Ubiquitin-specific protease 1 (USP1) is one of the deubiquitinating enzymes which has received increasing attention in cancer research. USP1 is overexpressed in many types of cancer cells, and has been found to control tumorigenesis and progression by regulating various proteins associated with tumors, such as SIK2, GSK-3β, and Bcl-2. Knockdown or pharmacological inhibition of USP1 can effectively suppress tumors and is also expected to address the issues of cisplatin and poly ADP-ribose polymerase (PARP) inhibitor resistance. This review describes the structure and function of USP1 and the relationship between USP1 targets and tumors and systematically summarizes the structure-activity relationships of small molecule USP1 inhibitors disclosed from 2013 to 2023. Finally, this review discusses the challenges and opportunities in developing small molecule USP1 inhibitors.

Objective To explore the role and possible molecular mechanism of Isocitrate dehydrogenase 1(IDH1)gene in proliferation and migration of intrahepatic cholangiocarcinoma(iCCA)cell HuCCT1.Methods HuCCT1 cells with IDH1 gene knockout(HuCCT1IDH1-/-)were constructed by CRISPR/Cas9 gene editing technology.To investigate the capacities of proliferation,migration and invasion of HuCCT1WT(HuCCT1 cells with wild-type IDH1 gene)and HuCCT1IDH1-/-cells,assays of CCK-8,clone formation,scratch and transwell were performed.Western blotting was used to detect the expression levels of epithelial-mesenchymal transition(EMT)associated proteins E-cadherin,N-cadherin,Vimentin,MMP-9,Wnt3a and β-catenin in two groups of cells.The transcriptome sequencing data of HuCCT1WT and HuCCT1IDH1-/-cells were analyzed by bioinformatics methods,Western blotting was used to verify the expression of signaling pathway-related proteins.Results Compared with HuCCT1WT cells,HuCCT1IDH1-/-cells showed the number of proliferation and clone formation significantly reduced(P<0.05),the proportion of cells blocked in G2/M phase was significantly increased(P<0.01),the rate of scratch healing was significantly decreased(P<0.01),and the number of migrated cells(P<0.001)and invaded cells(P<0.05)was significantly reduced.qRT-PCR assay showed that the expression levels of IDH1,Vimentin,MMP-9 and genes related to the regulation of G2/M cycle proliferation,Cyclin A2,Cyclin B1 and CDK1 mRNA were down-regulated in HuCCT1IDH1-/-cells(P<0.05),and the expression of CDH1 mRNA encoding E-cadherin was up-regulated(P<0.01);Western blotting assay showed that the expression level of E-cadherin in HuCCT1IDH1-/-cells was significantly increased(P<0.05),and the expression level of N-cadherin,Vimentin and MMP-9 protein was significantly decreased(P<0.05)than that in HuCCT1WT cells.Data of transcriptome sequencing revealed 1476 differentially expressed genes(DEGs)between two groups of HuCCT1 cells.Go enrichment analysis showed the DEGs were significantly enriched in cell biological processes associated with inflammatory response,cell signaling and cell metabolism.Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway analysis suggested that the DEGs may be involved in some signaling pathways such as Wnt,MAPK,Rap1,Hippo and TNF,which are closely related to the regulation of proliferation and invasion of tumor cells.Western blotting verification results showed that compared with HuCCT1WT cells,the relative expression of Wnt3a and β-catenin proteins of HuCCT1IDH1-/-cells was significantly decreased(P<0.05).Conclusions IDH1 gene may participate in the control of biological functions of HuCCT1 cells,including cell proliferation,migration,invasion and epithelial mesenchymal transition.The mechanism may be related to the activation of the Wnt/β-catenin signaling pathway.

Leonurine(SCM-198)was discovered as one of the active constituents of the Herba Leonuri(HL).Now it can be artificially synthesized.Several recent researches has proven that it exhibits anti-inflammatory effect in several systems in animal models and cell culture in vitro.The key mechanism involves downgrading the activity of nuclear transcription factor-κB(NF-κB),thereby inhibiting the phosphorylation of several signal pathways such as PI3K/Akt,MAPK,ERK,and JNK,or upregulating the activity of Nrf2 related pathways,resulting in downregulated expression of inflammatory cytokines such as tumor necrosis factor-α(TNF-α),IL-1β,IL-2,IL-6,IL-8,inducible nitric oxide synthase(iNOS),cyclooxygenase-2(COX-2),chemokines,adhesion molecules,etc.Owing to the advantages of high safety and efficiency,the ease of administration,as well as its effectiveness in many organs and systems,leonurine has a widely prospect for future research and clinical applications.This article reviews the progress in the fundamental research of leonurine in multiple inflammation-related disease,and it could be expect to offer new possibilities for the treatment of these disease.

An ultra-high performance liquid chromatography-tandem mass spectrometry(UHPLC-MS/MS) method was established for the determination of active components of Sarcandrae Herba, and applied to the pharmacokinetics study of multiple dosage forms. After SD rats were administered by gavage with three dosage forms [Sarcandrae Herba extract, commercial Sarcandrae Herba Guttate Pills, and polydopamine guttate pills loaded with active components of Sarcandrae Herba(PDA-Sg Guttate Pills)], blood samples were collected from the inner canthus at different time points. After protein precipitation, plasma samples were separated on ACQUITY UPLC C_(18) column(2.1 mm×100 mm, 1.7 μm). The mobile phase consisted of water containing 0.2% formic acid and acetonitrile in gradient elution. The negative ions were measured simultaneously in the multi-reaction monitoring(MRM) mode. The pharmacokinetic parameters were calculated and fitted by DAS 2.0. All four components could be detected in the plasma of rats in each group at each time point except the neochlorogenic acid and cryptochlorogenic acid in the Sarcandrae Herba extract group. The guttate pills group showed a significant increase in drug content at each time point. The exposure of the main components of Sarcandrae Herba in blood was effectively increased by PDA-drug loading effect in PDA-Sg Guttate Pills(The AUC_(0-24 h) of neochlorogenic acid, cryptochlorogenic acid, isaziridin and rosmarinic acid reached 2.45, 32.90, 1.54, 4.81 times that of the commercial guttate pills). This study proves the measurability of the above-mentioned multi-component in vitro-in vivo delivery process. The pharmacokinetic study has shown that PDA-Sg Guttate Pills can effectively delay the elimination time and improve the bioavailability of the four components, which can provide theoretical data for the production of the drug.
Animals ; Chromatography, High Pressure Liquid/methods* ; Drugs, Chinese Herbal/pharmacokinetics* ; Indoles ; Polymers ; Rats ; Rats, Sprague-Dawley ; Reproducibility of Results ; Tandem Mass Spectrometry/methods*

Long non-coding RNA (lncRNA) is a type of non-coding RNA with the more than 200 nucleotides. Several lncRNAs have been identified as the potential targets for cancer therapy. LncRNA00067110 is one of the differentially expressed genes in the transcriptome profiles of melanoma B16-F10 cells compared to normal mice melanocytes. To investigate whether lncRNA00067110 regulates the proliferation, apoptosis and melanogenesis of B16-F10 cells, the calcium-binding tyrosine phosphorylation regulated protein (Cabyr) target gene was predicted by LncTar and verified by dual luciferase activities. The regulating function of lncRNA00067110 was investigated by the analysis of transcriptome profiles and to detect the proliferation, apoptosis and melanin production of B16-F10 cells transfected by the overexpression plasmids of lncRNA00067110. The results showed that the relationship of lncRNA00067110 targeting Cabyr, the mRNA and protein levels of proliferation (MEK/ERK/MNK/CREB) and melanogenesis-related genes (TYR family and CREB) were significantly down-regulated, while the mRNA and protein levels of apoptosis-related genes (AKT and Bcl-2) were up-regulated in B16-F10 cells with lncRNA00067110 overexpression. The transcriptome profile of B16-F10 cells with lncRNA00067110 overexpression showed that 17 genes were differentially expressed, among which Cabyr was up-regulated. Furthermore, the effect of lncRNA00067110 on the phenotypes of cell proliferation and apoptosis were verified. The results suggested that lncRNA00067110 might be a novel target for the treatment of melanoma by targeting Cabyr, which regulate the expression of related genes to inhibit the proliferation and melanogenesis, as well as to induce the apoptosis of B16-F10 cells.

Objective:To summarize the midterm to long-term outcomes and experiences of endovascular treatment (ET) of spontaneous isolated superior mesenteric artery dissection (SISMAD).Methods:The clinical data of 31 SISMAD patients from Jan 2011 to Dec 2019 treated with ET was retrospectively analyzed.Results:Successful ET was achieved in 29 patients with a technical success rate of 93.5%. A total of 36 self-expandable bare stents were planted in 28 patients and plain old balloon angioplastry (POBA) was performed in 1 patient. Abdominal pain disappeared within 24 hours in 89.3% of the patients after stenting. The rate of perioperative complication was 3.2%. There was no SMA dissection rupture bleeding, nor perioperative death occurred. The mean follow-up time was 53.5 (range, 6 to 110) months. There was no dissecting aneurysm formation, no SMA rupture and bleeding, and no stent rupture during the follow-up. The post ET 1-year, 3-year, and 5-year free from reintervention rate were 100%, 100%, and 91.7%, respectively.Conclusions:ET for SISMAD is safe and effective with satisfactory perioperative and midterm to long-term outcomes.

OBJECTIVES: To study the effect of glucose metabolism disorders on the short-term prognosis in neonates with asphyxia. METHODS: A retrospective analysis was performed on the medical data of the neonates with asphyxia who were admitted to 52 hospitals in Hubei Province of China from January to December, 2018 and had blood glucose data within 12 hours after birth. Their blood glucose data at 1, 2, 6, and 12 hours after birth (with an allowable time error of 0.5 hour) were recorded. According to the presence or absence of brain injury and/or death during hospitalization, the neonates were divided into a poor prognosis group with 693 neonates and a good prognosis group with 779 neonates. The two groups were compared in the incidence of glucose metabolism disorders within 12 hours after birth and short-term prognosis. RESULTS: Compared with the good prognosis group, the poor prognosis group had a significantly higher proportion of neonates from secondary hospitals (48.5% vs 42.6%, CONCLUSIONS Recurrent hyperglycemia in neonates with asphyxia may suggest poor short-term prognosis, and it is necessary to strengthen the early monitoring and management of the nervous system in such neonates.
Asphyxia ; Asphyxia Neonatorum/epidemiology* ; Humans ; Hyperglycemia ; Infant, Newborn ; Prognosis ; Retrospective Studies

Dickkopf-3 (DKK3) , as a critical inhibitor of the Wnt/p-catenin signaling pathway, may he involved in melanogenesis.In the current study, we investigated the effects of DKK3 on melanogenesis in melanocytes of alpaca.Overexpression of DKK3 in alpaca melanocytes, the expression of Wntl, Lefl , Myc and the major target genes termed microphthalmia-associated transcription factor (M1TF) and its downstream genes, including tyrosinase (TYR), tyrosinase-related protein 1 (TYRP1) and tyrosinase- related protein 2 (TYRP2) were significantly decreased at both mRNA and protein levels (P<0.05); total alkali melanin, pheomelanin and eumelanin were decreased by 80.30%, 72.17% and 64.60% (P <0.05), respectively.In contrast, in the melanocytes transfected with siRNA-DKK3 (a small interference RNA targeting DKK3) , the expression of Wntl, Lefl, Myc, MITF, TYR, TYRPl and TYRP2 were significantly increased at both mRNA and protein levels (P<0.05) ; total alkali melanin, pheomelanin and eumelanin were significantly increased by 1.65 folds, 1.25 folds and 1.21 folds (P< 0.05) , respectively.These results indicate that DKK3 regulates melanogenesis in alpaca melanocytes via the Wnt/p-catenin signaling pathway and down-regulates MITF.

Although many microRNAs (miRNAs) are known to function as regulators of coat color and melanogenesis, the underlying molecular mechanisms of miR-100-5p governing melanogenesis were not completely known.The goal of this study was to determine the effect of miR-l()()-5p on melanogenesis in alpaca melanocytes.Fibroblast growth factor 21 (FGF21) is a predicted target gene of miR-100-5p and the luciferase reporter assay demonstrated that miR-100-5p regulates FGF21 by binding to its 3' untranslated region (3'UTR).In this study, alpaca melanocytes were transfected with miR-100-5p, inhibitor and negative control plasmid.Results showed that miR-100-5p overexpression significantly decreased mRNA and protein expression of FGF2\.Meanwhile, the ERK signal pathway was inhibited, with subsequent up-regulation of microphthalmia-associated transcription factor (MITF) , tyrosinase (TYR) and tyrosinase-related protein 2 (TYRP2), which increased melanin production.The results suggest that miR-100-5p may regulate melanogenesis by targeting FGF21 via extracellular regulated MAP kinase (ERK) signaling pathway.

Aim To investigate the neuroprotective effect and mechanism of salidroside (Sal) on rats with permanent middle cerebral artery occlusion model (pMCAO) by regulating the PI3 K/AKT signaling pathway. Methods A total of 80 healthy adult SPF male SD rats were randomly divided into sham operation group (sham group), model group (pMCAO group), drug administration group (pMCAO + Sal group) and inhibitor group (pMCAO + Sal + YL group). After the pMCAO model rats were prepared by the line bolt method, salidroside (50 mg · kg