AIM:To observe the effect and mech-anism of cuttlebone extract regulating vascular en-dothelial growth factor(VEGF)/phosphatidylinosi-tol 3-kinase(PI3K)/protein kinase B(AKT)pathway on refractory wounds in rats.METHODS:Cuttle-bone extract(CE)was obtained by water extraction of cuttlebone.Fifty SD rats were randomly divided into negative Control group,Model group,Cuttle-bone extract low-dose(CE(L))group,Cuttlebone extract high-dose(CE(H))group,and cuttlebone ex-tract high-dose+inhibitor(CE(H)+LY294002)group.After the refractory wound model was successfully established,0.02％furacillin solution or cuttlebone extract solution were applied to the wound area of rats in each group,and the treatment was adminis-tered once a day.After 14 days of treatment for re-fractory wounds,the changes in wound healing,angiogenesis,inflammation and expression of relat-ed regulatory proteins were quantitatively ana-lyzed by measuring skin ulcer wound area,patho-logical sections,immunofluorescence staining,Eli-sa,Western blot,RT-qPCR and other methods.RE-SULTS:Compared with Model group,CE(L)and CE(H)groups can increase the number of epithelial cells and collagen,and promote the healing of re-fractory wound in rats.Serum VEGF,skin tissue mi-crovascular density,P-PI3K,P-AKT,VEGF protein ex-pression and mRNA expression levels of PI3K,Akt,VEGF and eNOS were increased(P＜0.05),while se-rum TNF-α and IL-6 levels were decreased(P＜0.05).LY294002 could partially reverse the repair-ing effect of high dose cuttlebone extract on refrac-tory wound(P＜0.05).CONCLUSION:Cuttlebone ex-tract can regulate the VEGF/PI3K/AKT signaling pathway,inhibit the inflammatory response of re-fractory wounds in rats,induce angiogenesis and promote wound healing.

AIM:To elucidate the pharmacody-namic and network pharmacological mechanisms of total flavonoids of Carthamus tinctorius L.,to ex-plore their key targets and related pathways,and to clarify their mechanism of action against hepatic fibrosis.METHODS:The total flavonoids of Cartha-mus tinctorius L.were determined by LC-MS/MS and analysed for their compositions;the active in-gredients were screened by TCMSP database,SWISS ADME database and literature search;the targets related to total flavonoids of Carthamus tinctorius L.were screened by Swiss Target Predic-tion database;and the targets related to hepatic fi-brosis were screened by GeneCards database;the anti-hepatic fibrosis targets of total flavonoids of Carthamus tinctorius L.were obtained by taking the intersection of Venny.2.1.0;the protein interac-tions were analysed by STRING database;the visu-alization analysis was carried out by Cytoscape soft-ware;the GO function and KEGG pathway analysis was carried out by Metascape platform;and molec-ular docking was verified by using AutoDock soft-ware for the core targets and active ingredients.The mechanism of anti-hepatic fibrosis of total fla-vonoids of Carthamus tinctorius L.was verified by animal model and in vitro cell experiments.RE-SULTS:A total of 41 flavonoid components were identified in Carthamus tinctorius L.Through the network pharmacological analysis,149 anti-hepatic fibrosis targets of total flavonoids of Carthamus tinctorius L.were obtained,including 23 core tar-gets.The GO enrichment analyses involved a total of three aspects,namely,biological process(BP),cellular component(CC),and molecular function(MF).KEGG enrichment results showed that PI3K/Akt and MAPK are pathways involved in the devel-opment of hepatic fibrosis.Molecular docking veri-fied that the active ingredients Quercetin,Acacetin and Glabridin were tightly bound to Akt1 and HI-FIA,respectively.In animal model experiments,it was observed by HE and Masson staining that fibro-plasia was reduced,collagen deposition was re-duced,inflammatory cell infiltration was reduced,and fibrotic liver tissues were improved in total fla-vonoids of Carthamus tinctorius L.administration group.In isolated cell experiments:Western blot-ting results suggested that total flavonoids of Car-thamus tinctorius L.could decrease the hepatic fi-brosis marker factor α-SMA,Collagen1(P＜0.01)and PI3K,Akt protein expression(P＜0.01).CONCLU-SION:Total flavonoids of Carthamus tinctorius L.ex-erted anti-hepatic fibrosis effects through multi-components,multi-targets and multi-pathways,and their mechanism of action may be achieved by regulating the PI3K/Akt signalling pathway.

AIM:To investigated the mechanism of action of Yiqi tongfu xiere prescription(YTX)in treating mice with lipopolysaccharide(LPS)-in-duced acute lung injury(ALI).METHODS:According to the random number table,24 C57BL/6 mice were divided into 4 groups:control group(Control),model group(LPS),low dose group(YTX-L)and high dose group(YTX-H).Except for the control group,the mice models of acute lung injury were established by intratracheal instillation of LPS solu-tion(5 mg/kg).The low and high dose treatment groups were given intragastric administration con-tinuously for 14 days.After 24 hours,the lung tis-sue,bronchoalveolar lavage fluid(BALF)and serum of the four groups were taken for follow-up detec-tion.The degree of pulmonary edema was evaluat-ed by wet weight coefficient(wet to dry ratio,W/D)of lung tissue.The degree of alveolar inflamma-tion and pulmonary fibrosis were evaluated by HE and Masson staining,and the contents of BALF and serum inflammatory cytokines IL-1β and IL-6 were detected by ELISA.The protein expressions of α-SMA,FN,Col-Ⅰ and Col-Ⅲ were measured by West-ern blot.Determination of α-SMA,FN,Col-Ⅰ,MAPK,NF-κB mRNA expression by RT-PCR method.RE-SULTS:Compared with LPS group,the contents of BALF,IL-1β and IL-6 in serum,Wmax D ratio,lung pathology,serum α-SMA,FN,Col-Ⅰ,Col-Ⅲ protein expression and α-SMA,FN,Col-Ⅰ,MAPK,NF-κB mRNA expression in treatment group were signifi-cantly lower than those in control group.CONCLU-SION:YTX can significantly reduce the levels of pul-monary fibrosis markers such as α-SMA,FN,Col-Ⅰand Col-Ⅲ by inhibiting the activation of MAPK/NF-κB signal pathway,and improve alveolar inflamma-tion and pulmonary fibrosis in mice with lung inju-ry,suggesting that YTX can treat acute lung injury and provide a theoretical basis for the clinical use of YTX.

AIM:To develop a SAS macro tool for calculating pharmacokinetic(PK)parameters using non-compartmental analysis(NCA)that is applica-ble to various routes and frequencies of drug ad-ministration.METHODS:By incorporating the prin-ciples of NCA PK parameter calculations,the struc-ture of the SAS macro program is designed and pro-grammed.The usage of the macro program is dem-onstrated through simulated examples.RESULTS:Based on NCA,this study programmed a SAS macro using SAS macro language to calculate both single-dose and steady-state complete PK parameters.It supports three modes of drug administration:ex-travascular,intravenous infusion,and intravenous bolus injection,as well as four algorithms for calcu-lating area under the curve(AUC).By comparing with authoritative calculation software,the results were found to be highly consistent across various calculation scenarios,with more accurate calcula-tions for the time of first measurable concentration(Tlag).CONCLUSION:The％M_CREATE_PK_PARAM-ETERS macro is a SAS macro that supports compre-hensive PK parameter calculations in NCA,provid-ing an accurate,efficient,and flexible solution for PK parameter estimation with broad application prospects.

AIM:To establish a physiological-based pharmacokinetic(PBPK)model of ertapen-em in elderly patients with chronic kidney disease,and to analyze the pharmacokinetic/pharmacody-namic index f％ T＞MIC at different doses.METH-ODS:The physicochemical properties and pharma-cokinetic characteristics of ertapenem were collect-ed by reviewing the literature and databases,and a healthy adult model was established in PKSim? software,and then extrapolated to the PBPK model of the elderly.The clinical pharmacokinetic re-search data were used to optimize and validate the model,and the mean folding error(MFE)was used as the index to evaluate the prediction perfor-mance of the model.The final model was used to simulate the in vivo exposure of elderly patients with chronic kidney disease after administration,and the pharmacokinetic/pharmacodynamic index of commonly used clinical dosing regimens was an-alyzed,and the recommended dosing regimens were given.RESULTS:The MFE of the area under the curve(AUC0-t),peak concentration(Cmax)and peak time(Tmmax)predicted by the established PBPK model of ertapenem in adults were 0.92,0.79 and 1.02,respectively,and the predicted value of the optimized PBPK model of ertapenem in the elderly was also consistent with the observed value of 0.5＜MFE＜2 standards,all of which have good predictive performance.With f％ T＞MIC greater than 40％as the drug efficacy target,the minimum inhibitory concentration(MIC)is 0.5-1 μg/mL for sensitive bacteria,and elderly patients with chronic kidney disease can consider reducing the drug dose as ap-propriate.CONCLUSION:The PBPK model of ertap-enem in elderly patients with renal insufficiency has been successfully established,and the model has good prediction performance and provides a reference for clinical personalized medication in el-derly patients with renal insufficiency.

AIM:To evaluate the efficacy of inflix-imab in the maintenance of Perianal fstulizing Crohn's disease.METHODS:The clinical data of 24 patients with perianal fistula Crohn's disease(PFCD)treated with infliximab(IFX)in the Depart-ment of Anorectal Surgery of our hospital from No-vember 2020 to October 2023 were retrospectively collected.The clinical efficacy and safety were eval-uated by observing the clinical characteristics for 54 weeks.The fistula remission rate,clinical remis-sion rate,and endoscopic remission rate of pa-tients were calculated.The changes of laboratory indexes before and after treatment were recorded.Logistic regression was used to analyze the related factors of fistula remission.All adverse reactions oc-curred during IFX treatment were recorded.RE-SULTS:After 54 weeks of IFX treatment,the fistula remission rate,clinical remission rate,and endo-scopic remission rate were 37.5％,45.83％,and 33.33％,respectively.Fistula response at 14 weeks of treatment(OR=19.419,95％CI:1.267-297.559,P=0.033)was predictive factors for fistula remission at 54 weeks of treatment.The inflammatory index-es and nutritional indexes were significantly im-proved compared with those before treatment(P＜0.01).The scores of PDAI,CDAI and SES-CD were significantly different from those before treatment(P＜0.01).Five patients(20.83％)had adverse reac-tions,and the symptoms disappeared or improved after symptomatic treatment,and no patient had serious adverse reactions.CONCLUSION:IFX can ef-fectively promote the closure of PFCD fistula,im-prove the chronic inflammatory reaction of intesti-nal mucosa,alleviate clinical symptoms,and im-prove the quality of life of patients.IFX is effective and safe for PFCD maintenance treatment.

AIM:To investigate the efficacy and safety of TACE combined with lenvatinib and PD-1 inhitibors for hepatocellular carcinoma(HCC)with portal vein tumor thrombus(PVTT).METHO DS:HCC patients with PVTT who received TACE combined with lenvatinib and PD-1 inhitibors as first-line ther-apy in clinical practice were included in this study retrospectively.Therapeutic outcomes of this regi-men were calculated based on the target lesions evaluated using mRECIST criteria.Additionally,all the subjects were followed up regularly to obtain the prognostic outcomes.Safety profile observed during the combination therapy was collected and documented specifically.Log-rank test was used for exploratory analysis between prognosis and base-line characteristics,and Cox regression analysis was adopted for multivariate analysis.RESULTS:A total of 67 HCC patients with PVTT who received TACE combined with lenvatinib and PD-1 inhitibors were included in this study ultimately,4 patients achieved complete response,30 patients were par-tial response,25 patients were stable disease,5 pa-tients were disease progression and 3 patients were not available for the response outcomes.Therefore,the objective response rate(ORR)of this regimen was 50.7％and disease control rate(DCR)was 88.1％.Prognostic data suggested that the me-dian progression free survival(PFS)of the 67 HCC patients with PVTT was 9.3 months(95％CI:5.85-12.75),and the median overall survival(OS)was 24.4 months(95％CI:19.11-29.69).Safety profile highlighted that a total of 65 patients experienced adverse reactions regardless of grade when re-ceived TACE combined with lenvatinib and PD-1 in-hitibors(97.0％),among whom,a total of 34 pa-tients were deemed as grade ≥3 adverse reactions(50.7％).The most common adverse reactions were hypertension,fatigue,abnormal liver function,nau-sea and vomiting and diarrhea.CONCLUSION:TACE combined with lenvatinib and PD-1 inhitibors as first-line therapy for HCC with PVTT demonstrated encouraging efficacy and acceptable safety profile.

AIM:To evaluate the effects of liposo-mal bupivacaine for interscalene brachial plexus block on postoperative analgesia and diaphragmat-ic function in patients undergoing arthroscopic ro-tator cuff repair surgery based on a randomized controlled trial.METHODS:Forty patients who scheduled to undergo arthroscopic rotator cuff re-pair surgery,regardless of gender,aged 18 to 65 years,ASA grade Ⅰ or Ⅱ were selected from October 2023 to February 2024.The patients were random-ly divided into bupivacaine liposome group(group LB)and the levobupivacaine group(group BV),with 20 cases in each group.Patients in both groups re-ceived an ultrasound-guided interscalene brachial plexus block,15 mL mixed liquids(bupivacaine lipo-some 10 mL+0.5％levobupivacaine 10 mL)were in-jected into the level of C5-C6 nerve roots and 5 mL onto the surface of prevertebral fascia in the LB group,and same volume of 0.375％levobupiva-caine were injected at the same sites in the BV group respectively.Standardized general anesthe-sia and standardized postoperative analgesia were followed.The primary outcome measures included 48 h rest/motor numerical rating scale(NRS)scores after surgery and the incidence of hemidiaphrag-matic paralysis(HDP)after block.The secondary outcome measures included rest/motor NRS scores at other time points after surgery,pulse oxygen sat-uration(SpO2)30 min after block,duration of sen-sory and motor block,number of analgesic pump presses,time of first postoperative used of opioid drugs and opioid consumption,use of additional analgesics in the wards,satisfaction with analgesia,and the occurrence of perioperative adverse ef-fects and neurological complications.RESULTS:Compared with group BV,patients in LB group showed lower rest NRS scores at 48 h postopera-tion(P＜0.05)and higher incidence of HDP at 24 h after block(45％vs.5.3％,P＜0.05).However,there was no significant difference in motor NRS scores at 48 h,HDP incidence at 30 min and 6 h after block between the two groups(P＞0.05).Both groups showed a decrease in SpO2 after block com-pared to before block(P＜0.05).Compared with BV group,patients in LB group had a significantly lon-ger duration of sensory and motor block(P＜0.01),fewer effective presses with the analgesic pump(P＜0.01),delay in first opioid use and less opioid con-sumption(P＜0.05),higher level of satisfaction with analgesia(P＜0.01),and a lower rate of use of addi-tional analgesics in the ward(P＜0.05).There was no statistically significant difference in the total in-traoperative remifentanil consumption,incidence of perioperative adverse reactions and neurological complication between the two groups(P＞0.05).CONCLUSION:Compared with using levobupiva-caine alone,the addition of liposomal bupivacaine for interscalene brachial plexus block in arthroscop-ic rotator cuff repair can reduce postoperative NRS scores,decrease postoperative opioid dosage and significantly prolong blockduration,but can easily lead to longer duration of HDP in patients.

AIM:To analyze the clinical value of predicting drug resistance in pulmonary tuberculo-sis patients based on improved machine learning models,and to build a visualization system for veri-fication.METHODS:Retrospectively selected 1 025 pulmonary tuberculosis patients hospitalized in Zhuhai Sixth People's Hospital from March 2019 to March 2024 with drug sensitivity test results as the research object.According to the definition of drug-resistant tuberculosis,the patients were divided in-to 631 sensitive groups(drug sensitivity test results showed no drug resistance),271 RR/MDR groups(meeting the definition of rifampicin resistant tu-berculosis or multi drug resistant tuberculosis,but no drug resistance to any kind of fluoroquino-lones),and 123 pre XDR groups(on the basis of multi drug resistant tuberculosis,and at the same time,drug resistance to any kind of fluoroquino-lones).Analyze clinical data based on the improved machine learning model,help build a drug resistant tuberculosis prediction model,synchronously com-plete feature screening,conduct value analysis on the screened features,and build a visual system for verification.RESULTS:Three groups of patients with baseline data comparison shows:Age,Body mass index(BMI),basic treatment of classification,lung diseases,haemoptysis,second-line drug use history,damage to lung,with empty in all statisti-cally significant difference between the three groups(P<0.05);Based on the modified ma-chine learning model,8 variables were screened,which were history of second-line drug use,BMI,treatment classification,destructive lung,underly-ing lung diseases,cavitation,hemoptysis,and age.The modified machine learning model had the high-est prediction accuracy compared with the tradi-tional model,with AUC values of 0.9322(RR/MDR prediction was positive class)and 0.9545(pre-XDR prediction was positive class).CONCLUSION:The application of the improved machine learning mod-el can help predict the occurrence of drug-resistant tuberculosis and assist the clinical formulation of more effective treatment plans.

Cytoglobin(Cygb)is a recently discov-ered astrocyte specific globin that is widely distrib-uted in mammalian visceral organs such as the lung,heart,spleen,liver,pancreas,stomach,small intestine,kidney,neuron,and bone tissue.It plays an important role in clearing reactive oxygen spe-cies,nitric oxide and nitrite signal transduction,al-leviating oxidative stress,anti-fibrosis,regulation of cell apoptosis and treatment of cancer,etc.It is worth noting that the anti-fibrosis role of Cygb has attracted increasing attention in recent years.The existing research has involved various fibrotic dis-eases such as the liver,pancreas,kidney,spleen,etc.,especially in the study of liver fibrosis,which has made great progress.This article system re-views the role of Cygb in various fibrotic diseases,with a focus on its mechanism of alleviating oxida-tive stress.Although the application of Cygb in fi-brotic diseases is still in its infancy and the underly-ing mechanisms still require extensive research and exploration,there is no doubt that Cygb can serve as a promising therapeutic target,with the poten-tial to be widely used in the prevention and treat-ment of fibrotic diseases.