Hepatocellular carcinoma(HCC)is one of the most common tumor types and remains a major clinical challenge.Increasing evidence has revealed that mitophagy inhibitors can enhance the effect of chemotherapy on HCC.However,few mitophagy inhibitors have been approved for clinical use in humans.Pyrimethamine(Pyr)is used to treat infections caused by protozoan parasites.Recent studies have reported that Pyr may be beneficial in the treatment of various tumors.However,its mechanism of action is still not clearly defined.Here,we found that blocking mitophagy sensitized cells to Pyr-induced apoptosis.Mechanistically,Pyr potently induced the accumulation of autophagosomes by inhibiting autophagosome-lysosome fusion in human HCC cells.In vitro and in vivo studies revealed that Pyr blocked autophagosome-lysosome fusion by upregulating BNIP3 to inhibit synaptosomal-associated protein 29(SNAP29)-vesicle-associated membrane protein 8(VAMP8)interaction.Moreover,Pyr acted synergistically with sorafenib(Sora)to induce apoptosis and inhibit HCC proliferation in vitro and in vivo.Pyr enhances the sensitivity of HCC cells to Sora,a common chemotherapeutic,by inhibiting mitophagy.Thus,these results provide new insights into the mechanism of action of Pyr and imply that Pyr could potentially be further developed as a novel mitophagy inhibitor.Notably,Pyr and Sora combination therapy could be a promising treatment for malignant HCC.

Insufficient remyelination due to impaired oligodendrocyte precursor cell (OPC) differentiation and maturation is strongly associated with irreversible white matter injury (WMI) and neurological deficits. We analyzed whole transcriptome expression to elucidate the potential role and underlying mechanism of action of lipocalin-2 (LCN2) in OPC differentiation and WMI and identified the receptor SCL22A17 and downstream transcription factor early growth response protein 1 (EGR1) as the key signals contributing to LCN2-mediated insufficient OPC remyelination. In LCN-knockdown and OPC EGR1 conditional-knockout mice, we discovered enhanced OPC differentiation in developing and injured white matter (WM); consistent with this, the specific inactivation of LCN2/SCl22A17/EGR1 signaling promoted remyelination and neurological recovery in both atypical, acute WMI due to subarachnoid hemorrhage and typical, chronic WMI due to multiple sclerosis. This potentially represents a novel strategy to enhance differentiation and remyelination in patients with white matter injury.
Mice ; Animals ; Remyelination/physiology* ; Oligodendrocyte Precursor Cells/metabolism* ; White Matter ; Subarachnoid Hemorrhage/metabolism* ; Lipocalin-2/metabolism* ; Early Growth Response Protein 1/metabolism* ; Oligodendroglia/metabolism* ; Mice, Knockout ; Cell Differentiation/physiology* ; Brain Injuries/metabolism*

To compare the clinical efficacy of calcium sodium edetate （EDTA） and the low-dose sodium dimercaptopropanesulfonate（DMPS） in treating cerebral Wilson’s disease. Methods Eighty patients with neurological Wilson’s disease in the neurology department of the first affiliated hospital of Anhui traditional Chinese medicine from February 2019 to September 2021 were collected and divided into the EDTA treatment group（n=39） and the low-dose DMPS control group（n=41）based on treatments. Propensity score matching （PSM） was performed on the two groups of patients and the results were compared after matching. The copper displacement effects of the two groups were compared，and the deterioration of copper displacement and adverse reactions were observed. Results After PSM，35 patients in EDTA group and 35 patients in the low-dose DMPS group were included. UWDRS Ⅰ in EDTA group showed significant statistical difference after treatment［（57.03±21.06） versus （54.40±20.02），t=7.256，P<0.001］，while UWDRS Ⅰ in the low-dose DMPS group showed no significant statistical difference［（53.49±26.82） versus （52.37±27.17），t=1.544，P=0.129］. Compared with the low-dose DMPS group，there was no significant difference in 24-hour urinary copper detection in the EDTA group［551.18 （417.77，843.47） versus 489.20 （389.64，839.47），Z=0.029，P>0.05］. The neurological deterioration （P=0.025） and adverse reactions were significantly reduced. Conclusion EDTA and low-dose DMPS have the same effect in expelling copper in patients with neurological WD，with better improvement，less neurological deterioration probability，and fewer adverse reactions. EDTA can be used as a copper removing treatment for patients with neurological WD.

Objective:Analyze the perioperative data of children undergoing cardiopulmonary bypass(CPB) for congenital heart disease under the management of ultra-fast track anesthesia(UFTA), the factors of CPB are discussed.Methods:1 034 children who underwent CPB from May 2018 to August 2019 were analyzed retrospectively. According to the success of anesthesia, they were divided into two groups: UFTA group and UFTA failure group. Propensity score matching was used to screen the children with preoperative baseline data matching. Finally 346 cases in each group. The possible CPB factors of the two groups were analyzed by single factor analysis, and the statistically significant factors were analyzed by logistic regression analysis. Results:Univariate analysis showed that the CPB and aortic occlusion time, the lowest temperature and lowest hematocrit in CPB, the dosage of crystalloid and suspended erythrocytes, the second or more times of CPB, and the blood lactate after CPB were the factors influencing the ultra-fast track anesthesia. Logistic regression analysis showed that the time of CPB and aortic occlusion, the value of blood lactate, the dosage of suspended erythrocytes, and the second or more times of CPB were the independent influencing factors of ultra-fast track anesthesia. In the UFTA failure group, the postoperative hospitalization time, the length of stay in the ICU and the hospitalization cost were all higher than those in the ultra-fast track group. Conclusion:CPB time, aortic occlusion time, blood lactate after CPB, the dosage of suspended erythrocytes, secondary or multiple CPB were independent risk factors for UFTA.UFTA is beneficial to shorten the postoperative hospital stay, the ICU stay and the cost of hospitalization.

Objective To evaluate the relationship of the plasma levels of osteopontin(OPN),lipoprotein (a) [Lp (a)] and apolipoproteinA/apolipoproteinB (ApoB/ApoA1) ratio with atherosclerosis.Methods 120 elderly patients with atherosclerosis (observation group) and another 120 healthy elderly subjects (control group) from Health Check Department in Tianjin Third Center Hospital were enrolled from Mar.2014 to Nov.2015.The levels of plasma OPN,Lp(a) and ApoB / ApoA1 ratio were measured and their relationship with atherosclerosis was analyzed.Results In observation group versus control group,the levels of plasma OPN[(33.2±10.1) μg/L vs.(30.6± 9.1) μg/L],ApoB/ApoA1 ratio[(0.8±0.7) vs.(0.6±0.1)]and Lp(a)[(357.6±66.5) mg/L vs.(120.5±35.7) mg/L] were increased with statistically significant differences (t =8.91,8.43,6.01;P=0.021,0.035,0.041).The concentrations of plasma OPN,ApoB/ApoA1 ratio and Lp (a) were increased along with aggravation of artery lesion,with statistically significant differences (F =8.50,7.38,6.41;P=0.031,0.039,0.037).Conclusions The plasma levels of OPN,Lp(a) and ApoB/ ApoA1 ratio are increased in patients with atherosclerosis and increased along with the lesion aggravation.

Objective:To compare the clinical effects of high volume zero-balanced ultraifltration (ZBUF) with different replacement lfuid in infant patients.
Methods: A total of 40 infant patients who received aortic coarctation with deep hypothermic circulatory arrest operation in our hospital from 2012-11 to 2014-02 were summarized. The patients were randomized into 2 groups, Group A, the patients had ZBUF with plasmalyte A, n=21 and Group B, the patients had ZBUF with modiifed replacement lfuid n=19. All patients received ZBUF (15-20) ml/kg during re-warming period until the temperature reached 34°C at rectum. Blood gas analysis were conducted at 4 time points as T1 (before CPB), T2 (open ascending aorta and 5 min after calcium perfusion), T3 (ifnishing ZBUF) and T4 (end of CPB). The intra-operative CPB time and the post-operative recovery with the complication were recorded in all patients.
Results: For blood gas analysis, the calcium concentration was higher in Group B than that in Group A at T3 time point, P<0.01 and the base excess was higher in Group A than that in Group B at T3 time point, P<0.05. Those indexes were similar at T1, T2 and T4, all P>0.05. The other indexes were similar between 2 groups, P>0.05 and the post-operative recovery was similar between 2 groups, P>0.05.
Conclusion: ZBUF with modiifed replacement lfuid could avoid decreased calcium concentration and acidosis, therefore, provide a relative stable homeostasis in infant patients.

Objective To explore the effects of diethylenetriamine/nitric oxide (DETA/NO)on capillary spasm and early brain injury (EBI)after subarachnoid hemorrhage (SAH)in rats.Methods Sixty-nine male Sprague-dawley rats were randomized into three groups:sham group,SAH group and DETA/NO group.SAH model was established by wearing out the willis ring with thread and then Garcia neurological score was observed in the general animals.The expressions of alpha smooth muscle actin (αSMA)and PDGFRβwere detected by dual immunofluorescence staining;nitric oxide kit was used for detecting brain tissue NO concentration.Changes in the hemoglobin-stimulated capillaries were observed in rat slices.Results Three days after surgery,neurological deficit score was remarkably improved in DETA/NO group compared with that in SAH group (P<0 .0 5 ). Immunofluorescence results showed that the expressions of peri-capillaryαSMA and PDGFRβwere significantly increased after SAH (P<0.05 ),and that DETA/NO could down-regulate the expressions (P<0.05 ).NO concentration was greatly reduced about 3 hours after SAH and then gradually increased;DETA/NO could maintain the concentration of NO at an early stage (P<0 .0 5 ).The capillary contraction was observed in slices perfused with hemoglobin;DETA/NO could alleviate capillary spasm.Conclusion DETA/NO can alleviate the severity of capillary spasm and EBI after SAH in rats.

Objective To evaluate the relationship between extracellular signal-regulated kinase (ERK)and ketamine-induced apoptosis in rat hippocampal neurons.Methods Sprague-Dawley rats at 18 days of gestation were anesthetized.The fetal rats were obtained under the sterile condition and decapitated.The hippocampal neurons were isolated and primarily cultured for 5 days,and were seeded in 6-well plates (2 ml/well) or in 96-well plates (100μl/well) at a density of 5 × 105/ml.The cells were randomly divided into 4 groups (n =18 each):control group (group C),fibroblast growth factor (FGF-2,an ERK agonist) group (group F),ketamine group (group K) and FGF-2 + ketamine group (group FK).The cells were cultured in the plain culture medium in group C.FGF-2 50 ng/ml was added to the culture medium in group F.Ketamine was added to the culture medium in group K.FGF-2 50 ng/ml was added to the culture medium at 20 min before ketamine 100 μmol/L was added in group FK.The phosphorylation of ERK in hippocampal neurons was detected by Western blot at 10 min after treatment.At 24 h after treatment,the neuronal apoptosis was detected by Hoechst33342/PI staining,and the cell survival rate was detected by MTT assay.The apoptosis rate was calculated.Results Compared with group C,the phosphorylation of ERK in hippocampal neurons and the cell survival rate was significantly decreased and the apoptosis rate was increased in K and FK groups (P ＜ 0.05).There was no significant difference in the parameters mentioned above between F and C groups (P ＞ 0.05).The phosphorylation of ERK in hippocampal neurons and the cell survival rat was significantly higher and the apoptosis rate was lower in group FK than in group K (P ＜0.05).Conclusion Ketamine induces apoptosis in rat hippocampal neurons by inhibiting activation of ERK in hippocampal neurons.

Neurobiology is to study the structure,function,development and regeneration of the nervous system at molecular,cellular and whole level.The objective of neurobiological teaching is to explore the importont and difficult points in teaching' the present article attempts to design a project pattern in practical course of neurobiology,which is suited to learning mode of medical college students.

To study the expression of hypoxia inducible factor-1alpha (HIF-1alpha) protein in prostate cancer (Pca) and its biological significance, the expression of HIF-1alpha was assayed by means of immunohistochemical technique in 42 prostate cancer, 12 prostatic intraepithelial neoplasm (PIN) and 9 normal prostate tissue (NP) specimens. Western blot was used to examine the expression of HIF-1alpha in prostate cancer cell line (PC-3M) induced by different oxygen tension. HIF-1alpha expression was positive in 33 Pca and 9 PIN specimens, and the positive rate of HIF-1alpha was higher in distant metastasis patients than in patients without metastasis of prostate cancer (P<0.05), while there was no expression of HIF-1alpha in NP. The level of HIF-1alpha in PC-3M significantly increased with the decrease of oxygen tension (P<0.01). Overexpression of HIF-1alpha is the preliminary event of the formation of Pca, which may induce carcinoma into malignant phenotype. Thus it may serve as an early diagnosis marker and the novel target for Pca treatment.
Adenocarcinoma ; metabolism ; Biomarkers, Tumor ; biosynthesis ; Cell Line, Tumor ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit ; biosynthesis ; genetics ; Male ; Prostatic Neoplasms ; metabolism