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Biomedical subjects

Kenjiro Kimura

Publications and source records attributed to Kenjiro Kimura.

At least 19 recordsLinked to original sources
PubMed2006

Transplantation of myocyte precursors derived from embryonic stem cells transfected with IGFII gene in a mouse model of muscle injury.

BACKGROUND: Reconstruction of skeletal muscle tissue is hampered by the lack of availability of functional substitution of the tissue. METHODS: Embryonic stem (ES) cells were transfected with the insulin-like growth factor (IGF) II gene and were selected with G418. The resultant cell clones were analyzed regarding their myogenic differentiation in vitro and in vivo. RESULTS: The cells expressed early and late myogenic differentiation markers, including myoD, myogenin, and dystrophin in vitro. They had phosphorylated Akt within the cells, suggesting their activation by the secreted IGFII. Transplantation of the cells to injured anterior tibial muscle of mice significantly improved their motor functions compared to injured mice transplanted with undifferentiated ES cells and injured mice given vehicle alone. The transfected cells adapted to the injured muscle, formed myofibers positive for dystrophin and negative for MyoD and myogenin. Trichrome staining and toluidine blue staining support myofiber formation in vivo. The enzymatic activity of acetylcholine esterase suggested the functional activity of the regenerated motor units. The evoked electromyogram of anterior tibial muscle transplanted with the transfected cells showed significantly higher potentials compared to that transplanted with undifferentiated ES cells and that injected with phosphate-buffered saline (control injury). Electron microscopic examination confirmed the myofiber formation in the cells in vivo. CONCLUSIONS: Transfection of IGFII gene into ES cells may be applicable for transplantation therapy of muscle damage due to injury and myopathies.

Adaptation, Physiological↗
PubMed2006

Antitumor effect of trastuzumab for pancreatic cancer with high HER-2 expression and enhancement of effect by combined therapy with gemcitabine.

PURPOSE: The purpose of the present study was to evaluate whether trastuzumab has antitumor effect against pancreatic cancer and whether this effect is concordant with levels of HER-2, which is reportedly overexpressed in pancreatic cancer. We also investigated whether the effect is potentiated in combined therapy with gemcitabine. EXPERIMENTAL DESIGN: Using immunohistochemistry and FACScan, we analyzed HER-2 expression in 16 pancreatic cancer cell lines. The in vitro antiproliferative effect of trastuzumab, alone and in combination with gemcitabine, was examined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The in vitro antibody-dependent cell-mediated cytotoxicity of trastuzumab was investigated by (51)Cr release assay. The in vivo antitumor effect of trastuzumab, alone and in combination with gemcitabine, was evaluated in nude mouse xenograft growth. The survival benefit was evaluated in a Capan-1 orthotopic implanted nude mouse model. RESULTS: HER-2 expression of 2+ or more was observed in 10 and of 3+ in 2 of the 16 cell lines. No in vitro growth-inhibitory effect of trastuzumab was found in any cell line, but trastuzumab induced antibody-dependent cell-mediated cytotoxicity in proportion to HER-2 expression level. Trastuzumab inhibited tumor growth in Capan-1 (HER-2: 3+) xenografts and prolonged survival in the orthotopic model. These effects were increased by combined therapy with gemcitabine. In contrast, trastuzumab exhibited no antitumor effect against PANC-1 (HER-2: 1+) or SW1990 (HER-2: 2+) xenografts. CONCLUSIONS: The antitumor effect of trastuzumab in pancreatic cancer with high HER-2 expression was shown in vitro and in vivo. Clinical application of trastuzumab is expected in pancreatic cancer with 3+ HER-2 expression.

Animals↗
PubMed2006

Urinary fatty acid binding protein in renal disease.

The number of patients with end stage renal failure has been increasing throughout the world. The importance of measuring clinical parameters in renal injury has been emphasized for administering appropriate treatment and preventing a worsening of the disease. However, there are no clinically useful markers in predicting and monitoring the progression of renal disease. Liver type fatty acid binding protein (L-FABP) of 14.4 kDa is expressed in human proximal tubules. In order to evaluate the clinical significance of urinary L-FABP as a biomarker in renal disease, a monoclonal antibody against human L-FABP was developed and a two step sandwich enzyme linked immunosorbent assay (ELISA) method was established for determining human L-FABP in urine. In some clinical studies, urinary excretion of L-FABP was shown to be an excellent clinical marker that can help predict and monitor the progression of renal disease. The dynamics of renal L-FABP in pathophysiological settings has been revealed in experimental studies using transgenic mice with the human L-FABP gene. This review presents recent findings on the function and pathophysiological role of L-FABP, and summarizes the clinical importance of measuring urinary L-FABP in renal disease.

Biomarkers↗
PubMed2006

Urinary liver-type fatty acid binding protein as a useful biomarker in chronic kidney disease.

BACKGROUND: We reported that urinary L-FABP reflected the progression of chronic kidney disease (CKD). This study is aimed to evaluate the clinical significance of urinary liver type fatty acid binding protein (L-FABP) as a biomarker for monitoring CKD. METHODS: Urinary L-FABP was measured using human L-FABP ELISA kit (CMIC.Co., Ltd., Tokyo, Japan). The relations between urinary L-FABP and clinical parameters were evaluated in non-diabetic CKD (n = 48) for a year. In order to evaluate the influence of serum L-FABP derived from liver upon urinary L-FABP, both serum and urinary L-FABP were simultaneously measured in patients with CKD (n = 73). RESULTS: For monitoring CKD, the cut-off value in urinary L-FABP was determined as 17.4 microg/g.cr. by using a receiver operating characteristics (ROC) curve. Renal function deteriorated significantly more in patients with 'high' urinary L-FABP (n = 36) than in those with 'low' L-FABP (n = 12). The decrease in creatinine clearance was accompanied by an increase in urinary L-FABP, but not in urinary protein. Serum L-FABP in patients with CKD was not correlated with urinary L-FABP. CONCLUSION: Urinary excretion of L-FABP increases with the deterioration of renal function. Serum L-FABP did not influence on urinary L-FABP. Urinary L-FABP may be a useful clinical biomarker for monitoring CKD.

Adult↗
PubMed2006

Liver-type fatty acid-binding protein attenuates renal injury induced by unilateral ureteral obstruction.

Liver-type fatty-acid-binding protein (L-FABP), which has high affinity for long-chain fatty acid oxidation products, may be an effective endogenous antioxidant. To examine the role of L-FABP in tubulointerstitial damage, we used a unilateral ureteral obstruction (UUO) model. We established human L-FABP (hL-FABP) gene transgenic (Tg) mice and compared the tubulointerstitial pathology of the Tg mice (n = 23) with that of the wild-type (WT) mice (n = 23). Mice were sacrificed on days 2, 4, 5, or 7 after UUO. Although mouse L-FABP was not expressed in WT mice, hL-FABP was expressed in the proximal tubules of the Tg mice with UUO (UUO-Tg) and in sham-operated Tg mice. The expression of renal hL-FABP was significantly increased in UUO-Tg compared with sham-operated Tg mice. The number of macrophages (F4/80) infiltrating the interstitium and the level of expression of MCP-1 and MCP-3 were significantly lower in UUO-Tg kidneys compared with UUO-WT kidneys. In UUO-Tg kidneys, the degree of the tubulointerstitial injury and the deposition of type I collagen were significantly lower than that of UUO-WT kidneys. On day 7, lipid peroxidation product accumulated in the UUO-WT kidneys but not in that of UUO-Tg kidneys. In conclusion, renal L-FABP may reduce the oxidative stress in the UUO model, ameliorating tubulointerstitial damage.

Animals↗
PubMed2006

[A case of advanced gastric cancer with malignant ascites responding to weekly paclitaxel therapy].

A 54-year-old woman with scirrhous gastric cancer in the upper third area was admitted to our hospital. She was diagnosed with advanced gastric cancer that was inoperable due to peritoneal metastasis, so weekly paclitaxel (PTX) therapy was carried out. After 2 courses, malignant ascites completely disappeared and bilateral hydronephrosis improved. After 4 courses, no ascites or hydronephrosis were seen. Only neutropenia (grade 2) and alopecia (grade 1) were observed as adverse events during the therapy, but no major adverse events were noted. We also investigated the concentration of paclitaxel in ascites. Two hours after intravenous injection of PTX, the concentration of PTX in ascites rose over the reported cytotoxic dose of PTX, and this available concentration was maintained after 48 hours. Weekly paclitaxel therapy is suggested to be one of the safe and useful treatments for advanced gastric cancer with malignant ascites.

Adenocarcinoma, Scirrhous↗
PubMed2005

Urinary excretion of liver fatty acid-binding protein in health-check participants.

BACKGROUND: Messenger RNA of liver fatty acid-binding protein (L-FABP) is expressed in proximal tubules of the kidney, and a certain amount is excreted into urine. We analyzed factors relating to the urinary L-FABP excretion in health-check participants. METHODS: We measured L-FABP in the first morning urine by ELISA in 715 men and 193 women 30-79 years of age who entered a 2-day hospitalized health checkup program. In addition to the routine physical examination and laboratory tests, plasma high-sensitivity C-reactive protein (HSCRP) was assayed. RESULTS: In 150 healthy subjects, urinary L-FABP averaged 3.6 +/- 0.2 microg/g creatinine, whereas the values were significantly increased in patients with hypertension (5.2 +/- 0.4, P = 0.010), diabetes mellitus (5.5 +/- 0.5, P < 0.001), and chronic hepatitis (5.8 +/- 1.0, P = 0.022). Urinary L-FABP excretion was significantly greater in women than in men when the value was related to creatinine. In regression analysis in men, urinary L-FABP was positively correlated with fasting plasma glucose (r = 0.103, P = 0.033) and plasma HSCRP (r = 0.135, P = 0.006). CONCLUSIONS: It is suggested that renal production and urinary excretion of L-FABP are increased in situations in which arteriosclerosis is promoted, such as hypertension, diabetes mellitus, and cardiovascular inflammation.

Adult↗
PubMed2005

Imbalance between production and scavenging of hydroxyl radicals in patients maintained on hemodialysis.

BACKGROUND: Reactive oxygen species are as being related to the pathophysiology of endstage renal disease (ESRD). We measured the plasma hydroxyl radical (.OH)-producing ability and .OH-scavenging activity in patients with ESRD to clarify the pathophysiological states involved. METHODS: We used electron spin resonance to measure plasma N-t-butyl-alpha-phenylnitron radical spin adduct (pPBN rsa) as .OH-producing ability and plasma 3,3,5,5-tetramethyl-1-pyrroline-N-oxide radical spin adduct (pM4PO rsa) as .OH-scavenging activity. Oxidative injuries were evaluated by determining oxidised low-density lipoprotein (Ox-LDL). RESULTS: The pPBN rsa of the ESRD patients was lower than that of the controls (1.83 vs 2.94 micromol/g protein). The pM4PO rsa of the ESRD patients was higher than that of the controls (3.85 vs 3.15 mmol L: -ascorbic acid 2-[3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-2H-1-benzopyran-6-yl hydrogen phosphate] potassium salt (EPC-K1)/g protein). The pPBN rsa and pM4PO rsa were correlated, both in the ESRD patients and in the controls (r = 0.47 and r = 0.53). Ox-LDL was correlated with hemodialysis (HD) duration (r = 0.49) and was negatively correlated with pPBN rsa (r = -0.54), which indicates that oxidative stress was increased as HD therapy was prolonged and suppressed pPBN rsa. CONCLUSIONS: There was an imbalance between .OH-producing ability and .OH-scavenging activity, in the ESRD patients, and this may be responsible for compromising the health of ESRD patients.

Aged↗
PubMed2005

Clinical evaluation of urinary excretion of liver-type fatty acid-binding protein as a marker for the monitoring of chronic kidney disease: a multicenter trial.

To confirm the clinical usefulness of the measurement of urinary liver-type fatty acid-binding protein (L-FABP) in chronic kidney disease (CKD), we carried out a multicenter trial. Clinical markers were measured in patients with nondiabetic CKD (n = 48) every 1 to 2 months for a year. We divided patients retrospectively into progression (n = 32) and nonprogression (n = 16) groups on the basis of the rate of disease progression, then assessed several clinical markers. Initially creatinine clearance (Ccr) was similar in the 2 groups; however, the urinary L-FABP level was significantly higher in the former group than in the latter (111.5 vs 53 microg/g creatinine, P < .001). For the monitoring CKD, we set the cutoff values for urinary L-FABP and urinary protein at 17.4 microg/g creatinine and 1.0 g/g creatinine, respectively. Urinary L-FABP was more sensitive than urinary protein in predicting the progression of CKD (93.8% and 68.8%, respectively). However, urinary protein showed greater specificity than did urinary L-FABP (93.8% and 62.5%, respectively). Over time, the progression of CKD tended to correlate with changes in urinary L-FABP (r = - .32, P < .05), but not in urinary protein (r = .18, not significant). The dynamics of urinary protein differed from that of urinary L-FABP, which increased as Ccr declined. Urinary L-FABP is more sensitive than urinary protein in predicting the progression of CKD. Urinary excretion of L-FABP increases with the deterioration of kidney function. Urinary L-FABP is therefore a useful clinical marker in the monitoring of CKD.

Adult↗
PubMed2005

Long-term effect of imidapril hydrochloride compared with dilazep hydrochloride administration on blood pressure and renal function in patients with chronic glomerulonephritis.

The objective of the present study was to compare the effects of imidapril hydrochloride, an angiotensin converting enzyme inhibitor, and dilazep hydrochloride, an antiplatelet agent, on urinary protein excretion and renal function in patients with chronic glomerulonephritis. Imidapril (2.5 or 5 mg/day) or dilazep (300 or 450 mg/day) was administered for 3 years. Blood pressure, proteinuria, and renal function were measured before and during the treatment. In the group administered imidapril (n = 11), urinary protein decreased by approximately 50% (2.16 +/- 1.57 versus 0.90 +/- 0.53 g/g Cr, P < 0.01) and blood pressure by 14/10 mmHg (139.6 +/- 17.4/93.6 +/- 8.7 mmHg versus 122.7 +/- 10.5/81.8 +/- 9.9 mmHg, P < 0.01) and both remained at low levels during the three years of treatment. No correlation was observed between the extent of blood pressure reduction and changes in urinary protein. Serum creatinine concentrations did not change significantly (1.3 +/- 0.3 versus 1.3 +/- 0.3 mg/dL, NS). In the dilazep group (n = 12), there were no significant changes in blood pressure, urinary protein, or serum creatinine. These findings demonstrate that imidapril reduces proteinuria and contributes to preserve renal function, suggesting its usefulness in the treatment of patients with chronic glomerulonephritis.

Adult↗
PubMed2005

More stable and reliable pharmacokinetics with preprandial administration of cyclosporine compared with postprandial administration in patients with refractory nephrotic syndrome.

STUDY OBJECTIVE: To compare the absorption profile of cyclosporine after preprandial administration with that after postprandial administration, and to determine which administration time resulted in a more stable absorption profile and the timing of the drug concentration that was the most reliable marker for monitoring drug absorption. DESIGN: Prospective analysis. SETTING: University teaching hospital in Japan. PATIENTS: Sixteen patients with refractory nephrotic syndrome. INTERVENTION: Thirteen patients received cyclosporine after breakfast (postprandial group) and eight received the drug 30 minutes before breakfast (preprandial group). MEASUREMENTS AND MAIN RESULTS: Blood cyclosporine concentration was measured 5 times serially: before administration (C 0 ) and at 1-hour intervals until 4 hours after administration of cyclosporine (C 1 -C 4 ). Also, area under the concentration-time curve from 0-4 hours (AUC 0-4 ) was calculated. Of the 13 patients in the postprandial group, six (46%) showed fair absorption and exhibited a peak concentration at C 1 or C 2 (high-absorption pattern); seven (54%) showed poor absorption and did not reach the peak concentration within the 4-hour period (low-absorption pattern). Five of the seven patients with the low-absorption pattern were switched from postprandial to preprandial administration. All patients in the preprandial administration group showed a high-absorption pattern and reached the peak cyclosporine concentration at C 1 . The C 2 value showed the best correlation with AUC 0-4 in both groups, and the C 0 parameter did not correlate with AUC 0-4 in either group. CONCLUSION: Preprandial administration provided a more stable absorption profile of cyclosporine compared with postprandial administration. From the correlation with AUC 0-4 , we concluded that C 2 , and not C 0 , is a reliable marker for monitoring cyclosporine exposure.

Absorption↗
PubMed2005

Plasminogen activator inhibitor-1 (PAI-1) gene transfection inhibits the liver metastasis of pancreatic cancer by preventing angiogenesis.

Plasminogen activator inhibitor-1 (PAI-1) is a unique type of serine protease inhibitor and one of the key regulators of tumor invasion and metastasis. The purpose of this study was to elucidate the effect of PAI-1 gene transfection on liver metastasis and its mechanism by using the human high liver metastasis pancreatic cancer cell line, SW1990. PAI-1-transfected SW1990 (SW/PAI-1) produced a significantly higher level of PAI-1 in supernatant than parental cells. While no difference was observed for the production of u-PA and u-PA activity in the supernatant, cell proliferation of SW/PAI-1 was slightly suppressed on the 7th day of incubation compared to parental cells. Cellular invasion, in vivo tumorigenesis in xenograft and liver metastasis were significantly suppressed in SW/PAI-1 cells compared to parental cells. The angiogenesis of xenograft by detecting microvascular density and the production of metastasis-related factors, such as VEGF and TGF-beta1, were also decreased in SW/PAI-1 cells. These findings suggested that PAI-1 gene transfection might have the ability to prevent the liver metastasis of pancreatic cancer by modulating angiogenesis.

Animals↗
PubMed2004

Nitric oxide generated by nNOS in the macula densa regulates the afferent arteriolar diameter in rat kidney.

Nitric oxide (NO) derived from neuronal NO synthase (nNOS) in the macula densa is a modulator of tubuloglomerular feedback. However, little is known about the regulation of the afferent arteriolar diameter by NO from the macula densa in salt-sensitive hypertension. We investigated the relationship between nNOS in the macula densa and the afferent arteriolar diameter in deoxycorticosterone acetate (DOCA)-salt hypertensive rats treated with angiotensin converting enzyme (ACE) inhibitor or thiazide for 5 weeks. DOCA rats had reduced nNOS expression in the macula densa compared to controls and reduction of NO production evaluated with 4,5-diaminofluorescein diacetate in the juxtaglomerular apparatus (JGA). Treatment with ACE inhibitor and thiazide increased nNOS and NO production in the JGA. The diameter of the afferent arteriole observed by SEM using microvascular casts was smaller in DOCA rats compared to control rats, and ACE inhibitor or thiazide dilated the afferent arteriole with a positive correlation to nNOS immunoreactivity in the macula densa. In conclusion, the afferent arteriolar diameter might be regulated by NO derived from nNOS in the macula densa in DOCA-salt hypertensive rats.

Animals↗
PubMed2004

Urinary fatty acid-binding protein as a new clinical marker of the progression of chronic renal disease.

Previous studies have indicated that in massive proteinuria, free fatty acids (FFAs) bound to albumin were overloaded in the proximal tubule and exacerbated tubulointerstitial damage. Liver-type fatty acid-binding protein (L-FABP) is an intracellular carrier protein of FFAs that is expressed in the proximal tubule of human kidney. We sought to evaluate urinary L-FABP as a clinical marker in chronic renal disease. Urinary L-FABP was measured in patients with nondiabetic chronic renal disease (n = 120) with the use of a newly established ELISA method. We then monitored these patients for 15 to 51 months. Clinical data were analyzed with multivariate analysis. Urinary L-FABP was correlated with urinary protein, urinary alpha(1)-microglobulin, and serum creatinine concentrations. Urinary L-FABP at the start of follow-up (F = 17.1, r =.36, P <.0001) was selected as a significant clinical factor correlated with the progression rate, defined as a slope of a reciprocal of serum creatinine over time. We next selected the patients with mild renal dysfunction (n = 35) from all 120 patients and divided them into 2 groups according to progression rate: the progression group (n = 22) and the nonprogression group (n = 13). Serum creatinine and urinary protein concentrations and blood pressure at the start of follow-up were higher in the progression group than in the nonprogression group, although we detected no significant difference between the 2 groups. Urinary L-FABP was significantly higher in the former group than in the latter (P <.05). The results showed that urinary L-FABP reflected the clinical prognosis of chronic renal disease. Urinary L-FABP may be a clinical marker that can help predict the progression of chronic glomerular disease.

Animals↗
PubMed2004

Urinary excretion of fatty acid-binding protein reflects stress overload on the proximal tubules.

Urinary excretion of human liver-type fatty acid-binding protein (hL-FABP), which is expressed in human proximal tubules and engaged in free fatty acid (FFA) metabolism, was reported to reflect the clinical prognosis of chronic kidney disease. Here we have investigated the pathophysiological significance of hL-FABP in a model of protein overload nephropathy. Because L-FABP is not expressed in the wild-type mice, we generated hL-FABP chromosomal gene transgenic (Tg) mice. Tg mice were intraperitoneally injected with bovine serum albumin (BSA) replete with FFAs (r-BSA group) or FFA-depleted BSA (d-BSA group). The r-BSA group developed significantly more severe tubulointerstitial damage than did the d-BSA group. Renal expression of the hL-FABP gene was more up-regulated, and urinary excretion of hL-FABP was significantly higher, in the r-BSA group than in the d-BSA group. Furthermore, compared with their wild-type littermates injected with r-BSA, the number of infiltrated macrophages was significantly attenuated in Tg mice injected with it on day 28. In patients with kidney disease (n = 50), urinary hL-FABP was correlated with both urinary protein and the severity of tubulointerstitial injury. In conclusion, our experimental model suggests that urinary excretion of hL-FABP reflects stresses, such as urinary protein overload, on the proximal tubules. The clinical observations support this hypothesis.

Animals↗