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.

Aim To study the effect of three kinds of active ingredients of traditional Chinese medicine (sinomenine, rhynchophylline and isorhynchophylline) on dre-miR-723-5p expression in morphine-induced zebrafish brain. Methods Morphine was injected intraperitoneally to zebrafish, conditional position preference (CPP) was trained and then the behavioral of animals were observed; the miRNA expression profiles of morphine-additive zebrafish were determined by small RNA sequencing; qRT-PCR was used to verify the expression of dre-miR-723-5p, three target gene databases (miRanda, miRDB, andRNAhybrid) were used to predict the target genes of dre-miR-723-5p; Kobas 3.0 was used to perform Gene Ontology (GO) and KEGG pathway analysis of these target genes. Results Morphine-induced CPP model was established successfully. Compared with control group, the resident time and movement map in drug-pair box of zebrafish in model group significantly increased. After drug administration, the resident time and movement map in drug-pair box of zebrafish decreased. The verification results of qRT-PCR were consistent with the results of small RNA sequencing. Ninety-nine putative target genes of dremiR-723-5p that were common to all three target gene databases, which were mainly enriched in biological process, cell composition and molecular function, involved in the positive regulation of MAPK signaling pathway, lysosome, cytokine-cytokine receptor interaction, and apoptosis. Conclusion Morphine can increase the expression of dre-miR-723-5p in the zebrafish brain, which can be reversed by sinomenine, isorhynchophylline, and rhynchophylline treatment, and dre-miR-723-5p may participate in the mechanism underlying morphine-induced damage of brain.

Objective: To explore the effect of perioperative chemotherapy on the prognosis of gastric cancer patients under real-world condition. Methods: A retrospective cohort study was carried out. Real world data of gastric cancer patients receiving perioperative chemotherapy and surgery + adjuvant chemotherapy in 33 domestic hospitals from January 1, 2014 to January 31, 2016 were collected. Inclusion criteria: (1) gastric adenocarcinoma was confirmed by histopathology, and clinical stage was cT2-4aN0-3M0 (AJCC 8th edition); (2) D2 radical gastric cancer surgery was performed; (3) at least one cycle of neoadjuvant chemotherapy (NAC) was completed; (4) at least 4 cycles of adjuvant chemotherapy (AC) [SOX (S-1+oxaliplatin) or CapeOX (capecitabine + oxaliplatin)] were completed. Exclusion criteria: (1) complicated with other malignant tumors; (2) radiotherapy received; (3) patients with incomplete data. The enrolled patients who received neoadjuvant chemotherapy and adjuvant chemotherapy were included in the perioperative chemotherapy group, and those who received only postoperative adjuvant chemotherapy were included in the surgery + adjuvant chemotherapy group. Propensity score matching (PSM) method was used to control selection bias. The primary outcome were overall survival (OS) and progression-free survival (PFS) after PSM. OS was defined as the time from the first neoadjuvant chemotherapy (operation + adjuvant chemotherapy group: from the date of operation) to the last effective follow-up or death. PFS was defined as the time from the first neoadjuvant chemotherapy (operation + adjuvant chemotherapy group: from the date of operation) to the first imaging diagnosis of tumor progression or death. The Kaplan-Meier method was used to estimate the survival rate, and the Cox proportional hazards model was used to evaluate the independent effect of perioperative chemo therapy on OS and PFS. Results: 2 045 cases were included, including 1 293 cases in the surgery+adjuvant chemotherapy group and 752 cases in the perioperative chemotherapy group. After PSM, 492 pairs were included in the analysis. There were no statistically significant differences in gender, age, body mass index, tumor stage before treatment, and tumor location between the two groups (all P>0.05). Compared with the surgery + adjuvant chemotherapy group, patients in the perioperative chemotherapy group had higher proportion of total gastrectomy (χ(2)=40.526, P<0.001), smaller maximum tumor diameter (t=3.969, P<0.001), less number of metastatic lymph nodes (t=1.343, P<0.001), lower ratio of vessel invasion (χ(2)=11.897, P=0.001) and nerve invasion (χ(2)=12.338, P<0.001). In the perioperative chemotherapy group and surgery + adjuvant chemotherapy group, 24 cases (4.9%) and 17 cases (3.4%) developed postoperative complications, respectively, and no significant difference was found between two groups (χ(2)=0.815, P=0.367). The median OS of the perioperative chemotherapy group was longer than that of the surgery + adjuvant chemotherapy group (65 months vs. 45 months, HR: 0.74, 95% CI: 0.62-0.89, P=0.001); the median PFS of the perioperative chemotherapy group was also longer than that of the surgery+adjuvant chemotherapy group (56 months vs. 36 months, HR=0.72, 95% CI:0.61-0.85, P<0.001). The forest plot results of subgroup analysis showed that both men and women could benefit from perioperative chemotherapy (all P<0.05); patients over 45 years of age (P<0.05) and with normal body mass (P<0.01) could benefit significantly; patients with cTNM stage II and III presented a trend of benefit or could benefit significantly (P<0.05); patients with signet ring cell carcinoma benefited little (P>0.05); tumors in the gastric body and gastric antrum benefited more significantly (P<0.05). Conclusion: Perioperative chemotherapy can improve the prognosis of gastric cancer patients.
Chemotherapy, Adjuvant ; Female ; Gastrectomy ; Humans ; Male ; Neoadjuvant Therapy ; Neoplasm Staging ; Prognosis ; Retrospective Studies ; Stomach Neoplasms/surgery*

ObjectiveTo study the mechanism of renal injury in urogenic sepsis and explore the effect of H2S on the expression of p38 mitogen-activated protein kinase (p38MAPK) and Cysteine protease 3(Caspase3) and apoptosis in renal tissue of urogenic sepsis. Hydrogen sulfide (H2S) has a wide range of biological effects and has a certain protective effect on the kidney. The main objective of this study is to investigate the effect of H2S on the expression of p38 mitogen-activated protein kinase (p38MAPK), cysteine proteinase 3 (Caspase3), and cell apoptosis in renal tissue of urogenic sepsis, and further to study the mechanism of urinary sepsis renal injury.MethodsNew Zealand rabbits (n=40) were divided into five groups Control, Sham, Sepsis, NaHS, and PAG, with eight rabbits in each group. The vital signs, blood routine white blood cell count, neutrophil count, and renal function (Cr, BUN) of five groups of New Zealand rabbits were recorded before the operation, 24 hrs after the operation, 48 hrs after the operation, and 72 hrs after the operation. 72 hrs after the operation, the left kidney tissue was taken for HE staining to observe the changes of cell morphology and structure of the kidney tissue. The apoptotic cells in renal tissue were labeled by Tunel assay (in situ terminal transferase labeling technique). The expression levels of p38MAPK and Caspase3 in renal tissue were tested by ELISA.Results The apoptosis indexes of renal tissue cells in group Control and group Sham were (5.65±2.43)% and (5.57±2.72)%, respectively, with no statistically significant difference (P>0.05). The apoptosis index of rabbit kidney tissue in group Sepsis was (25.26±2.70)%, which was significantly higher than that in group Control and group Sham (P<0.05). The apoptosis index (16.93±2.03)% in group NaHS was significantly lower than that in group Sepsis (P<0.05). The apoptosis index of group PAG (33.09±3.70)% was significantly higher than that of group Sepsis and group NaHS (P<0.05). There was no significant difference between group Control and group Sham (P>0.05). Pairwise comparison between groups Sepsis, NaHS, and PAG showed statistically significant differences (P<0.05). The expression levels of group Sepsis and group PAG were significantly higher than that of group NaHS (P<0.05). The expression level of group PAG was significantly higher than that of group Sepsis (P<0.05).Conclusion H2S can alleviate renal damage caused by urine-derived sepsis, and its mechanism combined with H2S to suppress the expression of p38MAPK and Caspase3 in the renal tissue of urogenous sepsis, thereby reducing renal cell apoptosis Death.

Objective To establish a high throughput targeted method to study phospholipids profding and to screen out and quantitate the potential biomarkers in urine samples.Methods The phospholipids in urine was extracted by modified MTBE(methyl tert-butyl ether)method.Semi -quantitative analysis of phospholipids in urine was realized by using high performance liquid chromatography-electrospray ionization-qua-drupoles/trap (HPLC-ESI-Q/Trap) technique.7 standards and 15 endogenous phospholipids were chosen to conduct method validation,including specificity,sensitivity,precision,matrix effect,carryover effect,stability and recovery.Principal component analysis (PCA) of quality control (QC) samples interspersed during the detection process was used to evaluate the reliability of the data obtained.Results The lower limit of quantitation of 7 phospholipids were phosphatidylcholine and lysophosphatidylcholine 0.25 ng· mL-1,phosphatidylethanolamine and phosphatidylserine 2.00 ng· mL-1,phosphatidylglycerol and phosphatidylinositol 1.00 ng · mL-1,sphingomyelin 625.00 pg · mL-1,respectively.During the continuous analysis,the relative standard deviation (RSD) of the retention time was 0.72％-3.44％,the peak area was 0.71％-10.53％.The recoveries of the 7 phospholipids were in the range of 54.05％-105.73％.All samples were stable after being stored 12 h at room temperature,being stored 24h after preparation,two freeze-thaw cycles and being cryopreserved 1 month at-80 ℃.QC samples in the first principal component diagram showed that the data was reliable.Conclusion The developed HPLC-ESI-Q/Trap method was simple,stable and sensitive,which can be applied to the subsequent study of large sample size of phospholipidomics research and quantitative analysis of potential urinary phospholipids biomarkers.

Objective To observe and analyze the clinical outcomes of perfluoropropane (C3 Fs) injection and laser photocoagulation on myopic foveoschisis.Methods A total of 14 patients (18 eyes) diagnosed as myopic foveoschisis were enrolled in this retrospective study.All patients received intraocular tamponade of 0.5-0.7 mL C3 F8,and after 1 week,underwent macular photocoagulation.These patients were given the best-corrected visual acuity (BCVA) and optical coherence tomography (OCT) examination for central foveal thickness (CFT) and maximal macular thickness (MMT) before and after treatment.Results OCT examination showed that the mean CFT decreased significantly from (494.00 ±454.80) iμm before treatment to (193.61 ± 97.42) μm at the last follow-up,with statistical significance (P =0.01),and the mean MMT decreased from (687.33 ± 385.15)pμn to (331.06 ± 109.31)μm at the same duration,approaching significant difference (P =0.001).The foveoschisis healed completely and partially in 14 eyes at the last follow-up,the mean CFT decreased significantly from (567.36 ±493.01) μm before treatment to (171.43 ± 90.84) μm after treatment,with statistical significance (P =0.006),and the mean MMT decreased from (744.14 ± 417.38)μm to (303.86 ± 8.62)prn at the same duration,approaching significant difference (P =0.002).Patients' BCVA before treatment was (0.94 ± 0.39) logMAR,of which 13 eyes had BCVA ＜ 0.6 logMAR,and increased to (0.92 ± 0.36) logMAR at the last follow-up,with no significant difference (P =0.78).The foveoschisis healed completely and partially in 14 eyes,and the BCVA was (1.04 ± 0.37) logMAR before treatment,up to (0.90 ± 0.34) logMAR after treatment,and the difference was not statistically significant (P =0.16).At the last follow-up,the vision of 4 eyes was increased by 2 lines and above,and unchanged in 10 eyes.All patients had no visual symptoms such as dark spots and no increase in intraocular pressure after treatment.Conclusion Intraocular C3 F8 tamponade and macular photocoagulation can be an satisfying alternative treatment for patients with myopic foveoschisis.

OBJECTIVETo evaluate the application effect of Chinese medical clinical pathway for treating attention-deficit hyperactivity disorder (ADHD), and to provide evidence for further improving clinical pathways.

METHODSTotally 270 ADHD children patients were recruited and treated at pediatrics clinics of 9 cooperative hospitals from December 2011 to December 2012. The treatment course for all was 3 months. Scores of attention deficit and hyperactivity rating scale, scores of behavior, Conners index of hyperactivity (CIH), and Chinese medical syndrome scores were compared between before and after treatment. The efficacy difference in various sexes, ages, and disease courses were evaluated by judging standards for Chinese medical syndrome and ADHD.

RESULTSFifteen children patients who entered clinical pathway dropped out, and the rest 255 completed this trial. Compared with before treatment, total scores of attention deficit and hyperactivity rating scale, scores of attention deficit and hyperactivity rating scale, CIH, and Chinese medical syndrome scores obviously decreased (all P < 0.01). The total effective rate in disease efficacy was 87.8% (224/255 cases), and the total effective rate in Chinese medical syndrome curative effect was 87.5% (223/255 cases). The clinical curative effect was not influenced by age, gender, or course of disease when statistically analyzed from judging standards for Chinese medical syndrome or for disease efficacy.

CONCLUSIONIntervention by Chinese medical clinical pathway could improve ADHD patients' symptoms, and its efficacy was not influenced by sex, age, or course of disease.

Attention ; Attention Deficit Disorder with Hyperactivity ; therapy ; Child ; Critical Pathways ; Humans ; Medicine, Chinese Traditional

OBJECTIVETo identify factors that can effectively predict the efficacy of laparoscopic splenectomy (LS) in the treatment of immune thrombocytopenic purpura (ITP).

METHODSFrom January 2007 to September 2012, 78 patients with ITP underwent laparoscopic splenectomy were retrospectively analyzed. According to the postoperative platelet (PLT) count and haemorrhagic manifestations, they were divided into effective group and ineffective group. Nine influencing factors were univariate analyzed and multivariate analyzed.

RESULTSIn effective group (65 cases) and ineffective group (13 cases), average PLT count of 1 day before surgery was 47×10(9)/L vs. 21×10(9)/L, average operative time was (166 ± 46) minutes vs. (139 ± 29) minutes. Univariate analysis result: PLT count of 1 day before surgery (Z = -2.776, P = 0.005) and operative time (t = 2.723, P = 0.011) was statistically significant in 2 groups, the rest factors did not significantly influence the result. Multivariate analysis revealed that only PLT count of 1 day before surgery was statistically significant (OR = 0.964, 95%CI: 0.932-0.997, P = 0.031) in 2 groups, but operative time (P = 0.051) was not statistically significant.

CONCLUSIONSPLT count of 1 day before surgery is a predict factor in LS for ITP. Because of the limited sample number, further multi-center prospective study with large sample is warrant.

Adolescent ; Adult ; Aged ; Female ; Humans ; Laparoscopy ; Male ; Middle Aged ; Multivariate Analysis ; Purpura, Thrombocytopenic, Idiopathic ; surgery ; Retrospective Studies ; Splenectomy ; Treatment Outcome ; Young Adult

To use the single-pass intestine perfusion (SPIP) model and HPLC to determine the concentration of formononetin, the effect of quality concentrations of formononetin, different intestinal segments and P-glycoprotein inhibitor on intestinal absorption of formononetin, in order to observe the intestinal absorption mechanism of formononetin from Millettia nitita var. hirsutissima in rats. The experimental results showed that the qulaity concentration of formononetin in the perfusate had no significant effect on the absorption rate constant (K(a)) and the apparent absorption coefficient (P(app)); K(a) and P(app) of formononetin in duodenum, jejunum and ileum showed no significant difference. However, K(a) was significantly higher than that in colon (P < 0.05), with significant difference between that in intestinum tenue and colon. P-glycoprotein inhibitor verapamil showed significant difference in K(a) and P(app) in intestinal segments (P < 0.05). This indicated that the absorption mechanism of formononein in rat intestinal tracts passive diffusion, without any saturated absorption. Formononein is absorbed well in all intestines. Their absorption windows were mainly concentrated in the intestinum tenue, without specific absorption sites. Formononein may be the substrate of P-glycoprotein.
Animals ; Drugs, Chinese Herbal ; pharmacokinetics ; Humans ; Intestinal Absorption ; Intestines ; chemistry ; metabolism ; Isoflavones ; pharmacokinetics ; Kinetics ; Male ; Millettia ; chemistry ; Rats