A Multipotent PROX1+ Tumor Stem/Progenitor Cell Population Emerges During Intestinal Tumorigenesis and Mediates Radioresistance in Colorectal Cancer.

Colorectal carcinoma (CRC) progression is associated with an increase in PROX1+ tumor cells, which exhibit features of CRC stem cells and contribute to metastasis. Here, we aimed to provide a better understanding to the function of PROX1+ cells in CRC, investigating their progeny and their role in therapy resistance. PROX1+ cells in intestinal adenomas of ApcMin/+ mice expressed intestinal epithelial and CRC stem cell markers, and cells with high PROX1 expression could both self-renew tumor stem/progenitor cells and contribute to differentiated tumor cells.

Predicting Visit Cost of Obstructive Sleep Apnea Using Electronic Healthcare Records With Transformer.

Background: Obstructive sleep apnea (OSA) is growing increasingly prevalent in many countries as obesity rises. Sufficient, effective treatment of OSA entails high social and financial costs for healthcare.

Objective: For treatment purposes, predicting OSA patients' visit expenses for the coming year is crucial.

School success in childhood and subsequent prodromal symptoms and psychoses in the Northern Finland Birth Cohort 1986.

Background: Low IQ is a risk factor for psychosis, but the effect of high IQ is more controversial. The aim was to explore the association of childhood school success with prodromal symptoms in adolescence and psychoses in adulthood.

Methods: In the general population-based Northern Finland Birth Cohort 1986 (n = 8 229), we studied the relationship between teacher-assessed learning deficits, special talents and general school success at age 8 years and both prodromal symptoms (PROD-screen) at age 15-16 years and the occurrence of psychoses by age 30 years.

beta-Catenin mediates adriamycin-induced albuminuria and podocyte injury in adult mouse kidneys.

Background: Glomerular slit diaphragm (SD) represents a modified adherens junction composed of molecules belonging to both immunoglobulin and cadherin superfamilies. Cadherins associate with the cytosolic scaffolding protein beta-catenin, but the precise role of beta-catenin in mature or injured podocytes is not known.

Methods: The conditional podocyte-specific beta-catenin-deficient mouse line was generated using the doxycycline-inducible Cre-loxP system.

Inducible nephrin transgene expression in podocytes rescues nephrin-deficient mice from perinatal death.

Mutations leading to nephrin loss result in massive proteinuria both in humans and mice. Early perinatal lethality of conventional nephrin knockout mice makes it impossible to determine the role of nephrin protein in the adult kidney and in extra-renal tissues. Herein, we studied whether podocyte-specific, doxycycline-inducible, rat nephrin expression can rescue nephrin-deficient mice from perinatal lethality.

Inositols and methylinositols in sea buckthorn (Hippophaë rhamnoides) berries.

Sea buckthorn (Hippophaë rhamnoides L.) berries, especially of ssp. sinensis, contain significant quantities of an unknown, water-soluble compound, evidently a cyclitol derivative.

The MIF receptor CD74 in diabetic podocyte injury.

Although metabolic derangement plays a central role in diabetic nephropathy, a better understanding of secondary mediators of injury may lead to new therapeutic strategies. Expression of macrophage migration inhibitory factor (MIF) is increased in experimental diabetic nephropathy, and increased tubulointerstitial mRNA expression of its receptor, CD74, has been observed in human diabetic nephropathy. Whether CD74 transduces MIF signals in podocytes, however, is unknown.

A slit in podocyte death.

Recent advances have identified the podocyte as a key target in glomerular injury. The podocyte is a highly specialized cell which is responsible for the glomerular permselectivity for proteins in the kidney. Podocyte injury or loss leads to proteinuria.

Densin and beta-catenin form a complex and co-localize in cultured podocyte cell junctions.

Densin is a member of LAP (leucine-rich repeat and PDZ domain) protein family that localizes in kidney to slit diaphragms, which are essential components of the glomerular filtration barrier. We have previously shown that densin interacts with a crucial slit diaphragm protein, nephrin. Here, we searched for novel binding partners of densin by yeast-two hybrid assay and identified beta-catenin.

Expression of filtrin in human glomerular diseases.

Background: Filtrin (NEPH3/KIRREL2) is a recently characterized member of the nephrin-like proteins of the immunoglobulin superfamily, and it has been suggested to participate in the maintenance of the glomerular filtration barrier in the kidney. In this study, the gene and protein expression of filtrin were examined in patients with acquired proteinuric diseases.

Methods: Filtrin mRNA levels in renal biopsies were measured with quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) in two sets of patients with proteinuria.

Plasminogen activator inhibitor-1 production is pathogenetic in experimental murine diabetic renal disease.

Aims/hypothesis: Plasminogen activator inhibitor-1 (PAI-1, also known as serpin peptidase inhibitor, clade E [nexin, plasminogen activator inhibitor type 1], member 1 [SERPINE1]) plays a pathogenetic role in renal fibrosis. It is upregulated in experimental and human diabetic nephropathy. These studies assessed the effect of PAI-1 deficiency and overproduction on renal disease in experimental diabetes.

Increased atherosclerosis following treatment with a dual PPAR agonist in the ApoE knockout mouse.

Objective: Recent reports have suggested that dual peroxisome proliferator-activated receptor (PPAR) alpha/gamma agonists are associated with adverse cardiovascular events. This study aimed to investigate the actions of the non-thiazolidinedione PPARalpha/gamma agonist, compound 3q, on plaque development in the apolipoprotein E knockout (apoE KO) mouse, a recognised model of accelerated plaque development.

Methods: Six-week-old male apoE KO mice were randomised to receive the dual PPARalpha/gamma agonist, compound 3q (3 mg/kg/day), the PPARgamma agonist, rosiglitazone (20 mg/kg/day), the PPARalpha agonist, gemfibrozil (100 mg/kg/day) by gavage or no treatment for 20 weeks (n=12/group).

Densin is a novel cell membrane protein of Sertoli cells in the testis.

Cell-cell interactions between Sertoli cells and germ cells are crucial for the maturation of germ cells in spermatogenesis but the structural and functional aspects of the interactions remain to be fully elucidated. Densin is a junction protein suggested to play a role in establishment of specific cell-cell contacts in the post-synaptic densities of the brain and the slit diaphragm of the kidney podocyte. In the present study, densin was discovered to be expressed in the testis of the man and the mouse.

Podocyte-associated proteins FAT, alpha-actinin-4 and filtrin are expressed in Langerhans islets of the pancreas.

Nephrin is a crucial podocyte molecule in the kidney glomerular filtration barrier and it is also expressed in Langerhans islet beta cells of the pancreas. Recently, genetic mapping of proteinuric kidney disease genes and animal models have revealed further important molecules for the kidney filtration function including alpha-actinin-4, podocin, FAT, and NEPH1. This study was addressed to explore the pancreatic expression of the podocyte molecules podocin, FAT, alpha-actinin-4, NEPH1, NEPH2, filtrin/NEPH3, synaptopodin and CD2 associated protein (CD2AP).

Densin and filtrin in the pancreas and in the kidney, targets for humoral autoimmunity in patients with type 1 diabetes.

Background And Aim: The development of autoantibodies against antigens of the pancreatic islet cells is a typical phenomenon in patients with type 1 diabetes. The expression of densin, recently shown to be present in kidney podocytes, was explored in the pancreas. Additionally, we studied whether densin and filtrin, another molecule shared between the kidney podocytes and pancreatic islet cells, can act as autoantigens and whether autoantibodies against these can be detected in patients with type 1 diabetes.

Podocyte cell-specific expression of doxycycline inducible Cre recombinase in mice.

Conventional silencing of many podocyte-specific genes in mice is associated with embryonic or perinatal lethality. Therefore, it would be of great importance to generate mouse models that allow the modification of genes that are expressed in podocytes at later stages of age. Herein is described a transgenic mouse with doxycycline-inducible podocyte-specific expression of Cre recombinase.

Anti-atherosclerotic and renoprotective effects of combined angiotensin-converting enzyme and neutral endopeptidase inhibition in diabetic apolipoprotein E-knockout mice.

Objective: To investigate the effects of the combined angiotensin-converting enzyme (ACE)/neutral endopeptidase (NEP) inhibitor omapatrilat on atherosclerosis and renal injury in a model of diabetes-associated accelerated atherosclerosis and renal injury.

Design: The study was performed using diabetic apolipoprotein E-knockout (apo E-KO) mice, a model combining hyperlipidemia and hyperglycemia, which leads to accelerated atherosclerosis and renal injury.

Methods: Diabetes was induced by the injection of streptozotocin in 6-week old apo E-KO mice.

Advanced glycation end products in diabetes-associated atherosclerosis and renal disease: interventional studies.

There is increasing evidence that advanced glycation end products (AGEs) and their interactions with various receptors (in particular, the receptor RAGE) play a pivotal role in the development and progression of diabetic macro- and microvascular complications. Several approaches have been used to inhibit tissue accumulation of AGEs in diabetes, including inhibitors of AGE formation such as aminoguanidine, ALT 946, and pyridoxamine-or putative cross-link breakers such as ALT 711. Alternative interventions have also included the administration of a soluble receptor for RAGE, sRAGE, thus capturing circulating AGEs and preventing them from binding to the cell-bound full-length receptor RAGE, thereby inhibiting the proinflammatory and profibrotic response following AGE-RAGE binding.

Rosiglitazone attenuates atherosclerosis in a model of insulin insufficiency independent of its metabolic effects.

Objective: Recent studies have demonstrated a role for thiazolidinediones in attenuating atherosclerosis. However, these studies were performed in insulin-resistant animal models in association with reductions in insulin and glucose levels. To assess the vascular effects of thiazolidinediones, independent of their metabolic effects, we observed the effect of rosiglitazone on diabetes-associated atherosclerosis in a model of insulin insufficiency.

Imatinib attenuates diabetic nephropathy in apolipoprotein E-knockout mice.

In the diabetic kidney, clinical as well as experimental observations have shown an upregulation of growth factors such as PDGF. These studies, however, were not designed to address whether upregulation of PDGF is merely a manifestation of diabetic renal injury or whether PDGF plays an active role in the pathophysiology of diabetic nephropathy. The objectives of this study were first to assess whether PDGF-dependent pathways are involved in the development of diabetic nephropathy and second to determine the effects of PDGF receptor antagonism on this disorder and associated molecular and cellular processes.

Antiproteinuric effect of RAS blockade: new mechanisms.

Experimental and clinical studies have shown that blockade of the renin-angiotensin system (RAS) is effective in reducing proteinuria in conditions such as diabetes by reducing systemic and intraglomerular hydrostatic pressure. However, increasing evidence suggests that nonhemodynamic effects, such as preservation of the podocyte slit diaphragm structure and function, may also mediate the antiproteinuric effects of RAS blockade. In this review, we analyze in detail the evidence for known and novel mechanisms considered to play important roles in mediating the antiproteinuric effect of RAS blockers, with a particular focus on diabetic nephropathy.

Accelerated nephropathy in diabetic apolipoprotein e-knockout mouse: role of advanced glycation end products.

Hyperlipidemia not only may be relevant to cardiovascular disease in diabetes but may also play a role in the development and progression of diabetic nephropathy. Furthermore, there is increasing evidence that advanced glycation end products (AGE) play an important role in diabetic renal disease. The objectives of this study were first to characterize renal injury in diabetic apolipoprotein E knockout (apo E-KO) mice and second to explore the role of AGE in the development and progression of renal disease in this model.

Advanced glycation end product interventions reduce diabetes-accelerated atherosclerosis.

Advanced glycation end product (AGE) formation may contribute to the progression of atherosclerosis, particularly in diabetes. The present study explored atherosclerosis in streptozotocin-induced diabetic apolipoprotein E-deficient (apoE-/-) mice that were randomized (n = 20) to receive for 20 weeks no treatment, the AGE cross-link breaker ALT-711, or the inhibitor of AGE formation aminoguanidine (AG). A sixfold increase in plaque area with diabetes was attenuated by 30% with ALT-711 and by 40% in AG-treated mice.

Irbesartan but not amlodipine suppresses diabetes-associated atherosclerosis.

Background: It remains controversial whether specific blockade of the renin-angiotensin system confers superior antiatherosclerotic effects over other antihypertensive agents in diabetes. Therefore, the aim of this study was to compare equihypotensive doses of the angiotensin II subtype 1 (AT1) receptor blocker irbesartan with the calcium antagonist amlodipine on diabetes-induced plaque formation in the apolipoprotein E (apoE)-null mouse and to explore molecular and cellular mechanisms linked to vascular protection.

Methods And Results: Diabetes was induced by injection of streptozotocin in 6-week-old apoE-null mice.

Imatinib attenuates diabetes-associated atherosclerosis.

Objective: Diabetes is associated with accelerated atherosclerosis, the major factor contributing to increased mortality and morbidity in the diabetic population. The molecular mechanisms by which diabetes promotes atherosclerosis are not fully understood. Platelet-derived growth factor has been shown to play a major role in the pathology of vascular diseases, but whether it plays a role in atherosclerosis associated with diabetes remains unknown.