The efficient clinical treatment of oral squamous cell carcinoma(OSCC)is still a challenge that demands the development of effective new drugs.Phenformin has been shown to produce more potent anti-tumor activities than metformin on different tumors,however,not much is known about the influence of phenformin on OSCC cells.We found that phenformin suppresses OSCC cell proliferation,and promotes OSCC cell autophagy and apoptosis to significantly inhibit OSCC cell growth both in vivo and in vitro.RNA-seq analysis revealed that autophagy pathways were the main targets of phenformin and identified two new targets DDIT4(DNA damage inducible transcript 4)and NIBAN1(niban apoptosis regulator 1).We found that phenformin significantly induces the expression of both DDIT4 and NIBAN1 to promote OSCC autophagy.Further,the enhanced expression of DDIT4 and NIBAN1 elicited by phenformin was not blocked by the knockdown of AMPK but was suppressed by the knockdown of transcription factor ATF4(activation transcription factor 4),which was induced by phenformin treatment in OSCC cells.Mechanistically,these results revealed that phenformin triggers endoplasmic reticulum(ER)stress to activate PERK(protein kinase R-like ER kinase),which phosphorylates the transitional initial factor eIF2,and the increased phosphorylation of eIF2 leads to the increased translation of ATF4.In summary,we discovered that phenformin induces its new targets DDIT4 and especially NIBAN1 to promote autophagic and apoptotic cell death to suppress OSCC cell growth.Our study supports the potential clinical utility of phenformin for OSCC treatment in the future.

Sepsis is a life-threatening organ dysfunction caused by dysregulated host responses to infection. Despite significant advances in anti-infective, immunomodulatory, and organ function support technologies, the precise and targeted management of sepsis remains a challenge due to its high heterogeneity. Studies have identified disturbed tryptophan (TRP) metabolism as a common mechanism in multiple diseases, which is involved in both immune regulation and the development of multi-organ damages. The rise of research on intestinal microflora has further highlighted the critical role of microflora-regulated TRP metabolism in pathogen-host interactions and the "cross-talk" among multi-organs, making it a potential key target for precision medicine in sepsis. This article reviews TRP metabolism, the regulation of TRP metabolism by the intestinal microflora, and the characteristics of TRP metabolism in sepsis, providing clues for further clinical targeting of TRP metabolism for precision medicine in sepsis.
Humans ; Gastrointestinal Microbiome/physiology* ; Tryptophan/metabolism* ; Precision Medicine ; Sepsis

Objective:To investigate the dynamic changes of intestinal flora in septic model mice.Methods:Forty-two male SPF C57BL/6 mice were selected, the sepsis model was reproduced by cecal ligation and puncture (CLP), and the experimental mice were divided into CLP 6-12 hours group ( n = 9) and 1, 2, 3 days group (all n = 10) and Sham group ( n = 3) according to the time points after modeling. Intestinal flora 16S rRNA sequencing was carried out within feces from the colonic lumen of mice, and the effective sequences were clustered to obtain an operational classification unit (OTU) for statistical analysis of biological information, including Alpha diversity analysis, species composition analysis, principal coordinate analysis (PCoA analysis) and species difference analysis (LEfSe analysis), the dynamic changes of intestinal flora after CLP modeling were analyzed. Results:Compared with Sham group, with the prolongation of modeling time, the Alpha diversity of intestinal flora decreased, showing a decrease in community richness index (3 days after CLP: Chao index 1 was 367.9±162.6 vs. 508.3±105.9, Ace index was 372.5±151.9 vs. 498.8±104.2), Shannon index decreased in community diversity index (3 days after CLP: 2.57±1.06 vs. 4.30±0.57, Simpson index increased (3 days after CLP: 0.26±0.19 vs. 0.04±0.03), suggesting that with the progress of CLP modeling time, the richness and diversity of intestinal flora decreased. According to species composition analysis, in OTU level, OTU 633 accounted for the highest proportion in CLP 1 day group (24.79%), OTU 1016 was dominant in CLP 2 days and 3 days groups, and the highest proportion was 61.75% in CLP 3 days group; in genus level, the abundance of norank_f_Muribaculaceae showed a slight increase and then a significant decrease with time, the abundance of Escherichia-Shigella increased significantly in CLP 2 days and 3 days groups, the abundance of Lactobacillus increased first and then decreased with time, the abundance of Bacteroides showed a trend of gradual increase with time. PCoA analysis suggested that CLP 6-12 hours group had a higher structural similarity with Sham group. The flora structure changed gradually with the time after modeling, and the change was significant after 3 days of CLP. LEfSe analysis indicated that the main components that caused the differences among the groups were g _norank_f_Muribaculaceae, g _Prevotellaceae_UCG-001, s_uncultured_Bacteroidales_bacterium_g_norank_f_Muribaculaceae, g_Parabacteroides, Escherichia-Shigella and OTU 1016. The differences in abundance of Escherichia-Shigella and OTU 1016 among the five groups ranked first in the genus level and OTU level respectively; the abundance of Escherichia-Shigella gradually increased from 0.01% (0%, 0.02%) in 6-12 hours after CLP to 44.79% (3.71%, 53.75%) in 3 days with time, and the abundance of OTU 1016 increased from 0.01% (0%, 0.02%) in 6-12 hours after CLP to 44.69% (3.66%, 53.64%) in 3 days with time. Conclusion:Intestinal dysbiosis occurred in all CLP model groups, the diversity of the flora gradually decreased with the progress of modeling time, Escherichia-Shigella gradually became the dominant bacteria.

Objective: To explore the lung damage caused by repeated inhalation of polyhexamethyleneguanidine (PHMG) disinfectant aerosol and the corresponding toxicological characteristics. Methods: Thirty four-week-old mice of C57BL/6N strain were randomly divided into three groups, the control group, low-dose group, and high-dose group. Each group had 5 male mice and 5 female mice. Lab II-level purified water was used in the control group. The PHMG disinfectant aerosol was generated by using the ultrasonic atomization of the aqueous solution containing PHMG. The PHMG concentrations in the low-and high-dose groups were 0.1 mg/ml (0.01%) and 1 mg/ml (0.1%), respectively. The concentration of PHMG in the post-chemical exposure room was 1.03 mg/m³ and 9.09 mg/m³ according to the air sampler analysis. The experimental mice were exposed to the PHMG in dynamic respiratory exposure mode for 4 hours every day in 21 days. After 21-day exposure, bronchia alveolus lung fluids (BALFs) were used to evaluate the inflammatory cells in the lungs, and pathological evaluation, special staining and immunohistochemical methods were further performed to evaluate the key indicators of pulmonary fibrosis. Results: Compared to the control group, the body weight of mice in the high-dose group was significantly decreased (P<0.05), while that of mice in the low-dose group did not significantly differ (P>0.05). The number of inflammatory cells in BALFs of low-dose exposed mice was slightly reduced, and the lung tissue pathology began to show lung damage with early fibrosis symptoms (P<0.05). The pathological examination of mice in the high-dose group showed changes in pulmonary fibrosis. Immunohistochemical staining showed that pulmonary fibrosis marker, α-SMA, was significantly increased in low-dose group and high-dose group (P<0.05). Conclusion The repeated inhalation of PHMG disinfectant could cause lung damage such as pulmonary fibrosis in mice. It could suggest that special warnings should be given to this common disinfectant and respiratory protection measures should be adopted during industrial production and daily use.

Objective:To investigate the measurement of small airways by high-resolution CT and image post-processing software. Screen and analyze the reconstructed airway parameters in order to find the best imaging biomarker parameters of small airway changes and calculate the reference value range; meanwhile, explore its influencing factors.Methods:From a water plant and a medical school, 169 cases of the general population aged 20 to 60 were selected as research objects, and questionnaire surveys and CT tests were performed, and CT data were reconstructed with image post-processing software. The reference value range of the general population was evaluated, and a linear mixed effect model was used to adjust the age, gender, height, BMI, and smoking status, and analyze the influencing factors of airway parameters.Results:The ratio of sixth-grade tracheal wall area to total tracheal area in the Left B1+2 to carina was (53.01±13.35) %, Left B9 to carina was (50.44±12.98) %, Right B1 to carina was (52.73±12.22) %, and Right B9 to carina was (52.93±11.85) %. The ratio of nineth-grade tracheal wall area to total tracheal area in the Left B1+2 to carina was (44.08±14.66) %, Left B9 to carina was (42.44±15.89) %, Right B1 to carina was (46.51±14.03) %, and Right B9 to carina is (43.54±15.87) %. BMI affect the area of the tracheal wall, all p value<0.05.Conclusion:High-resolution CT small airway morphology can make a preliminary assessment of the susceptible population of small airway-related diseases based on a range of reference values, and prevent and control it in combination with influencing factors.

Objective:To investigate the measurement of small airways by high-resolution CT and image post-processing software. Screen and analyze the reconstructed airway parameters in order to find the best imaging biomarker parameters of small airway changes and calculate the reference value range; meanwhile, explore its influencing factors.Methods:From a water plant and a medical school, 169 cases of the general population aged 20 to 60 were selected as research objects, and questionnaire surveys and CT tests were performed, and CT data were reconstructed with image post-processing software. The reference value range of the general population was evaluated, and a linear mixed effect model was used to adjust the age, gender, height, BMI, and smoking status, and analyze the influencing factors of airway parameters.Results:The ratio of sixth-grade tracheal wall area to total tracheal area in the Left B1+2 to carina was (53.01±13.35) %, Left B9 to carina was (50.44±12.98) %, Right B1 to carina was (52.73±12.22) %, and Right B9 to carina was (52.93±11.85) %. The ratio of nineth-grade tracheal wall area to total tracheal area in the Left B1+2 to carina was (44.08±14.66) %, Left B9 to carina was (42.44±15.89) %, Right B1 to carina was (46.51±14.03) %, and Right B9 to carina is (43.54±15.87) %. BMI affect the area of the tracheal wall, all p value<0.05.Conclusion:High-resolution CT small airway morphology can make a preliminary assessment of the susceptible population of small airway-related diseases based on a range of reference values, and prevent and control it in combination with influencing factors.

Objective To assess the nutritional status of severe malnutrition patients with anorexia nervosa by multi-frequency bioelectrical impedance technique, and to provide the basis for nutritional support therapy. Methods A prospective study was conducted. Twenty-six severe malnutrition patients with anorexia nervosa, body mass index (BMI)≤16 kg/m2admitted to intensive care unit (ICU) of Peking University Third Hospital and general three ward of Peking University Sixth Hospital from June 1st to September 30th, 2017 were enrolled. The extracellular water (ECW), intracellular water (ICW), ECW/ICW ratio, adipose tissue mass (ATM), lean tissue mass (LTM), total body water/body weight (TBW/WT), ATM/WT, and LTM/WT were measured by multi-frequency bioelectrical impedance meter. Thirty-eighty healthy volunteers with normal nutritional status (23.0 kg/m2> BMI > 18.5 kg/m2) matched by gender and height were enrolled as healthy control group. The predictive value of main body composition for nutritional status were analyzed by receiver operating characteristic (ROC) curve. Results All the patients were female. There was no significant difference in height between two groups, but WT and BMI in the severe malnutrition group were significantly higher than those in the healthy control group [WT (kg): 38.1±4.9 vs. 54.2±3.3, BMI (kg/m2): 13.6±2.5 vs. 21.2±1.1, both 1 < 0.01]. Compared with the healthy control group, the ECW, ICW, ATM, LTM, ATM/WT and LTM/WT were significantly decreased in the severe malnutrition group [ECW (L): 9.02±0.42 vs. 10.19±0.77, ICW (L):12.6±0.9 vs.19.1±1.3, ATM (kg): 9.3±1.1 vs. 16.6±1.9, LTM (kg): 16.5±1.5 vs. 26.1±1.7, ATM/WT: 0.26±0.02 vs. 0.30±0.02, LTM/WT: 0.22±0.02 vs. 0.26±0.01, all 1 < 0.01], the ECW/ICW and TBW/WT were significantly increased in the severe malnutrition group (ECW/ICW: 0.72±0.06 vs. 0.54±0.06, TBW/WT: 0.58±0.02 vs. 0.52±0.02, both 1 < 0.01). It was shown by ROC curve analysis that the area under ROC curve (AUC) of TBW/WT、ATM/WT、LTM/WT for evaluating severe malnutrition were 0.999, 0.919, 0.954 respectively; when the cut-off of TBW/WT,ATM/WT, LTM/WT were 0.58, 0.28, 0.24 respectively, the sensitivity were 100%, 85%, 80% respectively, and the specificity were 95%, 80%, 91% respectively. Conclusion Main body composition of severe malnutrition patients with anorexia nervosa changed significantly. Bioelectrical impedance technology can be an effective assessment tool for the nutritional status of such patients.

Antibiotics are the cornerstone to cure infectious diseases, however, it also destroys the intestinal inherent microflora, and may cause serious gastrointestinal dysfunction, such as abdominal distension, diarrhea, mucosal barrier damage etc. In severe conditions, it may induce intestinal sepsis. With the development of the human microbiology group program and the popularity of microbial sequencing technology, people can comprehend the effects of antibiotics on intestinal flora deeply, meanwhile the traditional biomedical model (the basis of bacterial disease) is questioned. It presents the effects and mechanisms of antibiotics on intestinal microflora and intestinal mucosal barrier function in detail and demonstrates the feasibility by the treatment of probiotics and fecal transplantation to construct "health-promoting microbes" to adjust gastrointestinal function, in addition, it can promote the rational use of antibiotics.

BACKGROUND: During spinal orthopedic repair, the main difficulty is to maximize the correction of the deformity, simultaneously, to reduce the incidence of trauma and complications, especial y to avoid the corresponding spinal nerve injury. OBJECTIVE: To evaluate the curative effect of one-stage posterior pedicle subtraction osteotomy of apical vertebra with transpedicular instrumentation in the treatment of rigid angular kyphosis of thoracolumbar spine. METHODS: We retrospectively analyzed the data of 42 cases of rigid angular kyphosis of thoracolumbar spine that were treated by one-stage posterior pedicle subtraction osteotomy of apical vertebra with transpedicular instrumentation. Al patients received detailed imaging examination before and after operation. Kyphosis angle, Frankel grading and perioperative complications were recorded in al patients. X-ray films or CT films showed the bone graft fusion during fol ow-up. RESULTS AND CONCLUSION: Patients were fol owed up for 10-36 months after treatment. The average time of bone graft fusion was 5.1 months. Cobb’s angle of kyphosis was corrected from 78.4° (38°-110°) preoperatively to 7°(-8°-24°) at 10 days after treatment. The correction rate was 90%. The average angle during final fol ow-up was 7.9°, with an average loss of 0.9°. In 16 paresis patients, Frankel grading results showed grade B in 0 case, grade C in 3 cases, grade D in 5 cases, and grade E in 8 cases during final fol ow-up, showing significant improvement as compared with that pre-treatment (P < 0.05). Among 42 patients, 5 cases had complications. At 7 months after treatment, there were screw and titanium rod loosening at the distal end of the fusion segment in 1 case, cerebrospinal fluid leakage in 2 cases, transient double lower limb weakness in 1 case, pain in one side of lower limb in 1 case, and no severe complications appeared. These results verified that one-stage posterior pedicle subtraction osteotomy of apical vertebra with transpedicular instrumentation could achieve satisfactory clinical outcomes in rigid angular kyphosis of thoracolumbar spine. The internal fixation was stable and with a high fusion rate and few complications. The medium-term effect was satisfactory.

Objective To estimate the prevalence and risk factors for irritable bowel syndrome (IBS) in China.Methods Cross-sectional studies relevant to IBS conducted among Chinese were identified through the databases including PubMed,Web of Science,the Cochrane Library,CBM,CNKI,Wanfang data and VIP.Quality of studies was assessed according to the criteria for cross-sectional studies recommended by Agency for Healthcare Research and Quality(AHRQ).Analysis of data,publication bias and sensitivity were performed with Stata (Version 12.0).Results A total of twenty-three studies were extracted.No obvious publication bias was detected in all analysis except the effect of depression on IBS prevalence.Pooled prevalence of IBS in China was 6.5％.IBS was more common in women than in men (8.1％ vs 6.8％;OR=1.23,95％CI 1.09-1.38) and high rate in age group between 30 to 59 years (6.9％ ; OR =1.22,95％ CI 1.12-1.32).Intestinal infection history(OR =2.39,95％ CI 1.69-3.38),anxiety (OR =2.95,95 ％ CI 1.94-4.49),depression (OR =1.85,95 ％ CI 1.11-3.09),food allergy (OR =2.80,95％ CI 2.12-3.67) and alcohol consumption (OR =1.15,95％ CI 1.07-1.24) might increase the risk for IBS.There were no significant difference of IBS prevalence between urban and rural areas (OR =0.97,95％ CI 0.72-1.29),neither in different education classes (OR =0.85,95％ CI 0.70-1.03).Sub-group analysis showed IBS prevalence varied apparently with different diagnostic criteria:prevalence defined by Manning was 11.8％ and by Rome Ⅱ and Rome Ⅲ prevalence values were 4.4％ and 8.9％ respectively.Conclusions Pooled prevalence of IBS in China was 6.5％.IBS is more common in age group between 30 to 59 years.Female,history of intestinal infection,anxiety,depression,food allergy and alcohol consumption were risk factors for IBS in Chinese population.