Traditional Chinese medicine can regulate the hypoxia-inducible factor-1α(HIF-1α)signalling pathway and slow down tumour progression mainly by inhibiting tumour angiogenesis,glycolysis,epithelial mesenchymal transition and other pathological processes.This paper,starting from HIF-1α and related factors,reviews its pathological mechanism in tumours and the research of traditional Chinese medicine interventions with the aim of providing theoretical references for the treatment of tumours with traditional Chinese medicine.

OBJECTIVE To explore the effects of levosimendan on cardiac function， hemodynamics and prognosis of patients with septic shock complicated with myocardial depression， and evaluate the safety of levosimendan. METHODS Patients with septic shock complicated with myocardial depression who were admitted to the Department of Critical Care Medicine of Chongqing University Three Gorges Hospital from April 2021 to August 2023， underwent adequate fluid resuscitation， had a mean arterial pressure （MAP） ≥65 mmHg， and received pulse indicator continuous cardiac output （PiCCO） monitoring were enrolled. The patients were randomly divided into dobutamine group and levosimendan group according to a random number table， with 20 patients in each group. Both groups received intravenous infusion of Norepinephrine bitartrate injection at a dose of 0.1-2.0 μg/（kg·min）. On this basis， the dobutamine group additionally received intravenous infusion of Dobutamine hydrochloride injection at a dose of 5- 10 μg/（kg·min） for 3 to 7 days， while the levosimendan group additionally received intravenous infusion of Levosimendan injection at a dose of 0.1-0.2 μg/（kg·min） for 24 hours. Heart rate （HR） and hemodynamic parameters [systolic blood pressure， diastolic blood pressure， MAP， central venous pressure （CVP）]， PiCCO monitoring parameters [cardiac function index （CFI）， cardiac index （CI）， stroke volume index （SVI）， extravascular lung water index， global end-diastolic volume index， pulmonary vascular permeability index （PVPI）， global ejection fraction （GEF）， systemic vascular resistance index， left ventricular contractility index]， and prognosis indicators [death within 3 days after administration， mechanical ventilation time，intensive care unit （ICU） stay time， 28-day mortality rate] were compared between the two groups before treatment and at 24 and 72 hours after treatment. Adverse reactions were E-mail：recorded for both groups. RESULTS Compared with before treatment in the same group， CFI， CI and GEF at 24 hours after treatment， CI and GEF at 72 hours after treatment in the dobutamine group， as well as SVI at 24 hours after treatment and SVI and GEF at 72 hours after treatment in the levosimendan group were significantly increased； PVPI at 72 hours after treatment in the dobutamine group was significantly decreased （P＜0.05）. Compared with the dobutamine group during the same period， patients in the levosimendan group had significantly lower HR and significantly higher CVP at 24 hours after treatment （P＜0.05）. Within 3 days after administration， there were no deaths in either group； there were no statistically significant differences in mechanical ventilation time， ICU stay time， 28-day mortality rate， or the incidence of adverse reactions between the two groups （P＞0.05）. CONCLUSIONS For patients with septic shock complicated with myocardial depression who have undergone adequate fluid resuscitation and have a MAP of ≥65 mmHg， levosimendan is comparable to dobutamine in improving cardiac function and hemodynamic parameters， without affecting patients’ prognosis or increasing the risk of adverse reactions such as hypotension.

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.

As the second largest cofactor after ATP in body, S-adenosyl-L-methionine (SAM) is responsible for methyl donor in SAM-dependent methyltransferases (MTases). The methylation of essential ingredients (e.g., DNA, RNA, protein) plays a critical role in epigenetic regulation, cellular signal transduction and metabolic cycles, which is closely related to different kinds of diseases. Therefore, SAM-dependent methyltransferases are considered as promising drug targets. Currently, a growing number of nucleoside analogues have been developed as SAM-competitive inhibitors, blocking the downstream signaling pathways to cure diseases. In the review, we outline the design strategy and optimization process of methyltransferase inhibitors, analyze the shortcomings and solutions of developing nucleoside derivatives as MTase inhibitors, to provide guidance and broad direction to the development of nucleoside MTase inhibitors.

Objective To observe the influence of dapagliflozin tablets on myocardial enzymes,mitral valve blood flow and major adverse cardiovascular events(MACE)in patients with acute myocardial infarction(AMI)complicated with type 2 diabetes mellitus(T2DM)after interventional therapy.Methods AMI patients with T2DM were divided into control group and treatment group by cohort method.The control group was given aspirin tablets 300 mg and ticagrelor 180 mg orally,qd,until the day of interventional treatment.After interventional therapy,aspirin tablets 100 mg,qd,oral ticagrelor tablets 90 mg each time,once in the morning and once in the evening.On the basis of the treatment in the control group,the patients in the treatment group were given dapagliflozin tablets 5-10 mg,qd,every morning after admission.After 3 months of continuous treatment,the clinical efficacy,blood glucose control effect[fasting plasma glucose(FPG),2 hour postprandial blood glucose(2 h PG)],myocardial enzymes indicators[creatine kinase(CK),creatine kinase isoenzyme-MB(CK-MB)],ventricular remodeling indicators[left ventricular ejection fraction(LVEF),left ventricular end systolic diameter(LVESD)],adverse drug reactions and MACE were compared between the two groups.Results There were 55 cases in the control group and 59 cases in the treatment group.After treatment,the total effective rates of the treatment group and the control group were 88.14％(52 cases/59 cases)and 72.73％(40 cases/55 cases),respectively,the difference was statistically significant(P＜0.05).After treatment,the FPG of the treatment group and the control group were(7.29±0.71)and(7.81±0.75)mmol·L-1,respectively;the 2 h PG were(8.66±1.33)and(9.59±1.38)mmol·L-1,respectively;the CK were(145.68±29.82)and(163.68±42.16)U·L-1,respectively;the CK-MB were(8.21±2.37)and(10.33±3.08)U·L-1,respectively;the LVEF were(57.63±8.74)％and(51.41±6.49)％,respectively;LVESD were(33.26±5.33)and(39.51±5.38)mm,respectively.The above indexes in the treatment group were significantly different from those in the control group(all P＜0.05).During the treatment,the adverse drug reactions in the treatment group mainly included nausea and vomiting,diarrhea,constipation.The adverse drug reactions in the control group mainly included hypoglycemia,diarrhea,headache.The total incidence of adverse drug reactions in the treatment group and the control group was 6.68％(4 cases/59 cases)and 9.09％(5 cases/55 cases),respectively,and the difference was not statistically significant(P＞0.05).After 3 months of follow-up,the total incidence of MACE in the treatment group and the control group was 5.08％and 18.18％,respectively,the difference was statistically significant(P＜0.05).Conclusion Dapagliflozin has a significant efficacy in the treatment of AMI patients with T2DM,and it can enhance the effect of blood glucose control,reduce the myocardial injury,inhibit the ventricular remodeling,and reduce the risk of MACE,with high safety.

Background::Although some well-established oncogenes are involved in cancer initiation and progression such as prostate cancer (PCa), the long tail of cancer genes remains to be defined. Goosecoid ( GSC) has been implicated in cancer development. However, the comprehensive biological role of GSC in pan-cancer, specifically in PCa, remains unexplored. The aim of this study was to investigate the role of GSC in PCa development. Methods::We performed a systematic bioinformatics exploration of GSC using datasets from The Cancer Genome Atlas, Genotype-Tissue Expression, Gene Expression Omnibus, German Cancer Research Center, and our in-house cohorts. First, we evaluated the expression of GSC and its association with patient prognosis, and identified GSC-relevant genetic alterations in cancers. Further, we focused on the clinical characterization and prognostic analysis of GSC in PCa. To understand the transcriptional regulation of GSC by E2F transcription factor 1 ( E2F1), we performed chromatin immunoprecipitation quantitative polymerase chain reaction (qPCR). Functional experiments were conducted to validate the effect of GSC on the tumor cellular phenotype and sensitivity to trametinib. Results::GSC expression was elevated in various tumors and significantly correlated with patient prognosis. The alterations of GSC contribute to the progression of various tumors especially in PCa. Patients with PCa and high GSC expression exhibited worse progression-free survival and biochemical recurrence outcomes. Further, GSC upregulation in patients with PCa was mostly accompanied with higher Gleason score, advanced tumor stage, lymph node metastasis, and elevated prostate-specific antigen (PSA) levels. Mechanistically, the transcription factor, E2F1, stimulates GSC by binding to its promoter region. Detailed experiments further demonstrated that GSC acted as an oncogene and influenced the response of PCa cells to trametinib treatment. Conclusions::GSC was highly overexpressed and strongly correlated with patient prognosis in PCa. We found that GSC, regulated by E2F1, acted as an oncogene and impeded the therapeutic efficacy of trametinib in PCa.

Objective To observe the clinical effect of Peiyuan Yangxin(cultivating vital essence and nourishing heart)acupuncture and moxibustion method combined with Gubu Pills in the treatment of type 2 diabetes mellitus complicated with osteoporosis(T2DOP).Methods A total of 70 patients with T2DOP were randomly divided into treatment group and control group,with 35 cases in each group.The control group was treated with conventional hypoglycemic and calcium supplementation.On the basis of the control group,the treatment group was treated with Peiyuan Yangxin acupuncture and moxibustion method combined with Gubu Pills for eight weeks.After two months of treatment,the clinical efficacy of the two groups was evaluated,and the changes of serum osteocalcin(OC),total type 1 collagen amino acid extension peptide(PINP),β-collagen special sequence(β-CTX),inorganic phosphorus(P)and glycosylated hemoglobin(HbA1c)were observed before and after treatment.The changes of pain Visual Analogue Scale(VAS),Hamilton anxiety scale(HAMA)and diabetes specific quality of life scale(DSQL)scores were compared before and after treatment between the two groups.The safety and adverse reactions of the two groups were evaluated,and the recurrence rate and rehospitalization rate of the two groups were counted.Results(1)After treatment,the serum OC,PINP,β-CTX and P levels of patients in the two groups were significantly improved(P＜0.05),and the observation group was significantly superior to the control group in improving serum OC,PINP,β-CTX and P levels,with a statistically significant difference(P＜0.05).(2)After treatment,the HbA1c level of patients in both groups was significantly improved(P＜0.05),and the treatment group was significantly superior to the control group in improving HbA1c level,with statistically significant differences(P＜0.05).(3)After treatment,the VAS,HAMA and DSQL scores of patients in the two groups were significantly improved(P＜0.05),and the treatment group was significantly superior to the control group in improving VAS,HAMA and DSQL scores,with statistically significant differences(P＜0.05).(4)The total effective rate was 88.57％(31/35)in the treatment group and 68.57％(24/35)in the control group.The efficacy of the treatment group was superior to that of the control group,and the difference was statistically significant(P＜0.05).(5)The recurrence in the treatment group was significantly less than that in the control group,and the difference was statistically significant(P＜0.05).(6)There were no statistically significant differences of the incidence of adverse reactions between the two groups of patients(P＞0.05).Conclusion Peiyuan Yangxin acupuncture and moxibustion method combined with Gubu Pills in the treatment of T2DOP can significantly reduce the pain and anxiety symptoms of patients,improve the biochemical indexes of bone metabolism,thereby improving the quality of life of patients,increasing the effective rate of treatment,and reducing the recurrence rate and the rate of rehospitalization in the short term.

Tinnitus is a clinically refractory disease with a high incidence.LAI's Tongyuan acupuncture method believes that tinnitus is nothing more than the two ends of deficiency and excess.The deficiency is closely related to original spirit,and the excess is related to the pathological factors such as externally-contracted six pathogenic factors,phlegm-damp and blood stasis,and qi stagnation and yang constraint.The Tongyuan acupuncture method is based on original spirit,takes the two vessels of conception vessel(CV)and governor vessel(GV)as the general outline,takes the regulation of yin and yang as the main method,pays attention to the combination of local and overall,and emphasizes the application of tonification and purgation,and has the clinical effect of reinforcing healthy qi and dispelling pathogen,cultivating the vital essence.In clinical application,the method of'unblocking governor vessel and nourishing spirit'is used to play the role of heart and brain nourishing spirit and warming and supporting yang qi.The method of'conducting qi back to its source'has the effect of cultivating the vital essence and regulating qi movement.The treatments should be cooperated according to the syndromes,so that the pathogens can be expelled and healthy qi can be settled.Qi and blood have origins of generation and transformation and normally nourishing in the ear,so as to effectively alleviate the patient's tinnitus symptoms.This paper summarizes and analyzes Professor LAI Xin-Sheng's Experience in the diagnosis and treatment of tinnitus by Tongyuan acupuncture method,and provides a new acupuncture treatment plan for clinical application.

Objective To explore the mechanism of'Wenyang Tongmai'(warming yang to unblock meridians)moxibustion in preventing and treating atherosclerosis.Methods Ten C57BL/6J mice fed with normal diet were set as blank group.Thirty ApoE-/-mice were fed with high-fat diet to establish atherosclerosis model,and were randomly divided into model group,Simvastatin group and moxibustion group,with 10 mice in each group.The intervention began on the first day of modeling.The mice in the moxibustion group were given moxibustion at Danzhong(RN17),Shenque(RN8),Neiguan(PC6),Xuehai(SP10)points,and the Simvastatin group was given Simvastatin distilled water suspension by gavage for 12 weeks.After administration,the pathological structure of thoracic aorta in mice was observed by hematoxylin-eosin(HE)staining method.The ultrastructure of thoracic aortic endothelial cells in mice was observed by transmission electron microscopy.The levels of serum tumor necrosis factor α(TNF-α),intercellular adhesion molecule 1(ICAM-1)and vascular cell adhesion molecule 1(VCAM-1)in mice were detected by enzyme-linked immunosorbent assay(ELISA).The mRNA expression levels of silent information regulator 1(SIRT1)and forkhead box O3a(FOXO3a)in thoracic aorta were detected by real-time quantitative polymerase chain reaction(qRT-PCR).The protein expression levels of SIRT1 and FOXO3a in thoracic aorta were detected by Western Blot.Results Compared with the blank group,the pathological changes of thoracic aorta and vascular endothelial cells in the model group were obvious,the levels of serum inflammatory factor TNF-α,ICAM-1 and VCAM-1 were increased(P＜0.05 or P＜0.01),the mRNA and protein expressions of SIRT1 in thoracic aorta were decreased(P＜0.01),and the mRNA and protein expressions of FOXO3a had no significant difference(P＞0.05).Compared with the model group,the thoracic aorta and vascular endothelial cell structure of the mice in the Simvastatin group and the moxibustion group were obviously improved,the levels of serum TNF-α,ICAM-1 and VCAM-1 were decreased(P＜0.05),the mRNA and protein expressions of SIRT1 in the thoracic aorta were increased(P＜0.05 or P＜0.01),and the mRNA and protein expressions of FOXO3a had no significant difference(P＞0.05).There was no significant difference in the above indexes between the Simvastatin group and the moxibustion group(P＞0.05).Conclusion'Wenyang Tongmai'moxibustion can prevent and treat atherosclerotic in rats via regulating and controlling SIRT1/FOXO3a signaling pathway to reduce inflammatory response.

Objective To detect and analyze the expression levels of serum microRNA(miR)-455 and miR-383 in patients with non-small cell lung cancer(NSCLC),and to explore their clinical diagnostic value.Methods A total of 98 NSCLC patients in our hospital from March 2020 to January 2023 were regarded as the NSCLC group,98 patients with benign lung diseases admitted during the same period were regarded as the benign lung disease group,and another 98 healthy volunteers who underwent physical examination in our hospital during the same period were collected as the health group.Real-time fluorescence quantitative PCR(RT-qPCR)method was applied to detect the expression levels of miR-455 and miR-383 in serum.Pearson was applied to analyze the correlation between serum miR-455 expression level and miR-383 level in NSCLC patients;multivariate Logistic regression and ROC curve was applied to analyze the influencing factors and diagnostic value of NSCLC occurrence.Results The expression levels of miR-455 and miR-383 in the serum of the healthy group,benign lung disease group,and NSCLC group decreased sequentially.Pearson analysis showed there was a positive correlation between serum miR-455 expression level and miR-383 level in NSCLC patients(r=0.582,P＜0.05).Logistic analysis found that low expression levels of miR-455 and miR-383 were risk factors for the occurrence of NSCLC(P＜0.05).ROC curve analysis showed that the AUC of NSCLC diagnosed by the combination of miR-455 and miR-383 was obviously higher than that diagnosed by miR-455 alone(Z=3.604,P=0.000)and miR-383 alone(Z=2.594,P=0.010).Conclusion The relative expression levels of miR-455 and miR-383 in serum of NSCLC patients are obviously down-regulated.The combined detection of the two has high diagnostic value for NSCLC.