Design of a highly potent GLP-1R and GCGR dual-agonist for recovering hepatic fibrosis

Currently, there is still no effective curative treatment for the development of late-stage liver fibrosis. Here, we have illustrated that TB001, a dual glucagon-like peptide-1 receptor/glucagon receptor(GLP-1 R/GCGR) agonist with higher affinity towards GCGR, could retard the progression of liver fibrosis in various rodent models, with remarkable potency, selectivity, extended half-life and low toxicity. Four types of liver fibrosis animal models which were induced by CCl_(4), a-naphthyl-isothiocyanate(ANIT), bile duct ligation(BDL) and Schistosoma japonicum were used in our study. We found that TB001 treatment dose-dependently significantly attenuated liver injury and collagen accumulation in these animal models. In addition to decreased levels of extracellular matrix(ECM) accumulation during hepatic injury, activation of hepatic stellate cells was also inhibited via suppression of TGF-β expression as well as downstream Smad signaling pathways particularly in CCl_(4)-and S. japonicum-induced liver fibrosis. Moreover, TB001 attenuated liver fibrosis through blocking downstream activation of proinflammatory nuclear factor kappa B/NF-kappa-B inhibitor alpha(NFκB/IKBa) pathways as well as cJun N-terminal kinase(JNK)-dependent induction of hepatocyte apoptosis. Furthermore, GLP-1 R and/or GCGR knock-down results represented GCGR played an important role in ameliorating CCl_(4)-induced hepatic fibrosis. Therefore, TB001 can be used as a promising therapeutic candidate for the treatment of multiple causes of hepatic fibrosis demonstrated by our extensive pre-clinical evaluation of TB001.

Recombinant protein Schistosoma japonicum-derived molecule attenuates dextran sulfate sodium-induced colitis by inhibiting miRNA-217-5p to alleviate apoptosis

BACKGROUND Inflammatory bowel disease(IBD)affects millions of people worldwide and has emerged as a growing problem in industrialized nations.The lack of therapeutic targets has limited the treatment of IBD.Studies found that parasitic nematode infections can ameliorate clinical and experimental colitis.Our previous study found that rSj16,a 16-kDa secreted protein of Schistosoma japonicum produced by Escherichia coli,has protective effects on dextran sulfate sodium(DSS)-induced colitis in mice.Apoptosis is an important factor in the pathogenesis of colitis.However,it is not clear whether the effect of rSj16 on colitis is related to apoptosis.AIM To investigate whether the protective effects of rSj16 on colitis is related to apoptosis and its mechanism.METHODS In-vivo,colitis was induced by DSS.The severity of colitis was assessed.WB was used to detect the changes of apoptosis-related genes in colon tissues.Q-PCR was used to detect the changes of miRNA-217-5p and HNF1B.In-vitro,WB was used to detect the changes of apoptosis-related genes in intestinal epithelial cells.TUNNEL staining and flow cytometry were used to detect cell apoptosis.RESULTS rSj16 attenuates clinical activity in DSS-induced colitis mice.TUNNEL staining and WB results showed that apoptosis was increased in colon tissue after treatment with DSS,and the apoptosis of colon tissue was significantly reduced after treatment with rSj16.Compared with normal mice,the expression of miR-217-5p was increased in colon tissue of DSS-induced colitis mice.In addition,the miR-217-5p target gene hnf1b was decreased after administration of DSS.After treatment with rSj16,the expression of miR-217-5p was decreased and the expression of HNF1B was increased compared with the DSS-treated group.When Etoposide was used in combination with miR-217-5p mimic on MODE-K cells,the expression of cleaved-Caspase-3 and Bax was increased,and Bcl-2 was decreased compared with only Etoposide treatment,the expression of HNF1B was significantly reduced,suggesting that miR-217-5p acts as a pro-apoptotic in colon epithelial cells and down-regulates the target gene hnf1b.After rSj16 administration in MODE-K cells,miR-217-5p expression was significantly decreased,HNF1B expression was increased,and apoptosis was reduced.CONCLUSION The protective effects of rSj16 on colitis is related to apoptosis and miRNA-217-5p may be a further target for therapeutic intervention against IBD.

Parasitology should not be abandoned:data from outpatient parasitological testing in Guangdong,China

Over the past six decades,the Chinese government made parasitoses with a high disease burden,including soiltransmitted nematode infections,malaria,leishmaniasis,filariasis,and schistosomiasis,a public health priority because they were seen to be crucial impediments to the development of rural areas.As a result,these debilitating parasitic diseases that used to be widely prevalent have been well controlled or eliminated.Consequently,less attention has been paid to parasitic infection during the rapid development of the economy,especially in developed areas.However,our investigations conducted in the parasitological laboratory of Sun Yat-sen University(Guangzhou,Guangdong,China)show that emerging parasitic diseases still threaten many people’s health,with 340 of 880 outpatients(38.6%)receiving a diagnosis of parasitic disease,among whom 201(59.1%)had clonorchiasis and 120(35.3%)had taeniasis/cysticercosis.Furthermore,our doctors are not equipped with sufficient parasitology knowledge because this discipline is not able to maintain attraction.Many parasitic infections that result in severe consequences are treatable and preventable,but the phenomena of misdiagnosis and missed diagnosis are common and merit attention.

Laboratory-acquired infections with Brucella bacteria in China

Brucellosis is an important zoonotic infectious disease and is an important public health problemthat causes serious economic consequences to the livestock industry.Brucella spp.comprise one of the most common pathogens causing laboratory-acquired infections(LAIs)and are becoming an increasingly important biosafety issue.To understand the significance of Brucella LAIs in China,related papers were search based on three Chinese databases(CNKI,Wanfang,and VIP),as well as PubMed.After assessment,37 total cases were evaluated,including 27 students,seven laboratory technicians(one pregnant),two housekeeping staff,and one instructor.The age,sex,incubation period,pathogen detection results,and potential routes of infections were collected and analyzed.All LAIs occurred due to improper operations,inadequate biosafety training,and substandard laboratory safety conditions.Therefore,it is urgent to establish a comprehensive and systematic biosafety prevention/control system in laboratories to protect staff members from accidental exposures and LAIs;further,possible risks and control measures for the management of such infections were proposed.