Objective To develop a matrix metalloproteinase(MMP)-responsive hyaluronic acid(HA)-based controlled-release material for brain-derived neurotrophic factor(BDNF)to provide a novel therapeutic strategy for intervention and repair of traumatic brain injury(TBI).Methods HA was modified with amination,followed by condensation with Suflo-SMCC carboxyl group to form amide,and then linked with glutathione(GSH)to synthesize HA-GSH.The recombinant glutathione S-transferase(GST)-tissue inhibitor of metalloproteinase(TIMP)-BDNF(GST-TIMP-BDNF)expression plasmid was constructed using molecular cloning technique with double enzyme digestion by Bam H Ⅰ and Eco R Ⅰ.The recombinant GST-TIMP-BDNF protein was expressed in the Escherichia coli prokaryotic expression system,and purified by ion exchange chromatography,confirmed by Western blotting.MMP diluents were supplemented with PBS,MMP inhibitor marimastat,and varing concentrations(0.4,0.6,0.8 mg/ml)of GST-TIMP-BDNF or GST-BDNF.MMP-2 activity was analyzed using an MMP activity detection kit to evaluate the inhibitory effect of the recombinant protein on MMP.Primary rat neurons were extracted and cultured to establish an iron death model induced by RSL3.The effect of recombinant protein GST-TIMP-BDNF on neuronal injury was detected by immunofluorescence staining.Results MRI hydrogen spectrum identification confirmed the successful synthesis of HA-GSH.Western blotting results showed the successful expression of the recombinant protein GST-TIMP-BDNF containing the GST tag using the E.coli prokaryotic expression system.MMP activity detection results indicated that the recombinant protein GST-TIMP-BDNF had a superior inhibitory effect on MMP-2 activity compared to GST-BDNF(P<0.05).Immunofluorescence staining results showed a significant increase in fluorescence intensity in rat neurons treated with GST-TIMP-BDNF after RSL3 induction(P<0.05).Conclusion A MMP-responsive HA-based BDNF controlled-release material has been successfully developed,exhibiting a protective effect on neuron damage.

Deficiencies in the clearance of peripheral amyloid β (Aβ) play a crucial role in the progression of Alzheimer's disease (AD). Previous studies have shown that the ability of blood monocytes to phagocytose Aβ is decreased in AD. However, the exact mechanism of Aβ clearance dysfunction in AD monocytes remains unclear. In the present study, we found that blood monocytes in AD mice exhibited decreases in energy metabolism, which was accompanied by cellular senescence, a senescence-associated secretory phenotype, and dysfunctional phagocytosis of Aβ. Improving energy metabolism rejuvenated monocytes and enhanced their ability to phagocytose Aβ in vivo and in vitro. Moreover, enhancing blood monocyte Aβ phagocytosis by improving energy metabolism alleviated brain Aβ deposition and neuroinflammation and eventually improved cognitive function in AD mice. This study reveals a new mechanism of impaired Aβ phagocytosis in monocytes and provides evidence that restoring their energy metabolism may be a novel therapeutic strategy for AD.
Animals ; Mice ; Alzheimer Disease ; Amyloid beta-Peptides ; Monocytes ; Cognition ; Energy Metabolism ; Phagocytosis

BACKGROUND: The prevalence of skin diseases and diabetes mellitus (DM) are prominent around the world. The current scope of knowledge regarding the prevalence of skin diseases and comorbidities with type 2 DM (T2DM) is limited, leading to limited recognition of the correlations between skin diseases and T2DM. METHODS: We collected 383 subjects from the Da Qing Diabetes Study during the period from July 9th to September 1st, 2016. The subjects were categorized into three groups: Normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and T2DM. The prevalence and clinical characteristics of skin diseases were recorded and investigated. RESULTS: In this cross-sectional study, 383 individuals with ages ranging from 53 to 89-year-old were recruited. The overall prevalence of skin diseases was 93.5%, and 75.7% of individuals had two or more kinds of skin diseases. Additionally, there were 47 kinds of comorbid skin diseases in patients with T2DM, of which eight kinds of skin diseases had a prevalence >10%. The prevalence of skin diseases in NGT, IGT, and T2DM groups were 93.3%, 91.5%, and 96.6%, respectively; stratified analysis by categories showed a statistically significant difference in "disturbances of pigmentation" and "neurological and psychogenic dermatoses". The duration of T2DM also significantly associated with the prevalence of "disturbances of pigmentation" and "neurological and psychogenic dermatoses". Subsequently, the prevalence of "disturbances of pigmentation" was higher in males than females in NGT (P < 0.01) and T2DM (P < 0.01) groups. In addition, the difference in the prevalence of "disturbances of pigmentation" was also significant in NGT and T2DM groups (P < 0.01). CONCLUSIONS There was a high prevalence of skin diseases in the Da Qing Diabetes Study. To address the skin diseases in the Da Qing Diabetes Study, increased awareness and intervention measures should be implemented.
Aged ; Aged, 80 and over ; Blood Glucose ; Cross-Sectional Studies ; Diabetes Mellitus, Type 2/epidemiology* ; Female ; Glucose Intolerance/epidemiology* ; Glucose Tolerance Test ; Humans ; Male ; Middle Aged ; Skin Diseases/epidemiology*

OBJECTIVE: To evaluate the impact of deep invasive tumor thrombus on the surgical complexity and prognosis of patients with renal cell carcinoma complicated with inferior vena cava tumor thrombus. METHODS: We retrospectively reviewed the clinical data of 94 patients with non-metastatic renal cell carcinoma complicated with inferior vena cava tumor thrombus, who underwent surgical treatment in Peking University Third Hospital from January 2017 to June 2020. The patient's general condition, clinicopathological characteristics, surgery and survival information were collected. The patients were divided into two groups based on the intra-operative findings of tumor thrombus adhesion to the venous wall, of which 64 cases were in the deep invasive tumor thrombus (DITT) group and 30 cases were in the non-invasive tumor thrombus (NITT) group. Chi-square, t test and Mann-Whitney U test were used for categorical and continuous variables respectively. Kaplan-Meier plots and multivariable Cox regressions were performed to evaluate the influence of DITT on the prognosis of the patients with renal cell carcinoma with inferior vena cava tumor thrombus. RESULTS: DITT significantly increase the difficulty of surgery for the patients with renal cell carcinoma with venous tumor thrombus, which was mainly reflected in the longer operation time (362.5 vs. 307.5 min, P=0.010), more surgical bleeding (1 200 vs. 450 mL, P=0.006), more surgical blood transfusion (800 vs. 0 mL, P=0.021), more plasma transfusion (200 vs. 0 mL, P=0.001), a higher proportion of open surgery (70.3% vs. 36.7%, P=0.002), a longer post-operative hospital stay (9.5 vs. 8 days, P=0.036), and a higher proportion of post-operative complications (46.9% vs. 13.8%, P=0.002). DITT was associated with worse overall survival of the patients with renal cell carcinoma with inferior vena cava tumor thrombus (P=0.022). Even in the multivariate analysis, DITT was still a poor prognostic factor for the overall survival of these patients [HR: 4.635 (1.017-21.116), P=0.047]. CONCLUSION For patients with non-metastatic renal cell carcinoma with inferior vena cava tumor thrombus, DITT will significantly increase the difficulty of surgery, and may lead to poor prognosis.
Blood Component Transfusion ; Carcinoma, Renal Cell/surgery* ; Humans ; Kidney Neoplasms/surgery* ; Nephrectomy ; Plasma ; Prognosis ; Retrospective Studies ; Thrombectomy ; Thrombosis/surgery* ; Vena Cava, Inferior

Objective: To explore the effect of perioperative airway management based on the concept of enhanced recovery after surgery (ERAS) on the improvement of preoperative pulmonary function in patients with aspirin intolerance triad (AIT). Methods: Thirty patients with AIT (including 13 males and 17 females, aged from 29 to 75 years old) for sinus surgery from January 2018 to December 2019 were selected, 172 patients (including 105 males and 67 females, aged from 17 to 83 years old) with chronic rhinosinusitis with nasal polyps (CRSwNP) without lower airway disease were selected by random number table at the same period, and their clinical data and preoperative pulmonary function were analyzed and compared retrospectively. FEV₁%pred<80% after bronchodilation test was considered as high risk for surgery. Preoperative evaluation and standardized drug intervention were applied in patients with pulmonary function abnormalities at risk for surgery, and improvement of preoperative pulmonary function and tolerability to general anesthesia surgery in the two groups were evaluated. All the statistical analyses were conducted using SPSS 22.0. Results: The main pulmonary function indexes (FEV₁%pred, FEV₁/FVC%pred, FEF₅₀%pred, FEF₇₅%pred, MMEF%pred) in AIT group decreased significantly than those in CRSwNP group (t values were 10.882, 10.506, 9.141, 10.182, 9.099, respectively, all P<0.001). At admission 86.7% (26/30) patients in the AIT group and 11.6% (20/172) patients in CRSwNP group had high surgical risk for lung function, with significantly difference (χ² = 81.788, P<0.05); after 3 days with individualized drug intervention, 57.7% (15/26) patients in AIT group reached the standard for surgery, which was significantly less than 90.0% (18/20) patients in CRSwNP group (χ²=4.335,P<0.05); and after 6 days with drug intervention, the patients who reached the standard for surgery in pulmonary function accounted for 92.3% (24/26) in the AIT group and 100% (20/20) in the CRSwNP group. FEV₁%pred in the two groups before surgery were significantly improved compared with those at admission respectively ((90.00±6.32)% vs. (64.79±13.60)%,t value was 10.110 in AIT group; (91.65±11.86)% vs. (76.40±9.35)%, t value was 9.346 in CRSwNP group; all P<0.05), and also FEV₁/FVC%pred, FEF₅₀%pred, FEF₇₅%pred and MMEF%pred were all significantly improved (all P<0.05). Surgery was completed successfully in the two groups of patients with lung function meeting the surgical standard, and no intraoperative or postoperative airway adverse events occurred. Conclusion: AIT patients have high airway risk for sinus surgery due to poor pulmonary function. Standardized airway management based on the concept of ERAS can improve the pulmonary function of patients, and decrease the incidence of perioperative airway adverse events.
Adolescent ; Adult ; Aged ; Aged, 80 and over ; Airway Management ; Aspirin ; Enhanced Recovery After Surgery ; Female ; Humans ; Lung/surgery* ; Male ; Middle Aged ; Retrospective Studies ; Young Adult

ObjectiveMild hypothermia was an effective way of cerebral resuscitation after cardiac arrest. The expression of cold-induced RNA binding protein (CIRP) was significantly enhanced when the temperature was lowered. This study was to evaluate the effects and the mechanisms of CIRP inhibition on hippocampal neurological and mitochondria function after mild hypothermia in a rat model of cardiac arrest.MethodsFive male Sprague-Dawley rats were injected with AAV9 in the hippocampus, 1 μL on each side, speeding 0.2 μL/min. The expression of GFP was observed by fluorescence microscopy after 2w. Sixty rats were randomly divided into 5 groups (n= 12 for each group): sham operation group, model group, mild hypothermia group, mild hypothermia + CIRP inhibition group and mild hypothermia + normal control group. Injection of AAV9 was performed on mild hypothermia + CIRP inhibition group, same amount of empty vector on mild hypothermia + normal control group, while normal saline on the other groups. Animal models of global cerebral IR were established by transesophageal cardiac pacing inducing cardiac arrest followed by cardiopulmonary resuscitation at 2w after injection. Cooling to 32-34℃ was initiated and the temperature was maintained for 6h on mild hypothermia groups. NDS score, HE staining and pyramidal cell counting on hippocampal CA1 area were performed at 72h after reperfusion. At 24h after reperfusion, mitochondrial structure of pyramidal cells in hippocampal CA1 was observed under electronic microscope and the expressions of CIRP, dynamin-related protein 1 (Drp1) and cytochrome C (Cyt-C) were detected by Western blot.ResultsThe NDS score of model group was decreased, the number of pyramidal cells was reduced, and the mitochondria were severely damaged. The NDS score of mild hypothermia group was increased, and the number of pyramidal cells was increased (all P<0.05), and mitochondrial damage was reduced compared with model group. In mild hypothermia + CIRP inhibition group, the NDS score was no significant difference compared with mild hypothermia + normal control group and model group, and the number of pyramidal cells was lower than that in mild hypothermia + normal control group [(27.2±4.9) vs (50.2±4.4), P<0.05], similar to model group (25.2±3.8), the damage of mitochondria was severe. After 2 weeks of AAV9 injection, GFP was widely expressed in the hippocampus. The expression of CIRP in mild hypothermia + CIRP inhibition group was respectively small compared with sham operation group [(0.14±0.03) vs (0.03±0.01),P<0.05], which was successfully inhibited by injection of AAV9. The expression of CIRP in model group (0.25±0.05) was significantly higher than that in sham operation group. The expression of CIRP in mild hypothermia group (0.37±0.08) and mild hypothermia + normal control group (0.39±0.04) were higher than that in model group (all P<0.05). The trends of Drp1 and Cyt-C expression were the same, in model group was higher than that in sham operation group, in mild hypothermia group was lower than that in model group, in mild hypothermia + CIRP inhibition group was higher than in mild hypothermia + normal control group (all P<0.05); There were no significant differences between model group and mild hypothermia + CIRP inhibition group, and between mild hypothermia group and mild hypothermia + normal control group.ConclusionInhibition of CIRP expression in hippocampus can weaken the protective effects of mild hypothermia on neurons in a rat model of cardiac arrest. The mechanism of those effects might be association with mitochondrial division.

The study aims at developing a convenient and specific method for the identification of Fel Serpentis DNA. The methods of Fel Serpentis genomic DNA purification were tested and optimized, four pairs of specific primers for the amplification of COⅠ, Cyt b and 16S were designed. Then the best pair of primers were selected according to the specificity and efficiency. The DNA fragment about 400 bp was amplified from 20 kinds of Fel Serpentis, whereas no DNA fragment was amplified from other animal samples under the same condition. This method is specific,accurate and reproducible, which provides a useful tool for the quality control of Fel Serpentis.

Objective: To explore the clinical efficacy and safety of unrelated umbilical cord blood transplantation (UCBT) in the treatment of refractory and relapsed acute leukemia (AL) patients. Methods: The clinical data of 22 refractory and relapsed AL patients who were treated with UCBT as salvage therapy from November 2009 to May 2017 were retrospectively analyzed. All patients received a myeloablative conditioning regimen for prevention of graft-versus-host disease (GVHD) with cyclosporine A (CSA)/short course of mycophenolate mofetil (MMF). Results: ①Of 22 patients, 9 cases were male and 13 female. The median age was 23 (15-44) years and median weight of 52.5 (43-82) kg. All patients were transplanted with a median umbilical cord blood nucleated cells of 3.07 (1.71-5.30)×10⁷/kg (by weight), the median CD34⁺ cells was 1.60 (0.63-3.04)×10⁵/kg (by weight). ②The myeloid cumulative implantation rate was 95.5% (95%CI 45.2-99.7%) after transplantation of 42 d, with the median implantation time of 19 (13-27) d. The platelet cumulative implantation rate after transplantation of 120 d was 81.8% (95%CI 54.2-93.6%), the median implantation time of 42 (20-164) d. ③The incidence of Ⅱ-Ⅳ, Ⅲ-Ⅳ aGVHD and the 2 year cumulative incidence of cGVHD were 36.4%, 13.6% and 40.3% respectively. ④ The transplant related mortality (TRM) after transplantation of 180d was 22.7%, 2 year cumulative rate of relapse was 18.7% (95%CI 3.6-42.5%), 2 year disease-free survival rate (DFS) and overall survival rate (OS) were 53.7% and 58.1%, respectively. Conclusion: The preliminary results show that the use of UCBT is safe and effective for refractory and relapsed AL patients who fail to respond to conventional chemotherapy.
Acute Disease ; Adolescent ; Adult ; Cord Blood Stem Cell Transplantation ; Female ; Graft vs Host Disease ; Hematopoietic Stem Cell Transplantation ; Humans ; Leukemia/therapy* ; Male ; Peripheral Blood Stem Cell Transplantation ; Retrospective Studies ; Transplantation Conditioning ; Young Adult

In this study, a network pharmacological screening method was adopted to further study the active ingredients and action mechanism of total flavonoids of Hippophae rhamnoides(TFH) for the treatment of myocardial ischemia. Firstly TCMSP database and PubChem database were searched, and then the data were combined with oral bioavailability and drug analysis to screen flavonoids of H.rhamnoides compounds. Then predictive analysis was conducted for the 7 screened compounds by ChemMapper server.The obtained potential targets were imported into MAS 3.0. Database, and KEGG database was also used for targets analysis and pathway analysis. Finally Cystoscope 3.3.0 software was used to draw "compounds-targets-pathway" network diagram. Virtual experiments predicted 68 potential targets and 60 signaling pathways, and 31 targets and 23 pathways of them were directly or indirectly associated with myocardial ischemia. The results showed that TFH played a synergistic rolemainly through the regulation of calcium signaling pathway, VEGF signaling pathway and gap junction signaling pathway, which was consistent with literature reports. These results indicated that it can enhance heart function, protect vascular endothelial cells, and fight against myocardial ischemia probably by regulating platelet aggregation, lipid metabolism, inflammation and other processes.