Objectives
Searching for more effective and selective therapies for head and neck cancer, we demonstrated the therapeutic effect of boron neutron capture therapy (BNCT) to treat oral cancer and ...inhibit long‐term tumor development from field‐cancerized tissue in the hamster cheek pouch model. However, BNCT‐induced mucositis in field‐cancerized tissue was dose limiting. In a clinical scenario, oral mucositis affects patients’ treatment and quality of life. Our aim was to evaluate different radioprotectors, seeking to reduce the incidence of BNCT‐induced severe mucositis in field‐cancerized tissue.
Materials and Methods
Cancerized pouches treated with BNCT mediated by boronophenylalanine at 5 Gy were treated as follows: control: saline solution; Hishigh: histamine 5 mg kg−1; Hislow: histamine 1 mg kg−1; and JNJ7777120: 10 mg kg−1.
Results
Hislow reduced the incidence of severe mucositis in field‐cancerized tissue to 17% vs CONTROL: 55%; Hishigh: 67%; JNJ7777120: 57%. Hislow was non‐toxic and did not compromise the long‐term therapeutic effect of BNCT or alter gross boron concentration. Conclusion: Histamine reduces BNCT‐induced mucositis in experimental oral precancer without jeopardizing therapeutic efficacy. The fact that both histamine and boronophenylalanine are approved for use in humans bridges the gap between experimental work and potential clinical application to reduce BNCT‐induced radiotoxicity in patients with head and neck cancer.
Objective
The objective of this study was to investigate whether histamine H4 receptor (H4R) antagonists could prevent experimental periodontitis (EP)‐induced histological, functional and ...inflammatory alterations in submandibular gland (SMG), periodontal bone and gingiva.
Methods
Bilateral EP was induced for 2 weeks in anaesthetized male rats. The effect of systemic and local administration of H4R antagonists (JNJ7777120, JNJ10191584) on histopathology and functionality of SMG, bone loss and gingival inflammation was evaluated.
Results
The subcutaneous administration of JNJ7777120 prevented periodontitis‐induced SMG histological injury, reducing vacuolization and apoptosis and additionally reversed the increased prostaglandin E2 (PGE2) levels in SMG while it partially reversed the methacholine‐induced salivation reduction produced by periodontitis. JNJ7777120 attenuated bone loss and the increased PGE2 levels and inflammatory infiltration in gingival tissue of rats with periodontitis. Finally, local administration of JNJ7777120 and JNJ10191584 was also beneficial for improving periodontal parameters.
Conclusions
H4 receptor antagonists are able to ameliorate periodontitis‐induced injury on SMG, gingival tissue and bone structure, suggesting that pharmacological targeting of H4R could be an attractive strategy to improve periodontal health.
The aim of the present work was to evaluate the potential protective effect of histamine on Doxorubicin (Dox)-induced hepatic and cardiac toxicity in different rodent species and in a triple-negative ...breast tumor-bearing mice model. Male Sprague Dawley rats and Balb/c mice were divided into four groups: control (received saline), histamine (5 mg/kg for rats and 1 mg/kg for mice, daily subcutaneous injection starting 24 h before treatment with Dox), Dox (2 mg/kg, intraperitoneally injected three times a week for 2 weeks) and Dox+histamine (received both treatments). Tissue toxicity was evaluated by histopathological studies and oxidative stress and biochemical parameters. The combined effect of histamine and Dox was also investigated in vitro and in vivo in human MDA-MB-231 triple-negative breast cancer model. Heart and liver of Dox-treated animals displayed severe histological damage, loss of tissue weight, increased TBARS levels and DNA damage along with an augment in serum creatine kinase-myocardial band. Pretreatment with histamine prevented Dox-induced tissue events producing a significant preservation of the integrity of both rat and mouse myocardium and liver, through the reduction of Dox-induced oxidative stress and apoptosis. Histamine treatment preserved anti-tumor activity of Dox, exhibiting differential cytotoxicity and increasing the Dox-induced inhibition of breast tumor growth. Findings provide preclinical evidence indicating that histamine could be a promising candidate as a selective cytoprotective agent for the treatment of Dox-induced cardiac and hepatic toxicity, and encourage the translation to clinical practice.
Objective
The objective of this study was to investigate whether histamine H
4
receptor (H
4
R) antagonists could prevent experimental periodontitis (
EP
)‐induced histological, functional and ...inflammatory alterations in submandibular gland (
SMG
), periodontal bone and gingiva.
Methods
Bilateral
EP
was induced for 2 weeks in anaesthetized male rats. The effect of systemic and local administration of H
4
R antagonists (
JNJ
7777120,
JNJ
10191584) on histopathology and functionality of
SMG
, bone loss and gingival inflammation was evaluated.
Results
The subcutaneous administration of
JNJ
7777120 prevented periodontitis‐induced
SMG
histological injury, reducing vacuolization and apoptosis and additionally reversed the increased prostaglandin E2 (PGE2) levels in
SMG
while it partially reversed the methacholine‐induced salivation reduction produced by periodontitis.
JNJ
7777120 attenuated bone loss and the increased
PGE
2 levels and inflammatory infiltration in gingival tissue of rats with periodontitis. Finally, local administration of
JNJ
7777120 and
JNJ
10191584 was also beneficial for improving periodontal parameters.
Conclusions
H
4
receptor antagonists are able to ameliorate periodontitis‐induced injury on
SMG
, gingival tissue and bone structure, suggesting that pharmacological targeting of H
4
R could be an attractive strategy to improve periodontal health.
The involvement of histamine in cancer growth represents an old controversy and direct experimental evidence proving this hypothesis is not still available. In this paper we review the most relevant ...mechanisms referring to the role of histamine receptors, histidine decarboxylase and histamine release in the onset of an autocrine loop, that enables histamine to act as an autocrine growth factor. We postulate that this autocrine loop, that has been studied in an experimental mammary carcinoma model induced in rats, may be present in different human neoplasias. Therefore, the better understanding of this novel regulatory pathway that is controlled by histamine may contribute to identifying new therapeutic targets.
Background Interleukin‐6 (IL‐6) is a bifunctional growth factor in malignant melanoma; its expression increases during the malignant progression of the disease. Histamine, detected in large amounts ...in normal and pathological proliferating tissues, is an important paracrine and autocrine regulator of normal and tumour cell proliferation as well.
Materials and methods We investigated the presence and function of IL‐6 and histamine in the WM35 primary human melanoma cell line with respect to their direct role in cell proliferation and their regulatory interactions.
Results IL‐6 inhibited the proliferation of WM35 melanoma cells and increased significantly the expression of histidine decarboxylase as well as histamine production. It had dose‐dependent effects on the proliferation: high concentration (10−5 M) was inhibitory through H1 histamine receptors while low histamine concentration acting on H2 receptors, with a simultaneous increase of cAMP, enhanced colony formation in the monolayer. Furthermore, IL‐6 increased the H1‐ but decreased the H2‐histamine receptor expression of the melanoma cells. On the other hand, histamine was locally synthesized by the WM35 melanoma cells.
Conclusion We suggest that the growth arrest induced by IL‐6 is in part mediated by its dual action on histamine: a shift toward H1 receptor predominance and an elevation of locally produced histamine with prevalent action on the inhibitory response triggered through the H1 receptor. These findings suggest a local cross‐talk between histamine and IL‐6 in the regulation of melanoma growth.
Histidine decarboxylase (HDC) is the single enzyme responsible for histamine synthesis. HDC-deficient mice (HDC−/−) have no histamine in their tissues when kept on a histamine-free diet. Therefore, ...the HDC−/− mice provide a suitable model to investigate the involvement of histamine in the regulation of histamine receptor expression. Gene expression of H1 and H2 histamine receptors was studied in several organs of HDC−/− mice and compared to standard (HDC+/+) mice. In many tissues, prolonged absence of histamine induced down-regulation of the H2 receptor subtype. The expression of the H1 receptor was less sensitive to histamine deficiency. Exogenous histamine present in the diet abolished the differences observed in H2 receptor expression. These results suggest that the expression of mouse H2 receptor is under the control of histamine in a tissue-specific manner.
Two specific binding sites for histamine were characterized in the cell membrane of
Nnitroso-
N-methylurea (NMU)-induced tumors. The first one, with higher affinity (
K
d
= 4 ± 2 nM), was further ...identified as an H
2 type, while the lower affinity one (35 ± 10 nM) corresponded to an H
1 receptor. Histamine concentrations up to 50 nM, as well as H
2 agonists, significantly enhanced the phosphoinositide turnover by acting through higher affinity H
2 receptors. On the other hand, histamine at concentrations over 50 nM and H
1 agonists produced a 100% increase in cAMP levels in a response specifically blocked by mepyramine. These H
1 and H
2 histamine receptors that exhibit different linkages to second messenger systems may prove to be a characteristic of cells with a high proliferating capacity, such as undifferentiated or transformed cells.
This study sought to evaluate the effects of veno-venous ultrafiltration on myocardial contractility in children undergoing cardiopulmonary bypass (CPB) for repair of congenital heart defects.
...Ultrafiltration (UF) is currently used to diminish postoperative fluid accumulation following CPB in children. Previous reports indicate improvement in hemodynamics immediately after UF, but the mechanism of its action is unknown.
Twenty-three patients (ages 2 months to 9.1 years; 13 males, 10 females) underwent UF for 10 min after CPB. Twelve patients underwent UF immediately after CPB (Group A). They were studied: (1) before and (2) after CPB, (3) after UF, and (4) 10 min after UF. Eleven patients underwent UF 10 min after CPB (Group B). They were studied: (1) before and (2) after CPB, (3) after a 10-min delay before UF, and (4) after UF. Contractility was determined by the difference in the observed and predicted velocity of circumferential fiber shortening for the measured wall stress, using transesophageal echocardiography. Left ventricular wall thickness was also measured.
There was significant improvement in contractility after UF in both groups (mean+/-SD, Group A: -0.28+/-0.13 to -0.01+/-0.21 circ/s, p < 0.05; Group B: -0.26+/-0.16 to -0.11+/-0.17 circ/s, p < 0.05). Myocardial thickness to cavity dimension decreased in both groups following UF (Group A: 0.19+/-0.04 to 0.14+/-0.03, p < 0.05; Group B: 0.18+/-0.04 to 0.14+/-0.03, p < 0.05).
UF improves hemodynamics by improving contractility and possibly by reducing myocardial edema in children following cardiac surgery. Enhanced patient outcome after ultrafiltration may in part be due to these changes.
The aim of this work was to analyze the effect of estradiol (E(2)), medroxyprogesterone and the two selective estrogen receptor modulators (SERMs) (tamoxifen (Tam) and raloxifene (Ral)) on the ...estrogen receptor (ER) conformers profile performed by size exclusion HPLC in relation to hormone dependence of mammary tumors.
Two types of mammary tumors were studied: tumors transplanted in BALB/c mice that are medroxyprogesterone acetate (MPA)-dependent for growth, and tumors induced in Sprague-Dawley rats by intraperitoneal injection of N-nitroso-N-methylurea (NMU). Tumors from mice treated with MPA, E(2), Tam or Ral and NMU-treated rats were analyzed and compared to that of control.
The tumor conformer profiles were as follows: control and MPA-treated mice showed only one peak (oligomeric form); E(2)-treated mice also showed only one peak (dimer); Tam-treated mice showed one peak corresponding to a possible proteolytic fragment, and Ral-treated mice showed two peaks (oligomeric and a possible proteolytic fragment). On the other hand, NMU-induced mammary tumors from rats showed three peaks (oligomeric, monomeric and proteolytic).
Our findings may indicate that SERMs affect the aggregation state of ER and thereby its ability to modulate genomic transcription mechanisms related to growth rate.
PDF
