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.

Atherosclerosis is a chronic vascular wall disease and the most common pathological change in cardiovas-cular disease.Its pathogenesis is closely related to inflammation,oxidative stress,and lipid deposition.Bilirubin itself has biological activities such as antioxidant and anti-inflammatory effects,and has a protective effect on the cardiovascular system.This article summarizes the mechanism of bilirubin in the development of atherosclerosis and its research pro-gress.

Bioactive compounds derived from herbal medicinal plants modulate various therapeutic targets and signaling pathways associated with cardiovascular diseases (CVDs), the world's primary cause of death. Ginkgo biloba, a well-known traditional Chinese medicine with notable cardiovascular actions, has been used as a cardio- and cerebrovascular therapeutic drug and nutraceutical in Asian countries for centuries. Preclinical studies have shown that ginkgolide B, a bioactive component in Ginkgo biloba, can ameliorate atherosclerosis in cultured vascular cells and disease models. Of clinical relevance, several clinical trials are ongoing or being completed to examine the efficacy and safety of ginkgolide B-related drug preparations in the prevention of cerebrovascular diseases, such as ischemia stroke. Here, we present a comprehensive review of the pharmacological activities, pharmacokinetic characteristics, and mechanisms of action of ginkgolide B in atherosclerosis prevention and therapy. We highlight new molecular targets of ginkgolide B, including nicotinamide adenine dinucleotide phosphate oxidases (NADPH oxidase), lectin-like oxidized LDL receptor-1 (LOX-1), sirtuin 1 (SIRT1), platelet-activating factor (PAF), proprotein convertase subtilisin/kexin type 9 (PCSK9) and others. Finally, we provide an overview and discussion of the therapeutic potential of ginkgolide B and highlight the future perspective of developing ginkgolide B as an effective therapeutic agent for treating atherosclerosis.

Objective To analyze the onset characteristics of type 2 diabetes mellitus (T2DM) with cognitive impairment in Baotou area, and study the improvement effect of GLP-1 receptor agonists. Methods A total of 320 patients with T2DM admitted between September 2021 and September 2022 were selected and divided into the observation group with T2DM and cognitive dysfunction and the negative control group without cognitive dysfunction according to their cognitive function status , Among the 160 cases in each group; Patients with type 2 diabetes and cognitive impairment were randomly divided into a treatment group and a control group, 80 cases in each group; the control group was treated with conventional treatment, and the treatment group was additionally treated with semaglutide; Logistics multiple regression model was used to analyze T2DM The related risk factors of cognitive impairment in patients were assessed by the Mini-Mental State Examination (MMSE) score to evaluate the cognitive function of the patients. Results Multivariate regression model showed that course of disease, age, vitamin D, HbA1c, LDL-C, BMI, Hcy, Lp-PLA2, TNF-α, IL-6 and folic acid levels were also independent risk factors for cognitive impairment in T2DM patients (P<0.05); There was a significant positive correlation between GLP-1 receptor agonists and cognitive function recovery in T2DM patients with cognitive impairment (P<0.05). Conclusion The onset of T2DM with cognitive impairment in Baotou area is often accompanied by a long course of disease, older age, abnormal levels of vitamin D, HbA1c, LDL-C, BMI, Hcy, Lp-PLA2, TNF-α, IL-6 and folic acid, and GLP -1 receptor agonists have a clear role in improving the cognitive function of patients.

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*

The clinical utilization of doxorubicin (Dox) in various malignancies is restrained by its major adverse effect: irreversible cardiomyopathy. Extensive studies have been done to explore the prevention of Dox cardiomyopathy. Currently, ferroptosis has been shown to participate in the incidence and development of Dox cardiomyopathy. Sorting Nexin 3 (SNX3), the retromer-associated cargo binding protein with important physiological functions, was identified as a potent therapeutic target for cardiac hypertrophy in our previous study. However, few study has shown whether SNX3 plays a critical role in Dox-induced cardiomyopathy. In this study, a decreased level of SNX3 in Dox-induced cardiomyopathy was observed. Cardiac-specific Snx3 knockout (Snx3-cKO) significantly alleviated cardiomyopathy by downregulating Dox-induced ferroptosis significantly. SNX3 was further demonstrated to exacerbate Dox-induced cardiomyopathy via induction of ferroptosis in vivo and in vitro, and cardiac-specific Snx3 transgenic (Snx3-cTg) mice were more susceptible to Dox-induced ferroptosis and cardiomyopathy. Mechanistically, SNX3 facilitated the recycling of transferrin 1 receptor (TFRC) via direct interaction, disrupting iron homeostasis, increasing the accumulation of iron, triggering ferroptosis, and eventually exacerbating Dox-induced cardiomyopathy. Overall, these findings established a direct SNX3-TFRC-ferroptosis positive regulatory axis in Dox-induced cardiomyopathy and suggested that targeting SNX3 provided a new effective therapeutic strategy for Dox-induced cardiomyopathy through TFRC-dependent ferroptosis.

Objective: To analyze the clinical and genetic features of patients with mitochondrial pyruvate carrier deficiency (MPYCD). Methods: This was a case series research. The clinical data, genetic characteristics, and glutamine treatment efficacy of 3 patients diagnosed with MPYCD at the Department of Neurology, Beijing Children's Hospital, Capital Medical University and Department of Pediatrics, Guizhou Provincial People's Hospital, from August 2019 to June 2023 were retrospectively collected. A literature search with "MPC1 gene" "MPC2 gene and" "mitochondrial pyruvate carrier deficiency" as keywords was conducted at the Wanfang Data Knowledge Service Platform, China National Knowledge Infrastructure (CNKI) and PubMed (up to June 2023). Clinical and genetic characteristics of patients with MPYCD were summarized. Results: Case 1 was a 3 years and 11 months old boy, while case 2 was a 4 years and 10 months old boy and case 3 was an 8 years and 9 months old girl. Case 2 and case 3 were siblings from one consanguineous family. All 3 patients presented with general developmental delay, growth failure and elevated serum lactate. Cranial magnetic resonance imaging (MRI) showed subtle bilateral symmetrical T2 signal hyperintensity in basal ganglia and thalamus in case 1, but normal in case 2 and 3. Trio-WES revealed case 1 harboring compound heterozygous missense variants c.208G>A (p.Ala70Thr) and c.290G>A (p.Arg97Gln) in MPC1 gene, while case 2 and 3 revealed a homozygous variant c.290G>A (p.Arg97Gln) in the same gene. All 3 cases were diagnosecl as MPYCD. Clinical symptoms including motor ability, cognition and activity endurance were improved in these 3 patients after taking glutamine for 2 years. A total of 5 articles published in English were reviewed, and no Chinese literature was found. Including these 3 cases, 15 cases were enrolled for analysis. Eleven patients carried MPC1 gene variants and 4 cases carried MPC2 gene variants. Except for 3 cases died during prenatal period, 9 of 12 enrolled born cases were onset before 6 months old. The most common clinical symptoms were mental and motor general developmental delay, microcephaly, growth failure and hypotonia. All patients had elevated blood lactate and pyruvate, but the ratio of lactate/pyruvate was normal. Seven patients performed cranial MRI, 3 exhibited non-specific changes, 2 showed bilateral symmetrical T2 signal hyperintensity in basal ganglia and thalamus, and 3 were normal. A total of 5 MPC1 gene missense variants and 2 MPC2 gene variants were identified in 15 cases. Conclusions: Onset age of patients with MPYCD is usually within 6 months. The main clinical characteristics are developmental delay, microcephaly and growth failure, accompanied by increased serum lactate and pyruvate. Glutamine supplement could lead to clinical improvements.
Child ; Female ; Humans ; Male ; Glutamine ; Lactates ; Microcephaly ; Monocarboxylic Acid Transporters ; Pyruvates ; Retrospective Studies ; Child, Preschool