Hepatocellular carcinoma (HCC) occurs more frequently and aggressively in men than women, but the mechanistic basis of this gender disparity is obscure. Chronic inflammation is a major etiologic factor in HCC, so we investigated the role of cortisol in gender discrepancy in a zebrafish model of HCC. Inducible expression of oncogenic Kras in hepatocytes of transgenic zebrafish resulted in accelerated liver tumor progression in males. These tumors were more heavily infiltrated with tumor-associated neutrophils (TAN) and tumor-associated macrophages (TAM) versus females, and they both showed protumor gene expression and promoted tumor progression. Interestingly, the adrenal hormone cortisol was predominantly produced in males to induce Tgfb1 expression, which functioned as an attractant for TAN and TAM. Inhibition of cortisol signaling in males, or increase of cortisol level in females, decreased or increased the numbers of TAN and TAM, respectively, accompanied by corresponding changes in protumor molecular expression. Higher levels of cortisol, TGFB1, and TAN/TAM infiltration in males were also confirmed in human pre-HCC and HCC samples, features that positively correlated in human patients. These results identify increased cortisol production and TAN/TAM infiltration as primary factors in the gender disparity of HCC development in both fish and human. .

To better understand the structural origins of inhibitor selectivity of human phosphodieasterase families (PDEs 1-11), here we report the X-ray crystal structure of PDE2 in complex with a highly selective, nanomolar inhibitor (BAY60-7550) at 1.9 Å resolution, and the structure of apo PDE2 at 2.0 Å resolution. The crystal structures reveal that the inhibitor binds to the PDE2 active site by using not only the conserved glutamine-switch mechanism for substrate binding, but also a binding-induced, hydrophobic pocket that was not reported previously. In silico affinity profiling by molecular docking indicates that the inhibitor binding to this pocket contributes significantly to the binding affinity and thereby improves the inhibitor selectivity for PDE2. Our results highlight a structure-based design strategy that exploits the potential binding-induced pockets to achieve higher selectivity in the PDE inhibitor development.

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Beiging of white adipose tissue (WAT) is capable of adaptive thermogenesis and dissipating energy. The beiging processes have been associated with the increase of anti-inflammatory M2 macrophages, however the function of M2 macrophage on beiging and the underlying mechanism are not fully understood. Here we identified a macrophage cytokine Slit3 by analyzing the transcriptome of M2 macrophages collected with FACS in inguinal WAT (iWAT) of mice after cold exposure. Once released from macrophages, Slit3 bound to the ROBO1 receptor on sympathetic neuron and activated tyrosine hydrolase (TH) through PKA and CaMKⅡ signaling, and thus stimulated norepinephrine (NE) synthesis and release. NE acts on adipocytes and stimulate thermogenesis. Adoptive transfer of Slit3-overexpressing M2 macrophages to iWAT depot acquired local adipocytes with beiging phenotype and enhanced thermogenesis. In addition, mice bearing the myeloid inactivation of Slit3 were cold intolerant and gained more weight due to the lowered metabolic rate.Collectively, we demonstrate Slit3 is a macrophage cytokine and promotes beiging and thermogenesis through intensifying the sympathetic nerve function. As the expanded M2 macrophages are integral cell population in adipose tissue, the macrophage-Slit3-sympathetic neuron-adipocyte axis assures the long-term cold adaption.

Background & AimsHepatocellular carcinoma (HCC) occurs more frequently and aggressively in men than in women. Although sex hormones are believed to play a critical role in this disparity, the possible contribution of other factors largely is unknown. We aimed to investigate the role of serotonin on its contribution of sex discrepancy during HCC.MethodsBy using an inducible zebrafish HCC model through hepatocyte-specific transgenic krasV12 expression, differential rates of HCC in male and female fish were characterized by both pharmaceutical and genetic interventions. The findings were validated further in human liver disease samples.ResultsAccelerated HCC progression was observed in krasV12-expressing male zebrafish and male fish liver tumors were found to have higher hepatic stellate cell (HSC) density and activation. Serotonin, which is essential for HSC survival and activation, similarly were found to be synthesized and accumulated more robustly in males than in females. Serotonin-activated HSCs could promote HCC carcinogenesis and concurrently increase serotonin synthesis via transforming growth factor (Tgf)b1 expression, hence contributing to sex disparity in HCC. Analysis of liver disease patient samples showed similar male predominant serotonin accumulation and Tgfb1 expression.ConclusionsIn both zebrafish HCC models and human liver disease samples, a predominant serotonin synthesis and accumulation in males resulted in higher HSC density and activation as well as Tgfb1 expression, thus accelerating HCC carcinogenesis in males.

Dibenzo­[hi,st]­ovalene (DBOV) has excellent photophysical properties, including strong fluorescence and high ambient stability. Moreover, the optical blinking properties of DBOV have enabled optical super-resolution single-molecule localization microscopy with an imaging resolution beyond the diffraction limit. Various organic and inorganic fluorescent probes have been developed for super-resolution imaging, but those sensitive to pH and/or metal ions have remained elusive. Here, we report a diaza-derivative of DBOV (N-DBOV), synthesized in eight steps with a total yield of 15%. Nitrogen (N)-bearing zigzag edges were formed through oxidative cyclization of amino groups in the last step. UV–vis and fluorescence spectroscopy of N-DBOV revealed its promising optical properties comparable to those of the parent DBOV, while cyclic voltammetry and density functional theory calculations highlighted its lower orbital energy levels and potential n-type semiconductor character. Notably, in contrast to that of the parent DBOV, the strong luminescence of N-DBOV is dependent on pH and the presence of heavy metal ions, indicating the potential of N-DBOV in sensing applications. N-DBOV also exhibited pH-responsive blinking, which enables pH-sensitive super-resolution imaging. Therefore, N-DBOV appears to be a highly promising candidate for fluorescence sensing in biology and environmental analytics.

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Author: Please verify that the changes made to improve the English still retain your original meaning.Detection of microRNA (miRNA) in dermal interstitial fluid (ISF) has emerged as clinically useful in health status monitoring. However, it remains a great challenge owing to the difficult sampling and low abundance. Here, we report a DNA hydrogel microneedles (MNs) array to realize rapid enrichment and sensitive detection of miRNA in ISF. The MNs' patch consists of methacrylate hyaluronic acid (MeHA) equipped with a smart DNA circuit hydrogels' system (MeHA/ DNA), in which an appropriate miRNA input enables triggering a cascading toehold-mediated DNA displacement reaction to catalytically cleave cross-linking points to generate amplified fluorescence (FL) for miRNA detection. The MeHA/DNA-MNs patch with high mechanical strength can extract adequate ISF in a short time (0.97 ± 0.2 mg in 5 min) in vivo because of its supreme water affinity. Additionally, the cascading toehold-mediated DNA displacement signal amplification reaction allows for sensitive detection of the low-abundant miRNAs down to 241.56 pM. The DNA hydrogels' MNs present potential for minimally invasive personalized diagnosis and real-time health monitoring in clinical applications.