ObjectiveTo investigate the potential mechanism of Renshen Yangrongtang in alleviating myelosuppression by regulating the expression of reactive oxygen species （ROS）， myeloperoxidase （MPO）， and neutrophil extracellular traps （NETs）. MethodsK562 cells were divided into blank group， etoposide group （40 μmol·L^-1）， and etoposide+Renshen Yangrongtang freeze-dried powder groups with low-， medium-， and high-dose （2， 4， 8 g·L^-1）. Liquid chromatography-mass spectrometry （LC-MS） was used to determine the freeze-dried powder of Renshen Yangrongtang. Enzyme-Linked Immunosorbent Assay （ELISA） was used to detect ROS， MPO， and NETs expression in each group. Western blot analysis was performed to assess intracellular MPO and NE expressions. Twenty 8-week-old male mice were randomly divided into blank group， etoposide group （100 mg·kg^-1）， and etoposide + Renshen Yangrongtang groups with low-， medium-， and high-dose （0.1， 0.5， 2.0 g·kg^-1）. Except for the blank group that received PBS via gavage at room temperature， and the etoposide group that received an intraperitoneal injection for 3 days， the remaining groups received gavage of Renshen Yangrongtang for 14 consecutive days after 3 days of etoposide administration. The peripheral blood related indicators were detected through an automated hematology analyzer； Western blot analysis was performed to assess MPO and neutrophil elastase （NE） expression changes in the marrow cells of mice. Enzyme-linked immunosorbent assay （ELISA） was used to detect ROS， MPO， and NETs changes in the marrow cells of mice. MPO and NE on femur bones were stained through immunohistochemistry. Scanning electron microscopy was used to analyze the structural changes of NETs in the marrow cells of mice after drug administration. ResultsLC-MS results showed that the freeze-dried powder of Renshen Yangrongtang contained complete technical materials such as Chinese angelica， Astragalus mongholicus， and ginseng. In K562 cells， compared with the etoposide group， ELISA results indicated that the concentrations of MPO， ROS， and NETs in the etoposide + Renshen Yangrongtang medium and high-dose groups were decreased （P<0.05， P<0.01）， and Western blot data showed that the etoposide high-dose group significantly reduced the expression of MPO and NE protein in K562 cells （P<0.05， P<0.01）. In vivo， compared with the etoposide group， the number of RBC， WBC， and PLT in the etoposide+Renshen Yangrongtang high-dose group increased significantly （P<0.05）. ELISA results suggested that in the etoposide+Renshen Yangrongtang low-， medium-， and high-dose groups， the concentration of mice ROS， MPO， and NETs significantly decreased （P<0.05， P<0.01）. Western blot results revealed that compared with the etoposide group， the expressions of MPO and NE in the marrow cells of mice in the etoposide + Renshen Yangrongtang low-， medium- and high-dose groups were significantly decreased （P<0.05， P<0.01）. Scanning electron microscopy observations revealed that Renshen Yangrongtang reduced the NETs structure generation in the marrow cells of mice after the influence of etoposide. ConclusionRenshen Yangrongtang can alleviate etoposide-induced myelosuppression by inhibiting ROS/MPO and reducing the formation of intracellular NETs.

OBJECTIVE To explore the effects of isorhamnetin on the development of gastric cancer through up-regulation of solute carrier family 25 member 25 antisense RNA 1（SLC25A25-AS1）. METHODS Using BALB/c nude mice as the subjects， the xenograft tumor model was established by subcutaneously inoculating human gastric cancer MKN28 cells into the axillary region. The effects of low and high doses of isorhamnetin （20 and 40 mg/kg） on the tumor volume and mass in nude mice were investigated. MKN28 cells were selected and divided into control group， isorhamnetin group （70 μmol/L， similarly hereinafter）， isorhamnetin+knocking down negative control group， isorhamnetin+knocking down SLC25A25-AS1 group， isorhamnetin+ overexpression negative control group and isorhamnetin+overexpressing SLC25A25-AS1 group. Effects of knocking down/ overexpressing SLC25A25-AS1 on viability， apoptosis， migration and invasion ability of isorhamnetin-treated cells were detected. After verifying the targeting relationships between microRNA-212-3p （miR-212-3p） and SLC25A25-AS1， as well as phosphatase and tensin homologue deleted on chromosome 10 （PTEN）， the effects of knocking down/overexpressing SLC25A25-AS1 on the expression of miR-212-3p， PTEN mRNA， and PTEN protein in isorhamnetin-treated cells were investigated. RESULTS Compared with the model control group， tumor volume and mass of nude mice in the isorhamnetin low-dose and high-dose groups were reduced significantly， and the isorhamnetin high-dose group was significantly lower than the isorhamnetin low-dose group （P＜0.05）. miR-212-3p had targeting relationships with SLC25A25-AS1 and PTEN. Compared with the control group， the cell viability （intervened for 24， 48 h）， migration number， invasion number and miR-212-3p expression of cells in the isorhamnetin group， isorhamnetin+knocking down negative control group and isorhamnetin+overexpressing negative control group were significantly reduced or decreased or down-regulated， while the apoptosis rate， mRNA and protein expressions of PTEN were significantly increased or up-regulated （P＜0.05）. Compared with isorhamnetin group and isorhamnetin+knocking down negative control group， the cell viability， migration number， invasion number and miR-212-3p expression of cells in the isorhamnetin+knocking down SLC25A25-AS1 group were significantly increased or up- regulated， while the apoptosis rate， mRNA and protein expressions of PTEN were significantly reduced or down-regulated （P＜ 0.05）. Compared with isorhamnetin group and isorhamnetin+overexpressing negative control group， the cell viability， migration number， invasion number and miR-212-3p expression of cells in isorhamnetin+overexpressing SLC25A25-AS1 group were significantly reduced or decreased or down-regulated， while the apoptosis rate， PTEN mRNA and protein expressions were significantly increased or up-regulated （P＜0.05）. CONCLUSIONS Isorhamnetin may inhibit the development of gastric cancer by up-regulating the expression of SLC25A25-AS1， down-regulating miR-212-3p， and up-regulating the expression of PTEN， which is a downstream target of miR-212-3p.

Purpose: This Phase II trial was objected to evaluate the efficacy and safety of adding fulvestrant to neoadjuvant chemotherapy in patients with estrogen receptor (ER)+/human epidermal growth factor receptor 2 (HER2)– locally advanced breast cancer (LABC). Additionally, the study aimed to investigate the association of 16α-18F-fluoro-17β-fluoroestradiol (18F-FES) positron emission tomography (PET)–computed tomography (CT) and metabolites with efficacy. Materials and Methods: Fulvestrant and EC-T regimen were given to ER+/HER2– LABC patients before surgery. At baseline, patients received 18F-FES PET-CT scan, and plasma samples were taken for liquid chromatography–mass spectrometry analysis. The primary endpoint was objective response rate (ORR). Secondary endpoints included total pathologic complete response (tpCR) and safety. Results: Among the 36 patients enrolled, the ORR was 86.1%, the tpCR rate was 8.3%. The incidence of grade ≥ 3 treatment-emergent adverse events was 22%. The decrease in ER value in sensitive patients was larger than that in non-sensitive patients, as was Ki-67 (p < 0.05). The maximum standardized uptake value, mean standardized uptake values, total lesion ER expression of 18F-FES PET-CT in sensitive patients were significantly higher than those in non-sensitive patients (p < 0.05). Moreover, these parameters were significantly correlated with Miller and Payne grade and the change in ER expression before and after treatment (p < 0.05). Thirteen differential expressed metabolites were identified, which were markedly enriched in 19 metabolic pathways. Conclusion This regimen demonstrated acceptable toxicity and encouraging antitumor efficacy. 18F-FES PET-CT might serve as a tool to predict the effectiveness of this therapy. Altered metabolites or metabolic pathways might be associated with treatment response.

Background: s/Aims: Non-invasive models stratifying clinically significant portal hypertension (CSPH) are limited. Herein, we developed a new non-invasive model for predicting CSPH in patients with compensated cirrhosis and investigated whether carvedilol can prevent hepatic decompensation in patients with high-risk CSPH stratified using the new model. Methods: Non-invasive risk factors of CSPH were identified via systematic review and meta-analysis of studies involving patients with hepatic venous pressure gradient (HVPG). A new non-invasive model was validated for various performance aspects in three cohorts, i.e., a multicenter HVPG cohort, a follow-up cohort, and a carvediloltreating cohort. Results: In the meta-analysis with six studies (n=819), liver stiffness measurement and platelet count were identified as independent risk factors for CSPH and were used to develop the new “CSPH risk” model. In the HVPG cohort (n=151), the new model accurately predicted CSPH with cutoff values of 0 and –0.68 for ruling in and out CSPH, respectively. In the follow-up cohort (n=1,102), the cumulative incidences of decompensation events significantly differed using the cutoff values of <–0.68 (low-risk), –0.68 to 0 (medium-risk), and >0 (high-risk). In the carvediloltreated cohort, patients with high-risk CSPH treated with carvedilol (n=81) had lower rates of decompensation events than non-selective beta-blockers untreated patients with high-risk CSPH (n=613 before propensity score matching [PSM], n=162 after PSM). Conclusions Treatment with carvedilol significantly reduces the risk of hepatic decompensation in patients with high-risk CSPH stratified by the new model.

Purpose: This Phase II trial was objected to evaluate the efficacy and safety of adding fulvestrant to neoadjuvant chemotherapy in patients with estrogen receptor (ER)+/human epidermal growth factor receptor 2 (HER2)– locally advanced breast cancer (LABC). Additionally, the study aimed to investigate the association of 16α-18F-fluoro-17β-fluoroestradiol (18F-FES) positron emission tomography (PET)–computed tomography (CT) and metabolites with efficacy. Materials and Methods: Fulvestrant and EC-T regimen were given to ER+/HER2– LABC patients before surgery. At baseline, patients received 18F-FES PET-CT scan, and plasma samples were taken for liquid chromatography–mass spectrometry analysis. The primary endpoint was objective response rate (ORR). Secondary endpoints included total pathologic complete response (tpCR) and safety. Results: Among the 36 patients enrolled, the ORR was 86.1%, the tpCR rate was 8.3%. The incidence of grade ≥ 3 treatment-emergent adverse events was 22%. The decrease in ER value in sensitive patients was larger than that in non-sensitive patients, as was Ki-67 (p < 0.05). The maximum standardized uptake value, mean standardized uptake values, total lesion ER expression of 18F-FES PET-CT in sensitive patients were significantly higher than those in non-sensitive patients (p < 0.05). Moreover, these parameters were significantly correlated with Miller and Payne grade and the change in ER expression before and after treatment (p < 0.05). Thirteen differential expressed metabolites were identified, which were markedly enriched in 19 metabolic pathways. Conclusion This regimen demonstrated acceptable toxicity and encouraging antitumor efficacy. 18F-FES PET-CT might serve as a tool to predict the effectiveness of this therapy. Altered metabolites or metabolic pathways might be associated with treatment response.

Background: s/Aims: Non-invasive models stratifying clinically significant portal hypertension (CSPH) are limited. Herein, we developed a new non-invasive model for predicting CSPH in patients with compensated cirrhosis and investigated whether carvedilol can prevent hepatic decompensation in patients with high-risk CSPH stratified using the new model. Methods: Non-invasive risk factors of CSPH were identified via systematic review and meta-analysis of studies involving patients with hepatic venous pressure gradient (HVPG). A new non-invasive model was validated for various performance aspects in three cohorts, i.e., a multicenter HVPG cohort, a follow-up cohort, and a carvediloltreating cohort. Results: In the meta-analysis with six studies (n=819), liver stiffness measurement and platelet count were identified as independent risk factors for CSPH and were used to develop the new “CSPH risk” model. In the HVPG cohort (n=151), the new model accurately predicted CSPH with cutoff values of 0 and –0.68 for ruling in and out CSPH, respectively. In the follow-up cohort (n=1,102), the cumulative incidences of decompensation events significantly differed using the cutoff values of <–0.68 (low-risk), –0.68 to 0 (medium-risk), and >0 (high-risk). In the carvediloltreated cohort, patients with high-risk CSPH treated with carvedilol (n=81) had lower rates of decompensation events than non-selective beta-blockers untreated patients with high-risk CSPH (n=613 before propensity score matching [PSM], n=162 after PSM). Conclusions Treatment with carvedilol significantly reduces the risk of hepatic decompensation in patients with high-risk CSPH stratified by the new model.

Purpose: This Phase II trial was objected to evaluate the efficacy and safety of adding fulvestrant to neoadjuvant chemotherapy in patients with estrogen receptor (ER)+/human epidermal growth factor receptor 2 (HER2)– locally advanced breast cancer (LABC). Additionally, the study aimed to investigate the association of 16α-18F-fluoro-17β-fluoroestradiol (18F-FES) positron emission tomography (PET)–computed tomography (CT) and metabolites with efficacy. Materials and Methods: Fulvestrant and EC-T regimen were given to ER+/HER2– LABC patients before surgery. At baseline, patients received 18F-FES PET-CT scan, and plasma samples were taken for liquid chromatography–mass spectrometry analysis. The primary endpoint was objective response rate (ORR). Secondary endpoints included total pathologic complete response (tpCR) and safety. Results: Among the 36 patients enrolled, the ORR was 86.1%, the tpCR rate was 8.3%. The incidence of grade ≥ 3 treatment-emergent adverse events was 22%. The decrease in ER value in sensitive patients was larger than that in non-sensitive patients, as was Ki-67 (p < 0.05). The maximum standardized uptake value, mean standardized uptake values, total lesion ER expression of 18F-FES PET-CT in sensitive patients were significantly higher than those in non-sensitive patients (p < 0.05). Moreover, these parameters were significantly correlated with Miller and Payne grade and the change in ER expression before and after treatment (p < 0.05). Thirteen differential expressed metabolites were identified, which were markedly enriched in 19 metabolic pathways. Conclusion This regimen demonstrated acceptable toxicity and encouraging antitumor efficacy. 18F-FES PET-CT might serve as a tool to predict the effectiveness of this therapy. Altered metabolites or metabolic pathways might be associated with treatment response.

Background: s/Aims: Non-invasive models stratifying clinically significant portal hypertension (CSPH) are limited. Herein, we developed a new non-invasive model for predicting CSPH in patients with compensated cirrhosis and investigated whether carvedilol can prevent hepatic decompensation in patients with high-risk CSPH stratified using the new model. Methods: Non-invasive risk factors of CSPH were identified via systematic review and meta-analysis of studies involving patients with hepatic venous pressure gradient (HVPG). A new non-invasive model was validated for various performance aspects in three cohorts, i.e., a multicenter HVPG cohort, a follow-up cohort, and a carvediloltreating cohort. Results: In the meta-analysis with six studies (n=819), liver stiffness measurement and platelet count were identified as independent risk factors for CSPH and were used to develop the new “CSPH risk” model. In the HVPG cohort (n=151), the new model accurately predicted CSPH with cutoff values of 0 and –0.68 for ruling in and out CSPH, respectively. In the follow-up cohort (n=1,102), the cumulative incidences of decompensation events significantly differed using the cutoff values of <–0.68 (low-risk), –0.68 to 0 (medium-risk), and >0 (high-risk). In the carvediloltreated cohort, patients with high-risk CSPH treated with carvedilol (n=81) had lower rates of decompensation events than non-selective beta-blockers untreated patients with high-risk CSPH (n=613 before propensity score matching [PSM], n=162 after PSM). Conclusions Treatment with carvedilol significantly reduces the risk of hepatic decompensation in patients with high-risk CSPH stratified by the new model.

OBJECTIVE: To investigate the potential mechanism by which electroacupuncture (EA) induces macrophage polarization to promote muscle satellite cell proliferation and differentiation, accelerating the repair of acute skeletal muscle injury. METHODS: Forty-two SPF-grade SD rats were randomly divided into three groups: a blank group (n=6), a model group (n=18), and an EA group (n=18). The model and EA groups established acute blunt contusion model of the right gastrocnemius muscle using a self-made striking device. From day 1 after modeling, rats in the EA group received EA at "Chengshan" (BL57) and "Yanglingquan" (GB34) on the right side, using disperse-dense wave with a frequency of 2 Hz/100 Hz and a current of approximately 2 mA. The EA treatment was administered once daily for 30 minutes for 3, 7, or 14 days based on the designated sampling time points. Gait analysis was performed using the Cat Walk XT^TM system. Hematoxylin-eosin (HE) staining was used to observe the morphological changes in the gastrocnemius muscle. Masson staining was applied to evaluate collagen fiber content. Immunofluorescence was used to detect the expression of proliferating cell nuclear antigen (PCNA) in muscle satellite cells. Immunohistochemistry was used to assess the expression levels of CD68 and CD206, markers of macrophages. Serum levels of pro-inflammatory cytokines (TNF-α, IL-1β) and anti-inflammatory cytokines (IL-10, IL-13) were detected using ELISA. RESULTS: Compared with the blank group, the model group showed a significant reduction in average movement speed on days 3 and 7 after modeling (P<0.05), and a decrease in the right hind limb stride length on day 3 (P<0.05). Compared with the model group, the EA group showed increased average movement speed and right hind limb stride length on day 7 (P<0.05). In the blank group, the gastrocnemius muscle on the right side showed uniform and consistent inter-fiber spacing, with neatly and regularly arranged muscle cells. In contrast, the model group exhibited enlarged inter-fiber spacing, edema, and significant infiltration of red blood cells and inflammatory cells, with progressively increasing fibrosis over time. By day 14 after modeling, the EA group showed a return to baseline levels of inflammatory cell infiltration, and the degree of fibrosis was significantly lower than that observed in the model group. Compared with the blank group, the ratio of collagen fibers in the gastrocnemius muscle of the model group increased significantly on days 3, 7, and 14 after modeling (P<0.05). Compared with the model group, the EA group exhibited a lower collagen fiber ratio on days 3, 7, and 14 (P<0.05). Compared with the blank group, PCNA positive expression in the gastrocnemius muscle of the model group was significantly increased on days 3, 7, and 14 after modeling (P<0.05). Compared with the model group, the EA group exhibited significantly higher PCNA positive expression on days 3 and 7 (P<0.05). Compared with the blank group, the model group showed a significant increase in CD68-positive macrophage expression in the gastrocnemius muscle on day 3 after modeling (P<0.05), while CD206-positive macrophage expression increased on days 3, 7, and 14 (P<0.05). Compared with the model group, CD68 expression was significantly lower in the EA group on day 3 (P<0.05), whereas CD206 expression was significantly higher on days 3 and 7 (P<0.05), peaking on day 7 with CD206 expression. Compared with the blank group, serum TNF-α levels were significantly elevated in the model group on days 3 and 7 after modeling (P<0.05), while serum IL-1β levels were increased on days 3, 7, and 14 (P<0.05). Serum IL-10 and IL-13 levels were significantly higher on day 7 after modeling (P<0.05). Compared with the model group, the EA group exhibited lower serum TNF-α level on day 3 (P<0.05) and reduced serum IL-1β levels on days 3 and 7 (P<0.05), while serum IL-10 and IL-13 levels were significantly increased on day 7 (P<0.05). CONCLUSION EA could promote the repair of acute blunt contusion-induced gastrocnemius muscle injury by regulating the proliferation and differentiation of muscle satellite cells. This process is closely related to macrophage polarization.
Animals ; Electroacupuncture ; Rats, Sprague-Dawley ; Rats ; Macrophages/immunology* ; Muscle, Skeletal/immunology* ; Male ; Humans ; Female ; Tumor Necrosis Factor-alpha/immunology* ; Cell Proliferation

BACKGROUND: The available evidence regarding the benefits of percutaneous coronary intervention (PCI) on patients receiving dialysis with coronary artery disease (CAD) is limited and inconsistent. This study aimed to evaluate the association between PCI and clinical outcomes as compared with medical therapy alone in patients undergoing dialysis with CAD in China. METHODS: This multicenter, retrospective study was conducted in 30 tertiary medical centers across 12 provinces in China from January 2015 to June 2021 to include patients on dialysis with CAD. The primary outcome was major adverse cardiovascular events (MACE), defined as a composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke. Secondary outcomes included all-cause death, the individual components of MACE, and Bleeding Academic Research Consortium criteria types 2, 3, or 5 bleeding. Multivariable Cox proportional hazard models were used to assess the association between PCI and outcomes. Inverse probability of treatment weighting (IPTW) and propensity score matching (PSM) were performed to account for potential between-group differences. RESULTS: Of the 1146 patients on dialysis with significant CAD, 821 (71.6%) underwent PCI. After a median follow-up of 23.0 months, PCI was associated with a 43.0% significantly lower risk for MACE (33.9% [ n  = 278] vs . 43.7% [ n  = 142]; adjusted hazards ratio 0.57, 95% confidence interval 0.45-0.71), along with a slightly increased risk for bleeding outcomes that did not reach statistical significance (11.1% vs . 8.3%; adjusted hazards ratio 1.31, 95% confidence interval, 0.82-2.11). Furthermore, PCI was associated with a significant reduction in all-cause and cardiovascular mortalities. Subgroup analysis did not modify the association of PCI with patient outcomes. These primary findings were consistent across IPTW, PSM, and competing risk analyses. CONCLUSION This study indicated that PCI in patients on dialysis with CAD was significantly associated with lower MACE and mortality when comparing with those with medical therapy alone, albeit with a slightly increased risk for bleeding events that did not reach statistical significance.
Humans ; Percutaneous Coronary Intervention/methods* ; Male ; Female ; Coronary Artery Disease/drug therapy* ; Retrospective Studies ; Renal Dialysis/methods* ; Middle Aged ; Aged ; China ; Proportional Hazards Models ; Treatment Outcome