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

Malignant liver tumors have a high incidence and mortality rate. Therefore, it is of great significance to promptly learn about tumor advancement status through relevant examinations for patients' follow-up, diagnosis, and therapy as well as the improvement of the five-year survival rate. The primary lesions and intrahepatic metastases of malignant liver tumors have been better demonstrated in the clinical study with the use of various isotope-labeled fibroblast activating protein inhibitors because of their low uptake in liver tissues and high tumor/background ratio, which provides a new method for early diagnosis, precise staging, and radionuclide therapy. In light of this context, a review of the research progress of fibroblast-activating protein inhibitors for the diagnosis of liver malignant tumors is presented.
Humans ; Positron Emission Tomography Computed Tomography ; Carcinoma, Hepatocellular ; Liver Neoplasms

Objective:To investigate the effects of theta burst stimulation(TBS)mode repeated transcranial magnetic stimulation (r-TMS) in the left prefrontal on negative symptoms and cognitive function in the elderly chronic schizophrenic patients.Methods:Totally 48 patients with stable chronic senile schizophrenia (24 cases in r-TMS treatment group and 24 cases in r-TMS pseudo stimulation control group) were selected. The treatment group was given the TBS mode r-TMS performed in the left dorsolateral prefrontal cortex. The control group was given pseudo stimulation at the same site. Before and after treatment, the brief psychiatric rating scale(BPRS), scale for assessment of negative symptoms(SANS), and positive and negative syndrome scale(PANSS)were used to assess mental symptoms, while Mattis-dementia rating scale(MDRS-2)and social adaptation functioning evaluation(SAFE)were used to assess cognitive function and social function. SPSS 20.0 was used for statistical analysis.Comparisons of the differences between inter groups and intra groups were conducted by independent sample t test and paired t-test. Results:(1)There were significant differences in the total score of PANSS scale((60.17±3.73), (56.67±3.12)), the negative symptom subscale score of PANSS((20.88±2.94), (17.96±2.33)) and the score of SANS((30.67±1.66), (30.25±1.45)) before and after treatment in the treatment group (all P<0.05). The D-value before and after treatment in the scores of BPRS ( t=3.513, P=0.001), PANSS ( t=6.048, P<0.01), negative symptom subscale ( t=6.610, P<0.01) and SANS ( t=8.239, P<0.01) were significantly different between the two groups. (2)There were significant differences in the scores of MDRS-2 and its sub scales before and after treatment in the treatment group (all P<0.05). The D-value before and after treatment in the scores of MDRS-2 ( t=6.216, P<0.01), attention ( t=4.596, P<0.01), start/maintain ( t=6.424, P<0.01), concept formation ( t=3.974, P<0.01), construction( t=2.194, P=0.033) and memory ( t=3.162, P=0.003) were significantly different between the two groups.(3)There was no significant difference in the SAFE score between the treatment group and the control group before and after treatment ( t=0.138, 0.142, both P>0.05). Conclusion:TBS can improve the negative symptoms and cognitive function in patients with the elderly chronic schizophrenic, but the effect of social function is not clear.

BACKGROUND: Delivery room resuscitation assists preterm infants, especially extremely preterm infants (EPI) and extremely low birth weight infants (ELBWI), in breathing support, while it potentially exerts a negative impact on the lungs and outcomes of preterm infants. This study aimed to assess delivery room resuscitation and discharge outcomes of EPI and ELBWI in China. METHODS: The clinical data of EPI (gestational age [GA] <28 weeks) and ELBWI (birth weight [BW] <1000 g), admitted within 72 h of birth in 33 neonatal intensive care units from five provinces and cities in North China between 2017 and 2018, were analyzed. The primary outcomes were delivery room resuscitation and risk factors for delivery room intubation (DRI). The secondary outcomes were survival rates, incidence of bronchopulmonary dysplasia (BPD), and risk factors for BPD. RESULTS: A cohort of 952 preterm infants were enrolled. The incidence of DRI, chest compressions, and administration of epinephrine was 55.9% (532/952), 12.5% (119/952), and 7.0% (67/952), respectively. Multivariate analysis revealed that the risk factors for DRI were GA <28 weeks (odds ratio [OR], 3.147; 95% confidence interval [CI], 2.082-4.755), BW <1000 g (OR, 2.240; 95% CI, 1.606-3.125), and antepartum infection (OR, 1.429; 95% CI, 1.044-1.956). The survival rate was 65.9% (627/952) and was dependent on GA. The rate of BPD was 29.3% (181/627). Multivariate analysis showed that the risk factors for BPD were male (OR, 1.603; 95% CI, 1.061-2.424), DRI (OR, 2.094; 95% CI, 1.328-3.303), respiratory distress syndrome exposed to ≥2 doses of pulmonary surfactants (PS; OR, 2.700; 95% CI, 1.679-4.343), and mechanical ventilation ≥7 days (OR, 4.358; 95% CI, 2.777-6.837). However, a larger BW (OR, 0.998; 95% CI, 0.996-0.999), antenatal steroid (OR, 0.577; 95% CI, 0.379-0.880), and PS use in the delivery room (OR, 0.273; 95% CI, 0.160-0.467) were preventive factors for BPD (all P < 0.05). CONCLUSION Improving delivery room resuscitation and management of respiratory complications are imperative during early management of the health of EPI and ELBWI.
Birth Weight ; Bronchopulmonary Dysplasia ; China/epidemiology* ; Delivery Rooms ; Female ; Gestational Age ; Humans ; Infant ; Infant, Extremely Low Birth Weight ; Infant, Extremely Premature ; Infant, Newborn ; Male ; Pregnancy

Objective To explore the characteristics and differences of the distribution of skeletal muscle content between the Han adult population in Tibet and Liaoning Han adult population. Methods Randomly selected healthy adults of Han worked in Tibet and Liaoning Han nationality as the research object, a total of 223 Han adults worked in Tibet ( 95 males, 128 females); 302 adults of Han nationality in Liaoning (126 males, 176 females) were selected by body composition analyzer. The body weight, total muscle mass, trunk muscle mass, left upper limb muscle mass, right upper limb muscle mass, left lower limb muscle mass, and right lower limb muscle mass of the subject were measured. All the result were input into SPSS 22. 0 statistical analysis, and related statistical processing such as independent sample t test was applied. Results The body weight, trunk muscle mass, left upper limb muscle mass, right upper limb muscle mass, left lower limb muscle mass, and lower right muscle mass of the Tibetan Han population were lower than those of the Han adults in Liaoning, and the comparison result was significantly different (P<0.01 or P<0.05), the Han adults in Liaoning and the Tibetan Han population, male muscle mass was greater than the female adults (P<0.01 or P<0.05). Conclusion After the Han people in Liaoning entered the Tibetan Plateau, the muscle mass of each part of the body decrease significantly. The change of human body composition can be affected by various factors such as gender and high altitude hypoxia environment.

Objective To explore the clinical characteristics of relapsing polychondritis(RP)patients presented with arthropathy. Methods We retrospectively analyzed the clinical data of 201 RP patients who were hospitalized in our center between December 2005 and February 2019.After 16 patients with co-existing other autoimmune diseases and malignancies were ruled out,185 RP patients entered the final analysis,among whom 16 RP patients were presented with arthropathy and 169 without arthropathy.The demographic data,clinical manifestations,laboratory findings,and prognosis were compared between these two groups. Results Five of the 16 RP patients with arthropathy at presentation were misdiagnosed as rheumatoid arthritis.Compared with RP patients without arthropathy at presentation,RP patients with arthropathy at presentation had a longer disease course[(37.50±66.50)months
Arthritis, Rheumatoid ; Delayed Diagnosis ; Diagnostic Errors ; Humans ; Joint Diseases/diagnosis* ; Polychondritis, Relapsing/diagnosis* ; Prognosis ; Retrospective Studies

Intracardiac thrombus is a rare complication of Antiphospholipid syndrome secondary to systemic lupus erythematosus (SLE). Its treatment is extremely tough and requires a multidisciplinary approach. We reported a case of SLE with intracardiac thrombus and pulmonary embolism. The patient was complicated with hemoptysis and kidney injury，and had a high risk of sudden death from incidental thrombus shedding off. In the state of thrombosis and hemorrhage，the management of anticoagulation and the evaluation and treatment of the primary disease complicated with infection are challenging. The multidisciplinary collaboration helped us to create a more favorable surgical condition while controlling SLE aggressively. After surgical treatment at the proper time，the outcome of the patient was satisfying.

OBJECTIVE: To evaluate the effects of a 48-week course of adefovir dipivoxil (ADV) plus Chinese medicine (CM) therapy, namely Tiaogan Jianpi Hexue () and Tiaogan Jiedu Huashi () fomulae, in hepatitis B e antigen (HBeAg)-positive Chinese patients. METHODS: A total of 605 HBeAg-positive Chinese CHB patients were screened and 590 eligible participants were randomly assigned to 2 groups in 1:1 ratio including experimental group (EG, received ADV plus CM) and control group (CG, received ADV plus CM-placebo) for 48 weeks. The major study outcomes were the rates of HBeAg and HBV-DNA loss on week 12, 24, 36, 48, respectively. Secondary endpoints including liver functions (enzymes and bilirubin readings) were evaluated every 4 weeks at the beginning of week 24, 36, and 48. Routine blood, urine, and stool analyses in addition to electrocardiogram and abdominal B scan were monitored as safety evaluations. Adverse events (AEs) were documented. RESULTS: The combination therapy demonstrated superior HBeAg loss at 48 weeks, without additional AEs. The full analysis population was 560 and 280 in each group. In the EG, population achieved HBeAg loss on week 12, 24, 36, and 48 were 25 (8.90%), 34 (12.14%), 52 (18.57%), and 83 (29.64%), respectively; the equivalent numbers in the CG were 20 (7.14%), 41 (14.64%), 54 (19.29%), and 50 (17.86%), respectively. There was a statistically significant difference between these group values on week 48 (P<0.01). No additional AEs were found in EG. Subgroup analysis suggested different outcomes among treatment patterns. CONCLUSION Combination of CM and ADV therapy demonstrated superior HBeAg clearance compared with ADV monotherapy. The finding indicates that this combination therapy may provide an improved therapeutic effect and safety profile (ChiCTR-TRC-11001263).
Adenine ; analogs & derivatives ; therapeutic use ; Adult ; Antiviral Agents ; therapeutic use ; Double-Blind Method ; Drug Therapy, Combination ; Drugs, Chinese Herbal ; therapeutic use ; Female ; Hepatitis B e Antigens ; immunology ; Hepatitis B, Chronic ; drug therapy ; immunology ; Humans ; Male ; Medicine, Chinese Traditional ; Organophosphonates ; therapeutic use ; Young Adult

BACKGROUND: Alcohol consumption has been observed to be a contributing factor in liver damage. However, very few studies have tried to decipher the correlation between patients with liver disease and alcohol consumption. Therefore, this study was planned to determine the prevalence of alcohol consumption among patients with liver disease, and to evaluate the risk factors, liver diseases, and chronic medical conditions associated with alcohol drinking. METHODS: A cross-sectional study was conducted among patients with liver disease in 30 provinces, autonomous regions, and municipalities across China. All participants answered the questionnaire, which led to the calculation of Alcohol Use Disorders Inventory Test (AUDIT) score for each patient. Based on this score, low-risk drinkers, hazardous drinkers, and harmful drinkers were defined as having AUDIT score of <8, between 8 and 15, and ≥16, respectively. RESULTS: A total of 1489 participants completed the questionnaire. Based on this information, 900 (60.44%) participants were classified as alcohol drinkers. Among these, 8.66% were ex-drinkers, 22.10% were low-risk drinkers, 17.13% were hazardous drinkers, and 12.56% were harmful drinkers. Further investigation of the association between alcohol consumption and other baseline characteristics of patients with liver disease revealed that usually men <40 years old, participants having higher family annual income, having college degree or higher education, living alone, having higher body mass index (BMI), current smokers, and ex-smokers had significant association with higher risk of alcohol consumption. In addition, among the 18.07% of the participants with cirrhosis, it was observed that risk of cirrhosis increased with higher alcohol consumption. Furthermore, harmful drinkers showed greater odds of hypertension and heart diseases, while hazardous drinkers and harmful drinkers, both had greater odds of hyperlipidemia. CONCLUSIONS Overall our analyses indicated that among the patients with liver disease in China, there was high rate of alcohol consumption and dependence. Alcohol consumption usually associated with men <40 years old, higher family income, education level, living alone, high BMI, and smoking. Increased alcohol consumption not only increased the risk of cirrhosis, but also enhanced the risk of hypertension, heart diseases, and hyperlipidemia.
Adult ; Aged ; Alcohol Drinking ; adverse effects ; Alcoholism ; etiology ; Cross-Sectional Studies ; Female ; Humans ; Liver Diseases ; etiology ; Male ; Middle Aged ; Smoking ; adverse effects

Ginger, one of worldwide consumed dietary spice, is not only famous as food supplements, but also believed to exert a variety of remarkable pharmacological activity as herbal remedies. In this study, a ginger constituent, 12-dehydrogingerdione (DHGD) was proven that has comparable anti-inflammatory activity with positive control 6-shogaol in inhibiting LPS-induced interleukin (IL)-6, tumor necrosis factor (TNF)-α, prostaglandin (PG) E₂, nitric oxide (NO), inducible NO synthase (iNOS) and cyclooxygenase (COX)-2, without interfering with COX-1 in cultured microglial cells. Subsequent mechanistic studies indicate that 12-DHGD may inhibit neuro-inflammation through suppressing the LPS-activated Akt/IKK/NF-κB pathway. Furthermore, 12-DHGD markedly promoted the activation of NF-E2-related factor (Nrf)-2 and heme oxygenase (HO)-1, and we demonstrated that the involvement of HO-1 on the production of pro-inflammatory mediators such as NO and TNF-α by using a HO-1 inhibitor, Zinc protoporphyrin (Znpp). These results indicate that 12-DHGD may protect against neuro-inflammation by inhibiting Akt/IKK/IκB/NF-κB pathway and promoting Nrf-2/HO-1 pathway.
Dietary Supplements ; Ginger ; Heme Oxygenase (Decyclizing) ; Interleukins ; Microglia* ; Nitric Oxide ; Nitric Oxide Synthase ; Prostaglandin-Endoperoxide Synthases ; Spices ; Tumor Necrosis Factor-alpha ; Zinc