To systematically review the efficacy and safety of popular HIFPHIs-roxadustat.(2)Explore the medication patterns of TCM for treating renal anemia and summarize the core prescription.(3)Predicting the potential mechanism of the combination of core prescription and roxadustat in the treatment of renal anemia.(4)Using animal experiment to research the efficacy of the core prescription combined with roxadustat in treating renal anemia,and verifying the specific mechanism.Methods:(1)Systematic review and meta-analysis: Firstly,systematically search the main Chinese and English databases based on the search strategy,and screen for randomized controlled trials(RCTs)of roxadustat in the treatment of renal anemia based on inclusion and exclusion criteria.Then,using the Cochrane Collaboration’s tool to evaluate the risk of bias of RCTs.Finally,using Rev Man software for meta-analysis of the included RCTs to evaluate the efficacy and safety of roxadustat in the treatment of renal anemia.(2)Core prescription mining of TCM: Firstly,systematically search the main Chinese and English databases based on the search strategy,and screen for clinical studies on the treatment of renal anemia with TCM based on inclusion and exclusion criteria.Then,extract general information and data of the included studies using Excel software,and calibrate and clean the data.Finally,cluster and association rule analysis were conducted on the TCM included using R software,ultimately summarizing the core prescription and commonly used dosage of TCM for treating renal anemia.(3)Network Pharmacology research: Firstly,retrieve from Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP)and screen out the effective ingredients and targets of each TCM in the core prescription with oral bioavailability ≥ 30% and drug-likeness ≥ 0.18 as conditions,and search all pharmacophore of roxadustat from the Pharm Mapper database.Secondly,screen targets of renal anemia from Gene Cards and OMIM databases,and using R software to calculate the potential therapeutic targets of the core prescription combined with roxadustat in the treatment of renal anemia.Finally,using the Cytoscape software,DAVID database and KEGG database to analyze PPI,GO and KEGG,and predict potential targets and mechanisms,laying the foundation for animal experiment.(4)Animal experiment: Firstly,after modeling male rats,divided them into 5 groups:control group(simulated nephrectomy surgery without actual removal),model group,core prescription group,roxadustat group,and combined medication group.Secondly,a 12 weeks medication intervention is conducted.Thirdly,observe the general situation and weight changes of rats in each group,the changes in hemoglobin(Hb),red blood cell(RBC),and red blood cell specific volume(HCT)in blood routine examination,as well as the changes in urea nitrogen,creatinine,serum iron,total iron binding capacity,and transferrin in blood biochemical examination.Meanwhile,ELISA is used to detect IL-6 and TNF in serum-α,and q-PCR,Western Blot and Immunohistochemistry are used to detect the relative expression levels of major targets in renal tissue.Finally,using the above methods and results to explore the mechanism of core prescription combined with roxadustat in the treatment of renal anemia.Results:(1)Systematic review and meta-analysis of the efficacy and safety for roxadustat in the treatment of renal anemia: 13 RCTs with a total sample size of 7078 were included.The bias risk assessment showed that the quality of most RCTs was acceptable.Meta-analysis showed that roxadustat could significantly improve hemoglobin,transferrin,total iron binding capacity and serum iron levels in dialysis patients than that in erythropoiesis stimulating agents(ESA)group.Roxadustat can also significantly increase hemoglobin,transferrin,total iron binding capacity,and reduce hepcidin,ferritin and transferrin saturation in non-dialysis patients than that in placebo group.Meta-analysis also showed that roxadustat has a higher incidence of serious adverse events than that in ESA group,mainly in the cardiovascular,cerebrovascular,and digestive systems.The common symptoms included hypertension,cardiac dysfunction,nausea,diarrhea,and vomiting.(2)Mining of core prescription: a total of268 studies were included,including 227 TCM prescriptions,5 Chinese patent drug,169 TCM,with 3919 usage times.The medicinal taste was mainly warm and sweet,the meridian was mainly focused on the spleen,liver,and kidney,and the efficacy was mainly to replenish qi,nourish blood,promote blood circulation and remove stasis and promote water infiltration and dampness.The association rule,cluster and drug dosage analysis showed that the core prescription was 30 g of Astragalus membranaceus,15 g of Chinses angelica,15 g of Atractylodes macrocephala,15 g of Poria cocos,and 10 g of Codonopsis pilosula.(3)Network Pharmacology: there were four potential targets for the treatment of renal anemia with the combination of core prescription and roxadustat,namely AR,NR3C2,NR1I3,and RUNX1T1.GO and KEGG analysis found that promoting angiogenesis(VEGF signaling pathway),improving oxidative stress(c AMP signaling pathway),improving inflammatory response(m TOR signaling pathway),and regulating cell apoptosis(PI3K-Akt signaling pathway)were the main biological processes involved in these four target proteins.PPI analysis found a mutual relationship between AR and NR3C2,indicating that the combination therapy in treating renal anemia was more closely related to the target proteins AR and NR3C2.(4)Animal experiment: both core prescription and roxadustat alone can reduce the levels of IL-6 and hepcidin in rats,and increase the levels of serum iron,total iron binding capacity and transferrin.The combination of core prescription and roxadustat can significantly reduce IL-6,TNF-α,hepcidin,urea nitrogen,creatinine,and increase the levels of Hb,RBC,HCT,serum iron,total iron binding capacity and transferrin.Additionally,the combination of core prescription and roxadustat can significantly upregulate the expression of AR and downregulate the expression of NR3C2 in rat kidney tissue,with the best improvement effect and the greatest benefit.Core prescription or roxadustat can also upregulate AR expression and downregulate NR3C2 expression.Conclusions:(1)Roxadustat had a definite therapeutic effect in the treatment of renal anemia,but the incidence of serious adverse events related to drugs was also higher than ESA.The common symptoms include cardiovascular adverse events,digestive adverse events,and infections.(2)The combination of TCM and roxadustat in the treatment of renal anemia can achieve reduced toxicity and increased efficacy.The core prescription included 30 g of Astragalus membranaceus,15 g of Chinses angelica,15 g of Atractylodes macrocephala,15 g of Poria cocos,and 10 g of Codonopsis pilosula.(3)AR and NR3C2 were the main targets in the treatment of renal anemia by the combination of core prescription and roxadustat.(4)The combination of core prescription and roxadustat in the treatment of renal anemia mainly affects the secretion of inflammatory factors and oxidative stress state by regulating the expression levels of AR and NR3C2,thereby inducing the secretion of erythropoietin,improving renal function,and achieving the effect of treating renal anemia. |
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