This study explores the mechanism of Guben Jiannao Liquid on Alzheimer's disease(AD) by regulating autophagy based on the liver kinase B1(LKB1)/adenosine monophosphate-activated protein kinase(AMPK)/mammalian target of rapamycin(mTOR) pathway. Male SD rats were randomly divided into the blank group, model group, low-dose and high-dose groups of Guben Jiannao Liquid, and rapamycin group, with 10 rats in each group. Except for the blank group, all other groups of rats were injected bilaterally in the hippocampus with β-amyloid(Aβ)_(1-42) to establish the AD model. The low-dose(6.21 g·kg~(-1)) and high-dose(12.42 g·kg~(-1)) groups of Guben Jiannao Liquid and rapamycin group(1 mg·kg~(-1)) were given the corresponding drugs by gavage, and the blank and model groups were given an equal volume of saline by gavage for four weeks. Morris water maze was used to test the learning and memory ability of rats in each group; hematoxylin-eosin(HE) and Nissl staining were used to observe the morphological and quantitative changes of neurons and Nissl bodies in the CA1 region of rat hippocampus; immunohistochemistry was utilized to detect Aβ-positive cell expression in the CA1 region of rat hippocampus; transmission electron microscopy was employed to observe ultrastructural changes in rat hippocampal tissue, and Western blot was used to examine the protein expression levels of LKB1, p-AMPK/AMPK, p-mTOR/mTOR, Beclin1, p62, and LC3-Ⅱ in the hippocampal tissue of the rats. The results showed that compared with those in the blank group, rats in the model group had elevated evasion latency and decreased number of platform transversal and residence time in the platform quadrant. The number of neurons in the hippocampal area was reduced, and the morphology was impaired. The average integral optical density value of Aβ-positive cells was elevated; the expression levels of LKB1, p-AMPK/AMPK, Beclin1, and LC3-Ⅱ were decreased, and the expression levels of p-mTOR/mTOR and p62 were increased. Compared with those in the model group, rats in the low-dose and high-dose groups of Guben Jiannao Liquid had shorter evasion latency, higher number of platform transversal, longer residence time in the platform quadrant, increased number of neurons, decreased expression of Aβ-positive cells and average integral optical density values, and increased number of autophagic lysosomes in hippocampal tissue. The expression levels of LKB1, Beclin1, and LC3-Ⅱ were elevated in the hippocampus of rats in the low-dose group of Guben Jiannao Liquid. The expression levels of LKB1, p-AMPK/AMPK, Beclin1, and LC3-Ⅱ were elevated in the hippocampal tissue of rats in the high-dose group of Guben Jiannao Liquid, and the expression levels of p-mTOR/mTOR and p62 were decreased. The findings suggest that Guben Jiannao Liquid can improve cognitive impairment in AD rats, and its mechanism of action may be related to the activation of the LKB1/AMPK/mTOR signaling pathway and the up-regulation of autophagy level.
Animals ; Alzheimer Disease/physiopathology* ; Male ; TOR Serine-Threonine Kinases/genetics* ; Autophagy/drug effects* ; Rats, Sprague-Dawley ; Protein Serine-Threonine Kinases/genetics* ; AMP-Activated Protein Kinases/genetics* ; Rats ; Drugs, Chinese Herbal/administration & dosage* ; Signal Transduction/drug effects* ; AMP-Activated Protein Kinase Kinases ; Humans ; Hippocampus/metabolism*

OBJECTIVE: To investigate the influencing factors of differentiation syndrome (DS) during induction chemotherapy for acute promyelocytic leukemia (APL), and establish a prediction model for DS in newly diagnosed APL patients, in order to guide clinical treatment. METHODS: The clinical data of 324 newly diagnosed APL patients were retrospectively analyzed, and the patients were divided into DS group and non-DS group according to whether or not DS was present. Statistically significant factors from comparison of the two groups were selected and included in univariate and multivariate logistic regression to explore the influencing factors of DS in APL. R software was used to build the nomogram model, Bootstrap method was used for internal verification, and concordance index (C-index) and calibration curve were used to evaluate the accuracy of the model. RESULTS: The incidence of DS in 324 patients with newly diagnosed APL was 30.86% (100/324). Univariate logistic regression analysis showed that high risk, delayed retinoic acid, no hormonal prophylaxis, combined with disseminated intravascular coagulation, increased white blood cell count (WBC) at initial diagnosis and neutrophil count, prothrombin prolongation, decreased fibrinogen and albumin (ALB), increased proportion of bone marrow original cells, increased proportion of peripheral blood original cells, and increased peak of WBC after chemotherapy were risk factors for DS in newly diagnosed APL patients (all P < 0.01). Multivariate logistic regression analysis showed that the increased peak value of WBC after chemotherapy, prophylactic use of hormone, and ALB level were independent factors influencing the occurrence of DS in newly diagnosed APL patients (all P < 0.01). The C-index of DS in APL predicted by the nomogram model was 0.847(95%CI : 0.786-0.908). The calibration curve showed that the nomogram was in good agreement with the actual incidence of DS. CONCLUSION The independent influencing factors of DS in newly diagnosed APL are the increased peak value of WBC after chemotherapy, ALB and prophylactic use of hormone. The nomogram model based on the above factors can predict the risk of DS in APL patients, which is consistent with clinical observation.
Humans ; Leukemia, Promyelocytic, Acute/drug therapy* ; Nomograms ; Retrospective Studies ; Male ; Female ; Logistic Models ; Middle Aged ; Induction Chemotherapy ; Adult

Periodontitis is a common oral disease caused by bacteria coupled with an excessive host immune response. Stem cell therapy can be a promising treatment strategy for periodontitis, but the relevant mechanism is complicated. This study aimed to explore the therapeutic potential of mitochondria from human embryonic stem cell-derived mesenchymal stem cells (hESC-MSCs) for the treatment of periodontitis. The gingival tissues of periodontitis patients are characterized by abnormal mitochondrial structure. Human gingival fibroblasts (HGFs) were exposed to 5 μg/mL lipopolysaccharide (LPS) for 24 h to establish a cell injury model. When treated with hESC-MSCs or mitochondria derived from hESC-MSCs, HGFs showed reduced expression of inflammatory genes, increased adenosine triphosphate (ATP) level, decreased reactive oxygen species (ROS) production, and enhanced mitochondrial function compared to the control. The average efficiency of isolated mitochondrial transfer by hESC-MSCs was determined to be 8.93%. Besides, a therapy of local mitochondrial injection in mice with LPS-induced periodontitis showed a reduction in inflammatory gene expression, as well as an increase in both the mitochondrial number and the aspect ratio in gingival tissues. In conclusion, our results indicate that mitochondria derived from hESC-MSCs can reduce the inflammatory response and improve mitochondrial function in HGFs, suggesting that the transfer of mitochondria between hESC-MSCs and HGFs serves as a potential mechanism underlying the therapeutic effect of stem cells.
Humans ; Gingiva/cytology* ; Fibroblasts/metabolism* ; Mitochondria/physiology* ; Mesenchymal Stem Cells/cytology* ; Animals ; Periodontitis/therapy* ; Mice ; Reactive Oxygen Species/metabolism* ; Inflammation ; Lipopolysaccharides ; Human Embryonic Stem Cells/cytology* ; Cells, Cultured ; Adenosine Triphosphate/metabolism* ; Male

Objective To explore the clinical value of fibrinogen-albumin-ratio (FAR) in adult extracorporeal membrane oxygenation (ECMO) hemorrhage. Methods The clinical data of adult patients receiving ECMO in the West China Hospital from 2018 to 2020 were analyzed retrospectively. Patients were divided into a bleeding group and a non-bleeding group based on whether they experienced bleeding after ECMO. Logistic regression analysis was used to study the relationship between FAR and bleeding, as well as risk factors for death. Receiver operating characteristic (ROC) curve and area under the curve (AUC) were used to analyze the predictive ability of FAR. According to the optimal cut-off value of FAR for predicting hemorrhage, patients were divided into a high-risk group and a low-risk group, and the occurrence of bleeding was compared between the two groups. Results A total of 125 patients were enrolled in this study, including 85 males and 40 females, aged 46.00 (31.50, 55.50) years. Among them, 58 patients received veno-arterial extracorporeal membrane oxygenation (VA-ECMO) and 67 patients received veno-venous extracorporeal membrane oxygenation (VV-ECMO). There were 49 patients having bleeding, and the lactate level was higher (P=0.026), the platelet count before ECMO initiation and 24 h after ECMO initiation was lower (P=0.031, 0.020), the fibrinogen level 24 h after ECMO initiation was lower (P=0.049), and the proportion of myocarditis patients was higher (P=0.017) in the bleeding group than those of the non-bleeding group. In the subgroup analysis of ECMO mode, the higher D-Dimer, lactate level and lower FAR before and 24 h after ECMO initiation were associated with bleeding in the VA-ECMO group (P=0.017, 0.011, 0.033, 0.005). The 24 h FAR was independently correlated with bleeding (P=0.048), and AUC was 0.714. The cut-off value was 55.73. According to this optimal cut-off value, 25 patients were divided into the high-risk group (≤55.73) and 33 into the low-risk group (>55.73). There was a higher incidence of bleeding in the high-risk group compared to the low-risk group (unadjusted P=0.002; P=0.013 for multivariable adjustment). In the VV-ECMO group, the relationship between FAR and bleeding events was not significant (P>0.05). Conclusion Low 24 h FAR is an independent risk factor for bleeding in VA-ECMO patients, and the diagnostic cut-off value is 55.73.

Isocitrate dehydrogenase 1 (IDH1) R132H is the most common mutated gene in grade II-III gliomas and oligodendrogliomas. Instead of activating telomerase (a reverse transcriptase which using RNA as a template to extend telomere length), the majority of IDH1^R132H mutant glioma maintain telomere length through an alternative mechanism that relies on homologous recombination (HR), which is known as alterative lengthening of telomere (ALT).The phenotype of ALT mechanism include: ALT associated promyelocytic leukemia protein (PML) bodies (APBs); extrachromosomal telomeric DNA repeats such as C- and T-loops; telomeric sister chromatid exchange (T-SCE), etc. The mechanism of ALT activation is not fully understood. Recent studies have shown that mutation IDH1 contributes to ALT phenotype in glioma cells in at least three key ways. Firstly, the IDH1^R132H mutation mediates RAP1 down-regulation leading to telomere dysfunction, thus ensuring persistent endogenous telomeric DNA damage, which is important for ALT activation. Spontaneous DNA damage at telomeres may provide a substrate for mutation break-induced replication (BIR)‑mediated ALT telomere lengthening, and it has been demonstrated that RAP1 inhibits telomeric repeat-containing RNA, transcribed from telomeric DNA repeat sequences (TERRA) transcription to down-regulate ALT telomere DNA replication stress and telomeric DNA damage, thereby inhibiting ALT telomere synthesis. Similarly, in ALT cells, knockdown of telomere-specific RNaseH1 nuclease triggers TERRA accumulation, which leads to increased replication pressure. Overexpression of RNaseH1, on the other hand, attenuates the recombination capacity of ALT telomeres, leading to telomere depletion, suggesting that RAP1 can regulate the level of replication pressure and thus ALT activity by controlling TERRA expression. Secondly, the IDH1^R132H also alters the preference of the telomere damage repair pathway by down-regulating XRCC1, which inhibits the alternative non-homologous end joining (A-NHEJ) pathway at telomeres and alters cellular preference for the HR pathway to promote ALT. Finally, the IDH1^R132H has a decreased affinity for isocitric acid and NADP+ and an increased affinity for α ketoglutarate (α‑KG) and NADPH, so that the mutant IDH1^R132H catalyzes the hydrogenation of α‑KG to produce 2-hydroxyglutarate (2-HG)in a NADPH-dependent manner. Because 2-HG is structurally similar to α‑KG, which maintains the trimethylation level of H3k9me3 by competitively inhibiting the activity of the α‑KG-dependent histone demethylase KDM4B, and recruits heterochromatin protein HP1α to heterochromatinize telomeres, and promote ALT phenotypes in cooperation with the inactivating of ATRX. In addition, it has been shown that APBs contain telomeric chromatin, which is essentially heterochromatin, and HP1α is directly involved in the formation of APBs. Based on these studies, this article reviews the mechanism of IDH1^R132H mediated telomere dysfunction and the preference of DNA repair pathway at telomeres in cooperate with ATRX loss to promote ALT, which may provide references for clinical targeted therapy of IDH1^R132H mutant glioma.

Patients with severe trauma require an extremely timely treatment and transfusion plays an irreplaceable role in the emergency treatment of such patients. An increasing number of evidence-based medicinal evidences and clinical practices suggest that patients with severe traumatic bleeding benefit from early transfusion of low-titer group O whole blood or hemostatic resuscitation with red blood cells, plasma and platelet of a balanced ratio. However, the current domestic mode of blood supply cannot fully meet the requirements of timely and effective blood transfusion for emergency treatment of patients with severe trauma in clinical practice. In order to solve the key problems in blood supply and blood transfusion strategies for emergency treatment of severe trauma, Branch of Clinical Transfusion Medicine of Chinese Medical Association, Group for Trauma Emergency Care and Multiple Injuries of Trauma Branch of Chinese Medical Association, Young Scholar Group of Disaster Medicine Branch of Chinese Medical Association organized domestic experts of blood transfusion medicine and trauma treatment to jointly formulate Chinese expert consensus on blood support mode and blood transfusion strategies for emergency treatment of severe trauma patients ( version 2024). Based on the evidence-based medical evidence and Delphi method of expert consultation and voting, 10 recommendations were put forward from two aspects of blood support mode and transfusion strategies, aiming to provide a reference for transfusion resuscitation in the emergency treatment of severe trauma and further improve the success rate of treatment of patients with severe trauma.

Objective:Comparison with non-elderly patients to analyze the clinicopathological characteristics of elderly female breast cancer(BC)patients and to explore the factors influencing their prognosis.Methods:Data were collected from 86, 064 female BC patients in the National Cancer Institute's Surveillance, Epidemiology, and End Results(SEER)database, spanning from 1975 to 2015.Patients aged 65 and older were classified as the elderly group, while those under 65 were designated as the non-elderly group.The baseline characteristics and clinicopathological differences between the two groups were analyzed using the chi-square test.The Kaplan-Meier method was employed to plot overall survival(OS)and breast cancer-specific survival(BCSS)curves for both groups.Additionally, factors influencing OS and BCSS in elderly BC patients were examined through univariate and multivariate Cox regression analyses.Results:In comparison to the non-elderly group, elderly BC patients exhibited a higher proportion of white individuals, widows, residents from non-metropolitan areas, lower median household income, lower histological grade, and earlier clinical stage.Furthermore, this group demonstrated a greater prevalence of estrogen receptor(ER)and progesterone receptor(PR)positivity, a lower prevalence of human epidermal growth factor receptor 2(HER2)positivity, and fewer individuals received standard treatment(all P<0.001).The prognosis for the elderly group was poorer, characterized by increased risks of all-cause mortality and breast cancer-specific mortality( P<0.001).Multivariate analysis revealed that receiving standard treatment served as a protective factor for both OS and BCSS in elderly patients. Conclusions:In this cohort, elderly breast cancer patients were characterized by an earlier clinical stage, lower histological grade, higher rates of ER and PR positivity, and a lower rate of HER2 positivity.Their OS and BCSS rates were significantly worse than those of the non-elderly group.The analysis indicates that inadequate and non-standard treatment is a major influencing factor, necessitating increased attention from clinicians.

Objective:To study the influence of serum triggering receptor expressed on myeloid cells 1(TREM-1)level on prognosis in elderly patients with sepsis and acute respiratory distress syndrome(ARDS).Methods:A total of 100 elderly patients with sepsis were selected as the research objects.All the patients with sepsis were divided into sepsis ARDS group and sepsis non-ARDS group.General data and TREM-1 level were compared between the two groups.The patients with sepsis ARDS were divided into death group and survival group according to the survival status during the 28-day follow-up.TREM-1 level, acute physiology and chronic health evaluation(APACHE)Ⅱ score and SOFA score were compared between the two groups.The correlation between serum TREM-1 level and procalcitonin(PCT), APACHE Ⅱ score and SOFA score was analyzed.The survival rate of high TREM-1 level group and low TREM-1 level group was compared.Results:The age, white blood cell(WBC), PCT, APACHE Ⅱ score, SOFA score and TREM-1 level of sepsis ARDS patients were significantly higher than those of non-ARDS patients( t=2.722, 6.088, 11.55, 6.889, 4.661, 6.122, all P<0.05). The incidence of sepsis ARDS patients with chronic obstructive pulmonary disease was significantly higher than that of non-ARDS patients( χ2=7.895, P<0.05). Serum TREM-1 level, APACHE Ⅱ score and SOFA score of ARDS patients in death group were significantly higher than those in survival group( t=3.293, 6.173, 4.255, all P<0.05). Serum TREM-1 level was positively correlated with PCT, APACHE Ⅱ score and SOFA score( t=0.553, 0.602, 0.636, P<0.001). The Kaplan-Meier survival curve showed that the survival rate of high TREM-1 level group was significantly lower than that of low TREM-1 level group( χ2=3.999, P=0.036). Cox regression analysis showed that TREM-1 level was a risk factor for the prognosis of ARDS patients with sepsis( HR=1.893, 95% CI: 1.049-3.414). Conclusions:Serum TREM-1 level is significantly increased in elderly patients with sepsis ARDS, which is closely related to the prognosis and can be used as a potential prognostic biomarker.

Objective: To establish and evaluate a method of enriching bacteriophages in natural water based on ferric trichloride-polyvinylidene fluoride (FeCl₃-PVDF)membrane filter. Methods: Based on the principle of flocculation concentration, the method of recovering bacteriophage from water sample was established by using iron ion flocculation combined with membrane filter. The titer of phage was determined by Agar double layer method. The recovery efficiency of phage was detected by phage fluorescence staining and real-time fluorescence PCR reaction. Water samples from different sources were collected for simulation experiment to evaluate the enrichment effect. At the same time, the sewage discharged from hospitals was taken as the actual water sample, and the common clinical drug-resistant bacteria were used as the host indicator bacteria to further analyze the enrichment effect of FeCl₃-PVDF membrane filter rapid enrichment method on the bacteriophage in natural water samples. Results: The method of enrichment of bacteriophages in natural water by iron ion concentration 50 mg/L and PVDF membrane filter was established. The recovery rate of this method for bacteriophage was 93%-100%. Under the multi-functional microscope, it was found that the bacteriophage of the enriched water sample increased significantly and the fluorescence value of the enriched water sample determined by the enzyme labeling instrument was about 13 times as high as that before enrichment. After concentration of the actual water samples from the hospital drainage, the positive rate of bacteriophage isolation in the concentrated group and the non-concentrated group was 23% and 4%, and the fluorescence value in the concentrated group was 2-24 times as high as that of the non-concentrated group. Conclusion: The method of FeCl₃-PVDF membrane filter is a simple, efficient and rapid method for enriching bacteriophages in different water samples.
Humans ; Bacteriophages ; Bacteria ; Iron ; Iron, Dietary ; Water