Exosomes are cell-derived nanovesicles with diameters from 30 to 150 nm, released upon fusion of multivesicular bodies with the cell surface. They can transport nucleic acids, proteins, and lipids for intercellular communication and activate signaling pathways in target cells. In cancers, exosomes may participate in growth and metastasis of tumors by regulating the immune response, blocking the epithelial-mesenchymal transition, and promoting angiogenesis. They are also involved in the development of resistance to chemotherapeutic drugs. Exosomes in liquid biopsies can be used as non-invasive biomarkers for early detection and diagnosis of cancers. Because of their amphipathic structure, exosomes are natural drug delivery vehicles for cancer therapy.

Glioblastoma multiforme (GBM) in the central nervous system is the most lethal advanced glioma and currently there is no effective treatment for it. Studies of sinomenine, an alkaloid from the Chinese medicinal plant,

Glioblastoma is the most common and aggressive primary tumor in the central nervous system, accounting for 12%-15% of all brain tumors. 3--Acetyl-11-keto--boswellic acid (AKBA), one of the most active ingredients of gum resin from Birdw., was reported to inhibit the growth of glioblastoma cells and subcutaneous glioblastoma. However, whether AKBA has antitumor effects on orthotopic glioblastoma and the underlying mechanisms are still unclear. An orthotopic mouse model was used to evaluate the anti-glioblastoma effects of AKBA. The effects of AKBA on tumor growth were evaluated using MRI. The effects on the alteration of metabolic landscape were detected by MALDI-MSI. The underlying mechanisms of autophagy reducing by AKBA treatment were determined by immunoblotting and immunofluorescence, respectively. Transmission electron microscope was used to check morphology of cells treated by AKBA. Our results showed that AKBA (100 mg/kg) significantly inhibited the growth of orthotopic U87-MG gliomas. Results from MALDI-MSI showed that AKBA improved the metabolic profile of mice with glioblastoma, while immunoblot assays revealed that AKBA suppressed the expression of ATG5, p62, LC3B, p-ERK/ERK, and P53, and increased the ratio of p-mTOR/mTOR. Taken together, these results suggested that the antitumor effects of AKBA were related to the normalization of aberrant metabolism in the glioblastoma and the inhibition of autophagy. AKBA could be a promising chemotherapy drug for glioblastoma.

Mitochondrial diseases are maternally inherited heterogeneous disorders that are primarily caused by mitochondrial DNA (mtDNA) mutations. Depending on the ratio of mutant to wild-type mtDNA, known as heteroplasmy, mitochondrial defects can result in a wide spectrum of clinical manifestations. Mitochondria-targeted endonucleases provide an alternative avenue for treating mitochondrial disorders via targeted destruction of the mutant mtDNA and induction of heteroplasmic shifting. Here, we generated mitochondrial disease patient-specific induced pluripotent stem cells (MiPSCs) that harbored a high proportion of m.3243A>G mtDNA mutations and caused mitochondrial encephalomyopathy and stroke-like episodes (MELAS). We engineered mitochondrial-targeted transcription activator-like effector nucleases (mitoTALENs) and successfully eliminated the m.3243A>G mutation in MiPSCs. Off-target mutagenesis was not detected in the targeted MiPSC clones. Utilizing a dual fluorescence iPSC reporter cell line expressing a 3243G mutant mtDNA sequence in the nuclear genome, mitoTALENs displayed a significantly limited ability to target the nuclear genome compared with nuclear-localized TALENs. Moreover, genetically rescued MiPSCs displayed normal mitochondrial respiration and energy production. Moreover, neuronal progenitor cells differentiated from the rescued MiPSCs also demonstrated normal metabolic profiles. Furthermore, we successfully achieved reduction in the human m.3243A>G mtDNA mutation in porcine oocytes via injection of mitoTALEN mRNA. Our study shows the great potential for using mitoTALENs for specific targeting of mutant mtDNA both in iPSCs and mammalian oocytes, which not only provides a new avenue for studying mitochondrial biology and disease but also suggests a potential therapeutic approach for the treatment of mitochondrial disease, as well as the prevention of germline transmission of mutant mtDNA.
Animals ; DNA, Mitochondrial ; genetics ; Humans ; Induced Pluripotent Stem Cells ; cytology ; metabolism ; MELAS Syndrome ; genetics ; Male ; Mice ; Microsatellite Repeats ; genetics ; Mitochondria ; genetics ; metabolism ; Mutation ; genetics

Gangliosides are a class of important glycosphingolipids containing sialic acid that are widely distributed on the outer surface of cells and are abundantly distributed in brain tissue. Disialoganglioside with three glycosyl groups (GD3) and disialoganglioside with two glycosyl groups (GD2) are markedly increased in pathological conditions such as cancers and neurodegenerative diseases. GD3 and GD2 were found to play important roles in cancers by mediating cell proliferation, migration, invasion, adhesion, angiogenesis and in preventing immunosuppression of tumors. GD3 synthase (GD3S) is the regulatory enzyme of GD3 and GD2 synthesis, and is important in tumorigenesis and the development of cancers. The study of GD3S as a drug target may be of great significance for the discovery of new drugs for cancer treatment. This review will describe the gangliosides and their roles in physiological and pathological conditions; the roles of GD3 and GD2 in cancers; the expression, functions and mechanisms of GD3S, and its potential as a drug target in cancers.

With the sequence of the vasoactive intestinal peptiepeptide (VIP) from humans and according to the condon bias of Pichia pastoris, we designed PCR primers of VIP and obtained the sequence of VIP by SOE-PCR. Then VIP gene was cloned into Pichia pastoris secretory expression vector and the cell secretary system GS115-pPICZαA-vip was constructed. The recombinant strain was induced by methanol for 96 hours, and we collected the supernatant and identified the VIP by mass spectrometry. The molecular weight of VIP was consistent with theoretical molecular weight. The final result showed that the target peptide VIP was successfully expressed. The experimental investigations of agarose gel diffusion revealed that the recombinant expression modified VIP had relatively strong antibacterial activity to E. coli ATCC25922 and S. aureus ATCC25923. The minimal inhibitory concentration (MIC) of VIP to E. coli ATCC25922 and S. aureus ATCC25923 was 8 mmol/L and 16 mmol/L. Further cytotoxicity and hemolytic experiments indicated that recombinant VIP was non-toxic to normal cells NCM460 and IPEC-J2, had little hemolysis activity to SD rat erythrocytes. Meanwhile, by transmission electron microscopy, we found that VIP mainly inhibited bacteria by disrupting the cell membrane. These experiments established a useful system for further studies, application and mass production of antimicrobial peptide VIP.

Objective To compare the safety and efficacy of insulin degludec (IDeg) with those of insulin glargine (IGlar) in insulin-naive subjects with type 2 diabetes (T2DM).Methods This was a 26-week,randomized,open-label,parallel-group,treat-to-target trial in 560 Chinese subjects with T2DM (men/women:274/263,mean age 56 years,mean diabetes duration 7 years) inadequately controlled on oral antidiabetic drugs (OADs).Subjects were randomized 2:1 to once-daily IDeg (373 subjects) or IGlar(187 subjects),both in combination with metformin.The primary endpoint was changes from baseline in glycosylated hemoglobin(HbA1c) after 26 weeks.Results Mean HbA1c decreased from 8.2％ in both groups to 6.9％ in IDeg and 7.0％ in IGlar,respectively.Estimated treatment difference (ETD) of IDegIGlar in change from baseline was-0.10％ points (95％ CI-0.25-0.05).The proportion of subjects achieving HbA1c ＜ 7.0％ was 56.3％ and 49.7％ with IDeg and IGlar,respectively [estimated odds ratio of IDeg/IGlar:1.26 (95 ％ CI 0.88-1.82)].Numerically lower rateof overall confirmed hypoglycaemia and statistically significantly lower nocturnal confirmed hypoglycemia were associated with IDeg compared with IGlar,respectively [estimated rateratio of IDeg/IGlar 0.69 (95％ CI 0.46-1.03),and 0.43 (95％ CI 0.19-0.97)].No differences in other safety parameters were found between the two groups.Conclusions IDeg was non-inferior to IGlar in terms of glycaemic control,and was associated with a statistically significantly lower rate of nocturnal confirmed hypoglycaemia.IDeg is considered to be suitable for initiating insulin therapy in Chinese T2DM patients on OADs requiring intensified treatment.Clinical trail registration Clinicaltrials.gov,NCT01849289.

Objective To observe the effect and safety of the human glucagon-like peptide-1 analogue,liraglutide,versus insulin glargine in patients with type 2 diabetes mellitus inadequately controlled with metformin alone.Method Ninty patients with type 2 diabetes mellitus(aged 18-79 years,HbA1C 7.5％-10.0％,body mass index＜40 kg/m2) who had inadequate glycaemic control on metformin were allocated for the research with an open,randomized,parallel controlled clinical research method.The patients kept the original dose of metformin unchanged and were randomly assigned to the liraglutide group or the insulin glargine group according to a proportion of 1 ∶ 1.Liraglutide group started with a dose of 0.6 mg subcutaneous injection qd,changed to 1.2 mg subcutaneous injection qd after one week and kept unchanged until the end of the research.Insulin glargine group started with a dose of 0.1-0.2 U/kg according to the fingertips peripheral blood glucose level before breakfast on the continuous 3 d before every follow-up.At the baseline,after 4 weeks,12 weeks,20 weeks,and 26 weeks of treatment,HbA1C,blood glucose,lipids weight,blood pressure were arranged to measured.86 patients finally completed the study.Results Mean HbA1C and the success rate of HbA1C ＜7％ were similar between liraglutide group and insulin glargine group [(7.06 ± 0.87) ％ vs (7.25 ± 1.20) ％,47.73 ％ vs 45.23 ％,P＞0.05],while the percentage of subjects reaching the composite endpoint of HbA1C＜7％ with no hypoglycemia and no weight gain was significantly higher in liraglutide group than insulin group(P＜0.05) ; Fasting plasma glucose decreased more markedly in insulin glargine group,2 h postprandial plasma glucose was decreased more markedly in liraglutide group(P＜0.05 or P＜0.01).Liraglutide significantly reduced mean body weight by (3.21 ± 1.18) kg,waist circumference by (3.82 ± 1.21) cm,and body mass index by (1.95 ± 0.61) kg/m2 (P＜0.01 or P＜0.05),while in the insulin glargine group there sere rise of respective figure of(2.86 ± 0.43) kg,(1.52 ± 0.56) cm,and (0.61 ± 0.25) kg/m2 (P＜0.05),systolic blood pressure and serum triglyceride declined.There was no serious adverse affect in both groups,the incidence of mild hypoglycemia was significantly less in liraglutide group and has a statistically significant difference (4.55％ vs 21.43％,P＜0.05).Conclusions Liraglutide showed a good effect on reducing weight,systolic blood pressure,blood lipid and in addition to blood glucose control which is comparable to insulin glargine.What is more,liraglutide had good safety and tolerability,which can be regarded as a good choice for patients with type 2 diabetes mellitus inadequately controlled with metformin alone.

Objective To evaluate the effects and safety of tarcrolimus on children difficult nephritic syndrome.Methods Databases including the Cochrane Library,Pubmed,Medline,OVID,CNKI,Wan Fang Data and VIP were searched to collect the controlled trials on tacrolimus capsule published from Jan 2003 to Jun 2013.The quality of the included randomized controlled trials was assessed by Jadad,and the complete remission,the fail,the relapsing rate of 12 month and side effects after treatment were extracted,meta-analysis was performed using RevMan 5.0 software.Results Among 179 articles,6 articles were included,4 of them were English and the other 2 were Chinese.The results of meta-analysis based on stratified therapeutic strategies showed that:(1) comparing with cyclophosphamide,tacrolimus could decrease the fail and relapsing rate of 12 month,but could not increase the complete remission (P ＞ 0.05).(2) Comparing with cyclosporine A,tacrolimus had no difference in complete remission and the relapsing rate of 12 month (P ＞ 0.05),but could decrease the fail.(3) Tacrolimus could increase the complete remission and decrease fail,but had no difference in relapsing rate (P ＞ 0.05).(4) There was no significant difference in relapsing rate between tacrolimus and rituximab(P ＞ 0.05).(5) Tacrolimus had less side effects than cyclophosphamide.Conclusion Tacrolimus have advantages to cyclophosphamide,cyclosporine A and prednisolone,but not to rituximab,and have less side effects than cyclophosphamide.

Objective To assess the efficacy of combined vitamin D with calcium and vitamin D or cal-cium alone in rickets of vitamin D deficiency by meta-analysis method. Methods Searches were made in Cochrance Library , Pubmed, Web of science, Scirus, CNKI, Chinese Biological Medical Literature Database, (CBM),Wangfang from the establishment of the data base till March 2013. All randomized controlled trials about combined with vitamin D and calcium in rickets of vitamin D deficiency were eligible. Serum 25-( OH) ritamin D,phosphate ,ALP,calcium,PTH,phosphate,albumin ,radiographic score were chosen as evaluation in-dex to evaluate the weighted mean diffreence ( WMD) and 95% confidence interval ( CI) for continuous data. RevMan 5. 0. 2 software was used to make meta-analysis. Results 437 literatures were reviewed. Three eligible trials were used for meta-analysis. Meta-analysis showed that:(1)the increase of Serum 25-(OH)vitamin D:Combined therapy group and vitamin D group (MD= -7. 88,95%CI:-12. 24~ -3. 52);Combined therapy group and calcium group (MD= -18. 32,95%CI:-22. 61~ -14. 04). (2)the increase of serum phosphate:Combined therapy group and vitamin D group ( MD= -0. 64 ( 95%CI:-0. 86 ~ -0. 42 );Combined therapy group and calcium group MD= -0. 16 ( 95%CI:-0. 84 ~0. 51 ) . ( 3 ) the decrease of Serum ALP:Combined therapy group and vitamin D group (MD= 109. 99,95%CI:20. 40 ~199. 58);Combined therapy group and calcium group (MD=59. 89,95%CI:10. 09~109. 59 ). (4)the increase of serum calcium :Combined therapy group and vitamin D group (MD= -0. 71,95%CI:-0. 91,-0. 52);the decrease of Radiographic score:Com-bined therapy group and vitamin D group( MD=0. 68,95%CI:0. 42~ 0. 95). Except that the increase of serum phosphate between combined therapy group and calcium group had no significant difference,the rest had signifi-cant difference. Conclusion The long term efficacy in combined therapy group is much effective than vitamin D group or calcium group.