Circulating cytokines and vascular dementia: A bi-directional Mendelian randomization study.

Inflammatory responses are associated with the development of vascular dementia (VaD). Circulating cytokines modulate the inflammatory response and are important for the immune system. To further elucidate the role of the immune system in VaD, we used Mendelian randomization (MR) to comprehensively and bi-directionally assess the role of circulating cytokines in VaD. Using state-of-the-art genome-wide association studies, we primarily assessed whether different genetic levels of 41 circulating cytokines affect the risk of developing VaD and, in turn, whether the genetic risk of VaD affects these circulating cytokines. We used inverse variance weighting (IVW) and several other MR methods to assess the bidirectional causality between circulating cytokines and VaD, and performed sensitivity analyses. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) was inversely associated with VaD risk [odds ratio (OR): 0.74, 95 % confidence interval (CI): 0.60-0.92, P = 0.007, 0.007]. VaD was associated with seven circulating cytokines: macrophage inflammatory protein 1b (MIP-1 beta) [OR: 1.05, 95 % CI: 1.01-1.08, P = 0.009], Interleukin-12p70 (IL-12) [OR: 1.04, 95 % CI: 1.00-1.08, P = 0.047], Interleukin-17 (IL-17) [OR: 1.04, 95 % CI: 1.00-1.07, P = 0.038], Interleukin-7 (IL-7) [OR: 1.07, 95 % CI: 1.02-1.12, P = 0.009], Interferon gamma (IFN-γ) [OR: 1.03, 95 % CI: 1.00-1.07, P = 0.046], Granulocyte-colony stimulating factor (GCSF) [OR: 1.06, 95 % CI: 1.02-1.09, P = 0.001], Fibroblast growth factor (FGF) [P = 0.001], and Fibroblast growth factor (FGF) [P = 0.001]. Fibroblast growth factor basic (FGF-Basic) [OR: 1.04, 95 % CI: 1.01-1.08, P = 0.02] were positively correlated. Circulating cytokines are associated with VaD, and further studies are needed to determine whether they are effective targets for intervention to prevent or treat VaD.

The involvement of AMP-activated protein kinase α in regulating glycolysis in Yesso scallop Patinopecten yessoensis under high temperature stress.

AMP-activated protein kinase α subunit (AMPKα), the central regulatory molecule of energy metabolism, plays an important role in maintaining energy homeostasis and helping cells to resist the influence of various adverse factors. In the present study, an AMPKα was identified from Yesso scallop Patinopecten yessoensis (PyAMPKα). The open reading frame (ORF) of PyAMPKα was of 1599 bp encoding a putative polypeptide of 533 amino acid residues with a typical KD domain, a α-AID domain and a α-CTD domain. The deduced amino acid sequence of PyAMPKα shared 59.89-74.78% identities with AMPKαs from other species. The mRNA transcripts of PyAMPKα were found to be expressed in haemocytes and all the examined tissues, including gill, mantle, gonad, adductor muscle and hepatopancreas, with the highest expression level in adductor muscle. PyAMPKα was mainly located in cytoplasm of scallop haemocytes. At 3 h after high temperature stress treatment (25 °C), the mRNA transcripts of PyAMPKα, the phosphorylation level of PyAMPKα at Thr170 and the lactic acid (LD) content in adductor muscle all increased significantly, while the glycogen content decreased significantly. The activity of pyruvate kinase (PyPK) and the relative mRNA expression level of phosphofructokinase (PyPFK) were significantly up-regulated at 3 h after high temperature stress treatment (25 °C). Furthermore, the PyAMPKα activator AICAR could effectively upregulate the phosphorylation level of PyAMPKα, and increase activities of PyPFK and pyruvate kinase (PyPK). Meanwhile the glycogen content also declined under AICAR treatment. These results collectively suggested that PyAMPKα was involved in the high temperature stress response of scallops by enhancing glycolysis pathway of glycogen. These results would be helpful for understanding the functions of PyAMPKα in maintaining energy homeostasis under high temperature stress in scallops.

The expression profile of a multi-stress inducible transient receptor potential vanilloid 4 (TRPV4) in Pacific oyster Crassostrea gigas.

Transient receptor potential vanilloid 4 (TRPV4) is one of the major non-selective cation channel proteins, which plays a crucial role in sensing biotic and abiotic stresses, such as pathogen infection, temperature, mechanical pressure and osmotic pressure changes by regulating Ca2+ homeostasis. In the present study, a TRPV4 homologue was identified in Pacific oyster Crassostrea gigas, designated as CgTRPV4. The open reading frame (ORF) of CgTRPV4 was of 2298 bp encoding a putative polypeptide of 765 amino acid residues with three typical ankyrin domains and six conserved transmembrane domains of TRPV4 subfamily proteins, as well as multiple N-glycosylation sites, cAMP- and cGMP-dependent protein kinase phosphorylation sites, protein kinase C phosphorylation sites, casein kinase II phosphorylation sites, and prokaryotic membrane lipoprotein lipid attachment site. The deduced amino acid sequence of CgTRPV4 shared 20.5%-26.2% similarity with TRPV4s from other species. During the early ontogenesis stages of oyster, the mRNA transcripts of CgTRPV4 were detectable in all the stages with the highest expression level in fertilized eggs and the lowest in D-hinged larvae. In adult oyster, the CgTRPV4 mRNA could be detected in all the examined tissues, including gill, hepatopancreas, adductor muscle, labial palp, mantle and haemocyte, with the highest expression level in gill (45.08-fold of that in hepatopancreas, p < 0.05). In immunocytochemical assay, the CgTRPV4 positive signals were distributed in both endoplasmic reticulum and cytoplasmic membrane of oyster haemocytes. The mRNA expression of CgTRPV4 in gill was significantly up-regulated after high temperature stress at 30°C (p < 0.05) and after Vibrio splendidus stimulation (p < 0.05). These results indicated that CgTRPV4 was a classical member of TRPV4 family in oyster, which was induced by either biotic or abiotic stimulations and involved in mediating the stress response of oysters.

S100A8 as a Promising Biomarker and Oncogenic Immune Protein in the Tumor Microenvironment: An Integrative Pancancer Analysis.

Background: S100 Calcium Binding Protein A8 (S100A8) is beneficial for cancer immunotherapy. However, the processes underlying its therapeutic potential have not been completely studied. Methods: The Cancer Genome Atlas provides raw data on 33 different cancer types. GEO made available GSE67501, GSE78220, and IMvigor210. We investigated S100A8's genetic changes, expression patterns, and survival studies. The linkages between S100A8 and TME, as well as its association with immunological processes/elements and the major histocompatibility complex, were explored to effectively understand the role of S100A8 in cancer immunotherapy. Three distinct immunotherapeutic cohorts were employed to examine the relationship between S100A8 and immunotherapeutic response. Results: S100A8 expression was high in tumor tissue. The overexpression of S100A8 is associated with poor clinical outcome in patients with overall survival. S100A8 is associated with immune cell infiltration, immunological modulators, and immunotherapeutic indicators. S100A8 overexpression is connected to immune-related pathways. However, no statistically significant connection between S100A8 and immunotherapeutic response was identified. Conclusions: S100A8 may be a reliable biomarker for tumor prognosis and a viable prospective therapeutic target for human cancer immunotherapy (e.g., GBM, KIRC, LGG, and LIHC).

The involvement of PyBeclin 1 and PyLC3 in regulating the activation of autophagy in scallop Patinopecten yessoensis after acute high temperature stress.

Beclin 1 and LC3 are important autophagy regulation proteins involved in vesicle nucleation and extension stage, respectively. In the present study, a Beclin 1 and a LC3 were identified from Yesso scallop Patinopecten yessoensis (PyBeclin 1 and PyLC3). The open reading frame (ORF) of PyBeclin 1 was of 1335 bp encoding a putative polypeptide of 444 amino acid residues with an N-terminal BCL-2 homology 3 (BH3) domain, a central coiled-coil domain (CCD), and a C-terminal evolutionarily conserved domain (ECD). The ORF of PyLC3 was of 369 bp encoding a putative polypeptide of 122 amino acid residues with an APG12 domain. The deduced amino acid sequences of PyBeclin 1 and PyLC3 shared 31.92-74.09% and 68.38-79.50% identities with Beclin 1s and LC3s from other species, respectively. The mRNA transcripts of PyBeclin 1 and PyLC3 were found to be expressed in all the examined tissues, including adductor muscle, gonad, gill, haemocytes and mantle, with the highest expression level in gill and haemocytes. The mRNA expression level of PyBeclin 1 in haemocytes increased significantly at 1, 3, 6, 12 and 24 h (2.98-4.07 fold of that in the Blank group, p < 0.05), and returned to normal level at 48 h after acute high temperature stress at 25 °C. Unlike PyBeclin 1, the mRNA transcripts of PyLC3 in haemocytes were significantly up-regulated at1, 3, 6 and 12 h (1.80-2.54 fold of that in the Blank group, p < 0.05), then decreased to blank level at 24 h (p > 0.05), and increased significantly again at 48 h (3.70 fold of that in the Blank group, p < 0.05) after high temperature. PyBeclin 1 and PyLC3 were mainly located in the cytoplasm and a small amount in the nucleus with few puncta, and the numbers of PyBeclin 1 and PyLC3 puncta increased at 3 h after acute high temperature stress. The LC3-II levels in gill and haemocytes were significantly up-regulated at 1 h and 3 h after acute high temperature stress. These results collectively suggested that PyBeclin 1 and PyLC3 were conserved members of Beclin 1 and LC3 family in scallops, and involved in regulating the activation of autophagy in scallops after acute high temperature stress.

Construction and Optimization of an Endometrial Injury Model in Mice by Transcervical Ethanol Perfusion.

This study aimed to establish a stable animal model of intrauterine adhesion (IUA) using a minimally invasive method that recapitulates the clinicopathologic characteristics of IUA. Mice were randomly divided into groups based on the ethanol treatment time (the EtOH-10 s, EtOH-20 s, EtOH-40 s, EtOH-1 min, and sham operation groups), and after the cervix was relaxed with phloroglucinol, the uterine horn was perfused with 95% ethanol through the cervix to induce endometrial injury. Eight days after the procedure, routine biochemical assays were performed to assess liver and kidney function; HE and Masson staining were used to assess uterine morphology and fibrosis; and immunohistochemistry was performed to evaluate the expression of CD31 and F4/80 in the endometrium. Furthermore, the fertility of mice in the EtOH-40 s group and the sham operation group was compared. As expected, the ethanol treatment time was positively correlated with the degree of uterine damage and kidney dysfunction in mice. In particular, the endometria of mice in the EtOH-40 s group were significantly thinner than those of mice in the sham operation group and exhibited severe necrosis, glandular loss, incomplete epithelial and glandular epithelial cell structure, severe tissue fibrosis, an activated inflammatory response, and a significant decrease in the number of fetuses, consistent with the clinical characteristics of severe IUA. In conclusion, this study resulted in successful establishment, by a minimally invasive transcervical ethanol perfusion technique, of a mouse model of endometrial injury, which could support an in-depth study of IUA pathogenesis and further promote the development of IUA therapies.

The expression profile of calnexin in Patinopecten yessoensis after acute high temperature stress.

Calnexin (CNX) is one of the major calcium-binding proteins in endoplasmic reticulum (ER) and plays a crucial role in regulating Ca2+ homeostasis and unfolded protein response (UPR). In the present study, PyCNX was identified in Yesso Scallop Patinopecten yessoensis. The open reading frame (ORF) of PyCNX was of 1794 bp encoding a putative polypeptide of 598 amino acid residues with an N-terminal signal peptide, a typical calreticulin (CRT) domain and a C-terminal transmembrane domain. The deduced amino acid sequence of PyCNX shared 47.91%-70.16% identities with CNXs from other species. The mRNA transcripts of PyCNX were constitutively expressed in all the examined tissues, including gills, gonad, hepatopancreas, mantle and haemocytes, with the highest expression level in gills. The mRNA transcripts of PyCNX in gills were significantly up-regulated at 1 h (p < 0.01), down-regulated to similar level of Blank group at 3 h (p > 0.05) and 6 h (p > 0.05), and decreased significantly from 12 to 48 h (p < 0.05) after acute high temperature stress (25 °C). PyCNX was mainly located in the ER of haemocytes. The expression profiles of PyATF6, PyIRE1 and PyGRP78 in the gills of scallops after acute high temperature stress were investigated using quantitative real-time PCR. The mRNA transcripts of PyATF6 increased significantly at 1 h, 3 h and 6 h after acute high temperature stress (p < 0.01), then down-regulated to similar level of Blank group at 12 h (p > 0.05) and 24 h (p > 0.05), and finally significantly up-regulated again at 48 h (p < 0.05). Similar to PyATF6, the mRNA transcripts of PyIRE1 were significantly up-regulated at 1 h (p < 0.05), 3 h (p < 0.01), 6 h (p < 0.05) and 48 h (p < 0.05) after acute high temperature stress. The mRNA transcripts of PyGRP78 were significantly up-regulated at 3 h (p < 0.05), reached the highest level at 6 h (p < 0.01) after acute high temperature stress, and kept significant higher level at 12-48 h (p < 0.05). These results indicated that PyCNX was involved in the response upon the acute high temperature stress of scallops probably by regulating UPR.