VEGFR-1 Regulates EGF-R to Promote Proliferation in Colon Cancer Cells.

The relationship between epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF) pathways in tumor growth is well established. EGF induces VEGF production in cancer cells, and the paracrine VEGF activates vascular endothelial cells to promote tumor angiogenesis and thus supports tumor cell growth in an angiogenesis-dependent manner. In this study, we found angiogenesis-independent novel crosstalk between the VEGF and the EGF pathways in the regulation of colon cancer cell proliferation.

VEGF pathway-targeting drugs induce evasive adaptation by activation of neuropilin-1/cMet in colon cancer cells.

Anti-angiogenic therapies targeting vascular endothelial growth factor (VEGF) and its receptor (VEGF-R) are important treatments for a number of human malignancies, including colorectal cancers. However, there is increasing evidence that VEGF/VEGF-R inhibitors promote the adaptive and evasive resistance of tumor cells to the therapies. The mechanism by which the cancer cells become resistant remains unclear.

Reactive oxygen species upregulate expression of muscle atrophy-associated ubiquitin ligase Cbl-b in rat L6 skeletal muscle cells.

Unloading-mediated muscle atrophy is associated with increased reactive oxygen species (ROS) production. We previously demonstrated that elevated ubiquitin ligase casitas B-lineage lymphoma-b (Cbl-b) resulted in the loss of muscle volume (Nakao R, Hirasaka K, Goto J, Ishidoh K, Yamada C, Ohno A, Okumura Y, Nonaka I, Yasutomo K, Baldwin KM, Kominami E, Higashibata A, Nagano K, Tanaka K, Yasui N, Mills EM, Takeda S, Nikawa T. Mol Cell Biol 29: 4798-4811, 2009).

Regorafenib induces adaptive resistance of colorectal cancer cells via inhibition of vascular endothelial growth factor receptor.

Recently, inhibition of tumor angiogenesis has become an important anti-cancer therapy. Tumor angiogenesis is regulated by multiple signaling pathways, including VEGF and VEGF receptor (VEGF-R), FGF and FGF receptor (FGF-R), and PDGF and PDGF receptor (PDGF-R) pathways. Thus, the antiangiogenic agents, such as regorafenib, simultaneously target those receptors on vascular endothelial cells.

Antiangiogenic agent sunitinib induces epithelial to mesenchymal transition and accelerates motility of colorectal cancer cells.

Although vascular endothelial growth factor receptor (VEGF-R)-targeted antiangiogenic agents are important treatment for a number of human malignancies, there is accumulating evidence that the therapies may promote disease progression, such as invasion and metastasis. How tumors become to promote their evasiveness remains fully uncertain. One of possible mechanisms for the adaptation may be a direct effect of VEGF-R inhibitors on tumor cells expressing VEGF-R.

Capric Acid Up-Regulates UCP3 Expression without PDK4 Induction in Mouse C2C12 Myotubes.

Uncoupling protein 3 (UCP3) and pyruvate dehydrogenase kinase 4 (PDK4) in skeletal muscle are key regulators of the glucose and lipid metabolic processes that are involved in insulin resistance. Medium-chain fatty acids (MCFAs) have anti-obesogenic effects in rodents and humans, while long-chain fatty acids (LCFAs) cause increases in body weight and insulin resistance. To clarify the beneficial effects of MCFAs, we examined UCP3 and PDK4 expression in skeletal muscles of mice fed a MCFA- or LCFA-enriched high-fat diet (HFD).

The malignant progression effects of regorafenib in human colon cancer cells.

A number of anti-angiogenic drugs targeting vascular endothelial growth factor receptors (VEGF-R) have developed and enabled significant advances in cancer therapy including colorectal cancer. However, acquired resistance to the drugs occurs, leading to disease progression, such as invasion and metastasis. How tumors become the resistance and promote their malignancy remains fully uncertain.

Chronic exposure of VEGF inhibitors promotes the malignant phenotype of colorectal cancer cells.

VEGF-targeting anti-angiogenic drugs have enabled significant advances in cancer therapy. However, acquired resistance to VEGF-targeting drugs occurs, leading to disease progression. How tumors become the resistance remains fully uncertain.

[Space flight/bedrest immobilization and bone. Development of inhibitors for atrophy caused by unloading stress].

Muscle atrophy caused by unloading stress is a serious problem in bed rest patients or astronauts. In our previous studies, we revealed that induction and activation of ubiquitin ligase Cbl-b played an important role in skeletal muscle atrophy caused by unloading stress. Under muscle atrophy conditions, Cbl-b interacted with and degraded IRS-1 (insulin receptor substrate 1) that is a central molecule in the IGF-1 signaling pathway.

Chronic renal failure with severe mesangiolysis in a hematopoietic stem cell transplant recipient.

Chronic progressive renal failure is a well-recognized complication in hematopoietic stem cell transplantation (HSCT) recipients. Although thrombotic microangiopathy or chemotherapeutic agents are frequently associated, total body irradiation might also be one of the suspected etiologic factors. This study describes a 38-year-old female patient with acute lymphoblastic leukemia treated with HSCT who developed chronic renal dysfunction after transplantation.

Deoxyspergualin, an immunosuppressant, in patients suffering from nephropathies with crescent formation: an open-label trial to evaluate safety and efficacy.

Background: Crescent formation in glomeruli means an acute active lesion that develops a rapidly progressive course. Therapies using pulse methylprednisolone, oral corticosteroids, and cyclophosphamide are recommended, but no agreement has been reached on the optimal therapy. There have been no controlled trials, because of the severity of this condition and because withholding treatment would become an ethical issue.

Mitochondrial DNA mutations in focal segmental glomerulosclerosis lesions.

Glomerular epithelial cells are primary pathogenic sites in focal segmental glomerulosclerosis (FGS) lesions. Glomerular epithelial cells are regarded as terminally differentiated cells that do not proliferate. These characteristics are also noted for neurons and muscular cells, which are major sites of mitochondrial DNA (mtDNA) mutation accumulation.

Prognosis of asymptomatic hematuria and/or proteinuria in men. High prevalence of IgA nephropathy among proteinuric patients found in mass screening.

Aim: To elucidate prognosis and prevalence of chronic renal diseases among proteinuric and/or hematuric subjects found in mass screening, a long-term follow-up study (6.35 years, range 1.03-14.

Heterogeneity of prognosis in adult IgA nephropathy, especially with mild proteinuria or mild histological features.

Objective: The present study was undertaken to clarify the clinical course and prognosis of adult patients with primary IgA nephropathy (IgAN), especially with mild proteinuria or mild histological alternations.

Patients And Methods: A population of 735 IgAN patients whom we were able to observe for more than two years was examined.

Results: A total of 115 patients (15.

Role of nitric oxide in the synthesis of guanidinosuccinic acid, an activator of the N-methyl-D-aspartate receptor.

Background: We propose that reactive oxygen and argininosuccinic acid (ASA) form guanidinosuccinic acid (GSA). An alternative to this hypothesis is the so-called guanidine cycle, which consists of a series of hydroxyurea derivatives that serve as intermediates in a pathway leading from urea to GSA. We compare the role of the guanidine cycle to that of nitric oxide (NO) in the synthesis of GSA.

Hemodialysis does not influence the peroxidative state already present in uremia.

Hemodialysis (HD) patients are exposed to high oxidative stress, however, the nature of this stress is still unclear. In this study, we employed a specific lipid peroxidative product, phosphatidylcholine hydroperoxide (PCOOH), and evaluated the peroxidative effect of end stage renal disease by measuring thiobarbituric acid reactive substances (TBARS) and PCOOH in both plasma and erythrocyte membrane. We also surveyed plasma TBARS and PCOOH before and after HD sessions thereby assessing oxidative stress by a single HD procedure.

Prevalence of Japanese dialysis patients with an A-to-G mutation at nucleotide 3243 of the mitochondrial tRNA(Leu(UUR)) gene.

Background: A high prevalence of an A-to-G mutation at nucleotide 3243 of the mitochondrial genome in patients with diabetes mellitus (DM) and/or deafness has been reported previously. We investigated the prevalence of this mutation in Japanese dialysis patients with associated DM and/or deafness.

Methods: We studied 106 dialysis patients with DM, 26 with DM and deafness, and 26 with deafness alone, using peripheral leucocytes to detect an A-to-G transition at nucleotide 3243 of the mitochondrial gene.

Creatol, an oxidative product of creatinine in hemodialysis patients.

Creatol (CTL) is a product resulting from the reaction of creatinine (Cr) with the hydroxyl radical and is identified as a precursor of methylguanidine (MG), a uremic toxin. In this study, we investigated serum CTL levels together with those of Cr and MG in 66 patients who were on maintenance hemodialysis (HD). Prior to dialysis, the mean serum levels of Cr, CTL and MG were 967 (= 11.

Formation of guanidinosuccinic acid, a stable nitric oxide mimic, from argininosuccinic acid and nitric oxide-derived free radicals.

Guanidinosuccinic acid (GSA) is noted for its nitric oxide (NO) mimicking actions such as vasodilatation and activation of the N-methyl-D-aspartate (NMDA) receptor. We have reported that GSA is the product of argininosuccinate (ASA) and some reactive oxygen species, mainly the hydroxyl radical. We tested for GSA synthesis in the presence of NO donors.

Imaging of hydroperoxides in a rat glomerulus stimulated by puromycin aminonucleoside.

Background: To determine the locus of the increased oxidation induced by puromycin aminonucleoside (PAN), we imaged hydroperoxides in glomeruli stimulated by PAN in vivo and in vitro.

Methods: Dichlorofluorescein diacetate (DCFH-DA) in cells makes dichlorofluorescein, a substance that fluoresces when reacted with hydroperoxides. Fluorescence was detected using a photon detection video camera connected to a microscope.

[A case of nephrotic syndrome associated with myasthenia gravis and malignant thymoma].

A 26-year-old woman who presented facial and lower leg edema associated with massive proteinuria was admitted to our hospital in February 1992. Nine months before this admission, she exhibited myasthenia gravis and malignant thymoma, and underwent total thymectomy. On admission, there was no symptom of myasthenia gravis.

Intraperitoneal hyaluronan production in stable continuous ambulatory peritoneal dialysis patients.

Objective: Several cytokines and proteins are excreted intraperitoneally during the course of peritonitis and stable states in continuous ambulatory peritoneal dialysis (CAPD) patients. Dialysate hyaluronan (HYA) is also regarded as a marker of peritoneal healing during bacterial peritonitis. We examined here, intraperitoneal HYA production in stable CAPD patients and compared the results to those of the peritoneal equilibration test (PET), the length of time on dialysis, and other marker proteins.