The incidence of intrahepatic cholangiocarcinoma (ICC) continues to rise, and there are no effective drugs to treat it. The immune microenvironment plays an important role in the development of ICC and is currently a research hotspot. Icaritin (ICA) is an innovative traditional Chinese medicine for the treatment of advanced hepatocellular carcinoma. It is considered to have potential immunoregulatory and anti-tumor effects, which is potentially consistent with the understanding of "Fuzheng" in the treatment of tumor in traditional Chinese medicine. However, whether ICA can be used to treat ICC has not been reported. Therefore, in this study, sgp19/kRas, an in situ ICC mouse model with intact immune system, was selected to evaluate the efficacy of ICA in the treatment of ICC in vivo for the first time, and the effects of ICA on the tumor immune microenvironment of ICC mice were analyzed by flow cytometry. This experiment was approved by the Experimental Animal Ethics Committee of Capital Medical University (approval number: AEEI-2023-138). In this study, sgp19/kRas ICC mouse model was treated with oral gavage of 100 mg·kg^-1 ICA. We found that ICA significantly inhibited tumor growth and tumor cell proliferation in the sgp19/kRas ICC mouse model after 3 weeks of treatment. Flow cytometry analysis indicated that ICA treatment markedly reduced the proportion of M2 macrophages and increased the number of CD3⁺CD4⁺ T cells. In vitro experiments demonstrated that ICA promoted macrophage polarization towards the M1 phenotype while inhibiting polarization towards the M2 phenotype. Furthermore, transcriptomic analysis suggested that ICA enhanced Toll-like receptor 9 (TLR9) expression, influencing macrophage nitric oxide metabolism synthesis pathways and receptor-related activities, thereby regulating macrophage polarization. In summary, this study demonstrates that ICA treatment significantly delays tumor progression in sgp19/kRas ICC mouse models. Mechanistically, ICA may achieve its anti-ICC effects by upregulating TLR9 receptor expression levels, promoting macrophage polarization towards the M1 phenotype, and altering the tumor immune microenvironment.

The 3-succinate-30-stearyl glycyrrhetinic acid(18-GA-Suc) was inserted into glycyrrhetinic acid(GA)-tanshinone Ⅱ_A(TSN)-salvianolic acid B(Sal B) liposome(GTS-lip) to prepare liver targeting compound liposome(Suc-GTS-lip) mediated by GA receptors. Next, pharmacokinetics and tissue distribution of Suc-GTS-lip and GTS-lip were compared by UPLC, and in vivo imaging tracking of Suc-GTS-lip was conducted. The authors investigated the effect of Suc-GTS-lip on the proliferation inhibition of hepatic stellate cells(HSC) and explored their molecular mechanism of improving liver fibrosis. Pharmacokinetic results showed that the AUC_(Sal B) decreased from(636.06±27.73) μg·h·mL~(-1) to(550.39±12.34) μg·h·mL~(-1), and the AUC_(TSN) decreased from(1.08±0.72) μg·h·mL~(-1) to(0.65±0.04) μg·h·mL~(-1), but the AUC_(GA) increased from(43.64±3.10) μg·h·mL~(-1) to(96.21±3.75) μg·h·mL~(-1). The results of tissue distribution showed that the AUC_(Sal B) and C_(max) of Sal B in the liver of the Suc-GTS-lip group were 10.21 and 4.44 times those of the GTS-lip group, respectively. The liver targeting efficiency of Sal B, TSN, and GA in the Suc-GTS-lip group was 40.66%, 3.06%, and 22.08%, respectively. In vivo imaging studies showed that the modified liposomes tended to accumulate in the liver. MTT results showed that Suc-GTS-lip could significantly inhibit the proliferation of HSC, and RT-PCR results showed that the expression of MMP-1 was significantly increased in all groups, but that of TIMP-1 and TIMP-2 was significantly decreased. The mRNA expressions of collagen-I and collagen-Ⅲ were significantly decreased in all groups. The experimental results showed that Suc-GTS-lip had liver targeting, and it could inhibit the proliferation of HSC and induce their apoptosis, which provided the experimental basis for the targeted treatment of liver fibrosis by Suc-GTS-lip.
Humans ; Liposomes ; Hepatic Stellate Cells ; Glycyrrhetinic Acid/pharmacology* ; Liver ; Liver Cirrhosis/genetics* ; Collagen/pharmacology*

ObjectiveThis study aimed to assess the circulating bilirubin profile ［total bilirubin （TBIL）， conjugated bilirubin （DBIL）， unconjugated bilirubin （IBIL）］ and their associations with nonproliferative diabetic retinopathy （NPDR）. MethodsA case-control study which enrolled 312 type 2 diabetic mellitus （T2DM） patients （78 newly diagnosed NPDR 1：3 matched with 234 T2DM without diabetic retinopathy） was conducted. Diabetic retinopathy was screened by artificial intelligence fundus camera and further confirmed by the ophthalmologist， and demographic and clinical information were collected. Serum bilirubin and related biochemical indicators were assessed. ResultsPatients with NPDR had significantly lower serum TBIL， DBIL and IBIL concentrations （P values were 0.003， 0.001 and 0.006）， which were not associated with glycated hemoglobin （HbA1c） concentration （all P values >0.05）. The association persisted after adjustment for traditional risk factors including gender， diabetes duration， HbA1c and systolic blood pressure. Moreover， low IBIL had a higher risk of NPDR with odds ratio （OR） 95%CI of 3.44 （1.04， 11.38） in well glycemic controlled T2DM patients （HbA1c ≤7%） or of 2.53 （1.10， 5.82） in T2DM patients without microalbuminuria ［urine albumin creatine ratio （UACR） ≤30mg/g］； low DBIL had a higher risk of NPDR with OR 95%CI of 2.05 （1.09， 3.86） in poor glycemic controlled T2DM patients （HbA1c>7%） or of 2.40 （1.14， 5.02） in T2DM patients with microalbuminuria （UACR >30mg/g）. ConclusionOur results suggested that circulating bilirubin level is inversely and independently associated with NPDR which might be an early clinical biomarker for predicting and preventing diabetic retinopathy.

In the clinical practice of rheumatic immune diseases in traditional Chinese medicine （TCM），it`s still unclear about the dominant diseases and breakthrough points. It`s urgent missions to formulate TCM diagnosis and treatment guidelines widely recognized and integrated by traditional Chinese medicine and Western medicine. In order to clarify the dominant diseases and breakthrough points in rheumatism，China association of Chinese medicine initiated a research group covering experts in the field of rheumatism of traditional Chinese medicine and Western medicine. Based on questionnaire survey and on-site discussion，experts had reached the following consensus. Evidence-based medicine research using modern medical methods and scientific methods should be carried out to provide objective clinical evidences. "Four mutuality" were put forward as the basis for the work of integrated traditional Chinese and Western medicine，that is the mutual communication using the exchangeable context，the mutual explanation using common theories，the mutual certification using common standards，and the mutual integration using common means. Key works should focus on solving refractory rheumatism in the future. In terms of dominant diseases and breakthrough points，this paper introduces 21 breakthrough points in 6 dominant diseases，including rheumatoid arthritis，ankylosing spondylitis，Sjogren's syndrome，hyperuricemia and gout，systemic lupus erythematosus and fibromyalgia syndrome. Advice on this discussion can provide valuable references for developing the treatment scheme of rheumatism with TCM and integrated Chinese and Western medicine and clinical practice and scientific research.

Nitrogen fertilizer has been the long-lasting crucial component in cultivation of Chinese materia medica(CMM) and crops for its profound effects on enhancing the productivity. In consideration of its role in better production, intensive and excessive application of N fertilizer is often found in CMM cultivation. Therefore, firstly, this review summarized various concentrations of N application with regards to different CMM and districts from the literatures published in the last two decades. The recommended concentration of nitrogen application of forty seven CMM species were covered in this review. We found that the optimum rates of nitrogen fertili-zer for different medicinal plants species were varied in the range between 0-1 035.55 kg·hm~(-2). Most of the optimum rates of nitrogen fertilizer for CMM in published researches fell between 100-199 kg·hm~(-2). The optimum rate of nitrogen fertilizer is not only related to amount of nitrogen required for different medicinal plants but also to soil fertilities of different fields. In addition, we outlined the diffe-rent effects of proper and excessive nitrogen deposition on yield of CMM. Proper nitrogen deposition benefits the yield of CMM, howe-ver, excessive nitrogen use accounts for a decrease in CMM yield. We elucidated that nutritional content, water use efficiencies, and photosynthesis capacity were major influencing factors. Researches showed that proper nitrogen fertilizer could promote the water use efficiencies of plants and boost photosynthesis. Consequently, the yield of CMM can be enhanced after nitrogen deposition. However, negative effects of nitrogen fertilizer were also found on plant including producing toxic substances to the soil and causing severe pest damages. Lastly we analyzed the impact of N fertilizer application on secondary metabolites which accounts for a large part of active pharmaceutical ingredients of CMM. It usually caused an increase in nitrogen-containing secondary metabolites content and a decrease in non-nitrogen-containing secondary metabolites content respectively. The potential underlying mechanisms are the different synthetic pathways of these metabolites and the plant nutritional status. Synthesis of non-nitrogen-containing secondary metabolites like phenols can be inhibited after nitrogen application because of the competition of the same precursor substances between metabolites synthesis and plant growth. To sum up, impacts and mechanisms of nitrogen fertilizer on yield and quality enhancement of CMM were discussed in this review. Negative effects of excessive nitrogen application on CMM should be paid special attention in CMM cultivation and prescription fertilization based on the field soil quality is strongly recommended. Overall, this review aims to provides insights on improving the proper application of N fertilizer in the cultivation of CMM.
Agriculture ; China ; Fertilizers ; Materia Medica ; Nitrogen/analysis* ; Soil

Nitrogen is one of the most frequently used fertilizers in growth of Chinese medicinal plants(CMP). As in many other ecosystems, CMP ecosystem is also composed of plant-herbivore-natural enemy(tritrophic) interactions. Nitrogen fertilizer influences the growth and reproduction of CMP, and it is also able to heavily shape the ecosystem functions of CMP ecosystem through bottom-up forces. Understanding the specific effects of nitrogen fertilizer towards each trophic level will be beneficial to improve the resistance of CMP to herbivore and enhance the control efficiency of nature enemies to herbivore, and eventually, maximize the yield and quality of CMP. Most papers published on nitrogen use in plants focused mainly on the impact of nitrogen fertilization on CMP yield and quality. Influences of nitrogen application on CMP ecosystem get little attention at present. Therefore, this review summed up the potential effects of nitrogen fertilization on CMP ecosystem from perspectives of soil and tritrophic interactions. First of all, nitrogen fertilizer might decrease soil microbial biomass and altered the community structures of soil bacteria, fungi and protozoa. Negative effects of nitrogen fertilizer were found on biodiversity of soil bacteria and protozoa. Different fungi species respond differently to nitrogen fertili-zers. Nitrogen deposition can also decrease the soil pH. Decreases in soil microbial diversity and soil acidification can cause negative effects on CMP growth. In addition, nitrogen fertilizer could regulate the pest resistance of CMP including constitutive and inducible resistance. Both positive and negative effects of nitrogen application were found on pest resistance of CMP. Moreover, the development and predation of natural enemies were influenced by nitrogen deposition. Nitrogen influences natural enemies in many ways including plant volatiles, plant nutrient and structure and the supplementary food quality. Nectar and honeydew of plants and preys serve as important food source for natural enemies especially in early season when preys are still not available. Finally, the interactions between herbivores and their natural enemies were also shaped by nitrogen fertilizer in many aspects like increasing the nutritional content of prey and changing control efficiency of natural enemies. Some herbivores have evolved a strategy to sequester secondary metabolites which they absorbed from plant during their feeding. Studies showed that sequestration efficiency of secondary metabolites in prey could also be regulated by nitrogen. Parasitic, emergence, reproduction rate and longevity of parasites were found positively correlated with nitrogen deposition. Hopefully this study will shed light on practicable and economical application of nitrogen in cultivation of CMP.
China ; Ecosystem ; Fertilizers ; Nitrogen ; Plants, Medicinal ; Soil

Nitrogen fertilizers play an important role in the regulation of plant stress resistance. Impacts of nitrogen fertilizers on abiotic stress resistance and biotic stress resistance of Chinese materia medica(CMM) were summarized in this study. Adequate nitrogen application improves the abiotic stress resistance and weed resistance of CMM, however adverse effect appears when excess nitrogen is used. Generally, pest resistance decreases along with nitrogen deposition, while effects of nitrogen application on disease resistance vary with different diseases. Mechanisms underlying the impact of nitrogen fertilizers on plant stress resistance were also elucidated in this study from three aspects including physical defense mechanisms, biochemistry mechanisms and molecular defense mechanisms. Nitrogen availability modulates physical barrier of CMM like plant growth, formation of lignin and wax cuticle, and density of stomata. Growth of CMM promoted by nitrogen fertilizer may cause some decrease in pest resistance of CMM due to an increase in hiding places for pest along with plant growth. High ambient humidity caused by excessive plant growth facilitates the growth and development of CMM pathogen. Nitrogen application can also interfere with the accumulation of lignin in CMM which makes CMM more vulnerable to pest and pathogen attack. Stomatal closing delays due to nitrogen application is also a causal factor of increasing pathogen infection after nitrogen deposition. Biochemical defenses of plants are mainly achieved through nutrient elements, secondary metabolites, defense-related enzymes and proteins. Nutritional level of CMM and various antioxidant enzymes and resistance-related protein activities are elevated along with nitrogen deposition. These antioxidant enzymes can reduce the damage of reactive oxygen species content produced by plant in response to adversity and therefore enhance stress resistance of CMM. Researches showed that nitrogen application could also cause an increase in nitrogen-containing secondary metabolites content and a decrease in non-nitrogen-containing secondary metabolites content respectively. Nitrogen-mediated molecular defense mechanisms includes multiple plant hormones and nitric oxide signals. Plant hormones related to plant defense like salicylic acid, jasmonic acid and abscisic acid can be modulated by nitrogen application. Negative effect of nitrogen deposition was found on salicylic acid accumulation and the expression of related plant disease resistance genes. However, jasmonic acid level can be elevated by nitrogen. Nitric oxide signals constitute an important part of nitrogen mediated defense mechanisms. Nitric oxide signaling is related to many aspects of plant immunity. The roles of nitrogen fertilizers in CMM stress resistance are complex and may vary with different CMM varieties and environments. Further studies are urgently needed to provide a comprehensive understanding of how to improve stress resistance of CMM by using fertilizers.
Abscisic Acid ; China ; Materia Medica ; Nitrogen ; Plant Growth Regulators

Adolescent ; Child ; China/epidemiology* ; Humans ; Malnutrition ; Nutritional Status ; Prevalence

Dyslipidemia is a disease of lipid metabolism. At present, the prevalence of dyslipidemia in adults in China is as high as 40.40%. In the United States, there are more than 100 million individuals with abnormal low-density lipoprotein cholesterol (LDL-C), and the incidence rate is increasing year by year and showing a trend of becoming younger. Dyslipidemia is closely related to a variety of diseases such as fatty liver, atherosclerosis , hypertension, coronary heart disease, diabetes, and stroke. It has now developed into a global public health problem that seriously threatens human life and health. Modern medicine believes that its pathogenesis is complicated and is related to abnormal glucose and lipid metabolism, insulin resistance (IR) and other factors. Chinese medicine ascribes it to primary asthenia-secondary sthenia syndrome, which is closely related to the liver, spleen, and kidney. It is believed that excessive fat and grease can cause phlegm and cause many diseases. In terms of its treatment, western medicine mainly uses statin chemical synthesis preparations, with stable therapeutic effect, but many adverse reactions such as myalgia, myositis, rhabdomyolysis and acute renal injury are the main factors restricting its clinical application. Traditional Chinese medicine (TCM) has a long history, and multi-pathway, multi-target, multi-level regulation of dyslipidemia, few adverse reactions and low drug dependence are the principal advantages of TCM in treating dyslipidemia. At present, there are more and more researches on the prevention and treatment of dyslipidemia by TCM, but they are mainly focused on the observation of curative effect and the summary of prescription, and there are relatively few in-depth discussion and summary of the mechanism of TCM. Through comprehensively retrieving and collating the relevant domestic and foreign literatures in the past five years, we reviews from the perspective of effective ingredients, therapeutic pathways, and targets of action, and comprehensively introduces the latest research progress of TCM on the mechanism of regulating dyslipidemia, and put forward some suggestions for the possible research direction in the future, in order to provide new ideas and theoretical basis for TCM in clinical prevention and treatment of this disease.

With the rapid development of comprehensive health industry, the demand for Chinese medicinal materials is increasing. There is also a growing demand for land for the cultivation of Chinese medicinal materials.Based on the analysis of the demand characteristics of planting habitats for Chinese medicinal herbs, this paper finds that compared with the cultivated environment, the wild environment is more conducive to the improvement of the quality and stress resistance of medicinal plants. The eco-planting for Chinese medicinal materials is the only way to achieve high quality, efficient and sustainable production of traditional Chinese medicine. Therefore, according to the habitat distribution characteristics of wild medicinal plants, combined with the current situation of land resource utilization in China and the increasing demand for land for Chinese herbal medicine cultivation, the land use strategy of Chinese herbal medicine ecological agriculture was proposed. ① To vigorously develop underwood planting and change the existing field cultivation mode. ② To make full use of mountainous areas and barren slopes to carry out wild planta tending or planting imitates wild condition. ③ According to the development law and biological characteristics of medicinal plants, the land resources should be developed and used rationally according to local conditions.This can not only meet the requirements of the specific growth environment of Chinese medicinal materials, realize the sustainable development of the Chinese medicinal materials industry, but also increase the economic income of people in mountainous areas, provide scientific and effective solutions for the land use of Chinese medicinal materials, and also have important significance for the protection of wild Chinese medicinal materials.
Agriculture ; China ; Drugs, Chinese Herbal ; Materia Medica ; Medicine, Chinese Traditional ; Plants, Medicinal