Gamma-aminobutyric acid(GABA)is a widely distributed non-protein amino acid.As an inhibitory neurotransmit-ter,GABA plays an important role in negative regulatory process of vertebrate nervous system,which is essential for maintaining the balance of neuronal stimulation and inhibition.With continued exploration,it was found that GABA in immune system and immune cell development can not be ignored.T cells are important components of lymphocytes and the immune system,and participate in the body's cellular immune response to prevent infection and tumor formation.Evidence in recent years showed that GABA can inhibit T cell activation and proliferation,involve in the development of tumor,diabetes and autoimmune diseases.The development of drugs targeting specific diseases is still far away due to structural heterogeneity of GABA-A receptors.In this review,we will review advances in GABA metabolism,mechanism of action for T cells and its relevance with human diseases.

Ketone bodies have beneficial metabolic activities, and the induction of plasma ketone bodies is a health promotion strategy. Dietary supplementation of sodium butyrate (SB) is an effective approach in the induction of plasma ketone bodies. However, the cellular and molecular mechanisms are unknown. In this study, SB was found to enhance the catalytic activity of 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), a rate-limiting enzyme in ketogenesis, to promote ketone body production in hepatocytes. SB administrated by gavage or intraperitoneal injection significantly induced blood ß-hydroxybutyrate (BHB) in mice. BHB production was induced in the primary hepatocytes by SB. Protein succinylation was altered by SB in the liver tissues with down-regulation in 58 proteins and up-regulation in 26 proteins in the proteomics analysis. However, the alteration was mostly observed in mitochondrial proteins with 41% down- and 65% up-regulation, respectively. Succinylation status of HMGCS2 protein was altered by a reduction at two sites (K221 and K358) without a change in the protein level. The SB effect was significantly reduced by a SIRT5 inhibitor and in Sirt5-KO mice. The data suggests that SB activated HMGCS2 through SIRT5-mediated desuccinylation for ketone body production by the liver. The effect was not associated with an elevation in NAD⁺/NADH ratio according to our metabolomics analysis. The data provide a novel molecular mechanism for SB activity in the induction of ketone body production.
Mice ; Animals ; Butyric Acid/metabolism* ; Ketone Bodies/metabolism* ; Liver/metabolism* ; Hydroxybutyrates/metabolism* ; Down-Regulation ; Sirtuins/metabolism* ; Hydroxymethylglutaryl-CoA Synthase/metabolism*

Metformin has been used for the treatment of type II diabetes mellitus for decades due to its safety, low cost, and outstanding hypoglycemic effect clinically. The mechanisms underlying these benefits are complex and still not fully understood. Inhibition of mitochondrial respiratory-chain complex I is the most described downstream mechanism of metformin, leading to reduced ATP production and activation of AMP-activated protein kinase (AMPK). Meanwhile, many novel targets of metformin have been gradually discovered. In recent years, multiple pre-clinical and clinical studies are committed to extend the indications of metformin in addition to diabetes. Herein, we summarized the benefits of metformin in four types of diseases, including metabolic associated diseases, cancer, aging and age-related diseases, neurological disorders. We comprehensively discussed the pharmacokinetic properties and the mechanisms of action, treatment strategies, the clinical application, the potential risk of metformin in various diseases. This review provides a brief summary of the benefits and concerns of metformin, aiming to interest scientists to consider and explore the common and specific mechanisms and guiding for the further research. Although there have been countless studies of metformin, longitudinal research in each field is still much warranted.
Humans ; Metformin/pharmacokinetics* ; Diabetes Mellitus, Type 2/metabolism* ; Hypoglycemic Agents/pharmacology* ; AMP-Activated Protein Kinases/metabolism* ; Aging

In this study, we designed a core competency-oriented formative assessment system for standardized residency training. A formative assessment information platform was established according to this formative assessment system. We described the business process design in detail and how to use information technology for assessment data application. The corresponding data were fed back to residents, instructors, rotation departments, specialty bases, and residency training management departments to promote continuous quality improvement. Meanwhile, we demonstrated the difficulties, deficiencies, and future direction of the construction of formative assessment information platform.

Objective:To analyze the value of alpha-fetoprotein(AFP) in predicting survival of patients who underwent salvage surgery after tumor downstaging therapy in patients with advanced hepatocellular carcinoma.Methods:The data of 50 patients with Barcelona Clinic Liver Cancer Staging (BCLC) C hepatocellular carcinoma treated at the Faculty of Hepato-Pancreato-Biliary Surgery, Chinese PLA General Hospital from December 2018 to December 2021 were collected. There were 45 males and 5 females, with the age of (53.0±10.5) years. The patients were divided into two groups based on the serum AFP level after tumor downstaging therapy, AFP normal group ( n=27, AFP≤20 μg/L) and the control group ( n=23, AFP>20 μg/L). Patient survival and tumor recurrence were followed up by outpatient review or telephone follow-up. The survival rate was calculated by the Kaplan-Meier method and compared by the log-rank test. The efficacy of combined immunotargeted therapy were compared between the two groups. Univariate and multivariate Cox regression analysis were carried to analyse the factors influcing prognosis. Results:The median survival time was not reached in both groups. The 1-year and 2-year cumulative survival rates were 95.0% and 88.2% in the normal group and 73.4% and 54.1% in the control group, respectively. The median relapse-free survival time of the normal group was not reached, and the median relapse-free survival time of the control group was 11 months. The 1-year recurrence-free survival rate was 78.1% in the normal group and 39.5% in the control group. The cumulative survival rate and relapse-free survival rate in the normal group were significantly higher than those in the control group (χ 2=7.60, 8.83, P=0.006, 0.003). The complete response, partial response and pathological complete response of tumors in the normal group were significant better than those in the control group. Multivariate Cox regression analysis showed that patients with serum AFP >20 μg/L ( HR=2.952, 95% CI: 1.023-8.517, P=0.045) after immunotherapy combined with targeted therapy had an increased risk of postoperative recurrence. Conclusion:The reduction of serum AFP to normal after downstaging therapy could be used as a prognostic indicator of salvage surgical in patients with BCLC C hepatocellular carcinoma, and AFP was related to the efficacy of downstaging therapy in patients.

Objective:To study the use of perfluorobutane contrast-enhanced ultrasound (CEUS) in preoperative detection of microvascular invasion (MVI), and postoperative short-term recurrence of hepatocellular carcinoma (HCC).Methods:Patients who underwent hepatectomy with curative intent at the Chinese PLA General Hospital from January 2021 to April 2021 were prospectively enrolled into this study. Of 42 patients in this study, there were 36 males and 6 females, with age of (56.51±11.95) years old. All patients underwent preoperative perfluorobutane CEUS, and the characteristics of ultrasound, the vascular phase and Kupffer phase of perfluorobutane CEUS were recorded. Based on the pathological results, these patients were divided into the MVI and non-MVI groups. These patients underwent liver MRI once every 3 months postoperatively to diagnose tumor recurrence. According to the recurrence of HCC 6 months after operation, these patients were divided into the non-recurrence and the recurrence groups. Independent risk factors for MVI and short-term recurrence were analyzed by univariate and multivariate analyses.Results:Two patients had two lesions, and the remaining 40 patients had a single lesion. The pathological diagnosis of all the lesions were HCC (14 patients in the MVI group and 28 patients in the non-MVI group). The median follow-up was 6 (3, 6) months, and there were 8 patients in the recurrence group and 34 patients in the non-recurrence group. On logistic analysis, independent risk factors for MVI included the number of vessels detected on color Doppler flow imaging (CDFI) ( OR=5.762, 95% CI: 1.597-20.785, P=0.007), increased tumor size by more than 10% after CEUS arterial enhancement ( OR=10.186, 95% CI: 3.647-28.447, P=0.037), and thickness of corona enhancement at Kupffer phase of greater than 5 mm ( OR=17.340, 95% CI: 6.124-49.095, P=0.040). Cox regression showed the independent risk factors for short-term recurrence to include the number of vessels in CDFI ( RR=7.519, 95% CI: 1.086-52.051, P=0.041) and thickness of corona enhancement at Kupffer phase of greater than 5 mm ( RR=10.623, 95% CI: 1.265-89.218, P=0.030). Conclusion:Preoperative perfluorobutane CEUS had potential values in detecting MVI and in predicting postoperative short-term recurrence of HCC.

Objective:To evaluate the safety and efficacy of endoscopic cryoablation (ECA) in patients with upper tract urothelial carcinoma (UTUC).Methods:The clinical data of 9 patients with UTUC treated with ECA from April 2018 to September 2019 were retrospectively analyzed. Patients consisted of 3 males and 6 females, with median age of 76 years old (ranging from 50 to 88 years old). Among the patients, 6 cases had tumors of ureter, 1 case had tumor of renal pelvis and 2 cases had tumors of renal pelvis combined with ureter. Of the 9 patients, two had bilateral UTUC, six were presented with single lesion, three were presented with multiple lesion. The size of tumors were (1.53±0.91)cm. The tumors of all cases were localized (≤stage T 2), and there was no carcinoma or suspicious lymph node/distant metastasis. All patients enrolled in this study had strong will to choose kidney-sparing therapy. Biopsy, resection of intraluminal lesion with laser and cryoablation under ureteroscopy or percutaneous nephroscopy was performed under general aneasthesia.Ureteroscopy was performed 3 months after cryoablation. Perioperative complications and follow-up results were recorded and assessed. Results:Cryoablation was successfully performed in patients under ureteroscopy (n=8) or nephroscopy (n=1). The median cryoablation time was 6 (ranging from 4-16) minutes. The median follow-up was 16 months (ranging from 4-24 months). No tumor recurrence was observed at primary sites during follow-up. Two patients with multiple lesions were observed denovo ureteral neoplasms outside the primary sites 3 months and 6 months after cryoablation and treated with second cryoablation. One case died due to cardiovascular events 4 months after surgery. One patient underwent ureteral stricture during follow-up and received ureteroscopic balloon dilatation. No recurrent stricture was found in this case during the subsequent follow-up of 16 months. The other 5 cases showed no recurrence or complications like stricture during follow-up.Conclusions:ECA could probably be a promising treatment for localized UTUC. No recurrence in primary site and low incidence of ureteral stricture was observed during follow-up. The efficacy and safety of ECA need to be verified with large sample study.

Objective: To investigate the risk factors of poor graft function (PGF) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for severe aplastic anemia (SAA) . Methods: Clinical data from 111 SAA patients who received allo-HSCT were analyzed retrospectively. Factors including age, gender, interval to transplantation, the level of serum ferritin before transplantation were analyzed by Cox multivariate regression analysis. Results: Among the 111 patients who underwent allo-HSCT, 16 developed PGF (14.4%) . Multivariate analysis showed donor type (HR=2.656, 95%CI 1.204-5.858, P= 0.016) and the level of serum ferritin before tansplantation (HR=3.170, 95%CI 1.400-7.180, P=0.006) were significant risk factors for PGF. Conclusion Unrelated donor transplantation and the high level of serum ferritin before transplantation are risk factors for PGF.

Objective: To explore the correlation of left descending anterior (LDA) myocardial bridge (MB) and atherosclerosis at proximal to a segment with MB in patients elderly than 60 years and to identify if LDAMB could become the independent risk factor of atherosclerotic stenosis at proximal to a segment with MB. Methods: A total of 986 patients with multi-slice spiral CT diagnosed coronary artery disease (CAD) were studied and 389 patients with 486 MB in left heart were found. General information as the age, gender, diabetes, hypertension, dyslipidemia and smoking conditions were collected, relationship between LDAMB and atherosclerotic stenosis at proximal to a segment with MB was studied by Logistic regression analysis. Results: There were 48/389 (12.3%) cases with MB at proximal segment of LDA, 254 (65.3%) cases with MB at middle segment of LDA, 51 (13.1%) cases with MB at distal segment of LDA, 19 (4.9%) cases with MB at the ifrst diagonal branch and 17 (4.4%) cases with MB at obtuse marginal branch respectively. Logistic regression analysis presented that age (OR=1.07, 95% CI 0.02-0.09,P<0.01), diabetes (OR=4.48, 95% CI 0.75-2.24,P<0.01) and MB at middle segment of LDA (OR=4.98, 95% CI 0.81-2.41, P<0.01) were related to atherosclerotic stenosis at proximal to a segment with MB; age (OR=1.08, 95% CI 0.04-0.12,P<0.01) and diabetes (OR=3.49, 95% CI 0.30-2.19,P=0.01) were related to the atherosclerosis at LAD middle segment; the MB at LAD middle segment was not related to atherosclerosis of middle and distal LAD segments,P>0.05. Conclusion: MB at middle segment of LDA was with the higher occurrence rate of atherosclerotic stenosis at proximal to a segment with MB in elderly patients, which could be used as an independence risk factor for clinical diagnosis.

BACKGROUND:To date, there are few domestic reports about the influence of bone marrow mesenchymal stem cel s on T cel s proliferation in patients with aplastic anemia. And no study addresses the topic that if bone marrow mesenchymal stem cel s achieve immune regulation in aplastic anemia patients through inhibiting T cel s proliferation.
OBJECTIVE:To explore the effects of human bone marrow mesenchymal stem cel s on T cel s immune regulation in patients with aplastic anemia.
METHODS:Human bone marrow mesenchymal stem cel s were isolated, cultured and subcultivated in vitro. The morphological appearance of bone marrow mesenchymal stem cel s was observed and surface markers were measured by flow cyometry. The bone marrow mesenchymal stem cel s were co-cultured with T cel s extracted from peripheral blood of healthy volunteers and aplastic anemia patients for 7 days. The expressions of interferon-γ, interleukin-4 and interleukin-10 in the supernatants were detected with enzyme linked immunosorbent assay.
RESULTS AND CONCLUSION:The levels of interleukin-2 and interferon-γin the supernatant of aplastic anemia patients were significantly higher (P<0.05), while levels of interleukin-4 and interleukin-10 were significantly lower than that in healthy controls (P<0.05). Bone marrow mesenchymal stem cel s suppressed the elevated levels of interleukin-2 and interferon-γ, and enhanced the decreased levels of interleukin-4 and interleukin-10, thus regulating the immune dysfunction of aplastic anemia patients.