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.

Turning to critical illness is a common stage of various diseases and injuries before death. Patients usually have complex health conditions, while the treatment process involves a wide range of content, along with high requirements for doctor′s professionalism and multi-specialty teamwork, as well as a great demand for time-sensitive treatments. However, this is not matched with critical care professionals and the current state of medical care in China. Telemedicine, which shortens the distance of medical professionals and the gap of disease diagnosis and treatments in various regions through electronic information, can effectively solve the current problem. Therefore, there is an urgent need to develop a standardized, high-quality visualization telemedicine round system .Therefore, experts have been organized to search domestic and foreign literature on telemedicine round for critically ill patients and to form this consensus based on clinical experiences so as to further improve the level of critical care treatments in regions.

Objective:To explore the mechanism of Amomi Fructus in ameliorating ethanol-induced gastric ulcer (GU) in mice using metabolomics, network pharmacology and molecular docking techniques.Methods:The mice were divided into the blank group, model group, aqueous extract of Amomi Fructus group, volatile oil of Amomi Fructus group, combined aqueous extract and volatile oil of Amomi Fructus group and omeprazole group according to the random number table method, with 10 mice in each group. The blank and model groups were gavaged with sodium carboxymethyl cellulose, the Amomi Fructusaqueous extract group was gavaged with 0.152 5 g/kg of Amomi Fructus aqueous extract, the Amomi Fructus volatile oil group was gavaged with 26 μl/kg of Amomi Fructus volatile oil, the Amomi Fructus aqueous extract and volatile oil combined group was gavaged with 0.152 5 g/kg+26 μl/kg of Amomi Fructus aqueous extract and volatile oil synergistic solution, and the omeprazole group was gavaged with 5.2 mg/kg of omeprazole, 1 time/day, which was administered continuously for 7 d. The gastric ulcer model was established by using ethanol 2 h after the last administration, and the pathological changes of gastric histology were observed by using HE staining; the main differential metabolites were detected by UPLC-Q-TOF-MS/MS non-targeted metabolomics technique, and the metabolic pathway enrichment analysis was carried out; the potential targets and key pathways of the anti-GU action of Amomi Fructus were predicted by network pharmacology; the "metabolite-response-enzyme-gene" network was established by combining the serum metabolomics and network pharmacology; and the key targets were verified by molecular docking technology.Results:HE staining showed that the gastric mucosa of mice in the model group was severely damaged, with cellular tissue damage and inflammatory cell infiltration, whereas the drug administration group showed some protective effects; the results of non-targeted metabolomics showed that 2 metabolites were up-regulated and 17 metabolites were down-regulated in sera of mice in the co-administration group of aqueous extract and volatile oil of Amomi Fructus compared with the control group, and the 19 metabolites were strongly correlated and well clustered, involving nicotinic acid and nicotinamide metabolism, citric acid cycle, glyoxylate and dicarboxylic acid metabolism, phenylalanine metabolism, alanine, aspartate and glutamate metabolism and other metabolic pathways; the results of network pharmacology showed that Amomi Fructus improved GU by affecting target proteins, such as STAT3, AKT1, SRC, and TLR4, which were closely linked to the signaling pathways of cancer pathway, human cytomegalovirus infection, and lipids and atherosclerosis; the joint analysis of network pharmacology and the combined analysis of network pharmacology and metabolomics identified the glycerophospholipid metabolic pathway as the main metabolic pathway in which Amomi Fructus may exert gastroprotective effects; the molecular docking results showed that the main active component of quercetin had a better binding ability to the key targets.Conclusion:Amomi Fructus exerts a protective effect on ethanol induced GU model by regulating the glycerophospholipid metabolism pathway, providing theoretical basis for further research on Amomi Fructus.

Turning to critical illness is a common stage of various diseases and injuries before death. Patients usually have complex health conditions, while the treatment process involves a wide range of content, along with high requirements for doctor′s professionalism and multi-specialty teamwork, as well as a great demand for time-sensitive treatments. However, this is not matched with critical care professionals and the current state of medical care in China. Telemedicine, which shortens the distance of medical professionals and the gap of disease diagnosis and treatments in various regions through electronic information, can effectively solve the current problem. Therefore, there is an urgent need to develop a standardized, high-quality visualization telemedicine round system .Therefore, experts have been organized to search domestic and foreign literature on telemedicine round for critically ill patients and to form this consensus based on clinical experiences so as to further improve the level of critical care treatments in regions.

Objective To analyze the influence of different processing methods,including frying,ginger frying,and salt frying,on the volatile components of A.fructus.Methods The volatile components in different processed products of A.fructus were detected and analyzed by gas chromatography-mass spectrometry(GC-MS)based on multivariate statistical analysis.After OPLS-DA analysis,the different components were screened under the conditions of VIP＞1.5 and P＜0.05 and were qualitatively searched using the NIST 11 spectral library.Results A total of 49 different components were identified,with 14 components only changing in the seed mass and 22 components changing in the peel.The content of camphor could be significantly reduced in the seed mass after A.fructus was processed and the content of bornyl acetate significantly increased in the peel of frying A.fructus.Salt frying had a great influence on the alkanes in A.fructus,and ginger processing did not only increase the volatile components in ginger,which reflected the complexity of the processing mechanism.Conclusion At present,the specific processing mechanism is not clear,but the experimental results provide theoretical data for the "detoxification and efficiency enhancement" effect of A.fructus processing,reflecting the scientific nature of the processing,enriching the processing theory of A.fructus,and providing a reference for further in-depth research on the activity of different processed products of A.fructus.

Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease with cellular and molecular mechanisms yet to be fully described. Mutations in a number of genes including SOD1 and FUS are associated with familial ALS. Here we report the generation of induced pluripotent stem cells (iPSCs) from fibroblasts of familial ALS patients bearing SOD1 and FUS mutations, respectively. We further generated gene corrected ALS iPSCs using CRISPR/Cas9 system. Genome-wide RNA sequencing (RNA-seq) analysis of motor neurons derived from SOD1 and corrected iPSCs revealed 899 aberrant transcripts. Our work may shed light on discovery of early biomarkers and pathways dysregulated in ALS, as well as provide a basis for novel therapeutic strategies to treat ALS.
Amyotrophic Lateral Sclerosis ; genetics ; metabolism ; therapy ; Cell Line ; Clustered Regularly Interspaced Short Palindromic Repeats ; Genetic Therapy ; Genome-Wide Association Study ; Humans ; Induced Pluripotent Stem Cells ; metabolism ; Mutation, Missense ; RNA-Binding Protein FUS ; genetics ; metabolism ; Superoxide Dismutase-1 ; genetics ; metabolism

Objective To investigate the efficacy and safety of tirofiban for emergency interventional therapy in patients with acute ST segment elevation myocardial infarction.Methods The 96 acute ST segment elevation myocardial infarction patients having accepted emergency percutaneous coronary intervention (PCI) were divided into treatment group and control group according to the treatment method with 48 cases each.The treatment group was given conventional standard treatment combined with tirofiban treatment [tirofiban intracoronary injection 10 μ g/kg and then intravenous 0.15 μ g/(kg· min) for 24-48 h].The control group was given conventional standard treatment only.The postoperative 60 min electrocardiogram ST segment recovery,the coronary blood flow TIMI grade,the major adverse cardiac events (angina,myocardial infarction,heart failure,death) and postoperative bleeding in 4 weeks were compared between the two groups.Results The patients having postoperative 60 min electrocardiogram ST segment recovery in treatment group was 45 cases (93.8％,45/48),in control group was 35 cases (72.9％,35/48),and there was statistical difference (P ＜ 0.05).The incidence rate of infarction vascular TIMI grade ≥ 3 grade flow in treatment group was 95.8％ (46/48),in control group was 75.0％ (36/48),and there was statistical difference (P ＜ 0.05).The incidence rate of the major adverse cardiac events 4 weeks in treatment group was significantly lower than that in control group,and there was statistical difference (P ＜ 0.05).There was no statistical difference in the incidence rate of bleeding between the two groups (P ＞ 0.05).Conclusion In patients with acute ST segment elevation myocardial infarction,the emergency interventional therapy with tirofiban is efficacy and safety.

Objective To investigate the effects of p-cresol on human umbilical vein endothelial cells.Methods The effects of p-cresol on endothelial cell growth,cell cycle,cell morphological change and p21 protein were detected by the CCK-8 assay,flow cytometry assay,inverted microscope and Western blotting.Results P-cresol could inhibit the growth of human umbilical vein endothelial cells in dose-and time-dependent manners (all P ＜ 0.05).The human umbilical vein endothelial cells treated with p-cresol became elongated processes,cloudy cytoplasm,and irregular shapes.The p-cresol stopped human umbilical vein endothelial cells at cell cycle G1 and had no effect on cell apoptosis.The p-cresol could increase protein expression of p21 in a dose dependent manner (P ＜ 0.05).Conclusion P-cresol can increase protein expression of p21,induce cell cycle arrest at G1 stage and inhibit the proliferation of human umbilical vein endothelial cells.

OBJECTIVETo observe the ability of triple helix-forming oligonucleotides (TFOs) modified with manganese porphyrin to combine with and cleave HBV DNA fractions.

METHODSTFO were modified with manganese porphyrin and acridines, and then reacted with the (32)P labeled HBV DNA fragments at 37 degrees C in vitro (pH 7.4). Electrophoretic mobility shift assays and DNase I footprinting tests were used to show the affinity and specificity of TFO to bind to target sequences. The ability of TFO to cleave HBV DNA fragments was tested by cleavage experiments.

RESULTSTFO modified with manganese porphyrin and acridine could bind to the target sequence in a sequence-dependent manner, with a Kd value of 3.5 x 10(-7) mol/L and a relative affinity of 0.008. In the presence of potassium monopersulfate (KHSO(5)), TFO modified with manganese porphyrin and acridine could cleave the target sequence where the triplex DNA was formed.

CONCLUSIONIn the presence of KHSO(5), TFO modified with manganese porphyrin and acridine could bind and cleave the target HBV-DNA in a sequence-dependent manner.

DNA ; drug effects ; pharmacology ; DNA, Viral ; chemistry ; drug effects ; Hepatitis B virus ; genetics ; Manganese ; pharmacology ; Metalloporphyrins ; pharmacology ; Potassium Compounds ; pharmacology ; Sulfates ; pharmacology