Sonodynamic therapy (SDT) can potentially induce immunogenic cell death in tumor cells, leading to the release of ATP, and facilitating the initiation of an immune response. Nevertheless, the enzymes CD39 and CD73 can swiftly convert ATP into immunosuppressive adenosine (ADO), resulting in an immunosuppressive tumor microenvironment (TME). This study introduced a nanomedicine (QD/POM1@NP@M) engineered to reprogram TME by modulating the CD39/CD73/ADO pathway. The nanomedicine encapsulated sonosensitizers silver sulfide quantum dots, and the CD39 inhibitor POM1, while also incorporating homologous tumor cell membranes to enhance targeting capabilities. This integrated approach, on the one hand, stimulates the release of ATP via SDT, thereby initiating the immune response. In addition, it reduced the accumulation of ADO by inhibiting CD39 activity, which ameliorated the immunosuppressive TME. Upon administration, the nanomedicine demonstrated substantial anti-tumor efficacy by facilitating the infiltration of anti-tumor immune cells, while reducing the immunosuppressive cells. This modulation effectively transformed the TME from an immunologically "cold" state to a "hot" state. Furthermore, combined with the checkpoint inhibitor α-PDL1, the nanomedicine augmented systemic anti-tumor immunity and promoted the establishment of long-term immune memory. This study provides an innovative strategy for combining non-invasive SDT and ATP-driven immunotherapy, offering new ideas for future cancer treatment.

BACKGROUND:Topical administration of tranexamic acid can be used for anti-skin pigmentation,but its large polarity makes it difficult to break through the cuticle barrier and cell membrane when administered topically,and the subcutaneous accumulation concentration is not easy to reach the effective therapeutic concentration.OBJECTIVE:To design functionalized self-assembled micelles to enhance the anti-pigmentation effect of tranexamic acid.METHODS:The plant polyphenol derivative epigallocatechin gallate palmitate and metformin were used as carrier materials.The self-assembled micelles with synergistic anti-pigging activity and enhanced drug permeability were prepared by hydrogen bonding and electrostatic interaction.The nanoscale properties and stability of self-assembled drug-loaded micelles were tested,and their transdermal permeability was evaluated,and their biocompatibility and cellular effects were investigated.RESULTS AND CONCLUSION:(1)Functional self-assembled drug-carrying micelles with average particle size of(176.27±5.23)nm,polydispersity coefficient of 0.23±0.02,and the Zeta potential of(-25.67±0.98)mV had good stability.The mass concentrations of tranexamic acid and metformin in the self-assembled drug-carrying micelles were(20.03±0.12)and(6.67±0.08)mg/mL,respectively.The drug loadings of tranexamic acid and metformin in the self-assembled drug-carrying micelles were(19.97±0.12)％and(6.65±0.08)％,respectively.(2)In vitro transdermal results showed that the self-assembled drug-carrying micelles had higher penetration and intradermal retention per unit skin area,and could penetrate and diffuse to deeper parts of the skin.(3)MTT assay results demonstrated that undrug-loaded self-assembled micelles containing tranexamic acid 50-250 μg/mL had no toxic effects on mouse fibroblasts and mouse skin melanoma cells.The self-assembled drug-carrying micelles containing tranexamic acid 500 μg/mL had a slight toxic effect on mouse skin melanoma cells.The self-assembled drug-carrying micelles containing 50-500 μg/mL of tranexamic acid did not cause hemolysis and had good biological safety.(4)In vitro cell culture results showed that self-assembled drug-carrying micelles containing 500 μg/mL tranexamic acid could significantly inhibit the tyrosinase activity and melanin release of mouse skin melanoma cells,and the inhibitory effect was stronger than that of tranexamic acid solution or metformin solution alone.These results indicated that functionalized self-assembled micelles could synergize with tranexamic acid to inhibit tyrosinase activity,reduce melanin synthesis,and enhance the anti-skin pigmentation effect of tranexamic acid.

Objective To analyze the efficacy of the"sandwich"technique for treating varicocele(VC).Methods A total of 310 patients with VC(365 affected veins)were selected and divided into interventional treatment group and non-interventional treatment group.The baseline data,hospitalization data,and 6-month follow-up data of the two groups were analyzed.Results The age of patients in the interventional treatment group was significantly lower than that in the non-interventional treatment group(P＜0.05).The surgical time and hospital stay in the interventional treatment group were significantly lower than those in the non-interventional treatment group(P＜0.05).In the non-interventional treatment group,two patients experienced surgical site infections,and one patient opted for interventional treatment due to recurrence after non-interventional treatment.After surgery,the diameter of the spermatic vein significantly decreased in both the interventional and non-interventional treatment(P＜0.05).Conclusion The"sandwich"technique(embolization coil combined with foam sclerotherapy)is an effective treatment for VC.

Objective:To investigate the differential expression profiles of long non-coding RNAs(LncRNAs) and messenger RNAs(mRNAs) regulated by soluble dipeptidyl peptidase-4(sDPP4) during vascular smooth muscle cell calcification, and to explore the potential underlying calcification mechanisms.Methods:DPP4 levels in blood vessels and peripheral blood of diabetic patients were measured using Western blotting(WB) and real-time quantitative PCR(RT-qPCR). A cellular calcification model was established by treating human aortic vascular smooth muscle cells(HASMCs) with sDPP4. The effects of sDPP4 on HASMCs were assessed by WB, RT-qPCR, alizarin red staining, and calcium content determination. High-throughput sequencing was performed to analyze the differential expression profiles of LncRNA and mRNA following sDPP4 treatment. Among them, LncRNA ENST00000540293, which exhibited the most pronounced downregulation and was located adjacent to the matrix metalloproteinase-1(MMP-1) gene, was selected for further investigation. The osteogenic transdifferentiation of HASMCs after silencing LncRNA ENST00000540293 was evaluated using WB, RT-qPCR, alizarin red staining, and immunofluorescence-based cytoskeletal staining.Results:DPP4 expression was significantly elevated in both blood vessels and peripheral blood of diabetic patients. sDPP4 stimulation upregulated the protein levels of osteopontin(OPN) and runt-related transcription factor 2(RUNX2) in HASMCs, enhanced alizarin red staining, and increased intracellular calcium deposition. RNA sequencing revealed significant downregulation of LncRNA ENST00000540293 following sDPP4 exposure, while GO and pathway analysis indicated a marked increase in extracellular matrix binding activity(GO: 0050840). Silencing LncRNA ENST00000540293 suppressed α-smooth muscle actin(α-SMA) expression, promoted OPN and RUNX2 expression, increased calcification as shown by positive alizarin red staining, and cytoskeletal staining demonstrated osteogenic transdifferentiation of HASMCs, accompanied by a significant rise in MMP-1 protein level.Conclusion:sDPP4 promotes osteogenic transdifferentiation of HASMCs, potentially by downregulating LncRNA ENST00000540293. MMP-1 may be a potential target regulated by LncRNA ENST00000540293.

BACKGROUND:Topical administration of tranexamic acid can be used for anti-skin pigmentation,but its large polarity makes it difficult to break through the cuticle barrier and cell membrane when administered topically,and the subcutaneous accumulation concentration is not easy to reach the effective therapeutic concentration.OBJECTIVE:To design functionalized self-assembled micelles to enhance the anti-pigmentation effect of tranexamic acid.METHODS:The plant polyphenol derivative epigallocatechin gallate palmitate and metformin were used as carrier materials.The self-assembled micelles with synergistic anti-pigging activity and enhanced drug permeability were prepared by hydrogen bonding and electrostatic interaction.The nanoscale properties and stability of self-assembled drug-loaded micelles were tested,and their transdermal permeability was evaluated,and their biocompatibility and cellular effects were investigated.RESULTS AND CONCLUSION:(1)Functional self-assembled drug-carrying micelles with average particle size of(176.27±5.23)nm,polydispersity coefficient of 0.23±0.02,and the Zeta potential of(-25.67±0.98)mV had good stability.The mass concentrations of tranexamic acid and metformin in the self-assembled drug-carrying micelles were(20.03±0.12)and(6.67±0.08)mg/mL,respectively.The drug loadings of tranexamic acid and metformin in the self-assembled drug-carrying micelles were(19.97±0.12)％and(6.65±0.08)％,respectively.(2)In vitro transdermal results showed that the self-assembled drug-carrying micelles had higher penetration and intradermal retention per unit skin area,and could penetrate and diffuse to deeper parts of the skin.(3)MTT assay results demonstrated that undrug-loaded self-assembled micelles containing tranexamic acid 50-250 μg/mL had no toxic effects on mouse fibroblasts and mouse skin melanoma cells.The self-assembled drug-carrying micelles containing tranexamic acid 500 μg/mL had a slight toxic effect on mouse skin melanoma cells.The self-assembled drug-carrying micelles containing 50-500 μg/mL of tranexamic acid did not cause hemolysis and had good biological safety.(4)In vitro cell culture results showed that self-assembled drug-carrying micelles containing 500 μg/mL tranexamic acid could significantly inhibit the tyrosinase activity and melanin release of mouse skin melanoma cells,and the inhibitory effect was stronger than that of tranexamic acid solution or metformin solution alone.These results indicated that functionalized self-assembled micelles could synergize with tranexamic acid to inhibit tyrosinase activity,reduce melanin synthesis,and enhance the anti-skin pigmentation effect of tranexamic acid.

Objective:To investigate the differential expression profiles of long non-coding RNAs(LncRNAs) and messenger RNAs(mRNAs) regulated by soluble dipeptidyl peptidase-4(sDPP4) during vascular smooth muscle cell calcification, and to explore the potential underlying calcification mechanisms.Methods:DPP4 levels in blood vessels and peripheral blood of diabetic patients were measured using Western blotting(WB) and real-time quantitative PCR(RT-qPCR). A cellular calcification model was established by treating human aortic vascular smooth muscle cells(HASMCs) with sDPP4. The effects of sDPP4 on HASMCs were assessed by WB, RT-qPCR, alizarin red staining, and calcium content determination. High-throughput sequencing was performed to analyze the differential expression profiles of LncRNA and mRNA following sDPP4 treatment. Among them, LncRNA ENST00000540293, which exhibited the most pronounced downregulation and was located adjacent to the matrix metalloproteinase-1(MMP-1) gene, was selected for further investigation. The osteogenic transdifferentiation of HASMCs after silencing LncRNA ENST00000540293 was evaluated using WB, RT-qPCR, alizarin red staining, and immunofluorescence-based cytoskeletal staining.Results:DPP4 expression was significantly elevated in both blood vessels and peripheral blood of diabetic patients. sDPP4 stimulation upregulated the protein levels of osteopontin(OPN) and runt-related transcription factor 2(RUNX2) in HASMCs, enhanced alizarin red staining, and increased intracellular calcium deposition. RNA sequencing revealed significant downregulation of LncRNA ENST00000540293 following sDPP4 exposure, while GO and pathway analysis indicated a marked increase in extracellular matrix binding activity(GO: 0050840). Silencing LncRNA ENST00000540293 suppressed α-smooth muscle actin(α-SMA) expression, promoted OPN and RUNX2 expression, increased calcification as shown by positive alizarin red staining, and cytoskeletal staining demonstrated osteogenic transdifferentiation of HASMCs, accompanied by a significant rise in MMP-1 protein level.Conclusion:sDPP4 promotes osteogenic transdifferentiation of HASMCs, potentially by downregulating LncRNA ENST00000540293. MMP-1 may be a potential target regulated by LncRNA ENST00000540293.

Objective To analyze the efficacy of the"sandwich"technique for treating varicocele(VC).Methods A total of 310 patients with VC(365 affected veins)were selected and divided into interventional treatment group and non-interventional treatment group.The baseline data,hospitalization data,and 6-month follow-up data of the two groups were analyzed.Results The age of patients in the interventional treatment group was significantly lower than that in the non-interventional treatment group(P＜0.05).The surgical time and hospital stay in the interventional treatment group were significantly lower than those in the non-interventional treatment group(P＜0.05).In the non-interventional treatment group,two patients experienced surgical site infections,and one patient opted for interventional treatment due to recurrence after non-interventional treatment.After surgery,the diameter of the spermatic vein significantly decreased in both the interventional and non-interventional treatment(P＜0.05).Conclusion The"sandwich"technique(embolization coil combined with foam sclerotherapy)is an effective treatment for VC.

Objective To observe the effect of in situ needle fenestration thoracic endovascular aortic repair(TEVAR)for treating aortic dissection(AD)involving aortic arch.Methods Data of 16 patients with AD involving aortic arch who underwent in situ needle fenestration TEVAR for reconstruction of aortic arch branches were retrospectively analyzed,and the number of fenestration,technical success rate and TEVAR related complications were recorded.Regular follow-up was conducted after TEVAR,the repair of dissection and the patency of fenestrated branch blood vessels were evaluated,the endoleak was assessed,and the survival of patients were recorded.Results The main aortic stent was successfully implanted in all 16 cases.Among them,4 received triple fenestration stent implantation in zones Z0,Z1 and Z2,6 received double fenestration stent implantation in zones Z1 and Z2,2 received double fenestration stent implantation in zones Z0 and Z1 and 4 received single fenestration stent implantation in zone Z2.The success rate of brachiocephalic trunk(BCT)fenestration was 83.33%(5/6).Left common carotid artery(LCCA)-right common carotid artery bypass was performed in 1 case without successful fenestration.The success rate of LCCA fenestration was 100%(12/12).The success rate of left subclavian artery(LSA)fenestration was 87.50%(14/16),2 cases with not successful fenestration were treated with axillar-axillary artery artificial vascular bypass.The technical success rate of intervention was 100%(16/16).Type Ⅰa endoleak occurred in 1 case during TEVAR process and improved after embolization with spring coil.One patient died of pericardial tamponade at the end of TEVAR.Fifteen patients were followed up for a median follow-up time of 20 months.During this period,transient ischemic attack and local small dissection at the proximal beginning of the main stent occurred each in 1 case,which improved after no special treatment.Type Ⅰ endoleak occurred in 1 case,type Ⅲ endoleak occurred in 2 cases,all improved after proximal fenestrated membrane stent implantation or spring coil embolization treatment.One case died of coronary heart disease.Conclusion In situ needle fenestration TEVAR was effective and safe for treating AD involving aortic arch.

Objective To evaluate the medium-to-long-term efficacy of parallel stenting technology in treating aortoiliac occlusive disease(AIOD).Methods The clinical data of 18 patients with symptomatic AIOD,who received parallel stenting(using metal bare stent or covered stent)to reconstruct the aortoiliac artery at the Affiliated Hospital of Southwest Medical University of China from March 2017 to May 2019,were retrospectively analyzed.The patients included 14 males and 4 females with a mean age of(64.78±9.04)years.The surgical details,clinical success,complications,and stent patency rate were recorded.Results Both technical success and clinical success were achieved in all patients.A total of 62 stents were implanted,including 52 bare metal stents,9 covered stents and one renal artery balloon dilatation stent.After stent implantation,one patient each developed lacunar cerebral infarction,brachial artery pseudoaneurysm,decreased hemoglobin level,and thrombus migration into the renal artery,and after active management the patients were well discharged.The incidence of complications was 22％(4/18).During the follow-up period,3 patients developed in-stent restenosis,and the vascular lumen returned to patency after a second time of endovascular intervention.The postoperative 12-,18-,24-,30-,and 36-month main patency rates were 100％,95％,90％,85％,and 85％,respectively.Conclusion For the treatment of AIOD,parallel stenting technology has obtained satisfactory 3-year results.For the patients with complicated AIOD,this technique also carries a high technical success rate and an acceptable medium-to-long-term patency rate.

BACKGROUND:Premature birth is a major global health problem associated with high mortality and morbidity.White matter injury is the most common brain injury in preterm infants.Salvia miltiorrhiza is a traditional herbal plant that is commonly used to treat cardiovascular and cerebrovascular diseases in Asian countries. OBJECTIVE:To investigate the therapeutic effect of Salvia miltiorrhiza on white matter injury in preterm infants. METHODS:Eighteen neonatal male Sprague-Dawley rats at 3-day gestational age were selected and randomized into normal group,white matter injury group,and Salvia miltiorrhiza group.Animal models of preterm white matter injury were established by permanent ligation of the right common carotid artery in the latter two groups.Rats in the Salvia miltiorrhiza group were given intraperitoneal injection of Salvia miltiorrhiza(5 mg/kg·d)for 7 consecutive days.Normal group and white matter injury group were given the same volume of PBS for intervention.On the 14th day after modeling,the rats were sacrificed.Brains were pathologically observed by hematoxylin-eosin staining under microscope,and the expression levels of myelin basic protein and CC1 in brain tissue were visualized using immunofluorescence.Furthermore,liquid chromatography-tandem mass spectrometry was used to analyze possible pathways for the action of Salvia miltiorrhiza. RESULTS AND CONCLUSION:In the white matter injury group,the structure of the corpus callosum was irregular and the cells appeared swollen and necrotic.In addition,induction of white matter injury resulted in significantly reduced myelin formation,with irregular and loosely arranged nerve fibers and significantly decreased myelin sheaths.Interestingly,white matter injury rats treated with Salvia miltiorrhiza had reduced cellular swelling,reduced lesions,and increased myelin sheaths.The expression of myelin basic protein was closely related to myelin formation,and CC1 was a marker of myelin oligodendrocytes.Salvia miltiorrhiza significantly up-regulated the expressions of myelin basic protein and CC1 in white matter injury rats(P＜0.000 1),indicating that Salvia miltiorrhiza alleviated white matter injury.Liquid chromatography-tandem mass spectrometry analysis showed that the therapeutic effect of Salvia miltiorrhiza in the rat model of white matter injury was closely related to the regulation of complement and coagulation cascades.To conclude,Salvia miltiorrhiza may be a potential therapeutic agent for treating preterm white matter injury.