OBJECTIVE: To identify the CDYL-interacting proteins in murine testis and investigate the mechanism of CDYL involved in spermatogenesis. METHODS: CDYL-interacting partners in testis were identified using co-immunoprecipitation coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS). Expression pattern of CDYL-interacting protein MYH9 was analyzed through immunohistochemistry (IHC), confocal immunofluorescence (IF) and Western blot (WB) in mouse testicular cells. The effect of the Cdyl conditional knockout (CdylcKO) in spermatogenic cell on Myh9 expression was quantified via RT-qPCR, WB and IF imaging in both spermatids and spermatozoa from cauda epididymides. RESULTS: Direct interaction between MYH9 and CDYL was confirmed in murine testis. During spermiogenesis, MYH9 exhibited co-localization with CDYL at the manchette structure, and binding to F-ACTIN, the component of manchette. In cauda epididymal spermatozoa, MYH9 signal concentrated on acrosomal region and continuously distributed along the tail length. Conditional deletion of Cdyl in spermatogenic cell resulted in the transcriptional downregulation of Myh9. In spermatids, CdylcKO led to reduced but retained MYH9 localization to the disorganized manchette structure. In spermatozoa from CdylcKO mice, abnormalities of MYH9 localization were observed, including attenuation of acrosomal signal and/or partial vanishment/enhancement of tail signal. CONCLUSION In murine spermatids, MYH9 protein is localized to the manchette structure, with its expression and subcellular distribution is affected by CDYL protein. CDYL-MYH9 interaction is essential for the spermiogenesis.
Animals ; Male ; Mice ; Testis/metabolism* ; Myosin Heavy Chains/metabolism* ; Spermatogenesis ; Mice, Knockout

Atrial fibrillation (AF) is the most common arrhythmia in clinical practice. It has a high prevalence and poor prognosis. The application of antiarrhythmic drugs and even surgery cannot completely treat the disease, and there are many sequelae. AF can be classified into the category of "palpitation" in Chinese medicine according to its symptoms. Acupuncture has a significant effect on AF. The authors find that an important mechanism of acupuncture in AF treatment is to regulate the cardiac vagus nerve. Therefore, this article intends to review the distribution and function of vagus nerve in the heart, the application and the regulatroy effect for the treatment of AF.
Atrial Fibrillation/physiopathology* ; Humans ; Acupuncture Therapy ; Vagus Nerve/physiology* ; Animals

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

G protein-coupled receptor (GPR) 40, as one of GPRs family, plays a potential role in regulating glucose and lipid metabolism. To study the effect of GPR40 novel agonist SZZ15-11 on hyperglycemia and hyperlipidemia and its potential mechanism, spontaneous type 2 diabetic KKA^y mice, human hepatocellular carcinoma HepG2 cells and murine mature adipocyte 3T3-L1 cells were used. KKA^y mice were divided into four groups, vehicle group, TAK group, SZZ (50 mg·kg^-1) group and SZZ (100 mg·kg^-1) group, with oral gavage of 0.5% sodium carboxymethylcellulose (CMC), 50 mg·kg^-1 TAK875, 50 and 100 mg·kg^-1 SZZ15-11 respectively for 45 days. Fasting blood glucose, blood triglyceride (TG) and total cholesterol (TC), non-fasting blood glucose were tested. Oral glucose tolerance test and insulin tolerance test were executed. Blood insulin and glucagon were measured via enzyme-linked immunosorbent assay (ELISA). After mice′s execution, liver tissue was harvested to test TG and TC content. Then pathological morphology of liver was observed through hematoxylin-eosin (HE) staining, and the lipid metabolism relative signal pathway was analyzed by Western blot and RT-PCR. The experiments were approved by the Institutional Animal Care and Use Committee of the Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College. At the same time, Akt phosphorylation level in HepG2 cells and adiponectin in 3T3-L1 cells treated with TNFα were measured with Western blot. The results show that SZZ15-11 not only decreased blood glucose and lipid, improved insulin sensitivity, but also increased fasting blood glucagon and promoted insulin secretion after glucose loading in KKA^y mice. Additionally, SZZ15-11 alleviated hepatic steatosis and liver dysfunction in KKA^y mice. In liver tissue, SZZ15-11 increased AMPKα phosphorylation level and cholesterol metabolism relative gene Abcg8 transcription. In HepG2 cells, SZZ15-11 increased Akt phosphorylation level. In adipocyte 3T3-L1, SZZ15-11 recovered the decreased adiponectin expression by TNFα. This study proved that GPR40 agonist SZZ15-11 could be a candidate compound for regulating glucolipid metabolic disorder.

AIM:To explore the expression of RhoC in oral squamous cell carcinoma(OSCC)and its effects on the malignant biological behavior of OSCC cells.METHODS:The UALCAN and K-M plotter databases,alongside tis-sue sample analyses,facilitated understanding RhoC expression in cancer and its links to clinicopathological traits.Two small interfering RNAs(RhoC-siRNA)were constructed according to the RhoC gene sequence.The mRNA and protein ex-pression levels of RhoC in OSCC cells were determined.The protein levels of FAK,p-FAK,MAPK,p-MAPK,matrix me-talloproteinase-2(MMP-2)and MMP-9 were also examined by Western blot.Furthermore,the invasion and migration of OSCC cells were analyzed by Transwell assay and scratch test.Finally,the pulmonary metastasis model of nude mice was established.RESULTS:The results of the databases showed that RhoC was highly expressed in OSCC tissues,which was closely related to pathological stage,pathological grade and lymph node metastasis,but not significantly related to the sur-vival rate of patients.Furthermore,compared with paracancer tissues,the mRNA and protein expression levels of RhoC were increased in OSCC tissues(P<0.01).Silencing of RhoC prominently reduced the migration and invasion of OSCC cells as well as the protein levels of p-FAK,p-MAPK,MMP2 and MMP9(P<0.05).The protein levels of MAPK and FAK were unchanged(P>0.05).The fluorescence intensity of the experimental group was significantly lower than that of the control group,and the results of HE staining showed that the number of lung nodules in the experimental group was sig-nificantly reduced(P<0.05).CONCLUSION:RhoC can effectively influence the migration and invasion of OSCC cells,and its potential mechanism may be related to FAK/MAPK/MMPs signaling pathway.

Interventions for endometriosis(EMs)include surgical excision of lesions and hormonal therapy,which usually have limited efficacy and adverse drug reactions.Traditional Chinese medicine(TCM)has the multi-component and multi-target characteristics,which can help patients achieve good clinical benefits by intervening in different parts of the disease.In this paper,we briefly discuss the modern pharmacology of Sanlang and Curcuma longa,and deeply summarize the possible mechanisms of action of TCM monomer and classical compound extracts and their active ingredients through signal pathways in inflammation,immune system,angiogenesis,hormone regulation,etc.,so as to provide theoretical bases for the clinical use of TCM monomers,drug-to-drug groups and compounds in the treatment of EMs.

Objective: To assess the role of dynamic contrast-enhanced (DCE)-MRI of the extraocular muscles (EOMs) for determining the activity of thyroid-associated ophthalmopathy (TAO) and treatment response to glucocorticoids (GCs). Materials and Methods: We prospectively enrolled 65 patients with TAO (41 active, 82 eyes; 24 inactive, 48 eyes). Twenty-two active patients completed the GC treatment and follow-up assessment, including 15 patients (30 eyes) and 7 patients (14 eyes), defined as responsive and unresponsive, respectively. Model-free (time to peak [TTP], area under the curve [AUC], and Slope max) and model-based (Ktrans , Kep, and Ve) parameters of EOMs in embedded simplified histogram analyses were calculated and compared between groups. Multivariable logistic regression analysis was used to identify the independent predictors. The area under the receiver operating characteristic curve (AUROC) was used to evaluate the diagnostic performance. Results: Active patients exhibited significantly higher TTP at the 10th percentile (-10th), TTP-mean, and TTP at the 90th percentile (-90th); AUC-10th, AUC-mean, AUC-90th, and AUC-max; Ktrans -10th and Ktrans -mean; and Ve-10th, Ve-mean, Ve-90th, and Ve-max than inactive patients (P < 0.05). Responsive patients exhibited significantly lower TTP-min; higher Ktrans -mean and Ktrans -max; and higher Kep-10th, Kep-mean, and Kep-max than unresponsive patients (P < 0.05). TTP-mean and Ve-mean were independent variables for determining disease activity (P = 0.017 and 0.022, respectively). A combination of the two parameters could determine active TAO with moderate performance (AUROC = 0.687). TTP-min and Ktrans -mean were independent predictors of the response to GCs (P = 0.023 and 0.004, respectively), uniting which could determine the response to GCs with decent performance (AUROC = 0.821). Conclusion DCE-MRI-derived model-free and model-based parameters of EOMs can assist in the evaluation of TAO. In particular, TTP-mean and Ve-mean could be useful for determining the activity of TAO, whereas TTP-min and K trans -mean could be promising biomarkers for determining the response to GCs.

Objective: To assess the role of dynamic contrast-enhanced (DCE)-MRI of the extraocular muscles (EOMs) for determining the activity of thyroid-associated ophthalmopathy (TAO) and treatment response to glucocorticoids (GCs). Materials and Methods: We prospectively enrolled 65 patients with TAO (41 active, 82 eyes; 24 inactive, 48 eyes). Twenty-two active patients completed the GC treatment and follow-up assessment, including 15 patients (30 eyes) and 7 patients (14 eyes), defined as responsive and unresponsive, respectively. Model-free (time to peak [TTP], area under the curve [AUC], and Slope max) and model-based (Ktrans , Kep, and Ve) parameters of EOMs in embedded simplified histogram analyses were calculated and compared between groups. Multivariable logistic regression analysis was used to identify the independent predictors. The area under the receiver operating characteristic curve (AUROC) was used to evaluate the diagnostic performance. Results: Active patients exhibited significantly higher TTP at the 10th percentile (-10th), TTP-mean, and TTP at the 90th percentile (-90th); AUC-10th, AUC-mean, AUC-90th, and AUC-max; Ktrans -10th and Ktrans -mean; and Ve-10th, Ve-mean, Ve-90th, and Ve-max than inactive patients (P < 0.05). Responsive patients exhibited significantly lower TTP-min; higher Ktrans -mean and Ktrans -max; and higher Kep-10th, Kep-mean, and Kep-max than unresponsive patients (P < 0.05). TTP-mean and Ve-mean were independent variables for determining disease activity (P = 0.017 and 0.022, respectively). A combination of the two parameters could determine active TAO with moderate performance (AUROC = 0.687). TTP-min and Ktrans -mean were independent predictors of the response to GCs (P = 0.023 and 0.004, respectively), uniting which could determine the response to GCs with decent performance (AUROC = 0.821). Conclusion DCE-MRI-derived model-free and model-based parameters of EOMs can assist in the evaluation of TAO. In particular, TTP-mean and Ve-mean could be useful for determining the activity of TAO, whereas TTP-min and K trans -mean could be promising biomarkers for determining the response to GCs.

Objective: To assess the role of dynamic contrast-enhanced (DCE)-MRI of the extraocular muscles (EOMs) for determining the activity of thyroid-associated ophthalmopathy (TAO) and treatment response to glucocorticoids (GCs). Materials and Methods: We prospectively enrolled 65 patients with TAO (41 active, 82 eyes; 24 inactive, 48 eyes). Twenty-two active patients completed the GC treatment and follow-up assessment, including 15 patients (30 eyes) and 7 patients (14 eyes), defined as responsive and unresponsive, respectively. Model-free (time to peak [TTP], area under the curve [AUC], and Slope max) and model-based (Ktrans , Kep, and Ve) parameters of EOMs in embedded simplified histogram analyses were calculated and compared between groups. Multivariable logistic regression analysis was used to identify the independent predictors. The area under the receiver operating characteristic curve (AUROC) was used to evaluate the diagnostic performance. Results: Active patients exhibited significantly higher TTP at the 10th percentile (-10th), TTP-mean, and TTP at the 90th percentile (-90th); AUC-10th, AUC-mean, AUC-90th, and AUC-max; Ktrans -10th and Ktrans -mean; and Ve-10th, Ve-mean, Ve-90th, and Ve-max than inactive patients (P < 0.05). Responsive patients exhibited significantly lower TTP-min; higher Ktrans -mean and Ktrans -max; and higher Kep-10th, Kep-mean, and Kep-max than unresponsive patients (P < 0.05). TTP-mean and Ve-mean were independent variables for determining disease activity (P = 0.017 and 0.022, respectively). A combination of the two parameters could determine active TAO with moderate performance (AUROC = 0.687). TTP-min and Ktrans -mean were independent predictors of the response to GCs (P = 0.023 and 0.004, respectively), uniting which could determine the response to GCs with decent performance (AUROC = 0.821). Conclusion DCE-MRI-derived model-free and model-based parameters of EOMs can assist in the evaluation of TAO. In particular, TTP-mean and Ve-mean could be useful for determining the activity of TAO, whereas TTP-min and K trans -mean could be promising biomarkers for determining the response to GCs.

Objective: To assess the role of dynamic contrast-enhanced (DCE)-MRI of the extraocular muscles (EOMs) for determining the activity of thyroid-associated ophthalmopathy (TAO) and treatment response to glucocorticoids (GCs). Materials and Methods: We prospectively enrolled 65 patients with TAO (41 active, 82 eyes; 24 inactive, 48 eyes). Twenty-two active patients completed the GC treatment and follow-up assessment, including 15 patients (30 eyes) and 7 patients (14 eyes), defined as responsive and unresponsive, respectively. Model-free (time to peak [TTP], area under the curve [AUC], and Slope max) and model-based (Ktrans , Kep, and Ve) parameters of EOMs in embedded simplified histogram analyses were calculated and compared between groups. Multivariable logistic regression analysis was used to identify the independent predictors. The area under the receiver operating characteristic curve (AUROC) was used to evaluate the diagnostic performance. Results: Active patients exhibited significantly higher TTP at the 10th percentile (-10th), TTP-mean, and TTP at the 90th percentile (-90th); AUC-10th, AUC-mean, AUC-90th, and AUC-max; Ktrans -10th and Ktrans -mean; and Ve-10th, Ve-mean, Ve-90th, and Ve-max than inactive patients (P < 0.05). Responsive patients exhibited significantly lower TTP-min; higher Ktrans -mean and Ktrans -max; and higher Kep-10th, Kep-mean, and Kep-max than unresponsive patients (P < 0.05). TTP-mean and Ve-mean were independent variables for determining disease activity (P = 0.017 and 0.022, respectively). A combination of the two parameters could determine active TAO with moderate performance (AUROC = 0.687). TTP-min and Ktrans -mean were independent predictors of the response to GCs (P = 0.023 and 0.004, respectively), uniting which could determine the response to GCs with decent performance (AUROC = 0.821). Conclusion DCE-MRI-derived model-free and model-based parameters of EOMs can assist in the evaluation of TAO. In particular, TTP-mean and Ve-mean could be useful for determining the activity of TAO, whereas TTP-min and K trans -mean could be promising biomarkers for determining the response to GCs.