Platelet derived growth factor promotes the recovery of traumatic brain injury by inhibiting endoplasmic reticulum stress and autophagy-mediated pyroptosis.

Autophagy and endoplasmic reticulum stress (ER stress) are important in numerous pathological processes in traumatic brain injury (TBI). Growing evidence has indicated that pyroptosis-associated inflammasome is involved in the pathogenesis of TBI. Platelet derived growth factor (PDGF) has been reported to be as a potential therapeutic drug for neurological diseases. However, the roles of PDGF, autophagy and ER stress in pyroptosis have not been elucidated in the TBI. This study investigated the roles of ER stress and autophagy after TBI at different time points. We found that the ER stress and autophagy after TBI were inhibited, and the expressions of pyroptosis-related proteins induced by TBI, including NLRP3, Pro-Caspase1, Caspase1, GSDMD, GSDMD P30, and IL-18, were decreased upon PDGF treatment. Moreover, the rapamycin (RAPA, an autophagy activator) and tunicamycin (TM, an ER stress activator) eliminated the PDGF effect on the pyroptosis after TBI. Interestingly, the sodium 4-phenylbutyrate (4-PBA, an ER stress inhibitor) suppressed autophagy but 3-methyladenine (3-MA, an autophagy inhibitor) not for ER stress. The results revealed that PDGF improved the functional recovery after TBI, and the effects were markedly reversed by TM and RAPA. Taken together, this study provides a new insight that PDGF is a potential therapeutic strategy for enhancing the recovery of TBI.

ALG-bFGF Hydrogel Inhibiting Autophagy Contributes to Protection of Blood-Spinal Cord Barrier Integrity via PI3K/Akt/FOXO1/KLF4 Pathway After SCI.

Promoting blood-spinal cord barrier (BSCB) repair at the early stage plays a crucial role in treatment of spinal cord injury (SCI). Excessive activation of autophagy can prevent recovery of BSCB after SCI. Basic fibroblast growth factor (bFGF) has been shown to promote BSCB repair and locomotor function recovery in SCI. However, the therapeutic effect of bFGF via direct administration on SCI is limited because of its rapid degradation and dilution at injury site. Based on these considerations, controlled release of bFGF in the lesion area is becoming an attractive strategy for SCI repair. At present, we have designed a sustained-release system of bFGF (called ALG-bFGF) using sodium alginate hydrogel, which is able to load large amounts of bFGF and suitable for in situ administration of bFGF in vivo. Here, traumatic SCI mice models and oxygen glucose deprivation (OGD)-stimulated human brain microvascular endothelial cells were performed to explore the effects and the underlying mechanisms of ALG-bFGF in promoting SCI repair. After a single in situ injection of ALG-bFGF hydrogel into the injured spinal cord, sustained release of bFGF from ALG hydrogel distinctly prevented BSCB destruction and improved motor functional recovery in mice after SCI, which showed better therapeutic effect than those in mice treated with bFGF solution or ALG. Evidences have demonstrated that autophagy is involved in maintaining BSCB integrity and functional restoration in animals after SCI. In this study, SCI/OGD exposure-induced significant upregulations of autophagy activation-related proteins (Beclin1, ATG5, LC3II/I) were distinctly decreased by ALG-bFGF hydrogel near the baseline and not less than it both in vivo and in vitro, and this inhibitory effect contributed to prevent BSCB destruction. Finally, PI3K inhibitor LY294002 and KLF4 inhibitor NSC-664704 were applied to further explore the underlying mechanism by which ALG-bFGF attenuated autophagy activation to alleviate BSCB destruction after SCI. The results further indicated that ALG-bFGF hydrogel maintaining BSCB integrity by inhibiting autophagy activation was regulated by PI3K/Akt/FOXO1/KLF4 pathway. In summary, our current study revealed a novel mechanism by which ALG-bFGF hydrogel improves BSCB and motor function recovery after SCI, providing an effective therapeutic strategy for SCI repair.

Preoperative Blood Glucose Level Predicts Postsurgical Gastroparesis Syndrome after Subtotal Gastrectomy: Development of an Individualized Usable Nomogram.

BACKGROUND: Postsurgical gastroparesis syndrome (PGS) after subtotal gastrectomy imposes significant social and economic burdens. We aimed to investigate the relationship between preoperative blood glucose level and PGS and develop a nomogram for individualized prediction. Patients and Methods. We retrospectively analyzed 633 patients with gastric cancer who underwent subtotal gastrectomy. Preoperative blood glucose levels were evaluated via receiver operating characteristic (ROC) curve analysis. Chi-squared tests and multivariable logistic regression analyses were used to develop a predictive model for PGS, presented as a nomogram, which was assessed for its clinical usefulness. RESULTS: Thirty-eight of 633 patients were diagnosed with PGS. Based on the ROC curve analysis, the preoperative blood glucose cutoff value for PGS was 6.25 mmol/L. The predictors of PGS included preoperative hyperglycemia (odds ratio (OR) 2.3, P = 0.03), body mass index (BMI; OR 0.21, P = 0.14 for BMI < 18.5 and OR 3.0, P = 0.004 for BMI > 24), and the anastomotic method (OR 7.3, P = 0.001 for Billroth II and OR 5.9, P = 0.15 for Roux-en-Y). The predictive model showed good discrimination ability, with a C-index of 0.710, and was clinically useful. CONCLUSIONS: Preoperative hyperglycemia effectively predicts PGS. We present a nomogram incorporating the preoperative blood glucose level, BMI, anastomotic method, and tumor size, for individualized prediction of PGS.

Preoperative Cachexia predicts poor outcomes in young rather than elderly gastric cancer patients: a prospective study.

BACKGROUND: Cachexia affects nearly 50-80% of cancer patients, and most studies have only focused on elderly patients. We investigated preoperative cachexia in gastric cancer (GC) patients by age group and comprehensively analyzed the impact of preoperative cachexia on the prognosis of GC patients in all age groups. METHODS: In total, 575 patients were prospectively analyzed. The effect of preoperative cachexia on overall survival (OS) in all the patients and in patients with different age groups were investigated using log-rank test and Cox proportional hazards regression, respectively. RESULTS: In total, 35.8% (206 of 575) individuals were diagnosed with cachexia. The median survival of cachexia patients (29.2 months) was shorter than that of non-cachexia patients (35.7 months). Cachexia (HR =1.976, P<0.001), age (HR =1.811, P<0.001), readmission (HR =2.559, P<0.001), tumor size (HR =1.639, P=0.003), TNM stage (stage II: HR =2.215, P=0.017; stage III: HR =5.758, P<0.001), whole stomach cancer (HR =2.639, P<0.001), and combined operation (HR =1.598, P=0.032) were independently associated with worse OS. After grouping by age, cachexia was associated with OS in patients younger than 50 years old (HR =4.947, P=0.029), patients 51-60 years old (HR =2.232, P=0.026), and patients 61-70 years old (HR =1.806, P=0.032), but not in patients older than 71 years (HR =1.411, P=0.119). Further, cachexia only significantly affected the postoperative length of stay (P=0.015) and hospitalization costs (P=0.032) in patients younger than 50 years old. CONCLUSIONS: Preoperative cachexia predicts poor outcome in younger GC patients, and greater attention should be paid to these patients.

Analysis of posttraumatic stress disorder in children with road traffic injury in Wenzhou, China.

OBJECTIVE: Road traffic accidents are the leading health threat to children and cause significant long-term mental health problems. This study aimed to characterize posttraumatic stress disorder (PTSD) in children suffering from road traffic injuries (RTIs) in Wenzhou, China. METHODS: We conducted a retrospective study of 537 children (aged 1 to 13 years old) with RTIs. The epidemiological features, PTSD incidence, clinical manifestation, and risk factors were analyzed based on a customized PTSD risk factor questionnaire. The outcome factors were also evaluated by means of the logistic regression method. RESULTS: The PTSD incidence was 24.77% in children with RTIs. The incidence of PTSD was related to the personality, family environment, and family care of the children. It was found that early psychological intervention and reasonable family care from the family might promote physical and mental welfare as well as contribute to the development of more effective treatments to prevent PTSD. CONCLUSION: For susceptible children, in addition to dealing with the somatic injury, psychological intervention and family care should be carried out as early as possible.

A correlation study of the expression of resistin and glycometabolism in muscle tissue after traumatic brain injury in rats.

OBJECTIVE: To investigate the expression pattern of resistin (RSTN) in skeletal muscle tissue and its influence on glycometabolism in rats with traumatic brain injury (TBI). METHODS: Seventy-eight SD rats were randomly divided into traumatic group (n=36), RSTN group (n=36) and sham operation group (n=6). Fluid percussion TBI model was developed in traumatic and RSTN groups and the latter received additional 1 mg RSTN antibody treatment for each rat. At respectively 12 h, 24 h, 72 h, 1 w, 2 w, and 4 w after operation, venous blood was collected and the right hind leg skeletal muscle tissue was sampled. We used real-time PCR to determine mRNA expression of RSTN in skeletal muscles, western blot to determine RSTN protein expression and ELISA to assess serum insulin as well as fasting blood glucose (FBG) levels. Calculation of the quantitative insulin sensitivity check index (Q value) was also conducted. The above mentioned indicators and their correction were statistically analyzed. RESULTS: Compared with sham operation group, the RSTN expression in the skeletal muscle as well as serum insulin and FBG levels revealed significant elevation (P<0.05), and reduced Q value (P<0.05) in traumatic group. Single factor linear correlation analysis showed a significant negative correlation between RSTN expression and Q values (P<0.001) in traumatic group. CONCLUSION: The expression of RSTN has been greatly increased in the muscular tissue of TBI rats and it was closely related to the index of glycometabolism. RSTN may play an important role in the process of insulin resistance after TBI.