Regulation of psoriasis, colitis, and the intestinal microbiota by clusterin.

Psoriasis, a chronic and systemic inflammatory disorder characterized by activation of the interleukin (IL)-23/IL-17 axis, may be associated with the intestinal microbiota through the so-called "gut-skin axis." Clusterin is a glycoprotein ubiquitously distributed in mammalian tissues; however, its role in psoriasis is unclear. Therefore, we evaluated the role of clusterin in psoriatic skin inflammation, systemic inflammation, and colitis using a murine model of IMQ-induced psoriasis. In IMQ-treated clusterin-knockout (clusterin-/-) mice, the expressions of inflammatory cytokines in clusterin-silenced human keratinocytes and intestinal microbial composition were analyzed. We also examined clusterin expression in the skin tissues of patients with psoriasis. IMQ-induced psoriatic skin inflammation is suppressed in clusterin-/- mice. Long-term administration of IMQ induced systemic inflammation and colitis; however, both were alleviated by the genetic deletion of clusterin. Genetic silencing of clusterin in human keratinocytes inhibited the production of inflammatory cytokines involved in the initiation and progression of psoriasis. The composition of the intestinal microbiota in IMQ-treated clusterin-/- and wild-type mice was different. Genetic deletion of clusterin suppressed the increase in the Firmicutes/Bacteroidetes (F/B) ratio. Skin tissues of patients with psoriasis showed high clusterin expression. In conclusion, inhibition of clusterin decreased psoriatic skin inflammation, systemic inflammation, colitis, and altered the F/B ratio in an IMQ-induced murine psoriasis model.

Neuroprotective Effects and Therapeutic Potential of Transcorneal Electrical Stimulation for Depression.

Transcorneal electrical stimulation (TES) has emerged as a non-invasive neuromodulation approach that exerts neuroprotection via diverse mechanisms, including neurotrophic, neuroplastic, anti-inflammatory, anti-apoptotic, anti-glutamatergic, and vasodilation mechanisms. Although current studies of TES have mainly focused on its applications in ophthalmology, several lines of evidence point towards its putative use in treating depression. Apart from stimulating visual-related structures and promoting visual restoration, TES has also been shown to activate brain regions that are involved in mood alterations and can induce antidepressant-like behaviour in animals. The beneficial effects of TES in depression were further supported by its shared mechanisms with FDA-approved antidepressant treatments, including its neuroprotective properties against apoptosis and inflammation, and its ability to enhance the neurotrophic expression. This article critically reviews the current findings on the neuroprotective effects of TES and provides evidence to support our hypothesis that TES possesses antidepressant effects.

Effect of Vibrio-Derived Extracellular Protease vEP-45 on the Blood Complement System.

Vibrio vulnificus is a pathogenic bacterium that can causes wound infections and fetal septicemia. We have reported that V. vulnificus ATCC29307 produces an extracellular zinc-metalloprotease (named vEP-45). Our previous results showed that vEP-45 can convert prothrombin to active thrombin and also activate the plasma kallikrein/kinin system. In this study, the effect of vEP-45 on the activation of the complement system was examined. We found that vEP-45 could proteolytically convert the key complement precursor molecules, including C3, C4, and C5, to their corresponding active forms (e.g., C3a, C3b, C4a, C4b, and C5a) in vitro cleavage assays. C5b production from C5 cleavage mediated by vEP-45 was not observed, whereas the level of C5a was increased in a dose-dependent manner compared to that of the non-treated control. The cleavage of the complement proteins in human plasma by vEP-45 was also confirmed via Western blotting. Furthermore, vEP-45 could convert C3 and C5 to active C3a and C5a as a proinflammatory mediator, while no cleavage of C4 was observed. These results suggest that vEP-45 can activate the complement system involved in innate immunity through an alternative pathway.

Toll-like receptor 4 regulates intestinal fibrosis via cytokine expression and epithelial-mesenchymal transition.

Intestinal fibrosis induced by chronic and recurrent colitis, which is exacerbated by bowel stenosis, stricture, and obstruction, is challenging to treat. Toll-like receptor 4 (TLR4) stimulates innate and acquired immunity in response to specific microbial components, but the role of TLR4 in intestinal fibrosis is largely unknown. We investigated its role in intestinal fibrosis using not only a murine fibrosis model but also human myofibroblasts and intestinal epithelial cells. Colon fibrosis was induced in TLR4-deficient (TLR4-/-) mice and its wild-type counterparts with 3% dextran sulfate sodium. Absence of TLR4 gene attenuated chronic inflammation and colonic macrophages infiltration; intestinal fibrosis and collagen deposition were suppressed. Also, the production of tumor necrosis factor-α, interleukin-12p40, and transforming growth factor-ß was reduced in TLR4-deficient peritoneal macrophages. TLR4 was silenced in CCD-18Co cells by small interfering RNA (siRNA), and matrix metalloproteinase-1, tissue inhibitor of metalloproteinase, and collagen α1 expression was evaluated. Role of TLR4 in epithelial-mesenchymal transition (EMT) was evaluated in HCT116 cells. Suppression of TLR4 transcription by siRNAs affected myofibroblasts activity, collagen synthesis, and EMT in the human cancer cell line. Thus, we suggest that TLR4 can be an essential mediator in intestinal chronic inflammation and fibrosis, indicating that TLR4 signaling is a potential therapeutic target for intestinal fibrosis.

Importance of Monitoring Physical Function for Quality of Life Assessments in Hematopoietic Stem Cell Transplantation Patients: A Prospective Cohort Study.

BACKGROUND/AIM: Physical function is known to decrease after hematopoietic stem cell transplantation (HSCT), with the most substantial impairment noted at 90 days post-transplantation. Little is known about the natural course of physical function during the acute post-transplant period preciously. The aim of the study was to monitor the changes in physical function through serial evaluations of the physical function, and identify the effect of physical function on QoL during the acute post-transplant period. PATIENTS AND METHODS: This prospective cohort study included 41 patients admitted for planned autologous or allogeneic HSCT. Physical impairment was evaluated with decrease in the de Morton Mobility Index (DEMMI) every week and defined as a DEMMI score of more than 2 points after HSCT. The outcome variables for QoL included visual analogue scale (VAS), European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), and Zung Self-rating Depression Scale (SDS) at enrollment and discharge. RESULTS: Based on DEMMI scores, 24.40% of all HSCT patients showed physical impairment, for whom the DEMMI score showed an overall decrease during hospitalization with significant differences in scores at 1, 2, and 3 weeks after HSCT, between 1 week before and 3 weeks after HSCT, and between 1 and 3 weeks after HSCT. There was no significant difference of VAS between admission and discharge between the groups. Each functional subscale of EORTC QLQ-C30 differed significantly between the groups, with lower scores in the physical impairment group. There was only a significant difference in SDS at discharge between the groups. QoL pre-transplantation can be a predictive factor for physical impairment during the acute post-transplant period, which can be detected in the early period after HSCT. CONCLUSION: Patients during acute post-transplant period had physical impairment and QoL of pre-transplantation was considered a predictive factor for physical impairment. The physical impairment can be detected in the early period after HSCT. Therefore, monitoring of standardized functional outcome measures is important to prevent physical impairment following HSCT.

Amyloid light-chain amyloidosis presented as focal segmental glomerulosclerosis in a kidney transplant recipient.

Amyloid light-chain (AL) amyloidosis after kidney transplantation is a rare disease in the world, and only one case of systemic AL amyloidosis after kidney transplantation is reported in Korea. We here report a 46-year-old woman with AL amyloidosis developed after kidney transplantation. The underlying disease of our case was focal segmental glomerulosclerosis (FSGS), and was admitted to hospital for evaluation of proteinuria developed 2 years after kidney transplantation. The patient was initially diagnosed as recurrent FSGS on light microscopy. But, electron microscopic finding was suggestive of amyloidosis and systemic evaluation was consistent with systemic AL amyloidosis. This case provides the importance of differential diagnosis of proteinuria in kidney transplant recipients.

Clinical Characteristics of Acute Appendicitis in Kidney Transplant Recipients.

BACKGROUND Clinical characteristics of acute appendicitis in kidney transplant recipients may be different from those in the general population due to kidney transplant recipient's immunosuppressive state and position change of appendix caused by graft. MATERIAL AND METHODS Clinical characteristics of 10 cases of acute appendicitis among 2880 cases of kidney transplantation were evaluated, including diagnostic rate, location of appendix and complication in kidney transplant recipients. RESULTS Acute appendicitis was suspected in 9 of 10 patients (90%) with acute appendicitis based on clinical and laboratory findings. Five patients (50%) presented with typical migrating pain and 1 patient (10%) had only periumbilical pain. Leukocytosis (WBC >10 000) was present in 8 patients (80%). Radiologic study revealed various locations of appendix relative to grafted kidney. Computed tomography scan was superior to ultrasonography in diagnosis of acute appendicitis. The complication rate was 50%. Complicated patients showed longer duration from symptoms onset to operation (69±48 hours versus. 25±6 hours, P<0.05) and hospital stay (15.4±15 days versus 5.4±1.8 days, P<0.05) than uncomplicated patients. CONCLUSIONS Clinical suspicion and differential diagnosis are needed for kidney transplantation patients with acute appendicitis. Early diagnosis with radiologic study is essential to reduce complications of acute appendicitis.

Unusual Cause of Dysphagia in a Post-Stroke Patient.

Vallecular cysts are formed when the duct of a mucous gland or lingual tonsillar crypt is dilated owing to obstruction from inflammation, irritation, or trauma. Small cysts are usually asymptomatic; however, cyst growth results in dysphagia, odynophagia, and acute airway complications. As complete transoral laser excision of a vallecular cyst often results in cyst resolution and improved symptoms, proper diagnosis and management of vallecular lesions are important. We describe the evaluation and treatment of a 53-year-old man with a history of intracerebral hemorrhage in the left basal ganglia who presented with dysphagia caused by a vallecular cyst.

Accelerated Lactate Dehydrogenase Activity Potentiates Osteoclastogenesis via NFATc1 Signaling.

Osteoclasts seem to be metabolic active during their differentiation and bone-resorptive activation. However, the functional role of lactate dehydrogenase (LDH), a tetrameric enzyme consisting of an A and/or B subunit that catalyzes interconversion of pyruvate to lactate, in RANKL-induced osteoclast differentiation is not known. In this study, RANKL treatment induced gradual gene expression and activation of the LDH A2B2 isotype during osteoclast differentiation as well as the LDH A1B3 and B4 isotypes during osteoclast maturation after pre-osteoclast formation. Glucose consumption and lactate production in growth media were accelerated during osteoclast differentiation, together with enhanced expression of H+-lactate co-transporter and increased extracellular acidification, demonstrating that glycolytic metabolism was stimulated during differentiation. Further, oxygen consumption via mitochondria was stimulated during osteoclast differentiation. On the contrary, depletion of LDH-A or LDH-B subunit suppressed both glycolytic and mitochondrial metabolism, resulting in reduced mature osteoclast formation via decreased osteoclast precursor fusion and down-regulation of the osteoclastogenic critical transcription factor NFATc1 and its target genes. Collectively, our findings suggest that RANKL-induced LDH activation stimulates glycolytic and mitochondrial respiratory metabolism, facilitating mature osteoclast formation via osteoclast precursor fusion and NFATc1 signaling.

The Arabidopsis thaliana NGATHA transcription factors negatively regulate cell proliferation of lateral organs.

The cell proliferation process of aerial lateral organs, such as leaves and flowers, is coordinated by complex genetic networks that, in general, converge on the cell cycle. The Arabidopsis thaliana NGATHA (AtNGA) family comprises four members that belong to the B3-type transcription factor superfamily, and has been suggested to be involved in growth and development of aerial lateral organs, although its role in the cell proliferation and expansion processes remains to be resolved in more detail. In order to clarify the role of AtNGAs in lateral organ growth, we took a systematic approach using both the loss- and gain-of-functional mutants of all four members. Our results showed that overexpressors of AtNGA1 to AtNGA4 developed small, narrow lateral organs, whereas the nga1 nga2 nga3 nga4 quadruple mutant produced large, wide lateral organs. We found that cell numbers of the lateral organs were significantly affected: a decrease in overexpressors and, inversely, an increase in the quadruple mutant. Kinematic analyses on leaf growth revealed that, compared with the wild type, the overexpressors displayed a lower activity of cell proliferation and yet the mutant a higher activity. Changes in expression of cell cycle-regulating genes were well in accordance with the cell proliferation activities, establishing that the AtNGA transcription factors act as bona fide negative regulators of the cell proliferation of aerial lateral organs.

Larval chigger mites collected from small mammals in 3 provinces, Korea.

A total of 9,281 larval chigger mites were collected from small mammals captured at Hwaseong-gun, Gyeonggi-do (Province) (2,754 mites from 30 small mammals), Asan city, Chungcheongnam-do (3,358 mites from 48 mammals), and Jangseong-gun, Jeollanam-do (3,169 for 62 mammals) from April-November 2009 in the Republic of Korea (= Korea) and were identified to species. Leptotrombidium pallidum was the predominant species in Hwaseong (95.8%) and Asan (61.2%), while Leptotrombidium scutellare was the predominant species collected from Jangseong (80.1%). Overall, larval chigger mite indices decreased from April (27.3) to June (4.9), then increased in September (95.2) and to a high level in November (169.3). These data suggest that L. pallidum and L. scutellare are the primary vectors of scrub typhus throughout their range in Korea. While other species of larval chigger mites were also collected with some implications in the transmission of Orientia tsutsugamushi, they only accounted for 11.2% of all larval chigger mites collected from small mammals.

Lithium chloride inhibits TGF-ß1-induced myofibroblast transdifferentiation via PI3K/Akt pathway in cultured fibroblasts from Tenon's capsule of the human eye.

Excess scarring of the conjunctiva after glaucoma filtration surgery is a major cause of failure. Transforming growth factor (TGF)-ß is critically involved in post-operative scarring. Lithium inhibits TGF-ß-induced gene protein expression in corneal fibroblasts and inhibits TGF-ß-induced epithelial mesenchymal transition. Here, we investigated the effects of LiCl on TGF-ß1-mediated signaling pathways and on myofibroblast transdifferentiation of human Tenon's capsule fibroblasts (HTFs). LiCl treatment reduced expression of TGF-ß1-induced α-SMA expression in HTFs. LiCl also decreased Akt phosphorylation induced by TGF-ß1. TGF-ß1-induced α-SMA expression was significantly decreased by LY294002 and Akt siRNA indicating that these changes are mediated by the PI3K/Akt pathway. Thus, LiCl induces the suppression of transdifferentiation stimulated by TGF-ß1 by the regulation of PI3K/Akt signaling in HTFs.

Overexpression of a Brassica rapa NGATHA gene in Arabidopsis thaliana negatively affects cell proliferation during lateral organ and root growth.

In an effort to elucidate biological functions of transcription factors of Brassica rapa L. (ssp. pekinensis), an NGATHA homolog, BrNGA1, that belongs to the B3-type transcription factor superfamily was identified and expressed in Arabidopsis thaliana under the control of the cauliflower mosaic virus (CaMV) 35S promoter. Arabidopsis plants overexpressing BrNGA1, named BrNGA1ox, displayed markedly reduced organ growth compared with the wild type: lateral organs, such as leaves, flowers and cotyledons, were small and distinctively narrow, and their root growth was also severely retarded. Reduced sizes of BrNGA1ox organs were mainly due to reduction in cell numbers. Kinematic analysis of leaf growth revealed that both the rate and duration of cell proliferation declined during organogenesis, which was consistent with the reduced expression of cyclin genes. Reduction in organ growth was strongly correlated with the small size of meristematic cell pools in the shoot and root meristems. Taken together, these data indicate that BrNGA1 acts as a negative regulator of cell proliferation and may do so, in part, by regulating the size of the meristematic cell pool.