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.

Aim To construct a diabetic atherosclerosis mouse model and study the pathological characteristics of diabetic atherosclerosis.Methods Fifty 8-week-old male LDLR-/-mice were fed with standard diet for 2 weeks and then changed to high-fat diet,they were randomly divided into two groups.The diabetic atherosclerosis group was given intraperitoneal injection of low dose streptozotocin(STZ)for 5 days continuouly to establish the model,and the atheroscle-rosis group was given citrate buffer injection at the same time.The body mass,blood glucose and blood lipids of the mice in the two groups were detected for many times.At the age of 23 weeks,the mice were euthanized after glucose tolerance test.HE staining and oil red O staining were used to detect the gross and aortic root atherosclerosis,immunohistochemical staining was used to detect CD4,α-smooth muscle actin(α-SMA),EGF-like module-containing mucin-like hormone re-ceptor-like 1(EMR1),monocyte chemotactic protein-1(MCP-1),NOD-like receptor protein 3(NLRP3),vascular cell adhesion molecule-1(VCAM-1),matrix metalloproteinase-2(MMP-2)and tissue inhibitor of metalloproteinase-1(TIMP-1),Western blot was used to detect α-SMA,CD4,tumor necrosis factor-α(TNF-α),NLPR3,intercellular adhesion molecule-1(ICAM-1),and type Ⅰ and Ⅲ collagen.Results Compared with the atherosclerosis group,the body mass decreased,the levels of total cholesterol(TC),triglyceride(TG),low density lipoprotein cholesterol(LDLC)increased,and the levels of high density lipoprotein cholesterol(HDLC)decreased(P＜0.05)in the diabetic atherosclerosis group.Compared with the atherosclerosis group,the distribution of atherosclerotic plaques was diffuse and the area was increased in the diabetic atherosclerosis group,and the contents of lipids,T cells,macrophages,smooth muscle cells,type Ⅰ and Ⅲ colla-gen were increased(P＜0.05);the protein levels of TNF-α,MCP-1,MMP-2,NLRP3,ICAM-1 and VCAM-1 in vascular tissues were increased,while the content of TIMP-1 were decreased and MMP2/TIMP-1 were increased(P＜0.05).Conclusions LDLR-mouse model of diabetic atherosclerosis can be successfully established by STZ induction combined with high-fat diet,which can reflect the plaque composition and inflammatory characteristics of diabetes promoting atheroscle-rosis.It can be used as a relatively ideal pathological model for the study of diabetic macroangiopathy.

Background::Breast cancer is ranked among the most prevalent malignancies in the Chinese female population. However, comprehensive reports detailing the latest epidemiological data and attributable disease burden have not been extensively documented.Methods::In 2018, high-quality cancer surveillance data were recorded in 700 population-based cancer registries in China. We extracted data on female breast cancers (International Classification of Diseases, Tenth Revision [ICD-10]: C50) and estimated the incidence and mortality in 2022 according to the baseline data and corresponding trends from 2010 to 2018. Pathological types were classified according to the ICD for Oncology, 3rd Edition codes. Disability-adjusted life years (DALYs) were calculated as the sum of the years of life lost (YLLs) and years lived with disability (YLDs).Results::In 2022, approximately 357,200 new female breast cancer cases and 75,000 deaths occurred in China, accounting for 15.59% and 7.94% of total new cancer cases and deaths, respectively. The age-standardized incidence rate (ASIR) was 33.04 per 100,000. When analyzed by pathological type, the ASIRs for papillary neoplasms, invasive breast carcinoma, rare and salivary gland-type tumors, and other types were 1.13, 29.79, 0.24, and 1.88 per 100,000, respectively. The age-standardized mortality rate (ASMR) was 6.10 per 100,000. A total of 2,628,000 DALYs were found to be attributable to female breast cancer in China, comprising 2,278,300 YLLs and 349,700 YLDs. The ASIR, ASMR, and age-standardized rate (ASR) for DALYs in urban areas were consistently higher than those in rural areas. We observed a four-fold increase in the ASIR and ASR for DALYs and an eight-fold increase in the ASMR among females over 55 years compared with those aged under 55 years.Conclusion::These data provide invaluable insights into the latest epidemiology of female breast cancer in China and highlight the urgency for disease prevention and control strategy formulation.

ObjectiveTo observe the effect of Banxia Xiexintang containing intestinal absorption solution （BXCIAS） on migration and invasion of polymorphonuclear myeloid-derived suppressor cells （PMN-MDSCs） in gastric cancer microenvironment. MethodThe complex solution （containing 0.63 g·mL^-1 crude drug） was prepared. Gastric cancer cells were subjected to non-contact co-culture with PMN-MDSCs in Transwell chamber to create gastric cancer microenvironment. Cell counting kit-8 （CCK-8） assay was used to screen the optimal intervention concentration and time of BXCIAS on PMN-MDSCs for subsequent experiment. The blank group， model group， FAK inhibitor group， and BXCIAS groups （26%， 18%， and 10%） were designed. Scratch assay and Transwell assay were employed to detect the migration and invasion ability of PMN-MDSCs， and enzyme-linked immunosorbent assay （ELISA） to measure the expression of vascular endothelial cell growth factor （VEGF） and matrix metalloproteinase-9 （MMP-9） in tumor microenvironment. The expression levels of PMN-MDSCs pathway-related proteins FAK， phosphorylated （p）-FAK， protein tyrosine kinase （Src）， and p-Src were detected by Western blot. ResultThe inhibition rates of PMN-MDSCs by 5%， 50%， 75%， and 100% BXCIAS at 48 h were higher than those at 24 h （P<0.05， P<0.01）. The inhibition rate of PMN-MDSCs by 50% BXCIAS at 72 h was lower than that at 48 h （P<0.01）， and the inhibition rates by 5% and 100% BXCIAS at 72 h were higher than those at 48 h （P<0.05， P<0.01）. There was no significant difference in the inhibition rate by other concentration levels at 48 h. The half-maximal inhibitory concentration （IC₅₀） at 48 h was 18.09%， indicating that 18% BXCIAS and 48 h were the optimal concentration and time， respectively. The migration distance of PMN-MDSCs was large （P<0.01）， and the number of migrating and invading cells increased （P<0.01） in the mode group compared with those in the blank group. Compared with model group， FAK inhibitor and BXCIAS at different concentration decreased the migration distance of PMN-MDSCs （P<0.01）， and the number of migrating and invading cells （P<0.01）， especially the 26% BXCIAS （P<0.01）. The expression of PMN-MDSCs pathway-related proteins FAK， p-FAK， Src and p-Src （P<0.01） and the expression of VEGF and MMP-9 （P<0.01） were higher in the model group than in the blank group. Compared with model group， FAK inhibitor and BXCIAS （26%， 18%， 10%） decreased the expression of FAK， p-FAK， and Src （P<0.01）， and FAK inhibitor and 18% BXCIAS reduced the expression of p-Src （P<0.01）， and the expression of VEGF and MMP-9 （P<0.01）. ConclusionBXCIAS can inhibit the migration and invasion of PMN-MDSCs by down-regulating the expression of FAK， p-FAK， Src， and p-Src proteins in the FAK signaling pathway of PMN-MDSCs in gastric cancer microenvironment.

ObjectiveTo observe the effect of Banxia Xiexintang （BXT）-containing intestinal absorption solution on the apoptosis of polymorphonuclear myeloid-derived suppressor cells （PMN-MDSCs） in gastric cancer microenvironment. MethodBXT-containing intestinal absorption solution was prepared， and gastric cancer cells and PMN-MDSCs were non-contact co-cultured in Transwell chamber to establish gastric cancer microenvironment. Cell counting kit-8 （CCK-8） assay was used to screen the optimal intervention concentration and time of 0-100% BXT-containing intestinal absorption solution prepared by 0.63 g·mL^-1 reconstitution solution. Cells were classified into blank group， model group， oxaliplatin group （10 mg·L^-1）， and BXT （26%， 18%， 10% BXT-containing intestinal absorption solution） group， and the apoptosis of PMN-MDSCs was detected by flow cytometry. The expression of apoptosis-related B-cell lymphoma 2 （Bcl-2）， Bcl-2-associated X protein （Bax）， and cysteine-aspartic acid protease-3 （Caspase-3） in PMN-MDSCs was detected by Western blot. ResultAfter treatment for 24 h and 48 h， the PMN-MDSCs-inhibiting rate was increased by 5%， 50%， 75%， and 100% BXT-containing intestinal absorption solution compared with that in the blank group （P<0.05， P<0.01）. At 72 h， the PMN-MDSCs-inhibiting rate by 50% BXT-containing intestinal absorption solution was lower than that at 48 h （P<0.01）， and the PMN-MDSCs-inhibiting rate by 5%， 75%， and 100% BXT-containing intestinal absorption solution showed no significant difference from that at 48 h. Moreover， the half-maximal inhibitory concentration （IC₅₀） at 48 h was 18.40%. Thus， 18% BXT-containing intestinal absorption solution and 48 h were the optimal intervention concentration and time. The survival rate of PMN-MDSCs in model group was higher than that in the blank group （P<0.05）， and the apoptosis rate was lower than that in the blank group （P<0.05）. Compared with model group， BXT containing intestinal absorption solution lowered the survival rate and raised apoptosis rate of PMN-MDSCs （P<0.05）， particularly the 26% BXT-containing intestinal absorption solution （P<0.05）. The expression of Bax and Caspase-3 in PMN-MDSCs was lower in the model group than in the blank group （P<0.05）， and the expression of Bcl-2 was higher in the model group than in the blank group （P<0.05）. The expression of Caspase-3 in PMN-MDSCs increased （P<0.05） and the expression of Bcl-2 decreased （P<0.05） in oxaliplatin group and BXT group compared with those in the model group. The expression of Bax rose in oxaliplatin group and BXT group （10% BXT-containing intestinal absorption solution） （P<0.05）. ConclusionBXT can induce the apoptosis of PMN-MDSCs by regulating the expression of apoptosis-related proteins Bax， Caspase-3， and Bcl-2 in gastric cancer microenvironment.

Gastric cancer （GC） is one of the common malignant tumors， and the incidence and mortality of GC in China rank first in the world. At present， the pathogenesis of GC has not been fully clarified. Although surgery， radiotherapy， chemotherapy， targeted therapy， and immunotherapy have achieved good results in the treatment of GC， there are still many complications， decreased sensitivity， and severe side effects. Banxia Xiexintang， derived from Treatise on Cold Damage and Miscellaneous Diseases（《伤寒杂病论》）， has been clinically used for more than 2000 years with the effects of combining cold and warm drugs， dissipating mass， and relieving stuffiness， and is a classic prescription for treating digestive tract diseases in later generations. Through clinical observation and experimental research， it is found that Banxia Xiexintang and its single drugs have good effect in preventing and treating GC. Chinese medicine has multi-component and multi-target characteristics and can treat GC through various mechanisms. Therefore， it is necessary to carry out systematic and in-depth research from the aspects of molecular biology and network pharmacology， and comprehensively reveal the mechanism of Banxia Xiexintang in preventing and treating GC. At present， the mechanism of Banxia Xiexintang in treating GC mainly focuses on inducing apoptosis of GC cells， inhibiting proliferation， migration， and invasion of GC cells， protecting peritoneal mesothelial cells， inhibiting peritoneal metastasis of GC cells， regulating GC microenvironment， and inhibiting the malignant transformation of bone marrow mesenchymal stem cells （BMSCs）. This research group is committed to the prevention and treatment of GC with Banxia Xiexintang， aiming to comprehensively reveal the mechanism of action and the pharmacodynamic material basis of Banxia Xiexintang in the prevention and treatment of GC， and provide an important scientific basis for further clinical application of Banxia Xiexintang. After searching CNKI， PubMed， Wanfang Data， VIP， and other databases， this paper summarized Banxia Xiexintang in the treatment of GC from the aspects of prescription basis， material basis， network pharmacology， clinical and experimental studies， etc.， so as to provide references for further research on pharmacological effect of Banxia Xiexintang and its application in the clinical treatment of GC.

BACKGROUND: Three-dimensional shear wave elastography (3D-SWE) is a promising method in distinguishing benign and malignant thyroid nodules. By combining with conventional method, it may further improve the diagnostic value. The study aimed to assess the diagnostic value of American College of Radiology (ACR) thyroid imaging reporting and data system (TI-RADS) combined with 3D-SWE in ACR TI-RADS 4 and 5 thyroid nodules. METHODS: All nodules were examined by conventional ultrasonography, ACR TI-RADS classification, and 3D-SWE examination. Conventional ultrasonography was used to observe the location, size, shape, margin, echogenicity, taller-than-wide sign, microcalcification, and blood flow of thyroid nodules, and then ACR TI-RADS classification was performed. The Young's modulus values (3D-C-Emax, 3D-C-Emean, and elastography standard deviation [3D-C-Esd]) were measured on the reconstructed coronal plane images. According to the receiver operating characteristic (ROC) curve, the best diagnostic efficiency among 3D-C-Emax, 3D-C-Emean, and 3D-C-Esd was selected and the cut-off threshold was calculated. According to the surgical pathology, they were divided into benign group and malignant group. And appropriate statistical methods such as t -test and Mann-Whitney U test were used to compare the difference between the two groups. On this basis, 3D-SWE combined with conventional ACR TI-RADS was reclassified as combined ACR TI-RADS to determine benign or malignant thyroid nodules. RESULTS: Of the 112 thyroid nodules, 62 were malignant and 50 were benign. The optimal cut-off value of three-dimensional maximum Young's modulus in coronal plane (3D-C-Emax) was 51.5 kPa and the area under the curve (AUC) was 0.798. The AUC, sensitivity, specificity, and accuracy of conventional ACR TI-RADS were 0.828, 83.9%, 66.0%, and 75.9%, respectively. The AUC, sensitivity, specificity, and accuracy of combined ACR TI-RADS were 0.845, 90.3%, 66.0%, and 79.5%, respectively. The difference between the two AUC values was statistically significant. CONCLUSIONS Combined ACR TI-RADS has higher diagnostic efficiency than conventional ACR TI-RADS. The sensitivity and accuracy of combined ACR TI-RADS showed significant improvements. It can be used as an effective method in the diagnosis of thyroid nodules.
Humans ; Thyroid Nodule/pathology* ; Elasticity Imaging Techniques/methods* ; Retrospective Studies ; Ultrasonography/methods*

Objective:To analyse the changes in color Doppler and contrast-enhanced ultrasound (CEUS) blood flow parameters in patients with septic acute kidney injury (AKI) from the perspective of macroscopic circulation and microscopic circulation perfusion, in order to explore the value of clinical application of ultrasound in this disease.Methods:A total of 53 ICU-admitted patients diagnosed with septic AKI at the Second Affiliated Hospital of Soochow University from January 2021 to May 2022 were selected.Patients with septic AKI were classified into stages 1-3 according to the 2012 Kidney Disease: Improving Global Outcomes (KDIGO) AKI diagnostic criteria, with stage 1 being the mild group(17 cases), stages 2 and 3 being the severe group(21 cases), and septic patients without AKI in the same period being the control group(15 cases). The ultrasound parameters such as the relative blood flow(RBF) and time-averaged velocity(TAV) of the renal artery as well as the cardiac output (CO) and cardiac index (CI) in the macroscopic circulation were measured, and the time-intensity curve was analysed by the CEUS analysis software to calculate the microscopic parameters such as time to peak(TTP), rise time(RT), fall half time(FHT) and mean transit time(MTT), and the cardiac output and cardiac index were also measured. The differences in ultrasound Doppler and CEUS parameters among the various groups were compared. The diagnostic effectiveness of each parameter for severe AKI was assessed using ROC curve analysis.Results:①In macrocirculation, the renal blood flow (RBF) and time-averaged velocity (TAV) gradually decreased ( P=0.004, P<0.001) as the disease progressed in AKI patients. But the difference of CO and CI among the three groups were not statistically significant in each group ( P=0.17, 0.12). ②In microcirculation, the renal interlobar artery Doppler parameters pulsatility index (PI), resistance index (RI), and systolic/diastolic flow ratio (S/D) gradually increase in patients with septic AKI ( P<0.05) and the CEUS parameters TTP, RT, FHT and MTT were prolonged ( P<0.001, P=0.003, P=0.004, P=0.009). ③The combined diagnosis of RI and TTP was more beneficial in diagnosing septic AKI in critically ill patients [AUC=0.93(0.85-1.00)]. Conclusions:Color Doppler ultrasound combined with CEUS can detect reduced macroscopic and microscopic circulation in patients with septic AKI, especially in those with severe AKI, and this is independent of changes in CO or CI.

Pathological cardiac hypertrophy serves as a significant foundation for cardiac dysfunction and heart failure. Recently, growing evidence has revealed that microRNAs (miRNAs) play multiple roles in biological processes and participate in cardiovascular diseases. In the present research, we investigate the impact of miRNA-34c-5p on cardiac hypertrophy and the mechanism involved. The expression of miR-34c-5p was proved to be elevated in heart tissues from isoprenaline (ISO)-infused mice. ISO also promoted miR-34c-5p level in primary cultures of neonatal rat cardiomyocytes (NRCMs). Transfection with miR-34c-5p mimic enhanced cell surface area and expression levels of foetal-type genes atrial natriuretic factor (Anf) and β-myosin heavy chain (β-Mhc) in NRCMs. In contrast, treatment with miR-34c-5p inhibitor attenuated ISO-induced hypertrophic responses. Enforced expression of miR-34c-5p by tail intravenous injection of its agomir led to cardiac dysfunction and hypertrophy in mice, whereas inhibiting miR-34c-5p by specific antagomir could protect the animals against ISO-triggered hypertrophic abnormalities. Mechanistically, miR-34c-5p suppressed autophagic flux in cardiomyocytes, which contributed to the development of hypertrophy. Furthermore, the autophagy-related gene 4B (ATG4B) was identified as a direct target of miR-34c-5p, and miR-34c-5p was certified to interact with 3' untranslated region of Atg4b mRNA by dual-luciferase reporter assay. miR-34c-5p reduced the expression of ATG4B, thereby resulting in decreased autophagy activity and induction of hypertrophy. Inhibition of miR-34c-5p abolished the detrimental effects of ISO by restoring ATG4B and increasing autophagy. In conclusion, our findings illuminate that miR-34c-5p participates in ISO-induced cardiac hypertrophy, at least partly through suppressing ATG4B and autophagy. It suggests that regulation of miR-34c-5p may offer a new way for handling hypertrophy-related cardiac dysfunction.

The bromodomain and extraterminal (BET) family member BRD4 is pivotal in the pathogenesis of cardiac hypertrophy. BRD4 induces hypertrophic gene expression by binding to the acetylated chromatin, facilitating the phosphorylation of RNA polymerases II (Pol II) and leading to transcription elongation. The present study identified a novel post-translational modification of BRD4: poly(ADP-ribosyl)ation (PARylation), that was mediated by poly(ADP-ribose)polymerase-1 (PARP1) in cardiac hypertrophy. BRD4 silencing or BET inhibitors JQ1 and MS417 prevented cardiac hypertrophic responses induced by isoproterenol (ISO), whereas overexpression of BRD4 promoted cardiac hypertrophy, confirming the critical role of BRD4 in pathological cardiac hypertrophy. PARP1 was activated in ISO-induced cardiac hypertrophy and facilitated the development of cardiac hypertrophy. BRD4 was involved in the prohypertrophic effect of PARP1, as implied by the observations that BRD4 inhibition or silencing reversed PARP1-induced hypertrophic responses, and that BRD4 overexpression suppressed the anti-hypertrophic effect of PARP1 inhibitors. Interactions of BRD4 and PARP1 were observed by co-immunoprecipitation and immunofluorescence. PARylation of BRD4 induced by PARP1 was investigated by PARylation assays. In response to hypertrophic stimuli like ISO, PARylation level of BRD4 was elevated, along with enhanced interactions between BRD4 and PARP1. By investigating the PARylation of truncation mutants of BRD4, the C-terminal domain (CTD) was identified as the PARylation modification sites of BRD4. PARylation of BRD4 facilitated its binding to the transcription start sites (TSS) of hypertrophic genes, resulting in enhanced phosphorylation of RNA Pol II and transcription activation of hypertrophic genes. The present findings suggest that strategies targeting inhibition of PARP1-BRD4 might have therapeutic potential for pathological cardiac hypertrophy.