Recent studies have indicated that the expression of ubiquitin-specific protease 51 (USP51), a novel deubiquitinating enzyme (DUB) that mediates protein degradation as part of the ubiquitin‒proteasome system (UPS), is associated with tumor progression and therapeutic resistance in multiple malignancies. However, the underlying mechanisms and signaling networks involved in USP51-mediated regulation of malignant phenotypes remain largely unknown. The present study provides evidence of USP51's functions as the prominent DUB in chemoresistant triple-negative breast cancer (TNBC) cells. At the molecular level, ectopic expression of USP51 stabilized the 78 kDa Glucose-Regulated Protein (GRP78) protein through deubiquitination, thereby increasing its expression and localization on the cell surface. Furthermore, the upregulation of cell surface GRP78 increased the activity of ATP binding cassette subfamily B member 1 (ABCB1), the main efflux pump of doxorubicin (DOX), ultimately decreasing its accumulation in TNBC cells and promoting the development of drug resistance both in vitro and in vivo. Clinically, we found significant correlations among USP51, GRP78, and ABCB1 expression in TNBC patients with chemoresistance. Elevated USP51, GRP78, and ABCB1 levels were also strongly associated with a poor patient prognosis. Importantly, we revealed an alternative intervention for specific pharmacological targeting of USP51 for TNBC cell chemosensitization. In conclusion, these findings collectively indicate that the USP51/GRP78/ABCB1 network is a key contributor to the malignant progression and chemotherapeutic resistance of TNBC cells, underscoring the pivotal role of USP51 as a novel therapeutic target for cancer management.

ObjectiveBased on serum pharmacochemistry and ultra performance liquid chromatography-quadrupole-time-of-flight mass spectrometry（UPLC-Q-TOF-MS） the transitional components in the serum of rats after intragastric administration of water extract of Alismatis Rhizoma（AR）and salt-processed Alismatis Rhizoma（SAR） were compared. MethodSD rats were randomly divided into blank group, AR group（10 g·kg^-1） and SAR group（10 g·kg^-1）, 3 rats in each group, the administration groups were given AR and SAR aqueous extracts by gavage, respectively, and the blank group was given an equal volume of drinking water by gavage once in the morning and once in the evening, for 3 consecutive days. Sixty minutes after the last administration, blood was collected from the eye orbits, and the serum samples were prepared. The serum samples were prepared on an ACQUITY UPLC BEH C18 column（2.1 mm×50 mm, 1.7 μm） with the mobile phase of acetonitrile（A）-0.1% formic acid aqueous solution（B） in a gradient elution（0-10 min, 10%-50% A; 10-27 min, 50%-95%A; 27-27.1 min, 95%-10% A; 27.1-30 min, 10%A）, the data were collected at a flow rate of 0.3 mL·min^-1 in positive ion mode with a scanning range of m/z 100-1 200. Based on the self-constructed chemical composition library of AR, the total ion flow diagrams and secondary MS fragmentation information of the aqueous extracts of AR and SAR, as well as the administered serum and the blank serum, were compared with each other by UNIFI 1.9.2, so as to deduce the possible blood-migrating constituents and their cleavage patterns in the aqueous extracts, and the response intensity ratios of each chemical component were calculated before and after processing. ResultA total of 20 components, including 5 prototypical components and 15 metabolites, were analyzed and deduced from the serum of rats given aqueous extract of AR. And 14 components, including 5 prototypical components and 9 metabolites, were analyzed and deduced from the serum of rats given aqueous extract of SAR. Of these, 13 components were common to both of them, including 5 prototypical components and 8 metabolites. The 5 prototypical components were 16-oxoalisol A, alisol A 24-acetate, alisol A, alisol B and alisol C. The metabolites were mainly involved in phase Ⅰ metabolism（oxidation） and phase Ⅱ metabolism（glucuronidation）. There was a big change in the intensity of response of the common components before and after salt-processing, and the response intensities of the prototypical components, 16-oxoalisol A, alisol B and alisol C, were elevated, while the type and response intensity of metabolites were generally decreased, and it was hypothesized that the metabolic rate of terpenoids might be slowed down after salt-processing of AR, so that the blood-migrating constituents could participate in the metabolism of the body more in the form of prototypes. ConclusionSalt-processing of AR may promote the absorption of prototypical components into the blood by slowing down the metabolic rate of terpenoids, which can provide support for the research on material basis of AR and SAR.

ObjectiveTo investigate the effect of microemulsion on the distribution of index components in different phases of Zexietang extract based on high performance liquid chromatography（HPLC） and phase separation process. MethodParticle size meter and transmission electron microscope were used to characterize the colloidal particles in blank microemulsion， aqueous extract of Zexietang and microemulsion extract of Zexietang. The phase separation process was established by high-speed centrifugation and dialysis， and based on this process， the aqueous extract and microemulsion extract of Zexietang were separated into the true solution phase， the colloidal phase and the precipitation phase， respectively. The contents of six components， including atractylenolide Ⅲ， atractylenolide Ⅱ， 23-acetyl alisol C， alisol A， alisol B and alisol B 23-acetate， were determined by HPLC with the mobile phase of water（A）-acetonitrile（B） for gradient elution（0-5 min， 40%-43%B； 5-20 min， 43%-45%B； 20-45 min. 45%-60%B； 45-75 min， 60%-80%B）. The solubility of the index components in water and microemulsion was determined by saturation solubility method. ResultThe colloidal particles in the aqueous extract， microemulsion extract and blank microemulsion were all spherical， and the particle size， polydispersity index（PDI） and Zeta potential of the colloidal particles were in the order of aqueous extract >microemulsion extract >blank microemulsion. The results of phase separation showed that the colloidal phase and the true solution phase could be completely separated by dialysis for 2.5 h， and the phase separation process was tested to be stable and feasible. Compared with the aqueous extract of Zexietang， the use of microemulsion as an extraction solvent could increase the contents of atractylenolide Ⅲ， 23-acetyl alisol C， atractylenolide Ⅱ ， alisol A， alisol B and alisol B 23-acetate by 3.75， 6.82， 35.47， 10.66， 35.41， 27.75-fold， and could increase the extraction efficiencies of the latter five constituents by 2.03， 1.15， 1.70， 6.43， 5.53 times. The solubility test showed that the microemulsion could significantly improve the solubility of atractylenolide Ⅱ， alisol A， alisol B and alisol B 23-acetate， but it had less effect on the solubility of atractylenolide Ⅲ and 23-acetyl alisol C. ConclusionMicroemulsion can improve the extraction efficiency and increase the distribution of the index components in the colloidal phase state of Zexietang to different degrees， providing a reference for the feasibility of microemulsion as an extraction solvent for traditional Chinese medicine.

ObjectiveTo evaluate the pharmacological effect of Alismatis Rhizoma （AR） and its processed product on rats with edema of kidney Yin deficiency and explore the mechanism. MethodA total of 42 male SPF SD rats were randomized into normal group （equivalent volume of distilled water）， model group （equivalent volume of distilled water）， positive medicine Liuwei Diguangwan group （1.4 g·kg^-1）， low- and high-dose AR groups （1， 4 g·kg^-1， respectively）， and low- and high-dose salt-processed AR （SAR） groups （1， 4 g·kg^-1， respectively）， with six rats in each group. Adriamycin （tail vein injection） and thyroxine （gavage） were used to induce edema of kidney Yin deficiency in rats except the normal group. The administration lasted 4 weeks for all the groups. After the last administration， histopathological changes of rat kidneys were observed based on hematoxylin-eosin （HE） staining. Serum content of triiodothyronine （T₃）， thyroxine （T₄）， follicle-stimulating hormone （FSH）， and testosterone （T） was determined by radioimmunoassay， and serum content of creatinine （CREA）， urea （UREA），cholesterol （CHOL） and triglyceride （TG） by automatic biochemical analyser. The levels of gonadotropin-releasing hormone （GnRH）， cyclic adenosine monophosphate （cAMP）， and cyclic guanosine monophosphate （cGMP） in plasma were measured by enzyme-linked immunosorbent assay （ELISA）， and the expression of aquaporin（AQP）-1 and AQP-2 and the transcription of mRNA in kidney were measured by immunohistochemistry and real-time fluorescent quantitative polymerase chain reaction （Real-time PCR）， respectively. ResultCompared with normal group， the rats in model group showed decrease in body mass and urine volume （P<0.01）， increase in water consumption （P<0.05）， infiltration of a large number of inflammatory cells and fibrous tissue proliferation in the kidney， rise of the expression and transcript levels of T₃， T₄， cAMP/cGMP， CREA， FSH， AQP-1， and AQP-2 （P<0.01）， the contents of CHOL and TG were significantly increased （P<0.05）， and reduction in the levels of GnRH and T （P<0.01）. Body mass increased in both the low- and high- dose groups of AR and SAR compared with that in model group， with significant differences between the low-dose AR group and the low-dose SAR group （P<0.01）. Moreover， compared with model group， low- and high-dose AR and SAR insignificantly increased the urine volume of rats， reduced the inflammatory cells in kidney tissues， significantly decreased the levels of T₄， cAMP/cGMP， UREA， CREA， FSH， CHOL and TG in serum （P<0.05，P<0.01）， and elevated the level of GnRH （P<0.01）， high-dose AR， low- and high-dose SAR significantly lowered the transcription levels of AQP-1 and AQP-2 mRNA in the kidneys of rats （P<0.01）. ConclusionBoth AR and SAR alleviated the edema of kidney Yin deficiency in rats by down-regulating the expression of AQP-1 and AQP-2 and correcting the hypothalamic-pituitary-gonadal （HPG） axis disorder.

Objective To study the effects of half marathon loading on the T2* mapping assessment of knee joint cartilage. Methods Twenty male amateur marathon runners with more than three years of running age were enrolled. The T1WI, PDWI, 3D?DESS, and T2*mapping were performed on right knee joint before and after the half marathon within 3h and after a period of approximately 1 week. Cartilage was divided into 6 regions: medial and lateral femoral cartilage, medial and lateral tibial cartilage and patella and trochlea cartilage. Femoral cartilage was partitioned into central weight?bearing regions, posterior cartilage nonweight?bearing regions with the posterior boundary of the meniscus as the dividing mark. All cartilage was further divided into deep and superficial layers according to the thickness 1/2, and the ROI was delineated to obtain the T2* value of the corresponding area. One?way repeated measures analysis was performed to test the difference of T2*values pre?and post?marathon. LSD tests were used to estimate the different influences of physiological activities on each articular cartilage area. Results All cartilage areas of the knee joint did not show cartilage injury during the examination. The differences in the global T2*values of the superficial layers of the knee cartilage before and after the half?marathon marathon were statistically significant (t=5.145, P<0.05), but the global T2*value of the deep region were not (t=1.864, P>0.05). After a week, the T2* values of all cartilage areas were not statistically different from those before running (t=1.062, 0.309; P>0.05). Conclusion After a single half marathon, the changes of knee cartilage composition in male amateur marathon runners are reversible. In the absence of positive findings in conventional MRI, T2* mapping can indirectly reflect changes in biochemical composition of the articular cartilage during exercise.

Objective: To study the effects of half marathon loading on the T₂* mapping assessment of knee joint cartilage. Methods: Twenty male amateur marathon runners with more than three years of running age were enrolled. The T₁WI, PDWI, 3D-DESS, and T₂* mapping were performed on right knee joint before and after the half marathon within 3h and after a period of approximately 1 week. Cartilage was divided into 6 regions: medial and lateral femoral cartilage, medial and lateral tibial cartilage and patella and trochlea cartilage. Femoral cartilage was partitioned into central weight-bearing regions, posterior cartilage nonweight-bearing regions with the posterior boundary of the meniscus as the dividing mark. All cartilage was further divided into deep and superficial layers according to the thickness 1/2, and the ROI was delineated to obtain the T₂* value of the corresponding area. One-way repeated measures analysis was performed to test the difference of T₂* values pre- and post-marathon. LSD tests were used to estimate the different influences of physiological activities on each articular cartilage area. Results: All cartilage areas of the knee joint did not show cartilage injury during the examination. The differences in the global T₂* values of the superficial layers of the knee cartilage before and after the half-marathon marathon were statistically significant (t=5.145, P<0.05), but the global T₂* value of the deep region were not (t=1.864, P>0.05). After a week, the T₂* values of all cartilage areas were not statistically different from those before running (t=1.062, 0.309; P>0.05). Conclusion After a single half marathon, the changes of knee cartilage composition in male amateur marathon runners are reversible. In the absence of positive findings in conventional MRI, T₂* mapping can indirectly reflect changes in biochemical composition of the articular cartilage during exercise.

Human epidermal growth factor receptor 2 (HER2) proteins are overexpressed in a high proportion of gastric cancer (GC) cases and affect the maintenance of cancer stem cell (CSC) subpopulations, which are used as targets for the clinical treatment of patients with HER2-positive GC. Despite improvements in survival, numerous HER2-positive patients fail treatment with trastuzumab, highlighting the need for more effective therapies. In this study, we generated a novel type of genetically modified human T cells, expressing a chimeric antigen receptor (CAR), and targeting the GC cell antigen HER2, which harbors the CD137 and CD3ζ moieties. Our findings show that the expanded CAR-T cells, expressing an increased central memory phenotype, were activated by the specific recognition of HER2 antigens in an MHC-independent manner, and effectively killed patient-derived HER2-positive GC cells. In HER2-positive xenograft tumors, CAR-T cells exhibited considerably enhanced tumor inhibition ability, long-term survival, and homing to targets, compared with those of non-transduced T cells. The sphere-forming ability and in vivo tumorigenicity of patient-derived gastric cancer stem-like cells, expressing HER2 and the CD44 protein, were also inhibited. Our results support the future development and clinical application of this adoptive immunotherapy in patients with HER2-positive advanced GC.
Animals ; Humans ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Neoplasms, Experimental ; immunology ; pathology ; therapy ; Receptor, ErbB-2 ; immunology ; Receptors, Antigen, T-Cell ; immunology ; Stomach Neoplasms ; immunology ; pathology ; therapy ; Tumor Cells, Cultured

OBJECTIVE: To compare the effect of rehabilitation of prelingual deaf children who used a cochlear implant (CI) in one ear and a hearing aids in the opposite ear while the hearing level of the opposite ears are different. Hearing ability, language ability and learning ability was included in the content. The aim of this research is to investigate better style of rehabilitation, and to offer the best help to the prelingual deaf children. METHOD: Accord ing to the hearing level of the ear opposite to the one wearing a cochlear implant and whether the opposite ear wear a hearing aid or not, 30 prelingual deaf children were divided into three groups, including cochlear implant with opposite severe hearing loss and hearing aid ear (CI+SHA), cochlear implant with opposite profound hearing loss and hearing aid ear (CI+PHA), cochlear implant only (CI). The effect of rehabilitation was assessed in six different times (3,6,9,12,15 and 18 months after the cochlear implants and hearing aids began to work). RESULT: The longer time the rehabilitation spends, the better the hearing ability,language ability and the learning ability were. The hearing ability of CI+SHA was better than those of CI+PHA (P<0.05) and CI (P<0.05). The language ability and learning ability of CI-SHA was nearly equal to those of the other two groups. CONCLUSION The prelingual deaf children should take much more time on rehabilitation. The effect of rehabilitation for prelingual deaf children who used cochlear implant in one ear and hearing aid in the other depend on the residual hearing level of the other ear. If a prelingual deaf children still has any residual hearing level in the ear opposite to the cochlear implant ear, it is better for him/her to wear a hearing aid in the ear.
Child ; Child, Preschool ; Cochlear Implantation ; Cochlear Implants ; Deafness ; physiopathology ; rehabilitation ; Female ; Hearing Aids ; Humans ; Male ; Persons With Hearing Impairments ; rehabilitation ; Sound Localization ; Speech Perception ; Treatment Outcome

Objective To explore the epidemiological status of abnormal glucose metabolism and its influential factors among middle and aged population with hypertension in Chengdu area. Methods In 2008, after adopting the methods of stratified cluster sampling, the authors investigated 4685 subjects of the middle and aged population between the age of 40-79 in Chengdu urban and rural area by checking blood pressure and oral glucose tolerance test (OGTY). Patients with previously known diabetes mellitus (DM) were only asked to perform fasting glucose and to carry out a questionnaire. Comparison of the prevalence rates of abnormal glucose metabolism in hypertensive and non-hypertensive subjects was carried out. The prevalence rates of isolated impaired glucose tolerance (I-IGT) and isolated postprandial hyperglycemia (IPH) among middle and aged subjects with hypertension were acquired and the influential factors of abnormal glucose metabolism among middle and aged subjects with hypertension were analyzed. Results The prevalence rate of abnormal glucose metabolism in the hypertensive subjects was obviously higher than that in the non-hypertensive subjects; without using OGTT, 72.9% of the pre-diubetic and 54. 4% of the new diagnosed DM patients would remain undiagnosed if fasting plasma glucose detection was used alone. Age, diabetic history of first degree relatives ,overweight or obesity were the risk factors for the development of abnormal glucose metabolism among middle and aged male subjects with hypertension in Chengdu area. Exercise training and high education level were the protective factors. Age, diabetic history of first degree relatives,abdominal obesity and hypertriglyceridemia were the risk factors for the development of abnormal glucose metabolism among middle and aged female subjects with hypertension in Chengdu area. Conclusions More than 50% of middle and aged subjects with hypertension in Chengdu area has accompanying abnormal glucose metabolism. OGTT easily discloses the abnormal status and should be a routine procedure in the diagnosis of pre-diabetes or DM in such population. Appropriate exercise, learning diabetes-related knowledge to take reasonable lifestyle, and intervention of metabolic factors such as overweight or obesity are advised. Abdominal obesity and hypertriglyceridemia play important roles in leading to abnormal glucose metabolism among middle and aged population with hypertension.