Many decades after an outbreak of severe cadmium poisoning, known as Itai-itai disease, cadmium continues to pose a significant threat to human health worldwide. This review provides an update on the effects of this environmental toxicant cadmium, observed in numerous populations despite modest exposure levels. In addition, it describes the current knowledge on the link between heme catabolism and glycolysis. It examines novel functions of heme oxygenase-2 (HO-2) that protect against type 2-diabetes and obesity, which have emerged from diabetic/obese phenotypes of the HO-2 knockout mouse model. Increased cancer susceptibility in type-2 diabetes has been noted in several large cohorts. This is a cause for concern, given the high prevalence of type-2 diabetes worldwide. A lifetime exposure to cadmium is associated with pre-diabetes, diabetes, and overall cancer mortality with sex-related differences in specific types of cancer. Liver and kidney are target organs for the toxic effects of cadmium. These two organs are central to the maintenance of blood glucose levels. Further, inhibition of gluconeogenesis is a known effect of heme, while cadmium has the propensity to alter heme catabolism. This raises the possibility that cadmium may mimic certain HO-2 deficiency conditions, resulting in diabetic symptoms. Intriguingly, evidence has emerged from a recent study to suggest the potential interaction and co-regulation of HO-2 with the key regulator of glycolysis: 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4). HO-2 could thus be critical to a metabolic switch to cancer-prone cells because the enzyme PFKFB and glycolysis are metabolic requirements for cell proliferation and resistance to apoptosis.
Gastric cancer is one of the most common malignant tumors causing death in Fujian Province, China. However, the mortality of gastric cancer is greatly varied in different areas in Fujian; for example, the mortality in Changle City is 7.4 times higher than that in Fuan City. In this study, we compared the differences in serological parameters, pepsinogen (PG) I, PG II, gastrin-17 (G-17), and Helicobacter pylori (H. pylori) antibody, between the two cities. It has been reported that low serum PG I is correlated with atrophic gastritis, a high-risk condition for developing gastric cancer, while high serum G-17 has been used for serological detection of atrophic corpus gastritis. We recruited 224 healthy subjects in Changle and 229 healthy subjects in Fuan, matched in age and sex. The serum levels of PG II and G-17 were significantly higher in Changle than those in Fuan. Importantly, the frequency of the subjects with low serum PG I (< 25 μg/L) was significantly higher in Changle than in Fuan, although the serum PG I levels were similar between the two cities. Moreover, the percentage of the subjects with high serum G-17 (≥ 2 pmol/L) and the positive rate of serum IgG antibody against H. pylori were significantly higher in Changle than those in Fuan. The detected differences in these serological parameters are consistent with the notion that the prevalence of atrophic gastritis may be higher in Changle than in Fuan, which results in a higher risk condition for developing gastric cancer in Changle.
Primary myelofibrosis is a hematologic neoplasm characterized by bone marrow fibrosis and extramedullary hematopoiesis. A similar clinical condition can occur at late stage of myeloproliferative neoplasms such as polycythemia vera and essential thrombocythemia. Although allogeneic hematopoietic stem cell transplantation (HSCT) is currently the only curative strategy for both conditions, massive splenomegaly frequently observed in patients with myelofibrosis is considered to be a risk factor for graft failure or engraftment delay after transplantation. A proportion of patients can benefit from splenectomy before transplantation but such procedures have been associated with substantial surgical morbidity. Here, we report two elderly patients with myelofibrosis who received scheduled splenic irradiation for massive splenomegaly immediately prior to allogeneic HSCT instead of undergoing splenectomy. The first patient was a 60-year-old woman who received peripheral blood stem cell transplantation for post-essential thrombocythemia myelofibrosis from an HLA-identical sibling; the second patient was a 60-year-old man who received unrelated bone marrow transplantation for primary myelofibrosis. After receiving fractionated splenic irradiation and fludarabine-based reduced-intensity conditioning regimens, these patients showed remarkable reduction of their splenomegaly at the time of transplantation. They attained successful donor cell engraftment without severe complications related to splenic irradiation, while improvement in splenomegaly was durable. Our experience suggests that splenic irradiation before allogeneic HSCT might be a safe and effective alternative to splenectomy for myelofibrosis patients with massive splenomegaly in terms of reducing the risk of surgical morbidity.
Left ventricular noncompaction (LVNC) represents arrest of the normal myocardial compaction process and results in the persistence of multiple prominent ventricular trabeculations and deep intertrabecular recesses. LVNC can be classified into 2 forms: isolated LVNC in the absence of other cardiac anomalies and non-isolated LVNC associated with congenital heart disease. The clinical presentation and the natural history of LVNC are highly variable, ranging from no symptoms to congestive heart failure, arrhythmias, and systemic thromboemboli. LVNC is genetically heterogeneous and can be inherited as an autosomal dominant or X-linked recessive disorder. It is also linked to mutations in several genes, encoding the sarcomeric proteins, such as myosin heavy chain 7 (MYH7). MYH7 encodes the β-myosin heavy chain, expressed in the cardiac muscle. The operative indication for patients with non-isolated LVNC is unclear. Here, we report the first successful case of surgical repair of a ventricular septal defect (VSD) in an infant with non-isolated LVNC associated with a novel MYH7 mutation. This mutation leads to the substitution of 7 amino acid residues (671-677) in the actin-binding region of the protein. After the VSD operation, the patient's congestive heart failure and pulmonary hypertension improved. His condition has remained stable for 18 months with pharmacotherapy comprising diuretics, an angiotensin converting enzyme inhibitor, and a β-blocker. Although the postsurgical observational period was short, the findings indicate that LVNC mutation analyses may facilitate surgical decisions and help predict clinical courses.
Many studies have aimed to identify anti-atherogenic agents in cardiovascular medicine. We have recently demonstrated that the combination therapy with olmesartan (OLM), an angiotensin II receptor blocker, and azelnidipine (AZL), a dihydroprydine calcium-channel blocker, improves endothelial function in diabetic Apolipoprotein-deficient (ApoE−/−) mice. In the present study, we examined whether this combination therapy also inhibits atherosclerosis in mice. We used male control and streptozocin-induced diabetic ApoE−/− mice. Diabetic ApoE−/− mice were orally treated for 5 weeks with vehicle (Untreated), OLM (30 mg/kg/day), AZL (10 mg/kg/day), their combination (OLM+AZL), or hydralazine (HYD, 5 mg/kg/day) as an antihypertensive control. At 5 weeks, systolic blood pressure was significantly elevated in Untreated but was normalized in OLM+AZL and HYD. The atherosclerosis area in the thoracic aorta, perivascular fibrosis and medial thickness of the coronary arteries were increased in Untreated and were ameliorated in OLM+AZL but not in HYD. Staining with a fluorescent probe dihydroethidium showed that production of reactive oxygen species was increased in Untreated, and ameliorated in OLM+AZL. Consistent with these findings, macrophage infiltration in the kidney and the expression of receptor for advanced glycation end-products in the heart, kidney and liver were increased in Untreated and were all ameliorated in OLM+AZL, associated with up-regulation of endothelial NO syntheses (eNOS). In conclusion, the combination therapy with OLM and AZL exerts anti-atherogenic effect in diabetic ApoE−/− mice through suppression of oxidative stress and activation of eNOS, independent of its blood pressure-lowering effects. Clinically, this combination therapy may be useful for patients with hypertension, hyperlipidemia and diabetes.
Nanomaterials have great potential in the field of medicine and have been studied extensively. In a previous study, we addressed the potential of silver iodide (AgI) as X-ray contrast media, because it possessed high imaging ability in the measurement by X-ray computed tomography (X-CT) in vitro, and its surface can be modified with many functional groups. We developed the method of silica coating to make AgI nanoparticles more stable and uniform in size. However, the safety and metabolism of nanoparticles in vivo remains to be determined. The objective of the present study was to evaluate the in vivo biodistribution of silica-coated AgI nanoparticles (SAgINPs). X-CT, transmission electron microscopy (TEM), and inductively coupled plasma atomic emission spectrometry (ICP-AES) were performed prior to and at intervals following the intravenous administration of SAgINPs to rats and rabbits. ICP-AES is a spectral technique that can determine the presence and concentrations of metal samples. The X-CT study showed long-period enhancement in the liver and spleen, but not in the bladder of rats. The TEM study demonstrated that SAgINPs were found in hepatocytes. Using ICP-AES, Ag was detected in the bile juice of rabbits, but not found in the urine of these animals, suggesting that SAgINPs are excreted via the liver. This study shows the quantitative biodistribution of silica-coated nanoparticles for the first time, indicating that our silica coating technique is useful for development of nanoparticles with hepatic excretion. In conclusion, the SAgINPs may provide X-ray contrast media with high imaging ability and biocompatibility.
Psoriasis, characterized by circumscribed, red, thickened plaques with an overlying silver-white scale, is a common T-cell-mediated chronic inflammatory skin disease. Although hydrogen sulfide (H2S) has been shown to be a signaling molecule with both pro- or anti-inflammatory effects, its relationship with psoriasis has not been elucidated. In the present study, 15 patients with chronic progressive psoriasis and 15 healthy volunteers were investigated. Serum H2S levels in psoriasis patients were significantly lower than those of healthy controls (16.69 ± 5.47 μM vs. 34.5 ± 6.39 μM). In contrast, serum levels of tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6) and interleukin-8 (IL-8) were significantly higher in psoriasis patients than healthy controls (22.88 ± 6.24 pg/ml vs. 12.07 ± 3.68 pg/ml; 61.47 ± 8.21 pg/ml vs. 31.54 ± 13.73 pg/ml; and 39.43 ± 8.56 pg/ml vs. 20.55 ± 6.45 pg/ml, respectively). The serum H2S levels negatively correlated with clinical disease severity. Furthermore, treatment of HaCaT human keratinocytes with TNF-α increased the levels of nitric oxide (NO), IL-6 and IL-8 (32.21 ± 5.71 μM vs. 3.22 ± 0.98 μM; 203.96 ± 13.16 pg/ml vs. 13.57 ± 3.75 pg/ml; and 301.24 ± 30.17 pg/ml vs. 29.06 ± 10.91 pg/ml, respectively) in the culture media. Exogenous H2S inhibited the TNF-α-mediated upregulation of NO, IL-6 and IL-8 in a dose-dependent manner. In addition, H2S inhibited TNF-α-mediated activation of p38, extracellular-signal-regulated kinase and nuclear factor kappa B. In conclusion, H2S may play a protective role in the pathogenesis of psoriasis. H2S-releasing agents may be promising therapeutics for psoriasis.
Intrarenal renin-angiotensin system (RAS) plays an important role for the pathogenesis of renal injuries. Experimental studies have demonstrated that angiotensinogen levels in renal tissues reflect the activity of intrarenal RAS. However, dynamics of urinary angiotensinogen have not been investigated in detail. Therefore, we examined the preservation conditions of the measured values of urinary angiotensinogen concentrations and an ultradian rhythm of urinary angiotensinogen excretion in humans. Urine samples were collected from 24 healthy volunteers. The urinary concentrations of angiotensinogen were measured by using ELISA. Two different urine preservation conditions were examined. One cycle of freeze-and-thaw did not change the measured values of urinary angiotensinogen concentrations. Moreover, to keep urine samples at room temperature for 12 hours did not change the measured values of urinary angiotensinogen concentrations. Thus, preservation conditions do not change the measured values of urinary angiotensinogen concentrations. Regarding an ultradian rhythm, blood pressure and the urinary concentrations of angiotensinogen were measured at 09:00, 13:00, and 16:00. The averaged levels of blood pressure were similar over the time. The average of urinary angiotensinogen/creatinine (Cr) ratios was 8.73 ± 1.15 ng/mg Cr at 09:00, 9.53 ± 1.58 ng/mg Cr at 13:00, and 8.58 ± 1.26 ng/mg Cr at 16:00. The urinary angiotensinogen excretion in healthy volunteers does not have an ultradian change during the daytime (P = 0.482). This may be another indication that the intrarenal RAS is independent of the systemic RAS. We have to pay attention to these findings in handling urine samples for measurements of angiotensinogen.
Chronic venous insufficiency (CVI) is a common disease characterized by structural and functional abnormalities of the venous system. Until recently, the pathogenesis of CVI remains largely unknown. MicroRNAs (miRNAs) are a family of endogenous small non-coding RNAs emerged as post-transcriptional gene repressors and play essential roles in diverse pathological processes including vascular disease. However, their roles in CVI have not been elucidated. In this study, we employed oligonucleotide microarrays to perform a genome-wide miRNAs profiling in the great saphenous vein (GSV) tissues of patients with CVI. Our results revealed a total of 14 miRNAs that are expressed differentially in GSV tissues. Among them nine miRNAs were found significantly up-regulated, while five miRNAs were down-regulated significantly. Real-time RT-PCR verified statistically consistent expression of three selected miRNAs (miR-34a, miR-155 and miR-202) with microarrays analysis. These three miRNAs, which were described as crucial regulators in many biological processes and vascular diseases, might also play important roles in CVI. Functional annotation of target genes of differentially expressed miRNAs via bioinformatics approaches revealed that these predicted targets were significantly enriched and involved in several key signaling pathways important for CVI, including mitogen-activated protein kinase pathways, pathways in cancer, apoptosis, and cell cycle, and p53 signaling pathways. In summary, miRNAs might involve in multiple signaling pathways contributing to the pathological processes of CVI. These data may provide fundamental insights into the molecular basis of CVI, which may aid in designing novel approaches for prevention and treatment of this complex disease.
Kawasaki Disease (KD) is acute, febrile, multisystem vasculitis of early childhood, the detailed mechanism of which is still unclear. Skin symptoms occur in KD, such as edema of the hands and feet with subsequent desquamation and redness at the inoculation site of bacillus Calmette-Guerin (BCG). The change at the BCG inoculation site has been considered as a specific feature of KD, although its mechanism is not fully understood. We present an 11-month-old boy who developed fever with redness of the BCG site due to infection with human herpes virus type 6 (HHV6). At the age of 3 months, the patient received BCG. His fever remitted 7 days after the onset of skin redness, with sequential desquamation at the BCG site and extremities, which is not a common feature of HHV6 infection that typically lasts for 3 days. The final diagnosis was exanthema subitum. Characteristically, the HHV6 infection in our patient appeared to be associated with the invigoration of the T cell system, as represented by the elevated serum levels of soluble interleukin-2 receptor (3,490 U/ml vs. normal range 145-519 U/ml). This patient clearly showed redness and crusting at the BCG inoculation site, suggesting that HHV6 infection might cause skin changes similar to those of KD via an unknown mechanism. In addition, we suggest that the activation of the T cell system may account for the skin lesions in KD, characterized by redness and subsequent crusting of the BCG inoculation site and desquamation of the extremities.
Stromal cell-derived factor-1 (SDF-1) is expressed in a wide variety of organs, such as heart, and plays a pivotal role in the mobilization of hematopoietic stem and progenitor cells in bone marrow. SDF-1α, a common subtype of SDF-1, may control hematopoiesis and angiogenesis, but its role in the pathogenesis of hyperlipidemia is unknown. The aim of this study was to determine the role of SDF-1α in the pathogenesis of hyperlipidemia. First, log-transformed SDF-1α serum levels (logSDF-1α) were significantly higher in male patients with borderline high lipid profile (BHLP; n = 28; 2.15 ± 0.08 ng/ml) compared to control subjects (n = 37; 1.94 ± 0.06 ng/ml; P < 0.01). The logSDF-1α in male patients with high lipid profile (HLP; n = 33; 1.95 ± 0.08 ng/ml) were lower than BHLP patients (P < 0.01). The logSDF-1α was positively associated with HDL-C only in female patients (n = 125; r = 0.379, P = 0.016). These results suggest the different pathophysiology in male and female patients with hyperlipidemia. Moreover, flow cytometry analysis showed that expression of the SDF-1α receptor, CXC-chemokine receptor 4, was lower in peripheral blood mononuclear cells of patients with BHLP (n = 10) and HLP (n = 10), compared to control subjects (n = 10; P < 0.001). Lastly, peripheral blood leukocyte, neutrophil and lymphocyte counts were higher in BHLP patients (n = 62; P < 0.05). Taken together, we suggest SDF-1α as a biomarker of hyperlipidemia that may be helpful to uncover the pathogenesis of hyperlipidemia.
Endometrial cancer (EC) is the most prevalent gynecologic malignancy in Japan. Atypical endometrial hyperplasia (AEH) is viewed as the premalignant lesion of EC, however it is often difficult to distinguish EC from AEH. The rate of concurrent EC in women diagnosed preoperatively with AEH based on endometrial biopsy was reported as 17-52%. Although hysteroscopic inspection and total curettage are considered as useful methods to make diagnosis of endometrial lesions, there is no report using this combined method to discriminate EC from AEH. The purpose of this study was to examine whether hysteroscopic inspection and total curettage improve the prevalence of EC among women diagnosed preoperatively with AEH. We reviewed 22 patients who underwent hysteroscopic inspection and total curettage and were diagnosed with AEH before undergoing hysterectomy between November 2001 and May 2011. The diagnosis made with the hysterectomy specimens revealed AEH in 10 patients (45.5%), endometrial hyperplasia without atypia in 3 (13.6%), and endometrioid adenocarcinoma, the most common type of EC, in 9 (40.9%). Endometrioid adenocarcinoma included 7 patients without myometrial invasion (31.8%) and 2 patients with superficial myometrial invasion (9.1%). There was no hysteroscopic finding that was specific for EC or AEH. In conclusion, about 41% of women who underwent hysterectomy under a diagnosis of AEH were found to have coexisting adenocarcinoma, although the prevalence of EC among those women was similar to that in earlier reports with endometrial biopsy. Accordingly, we must be careful in planning the therapeutic strategy for women with a preoperative diagnosis of AEH.
Amyotrophic lateral sclerosis (ALS) is a progressive debilitating neurological disease. ALS disturbs the quality of life by affecting speech, swallowing and free mobility of the arms without affecting intellectual function. It is therefore of significance to improve intelligibility and quality of speech sounds, especially for ALS patients with slowly progressive courses. Currently, however, there is no effective or established approach to improve speech disorder caused by ALS. We investigated a surgical procedure to improve speech disorder for some patients with neuromuscular diseases with velopharyngeal closure incompetence. In this study, we performed the surgical procedure for two patients suffering from severe speech disorder caused by slowly progressing ALS. The patients suffered from speech disorder with hypernasality and imprecise and weak articulation during a 6-year course (patient 1) and a 3-year course (patient 2) of slowly progressing ALS. We narrowed bilateral lateral palatopharyngeal wall at velopharyngeal port, and performed this surgery under general anesthesia without muscle relaxant for the two patients. Postoperatively, intelligibility and quality of their speech sounds were greatly improved within one month without any speech therapy. The patients were also able to generate longer speech phrases after the surgery. Importantly, there was no serious complication during or after the surgery. In summary, we performed bilateral narrowing of lateral palatopharyngeal wall as a speech surgery for two patients suffering from severe speech disorder associated with ALS. With this technique, improved intelligibility and quality of speech can be maintained for longer duration for the patients with slowly progressing ALS.