ObjectiveTo investigate the ameliorative effect of Wendantang combined with Danshenyin and Dushentang （WDD） on mice with ischemic heart disease （IHD） presenting phlegm-stasis syndrome based on the inflammatory phenotype and differentiation of circulating monocytes. MethodsA model of IHD with phlegm-stasis syndrome was established using left anterior descending coronary artery ligation supplemented with a high-fat diet. Eighty model mice were randomly assigned to the model group， WDD low-dose group （WDD-L）， WDD medium-dose group （WDD-M）， WDD high-dose group （WDD-H）， and atorvastatin calcium tablet group， with 16 mice in each group. An additional 16 C57BL/6J mice were designated as the sham-operation group. The WDD groups received intragastric administration at doses of 8.91， 17.81， 35.62 g·kg^-1， and the atorvastatin calcium tablet group received the corresponding drug at 1.3 mg·kg^-1， twice daily. The sham-operation and model groups were given the same volume of pure water by gavage each day. After 5 consecutive weeks of administration， the cardiac index was calculated. Cardiac function was assessed by echocardiography. Myocardial histopathology was examined by hematoxylin-eosin （HE） staining. Serum N-terminal pro-B-type natriuretic peptide （pro-BNP） content was measured by enzyme-linked immunosorbent assay （ELISA）. Hemorheological parameters were analyzed using an automated hemorheology analyzer. Serum levels of total cholesterol （TC）， triglycerides （TG）， low-density lipoprotein （LDL）， and high-density lipoprotein （HDL） were determined using an automated biochemical analyzer. Changes in circulating monocytes were detected by flow cytometry. Mouse bone marrow mononuclear cells were isolated in vitro and divided into blank group， model serum group， WDD-L drug-containing serum group， WDD-M drug-containing serum group， and WDD-H drug-containing serum group. CD36 expression and macrophage differentiation in each group were assessed by flow cytometry. The mechanism by which WDD mediates circulating monocyte differentiation was further explored using CD36 knockdown/overexpression RAW264.7 cell lines. ResultsCompared with the sham-operation group， the model group showed a significantly increased cardiac index （P0.01）， significantly decreased fractional shortening （FS） （P0.01）， and significantly increased left ventricular end-diastolic internal diameter （LVDD） and left ventricular end-systolic internal diameter （LVDS） （P0.01）. Cardiomyocytes exhibited marked deformation and necrosis with inflammatory cell infiltration. Serum pro-BNP levels were significantly elevated （P0.01）， and whole-blood viscosity （BV） at high， medium， and low shear rates was significantly increased （P0.01）. Compared with the model group， the WDD groups showed significantly reduced cardiac index （P0.05， P0.01）， significantly increased FS （P0.05， P0.01）， significantly decreased LVDD and LVDS （P0.01）， markedly improved cardiomyocyte morphology， significantly reduced inflammatory infiltration， significantly decreased serum pro-BNP levels （P0.01）， and significantly decreased BV at high， medium， and low shear rates （P0.01）， with the most pronounced improvement observed in the WDD-M group. Compared with the sham-operation group， TC， TG， and LDL levels were significantly increased in the model group （P0.05， P0.01）， while HDL levels were significantly decreased （P0.05）. After WDD-H treatment， TC， TG， and LDL levels were significantly reduced and HDL levels were significantly increased in mice （P0.05， P0.01）. Compared with the sham-operation group， classical monocytes in blood and bone marrow and intermediate monocytes in blood were significantly increased in the model group （P0.01）， whereas intermediate monocytes in bone marrow and non-classical monocytes in blood were significantly decreased （P0.01）. After WDD administration， all circulating monocyte subsets in blood and bone marrow were significantly alleviated （P0.05， P0.01）， with the WDD-M group showing the optimal effect. In vitro， compared with the blank group， CD36 expression on bone marrow monocytes and the proportion of differentiated macrophages were significantly increased in the model serum group （P0.01）， and CD36 expression was significantly upregulated on RAW264.7 cells （P0.01）. Compared with the model serum group， all drug-containing serum groups exhibited significantly reduced CD36 expression on bone marrow monocytes and significantly reduced macrophage differentiation （P0.01）. WDD downregulated CD36 expression in both CD36 knockdown and overexpression RAW264.7 cell lines （P0.05， P0.01）， with the strongest regulatory effect observed in the WDD-M drug-containing serum group. ConclusionWDD can significantly improve the manifestations of phlegm-stasis syndrome in IHD mice and reduce the proportion of classical circulating monocytes. Its mechanism may be related to the inhibition of CD36 expression on classical circulating monocytes.

ObjectiveTo investigate the ameliorative effect of Wendantang combined with Danshenyin and Dushentang （WDD） on mice with ischemic heart disease （IHD） presenting phlegm-stasis syndrome based on the inflammatory phenotype and differentiation of circulating monocytes. MethodsA model of IHD with phlegm-stasis syndrome was established using left anterior descending coronary artery ligation supplemented with a high-fat diet. Eighty model mice were randomly assigned to the model group， WDD low-dose group （WDD-L）， WDD medium-dose group （WDD-M）， WDD high-dose group （WDD-H）， and atorvastatin calcium tablet group， with 16 mice in each group. An additional 16 C57BL/6J mice were designated as the sham-operation group. The WDD groups received intragastric administration at doses of 8.91， 17.81， 35.62 g·kg^-1， and the atorvastatin calcium tablet group received the corresponding drug at 1.3 mg·kg^-1， twice daily. The sham-operation and model groups were given the same volume of pure water by gavage each day. After 5 consecutive weeks of administration， the cardiac index was calculated. Cardiac function was assessed by echocardiography. Myocardial histopathology was examined by hematoxylin-eosin （HE） staining. Serum N-terminal pro-B-type natriuretic peptide （pro-BNP） content was measured by enzyme-linked immunosorbent assay （ELISA）. Hemorheological parameters were analyzed using an automated hemorheology analyzer. Serum levels of total cholesterol （TC）， triglycerides （TG）， low-density lipoprotein （LDL）， and high-density lipoprotein （HDL） were determined using an automated biochemical analyzer. Changes in circulating monocytes were detected by flow cytometry. Mouse bone marrow mononuclear cells were isolated in vitro and divided into blank group， model serum group， WDD-L drug-containing serum group， WDD-M drug-containing serum group， and WDD-H drug-containing serum group. CD36 expression and macrophage differentiation in each group were assessed by flow cytometry. The mechanism by which WDD mediates circulating monocyte differentiation was further explored using CD36 knockdown/overexpression RAW264.7 cell lines. ResultsCompared with the sham-operation group， the model group showed a significantly increased cardiac index （P<0.01）， significantly decreased fractional shortening （FS） （P<0.01）， and significantly increased left ventricular end-diastolic internal diameter （LVDD） and left ventricular end-systolic internal diameter （LVDS） （P<0.01）. Cardiomyocytes exhibited marked deformation and necrosis with inflammatory cell infiltration. Serum pro-BNP levels were significantly elevated （P<0.01）， and whole-blood viscosity （BV） at high， medium， and low shear rates was significantly increased （P<0.01）. Compared with the model group， the WDD groups showed significantly reduced cardiac index （P<0.05， P<0.01）， significantly increased FS （P<0.05， P<0.01）， significantly decreased LVDD and LVDS （P<0.01）， markedly improved cardiomyocyte morphology， significantly reduced inflammatory infiltration， significantly decreased serum pro-BNP levels （P<0.01）， and significantly decreased BV at high， medium， and low shear rates （P<0.01）， with the most pronounced improvement observed in the WDD-M group. Compared with the sham-operation group， TC， TG， and LDL levels were significantly increased in the model group （P<0.05， P<0.01）， while HDL levels were significantly decreased （P<0.05）. After WDD-H treatment， TC， TG， and LDL levels were significantly reduced and HDL levels were significantly increased in mice （P<0.05， P<0.01）. Compared with the sham-operation group， classical monocytes in blood and bone marrow and intermediate monocytes in blood were significantly increased in the model group （P<0.01）， whereas intermediate monocytes in bone marrow and non-classical monocytes in blood were significantly decreased （P<0.01）. After WDD administration， all circulating monocyte subsets in blood and bone marrow were significantly alleviated （P<0.05， P<0.01）， with the WDD-M group showing the optimal effect. In vitro， compared with the blank group， CD36 expression on bone marrow monocytes and the proportion of differentiated macrophages were significantly increased in the model serum group （P<0.01）， and CD36 expression was significantly upregulated on RAW264.7 cells （P<0.01）. Compared with the model serum group， all drug-containing serum groups exhibited significantly reduced CD36 expression on bone marrow monocytes and significantly reduced macrophage differentiation （P<0.01）. WDD downregulated CD36 expression in both CD36 knockdown and overexpression RAW264.7 cell lines （P<0.05， P<0.01）， with the strongest regulatory effect observed in the WDD-M drug-containing serum group. ConclusionWDD can significantly improve the manifestations of phlegm-stasis syndrome in IHD mice and reduce the proportion of classical circulating monocytes. Its mechanism may be related to the inhibition of CD36 expression on classical circulating monocytes.

Objective To compare the application value of direct arteriovenous fistula(AVF),after ultrasound-guided percutaneous transluminal angioplasty(PTA)dilation of radial artery AVF formation and reverse"J"arteriovenous graft(AVG)in hemodialysis patients with small diameter vessels.Methods Totally 96 end-stage renal disease patients with distal radial artery＜1.5 mm and cephalic vein≥2.0 mm who planning to receive hemodialysis were retrospectively enrolled.The patients were divided into AVF group(n=30),PTA+AVF group(n=34)and AVG group(n=32)according to fistulization methods.The technical success rate,clinical success rate,primary patency rate and secondary patency rate were compared among groups.Results The technical success rate of AVF group,PTA+AVF group and AVG group was 80.00%,94.12%and 100%,respectively,and the clinical success rate was 30.00%,82.35%and 93.75%,respectively,with significant differences among 3 groups(both P＜0.05).The primary patency rate 1,3,6,9 and 12 months after fistulization in AVF group was 80.00%,30.00%,27.59%,27.59%and 24.14%,respectively,in PTA+AVF group was 94.12%,82.35%,78.79%,68.75%and 62.50%,respectively,while in AVG group was 100%,93.33%,83.33%,76.67%and 66.67%,respectively,all being significant different among 3 groups(all P＜0.05).The secondary patency rate 1,3,6,9 and 12 months after fistulization in AVF group was 83.33%,75.00%,75.00%,70.83%and 58.33%,respectively,in PTA+AVF group was 93.33%,93.33%,83.33%,83.33%and 80.00%,respectively,while in AVG group was 100%,100%,93.33%,90.00%and 80.00%,respectively,also being significant different among 3 groups(all P＜0.05).Conclusion Compared with direct and after ultrasound-guided PTA dilation of radial artery AVF formation,AVG formation was more valuable for hemodialysis patients with small diameter vessels.

Objective To investigate the impact and underlying mechanism of curcumin(Cur)on the aberrant proliferation and migration of VSMC.Methods VSMC was treated with Ang Ⅱ to establish a cell proliferation model.The experiment included blank control group,model group,and low-,medium-and high-dose Cur treatment groups(1.5,3.0 and 4.5 pmol/L,n=11).To explore the effect of Cur on the AMPK/mTOR signaling pathway,VSMC was also assigned into blank control,Ang Ⅱ(10-6 mol/L),Cur(3.0 μmol/L)and Ang Ⅱ+Cur groups(n=3).Western blotting was employed to detect the expression of VSMC differentiation markers(α-SMA),dedif-ferentiation marker(OPN),autophagy-related proteins(P62 and Beclin-1),and proteins involved in the AMPK/mTOR pathway(AMPK,p-AMPK,mTOR,p-mTOR,p70S6K,p-p70S6K).Results Exposure to Ang Ⅱ enhanced the proliferation and migration of VSMC when compared with the blank control group(155％vs 100％,66％vs 48％,P＜0.05).When compared with the model group,the proliferative rate was significantly lower in the medium-and high-dose Cur groups,and the migratory rate was obviously decreased in the three Cur groups(P＜0.05).The α-SMA expression was increased in the medium-and high-dose Cur groups,and that of OPN was decreased in the three Cur groups when compared with the model group(P＜0.05).Enhanced Be-clin-1 and p-AMPK/AMPK and down-regulated P62,p-mTOR/mTOR,and p-p70S6K/p70S6K were observed in the Ang Ⅱ and Cur groups than the blank control group(P＜0.05).The Cur Ang Ⅱ and Cur+AngⅡ groups had notably higher Beclin-1 and p-AMPK/AMPK but lower P62,p-mTOR/mTOR,and p-p70S6K/p70S6K than the Ang Ⅱ group(P＜0.05).Conclusion Cur in-hibits the proliferation and migration of VSMC induced by Ang Ⅱ,potentially through its activa-ting the AMPK/mTOR signaling pathway and enhancing autophagy in VSMC.

Objective To compare the application value of direct arteriovenous fistula(AVF),after ultrasound-guided percutaneous transluminal angioplasty(PTA)dilation of radial artery AVF formation and reverse"J"arteriovenous graft(AVG)in hemodialysis patients with small diameter vessels.Methods Totally 96 end-stage renal disease patients with distal radial artery＜1.5 mm and cephalic vein≥2.0 mm who planning to receive hemodialysis were retrospectively enrolled.The patients were divided into AVF group(n=30),PTA+AVF group(n=34)and AVG group(n=32)according to fistulization methods.The technical success rate,clinical success rate,primary patency rate and secondary patency rate were compared among groups.Results The technical success rate of AVF group,PTA+AVF group and AVG group was 80.00%,94.12%and 100%,respectively,and the clinical success rate was 30.00%,82.35%and 93.75%,respectively,with significant differences among 3 groups(both P＜0.05).The primary patency rate 1,3,6,9 and 12 months after fistulization in AVF group was 80.00%,30.00%,27.59%,27.59%and 24.14%,respectively,in PTA+AVF group was 94.12%,82.35%,78.79%,68.75%and 62.50%,respectively,while in AVG group was 100%,93.33%,83.33%,76.67%and 66.67%,respectively,all being significant different among 3 groups(all P＜0.05).The secondary patency rate 1,3,6,9 and 12 months after fistulization in AVF group was 83.33%,75.00%,75.00%,70.83%and 58.33%,respectively,in PTA+AVF group was 93.33%,93.33%,83.33%,83.33%and 80.00%,respectively,while in AVG group was 100%,100%,93.33%,90.00%and 80.00%,respectively,also being significant different among 3 groups(all P＜0.05).Conclusion Compared with direct and after ultrasound-guided PTA dilation of radial artery AVF formation,AVG formation was more valuable for hemodialysis patients with small diameter vessels.

Objective To explore the primary patency rate and impact factors of autogenous arteriovenous fistula success after preop-erative ultrasound-guided percutaneous transluminal angioplasty(PTA)in patient with small-caliber artery on maintenance hemodialysis(MHD).Methods We included 128 end-stage renal disease patients with distal radial artery diameters＜1.5mm,treated with ultra-sound-guided percutaneous transluminal angioplasty(PTA)to establish an arteriovenous fistula(AVF)at Guizhou Medical University Affiliated Tumor Hospital between January 1,2019 and December 31,2021.Patients were classified into failure and patency groups based on AVF patency.We assessed the surgical technical success rate,clinical success rate,and primary patency rate,and analyzed factors af-fecting AVF failure.Results In these patients,the technical success rate of AVF creation after PTA was 91.4％,the clinical success rate was 83.6％,and the 12-month primary patency rate was 54.4％.Female gender,diabetes,and a preoperative radial artery diame-ter ≤ 1 mm were independent risk factors for AVF failure after PTA(P＜0.05).Conclusion Establishing AVF after PTA dilation of ar-teries in patients with small-caliber arteries undergoing maintenance hemodialysis has a high technical success rate and primary patency rate.Diabetes,female gender,and preoperative radial artery diameter ≤1.Omm are independent risk factors for AVF failure in these pa-tients.

Objective To study the influence of imaging parameters on the dosimetric parameters of the lung in intensity modulated radiotherapy(IMRT)for thoracic esophageal cancer,and provide a guideline for dose limitation in IMRT for thoracic esophageal cancer.Methods The imaging and pulmonary dosimetric parameters were collected from 142 patients with thoracic esophageal cancer receiving IMRT at Chongqing University Three Gorges Hospital from February 2017 to January 2019.The linear correlation analysis between the im-aging parameters and pulmonary dosimetric parameters was conducted using bivariate Pearson test.The regression model was established by multiple linear regression.Results The maximum transverse diameter of planning target volume(PTV)was moderately correlated with lung V30 and mean lung dose(MLD,both 0.40,all P<0.05).The volume of PTV intersecting with the lung was moderately positively correlated with lung V20,V30,and MLD(all 0.4

Objective To investigate the impact and underlying mechanism of curcumin(Cur)on the aberrant proliferation and migration of VSMC.Methods VSMC was treated with Ang Ⅱ to establish a cell proliferation model.The experiment included blank control group,model group,and low-,medium-and high-dose Cur treatment groups(1.5,3.0 and 4.5 pmol/L,n=11).To explore the effect of Cur on the AMPK/mTOR signaling pathway,VSMC was also assigned into blank control,Ang Ⅱ(10-6 mol/L),Cur(3.0 μmol/L)and Ang Ⅱ+Cur groups(n=3).Western blotting was employed to detect the expression of VSMC differentiation markers(α-SMA),dedif-ferentiation marker(OPN),autophagy-related proteins(P62 and Beclin-1),and proteins involved in the AMPK/mTOR pathway(AMPK,p-AMPK,mTOR,p-mTOR,p70S6K,p-p70S6K).Results Exposure to Ang Ⅱ enhanced the proliferation and migration of VSMC when compared with the blank control group(155％vs 100％,66％vs 48％,P＜0.05).When compared with the model group,the proliferative rate was significantly lower in the medium-and high-dose Cur groups,and the migratory rate was obviously decreased in the three Cur groups(P＜0.05).The α-SMA expression was increased in the medium-and high-dose Cur groups,and that of OPN was decreased in the three Cur groups when compared with the model group(P＜0.05).Enhanced Be-clin-1 and p-AMPK/AMPK and down-regulated P62,p-mTOR/mTOR,and p-p70S6K/p70S6K were observed in the Ang Ⅱ and Cur groups than the blank control group(P＜0.05).The Cur Ang Ⅱ and Cur+AngⅡ groups had notably higher Beclin-1 and p-AMPK/AMPK but lower P62,p-mTOR/mTOR,and p-p70S6K/p70S6K than the Ang Ⅱ group(P＜0.05).Conclusion Cur in-hibits the proliferation and migration of VSMC induced by Ang Ⅱ,potentially through its activa-ting the AMPK/mTOR signaling pathway and enhancing autophagy in VSMC.

BACKGROUND: Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation and joint destruction. Iguratimod (IGU) is a novel conventional synthetic disease-modifying antirheumatic drugs (csDMARD) with good efficacy and safety for the treatment of active RA in China and Japan. However, the long-term effects of IGU on the progression of bone destruction or radiographic progression in patients with active RA remain unknown. We aimed to investigate the efficacy and safety of iguratimod (IGU), a combination of methotrexate (MTX) and IGU, and IGU in patients with active rheumatoid arthritis (RA) who were naïve to MTX. METHODS: This multicenter, double-blind, randomized, non-inferiority clinical trial was conducted at 28 centers for over 52 weeks in China. In total, 911 patients were randomized (1:1:1) to receive MTX monotherapy (10-15 mg weekly, n = 293), IGU monotherapy (25 mg twice daily, n = 297), or IGU + MTX (10-15 mg weekly for MTX and 25 mg twice daily for IGU, n = 305) for 52 weeks. The patients' clinical characteristics, Simplified Disease Activity Index (SDAI), Clinical Disease Activity Index (CDAI), disease activity score in 28 joints-C-reactive protein (DAS28-CRP) level, and disease activity score in 28 joints-erythrocyte sedimentation rate (DAS28-ESR) were assessed at baseline. The primary endpoints were the proportion of patients with ≥20% improvement according to the American College of Rheumatology (ACR20) response and changes in the van der Heijde-modified total Sharp score (vdH-mTSS) at week 52. RESULTS: The proportions of patients achieving an ACR20 response at week 52 were 77.44%, 77.05 %, and 65.87% for IGU monotherapy, IGU + MTX, and MTX monotherapy, respectively. The non-inferiority of IGU monotherapy to MTX monotherapy was established with the ACR20 (11.57%; 95% confidence interval [CI], 4.35-18.79%; P <0.001) and vdH-mTSS (-0.37; 95% CI, -1.22-0.47; P = 0.022). IGU monotherapy was also superior to MTX monotherapy in terms of ACR20 ( P = 0.002) but not the vdH-mTSS. The superiority of IGU + MTX over MTX monotherapy was confirmed in terms of the ACR20 (11.18%; 95% CI, 3.99-18.37%; P = 0.003), but not in the vdH-mTSS (-0.68; 95% CI, -1.46-0.11; P = 0.091). However, the difference in the incidence rates of adverse events was not statistically significant. CONCLUSIONS: IGU monotherapy/IGU + MTX showed a more favorable clinical response than did MTX monotherapy. IGU may have some clinical benefits over MTX in terms of radiographic progression, implying that IGU may be considered as an initial therapeutic option for patients with active RA. TRIAL REGISTRATION https://classic.clinicaltrials.gov/ , NCT01548001.
Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Antirheumatic Agents/therapeutic use* ; Arthritis, Rheumatoid/drug therapy* ; Chromones/adverse effects* ; Double-Blind Method ; Drug Therapy, Combination ; Methotrexate/adverse effects* ; Treatment Outcome ; Sulfonamides

Ferroptosis is a form of programmed cell death characterized by overwhelmed lipid oxidation, and it has emerged as a promising strategy for cancer therapy. Enhanced ferroptosis could overcome the limitations of conventional therapeutic modalities, particularly in difficult-to-treat tumors. In this study, we developed a dual-modality therapy in nanomedicine by combining paclitaxel (PTX) chemotherapy and pyropheophorbide-a (Ppa) phototherapy. Heparin (HP) was grafted with poly(N-(2'-hydroxy) propyl methacrylamide) (pHPMA) using reversible addition-fragmentation chain transfer polymerization to form HP-pHPMA (HH), which was utilized to deliver Ppa and PTX, yielding HP-pHPMA-Ppa (HH-Ppa) and HP-pHPMA-PTX (HH-PTX), respectively. The prodrug-based combinational nanomedicine (HH-PP) was formed by co-assembly of HH-PTX and HH-Ppa. It was found that HH-PP treatment significantly disrupted lipid metabolism in triple-negative breast cancer (TNBC) cells, induced extensive lipid oxidation, and promoted ferroptosis. In vivo, HH-PP intervention achieved a tumor growth inhibition rate of 86.63% and activated adaptive immunity with an elevated CD8⁺ cytotoxic T cell infiltration level. This combinational nanomedicine offers a promising platform for co-delivery of multiple therapeutic agents. It exerts a promising anti-tumor effect via enhanced ferroptosis and ferroptosis-induced immune activation by disrupting lipid metabolism in TNBC cancer cells.