Despite plenty of evidence supports an inverse association between alcohol drinking and risk of renal cell carcinoma (RCC), sex-specific and beverage-specific dose-response relationships have not been well established. We examined this association by performing a systematic review and meta-analysis of prospective studies. Studies were identified by comprehensively searching PubMed and EMBASE databases through February 21, 2015. Categorical and dose-response meta-analyses were conducted to identify the effects of alcohol on RCC. A total of eight publications (including seven cohort studies and one pooled analysis of 12 cohort studies) were eligible for this meta-analysis. Dose-response analysis showed that each 5 g/day increment of alcohol intake corresponded to a 5% decrease in risk of RCC for males and 9% for females. Alcohol intakes from wine, beer, and liquor were each associated with a reduced risk of RCC. When these associations were examined separately by gender, statistically significant inverse associations were restricted to alcohol from wine among females (RR = 0.82, 95% CI 0.73-0.91) and to alcohol from beer and from liquor among males (RR = 0.87, 95% CI 0.83-0.91 and RR = 0.95, 95% CI 0.92-0.99, respectively). In conclusion, there exist gender-specific and beverage-specific differences in the association between alcohol intake and RCC risk.

The nucleophosmin (NPM1) activates cancer development and progression in many malignant tumors. However, the regulatory role and underlying mechanisms of NPM1 in pancreatic cancer are unknown. In this study, we showed that NPM1 was up-regulated in PDAC, which indicated a poor prognosis. We also identified NPM1 could stimulate aerobic glycolysis and repress fructose-1, 6-bisphosphatase 1 (FBP1) in pancreatic cancer cells. Restoring FBP1 expression partially reversed the tumor-promoting effects of NPM1, while the loss of FBP1 in PDAC tissues was indicative of a poorer prognosis. In sum, NPM1 promotes aerobic glycolysis and tumor progression in patients with pancreatic cancer by inhibiting FBP1.

Polycomb group (PcG) proteins Ring1B and EZH2, which have been characterized as catalyzing the two epigenetic modifications H2AK119 monoubiquitination (H2AK119Ub1) and H3K27 trimethylation (H3K27Me3), are well-known epigenetic silencers implicated in embryonic development and tumorigenesis. However, the status of polycomb-associated histone modifications and their clinical implications in pancreatic cancer remain unclear. Here, we performed immunohistochemistry on tissue microarrays (TMAs) containing 80 pairs of human pancreatic cancer specimens to assess the expression levels of Ring1B, H2AK119Ub1, EZH2, and H3K27Me3 in tumors. More than 50% of the tumor cells showed a high expression of H2AK119Ub1, Ring1B, and EZH2, whereas more than 50% of the tumor cells showed a low level of H3K27Me3. Different expression patterns of H2AK119Ub1 and H3K27Me3 in tumors were negatively correlated (r = -0.247, P = 0.027). Both H2AK119Ub1 and H3K27Me3 independently predicted the clinical prognosis. In particular, a combinatorial pattern of elevated H2AK119Ub1 and decreased H3K27Me3 in tumors was significantly correlated with a poorer prognosis. Furthermore, compared to the tumor, lymph node, metastasis (TNM) staging system, histone modifications can discriminate the survival difference more accurately, especially for patients with stage I or stage II tumors. Simultaneous silencing of Ring1B and EZH2 via shRNA depleted H2AK119Ub1 and H3K27Me3 in the pancreatic cancer cells PanC1 and AsPC1, enhanced HOX gene derepression, and inhibited tumor cell growth in vitro and in tumor xenograft models. These results demonstrated that H2AK119Ub1 and H3K27Me3 cooperate in tumors and are associated with the clinical prognosis in combinatorial patterns. We have proposed that epigenetic modifications may serve as discriminatory biomarkers for molecular staging of pancreatic cancer.

Increasing evidence has suggested that dysregulation of certain microRNAs (miRNAs) may contribute to human disease including carcinogenesis and tumor metastasis in human. miR-124-3p is down-regulated in various cancers, and modulates proliferation and aggressiveness of cancer cells. However, the roles of miR-124-3p in human bladder cancer are elusive. Thus, this study was conducted to investigate the biological functions and its molecular mechanisms of miR-124-3p in human bladder cancer cell lines, discussing whether it has a potential to be a therapeutic biomarker of bladder cancer.

Neuropathic pain remains notoriously difficult to treat despite numerous drug targets. Here, we offer a novel explanation for this intractability. Computer simulations predicted that qualitative changes in primary afferent excitability linked to neuropathic pain arise through a switch in spike initiation dynamics when molecular pathologies reach a tipping point (criticality), and that this tipping point can be reached via several different molecular pathologies (degeneracy). We experimentally tested these predictions by pharmacologically blocking native conductances and/or electrophysiologically inserting virtual conductances. Multiple different manipulations successfully reproduced or reversed neuropathic changes in primary afferents from naïve or nerve-injured rats, respectively, thus confirming the predicted criticality and its degenerate basis. Degeneracy means that several different molecular pathologies are individually sufficient to cause hyperexcitability, and because several such pathologies co-occur after nerve injury, that no single pathology is uniquely necessary. Consequently, single-target-drugs can be circumvented by maladaptive plasticity in any one of several ion channels. DOI: http://dx.doi.org/10.7554/eLife.02370.001.

Although brucea javanica oil liposomes (BJOLs) have been used clinically to treat ovarian cancer, its clinical efficacy is often limited by systemic side effects due to non-specific distribution. Luteinizing hormone releasing hormone receptor (LHRHR) is overexpressed in most ovarian cancers but negligibly expressed in most of the other visceral organs. In this study, we aimed to develop a novel LHRHa targeted and BJO-loaded liposomes (LHRHa-BJOLs), and investigate its characteristics, targeting ability and anti-ovarian cancer efficiency both in vitro and in vivo.

Disheveled-binding antagonist of beta-catenin 1 (DACT1) is involved in tumorigenesis through influencing cell apoptosis and proliferation. We aimed to investigate the effect of three tag single-nucleotide polymorphisms (SNPs) in DACT1 (rs863091 C>T, rs17832998 C>T, and rs167481 C>T) on the occurrence of gastric cancer (GC), their association with specific clinical characteristics, and consideration of the functional relevance of GC-related SNPs.

MUC4 mucin is well known as an important potential target to overcome pancreatic cancer. Three unique domains (NIDO, AMOP, and vWD) with unclear roles only present in MUC4 but are not found in other membrane-bound mucins. Our previous studies first reported that its splice variant, MUC4/Y can be a model of MUC4 (MUC4 gene fragment is more than 30KB, too huge to clone and eukaryotic express) in pancreatic cancer. More importantly, based on MUC4/Y with the appropriate length of gene sequence, it is easy to construct the unique domain-lacking models of MUC4/Y (MUC4) for research. The present study focuses on investigation of the respective role of the unique NIDO, AMOP, and vWD domain or their synergistic effect on MUC4(MUC4/Y)-mediated functions and mechanisms by series of in vitro assays, sequence-based transcriptome analysis, validation of qRT-PCR & Western blot, and systematic comparative analysis. Our results demonstrate: 1) NIDO, AMOP, and vWD domain or their synergy play significant roles on MUC4/Y-mediated malignant function of pancreatic cancer, downstream of molecule mechanisms, particularly MUC4/Y-triggered malignancy-related positive feedback loops, respectively. 2) The synergistic roles of three unique domains on MUC4/Y-mediated functions and mechanisms are more prominent than the respective domain because the synergy of three domain plays the more remarkable effects on MUC4/Y-mediated signaling hub. Thus, to improve reversed effects of domain-lacking and break the synergism of domains will contribute to block MUC4/Y(MUC4) triggering various oncogenic signaling pathways.

Biocompatibility of intraocular lens (IOL) is critical to vision reconstruction after cataract surgery. Foldable hydrophobic acrylic IOL is vulnerable to the adhesion of extracellular matrix proteins and cells, leading to increased incidence of postoperative inflammation and capsule opacification. To increase IOL biocompatibility, we synthesized a hydrophilic copolymer P(MPC-MAA) and grafted the copolymer onto the surface of IOL through air plasma treatment. X-ray photoelectron spectroscopy, atomic force microscopy and static water contact angle were used to characterize chemical changes, topography and hydrophilicity of the IOL surface, respectively. Quartz crystal microbalance with dissipation (QCM-D) showed that P(MPC-MAA) modified IOLs were resistant to protein adsorption. Moreover, P(MPC-MAA) modification inhibited adhesion and proliferation of lens epithelial cells (LECs) in vitro. To analyze uveal and capsular biocompatibility in vivo, we implanted the P(MPC-MAA) modified IOLs into rabbits after phacoemulsification. P(MPC-MAA) modification significantly reduced postoperative inflammation and anterior capsule opacification (ACO), and did not affect posterior capsule opacification (PCO). Collectively, our study suggests that surface modification by P(MPC-MAA) can significantly improve uveal and capsular biocompatibility of hydrophobic acrylic IOL, which could potentially benefit patients with blood-aqueous barrier damage.

Hyperhomocysteinemia (HHcy), as an independent risk factor of atherosclerosis, facilitates endothelial dysfunction and activation of vascular smooth muscle cells (VSMCs). However, little is known about the crosstalk between endothelial cells (ECs) and VSMCs under HHcy. We investigated whether homocysteine (Hcy) activates VSMCs by aberrant secretion of mitogen platelet-derived growth factors (PDGFs) from ECs in human and in mice. In this study, we found that increased Hcy level did not affect VSMC activity in 24 hrs until the concentration reached 500 μM. In contrast, Hcy at 100 μM significantly promoted proliferation and migration of VSMCs co-cultured with human ECs. This effect was partially reversed by pretreatment with a PDGF receptor inhibitor. Hcy concentration-dependently upregulated the mRNA level of PDGF-A, -C and -D but not PDGF-B in ECs. Hcy reduced the expression and activity of DNA methyltransferase 1, demethylation of PDGF-A, -C and -D promoters and enhanced the binding activity of transcriptional factor SP-1 to the promoter. Hcy upregulation of PDGF was confirmed in the aortic intima of mice with HHcy. Multivariate regression analysis revealed HHcy was a predictor of increased serum PDGF level in patients. Thus, Hcy upregulates PDGF level via DNA demethylation in ECs, affects cross-talk between ECs and VSMCs and leads to VSMC activation.

It is increasingly clear that microRNAs play a crucial role in tumorigenesis. Recently, emerging evidence suggested that miR-26a is aberrantly expressed in tumor tissues. In our study, frequent down-regulation of miR-26a was observed in 10 human bladder cancer tissues. Forced expression of miR-26a in the bladder cancer cell line T24 inhibited cell proliferation and impaired cell motility. High mobility group AT-hook 1 (HMGA1), a gene that modulates cell cycle transition and cell motility, was verified as a novel target of miR-26a in bladder cancer. These findings indicate an important role for miR-26a in the molecular etiology of bladder cancer and implicate the potential application of miR-26a in bladder cancer therapy.

Singapore Grouper Iridovirus (SGIV) is a member of nucleo cytoplasmic large DNA viruses (NCLDV). This paper reports the functional analysis of ORF75R, a major structural protein of SGIV. Immuno fluorescence studies showed that the protein was accumulated in the viral assembly site. Immunogold-labelling indicated that it was localized between the viral capsid shell and DNA core. Knockdown of ORF75R by morpholinos resulted in the reduction of coreshell thickness, the failure of DNA encapsidation, and the low yield of infectious particles. Comparative proteomics further identified the structural proteins affected by ORF75R knockdown. Two-dimensional gel electrophoresis combined with proteomics demonstrated that ORF75R was phosphorylated at multiple sites in SGIV-infected cell lysate and virions, but the vast majority of ORF75R in virions was the dephosphorylated isoform. A kinase assay showed that ORF75R could be phosphorylated in vitro by the SGIV structural protein ORF39L. Addition of ATP and Mg(2+) into purified virions prompted extensive phosphorylation of structural proteins and release of ORF75R from virions. These data suggest that ORF75R is a novel scaffold protein important for viral assembly and DNA encapsidation, but its phosphorylation facilitates virion disassembly. Compared to proteins from other viruses, we found that ORF75R shares common features with herpes simplex virus VP22.

Pathological expansion of adipose tissue contributes to the metabolic syndrome. Distinct depots develop at various times under different physiological conditions. The transcriptional cascade mediating adipogenesis is established in vitro, and centres around a core program involving PPARγ and C/EBPα. We developed an inducible, adipocyte-specific knockout system to probe the requirement of key adipogenic transcription factors at various stages of adipogenesis in vivo. C/EBPα is essential for all white adipogenic conditions in the adult stage, such as adipose tissue regeneration, adipogenesis in muscle and unhealthy expansion of white adipose tissue during high-fat feeding or due to leptin deficiency. Surprisingly, terminal embryonic adipogenesis is fully C/EBPα independent, but does however depend on PPARγ; cold-induced beige adipogenesis is also C/EBPα independent. Moreover, C/EBPα is not vital for adipocyte survival in the adult stage. We reveal a surprising diversity of transcriptional signals required at different stages of adipogenesis in vivo.

A meta-analysis was conducted to quantitatively evaluate the correlation between night shift work and the risk of colorectal cancer. We searched for publications up to March 2015 using PubMed, Web of Science, Cochrane Library, EMBASE and the Chinese National Knowledge Infrastructure databases, and the references of the retrieved articles and relevant reviews were also checked. OR and 95% CI were used to assess the degree of the correlation between night shift work and risk of colorectal cancer via fixed- or random-effect models. A dose-response meta-analysis was performed as well. The pooled OR estimates of the included studies illustrated that night shift work was correlated with an increased risk of colorectal cancer (OR = 1.318, 95% CI 1.121-1.551). No evidence of publication bias was detected. In the dose-response analysis, the rate of colorectal cancer increased by 11% for every 5 years increased in night shift work (OR = 1.11, 95% CI 1.03-1.20). In conclusion, this meta-analysis indicated that night shift work was associated with an increased risk of colorectal cancer. Further researches should be conducted to confirm our findings and clarify the potential biological mechanisms.

Nerve growth factors and their receptors have received an increasing attention in certain cancers since they play an important role in regulating tumorigenesis, biological process and metastasis. Here we aimed at characterizing a new function of one of the subtypes of growth factor receptors (GFR), GFRα2, in pancreatic cancer. In this study, we showed that GFRα2 was up-regulated in pancreatic adenocarcinoma and was positively correlated with tumor size and perineural invasion, which indicated that it may be associated with cell growth and apoptosis. Mechanically, we discovered that high GFRα2 expression level leads to PTEN inactivation via enhancing Mir-17-5p level.

Activated vascular endothelium inflammation under persistent hyperlipidemia is the initial step of atherogenesis. ATP-binding cassette G1 (ABCG1) is a crucial factor maintaining sterol and lipid homeostasis by transporting cholesterol efflux to high-density lipoprotein. In this study, we investigated the protective effects of ABCG1 in endothelial inflammation activation during early-stage atherogenesis in mice and the underlying mechanisms. Endothelial cell (EC)-specific ABCG1 transgenic (EC-ABCG1-Tg) mice were generated and cross-bred with low-density lipoprotein receptor-deficient (Ldlr(-/-)) mice. After a 4-week Western-type diet, the mice were sacrificed for assessing atherosclerosis. Human umbilical vein ECs were treated with different flows, and ABCG1 was adenovirally overexpressed to investigate the mechanism in vitro. Compared with Ldlr(-/-) mouse aortas, EC-ABCG1-Tg/Ldlr(-/-) aortas showed decreased early-stage lesions. Furthermore, the lesion area in the EC-ABCG1-Tg/Ldlr(-/-) mouse aortic arch but not thoracic aorta was significantly reduced, which suggests a protective role of ABCG1 under atheroprone flow. In vitro, overexpression of ABCG1 attenuated EC activation caused by oscillatory shear stress. Overexpression of ABCG1 blunted cholesterol-activated ECs in vitro. In exploring the mechanisms of ABCG1 attenuating endothelial inflammation, we found that ABCG1 inhibited oscillatory flow-activated nuclear factor kappa B and NLRP3 inflammasome in ECs. ABCG1 may play a protective role in early-stage atherosclerosis by reducing endothelial activation induced by oscillatory shear stress via suppressing the inflammatory response.

Hepatic nuclear factor 4α (HNF4α) modulates the transcriptional activation of numerous metabolic genes in liver. In this study, gene-array analysis revealed that HNF4α overexpression increased peroxisome proliferator-activated receptorγ (PPARγ) greatly in cultured rat primary hepatocytes. PPAR-response-element-driven reporter gene expression could be elevated by HNF4α. Bioinformatics analysis revealed a high-affinity HNF4α binding site in the human PPARγ2 promoter and in vitro experiments showed that this promoter could be transactivated by HNF4α. The presence of HNF4α on the promoter was then confirmed by ChIP assay. In vivo, hepatic overexpression of HNF4α decreased cholesterol levels both in plasma and liver and several hepatic genes related to cholesterol metabolism, including scavenger receptor BI (SR-BI), were upregulated. The upregulation of SR-BI by HNF4α could be inhibited by a PPARγ antagonist in vitro. In conclusion, HNF4α regulates cholesterol metabolism in rat by modulating the expression of SR-BI in the liver, in which the upregulation of PPARγ was involved.

Prostaglandin E2 (PGE2) has been reported to modulate angiogenesis, the process of new blood vessel formation, by promoting proliferation, migration and tube formation of endothelial cells. Endothelial progenitor cells are known as a subset of circulating bone marrow mononuclear cells that have the capacity to differentiate into endothelial cells. However, the mechanism underlying the stimulatory effects of PGE2 and its specific receptors on bone marrow-derived cells (BMCs) in angiogenesis has not been fully characterized. Treatment with PGE2 significantly increased the differentiation and migration of BMCs. Also, the markers of differentiation to endothelial cells, CD31 and von Willebrand factor, and the genes associated with migration, matrix metalloproteinases 2 and 9, were significantly upregulated. This upregulation was abolished by dominant-negative AMP-activated protein kinase (AMPK) and AMPK inhibitor but not protein kinase, a inhibitor. As a functional consequence of differentiation and migration, the tube formation of BMCs was reinforced. Along with altered BMCs functions, phosphorylation and activation of AMPK and endothelial nitric oxide synthase, the target of activated AMPK, were both increased which could be blocked by EP4 blocking peptide and simulated by the agonist of EP4 but not EP1, EP2 or EP3. The pro-angiogenic role of PGE2 could be repressed by EP4 blocking peptide and retarded in EP4(+/-) mice. Therefore, by promoting the differentiation and migration of BMCs, PGE2 reinforced their neovascularization by binding to the receptor of EP4 in an AMPK-dependent manner. PGE2 may have clinical value in ischemic heart disease.

Senescent cells accumulate with aging and at sites of pathology in multiple chronic diseases. Senolytics are drugs that selectively promote apoptosis of senescent cells by temporarily disabling the pro-survival pathways that enable senescent cells to resist the pro-apoptotic, pro-inflammatory factors that they themselves secrete. Reducing senescent cell burden by genetic approaches or by administering senolytics delays or alleviates multiple age- and disease-related adverse phenotypes in preclinical models. Reported senolytics include dasatinib, quercetin, navitoclax (ABT263), and piperlongumine. Here we report that fisetin, a naturally-occurring flavone with low toxicity, and A1331852 and A1155463, selective BCL-XL inhibitors that may have less hematological toxicity than the less specific BCL-2 family inhibitor navitoclax, are senolytic. Fisetin selectively induces apoptosis in senescent but not proliferating human umbilical vein endothelial cells (HUVECs). It is not senolytic in senescent IMR90 cells, a human lung fibroblast strain, or primary human preadipocytes. A1331852 and A1155463 are senolytic in HUVECs and IMR90 cells, but not preadipocytes. These agents may be better candidates for eventual translation into clinical interventions than some existing senolytics, such as navitoclax, which is associated with hematological toxicity.

Diabetes and vascular calcification are intrinsically linked. We previously reported that advanced glycation end products (AGEs) accelerate calcium deposition in vascular smooth muscle cells (VSMCs) via excessive oxidative stress. However, the underlying mechanism remains poorly understood. Pyruvate dehydrogenase kinase 4 (PDK4) is an important mitochondrial matrix enzyme in cellular energy metabolism. Since hyperactivation of PDK4 has been reported in calcified vessels and in patients with diabetes mellitus, inhibition of PDK4 expression may be a strategy for the prevention of diabetic vascular calcification. In this study, we used a rat VSMC model to investigate the role of PDK4 in diabetic vascular calcification and further explore the underlying mechanisms. We observed that Nε-carboxymethyl-lysine (CML), which is a major immunogen of AGEs, accelerated calcium deposition in VSMCs through PDK4 activation. An elevated level of reactive oxygen species (ROS) acted as a signal transduction intermediate to increase PDK4 expression. Either inhibition of PDK4 expression or RAGE (receptor for AGEs) blockade attenuated CML-induced VSMC calcification, as shown by decreased alkaline phosphatase (ALP) activity and runt-related transcription factor 2 (RUNX2) expression. Glucose consumption and lactate production were increased during CML-induced VSMC calcification. Importantly, CML accelerates glycolysis in VSMCs via a PDK4-dependent pathway. In conclusion, this study demonstrates a novel mechanism by which CML promotes VSMC calcification via PDK4 activation and alters glucose metabolism in VSMCs.