Stapled peptides with significantly enhanced pharmacological profiles have emerged as promising therapeutic molecules due to their remarkable resistance to proteolysis and performance to penetrate cells. The all-hydrocarbon peptide stapling technique has already widely adopted with great success, yielding numerous potent peptide-based molecules. Based on our prior efforts, we conceived and prepared a double-stapled peptide in this study, termed FRNC-1, which effectively attenuated the bone resorption capacity of mature osteoclasts in vitro through specific inhibition of phosphorylated GSK-3β. The double-stapled peptide FRNC-1 displayed notably improved helical contents and resistance to proteolysis than its linear form. Additionally, FRNC-1 effectively prevented osteoclast activation and improved bone density for ovariectomized (OVX) mice after intravenous injection and importantly, after oral (intragastric) administration. The double-stapled peptide FRNC-1 is the first orally effective peptide that has been validated to date as a therapeutic candidate for postmenopausal osteoporosis (PMOP).

Autophagy is a cellular process in which proteins and organelles are engulfed in autophagosomal vesicles and transported to the lysosome/vacuole for degradation. Protein-protein interactions (PPIs) play a crucial role at many stages of autophagy, which present formidable but attainable targets for autophagy regulation. Moreover, selective regulation of PPIs tends to have a lower risk in causing undesired off-target effects in the context of a complicated biological network. Thus, small-molecule regulators, including peptides and peptidomimetics, targeting the critical PPIs involved in autophagy provide a new opportunity for innovative drug discovery. This article provides general background knowledge of the critical PPIs involved in autophagy and reviews a range of successful attempts on discovering regulators targeting those PPIs. Successful strategies and existing limitations in this field are also discussed.

Peptide inhibition of the interactions of the tumor suppressor protein P53 with its negative regulators MDM2 and MDMX activates P53

OBJECTIVE: To explore the genetic basis of cerebral palsy (CP). METHODS: A pair of twins with cerebral palsy and different phenotypes were subjected to whole genome sequencing, and other 8 children with CP were subjected to whole exome sequencing. Genetic variations were screened by a self-designed filtration process in order to explore the CP-related biological pathways and genes. RESULTS: Three biological pathways related to CP were identified, which included axon guiding, transmission across chemical synapses and protein-protein interactions at synapses, and 25 susceptibility genes for CP were identified. CONCLUSION The molecular mechanism of CP has been explored, which may provide clues for development of new treatment for CP.
Cerebral Palsy ; genetics ; Child ; Genetic Testing ; Humans ; Phenotype ; Whole Exome Sequencing ; Whole Genome Sequencing

Objective To investigate the expression pattern of skeletal muscle specific miR-206,myogenesis related myoD which change with time in dcnervated muscle atrophy rats.Methods From June,2015 to January,2016,40 SPF sprague-dawley rats were equally classified into 5 groups randomly according to standard settled before,5 groups were separately defined as denervated 0d group,denervated 1d group,denervated 7d group,denervated 14d group,and denervated 28d group.Each group contained 8 rats.The rats atrophy models were established by cutting sciatic never on left side.According to the different denervated time,the gastrocnemii on both sides were obtained under anesthesia,respectively.The wet weight ratio of two compared gastrocnemii were measured,and the gastrocnemii transection was observed by HE stain,measured the expression of myoD protein by western blot,obtained the expression of miR-206,myoD mRNA by qPCR.Results According to our study on rats denervated atrophy models,the wet ratio of compared gastrocnemius would decrease rapidly,by HE stain,decease of cross sectional area in muscle fiber was observed as well as degeneration.Collagen fibers hyperplasia appeared and increased with time change.Wet ratio and transaction aera ratio of group Od,1d,7d,14d,28d were 0.99±0.04,0.92±0.07,0.68±0.11,0.39±0.06,0.27±0.07 and 0.99±0.02,0.96±0.04,0.51±0.09,0.34±0.08,0.23±０.03 respectively,difference between experimental groups and control group were statistically significant (P＜ 0.05),the differences between each experimental groups were also statistically significant (P＜ 0.05).After qPCR test of miR-206,myoD mRNA expression,it was found that their expression patterns were similar,miR-206,myoD mRNA increased at first and would reach the expression peak at the 7 th day,after that their contents decreased but still higher at the 14th day when compared with that at the 1 st day.Their expression of group 0d,1 d,7d,14d,28d were 0.24±0.06,0.34±0.04,0.68±0.04,0.49± 0.07,0.25±0.03 and 0.41 ±0.06,0.49±0.09,0.93±0.06,0.66±0.03,0.39±0.04,respectively.All experimental groups were statistically significant different when compared with 0d group except 1d group (P＜ 0.05),the differences between each experimental groups were also statistically significant(P＜ 0.05).The protein expression of myoD was also measured by western blot test,which showed nearly the same expression pattern as the mRNA expression pattern.After injury,the protein expression increased and reached the expression peak at the 7th day.The relative expression of myoD of group 0d,1d,7d,14d,28d measured by grey ratio were 1.03±0.05,1.06±0.06,1.42±0.10,0.66±0.13,0.24±0.07,respectively.The difference between experimental groups and control group were statistically significant (P ＜ 0.05),the differences between each experimental groups were statistically significant (P ＜ 0.05) as well.Conclusion The degree of muscle denervation atrophy was related to the denervated duration in rats.The expression regulation of miR-206 and myoD in gastrocnemius was similar during the muscle denervation atrophy,which suggesting having internal relationship between miR-206 and myoD.

Tumor diseases have attracted great attention of the society because of the increasing morbidity in recent years .To inhibit the P53-MDM2 interaction has become an important target for design of cancer drug ,and a lot of peptide and small molecule inhibitors have been found with various kinds of drug screening and research tools .This paper summarized the recent progress of the peptide and peptidomimetic inhibitors of P53-MDM2 at home and abroad lately .

Severe fever with thrombocytopenia syndrome virus (SFTSV), a member of the Phlebovirus genus from the Bunyaviridae family endemic to China, is the causative agent of life-threatening severe fever with thrombocytopenia syndrome (SFTS), which features high fever and hemorrhage. Similar to other negative-sense RNA viruses, SFTSV encodes a nucleocapsid protein (NP) that is essential for viral replication. NP facilitates viral RNA encapsidation and is responsible for the formation of ribonucleoprotein complex. However, recent studies have indicated that NP from Phlebovirus members behaves in inhomogeneous oligomerization states. In the present study, we report the crystal structure of SFTSV NP at 2.8 Å resolution and demonstrate the mechanism by which it processes a ringshaped hexameric form to accomplish RNA encapsidation. Key residues essential for oligomerization are identified through mutational analysis and identified to have a significant impact on RNA binding, which suggests that correct formation of highly ordered oligomers is a critical step in RNA encapsidation. The findings of this work provide new insights into the discovery of new antiviral reagents for Phlebovirus infection.
Binding Sites ; Crystallography, X-Ray ; Mutation ; Nucleocapsid Proteins ; chemistry ; genetics ; metabolism ; Phlebovirus ; metabolism ; Protein Binding ; Protein Multimerization ; Protein Structure, Quaternary ; RNA, Viral ; metabolism ; Recombinant Proteins ; biosynthesis ; chemistry ; genetics

Objective To explore clinical value of intraoperative extra strong electrical stimulation in the treatment of birth brachial plexus palsy. MethodsFrom July 2008 to September 2011,intraoperative extra strong electrical stimulation was applied in 9 cases of incomplete birth brachial plexus palsy after neurolysis.The latency and amplitude of compound muscle action potentials before and after electrical stimulation were recorded and the extent of improvement was compare.ResultsThe latency was improved in 7 cases with 8.02％ in average,amplitude in 8 cases with 185.97％ in average.The related nerve recover partial motor function in 8 cases in 2 weeks after operation.ConclusionIntraoperative extra strong electrical stimulation is a effective assistant technique to promote motor functional recovery of birth brachial plexus palsy.

ObjectiveTo evaluate the value of MR imaging(MRI)in diagosing of obstetrical brachial plexus.MethodsBetween September 2006 to September 2011,eighteen cases (12 males and 6 females)of obstetrical brachial plexus injury had being used for investigation,aging from 2 month to 3 years, average of 10.6 month. Eight left side and 10 right side. Tassin Ⅰ was 4 cases,Tassin Ⅱ was 6 eases, Tassin Ⅲwas 5 eases, Tassin Ⅳ was 4 cases. All cases were performed to MRI test before operating and the result compare with finding during operating. ResultsFindings of MRI:pseudomeningocele was in 13 of the 18cases while 10 of the 15 patients had multiple pseudomeningoceles. Displacement of spinal cord was in 6 cases; Normal was 2 cases; thickening of nerve root was in 2 cases.ConclusionMR imaging is an effective tool for demonstrating lesions of the brachial plexus worthy of surgical exploration.

Objective To observe the clinical therapial value of functional reconstruction with Botulinum Toxin A (BTA) on spasitic cerebral palsy. Methods Thirty-two patients were treated by Achilles tendon lengthening and anterior transfer of posterior tibial tendon.According to the spasticity of triceps surae muscle,all cases were arranged by BTA injection 2 months later after operation.Results From Jan.2000 to Jan.2009,thirty-two cases with equinovarus foot of spasticitical cerebral palsy were collected,the muscle strength of ankle dorsal extensor increased from 0-2 grades to 4-5 grades,there was significant difference between preoperational muscle strength and postoperational one.There was also significant improvement to adjust yarus degrees of ankle joint.the musclar tension of triceps muscle of calf decreased from Ⅱ-Ⅳ grades to Ⅰ-Ⅱ grades. Conclusion Anterior transfer of posterior tibial tendon corresponding with Botulinum Toxin A injection not only release muscle spasticity but also improve dorsal extending strength of ankle joint.The clinical effect of these methods was reliable on cerebral palsy.