Anuria after kidney transplantation diagnosed as early recurrence of focal segmental glomerulosclerosis combined with acute calcineurin inhibitor nephrotoxicity: a case report and literature review.

BACKGROUND: Primary focal segmental glomerulosclerosis (FSGS) is a glomerular disease that sometimes recurs in patients after kidney transplantation (KT) and increases the risk of graft loss. Proteinuria is a common early sign of recurrent FSGS, but an abrupt decrease in urine volume is rare. Herein, we report a patient with early recurrence of FSGS with anuria following KT. CASE PRESENTATION: A 55-year-old man with end-stage kidney disease caused by primary FSGS experienced anuria on postoperative day 2 following deceased donor KT. Laboratory results revealed that serum tacrolimus trough levels were consistently elevated at the time of anuria. At first, we considered acute calcineurin inhibitor (CNI) nephrotoxicity based on graft biopsy on light microscopy, laboratory findings, and clinical courses. However, the allograft function did not recover even after discontinuation of CNI, and recurrent FSGS was diagnosed 2 weeks later on electron microscopy. A total of 13 sessions of plasmapheresis and two administrations of rituximab (375 mg/m2) were required to treat recurrent FSGS. The patient achieved a partial response, and the spot urine protein-to-creatinine ratio decreased from 15.5 g/g creatinine to 5.2 g/g creatinine. At 5 months following KT, the serum creatinine level was stable at 1.15 mg/dL. CONCLUSIONS: These findings highlight that anuria can occur in cases of early recurrence of FSGS combined with acute CNI nephrotoxicity.

TAK-981, a SUMOylation inhibitor, suppresses AML growth immune-independently.

Acute myeloid leukemia (AML) generally has an unsatisfactory prognosis despite the recent introduction of new regimens, including targeted agents and antibodies. To find a new druggable pathway, we performed integrated bioinformatic pathway screening on large OHSU and MILE AML databases, discovered the SUMOylation pathway, and validated it independently with an external data set (totaling 2959 AML and 642 normal sample data). The clinical relevance of SUMOylation in AML was supported by its core gene expression which is correlated with patient survival, European LeukemiaNet 2017 risk classification, and AML-relevant mutations. TAK-981, a first-in-class SUMOylation inhibitor currently under clinical trials for solid tumors, showed antileukemic effects with apoptosis induction, cell-cycle arrest, and induction of differentiation marker expression in leukemic cells. It exhibited potent nanomolar activity, often stronger than that of cytarabine, which is part of the standard of care. TAK-981's utility was further demonstrated in in vivo mouse and human leukemia models as well as patient-derived primary AML cells. Our results also indicate direct and cancer cell-inherent anti-AML effects by TAK-981, different from the type 1 interferon and immune-dependent mechanism in a previous solid tumor study. Overall, we provide a proof-of-concept for SUMOylation as a new targetable pathway in AML and propose TAK-981 as a promising direct anti-AML agent. Our data should prompt studies on optimal combination strategies and transitions to clinical trials in AML.

Environmental enrichment modulates silent information regulator 1 (SIRT1) activity to attenuate central presbycusis in a rat model of normal aging.

Age-related hearing loss (ARHL) is sensory impairment in the elderly. This study aimed to identify a critical molecular mechanism that can maintain young phenotypes. We focused on the effect of exposure to environmental enrichment (EE) for 12 weeks in the central auditory pathway and limbic system of aged rats. The effects of EE were compared with the effects of dexamethasone administration. We found that in 74-week-old rats hearing function was significantly reduced and the number of neuronal specific nuclear protein (NeuN)-positive cells was decreased by 10-15% in the auditory cortex, amygdala, and hippocampus. EE exposure did not significantly affect the number of neurons, but DX administration significantly decreased their numbers in the amygdala compared with untreated aged rats. Both treatments reduced inducible nitric oxide synthase (iNOS) expression in the auditory pathway and limbic system. Exposure to EE significantly increased silent information regulator 1 (SIRT1) expression and activity, and nicotinamide phosphoribosyltransferase (NAMPT) concentration. In this study, the exposure to EE resulted in attenuated age-related hearing loss accompanied by reduction of iNOS expression and increase SIRT1 activity and NAMPT level. These data showed that EE may be a potential therapeutic to prevent ARHL.

Neurovascular integrative effects of long-term environmental enrichment on chronic cerebral hypoperfusion rat model.

Vascular dementia (VaD) is one of the most common types of dementia followed by Alzheimer's disease (AD). Recent studies showed that approximately 30 %-35 % of patients with AD at post-mortem exhibited vascular pathologies, which suggested that mixed dementia may be the most common type of dementia. Permanent bilateral common carotid artery occlusion (2VO) is a well-characterized method for investigating cognitive functions and the histopathological consequences of chronic cerebral hypoperfusion (CCH) in rats. In the present study, we investigated the effects of environmental enrichment (EE) on cognitive impairment after CCH, as well as the effects of CCH-induced neurovascular damage on cognitive function. Wistar rats were randomly allocated to a sham group, a 2VO group, and a 2VO + EE group. The 2VO procedure was performed at 12 weeks, while EE was performed for 8 weeks before and 6 weeks after 2VO. The effect of EE on cognitive functions in 2VO rats was investigated using the radial-arm maze and Morris Water Maze tests. Neurovascular integrity was assessed based on immunoreactivity for glial fibrillary acidic protein (GFAP), morphological changes in microvessels, and the expression of matrix metalloproteinase-9 (MMP-9) and zonula occludens-1 (ZO-1) in the motor cortex and hippocampus. EE ameliorated microvessel fragmentation by sustaining the tight junction through increases of ZO-1 expression after CCH, resulting in preserving the neurovascular unit. In summary, EE mitigated cognitive impairment by restoring neurovascular integrity. These findings suggest that EE can be a valuable and meaningful environmental intervention for patients with cognitive impairment.

Genome­wide DNA methylation profiling in a rat model with vascular dementia.

Vascular dementia (VaD), the second most prevalent type of dementia, is caused by reduced blood supply to the brain that results in cognitive impairment. Despite the efforts of numerous studies, the pathological mechanisms behind VaD remain unclear. The aim of the present study was to identify candidate genes that undergo changes in hippocampal DNA methylation owing to VaD. A genome­wide DNA methylation analysis was performed, using methylated DNA­binding domain sequencing. VaD model rats with cognitive impairment induced by bilateral common carotid artery occlusion were confirmed using the radial arm maze test. A total of 1,180 differentially methylated genes (DMGs) were identified, and functional annotation analysis revealed the DMGs to be enriched in 10 Gene Ontology biological processes. Network analysis using the STRING database indicated that seven genes were closely connected. Rats in the VaD model group demonstrated relative hypomethylation in the promoter region and increased mRNA expression of the hippocampal genes vascular endothelial growth factor (VEGFA) and kinase insert domain receptor, but only differences in VEGFA mRNA expression levels were determined to be statistically significant. In conclusion, these preliminary data from the functional annotation of hippocampal DMGs in the promoter region highlighted candidate genes for VaD that may contribute to the elucidation of its pathophysiology.

Decursin and decursinol angelate improve wound healing by upregulating transcription of genes encoding extracellular matrix remodeling proteins, inflammatory cytokines, and growth factors in human keratinocytes.

The coumarins decursin and decursinol angelate, which are found in Angelica gigas Nakai, have a variety of biological functions. Here, we show that treatment with these compounds improves wound healing by HaCaT human keratinocytes. Wound healing was increased by treatment with up to a threshold concentration of decursin, decursinol angelate, a mixture of both, and a nano-emulsion of these compounds, but inhibited by treatment with higher concentrations. Immunoblotting and fluorescence imaging of cells expressing an epidermal growth factor receptor (EGFR) biosensor demonstrated that these compounds did not stimulate wound healing by inducing EGFR phosphorylation. Rather, transcriptional analysis revealed that decursin and decursinol angelate improved wound healing by upregulating the expression of genes encoding extracellular matrix remodeling proteins, inflammatory cytokines, and growth factors.

Comparison of the behavioral effects of exercise and high fat diet on cognitive function in adolescent rats.

Adolescence is a critical period for neurodevelopment, neuronal plasticity, and cognitive function. Experiences of adolescence can be exerted positive and negative effects on brain development. Physical exercise has a positive effect on brain function, which is characterized by improving memory function and increased neural plasticity. High fat diet (HFD)-induced obesity has a negative effect on brain function, which is characterized by insulin resistance and neuroinflammation and reduced microvessel constructure. Although the positive effect of exercise and negative effect of obesity on cognitive function have been documented, it has not been well whether comparison of the effects of exercise and obesity on cognitive function in adolescent rats. In the present study, we evaluated the behavioral changes related to cognitive function induced by exercise and obesity in adolescent rats. Male Wistar rats were randomly divided into three groups: the control group (CON), the exercise group (Ex), the high fat diet group (HFD). The HFD containing fat 60% was freely provided. The present results showed that spatial learning ability and short-term memory did not show significant effect exercise as compared to the control group. The present results showed that spatial learning ability and short-term memory was significantly decreased HFD-induced obesity group as compared to the control group. These results suggest that positive effect of physical exercise in adolescence rats may be exerted no significant effect on cognitive function. But, negative effect of HFD-induced obesity might induce cognitive impairment. HFD-induced obesity in adolescent rats may be used as an animal model of neurodevelopmental disorders.

Acute exposure to silica nanoparticles aggravate airway inflammation: different effects according to surface characteristics.

Silica nanoparticles (SNPs) are widely used in many scientific and industrial fields despite the lack of proper evaluation of their potential toxicity. This study examined the effects of acute exposure to SNPs, either alone or in conjunction with ovalbumin (OVA), by studying the respiratory systems in exposed mouse models. Three types of SNPs were used: spherical SNPs (S-SNPs), mesoporous SNPs (M-SNPs), and PEGylated SNPs (P-SNPs). In the acute SNP exposure model performed, 6-week-old BALB/c female mice were intranasally inoculated with SNPs for 3 consecutive days. In the OVA/SNPs asthma model, the mice were sensitized two times via the peritoneal route with OVA. Additionally, the mice endured OVA with or without SNP challenges intranasally. Acute SNP exposure induced significant airway inflammation and airway hyper-responsiveness, particularly in the S-SNP group. In OVA/SNPs asthma models, OVA with SNP-treated group showed significant airway inflammation, more than those treated with only OVA and without SNPs. In these models, the P-SNP group induced lower levels of inflammation on airways than both the S-SNP or M-SNP groups. Interleukin (IL)-5, IL-13, IL-1ß and interferon-γ levels correlated with airway inflammation in the tested models, without statistical significance. In the mouse models studied, increased airway inflammation was associated with acute SNPs exposure, whether exposed solely to SNPs or SNPs in conjunction with OVA. P-SNPs appear to be relatively safer for clinical use than S-SNPs and M-SNPs, as determined by lower observed toxicity and airway system inflammation.

Profiles of IgE Sensitization to Der f 1, Der f 2, Der f 6, Der f 8, Der f 10, and Der f 20 in Korean House Dust Mite Allergy Patients.

PURPOSE: Measurement of IgE specific to purified house dust mite (HDM) allergens may improve allergy diagnosis. This study aimed to investigate the sensitization profiles of Korean HDM allergic subjects suffering from respiratory allergy and atopic dermatitis (AD) to Der f 1, Der f 2, Der f 6, Der f 8, Der f 10, and Der f 20. METHODS: Recombinant HDM allergens were produced in Pichia pastoris (Der f 1) or Escherichia coli (5 allergens). IgE reactivity to the individual recombinant allergens and total extract of mite was assessed by ELISA. RESULTS: Der f 1 was recognized by 79.1%, Der f 2 by 79.1%, Der f 6 by 9.3%, Der f 8 by 6.2%, Der f 10 by 6.2%, and Der f 20 by 6.6% of the patients' sera tested, while the prevalence of IgE reactivity to total mite extract was 94.7%. Combination of Der f 1 and Der f 2 had a sensitivity of 87.6%. Specific IgE to Der f 2 alone was detected from 89.4% of HDM-sensitized respiratory allergy subjects and 92.3% to the combination of the 2 major allergens Der f 1 and Der f 2. However, sera from fewer patients with AD, namely 72.4% and 71.0%, recognized Der f 1 and Der f 2, respectively. The combination of 2 major allergens allowed diagnosis of 84.5% of the AD patients. No correlation between sensitization to specific allergens and HDM allergy entity was found. CONCLUSIONS: Der f 2 was the most frequently sensitized allergen among the HDM-sensitized respiratory and AD patients in Korea, and the combination of the group 1 and 2 major allergens increased the diagnostic sensitivity. Minor allergens did not significantly improve diagnostic sensitivity. However, further studies are needed to analyze the relationship between sensitization to other HDM allergens and the disease entity of the HDM allergy.

Hypoxia-mediated mechanism of MUC5AC production in human nasal epithelia and its implication in rhinosinusitis.

BACKGROUND: Excessive mucus production is typical in various upper airway diseases. In sinusitis, the expression of MUC5AC, a major respiratory mucin gene, increases. However, the mechanisms leading to mucus hypersecretion in sinusitis have not been characterized. Hypoxia due to occlusion of the sinus ostium is one of the major pathologic mechanisms of sinusitis, but there have been no reports regarding the mechanism of hypoxia-induced mucus hypersecretion. METHODS AND FINDINGS: This study aims to identify whether hypoxia may induce mucus hypersecretion and elucidate its mechanism. Normal human nasal epithelial (NHNE) cells and human lung mucoepidermoid carcinoma cell line (NCI-H292) were used. Sinus mucosa from patients was also tested. Anoxic condition was in an anaerobic chamber with a 95% N2/5% CO2 atmosphere. The regulatory mechanism of MUC5AC by anoxia was investigated using RT-PCR, real-time PCR, western blot, ChIP, electrophoretic mobility shift, and luciferase assay. We show that levels of MUC5AC mRNA and the corresponding secreted protein increase in anoxic cultured NHNE cells. The major transcription factor for hypoxia-related signaling, HIF-1α, is induced during hypoxia, and transfection of a mammalian expression vector encoding HIF-1α results in increased MUC5AC mRNA levels under normoxic conditions. Moreover, hypoxia-induced expression of MUC5AC mRNA is down-regulated by transfected HIF-1α siRNA. We found increased MUC5AC promoter activity under anoxic conditions, as indicated by a luciferase reporter assay, and mutation of the putative hypoxia-response element in MUC5AC promoter attenuated this activity. Binding of over-expressed HIF-1α to the hypoxia-response element in the MUC5AC promoter was confirmed. In human sinusitis mucosa, which is supposed to be hypoxic, expression of MUC5AC and HIF-1α is higher than in control mucosa. CONCLUSION: The results indicate that anoxia up-regulates MUC5AC by the HIF-1α signaling pathway in human nasal epithelia and suggest that hypoxia might be a pathogenic mechanism of mucus hypersecretion in sinusitis.

Human salivary gland stem cells ameliorate hyposalivation of radiation-damaged rat salivary glands.

Salivary function in mammals may be defective for various reasons, such as aging, Sjogren's syndrome or radiation therapy in head and neck cancer patients. Recently, tissue-specific stem cell therapy has attracted public attention as a next-generation therapeutic reagent. In the present study, we isolated tissue-specific stem cells from the human submandibular salivary gland (hSGSCs). To efficiently isolate and amplify hSGSCs in large amounts, we developed a culture system (lasting 4-5 weeks) without any selection. After five passages, we obtained adherent cells that expressed mesenchymal stem cell surface antigen markers, such as CD44, CD49f, CD90 and CD105, but not the hematopoietic stem cell markers, CD34 and CD45, and that were able to undergo adipogenic, osteogenic and chondrogenic differentiation. In addition, hSGSCs were differentiated into amylase-expressing cells by using a two-step differentiation method. Transplantation of hSGSCs to radiation-damaged rat salivary glands rescued hyposalivation and body weight loss, restored acinar and duct cell structure, and decreased the amount of apoptotic cells. These data suggest that the isolated hSGSCs, which may have characteristics of mesenchymal-like stem cells, could be used as a cell therapy agent for the damaged salivary gland.

α-Melanocyte-stimulating hormone inhibits tumor necrosis factor α-stimulated MUC5AC expression in human nasal epithelial cells.

Mucin hypersecretion is an important clinical feature of several respiratory diseases, including asthma, cystic fibrosis, nasal allergy, rhinitis, and sinusitis. It has been shown that α-melanocyte-stimulating hormone (α-MSH), a proopiomelanocortin (POMC)-derived peptide, has immunomodulatory activities by inhibiting NF-κB activation induced by proinflammatory cytokines such as TNF-α. Because MUC5AC expression is known to be up-regulated by TNF-α via NF-κB activation, we evaluated the inhibitory effect of α-MSH on MUC5AC gene expression induced by TNF-α in normal human nasal epithelial (NHNE) cells. Melanocortin-1-receptor (MC-1R) was detected by RT-PCR, Western blotting, and immunofluorescent labeling in NHNE cells. α-MSH suppressed NF-κB/p65 phosphorylation induced by TNF-α as well as IkB-α degradation in a dose-dependent manner, as assessed by Western blotting. In addition, α-MSH inhibited TNF-α-induced nuclear translocation of NF-κB and NF-κB luciferase activity. Real-time quantitative PCR data showed that α-MSH inhibited TNF-α-induced expression of MUC5AC, and this effect of α-MSH was neutralized by knockdown of MC-1R using MC-1R shRNA lentivirus. Analyses using RT-PCR and Western blotting showed the expression of POMC and two key enzymes in the POMC processing, proprotein convertases (PC)1 and PC2, and 7B2, which is required for enzymatic activity of PC2, in normal human nasal mucosa. We conclude that α-MSH down-regulates MUC5AC expression by inhibiting TNF-α-induced NF-κB activity through MC-1R stimulation in NHNE cells and that normal human nasal mucosa possesses the POMC processing machinery. Therefore, α-MSH may be a promising candidate to decrease mucin overproduction initiated by NF-κB activation.

AP2alpha is essential for MUC8 gene expression in human airway epithelial cells.

Mucins are high molecular weight proteins that make up the major components of mucus. Hypersecretion of mucus is a feature of several chronic inflammatory airway diseases. MUC8 is an important component of airway mucus, and its gene expression is upregulated in nasal polyp epithelium. Little is known about the molecular mechanisms of MUC8 gene expression. We first observed overexpression of activator protein-2 alpha (AP2 alpha) in human nasal polyp epithelium. We hypothesized that AP2 alpha overexpression in nasal polyp epithelium correlates closely with MUC8 gene expression. We demonstrated that phorbol 12-myristate 13-acetate (PMA) treatment of the airway epithelial cell line NCI-H292 increases MUC8 gene and AP2 alpha expression. In this study, we sought to determine which signal pathway is involved in PMA-induced MUC8 gene expression. The results show that the protein kinase C and mitogen-activating protein/ERK kinase (MAPK) pathways modulate MUC8 gene expression. PD98059 or ERK1/2 siRNA and RO-31-8220 or PKC siRNA significantly suppress AP2 alpha as well as MUC8 gene expression in PMA-treated cells. To verify the role of AP2 alpha, we specifically knocked down AP2 alpha expression with siRNA. A significant AP2 alpha knock-down inhibited PMA-induced MUC8 gene expression. While dominant negative AP2 alpha decreased PMA-induced MUC8 gene expression, overexpressing wildtype AP2 alpha increased MUC8 gene expression. Furthermore, using lentiviral vectors for RNA interference in human nasal polyp epithelial cells, we confirmed an essential role for AP2 alpha in MUC8 gene expression. From these results, we concluded that PMA induces MUC8 gene expression through a mechanism involving PKC, ERK1/2, and AP2 alpha activation in human airway epithelial cells.