Non-occlusive mesenteric ischemia (NOMI) is an acute form of intestinal ischemia that occurs in the absence of organic stenosis of the mesenteric arteries. Vasoconstrictive agents have been recognized as potential etiological factors. This report describes the first documented Japanese autopsy case of NOMI induced by methamphetamine (MA), a potent sympathomimetic agent. A forensic autopsy was performed on a man in his 60s who died suddenly. Gross and histopathological findings of the small intestine and mesenteric arteries were examined, and post-mortem toxicological analysis was performed to quantify the blood MA concentration. Autopsy revealed a dilated small intestine without mechanical obstruction, accompanied by non-contiguous ischemic necrosis and no signs of organic stenosis in the mesenteric arteries. Histopathological examination of the small intestine showed hemorrhage and necrosis, consistent with a diagnosis of NOMI. The blood concentration of MA was within the toxic range but below the fatal threshold, suggesting a causal relationship between MA use and the onset of NOMI. Given the fatal outcome despite an MA concentration below the reported fatal range, prolonged mucosal exposure from oral ingestion may have locally intensified vasoconstrictive effects, contributing to intestinal ischemia. This case highlights the importance of considering MA-induced NOMI in the differential diagnosis of sudden death among MA users and highlights the risk of fatal ischemic complications even at non-fatal MA concentrations.

Tongue squamous cell carcinoma (SCC), the most common type of oral cancer, remains a major clinical challenge due to its aggressive behavior and poor prognosis in advanced stages. Standard treatments, including surgery, radiation therapy, and chemotherapy, provide limited benefit highlighting the need for novel therapeutic strategies. Recently, immunotherapy has emerged as a promising approach, largely through its ability to reshape the tumor microenvironment (TME). Increasing evidence indicates that chemokine signaling plays a critical role in tongue SCC by orchestrating the recruitment and function of immune regulatory cells. In particular, CC chemokine ligand 22 (CCL22), mainly produced by tumor-associated macrophages and dendritic cells, promotes the accumulation of CC chemokine receptor 4 (CCR4)-expressing regulatory T cells, consequently establishing an immunosuppressive TME and facilitating tumor progression and immune evasion. Furthermore, emerging studies suggest that histamine-related pathways within the TME can induce CCL22 expression, subsequently amplifying immunosuppressive feedback loops and further modulate tumor-immune interactions, although their precise roles in tongue SCC remain incompletely understood. A deeper understanding of these intertwined networks may uncover new therapeutic targets and enhance the efficacy of existing immunotherapies, including immune checkpoint inhibitors. This review provides an updated overview of the immune landscape of tongue SCC, with special emphasis on the CCL22-CCR4 axis and its interaction with histamine signaling. A deeper understanding of CCL22- and histamine-mediated pathways may contribute to the development of more effective and personalized immunotherapy strategies for tongue SCC.

Background: Ammonia is toxic at high concentrations, and those who handle corpses should be cautious about the ammonia produced by decomposition. However, there is a dearth of reports showing an appropriate index for the ammonia level of corpses. Methods: The progression of decomposition was divided into four stages based on easily visible changes in appearance, namely, skin discoloration and soft tissue destruction. Ammonia was quantified in the liquid decomposition products on the surface of the corpse and in the air surrounding it. Results: During moderate to severe decomposition, ammonia concentrations rose to levels that could cause serious damage to the respiratory system and ocular mucosa due to chemical irritation. However, as decay progressed and bone became exposed, ammonia concentration decreased. Conclusion: This study revealed that ammonia levels can be predicted from the visual stage of corpse decomposition. We believe that these results can guide the safe handling of bodies.

Study objective: Acute thoracic aortic dissection (ATAD) has a high mortality rate. Factors that contribute to its onset include the environment, genetic factors, and infectious diseases. Recently, the presence of monocytes/macrophages has been suggested to attract inflammatory and immune cells to lesions. This, together with levels of D-dimer, brain natriuretic peptide (BNP), aspartate aminotransferase (AST), and lactate dehydrogenase (LD), may be useful in predicting a prognosis for ATAD. This study examined the relationship between a combination of such laboratory data and prognosis in ATAD. Design: A single-center retrospective study. The association between early mortality from ATAD and laboratory data was statistically investigated. Setting: Treatment strategies were at the discretion of each attending physician. Participants: A total of 118 patients with ATAD (59 early deaths and 59 survivors). Main outcome measures: The value of D-dimer, BNP, AST, and LD levels, and the peripheral blood monocyte ratio as scores for the early prediction of a prognosis without requiring advanced testing equipment. Results: The AST/LD, D-dimer, and BNP levels were significantly elevated in those who died prematurely. In contrast, the monocyte ratio in the peripheral blood leukocyte fraction was significantly decreased. The AST/LD, which was associated with cardiac troponin I, was the most significant variable. An average positive value from each test was defined as an acute aortic dissection prognostic score (AAD-PS). The area under the curve on the receiver operating characteristic was 0.895. Conclusion: In ATAD patients, the AAD-PS may be a potentially new and useful test item for predicting prognosis.

The surface of a rotting corpse is covered with liquid decomposition products that have flowed out of the body that include putrefactive amines produced via putrefaction and decarboxylation reactions of proteins. Ammonia generated by deamination is also present around the corpse as a liquid or gas. As these putrefactive substances are toxic to humans, we attempted to measure the concentration of putrefactive substances in decomposed corpses in this study. Liquid putrefaction products were collected from the surface of a corpse, and the concentrations of putrefactive amines such as histamine, tyramine, phenethylamine, and tryptamine were analyzed by LC-MS/MS. Ammonia in the liquid and air around the corpse was also measured. Putrefactive amines and ammonia were present on all corpse surfaces. The highest concentrations and postmortem days in parentheses were as follows: histamine 2.26 mg/g (15 days), tyramine 1.77 mg/g (16 days), phenethylamine 4.90 mg/g (24 days), tryptamine 1.58 mg/g (17 days) and ammonia 25.6 mg/g (24 days postmortem). The highest concentration of ammonia in the air was 1310 ppm at 24 days postmortem. The ammonia level in the air around a corpse is toxic to humans. Inhalation of putrefactive amines and ammonia can cause chemical irritation to the respiratory tract and the skin and damage the mucous membrane of the eye. Oral ingestion can also cause poisoning symptoms such as blood pressure changes and headaches. Adequate protection against putrefactive substances is required when in contact with decaying corpses.

BACKGROUND:Although not widely known, several types of cancers express histamine. Squamous cell carcinoma (SCC) of the tongue is one such cancer, and histamine expression is associated with the tumor microenvironment. Our aim was to examine whether histamine expression is a useful prognostic factor for tongue SCC. METHODS:Histamine cannot be accurately measured directly because it is rapidly degraded after secretion. Therefore, L-histidine decarboxylase (HDC), an enzyme that synthesizes histamine in a single step, was used to estimate histamine secretion. In a retrospective study, tongue SCC samples from patients were immunohistochemically stained for HDC; the staining intensity was semi-quantified and evaluated relative to indices used in histopathological diagnosis. RESULTS:High expression of HDC was associated with the worst tumor invasion and tumor budding. Overall survival curves revealed that patients with tongue SCC showing high HDC expression had a poor prognosis. CONCLUSION:The expression of histamine may be a prognostic indicator for tongue SCC.

A woman in her 30s who was being treated for a mental illness with several psychotropic drugs was admitted to the hospital after being found in a state of unconsciousness and respiratory arrest at home. She was pronounced dead 12 hours after she was discovered. Her autopsy revealed symmetrical hemorrhagic necrosis in the putamen on both sides of her cerebrum. Although many drugs were detected in her blood, all of those other than dextromethorphan (DXM) were within or below the therapeutic range. Her blood DXM was 1.73 μg/ml at admission and 1.61 μg/ml at autopsy, which were within the toxic range or coma-to-death range. The cause of death was diagnosed as DXM poisoning. DXM can cause hallucinations and euphoria if taken in excess, but since it is available as an over-the-counter drug at general pharmacies, an increasing number of young people are overdosing on it, mistakenly believing it to be a safe drug with few side effects. We believe that further social measures against DXM are necessary in Japan, such as disseminating correct knowledge in society and regulating over-the-counter sales.

Background: Acute aortic dissection has a high mortality rate, especially for Stanford type A with a dissected ascending aorta. Cardiac tamponade is one of the most common complications of acute type A aortic dissection (ATAAD) and can cause death. However, the pathogenesis is often unclear. We aimed to examine laboratory findings at the onset of disease and macrophage involvement. Methods: Hematological and biochemical parameters, and D-dimer, brain natriuretic peptide (BNP), and high-sensitivity troponin I (hs-cTnI) levels in 70 patients with ATAAD at our hospital were investigated. Additionally, the myocardium and aorta after autopsy of an ATAAD case with cardiac tamponade were pathologically examined.Results: Forty-four ATAAD cases were complicated by cardiac tamponade. The mean age of patients with cardiac tamponade and proportion of patients over 70 years of age were both significantly higher than for those without cardiac tamponade. Evaluable D-dimer values were higher than 0.5 mu g/mL in all patients. Significantly elevated laboratory parameters in patients with cardiac tamponade included: lactate dehydrogenase, aspartate aminotransferase, C-reactive protein, lactate, BNP, and hs-cTnI. However, multivariate analysis showed only hs-cTnI was significantly associated with cardiac tamponade. Histological examination revealed numerous M2-like macrophages infiltrating the myocardium and dissecting aorta, expressing CC chemokine ligand (CCL)2 together with vascular endothelial growth factor-C and matrix metalloproteinase-9. The peripheral monocyte-to-neutrophil ratio (MNR) was also significantly higher in cardiac tamponade.Conclusions: In ATAAD patients with cardiac tamponade, hs-cTnI was significantly elevated and CCL2 expression was observed, which may be involved in the expression of M2-like macrophages via an increased MNR.

The C-C motif chemokine ligand 22 (CCL22) chemokine is produced by M2-like tumor-associated macrophages (TAMs) in the tumor microenvironment. Chemokine C-C motif receptor 4 (CCR4), the CCL22 receptor, on T helper2 (Th2) cells leads to a Th2 cytokine-dominant environment. In our previous study, lymph node metastasis was the main predictor of tongue squamous cell carcinoma (SCC) via CCL22. Therefore, the present study aimed to investigate the effects of CCL22 and a Th2 cytokine-predominant tumor microenvironment on vascular endothelial growth factor (VEGF)-C expression and lymphangiogenesis. The post-operative courses of 110 patients with early-stage tongue SCC with a histopathological diagnosis based on the 8th TNM classification were followed up (mean/median follow-up time, 47.1/42.0 months) from surgery until death or the last follow-up visit, and subsequent lymph node relapse was assessed. Lymphangiogenesis and the immunohistochemical expression of several markers (CCL22, CCR4 and VEGF-C) were evaluated. The Kaplan-Meier method was used to plot lymph node relapse-free survival and overall survival curves, which were compared using the log-rank test. In vitro, the association between CCL22 and VEGF-C by interleukin (IL)-4/signal transducer and activator of transcription 6 (STAT6) stimulation was examined. Lymphangiogenesis was significantly associated with lymph node relapse (P<0.001) and a CCL22+ macrophage ratio (P<0.001). CCL22+ TAMs were positive for VEGF-C and surrounded by CCR4+ cells. Additionally, VEGF-C expression was increased in IL-4/STAT6-stimulated macrophages. In addition, the STAT6 signaling pathway was activated in the SCC cells in the deeply invaded part of the tumor along with the aggregated macrophages. In conclusion, TAM CCL22 expression led to lymph node relapse via VEGF-C expression within the tumor microenvironment and the IL-4/STAT6 signaling pathway in early stage tongue SCC. Additionally, the worst pattern of invasion and depth of invasion were revealed to be useful parameters for lymph node relapse in patients with tongue SCC. The present study suggested that CCL22 contributed to the role of M2-like differentiated TAMs in prognosis and lymph node relapse via IL-4/STAT6 and VEGF. The IL-4/STAT6 signaling pathway may be a new molecular target for tongue SCC.

Heterotopic gastric mucosa in the duodenal bulb is a rare congenital disorder with varied clinical presentations. The mechanism of formation of a duodenal ulcer is failure of balance of the attack factor and the defense factor, which is the same as the mechanism of formation of a gastric ulcer. However, the true etiology of the duodenal ulcer remains unknown. Gastric mucosa can secrete gastric juice which injures itself, but the duodenal mucosa does not contain cells secreting a digestive enzyme. We assume that duodenal ulcers are caused by the presence of heterotopic gastric mucosa that can secrete gastric acid. This study was designed to assess the prevalence and associations of heterotopic gastric mucosa in duodenal ulcers. The present study included 137 patients who underwent biopsy or resection of duodenal ulcer. We detected gastric foveolar metaplasia due to inflammation from a heterotopic gastric mucosa using immunohistochemical staining. Heterotopic gastric mucosa consists of foveolar epithelium (MUC5AC-positive) and fundic gland (H⁺K⁺ ATPase-positive parietal cells, pepsinogen I-positive chief cells and MUC6-positive mucous neck cells), whereas gastric metaplasia is composed of foveolar epithelium without fundic glands. These specimens were stained with toluidine blue for detection of Helicobacter pylori infection. Among the 137 patients with duodenal ulcer, 76 cases (55%) had heterotopic gastric mucosa in the obtained specimens, and Helicobacter pylori was found in 45 cases (59%,45/76) among those with heterotopic gastric mucosa. Our results suggest that heterotopic gastric mucosa was strongly associated with concurrent duodenal ulcer.

Background CCL22, mainly synthesized by monocyte-derived alternative (M2) macrophages, belongs to the CC family of chemokines. CCR4, the receptor for CCL22, is expressed in regulatory T cells (Tregs) and Th2 cells. The Yamamoto-Kohama (YK) mode of invasion has been associated with tumor prognosis. Herein, we investigated the role of CCL22 in the tumor microenvironment and its effect on the overall survival rate in patients with tongue squamous cell carcinoma (SCC). Methods Tumor sections obtained from 92 patients with tongue SCC were graded based on the mode of invasion according to the YK classification. The expressions of several markers (CCL22, CD8, and Ki-67 by immunohistochemistry; CCR4 and FoxP3 by immunofluorescent staining) were evaluated. Student's t test and chi-square tests were used to compare differences between numerical variables and groups, respectively. Survival curves were plotted according to the Kaplan-Meier method and compared using a log-rank test. Hazard ratios and 95% confidence intervals were estimated using univariate or multivariate Cox proportional hazard models. Results The expression of CCL22 was significantly correlated with YK classification, overall survival rate (P < 0.001), a decrease in the number of CD8-positive cells, and an increase in the tumor Ki-67 index. In addition, CCR4-positive cells were observed around CCL22-positive macrophages. Conclusion These findings indicate that the expression of CCL22 in the tumor microenvironment led to a deterioration in the prognosis of patients with tongue SCC by influencing the balance of M1- and M2-like macrophages.

Aim: CCL22 is a member of the CC-chemokines. The functional role of CCL22 involves migration and recruitment of monocytes. CCL22 is expressed in M2-macrophages. In this study we investigated the hypothesis that CCL22 is involved in the processes of atherosclerosis via the balance of M1- and M2-macrophage due to switching of histamine H1receptor (H1R) and H2receptor (H2R).

Aim: CCL22, mainly synthesized by monocyte-derived alternative (M2) macrophages, belongs to the CC family of chemokines and is involved in monocyte migration and recruitment. We have previously investigated CCL22 and histamine in atherosclerosis. Here, we investigated the hypothesis that CCL22 is involved in atherosclerosis, which is influenced by the differentiation of macrophage phenotypes via histamine. Methods: CCL22 expression was investigated in human carotid arteries and coronary arteries with bare metal stents. Ligated carotid arteries of wild-type (C57BL/6J) and apolipoprotein E-deficient mice were also used as atherosclerotic models. The localization and expression of CCL22 and classical (M1)-like and M2-like macrophages in various human and mouse atherosclerotic lesions were investigated by immunohistochemical examination and quantitative real-time polymerase chain reaction. Histamine is expressed in atherosclerosis, and it induces inflammation and immunity. Human- and mice-derived monocytes and macrophages were used to examine the role of histamine in macrophage differentiation and CCL22-expression. Macrophages derived from histamine receptor 1 (H1R)- and 2 (H2R)-knockout (KO) mice were also examined. Results: Atherosclerotic lesions showed a distribution of heterogeneous macrophage phenotypes with M1-like and M2-like macrophage dominant sites. CCL22 was distributed in sparse areas of vascular smooth muscle cells (VSMCs) and associated with M2-like macrophages. Moreover, H2R stimulation was associated with CCL22 expression via M2-like macrophage dominant differentiation. Conclusion: The expression of M1- or M2-like macrophages in atherosclerosis were observed to be dependent on the distribution of VSMCs owing to differences in causal stimuli and the switching of histamine receptors via Th1 or Th2 cytokines. These results suggest that CCL22 may control atherosclerosis.

A 55-year-old postmenopausal female presented with genital bleeding and lower abdominal mass. An abdominal MRI revealed a heterogeneously enhanced, 15 × 10 cm mass, completely filling the lumen of the enlarged uterus. The cytologic analysis of the mass showed tumor cells in small clusters and as individual cells showing hyperchromatic round to oval nuclei, and pleomorphic and occasionally unipolar “tadpole”-shaped cytoplasm, in a background of severe necrosis and many degenerated squamous cells. We first interpreted it merely as atypical cells, possibly originated from sarcoma. A total abdominal hysterectomy and salpingo-oophorectomy were performed, and gross examination showed an exophytic polypoid mass with a whitish to white-grayish, necrotic appearance, protruding from the endometrial mucosa. Microscopically, the tumor was composed of a diffuse proliferation of highly atypical spindle-shaped cells, admixed with many characteristic rhabdomyoblasts having abundant densely eosinophilic cytoplasm with sometimes distinct cross-striations, coexisted with cellular primitive small blue round to oval cells foci. However, neither carcinoma nor additional heterologous sarcoma components were completely seen within our thorough investigation. Therefore, we finally made a diagnosis of embryonal rhabdomyosarcoma arising from the uterine corpus. We should be aware that owing to its characteristic features, cytopathologists might be able to determine a genuine diagnosis, based on multiple and adequate cytology samplings.

Introduction: CCL22 (macrophage-derived chemokine) is a member of the CC-family of chemokines. The functional role of CCL22 as a chemokine involves migration/ recruitment of monocytes and the stimulation of platelet activity. In this study, we investigated the relationship between CCL22 and atherosclerosis in monocytes/ macrophages of mice and humans with respect to atherosclerosis. Hypothesis: We assessed the hypothesis that CCL22 is involved in the process of atherosclerosis and can be a biological marker for progression of atherosclerosis and atherosclerotic disease. Methods: Apolipoprotein E deficient (apoE-/-) mice as atherosclerotic models were used for this study. Male apoE-/- mice were weaned at 8 weeks of age onto a high-cholesterol diet consisting of 1.25% cholesterol and were maintained on this diet for 12 weeks or 24 weeks. Another group of apoE-/- mice was maintained for 30 weeks on a normal chow diet. Serum CCL22 concentrations were measured by ELISA and expression of CCL22 mRNA in the atheroma were evaluated by real-time PCR. Furthermore immunohistochemical staining was performed. In vitro, the expressions of CCL22 in the mouse monocytes and macrophages were examined and discussed. The expression of CCL22 human monocytes/ macrophages and human atherosclerotic lesions were similarly investigated. Results: ApoE-/- mice had predominately high concentrations of CCL22 compared with wild-type (C57BL/6J) mice. ApoE-/- mice developed atherosclerotic lesions with aging and this was influenced by a high-cholesterol diet. CCL22 concentrations increased with aging and a high-cholesterol diet. Their atherosclerotic lesions, especially in macrophages contained abundant levels of CCL22. When the mouse monocyte differentiated into macrophage, the cells showed similar expression of CCL22. Similarly, human macrophages also expressed abundant levels of CCL22 more than monocytes. In addition, immunohistochemical analysis of human atherosclerotic lesions and coronary stenotic lesion revealed that macrophages express CCL22. Conclusion: In conclusion, these results suggested that this molecule is involved in the atherogenic processes and CCL22 may represent an attractive molecular marker for progression of atherosclerosis.

AIM Macrophage-derived chemokine (CCL22) is a member of the CC-family of chemokines synthesized by monocyte-derived macrophages. Previous studies have reported a relationship between CCL22 and atherosclerosis and the role of histamine in this pathway. Histamine ncreases the CCL22 expression in human monocytes via the H2 receptor. In this study, we investigated the effects of CCL22 and the role of histamine in mouse monocytes with respect to atherosclerosis. METHODS AND RESULTS The expression of CCL22 was investigated in apolipoprotein E (apoE)-deficient mice. The mice had high serum concentrations of CCL22 and their atherosclerotic lesions contained abundant levels of CCL22. In addition, when the mouse monocyte cell line (J774A.1 cells) differentiated into macrophage-like cells, the cells showed a similar expression of CCL22 and reduced expression of H2 receptors. Histamine is synthesized from l-histidine by histidine decarboxylase (HDC) in a single enzymatic step. HDC knockout mice were compared with apoE/HDC double knockout mice. The findings indicated that the expression of CCL22 in atherosclerosis models is under the influence of histamine. In addition, in vitro studies using J774A.1 cells and an in vivo study using histamine receptor knockout mice showed that histamine stimulates the CCL22 expression via the histamine H2 receptor. CONCLUSIONS The current results support our previous CCL22 studies in the setting of human atherosclerosis and suggest that this molecule is involved in the atherogenic processes in a mouse model of atherosclerosis.

A mammary nodular lesion was recognized one month before the surgery in the right upper breast of a 55-year-old female. The fine needle aspiration cytology specimens contained many individual bizarre, multi-nucleated, and/or giant cells having hyperchromatic pleomorphic nuclei, prominent nucleoli, and relatively abundant cytoplasm, admixed with numerous mitotic figures in a hemorrhagic or inflammatory background. A small amount of sheet-like or three-dimensional clusters of malignant cells coexisted. We first interpreted it as high-grade malignancy, such as invasive carcinoma, not otherwise specified. A right breast-conserving surgery was performed, and gross examination revealed a cystic cavity-formed and solid tumor lesion, measuring 35 × 35 × 25 mm and looking gray-yellowish to -whitish. On microscopic examination, the tumor was composed of a diffuse proliferation of highly atypical cells devoid of adhesive characteristics, including many multi-nucleated giant bizarre cells, in a haphazard fashion with stromal invasion, alternating with sarcomatoid features of spindle tumor cells. The cystic cavity was surrounded by hemorrhagic and inflammatory granulation tissue and lined by mostly denuded but atypical tumor cells or bland-looking flattened epithelial cells. Immunohistochemically, these tumor cells are specifically positive for all epithelial markers. Therefore, we made a conclusive diagnosis of pleomorphic carcinoma of the breast with cyst formation. We should be aware that, owing to its characteristic findings, cytopathologists can diagnose correctly, based on careful cytological examination of adequate samplings.

Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase kinase kinase that plays a crucial role in stress-induced apoptosis. Recently, we have reported that suppressed macrophage apoptosis in ASK1 and apolipoprotein E double-knockout mice accelerates atheromatous plaques in the hyperlipidemia-induced atherosclerotic model. However, the pathogenic role of smooth muscle cell (SMC) apoptosis in atherosclerosis still remains unclear. We investigated neointimal remodeling in ligated carotid arteries of ASK1-deficient mice (ASK1(-/-)) for 3 weeks. ASK1(-/-) mice had significantly more suppressed intimal formation, inversely manifesting as potential anti-atherogenic aspects of ASK1 deficiency, characterized by fewer SMCs and less collagen synthesis; and fewer apoptotic SMCs, infiltrating T lymphocytes, and microvessels, associated with decreased apoptosis of luminal endothelial cells, compared with those of wild-type mice. Injured arteries of ASK1(-/-) mice also showed significantly down-regulated expression of pro-apoptotic markers, adhesion molecules, and pro-inflammatory signaling factors. Moreover, tumor necrosis factor-α-induced apoptosis was markedly suppressed in cultured aortic SMCs from ASK1(-/-) mice. These findings suggest that ASK1 accelerates mechanical injury-induced vascular remodeling with activated SMC migration via increased neovascularization and/or enhanced SMC and endothelial cell apoptosis. ASK1 expression, especially in the SMCs, might be crucial, and reciprocally responsible for various pro-atherogenic functions, and SMC apoptosis seems to be detrimental in this model.

Aims: Consumption of a high-fructose diet (HFrD) can induce the development of a metabolic syndrome, manifesting as nonalcoholic steatohepatitis (NASH) and/or type 2 diabetes mellitus (T2DM), via a process in which oxidative stress plays a critical role. Peroxiredoxin 4 (PRDX4) is a unique and only known secretory member of the PRDX antioxidant family. However, its putative roles in the development of NASH and/or T2DM have not been investigated. Results: To elucidate the functions of PRDX4 in a metabolic syndrome, we established a nongenetic mouse model of T2DM by feeding mice a HFrD after injecting a relatively low dose of streptozotocin. Compared with wild-type (WT), human PRDX4 transgenic (Tg) mice exhibited significant improvements in insulin resistance, characterized by a lower glucose and insulin concentration and faster responses in glucose tolerance tests. The liver of Tg also showed less severe vesicular steatosis, inflammation, and fibrosis, along with lower lipid concentrations, lower levels of oxidative stress markers, more decreased expression of hepatic aminotransferase, and more reduced stellate cell activation than those in the WT liver, reminiscent of human early NASH. Hepatocyte apoptosis was also significantly repressed in Tg mice. By contrast, serum adiponectin levels and hepatic adiponectin receptor expression were significantly lower in WT mice, consistent with greater insulin resistance in the peripheral liver tissue compared with Tg mice. Innovation and Conclusion: Our data for the first time show that PRDX4 may protect against NASH, T2DM, and the metabolic syndrome by ameliorating oxidative stress-induced injury. Antioxid. Redox Signal. 19, 1983-1998.

Macrophage-derived chemokine (CCL22) is a member of the CC-family of chemokines and is synthesized by monocyte-derived macrophages and dendritic cells (DCs). In this study, we investigate the relationship between monocytes/macrophages and histamine in atherosclerosis and discover that histamine levels regulate various immunologically important molecules and influences atherosclerotic progression. Immunohistochemical analysis of human atherosclerotic lesions revealed that macrophages and DCs express CCL22. The human acute monocytic leukemia cell line (THP-1) adhered to culture plates and morphologically changed to macrophage-like cells when treated with tetradecanoylphorbol-13-acetate (TPA). Macrophage-like cells derived from THP-1 cells and cultivated peripheral blood mononuclear cells (PBMCs) show similar expression of CCL22. Gene expression of CCL22 was also detected in THP-1 cells treated with histamine and the expression of the protein produced by the CCL22 gene is similar in PBMCs and THP-1 cells. In addition, the histamine H2 receptor mediated these reactions. Our results suggest that CCL22 expression in monocytes is regulated by histamine, and that CCL22 is involved centrally in the development of human atherosclerotic lesions. In conclusion, CCL22 is a marker that is a characteristic of the monocytes/ macrophages migrating into atherosclerotic lesions and histamine plays a role in regulating its expression.