Cancer history and physical function in patients with cardiovascular disease.

Both cancer and cardiovascular disease (CVD) cause skeletal muscle mass loss, thereby increasing the likelihood of a poor prognosis. We investigated the association between cancer history and physical function and their combined association with prognosis in patients with CVD. We retrospectively reviewed 3,796 patients with CVD (median age: 70 years; interquartile range [IQR]: 61-77 years) who had undergone physical function tests (gait speed and 6-minute walk distance [6MWD]) at discharge. We performed multiple linear regression analyses to assess potential associations between cancer history and physical function. Moreover, Kaplan-Meier curves and Cox regression analyses were used to evaluate prognostic associations in four groups of patients categorized by the absence or presence of cancer history and of high or low physical function. Multiple regression analyses showed that cancer history was significantly and independently associated with a lower gait speed and 6MWD performance. A total of 610 deaths occurred during the follow-up period (median: 3.1 years; IQR: 1.4-5.4 years). The coexistence of low physical function and cancer history in patients with CVD was associated with a significantly higher mortality risk, even after adjusting for covariates (cancer history/low gait speed, hazard ratio [HR]: 1.93, P < 0.001; and cancer history/low 6MWD, HR: 1.61, P = 0.002). Cancer history is associated with low physical function in patients with CVD, and the combination of both factors is associated with a poor prognosis.

Evidence of Nrf2/Keap1 Signaling Regulation by Mitochodria-Generated Reactive Oxygen Species in RGK1 Cells.

It has been known that reactive oxygen species (ROS) are generated from the mitochondrial electron transport chain (ETC). Majima et al. proved that mitochondrial ROS (mtROS) caused apoptosis for the first time in 1998 (Majima et al. J Biol Chem, 1998). It is speculated that mtROS can move out of the mitochondria and initiate cellular signals in the nucleus. This paper aims to prove this phenomenon by assessing the change in the amount of manganese superoxide dismutase (MnSOD) by MnSOD transfection. Two cell lines of the same genetic background, of which generation of mtROS are different, i.e., the mtROS are more produced in RGK1, than in that of RGM1, were compared to analyze the cellular signals. The results of immunocytochemistry staining showed increase of Nrf2, Keap1, HO-1 and 2, MnSOD, GCL, GST, NQO1, GATA1, GATA3, GATA4, and GATA5 in RGK1 compared to those in RGM1. Transfection of human MnSOD in RGK1 cells showed a decrease of those signal proteins, suggesting mtROS play a role in cellular signals in nucleus.

Nrf2 Expression Is Decreased in LRRK2 Transgenic Mouse Brain and LRRK2 Overexpressing SH-SY5Y Cells.

Mutations in leucine rich-repeat kinase 2 (LRRK2) cause autosomal-dominant, late-onset Parkinson's disease (PD). Accumulating evidence indicates that PD-associated LRRK2 mutations induce neuronal cell death by increasing cellular reactive oxygen species levels. However, the mechanism of increased oxidative stress associated with LRRK2 kinase activity remains unclear. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that protects cells from oxidative stress by inducing the expression of antioxidant genes. In the present, it was found that decreased expression of Nrf2 and mRNA expression of its target genes in Lrrk2-transgenic mouse brain and LRRK2 overexpressing SH-SY5Y cells. Furthermore, knockdown of glycogen synthase kinase-3ß (GSK-3ß) recovered Nrf2 expression and mRNA expression of its target genes in LRRK2 overexpressing SH-SY5Y cells. We concluded that since Nrf2 is transcriptional factor for antioxidative responses, therefore, reduction of Nrf2 expression by LRRK2 may be part of a mechanism that LRRK2-induces vulnerability to oxidative stress in neuronal cells.

Features of trunk muscle wasting during acute care and physical function recovery with aortic disease.

BACKGROUND: Low skeletal muscle area or density, such as myosteatosis, identified on computed tomography (CT) is associated with poor prognosis in patients with cardiovascular diseases. However, there is a lack of evidence regarding the clinical process of skeletal muscle decline as a short-term change during acute care settings. This study focused on the use of routine CT imaging for aortic disease management and investigated the changes in skeletal muscle before and after acute care. METHODS: This prospective study included 123 patients who underwent abdominal CT before and after acute care. The all-abdominal and each abdominal muscle areas were divided into eight parts (e.g. rectus abdominis, psoas, and erector spine), and their areas and densities were measured at the third lumbar vertebra level after the patients were discharged and de-identified with blinding to avoid measurement bias. Short physical performance battery (SPPB) was measured at the start and end of in-hospital cardiac rehabilitation. A generalized linear model with patients as random effects was made to investigate skeletal muscle loss during acute care. Multivariate linear regression analysis was also used to assess the relationship between the change in skeletal muscle during acute care and SPPB during in-hospital cardiac rehabilitation. RESULTS: The median age of the patients was 70 (interquartile: 58-77) years, and 69.9% (86/123) were men. The median day between acute care from the day of surgery or hospital admission and follow-up CT was 7 (interquartile: 3-8) days. Overall muscle density declined after acute care (estimate value: -3.640, 95% confidence interval [CI]: -4.538 to -2.741), and each abdominal muscle density consistently declined (interaction: F value = 0.099, P = 0.998). In contrast, there was no significant change in the overall muscle area (estimate value: -0.863, 95% CI: -2.925 to 1.200). Changes in the muscle area were different for each skeletal muscle (interaction: F value = 2.142, P = 0.037), and only the erector spine muscle significantly declined (estimate value: -1.836, 95% CI: -2.507 to -1.165). After adjusting for confounding factors, a greater decline in muscle density was associated with lower recovery score on SPPB (ß = 0.296, 95% CI: 0.066 to 0.400). CONCLUSIONS: Muscle density consistently declined after acute care, especially the erector spine muscles, which also significantly decreased in size. A higher decline in muscle density was associated with a slower recovery of physical function during in-hospital cardiac rehabilitation in patients with aortic diseases.

Low skeletal muscle density combined with muscle dysfunction predicts adverse events after adult cardiovascular surgery.

BACKGROUND AND AIMS: Although muscle dysfunctions are widely known as a poor prognostic factor in patients with cardiovascular disease, no study has examined whether the addition of low skeletal muscle density (SMD) assessed by computed tomography (CT) to muscle dysfunctions is useful. This study examined whether SMDs can strengthen the predictive ability of muscle dysfunctions for adverse events in patients who underwent cardiovascular surgery. METHODS AND RESULTS: We retrospectively reviewed 853 patients aged ≥40 years who had preoperative CT for risk management purposes and who measured muscle dysfunctions (weakness: low grip strength and slowness: slow gait speed). Low SMD based on transverse abdominal CT images was defined as a mean Hounsfield unit of the psoas muscle <45. All definitions of muscle dysfunction (weakness only, slowness only, weakness or slowness, weakness and slowness), the addition of SMDs was shown to significantly improve the continuous net reclassification improvement and integrated discrimination improvement for adverse events in all analyses (p < 0.05). Low SMDs combined with each definition of muscle dysfunction had the highest risk of all-cause death (hazard ratio: lowest 3.666 to highest 6.002), and patients with neither low SMDs nor muscle dysfunction had the lowest risk of all-cause and cardiovascular-related events. CONCLUSION: The addition of SMDs consistently increased the predictive ability of muscle dysfunctions for adverse events. Our results suggest that when CT is performed for any clinical investigation, the addition of the organic assessment of skeletal muscle can strengthen the diagnostic accuracy of muscle wasting.

Randomized study of prevention of gastrointestinal toxicities by nutritional support using an amino acid-rich elemental diet during chemotherapy in patients with esophageal cancer (KDOG 1101).

BACKGROUND: This randomized study was designed to evaluate the clinical effect of an elemental diet during chemotherapy in patients with esophageal cancer. METHODS: The inclusion criteria were as follows: (1) esophageal squamous cell carcinoma, (2) stage IB-IV, (3) schedule to receive docetaxel, cisplatin, and 5-fluorouracil (DCF chemotherapy), (4) 20-80 years old, (5) performance status of 0-2, (6) oral intake ability, and (7) written informed consent. Patients were divided into two groups: the elemental supplementary group and the non-supplementary group. Patients received ELENTAL® (160 g/day) orally 9 weeks after the start of chemotherapy. Primary endpoint was the incidence of grade 2 or higher gastrointestinal toxicity according to the Common Terminology Criteria for Adverse Events, version 4.0. Secondary endpoints were the incidence of all adverse events and the evaluation of nutritional status. RESULTS: Thirty-six patients in the elemental supplementary group and 35 patients in the non-supplementary group were included in the analysis. The incidence of grade 2 or higher gastrointestinal toxicity and all grade 3 or 4 adverse events did not differ significantly between the groups. In the elemental supplementary group, the body weight (p = 0.057), muscle mass (p = 0.056), and blood levels of transferrin (p = 0.009), total amino acids (p = 0.019), and essential amino acids (p = 0.006) tended to be maintained after chemotherapy. CONCLUSION: Nutritional support provided by an amino acid-rich elemental diet was ineffective for reducing the incidence of adverse events caused by DCF chemotherapy in patients with esophageal cancer.

Histamine H2-Receptor Antagonists Improve Non-Steroidal Anti-Inflammatory Drug-Induced Intestinal Dysbiosis.

Dysbiosis, an imbalance of intestinal flora, can cause serious conditions such as obesity, cancer, and psychoneurological disorders. One cause of dysbiosis is inflammation. Ulcerative enteritis is a side effect of non-steroidal anti-inflammatory drugs (NSAIDs). To counteract this side effect, we proposed the concurrent use of histamine H2 receptor antagonists (H2RA), and we examined the effect on the intestinal flora. We generated a murine model of NSAID-induced intestinal mucosal injury, and we administered oral H2RA to the mice. We collected stool samples, compared the composition of intestinal flora using terminal restriction fragment length polymorphism, and performed organic acid analysis using high-performance liquid chromatography. The intestinal flora analysis revealed that NSAID [indomethacin (IDM)] administration increased Erysipelotrichaceae and decreased Clostridiales but that both had improved with the concurrent administration of H2RA. Fecal levels of acetic, propionic, and n-butyric acids increased with IDM administration and decreased with the concurrent administration of H2RA. Although in NSAID-induced gastroenteritis the proportion of intestinal microorganisms changes, leading to the deterioration of the intestinal environment, concurrent administration of H2RA can normalize the intestinal flora.

Efficacy of Exercise Therapy Initiated in the Early Phase After Kidney Transplantation: A Pilot Study.

OBJECTIVE: In patients with kidney transplant (KT), frailty is a predictor of adverse outcomes. Outcomes of exercise therapy in patients with KT, particularly the efficacy of early exercise after KT, have not been evaluated. We investigated the effect of exercise intervention beginning early after KT on physical performance, physical activity, quality of life, and kidney function in patients with KT. METHODS: KT recipients who underwent surgery with usual care plus exercise training from a prospective cohort (exercise group; n = 10) and those with usual care alone from a historical cohort (control group; n = 14) were included in this study. Early exercise comprised supervised aerobic training and physical activity instruction from day 6 to 2 months after KT. The following outcomes were measured: 6-minute walking distance, isometric knee extensor strength, gait speed, physical activity, quality of life, and estimated glomerular filtration rate. RESULTS: Analyses of covariance, adjusted for baseline values, revealed significant mean differences between exercise and control groups at 2 months after KT in 6-minute walking distance (+44.4 m, P = .03) and isometric knee extensor strength (+8.1%body weight, P = .03). No significant between-group differences were found in gait speed, physical activity, and quality of life. The analysis of variance for comparison of the area under the recovery curves of estimated glomerular filtration rate after KT revealed no significant difference between groups. CONCLUSION: Supervised aerobic training and physical activity instruction initiated in the early phase after KT can improve physical performance without adversely affecting kidney function.

Usefulness of the Simplified Frailty Scale in Predicting Risk of Readmission or Mortality in Elderly Patients Hospitalized with Cardiovascular Disease.

The simplified frailty scale is a simple frailty assessment tool modified from Fried's phenotypic frailty criteria, which is easy to administer in hospitalized patients. The applicability of the simplified frailty scale to indicate prognosis in elderly hospitalized patients with cardiovascular disease (CVD) was examined.This cohort study was performed in 895 admitted patients ≥ 65 years (interquartile range, 71.0-81.0, 541 men) with CVD. Patients were classified as robust, prefrail, or frail based on the five components of the simplified frailty scale: weakness, slowness, exhaustion, low activity, and weight loss. The primary endpoint was the composite outcome of all-cause mortality and unplanned readmission for CVD.Patients positive for greater numbers of frailty components showed higher risk of all-cause mortality or unplanned CVD-related readmission (P for trend < 0.001). Classification as both frail (adjusted HR: 3.27, 95% confidence interval [CI]: 1.49-7.21, P = 0.003) and prefrail (adjusted HR: 2.19, 95% CI: 1.00-4.79, P = 0.049) independently predicted the composite endpoint compared with robust after adjusting for potential confounding factors. The inclusion of prefrail, frail, and number of components of frailty increased both continuous net reclassification improvement (0.113, P = 0.049; 0.426, P < 0.001; and 0.321, P < 0.001) and integrated discrimination improvement (0.007, P = 0.037; 0.009, P = 0.038; and 0.018, P = 0.002) for the composite endpoint.Higher scores on the simplified frailty scale were associated with increased risk of mortality or readmission in elderly patients hospitalized for CVD.

In vivo FRET analyses reveal a role of ATP hydrolysis-associated conformational changes in human P-glycoprotein.

P-glycoprotein (P-gp; also known as MDR1 or ABCB1) is an ATP-driven multidrug transporter that extrudes various hydrophobic toxic compounds to the extracellular space. P-gp consists of two transmembrane domains (TMDs) that form the substrate translocation pathway and two nucleotide-binding domains (NBDs) that bind and hydrolyze ATP. At least two P-gp states are required for transport. In the inward-facing (pre-drug transport) conformation, the two NBDs are separated, and the two TMDs are open to the intracellular side; in the outward-facing (post-drug transport) conformation, the NBDs are dimerized, and the TMDs are slightly open to the extracellular side. ATP binding and hydrolysis cause conformational changes between the inward-facing and the outward-facing conformations, and these changes help translocate substrates across the membrane. However, how ATP hydrolysis is coupled to these conformational changes remains unclear. In this study, we used a new FRET sensor that detects conformational changes in P-gp to investigate the role of ATP binding and hydrolysis during the conformational changes of human P-gp in living HEK293 cells. We show that ATP binding causes the conformational change to the outward-facing state and that ATP hydrolysis and subsequent release of γ-phosphate from both NBDs allow the outward-facing state to return to the original inward-facing state. The findings of our study underscore the utility of using FRET analysis in living cells to elucidate the function of membrane proteins such as multidrug transporters.

Preoperative skeletal muscle density is associated with postoperative mortality in patients with cardiovascular disease.

OBJECTIVES: Although skeletal muscle density (SMD) is useful for predicting mortality, the cut-off in an acute clinical setting is unclear, especially in patients with cardiovascular disease (CVD). This study was performed to determine the preoperative SMD cut-off using the psoas muscle and to investigate the effect on postoperative outcomes, including sarcopaenia, in CVD patients. METHODS: Preoperative psoas SMD was measured by abdominal computed tomography in CVD patients. Postoperative sarcopaenia was defined according to the criteria of the Asia Working Group for Sarcopaenia. The Youden index was used to test the predictive accuracy of survival models. The prognostic capability was evaluated using multivariable survival and receiver operating characteristic curve analyses. RESULTS: Continuous data were available for 1068 patients (mean age 65.5 years; 63.6% male). A total of 105 (9.8%) deaths occurred during the 1.99-year median follow-up period (interquartile range 0.71-4.15). The psoas SMD cut-off estimated by the Youden index was 45 Hounsfield units with high sensitivity and moderate specificity for all-cause mortality and was consistent in various stratified analyses. After adjusting for the existing prognostic model, EuroSCORE II, preoperative and postoperative physical status, psoas SMD cut-off was predicted for mortality (hazard ratio 2.42, 95% confidence interval 1.32-4.45). The psoas SMD cut-off was also significantly associated with postoperative sarcopaenia and provided additional prognostic information to EuroSCORE II on receiver operating characteristic curve analysis (area under the curve 0.627 vs 0.678, P = 0.011). CONCLUSIONS: Reduced psoas SMD was associated with postoperative mortality and added information prognostic for mortality to the existing prognostic model in CVD patients.

Oxidative stress increases megalin expression in the renal proximal tubules during the normoalbuminuric stage of diabetes mellitus.

Megalin, an endocytic receptor expressed in proximal tubule cells, plays a critical role in renal tubular protein reabsorption and is associated with the albuminuria observed in diabetic nephropathy. We have previously reported increased oxidant production in the renal cortex during the normoalbuminuric stage of diabetes mellitus (DM); however, the relationship between oxidative stress and renal megalin expression during the normoalbuminuric stage of DM remains unclear. In the present study, we evaluated whether oxidative stress affects megalin expression in the normoalbuminuric stage of DM in a streptozotocin-induced diabetic rat model and in immortalized human proximal tubular cells (HK-2). We demonstrated that increased expression of renal megalin accompanies oxidative stress during the early stage of DM, before albuminuria development. Telmisartan treatment prevented the diabetes-induced elevation in megalin level, possibly through an oxidative stress-dependent mechanism. In HK-2 cells, hydrogen peroxide significantly increased megalin levels in a dose- and time-dependent manner; however, the elevation in megalin expression was decreased following prolonged exposure to severe oxidative stress induced by 0.4 mmol/l hydrogen peroxide. High-glucose treatment also significantly increased megalin expression in HK-2 cells. Concurrent administration of the antioxidant N-acetyl-cysteine blocked the effects of high glucose on megalin expression. Furthermore, the hydrogen peroxide-induced increase in megalin expression was blocked by treatment with phosphatidylinositol 3-kinase and Akt inhibitors. Increase of phosphorylated Akt expression was also seen in the renal cortex of diabetic rats. Taken together, our results indicate that mild oxidative stress increases renal megalin expression through the phosphatidylinositol 3-kinase-Akt pathway in the normoalbuminuric stage of DM.

Heat-shock protein 72 promotes platelet aggregation induced by various platelet activators in rats.

Increase of thrombus in the coronary arteries is positively correlated with the level of heat-shock protein 72 (HSP72) in the blood of patients with acute myocardial infarction (AMI). Platelet aggregation participates in thrombus formation on ruptured plaque in AMI. In this study, we aimed to clarify the role of HSP72 in thrombus formation by evaluating the effects of HSP72 on platelet aggregation. Platelet aggregation activities were measured in platelet-rich plasma obtained from male Sprague-Dawley rats with or without the platelet activators, such as adenosine diphosphate (ADP), collagen, thrombin receptor-activating peptide-6 (TRAP-6), ristocetin, and arachidonic acid. Changes in aggregation were estimated by the co-addition of recombinant HSP72 and anti-HSP72 antibodies. Our results showed that addition of HSP72 increased platelet aggregation in the presence of low concentrations of ADP, collagen, TRAP-6, ristocetin, and arachidonic acid. Increased platelet aggregation stimulated by ADP and HSP72 was reduced by the co-addition of anti-HSP72 antibodies. Thus, these findings suggested that HSP72 was released extracellularly in response to stress, promoting thrombus formation and AMI. Additionally, treatment with anti-HSP72 antibodies may control platelet aggregation induced by extracellular HSP72.

Influence of an elemental diet on 5-fluorouracil-induced morphological changes in the mouse salivary gland and colon.

PURPOSE: The elemental diet (ED) Elental® reportedly reduces adverse reactions to chemotherapy in digestive system cancer patients; however, the mechanism is unclear. Therefore, we verified the protective effect of ED against gastrointestinal disorders induced by the antineoplastic drug 5-fluorouracil (5-FU). METHODS: After 5 days of tail vein injections of 40 mg/kg/day 5-FU in female BALB/c mice, the mice were given oral ED (ED group) or dextrin with the same number of calories (control group). We measured the weight of salivary glands and the PAS-positive area of colonic mucosa and verified the antitumor effect in tumor-bearing mice given 5-FU and ED. RESULTS: Although body weight decreased after 5-FU treatment, ED group mice weighed more than control group mice. Additionally, although control mice developed diarrhea after 5-FU treatment, the ED group showed only loose stools. The control group saliva volume was approximately one sixth of the vehicle group volume after 5-FU treatment; this was improved to approximately half in the ED group. The area ratio of PAS-positive cells in the colonic mucosa was reduced by 5-FU treatment, with the ratio being higher in the ED group than that in the control group. Similar tumor growth suppression was observed in the 5-FU and ED groups. CONCLUSIONS: ED alleviated adverse reactions to 5-FU without affecting antitumor activity. Protection against 5-FU-induced weight loss was potentially due to both improved nutritional support with combined ingredients and prevention of diarrhea that is associated with reduced colonic goblet cells and decreased saliva production from reduced salivary gland contraction.

Elemental diet moderates 5-fluorouracil-induced gastrointestinal mucositis through mucus barrier alteration.

PURPOSE: There are reports that elemental diet (ED) ameliorates oral mucositis caused by antineoplastic chemotherapy. Although this effectiveness may be partly due to high nutrient absorption, the effects of chemotherapy on mucosal defense mechanisms remain unclear. We investigated the effects of oral supplementation with ED on mucin in 5-fluorouracil (5-FU)-induced intestinal mucositis. METHODS: 5-FU was administered to rats orally once daily, and ED was supplied orally twice daily for 5 days. The severity of mucositis was assessed by length, dry tissue weight, and villus height of the intestinal tract. Using anti-mucin monoclonal antibody, we compared the immunoreactivity in the gastrointestinal (GI) tract and mucin content by histological and biochemical examinations. RESULTS: Oral supplementation with ED reduced histological damage and loss of length, dry tissue weight, and villus height induced by 5-FU administration. ED markedly altered PGM34 antibody immunoreactivity and mucin contents in the small intestine of rats with 5-FU-induced mucositis. CONCLUSIONS: ED may possibly be more effective for the prevention of antineoplastic chemotherapy-induced mucositis through the activation of GI mucus cells.

Peptide-based immunoadsorbents: molecular grafting of IgG-Fc-binding epitopes of Protein A onto a de novo-designed helix-loop-helix peptide.

The development of immunoadsorbents that have high specificity for immunoglobulin and no immunogenicity is essential for immunoadsorption treatment of autoimmune diseases. In this study, we designed peptide immunoadsorbents by molecular grafting of the IgG-Fc binding epitopes of Protein A onto a de novo-designed helix-loop-helix peptide. Linear (linG7A5) and cyclic (cyG7A5) grafted peptides were synthesized to test their binding affinity and specificity. Peptide cyG7A5 demonstrated high specificity for human IgG-Fc, with a K(D) of 19 µM, and demonstrated no affinity to other plasma proteins, human serum albumin, or fibrinogen. To evaluate their immunoadsorbance efficiency, the grafted peptides and Protein A were conjugated to polyvinyl acetate resin and tested in a batch-wise process for adsorption removal of IgG from human plasma. The IgG capture capacities of the peptides correlated well with their binding affinities. Interestingly, cyG7A5 showed a higher binding specificity for IgG than did Protein A.

The role of the interaction of the vinculin proline-rich linker region with vinexin α in sensing the stiffness of the extracellular matrix.

Although extracellular matrix (ECM) stiffness is an important aspect of the extracellular microenvironment and is known to direct the lineage specification of stem cells and affect cancer progression, the molecular mechanisms that sense ECM stiffness have not yet been elucidated. In this study, we show that the proline-rich linker (PRL) region of vinculin and the PRL-region-binding protein vinexin are involved in sensing the stiffness of ECM substrates. A rigid substrate increases the level of cytoskeleton-associated vinculin, and the fraction of vinculin stably localizing at focal adhesions (FAs) is larger on rigid ECM than on soft ECM. Mutations in the PRL region or the depletion of vinexin expression impair these responses to ECM stiffness. Furthermore, vinexin depletion impairs the stiffness-dependent regulation of cell migration. These results suggest that the interaction of the PRL region of vinculin with vinexin α plays a crucial role in sensing ECM stiffness and in mechanotransduction.

Leucine-rich repeat kinase 2 regulates tau phosphorylation through direct activation of glycogen synthase kinase-3ß.

Leucine-rich repeat kinase 2 (LRRK2) has been identified as the causal molecule for autosomal-dominant Parkinson's disease (PD). Experimental evidence indicates that LRRK2 may play an important role in the pathology induced by abnormal phosphorylation of tau. In the present study, we demonstrated that LRRK2 directly associates with GSK-3ß, and that this interaction enhances the kinase activity of GSK-3ß. Furthermore, we found that LRRK2-mediated activation of GSK-3ß induces high phosphorylation of tau at Ser396 in SH-SY5Y cells. From our present findings, we conclude that LRRK2 may function as a novel enhancer for GSK-3ß and as a physiological regulator of neurite outgrowth and axonal transport through regulation of the GSK-3ß-mediated phosphorylation of tau at the cellular level. Since LRRK2 is detected in tau-positive inclusions in brain tissue affected by various neurodegenerative disorders, including PD, LRRK2-stimulated phosphorylation of tau by GSK-3ß may be involved in development of pathological features in the initial stage of PD.

Changes in the mucus barrier during cisplatin-induced intestinal mucositis in rats.

AIM: Gastrointestinal mucositis is a frequent complication of antineoplastic chemotherapy, but the effects of chemotherapy on mucosal defense mechanisms remain poorly understood. We studied the effects of cisplatin on mucin, one of the principal defense factors of the gastrointestinal mucosa, and evaluated the efficacy of two different types of H2-receptor antagonists against cisplatin-induced mucositis. METHODS: Cisplatin (6 mg/kg) was administered intravenously to rats (day 0). The rats were sacrificed 1, 3, 7, and 11 days after treatment, and their stomach, jejunum, ileum, and colon were removed. Immunoreactivity of the mucosa was compared with the use of anti-mucin monoclonal antibody. To evaluate the efficacy of H2-receptor antagonists, either famotidine (3 mg/kg) or lafutidine (30 mg/kg) was given orally once daily on days 0, 1, and 2. Histological and biochemical findings were compared among the groups to assess effects on cisplatin-induced injury. RESULTS: Cisplatin significantly altered the immunoreactivity and content of mucin in the small intestinal mucosa, especially in the ileum. Lafutidine protected against cisplatin-induced mucosal injury and attenuated decreased mucin accumulation. CONCLUSION: Cisplatin appears to alter the mucus barrier function in the intestinal mucosa. Lafutidine might effectively prevent chemotherapy-induced mucositis by activating intestinal mucus cells.

LRRK2 phosphorylates tubulin-associated tau but not the free molecule: LRRK2-mediated regulation of the tau-tubulin association and neurite outgrowth.

Leucine-rich repeat kinase 2 (LRRK2), a large protein kinase containing multi-functional domains, has been identified as the causal molecule for autosomal-dominant Parkinson's disease (PD). In the present study, we demonstrated for the first time that (i) LRRK2 interacts with tau in a tubulin-dependent manner; (ii) LRRK2 directly phosphorylates tubulin-associated tau, but not free tau; (iii) LRRK2 phosphorylates tau at Thr181 as one of the target sites; and (iv) The PD-associated LRRK2 mutations, G2019S and I2020T, elevated the degree of tau-phosphorylation. These results provide direct proof that tau is a physiological substrate for LRRK2. Furthermore, we revealed that LRRK2-mediated phosphorylation of tau reduces its tubulin-binding ability. Our results suggest that LRRK2 plays an important role as a physiological regulator for phosphorylation-mediated dissociation of tau from microtubules, which is an integral aspect of microtubule dynamics essential for neurite outgrowth and axonal transport.