a b s t r a c t a r t i c l e i n f oBoth cadmium and arsenic are the important metal/metalloid pollutants in the Bohai Sea. In this work, we sampled the dominant species, shrimp Crangon affinis, from three sites, the Middle of the Bohai Sea (MBS), the Yellow River Estuary (YRE) and the Laizhou Bay (LZB) along the Bohai Sea. The concentrations of metals/metalloids in shrimps C. affinis indicated that the YRE site was polluted by Cd and Pb, while the LZB site was contaminated by As. The metabolic differences between shrimps C. affinis from the reference site (MBS) and metal-pollution sites (YRE and LZB) were characterized using NMR-based metabolomics. Results indicated that the metal pollutions in YRE and LZB induced disturbances in osmotic regulation and energy metabolism via different metabolic pathways. In addition, a combination of alanine and arginine might be the biomarker of Cd contamination, while BCAAs and tyrosine could be the biomarkers of arsenic contamination in C. affinis.

h i g h l i g h t s g r a p h i c a l a b s t r a c tAs (III) and As (V) induced differential proteomic responses in mussels. As (III) and As (V) induced osmotic and immune stresses in mussels. As (V) disturbed energy metabolism at metabolite level in mussels.a r t i c l e i n f o a b s t r a c tInorganic arsenic (As) is a known pollutant including two chemical forms (arsenite (As III) and arsenate (As V)), in marine and coastal environment. Marine mussel Mytilus galloprovincialis is an important environmental monitoring species around the world. In this study, we focused on valence-specific responses of As in juvenile mussel M. galloprovincialis using a combined proteomic and metabolomic approach. Metabolic responses indicated that As (III) mainly caused disturbance in osmotic regulation in juvenile mussels. As (V) caused disturbances in both osmotic regulation and energy metabolism marked by different metabolic responses, including betaine, taurine, glucose and glycogen. Proteomic responses exhibited that As (III) had a significant negative effect on cytoskeleton and cell structure (actin and collagen alpha-6(VI) chain). As (V) affected some key enzymes involved in energy metabolism (cytosolic malate dehydrogenase, cMDH) and cell development (ornithine aminotransferase and astacin). Overall, all these results confirmed the valence-specific responses in juvenile mussels to As exposures. These findings demonstrate that a combined metabolomic and proteomic approach could provide an important insight into the toxicological effects of environmental pollutants in organisms.

a b s t r a c tCadmium (Cd) has become an important metal contaminant and posed severe risk on the organisms in the coastal environments of the Bohai Sea. Marine mussel Mytilus galloprovincialis is widely distributed along the Bohai coast and consumed as seafood by local residents. Evidences indicate that the early stages of marine organisms are more sensitive to metal contaminants. In this study, we applied twodimensional electrophoresis-based proteomics to characterize the biological effects of Cd (50 mg L À1 ) in the early life stages (D-shape larval and juvenile) of mussels. The different proteomic responses demonstrated the differential responsive mechanisms to Cd exposure in these two early life stages of mussels. In details, results indicated that Cd mainly induced immune and oxidative stresses in both Dshape larval and juvenile mussels via different pathways. In addition, the significant up-regulation of triosephosphate isomerase and metallothionein confirmed the enhanced energy demand and mobilized detoxification mechanism in D-shape larval mussels exposed to Cd. In juvenile mussels, Cd exposure also induced clear apoptosis. Overall, this work suggests that Cd is a potential immune toxicant to mussel M. galloprovincialis at early life stages.

a b s t r a c tCadmium (Cd) and arsenic (As) are the main metal/metalloid contaminants in the coastal environments of the Bohai Sea, China. In this work, a combined proteomic and metabolomic approach was applied to investigate the biological effects of Cd and As (V) in the early life stage (D-shape larvae) of mussel Mytilus galloprovincialis. Results indicated that Cd was a potential immune toxicant to D-shape larval mussel because of the numerous proteomic responses related to immune system. Additionally, Cd induced oxidative stress, cellular injury and disturbance in nucleic acid metabolism in D-shape larval mussels. However, only two identified proteins were significantly altered in As (V)-treated group, suggesting that D-shape larval mussel was less sensitive to As (V) than to Cd at protein level. These two proteins in response to As (V) suggested that As (V) influenced anti-oxidative system and cell proliferation in Dshape larval mussels. Metabolic responses indicated that Cd and As (V) induced disturbances in osmotic regulation and energy metabolism in D-shape larval mussels via different metabolic pathways. In addition, Cd reduced lipid metabolism as well. This work demonstrated that a combination of proteomics and metabolomics could provide an insightful view in the biological effects of pollutants in mussel M. galloprovincialis at an early life stage.

Histamine receptor H3 (HRH3) is mainly expressed in the central nervous system, where it is involved in the regulation of the release of various neurotransmitters in the brain. Recent studies have demonstrated that the expression of HRH3 is upregulated in several types of cancer. However, the functional effect of HRH3 on tumor progression remains largely unknown, particularly in hepatocellular carcinoma (HCC). In the present study, the expression of HRH3 in 96 HCC patients was first evaluated, and its clinical significance was analyzed. Subsequently, the functional roles of HRH3 in HCC growth and metastasis were systematically explored in vitro and in vivo using its agonist (imetit) or antagonist (clobenpropit). It was observed that HRH3 was significantly upregulated in HCC tissues, while its expression was significantly associated with recurrence-free survival and overall survival in HCC patients. Functional experiments also demonstrated that HRH3 upregulation facilitated the growth and metastasis of HCC cells by inducing the formation of lamellipodia. These findings revealed that HRH3 serves an important role in the growth and metastasis of HCC cells, which provides experimental evidence supporting the application of HRH3 as a potential therapeutic target in HCC treatment.