Pyroptosis is an identified programmed cell death that has been highly linked to endoplasmic reticulum (ER) dynamics. However, the crucial proteins for modulating dynamic ER membrane curvature change that trigger pyroptosis are currently not well understood. In this study, a biotin-labeled chemical probe of potent pyroptosis inducer α-mangostin (α-MG) was synthesized. Through protein microarray analysis, reticulon-4 (RTN4/Nogo), a crucial regulator of ER membrane curvature, was identified as a target of α-MG. We observed that chemically induced proteasome degradation of RTN4 by α-MG through recruiting E3 ligase UBR5 significantly enhances the pyroptosis phenotype in cancer cells. Interestingly, the downregulation of RTN4 expression significantly facilitated a dynamic remodeling of ER membrane curvature through a transition from tubules to sheets, consequently leading to rapid fusion of the ER with the cell plasma membrane. In particular, the ER-to-plasma membrane fusion process is supported by the observed translocation of several crucial ER markers to the "bubble" structures of pyroptotic cells. Furthermore, α-MG-induced RTN4 knockdown leads to pyruvate kinase M2 (PKM2)-dependent conventional caspase-3/gasdermin E (GSDME) cleavages for pyroptosis progression. In vivo, we observed that chemical or genetic RTN4 knockdown significantly inhibited cancer cells growth, which further exhibited an antitumor immune response with anti-programmed death-1 (anti-PD-1). In translational research, RTN4 high expression was closely correlated with the tumor metastasis and death of patients. Taken together, RTN4 plays a fundamental role in inducing pyroptosis through the modulation of ER membrane curvature remodeling, thus representing a prospective druggable target for anticancer immunotherapy.
Pyroptosis/immunology* ; Humans ; Endoplasmic Reticulum/immunology* ; Animals ; Nogo Proteins/antagonists & inhibitors* ; Mice ; Cell Line, Tumor ; Xanthones/pharmacology* ; Neoplasms/pathology* ; Mice, Nude

With the increasing demand for dynamic,real-time and rapid qualitative analysis of chemical composition in areas such as emergency response and space exploration,chip-scale mass spectrometers have attracted significant attention.These devices are expected to drive the integration of mass spectrometry with micro/nano-fabrication and intelligent sensing technologies,fostering profound innovation and breakthroughs in analytical chemistry.As an excellent mass analyzer,the ion trap exhibits numerous advantages,and its miniaturization creates favorable conditions for the high-density integration of miniature mass spectrometers.However,the reduction in ion storage capacity may compromise its sensitivity and dynamic range,rendering the study of ion unidirectional ejection in highly miniaturized ion traps of significant practical importance.In this work,a research was conducted on achieving efficient ion unidirectional ejection while maintaining high mass resolution in the extremely miniature hyperbolic linear ion trap(M-HLIT)with a field radius of 1 mm,and an electric field compensation method was proposed,which combined asymmetric electrode stretching and unbalanced RF voltage to achieve high-precision optimization of the electric field composition.Simulations showed that in an ideal structure,this method achieved 100％unidirectional ejection efficiency with the mass resolution of 518,significantly outperforming traditional asymmetric structure method(365)and unbalanced voltage method(321).Following the introduction of ion ejection slots,further optimization through bidirectional stretching and electrical parameters improved the resolution to 790 while maintaining a unidirectional ejection efficiency of 93％.This method eliminated the requirement for additional excitation voltage,offering an ideal solution for the miniature mass analyzer with high detection performance of chip-level mass spectrometers.

Patients with severe trauma require an extremely timely treatment and transfusion plays an irreplaceable role in the emergency treatment of such patients. An increasing number of evidence-based medicinal evidences and clinical practices suggest that patients with severe traumatic bleeding benefit from early transfusion of low-titer group O whole blood or hemostatic resuscitation with red blood cells, plasma and platelet of a balanced ratio. However, the current domestic mode of blood supply cannot fully meet the requirements of timely and effective blood transfusion for emergency treatment of patients with severe trauma in clinical practice. In order to solve the key problems in blood supply and blood transfusion strategies for emergency treatment of severe trauma, Branch of Clinical Transfusion Medicine of Chinese Medical Association, Group for Trauma Emergency Care and Multiple Injuries of Trauma Branch of Chinese Medical Association, Young Scholar Group of Disaster Medicine Branch of Chinese Medical Association organized domestic experts of blood transfusion medicine and trauma treatment to jointly formulate Chinese expert consensus on blood support mode and blood transfusion strategies for emergency treatment of severe trauma patients ( version 2024). Based on the evidence-based medical evidence and Delphi method of expert consultation and voting, 10 recommendations were put forward from two aspects of blood support mode and transfusion strategies, aiming to provide a reference for transfusion resuscitation in the emergency treatment of severe trauma and further improve the success rate of treatment of patients with severe trauma.

The aim of the present study was to investigate the protective mechanism of Forsythia suspensa extracts(FSE)on S.aureus-induced inflammatory injury of rat mammary epithelial cells.Fifty lactating rats were selected and randomly divided into five groups with 10 rats each:the blank control group(the fourth pair of mammary glands were injected with saline),the model group(the fourth pair of mammary glands were injected with 100 pL of S.aureus bacterial solution),the high-dose group(the fourth pair of mammary glands were injected with S.aureus bacterial solu-tion for 24 h,and then the rats were administered by gavage of 3.750 g/(kg·d)FSE for 1-7 d),the medium-dose group(24 h after the fourth pair of mammary injections,the rats were adminis-tered by gavage 1.875 g/(kg·d)FSE for 1-7 d),and in the low-dose group(24 h after the fourth pair of mammary injections,the rats were administered by gavage 0.935 g/(kg·d)FSE for 1-7 d),blood samples were collected 24 h after the last administration of the drug and then the rats were executed.The results showed that the mammary tissue of the model group was severely dam-aged,and the mRNA expression of IKKβ,MyD88,NF-κB,and TLR4 was significantly increased in the mammary tissue(P＜0.05).The relative expression of IKKβ,MyD88,NF-κB,and TLR4 pro-teins in the mammary tissue of the model group was significantly decreased(P＜0.05)by medium and high doses of FSE compared with the model group.Therefore,FSE may play an anti-inflammatory role by inhibiting the Toll-like signaling pathway to improve S.aureus-induced inflammatory re-sponse in rat mammary epithelial cells and decrease the expression of the downstream pathway proteins IKKβ,MyD88,NF-κB,and TLR4.

Objective To investigate the effects of intrauterine perfusion with granulocyte colony-stimulating factor(G-CSF)on the endometrial thickness,volume,and blood flow parameters of patients with thin endometrium and their clinical outcomes.Methods We designed a prospective non-randomized synchronous controlled trial and recruited patients with thin endometrium who underwent frozen-thawed embryo transfer(FET)at Mianyang Central Hospital between September 1,2021 and September 1,2023.They were divided into two groups,an experimental group of patients who received the experimental treatment of intrauterine perfusion with G-CSF and a control group of patients who did not receive the experimental treatment.The general data and the clinical outcomes of the two groups were analyzed and compared.The endometrial thickness,volume and blood flow parameters of patients in the experimental group before and after intrauterine perfusion with G-CSF were analyzed.Results The clinical data of 83 patients were included in the study.The experimental group included 51 cases,while the control group included 31 cases.There were no significant differences in the baseline data between the two groups.The clinical pregnancy rate of the experimental group(56.86% )was higher than that of the control group(50.00% )and the rate of spontaneous abortion in the experimental group(27.59% )was lower than that in the control group(37.50% ),but the differences were not statistically significant(P>0.05).In the experimental group,the postperfusion endometrial thickness([0.67±0.1]cm)was greater than the preperfusion endometrial thickness([0.59±0.09]cm),the postperfusion([1.84±0.81]cm3)was greater than the preperfusion endometrial volume([1.54±0.69]cm3),and the postperfusion vascularization flow index(VFI)(1.97±2.82)was greater than the preperfusion VFI(0.99±1.04),with all the differences being statistically significant(P<0.05).Conclusion Intrauterine perfusion with G-CSF can enhance the endometrial thickness,volume,and some blood flow parameters in patients with thin endometrium.

Objective: To identify the predisposing factors, clinical characteristics, and risk factors of disease progression to establish a novel predictive survival model and evaluate its application value for hepatitis B virus-related acute-on-chronic liver failure. Methods: 153 cases of HBV-ACLF were selected according to the guidelines for the diagnosis and treatment of liver failure (2018 edition) of the Chinese Medical Association Hepatology Branch. Predisposing factors, the basic liver disease stage, therapeutic drugs, clinical characteristics, and factors affecting survival status were analyzed. Cox proportional hazards regression analysis was used to screen prognostic factors and establish a novel predictive survival model. The receiver operating characteristic curve (ROC) was used to evaluate predictive value with the Model for End-Stage Liver Disease (MELD) and the Chronic Liver Failure Consortium Acute-on-Chronic Liver Failure score (CLIF-C ACLF). Results: 80.39% (123/153) based on hepatitis B cirrhosis had developed ACLF. HBV-ACLF's main inducing factors were the discontinuation of nucleos(t)ide analogues (NAs) and the application of hepatotoxic drugs, including Chinese patent medicine/Chinese herbal medicine, non-steroidal anti-inflammatory drugs, anti-tuberculosis drugs, central nervous system drugs, anti-tumor drugs, etc. 34.64% of cases had an unknown inducement. The most common clinical symptoms at onset were progressive jaundice, poor appetite, and fatigue. The short-term mortality rate was significantly higher in patients complicated with hepatic encephalopathy, upper gastrointestinal hemorrhage, hepatorenal syndrome, and infection (P < 0.05). Lactate dehydrogenase, albumin, the international normalized ratio, the neutrophil-to-lymphocyte ratio, hepatic encephalopathy, and upper gastrointestinal bleeding were the independent predictors for the survival status of patients. The LAINeu model was established. The area under the curve for evaluating the survival of HBV-ACLF was 0.886, which was significantly higher than the MELD and CLIF-C ACLF scores (P < 0.05), and the prognosis was worse when the LAINeu score ≥ -3.75. Conclusion: Discontinuation of NAs and the application of hepatotoxic drugs are common predisposing factors for HBV-ACLF. Hepatic decompensation-related complications and infection accelerate the disease's progression. The LAINeu model can predict patient survival conditions more accurately.
Humans ; Hepatitis B virus ; Hepatic Encephalopathy/complications* ; Acute-On-Chronic Liver Failure/diagnosis* ; End Stage Liver Disease/complications* ; Severity of Illness Index ; Risk Factors ; ROC Curve ; Prognosis ; Retrospective Studies

Glaucoma is a chronic optic neuropathy that affects the retinal ganglion cells, characterized by optic disc atrophy, visual field defects, and visual acuity loss. Since glaucoma is a chronic disease, long-term use of topical intraocular pressure-lowering medications often leads to ocular surface diseases, thus reducing medication adherence and ultimately affecting treatment efficacy. Currently, topical intraocular pressure-lowering medications include prostaglandin derivatives, β-adrenergic blockers, α-adrenergic agonists, topical carbonic anhydrase inhibitors, and cholinergic drugs. This article provides a comprehensive review of the effects and related mechanisms of these five antiglaucoma medications on the ocular surface of glaucoma patients and offers preventative measures for the protection of ocular surface in glaucoma patients.

Objectives: To investigated the safety and efficacy of treating patients with acute non-ST-segment elevation myocardial infarction (NSTEMI) and elevated levels of N-terminal pro-hormone B-type natriuretic peptide (NT-proBNP) with levosimendan within 24 hours of first medical contact (FMC). Methods: This multicenter, open-label, block-randomized controlled trial (NCT03189901) investigated the safety and efficacy of levosimendan as an early management strategy of acute heart failure (EMS-AHF) for patients with NSTEMI and high NT-proBNP levels. This study included 255 patients with NSTEMI and elevated NT-proBNP levels, including 142 males and 113 females with a median age of 65 (58-70) years, and were admitted in the emergency or outpatient departments at 14 medical centers in China between October 2017 and October 2021. The patients were randomly divided into a levosimendan group (n=129) and a control group (n=126). The primary outcome measure was NT-proBNP levels on day 3 of treatment and changes in the NT-proBNP levels from baseline on day 5 after randomization. The secondary outcome measures included the proportion of patients with more than 30% reduction in NT-proBNP levels from baseline, major adverse cardiovascular events (MACE) during hospitalization and at 6 months after hospitalization, safety during the treatment, and health economics indices. The measurement data parameters between groups were compared using the t-test or the non-parametric test. The count data parameters were compared between groups using the χ² test. Results: On day 3, the NT-proBNP levels in the levosimendan group were lower than the control group but were statistically insignificant [866 (455, 1 960) vs. 1 118 (459, 2 417) ng/L, Z=-1.25,P=0.21]. However, on day 5, changes in the NT-proBNP levels from baseline in the levosimendan group were significantly higher than the control group [67.6% (33.8%,82.5%)vs.54.8% (7.3%,77.9%), Z=-2.14, P=0.03]. There were no significant differences in the proportion of patients with more than 30% reduction in the NT-proBNP levels on day 5 between the levosimendan and the control groups [77.5% (100/129) vs. 69.0% (87/126), χ²=2.34, P=0.13]. Furthermore, incidences of MACE did not show any significant differences between the two groups during hospitalization [4.7% (6/129) vs. 7.1% (9/126), χ²=0.72, P=0.40] and at 6 months [14.7% (19/129) vs. 12.7% (16/126), χ²=0.22, P=0.64]. Four cardiac deaths were reported in the control group during hospitalization [0 (0/129) vs. 3.2% (4/126), P=0.06]. However, 6-month survival rates were comparable between the two groups (log-rank test, P=0.18). Moreover, adverse events or serious adverse events such as shock, ventricular fibrillation, and ventricular tachycardia were not reported in both the groups during levosimendan treatment (days 0-1). The total cost of hospitalization [34 591.00(15 527.46,59 324.80) vs. 37 144.65(16 066.90,63 919.00)yuan, Z=-0.26, P=0.80] and the total length of hospitalization [9 (8, 12) vs. 10 (7, 13) days, Z=0.72, P=0.72] were lower for patients in the levosimendan group compared to those in the control group, but did not show statistically significant differences. Conclusions: Early administration of levosimendan reduced NT-proBNP levels in NSTEMI patients with elevated NT-proBNP and did not increase the total cost and length of hospitalization, but did not significantly improve MACE during hospitalization or at 6 months.
Male ; Female ; Humans ; Aged ; Natriuretic Peptide, Brain ; Simendan/therapeutic use* ; Non-ST Elevated Myocardial Infarction ; Heart Failure/drug therapy* ; Peptide Fragments ; Arrhythmias, Cardiac ; Biomarkers ; Prognosis

AIM: Meta-analysis was performed to systematically evaluate the macular vessel density(VD)and foveal avascular zone(FAZ)areas in patients with no diabetic retinopathy(NDR)by using optical coherence tomography angiography(OCTA). This study aimed to investigate the microcirculatory characteristics of the retina in the early stage of diabetes.METHODS: PubMed, Embase, Web of Science and Cochrane Library databases were searched for publications from 1 January, 2011 to 5 January, 2021 on OCTA analysis of VD in different regions of the macular area in diabetic patients with NDR. Compare the differences in the superficial parafoveal VD(spafVD), superficial perifoveal VD(spefVD), deep parafoveal VD(dpafVD), deep perifoveal vessel density(dpefVD), superficial FAZ area and best corrected visual acuity(BCVA)between NDR group and the normal control group(healthy population matched for the age at the same time and gender with patients in the NDR group).RESULTS: Thirteen publications with a total of 1 227 eyes(558 eyes in normal control group and 669 eyes in NDR group)were included in the study. Meta-analysis showed that compared with the control group, NDR group displayed a significant decrease in spafVD(MD=-1.90, 95%CI: -2.43--1.37, P<0.00001), spefVD(MD=-1.29, 95%CI: -2.14--0.44, P=0.003), dpafVD(MD=-2.18, 95%CI: -2.69--1.67, P<0.00001)and dpefVD(MD=-2.37, 95%CI: -3.27--1.46, P<0.00001), with a more significant reduction in dpefVD, and superficial FAZ area(MD=0.04, 95%CI: 0.03-0.06, P<0.00001)was increased. There was no difference in BCVA(MD=0.00, 95%CI: -0.01-0.02, P=0.44)between the two groups.CONCLUSION:Capillary injury in the deep perifoveal region of the macular area is the earliest manifestation of retinal microcirculation disturbance in diabetic patients, and is also a key indicator for clinical follow-up of diabetic retinopathy.

Objective: To investigate the role of inflammatory biomarkers in the relationship between blood lead levels and blood pressure changes. Methods: A total of 9 910 people aged 18-79 years who participated in the China National Human Biomonitoring in 2017-2018 were included in this study. A self-made questionnaire was used to collect demographic characteristics, lifestyle and other information, and the data including height, weight and blood pressure were determined through physical examination. Blood and urinary samples were collected for the detection of blood lead and cadmium levels, urinary arsenic levels, white blood cells, neutrophils, lymphocytes, and hypersensitive C-reactive protein (hs-CRP). Weighted linear regression models were used to evaluate the associations between blood lead, inflammatory biomarkers and blood pressure. Mediation analysis was performed to investigate the role of inflammation in the relationship between blood lead levels and blood pressure changes. Results: The median (Q₁, Q₃) age of all participants was 45.4 (33.8, 58.4)years, including 4 984 males accounting for 50.3%. Multivariate logistic regression model analysis showed that after adjusting for age, gender, residence area, BMI, education level, smoking and drinking status, family history of hypertension, consumption frequency of rice, vegetables, and red meat, fasting blood glucose, total cholesterol, triglycerides, blood cadmium and urinary arsenic levels, there was a positive association between blood lead levels, inflammatory biomarkers and blood pressure (P<0.05). Each 2.71 μg/L (log-transformed) increase of the lead was associated with a 2.05 (95%CI: 0.58, 3.53) mmHg elevation in systolic blood pressure (SBP), 2.24 (95%CI: 1.34, 3.14) mmHg elevation in diastolic blood pressure (DBP), 0.25 (95%CI: 0.05, 0.46) mg/L elevation in hs-CRP, 0.16 (95%CI: 0.03, 0.29)×10⁹/L elevation in white blood cells, and 0.11 (95%CI: 0.02, 0.21)×10⁹/L elevation in lymphocytes, respectively. Mediation analysis showed that the levels of hs-CRP significantly mediated the association of blood lead with SBP, with a proportion about 3.88% (95%CI: 0.45%, 7.32%). The analysis also found that the levels of hs-CRP and neutrophils significantly mediated the association of blood lead with SBP, with a proportion about 4.10% (95%CI: 1.11%, 7.10%) and 2.42% (95%CI: 0.07%, 4.76%), respectively. Conclusion: This study suggests that inflammatory biomarkers could significantly mediate the association of blood lead levels and blood pressure changes.
Adult ; Male ; Humans ; Blood Pressure/physiology* ; C-Reactive Protein/analysis* ; Lead ; Arsenic/analysis* ; Cadmium ; Biomarkers ; Hypertension/epidemiology* ; China/epidemiology*