Obstructive sleep apnea increases risk of female infertility: A 14-year nationwide population-based study.

OBJECTIVES: To determine the risk of having OSA in a cohort of female subjects who are infertile and the odds of being infertile in women with OSA. PATIENTS AND METHODS: A nationwide, case-control study of female patients 20 years or older diagnosed with female infertility living in Taiwan, from January 1, 2000, through December 31, 2013 (N = 4,078). We identified women who were infertile and created a 2:1 matched control group with women who were not infertile. We used multivariable logistic regression analysis to further estimate the effects of OSA on female infertility. RESULTS: In this 14- year retrospective study, we included 4,078 patients having an initial diagnosis of female infertility. Of those women with infertility, 1.38% had a history of OSA compared with 0.63% of fertile controls (p = 0.002). The mean ages in the study groups were 32.19 ± 6.20 years, whereas the mean ages in the control groups were 32.24 ± 6.37years. Women with OSA had 2.101- times the risk of female infertility compared to women without OSA (p<0.001). CONCLUSION: Our study showed that OSA is more commonly seen in infertile women and increases the odds that a woman will be infertile. More studies need to be done on the whether or not diagnosing and treating OSA can decrease the rate of infertility.

Non-apnea sleep disorder and its risk for all kinds of injuries: A 14-year follow-up for a nationwide population-based retrospective study.

ABSTRACT: Non-apnea sleep disorder (NASD) increases the risk of motor vehicle accidents. However, systemic review of NASD and its risk for all causes of injury is lacking. The aim of the present study was to provide a detailed demographic data on NASD and all causes of injury in a 14-year follow up.Our study utilized outpatient and inpatient data from the Longitudinal Health Insurance Database between 2000 and 2013 in Taiwan. We enrolled 989,753 individuals aged ≥20 years who were diagnosed with NASD as outpatients ≥3 times or inpatients ≥1 time. We matched the study cohort with a comparison cohort by age, index date and comorbidities at a ratio of 1:4. We used Cox proportional hazards regression to analyze the association of NASD and the cause of injury.In this 14-year follow up study, patients with NASD had 12.96% increased risk of injury compared to that of the control cohort. Fall was the first place of the cause of injury with 670.26 per 105 PYs. In the stratified age group, patients aged ≧65 years had the highest risk of injury (adjusted HR= 1.381; P < .001). Kaplan-Meier analysis showed that the incidence of injury between the with- and without-NASD cohorts started from the first year and persisted until the end of the follow-up.Our study demonstrates that NASD patients were associated with higher risk of all causes of injuries, with falling being the most prevalent diagnosis. The general public should be more aware of this neglected issue of NASD.

Discovery of T-1101 tosylate as a first-in-class clinical candidate for Hec1/Nek2 inhibition in cancer therapy.

Highly expressed in cancer 1 (Hec1) plays an essential role in mitosis and is correlated with cancer formation, progression, and survival. Phosphorylation of Hec1 by Nek2 kinase is essential for its mitotic function, thus any disruption of Hec1/Nek2 protein-protein interaction has potential for cancer therapy. We have developed T-1101 tosylate (9j tosylate, 9j formerly known as TAI-95), optimized from 4-aryl-N-pyridinylcarbonyl-2-aminothiazole of scaffold 9 by introducing various C-4' substituents to enhance potency and water solubility, as a first-in-class oral clinical candidate for Hec1 inhibition with potential for cancer therapy. T-1101 has good oral absorption, along with potent in vitro antiproliferative activity (IC50: 14.8-21.5 nM). It can achieve high concentrations in Huh-7 and MDA-MB-231 tumor tissues, and showed promise in antitumor activity in mice bearing human tumor xenografts of liver cancer (Huh-7), as well as of breast cancer (BT474, MDA-MB-231, and MCF7) with oral administration. Oral co-administration of T-1101 halved the dose of sorafenib (25 mg/kg to 12.5 mg/kg) required to exhibit comparable in vivo activity towards Huh-7 xenografts. Cellular events resulting from Hec1/Nek2 inhibition with T-1101 treatment include Nek2 degradation, chromosomal misalignment, and apoptotic cell death. A combination of T-1101 with either of doxorubicin, paclitaxel, and topotecan in select cancer cells also resulted in synergistic effects. Inactivity of T-1101 on non-cancerous cells, a panel of kinases, and hERG demonstrates cancer specificity, target specificity, and cardiac safety, respectively. Subsequent salt screening showed that T-1101 tosylate has good oral AUC (62.5 µM·h), bioavailability (F = 77.4%), and thermal stability. T-1101 tosylate is currently in phase I clinical trials as an orally administered drug for cancer therapy.

Accelerated and Severe Lupus Nephritis Benefits From M1, an Active Metabolite of Ginsenoside, by Regulating NLRP3 Inflammasome and T Cell Functions in Mice.

Chinese herbal medicines used in combination have long-term been shown to be mild remedies with "integrated effects." However, our study provides the first demonstration that M1, an active metabolite of ginsenoside, exerted its dramatic therapeutic effects on accelerated and severe lupus nephritis (ASLN) mice, featuring acute renal function impairment, heavy proteinuria, high serum levels of anti-dsDNA, and high-grade, diffuse proliferative renal lesions. In the present study, NZB/WF1 mice were given injections of lipopolysaccharide to induce the ASLN model. M1 (30 mg/kg) was then administered to the mice by gavage daily, and the mice were sacrificed on week 3 and week 5 after the induction of disease. To identify the potential mechanism of action for the pure compound, levels of NLRP3 inflammasome activation in bone marrow-derived dendritic cells (BMDCs), podocytes and macrophages, and antigen-specific T cell activation in BMDCs were determined in addition to mechanistic experiments in vivo. Treatment with M1 dramatically improved renal function, albuminuria and renal lesions and reduced serum levels of anti-dsDNA in the ASLN mice. These beneficial effects with M1 treatment involved the following cellular and molecular mechanistic events: [1] inhibition of NLRP3 inflammasome associated with autophagy induction, [2] modulation of T help cell activation, and [3] induction of regulatory T cell differentiation. M1 improved the ASLN mice by blunting NLRP3 inflammasome activation and differentially regulating T cell functions, and the results support M1 as a new therapeutic candidate for LN patients with a status of abrupt transformation of lower-grade (mesangial) to higher-grade (diffuse proliferative) nephritis.

Eye fixation-related fronto-parietal neural network correlates of memory retrieval.

Eye movements are considered to be informative with regard to the underlying cognitive processes of human beings. Previous studies have reported that eye movements are associated with which scientific concepts are retrieved correctly. Moreover, other studies have also suggested that eye movements involve the cooperative activity of the human brain's fronto-parietal circuits. Less research has been conducted to investigate whether fronto-parietal EEG oscillations are associated with the retrieval processing of scientific concepts. Our findings in this study demonstrated that the fronto-parietal network is indeed crucial for successful memory retrieval. In short, significantly lower theta augmentation in the frontal midline and lower alpha suppression in the right parietal region were observed at the 5th eye fixation for physics concepts that were correctly retrieved than for those that were incorrectly retrieved. Moreover, the visual cortex in the occipital lobe exhibits a significantly greater theta augmentation followed by an alpha suppression following each eye fixation, while a right fronto-parietal asymmetry was also found for the successful retrieval of presentations of physics concepts. In particular, the study results showed that eye fixation-related frontal midline theta power and right parietal alpha power at the 5th eye fixation have the greatest predictive power regarding the correctness of the retrieval of physics concepts.

Non-Apnea Sleep Disorder associates with increased risk of incident heart failure-A nationwide population-based cohort study.

PURPOSE: Non-apnea sleep disorder (NASD) increases the risk of cardiovascular events, such as hypertension and ischemic heart disease (IHD). Patients with heart failure (HF) are at higher risk for sleep disorder; however, there is no documentation on NASD's association with HF to date. Therefore, our study aimed to determine whether NASD increases the risk of incident HF. MATERIALS AND METHODS: Using the outpatient and inpatient data from Taiwan's Longitudinal Health Insurance Database, we conducted a nationwide cohort study of patients with a first-time diagnosis of NASD in the year 2000 and followed up the risk of incident heart failure until December 31, 2013. We calculated risks and incidence ratios of HF for patients with NASD compared with the general population. The cumulative incidence of NASD and the subsequent risk of HF are assessed by the Kaplan-Meier method and Cox regression using a matched comparison cohort of HF patients without NASD. RESULTS: The NASD cohort had an adjusted hazard ratio (HR) of incident HF 19.7% higher than that of the cohort without NASD (95% CI = 1.130-1.270; p<0.001). In the NASD population, the mean interval to HF in males and females were 5.00±3.69 years and 5.00±3.66 years, respectively. The Kaplan-Meier analysis indicated that after the seventh year, the incidence of HF was higher in the NASD cohort than in the control cohort till the end of the follow up. CONCLUSIONS: Our study demonstrates that NASD patients are associated with a higher risk of incident HF.

Evaluating the operational risks of biomedical waste using failure mode and effects analysis.

The potential problems and risks of biomedical waste generation have become increasingly apparent in recent years. This study applied a failure mode and effects analysis to evaluate the operational problems and risks of biomedical waste. The microbiological contamination of biomedical waste seldom receives the attention of researchers. In this study, the biomedical waste lifecycle was divided into seven processes: Production, classification, packaging, sterilisation, weighing, storage, and transportation. Twenty main failure modes were identified in these phases and risks were assessed based on their risk priority numbers. The failure modes in the production phase accounted for the highest proportion of the risk priority number score (27.7%). In the packaging phase, the failure mode 'sharp articles not placed in solid containers' had the highest risk priority number score, mainly owing to its high severity rating. The sterilisation process is the main difference in the treatment of infectious and non-infectious biomedical waste. The failure modes in the sterilisation phase were mainly owing to human factors (mostly related to operators). This study increases the understanding of the potential problems and risks associated with biomedical waste, thereby increasing awareness of how to improve the management of biomedical waste to better protect workers, the public, and the environment.

Inhibition of Hec1 as a novel approach for treatment of primary liver cancer.

PURPOSE: Highly expressed in cancer protein 1 (Hec1) is an oncogene and a promising molecular target for novel anticancer drugs. The purpose of this study was to evaluate the potential of a Hec1 inhibitor, TAI-95, as a treatment for primary liver cancer. METHODS: In vitro and in vivo methods were used to test the activity of TAI-95. Gene expression analysis was used to evaluate clinical correlation of the target. RESULTS: In vitro growth inhibition results showed that TAI-95 has excellent potency on a wide range of primary liver cancer cell lines (hepatoblastoma or hepatocellular carcinoma) (GI(50) 30-70 nM), which was superior to sorafenib and other cytotoxic agents. TAI-95 was relatively inactive in non-cancerous cell lines (GI(50) > 10 µM). TAI-95 disrupts the interaction between Hec1 and Nek2 and leads to degradation of Nek2, chromosomal misalignment, and apoptotic cell death. TAI-95 showed synergistic activity in selected cancer cell lines with doxorubicin, paclitaxel, and topotecan, but not with sorafenib. TAI-95 shows excellent potency in a Huh-7 xenograft mouse model when administered orally. Gene expression analysis of clinical samples demonstrated increased expression of Hec1/NDC80 and associated genes (Nek2, SMC1A, and SMC2) in 27 % of patients, highlighting the potential for using this therapeutic approach to target patients with high Hec1 expression. CONCLUSION: Inhibition of Hec1 using small molecule approach may represent a promising novel approach for the treatment of primary liver cancers.

Activity of a novel Hec1-targeted anticancer compound against breast cancer cell lines in vitro and in vivo.

Current cytotoxic chemotherapy produces clinical benefit in patients with breast cancer but the survival impact is modest. To explore novel cytotoxic agents for the treatment of advanced disease, we have characterized a new and pharmacokinetically improved Hec1-targeted compound, TAI-95. Nine of 11 breast cancer cell lines tested were sensitive to nanomolar levels of TAI-95 (GI(50) = 14.29-73.65 nmol/L), and more importantly, TAI-95 was active on a number of cell lines that were resistant (GI(50) > 10 µmol/L) to other established cytotoxic agents. TAI-95 demonstrates strong inhibition of in vivo tumor growth of breast cancer model when administered orally, without inducing weight loss or other obvious toxicity. Mechanistically, TAI-95 acts by disrupting the interaction between Hec1 and Nek2, leading to apoptotic cell death in breast cancer cells. Furthermore, TAI-95 is active on multidrug-resistant (MDR) cell lines and led to downregulation of the expression of P-glycoprotein (Pgp), an MDR gene. In addition, TAI-95 increased the potency of cytotoxic Pgp substrates, including doxorubicin and topotecan. Certain clinical subtypes of breast cancer more likely to respond to Hec1-targeted therapy were identified and these subtypes are the ones associated with poor prognosis. This study highlights the potential of the novel anticancer compound TAI-95 in difficult-to-treat breast cancers.

Urine annexin A1 as an index for glomerular injury in patients.

BACKGROUND: We recently demonstrated high urine levels of annexin A1 (ANXA1) protein in a mouse Adriamycin-induced glomerulopathy (ADG) model. OBJECTIVE: To establish ANXA1 as a potential biomarker for glomerular injury in patients. METHODS: A time-course study in the mouse ADG model, followed by renal tissues and urine samples from patients with various types of glomerular disorders for ANXA1. RESULTS: Urinary ANXA1 protein was (1) detectable in both the ADG model and in patients except those with minimal change disease (MCD); (2) positively correlated with renal lesions in patients; and (3) early detectable in diabetes patients with normoalbuminuria. CONCLUSIONS: ANXA1 is a universal biomarker that is helpful in the early diagnosis, prognostic prediction, and outcome monitoring of glomerular injury. Measurement of urinary ANXA1 protein levels can help in differentiating MCD from other types of glomerular disorders.

Characterization of the biological activity of a potent small molecule Hec1 inhibitor TAI-1.

BACKGROUND: Hec1 (NDC80) is an integral part of the kinetochore and is overexpressed in a variety of human cancers, making it an attractive molecular target for the design of novel anticancer therapeutics. A highly potent first-in-class compound targeting Hec1, TAI-1, was identified and is characterized in this study to determine its potential as an anticancer agent for clinical utility. METHODS: The in vitro potency, cancer cell specificity, synergy activity, and markers for response of TAI-1 were evaluated with cell lines. Mechanism of action was confirmed with western blotting and immunofluorescent staining. The in vivo potency of TAI-1 was evaluated in three xenograft models in mice. Preliminary toxicity was evaluated in mice. Specificity to the target was tested with a kinase panel. Cardiac safety was evaluated with hERG assay. Clinical correlation was performed with human gene database. RESULTS: TAI-1 showed strong potency across a broad spectrum of tumor cells. TAI-1 disrupted Hec1-Nek2 protein interaction, led to Nek2 degradation, induced significant chromosomal misalignment in metaphase, and induced apoptotic cell death. TAI-1 was effective orally in in vivo animal models of triple negative breast cancer, colon cancer and liver cancer. Preliminary toxicity shows no effect on the body weights, organ weights, and blood indices at efficacious doses. TAI-1 shows high specificity to cancer cells and to target and had no effect on the cardiac channel hERG. TAI-1 is synergistic with doxorubicin, topotecan and paclitaxel in leukemia, breast and liver cancer cells. Sensitivity to TAI-1 was associated with the status of RB and P53 gene. Knockdown of RB and P53 in cancer cells increased sensitivity to TAI-1. Hec1-overexpressing molecular subtypes of human lung cancer were identified. CONCLUSIONS: The excellent potency, safety and synergistic profiles of this potent first-in-class Hec1-targeted small molecule TAI-1 show its potential for clinically utility in anti-cancer treatment regimens.

Antroquinonol differentially modulates T cell activity and reduces interleukin-18 production, but enhances Nrf2 activation, in murine accelerated severe lupus nephritis.

OBJECTIVE: Accelerated severe lupus nephritis (ASLN), with an acute onset of severe clinical manifestations and histopathologic renal lesions, may represent transformation of mild LN to a severe form of glomerulonephritis. Abnormal activation of T and B cells and/or oxidative stress may play a major role in the pathogenesis of ASLN. This study tested the hypothesis that antroquinonol, a purified compound and major effective component of Antrodia camphorata with antiinflammatory and antioxidant activities, might prevent the transformation of mild LN into higher-grade (severe) nephritis in a murine lupus model. METHODS: Experimental ASLN was induced in (NZB×NZW)F1 mice by twice weekly intraperitoneal injections of Salmonella-type lipopolysaccharide (LPS). Starting 2 days after the first dose of LPS, mice were treated daily with antroquinonol, administered by gavage, for different durations up to 5 weeks. RESULTS: Antroquinonol administration significantly ameliorated the proteinuria, hematuria, impairment of renal function, and development of severe renal lesions, especially cellular crescent formation, neutrophil infiltration, fibrinoid necrosis, and T cell proliferation in the glomerulus, as well as periglomerular interstitial inflammation. Mechanistic analyses revealed that antroquinonol 1) inhibited T cell activation/proliferation, but enhanced Treg cell suppression and reduced renal production of interleukin-18 (IL-18); 2) inhibited production of reactive oxygen species and nitric oxide, but increased activation of Nrf2 in the kidney; and 3) suppressed renal inflammation via blocking of NF-κB activation. CONCLUSION: Antroquinonol may have therapeutic potential for the early treatment of ASLN via its differential regulation of T cell function and lowering of IL-18 production, but also via the promotion of Nrf2 activation.

Therapeutic potential of DCB-SLE1, an extract of a mixture of Chinese medicinal herbs, for severe lupus nephritis.

The pathogenesis of lupus nephritis is mainly attributable to a complex interaction between the innate and adaptive immune systems, including T and B cell function abnormalities. In addition to autoantibody production and immune complex deposition, Th1 and Th17 cytokines may play key roles in the development and progression of lupus nephritis. Acute onset of severe lupus nephritis remains a challenge in terms of prevention and treatment. In the present study, we evaluated the therapeutic effects of DCB-SLE1, an extract of a mixture of four traditional Chinese medicinal herbs (Atractylodis macrocephalae Rhizoma, Eucommiae cortex, Lonicerae caulis, and Hedyotidis diffusae Herba), on an accelerated severe lupus nephritis model, characterized by acute onset of proteinuria, azotemia, autoantibody production, and development of severe nephritis, induced by twice weekly injection of New Zealand black/white F1 mice with Salmonella-type lipopolysaccharide. DCB-SLE1 was administered daily by gavage starting 2 days after the first dose of induction of lipopolysaccharide, and the mice were euthanized at week 1 or week 5. The results showed that DCB-SLE1 significantly ameliorated the hematuria, proteinuria, renal dysfunction, and severe renal lesions by 1) suppression of B cell activation and decreased autoantibody production; 2) negative regulation of T cell activation/proliferation and natural killer cell activity; 3) suppression of IL-18, IL-6, and IL-17 production and blocking of NF-κB activation in the kidney; and 4) prevention of lymphoid and renal apoptosis. These results show that DCB-SLE1 can protect the kidney from autoimmune response-mediated acute and severe damage through systemic immune modulation and anti-inflammation pathways.

Epigallocatechin-3-gallate prevents lupus nephritis development in mice via enhancing the Nrf2 antioxidant pathway and inhibiting NLRP3 inflammasome activation.

Patients with lupus nephritis show an impaired oxidative status and increased levels of interleukin (IL)-1ß and IL-18, which are closely linked to inflammation and correlated with disease activity. Although epigallocatechin-3-gallate (EGCG), the major bioactive polyphenol present in green tea with antioxidant and free radical scavenging activities, has been reported to have anti-inflammatory effects by inhibiting nuclear factor-kappa B (NF-κB)-mediated inflammatory responses in vivo, its effectiveness for the treatment of lupus nephritis is still unknown. In the present study, 12-week-old New Zealand black/white (NZB/W) F1 lupus-prone mice were treated daily with EGCG by gavage until sacrificed at 34 weeks old for clinical, pathological, and mechanistic evaluation. We found that the administration (1) prevented proteinuria, renal function impairment, and severe renal lesions; (2) increased renal nuclear factor E2-related factor 2 (Nrf2) and glutathione peroxidase activity; (3) reduced renal oxidative stress, NF-κB activation, and NLRP3 mRNA/protein expression and protein levels of mature caspase-1, IL-1ß, and IL-18; and (4) enhanced splenic regulatory T (Treg) cell activity. Our data clearly demonstrate that EGCG has prophylactic effects on lupus nephritis in these mice that are highly associated with its effects of enhancing the Nrf2 antioxidant signaling pathway, decreasing renal NLRP3 inflammasome activation, and increasing systemic Treg cell activity.

Antroquinonol reduces oxidative stress by enhancing the Nrf2 signaling pathway and inhibits inflammation and sclerosis in focal segmental glomerulosclerosis mice.

Oxidative stress, inflammation, and fibrosis are involved in the development and progression of focal segmental glomerulosclerosis (FSGS), a common form of idiopathic nephrotic syndrome that represents a therapeutic challenge because it has a poor response to steroids. Antroquinonol (Antroq), a purified compound, is a major active component of a mushroom, namely Antrodia camphorata, that grows in the camphor tree in Taiwan, and it has inhibitory effects on nitric oxide production and inflammatory reactions. We hypothesized that Antroq might ameliorate FSGS renal lesions by modulating the pathogenic pathways of oxidative stress, inflammation, and glomerular sclerosis in the kidney. We demonstrate that Antroq significantly (1) attenuates proteinuria, renal dysfunction, and glomerulopathy, including epithelial hyperplasia lesions and podocyte injury; (2) reduces oxidative stress, leukocyte infiltration, and expression of fibrosis-related proteins in the kidney; (3) increases renal nuclear factor E2-related factor 2 (Nrf2) and glutathione peroxidase activity; and (4) inhibits renal nuclear factor-κB (NF-κB) activation and decreases levels of transforming growth factor (TGF)-ß1 in serum and kidney tissue in a mouse FSGS model. Our data suggest that Antroq might be a potential therapeutic agent for FSGS, acting by boosting Nrf2 activation and suppressing NF-κB-dependent inflammatory and TGF-ß1-mediated fibrosis pathways in the kidney.

(S)-armepavine from Chinese medicine improves experimental autoimmune crescentic glomerulonephritis.

OBJECTIVE: Intra-renal T cells and macrophages play a key pathogenic role in the development and progression of glomerular crescents. We aimed to establish (S)-armepavine [(S)-ARM], a major bioactive compound of a Chinese medicinal plant, Nelumbo nucifera, as a potential therapeutic agent in the treatment of autoimmune crescentic glomerulonephritis (ACGN). METHODS: A mouse ACGN model associated with T-cell dysregulation, was used to evaluate the therapeutic effects of (S)-ARM on the rapidly progressive glomerular disorder. RESULTS: The results showed that (S)-ARM administered in the established phase of ACGN is capable of dramatically decreasing glomerular crescents in the kidney and improving proteinuria and renal dysfunction. These effects were associated with greatly inhibited infiltration of T cells/macrophages and suppressed nuclear factor (NF)-κB activation in the kidney, lowered serum levels of autoantibodies and both serum and intra-renal levels of pro-inflammatory cytokines, suppressed T/B-cell activation and T-cell proliferation of the spleen, reduced glomerular immune deposits and apoptosis in both the spleen and kidney in (S)-ARM-treated ACGN mice, compared with the vehicle-treated (disease control) group of ACGN mice. CONCLUSION: We demonstrated therapeutic effects of (S)-ARM on ACGN as a result of: (i) early systemic negative modulation of T/B cells; (ii) intra-renal regulation of combined NF-κB activation and mononuclear leucocytic infiltration, thereby preventing glomerular crescent formation; and (iii) protection from apoptosis in both the spleen and kidney.

Decoy receptor 3 ameliorates an autoimmune crescentic glomerulonephritis model in mice.

Autoimmune crescentic glomerulonephritis (ACGN) is a variant of crescentic glomerulonephritis. The outcome of treatment of crescentic glomerulonephritis is poor. Binding of decoy receptor 3 (DCR3) to its ligand is capable of downregulating the alloresponsiveness of T cells. DCR3 has also been shown to benefit an experimental autoimmune model of diabetes. This study tested the hypothesis that a potential immune regulator, DCR3, could prevent the evolution of ACGN. With the use of an established ACGN model in mice, mice were treated with 100 microg/10 g body wt human DCR3 by hydrodynamics-based gene delivery at 14-d intervals. The results showed that the gene therapy resulted in (1) suppression of T and B cell activation and T cell proliferation; (2) a reduction in serum levels of proinflammatory cytokines; (3) improvement of proteinuria and renal dysfunction; (4) prevention of glomerular crescent formation, renal interstitial inflammation, and glomerulosclerosis; (5) a reduction in serum levels of autoantibodies and glomerular immune deposits; (6) inhibition of apoptosis in the spleen and kidney; (7) prevention of T cell and macrophage infiltration of the kidney; and (8) suppression of fibrosis-related gene expression in the kidney compared with empty vector-treated (disease control) ACGN mice. On the basis of these findings, it is proposed that human DCR3 exerts its preventive and protective effects on ACGN through modulation of T cell activation/proliferation, B cell activation, protection against apoptosis, and suppression of mononuclear leukocyte infiltration in the kidney.

Smad7 gene therapy ameliorates an autoimmune crescentic glomerulonephritis in mice.

Autoimmune crescentic glomerulonephritis is characterized by severe immune response with glomerular crescentic formation and fibrosis in the kidney. Recent studies indicate that overexpression of renal Smad7 attenuates both renal fibrosis and inflammation in rat remnant kidney. However, little attention has been paid to the potential role of TGF-beta/Smad signaling in autoimmune kidney disease. This study tested the hypothesis that blocking TGF-beta signaling by overexpression of Smad7 may have a therapeutic effect in a mouse model of autoimmune crescentic glomerulonephritis that was induced in C57BL/6 x DBA/2J F1 hybrid mice by giving DBA/2J donor lymphocytes. Smad7 gene was transfected into the kidney using the ultrasound-microbubble-mediated system. Results showed that overexpression of Smad7 blocked both renal fibrosis and inflammatory pathways in terms of Smad2/3 and NF-kappaB activation (P < 0.01), thereby inhibiting alpha-smooth muscle actin; collagen I, III, and IV accumulation; and expression of inflammatory cytokines (IL-1beta and IL-6), adhesion molecule/chemokine (intercellular adhesion molecule-1, monocyte chemoattractant protein-1), and inducible nitric oxide synthase (all P < 0.01). Leukocyte infiltration (CD4(+) cells and macrophages) was also suppressed (P < 0.005). Severe histologic damage (glomerular crescent formation and tubulointerstitial injury) and functional injury including proteinuria were significantly improved (all P < 0.05). This study provides important evidence that overexpression of Smad7 may have therapeutic potential for autoimmune kidney disease.