The histamine H(4) receptor is the most recently identified receptor and is considered to play a role in a variety of inflammatory diseases. Histamine levels in the plasma are known to be elevated in animal models of sepsis and in septic patients. The aim of this study was to test the hypothesis that the H(4) receptor may play a significant role in the pathophysiology of sepsis. Polymicrobial sepsis was induced by cecal ligation and puncture in BALB/c mice. Although the H(4) receptor gene was undetectable in normal peripheral key organs, with the exception of the spleen, the expression levels of this gene were highly up-regulated in all those organs of septic mice. In vivo transfection of nuclear factor-kappaB (NF-kappaB) decoy oligodeoxynucleotide, but not of its scrambled form, resulted in a great inhibition of sepsis-induced overexpression of the H(4) receptor gene. In septic mice, marked increases in caspase-3 activation and follicular lymphocyte apoptosis in spleens were strongly suppressed by systemic treatment with synthetic small interfering RNA (siRNA) targeted to the H(4) receptor. This was associated with the up-regulation of a number of antiapoptotic proteins. These antiapoptotic effects of H(4) receptor siRNA treatment were all inhibited by further application of NF-kappaB decoy oligonucleotide. Our results suggest that superinduction of the histamine H(4) receptor gene in peripheral key organs, including the spleen, that is promoted by sepsis is transcriptionally controlled by NF-kappaB, whereas stimulation of this receptor is involved in the development of sepsis-induced splenic apoptosis through counteraction of the antiapoptotic action of NF-kappaB.
"This process is a mechanism of tightly regulated disassembly of cells caused by activation of certain specialized proteases called caspases. A number of laboratories have demonstrated that sepsis induces extensive lymphocyte apoptosis, which can impairment of immunoresponses, thereby predisposing patients to septic death (Ayala & Chaudry, 1996; Wesche et al., 2005; Hotchkiss et al., 2005; Lang & Matute-Bello, 2009; Matsuda et al., 2010a). Parenchymal cells, including intestinal and lung epithelial cells, also have increased apoptotic cell death in animal models of sepsis (Coopersmith et al., 2002a, 2002b; Perl et al., 2007). "
"HRH4 has been reported to influence apoptosis in animal models of sepsis through counteracting the anti-apoptotic action of NF-kappaB , while the cAMP-PKA pathway is involved in HRH4 activation-mediated cell death in peripheral blood mononuclear cells (PBMCs) . In the current study, we showed that HRH4 activation could promote the 5-Fu-mediated cell apoptosis in colon cancer cells, which may provide new clues for histamine receptor-targeted therapies of CRCs. "
[Show abstract][Hide abstract] ABSTRACT: Earlier studies have reported the production of histamine in colorectal cancers (CRCs). The effect of histamine is largely determined locally by the histamine receptor expression pattern. Recent evidence suggests that the expression level of histamine receptor H4 (HRH4) is abnormal in colorectal cancer tissues. However, the role of HRH4 in CRC progression and its clinical relevance is not well understood. The aim of this study is to evaluate the clinical and molecular phenotypes of colorectal tumors with abnormal HRH4 expression.
Immunoblotting, real-time PCR, immunofluorescence and immunohistochemistry assays were adopted to examine HRH4 expression in case-matched CRC samples (n = 107) and adjacent normal tissues (ANTs). To assess the functions of HRH4 in CRC cells, we established stable HRH4-transfected colorectal cells and examined cell proliferation, colony formation, cell cycle and apoptosis in these cells.
The protein levels of HRH4 were reduced in most of the human CRC samples regardless of grade or Dukes classification. mRNA levels of HRH4 were also reduced in both early-stage and advanced CRC samples. In vitro studies showed that HRH4 over-expression caused growth arrest and induced expression of cell cycle proteins in CRC cells upon exposure to histamine through a cAMP -dependent pathway. Furthermore, HRH4 stimulation promoted the 5-Fu-induced cell apoptosis in HRH4-positive colorectal cells.
The results from the current study supported previous findings of HRH4 abnormalities in CRCs. Expression levels of HRH4 could influence the histamine-mediated growth regulation in CRC cells. These findings suggested a potential role of abnormal HRH4 expression in the progression of CRCs and provided some new clues for the application of HRH4-specific agonist or antagonist in the molecular therapy of CRCs.
BMC Cancer 05/2011; 11(1):195:1-11. DOI:10.1186/1471-2407-11-195 · 3.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Introduction:
Histamine H4 receptor (H4R) has been shown to be involved in various inflammatory conditions. Ligands acting on H4R show therapeutic potential in various diseases. For the first time, the positive proof-of-concept clinical trials of the H4 antagonist JNJ39758979 have demonstrated this potential in histamine-induced pruritus. Besides role of H4R in inflammatory conditions, preclinical results in cancer, neuropathic pain, vestibular disorders and type 2 diabetes show the diverse signaling network modulated by H4R. This suggests further potential for H4 ligands in such diseases.
In this review, we have summarized patent applications and papers of the H4R field published between 2012 and 2014. Additionally, we have analyzed the quality of the already described H4 ligands in terms of their ligand efficiency, lipophilic ligand efficiency and lipophilicity-corrected ligand efficiency.
We demonstrate that the number of published patent applications reached a maximum in 2009 and showed some decrease in the last few years. On the other hand, the field is still very lively, reflected by the numerous publications on novel potential therapeutic applications. The favorable property profile of H4 ligands in development shows promise for the upcoming human clinical trials.
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