Vasculogenic mimicry:a pivotal mechanism contributing to drug resistance in antiangiogenic therapy

The growth of solid tumors relies on establishing a robust blood supply,with angiogenesis playing a key role in this intricate process.Based on this understanding,therapeutic strategies targeting tumor angiogenesis have been developed.However,the clinical effectiveness of antiangiogenic therapy(AAT)in treating tumors has not lived up to expectations.In recent years,vasculogenic mimicry(VM)has attracted increasing attention from the academic community as a longstanding but often overlooked mechanism of nonangiogenic tumor vascularization.Within the tumor microenvironment,neoplastic cells can autonomously form vessel-like structures,creating a blood supply that does not rely on endothelial cells.This phenomenon,known as VM,is a critical marker of aggressive tumors and may play a significant role in conferring resistance to AAT.In this review,we thoroughly examine the evidence,clinical characteristics,and mechanisms of VM across various tumor types and explore its potential role and importance in resistance to AAT and the development of new antitumor therapies.

Effects of sphincter of Oddi motility on the formation of cholesterol gallstones

AIM: To investigate the mechanisms and effects of sphincter of Oddi(SO) motility on cholesterol gallbladder stone formation in guinea pigs.METHODS: Thirty-four adult male Hartley guinea pigs were divided randomly into two groups, the control group(n = 10) and the cholesterol gallstone group(n = 24), which was sequentially divided into four subgroups with six guinea pigs each according to time of sacrifice. The guinea pigs in the cholesterol gallstone group were fed a cholesterol lithogenic diet and sacrificed after 3, 6, 9, and 12 wk. SO manometry and recording of myoelectric activity were obtained by a multifunctional physiograph at each stage. Cholecystokinin-A receptor(CCKAR) expression levels in SO smooth muscle were detected by quantitative real-time PCR(q RT-PCR) and serum vasoactive intestinal peptide(VIP), gastrin, and cholecystokinin octapeptide(CCK-8) were detected by enzyme-linked immunosorbent assay at each stage in the process of cholesterol gallstone formation.RESULTS: The gallstone formation rate was 0%, 0%, 16.7%, and 83.3% in the 3, 6, 9, and 12 wk groups, respectively. The frequency of myoelectric activity in the 9 wk group, the amplitude of myoelectric activity in the 9 and 12 wk groups, and the amplitude and the frequency of SO in the 9 wk group were all significantly decreased compared to the control group. The SO basal pressure and common bile duct pressure increased markedly in the 12 wk group, and the CCKAR expression levels increased in the 6 and 12 wk groups compared to the control group. Serum VIP was elevated significantly in the 9 and 12 wk groups and gastrin decreased significantly in the 3 and 9 wk groups. There was no difference in serum CCK-8 between the groups.CONCLUSION: A cholesterol gallstone-causing diet can induce SO dysfunction. The increasing tension of the SO along with its decreasing activity may play an important role in cholesterol gallstone formation. Expression changes of CCKAR in SO smooth muscle and serum VIP and CCK-8 may be important causes of SO dysfunction.

Roles of sphincter of Oddi motility and serum vasoactive intestinal peptide,gastrin and cholecystokinin octapeptide

AIM: To investigate roles of sphincter of Oddi (SO) motility played in pigment gallbladder stone formation in model of guinea pigs.

The natural history of chronic hepatitis B:a retrospective study

OBJECTIVE: To clarify the natural history, of chronic hepatitis B so as to evaluate its long-term therapeutic outcome of the patients and the efficacy of antiviral drugs. METHODS: A cohort of 183 biopsy-proven chronic hepatitis B patients (mean age of 31.75±8.03 years, male/female ratio: 152:31) and 247 controls were followed up retrospectively for 11.81±4.08 years. This study was focused on long-term clinical outcome including the rates of liver cirrhosis, hepatocellular carcinoma and death, apart from the long-term effect of antiviral drugs and prognostic factors. RESULTS: In the 183 chronic hepatitis B patients, 22 (12.02%) developed liver cirrhosis, 12 (6.56%) developed hepatocellular carcinoma, and 20 (10.93%) died. The 5-, 10- and 15-year survival rates were 97. 27%, 91.62%, and 84.47%, respectively. The 5-, 10- and 15-year incidence rates of HCC were O, 3.19%, and 11.56%, respectively. In the 247 controls, 6 (2.43%) died; none of them developed cirrhosis or HCC. The rates of death, liver cirrhosis, and HCC in the hepatitis B patients were markedly different (P<0. 005) compared with the controls. The overall mortality of hepatitis B patients was 4.5-fold higher than the general population. Cox multiple regression analysis showed that old age, severe histological injury, and positive HBeAg were closely related to liver cirrhosis; old age, severe histological injury, and male were major factors leading to death. The independent variable of predicted HCC was not found. CONCLUSION: The long-term outcome of hepatitis B patients is poor and the efficacy of antiviral drugs needs further study.

Bmo-miR-3351 modulates glutathione content and inhibits BmNPV proliferation by targeting BmGSTe6 in Bombyx mori

MicroRNAs(miRNAs)are small non-coding RNAs that play pivotal roles in the host response to invading pathogens.Among these pathogens,Bombyx mori nu-cleopolyhedrovirus(BmNPV)is one of the main causes of substantial economic losses in sericulture,and there are relatively few studies on the specific functions of miRNAs in the B.mori-BmNPV interaction.Therefore,we conducted transcriptome sequencing to identify differentially expressed(DE)messenger RNAs(mRNAs)and miRNAs in the midgut of 2 B.mori strains(BmNPV-susceptible strain P50 and BmNPV-resistant strain A35)after BmNPV infection.Through correlation analysis of the miRNA and mRNA data,we identified a comprehensive set of 21 miRNAs and 37 predicted target mRNAs.Notably,miR-3351,which has high expression in A35,exhibited remarkable efficacy in suppressing BmNPV proliferation.Additionally,we confirmed that miR-3351 binds to the 3'untranslated region(3'UTR)of B.mori glutathione S-transferase epsilon 6(BmG-STeo),resulting in its downregulation.Conversely,BmGSTe6 displayed an opposite expres-sion pattern to miR-3351,effectively promoting BmNPV proliferation.Notably,BmGSTe6 levels were positively correlated with glutathione S-transferase activity,consequently in-fluencing intracellular glutathione content in the infected samples.Furthermore,our in-vestigation revealed the protective role of glutathione against BmNPV infection in BmN cells.In summary,miR-3351 modulates glutathione content by downregulating BmGSTe6 to inhibit BmNPV proliferation in B.mori.Our findings enriched the research on the role of B.mori miRNAs in the defense against BmNPV infection,and suggests that the an-tiviral molecule,glutathione,offers a novel perspective on preventing viral infection in sericulture.

Small molecule proteomics quantifies differences between normal and fibrotic pulmonary extracellular matrices

Background:Pulmonary fibrosis is a respiratory disease caused by the proliferation of fibroblasts and accumulation of the extracellular matrix(ECM).It is known that the lung ECM is mainly composed of a three-dimensional fiber mesh filled with various high-molecular-weight proteins.However,the small-molecular-weight proteins in the lung ECM and their differences between normal and fibrotic lung ECM are largely unknown.Methods::Healthy adult male Sprague-Dawley rats(Rattus norvegicus)weighing about 150 to 200 g were randomly divided into three groups using random number table:A,B,and C and each group contained five rats.The rats in Group A were administered a single intragastric(i.g.)dose of 500μL of saline as control,and those in Groups B and C were administered a single i.g.dose of paraquat(PQ)dissolved in 500μL of saline(20 mg/kg).After 2 weeks,the lungs of rats in Group B were harvested for histological observation,preparation of de-cellularized lung scaffolds,and proteomic analysis for small-molecular-weight proteins,and similar procedures were performed on Group C and A after 4 weeks.The differentially expressed small-molecular-weight proteins(DESMPs)between different groups and the subcellular locations were analyzed.Results::Of the 1626 small-molecular-weight proteins identified,1047 were quantifiable.There were 97 up-regulated and 45 downregulated proteins in B vs.A,274 up-regulated and 31 down-regulated proteins in C vs.A,and 237 up-regulated and 28 downregulated proteins identified in C vs.B.Both the up-regulated and down-regulated proteins in the three comparisons were mainly distributed in single-organism processes and cellular processes within biological process,cell and organelle within cellular component,and binding within molecular function.Further,more up-regulated than down-regulated proteins were identified in most sub-cellular locations.The interactions of DESMPs identified in extracellular location in all comparisons showed that serum albumin(Alb)harbored the highest degree of node(25),followed by prolyl 4-hydroxylase beta polypeptide(12),integrinβ1(10),apolipoprotein A1(9),and fibrinogen gamma chain(9).Conclusions::Numerous PQ-induced DESMPs were identified in de-cellularized lungs of rats by high throughput proteomics analysis.The DESMPs between the control and treatment groups showed diversity in molecular functions,biological processes,and pathways.In addition,the interactions of extracellular DESMPs suggested that the extracellular proteins Alb,Itgb1,Apoa1,P4hb,and Fgg in ECM could be potentially used as biomarker candidates for pulmonary fibrosis.These results provided useful information and new insights regarding pulmonary fibrosis.