BACKGROUND: Disease-modifying therapies have been approved for the treatment of relapsing multiple sclerosis (RMS). The present study aims to examine the safety of teriflunomide in Chinese patients with RMS. METHODS: This non-randomized, multi-center, 24-week, prospective study enrolled RMS patients with variant (c.421C>A) or wild type ABCG2 who received once-daily oral teriflunomide 14 mg. The primary endpoint was the relationship between ABCG2 polymorphisms and teriflunomide exposure over 24 weeks. Safety was assessed over the 24-week treatment with teriflunomide. RESULTS: Eighty-two patients were assigned to variant ( n  = 42) and wild type groups ( n  = 40), respectively. Geometric mean and geometric standard deviation (SD) of pre-dose concentration (variant, 54.9 [38.0] μg/mL; wild type, 49.1 [32.0] μg/mL) and area under plasma concentration-time curve over a dosing interval (AUC tau ) (variant, 1731.3 [769.0] μg∙h/mL; wild type, 1564.5 [1053.0] μg∙h/mL) values at steady state were approximately similar between the two groups. Safety profile was similar and well tolerated across variant and wild type groups in terms of rates of treatment emergent adverse events (TEAE), treatment-related TEAE, grade ≥3 TEAE, and serious adverse events (AEs). No new specific safety concerns or deaths were reported in the study. CONCLUSION: ABCG2 polymorphisms did not affect the steady-state exposure of teriflunomide, suggesting a similar efficacy and safety profile between variant and wild type RMS patients. REGISTRATION NCT04410965, https://clinicaltrials.gov .
Humans ; Crotonates/adverse effects* ; Toluidines/adverse effects* ; Nitriles ; Hydroxybutyrates ; Female ; Male ; Adult ; ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics* ; Middle Aged ; Multiple Sclerosis, Relapsing-Remitting/genetics* ; Prospective Studies ; Young Adult ; Neoplasm Proteins/genetics* ; East Asian People

Tripterygium wilfordii is widely used in the treatment of immune system disease and has a remarkable curative effect. Triptolide and Tripterygium glycosides are the most commonly used active ingredients in clinical practice， but their treatment window is narrow and there are many side effects. The damage involves the reproductive system， blood system， cardiovascular system， digestive system， etc. Based on clinical observations and literature summaries， the symptoms of adverse reactions mostly occur in the digestive system （liver and gastrointestinal tract）. Relevant scholars have launched a lot of studies of the manifestations of liver injury induced by T. wilfordii and the mechanism of liver injury. The mechanism is mainly related to liver cell apoptosis， induction of oxidative stress， immune injury， excessive autophagy of liver cells， abnormal fatty acid metabolism， and abnormal enzyme metabolism in liver tissues. This article reviewed and summarized relevant literature on gastrointestinal injury caused by T. wilfordii， but there are few studies on the manifestations and mechanisms of adverse reactions， which still need further research by scholars. In addition， this article also summarized the research on how to reduce toxicity and enhance efficacy of prescriptions prepared from T. wilfordii in the digestive system， mainly involving compatibility with western medicines （Methotrexate， Leflunomide， Iguratimod， etc.）， use along or combination with Chinese medicines （single Chinese medicine， Chinese medicine monomers， and Chinese medicine compounds）， acupuncture and moxibustion （electroacupuncture and moxibustion）， dosage form improvement （glycol plastid gel， self-dissolving microneedle， solid lipid nanoparticles， gastric floating sustained-release capsules， etc.）， processing （steaming， stir-frying， radish seed processing， money grass processing， licorice processing， etc.）， and other methods to reduce toxicity. To sum up， this article analyzed the manifestations， mechanisms， and methods of reducing toxicity and enhancing efficacy of T. wilfordii-induced liver injury and gastrointestinal injury by sorting out relevant literature， in order to provide a reference for the clinical application of T. wilfordii and some research ideas for the future in-depth study of T. wilfordii-induced digestive system injury.

ObjectiveTo observe the mechanism of chronic psychological stress aggravating idiopathic pulmonary fibrosis （IPF） in rats and the regulatory effect of Xiaoyaosan. MethodSixty SD rats were acclimatized for one week and then randomly divided into five groups： sham operation group， IPF group， IPF and depression model group， pirfenidone group， and pirfenidone + Xiaoyaosan group， with 12 rats in each group. The IPF group was induced by intratracheal instillation of bleomycin （5 mg·kg^-1） and administered 0.9% sodium chloride solution intragastrically. The model group was induced with bleomycin （5 mg·kg^-1） combined with chronic unpredictable mild stress to establish a rat model of IPF and depression and administered 0.9% sodium chloride solution intragastrically. Concurrently， the pirfenidone group was administered pirfenidone aqueous solution （50 mg·kg^-1） intragastrically， and the pirfenidone + Xiaoyaosan group was administered pirfenidone aqueous solution （50 mg·kg^-1） and Xiaoyaosan decoction （19.27 g·kg^-1） intragastrically. The experiment lasted for four weeks. Various parameters， including body weight， food intake， sucrose consumption rate， open field behavior， lung function， lung coefficient， pathological changes in lung tissue， and hydroxyproline （HYP） content were compared among the groups. Enzyme-linked immunosorbent assay （ELISA） was used to measure serum cortisol （CORT）， corticotropin-releasing hormone （CRH）， adrenocorticotropic hormone （ACTH） levels， and serotonin （5-HT） levels in serum and hippocampus. The levels of interleukin-1β （IL-1β）， interleukin-6 （IL-6）， and tumor necrosis factor-α （TNF-α） in serum and lung tissue were also measured. Real-time fluorescence quantitative polymerase chain reaction （Real-time PCR） was employed to determine the mRNA expression of IL-1β， TNF-α， IL-6， p38 mitogen-activated protein kinase （p38 MAPK）， and nuclear transcription factor-κB p65 （NF-κB p65） in lung tissue. Western blot was used to detect the expression of proteins related to the p38 MAPK/NF-κB signaling pathway. ResultCompared with the normal group， IPF and depression model group showed slow weight gain， reduced food intake， decreased sucrose consumption rate， reduced total distance and average speed of movement in the open field test， weakened lung function， increased lung coefficient （P<0.01）， significant inflammatory cell infiltration in lung tissue by hematoxylin-eosin （HE） staining， collagen fiber deposition by Masson staining， and increased HYP content （P<0.01）. There were elevated levels of serum CORT， CRH， and ACTH （P<0.05， P<0.01）， increased protein and mRNA levels of IL-1β， IL-6， and TNF-α in serum and lung tissue， decreased 5-HT levels in serum and hippocampus， and increased relative expression of p-p38 MAPK and p-NF-κB p65 proteins in lung tissue （P<0.01）. Compared with the IPF and depression model group， the depression and IPF of rats in the pirfenidone + Xiaoyaosan group were effectively ameliorated， as evidenced by faster weight gain， increased food intake and sucrose consumption rate， increased total distance and average speed of movement in the open field test， enhanced lung function， reduced lung coefficient （P<0.01）， decreased inflammatory cell infiltration by HE staining， reduced collagen fiber deposition by Masson staining in lung tissue， and decreased HYP content （P<0.01）. Decreased serum CORT， CRH， and ACTH levels （P<0.05， P<0.01）， decreased protein and mRNA levels of IL-1β， IL-6， and TNF-α in serum and lung tissue （P<0.05， P<0.01）， increased 5-HT levels in serum and hippocampus （P<0.05， P<0.01）， and decreased relative expression of p-p38 MAPK and p-NF-κB p65 proteins in lung tissue were also noted （P<0.05， P<0.01）， with the effects of Xiaoyaosan + pirfenidone being more significant. ConclusionChronic unpredictable stress exacerbates the progression of IPF in rats. The combination of Xiaoyaosan and pirfenidone not only improves depressive-like behavior but also alleviates pulmonary fibrosis， potentially through the regulation of the p38 MAPK/NF-κB signaling pathway and inhibition of excessive expression of inflammatory factors.

ObjectiveTo study the effect of Xiaoyusan new formula on the articular cartilage of knee osteoarthritis (KOA) rabbits and its mechanism. MethodsA total of 42 New Zealand white rabbits aged 6 months were randomly divided into normal group, model group, ointment of Xiaoyusan group, and ointment of Xiaoyusan new formula group, with 10 rabbits in each group (the other 2 rabbits were used for model validation). Except for the normal group, the right knee joints of all rabbits in the other groups were prepared as KOA models according to the modified Hulth method. After 5 weeks of molding, the rabbits in ointment of Xiaoyusan group, ointment of Xiaoyusan New Formula group were given corresponding ointments for knee arthritis treatment, once a day, each time for 10 hours. After 2-week continuous administration and treatment, the knee joint cartilage of the four groups of rabbits was taken and the cartilage damage of each group was evaluated by Outerbridge grading method. The pathological changes of the cartilage, calcified layer and subchondral bone of the knee joint of rabbits in each group were observed by HE staining method under the light microscope, and the degree of cartilage degeneration was evaluated by Mankin's method. The expression of matrix metalloproteinase-13 (MMP-13) in the cartilage of rabbit knee joint in each group was deteced by immunohistochemistry. Results After the general observation of articular cartilage, the Outerbridge grading showed that the number of high-grade animals in ointment of Xiaoyusan group was reduced compared with the model group (P<0.05), and the number of high-grade animals in ointment of Xiaoyusan new formula group was also reduced (P<0.05) compared with ointment of Xiaoyusan group. HE staining showed that Mankin's scores of articular cartilage in the four groups ranked from high to low: model group (10.82±1.76), ointment of Xiaoyusan group (6.19±1.23), ointment of Xiaoyusan new formula group (2.64±1.18) and normal group (0.28±0.17). The difference among four groups was statistically significant (P<0.05). Immunohistochemical detection showed that the positive rates of MMP-13 expression in rabbit articular cartilage tissues in each group were (67.90±13.94)% of model group, (37.10±19.16)% of ointment of Xiaoyusan group, (13.60±3.10)% of ointment of Xiaoyusan new formula group and (3.20±2.39) % of normal group, ranking from high to low, and the difference among four groups was statistically significant (P<0.05). ConclusionXiaoyusan new formula can repair articular cartilage degeneration in KOA rabbits and decrease the expression of MMP-13 in cartilage, which may be one of the mechanisms of the treatment.

Xiaoyaosan， a classical prescription for mental disorder recorded in Formulary of the Bureau of Taiping People's Welfare Pharmacy（《太平惠民合剂局方》）， is composed of Bupleuri Radix， Angelicae Sinensis Radix， Paeoniae Radix Alba， Atractylodis Macrocephalae Rhizoma， Poria， Zingiberis Rhizoma Praeparatum， Menthae Haplocalycis Herba， and Glycyrrhizae Radix Et Rhizoma Praeparata Cum Melle. Clinical practices and experiments have proved that it can be used for primary depression， anxiety， as well as the depression induced by various somatic disorders， such as gynecological diseases， internal diseases， and digestive system diseases， as evidenced the improvement of Hamilton depression rating scale score， self-rating depression scale score， etc. Xiaoyaosan has been verified to be remarkably effective， with high compliance and no obvious adverse reactions in patients. Xiaoyaosan mainly acts on monoamine neurotransmitters 5-hydroxytryptamine （5-HT）， norepinephrine （NE）， and dopamine （DA）， adrenocorticotropic hormone （ACTH） and corticosterone （CORT） in hypothalamic-pituitary-adrenal axis， pro-inflammatory cytokines interleukin-1β （IL-1β）， interleukin-6 （IL-6）， and tumor necrosis factored （TNF）-α， and orexin， ghrelin， and leptin in intestinal microecology and brain-gut axis， to regulate the neurobiochemical mechanism， endocrine mechanism， immune mechanism， and abnormal brain structure， thereby preventing and alleviating depression. However， the antidepressant mechanism of Xiaoyaosan needs to be further discussed. Through literature research， this paper analyzes the clinical application and basic mechanism of Xiaoyaosan in the treatment of depression， which is expected to serve as a reference for the application of this prescription in the clinical prevention and treatment of depression and improvement of the quality of life of patients， and further research on the antidepressant mechanism of Xiaoyaosan.

Adventitia ; Atherosclerosis/genetics* ; Cell Communication ; Humans ; Hyperhomocysteinemia/genetics* ; Sequence Analysis, RNA

Objective:To understand the influencing factors of death of epidemic Japanese encephalitis (EJE) cases in Longnan City of Gansu Province.Methods:In the EJE Monitoring Information Report Management System of the Chinese Disease Prevention and Control Information System, data on EJE cases with onset from 2014 to 2018 and current address in Longnan City were derived. An "Individual Questionnaire of Epidemic Japanese Encephalitis in Longnan City" was designed, retrospective study was conducted on enrolled cases, their information on demographic data, consultation, onset, clinical classification, and chronic underlying diseases were collected, characteristics of EJE cases and death-related factors were analyzed.Results:From 2014 to 2018, a total of 260 EJE cases were reported in Longnan City, and 259 cases completed the questionnaire. Among them, 70 cases (27.0%) were aged ≥60 years old, 67 cases (25.9%) were severe and extremely severe, and 55 cases (21.2%) had chronic underlying diseases. Among 259 EJE cases, 46 cases died, with a fatality rate of 17.8%. After multivariate unconditional logistic regression analysis, age ≥60 years old [odds ratio ( OR)=2.667, 95% confidence interval ( CI): 1.140-6.237], severe and extremely severe ( OR = 2.762, 61.820, 95% CI: 1.053-7.091, 5.149-742.239), and chronic underlying diseases ( OR = 2.489, 95% CI: 1.038-5.964) were risk factors for death in EJE cases. Conclusions:The influencing factors of death of EJE cases in Longnan City are age, clinical classification and chronic underlying diseases. Therefore, we should focus on patients over 60 years old, clinically classified as severe or extremely severe, and suffering from chronic underlying diseases, and strengthen the immunization of EJE vaccine for key populations.

Objective To study if IRF1 could regulate the polarization by IRF 1 and M1 status and affect M1 media-ted antitumor function .Methods U937 derived M1 macrophage ( U937-M1 ) model was established .The cells were devided into 4 groups:the PMA pretreated unpolarized macrophage (M0), the PMA, IFN-γand LPS induced M1 macrophage (M1), the siRNA of IRF1 knocked down M1 macrophage (siIRF1) and the negative control siR-NA treated M1 macrophage (siC).Furthermore, the expression of CD86 and CD206 was detected by flow cytome-try, the M1/M2 associated markers (IL-12p35,IL-12p40,IL-23p19,IL-6,TNF-α/IL-10) and IFNB1 were ana-lyzed by qPCR,the expression of IL-12p70 and IL-10 was examined by ELISA, the expression of IRF1 and IRF5 was detected by Western blot , the proliferration and apoptosis of HCC were analyzed by CCK 8 and flow cytometry , respectively.Results Compared with the U937-M1, the IRF1 knocked down group showed impaired CD 86 expres-sion, but enhanced CD206 expreesion ( P<0.05 ); the expression of M1 related cytokines including IL-12p35, IL-12p40,IL-23p19,IL-6,TNF-αand IFNB1 was decreased, but M2 related cytokine IL-10 level was increased (P<0.01);the expression of IFN-β, IL-12p70 and IRF5 was impaired, but IL-10 was enhanced (P<0.05).In IRF1 knocked down U937-M1, the CCK8 analysis indicated that the M1 mediated anti-proliferation effects on hepatoma carcinoma cell were turned to pro-proliferation ( P<0.05);the flow cytometry showed that the M 1 mediated pro-ap-optosis effects were reversed to anti-apoptosis ( P<0.01 ) .Interestingly , IRF5 and IFN-βwere decreased at both mRNA and protein levels in IRF1 knocked down U937-M1 compared with the U937-M1 (P<0.01).Conclusions IRF1 may partly modulate IRF5 and IFN-β, and further regulate M1 polarization and its antitumor effects .

Objective To investigate the effect of self decoction wet compress on puncture venous sclerosis.Methods 180 patients received intravenous therapy,they were randomly divided into group A,group B and group C,60 cases in each group.Group A was given with Traditional Chinese medicine decoction(rhubarb 20g,Xuan Ming powder 20g,Cortex Phellodendri 15g,20g purslane fried together) for in the direction of blood vessel along the direction of the blood vessel after operation of conventional intravenous infusion,8 layer 10cm×5cm sterile gauze soaked wet,then covered with plastic wrap plastic to the end of infusion 30 min after removal.Group B was given with Traditional Chinese medicine decoction at the end of intravenous infusion at the puncture point along the direction of the blood vessels,8 layer 10cm×5cm sterile gauze soaked wet and then with plastic wrap plastic cover 6h after removing.Group C was given with routine intravenous infusion operation without wet compress intervention.In 3d,5d,vein elasticity of each group was assessed,the normal was effective,mild,moderate and severe hardening was invalid.Results After 3d,5d treatment,the effective rates of group A were 100.0%,91.7% respectively,which in group B were 100.0%,81.7%,respectively,the effective rate at 5d had statistically significant difference between group A and group B (x2=5.17,P<0.05);after 3d,5d treatment,the effective rates of group C were 71.7%,60.0%,and the effective rate at 5 d had statistically significant difference compared with group B and group A (x2=21.07,6.82,all P<0.01).Conclusion The effect of intravenous infusion process to local decoction wet compress on the prevention of venous puncture hardening is significant,and the method is simple,has non-toxic side effects,it is worthy of clinical application.

Objective To observe the protective effect of Panaxadiol Saponins (PDS)on rabbit heart failure model induced by acute alcohol infusion, and to explore its action mechanism of protecting myocardium. Methods 1 5 healthy rabbits were randomly divided into control group, model group and PDS group, 5 rabbits in each group.The rabbits in control group were given 0.2 g·mL-1 saline by intravenous drip at constant speed,the rabbits in model group were given 20% ethanol with same method, and the rabbits in PDS group were given 0.025 g·kg-1 PDS by intravenous injection before intravenous drip of 20% ethanol.The hemodynamic changes were observed by ventricular intubation;the levels of serum lactate dehydrogenase (LDH),creatine kinase (CK), and creatine kinase isoenzyme (CKMB)were determined by colormetric method.The level of malondialdehyde (MDA)in myocardial tissue homogenate,the activities of superoxide dismutase (T-SOD),glutathione peroxidase (GSH-Px)and catalase (CAT)were also detected.Results Compared with control group,the left ventricular end-diastolic pressure (LVEDP)of the rabbits in model group was significantly decreased at 30 min(P<0.05);the serum LDH,CK and CKMB levels were increased(P<0.05),the MDA level in myocardial tissue homogenate was increased(P<0.05),and the T-SOD,GSH-Px and CAT activities were decreased (P<0.05).Compared with model group,the LVEDP of the rabbits in PDS group was increased,the serum LDH,CK,and CKMB levels were decreased(P<0.05),the MDA level was decreased(P<0.05),and the activities of T-SOD,GSH-Px and CAT were increased(P<0.05).Conclusion PDS has protective effect on heart failure induced by acute alcohol infusion,and its mechanism may be related to the improvement of cardiac peroxidation.