Melatonin supplementation protects against traumatic colon injury by regulating SERPINA3N protein expression.

Traumatic colon injury (TCI) is a typical injury with high mortality. Prolongation of the intervention time window is a potentially useful approach to improving the outcomes of TCI casualties. This study aimed to identify the pathological mechanisms of TCI and to develop effective strategies to extend the survival time. A semicircular incision was made to prepare a TCI model using C57BL/6 mice. An overview of microbiota dysregulation was achieved by metagenome sequencing. Protein expression reprogramming in the intestinal epithelium was investigated using proteomics profiling. The mice that were subjected to TCI died within a short period of time when not treated. Gut symbiosis showed abrupt turbulence, and specific pathogenic bacteria rapidly proliferated. The protein expression in the intestinal epithelium was also reprogrammed. Among the differentially expressed proteins, SERPINA3N was overexpressed after TCI modeling. Deletion of Serpina3n prolonged the posttraumatic survival time of mice with TCI by improving gut homeostasis in vivo. To promote the translational application of this research, the effects of melatonin (MLT), an oral inhibitor of the SERPINA3N protein, were further investigated. MLT effectively downregulated SERPINA3N expression and mitigated TCI-induced death by suppressing the NF-κB signaling pathway. Our findings prove that preventive administration of MLT serves as an effective regimen to prolong the posttraumatic survival time by restoring gut homeostasis perturbed by TCI. It may become a novel strategy for improving the prognosis of patients suffering from TCI.

Comparison of short-term efficacy between totally laparoscopic gastrectomy and laparoscopic assisted gastrectomy for elderly patients with gastric cancer.

BACKGROUND: Totally laparoscopic gastrectomy (TLG) entails both gastrectomy and gastrointestinal reconstruction under laparoscopy. Compared with laparoscopic assisted gastrectomy (LAG), TLG has been demonstrated in many studies to require a smaller surgical incision, result in a faster postoperative recovery and less pain and have comparable long-term efficacy, which has been a research hotspot in recent years. Whether TLG is equally safe and feasible for elderly patients remains unclear. AIM: To compare the short-term efficacy of and quality of life (QOL) associated with TLG and LAG in elderly gastric cancer (GC) patients. METHODS: The clinicopathological data of 462 elderly patients aged ≥ 70 years who underwent LAG or TLG (including distal gastrectomy and total gastrectomy) between January 2017 and January 2022 at the Department of General Surgery, First Medical Center, Chinese PLA General Hospital were retrospectively collected. A total of 232 patients were in the LAG group, and 230 patients were in the TLG group. Basic patient information, clinicopathological characteristics, operation information and QOL data were collected to compare efficacy. RESULTS: Compared with those in the LAG group, intraoperative blood loss in the TLG group was significantly lower (P < 0.001), and the time to first flatus and postoperative hospitalization time were significantly shorter (both P < 0.001). The overall incidence of postoperative complications in the TLG group was significantly lower than that in the LAG group (P = 0.01). Binary logistic regression results indicated that LAG and an operation time > 220 min were independent risk factors for postoperative complications in elderly patients with GC (P < 0.05). In terms of QOL, no statistically significant differences in various preoperative indicators were found between the LAG group and the LTG group (P > 0.05). Compared with the laparoscopic-assisted total gastrectomy group, patients who received totally laparoscopic total gastrectomy had lower nausea and vomiting scores and higher satisfaction with their body image (P < 0.05). Patients who underwent laparoscopic-assisted distal gastrectomy were more satisfied with their body image than patients in the totally laparoscopic distal gastrectomy group (P < 0.05). CONCLUSION: TLG is safe and feasible for elderly patients with GC and has outstanding advantages such as reducing intracorporeal blood loss, promoting postoperative recovery and improving QOL.

Oral administration of asparagine and 3-indolepropionic acid prolongs survival time of rats with traumatic colon injury.

BACKGROUND: Traumatic colon injury (TCI) is a common disease during wartime. Prolongation of posttraumatic survival time is an effective approach to patient outcome improvement. However, there is a lack of basic research in this field. This study aimed to elucidate the mechanisms underlying TCI progression and to develop novel regimens to buy time for TCI patients on the battlefield. METHODS: A total of 669 Sprague-Dawley rats were used in this study. Surgical colon incision was performed to generate the TCI rat model. The landscape of colon microbiota compositions was depicted using 16S rRNA sequencing and metabolites in the intestinal contents were detected by metabolomics profiling. The signaling transduction in the intestinal epithelium was investigated using antibody microarrays and Western blotting. The enzyme-linked immunosorbent assay was conducted to measure the levels of interleukin-6 and tumor necrosis factor-α in intestines and plasma for the detection of inflammatory responses. Diamine oxidase, D-lactate and endotoxin in plasma and protein expression of zonula occludens 1 and occludin were selected as the indicators of intestinal barrier permeability. To investigate alterations of microbiota symbiosis, the relative abundances of specific bacterial genera were detected using quantitative real-time PCR. RESULTS: As a type of lethal injury, TCI induced acute disruption of intestinal homeostasis, characterized by inflammatory responses, intestinal barrier hyperpermeability and microbiota dysbiosis (P < 0.05). Significant alterations in bacterial metabolic patterns were detected with decreases in many metabolites. After a series of screenings, we found that oral administration of asparagine (Asn) and 3-indolepropionic acid (IPA) effectively prolonged posttraumatic survival time [Asn plus IPA vs. Vehicle: hazard ratio (HR) = 0.105, 95% CI 0.031-0.356, P = 0.0003] and restored intestinal homeostasis in TCI rats (P < 0.05). Mechanistically, this combinational strategy protected the rats against TCI through synergistic activation of Akt signaling in the intestinal epithelium (P < 0.05). CONCLUSIONS: Abrupt dysregulation of intestinal homeostasis plays a critical role in the progression toward TCI-induced death. Oral administration of Asn plus IPA may serve as an effective regimen to restore intestinal functions and prolong the posttraumatic survival time.

Short and long-term outcomes between laparoscopic and open total gastrectomy for advanced gastric cancer after neoadjuvant chemotherapy.

BACKGROUND: Neoadjuvant chemotherapy (NACT) combined with surgery is regarded as an effective treatment for advanced gastric cancer (AGC). Laparoscopic surgery represents the mainstream of minimally invasive surgery. Currently, surgeons focus more on surgical safety and oncological outcomes of laparoscopic gastrectomy after NACT. Thus, we sought to evaluate short- and long-term outcomes between laparoscopic total gastrectomy (LTG) and open total gastrectomy (OTG) after NACT. AIM: To compare the short and long-term outcomes between LTG and OTG for AGC after NACT. METHODS: We retrospectively collected the clinicopathological data of 136 patients who accepted gastrectomy after NACT from June 2012 to June 2019, including 61 patients who underwent LTG and 75 who underwent OTG. Clinicopathological characteristics between the LTG and OTG groups showed no significant difference. SPSS 26.0, R software, and GraphPad PRISM 8.0 were used to perform statistical analyses. RESULTS: Of the 136 patients included, eight acquired pathological complete response, and the objective response rate was 47.8% (65/136). The LTG group had longer operation time (P = 0.015), less blood loss (P = 0.003), shorter days to first flatus (P < 0.001), and shorter postoperative hospitalization days (P < 0.001). LTG spent more surgical cost than OTG (P < 0.001), while total hospitalized cost of LTG was less than OTG (P < 0.001). 21 (28.0%) patients in the OTG group and 14 (23.0%) in the LTG group had 30-d postoperative complications, but there was no significant difference between the two groups (P = 0.503). The 3-year overall survival (OS) rate was 60.6% and 64.6% in the LTG and OTG groups, respectively [hazard ratio (HR) = 0.859, 95% confidence interval (CI): 0.522-1.412, P = 0.546], while the 3-year disease-free survival (DFS) rate was 54.5% and 51.8% in the LTG and OTG group, respectively (HR = 0.947, 95%CI: 0.582-1.539, P = 0.823). Multivariate cox analysis showed that body mass index and pTNM stage were independent risk factors for OS while vascular invasion and pTNM stage were independent risk factors for DFS (P < 0.05). CONCLUSION: After NACT, LTG shows comparable 30-d postoperative morbidity as well as 3-year OS and DFS rate to OTG. We recommend that experienced surgeons select LTG other than OTG for proper AGC patients after NACT.

Relationship between the expression of hypoxia-inducible factor-1alpha and chemotherapy response in gastric carcinoma / 中华胃肠外科杂志

<p><b>OBJECTIVE</b>To evaluate the relationship of hypoxia-inducible factor (HIF)-1alpha expression with chemotherapy response in gastric cancer and its clinical outcome.</p><p><b>METHODS</b>Leucovorin (CF) and 5-fluorouracil (5-FU) in combination with oxaliplatin (L-OHP) were used in 52 patients with gastric carcinoma (GC) at advanced stage. CF 200 mg/m(2) was intravenous drop for 2 h at day 1 and day 14. 5-FU 1500 mg/m(2) was continuously intravenous drop for 46 h at day 1 and day 14. L-OHP 85 mg/m(2) was intravenous drop for 2 h at day 1 and day 14. Four-week was one cycle. All the patients received 4 cycles of chemotherapy at least. Chemotherapy response and clinical outcome were evaluated. Immunohistochemistry was used to examine the protein expressions of HIF-1alpha, P-gp and MRP4 by tissue microarray in GC. Twenty-seven normal gastric tissue samples were used as control group.</p><p><b>RESULTS</b>The positive expression rates of HIF-lalpha, P-gp and MRP4 in tumor samples were 53.9%, 51.9% and 57.7% respectively, which were significantly higher than those in normal gastric tissues (0, 18.5% and 14.8% respectively) (P<0.05). In cases with positive expression of HIF-lalpha, the response rate was 14.3%; whereas in cases with negative expression of HIF-1alpha, the response rate was 50.0%. There was significant difference between two groups (P<0.05). In patients of HIF-1alpha positive expression,the median progression-free survival time was 4.7 months,the median survival time was 8.8 months, and 1-year, 2-year survival rates were 37.5% and 21.5% respectively. In patients of HIF-1alpha negative expression, the median progression-free survival time was 8.4 months, the median survival time was l2.6 months, and 1-year, 2-year survival rates were 51.2% and 33.5% respectively. There were significant differences between two groups (P<0.05).</p><p><b>CONCLUSION</b>HIF-1alpha expression may be a useful indicator to predict the chemotherapy response and clinical outcome in gastric carcinoma.</p>