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

Objective To observe the effect of omeprazole enteric-coated capsules on clinical symptoms and serum inflammatory factor levels in children with chronic gastritis and peptic ulcer.Methods Children with chronic gastritis and peptic ulcer were divided into treatment group and control group by random number table method.The control group was given triple therapy of ranitidine hydrochloride tablets,amoxicillin and clarithromycin,while the treatment group was treated with omeprazole enteric-coated capsules combined with amoxicillin and clarithromycin.Clinical efficacy,symptom relief time,and changes in serum motilin(MOT),gastrin(GAS)and inflammatory factors[interlrukin-6(IL-6)and interlrukin-8(IL-8)]were compared between the two groups.Results There were 48 cases in treatment group and 48 cases in control group.After treatment,the total effective rates in treatment group and control group were 93.74％(45 cases/48 cases)and 85.42％(41 cases/48 cases),with significant difference(P＜0.05).After treatment,the disappearance time of ulcer induced pain in treatment group and control group were(1.51±0.26)and(2.08±0.42)d;the disappearance time of acid regurgitation were(2.29±0.40)and(2.93±0.33)d;the disappearance time of burning sensation were(2.37±0.21)and(2.85±0.54)d;the length of hospital stay were(6.21±1.07)and(6.94±1.25)d;serum MOT levels were(298.48±35.15)and(273.58±31.25)pg·mL-1;serum GAS levels were(167.28±19.46)and(128.32±18.61)ng·L-1;IL-6 levels were(58.67±5.39)and(76.14±6.63)mg·mL-1;IL-8 levels were(50.08±5.16)and(58.68±5.49)mg·mL-1.The above indexes were significantly different between control group and treatment group(all P＜0.05).The total incidence of adverse drug reactions in treatment group and control group were 8.33％and 12.50％,with no statistical significance(P＞0.05).Conclusion Omeprazole enteric-coated capsules in the treatment of children with chronic gastritis and peptic ulcer can effectively alleviate various clinical symptoms and improve clinical efficacy.At the same time,it can lower serum levels of inflammatory factors and improve inflammation,with good effect.

Objective To explore the role of Panax notoginseng saponins(PNS)in regulating the expression of sortilin and ATP-binding cassette transporter A1(ABCA1)in macrophages,and the effect of PNS on inhibiting formation of foam cells and the potential mechanism of PNS adjusting sortilin expression and cholesterol metabolism.Methods The macrophages were divided into five groups as follows:group A(only added with cell culture),group B(transfected with negative control lentivirus),group C(transfected with lentivirus-mediated sortilin overexpression),group D(transfected with lentivirus-mediated sortilin overexpression+60 μg·mL-1PNS),group E(transfected with lentivirus-mediated sortilin overexpression+10 μmol·L-1 mitogen-activated protein kinase kinase(MEK)inhibitor PD98059+60 μg·mL-1 PNS).The protein contents of sortilin,ABCA1,extracellular signal-regulated kinase(ERK)and phosphorylated-ERK(p-ERK)were evaluated with Western blot.All the cells in five groups were cultured with 50 μg·mL-1ox-LDL to form foam cells.The lipid in macrophages was investigated with red O assay.Results The relative expression levels of sortilin protein were 1.00±0.08,0.91±0.15,2.28±0.13,1.62±0.09 and 2.01±0.08;the relative expression levels of ABCA1 protein were 1.00±0.01,0.92±0.07,0.29±0.04,0.66±0.09 and 0.44±0.07;the ratios of p-ERK/ERK protein were 1.00±0.09,0.92±0.05,1.03±0.12,2.00±0.12 and 1.64±0.14;the contents of lipid in macrophages were(4.82±2.19)％,(6.70±0.88)％,(44.56±4.15)％,(27.66±3.25)％and(41.67±5.45)％.Except the ratios of p-ERK/ERK,the other parameters between group C and group A were statistically significant difference(all P＜0.01).Meanwhile,there were also statistically significant difference between group D and group C as well as group D and group E(P＜0.05,P＜0.01).Conclusion PNS inhibits the lipid accumulation in macrophages through upregulating ABCA1 and downregulating sortilin,and ERK signaling pathway may be as one of important mechanisms influencing the expression of sortilin and ABCA1 mediated by PNS.

Objective To study the effect of Hedysarum polysaccharides(HPS)on the expression of transforming growth factor-β,(TGF-β1),smad homologue 3 recombinant protein(smad3)and smad7 in renal tissue of db/db mice with diabetic nephropathy(DN).Methods According to their body weight,6-week-old male db/db mice were randomly divided into 5 groups:model group(0.9％NaCl 0.2 mL·d-1),positive control group(22.75 mg·kg-1·d-1 irbesartan)and experimental-H,-M,-L groups(200,100,50 mg kg-1·d-1 HPS),with 10 mice in each group;another 10 SPF grade male C57BL/6 mice of the same week were selected as normal group(0.9％NaCl 0.2mL·d-1).The mice in the 6 groups were given intragastric administration once a day for 12 weeks.The blood glucose concentration of mice was measured before treatment and at the 4th,8th and 12th week after treatment.The expression levels of TGF-β1,smad3 and smad7 were detected by Western blotting.Results After treatment,the blood glucose levels of the model group was significantly higher than those of the normal group(all P＜0.01);compared with the model group,the levels of blood glucose in the experimental-H,-M groups decreased significantly,and the differences were statistically significant(P＜0.05,P＜0.01).The relative expression levels of TGF-β,protein in normal group,model group,positive control group and experimental-H,-M groups were 0.71±0.16,1.66±0.18,1.00±0.17,0.88±0.15 and 1.23±0.15;the relative expression levels of smad3 protein were 0.89±0.32,2.26±0.35,1.24±0.31,1.05±0.30 and 1.67±0.35;the relative expression levels of smad7 protein were 1.66±0.03,0.60±0.03,1.10±0.07,1.48±0.08 and 0.97±0.09;there were statistically significant differences between the experimental-H,-M groups and the model group(P＜0.05,P＜0.01).Conclusion Hedysarum polysaccharides can improve renal fibrosis and delay the development of diabetic nephropathy by regulating the level of blood glucose,inhibiting TGF-β1,smad3 and increasing the expression of smad7.

BACKGROUND:Irisin,a myokine isolated from the transmembrane protein FNDC5 by muscle cells during exercise,has the function of inducing the browning of white adipose tissue,but its effect on lipotoxicity-induced osteogenic differentiation and the mechanism is unclear. OBJECTIVE:To investigate the effect of irisin on the osteogenic ability of palmitic acid-induced bone marrow mesenchymal stem cells and the mechanism of action. METHODS:CCK-8 assay was used to detect the effect of different concentrations of palmitic acid on the proliferation of mouse bone marrow mesenchymal stem cells and the effect of irisin on the proliferation of mouse bone marrow mesenchymal stem cells in the presence of palmitic acid.After pretreatment with irisin and palmitic acid for 24 hours,osteogenic differentiation of mouse bone marrow mesenchymal stem cells was induced by alkaline phosphatase staining as well as qRT-PCR was performed to detect the expression of osteogenesis-related genes on day 7 of osteogenic induction culture.The expression of proteins related to the AMPK/BMP2/SMAD signaling pathway was detected by western blot assay.Alizarin red staining was conducted on day 21 to detect osteogenic differences. RESULTS AND CONCLUSION:(1)The CCK-8 assay results suggested that the amplification of bone marrow mesenchymal stem cells was inversely proportional to the concentration of palmitic acid,but at 0.02 mmol/L concentration,palmitic acid had no significant effect on the amplification of bone marrow mesenchymal stem cells,and irisin did not affect the proliferation of bone marrow mesenchymal stem cells when its mass concentration was in the range of 0.1-20 μg/L.(2)Alkaline phosphatase staining and alizarin red staining showed that palmitic acid inhibited the osteogenic differentiation ability of bone marrow mesenchymal stem cells.Irisin improved palmitic acid-induced osteogenic inhibition of bone marrow mesenchymal stem cells.qRT-PCR results showed that palmitic acid could cause the downregulation of osteogenic-related genes,and irisin could inhibit this trend.(3)Western blot assay results showed that compared with the palmitic acid intervention group,irisin treatment enhanced AMPK/BMP2/SMAD signal transduction in bone marrow mesenchymal stem cells.It is found that irisin can improve the osteogenic differentiation ability of bone marrow mesenchymal stem cells pretreated with palmitic acid,and proposed that the specific mechanism might be mediated by AMPK/BMP/SMAD signaling pathway.

Objective:To delve into the intricate relationship between common genetic variations across the entire genome and the risk of non-syndromic cleft lip with or without cleft palate(NSCL/P).Methods:Utilizing summary statistics data from genome-wide association studies(GW AS),a thorough investigation to evaluate the impact of common variations on the genome were undertook.This involved assessing single nucleotide polymorphism(SNP)heritability across the entire genome,as well as within specific genomic regions.To ensure the robustness of our analysis,stringent quality control measures were applied to the GWAS summary statistics data.Criteria for inclusion encompassed the absence of missing values,a minor allele frequency≥1％,P-values falling within the range of 0 to 1,and clear SNP strand orientation.SNP meeting these stringent criteria were then meticulously included in our analy-sis.The SNP heritability of NSCL/P was calculated using linkage disequilibrium score regression.Addi-tionally,hierarchical linkage disequilibrium score regression to partition SNP heritability within coding re-gions,promoters,introns,enhancers,and super enhancers were employed,and the enrichment levels within different genomic regions using LDSC(v1.0.1)software were further elucidated.Results:Our study drew upon GWAS summary statistics data obtained from 806 NSCL/P trios,comprising a total of 2 418 individuals from the Chinese population.Following rigorous quality control procedures,490 593 out of 492 993 SNP were deemed suitable for inclusion in SNP heritability calculations.The observed SNP heritability of NSCL/P was 0.55(95％CI:0.28-0.82).Adjusting for the elevated disease pre-valence within our sample,the SNP heritability scaled down to 0.37(95％CI:0.19-0.55)based on the prevalence observed in the general Chinese population.Notably,our enrichment analysis unveiled significant enrichment of SNP heritability within enhancer regions(15.70,P=0.04)and super enhan-cer regions(3.18,P=0.03).Conclusion:Our study sheds light on the intricate interplay between common genetic variations and the risk of NSCL/P in the Chinese population.By elucidating the SNP heritability landscape across different genomic regions,we contribute valuable insights into the genetic basis of NSCL/P.The significant enrichment of SNP heritability within enhancer and super enhancer re-gions underscores the potential role of these regulatory elements in shaping the genetic susceptibility to NSCL/P.This paves the way for further research aimed at uncovering novel genetic pathogenic factors un-derlying NSCL/P pathogenesis.

The identification of the components absorbed in serum of platycosides in total saponins fraction of Platycodonis Radix is great significance, but there are still great challenges. In this study, 8 types of 44 primordial components from Platycodon saponins were firstly identified using the ultra-performance liquid chromatography-linear ion trap electrostatic field orbitrap high resolution mass spectrometry (UPLC-LTQ-Orbitrap-MS) equipped with the software of Compound Discoverer 3.2 and Trace finder 2.1. Then, the platycosides and their deglycosylated metabolites were used as the template molecules to construct the intestinal microbiota mediated method to identify the primary components and the prototypes in serum. As results, 57 components originating from 44 prototypes of platycosides were identified from drug-containing plasma. Those compounds consist of 12 prototypes of platycosides and 45 metabolites, while the prototypes in serum are also deglycosylated metabolites of other platycosides. The results showed that the intestinal microbiota mediated method could be applied to identify the metabolites of platycosides in total saponins fraction of Platycodonis Radix; and reveal the potential existing forms of prototypes of platycosides in plasma; In addition, it could clearly illustrate the one to many and many to one network of the prototypes and metabolites of platycosides. All animal protocols were approved by the Animal Ethics Committee of Jiangxi University of Traditional Chinese Medicine (No.JZLLSC-202100322).

OBJECTIVE: To evaluate the clinical efficacy and safety of Wuziyuye Decoction in the treatment of type-II diabetes mellitus (DM) with qi-yin deficiency complicated by asthenospermia. METHODS: We selected 100 cases of type-II DM with qi-yin deficiency complicated by asthenospermia treated in the First Hospital Affiliated to Ningbo University from January 2023 to March 2024, and randomly assigned them to receive Wuziyuye Decoction (the trial group, n = 50) and oral L-carnitine solution (the control group, n = 50) in addition to Western medicine to reduce fasting blood glucose to normal in both groups. After 12 weeks of medication, we followed up the patients for 24 weeks, obtained their semen parameters, traditional Chinese medicine (TCM) syndrome scores and levels of reproductive hormones, and the clinical pregnancy outcomes of their partners, followed by comparison of the data collected between the two groups before and after treatment. RESULTS: After 12 weeks of treatment, the trial group showed significant improvement over the baseline in the percentage of progressive motility (PR%) (［35.5±6.1］% vs ［18.0±4.2］%, P<0.05), sperm concentration (［54.0±33.4］ vs ［40.0±36.1］ × 10⁶/ml, P<0.05), and TCM syndrome score (4.5±2.3 vs 18.5±5.2, P<0.05), but no statistically significant difference in the semen volume (［2.85±0.36］ vs ［2.84±0.59］ ml, P>0.05), while the controls exhibited markedly improved percentage of PR% (［29.5±6.2］% vs ［18.5±4.5］%, P<0.05) and sperm concentration (［45.0±34.1］ vs ［42.0±38.3］ × 10⁶/ml, P<0.05), but no statistically significant difference in the semen volume (［3.04±0.89］ vs ［2.90±0.78］ ml, P>0.05) and TCM syndrome score (17.2±4.5 vs 17.8±4.8, P>0.05). The patients treated with Wuziyuye Decoction achieved even more significant improvement than the controls in the percentage of PR%, sperm concentration and TCM syndrome score (P<0.05), but there were no statistically significant differences in the reproductive hormone levels and clinical pregnancy outcomes between the two groups of patients after treatment (P>0.05). And no severe adverse reactions were observed in either group. CONCLUSION Wuziyuye Decoction is safe and effective for the treatment of type-II DM with qi-yin deficiency complicated by asthenospermia by improving the sperm motility and concentration of the patient.
Humans ; Drugs, Chinese Herbal/therapeutic use* ; Male ; Asthenozoospermia/complications* ; Diabetes Mellitus, Type 2/drug therapy* ; Yin Deficiency/complications* ; Adult ; Medicine, Chinese Traditional ; Sperm Motility ; Qi ; Female ; Pregnancy

The purpose of this study was to investigate the effects of ethanol extract of Scutellaria baicalensis Georgi (SGE) on endogenous metabolites in toes of rats with inflammatory pain induced by complete Freund's adjuvant (CFA) based on ¹H NMR metabolomics, which would provide foundation for revealing the effects and mechanisms of SGE in improving inflammatory pain. This animal experiment was approved by the Committee on the Ethics of Animal Experiments of Shanxi University (SXULL2022062). The rats model of inflammatory pain was induced by subcutaneous injection of CFA (0.1 mL), and the effect of low, medium and high doses of SGE (1.5, 3, 6 g·kg^-1) on inflammatory pain were explored. The effects of SGE on relieving inflammatory pain was evaluated by mechanical nociceptive thresholds (MNTs) test. Western blot was used to detect the effects of SGE on protein expression of cyclooxygenase-2 (COX-2), nuclear factor kappa-B (NF-κB) and phospho-NF-κB (p-NF-κB). ¹H NMR metabolomics was used to analyze the regulatory effects of SGE on endogenous metabolites in the toes of rats with inflammatory pain. The results showed that SGE (6 g·kg^-1) could significantly relieve CFA-induced inflammatory pain, and also notably inhibit the protein expression of COX-2, NF-κB and p-NF-κB. SGE could markedly reverse the changes of 8 differential metabolites, such as glycine, glutamine, succinate, phosphorylcholine, etc. The metabolites were involved in eight metabolic pathways, such as glycine, serine and threonine metabolism, alanine, aspartate and glutamate metabolism, glyoxylate and dicarboxylate metabolism, glutathione metabolism, glycerophospholipid metabolism. These results suggest that SGE may relieve inflammatory pain by regulating NF-κB signaling pathway and metabolic abnormality.

Diabetic kidney disease is an important microvascular complication of diabetes and the leading cause of end-stage renal disease. Its pathological characteristics mainly include epithelial mesenchymal transition(EMT) in glomerulus, podocyte apoptosis and autophagy, and damage of glomerular filtration barrier. Transforming growth factor-β(TGF-β)/Smad signaling pathway is specifically regulated by a variety of mechanisms, and is a classic pathway involved in physiological activities such as apoptosis, proliferation and differentiation. At present, many studies have found that TGF-β/Smad signaling pathway plays a key role in the pathogenesis of diabetic kidney disease. Traditional Chinese medicine has significant advantages in the treatment of diabetic kidney disease for its multi-component, multi-target and multi-pathway characteristics, and some traditional Chinese medicine extracts, traditional Chinese medicines and traditional Chinese medicine compound prescription improve the renal injury of diabetic kidney disease by regulating TGF-β/Smad signaling pathway. This study clarified the mechanism of TGF-β/Smad signaling pathway in diabetic kidney disease by expounding the relationship between the key targets of the pathway and diabetic kidney disease, and summarized the research progress of traditional Chinese medicine in the treatment of diabetic kidney disease by interfering with TGF-β/Smad signaling pathway in recent years, to provide reference for drug research and clinical treatment of diabetic kidney disease in the future.
Humans ; Diabetic Nephropathies/genetics* ; Medicine, Chinese Traditional ; Kidney/pathology* ; Transforming Growth Factor beta/metabolism* ; Signal Transduction ; Epithelial-Mesenchymal Transition ; Smad Proteins/metabolism* ; Transforming Growth Factor beta1/metabolism* ; Diabetes Mellitus/genetics*