Abstract:Objective To explore the effects of sulforaphane(SFN)on Aβ42-activated U87 astrocyte-mediated apoptosis of SH-SY5Y neurons in vitro.Methods U87 cells treated with different concentrations of Aβ42,SFN or both were examined for changes in cell activity,IL-6 and TNF-α mRNA expression,release of IL-6 and TNF-α proteins,and expressions of p-p38,p-p65 and GFAP using CCK-8 assay,RT-qPCR,ELISA and Western blotting.SH-SY5Y neurons were co-cultured with U87 astrocytes treated with Aβ42 alone or in combination with SFN or SB203580 for 24 h,and the changes in Bax protein expression levels and viability of SH-SY5Y cells were examined.The effects of Aβ42,SFN,and their combination were also observed in astrocytes isolated from mouse brain tissues,and the indirect effects of astrocyte treatmentt on viability of the co-cultured primary neurons were assessed.Results The viability of U87 astrocytes increased significantly following treatment with 1.25 μmol/L Aβ 42 but decreased after Aβ42 treatment above 5 μmol/L.SFN treatments for 24 h below 5 μmol/L did not significantly affect U87 cell viability.Aβ42 treatment significantly increased protein expressions of p-p38,p-p65 and GFAP,mRNA expression levels of IL-6 and TNF-α,and IL-6 and TNF-α levels in culture supernatant of U87 cells.SH-SY5Y cells co-cultured with Aβ42-treated U87 cells showed significantly increased protein expressions of Bax,and exhibited lowered viability following co-culture with 5 μmol/L Aβ42-treated U87 cells.The isolated mouse astrocytes showed lowered viability following Aβ42 treatment above 10 μmol/L,but SFN treatment below 5 μmol/L for 24 did not obviously affect the cell viability.The primary neurons co-cultured with Aβ42-treated mouse astrocytes showed significantly lower cell viability than those co-cultured with the astrocytes treated with Aβ+SFN or Aβ+SB203580.Conclusion SFN attenuates astrocyte-mediated neuron apoptosis by inhibiting the MAPK/NF-κB signaling pathway in Aβ42 oligomer-activated astrocytes.

Abstract:Depression is a complex and globally prevalent mental disorder,for which conventional antidepressant medications face limitations such as delayed onset and insufficient efficacy.Classic psychedelics,most notably psilocybin,have recently emerged as promising candidates for treatment of depression and demonstrated rapid,robust,and sustained antidepressant effects in controlled clinical settings.Their unique mechanisms of action and clinical prospects have become a key research focus in psychiatry and neuroscience.This review synthesizes the latest advances in the field over the past 5 years.Results from multiple randomized controlled trials indicate that a single or limited number of sessions of psychedelic-assisted psychotherapy can induce rapid and durable antidepressant effects in patients with treatment-resistant depression.At the mechanistic level,psychedelics rapidly promote the release of neurotrophic factors,enhance neuroplasticity,and facilitate brain network reorganization,thereby creating a critical"neuroplastic window"for psychotherapeutic intervention.However,the specific molecular and circuit-level mechanisms have not been fully understood with ongoing debate primarily over the 5-HT2A receptor-dependent hypothesis versus the TrkB neurotrophic pathway-dependent hypothesis.Despite the promising outlook,translational applications of these substances faces several key challenges,including psychedelic-related risks,incomplete mechanistic understanding,lack of standardized treatment protocols,and insufficient long-term safety data.Future research should focus on elucidating the underlying neurobiological mechanisms,developing non-hallucinogenic derivatives,establishing standardized treatment frameworks,and identifying precise biomarkers to advance this therapeutic approach toward safer,more standardized,and personalized clinical implementation.

Abstract:Objective To evaluate the efficacy and safety of super electroconvulsive therapy(ECT)for treatment-resistant depression(TRD).Methods This cohort study was conducted among 292 patients with TRD,who received super ECT from December,2024 to June,2025.Eighty-eight of the patients received one electrical stimulation in each super ECT procedure(E1 group),89 had 2 electrical stimulations(E2 group),and 39 had 3 electrical stimulations(E3 group).The correlation between depression,anxiety and sleep quality at baseline was analyzed.The patients were evaluated using 17-items Hamilton Depression Scale(HAMD-17)at 1,3,and 6 months after the first super ECT session,and the treatment remission rate and response rate were compared among the 3 groups.The number of sessions and incidences of adverse events within 6 months were compared,and the EEG seizure duration at the first super ECT session was analyzed.Results Seventy-four patients(84.09%)in group E1,76(76.40%)in group E2,and 32(82.05%)in group E3 achieved remission within 6 months after super ECT.The average number of treatment sessions was 2.13±1.44 in Group E1,2.23±2.01 in Group E2,and 2.41±2.15 in Group E3 within 6 months.The baseline HAMA,HAMD-17 and PSQI scores were significantly correlated(P<0.001).The first seizure duration in E1 group was significantly longer than that in E2 and E3 groups(P<0.001).The rehospitalization rates were significantly higher in E2 group than in E1 group at 3 months(P=0.012)and 6 months(P=0.026).The short-term adverse effects included fever,headache/dizziness,general pain and dry mouth.Conclusion Super ECT is safe and effective for treatment of TRD patients with a total seizure duration longer than 180 s.The number of electrical stimulations in each treatment session does not significantly affect the therapeutic efficacy of super ECT.

Abstract:Objective To investigate the regulatory role of lncRNA SNHG12 in docetaxel(DTX)resistance of prostate cancer(PCa)cells.Methods Tumor-bearing male BALB/c nude mouse models were stablished by dorsal subcutaneous injection of PC-3 cells or DTX-resistant PC-3(PC-3R)cells,either with or without transfection with sh-SNHG12 prior to the injection(n=5).The expressions of the key genes and proteins in the tumor tissues were detected using RT-qPCR,Western blotting,immunofluorescence staining or immunohistochemistry.The proliferation and migration of the treated cells were evaluated with CCK-8,clone formation and Transwell migration assays.RIP-qPCR technique was used to determine the binding between the RNAs and proteins.Results SNHG12 expression was significantly up-regulated in PC-3R cells.SNHG12 knockdown effectively inhibited proliferation and migration of PC-3R cells in vitro and suppressed tumor growth in nude mice.While 10 nmol/L DTX treatment alone did not significantly affect proliferation or migration of PC-3R cells,its combination with SNHG12 knockdown strongly inhibited cell proliferation and migration both in vitro and in the tumor-bearing mice.The expression of ELAVL1 was obviously up-regulated in PC-3R cells,and increased activation level of PI3K/AKT signaling pathway was detected in both PC-3R cells and the xenografts.The effect of SNHG12 knockdown was significantly weakened by treatment with the PI3K activator 740 Y-P.SNHG12 was found to bind to ELAVL1 in PC-3R cells,and mechanistic studies showed that their binding activated the PI3K/AKT signaling pathway to result in DTX resistance in PCa.Conclusion SNHG12 knockdown inhibits DTX resistance of PCa cells by reducing SNHG12 binding to ELAVL1 to inhibit the activation the PI3K/AKT signaling pathway.

Abstract:Objective To explore the association between the use of β-blockers and the risks of all-cause mortality and major adverse cardiovascular events(MACEs)in patients with stable coronary artery disease(SCAD)after percutaneous coronary intervention(PCI).Methods We performed secondary analyses of the data of 55 SCAD patients receiving post-PCI β-blocker treatment and 149 patients without post-PCI β-blockers(control group)from the Dryad database.The clinical and coronary artery disease characteristics of the patients were analyzed,and propensity score matching was used to compare all-cause mortality and MACEs(including cardiovascular death,non-fatal myocardial infarction and non-fatal stroke)between the two groups.Results The overall patients(69.6%were male)had a mean age of 72.6±10.3 years with a median follow-up time of 783 days.A total of 18 patients(8.8%)died,and MACEs occurred in 19 patients(9.3%),including cardiovascular death in 6 cases(2.9%),non-fatal myocardial infarction in 3 cases(1.5%)and non-fatal stroke in 11 cases(5.4%).In the β-blocker group,deaths occurred in 5 cases(9.1%),and MACEs in 4 cases(7.3%),including 2 cases with cardiovascular death(3.6%)and 2 cases with non-fatal stroke(3.6%).Kaplan-Meier survival curve analysis showed that the use of β-blockers after PCI was not associated with a reduced all-cause mortality(8.7%vs 9.1%,log-rank P=0.870)or incidence of MACEs(10.1%vs 7.3%,log-rank P=0.510)either before or after adjusting for age,sex,aspartate aminotransferase,estimated glomerular filtration rate,left ventricular ejection fraction,and history of atrial fibrillation(HR=0.81,95%CI:0.24-2.72;HR=0.62,95%CI:0.22-1.69).No significant differences were found in all-cause death or MACEs between the two groups after propensity score adjustment,matching,or IPTW inverse probability weighting(all P>0.05).Conclusion Routine use of β-blockers after PCI does not reduce the incidence of all-cause death or MACEs in patients with SCAD.

Abstract:Objective To assess the association between urinary levels of volatile organic compound metabolites(mVOCs)and risks of metabolic dysfunction-associated steatotic liver disease(MASLD)in the general adult population.Methods Based on 4 cycles of cross-sectional surveys from the 2011-2018 National Health and Nutrition Examination Survey(NHANES),generalized linear models were employed to evaluate the associations between individual mVOC exposures and the risk of MASLD.A two-stage Least Absolute Shrinkage and Selection Operator-Weighted Quantile Sum(LASSO-WQS)regression model was constructed to investigate the relationship between mixed mVOCs exposures and MASLD risk,and the relative contributions of the individual compounds were quantitatively analyzed.Results The single-exposure analysis revealed significant positive associations of 2-aminothiazoline-4-carboxylic acid(ATCA),N-acetyl-S-(2-carboxyethyl)-L-cysteine(CEMA),and N-acetyl-S-(3,4-dihydroxybutyl)-L-cysteine(DHBMA)with MASLD risk after adjusting for confounders.In the two-stage mixed-exposure analysis,the first-stage LASSO regression identified 6 mVOCs with stronger association with MASLD risk.The second-stage WQS regression demonstrated a statistically significant positive association between mixed mVOCs exposures and MASLD risk(OR=1.306,95%CI:1.132-1.507;P<0.001),with CEMA contributing the highest weight(36%).Conclusion The study reveals a significant positive association between urinary levels of mVOCs mixtures and MASLD risk,suggesting potential hepatotoxic effects of VOC(especially CEMA)exposures,which urges future mechanistic studies of VOC mixture-related health impacts and listing of CEMA for health risk control.

Abstract:Objective To evaluate the inhibitory effect of antitumor component-Ⅰ in Agkistrodon halys venom(AHVAC-I)on proliferation and migration of cisplatin-resistant gastric cancer cells and explore the underlying mechanism.Methods Cisplatin-resistant MKN-28(MKN-28/DDP)cells were obtained by continuous exposure of MKN-28 cells to stepwise-increasing concentrations of cisplatin.MKN-28/DDP cells were treated with different concentrations of AHVAC-I,and the changes in proliferation,migration and invasion of the cells were examined with colony-forming assay,CCK-8 assay wound-healing assay,and Transwell assay.Western blotting was performed to examine the effect of AHVAC-I on expressions of epithelial-mesenchymal transition(EMT)markers of MKN-28/DDP cells;the changes in protein and mRNA expression of retinoic acid induced 14(RAI14)was detected with Western blotting and qRT-PCR.Results Treatment with 2,4,and 8 μg/mL AHVAC-I significantly inhibited proliferative,migratory and invasion abilities and reduced the expressions of EMT markers in MKN-28/DDP cells.Compared with MKN-28 cells,MKN-28/DP cells showed an increased expression of RAI14,which was significantly lowered after treatment with AHVAC-I.Supplementation with exogenous RAI14 obviously attenuated the inhibitory effect of AHVAC-I on proliferation and migration of MKN-28/DDP cells.Conclusion AHVAC-I decreases proliferation and invasion of MKN-28/DDP cells by downregulating RAI14 expression.

Abstract:Objective To explore the mechanism of Shihu Mixture(SHM)for improving diabetic cardiomyopathy.Methods Thirty male SD rats were randomized into 3 groups(n=10)for type 2 diabetes mellitus modeling by high-fat and-sugar feeding for 12 weeks and intraperitoneal streptozotocin injection,followed by treatment with daily gavage of normal saline(model group),metformin solution,or SHM extract for 4 weeks,with 10 normally fed rats as the normal control group.Fasting blood glucose and cardiac weight index of the rats were monitored,and their TG,TC,LDL-C,HDL-C,and LDH levels were determined;serum and myocardial levels of BNP,CRP,TNF-α and IL-6 were detected with ELISA.Myocardial pathological changes and ultrastructures of myocardial mitochondria and autophagosomes were examined with HE and Masson staining and transmission electron microscopy.Myocardial expressions of Sirt3,FoxO3a,PINK1,Parkin,P62,and LC3 mRNAs and proteins were detected with RT-qPCR,Western blotting,and immunohistochemistry.Results Compared with those in the control group,the rats in the other 3 groups showed significantly increased fasting blood glucose,cardiac weight index,serum TC,TG,LDL-C,LDH,CRP and BNP levels and myocardial levels of TNF-α and IL-6 with lowered HDL-C level,obvious myocardial and mitochondrial pathologies,and dysregulated expression of Sirt3,FoxO3a,p-FoxO3a,PINK1,Parkin,LC3 and P62.Treatment of the rat models with SHM extract significantly reduced fasting blood glucose level and cardiac weight index,lowered the levels of LDH,CRP,BNP,TNF-α,IL-6,TC,TG,and LDL-C,increased HDL-C level,alleviated myocardial and mitochondrial damages,promoted autophagosome formation,and improved dysregulation of mitochondrial autophagy-related gene expression,showing similar effects to metformin.Conclusion SHM alleviates myocardial damage and improves mitochondrial function in rats with diabetic cardiomyopathy by regulating the mitochondrial autophagy pathway through Sirt3.

Abstract:Objective To investigate the role of transmembrane protein EVA1A in liver lipid metabolism and development of non-alcoholic fatty liver disease(NAFLD).Methods Eight-week-old male ob/ob mice were randomized into control group injected with AAV null vector via the tail vein(AAV-null group)and AAV-Eva1a group injected with recombinant vector AAV-Eva1a(n=8).HepG2 cells transfected with the lentiviral vector LV-EVA1A or the null vector were induced with oleic acid to construct a cell model of NAFLD.The expression levels of EVA1A,lipid metabolism-related and autophagy-related genes in mouse livers were detected with RT-qPCR,Western blotting,and immunofluorescence staining,and lipid accumulation in mouse livers and blood and in the treated cells was examined with HE and Oil Red O staining and lipid detection kits.Serum levels of ALT,AST,IL-6,IL-1β,and TNF-α of the mice were detected,and hepatic lipophagy was observed with transmission electron microscopy.Results The mouse livers in AAV-Eva1a group and LV-EVA1A-transfected cells showed significantly increased expression levels of EVA1A mRNA and protein.The liver weight and coefficient and lipid deposition of the mice with AAV-Eva1a injection and triglyceride(TG)content in LV-EVA1A-transfected cells were significantly decreased.The mice in AAV-Eva1a group showed significantly reduced serum total cholesterol,LDL-C,and HDL-C levels and hepatic TG levels with lowered serum levels of ALT,AST,IL-6 and TNF-α.In both mouse livers in AAV-Eva1a group and LV-EVA1A-transfected HepG2 cells,acetyl-CoA carboxylase,fatty acid transport protein,and diacylglycerol acyltransferase expressions were all significantly decreased and adipose triglyceride lipase increased.Hepatic lipophagy,autophagosome numbers and LC3-II and ATG5 expressions were enhanced and p62 expression was lowered in the mice in AAV-Eva1a group and LV-EVA1A-transfected cells.Conclusion EVA1A overexpression alleviates fatty liver and inflammation in ob/ob mice by regulating lipid metabolism-related genes and enhancing lipophagy to promote clearance of accumulated hepatic lipids.

Abstract:Objective To explore pathological and immune cell infiltration characteristics of pigmented pretibial patches in diabetic patients.Methods Forty-two diabetic patients undergoing thigh amputation at Tianjin Medical University Chu Hsien-I Memorial Hospital were enrolled.Before the operation,the pretibial skin of the patients were examined and sampled for HE and Masson staining.The thickness of the epidermis and the density of blood vessels in the dermis were compared between patients with and without pigmented pretibial patches.The expressions of VEGFA and VEGFR2 in the skin tissues were detected using Western blotting,and CD4+and CD8+cells and the CD4/CD8 ratio were analyzed with immunohistochemical staining.Results Compared with the patients without pigmented pretibial patches,the patients with pigmented pretibial patches showed obvious thickening of the epidermal spinous layer,irregular downward extension of the epidermal projections,hyperkeratosis,melanin deposition in the basal layer,increased capillaries in the dermis,and localized,well-defined inflammatory cell infiltration around the blood vessels.In pigmented pretibial patches group,Masson staining revealed irregular arrangement,thickening and hyaline degeneration of collagen fibers,significantly increased epidermal thickness and blood vessel density in the dermis,increased CD4+cells and the CD4/CD8 ratio,and reduced CD8+cells.Conclusion The pigmented pretibial patches in diabetic patients show obvious pathological changes possibly due to vascular and immune abnormalities.

Abstract:Objective Sepsis patients exhibit diverse immune states,making it crucial to identify subtypes with distinct inflammatory profiles through Th1/Th2 cytokine data for personalized treatment and improved prognosis.Methods We retrieved data from sepsis patients who underwent Th1/Th2 cytokine testing in Nanfang Hospital,Southern Medical University from June 1,2020,to February 1,2022.An unsupervised K-means clustering method classified participants based on Th1/Th2 cytokine levels,with the primary outcome being the 7-day mortality rate post-ICU admission.Cox proportional hazards and Restricted Mean Survival Time(RMST)analyses were utilized to explore survival outcomes.Results A total of 321 sepsis patients were included.IL-6(HR 1.69,95%CI:1.22,2.34)and IL-10(HR 1.81,95%CI:1.37,2.40)emerged as independent predictors of 7-day mortality.Unsupervised K-means clustering revealed 3 inflammatory/immune subgroups:Cluster 1(n=166,low inflammatory response),Cluster 2(n=99,moderate inflammatory response with immune suppression),and Cluster 3(n=56,strong inflammatory and immune suppression).Compared to Cluster 1,Clusters 2 and 3 had higher 7-day mortality risks(14.4%vs 23.2%,HR=4.30,95%CI:1.51-12.26;14.4%vs 35.7%,HR=7.32,95%CI:2.57-20.79).Conclusion Septic patients in a protective immune response state(Cluster 1)exhibit better short-term prognoses,suggesting the importance of understanding inflammatory/immune states for precise treatment and improved outcomes.

Abstract:Large language models(LLMs)are emerging artificial intelligence technologies with strong text and image processing capabilities,offering critical support for the intelligent transformation of healthcare and improving clinical efficiency and quality.This review summarizes the current applications,technical features,and future directions of LLMs in cancer diagnosis,focusing on two key scenarios:automated analysis of textual reports(e.g.,imaging,pathology,and case summaries)and multimodal diagnosis combining text and medical images.Findings show that LLMs now perform at a level comparable to general resident physicians in cancer diagnosis but are still incapable of making specialized and precise judgments.They also exhibit application-specific traits,such as parameter-efficient models adapted for grassroots-level scenario and divergent versatility in multilingual report analysis.Future efforts should prioritize developing specialized,practical medical LLMs through optimized fine-tuning strategies,construction of high-quality Chinese medical datasets,and integration with vision-language models to promote the clinical application of these models and increase the accessibility of healthcare resources.

Abstract:Objective To observe temporal changes of pain-related behaviors in mice with chronic postsurgical pain(CPSP)and identify its key mediators in the dorsal root ganglion(DRG).Methods In mouse models of CPSP induced by plantar incision(INC)followed by a dorsal foot injection of prostaglandin E2(PGE2)and sham-operated mice,mechanical paw withdrawal thresholds(PWTs),thermal paw withdrawal latencies(PWLs),and cold withdrawal durations(WDs)were measured at different time points after modeling.Gene expression profiling of the DRG with RNA sequencing was performed on day 1 and day 8 after PGE2 injection.Bioinformatics analyses were conducted to explore the key mediators in the DRG for regulating CPSP,and the candidate genes and proteins were validated using RT-qPCR and ELISA.The effects of intrathecal injection of a CX3CL1-neuralizing antibody or JMS-17-2(a CX3CR1 antagonist)on CPSP were observed.Results In CPSP mouse models,incision-induced pain was resolved within 14 days,and PWTs and WDs decreased progressively till day 10 and day 12 after PGE2 injection,respectively,without significant changes in PWLs.RNA-Seq identified 975 differentially expressed genes(DEGs)on day 1 and 895 on day 8 following CPSP modeling,including 524 intersecting DEGs enriched in cell membrane,plasma membrane,and CX3C chemokine receptor binding.Cx3cl1 and Cxcl14 were the top two upregulated chemokine-related DEGs in early CPSP,whose mRNA and protein expression increased significantly in the ipsilateral DRG on day 1 but declined on day 8.Intrathecal injection of the CX3CL1-neutralizing antibody before PGE2 injection prevented CPSP development,while JMS-17-2 partially reversed CPSP during the maintenance phase.Conclusion This CPSP mouse model shows persistent mechanical and cold allodynia for at least 10 days after PGE2 injection without significant changes in heat hypersensitivity.CX3CL1 and related chemokine signaling in the DRG may contribute to the development of CPSP.

Abstract:Objective To monitor the changes in oxygenation levels of rat kidneys under step oxygen stimulation by high temporal resolution dynamic T2* weighted planar echo imaging(T2*W-EPI).Methods Step oxygen stimulation was applied to SD rats(n=10)in the sequence of 2 min of hyperoxia(100%O2)-10 min of hypoxia(10%O2)-10 min of hyperoxia(100%O2).Dynamic MRI data of the kidneys of multi-echo gradient echo(mGRE)sequence and gradient echo-planar imaging(EPI)sequence were continuously acquired on a 9.4T small animal magnetic resonance scanner.The time resolution of the two sequences were 9 s and 1 s,respectively.A second-order step response model was established for the dynamic time series curves of different regions of interest(ROIs)in rat kidneys,and the parameters of the step response model were obtained,including time delay ∆t,natural frequency ωn,damping constant D and oscillation period T.The performance of two MRI imaging methods with different temporal resolution in response to the step oxygen stimulation in the kidneys was compared.Results Compared with the control experiment results of mGRE,the dynamic T2*W-EPI technology proposed in this study increased the temporal resolution of monitoring renal step oxygen stimulation by 8 folds and improved the goodness of fit of the step response model.The model showed a shorter time delay ∆t(shortened by 29.4%,42.6%,56.4%,and 47.4%,respectively,in the CO,OSOM,ISOM and IM),a larger natural frequency ωn(increased by 21.1%,28.6%,52.2%,and 61.9%,respectively),and oscillation of each ROI(damping constant D<1)under the step oxygen stimulation.Conclusion In a step oxygen stimulation model of rat kidneys,the high temporal resolution dynamic T2*W-EPI technique proposed in this study is capable of real-time monitoring of the changes in renal oxygenation levels for detection of abnormal renal conditions.

Abstract:Objective To explore the therapeutic mechanism of Fuzheng Xiaoyan(FZXY)Granules for relieving cancer-related fatigue(CRF)during chemotherapy in breast cancer patients based on the traditional Chinese medicine(TCM)theory of"Fuzheng Quxie"(supporting healthy qi and eliminating pathogens).Methods Ninety CRF patients with breast cancer and Zhengxu Duyu syndrome were randomized equally into control group with chemotherapy and symptomatic treatment and study group with additional treatment with FZXY Granules,and their Piper Fatigue Scale(PFS),Karnofsky Performance Status(KPS),and TCM syndrome scores were compared.Network pharmacology analysis was used to identify the active components in FZXY Granules,the drug targets,and disease-related targets.Protein-protein interaction(PPI)network was constructed followed by enrichment analysis.Molecular docking study was conducted to explore the interactions between quercetin and the core targets.In a CRF mouse model bearing breast cancer xenograft,the effects of saline and FZXY Granule gavage were observed by assessing motor function,expressions of AKT1,p-AKT1,BCL-2,and BAD in the gastrocnemius muscle,and serum levels of IL-6 and IL-1β.Results The patients receiving FZXY Granules treatment showed significantly improved PFS,KPS,and TCM syndrome scores compared with the baseline levels and those in the control group(P<0.05).Fifty-seven overlapping drug-disease targets were screened,and 5 core targets were identified.Quercetin exhibited strong binding to AKT1 and acted likely via the apoptosis pathways.In the CRF mouse models,FZXY Granules obviously improved motor function of the mice,reversed abnormal apoptosis-related protein expressions in the gastrocnemius muscle,and reduced serum IL-6 and IL-1β levels.Conclusion FZXY Granules alleviate CRF and improve TCM symptoms and quality of life of breast cancer patients during chemotherapy possibly by suppressing skeletal muscle cell apoptosis via regulating the AKT1/BAD/BCL-2 pathway and reducing IL-6 and IL-1β levels.

Abstract:Objective To investigate the regulatory effect of Serpin Family E Member 1(SERPINE1)on immune microenvironment and paclitaxel(PTX)resistance of triple-negative breast cancer(TNBC)cells.Methods CCK-8 assay was used to determine the half-maximal inhibitory concentration of PTX in TNBC cell line MDA-MB-231.In wild-type MDA-MB-231 cells and a PTX-resistant MDA-MB-231 cell line(MDA-MB-231/PTX)established by stepwise increasing low-dose PTX treatment,the effects of Western blot-verified transfection with SERPINE1 overexpression plasmids or SERPINE1 siRNAs on cell apoptosis were evaluated using Hoechst 33258 staining and by detecting expression levels of cleaved caspase-3 using Western blotting.The changes in proliferation of the transfected cells were assessed using EdU and CCK-8 assays.The breast cancer cells with different treatments were co-cultured with macrophages,and M1 and M2 polarization of the macrophages were analyzed with flow cytometry and Western blotting.In nude mouse models bearing subcutaneous breast cancer cell xenografts,the effects of SERPINE1 overexpression and knockdown in the engrafted cells on tumor growth and PTX resistance were evaluated.Results SERPINE1 overexpression significantly inhibited apoptosis and promoted proliferation of MDA-MB-231 cells,and SERPINE1 knockdown obviously promoted apoptosis and inhibited proliferation of MDA-MB-231/PTX cells.The macrophages co-cultured with SERPINE1-overexpressing breast cancer cells showed enhanced M2 polarization and suppressed M1 polarization with a lowered M1/M2 ratio.In the tumor-bearing nude mouse models,SERPINE1 overexpression in the engrafted cells resulted in significantly accelerated tumor growth.Conclusion In MDA-MB-231 cells,SERPINE1 overexpression promotes cell proliferation,inhibits apoptosis,and enhances PTX resistance.SERPINE1 plays a regulatory role in macrophage polarization in the immune microenvironment of breast cancer,and its high expression promotes M2 polarization of the macrophages.

Abstract:Objective To investigate the effect of overwork on myocardial energy metabolism in mice.Methods Thirty-two C57BL/6J mice were randomized equally into a control group and 3 overwork groups with overwork for 2,4,and 6 weeks(W2,W4,and W6 groups,respectively).The mice in overwork groups were subjected to daily forced water standing and restraint.The changes in body weight and general condition of the mice were observed weekly.After successful modeling,the mice were examined for changes in echocardiography,blood glucose/lipid profiles,myocardial pathologies,myocardial TG and ATP levels,and expressions in CD36,GLUT1,CPT1B,PPARα,PFKM,and PKM2 using immunohistochemistry,RT-qPCR or Western blotting.Results The mice with prolonged overwork exhibited reduced activity with hair loss,dull fur,and slowed body weight gain without significant changes in cardiac index or function.Blood glucose levels increased significantly in W2 and W4 groups but decreased in W6 group.Serum TG level increased significantly while TC,HDL,and LDL decreased in W4 and W6 groups.HE staining revealed myocardial swelling,disorganization,and vacuolation in the mouse models.Myocardial TG was elevated in W4 and W6 groups and ATP level decreased in W6 group.The mRNA and protein expressions of CPT1B and PPARα were downregulated in W4 and W6 group,and CD36 expression increased significantly in W4 group.GLUT1 and PFKM/PKM2 expressions decreased obviously in W2 group but increased in W4 and W6 group compared with that in W2 group.Conclusion Short-term overwork causes elevation of blood glucose and suppresses glycolysis in mice,while prolonged overwork reduces glucose,increases TG,impairs fatty acid oxidation,and limits glycolytic compensation to eventually result in myocardial damage,lipid accumulation,and ATP deficiency.

Abstract:Objective To investigate whether indole-3-acetic acid(IAA)alleviates Cryptococcus neoformans(Cn)-induced pyroptosis in cerebral microvascular endothelial cells by modulating stress granules(SGs)formation and the NLRP3 inflammasome.Methods In vitro cultured cerebral microvascular endothelial cells were pretreated with different concentrations of IAA before Cn infection(10⁷/mL),and the changes in cellular expresisons of G3BP1,DDX3X,NLRP3 and pyroptosis-related proteins,cytokines,and cell viability were deceted using Western blotting,immunofluorescence staining,ELISA,and CCK-8 assay.In the animal experiment,C57BL/6 mice with cyclophosphamide-induced immunosuppression were pretreated with saline or IAA gavage for 7 days before intravenous Cn injection.The changes in blood-brain barrier(BBB)integrity of the mice was assessed with Evans blue assay,and the brain cortical tissues were analyzed for changes in protein expressions.Results Cn infection significantly downregulated G3BP1 expression and upregulated the expressions of DDX3X and NLRP3 in cultured cerebral microvascular endothelial cells.IAA intervention not only restored normal expressions of G3BP1,DDX3X,and NLRP3,but also effectively suppressed the activation of pyroptosis-related proteins,including NT-GSDMD/GSDMD and P20/caspase-1,and reduced the release of IL-18 and IL-1β.IAA treatment also inhibited the translocation of DDX3X to NLRP3 induced by Cn infection and promoted the binding between DDX3X and G3BP1.In Cn-infected C57BL/6 mice,IAA treatment significantly alleviated BBB injury,decreased the expression of ZO-1 in the cerebral cortex,and effectively ameliorated abnormal expressions of VEGFR2,G3BP1,DDX3X,NLRP3,NT-GSDMD/GSDMD and P20/caspase-1.Conclusion IAA effectively alleviates Cn infection-induced pyroptosis of cerebral microvascular endothelial cells by modulating the formation of SGs and activating the NLRP3 inflammasome.

Abstract:Objective To investigate the expression of the 26S proteasome non-ATPase regulatory subunit 11(PSMD11)in gastric cancer and its impact on long-term patient prognosis.Methods Tumor and adjacent tissue samples were collected from a cohort of 94 gastric cancer patients treated at our hospital from January,2016 to December,2019.Immunohistochemistry was used to detect PSMD11 and Ki67 expression levels in the tissues,whose correlations with clinicopathological parameters and postoperative 5-year survival of the patients were analyzed.PSMD11 expression in gastric cancer was also analyzed using data from the GEPIA and UALCAN databases,while the KM-plotter database was used to predict 5-year survival rates.KEGG and GO enrichment analyses were employed to predict the biological functions and mechanisms of PSMD11.In cultured HGC-27 cells,the effects of PSMD11 knockdown and overexpression on cell migration,invasion and expressions of epithelial-mesenchymal transition(EMT)markers and TGF-β/Smad pathway proteins were evaluated using scratch wound healing assay,Transwell assay,and Western blotting.Results Bioinformatic analysis showed that PSMD11 expression was significantly elevated in gastric cancer and positively correlated with Ki67 expression(r=0.73,P<0.05).Survival analysis suggested that high PSMD11 expression was correlated with a poorer prognosis in gastric cancer patients.Univariate and multivariate Cox regression analyses identified PSMD11 as an independent prognostic risk factor in gastric cancer(HR:2.167,95%CI:1.159-4.051,P=0.015).Enrichment analysis suggested involvement of PSMD11 in EMT and TGF-β signaling.In HGC-27 cells,PSMD11 overexpression significantly enhanced while PSMD11 knockdown suppressed cell migration and invasion.PSMD11 overexpression significantly increased the expression levels of vimentin,N-cadherin,TGF-β,and p-Smad2/3 and reduced E-cadherin expression,and PSMD11 knockdown produced the opposite changes.Conclusion PSMD11 is overexpressed in gastric cancer and adversely affects patient prognosis likely by driving EMT via activation of the TGF-β/Smad signaling pathway.

Abstract:Objective To assess the risk of major adverse cardiovascular and cerebrovascular events(MACCEs)in patients with ST-segment elevation myocardial infarction(STEMI)following percutaneous coronary intervention(PCI)by evaluating both the large coronary vessels and coronary microcirculation.Methods A total of 507 patients with STEMI undergoing successful percutaneous coronary intervention(PCI)were retrospectively enrolled from two centers.The optimal cut-off value(256.5 mmHg·s·m-1)of angio-based microvascular resistance(AMR)for predicting MACCEs was determined by ROC analysis.Combined with a quantitative flow ratio(QFR)threshold of 0.80,the patients were classified into 4 groups:Group 1(QFR≥0.8,AMR<256.5;n=271),Group 2(QFR≥0.8,AMR≥256.5;n=140),Group 3(QFR<0.8,AMR<256.5;n=77),and Group 4(QFR<0.8,AMR≥256.5;n=19).The primary endpoint was cardiac death or heart failure readmission within 2 years.Results Patients with elevated AMR(≥256.5 mmHg·s·m-1)had a significantly increased risk of MACCEs within two years after PCI(P<0.001).Kaplan-Meier analysis showed the lowest survival rate in patients with both QFR<0.8 and AMR≥256.5 mmHg·s·m-1.Multiple linear regression analysis suggested that diabetes(P<0.001),hyperlipidemia(P<0.001),smoking(P<0.014),systemic inflammation response index(P<0.007),and platelet to lymphocyte ratio(P<0.001)were independently associated with elevated AMR levels.Restricted cubic spline regression revealed a non-linear relationship between AMR and MACCEs risk(non-linear P<0.001),and the hazard ratio for MACCEs increased markedly for an AMR beyond the threshold of 259.45 mmHg·s·m-1.Conclusion The integrated assessment of QFR and AMR allows effective prediction of MACCEs risk in STEMI patients after PCI,and elevated AMR is an independent predictor of significantly increased risk of MACCEs.