Autophagy is an important homeostatic cellular recycling mechanism responsible for degrading injured or dysfunctional cellular organelles and proteins in all living cells. Aging is a universal phenomenon characterized by progressive deterioration of cells and organs due to accumulation of macromolecular and organelle damage. Growing evidences indicate that the rate of autophagosome formation and maturation and the efficiency of autophagosome/lysosome fusion decline with age. Dysfunctional autophagy has also been observed in age-related diseases. Autophagy disruption resulted accumulation of mutated or misfolded proteins is the essential feature of neurodegenerative disorders. However, in cancers, fibroproliferative diseases or cardiovascular diseases, autophagy can play either a protective or destructive role in different types of disease, and even in different stages of the same disease. The review will discuss the cellular and molecular mechanisms of autophagy and its important role in the pathogenesis of aging and age-related diseases, and the ongoing drug discovery strategies for therapeutic intervention.
Aging ; Autophagy ; Drug Discovery ; Humans ; Lysosomes ; metabolism ; Neurodegenerative Diseases ; Phagosomes ; metabolism ; Protein Folding

The nuclear transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) plays a crucial role in maintaining cellular redox homeostasis. The aberrant NRF2 signaling confers enhanced antioxidant capacity, which is linked to tumor progression and therapeutic resistance. The current study investigates the biological effects and molecular mechanism of tribbles homolog 3 (TRIB3), a stress-induced protein, in regulating cell survival and apoptosis in lung cancer. This study first performed the RNA sequencing data analysis with 576 lung adenocarcinoma patients from the cancer genome atlas (TCGA) database. The NRF2- antioxidant response element (ARE) signature was enriched in patients with high TRIB3 expression. Dual-luciferase reporter assay and real-time quantitative polymerase chain reaction (PCR) were used to confirm the effect of TRIB3 on the kelch-like ECH-associated protein-1 (KEAP1)-NRF2 pathway. Abrogation of TRIB3 impaired NRF2 transcriptional activity and reduced the expression of its target genes. Moreover, TRIB3 enhanced NRF2 stability via blocking KEAP1-NRF2 interaction. TRIB3-depletion promoted reactive oxygen species (ROS) production, restrained cell proliferation, and enhanced carboplatin-induced apoptosis. In addition, NRF2 overexpression recovered the tumor inhibition effect of TRIB3-depletion. Consistently, TRIB3 failed to modulate apoptosis in NRF2 depletion cells. In summary, this study shows that TRIB3 inhibits the KEAP1-NRF2 interaction and upregulates the transcriptional activity of NRF2, thereby promoting lung cancer cell proliferation and reducing the sensitivity to chemotherapy. Targeting the TRIB3-NRF2 signal axis may become a new strategy for ROS homeostasis and lung cancer treatment.

OBJECTIVETo investigate the effect of ADMA on macrophage migration inhibitory factor (MIF) expression and tumor necrosis factor-α (TNF-α) and IL-8 secretion in THP-1 monocyte-derived macrophages. METHIDS: THP-1 monocytes were induced to differentiate into macrophages by a 24-h incubation with 160 nmol/L PMA. The THP-1 monocyte-derived macrophages were exposed to different concentrations of ADMA for 24 h, and the changes in MIF mRNA and protein expressions were analyzed with RT-PCR and Western blotting, respectively. Enzyme-linked immunosorbent assay was used to detect the levels of TNF-α and IL-8 in the supernatant of THP-1-derived macrophages following ADMA treatments.

RESULTSADMA obviously up-regulated MIF mRNA and protein expressions in THP-1-derived macrophages in a concentration- dependent manner. Exposure of the cells to 15 µmol/L ADMA for 24 h showed the most potent effect in up-regulating MIF mRNA and protein expressions. ADMA treatment also resulted in a dose-dependent increase of the levels of TNF-α and IL-8 in the culture supernatant of the macrophages, and the peak levels occurred following the treatment with 15 µmol/L ADMA.

CONCLUSIONADMA can up-regulate MIF expression and induce TNF-α and IL-8 secretion in THP-1 monocyte-derived macrophages.

Arginine ; analogs & derivatives ; pharmacology ; Cell Differentiation ; Cell Line ; Humans ; Interleukin-8 ; secretion ; Intramolecular Oxidoreductases ; genetics ; metabolism ; Macrophage Migration-Inhibitory Factors ; genetics ; metabolism ; Macrophages ; cytology ; metabolism ; Monocytes ; cytology ; Phenanthrenes ; pharmacology ; RNA, Messenger ; genetics ; metabolism ; Tumor Necrosis Factor-alpha ; secretion

OBJECTIVEIdiopathic nephrotic syndrome (INS) is a common glomerular disease. The pathogenesis of the disease remains unclear. Recent studies indicate that transforming growth factor beta (TGF beta) is the main cytokine involved in glomerular disease. It plays an important role in the development of INS and in occurrence of glomerulosclerosis. The present study aimed to study changes and significance of TGF beta in children with idiopathic nephrotic syndrome (INS).

METHODSTotally 35 cases with INS (13 males, 22 females) were studied. The age of onset was between 2 years and 1 months and 14 years with an average of 8 years and 3 months. The active stage group had 35 cases and the remission stage groups had 25 cases. The cases in active stage group had first onset of the disease with obvious clinical symptoms and abnormal laboratory findings without use of corticosteroids. The cases in remission stage group were asymptomatic without abnormal laboratory findings. Protein in urine was negative over 4 weeks after oral administration of prednisone for 8 weeks. Twenty five cases were steroid responsive and 10 cases were steroid non-responsive among the 35 cases. Thirty healthy young children were enrolled as control. TGF beta was detected by ELISA in peripheral blood mononuclear cell (PBMC) culture medium. The TGF beta mRNA gene expression was measured by in situ PCR in PBMC.

RESULTS(1) Concentration of TGF beta(247 +/- 26) ng/L and TGF beta mRNA expression (0.57 +/- 0.18) in active stage of simple type or nephritis type INS were higher than those of remission stage and control (P < 0.01). Concentration of TGF beta[(125 +/- 16) ng/L] and TGF beta mRNA expression (0.30 +/- 0.12) in remission stage were higher than that of control (P < 0.05). (2) The level of TGF beta protein in nephritis type [(275 +/- 26) ng/L] was significantly higher than that in simple type [(220 +/- 18) ng/L] in active stage INS (t = 6.45, P < 0.01). No significant difference in TGF beta mRNA expression was found between the nephritis type (0.58 +/- 0.15) and simple type (0.55 +/- 0.16) in active stage INS, either (P > 0.05). But these two types were different from the control (P < 0.01). (3) Concentration of TGF beta and TGF beta mRNA expression after therapy was clearly lower than that before therapy in steroid responsive group (P < 0.01). Whereas no significant change was seen in steroid non-responsive group. Both indicators were higher in steroid non-responsive group than in steroid responsive group whether before or after therapy.

CONCLUSIONTGF beta may play an important role in the mechanism of INS and its level in PBMC can be used as an immunological indicator for the illness state, therefore, determination of TGF beta level and mRNA may be of some clinical significance.

Adolescent ; Child ; Child, Preschool ; Enzyme-Linked Immunosorbent Assay ; Female ; Humans ; Leukocytes, Mononuclear ; drug effects ; metabolism ; Male ; Nephrotic Syndrome ; blood ; drug therapy ; RNA, Messenger ; genetics ; metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Transforming Growth Factor beta ; genetics ; metabolism

OBJECTIVETo study the clinical results of surgery for rotationally and vertically unstable pelvis fracture.

METHODSThirty-four patients with rotationally and vertically unstable pelvis fractures were treated. There were 23 male and 11 female,with the average age of 36 years ranging from 13 to 56 years. There were 9 cases of type APC III, 14 cases of type LC III, and 11 cases of type VS according to Young-Burgess Classifiction. All patients' pelvis were treated with temporary external fixation after hospitalization, and were treated with open reduction and internal fixation through anterior approach after stabilization of body condition.

RESULTSAll patients were followed up for 12 to 48 months (average 21 months). All the incisions healed well, and the fractures got union for 3 to 6 months. According to the Majeed evaluation, the results were excellent in 21 cases, good in 10, fair in 3. All patients were not remained deformity of rotation and dislocation. But 3 patients remained lameness, 4 remained low back pain, 3 remained both leg and feet numbness.

CONCLUSIONIn the management of the rotationally and vertically unstable pelvis fractures, a stable pelvis can be reconstructed by effective open reduction and internal fixation through the anterior approaches, so that further sequelae can be reduced.

Adolescent ; Adult ; Female ; Fracture Fixation, Internal ; methods ; Fractures, Bone ; classification ; diagnostic imaging ; surgery ; Humans ; Male ; Middle Aged ; Pelvic Bones ; diagnostic imaging ; injuries ; surgery ; Radiography ; Treatment Outcome

OBJECTIVETo study magnetic resonance enhancement features of inflammatory lymph nodes using different doses of ultrasmall superparamagnetic iron oxide (USPIO) particles in order to establish a standardized protocol for USPIO enhanced magnetic resonance imaging of lymph nodes.

METHODSA total of 12 healthy New Zealand rabbits were injected complete Freund's adjuvant in foot pad to establish popliteal inflammatory lymph node model. Different doses (45, 90, 135 micromol Fe/kg) of USPIO were injected intravenously. Magnetic resonance scans were performed before and after USPIO injection to observe the enhancement features of different groups. T2 signal intensity, T1 signal intensity, T2 x value, and T2 value were measured and T2 enhancement ratio was calculated at different time points.

RESULTSTwenty-four hours after USPIO injection, there was no statistical difference in T2 signal intensity and T2 enhancement ratio between 90 and 135 micromol Fe/kg dose groups, but both were superior to 45 micromol Fe/kg group (P < 0.05). There were no statistical differences in T2 signal intensity, T1 signal intensity, T2 value, and T2 enhance ratio among different postcontrast time delays from 6 to 24 hours in 90 micromol Fe/kg group (P > 0.05), and signal reduction of lymph nodes peaked 18 hours after USPIO injection. Better images were acquired with a postcontrast delay of 18-24 hours.

CONCLUSIONSLymph nodes can be enhanced well with a dose of 90 micromol Fe/kg. Postcontrast delay of 18-24 hours is appropriate for acquiring satisfactory enhancement images.

Animals ; Contrast Media ; administration & dosage ; Dextrans ; administration & dosage ; Image Enhancement ; methods ; Lymphadenitis ; diagnosis ; pathology ; Magnetic Resonance Imaging ; methods ; Magnetite Nanoparticles ; administration & dosage ; Male ; Rabbits ; Random Allocation

OBJECTIVETo assess the characteristics of enhanced magnetic resonance image with ultrasmall superparamagnetic iron oxide (USPIO) in the inflammatory and tumor metastatic rabbit model, and explore its relevance with histologic ultrastructural findings.

METHODSTotally 36 New Zealand white rabbits were randomly divided into lymphadenitis group and metastatic group. Complete Freund's adjuvant was injected into the bilateral dorsal footpads of 18 rabbits to set up ipsilateral lymphadenitis model. The other 18 rabbits received a subcutaneous implantation of VX2 tumor cell suspension (1.5 x 10(7) cells/ml) in both thighs to set up metastatic lymph node model. Magnetic resonance scan were performed 24 hours before and after USPIO (90 micromol Fe/kg) injection. T2 values of each lymph node were measured and lymph node T2 enhancement rate was calculated as well. HE staining, Prussian blue staining, and electronic microscopy were performed to observe the pathological microstructure changes and the distribution of the iron particle in lymph node. Relationship between lymph nodes USPIO enhancement and its microstructures were further analyzed. Results Thirty-six lymph nodes in lymphadenitis group showed different degrees of reactive hyperplasia. Twenty-six lymph nodes in metastatic group were invaded by tumor cell. Non-enhanced scan showed mild difference between T2 signal intensity of the two pathological lymph node types. After USPIO enhancement, inflammatory lymph nodes showed distinct T2 signal reduction at the center, and metastatic lymph nodes showed homogenous and faint T2 signal reduction. Enhancement rate of benign and malignant lymph nodes were 57.39% and 29.45% respectively (P < 0.01). HE staining and Prussian blue staining indicated USPIO particles located mainly in the macrophages at inflammatory lymphatic medulla, while paracortical area and cortical area contained relatively much less USPIO particles due to less macrophages distribution. MRI findings were correlated with the pathological results. Electronic microscopy also verified that the majority of USPIO particles were located in the numerous cytophagic bubbles of macrophages. Lymph nodes metastasis including 4 lymph nodes with completed structure destruction due to entire tumor infiltration, 19 lymph nodes with partially lymph node structure destruction but reduced USPIO-contained macrophage numbers or reduced USPIO particles in macrophages, and 3 lymph nodes with only localized foci tumor metastasis at subcapsular area. Conclusions USPIO enhancement pattern of different lymph nodes is closely related to distribution and functional status of the intra-node macrophages. It may affect the accuracy of the lymph node property diagnosis based on USPIO enhanced image.

Animals ; Dextrans ; metabolism ; Female ; Image Enhancement ; methods ; Lymph Nodes ; ultrastructure ; Lymphadenitis ; diagnosis ; pathology ; Lymphatic Metastasis ; diagnosis ; ultrastructure ; Magnetic Resonance Imaging ; methods ; Magnetics ; Magnetite Nanoparticles ; Male ; Nanoparticles ; Rabbits ; Random Allocation

· AIM:To compare the clinical curative effect of triamcinolone acetonide and Ranibizumab on diffuse diabetic macular edema (DME).· METHODS:We collected 84 cases of patients with diffuse DME treated in our hospital from February 2016 to May 2017.According to 1:1 matching method,they were divided into Ⅰ,Ⅱ groups.They were all treated with laser photocoagulation.Preoperative auxiliary application of triamcinolone acetonide was given to Group Ⅰ,while Group Ⅱ received preoperative application of ranibizumab.After treatment,the efficacy of the two groups were analyzed and compared.· RESULTS:The total clinical efficiency of Group Ⅱ at 3mo after treatment was 93％,higher than that of Group Ⅰ (77％;x2 =4.981,P =0.025).Compared with before treatment,BCVA and CMT of the two groups at each time after treatment were significantly improved (P＜ 0.05).BCVA of Group Ⅱ at 1 and 3mo after treatment was better than that of Group Ⅰ (P＜0.05);CMT of Group Ⅱ at 1,3 and 6mo after treatment improved more than that of Group Ⅰ,with significant difference (P ＜ 0.05);occurrence rate of adverse reactions Group Ⅰ and Group Ⅱ were 17％ and 13％ with no significant statistical difference (X2 =0.243,P=0.621).There were no serious adverse reactions such as retinal detachment,endophthalmitis or cataract in the two groups.· CONCLUSION:Compared with triamcinolone acetonide,the effect of ranibizumab on diffuse diabetic macular edema is better,and has high clinical value.

OBJECTIVETo explore the relationship between human cyclin C (CCNC) gene and childhood acute lymphocytic leukemia (ALL).

METHODSThe total RNA isolated from myeloid tissues of normal children and of children with newly diagnosed ALL and from ALL cell line 6T-CEM was reversely transcribed into cDNA. Real-time fluorescence quantitative PCR method was used to detect CCNC gene expression.

RESULTSCCNC was expressed in myeloid tissues of normal children and of children with newly diagnosed ALL as well as 6T-CEM. The relative expression level of CCNC gene in children with newly diagnosed ALL was significantly lower than in normal controls (2.35 +/- 0.83 vs 13.5 +/- 0.30; P <0.05).

CONCLUSIONSCCNC gene shows lower expression in children with newly diagnosed ALL, suggesting that it may be a tumor suppressing gene in childhood ALL.

Child ; Cyclin C ; Cyclins ; genetics ; Female ; Fluorescence ; Humans ; Male ; Polymerase Chain Reaction ; methods ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; metabolism

Betulinic acid is a naturally occurring pentacyclic triterpenoid, which has antiretroviral, antimalarial, and anti-inflammatory properties. The purpose of this study is to investigate the HBV DNA replication inhibition in the mouse model with betulinic acid. Hydrodynamic injection method via the tail vein with the Paywl. 3 plasmid was used to establish the animal mode (n = 15), and the mice were randomly divided into the PBS control group (n = 5), Betulinic acid treatment group (n = 5) and lamivudine control group (n = 5). The day after successful modeling , the mice would have taken Betulinic acid (100 mg x kg(-1)), lamivudine (50 mg x kg(-1)), PBS drugs orally, once daily for 7 days, blood samples were acquired from the orbital venous blood at 3, 5, 7 days after the administering, HBsAg and HBeAg in serum concentration were measured by ELISA and the mice were sacrificed after 7 days, HBV DNA southern detections were used with part of mice livers. The results showed that betulinic acid significantly inhibited the expression of HbsAg in the mice model at the fifth day compared with the control group, and there was no significant differences between the effects of lamivudine and the PBS control group; both the betulinic acid and lamivudine groups had no significant inhibition for the HBeAg expression; the HBV DNA expressions of the liver tissue from the betulinic acid and lamivudine groups were inhibited compared with the control group. Taken together, these results reveal betulinic acid can inhibit the HBsAg expression and replication of the liver HBV DNA in the mouse model.
Acute Disease ; Animals ; Antiviral Agents ; pharmacology ; DNA Replication ; drug effects ; DNA, Viral ; biosynthesis ; Hepatitis B ; blood ; virology ; Hepatitis B Surface Antigens ; blood ; Hepatitis B virus ; drug effects ; genetics ; immunology ; physiology ; Male ; Mice ; Plasmids ; genetics ; Triterpenes ; pharmacology ; Virus Replication ; drug effects