Trilobolide-6-O-isobutyrate suppresses hepatocellular carcinoma tumorigenesis through inhibition of IL-6/STAT3 signaling pathway.

Currently available therapies for hepatocellular carcinoma (HCC), with a high morbidity and high mortality, are only marginally effective and with sharp adverse side effects, which makes it compulsory to explore novel and more effective anticancer molecules. Chinese medicinal herbs exhibited prominent anticancer effects and were applied to supplement clinical cancer treatment. Here, we reported a compound, trilobolide-6-O-isobutyrate (TBB), isolated from the flowers of Wedelia trilobata with a markedly cytotoxic effect on HCC cells. We found that TBB time- and dose-dependently inhibited HCC cells' growth and colony formation in vitro. Moreover, TBB induced cell cycle arrest at the G2/M phase, mitochondrial caspase-dependent apoptosis, and suppressed migration and invasion, as well as the glycolysis of HCC cells. Mechanistically, our data indicated that TBB inhibited the STAT3 pathway activation by directly interacting with the TYR 640/657 sites of the STAT3 protein and decreasing the level of p-STAT3. TBB also regulated the expression of PCNA, Ki67, Cyclin B1, Cyclin E, Bax, Bcl2, MMP2/9, and PGK1 through the inhibition of the IL-6/STAT3 signaling pathway. Lastly, we confirmed that TBB effectively eliminated tumor growth without causing overt toxicity to healthy tissues in the xenograft tumor model. The exploration of anticancer activity and the underlying mechanism of TBB suggested its usage as a promising chemotherapeutic agent for HCC.

Diosgenin exerts anti-tumor effects through inactivation of cAMP/PKA/CREB signaling pathway in colorectal cancer.

Colorectal cancer (CRC) is the most fatal gastrointestinal tumor and it is urge to explore powerful drugs for the treatment. Diosgenin (DSG) as a new steroidal had been reported exerts anti-tumor activity in multiple cancers, including CRC. However, the potential mechanism of DSG suppresses CRC remains further to be revealed. Here, we reported that DSG inhibited proliferation of CRC cells in dose- and time-dependent manner, induced apoptosis by modulating p53 and Bcl-2 family proteins expression to mediate mitochondrial apoptosis pathway, suppressed migration and invasion by reducing MMP-9 (matrix metalloproteinase) and decreased aerobic glycolysis by mediating glucose transporter (GLUT) like GLUT3 and GLUT4, and pyruvate carboxylase PC downregulation. Intriguingly, mechanistic study suggests those phenotypes involved DSG inhibited cAMP/PKA/CREB pathway in CRC cells, and result to inhibit the phosphorylation of CREB to regulate the transcription of genes above-mentioned. Finally, nude mice xenograft tumor model further indicated that DSG could be a great agent to suppress the growth of CRC cells in vivo and have no obvious side effects. Taken together, we revealed a unique mechanism that DSG suppresses CRC cells through cAMP/PKA/CREB pathway and DSG is a promising candidate drug for CRC treatment.

Generation of H11-albumin-rtTA Transgenic Mice: A Tool for Inducible Gene Expression in the Liver.

The modification of the mouse genome by site-specific gene insertion of transgenes and other genetic elements allows the study of gene function in different developmental stages and in the pathogenesis of diseases. Here, we generated a "genomic safe harbor" Hipp11 (H11) locus-specific knock-in transgenic mouse line in which the albumin promoter is used to drive the expression of the reverse tetracycline transactivator (rtTA) in the liver. The newly generated H11-albumin-rtTA transgenic mice were bred with tetracycline-operator-Histone-2B-green fluorescent protein (TetO-H2BGFP) mice to assess inducibility and tissue-specificity. Expression of the H2BGFP fusion protein was observed exclusively upon doxycycline (Dox) induction in the liver of H11-albumin-rtTA/TetO-H2BGFP double transgenic mice. To further analyze the ability of the Dox-inducible H11-albumin-rtTA mice to implement conditional DNA recombination, H11-albumin-rtTA transgenic mice were crossed with TetO-Cre and Ai14 mice to generate H11-albumin-rtTA/TetO-Cre/Ai14 triple transgenic mice. We successfully confirmed that the Cre-mediated recombination efficiency was as strong in Dox-induced H11-albumin-rtTA /TetO-Cre/Ai14 mice as in the control albumin-Cre/A14 mice. Finally, to characterize the expression-inducing effects of Dox in H11-albumin-rtTA/TetO-H2BGFP mice in detail, we examined GFP expression in embryos at different developmental stages and found that newly conceived H11-albumin-rtTA/TetO-H2BGFP embryos of Dox-treated pregnant female mice were expressing reporter GFP by E16.5. Our study demonstrates that these new H11-albumin-rtTA transgenic mice are a powerful and efficient tool for the temporally and spatially conditional manipulation of gene expression in the liver, and illustrates how genetic crosses with these new mice enable the generation of complex multi-locus transgenic animals for mechanistic studies.

MiR-590-5p alleviates intracerebral hemorrhage-induced brain injury through targeting Peli1 gene expression.

Intracerebral haemorrhage (ICH) is a common and devastating cerebrovascular disease with high morbidity and mortality, and its pathophysiological mechanisms were complex and still unclear. Increasing researches reported that microRNAs (miRNAs) played an important role in ICH-induced brain injury and microglial activation. In this study, we investigated the biological function of miR-590-5p and explored its molecular mechanism in ICH mice. The results of qRT-PCR showed that miR-590-5p expression level was down-regulated in perihematomal brain samples of ICH mice compared with that of sham group. In LPS-induced microglia cells, miR-590-5p level was also down-regulated at 24 h post-LPS compared with that of control group. Moreover, miR-590-5p overexpression remarkably increased the cerebral water content and neurological severity scores compared with that of scramble group in ICH mice. The production of inflammatory cytokine including IL-6, interleukin (IL)-1ß, and tumor necrosis factor (TNF)-α in ICH mice was notably inhibited by miR-590-5p overexpression. Furthermore, the results of dual-luciferase reporter assay indicated that Pellino-1 (Peli1) was a direct target of miR-590-5p. MiR-590-5p overexpression remarkably inhibited the Peli1 gene expression both mRNA and protein levels. In addition, Peli1 overexpression partly abrogated the inhibitory effect of miR-590-5p mimic. Taken together, these datas suggested that miR-590-5p attenuated brain injury in ICH mice through inhibiting Peli1 gene expression, indicating that miR-590-5p may be a promising molecular target for ICH treatment.

Ternary Alloys Encapsulated within Different MOFs via a Self-Sacrificing Template Process: A Potential Platform for the Investigation of Size-Selective Catalytic Performances.

Functional nanoparticles encapsulated within metal-organic frameworks (MOFs) as an emerging class of composite materials attract increasing attention owing to their enhanced or even novel properties caused by the synergistic effect between the two functional materials. However, there is still no ideal composite structure as platform to systematically analyze and evaluate the relation between the enhanced catalytic performance of composites and the structure of MOF shells. In this work, taking RhCoNi ternary alloy nanoflowers, for example, first the RhCoNi@MOF composite catalysts sheathed with different structured MOFs via a facile self-sacrificing template process are successfully fabricated. The structure type of MOF shells is easily adjustable by using different organic molecules as etchant and coordination reagent (e.g., 2,5-dihydroxyterephthalic acid or 2-methylimidazole), which can dissolve out the Co or Ni element in the alloy template in a targeted manner, thereby producing ZIF-67(Co) or MOF-74(Ni) shells accordingly. With the difference between the two MOF shells in the aperture sizes, the as-prepared two RhCoNi@MOF composites preform distinct size selectivity during the alkene hydrogenation. This work would help us to get more comprehensive understanding of the intrinsic role of MOFs behind the enhanced catalytic performance of nanoparticle@MOF composites.

Mapping the ecological dimensions and potential distributions of endangered relic shrubs in western Ordos biodiversity center.

Potential distributions of endemic relic shrubs in western Ordos were poorly mapped, which hindered our implementation of proper conservation. Here we investigated the applicability of ecological niche modeling for endangered relic shrubs to detect areas of priority for biodiversity conservation and analyze differences in ecological niche spaces used by relic shrubs. We applied ordination and niche modeling techniques to assess main environmental drivers of five endemic relic shrubs in western Ordos, namely, Ammopiptanthus mongolicus, Amygdalus mongolica, Helianthemum songaricum, Potaninia mongolica, and Tetraena mongolica. We calculated niche overlap metrics in gridded environmental spaces and compared geographical projections of ecological niches to determine similarities and differences of niches occupied by relic shrubs. All studied taxa presented different responses to environmental factors, which resulted in a unique combination of niche conditions. Precipitation availability and soil quality characteristics play important roles in the distributions of most shrubs. Each relic shrub is constrained by a unique set of environmental conditions, the distribution of one species cannot be implied by the distribution of another, highlighting the inadequacy of one-fits-all type of conservation measure. Our stacked habitat suitability maps revealed regions around Yellow River, which are highly suitable for most species, thereby providing high conservation value.

[Risk assessment of nerve conduction velocity in workers exposed to lead].

OBJECTIVE: To explore the dose-effect relationship between lead exposure and nerve conduction velocity, and to assess risk characteristics of nerve conduction velocity induced by lead exposure. METHODS: The external dose, internal dose (blood lead, urine lead) and the conduction velocity of peripheral nerve were examined. The benchmark dose of a population exposed to occupational lead was estimated to develop risk assessment of nerve conduction velocity in worker exposed to lead by use of BMDS (version 1.3.3). The BMDL in terms of blood lead and urine lead was calculated. RESULTS: There was correlation between blood lead and urine lead. The sense nerve conduction velocity was decreased significantly in the group of lead exposure workers (P < 0.05). The BMDLs-05 for median nerve conduct velocity, ulnar nerve conduction velocity, and superficial peroneal nerve conduction velocity in terms of blood lead were 456.99, 332.36 and 468.38 microg/L respectively; the BMDLs-05 in terms of urine lead were 14.1, 9.2 and 13.6 microg/gCr respectively. CONCLUSION: The internal dose is the better index to reflect the level of lead exposure. Blood lead is identified as a specific and sensitive biomarker for sense nerve conduction velocity reduction. Ulnar nerve conduction velocity can be used as highly sensitive biomarkers to screen the high risk population of lead exposure.

[Risk assessment of renal dysfunction caused by occupational lead exposure].

OBJECTIVE: To assess the risk of renal dysfunction caused by occupational lead exposure through epidemiological investigation. METHODS: The workers in a battery factory were selected as the subjects for the exposure and effect assessment. The occupational environmental monitoring data was collected and used to calculate the total external dose of lead. The relationship between external dose and internal dose of lead was analyzed. The external dose, blood lead (BPb) and urinary lead (UPb) were used as exposure biomarkers while the urinary N-acetyl-D-glucosaminidase (UNAG), and urinary albumin (UALB) were used as the effect biomarkers for the renal dysfunction caused by lead. Software of BMDS (BMDS 11311) was used to calculate BMD. RESULTS: The external and internal does of lead was positively correlated (BPb: r = 0.466, P < 0.01; UPb: r = 0.383, P < 0.01). The levels of BPb, UPb in exposure group (654.03 microg/L, 143.45 microg/g Cr) were significantly higher than those in the control group (57.12 microg/L, 7.20 microg/g Cr), so were UALB, UNAG; in addition, all of them presented significant dose-response relationship. The BPb BMD of UALB, UNAG were 607.76, 362.56 microg/L respectively and the UPb BMD of UALB, UNAG were 117.79, 78.79 microg/gCr respectively. CONCLUSION: Occupational lead exposure can cause renal dysfunction, which presents dose-response relationship; the risk assessment of renal dysfunction caused by occupational lead exposure is performed by BMD calculation of BPb and UPb.