Objective To investigate the regulatory mechanism of Rehmanniae Radix Praeparata and its active components rehmannioside D and catalpol on γ-aminobutyric acid(GABA)in the brain based on the xylosy-transferase I(xylt-1)signaling pathway.Methods(1)SD rats were randomly divided into normal group,model group and treatment group(Rehmanniae Radix Praeparata group,30 g·kg-1),with eight rats in each group,half male and half female.The rat model of yin deficiency was established by intragastric administration of traditional Chinese medicine compound(30 g·kg-1)with acrid-warm nature and dampness-drying and dampness-draining,once in the morning and once in the evening,for 10 consecutive days.After modeling,the treatment group was given Rehmanniae Radix Praeparata decoction by gavage,once in the morning and once in the evening,for 10 consecutive days.The body mass of rats was measured and recorded,and the activity,crossing times and total distance were detected by open field behavior experiment.The levels of serum gonadotropin-releasing hormone(GnRH),thyrotropin-releasing hormone(TRH),corticotropin-releasing hormone(CRH),luteinizing hormone(LH)and follicle-stimulating hormone(FSH)in rats were detected by ELISA.The mRNA and protein expression levels of xylt-1,multiligand proteoglycan 1(SDC-1),early growth response factor 1(EGR1)and glutamate decarboxylase 1(GAD67)in rat brain tissue were detected by qPCR and automatic capillary Western Blot.The content of GABA in brain tissue was detected by HPLC.(2)The xylt-1 gene of rat well-differentiated adrenal pheochromocytoma cells(PC12)was silenced by siRNA.The cells were divided into normal group,negative control group,silencing group,silencing+rehmannioside D(10 μmol·L-1)group,silencing+catalpol(10 μmol·L-1)group.The expression levels of xylt-1,SDC-1,EGR1 and GAD67 mRNA in cells were detected by qPCR.The content of GABA in intracellular and extracellular fluid was detected by HPLC.The expression level of SDC-1 in cells was detected by immunofluorescence.(3)PC12 cells were transfected with lentivirus to overexpress xylt-1 gene.The cells were divided into normal group,negative control group(empty vector group)and overexpression group.The mRNA expression levels of xylt-1,SDC-1,EGR1 and GAD67 in cells were detected by qPCR.Results(1)Compared with the normal group,the body mass of the rats in the model group was significantly decreased(P＜0.01),the activity was significantly increased(P＜0.01),and the number of crossings and the total distance were significantly increased(P＜0.01).The levels of serum LH,FSH,GnRH,CRH and TRH were significantly increased(P＜0.01).The content of GABA in hippocampus and cerebral cortex was significantly decreased(P＜0.05,P＜0.01).The expression of xylt-1,SDC-1,EGR1 and GAD67 mRNA(hippocampus,cerebral cortex)and protein(hypothalamus,cerebral cortex)in brain tissue were significantly down-regulated(P＜0.05,P＜0.01).Compared with the model group,the body mass of the rats in the treatment group was significantly increased(P＜0.05),the activity was significantly decreased(P＜0.01),and the total distance was significantly shortened(P＜0.05).The levels of serum LH,FSH,GnRH,CRH and TRH were significantly decreased(P＜0.01).The content of GABA in hippocampus and cerebral cortex was significantly increased(P＜0.05,P＜0.01).The content of GABA in hippocampus and cerebral cortex was significantly increased(P＜0.05,P＜0.01).The expressions of xylt-1,SDC-1,EGR1 and GAD67 mRNA(hippocampus,cerebral cortex)and protein(hypothalamus,cerebral cortex)in brain tissue were significantly up-regulated(P＜0.05,P＜0.01).(2)Compared with the negative control group,the mRNA expressions of xylt-1,SDC-1,EGR1 and GAD67 in the silencing group was significantly down-regulated(P＜0.01).The content of GABA in intracellular and extracellular fluid was significantly decreased(P＜0.05,P＜0.01).The expression of SDC-1 in cells was significantly down-regulated(P＜0.01).Compared with the silencing group,the expression of xylt-1 mRNA in the silencing+rehmannioside D group was up-regulated,but the difference was not statistically significant(P＞0.05).The mRNA expression of xylt-1 in the silencing+catalpol group was significantly up-regulated(P＜0.05).The mRNA expressions of SDC-1,EGR1 and GAD67 in the silencing+rehmannioside D group and the silencing+catalpol group was significantly up-regulated(P＜0.05,P＜0.01),the content of GABA in the intracellular and extracellular fluid was significantly increased(P＜0.01),and the expression of SDC-1 in the cells was significantly up-regulated(P＜0.05,P＜0.01).(3)Compared with the normal group and the negative control group,the mRNA expression of xylt-1 in the overexpression group was significantly up-regulated(P＜0.01).Compared with the negative control group,the mRNA expressions of SDC-1,EGR1 and GAD67 in the overexpression group was significantly up-regulated(P＜0.01),and the GABA content in the intracellular and extracellular fluid was significantly increased(P＜0.01).Conclusion There may be a xylt-1/SDC-1/EGR1/GAD67 pathway that regulates GABA synthesis in the brain.Rehmanniae Radix Praeparata may increase GABA levels in the brain by up-regulating this pathway.

Purpose: The prognosis of patients with hepatocellular carcinoma (HCC) and portal vein tumor thrombus (PVTT) is extremely poor, and systemic therapy is currently the mainstream treatment. This study aimed to assess the efficacy and safety of lenvatinib combined with anti–programmed cell death-1 antibodies and transcatheter arterial chemoembolization (triple therapy) in patients with HCC and PVTT. Materials and Methods: This retrospective multicenter study included patients with HCC and PVTT who received triple therapy, were aged between 18 and 75 years, classified as Child-Pugh class A or B, and had at least one measurable lesion. The overall survival (OS), progression-free survival (PFS), objective response rates, and disease control rates were analyzed to assess efficacy. Treatment-related adverse events were analyzed to assess safety profiles. Results: During a median follow-up of 11.23 months (range, 3.07 to 34.37 months), the median OS was greater than 24 months, and median PFS was 12.53 months. The 2-year OS rate was 54.9%. The objective response rate and disease control rate were 69.8% (74/106) and 84.0% (89/106), respectively; 20.8% (22/106) of the patients experienced grade 3/4 treatment-related adverse events and no treatment-related deaths occurred. The conversion rate to liver resection was 31.1% (33/106), with manageable postoperative complications. The median OS was not reached in the surgery group, but was 19.08 months in the non-surgery group. The median PFS in the surgery and non-surgery groups were 20.50 and 9.00 months, respectively. Conclusion Triple therapy showed promising survival benefits and high response rates in patients with HCC and PVTT, with manageable adverse effects.

Peptide dual agonists toward both glucagon-like peptide 1 receptor (GLP-1R) and glucagon receptor (GCGR) are emerging as novel therapeutics for the treatment of type 2 diabetes mellitus (T2DM) patients with obesity. Our previous work identified a Xenopus GLP-1-based dual GLP-1R/GCGR agonist termed xGLP/GCG-13, which showed decent hypoglycemic and body weight lowering activity. However, the clinical utility of xGLP/GCG-13 is limited due to its short in vivo half-life. Inspired by the fact that O-GlcNAcylation of intracellular proteins leads to increased stability of secreted proteins, we rationally designed a panel of O-GlcNAcylated xGLP/GCG-13 analogs as potential long-acting GLP-1R/ GCGR dual agonists. One of the synthesized glycopeptides 1f was found to be equipotent to xGLP/GCG-13 in cell-based receptor activation assays. As expected, O-GlcNAcylation effectively improved the stability of xGLP/GCG-13 in vivo. Importantly, chronic administration of 1f potently induced body weight loss and hypoglycemic effects, improved glucose tolerance, and normalized lipid metabolism and adiposity in both db/db and diet induced obesity (DIO) mice models. These results supported the hypothesis that glycosylation is a useful strategy for improving the in vivo stability of GLP-1-based peptides and promoted the development of dual GLP-1R/GCGR agonists as antidiabetic/antiobesity drugs.
Mice ; Animals ; Glucagon-Like Peptide 1/metabolism* ; Receptors, Glucagon/therapeutic use* ; Xenopus laevis/metabolism* ; Diabetes Mellitus, Type 2/drug therapy* ; Glycopeptides/therapeutic use* ; Obesity/drug therapy* ; Hypoglycemic Agents/pharmacology* ; Peptides/pharmacology*

Objective To investigate the relationships between serum osteocalcin (OC) levels and glycometabolism markers in nondiabetic post-traumatic male patients.Methods Populaitons were selected at the Department of Emergency Medicine of Shanghai Jiao Tong University Affiliated Sixth People's Hospital from October 2017 to February 2019.The age,injury severity score (ISS),and characteristic indicators were recorded.The inclusion criteria were age ≥ 18 years and blood collection time ＜ 24 h after the injury.The exclusion criteria were emergency surgery,acute brain trauma,and hemoglobin A1c (HbA1c) ≥ 6.0％.The patients were divided into two groups by fasting plasma glucose (FPG):stress hyperglycemia (SH) (FPG＞7.8 mmol/L) and nonstress hyperglycemia (NO-SH) (FPG ≤ 7.8 mmol/L) groups.The fasting venous blood samples were collected and examined.The characteristics and biochemical indicators in the two groups were compared statistically by LSD-t test,rank sum test and ANOVA,and the relationships between serum OC levels and glycometabolism markers were analyzed by partial correlation analysis.Results A total of 395 traumatic patients were enrolled and divided into the SH group (n=182) and NO-SH group (n=213).There were no differences in ISS,fasting insulin (FINS),and C-peptide (C-P) levels between groups.Age,HbAlc and FPG were higher (P=0.041,P=0.037,P＜0.01),while the OC level was lower (P=0.023),in the SH group than those in the NO-SH group.The serum OC level did not correlate with HbAlc,FPG,and FINS,but negatively correlated with C-P by partial correlation analysis (r=-0.262,P=0.008).The multivariate linear regression analysis showed that C-P was an independent factor affecting serum OC levels after trauma (β=-0.655,P=0.043).Conclusion A correlation existed between the serum OC level and glycometabolism markers in nondiabetic post-traumatic male patients.

Objective:To explore the clinical significance and underlying mechanism of changes in serum IL - 18 and IL - 1 beta after trauma.Methods:Enzyme-linked immunosorbent assay was used to detect the levels of IL-18 and IL-1β in trauma patients and healthy controls. The differences in serum IL-18 and IL-1β levels were compared between the two groups, and the levels of IL-18 and IL-1β in the traumatic subgroups were further compared.Results:The serum levels of IL-1β and IL-18 of trauma patients were 80±2.0 pg/mL and 27±3.0 pg/mL, respectively, which were significantly higher than those in healthy controls ( P < 0.01). Serum levels of IL-1β and IL-18 showed an upward trend on the 3rd day after trauma. There were also statistically significant differences within the trauma subgroups ( P < 0.01). Conclusions:The serum levels of IL-18 and IL-1β of post-traumatic patients are increased, indicating that NLRP3 inflammasomes are activated in peripheral blood cells in the early stage of trauma, which aggravates the inflammatory response. The AIS-ISS score is positively correlated with the expression levels of IL-18 and IL-1β in serum, indicating that the more severe the injury, the more severe the inflammatory response.

Objective:To explore the effect of intraoperative autologous blood transfusion on coagulation function and inflammatory reaction after cesarean section.Methods:By retrospective analysis, 114 parturients who underwent caesarean section in our hospital from March 2017 to February 2019 with intraoperative blood transfusion were selected and divided into autologous group (57 cases) and allogeneic group (57 cases) according to the source of intraoperative blood transfusion. The changes of coagulation markers and inflammatory reaction indexes were detected and recorded respectively before and 3 days after operation, respectively. And the complications after blood transfusion were compared between the two groups.Results:On the 3rd day after operation, the expression of P65 gene and the optical density of P65 in both groups increased significantly, but the autogenous group was lower than the allogeneic group ( P<0.01); the granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-6 and IL-1β in both groups increased significantly, but the autogenous group was lower than the allogeneic group ( P<0.01); the D-dimer (D-D), thrombomodulin (TM), tissue plasminogen activator (t-PA) and fibrinolytic-antifibrinolytic complex (PAP) in both groups were slightly higher than those before operation, and the data between the two groups also changed, but with no statistical significance ( P>0.05). In addition, the incidence of complications in the autogenous group was 5.26%(3/57), which was significantly lower than that in the allogeneic group (17.54%, 10/57) (χ 2=4.25, P=0.04). Conclusions:Autologous blood transfusion has no significant effect on the coagulation function of parturients during cesarean section, but compared with allogeneic blood transfusion, autologous blood transfusion can effectively reduce the inflammatory reaction of parturients after operation, and has a significant effect on reducing the occurrence of complications after operation, which is conducive to improving the prognosis.

BACKGROUND: Induced pluripotent stem cells are a type of reprogrammed cells with similar characteristics to embryonic stem cells, which are capable of differentiating into phenotypes associated with patient specific diseases. Moreover, their clinical application avoids ethical issues. OBJECTIVE: To review the research progress of induced pluripotent stem cells in myocardial regeneration and repair, cardiovascular disease models, drug development and screening, and drug toxicity testing. METHODS: PubMed (2006-2018) and CNKI (2013-2018) databases were retrieved for relevant articles using the keywords of "induction of pluripotent stem cells; myocardial infarction; arrhythmia; cardiovascular disease; heart failure; heart transplantation; disease model; drug toxicity" in English and Chinese, respectively. The data were reviewed one by one, and the citations involved in the literatures were also reviewed. RESULTS AND CONCLUSION: Induced pluripotent stem cells have great potential value in myocardial regeneration and repair, establishment of cardiovascular disease models, new drug development and screening, and drug toxicity detection. The application prospect of the cells is broad, but most of the research is still in the experimental stage. In addition, safety problems, such as low induction efficiency and tumorigenicity, will limit the clinical application of induced pluripotent stem cells.

Objective: To assess the diagnosis of thrombelastography (TEG) for trauma-induced coagulopathy (TIC) and explore whether TEG could guide transfusion for TIC patients. Methods: We retrospectively analyzed all trauma patients who underwent the TEG and conventional coagulation tests (CCTs) admission in the emergency intensive care unit from February to December 2018. The definition of TIC is prothrombin time (PT) 18 s, international normalized ratio (INR) 1.5, activated partial thromboplastin time (APTT) 60 s or platelet count (PLT) 100×10⁹/L. The diagnostic value of TEG for TIC was evaluated by receiver operating characteristic curve, area under the curve (AUC), sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV), and the transfusion guidance of TEG for TIC patients was assessed by multivariate regression analyses. Results: A total of 242 patients were included, including 62 patients in the TIC group and 180 patients in the non-TIC group. The differences in TEG between the two groups were statistically significant. The AUCs of TIC assessed by maximum amplitude (MA) and coagulation index (CI) were the largest, 0.779 and 0.786 respectively, and the sensitivity were greater than 80% and NPV were greater than 90%. The sensitivity, PPV and NPV of reaction time (R) were minimal. After confounders were controlled, all TEG values were correlated with blood volumes within the first 24 h and massive transfusion, of which R had the highest odds ratio and regression coefficient. Conclusions MA and CI have the highest diagnostic value, while R has little diagnostic value but a relatively large blood therapeutic significance of TIC. MA < 52.9 mm or CI < -1.0 can be used as a threshold for identifying TIC. The diagnosis of TIC and the guidance transfusion for TIC patients by TEG is beneficial.

In the present study, a series of novel nitric oxide-hydrogen sulfide releasing derivatives of (S)-3-n-butylphthalide ((S)-NBP) were designed, synthesized, and evaluated as potential antiplatelet agents. Compound NOSH-NBP-5 displayed the strongest activity in inhibiting the arachidonic acid (AA)- and adenosine diphosphate (ADP)-induced platelet aggregation in vitro, with 3.8- and 7.0-fold more effectiveness than (S)-NBP, respectively. Furthermore, NOSH-NBP-5 could release moderate levels of NO and HS, which would be beneficial in improving cardiovascular and cerebral circulation. Moreover, NOSH-NBP-5 could release (S)-NBP when incubated with rat brain homogenate. In conclusion, these findings may provide new insights into the development of novel antiplatelet agents for the treatment of thrombosis-related ischemic stroke.
Animals ; Benzofurans ; chemistry ; Humans ; Hydrogen Sulfide ; chemistry ; Male ; Molecular Structure ; Nitric Oxide ; chemistry ; Platelet Aggregation ; drug effects ; Platelet Aggregation Inhibitors ; chemical synthesis ; chemistry ; pharmacology ; Rabbits ; Rats ; Rats, Sprague-Dawley ; Thrombosis ; drug therapy ; physiopathology

We developed a three-dimensional finite element model of the pelvis. According to Letournel methods, we established a pelvis model of T-shaped fracture with its three different fixation systems, i. e. double column reconstruction plates, anterior column plate combined with posterior column screws and anterior column plate combined with quadrilateral area screws. It was found that the pelvic model was effective and could be used to simulate the mechanical behavior of the pelvis. Three fixation systems had great therapeutic effect on the T-shaped fracture. All fixation systems could increase the stiffness of the model, decrease the stress concentration level and decrease the displacement difference along the fracture line. The quadrilateral area screws, which were drilled into cortical bone, could generate beneficial effect on the T-type fracture. Therefore, the third fixation system mentioned above (i. e. the anterior column plate combined with quadrilateral area screws) has the best biomechanical stability to the T-type fracture.
Biomechanical Phenomena ; Bone Plates ; Bone Screws ; Finite Element Analysis ; Fracture Fixation, Internal ; Fractures, Bone ; pathology ; Humans ; Models, Anatomic ; Pelvis ; anatomy & histology ; injuries ; Posture