BACKGROUND: T-cell lymphoblastic lymphoma/acute lymphoblastic leukemia (T-LBL/ALL) is an aggressive form of hematological malignancy associated with poor prognosis in adult patients. Histone deacetylases (HDACs) are aberrantly expressed in T-LBL/ALL and are considered potential therapeutic targets. Here, we investigated the antitumor effect of a novel HDAC inhibitor, chidamide, on T-LBL/ALL. METHODS: HDAC1, HDAC2 and HDAC3 levels in T-LBL/ALL cell lines and patient samples were compared with those in normal controls. Flow cytometry, transmission electron microscopy, and lactate dehydrogenase release assays were conducted in Jurkat and MOLT-4 cells to assess apoptosis and pyroptosis. A specific forkhead box O1 (FOXO1) inhibitor was used to rescue pyroptosis and upregulated gasdermin E (GSDME) expression caused by chidamide treatment. The role of the FOXO1 transcription factor was evaluated by dual-luciferase reporter and chromatin immunoprecipitation assays. The efficacy of chidamide in vivo was evaluated in a xenograft mouse. RESULTS: The expression of HDAC1, HDAC2 and HDAC3 was significantly upregulated in T-LBL/ALL. Cell viability was obviously inhibited after chidamide treatment. Pyroptosis, characterized by cell swelling, pore formation on the plasma membrane and lactate dehydrogenase leakage, was identified as a new mechanism of chidamide treatment. Chidamide triggered pyroptosis through caspase 3 activation and GSDME transcriptional upregulation. Chromatin immunoprecipitation assays confirmed that chidamide led to the increased transcription of GSDME through a more relaxed chromatin structure at the promoter and the upregulation of FOXO1 expression. Moreover, we identified the therapeutic effect of chidamide in vivo . CONCLUSIONS This study suggested that chidamide exerts an antitumor effect on T-LBL/ALL and promotes a more inflammatory form of cell death via the FOXO1/GSDME axis, which provides a novel choice of targeted therapy for patients with T-LBL/ALL.
Humans ; Pyroptosis/drug effects* ; Forkhead Box Protein O1/genetics* ; Aminopyridines/pharmacology* ; Animals ; Mice ; Benzamides/pharmacology* ; Cell Line, Tumor ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy* ; Phosphate-Binding Proteins/metabolism* ; Histone Deacetylase Inhibitors/pharmacology* ; Jurkat Cells ; Histone Deacetylases/metabolism* ; Apoptosis/drug effects* ; Gasdermins

ObjectiveTo observe and compare the effects of different concentrations of cyclophosphamide (CTX) in inducing premature ovarian insufficiency (POI) model in mice and investigate the mechanism of injury. MethodsThirty-two 6~8-week-old female C57BL/6J mice were randomly divided into four groups (n=8 per group) using a weight-based block randomization method. The POI model was established via a single intraperitoneal injection of 75 mg/kg cyclophosphamide (CTX), 120 mg/kg CTX, 120 mg/kg CTX + 12 mg/kg Busulfan, or an equivalent volume of normal saline (control). Ovarian coefficients, serum estradiol (E₂) and follicle-stimulating hormone (FSH) levels were measured. Western blotting was performed to assess changes in ovarian expression levels of NAD-dependent deacetylase sirtuin-5 (SIRT5) and forkhead box O3a (FOXO3a) under different modeling conditions. After determining the optimal CTX concentration for modeling, an additional forty 6~8-week-old femal C57BL/6J mice were randomly divided into five groups (n=8 per group) using a weight-based block randomization method: saline control, 120 mg/kg CTX sampling at 1, 2, 7, or 14 days after modeling. Western blotting was used to evaluate temporal changes of ovarian SIRT5 and FOXO3a protein expression. ResultsCompared with the saline control, all concentrations of CTX (75 mg/kg CTX, 120 mg/kg CTX) and 120 mg/kg CTX + 12 mg/kg Busulfan induced POI injury in mice. The 120 mg/kg CTX group exhibited smaller changes in ovarian coefficients (P<0.001) and E₂ levels (P<0.05), whereas the 120 mg/kg CTX + 12 mg/kg Busulfan group showed rough and reduced luster fur, sluggish response and was in the worst state. Compared with the saline control group, FOXO3a expression was significantly down-regulated (P<0.05), while SIRT5 remained unchanged in the 75 mg/kg CTX group (P>0.05). In contrast, both SIRT5 (P<0.05) and FOXO3a (P<0.05) were significantly down-regulated in the 120 mg/kg CTX group. Further analysis revealed that on day 2 and 7 after 120 mg/kg CTX modeling, the expressions of SIRT5 (P<0.01) and FOXO3a (P<0.001) were significantly down-regulated, with the largest decrease observed on day 7 (SIRT5, P<0.000 1; FOXO3a, P<0.000 1). ConclusionOvarian injury in the POI model induced by 120 mg/kg CTX is milder than that in the POI model induced by 75 mg/kg CTX. Moreover, the expression changes of SIRT5 and FOXO3a are most significant on day 7 after modeling induced by 120 mg/kg CTX, which may be related to the inhibition of the SIRT5-FOXO3a signaling pathway.

Objective To explore the effect of ephedrine on airway remodeling and its regulation effect on transfor-ming growth factor-β1(TGF-β1)/Smads pathway in asthmatic mice.Methods All mice were randomly separated into control group,model group,dexamethasone group,ephedrine low-dose group,ephedrine high-dose group,and ephedrine high-dose+TGF-β1 activator group,with 12 mice in each group.Except for the control group,mice in other groups were intraperitoneally injected with 40 μg ovalbumin(OVA)and 2 mg 10％aluminium hydroxide sensitizer to induce asthma models.After 8 weeks,the airway hyperresponsiveness of mice in each group was detec-ted;eosinophils in bronchoalveolar lavage fluid(BALF)were counted;ELISA was applied to detect the levels of interleukin(IL)-4,IL-5,and IL-13 in BALF;hematoxylin-eosin(HE)staining and Masson staining were applied to observe the pathological changes and collagen fiber area of mouse lung tissue;immunohistochemistry was applied to detect the expression of α-smooth muscle actin(α-SMA)protein in mouse lung tissue;Western blot was applied to detect the expression of TGF-β1/Smads pathway related proteins in mouse lung tissue.Results Compared with the control group,the airway hyperreactivity at different doses of methacholine,total area of airway wall(Wat)/perimeter of the basement membrane(Pbm)ratio,collagen fiber area,eosinophil,the contents of IL-4,IL-5,IL-13,the expression of α-SMA,TGF-β1,the ratios of p-Smad2/Smad2 and p-Smad3/Smad3 in the model group in-creased(P＜0.05),the expression of Smad7 decreased(P＜0.05);compared with the model group,the airway hyperreactivity at different doses of methacholine,Wat/Pbm ratio,collagen fiber area,eosinophil,the contents of IL-4,IL-5,IL-13,the expression of α-SMA,TGF-β1,the ratios of p-Smad2/Smad2 and p-Smad3/Smad3 in the dexamethasone group,the ephedrine low-dose and high-dose groups decreased(P＜0.05),the expression of Smad7 increased(P＜0.05);compared with the ephedrine high-dose group,the airway hyperreactivity at different doses of methacholine,Wat/Pbm ratio,collagen fiber area,eosinophil,the contents of IL-4,IL-5,IL-13,the ex-pression of α-SMA,TGF-β1,the ratios of p-Smad2/Smad2 and p-Smad3/Smad3 in the ephedrine high-dose+TGF-β1 activator group increased(P＜0.05),the expression of Smad7 decreased(P＜0.05).Conclusion E-phedrine can improve airway remodeling in asthmatic mice,and its mechanism is related to the regulation of TGF-β1/Smads signaling pathway.

Objective Photoelectric volumetric tracing(PPG)exhibits high sensitivity and specificity in flap monitoring.Deep learning(DL)is capable of automatically and robustly extracting features from raw data.In this study,we propose combining PPG with 1D convolutional neural networks(1D-CNN)to preliminarily explore the method's ability to distinguish the degree of embolism and to localize the embolic site in skin flap arteries.Methods Data were collected under normal conditions and various embolic scenarios by creating vascular emboli in a dermatome artery model and a rabbit dermatome model.These datasets were then trained,validated,and tested using 1D-CNN.Results As the degree of arterial embolization increased,the PPG amplitude upstream of the embolization site progressively increased,while the downstream amplitude progressively decreased,and the gap between the upstream and downstream amplitudes at the embolization site progressively widened.1D-CNN was evaluated in the skin flap arterial model and rabbit skin flap model,achieving average accuracies of 98.36%and 95.90%,respectively.Conclusion The combined monitoring approach of DL and PPG can effectively identify the degree of embolism and locate the embolic site within the skin flap artery.

Alcohol abuse is a serious public health problem and biomedical safety problem that can lead to a variety of neuropsychiatric disorders. In recent years, numerous studies have shown that alcohol can induce structural and functional disregulation in the basolateral amygdala (BLA). Alcohol exposure and withdrawal can cause negative emotion such as anxiety and fear, primarily mediated by glutamatergic neurons and inhibitory γ-aminobutyric acid ergic(GABAergic) interneurons in the BLA. Glutamatergic neurons are responsible for excitatory neurotransmitter glutamate release, while γ-aminobutyric acid ergic(GABAergic) interneurons provide feedback inhibition to suppress BLA function and alleviate negative emotions. However, alcohol intake can disrupt the balance of glutamatergic-GABAergic neural network, altering neuron excitability and subsequently leading to the generation of anxiety and fear. Moreover, alcohol also interferes with the corticotropin-releasing factor(CRF) system within the BLA, increasing the release of CRF, further stimulating anxiety-related emotions. Additionally, alcohol affects BLA-related neural circuits, such as BLA →medial prefrontal cortex, BLA →nucleus accumbens, and BLA →bed nucleus of the stria terminali pathways, thereby impacting anxiety-like behaviors.This review discusses the progress of neural signaling and circuits within the BLA in mediating alcohol-induced negative emotions, aiming to further elucidate the neurobiological mechanisms underlying anxiety triggered by alcohol exposure and withdrawal, in order to provide theoretical basis for clinical treatment in the future.

Objective To investigate the effect and mechanism of Zhike Pingchuan Formula on reducing airway inflammation in mice with bronchial asthma(BA).Methods A total of 84 BALB/c mice were randomly separated into the control group,the BA group,the low-dose Zhike Pingchuan Formula group,the high-dose Zhike Pingchuan Formula group,the dexamethasone group,the lipopolysaccharide(LPS)group and the high-dose Zhike Pingchuan Formula+LPS group,with 12 mice in each group.The BA model was constructed in all groups of mice except the control group.After successful modeling,mice were treated with drug administration once a day for 3 weeks.Serum immunoglobulin E(IgE)concentration and levels of interleukin-17(IL-17)and tumor necrosis factor-α(TNF-α)in alveolar lavage fluid were detected by enzyme linked immunosorbent assay(ELISA).Pathological changes in lung tissue was detected by HE staining.The bronchial epithelium goblet cell proliferation and mucus secretion were determined by PAS staining.Flow cytometry was used to detect levels of T helper cell 17(Th17)and regulatory T(Treg)cell in mouse spleen tissue.Western blot assay was used to detect toll-like receptor 4(TLR4)/tumor necrosis factor receptor-associated factor 6(TRAF6)/nuclear factor kappa-B(NF-κB)pathway-related protein expression in lung tissue.Results Compared with the control group,damage of lung tissue was serious,the proliferation of bronchial epithelial goblet cells and the secretion of mucus increased,IgE concentration,TNF-α,IL-17 levels,Th17 cell proportion,Th17/Treg ratio,and TLR4,TRAF6,p-NF-κB p65 protein expression increased,while Treg cell proportion decreased in the BA group(P＜0.05).Compared with the BA group,the bronchial epithelial cupular cell proliferation and mucus secretion were reduced in the low-dose Zhike Pingchuan Formula group,the high-dose Zhike Pingchuan Formula group and the dexamethasone group,the lung tissue damage was improved,the concentration of IgE,levels of TNF-α,IL-17,the proportion of Th17 cells,the ratio of Th17/Treg and expression of protein levels of TLR4,TRAF6 and p-NF-κB p65 were reduced,and the proportion of Treg cell was elevated(P＜0.05).The trend of corresponding indexes in the LPS group was opposite to the above(P＜0.05).Compared with the high-dose Zhike Pingchuan Formula group,the pathological damage of lung tissue increased in the high-dose Zhike Pingchuan Formula+LPS group.The proliferation of bronchial epithelial goblet cells and the secretion of mucus increased,the IgE concentration,TNF-α,IL-17 levels,Th17 cell proportion,Th17/Treg ratio and TLR4,TRAF6,p-NF-κB p65 protein expression increased,while the Treg cell proportion decreased(P＜0.05).Conclusion Zhike Pingchuan Formula may reduce airway inflammation in BA mice by inhibiting TLR4/TRAF6/NF-κB pathway.

Objective To compare the inhibitory effects of remimazolam and dexmedetomidine on cough during emergence from general anesthesia after thyroid surgery.Methods Patients with 111 cases of thyroid surgery were randomly divided into 3 groups,37 in each group.Group A was given a bolus of 0.1 mg·kg-1 and 0.05 mg·kg-1·h-1 remimazolam intravenous infusion until extubation,group B was given 0.5 μg·kg-1 of the dexmedetomidine over 10 minutes,and group C was given same dose of normal saline.The incidence of cough during emergence from general anesthesia,the moderate and severe cough,the recovery time and extubation time,the Ramsay Sedation Scale(RSS)score,and the heart rate(HR),and mean arterial pressure(MAP)at different time points before and after intervention and before and after extubation were recorded and compared.Results There were significant differences in the incidence of coughing among group A,B and C(37.84％vs.67.57％vs.91.89％,adjusted P＜0.016 7,respectively).The incidence of moderate and severe cough was also lower in group A than in group B and C(8.11％vs.35.14％vs.67.57％,adjusted P＜0.001).The recovery time and extubation time were longer in group B than those of group A and C(adjusted P＜0.001).The RSS scores at the time of extubation and after extubation were higher in group B than in group A and C(adjusted P=0.002 and P=0.007,respectively).After intervention,compared with group C,the HR of group A and B decreased to different degree,and different drugs interacted with time,and the HR of group B patients decreased to a greater extent.Conclusion Remimazolam suppresses the occurrence and reduces the severity coughing during emergence from general anesthesia,and reduce the severity in patients treated with thyroid surgeries.Compared with dexmedetomidine,remimazolam did not prolong recovery time and extubation time,remaining more stable haemodynamics.

Objective To investigate the potential role of the traditional herbal medicine Datura metel L.in the treatment of psoriasis using TNF-α-induced inflammation in keratinocytes as a model.Methods Keratinocyte cell line HaCaT was used to establish a psoriasis cell model by tumor necrosis factor-alpha(TNF-α)treatment.The ex-periment comprised three groups:a blank control group,TNF-α-induced psoriasis model group,and TNF-α+Datura metel L.intervention group.Level of IL-17 and CCL20 was measured ELISA,expression of nuclear factor kappa B(NF-κB)subunit p65 protein was measured by Western blot.Endothelial cell tube formation experiment was conducted using an in vitro angiogenesis analysis kit.Results Compared to the TNF-α-induced psoriasis model group,the Datura metel L.extract significantly reduced the levels of IL-17 and CCL20 in the cell culture su-pernatant of TNF-α-induced psoriasis model(P＜0.001);Datura metel L.extract markedly decreased the NF-κB subunit p65 protein level in TNF-α-induced psoriasis model cells(P＜0.01);Datura metel L.extract effectively inhibited the induction of endothelial cell tube formation by the cell culture supernatant of the psoria-sis model group.Conclusions The Datura metel L.extract down-regulates NF-κB signaling pathway mole-cules,reducing the production of IL-17 and CCL20 inflammatory factors in inflammatory keratinocytes and in-hibiting angiogenesis.

Objective To explore the changes in serum energy metabolites in patients with peripheral T-cell lymphoma,and investigate serum biomarkers for monitoring peripheral T-cell lymphoma from the perspective of energy metabolism.Methods Multiple/selected reaction monitoring(MRM/SRM)was used to detect the energy-related metabolites in the sera of 16 patients with newly diagnosed peripheral T-cell lymphoma admitted in the Hematology Medical Center of the Second Affiliated Hospital of Army Medical University from November 2020 to December 2021,as well as 10 recruited healthy volunteers.The corresponding clinical data including medical history,laboratory results and image data were collected and retrospectively analyzed.Results Significant differences were seen in the contents and expression profiles of serum energy metabolism-related products between the patients and the healthy volunteers.The patients had significantly reduced serum contents of cyclic AMP,succinate,citrate and cis-aconitate(P＜0.05),and elevated D-glucose 6-phosphate content(P＜0.05).The serum contents of citrate and succinate were negatively correlated with the risk stratification(low-,moderate-and high-risk)and clinical stage of the disease(P＜0.05).Meanwhile,there was a negative correlation between the contents of L-malic acid and citrate and the mid-term efficacy evaluation results,such as complete/partial response(CR/PR)or stable disease(SD)(P＜0.05).For patients with extranodal NK/T cell lymphoma(n=10),there were also significant reductions in the contents of cyclic AMP,succinate,citrate,isocitrate and cis-aconitate in the sera of patients compared with healthy volunteers(P＜0.05),and the contents of citrate and succinate were negatively correlated with the clinical stage(P＜0.05)and were rather correlated with mid-term efficacy evaluation results(CR/PR or SD)(P＜0.05).For patients with angioimmunoblastic T-cell lymphoma(n=6),the serum contents of cyclic AMP,citrate and succinate were significantly lower,while the content of D-glucose 6-phosphate was higher when compared with the healthy volunteers(P＜0.05),and the content of succinate was negatively correlated with both clinical stage and risk grade of the patients(P＜0.05).Conclusion There are 5 serum differential metabolites identified between patients with peripheral T-cell lymphoma and healthy controls,and succinate and citrate are expected to be serum biomarkers of peripheral T-cell lymphoma.

Objective To evaluate safety and efficacy of linaclotide combined with polyethylene glycol(PEG)for bowel preparation.Methods A total of 612 patients from Department of Gastroenterology at the Affiliated Hospital of Qingdao University for colonoscopy examination from January to June 2023 were selected.They were divided into group 1(1 L PEG+2 L PEG),group 2(linaclotide+2 L PEG)and group 3(1 L PEG+linaclotide+1 L PEG)by random number table method,with 204 cases in each group.The Ottawa Bowel Preparation Quality Scale(OBPS),the insertion time of colonoscopy,the time of the first defecation,the frequency of defecations,the occurrence of adverse effects and patients'tolerability were compared among the three groups.Results A total of 601 patients completed bowel preparation and accepted colonoscopy.Group 1 exhibited no statistically significant differences to group 2 with regards to OBPS and insertion time.However,Group 2 demonstrated a shorter duration for the time of the first defecation in comparison to both group 1 and group 3(P＜0.05).Group 1 displayed a higher frequency of defecations as compared to Group 2 and Group 3(P＜0.05).The incidence of adverse reactions was significantly lower in group 2 and group 3 than in group 1(P＜0.05).The overall tolerance score of patients in group 1 was low-er than that in group 2 and group 3(P＜0.05).Conclusions The effect of combining 2 L PEG with 290 μg of lina-clotide for bowel preparation before colonoscopy is similar to that of 3 L PEG.It can reduce the incidence of adverse reactions and patients exhibit good tolerance.For patients who are intolerant to a single high-dose administration of PEG,they need divided-dose regimen of 2 L PEG in combination with linaclotide.