The Effect of Antihypertensive Therapy on Skeletal Muscle Mass and Bone Mineral Density in Patients With End-Stage Kidney Disease.

OBJECTIVE: Sarcopenia and osteoporosis substantially influence health and lifespan. However, the variables affecting skeletal muscle mass (SMM) or bone mineral density (BMD) remain unknown. DESIGN AND METHODS: From August 1, 2018 to July 31, 2019, we conducted a single-center, observational cohort study with 291 Japanese adult patients on maintenance hemodialysis due to end-stage kidney disease, who had their femoral neck BMD measured using dual-energy X-ray absorptiometry. After 1-year follow-up, we measured annual changes of BMD (ΔBMD) and SMM (ΔSMM), which were calculated through a modified creatinine index (mg/kg/day) using age, sex, serum creatinine, and single-pooled Kt/V for urea. The factors associated with ΔSMM/ΔBMD or progressive loss of SMM/BMD, defined as ΔSMM/ΔBMD < 0 per year, respectively, were analyzed with multivariable, linear regression or logistic regression models. RESULTS: The median age of the patients was 66 years and 33% were female. Dialysis vintage and ß-blocker-use were inversely correlated to ΔSMM. In comparison to nonusers, ß-blockers users had 2.5-fold higher SMM loss odd ratios [95% confidence interval, 1.3-4.8]. The risk for SMM loss caused by ß-blockers was not increased in users of renin-angiotensin system inhibitors. The ΔBMD was negatively correlated to the usage of calcium channel blockers. The risk of developing osteosarcopenia, which was defined as annual loss of both SMM and BMD, increased in calcium channel blockers users. CONCLUSIONS: The use of ß-blockers is associated with an elevated risk of developing sarcopenia, whereas renin-angiotensin system inhibitors may minimize this effect in patients with end-stage kidney disease. Use of calcium channel blocker therapy was associated with a faster decline of BMD.

Nursing practice to fulfill the information needs of parents of hospitalized children with cancer and related factors.

PURPOSE: This study aimed to clarify the current status of nursing practice to fulfill the information needs of parents of hospitalized children with cancer and to determine the associated factors. DESIGN AND METHODS: A cross-sectional survey using a questionnaire was administered to nurses working on wards admitting children with cancer in Japan. Data were analyzed using logistic regression analysis, after exploratory factor analysis. RESULTS: Three factors were extracted as nursing practice: "provision of information that supports the child's future and other family members' daily lives" (factor 1), "provision of information regarding care for the child in the treatment process" (factor 2), "provision of information regarding the child's disease and treatment" (factor 3). Among these three factors, factor 1 achieved the lowest score for the level of practice. Logistic regression analysis indicated that interprofessional information sharing increased the scores of factors 1 and 3 (Odds ratio: 6.150, and 4.932, respectively); assessment of parental information needs increased the scores of factors 1, 2, and 3 (Odds ratio: 3.993, 3.654, and 3.671, respectively); and participation in training increased the score of factor 2 (Odds ratio: 3.078). CONCLUSIONS: Nursing practice to fulfill the parents' information needs consisted of three factors. The degree of practice varied according to the information content and was primarily influenced by assessment of parental information needs, interprofessional information sharing, and participation in training. PRACTICE IMPLICATIONS: It is necessary for nurses to accurately assess parents' needs, and interprofessional sharing of information is important to fulfill the information needs of parents.

Prognostic impact and gene expression analysis of peri-tumoral alveolar macrophage in resected lung adenocarcinoma.

The prognostic significance and role of extratumoral alveolar macrophages (exAMs) in lung adenocarcinoma (LUAD) patients remain unknown. In this study, we investigated the prognostic impact and gene expression of exAMs in LUAD patients. The density of alveolar macrophages (AMs) in the peri-tumoral lung field (p-exAMs) and distant lung field (d-exAMs) was evaluated in 217 LUAD patients with lymph node metastasis. Patients with high p-exAMs showed significantly shorter recurrence-free (RFS) and shorter overall survival (OS) than those with low p-exAMs (p = 0.02 and p = 0.03, respectively), whereas there was no survival difference between patients with high d-exAMs and those with low d-exAMs. Multivariate analysis revealed that high p-exAMs was an independent predictive factor for RFS (HR: 1.54; 95% confidence interval [CI]:1.10-2.16; p = 0.01). Later, we collected AMs from the tumor periphery and distant segments in 13 resected lungs by bronchoalveolar lavage (BAL) procedure and compared mRNA expression. AMs in the tumor periphery expressed significantly higher levels of IL-10 and CCL2 than those in the distant segment (p < 0.01 and p = 0.03, respectively). Additionally, IL-10 and CCL2 significantly induced the growth and migration of the PC9 cells in vitro. This study suggests that p-exAMs should be considered as a tumor-promoting component in the tumor microenvironment.

Influence of Intestinal Barrier on Alleviating an Increase in Blood Pressure by Sodium Alginate Intake in 2-Kidney, 1-Clip Renovascular Hypertensive Rats.

Sodium alginate (SALG) is a substance derived from brown seaweed that has been shown to reduce blood pressure (BP). However, its effects on renovascular hypertension caused by 2-kidney, 1-clip (2K1C) are not yet clear. Previous research suggests that hypertensive rats have increased intestinal permeability, and that SALG improves the gut barrier in inflammatory bowel disease mouse models. Therefore, the goal of this study was to determine whether the antihypertensive effects of SALG involve the intestinal barrier in 2K1C rats. Rats were fed either a 1.0% SALG diet or a control diet for six weeks after being subjected to 2K1C surgery or a sham operation. The systolic BP was measured weekly, and the mean arterial BP was measured at the end of the study. Intestinal samples were taken for analysis, and plasma lipopolysaccharide (LPS) levels were measured. The results showed that BP in 2K1C rats was significantly higher than in SHAM rats when fed CTL, but not when fed SALG. The gut barrier in 2K1C rats was improved by SALG intake. Plasma LPS levels also differed depending on the animal model and diet. In conclusion, dietary SALG may alleviate 2K1C renovascular hypertension by altering the gut barrier.

Clinicopathological significance of peritumoral alveolar macrophages in patients with resected early-stage lung squamous cell carcinoma.

INTRODUCTION: This study aimed to clarify the correlation between the number of AMs and prognosis and to examine the gene expression of AMs in lung squamous cell carcinoma (SqCC). METHODS: We reviewed 124 stage I lung SqCC cases in our hospital and 139 stage I lung SqCC cases in The Cancer Genome Atlas (TCGA) cohort in this study. We counted the number of AMs in the peritumoral lung field (P-AMs) and in the lung field distant from the tumor (D-AMs). Moreover, we performed a novel ex vivo bronchoalveolar lavage fluid (BALF) analysis to select AMs from surgically resected lung SqCC cases and examined the expression of IL10, CCL2, IL6, TGFß, and TNFα (n = 3). RESULTS: Patients with high P-AMs had significantly shorter overall survival (OS) (p < 0.01); however, patients with high D-AMs did not have significantly shorter OS. Moreover, in TCGA cohort, patients with high P-AMs had a significantly shorter OS (p < 0.01). In multivariate analysis, a higher number of P-AMs were an independent poor prognostic factor (p = 0.02). Ex vivo BALF analysis revealed that AMs collected from the tumor vicinity showed higher expression of IL10 and CCL2 than AMs from distant lung fields in all 3 cases (IL-10: 2.2-, 3.0-, and 10.0-fold; CCL-2: 3.0-, 3.1-, and 3.2-fold). Moreover, the addition of recombinant CCL2 significantly increased the proliferation of RERF-LC-AI, a lung SqCC cell line. CONCLUSION: The current results indicated the prognostic impact of the number of peritumoral AMs and suggested the importance of the peritumoral tumor microenvironment in lung SqCC progression.

Factors Related to Early Childhood Caries in 17- to 23-Month-Old Children in Aichi Prefecture, Japan: A Cross-Sectional Study.

Dental caries is the most prevalent of chronic oral conditions. We investigated child and parental factors associated with early childhood caries (ECC) in 17- to 23-month-old children in Aichi Prefecture, Japan. Of the 61,714 children who underwent a health examination at 18 months of age, 54,206 (27,860 males, 26,346 females) were included in the analysis. The parents of the children completed a self-administered questionnaire comprising items related to the child's eating habits and lifestyle and the parent's lifestyle and childcare factors. Logistic regression analyses were performed using ECC as the dependent variable, and odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. The prevalence of ECC was 0.8%. In the multivariate analysis, children who consumed sweetened beverages daily and snacked frequently had significantly higher ORs for ECC: 1.29 (95% CI: 1.05-1.59) and 1.49 (95% CI: 1.15-1.91), respectively. Bedtime breastfeeding and bottle-feeding were significantly associated with higher ORs for ECC: 4.88 (95% CI: 4.01-5.94) and 2.31 (95% CI: 1.72-3.10), respectively. Not eating breakfast daily and late bedtime were associated with high ORs for ECC: 1.41 (95% CI: 1.02-1.96) and 1.31 (95% CI: 1.05-1.64), respectively. The OR for ECC was significantly higher in children whose father was a smoker than in those whose father was not: 1.44 (95% CI: 1.18-1.76). The OR for ECC was significantly higher in children with no childcare adviser than in those with a childcare adviser: 1.67 (95% CI: 1.06-2.65). Children who had not been vaccinated had a significantly higher OR for ECC compared to children who had: 1.49 (95% CI: 1.14-1.94). These results imply the importance of enhancing parental guidance on the lifestyle habits of children and creating an environment in which parents can consult with others regarding parenting.

Cancer-associated fibroblast-dependent and -independent invasion of gastric cancer cells.

PURPOSE: Cancer cells are known to exhibit a cancer-associated fibroblast (CAF)-dependent invasive mode in the presence of CAFs. The purpose of this study was to investigate whether intrinsic factors of gastric cancer cells influence the CAF-dependent invasive mode of cancer cells. METHODS: We observed dynamic movement of CAFs, and cancer cells, by time-lapse imaging of 2-D and 3-D collagen invasion models, and evaluated invasion modes of gastric cancer cell lines (MKN-7, MKN-45, and HSC44PE). We further examined whether modification of invasive capacity of CAFs can alter invasive mode of MKN-7, and HSC44PE cells. RESULTS: When MKN-7 and MKN-45 cells were co-cultured with CAFs, CAFs first invade collagen matrix followed by cancer cells (CAF-dependent invasion), whereas HSC44PE cells invaded collagen matrix independent of CAFs' invasion. Overexpression or suppression of podoplanin in CAFs, respectively, increased or decreased the invasive capacity of CAFs, and significantly increased or decreased the number of invading MKN-7 cells, respectively. CAFs overexpressing a podoplanin mutant, lacking the cytoplasmic domain, had significantly reduced invasive capacity, compared to CAFs overexpressing wild-type podoplanin, and it also reduced the number of invading MKN-7 cells significantly. When HSC44PE cells, and CAFs were co-cultured, changes in the podoplanin expression in CAFs similarly altered the invasive capacity of CAFs, but it did not affect the number of invading HSC44PE cells. CONCLUSIONS: These results indicate that in presence of CAFs, gastric cancer cells exhibit both CAF-dependent and -independent modes of invasion, the determinants of which may depend on the intrinsic properties of the gastric cancer cells.

Polymeric micelles effectively reprogram the tumor microenvironment to potentiate nano-immunotherapy in mouse breast cancer models.

Nano-immunotherapy improves breast cancer outcomes but not all patients respond and none are cured. To improve efficacy, research focuses on drugs that reprogram cancer-associated fibroblasts (CAFs) to improve therapeutic delivery and immunostimulation. These drugs, however, have a narrow therapeutic window and cause adverse effects. Developing strategies that increase CAF-reprogramming while limiting adverse effects is urgent. Here, taking advantage of the CAF-reprogramming capabilities of tranilast, we developed tranilast-loaded micelles. Strikingly, a 100-fold reduced dose of tranilast-micelles induces superior reprogramming compared to free drug owing to enhanced intratumoral accumulation and cancer-associated fibroblast uptake. Combination of tranilast-micelles and epirubicin-micelles or Doxil with immunotherapy increases T-cell infiltration, resulting in cures and immunological memory in mice bearing immunotherapy-resistant breast cancer. Furthermore, shear wave elastography (SWE) is able to monitor reduced tumor stiffness caused by tranilast-micelles and predict response to nano-immunotherapy. Micellar encapsulation is a promising strategy for TME-reprogramming and SWE is a potential biomarker of response.

Functional Impairment and Periodontitis in Rheumatoid Arthritis.

BACKGROUND: This study explored the association of functional impairment due to rheumatoid arthritis (RA) and RA disease activity with periodontal disease in patients with RA. METHODS: Ninety-three patients with RA were included. Their RA functional status was assessed using the Steinbrocker classification. The serum level of matrix metalloproteinase-3 (MMP-3) was used as an indicator of RA disease activity. Probing depth (PD) and clinical attachment level (CAL) were used as indicators of periodontal status. We examined the association of RA severity and MMP-3 levels with periodontal status using a generalised linear model (GLM). RESULTS: In a multivariate GLM, the coefficient for the mean PD was significantly positive in those with RA severity classes III or IV (reference: class I; ß = 0.14; 95% confidence interval [CI], 0.03-0.25; P = .02) independent of other confounding variables. In multivariate GLM using the mean CAL as the dependent variable, the coefficient was significant in patients with high MMP-3 levels (10 ng/mL; ß = 0.005; 95% CI, 0.001-0.008; P = .02). CONCLUSIONS: Functional impairment due to RA may affect PD, and high serum levels of MMP-3 may affect CAL.

Role of alginate in the mechanism by which brown seaweed Saccharina japonica intake alleviates an increase in blood pressure in 2-kidney, 1-clip renovascular hypertensive rats.

BACKGROUND: The intake of Saccharina japonica (SJ), a widely consumed brown seaweed, has been reported to decrease blood pressure (BP) in hypertensive rats. It has been suggested that this effect is related to an increase in fecal sodium excretion (SE) by alginate (Alg) to the gastrointestinal tract; however, the mechanism is still unclear. This study investigated how different seaweeds with different amounts of Alg suppressed BP increase and enhanced fecal SE in 2-kidney, 1-clip renovascular hypertensive (2K1C) rats given SJ diet. METHODS: Rats with 2K1C or sham operation were fed a normal-/high-salt diet with some kinds of seaweeds (5.0%, w/w) or SJ extract with different Alg contents for 6 weeks. We measured systolic BP every week and mean arterial pressure at the end, and measured the total and molecular weights of Alg in each seaweed. Then, we evaluated the relationship of the Alg amount in each seaweed with the suppression of BP increase in 2K1C rats. Finally, urinary and fecal SE for 24 h was measured. RESULTS: The intake of SJ, SJ extract, Saccharina ochotensis (SO) blades and SO roots suppressed BP increase in 2K1C rats, but the strength was not proportional to the amounts of Alg contained in the seaweeds. Although SJ intake increased fecal SE in 2K1C rats fed a high-salt diet, the fecal SE was much less than urinary SE. CONCLUSION: The sodium excretion in feces by Alg in SJ may not be one of the major mechanisms by which SJ intake attenuates hypertension in 2K1C rats.

Drug-exposed cancer-associated fibroblasts facilitate gastric cancer cell progression following chemotherapy.

BACKGROUND: Cancer progression following chemotherapy is a significant barrier to effective cancer treatment. We aimed to evaluate the role of drug-exposed cancer-associated fibroblasts (CAFs) in the growth and progression of drug-exposed gastric cancer (GC) cells and to explore the underlying molecular mechanism. METHODS: The human GC cell line 44As3 and CAFs were treated with 5-fluorouracil and oxaliplatin (5FU + OX). 5FU + OX-pretreated 44As3 cells were then cultured in a conditioned medium (CM) from 5FU + OX-pretreated CAFs, and the growth and migration/invasion ability of the cells were evaluated. We also compared the clinicopathological characteristics of the GC patients treated with S1 + OX in accordance with the properties of their resected specimens, focusing on the number of CAFs. Changes in gene expression in CAFs and 44As3 cells were comprehensively analyzed using RNA-seq analysis. RESULTS: The CM from 5FU + OX-pretreated CAFs promoted the migration and invasion of 5FU + OX-pretreated 44As3 cells. Although the number of cases was relatively small (n = 21), the frequency of positive cases of lymphovascular invasion and the recurrence rate were significantly higher in those with more residual CAF. RNA-seq analysis revealed 5FU + OX-pretreated CAF-derived glycoprotein 130 (gp130) as a candidate factor contributing to the increased migration of 5FU + OX-pretreated 44As3 cells. Administration of the gp130 inhibitor SC144 prevented the increased migration ability of 5FU + OX-pretreated 44As3 cells owing to drug-treated CAFs. CONCLUSIONS: Our findings provide evidence regarding the interactions between GC cells and CAFs in the tumor microenvironment following chemotherapy, suggesting that ligands for gp130 may be novel therapeutic targets for suppressing or preventing metastasis in GC.

Relationship between Tooth Loss and the Medications Used for the Treatment of Rheumatoid Arthritis in Japanese Patients with Rheumatoid Arthritis: A Cross-Sectional Study.

BACKGROUND: There is limited information regarding the association between tooth loss and the medications used for the treatment of rheumatoid arthritis (RA). Here, we examined the association between tooth loss, disease severity, and drug treatment regimens in RA patients. METHOD: This study recruited 94 Japanese patients with RA. The severity of RA was assessed using the Steinbrocker classification of class and stage. Data on RA medications were obtained from medical records. We examined the associations between tooth loss, RA severity, and drug treatment regi mens using multinomial logistic regression analyses. RESULTS: Patients with 1-19 teeth had significantly higher odds ratios (ORs) of taking methotrexate (MTX) (OR, 8.74; 95% confidence interval (CI), 1.11-68.8) and biologic disease-modifying antirheumatic drugs (bDMARDs) (OR, 21.0; 95% CI, 1.3-339.1) compared to those with 27-28 teeth when adjusted for RA severity (class). Furthermore, patients with 1-19 teeth had significantly higher ORs of taking MTX (OR, 9.71; 95% CI, 1.22-77.1) and bDMARDs (OR, 50.2; 95% CI, 2.55-990.6) compared to those with 27-28 teeth when adjusted for RA severity (stage). CONCLUSION: RA patients with fewer teeth were more likely to take stronger RA therapies, independent of RA severity and other factors.

Association Between the Extent of Periodontal Inflammation and the Severity of Rheumatoid Arthritis in Japanese Patients With Rheumatoid Arthritis.

OBJECTIVE: Periodontal inflammation can affect the progression of rheumatoid arthritis (RA), and RA drugs may influence the periodontal condition of patients with RA. We examined whether the association between periodontal inflammation and the severity of RA is influenced by RA medication. METHODS: This cross-sectional study recruited 98 Japanese patients with RA from an orthopaedic clinic. We assessed the severity of RA using the Steinbrocker class and stage. The periodontal inflamed surface area (PISA) was used as an indicator of periodontal status. We obtained data on RA medications from medical records. We examined the associations among periodontal tissue inflammation, RA medications, and RA severity using multinomial logistic regression analyses. RESULTS: In univariate multinomial logistic regression analyses, no significant association between PISA score and RA severity was observed. There was no significant association between PISA score and RA severity in multivariate analyses not including variables about RA drugs as independent variables. However, in multivariate analyses adjusted for RA drugs and other confounding variables, patients with a PISA >550 mm2 had significantly higher odds ratios (ORs) for Steinbrocker class III-IV and stage III-IV (OR, 20.24; 95% confidence interval [CI], 1.78-229.85 and OR, 12.42; 95% CI, 1.79-86.49, respectively) compared to patients with PISA score ≤550 mm2. CONCLUSION: The extent of periodontal inflammation is associated with the severity of RA independent of RA medications.

Calcium-based phosphate binder use is associated with lower risk of osteoporosis in hemodialysis patients.

Loss of bone mineral density (BMD) is a substantial risk of mortality in addition to fracture in hemodialysis patients. However, the factors affecting BMD are not fully determined. We conducted a single-center, cross-sectional study on 321 maintenance hemodialysis patients who underwent evaluation of femoral neck BMD using dual-energy X-ray absorptiometry from August 1, 2018, to July 31, 2019. We examined factors associated with osteoporosis defined by T-score of ≤ - 2.5, using logistic regression models. Median age of patients was 66 years, and 131 patients (41%) were diagnosed with osteoporosis. Older age, female, lower body mass index, diabetes mellitus, and higher Kt/V ratios were associated with higher osteoporosis risk. The only medication associated with lower osteoporosis risk was calcium-based phosphate binders (CBPBs) [odds ratio (OR), 0.41; 95% confidence interval (CI), 0.21-0.81]. In particular, CBPB reduced the osteoporosis risk within subgroups with dialysis vintage of ≥ 10 years, albumin level of < 3.5 mg/dL, active vitamin D analog use, and no proton pump inhibitor (PPI) use. In conclusion, CBPB use was associated with lower osteoporosis risk in hemodialysis patients. This effect might be partially attributable to calcium supplementation, given its higher impact in users of active vitamin D analogs or non-users of PPI, which modulate calcium absorption.

Relationship between podoplanin-expressing cancer-associated fibroblasts and the immune microenvironment of early lung squamous cell carcinoma.

AIM: Cancer-associated fibroblasts (CAFs) expressing podoplanin (PDPN) harbor a fibrous tumor microenvironment that promotes cancer progression in lung adenocarcinoma. In this study, we investigated whether tumor-promoting PDPN+ CAFs contribute to the immunosuppressive microenvironment in lung squamous cell carcinoma (SqCC). M&M: The gene expression profiles of immunosuppressive cytokines were compared using The Cancer Genome Atlas (TCGA) microarray lung SqCC data (n = 484) between a PDPN-high group and a PDPN-low group. Further, using patient-derived CAFs from surgically resected lung SqCC, the PDPN+ fraction was sorted and gene and protein expressions were analyzed. Finally, immunohistochemical staining was conducted on 131 surgically resected lung SqCC; CD8+ and FOXP3+ tumor infiltrating lymphocytes (TILs), and CD204+ tumor-associated macrophages (TAMs) were evaluated in cases with PDPN+ and PDPN- CAFs. RESULTS: Analysis of TCGA database revealed that the PDPN-high group exhibited significantly higher expression of interleukin (IL)-1A, IL-1B, IL-6, IL-10, monocyte chemoattractant protein-1 (CCL2), colony stimulating factor 1 (CSF1), fibroblast growth factor 2 (FGF2), galectin 1 (LGALS1), platelet derived growth factor subunit A (PDGFA), PDGFB, and transforming growth factor-ß1 (TGFB1) than those in the PDPN-low group. Among them, it was found that TGFB1 expression was higher in patient-derived PDPN+ CAFs. Immunohistochemical analyses revealed that more CD204+ TAMs infiltrated the tumor tissues in cases with PDPN+ CAFs than in cases with PDPN- CAFs (P <  0.03), while CD8+ and FOXP3+ TILs did not. Furthermore, in the same tumor, CD204+ TAMs infiltrated more in PDPN+ CAF-rich areas (P =  0.005). CONCLUSION: PDPN+ CAFs showed higher expression of TGFB1 and were associated with CD204+ TAM infiltration in stage-I lung SqCC, suggesting that PDPN+ CAFs were associated with the immunosuppressive tumor microenvironment.

Fibroblasts-dependent invasion of podoplanin-positive cancer stem cells in squamous cell carcinoma.

To clear whether podoplanin-positive cancer stem cells in squamous cell carcinoma have higher invasion activity during a fibroblasts-dependent invasion. A collagen gel invasion assay was performed using fluorescent ubiquitination-based cell cycle indicator-labeled A431 cells. The total number and number of invading cells in S/G2/M phase were counted using time-lapse imaging cocultured with fibroblasts. There was no significant difference between the number of invading podoplanin-positive and negative A431 cells when fibroblasts did not exist. On the contrary, the number of invading podoplanin-positive cells was significantly higher when fibroblasts existed. The frequency of cells in S/G2/M phase among invasion was no difference. Knockdown of podoplanin decreased the number of invaded A431 cells significantly when fibroblasts existed. Podoplanin-positive A431 cells display higher invasion activity when fibroblasts exist, suggesting that some biological functions of cancer stem cells might become evident only within the fibrous tumor microenvironment.

Renal TNFα activates the WNK phosphorylation cascade and contributes to salt-sensitive hypertension in chronic kidney disease.

The inappropriate over-activation of the with-no-lysine kinase (WNK)-STE20/SPS1-related proline/alanine-rich kinase (SPAK)-sodium chloride cotransporter (NCC) phosphorylation cascade increases sodium reabsorption in distal kidney nephrons, resulting in salt-sensitive hypertension. Although chronic kidney disease (CKD) is a common cause of salt-sensitive hypertension, the involvement of the WNK phosphorylation cascade is unknown. Moreover, the effect of immune systems on WNK kinases has not been investigated despite the fact that immune systems are important for salt sensitivity. Here we demonstrate that the protein abundance of WNK1, but not of WNK4, was increased at the distal convoluted tubules in the aristolochic acid nephropathy mouse model of CKD. Accordingly, the phosphorylation of both SPAK and NCC was also increased. Moreover, a high-salt diet did not adequately suppress activation of the WNK1-SPAK-NCC phosphorylation cascade in this model, leading to salt-sensitive hypertension. WNK1 also was increased in adenine nephropathy, but not in subtotal nephrectomy, models of CKD. By comparing the transcripts of these three models focusing on immune systems, we hypothesized that tumor necrosis factor (TNF)-α regulates WNK1 protein expression. In fact, TNF-α increased WNK1 protein expression in cultured renal tubular cells by reducing the transcription and protein levels of NEDD4-2 E3-ligase, which degrades WNK1 protein. Furthermore, the TNF-α inhibitor etanercept reversed the reduction of NEDD4-2 expression and upregulation of the WNK1-SPAK-NCC phosphorylation cascade in distal convoluted tubules in vivo in the aristolochic acid nephropathy model. Thus, salt-sensitive hypertension is induced in CKD via activation of the renal WNK1- SPAK-NCC phosphorylation cascade by TNF-α, reflecting a link with the immune system.

Dietary capsaicin-mediated attenuation of hypertension in a rat model of renovascular hypertension.

Background: Capsaicin, a pungent component of chili pepper, has been reported to decrease blood pressure (BP) and to cause vasorelaxation via nitric oxide (NO) production. However, it is still unclear how dietary capsaicin effects on renovascular hypertension. To examine this, we observed the effects of dietary capsaicin on BP in 2-kidney, 1-clip renovascular hypertension (2K1C) rats, and investigated the participation of NO in the mechanism.Methods: Rats with 2K1C or sham-operated rats (SHAM) were treated with 0.006% capsaicin diet (CAP) or control diet (CTL) for 6 weeks. Systolic BP (SBP) was measured by tail-cuff method once a week. In the end, mean arterial BP (MAP) was measured in the rats under anesthesia. These observations were performed also in the rats taking a NO synthase (NOS) inhibitor (LN). After rats were euthanized, thoracic aortas were collected and used for western blot analyses to evaluate the phosphorylated ratio of endothelial NOS (eNOS), protein kinase A (PKA) and B (Akt), in order to explore a mechanism of the effects on BP by dietary capsaicin.Results: SBP and MAP in 2K1C rats were significantly higher than in SHAM rats when fed CTL, but not when fed CAP. Those in 2K1C-CAP rats were significantly lower than in 2K1C-CTL rats. LN suppressed the effect of dietary capsaicin. The ratios of phosphorylated (p-) eNOS/eNOS and p-Akt/Akt, but not p-PKA/PKA, were significantly increased in rats fed CAP compared with rats fed CTL.Conclusion: Dietary capsaicin may alleviate 2K1C renovascular hypertension, probably via enhancing phosphorylation of Akt and eNOS.Abbreviations: 2K1C: 2-kidney, 1-clip hypertension model; Akt: protein kinase B; Ang II: angiotensin II; ANOVA: measures analysis of variance; BP: blood pressure; EC: endothelial cell; eNOS: endothelial nitric oxide synthase; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; L-NAME, LN: Nω-Nitro-L-arginine methyl ester hydrochloride; MA: mesenteric arteries; MAP: mean arterial blood pressure; NO: nitric oxide; PKA: protein kinase A; PVDF: polyvinylidene difluoride; SBP: Systolic blood pressure; SHR: spontaneously hypertensive rats; SN: sympathetic nervous; TRPV1: transient receptor potential vanilloid type 1; WKY: Wistar Kyoto rats.

Posterior occluding pairs of teeth or dentures and 1-year mortality in nursing home residents in Japan.

BACKGROUND: Associations between tooth loss and mortality have been reported in older individuals. However, limited information is available regarding the association between occlusion and mortality in nursing home residents. OBJECTIVE: We investigated the association between posterior occluding pairs (POPs) of teeth or dentures and 1-year mortality in nursing home residents. METHODS: The subjects of this study were residents from four nursing homes in Aichi prefecture, Japan, who were capable of eating and were enrolled in baseline examinations. We examined the number of present teeth and POPs (0-8 pairs), defined as pairs of occluding natural, restored or fixed prosthetic post-canine teeth. Then, we defined prosthetic POPs (0-8 pairs) as pairs of occluding natural, restored or fixed prosthetic post-canine teeth and removable dentures. Nutritional status, activities of daily living, cognitive function and comorbid conditions were assessed. One year later, we followed up the subjects. Ultimately, we analysed 173 elderly people (mean age ± SD: 87.1 ± 8.6 years; the survival group: N = 145, the deceased group: N = 28). RESULTS: In univariate analyses, mortality was significantly associated with age, peripheral vascular disease, nutritional status, diet texture and POPs. In multivariate logistic regression analysis, subjects who had 0 prosthetic POPs had significantly higher odds of a high mortality, compared with 8 prosthetic POPs. CONCLUSION: Lack of properly occluding posterior teeth, whether remaining teeth or dentures, is associated with 1-year mortality. (228 words/250).

Interaction between cancer cells and cancer-associated fibroblasts after cisplatin treatment promotes cancer cell regrowth.

Regrowth of cancer cells following chemotherapy is a significant problem for cancer patients. This study examined whether cancer-associated fibroblasts (CAFs), a major component of a tumor microenvironment, promote cancer cell regrowth after chemotherapy. First, we treated human lung adenocarcinoma cell line A549 and CAFs from four patients with cisplatin. Cisplatin treatment inhibited the viable cell number of A549 cells and induced epithelial-mesenchymal transition. After cisplatin was removed, A549 cells continued to manifest the mesenchymal phenotype and proliferated 2.2-fold in 4 days (regrowth of A549 cells). Cisplatin treatment inhibited the viable cell number of CAFs from four patients also. The CM (derived from cisplatin-pretreated CAFs from two patients) significantly enhanced the regrowth of cisplatin-pretreated A549 cells, and the CM derived from cisplatin-naïve CAFs marginally enhanced A549 regrowth. By contrast, the CM derived from either cisplatin-pretreated CAFs or cisplatin-naïve CAFs failed to enhance the growth of cisplatin-naïve A549 cells. The CM derived from cisplatin-pretreated CAFs did not enhance the proliferation of A549 cells in which epithelial-mesenchymal transition was induced by TGFß-1. Our findings indicate the possibility that humoral factors from cisplatin-pretreated CAFs promote the regrowth of cisplatin-pretreated A549 cells. These results suggest that interactions between cancer cells and CAFs may significantly enhance cancer cell regrowth within the tumor microenvironment after cisplatin treatment.