BACKGROUND:Rheumatoid arthritis is influenced by complex genetic and environmental factors.Although observational studies have found some correlation between plasma proteins and rheumatoid arthritis,the susceptibility to confounding and reverse causation makes it difficult to clarify whether these proteins are pathogenic factors of rheumatoid arthritis.OBJECTIVE:To explore the potential of plasma proteins as biomarkers and therapeutic targets in rheumatoid arthritis through Mendelian randomization analysis of plasma proteins in the onset and progression of rheumatoid arthritis.METHODS:A large-scale two-sample Mendelian randomization analysis was conducted to comprehensively assess the causal relationships between 1 553 circulating proteins and rheumatoid arthritis based on the Decode database(developed by Decode Genetics in Iceland,which contains genomic data from the Icelandic population),the MR-Base platform(developed by a team of researchers at the University of Oxford in the United Kingdom,specifically designed to provide genetic and phenotypic data for Mendelian randomization analyses),and the GWAS Catalog platform(developed by the European Institute of Bioinformatics,which provides data for genome wide association studies worldwide).The causal effects were estimated using the Wald ratio and inverse variance weighting methods,with Bonferroni correction applied to control for false positives caused by multiple testing.To ensure the robustness of the results,sensitivity analyses were performed to validate the positive causal relationship between circulating proteins and rheumatoid arthritis,and Bayesian colocalization and phenome scanning were used to exclude confounding effects and horizontal pleiotropy.Additionally,external validation was carried out using new plasma protein datasets to reduce the likelihood of false discoveries.Finally,small-molecule compounds associated with candidate proteins were identified using the Drug Signatures Database(DsigDB),and molecular docking was performed to predict the binding patterns and energies between proteins and compounds,identifying the most stable and likely binding molecules and mechanisms.RESULTS AND CONCLUSION:(1)Sensitivity analyses,including Bayesian colocalization and phenome scanning,identified four plasma proteins with reliable causal relationships with rheumatoid arthritis:FCRL3,IL6R,ICOSLG,and TNFAIP3.Their genetic effects were estimated as follows:FCRL3[odds ratio(OR)=1.12,95％confidence interval(CI):1.07-1.17],IL6R(OR=0.94,95％CI:0.91-0.96),ICOSLG(OR=2.42,95％CI:1.67-3.52),and TNFAIP3(OR=2.19,95％CI:1.88-2.56).Furthermore,molecular docking analysis revealed that the small-molecule compound benzo[a]pyrene exhibited favorable binding with these candidate proteins,suggesting its potential as a therapeutic agent for rheumatoid arthritis.(2)This study provides a comprehensive analysis of the genetic causal relationships of FCRL3,IL6R,ICOSLG,and TNFAIP3 in rheumatoid arthritis.These proteins not only serve as potential molecular biomarkers for rheumatoid arthritis risk screening and disease prevention,but also offer key candidate targets for further understanding the pathogenic mechanisms of rheumatoid arthritis and developing targeted therapies.Although the study is based on European populations,its findings offer important insights for biomedical research in China.By incorporating Mendelian randomization methods to analyze genetic causality,future research on rheumatoid arthritis in the Chinese population could provide more accurate causal inferences,offering theoretical support for localized risk assessment and treatment strategies.

BACKGROUND:Rheumatoid arthritis is influenced by complex genetic and environmental factors.Although observational studies have found some correlation between plasma proteins and rheumatoid arthritis,the susceptibility to confounding and reverse causation makes it difficult to clarify whether these proteins are pathogenic factors of rheumatoid arthritis.OBJECTIVE:To explore the potential of plasma proteins as biomarkers and therapeutic targets in rheumatoid arthritis through Mendelian randomization analysis of plasma proteins in the onset and progression of rheumatoid arthritis.METHODS:A large-scale two-sample Mendelian randomization analysis was conducted to comprehensively assess the causal relationships between 1 553 circulating proteins and rheumatoid arthritis based on the Decode database(developed by Decode Genetics in Iceland,which contains genomic data from the Icelandic population),the MR-Base platform(developed by a team of researchers at the University of Oxford in the United Kingdom,specifically designed to provide genetic and phenotypic data for Mendelian randomization analyses),and the GWAS Catalog platform(developed by the European Institute of Bioinformatics,which provides data for genome wide association studies worldwide).The causal effects were estimated using the Wald ratio and inverse variance weighting methods,with Bonferroni correction applied to control for false positives caused by multiple testing.To ensure the robustness of the results,sensitivity analyses were performed to validate the positive causal relationship between circulating proteins and rheumatoid arthritis,and Bayesian colocalization and phenome scanning were used to exclude confounding effects and horizontal pleiotropy.Additionally,external validation was carried out using new plasma protein datasets to reduce the likelihood of false discoveries.Finally,small-molecule compounds associated with candidate proteins were identified using the Drug Signatures Database(DsigDB),and molecular docking was performed to predict the binding patterns and energies between proteins and compounds,identifying the most stable and likely binding molecules and mechanisms.RESULTS AND CONCLUSION:(1)Sensitivity analyses,including Bayesian colocalization and phenome scanning,identified four plasma proteins with reliable causal relationships with rheumatoid arthritis:FCRL3,IL6R,ICOSLG,and TNFAIP3.Their genetic effects were estimated as follows:FCRL3[odds ratio(OR)=1.12,95％confidence interval(CI):1.07-1.17],IL6R(OR=0.94,95％CI:0.91-0.96),ICOSLG(OR=2.42,95％CI:1.67-3.52),and TNFAIP3(OR=2.19,95％CI:1.88-2.56).Furthermore,molecular docking analysis revealed that the small-molecule compound benzo[a]pyrene exhibited favorable binding with these candidate proteins,suggesting its potential as a therapeutic agent for rheumatoid arthritis.(2)This study provides a comprehensive analysis of the genetic causal relationships of FCRL3,IL6R,ICOSLG,and TNFAIP3 in rheumatoid arthritis.These proteins not only serve as potential molecular biomarkers for rheumatoid arthritis risk screening and disease prevention,but also offer key candidate targets for further understanding the pathogenic mechanisms of rheumatoid arthritis and developing targeted therapies.Although the study is based on European populations,its findings offer important insights for biomedical research in China.By incorporating Mendelian randomization methods to analyze genetic causality,future research on rheumatoid arthritis in the Chinese population could provide more accurate causal inferences,offering theoretical support for localized risk assessment and treatment strategies.

Cancer cachexia is a complex syndrome caused by multiple factors,which seriously affects the quality of life and prognosis of patients.Its overall pathogenesis is related to the deficiency of spleen qi,insufficiency of kidney essence,internal generation of turbid toxins,and the obstruction of the production of qi,blood and essential qi,which cannot nourish the muscles and bones.Under the guidance of the dynamic diagnosis and treatment system of"spleen and kidney exhaustion as the root cause and internal accumulation of turbid toxins as the manifestation",the overall regulation is carried out from four dimensions:opening and closing the spleen and stomach,nourishing the kidney and promoting transportation,transforming turbid toxins and detoxification,and tonifying qi and nourishing yin.It has shown unique value in the intervention of cancer cachexia and can provide ideas and references for the clinical practice of TCM in treating cancer cachexia.

Radiation enteritis(RE)is an inflammatory reaction caused by radiation exposure,commonly observed following radiotherapy for malignancies in the abdominal,pelvic and retroperitoneal regions.The authors believe that the pathogenesis of RE is complex,involving factors such as deficiency and excess,cold and heat,as well as qi and blood.The general pathogenesis can be summarized as"instability of the Zhongzhou,depletion of essence and blood,dysregulation of ascending and descending,and accumulation of heat-toxins".And"the instability of the Zhongzhou and subsequent malnutrition of the intestines"are the key drivers of disease progression.Based on theoretical exploration and clinical observations,this article proposed a comprehensive diagnostic and therapeutic approach centered on"stabilizing the Zhongzhou,replenishing essence and blood,regulating ascending and descending functions,and clearing heat-toxins".These four methods are often applied simultaneously,with"stabilizing the Zhongzhou and regulating the intestines"serving as the core of treatment.The approach is tailored according to the individual patient's condition of blood,qi and body fluids.A medical case was attached as evidence for verification.

Tumor-related insomnia is one of the common complications of tumor patients,which is secondary to tumor disease and related to tumor disease itself or tumor treatment.Combined with the unique pathogenesis of"heat-toxicity internal stagnation"of tumor-related insomnia,the important treatment methods are to clear away heat,attack toxicity,regulate qi and supplement healthy qi.This article explained the research status,etiology and pathogenesis,treatment principles of the disease,in order to provide new ideas and methods for the differentiation and treatment of tumor-related insomnia in TCM.

Radiation enteritis(RE)is an inflammatory reaction caused by radiation exposure,commonly observed following radiotherapy for malignancies in the abdominal,pelvic and retroperitoneal regions.The authors believe that the pathogenesis of RE is complex,involving factors such as deficiency and excess,cold and heat,as well as qi and blood.The general pathogenesis can be summarized as"instability of the Zhongzhou,depletion of essence and blood,dysregulation of ascending and descending,and accumulation of heat-toxins".And"the instability of the Zhongzhou and subsequent malnutrition of the intestines"are the key drivers of disease progression.Based on theoretical exploration and clinical observations,this article proposed a comprehensive diagnostic and therapeutic approach centered on"stabilizing the Zhongzhou,replenishing essence and blood,regulating ascending and descending functions,and clearing heat-toxins".These four methods are often applied simultaneously,with"stabilizing the Zhongzhou and regulating the intestines"serving as the core of treatment.The approach is tailored according to the individual patient's condition of blood,qi and body fluids.A medical case was attached as evidence for verification.

Tumor-related insomnia is one of the common complications of tumor patients,which is secondary to tumor disease and related to tumor disease itself or tumor treatment.Combined with the unique pathogenesis of"heat-toxicity internal stagnation"of tumor-related insomnia,the important treatment methods are to clear away heat,attack toxicity,regulate qi and supplement healthy qi.This article explained the research status,etiology and pathogenesis,treatment principles of the disease,in order to provide new ideas and methods for the differentiation and treatment of tumor-related insomnia in TCM.

Cancer cachexia is a complex syndrome caused by multiple factors,which seriously affects the quality of life and prognosis of patients.Its overall pathogenesis is related to the deficiency of spleen qi,insufficiency of kidney essence,internal generation of turbid toxins,and the obstruction of the production of qi,blood and essential qi,which cannot nourish the muscles and bones.Under the guidance of the dynamic diagnosis and treatment system of"spleen and kidney exhaustion as the root cause and internal accumulation of turbid toxins as the manifestation",the overall regulation is carried out from four dimensions:opening and closing the spleen and stomach,nourishing the kidney and promoting transportation,transforming turbid toxins and detoxification,and tonifying qi and nourishing yin.It has shown unique value in the intervention of cancer cachexia and can provide ideas and references for the clinical practice of TCM in treating cancer cachexia.

ObjectiveTo conduct a systematic comparative study on wild and cultivated Codonopsis pilosula（CP） from three aspects， including characters， microscopy， and contents of primary and secondary metabolites. MethodWild and cultivated CP samples were collected， their characters were measured using vernier caliper， tape measure and balance， the paraffin sections were stained with safranin-fixed green dyeing， and their microstructure were observed under the optical microscope. The content of alcohol-soluble extracts in wild and cultivated CP was determined according to the method for determination of extract under CP in the 2020 edition of Chinese Pharmacopoeia， the starch content was determined by anthrone colorimetry， the content of total polysaccharides was determined by kit method， Fiber analyzer was used to determine the content of fiber components， and ultra performance liquid chromatography（UPLC） was used to determine the content of monosaccharides， disaccharides and some secondary metabolites. Multivariate statistical analysis methods such as principal component analysis（PCA） and orthogonal partial least squares-discriminant analysis（OPLS-DA） were employed to screen key differential components between wild and cultivated CP on the basis of variable importance in the projection（VIP） value>1 and P<0.05. ResultIn terms of morphological characteristics， the "lion's head-like" shape， longitudinal wrinkles， and circumferential wrinkles below the root cap of wild CP were more pronounced in wild CP compared to the cultivated ones. Regarding transverse sectional features， wild CP had more fissures on the outer side of the cortex and a larger duramen. Under microscopic examination， wild CP had more stone cells， a larger proportion of xylem， and the presence of cork cells arranged in rings in the xylem， while cultivated CP has a larger proportion of phloem， smaller vessel diameters， and a more loosely arranged vascular system. In terms of primary metabolites， the contents of 45% ethanol-soluble extract and total polysaccharides in cultivated CP were significantly higher than those in the wild ones（P<0.05）， the contents of lignin， hemicellulose， cellulose， fructose and glucose in wild CP were significantly higher than those in the cultivated ones（P<0.05）， while sucrose content in the cultivated CP was significantly higher than that in the wild ones（P<0.05）. Concerning secondary metabolites， the contents of tryptophan and tangshenoside Ⅰ in cultivated CP were significantly higher than those in the wild ones（P<0.05）， whereas the contents of lobetyolinin， lobetyol and atractylenolide Ⅲ in wild CP were significantly higher than those in the cultivated ones（P<0.05）. ConclusionThere are significant differences between wild and cultivated CP in terms of morphological characteristics， microscopic features and chemical composition. Glucose， fructose， sucrose， tangshenoside Ⅰ， tryptophan and cellulose components are the key differential components between wild and cultivated CP. Wild CP contains more polyacetylenes and fructose， whereas cultivated CP has higher levels of tangshenoside Ⅰ and sucrose， with noticeably lower cellulose content. These distinctions may be related to their growth conditions， growth years and cultivation techniques. Based on the results of this study， it is recommended to increase polyacetylenes and the content ratio of fructose to sucrose as an indicators to characterize different production methods of CP， in order to guide the high-quality production of CP.

ObjectiveTo compare wild and cultivated Paeoniae Radix Rubra（PRR） in three aspects， including character， microscope， determination of primary and secondary metabolites. MethodSeventeen batches of wild and nine batches of cultivated PRR were collected，their character data were measured by vernier caliper and scales， and their paraffin sections were made by safranin-fixed green dyeing for the observation of microscopic features. The content of ethanol-soluble extracts and total tannin from wild and cultivated PRR was determined by the method of general principle 2201 and 2202 in the 2020 edition of Chinese Pharmacopoeia， the content of polysaccharides was determined by phenol-sulfuric acid method. Anthrone colorimetry was used to determine the content of starch， and Van Soest method of washing fiber was used to determine the content of fiber. The contents of fructose， glucose and sucrose in wild and cultivated PRR were determined by ultra-high performance liquid chromatography evaporative light scattering detection（UPLC-ELSD）， and the secondary metabolites（gallic acid， methyl gallate， catechin， oxypaeoniflorin， albiflorin， paeoniflorin， ellagic acid， 1，3，4，6-tetragalloylglucose， galloylpaeoniflorin， 1，2，3，4，6-O-pentagalloylglucose， naringenin， benzoylpaeoniflorin and benzoylalbiflorin） were determined by UPLC. Principal component analysis（PCA） and orthogonal partial least squares-discriminant analysis（OPLS-DA） were used to analyze the data of wild and cultivated PRR， the contribution of different factors to the difference was determined according to the variable importance in the projection（VIP） value>1 and P<0.05. ResultIn term of characters， wild PRR showed the traditional characteristic of Zaopi Fencha， its outer skin was loose and easy to fall off， its surface had longitudinal furrow and wrinkle， but the outer skin of cultivated PRR was not easy to fall off， and its surface was relatively smooth. The radial texture of xylem of wild PRR cross-section was more obvious， showing radial striations， vacuoles and more cracks， while the radial texture of xylem of cultivated PRR cross-section was not obvious， dense and some had cracks. Microscopically， the number of radial vessels arranged in the xylem of wild PRR was more than that of cultivated PRR， the number of calcium oxalate clusters in the phloem and xylem of wild PRR was more than that of cultivated PRR， while the number of starch grains was significantly higher in cultivated PRR. In terms of the content of primary chemical constituents， the contents of polysaccharides and starch of cultivated PRR were significantly higher than those of wild PRR（P<0.05）， while the contents of cellulose， lignin， fructose and glucose of wild PRR were significantly higher than those of cultivated PRR（P<0.05）. The results of determination of 13 secondary metabolites showed that the contents of paeoniflorin， methyl gallate， catechin and oxypaeoniflorin in wild PRR were significantly higher than those in cultivated PRR（P<0.05）， while the contents of albiflorin， gallic acid， ellagic acid， naringenin， benzoylpaeoniflorin and benzoylalbiflorin were significantly lower than those of cultivated PRR（P<0.05）. A total of 10 variables contributing to the differentiation between wild and cultivated PRR were screened， including albiflorin， cellulose， benzoylpaeoniflorin， oxypaeoniflorin， naringenin， ellagic acid， starch， lignin， paeoniflorin and total tannins. ConclusionThere are significant differences between wild and cultivated PRR in characters， microscopic characteristics， contents of primary and secondary metabolites. It is suggested that the content ratio of paeoniflorin and albiflorin， the contents of oxypaeoniflorin and cellulose can be used as indicators to characterize production methods of PRR so as to improve the quality standard of PRR. This study can provide reference for the improvement of quality standard of PRR and the guidance of high quality production of PRR.