Nanocarrier-based drug delivery systems can provide new research strategies for targeted intervention at atherosclerosis （AS） lesions by regulating the in vivo distribution and release behavior of drugs. Existing studies have shown that polymeric and lipid nanocarriers， cell membrane-coated systems， and microenvironment-responsive drug delivery strategies can intervene in the pathological progression of AS by modulating macrophage function， promoting cholesterol efflux， and controlling inflammation and oxidative stress； some systems have attempted to achieve multi-target synergistic intervention through combined delivery and theranostics； some drug delivery systems can improve drug enrichment in lesions and modulate related pathological processes. However， their long-term safety， lesion-targeting stability， scale-up manufacturing， and incremental clinical benefit remain to be validated. In the future， it is necessary to strengthen the matching between delivery mechanisms and pathological features and to establish evaluation systems for pharmacokinetics and safety， thereby providing a basis for the clinical translation of nanocarrier-based drug delivery systems.

Objective To explore the significance of the toxicity mechanism of butyl benzyl phthalate(BBP)in prevention and treatment of pulmonary fibrosis.Methods In this study,we used network toxicology combined with molecular docking technology to screen the targets of BBP and those related to pulmonary fibrosis through PubChem,GeneCards and other databases,and analyzed the intersecting genes by using a Wayne diagram.Protein-protein interaction networks were constructed to screen the core targets,and the pathway mechanisms were revealed by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes.Finally,molecular docking using AutoDock was performed to verify the binding patterns of core targets and BBP.Results A total of 91 potential targets of BBP-induced lung fibrosis were screened,among which PTGS2 and CYP3A4 were the core targets(binding energies of-1.84 kcal/mol and-1.68 kcal/mol,respectively).Enrichment analysis showed that BBP regulated the fibrosis process through G protein-coupled receptor signaling pathway,calcium signaling pathway and cyclic adenosine monophosphate signaling pathway.Molecular docking confirmed that BBP was stably bound to the core target through hydrogen bonding and hydrophobic interaction.Conclusion This study provides preliminary insights into the molecular mechanism of BBP-induced pulmonary fibrosis through network toxicology,and PTGS2 and CYP3A4 may play key roles in BBP-induced pulmonary fibrosis,which provides a novel reference for the exploration of the mechanism of toxicant-disease association.

Debates persist regarding the efficacy and safety of azvudine, particularly its real-world outcomes. This study involved patients aged ≥60 years who were admitted to 25 hospitals in mainland China with confirmed SARS-CoV-2 infection between December 1, 2022, and February 28, 2023. Efficacy outcomes were all-cause mortality during hospitalization, the proportion of patients discharged with recovery, time to nucleic acid-negative conversion (T _NANC), time to symptom improvement (T _SI), and time of hospital stay (T _HS). Safety was also assessed. Among the 5884 participants identified, 1999 received azvudine, and 1999 matched controls were included after exclusion and propensity score matching. Azvudine recipients exhibited lower all-cause mortality compared with controls in the overall population (13.3% vs. 17.1%, RR, 0.78; 95% CI, 0.67-0.90; P = 0.001) and in the severe subgroup (25.7% vs. 33.7%; RR, 0.76; 95% CI, 0.66-0.88; P < 0.001). A higher proportion of patients discharged with recovery, and a shorter T _NANC were associated with azvudine recipients, especially in the severe subgroup. The incidence of adverse events in azvudine recipients was comparable to that in the control group (2.3% vs. 1.7%, P = 0.170). In conclusion, azvudine showed efficacy and safety in older patients hospitalized with COVID-19 during the SARS-CoV-2 omicron wave in China.

Objective To explore the significance of the toxicity mechanism of butyl benzyl phthalate(BBP)in prevention and treatment of pulmonary fibrosis.Methods In this study,we used network toxicology combined with molecular docking technology to screen the targets of BBP and those related to pulmonary fibrosis through PubChem,GeneCards and other databases,and analyzed the intersecting genes by using a Wayne diagram.Protein-protein interaction networks were constructed to screen the core targets,and the pathway mechanisms were revealed by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes.Finally,molecular docking using AutoDock was performed to verify the binding patterns of core targets and BBP.Results A total of 91 potential targets of BBP-induced lung fibrosis were screened,among which PTGS2 and CYP3A4 were the core targets(binding energies of-1.84 kcal/mol and-1.68 kcal/mol,respectively).Enrichment analysis showed that BBP regulated the fibrosis process through G protein-coupled receptor signaling pathway,calcium signaling pathway and cyclic adenosine monophosphate signaling pathway.Molecular docking confirmed that BBP was stably bound to the core target through hydrogen bonding and hydrophobic interaction.Conclusion This study provides preliminary insights into the molecular mechanism of BBP-induced pulmonary fibrosis through network toxicology,and PTGS2 and CYP3A4 may play key roles in BBP-induced pulmonary fibrosis,which provides a novel reference for the exploration of the mechanism of toxicant-disease association.

Objective:To explore the efficacy of PVP combined with zoledronic acid in the treatment of postmenopausal osteoporotic vertebral fractures.Method:90 patients with postmenopausal osteoporotic vertebral fractures treated in our hospital from Jul. 2018 to Aug. 2020 were selected. According to different treatment methods, the patients were divided into observation group and control group. The patients in both groups were treated with PVP. The patients in the control group were given oral alendronate, calcitriol capsules and calcium, and the patients in the observation group were given zoledronic acid injection, calcitriol capsules and calcium were taken orally for 1 year. BMD of lumbar spine, femoral neck, greater trochanter and ward triangle, lumbar ODI index and VAS score, serum BGP and β-CTX, PINP levels and adverse reactions during treatment. Results:One year after operation, the lumbar ODI index and VAS score of the observation group were significantly lower than those of the control group ( P<0.05), and the BMD of lumbar spine, femoral neck, greater trochanter and ward triangle were higher than those of the control group ( P<0.05). The levels of serum BGP, β-CTX and PINP levels in the two groups were significantly higher than those in the control group ( P<0.05) . Conclusion:Zoledronic acid can significantly improve bone metabolism, accelerate bone formation, increase BMD, reduce low back pain and improve lumbar function in patients with osteoporotic vertebral compression fracture after PVP.

Since the 1970s， patients with chronic pancreatitis （CP） have benefited from total pancreatectomy with autologous islet cell transplantation （TPAIT）. With the continuous development of surgical techniques and perioperative management over the past few decades， there have been improvements in islet cell function， insulin independence rate， and the survival rate of patients. This article summarizes the preoperative indications for TPAIT， the development of surgical operations， postoperative management and monitoring， and prognosis， so as to help clinicians learn more about TPAIT.

OBJECTIVE: To explore the genetic etiology for a Chinese pedigree affected with Lesch-Nyhan syndrome. METHODS: Members of the pedigree who had visited the Genetic Counseling Clinic of Linyi People's Hospital on February 10, 2022 were selected as the study subjects. Clinical data and family history of the proband were collected, and trio-whole exome sequencing (trio-WES) was carried out for the proband and his parents. Candidate variants were verified by Sanger sequencing. RESULTS: Trio-WES revealed that both the proband and his cousin brother had harbored a hemizygous c.385-1G>C variant in intron 4 of the HPRT1 gene, which was unreported previously. A heterozygous c.385-1G>C variant of the HPRT1 gene was also found in the proband's mother, grandmother, two aunts, and a female cousin, whilst all phenotypically normal males in his pedigree were found to have a wild type for the locus, which has conformed to an X-linked recessive inheritance. CONCLUSION The heterozygous c.385-1G>C variant of the HPRT1 gene probably underlay the Lesch-Nyhan syndrome in this pedigree.
Male ; Humans ; Female ; Lesch-Nyhan Syndrome/genetics* ; Pedigree ; East Asian People ; Heterozygote ; Introns ; Mutation

Objective:To observe the effect of high expression of polypyrimidine tract-binding protein-associated splicing factor (PSF) on low concentration of 4-hydroxynonenal (4-HNE) induced human retinal microvascular endothelial cells (HRMECs), and explore the possible mechanism.Methods:The HRMECs cultured in vitro were divided into 4-HNE treated group, PSF overexpression group combined with 4-HNE group (PSF+4-HNE group), PSF overexpression+ML385 treatment combined with 4-HNE group (PSF+ML385+4-HNE group), and 4-HNE induced PSF overexpression group with LY294002 pretreatment (LY294002+4-HNE+PSF group). Cell culture medium containing 10 μmmol/L 4-HNE was added into 4-HNE treatment group, PSF+4-HNE group, PSF+ML385+4-HNE group for 12 hours to stimulate oxidative stress. 1.0 μg of pcDNA-PSF eukaryotic expression plasmid were transfected into PSF+4-HNE group and PSF+ML385+4-HNE group to achieve the overexpression of PSF. Also cells were pretreated with ML385 (5 μmol/L) for 48 hours in the PSF+ML385+4-HNE group, meanwhile within the LY294002+4-HNE+PSF group, after pretreatment with LY294002, cells were treated with plasmid transfection and 4-HNE induction. Transwell detects the migration ability of PSF to HRMECs. The effect of PSF on the lumen formation of HRMECs was detected by using Matrigel in vitro three-dimensional molding method. Flow cytometer was used to detect the effect of PSF overexpression on reactive oxygen (ROS) level in HRMECs. Protein immunoblotting was used to detect the relative expression of PSF, nuclear factor E2 related factor 2 (Nrf2), heme oxygenase-1 (HO-1) protein, and phosphoserine threonine protein kinase (pAkt) protein. The comparison between the two groups was performed using a t-test. Results:The number of live cells, migrating cells, and intact lumen formation in the 4-HNE treatment group and the PSF+4-HNE group were 1.70±0.06, 0.80±0.13, 24.00±0.58, 10.00±0.67, and 725.00±5.77, 318.7±12.13, respectively. There were significant differences in the number of live cells, migrating cells, and intact lumen formation between the two groups ( t=12.311, 15.643, 17.346; P<0.001). The results of flow cytometry showed that the ROS levels in the 4-HNE treatment group, PSF+4-HNE group, and PSF+ML385+4-HNE group were 816.70±16.67, 416.70±15.44, and 783.30±17.41, respectively. There were statistically significant differences between the two groups ( t=16.311, 14.833, 18.442; P<0.001). Western blot analysis showed that the relative expression levels of pAkt, Nrf2, and HO-1 proteins in HRMECs in the 4-HNE treatment group, PSF+4-HNE group and LY294002+4-HNE+PSF group were 0.08±0.01, 0.57±0.04, 0.35±0.09, 0.17±0.03, 1.10±0.06, 0.08±0.11 and 0.80±0.14, 2.50±0.07, 0.50±0.05, respectively. Compared with the PSF+4-HNE group, the relative expression of pAkt, Nrf2, and HO-1 proteins in the LY294002+4-HNE+PSF group decreased significantly, with significant differences ( t=17.342, 16.813, 18.794; P<0.001). Conclusion:PSF upregulates the expression of HO-1 by activating the phosphatidylinositol 3 kinase/Akt pathway and inhibits cell proliferation, migration, and lumen formation induced by low concentrations of 4-HNE.

Objective To investigate the clinical efficacy of hepatic artery ringed and restriction operation-associating liver partition and portal vein ligation for staged hepatectomy (HARO-ALPPS) in the treatment of giant hepatocellular carcinoma.Methods The retrospective and descriptive study was conducted.Clinical data of a 45-year-old male patient with giant hepatocellular carcinoma who was admitted to the First Affiliated Hospital of Guangxi Medical University in July 2018 were collected.In the first stage operation,right portal vein ligation+ in situ liver partition + right hepatic artery ringed operation was performed on the patient.In the second stage operation,right hemihepatectomy was performed on the patient.Observation indicators:(1) surgical and postoperative situations of the first stage operation;(2) surgical and postoperative situations of the second stage operation;(3) postoperative pathological examination;(4) changes in future liver remnant (FLR) and tumor volume;(5) perioperative hemodynamic changes of right hepatic artery,proper hepatic artery and left hepatic artery;(6) perioperative hemodynamic changes of left-portal vein and main portal vein;(7) follow-up.Follow-up using outpatient examination was performed to detect the prognosis of patients up to February 2019.Count data were described as absolute number.Results (1) Surgical and postoperative situations of the first stage operation:the patient underwent right portal vein ligation+ in situ liver partition+ right hepatic artery ringed operation successfully.The operation time and volume of intraoperative blood loss were 376 minutes and 400 mL.Inflammatory indicators including body temperature,white blood cells (WBC),C-reactive protein,procalcitonin,and liver function indices including total bilirubin (TBil),albumin (Alb),alanine aminotransferase (ALT),aspartate aminotransferase (AST),ascites,indocyanine green retention rate at15 min (ICG R15),score of model for end-stage liver disease (MELD) before the second stage operation were improved after symptomatic supportive treatment.Prothrombin time (PT) was in the normal range after the first stage operation.There was no complication of Clavien-Dindo classification Ⅱ or above.(2) Surgical and postoperative situations of the second stage operation:the patient underwent right hemihepatectomy successfully.The operation time and volume of intraoperative blood loss were 322 minutes and 900 mL.The patient received 300 mL of fresh frozen plasma infusion.Inflammatory indicators including body temperature,C-reactive protein,and liver function indices including Alb,ALT,AST,ascites,were recoved to normal level after symptomatic supportive treatment.WBC,procalcitonin,TBil,and PT were in the normal range.There was no complication of Clavien-Dindo classification Ⅱ or above.(3) Postoperative pathological examination:① Ⅱ stage hepatocellular carcinoma was confirmed,mass-like type,with tissue necrosis and microvascluar invasion.There was no distal metastasis and tumor did not invade liver capsule or surgical margin.Ishak score of surrounding tissues was 3 in the inflammation and 2 in the fibrosis.② Chronic inflammation was detected in the gallbladder mucosa.③ Reactive hyperplasia was found in the 2 lymph nodes of the group 8.④ One in the group 12 lymph nodes showed reactive hyperplasia.Immunohistochemistry showed positive Glypican-3,Hepatocyte,Arginase-1,NM23,weakly positive vascular endothelial growth factor,and negative Ki-67,vascular endothelial cell marker CD34,biliary epithelial marker CK19 and CK 7,tumor suppressor gene P21 and P23.(4) Changes in FLR and tumor volume:FLR was 565 mL and 580 mL at the 5th and 14th day after the first stage operation respectively,accounting for 54％ and 57％ of total liver volume.The FLR to body weight ratio was 0.96 and 0.98,and the growth rate of FLR was 194％ and 202％.Tumor volume was 1 210 mL and 1 297 mL at the 5th and 14th day after the first stage operation respectively.Tumor necrosis volume was 635 mL and 500 mL at the 5th and 14th day after the first stage operation respectively.At the 5th and 14th day after the first stage operation,the liver CT examination showed that HARO was successfully underwent and the blood supply of remnant liver was good.Preoperative CT aothgraphy (CTA) examination showed that the right hepatic tumor had rich arterial blood supply.At the 5th day after the first stage operation,the CTA examination confirmed the ringed site of right hepatic artery,and the blood supply of the tumor gradually decreased.At the 14th day after the first stage operation,CTA examination showed significant decrease in the blood supply of liver tumors.Liver CT examination showed rich supply of the remnant liver and the liver volume of 829 mL at the 7th day after the second stage operation.(5) Perioperative hemodynamic changes of the right hepatic artery,proper hepatic artery and left hepatic artery.① Blood flow of right hepatic artery was 224.3,574.7,827.5,222.7,153.0,282.5,279.1,247.9 and 150.2 mL/min before the first stage operation,before right portal vein ligation,after right portal vein ligation and before right hepatic artery ringed and restriction,after right portal vein ligation and right hepatic artery ringed and restriction,at the 1st,3th,5th and 7th day after the first stage operation.Blood flow of right hepatic artery in the second stage operation was 505.0 mL/min.② Blood flow of proper hepatic artery was 399.7,793.5,830.5,1 075.4,784.7.5,821.2,722.8,467.4 and 555.4 mL/min before the first stage operation,before right portal vein ligation,after right portal vein ligation and before right hepatic artery ringed and restriction,after right portal vein ligation and right hepatic artery ringed and restriction,at the 1st,3th,5th and 7th day after the first stage operation.Blood flow of proper hepatic artery was 505.0,473.3,158.5,627.0,103.8 and 139.8 mL/min before right hepatectomy in the second stage operation,after right hepatectomy,at the 1st,3th and 5th day after the second operation,respectively.③ Blood flow of left hepatic artery was 147.5,13.8,19.4,16.2,62.1,93.9,67.1,30.8 and 106.1 mL/min before the first stage operation,before right portal vein ligation,after right portal vein ligation and before right hepatic artery ringed and restriction,after right portal vein ligation and right hepatic artery ringed and restriction,at the 1st,3th,5th,7th and 10th day after the first stage operation.Blood flow ot left hepatic artery was 52.0,43.2,112.4,103.6,80.7 and 56.1 mL/min before right hepatectomy in the second stage operation,after right hepatectomy,at the 1st,3th and 5th day after the second operation,respectively.(6) Perioperative hemodynamic changes of left-portal vein and main portal vein.① Blood flow of left portal vein was 552.6,181.2,412.2,320.0,1 777.7,1 284.7,749.5 and 484.2 mL/min before the first stage operation,before right portal vein ligation,after right portal vein ligation and right hepatic artery ringed and restriction,at the 1st,3th,5th,7th and 10th day after the first stage operation,respectively.Blood flow of left portal vein was 793.3,979.0,485.2,1 042.5,803.5 and 548.3 mL/min before right hepatectomy in the second stage operation,after right hepatectomy,at the 1st,3th,5th and 7th day after the second operation respectively.② Blood flow of main portal vein was 1 186.0,696.7,833.7,431.7,1 319.1,668.4,890.7,550.8 mL/min before the first stage operation,before right portal vein ligation,after right portal vein ligation and right hepatic artery ringed and restriction,at the 1st,3th,5th,7th and 10th day after the first stage operation,respectively.Blood flow of main portal vein was 846.4,937.4,891.2,1 671.0,2 697.8,and 1 230.0 mL/min before right hepatotectomy in the second stage operation,after right hepatectomy,at the 1st,3th,5th and 7th day after the second stage operation,respectively.(7) Follow up:the patient was followed up for 6 months and survived well,with Child A of liver function and normal alpha fetoprotein level.Liver contrast CT examination showed increase in the remnant liver,good blood supply,and no tumor recurrence.The FLR was 727 mL at the 2 months after operation.Conclusion For patients with giant hepatocellular carcinoma,HARO-ALPPS can be performed to decrease blood supply of tumor,increase tumor necrosis area,and reduce the incidence of intrahepatic arteriovenous fistula,which ensure blood supply of remnant liver hyperplasia.

BACKGROUND: At present, there is evidence that domestic porous tantalum has good biocompatibility and osteogenic properties, but the specific osteogenic mechanism and its effect on osteogenic factors are still unclear. OBJECTIVE: To observe the effects of domestic porous tantalum materials on the expression of collagen type I, tissue transglutaminase-2 and calcium-binding protein A4 in MG63 cells. METHODS: MG63 cells in logarithmic growth phase were inoculated onto 24-well plates and cultured in three groups: in blank group, conventional medium was added; in tantalum extract group, porous tantalum material extract was added; and in tantalum scaffold group, porous tantalum material and conventional medium were added. On 1, 3, 5, 7 and 9 days of culture, the cell proliferation of each group was detected by cell counting kit-8 method. On 5 days of culture, the levels of collagen type I, tissue transglutaminase-2 and calcium-binding protein A4 secreted by MG63 cells in each group were detected by ELISA. Western blot assay was used to detect the expression of three proteins in each group. RESULTS AND CONCLUSION: (1) With the prolongation of culture time, the number of cells in each group increased gradually. There was no difference in cell proliferation among the three groups at different time points (P> 0.05). (2) The secretory levels of collagen type I and tissue transglutaminase-2 in the tantalum scaffold group were significantly higher than those in the blank group and tantalum extract group (P < 0.05), while the secretion of collagen type I and tissue transglutaminase-2 in the tantalum extract group was significantly higher than that in the blank group (P < 0.05). The secretion of calcium-binding protein A4 in the tantalum scaffold group was significantly lower than that in the other two groups (P < 0.05). (3) The expression of collagen type I and tissue transglutaminase-2 protein in the tantalum scaffold group was significantly higher than that in the blank group and tantalum extract group (P < 0.05), while the expression of collagen type I and tissue transglutaminase-2 protein in the tantalum extract group was significantly higher than that in the blank group (P < 0.05). The expression of calcium-binding protein A4 in the tantalum scaffold group was significantly lower than that in the blank group and tantalum extract group (P < 0.05). To conclude, domestic porous tantalum materials could promote the secretion of collagen type I and tissue transglutaminase-2 by MG63 cells, and inhibit the secretion of calcium-binding protein A4.