Resveratrol ameliorates irinotecan chemoresistance of colorectal cancer cells by down-regulating EGFR/AKT/mTOR signaling pathway / 中国药理学通报

Aim To explore the possibility of resveratrol ( RES) combined with irinotecan ( IRI) in the treatment of colorectal cancer ( CRC ) and the underlying molecular mechanism of RES ameliorating IRI chemoresistance of CRC cells. Methods CRC cells used in this study were HT-29 and RKO cells. The effects of RES, IRI and their combination on the proliferation of CRC cells were analyzed by MTT assay and colony formation assay. The effects of RES,IRI and their combination on the migration of CRC cells were assessed by Wound-healing assay. On this basis,the role of RES in regulating IRI chemoresistance of CRC cells and the underlying molecular mechanisms were further explored. Results The proliferation and migration ability of CRC cells in the RES and IRI combined treatment group were significantly lower than those in the IRI treated group, which showed that RES could enhance the inhibiting effect of IRI on the proliferation and migration of CRC cells, indicating that RES was able to a-meliorate the chemoresistance of CRC cells to IRI. And remarkably lower marker proteins expression levels of EGFR/AKT/mTOR signaling pathway in the RES and IRI combined treatment group was observed. Moreover, both EGFR activator (NSC 228155) and AKT activator (SC79) could reverse the ameliorating effect of RES on IRI chemoresistance of CRC cells, whereas AKT inhibitor (MK2206 ) could partially reverse the effect of NSC 228155. Conclusions RES can inhibit the proliferation and migration of CRC cells by down-regulating EGFR/AKT/mTOR signaling pathway, so as to ameliorate the chemoresistance of CRC cells to IRI, suggesting that RES combined with IRI can be a promising novel treatment for CRC.

Vomiting, weakness and glyceroluria after eating dessert / 中华实用儿科临床杂志

During 2 years,a 6-year-old girl was hospitalized for 2 times with recurrent onset of episodes of vomiting,weakness and fever after eating dessert at the Department of Neurology & Endocrine Pediatrics,the Affiliated Hospital of Qingdao University.The arterial blood gas analysis revealed severe hypoglycemia,lacticacidemia and metabolic acidosis,the urine ketone body was positive.After intravenous infusion of glucose,bicarbonate and antibiotics,there was a dramatic clinical improvement in a short time.Physical examination showed tachypnea and mild hepatomegaly,and she had normal physical and mental development.The laboratory findings revealed transient hyperuricacidemia.Urine organic acids analysis repeatedly showed an elevation of lactic acid,ketone and glycerol.Glyceroluria was a very distinctive trait.The literatures in PubMed was searched with glyceroluria as keyword.Three related diseases were identified:FBPase deficiency,glycerol kinase (GK) deficiency and complex GK deficiency.Further reading of related literatures to understand the characteristics of diseases and laboratory tests,the clinical diagnosis of GK deficiency and complex GK deficiency was excluded.The mutation analysis of FBPase gene (FBP1) was performed by Sanger sequencing and a novel compound heterozygous mutations of c.355G ＞A and c.960delG was discovered.Full analysis of disease-related traits and targeted gene testing is one of the effective methods for accurate diagnosis and treatment of inherited metabolic disorders.

Progress of fructose-1, 6-bisphosphatase deficiency / 国际儿科学杂志

Fructose-1,6-bisphosphatase(FBPase) deficiency is a rare inherited metabolic disease,which is an autosomal recessive metabolic disorder.Affected patients usually present with metabolic crisis including severe hypoglycemia and metabolic acidosis.Each attack occurred with a similar sequence.The triggering factors are removed and then clinical status is improved dramatically.As patients are usually symptomless in the plateau stage,it is often misdiagnosed.Metabolite assay in blood and urine is very useful for the diagnosis of FBPase deficiency.FBPase is a key enzyme in gluconeogenesis.Deficiency of FBPase impairs the formation of glucose from all precursors.FBP1 gene mutation contributes to the disease.More than 30 mutation types have been reported.There is no specific treatment.Early diagnosis and appropriate life-style can prevent repetitive metabolic derangements,improving life quality of these children and ensuring successful pregnancy.

TNF-α induces epithelial-mesenchymal transition through NF-κB in hepatocellular carcinoma / 第二军医大学学报

Objective To investigate the role of tumor necrosis factor-α (TNF-α) in epithelial-mesenchymal transition (EMT) of hepatocellular carcinoma (HCC) cells and the related mechanism. Methods HCC cell lines Hep3B and SMMC-7721 were treated with TNF-α for 24 h; then the cell morphological changes were observed by microscope and the expressions of the epithelial markers (E- cadherin and β-catenin), mesenchymal markers (Vimentin and N-cadherin), and EMT associated transcriptional factor Twist were examined by RT-PCR and Western blotting analysis. The invasion and metastasis ability was evaluated by Transwell and wound healing assay. Luciferase reporter assay and immunofluorescence were used to determine NF-κB transcriptional activity; Western blotting analysis was used to examine the expression levels of IκBα and p-IκBα protien. Cells was also incubated with TNF-α and NF-κB inhibitor (BAY11-7082) together, and then the phenotypeof EMT was detected by microscope, RT-PCR and Western blotting analysis. Results Hep3B and SMMC-7721 cells had EMT phenotype after treated with TNF-α. Wound healing assay showed that the wound healing rate of cells exposed to TNF-α was significantly increased compared with the non-treated group (P<0. 05), and Transwell assay showed that more cells penetrating the membrane after treatment with TNF-α (P < 0. 05). TNF-α effectively promoted IκBα phosphorylation and the subsequent NF-κB nuclear translocation We also found that TNF-α-mediated EMT could be converted by NF-κB inhibitor (BAY11-7082) (P<0. 05). Conclusion TNF-α induces EMT of HCC cells through NF-κB-dependent pathways, and subsequently promotes the invasion and metastasis of HCC.

Effect of 2,5-hexanedione on light-molecular-weight neurofilaments (NF-L) degradation of rat nerve tissues / 中华劳动卫生职业病杂志

<p><b>OBJECTIVE</b>To investigate the effect of 2,5-hexanedione (HD) on degradation of low-molecular-weight neurofilaments (NF-L) in nervous tissue of rats, and to explore the molecular mechanism of n-hexane neuropathy.</p><p><b>METHODS</b>Fifty male Wistar rats were randomly divided into one-week poisoning group (n = 10), two-week poisoning group (n = 10), three-week poisoning group (n = 10), four-week poisoning group (n = 10), and control group (n = 10). In the four poisoning groups, a rat model of n-hexane neuropathy was established by intraperitoneal injection of HD (400 mg/kg/d). The change in the sciatic nerve ultrastructure of each rat was observed under an electron microscope. The progression of HD-induced peripheral neuropathy was evaluated using a gait scoring system. The degradation rates of NF-L in the sciatic nerve and spinal cord of each rat were measured by Western Blotting.</p><p><b>RESULTS</b>The rats showed decrease in muscle strength and abnormal gait after two weeks of HD poisoning and mild or moderate paralysis after four weeks of HD poisoning. The sciatic nerve showed degenerative change, according to electron microscope observation. Compared with the control group, the two-week poisoning group, three-week poisoning group, and four-week poisoning group had the NF-L degradation rates decreased by 25.8%, 70.4%, and 69.7%, respectively, in the supernatant fraction of sciatic nerve, and by 14.7%, 64.6%, and 67.3%, respectively, in the sediment fraction of sciatic nerve, all showing a significant difference (P < 0.01). Compared with the control group, the one-week poisoning group had the NF-L degradation rate decreased by 33.87% in the supernatant fraction of spinal cord, the four-week poisoning group had the NF-L degradation rate increased by 16.2% in the supernatant fraction of spinal cord, and the one-week poisoning group and two-week poisoning group had the NF-L degradation rates decreased by 46.3% and 13.0% in the sediment fraction of spinal cord, all showing a significant difference (P < 0.01).</p><p><b>CONCLUSION</b>HD poisoning significantly inhibits NF-L degradation in the sciatic nerve, which may be associated with NF degeneration and accumulation in the axons of patients with n-hexane neuropathy.</p>

Changes in autophagy-related protein levels in nervous tissues of hens with tri-ortho-cresyl phosphate-induced delayed neuropathy / 中华劳动卫生职业病杂志

<p><b>OBJECTIVE</b>To study the changes in the levels of autophagy-related proteins, Atg1, Atg5, and Beclin1, in organophosphate-induced delayed neuropathy (OPIDN) caused by tri-ortho-cresyl phosphate (TOCP), and to investigate the molecular pathogenic mechanism of OPIDN.</p><p><b>METHODS</b>Thirty adult Roman hens were randomly and equally divided into control group and 1, 5, 10, and 21 d intoxication groups. Each hen in the intoxication group was administered TOCP by gavage at a single dose of 750 mg/kg, while each hen in the control group was administered the same volume of corn oil. The hens were killed at the corresponding time points, and their tibial nerves and spinal cords were collected. The levels of Atg1, Atg5, and Beclin1 in the tibial nerves and spinal cords were measured by immunoblotting.</p><p><b>RESULTS</b>Compared with those in the control group, the levels of Atg1 in tibial nerves decreased by 29.8%, 64.4%, 43.5%, and 19.8% at 1, 5, 10, and 21 d, respectively, after intoxication ((P < 0.05); the levels of Atg5 in tibial nerves decreased by 36.8%, 49.6%, 51.2%, and 31.5% at 1, 5, 10, and 21 d, respectively, after intoxication (P < 0.05); the levels of Beclin1 in tibial nerves decreased by 68.5%, 66.3%, and 32.2% at 1, 5, and 10 d, respectively, after intoxication (P < 0.05). Compared with those in the control group, the levels of Atg1 in spinal cords decreased by 23.5%, 48.7%, and 20% at 1, 5, and 10 d, respectively, after intoxication (P < 0.05); the levels of Atg5 in spinal cords decreased by 32.7%, 51.5%, 47.3%, and 39.6% at 1, 5, 10, and 21 d, respectively, after intoxication (P < 0.05); the levels of Beclin1 in spinal cords decreased by 28.9%, 50.2%, 43.2%, and 28.3% at 1, 5, 10, and 21 d, respectively, after intoxication (P < 0.05).</p><p><b>CONCLUSION</b>The intoxication of TOCP is associated with the significant changes in the levels of autophagy-related proteins in the nervous tissues of hens, which might be involved in the pathogenesis of OPIDN.</p>