Antiproliferative effects of D-allose associated with reduced cell division frequency in glioblastoma.

Recent studies have shown that D-allose, a rare sugar, elicits antitumor effects on different types of solid cancers, such as hepatocellular carcinoma, non-small-cell lung cancer, and squamous cell carcinoma of the head and neck. In this study, we examined the effects of D-allose on the proliferation of human glioblastoma (GBM) cell lines (i.e., U251MG and U87MG) in vitro and in vivo and the underlying mechanisms. D-allose treatment inhibited the proliferation of U251MG and U87MG cells in a dose-dependent manner (3-50 mM). However, D-allose treatment did not affect cell cycles or apoptosis in these cells but significantly decreased the cell division frequency in both GBM cell lines. In a subcutaneous U87MG cell xenograft model, intraperitoneal injection of D-allose (100 mg/kg/day) significantly reduced the tumor volume in 28 days. These data indicate that D-allose-induced reduction in cell proliferation is associated with a subsequent decrease in the number of cell divisions, independent of cell-cycle arrest and apoptosis. Thus, D-allose could be an attractive additive to therapeutic strategies for GBM.

Malignant mesothelioma cells with characteristic intracytoplasmic vacuolization and lipids.

In this brief report, we described some uncommon cytomorphological features of malignant mesothelioma (MM) cells in pleural effusions. The tumor cells exhibited abundant cytoplasmic vacuolization, with presence of single or multiple eccentric nuclei in several cells. In the Giemsa-stained smear, we observed a glossy spherical material in some cells, which tested positive in Sudan III stain. In immunocytochemical analysis, tumor cells were positive for calretinin, podoplanin, epithelial membrane antigen, and methylthioadenosine phosphorylase; tumor cells were negative for BRCA1-associated protein 1, CD68, and desmin. The intracytoplasmic vacuoles were positive for adipophilin expression.

Barriers to undergoing cervical cancer screening among health sciences university students in Japan: A cross-sectional study.

In most developed countries, cervical cancer screening and human papillomavirus vaccination have reduced cervical cancer incidence. However, the incidence has been increasing in Japan, possibly because of the low screening rate. Although cervical cancer incidence has increased in people in their 20s, the screening rate among 20-24-year-olds in Japan is only 10.2%, meaning that cervical cancer screening rates should be increased among young Japanese women. We conducted a questionnaire survey among students at health sciences universities to determine their knowledge of cervical cancer, screening rates, and barriers to screening. Students taking specialized medical courses were highly knowledgeable; recognition of the facts that "cervical cancer can be prevented through screening" and that "the risk of cervical cancer increases in one's 20s" was significantly high among those who underwent screening. On the other hand, only 7.5% of students used the free coupons provided for screening. Knowledge of cervical cancer improves screening rates. Therefore, educational programs to raise awareness of the importance of cervical cancer screening among non-medical and health sciences university students and young women in general are required.

Possible contribution of phosphate to the pathogenesis of chronic kidney disease in dolphins.

This study aimed to investigate whether phosphate contributes to the pathogenesis of chronic kidney disease (CKD) in dolphins. Renal necropsy tissue of an aged captive dolphin was analyzed and in vitro experiments using cultured immortalized dolphin proximal tubular (DolKT-1) cells were performed. An older dolphin in captivity died of myocarditis, but its renal function was within the normal range until shortly before death. In renal necropsy tissue, obvious glomerular and tubulointerstitial changes were not observed except for renal infarction resulting from myocarditis. However, a computed tomography scan showed medullary calcification in reniculi. Micro area X-ray diffractometry and infrared absorption spectrometry showed that the calcified areas were primarily composed of hydroxyapatite. In vitro experiments showed that treatment with both phosphate and calciprotein particles (CPPs) resulted in cell viability loss and lactate dehydrogenase release in DolKT-1 cells. However, treatment with magnesium markedly attenuated this cellular injury induced by phosphate, but not by CPPs. Magnesium dose-dependently decreased CPP formation. These data support the hypothesis that continuous exposure to high phosphate contributes to the progression of CKD in captive-aged dolphins. Our data also suggest that phosphate-induced renal injury is mediated by CPP formation in dolphins, and it is attenuated by magnesium administration.

The usefulness of nuclear area in the diagnosis of high-grade urothelial carcinoma cells in voided urine cytology.

OBJECTIVE: The Paris System for Reporting Urinary Cytology considered the nuclear-to-cytoplasmic (N:C) ratio as the most important cytomorphological feature for detecting high-grade urothelial carcinoma (HGUC) cells. Few quantitative studies have been conducted on other features although quantitative studies on the N:C ratio have been reported. Therefore, this study quantitatively analysed important cytomorphological features in distinguishing benign reactive cells from HGUC cells. METHODS: We analysed 2866 cells from the urine of 52 patients. A digital image analyser was used to quantitatively measure the nuclear area, cell area, N:C ratio, and nuclear roundness for HGUC cells and benign reactive cells. Additionally, the diagnostic value of quantitative cytomorphological criteria in HGUC cells was evaluated by the receiver operating characteristic curve. RESULTS: The area under the curve for the prediction of HGUC cells for all cells and the top five cells was in the following order: nuclear area (0.920 and 0.992, respectively), N:C ratio (0.849 and 0.977), cell area (0.781 and 0.920), and nuclear roundness (0.624 and 0.605). The best cutoff value of the N:C ratio to differentiate HGUC cells from benign reactive cells was 0.438, and using the N:C ratio of 0.702, the positive predictive value obtained was 100%. CONCLUSIONS: Our study indicated that nuclear area is a more important cytomorphological criterion than the N:C ratio for HGUC cell detection. Moreover, extracted data of the top five cells were more valuable than the data of all cells, which can be helpful in the routine practice and future criteria definition in urine cytology.

Competency for Japanese novice medical laboratory scientists: a Delphi method.

BACKGROUND: Competency is used to channel abilities into successful processes and is employed in the medical field. Globally, several laboratory competencies exist, but the job descriptions of Japanese medical laboratory scientists differ from those of other countries and little evidence-based information on novice medical laboratory scientist competency is available in Japan. This study clarified the competencies of novice medical laboratory scientists based on various expert opinions in Japan. METHODS: The Delphi method was used to achieve an expert consensus on novice medical laboratory scientist competencies. We asked the participants to evaluate the importance of each item using the Likert scale and set 70% as the final consensus rate. RESULTS: We obtained 106/400 (26.5%) and 95/106 (89.6%) responses from participants in rounds 1 and 2, respectively. Their professional experience mean ± standard deviation was 32.4 ± 6.0 years (range: 13-41). The average of each category consensus rate was > 99.1%. Ninety-five expert opinions converged and agreed that the competency comprised 8 categories and 54 items. CONCLUSIONS: The survey results revealed that novice medical laboratory scientists were expected to have relatively higher main laboratory skill competencies in the 'Preparation and analysis' category than in other categories. Nevertheless, competencies in other categories required basic skills. In addition, our competencies contained unique competencies compared with others due to their divergent roles and their environment. Further research is warranted to explore assessment tools by developing a competency scale, thereby helping clarify the differences between ability and correlated factors. The unique competencies scale can help assess the efficacy of educational programmes for Japanese medical laboratory scientists.

Association of Antihypertensive Effects of Esaxerenone with the Internal Sodium Balance in Dahl Salt-Sensitive Hypertensive Rats.

BACKGROUND: The nonsteroidal mineralocorticoid receptor blocker esaxerenone is effective in reducing blood pressure (BP). OBJECTIVE: In this study, we investigated esaxerenone-driven sodium homeostasis and its association with changes in BP in Dahl salt-sensitive (DSS) hypertensive rats. METHODS: In the different experimental setups, we evaluated BP by a radiotelemetry system, and sodium homeostasis was determined by an approach of sodium intake (food intake) and excretion (urinary excretion) in DSS rats with a low-salt diet (0.3% NaCl), high-salt diet (HSD, 8% NaCl), HSD plus 0.001% esaxerenone (w/w), and HSD plus 0.05% furosemide. RESULTS: HSD-fed DSS rats showed a dramatic increase in BP with a non-dipper pattern, while esaxerenone treatment, but not furosemide, significantly reduced BP with a dipper pattern. The cumulative sodium excretion in the active period was significantly elevated in esaxerenone- and furosemide-treated rats compared with their HSD-fed counterparts. Sodium content in the skin, skinned carcass, and total body tended to be lower in esaxerenone-treated rats than in their HSD-fed counterparts, while these values were unchanged in furosemide-treated rats. Consistently, sodium balance tended to be reduced in esaxerenone-treated rats during the active period. Histological evaluation showed that esaxerenone, but not furosemide, treatment attenuated glomerulosclerosis, tubulointerstitial fibrosis, and urinary protein excretion induced by high salt loading. CONCLUSIONS: Collectively, these findings suggest that an esaxerenone treatment-induced reduction in BP and renoprotection are associated with body sodium homeostasis in salt-loaded DSS rats.

Expression status of p53 and organic cation transporter 1 is correlated with poor response to preoperative chemotherapy in esophageal squamous cell carcinoma.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is a highly malignant neoplasm. DNA-damaging drugs, such as cisplatin (CDDP) and 5-fluorouracil (5-FU), are most frequently used in preoperative chemotherapy for ESCC. However, the response to preoperative chemotherapy varies among patients. p53, encoded by TP53, participates in apoptotic pathways following chemotherapy with DNA-damaging drugs, and mutation of TP53 contributes to chemoresistance. Organic cation transporter 1 (OCT1) participates in the uptake of CDDP, and its reduced expression is associated with CDDP resistance. The aim of this study was to evaluate the predictive impact of the expression status of p53 and OCT1 in response to preoperative chemotherapy in ESCC. METHODS: We retrospectively assessed 66 ESCC patients who received preoperative chemotherapy with CDDP/5-FU (CF) or docetaxel/CDDP/5-FU (DCF). p53 and OCT1 expression in pretreatment biopsy specimens was immunohistochemically determined and correlated with histological response to preoperative chemotherapy. RESULTS: p53 with wild-type (p53WT-ex) and mutant-type (p53MT-ex) expression patterns was identified in 40.9% and 59.1% of patients, respectively. High expression of OCT1 (OCT1High) was detected in 45.5%, and the remaining 54.5% showed low expression (OCT1Low). In a univariate analysis of the entire cohort, p53MT-ex was significantly correlated with poor response (P = 0.026), whereas OCT1Low showed marginal significance (P = 0.091). In a combined analysis, tumors with either p53MT-ex or OCT1Low showed a significant correlation with poor response compared with tumors with both p53WT-ex and OCT1High (P < 0.001). The sensitivity, specificity, and accuracy of combined p53/OCT1 were 93.9%, 47.1%, and 81.8%, respectively. Multivariate analysis identified p53 (P = 0.017), OCT1 (P = 0.032), and combined p53/OCT1 (P < 0.001) as independent predictors of histological response. When samples were stratified according to chemotherapy regimen in the univariate analysis, combined p53/OCT1 was the only significant factor for poor response in the CF (P = 0.011) and DCF (P = 0.021) groups, whereas p53 showed no statistical significance. CONCLUSIONS: Our results suggest that either p53MT-ex or OCT1Low expression in pretreatment biopsy specimens may be a potential predictor of poor response to preoperative chemotherapy with the CF-based regimens in ESCC, although the specificity needs to be improved.

Urinary Podocyte Count as a Potential Routine Laboratory Test for Glomerular Disease: A Novel Method Using Liquid-Based Cytology and Immunoenzyme Staining.

INTRODUCTION: This study investigated whether our urinary podocyte detection method using podocalyxin (PDX) and Wilms tumor 1 (WT1) immunoenzyme staining combined with liquid-based cytology can serve as a noninvasive routine laboratory test for glomerular disease. METHODS: The presence of PDX- and WT1-positive cells was investigated in 79 patients with glomerular disease and 51 patients with nonglomerular disease. RESULTS: The frequencies and numbers of PDX- and WT1-positive cells were significantly higher in the glomerular disease group than in the nonglomerular disease group. The best cutoffs for PDX- and WT1-positive cell counts for identifying patients with glomerular disease were 3.5 (sensitivity = 67.1% and specificity = 100%) and 1.2 cells/10 mL (sensitivity = 43.0% and specificity = 100%), respectively. CONCLUSION: Because our urinary podocyte detection method using PDX immunoenzyme staining can be standardized and it detected glomerular disease with high accuracy, it can likely serve as a noninvasive routine laboratory test for various glomerular diseases.

Overexpression of the PPAR-γ protein in primary Ta/T1 non-muscle-invasive urothelial carcinoma.

Peroxisome proliferator-activated receptor-γ (PPAR-γ) is a well-known nuclear receptor that is activated in the nucleus to regulate several transcription factors. Its expression patterns have been examined in various types of cancer. The present study investigated the expression patterns of PPAR-γ in non-muscle-invasive urothelial carcinoma. The expression rates of PPAR-γ, p53 and Ki-67 were compared to determine whether PPAR-γ may be considered as an immunobiomarker for bladder cancer. The intensity and extent of PPAR-γ expression were evaluated in 79 cases of non-muscle-invasive urothelial carcinoma (30 cases of papillary carcinoma low-grade, 30 cases of high-grade and 19 cases of carcinoma in situ) and 30 non-malignant cases. The nuclear overexpression of PPAR-γ was frequently observed in non-muscle-invasive urothelial carcinoma (63/79 cases) but was rarely detected in non-malignant cases (2/30 cases). The histological proliferation types of non-muscle-invasive urothelial carcinoma revealed that PPAR-γ was more frequently overexpressed in papillary carcinoma (54/60 cases) than in carcinoma in situ (9/19 cases). Immunohistochemical staining demonstrated that PPAR-γ was more useful as an immunobiomarker than p53 or Ki-67 (diagnostic odds ratios; 55.13, 16.82 and 11.13, respectively). In summary, this study demonstrated that the expression patterns of PPAR-γ were associated with histological proliferation type and that PPAR-γ was expressed in the nuclei of papillary carcinoma cells. These findings suggested that immunohistochemical staining for PPAR-γ may be used to comprehensively detect non-muscle-invasive urothelial carcinoma.

Peroxisome proliferator-activated receptor-α expression is associated with histological type in human gastric carcinoma.

Gastric carcinoma is one of the most common types of cancer worldwide and a leading cause of cancer-related mortality. Gastric carcinoma is histologically subdivided into differentiated and undifferentiated carcinoma, with the latter including poorly differentiated carcinoma and signet ring cell carcinoma (SRCC). Poorly differentiated carcinoma and SRCC have a worse prognosis compared with differentiated carcinoma. Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors and the PPAR-α subtype regulates important cellular functions, including cell proliferation, energy metabolism, oxidative stress, immune responses and cell differentiation. The aim of the present study was to elucidate the associations between clinicopathological factors and PPAR-α expression in patients with gastric carcinoma. The immunohistochemical staining of specimens obtained from 57 patients showed that PPAR-α expression was slightly weaker in undifferentiated carcinoma than in differentiated carcinoma (P<0.01). PPAR-α expression also significantly differed between poorly differentiated carcinoma (both positive and negative: 14/20, 70%) and SRCC (not expressed: 0/7, 0%) (P<0.01). However, PPAR-α expression was not significantly affected by age, lymph node invasion, venous invasion, lymph node metastasis, depth of invasion or stage. Collectively, the present results demonstrated that the downregulated expression of PPAR-α may play a key role in the biological transformation of tumors. Therefore, PPAR-α appears to be an important protein related to histology and may hold promise as a prognostic marker. Further studies with a larger number of subjects are needed to elucidate the relationship between PPAR-α expression and tumor progression and to analyze long-term clinical survival.

Hepatocellular carcinoma induces body mass loss in parallel with osmolyte and water retention in rats.

AIMS: The number of cancer survivors with cardiovascular disease is increasing. However, the effect of cancer on body fluid regulation remains to be clarified. In this study, we evaluated body osmolyte and water imbalance in rats with hepatocellular carcinoma. MAIN METHODS: Wistar rats were administered diethylnitrosamine, a carcinogenic drug, to establish liver cancer. We analyzed tissue osmolyte and water content, and their associations with aldosterone secretion. KEY FINDINGS: Hepatocellular carcinoma rats had significantly reduced body mass and the amount of total body sodium, potassium, and water. However, these rats had significantly increased relative tissue sodium, potassium, and water content per tissue dry weight. Furthermore, these changes in sodium and water balance in hepatocellular carcinoma rats were significantly associated with increased 24-h urinary aldosterone excretion. Supplementation with 0.25% salt in drinking water improved body weight reduction associated with sodium and water retention in hepatocellular carcinoma rats, which was suppressed by treatment with spironolactone, a mineralocorticoid receptor antagonist. Additionally, the urea-driven water conservation system was activated in hepatocellular carcinoma rats. SIGNIFICANCE: These findings suggest that hepatocellular carcinoma induces body mass loss in parallel with activation of the water conservation system including aldosterone secretion and urea accumulation to retain osmolyte and water. The osmolyte and water retention at the tissue level may be a causative factor for ascites and edema formation in liver failure rats.

p53 expression in repair/reactive renal tubular cells: A potential pitfall leading to a false-positive diagnosis of urine cytology.

BACKGROUND: p53 immunostaining is routinely used as a surrogate marker for TP53 mutational status. In urine cytology, p53 immunocytochemistry is reportedly useful in detecting urothelial carcinoma cells as well as in improving the detection sensitivity and specificity. However, to the best of our knowledge, p53 expression in repair/reactive renal tubular cells (RRTCs) from urine cytologic specimens has not been assessed to date. METHODS: We evaluated the immunoexpression of p53 and homogentisate 1,2-dioxygenase (HGD) antibody, a renal tubular cells marker, in RRTCs using voided urine and renal biopsy samples from 80 patients who were histologically diagnosed with glomerular disease. RESULTS: Repair/reactive renal tubular cells were detected in 68 (68/80, 85%) samples at a mean count of 141.1 cells per sample (range, 5-4220). Immunocytochemical analysis found p53-positive RRTCs in all the samples (68/68, 100%) with an average p53 positivity rate of RRTCs per sample at 47.7% (range, 3.8%-96.5%). Of the 68 p53-positive RRTC samples, 38 (55.9%) included cells that were HGD positive for cytoplasm. Similarly, renal biopsy analysis revealed p53-positive RRTCs in all the specimens (68/68, 100%). All 68 (100%) cases showed RRTCs that were positive for both p53 and HGD. CONCLUSION: To avoid false positives of p53 immunocytochemistry, cytologists must consider the fact that RRTCs from patients with glomerular disease are positive for p53.

Chronic AT1 blockade improves hyperglycemia by decreasing adipocyte inflammation and decreasing hepatic PCK1 and G6PC1 expression in obese rats.

Inappropriate activation of the renin-angiotensin system decreases glucose uptake in peripheral tissues. Chronic angiotensin receptor type 1 (AT1) blockade (ARB) increases glucose uptake in skeletal muscle and decreases the abundance of large adipocytes and macrophage infiltration in adipose. However, the contributions of each tissue to the improvement in hyperglycemia in response to AT1 blockade are not known. Therefore, we determined the static and dynamic responses of soleus muscle, liver, and adipose to an acute glucose challenge following the chronic blockade of AT1. We measured adipocyte morphology along with TNF-α expression, F4/80- and CD11c-positive cells in adipose and measured insulin receptor (IR) phosphorylation and AKT phosphorylation in soleus muscle, liver, and retroperitoneal fat before (T0), 60 (T60) and 120 (T120) min after an acute glucose challenge in the following groups of male rats: 1) Long-Evans Tokushima Otsuka (LETO; lean control; n = 5/time point), 2) obese Otsuka Long Evans Tokushima Fatty (OLETF; n = 7 or 8/time point), and 3) OLETF + ARB (ARB; 10 mg olmesartan/kg/day; n = 7 or 8/time point). AT1 blockade decreased adipocyte TNF-α expression and F4/80- and CD11c-positive cells. In retroperitoneal fat at T60, IR phosphorylation was 155% greater in ARB than in OLETF. Furthermore, in retroperitoneal fat AT1 blockade increased glucose transporter-4 (GLUT4) protein expression in ARB compared with OLETF. IR phosphorylation and AKT phosphorylation were not altered in the liver of OLETF, but AT1 blockade decreased hepatic Pck1 and G6pc1 mRNA expressions. Collectively, these results suggest that chronic AT1 blockade improves obesity-associated hyperglycemia in OLETF rats by improving adipocyte function and by decreasing hepatic glucose production via gluconeogenesis.NEW & NOTEWORTHY Inappropriate activation of the renin-angiotensin system increases adipocyte inflammation contributing to the impairment in adipocyte function and increases hepatic Pck1 and G6pc1 mRNA expression in response to a glucose challenge. Ultimately, these effects may contribute to the development of glucose intolerance.

Cytologic features of oral squamous cell carcinoma in an Indo-Pacific bottlenose dolphin (Tursiops aduncus): Papanicolaou stain and immunocytochemistry using liquid-based cytology.

Although oral cytology using Papanicolaou stain is useful for the early detection of oral premalignant lesions and squamous cell carcinoma (SCC) in people, little work has been conducted on this topic in veterinary medicine. This paper describes the features of oral cytology using Papanicolaou stain and immunocytochemistry on liquid-based cytology slides in a case of oral SCC in an Indo-Pacific bottlenose dolphin (Tursiops aduncus). In this case, dysplastic cells with koilocyte-like changes and SCC cells were identified using the Papanicolaou stain. These cells were positive for p53 using an immunocytochemistry analysis. A cytologic diagnosis of SCC was made. We believe that the early detection of premalignant oral lesions and SCC in dolphins can be significantly improved with cytology using liquid-based cytology, Papanicolaou staining, and immunocytochemistry.

Rapid Cell Transfer by Means of Nylon Mesh to Improve Cellular Diagnosis: The Role of Immunocytochemistry.

Immunocytochemistry (ICC) is an important ancillary technique in clinical cytology for not only identifying and characterizing tumor cells but also gaining prognostic or therapeutic information. Although cell blocks are often prepared for immunocytochemical evaluation of body cavity fluid and fine-needle aspiration specimens, they are not suitable for hypocellular samples. Liquid-based cytology can help prepare additional smears from residual cytological specimens. However, since conventional methods are used for nongynecological specimens in most laboratories, ICC is often limited by the number of cytological smears. Cell transfer methods permit to evaluate several immunocytochemical markers in a single cytological smear. Yet, these methods have some limitations; for example, they are time-consuming (about 3-40 h) and medium membranes with their attached cells are occasionally stretched or torn when peeled off the slides. Therefore, in an attempt to solve these problems, we developed a rapid and reliable cell transfer method using a nylon mesh. Our method requires no special equipment or reagent and can significantly reduce the turnaround time, as compared to previous methods.

Quantitative cytomorphological comparison of SurePath and ThinPrep liquid-based cytology using high-grade urothelial carcinoma cells.

OBJECTIVE: In The Paris System for Reporting Urinary Cytology (TPS), the important cytomorphological features for diagnosing high-grade urothelial carcinoma (HGUC) are a nuclear-to-cytoplasmic (N:C) ratio exceeding 0.7, hyperchromasia, coarse chromatin, and irregular nuclear borders. However, quantitative cytomorphological assessments of HGUC cells using SurePath slides are rare. Therefore, we evaluated HGUC cells on SurePath slides quantitatively using a digital image analysis system and compared these data with ThinPrep data. METHODS: The same urine samples were divided into two aliquots and used to prepare SurePath and ThinPrep slides. We used ImageJ to measure the N:C ratio, hyperchromasia, and irregular nuclear borders for HGUC cells on SurePath and ThinPrep slides. RESULTS: The total number of analysed HGUC cells on SurePath slides was 981, versus 889 on ThinPrep slides. Hyperchromasia and irregular nuclear borders were significantly more severe on SurePath than on ThinPrep slides. Conversely, the N:C ratio did not differ between the methods. Additionally, HGUC cells with N:C ratios exceeding 0.7 were present on almost all slides for both methods. CONCLUSIONS: Our data indicated the reasonableness of using the N:C ratio as the major criterion for TPS on both SurePath and ThinPrep slides, and an N:C ratio cut-off of 0.7 as suitable for identifying HGUC cells. However, the severity of hyperchromasia and irregular nuclear borders differed between the processing methods.

Cardioprotective Effects of a Nonsteroidal Mineralocorticoid Receptor Blocker, Esaxerenone, in Dahl Salt-Sensitive Hypertensive Rats.

We investigated the effects of esaxerenone, a novel, nonsteroidal, and selective mineralocorticoid receptor blocker, on cardiac function in Dahl salt-sensitive (DSS) rats. We provided 6-week-old DSS rats a high-salt diet (HSD, 8% NaCl). Following six weeks of HSD feeding (establishment of cardiac hypertrophy), we divided the animals into the following two groups: HSD or HSD + esaxerenone (0.001%, w/w). In survival study, all HSD-fed animals died by 24 weeks of age, whereas the esaxerenone-treated HSD-fed animals showed significantly improved survival. We used the same protocol with a separate set of animals to evaluate the cardiac function by echocardiography after four weeks of treatment. The results showed that HSD-fed animals developed cardiac dysfunction as evidenced by reduced stroke volume, ejection fraction, and cardiac output. Importantly, esaxerenone treatment decreased the worsening of cardiac dysfunction concomitant with a significantly reduced level of systolic blood pressure. In addition, treatment with esaxerenone in HSD-fed DSS rats caused a reduced level of cardiac remodeling as well as fibrosis. Furthermore, inflammation and oxidative stress were significantly reduced. These data indicate that esaxerenone has the potential to mitigate cardiac dysfunction in salt-induced myocardial injury in rats.

Aberrant (pro)renin receptor expression induces genomic instability in pancreatic ductal adenocarcinoma through upregulation of SMARCA5/SNF2H.

(Pro)renin receptor [(P)RR] has a role in various diseases, such as cardiovascular and renal disorders and cancer. Aberrant (P)RR expression is prevalent in pancreatic ductal adenocarcinoma (PDAC) which is the most common pancreatic cancer. Here we show whether aberrant expression of (P)RR directly leads to genomic instability in human pancreatic ductal epithelial (HPDE) cells. (P)RR-expressing HPDE cells show obvious cellular atypia. Whole genome sequencing reveals that aberrant (P)RR expression induces large numbers of point mutations and structural variations at the genome level. A (P)RR-expressing cell population exhibits tumour-forming ability, showing both atypical nuclei characterised by distinctive nuclear bodies and chromosomal abnormalities. (P)RR overexpression upregulates SWItch/Sucrose Non-Fermentable (SWI/SNF)-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 5 (SMARCA5) through a direct molecular interaction, which results in the failure of several genomic stability pathways. These data reveal that aberrant (P)RR expression contributes to the early carcinogenesis of PDAC.

Effects of post-renal anemia treatment with the HIF-PHD inhibitor molidustat on adenine-induced renal anemia and kidney disease in mice.

The kidneys are the major organs for erythropoietin (EPO) production in adults, and thus, kidney damage results in reduced EPO levels and anemia. Inhibitors of Hypoxia-inducible factor-prolyl hydroxylase domain-containing protein (HIF-PHD) are awaited as new therapeutic options for renal anemia. It can be predicted that most patients who receive HIF-PHD inhibitors have renal dysfunction as a cause of anemia. Therefore, in the present study, we investigated the effects of the HIF-PHD inhibitor molidustat on anemia and renal dysfunction when initiated after the onset of renal anemia. Male C57BL/6J mice received adenine orally to induce nephropathy. After the onset of nephropathy, the mice were treated with either vehicle or molidustat. After 4 weeks of administration, vehicle-treated mice displayed significant anemia, and molidustat ameliorated this anemia. Vehicle-treated mice exhibited reduced creatinine clearance and body weight, increased blood urea nitrogen levels, histopathological changes, immune cell infiltration, and dehydration. Molidustat reversed immune cell infiltration, dehydration, and renal fibrosis without improving renal functional parameters. In conclusion, molidustat treatment initiated after the onset of nephropathy and renal anemia reversed anemia in mice. Molidustat improved some parameters of renal abnormality, but it did not restore renal function.