Oxytocin, a nonapeptide hormone, has a key role in female reproductive functions as well as in social memory in the brain. In our recent Communications Biology article, we reported that oxytocin is ...transported from the peripheral blood into the brain by the receptor for advanced glycation end-products (RAGE) in endothelial cells at the blood−brain barrier. Additionally, we found that oral oxytocin is absorbed by RAGE on intestinal epithelial cells at the blood−intestinal barrier. From a physiological perspective, we herein outline the continuing research regarding oxytocin and social behaviour.Yamamoto and Higashido discuss the possible routes of the hormone oxytocin in the body, and highlight their recent study in Communications Biology where they showed that the RAGE receptor is a transporter for oxytocin across the blood−brain barrier.
Heme has been receiving considerable interest as a prosthetic group of ribozymes and deoxyribozymes, because heme-bound nucleic acids exhibit peroxidase-like catalytic activities (Travascio, P., Li, ...Y., and Sen, D. (1998) Chem. Biol, 5, 505–517). The interaction of heme with dimeric G-quadruplexes formed from d(TAGGGTTAGGGT) and d(TAGGGTTAGGGA) has been characterized to gain a deeper understanding of the molecular recognition of G-quadruplex DNAs by heme. We found that heme binds selectively to the 3′-terminal G-quartet of a dimeric parallel G-quadruplex of d(TAGGGTTAGGGT), whereas binding of heme to a dimeric antiparallel G-quadruplex of d(TAGGGTTAGGGA) does not occur, suggesting that an orderly arrangement of the constituent guanine deoxyribose rings, with respect to the G-quartet plane, is crucial for the binding of heme to the DNA. The preferential binding of heme to the 3′-terminal G-quartet of parallel G-quadruplex DNAs allowed a systematic modification of the heme environment in the complex through the DNA sequence. The activity of the complexes was found to increase with increasing number of adenine bases adjacent to the heme in the complexes, possibly due to improvement of the accessibility of aromatic substrate, i.e., 10-acetyl-3,7-dihydroxyphenoxazine, to the heme, and an increase in the frequency of appearance of a specific orientation of the adenine bases, with respect to the heme, optimized for its activity as an acid-base catalyst to enhance the peroxidase activity of the complex.
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•A two-repeat human telomeric sequence forms dimeric parallel and antiparallel G-quadruplex DNAs.•Heme does not bind to an antiparallel G-quadruplex DNA.•Heme binds selectively to the 3′-terminal G-quartet of a parallel G-quadruplex DNA.•The electrostatic potential due to the sugar ring oxygen atoms controls the binding of heme to a DNA.•The peroxidase activity of heme bound to a DNA increases with the number of adenines adjacent to the heme.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background
Tumor-associated macrophages (TAMs) of the M2 phenotype are known to promote tumor proliferation and to be associated with a poor prognosis in numerous cancers. Here, we investigated ...whether M2 macrophages participate in the development of peritoneal dissemination in gastric cancer.
Methods
The characteristics of peritoneal macrophages in gastric cancer patients with or without peritoneal dissemination were examined by flow cytometry and the real-time quantitative polymerase chain reaction. The effects of M2 macrophages on phenotypic changes of the gastric cancer cell line MKN45 were assessed with a direct or indirect co-culture system in vitro and an in vivo mouse xenograft model.
Results
The number of peritoneal macrophages with the M2 phenotype (CD68
+
CD163
+
or CD68
+
CD204
+
) was significantly higher in gastric cancer patients with peritoneal dissemination than in those without peritoneal dissemination. Higher expression of the M2-related messenger RNAs (IL-10, vascular endothelial growth factor A, vascular endothelial growth factor C, matrix metalloproteinase 1, and amphiregulin) and lower expression of M1-related messenger RNAs (TNF-α, CD80, CD86, and IL-12p40) were also confirmed in the TAMs. Macrophage co-culture with gastric cancer cells converted M1 phenotype into M2 phenotype. Moreover, the coexistence of MKN45 cells with M2 macrophages resulted in cancer cell proliferation and an acceleration of tumor growth in the xenograft model.
Conclusions
Intraperitoneal TAMs in gastric cancer patients with peritoneal dissemination were polarized to the M2 phenotype, and could contribute to tumor proliferation and progression. Therefore, intraperitoneal TAMs are expected to be a promising target in the treatment of peritoneal dissemination in gastric cancer.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
It remains unclear how hepatic steatosis links to inflammation. Leukocyte cell-derived chemotaxin 2 (LECT2) is a hepatokine that senses fat in the liver and is upregulated prior to weight gain. The ...aim of this study was to investigate the significance of LECT2 in the development of nonalcoholic steatohepatitis (NASH). In human liver biopsy samples, elevated LECT2 mRNA levels were positively correlated with body mass index (BMI) and increased in patients who have steatosis and inflammation in the liver. LECT2 mRNA levels were also positively correlated with the mRNA levels of the inflammatory genes CCR2 and TLR4. In C57BL/6J mice fed with a high-fat diet, mRNA levels of the inflammatory cytokines Tnfa and Nos2 were significantly lower in Lect2 KO mice. In flow cytometry analyses, the number of M1-like macrophages and M1/M2 ratio were significantly lower in Lect2 KO mice than in WT mice. In KUP5, mouse kupffer cell line, LECT2 selectively enhanced the LPS-induced phosphorylation of JNK, but not that of ERK and p38. Consistently, LECT2 enhanced the LPS-induced phosphorylation of MKK4 and TAB2, upstream activators of JNK. Hepatic expression of LECT2 is upregulated in association with the inflammatory signature in human liver tissues. The elevation of LECT2 shifts liver residual macrophage to the M1-like phenotype, and contributes to the development of liver inflammation. These findings shed light on the hepatokine LECT2 as a potential therapeutic target that can dissociate liver steatosis from inflammation.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The receptor for advanced glycation end-products (receptor for AGEs, RAGE) is a pattern recognition receptor. The interaction of RAGE with its ligands, such as AGEs, S100 proteins, high mobility ...group box-1 (HMGB1), and lipopolysaccharides (LPS), is known to play a pivotal role in the propagation of immune responses and inflammatory reactions. The ligand-RAGE interaction elicits cellular responses, for example, in myeloid and lymphoid cells, through distinct pathways by activating NF-κB and Rac1/cdc42, which lead to cytokine production, cell migration, phagocytosis, maturation, and polarization. Recently, oxytocin, a peptide hormone and neuropeptide, was identified as a novel binding molecule for the RAGE; however, it cannot compete with the interaction of RAGE with other ligands or induce RAGE intracellular signaling. The RAGE transports oxytocin from the blood into the brain and regulates brain functions. In this review, we summarize the current understanding of glycation reaction, AGEs, and the RAGE-mediated biological responses as well as the physiological role of RAGE in immunity and social behaviors, particularly, maternal bonding.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Water-soluble cationic gallium(III)-Pc complex (GaPc) is capable of photogenerating ROSs but does not exhibit photocytotoxicity in vivo. GaPc binds selectively, through a π-π stacking interaction, to ...the 5’-terminal G-quartet of a G-quadruplex DNA. The photo-excited state of GaPc of the complex is effectively quenched through electron transfer (ET) from the ground state of DNA guanine (G) bases to the photo-excited state of GaPc (ET
(G-GaPc)
). Hence the loss of the photocytotoxicity of GaPc in vivo is most likely to be due to the effective quenching of its photo-excited state through ET
(G-GaPc)
. In this study, we investigated the photochemical properties of GaPc in the presence of duplex DNAs formed from a series of sequences to elucidate the nature of ET
(G-GaPc)
. We found that ET
(G-GaPc)
is allowed in electrostatic complexes between GaPc and G-containing duplex DNAs and that the rate of ET
(G-GaPc)
(
k
ET(G-GaPc)
) can be reasonably interpreted in terms of the distance between Pc moiety of GaPc and DNA G base in the complex. We also found that the quantum yields of singlet oxygen (
1
O
2
) generation (Φ
Δ
s) determined for the GaPc-duplex DNA complexes were similar to the value reported for free GaPc (Fujishiro R, Sonoyama H, Ide Y, et al (2019) J Inorg Biochem 192:7–16), indicating that ET
(G-GaPc)
in the complex is rather limited. These results clearly demonstrated that photocytotoxicity of GaPc is crucially affected by ET
(G-GaPc)
. Thus elucidation of interaction of a photosensitizer with biomolecules, i.e., an initial process in PDT, would be helpful to understand its subsequent photochemical processes.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
C-C motif chemokine receptor (CCR)2 and its ligand, monocyte chemoattractant protein (MCP)-1, are pivotal for adipose tissue macrophage (ATM) recruitment and the development of insulin resistance. ...However, other chemokine systems also may play a role in these processes. In this study, we investigated the role of CCR5 in obesity-induced adipose tissue inflammation and insulin resistance. We analyzed expression levels of CCR5 and its ligands in white adipose tissue (WAT) of genetically (ob/ob) and high-fat (HF) diet-induced obese (DIO) mice. Furthermore, we examined the metabolic phenotype of Ccr5(-/-) mice. CCR5 and its ligands were markedly upregulated in WAT of DIO and ob/ob mice. Fluorescence-activated cell sorter analysis also revealed that DIO mice had a robust increase in CCR5(+) cells within ATMs compared with chow-fed mice. Furthermore, Ccr5(-/-) mice were protected from insulin resistance, glucose intolerance, and hepatic steatosis induced by HF feeding. The effects of loss of CCR5 were related to both reduction of total ATM content and an M2-dominant shift in ATM polarization. It is noteworthy that transplantation of Ccr5(-/-) bone marrow was sufficient to protect against impaired glucose tolerance. CCR5 plays a critical role in ATM recruitment and polarization and subsequent development of insulin resistance.
Until now, RNA G-quadruplexes were believed to only adopt a parallel G-quadruplex structure. In this study, we describe the first observation of an antiparallel RNA G-quadruplex formed by human ...telomere RNA. This newly described topology is of great interest as it shows that RNA G-quadruplexes can also be polymorphic and adopt structures that are different from the parallel configuration.
Background The receptor for advanced glycation end products (RAGE) shares common ligands and signaling pathways with TLR4, a key mediator of house dust mite ( Dermatophagoides pteronyssinus ) (HDM) ...sensitization. We hypothesized that RAGE and its ligand high-mobility group box-1 (HMGB1) cooperate with TLR4 to mediate HDM sensitization. Objectives To determine the requirement for HMGB1 and RAGE, and their relationship with TLR4, in airway sensitization. Methods TLR4−/− , RAGE−/− , and RAGE-TLR4−/− mice were intranasally exposed to HDM or cockroach ( Blatella germanica ) extracts, and features of allergic inflammation were measured during the sensitization or challenge phase. Anti-HMGB1 antibody and the IL-1 receptor antagonist Anakinra were used to inhibit HMGB1 and the IL-1 receptor, respectively. Results The magnitude of allergic airway inflammation in response to either HDM or cockroach sensitization and/or challenge was significantly reduced in the absence of RAGE but not further diminished in the absence of both RAGE and TLR4. HDM sensitization induced the release of HMGB1 from the airway epithelium in a biphasic manner, which corresponded to the sequential activation of TLR4 then RAGE. Release of HMGB1 in response to cockroach sensitization also was RAGE dependent. Significantly, HMGB1 release occurred downstream of TLR4-induced IL-1α, and upstream of IL-25 and IL-33 production. Adoptive transfer of HDM-pulsed RAGE+/+ dendritic cells to RAGE−/− mice recapitulated the allergic responses after HDM challenge. Immunoneutralization of HMGB1 attenuated HDM-induced allergic airway inflammation. Conclusion The HMGB1-RAGE axis mediates allergic airway sensitization and airway inflammation. Activation of this axis in response to different allergens acts to amplify the allergic inflammatory response, which exposes it as an attractive target for therapeutic intervention.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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