A strategy of vascular-targeted therapy for liver fibrosis.

BACKGROUND AND AIMS: No effective treatments are available for liver fibrosis. Angiogenesis is deeply involved in liver fibrogenesis. However, current controversial results suggest it is difficult to treat liver fibrosis through vascular targeting. There are three different microvessels in liver: portal vessels, liver sinusoids, and central vessels. The changes and roles for each of the three different vessels during liver fibrogenesis are unclear. We propose that they play different roles during liver fibrogenesis, and a single vascular endothelial cell (EC) regulator is not enough to fully regulate these three vessels to treat liver fibrosis. Therefore, a combined regulation of multiple different EC regulatory signaling pathway may provide new strategies for the liver fibrosis therapy. Herein, we present a proof-of-concept strategy by combining the regulation of leukocyte cell-derived chemotaxin 2 (LECT2)/tyrosine kinase with immunoglobulin-like and epidermal growth factor-like domains 1 signaling with that of vascular endothelial growth factor (VEGF)/recombinant VEGF (rVEGF) signaling. APPROACH AND RESULTS: The CCl4 -induced mouse liver fibrosis model and NASH model were both used. During fibrogenesis, vascular changes occurred at very early stage, and different liver vessels showed different changes and played different roles: decreased portal vessels, increased sinusoid capillarization and the increased central vessels the increase of portal vessels alleviates liver fibrosis, the increase of central vessels aggravates liver fibrosis, and the increase of sinusoid capillarization aggravates liver fibrosis. The combinational treatment of adeno-associated viral vector serotype 9 (AAV9)-LECT2-short hairpin RNA (shRNA) and rVEGF showed improved therapeutic effects, but it led to serious side effects. The combination of AAV9-LECT2-shRNA and bevacizumab showed both improved therapeutic effects and decreased side effects. CONCLUSIONS: Liver vascular changes occurred at very early stage of fibrogenesis. Different vessels play different roles in liver fibrosis. The combinational treatment of AAV9-LECT2-shRNA and bevacizumab could significantly improve the therapeutic effects on liver fibrosis.

Design, Synthesis, and Anticancer Activity Evaluation of Hybrids of Azoles and Barbituric Acids.

In order to find new drugs with potent antiproliferative effect, a series of novel barbituric acid derivatives containing azoles at the C-5 position were designed, synthesized, and evaluated for antiproliferative activity against three human cancer cell lines (BEL-7402, MCF-7, and HCT-116) using MTT assay. Several of the synthesized compounds exhibited potent antiproliferative effects. The most promising compound was 5-((1-(4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl) methylene)pyrimidine-2,4,6(1H,3H,5H)-trione (3s), which showed considerably high antiproliferative activity in the BEL-7402 cell line, with a half-maximal inhibitory concentration of 4.02 µM and 20.45-fold higher selectivity for BEL-7402 cells than for normal L02 cells. The apoptosis experiment showed that compound 3s induced apoptosis and cell necrosis in a concentration-dependent manner and exert its anti-proliferative activity. Therefore, compound 3s exhibited better therapeutic activity and specificity compared with the positive control 5-fluorouracil.

siRNAs Targeting Mouse-Specific lncRNA AA388235 Induce Human Tumor Cell Pyroptosis/Apoptosis.

Species-specific lncRNAs significantly determine species-specific functions through various ways, such as epigenetic regulation. However, there has been no study focusing on the role of species-specific lncRNAs in other species yet. Here, we found that siRNAs targeting mouse-specific lncRNA AA388235 could significantly induce death of human tumor cells, although it has no effect on mouse tumor cells and normal human cells. The mechanism studies showed that these siRNAs could activate the response of human tumor cells to exogenous nucleic acids, induce pyroptosis and apoptosis in the presence of GSDME, but induce apoptosis in the absence of GSDME. They also significantly inhibited the growth of human tumor cells in vivo. 17 siRNAs were designed for seven more mouse-specific lncRNAs selected randomly, among which 12 siRNAs targeting five lncRNAs induced death in human tumor cell. Our study not only demonstrates that the siRNAs designed for knocking down mouse-specific lncRNA AA388235 can be potential tumor therapeutic drugs, but also suggests that non-human species-specific lncRNAs are a huge potential library that can be used to design siRNAs for tumor treatment. Large-scale screening based on this is promising.

[Clinical Characteristics and Bone Marrow Histopathology Features in Essential Thrombocythaemia Patients with Different Gene Mutation in China].

OBJECTIVE: To investigate the clinical characteristics, laboratorial and bone marrow pathological features of primary thrombocytopenia (ET) patients with different mutations of CALR, JAK2 and MPL genes. METHODS: The chinical data of 120 cases of ET in Jiangsu provincial people's hospital/ The First Affiliated Hospital of Nanjing Medical University from January 2015 to December 2017 were collected and analyzed, including 76 cases with JAK2 gene mutation, 40 cases with CALR gene mutation, 2 cases with MPL gene mutations, 2 cases without gene mutation. RESULTS: Among the ET patients, compared with the JAK2 gene mutation, CALR gene mutation showed statistically significant deareament of white blood cells and hemoglobin (P=0.001, P=0.01) and the male platelets in CALR group showed significant increament (P=0.04). Fourthermore, the average number of megakaryocytes and its cluster numbers in each hight power field of vision showed statistically significant decreament in CALR group as compared with JAK2 group (P=0.001, P=0.001), and thrombotic events in CALR group were signicantly lower than those in JAK2 group (7.5% vs 18.4%) (P=0.03). CONCLUSION: Mutations of CALR, JAK2 have different clinical characteristics and blood pathological changes of Chinese ET patients, and their clinical significance is worth to explore.

LECT2, a Ligand for Tie1, Plays a Crucial Role in Liver Fibrogenesis.

Liver fibrosis is a very common condition seen in millions of patients with various liver diseases, and yet no effective treatments are available owing to poorly characterized molecular pathogenesis. Here, we show that leukocyte cell-derived chemotaxin 2 (LECT2) is a functional ligand of Tie1, a poorly characterized endothelial cell (EC)-specific orphan receptor. Upon binding to Tie1, LECT2 interrupts Tie1/Tie2 heterodimerization, facilitates Tie2/Tie2 homodimerization, activates PPAR signaling, and inhibits the migration and tube formations of EC. In vivo studies showed that LECT2 overexpression inhibits portal angiogenesis, promotes sinusoid capillarization, and worsens fibrosis, whereas these changes were reversed in Lect2-KO mice. Adeno-associated viral vector serotype 9 (AAV9)-LECT2 small hairpin RNA (shRNA) treatment significantly attenuates fibrosis. Upregulation of LECT2 is associated with advanced human liver fibrosis staging. We concluded that targeting LECT2/Tie1 signaling may represent a potential therapeutic target for liver fibrosis, and serum LECT2 level may be a potential biomarker for the screening and diagnosis of liver fibrosis.

HGF/R-spondin1 rescues liver dysfunction through the induction of Lgr5+ liver stem cells.

Induction of endogenous adult stem cells by administering soluble molecules provides an advantageous approach for tissue damage repair, which could be a clinically applicable and cost-effective alternative to transplantation of embryonic or pluripotent stem cell-derived tissues for the treatment of acute organ failures. Here, we show that HGF/Rspo1 induce liver stem cells and rescue liver dysfunction. Carbon tetrachloride treatment promotes both fibrosis and Lgr5+ liver stem cell proliferation, whereas Lgr5 knockdown worsens fibrosis. Injection of HGF in combination with Rspo1 increases the number of Lgr5+ liver stem cells and improves liver function by attenuating fibrosis. We observe Lgr5+ liver stem cells in human liver fibrosis tissues, and once they are isolated, these cells are able to form organoids, and treatment with HGF/Rspo1 promotes their expansion. We suggest that Lgr5+ liver stem cells represent a valuable target for liver damage treatment, and that HGF/Rspo1 can be used to promote liver stem cell expansion.

Diabetes-Invoked High-Density Lipoprotein and Its Association With Coronary Artery Disease in Patients With Type 2 Diabetes Mellitus.

Although high-density lipoprotein (HDL) can exhibit anti-inflammatory properties, these potent activities can become deficient and even transform into proinflammatory effects under various pathophysiological states. We investigated the effect of diabetic HDL on the inflammatory response in human monocytes and its relation to the existence of coronary artery disease (CAD) in patients with type 2 diabetes mellitus (DM). HDL was isolated from DM patients with (n = 61) or without (n = 31) CAD (diameter stenosis ≥50%) and healthy controls (n = 40). Human peripheral blood mononuclear cells were incubated with HDL and the proinflammatory ability of HDL was determined by tumor necrosis factor-α (TNF-α) secretion in peripheral blood mononuclear cells. Secretion of TNF-α in human monocytes in response to diabetic HDL was significantly increased compared with that of the control HDL. Of note, HDL from DM patients with CAD stimulated the release of TNF-α in monocytes to a greater extent than that of HDL from those without CAD. Multiple linear regression analysis showed that the proinflammatory ability of HDL was independently associated with diabetes duration, hemoglobin A1c, serum levels of high-sensitivity C-reactive protein (hs-CRP) and reduced glomerular filtration rate (GFR). Furthermore, the proinflammatory ability of HDL was a significant predictor for the presence of CAD in patients with DM.

Biosorption of Cd(II) by live and dead cells of Bacillus cereus RC-1 isolated from cadmium-contaminated soil.

The present study investigated the biosorption capacity of live and dead cells of Bacillus cereus RC-1 for Cd(II). The biosorption characteristics were investigated as a function of initial pH, contact time, and initial cadmium concentration. Equilibrium biosorption was modeled using Langmuir, Freundlich and Redlich-Peterson isotherm equations. It was found that the maximum biosorption capacities calculated from Langmuir isotherm were 31.95 mg/g and 24.01 mg/g for dead cells and live cells, respectively. The kinetics of the biosorption was better described by pseudo-second order kinetic model. Desorption efficiency of biosorbents was investigated at various pH values. These results indicated that dead cells have higher Cd(II) biosorption capacity than live cells. Furthermore, zeta potential, transmission electron microscopy (TEM), scanning electron microscopy (SEM) coupled with energy dispersive X-ray (EDX), and Fourier transform infrared spectroscopy (FTIR) studies were carried out to understand the differences in the Cd(II) biosorption behavior for the both biosorbents. The bioaccumulation of Cd(II) by B. cereus RC-1 was found to depend largely on extracellular biosorption rather than intracellular accumulation. Based on the above studies, dead biomass appears to be a more efficient biosorbent for the removal of Cd(II) from aqueous solution.

Neoplasm-like abdominal nonhematogenous disseminated tuberculous lymphadenopathy: CT evaluation of 12 cases and literature review.

AIM: To assess the diagnostic value of computed tomography (CT) imaging in screening for abdominal nonhematogenous disseminated tuberculous lymphadenopathy (TL). METHODS: The CT scans of 12 patients with abdominal nonhematogenous disseminated TL suggestive of neoplasm were retrospectively analyzed in this review. The final diagnoses were confirmed by lymph node pathology for seven patients and by laparoscopic surgery for five patients. All of the patients were treated at our institution between April 1995 and August 2009. RESULTS: The sites of involvement were the periportal (n = 6), peripancreatic (n = 3), periaortic (n = 3), and mesenteric (n = 2) regions. On the plain CT scan, the lymphadenopathy showed a heterogeneous isodensity or hypodensity in 11 patients and a low density in one patient. Peripheral enhancement was observed on the dynamic contrast-enhanced CT scans for all patients. In two cases, scans were more revealing during the portal venous and delayed phases. CONCLUSION: Abdominal lymphadenopathy with predominant peripheral rim-like enhancement on the dynamic contrast-enhanced CT scan may suggest a diagnosis of TL.

[Accuracy of MR perfusion weighted imaging for cerebral glioma grading: a meta-analysis].

OBJECTIVE: To evaluate values of MR perfusion weighted imaging(PWI) in the grading of intracranial gliomas by a meta-analysis. METHODS: All English and Chinese literatures published before November 2009 in PUBMED and CNKI (China National Knowledge Infrastructure) were searched. Literature searching requirements: (1) MR PWI with region of interest (ROI) must have been applied in the grading of gliomas; (2) histopathological results must have been used as the reference standards. In addition, after data extraction, a bivariate random-effect model and hierarchical weighted symmetric summary receiver-operating curve must have been utilized to pool the data. Furthermore, a meta regression method must have been applied to detect and analyze the factors that affected the diagnostic accuracy. RESULTS: Overall, fourteen studies were included with a total amount of 1021 patients. The pooled sensitivity, specificity and diagnostic odds ratio with 95% of CI were 93% (89% - 96%), 81% (73% - 87%) and 55 (28 - 107), respectively. The factors that affected the diagnostic accuracy were the sample size, the ratio of malignant glioma, the injection rate of contrast agents, the repetition time and the cutoff value. Heterogeneity did exist among the results obtained from different studies. CONCLUSION: the relative cerebral blood volume (rCBV) of MR PWI can be referred to differentiate malignant cerebral gliomas from benign ones with sound sensitivity and specificity. However, there is not a unified threshold applied in the researches that have been conducted so far, and techniques used differ among the studies. In summary, clinical application values of rCBV of MR PWI are to be corroborated by further studies with a larger sample size.