α/Sulfono-γ-AA peptide hybrids agonist of GLP-1R with prolonged action both in vitro and in vivo

Peptides are increasingly important resources for biological and therapeutic development, however, their intrinsic susceptibility to proteolytic degradation represents a big hurdle. As a natural agonist for GLP-1R, glucagon-like peptide 1 (GLP-1) is of significant clinical interest for the treatment of type-2 diabetes mellitus, but its in vivo instability and short half-life have largely prevented its therapeutic application. Here, we describe the rational design of a series of α/sulfono-γ-AA peptide hybrid analogues of GLP-1 as the GLP-1R agonists. Certain GLP-1 hybrid analogues exhibited enhanced stability (t 1/2 > 14 days) compared to t 1/2 (<1 day) of GLP-1 in the blood plasma and in vivo. These newly developed peptide hybrids may be viable alternative of semaglutide for type-2 diabetes treatment. Additionally, our findings suggest that sulfono-γ-AA residues could be adopted to substitute canonical amino acids residues to improve the pharmacological activity of peptide-based drugs.

Peptidomimetic-based antibody surrogate for HER2

Inhibition of human epidermal growth factor receptor 2 mediated cell signaling pathway is an important therapeutic strategy for HER2-positive cancers. Although monoclonal antibodies are currently used as marketed drugs, their large molecular weight, high cost of production and susceptibility to proteolysis could be a hurdle for long-term application. In this study, we reported a strategy for the development of artificial antibody based on

Laparoscopic ultrasound assisted hepatectomy in treatment of intrahepatic and extrahepatic bile duct stones / 中华肝胆外科杂志

Objective@#To study laparoscopic ultrasound assisted hepatectomy in treatment of intrahepatic and extrahepatic bile duct stones.@*Methods@#The data of 52 patients with hepatolithiasis who underwent laparoscopic hepatectomy from May 2014 to January 2019 at the Fuyang District First People's Hospital in Hangzhou were analyzed retrospectively. There were 28 men and 24 women. The median age was 56 years. Operative laparoscopic ultrasonography was used to detect the location, size, distribution of stones and their relations to blood vessels. A total of 43 patients underwent anatomic hepatectomy, while 38 patients underwent choledochoscopic stone extraction. A " T" tube was used according to intraoperative conditions.@*Results@#Laparoscopic surgery was successfully carried out in 50 patients, while conversion to open surgery was required in 2 patients because of adhesions and bleeding. Laparoscopic ultrasonography revealed intrahepatic calcifications in 5 patients and choledochoscopy in 2 patients. Postoperative complications included 5 patients who devleoped abdominal abscesses. The operation time was (289.0±132.0) minutes. The intraoperative blood loss was (451.0±256.0) ml. The hospitalization after operation was (12.0±3.0) days. In 52 patients, 4 patients had residual stones and the residual rate was 7.7%. All of them were completely removed by T-tube sinus 8 weeks after operation.@*Conclusions@#Laparoscopic ultrasound helped to detect relevant bile ducts containing stones, reduced chance of bleeding in surgery, helped to clarify location and distribution of stones, improved accuracy of diagnosis, and reduced unnecessary hepatectomy by clearly defining intrahepatic bile duct stones intraoperatively. The residual intrahepatic and intrahepatic bile duct stones rates were reduced, and the safety and accuracy of the operations were improved.

Laparoscopic ultrasound assisted hepatectomy in treatment of intrahepatic and extrahepatic bile duct stones / 中华肝胆外科杂志

Objective To study laparoscopic ultrasound assisted hepatectomy in treatment of intrahepatic and extrahepatic bile duct stones.Methods The data of 52 patients with hepatolithiasis who underwent laparoscopic hepatectomy from May 2014 to January 2019 at the Fuyang District First People's Hospital in Hangzhou were analyzed retrospectively.There were 28 men and 24 women.The median age was 56years.Operative laparoscopic ultrasonography was used to detect the location,size,distribution of stones and their relations to blood vessels.A total of 43 patients underwent anatomic hepatectomy,while 38 patients underwent choledochoscopic stone extraction.A "T" tube was used according to intraoperative conditions.Results Laparoscopic surgery was successfully carried out in 50 patients,while conversion to open surgery was required in 2 patients because of adhesions and bleeding.Laparoscopic ultrasonography revealed intrahepatic calcifications in 5 patients and choledochoscopy in 2 patients.Postoperative complications included 5 patients who devleoped abdominal abscesses.The operation time was (289.0 ± 132.0) minutes.The intraoperative blood loss was (451.0 ±256.0) ml.The hospitalization after operation was (12.0 ±3.0)days.In 52 patients,4 patients had residual stones and the residual rate was 7.7％.All of them were completely removed by T-tube sinus 8 weeks after operation.Conclusions Laparoscopic ultrasound helped to detect relevant bile ducts containing stones,reduced chance of bleeding in surgery,helped to clarify location and distribution of stones,improved accuracy of diagnosis,and reduced unnecessary hepatectomy by clearly defining intrahepatic bile duct stones intraoperatively.The residual intrahepatic and intrahepatic bile duct stones rates were reduced,and the safety and accuracy of the operations were improved.

Enhanced recovery after surgery combined with clinical pathway management in laparoscopic biliary exploration / 中华肝胆外科杂志

Objective To study the safety,efficacy and advantages of enhanced recovery after surgery (ERAS) combined with clinical pathway management in laparoscopic common bile duct exploration and lithotomy (Laparoscopic common bile duct exploration,LCBDE).Methods 78 patients who underwent LCBDE in the Department of Hepatobiliary and Pancreatic Surgery in the First Hospital of Fuyang District in Hangzhou were selected as the non-ERAS group (the control group).76 patients who underwent LCBDE treated with fast track surgery and ERAS clinical pathway management were selected as the ERAS group.The data between the two groups which included the postoperative insulin resistance index,changes in C-reactive protein,duration of postoperative analgesic use and analgesia,timing of first passage of postoperative flatus,postoperative abdominal tube removal,postoperative bile leakage,recurrence of biliary stones,intestinal ileus and other complications.Results All the two groups were discharged home successfully.On preoperative 7 day,the differences on the postoperative insulin resistance index and the levels of C reactive protein were significantly different (P＜0.05).The time to first get out of bed after operation,the postoperative analgesic use,the time to first passage of flatus,the time to postoperative abdominal drainage tube removal,and the time to clamping of the T tube after operation were significantly different (all P＜0.05).The postoperative complications of pulmonary infection,abdominal infection and the incidence of prolonged intestinal ileus were significantly different (all P＜0.05).Conclusions ERAS combined with clinical pathway management reduced postoperative stress reaction and complication rate.The treatment accelerated recovery and shortened hospital stay for patients who underwent LCBDE,which led to good social and economic benefits.

The application and research of Xueshuantong combined with radiofrequency thermocoagulation on the treatment of low back pain caused by lumbar degeneration / 中国生化药物杂志

Objective To investigate the value of Xueshuangtong combined with radiofrequency thermocoagulation in the treatment of lumbar degenerative lumbar pain.MethodsFrom January 1, 2014 to December 30, 2015, 60 patients with lumbar degenerative low back pain admitted in Jiashan Traditional Chinese Medicine Hospital.All of them were randomly divided into observation group and control group, and each with 30 cases.All patients received radiofrequency thermocoagulation, while the observation group received Xueshuantong for further treatment.All of the patients were assessed by the international Pain Association recommended the use of visual analogue scale (VAS) and McGill pain questionnaire (SF-MPQ) and CRP when treatment before starting and after 1, 3, 7, 14, 30 and 90d of the treatment.ResultsThere were no significant differences between the two groups in VAS, SF-MPQ and CRP before treatment (P<0.05).However, when compared with the control group, patients in the observation group got significantly lower levels of VAS at 1, 3, 7 and 14d after the operation;significantly lower levels of SF-MPQ at 1, 3, 7, 14 and 30d after the operation;and significantly lower levels of CRP at 14, 30 and 90d after the operation (P<0.05).And we found no serious complications occurred in the two groups.ConclusionThe Xueshuantong combined with radiofrequency thermocoagulation treatment of lumbar facet joint is a safe, effective and inexpensive for the low back pain which caused by lumbar degeneration.

Efficacy of minimally invasive percutaneous intervertebral disc approach for treatment of sympathet-ic cervical spondylosis / 中华麻醉学杂志

Objective To evaluate the efficacy of minimally invasive percutaneous intervertebral disc approach for treatment of sympathetic cervical spondylosis. Methods Fifty?six patients diagnosed as having sympathetic cervical spondylosis from January 2009 to August 2014, aged 22-64 yr, with the dis?ease course ranged from 6 months to 15 yr and a follow?up period of 6 months, were enrolled in the study. The related minimally invasive approach was selected according to the height of the diseased intervertebral space. When the ratio of the height of diseased intervertebral space∕normal intervertebral space≤1∕3, per?cutaneous radiofrequency ablation was used ( groupⅠ, n=19); when the ratio within the range of 1∕3-2∕3, percutaneous laser disk decompression was used ( groupⅡ, n=12); when the ratio≥2∕3, low?tem?perature plasma radiofrequency ablation was used ( group Ⅲ, n=25) . Before operation, at 2 weeks after operation, and at 1, 3 and 6 months after operation, the sympathetic symptoms were evaluated using the 20?point score. At 2 weeks and 6 months after operation, the patients′ subjective satisfaction was assessed and graded ( excellent, good, medium and poor ) . Results All the patients were followed up for 6 months. The sympathetic symptom scores were significantly lower at each time point after operation in Ⅰand Ⅲ groups and at 2 weeks and 3 and 6 months after operation in group Ⅱ than those before operation ( P<0.05) . The excellent and good rate of patients′subjective satisfaction was 67.9% at 2 weeks after op?eration, and 76.8% in the last follow?up period at 6 months after operation. Conclusion The minimally invasive percutaneous intervertebral disc approach has a marked short?term effect on sympathetic cervical spondylosis.

Investigation of the action mechanisms of poly-ADP-ribosylation in hexavalent chromium induced cell damage / 中华预防医学杂志

<p><b>OBJECTIVE</b>To investigate the effect of poly-ADP-ribosylation in hexavalent chromium Cr(VI) induced cell damage.</p><p><b>METHODS</b>The study object, poly (ADP-ribose) glycohydrolase (PARG) deficient human bronchial epithelial cells (16HBE cells), was constructed previously by our research group. Normal 16HBE cells and PARG-deficient cells were treated with different doses of Cr (VI) for 24 h to compare the differences to Cr (VI) toxicity, meanwhile set up the solvent control group. On this basis, 5.0 µmol/L of Cr (VI) was selected as the exposure dose, after the exposure treatment, total proteins of both cells were extracted for two dimension fluorescence difference gel electrophoresis (2D-DIGE) separation, statistically significant differential protein spots were screened and identified by matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF-MS/MS), and further validated by Western blot.</p><p><b>RESULTS</b>After Cr (VI) treatment, the survival rate of PARG-deficient cells was higher than normal 16HBE cells. When the doses reached up to 5.0 µmol/L, the survival rate of 16HBE cells and PARG-deficient cells were respectively (59.67 ± 6.43)% and (82.00 ± 6.25)%, the difference between which was significant (t = -4.32, P < 0.05). 18 protein spots were selected and successfully identified after 2D-DIGE comparison of differential proteins between normal 16HBE cells and PARG-deficient cells before and after exposure. The function of those proteins was involved in the maintenance of cell shape, energy metabolism, DNA damage repair and regulation of gene expression. The differential expression of cofilin-1 was successfully validated by Western blot. The expression level of cofilin-1 in the 16HBE cells increased after Cr (VI) exposure with the relative expression quantity of 1.41 ± 0.04 in treated group and 1.00 ± 0.01 in control group, the difference of which was statistically significant (t = -18.00, P < 0.05), while the expression level in PARG-deficient cells had no statistically significant difference (t = -8.61, P > 0.05).</p><p><b>CONCLUSION</b>Most of the identified differential proteins are closely related to tumorigenesis, suggesting that poly-ADP-ribosylation reaction may resist the cytotoxicity of Cr(VI) by inhibiting Cr (VI) induced tumorigenesis, which provides important reference data to clarify the mechanisms of poly-ADP-ribosylation in Cr (VI) induced cell damage.</p>

Effect of poly-ADP-ribosylation on the alteration of DNA methylation level of human bronchial epithelial cells induced by Cr (VI) / 中华预防医学杂志

<p><b>OBJECTIVE</b>To reveal the role of poly-ADP-ribosylation and DNA methylation in carcinogenic process induced induced by Cr (VI), and to discuss the relations between them.</p><p><b>METHODS</b>The pre-established Poly (ADP-ribose) glycohydrolase (PARG) deficient cells and 16HBE cells were treated with different concentrations of Cr (VI), and the changes of total genomic DNA methylation level in different groups were detected by methylation immunofluorescent detection, as well as the changes of the activity of methyltransferases. Moreover, RT-PCR and western blotting method were applied to analyze the changes of expression of DNMT1, DNMT3a, DNMT3b and MBD2, upon the protein level.</p><p><b>RESULTS</b>After treated by Cr(VI) for 24 h, the healthy 16HBE cells showed a significant lower level of genomic DNA methylation; however, there was no significant changes (P > 0.05) found in PARG deficient cells by immunofluorescence assay. When the dose of Cr (VI) reached 5.0 µmol/L, the activity of methyltransferases in 16HBE cells and PARG deficient cells (49.33 ± 2.65, 80.05 ± 2.05) decreased by 20% and 50% comparing with contrast group (99.27 ± 1.10, 99.30 ± 0.60) . After treated by Cr (VI) for 24 h, the expression of mRNA and protein level among DNMT1, DNMT3a, DNMT3b and MBD2 decreased significantly in healthy 16HBE cells; and the expression of DNMT1 and DNMT3a decreased in PARG deficiency cells. The relevant expression levels of mRNA of DNMT1 were separately (0.99 ± 0.09), (0.79 ± 0.10), (0.59 ± 0.13) and (0.39 ± 0.02) (F = 247.17, P < 0.01), the expression levels of protein were separately (1.00 ± 0.03), (0.69 ± 0.15), (0.65 ± 0.10) and (0.55 ± 0.13) (F = 214.12, P < 0.01), the expression levels of DNMT3a mRNA were separately (1.00 ± 0.04) , (0.93 ± 0.11) , (0.79 ± 0.07) , (0.59 ± 0.05) (F = 498.16, P < 0.01) , and the expression levels of protein were separately (1.00 ± 0.14) , (0.97 ± 0.11) , (0.79 ± 0.17) , (0.57 ± 0.15) (F = 390.11, P < 0.01) when the dose of Cr (VI) at 0, 0.3, 1.2 and 5.0 µmol/L. However, there were no significant changes of expression found in DNMT3b and MBD2.</p><p><b>CONCLUSION</b>Poly-ADP-ribosylation could regulate the activity of DNMT3b and MBD2, protect cells against the DNA methylation alteration induced by Cr(VI) and maintain the global genomic DNA methylation level.</p>

Benign familial chronic pemphigus in a family: a clinical survey and mutation analysis of ATP2C1 gene / 中华皮肤科杂志

Objective To report a Chinese pedigree with benign familial chronic pemphigus (BFCP),and to screen mutations of ATP2C 1 gene in this family.Methods A 39-year-old male patient with BFCP andhis family members underwent a clinical investigation.Blood samples were collected from all the members in this family and from 50 unrelated healthy controls.Genomic DNA was extracted from the blood samples,and PCR was performed to amplify all the 28 exons and flanking sequences of the ATP2C1 gene followed by DNA direct sequencing.The resulted DNA sequences were compared with the reported sequences of APT2C1 gene in Genbank (Number:NM_014382.2 and NC_000003.9).Results There were 24 family members in the four-generation pedigree,with 8 members affected by BFCP.A single-nucleotide substitution,c(1696C→T),in exon 17 of the ATP2C1 gene was identified in all of the members with BFCP,but not in unaffected third-or second-generation members or unrelated healthy controls.This substitution was also found in 1 out of 4 family members of fourth-generation.Conclusions The nonsense mutation c(1696C→T) in the ATP2C1 gene,is likely to be responsible for BFCP in this Chinese four-generation pedigree.The underage family member of fourth-generation who carried the mutation c(1696C→T) but had no clinical symptoms of BFCP,should be closely followed.

The Pathology of Skin Lesions with Different Clinical Manifestations of Plane Warts / 中华皮肤科杂志

Objective To find out the pathologic changes and possible influencing factors in the process of spontaneous regression of plane warts.Methods One hundred and five lesional specimens taken from patients with plane warts were observed microscopically.Results The histologic features indicated slight hyperkeratosis,acanthosis and ballooning degeneration of keratinocytes in stable lesions;a combination of tower-peak shaped hyperkeratosis,cuneate hypergranulosis and ballooning degeneration in progressively increasing lesions;and infiltration of lymphocytes and necrosis of keratinocytes in inflammatory icthing lesions.Conclusions Specific cell-mediated immunity against keratimocytes may be involved in the process of regression of plane warts.There is a positive correlation between the activity of skin lesions and the induction of cellular immunity.