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Low plasma sex hormone-binding globulin (SHBG) levels are present in fatty liver disease, which represents a spectrum of diseases ranging from hepatocellular steatosis through steatohepatitis to fibrosis and irreversible cirrhosis. We have previously determined that fat accumulation reduces SHBG production in different nonalcoholic fatty liver disease mouse models. In the present work, we are interested in elucidating the molecular mechanisms reducing SHBG plasma levels in liver fibrosis. For this purpose, in vivo studies were performed using the human SHBG transgenic mice developing liver fibrosis induced by carbon tetrachloride (CCl

Context There is emerging evidence that SHBG is substantially reduced in chronic metabolic diseases, including obesity and nonalcoholic fatty liver disease (NAFLD). We have recently reported, through use of in vitro (HepG2 cells) and in vivo (SHBG-C57BL/ksJ-db/db mice) models, that SHBG could play a role in arresting the progression of NAFLD by downregulating lipogenesis. Objective The main aim of this study was to investigate the mechanisms by which SHBG prevents hepatic lipogenesis by examining the relationship between SHBG and a key lipogenic enzyme, such as acetyl-coenzyme A carboxylase (ACC) in the liver of obese persons. Participants and methods SHBG and ACC mRNA levels, as well as triglyceride content, were analyzed in 41 liver samples from nondiabetic obese patients with NAFLD who had undergone bariatric surgery. We also studied the effect of SHBG overexpression in HepG2 cells cultured under high-glucose conditions. Results SHBG mRNA and protein levels were lower in patients with metabolic syndrome than in those without metabolic syndrome; however, these differences were significant only for mRNA level. SHBG mRNA levels correlated positively with SHBG protein levels and hepatic triglyceride content. In addition, SHBG mRNA and protein levels correlated negatively with ACC mRNA levels and triglyceride content. Furthermore, SHBG overexpression abrogated the increase in ACC expression induced by high-glucose treatment in HepG2 cells. Conclusions Our findings suggest that SHBG plays a role in regulating hepatic lipogenesis by reducing ACC levels. These results suggest a strategy for the treatment of NAFLD.

Restoration of kidney tubular epithelium following sublethal injury sequentially involves partial epithelial–mesenchymal transition (pEMT), proliferation, and further redifferentiation into specialized tubule epithelial cells (TECs). Because the immunosuppressant cyclosporine-A produces pEMT in TECs and inhibits the peptidyl-prolyl isomerase (PPIase) activity of cyclophilin (Cyp) proteins, we hypothesized that cyclophilins could regulate TEC phenotype. Here we demonstrate that in cultured TECs, CypA silencing triggers loss of epithelial features and enhances transforming growth factor β (TGFβ)-induced EMT in association with upregulation of epithelial repressors Slug and Snail. This pro-epithelial action of CypA relies on its PPIase activity. By contrast, CypB emerges as an epithelial repressor, because CypB silencing promotes epithelial differentiation, prevents TGFβ-induced EMT, and induces tubular structures in 3D cultures. In addition, in the kidneys of CypB knockout mice subjected to unilateral ureteral obstruction, inflammatory and pro-fibrotic events were attenuated. CypB silencing/knockout leads to Slug, but not Snail, downregulation. CypB support of Slug expression depends on its endoplasmic reticulum location, where it interacts with calreticulin, a calcium-buffering chaperone related to Slug expression. As CypB silencing reduces ionomycin-induced calcium release and Slug upregulation, we suggest that Slug expression may rely on CypB modulation of calreticulin-dependent calcium signaling. In conclusion, this work uncovers new roles for CypA and CypB in modulating TEC plasticity and identifies CypB as a druggable target potentially relevant in promoting kidney repair., Graphical abstract

Context: The dynamics of anti-phospholipase A2 antibody titers during treatment could predict clinical responses in patients with membranous nephropathy.Objectives: We analyzed the predictive value of the dynamics of these antibodies on clinical responses.Materials and methods: The serum antibody levels were measured before and during treatment in 79 patients with anti-phospholipase A2 receptor antibody membranous nephropathy treated with two different immunosuppression regimensResults: In both groups of patients, the relative reduction in antibody titers at 3 and 6 months preceded and predicted the clinical responses.Conclusions: Antibody titer dynamics was useful for predicting clinical responses.

Aims Restrictive Allograft Syndrome (RAS) and idiopathic pleuroparenchymal fibroelastosis (IPPFE) are two different diseases reported to share the same histology. RAS relates to chronic allograft dysfunction in lung transplantation with IPPFE being a rare condition in native lungs. Our aim is to compare their histologies, alongside biopsies of usual interstitial pneumonia (UIP), to determine if there are differences that might help to elucidate the pathogenesis. Methods and Results We selected 4 post-mortem allograft lungs from patients who developed clear clinical RAS pattern, 5 biopsies diagnosed as IPPFE, 5 UIP biopsies and 5 sections of normal lung. Histopathologic features were described without knowledge of clinical and radiological features. Both RAS allografts and IPPFE biopsies showed intra-alveolar fibrosis and elastosis (IAFE), but RAS allografts also showed concomitant obliterative bronchiolitis, vascular lymphoplasmacytic inflammation within fibro-intimal thickening, less fibroblastic foci at the advancing edge of the fibrosis (1 against 14.4 FF in 2mm2) and a slight reduction of the capillary network compared to UIP (p=0.07) and controls (p=0.06). The main differences seen in UIP were the lack of IAFE and the presence of honeycomb change. Conclusions RAS and PPFE histopathology both show IAFE, but display various differences, particularly in their vascular morphology that may allow further understanding of pathogenesis. This article is protected by copyright. All rights reserved.

A 40-year-old man of Pakistani origin presented with a 2-week history of fever (39.5 8C), malaise and arthralgias. He had been living in Spain for 16 years, and he had not travelled to a foreign country in the prior 4 years. Three days before, conjunctival erythema and multiple painful and violaceous-erythematous nodules (red arrows in Panel B) appeared in both pretibial regions, preventing him from walking because of pain. Physical examination showed bilateral metacarpophalangeal, wrist, knee and ankle arthritis. Ophthalmologic examination showed bilateral anterior scleritis, with preserved visual acuity and without signs of uveitis (Panel A). A chest X-ray study demonstrated bilateral hilar and mediastinal adenopathies (blue arrows in Panel C). He was admitted to the internal medicine ward. Serum angiotensin conversor enzyme levels were normal. Human immunodeficiency virus serologies, Mantoux test, three sputum cultures with Ziehl–Neelsen staining and a bronchoalveolar lavage (BAL) ruled out infectious disease. The CD4/CD8 ratio in the BAL was 2:1. A transbronchial biopsy of an adenopathy showed nonnecrotizing granulomas, without microbiological findings. The patient was diagnosed as a case of sarcoidosis, with the clinical presentation of a Lofgren’s syndrome. Lung alterations corresponded to a stage II pulmonary sarcoidosis. The patient was treated with dexamethasone eye drops and oral dexketoprofen. Scleritis, temperature, joint swelling and arthralgias disappeared, and he was discharged home. Two weeks later, he again developed fever and mild dyspnoea. Lung functional tests were normal, with the exception of a slightly lowered carbon monoxide lung diffusion (71 %), which was normalized after volume correction. After ruling out etiologies different from sarcoidosis, oral prednisone 20 mg/day was administered for a 4-week course as indicated in refractory disease, with total disappearance of symptomology. Adenopathies and parenchymal lung alterations remained stable. Currently, he has completed the treatment, and remains asymptomatic. We have presented a case of sarcoidosis with a typical Lofgren’s syndrome, consisting of hilar adenopathies, erythema nodosum and polyarthralgia or polyarthritis. This syndrome is found more frequently in women, and the course is usually benign often with [1] spontaneous remission. Anterior scleritis is an unusual ophthalmologic finding in sarcoidosis, and it has been related with Lofgren’s syndrome in a few cases [2]. Sporadic case reports [3] describe a good response to corticosteroids, but in this case, the scleritis responded well to non-steroidal antiinflamatory medication. The treatment of sarcoidosis with corticosteroids is not recommended [4] for stage II pulmonary sarcoidosis because 50 % of the untreated patients heal spontaneously. Nevertheless, symptomatic Electronic supplementary material The online version of this article (doi:10.1007/s11739-014-1067-6) contains supplementary material, which is available to authorized users.

Background and objectivesSeveral studies have suggested that activation of the complement system is a contributing pathogenic mechanism in IgA nephropathy (IgAN). C4d staining is an inexpensive and easy-to-perform method for the analysis of renal biopsies. This study aimed to assess the clinical and prognostic implications of C4d staining in IgAN.Design, setting, participants, & measurementsThis retrospective cohort study included 283 patients with IgAN in 11 hospitals in Spain who underwent a renal biopsy between 1979 and 2010. The primary predictor was mesangial C4d staining. Secondary predictors included demographic, clinical, and laboratory characteristics, and Oxford pathologic classification criteria. The primary end point was the cumulative percentage of patients who developed ESRD, defined as onset of chronic dialysis or renal transplantation. C4d was analyzed by immunohistochemical staining using a polyclonal antibody. Kaplan-Meier and Cox proportional hazards analyses were performed to evaluate the effect of C4d staining on renal survival.ResultsThere were 109 patients (38.5%) and 174 patients (61.5%) who were classified as C4d positive and C4d negative, respectively. Renal survival at 20 years was 28% in C4d-positive patients versus 85% in C4d-negative patients (P50%; HR, 4.42; 95% CI, 1.40 to 13.88; P=0.01), and C4d-positive staining (HR, 2.45; 95% CI, 1.30 to 4.64; P=0.01).ConclusionsC4d-positive staining is an independent risk factor for the development of ESRD in IgAN. This finding is consistent with the possibility that complement activation is involved in the pathogenesis of this disease.