Network Pharmacology and Molecular Docking Analysis to Explore the Mechanism of Huaiqihuang-Mediated Alleviation of Henoch-Schönlein Purpura Nephritis.

Objective: Henoch-Schönlein purpura nephritis (HSPN) is considered a major cause of chronic renal failure and is the most common secondary glomerular disease in children. Huaiqihuang (HQH), a traditional Chinese herbal formula, exhibits therapeutic effects against HSPN in clinical practice. However, the potential molecular targets and mechanisms underlying HSPN treatment remain unclear. Methods: By constructing a protein-protein interaction (PPI) network, core targets related to HQH and HSPN were identified. Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathways were analyzed to identify the main pathways related to HSPN based on the core targets. To screen the main active ingredients of HQH against HSPN, an ingredient-target-pathway network was constructed using the top 10 main pathways associated with HSPN. Then, molecular docking was performed to explore the interactions and binding patterns between molecules and proteins. Results: Clinical data showed that HQH combined with conventional medicine significantly reduced 24-hour urine protein excretion, urine microalbumin levels, and erythrocyte counts in the urine sediment of HSPN patients. By constructing PPI models, 15 potential core targets were identified. The top 10 main pathways showed higher enrichment ratios, including the cytokine-cytokine receptor interaction and signaling pathways related to NOD-like receptor, IL-17, etc. Through the ingredient-target-pathway network and molecular docking, we revealed that five active ingredients of HQH had good affinities with three core targets, AKT1, MMP9, and SERPINE1, which may be vital in treating HSPN. Conclusions: The study preliminarily explored the active ingredients, targets, and pathways involved in HQH therapy for HSPN. The mechanism of HQH therapy may be attributed to the modulation of inflammatory response, immune response, and oxidative stress. Combined with clinical data, our results indicate that HQH is highly effective in treating HSPN.

Anti-Inflammatory and Antioxidative Properties of Isoflavones Provide Renal Protective Effects Distinct from Those of Dietary Soy Proteins against Diabetic Nephropathy.

SCOPE: Dietary soy reportedly protects from diabetic nephropathy (DN), but its active components and mechanism of action remain unknown. METHODS AND RESULTS: In this study, KKAy mice are fed three types of diet: Dietary soy isoflavones with soy protein (Soy-IP) diet, reduced isoflavones soy protein (RisoP), and oral administration of isoflavones aglycones (IsoAgc). Albuminuria and glycosuria are decreased only in the soy-IP group. The risoP group show reduced expansion of mesangial matrix and renal fibrosis, the IsoAgc group show renal anti-fibrotic and anti-inflammatory effects; however, these renal pathological changes are repressed in the soy-IP group, suggesting the distinct protective roles of soy protein or isoflavones in DN. The isoflavone genistein has a better inhibitory effect on the inflammatory response and cellular interactions in both mouse tubular cells and macrophages when exposed to high glucose and albumin (HGA). Genistein also represses HGA-induced activator protein 1 activation and reactive oxidases stress generation, accompanied by reduced NADPH oxidase (NOX) gene expression. Finally, diabetic mice show a decrease in lipid peroxidation levels in both plasma and urine, along with lower NOXs gene expression. CONCLUSION: The data elucidate the detailed mechanism by which isoflavones inhibit renal inflammation and provide a potential practical adjunct therapy to restrict DN progression.

Curcumin ameliorates glyoxylate-induced calcium oxalate deposition and renal injuries in mice.

BACKGROUND: Nephrolithiasis is one of the most common and frequent urologic diseases worldwide. Several pathophysiological mechanisms are involved in stone formation, including oxidative stress, inflammation, apoptosis, fibrosis and autophagy. Curcumin, the predominant active component of turmeric, has been shown to have pleiotropic biological and pharmacological properties, such as antioxidant, anti-inflammatory and antifibrotic effects. PURPOSE: The current study proposed to systematically investigate the protective effects and the underlying mechanisms of curcumin in a calcium oxalate (CaOx) nephrolithiasis mouse model. METHODS: The animal model was established in male C57BL/6 mice by successive intraperitoneal injection of glyoxylate (100 mg/kg) for 1 week. Curcumin was orally given to mice 7 days before the injection of glyoxylate and for a total of 14 days at 50 mg/kg or 100 mg/kg. Bilateral renal tissue was harvested and processed for oxidative stress index detection, histopathological examinations and other analyses. RESULTS: Coadministration of curcumin could significantly reduce glyoxylate-induced CaOx deposition and simultaneous tissue injury in mouse kidneys. Meanwhile, curcumin alleviated the oxidative stress response via reducing MDA content and increasing SOD, CAT, GPx, GR and GSH levels in this animal model. Moreover, treatment with curcumin significantly inhibited apoptosis and autophagy induced by hyperoxaluria. Curcumin also attenuated the high expression of IL-6, MCP-1, OPN, CD44, α-SMA, Collagen I and collagen fibril deposition, which were elevated by hyperoxaluria. Furthermore, the results revealed that both the total expression and nuclear accumulation of Nrf2, as well as its main downstream products such as HO-1, NQO1 and UGT, were decreased in the kidneys of mice in the crystal group, while treatment with curcumin could rescue this deterioration. CONCLUSION: Curcumin could significantly alleviate CaOx crystal deposition in the mouse kidney and the concurrent renal tissue injury. The underlying mechanism involved the combination of antioxidant, anti-apoptotic, inhibiting autophagy, anti-inflammatory, and antifibrotic activity and the ability to decrease expression of OPN and CD44 through the Nrf2 signaling pathway. The pleiotropic antilithic properties, combined with the minimal side effects, make curcumin a good potential choice to prevent and treat new or recurrent nephrolithiasis.

Inflammation and kidney injury attenuated by prior intake of Brazil nuts in the process of ischemia and reperfusion / Inflamação e lesão renal atenuadas pela ingestão prévia de castanha-do-Brasil no processo de isquemia e reperfusão

ABSTRACT Introduction: Ischemia and reperfusion (IR) is a process inherent to the procedures involved in the transplantation of organs that causes inflammation, cell death and cell injury, and may lead to rejection of the graft. It is possible that the anti-inflammatory properties of the Brazil nuts (BN) can mitigate the renal injury caused by IR. Objective: To investigate whether the previous intake of BN reduces the expression of markers of inflammation, injury, and cell death after renal IR. Methods: Male Wistar rats were distributed into six groups (N = 6/group): SHAM (control), SHAM treated with 75 or 150 mg of BN, IR, and IR treated with 75 or 150 mg of BN. The IR procedure consisted of right nephrectomy and occlusion of the left renal artery with a non-traumatic vascular clamp for 30 min. BN was given daily from day 1 to 7 before surgery (SHAM or IR), and maintained until sacrifice (48 h after surgery). Inflammation was evaluated by renal expression of COX-2 and TGF-β, injury by the expression of vimentin, and cell death by apoptosis through caspase-3 expression (immunohistochemistry). Results: Pretreatment with 75 mg of BN reduced renal expression of the COX-2, TGF-β, vimentin, and caspase-3. The dose of 150 mg caused increased expression of COX-2. Conclusion: In experimental IR, the damage can be minimized with a prior low-dose intake of BN, improving inflammation, injury, and cell death.

RESUMO Introdução: Isquemia e reperfusão (IR) é um processo inerente aos procedimentos envolvidos no transplante de órgãos, que causa inflamação, morte celular e lesão, podendo levar à rejeição do enxerto. É possível que a castanha-do-brasil (CB), por suas propriedades anti-inflamatórias, possa atenuar a lesão renal causada pela IR. Objetivo: Investigar se a ingestão prévia de CB reduz a expressão de marcadores renais de inflamação, lesão e morte celular após a IR. Métodos: Ratos Wistar machos foram distribuídos em seis grupos (N = 6/grupo): SHAM (controle), SHAM tratado com 75 ou 150 mg de CB, IR, e IR tratado com 75 ou 150 mg de CB. O procedimento de IR consistiu na nefrectomia à direita e oclusão da artéria renal esquerda por 30 minutos. A castanha foi administrada diariamente por sete dias antes da cirurgia (SHAM ou IR), e mantida até o sacrifício (48 horas pós-cirurgia). A inflamação foi avaliada pela expressão renal de COX-2 e TGF-β; a lesão pela expressão de vimentina, e a morte celular por apoptose pela expressão de caspase-3, por imuno-histoquímica. Resultados: O pré-tratamento com 75 mg de CB reduziu a expressão renal de COX-2, de TGF-β, de vimentina e de caspase-3. A dose de 150 mg causou elevação da expressão de COX-2. Conclusão: No modelo experimental de IR renal, os danos podem ser minimizados com a ingestão prévia de baixas doses de CB, melhorando a inflamação, a lesão e a morte celular.

Inflammation and kidney injury attenuated by prior intake of Brazil nuts in the process of ischemia and reperfusion.

INTRODUCTION: Ischemia and reperfusion (IR) is a process inherent to the procedures involved in the transplantation of organs that causes inflammation, cell death and cell injury, and may lead to rejection of the graft. It is possible that the anti-inflammatory properties of the Brazil nuts (BN) can mitigate the renal injury caused by IR. OBJECTIVE: To investigate whether the previous intake of BN reduces the expression of markers of inflammation, injury, and cell death after renal IR. METHODS: Male Wistar rats were distributed into six groups (N = 6/group): SHAM (control), SHAM treated with 75 or 150 mg of BN, IR, and IR treated with 75 or 150 mg of BN. The IR procedure consisted of right nephrectomy and occlusion of the left renal artery with a non-traumatic vascular clamp for 30 min. BN was given daily from day 1 to 7 before surgery (SHAM or IR), and maintained until sacrifice (48 h after surgery). Inflammation was evaluated by renal expression of COX-2 and TGF-ß, injury by the expression of vimentin, and cell death by apoptosis through caspase-3 expression (immunohistochemistry). RESULTS: Pretreatment with 75 mg of BN reduced renal expression of the COX-2, TGF-ß, vimentin, and caspase-3. The dose of 150 mg caused increased expression of COX-2. CONCLUSION: In experimental IR, the damage can be minimized with a prior low-dose intake of BN, improving inflammation, injury, and cell death.

Elsholtzia ciliata (Thunb.) Hylander attenuates renal inflammation and interstitial fibrosis via regulation of TGF-ß and Smad3 expression on unilateral ureteral obstruction rat model.

BACKGROUND: Renal interstitial fibrosis is characterized by excessive accumulation of extracellular matrix, which leads to end-stage renal failure. PURPOSE: The aim of this study was to explore the effect of Elsholtzia ciliata (Thunb.) Hylander ethanol extract (ECE) on renal interstitial fibrosis induced by unilateral ureteral obstruction (UUO). STUDY DESIGN: After quantitative analysis of ECE using the high performance liquid chromatography-photodiode array (HPLC-PDA) method, an in vitro study was performed to assess the anti-inflammatory and anti-fibrotic effects of ECE, using lipopolysaccharide (LPS) and transforming growth factor-ß (TGF-ß), respectively. METHODS: For in vivo study, all male Sprague Dawley (SD) rats (n=10/group), except for those in the control group, underwent UUO. The rats were orally treated with water (control), captopril (positive control, 200 mg/kg), and ECE (300 and 500 mg/kg) for 14 days. RESULTS: In ECE, luteolin and rosmarinic acid were relatively abundant among the other flavonoids and phenolic acids. ECE treatment ameliorated LPS-induced overexpression of nuclear factor-κB, tumor necrosis factor (TNF-α), and interleukin-6 and improved oxidative stress in RAW 264.7 cells. Furthermore, ECE treatment suppressed TGF-ß-induced α-smooth muscle actin and matrix metalloproteinase 9 expression in human renal mesangial cells. In the UUO model, 14 consecutive days of ECE treatment improved UUO-induced renal damage and attenuated histopathological alterations and interstitial fibrosis. Moreover, the renal expression of TNF-α, TGF-ß, and Smad 3 were inhibited by ECE treatment. CONCLUSION: Taken together, the effects of ECE may be mediated by blocking the activation of TGF-ß and inflammatory cytokines, leading subsequently to degradation of the ECM accumulation pathway. Based on these findings, ECE might serve as an improved treatment strategy for renal fibrotic disease.

Paradigm Shifts in Atherosclerotic Renovascular Disease: Where Are We Now?

Results of recent clinical trials and experimental studies indicate that whereas atherosclerotic renovascular disease can accelerate both systemic hypertension and tissue injury in the poststenotic kidney, restoring vessel patency alone is insufficient to recover kidney function for most subjects. Kidney injury in atherosclerotic renovascular disease reflects complex interactions among vascular rarefication, oxidative stress injury, and recruitment of inflammatory cellular elements that ultimately produce fibrosis. Classic paradigms for simply restoring blood flow are shifting to implementation of therapy targeting mitochondria and cell-based functions to allow regeneration of vascular, glomerular, and tubular structures sufficient to recover, or at least stabilize, renal function. These developments offer exciting possibilities of repair and regeneration of kidney tissue that may limit progressive CKD in atherosclerotic renovascular disease and may apply to other conditions in which inflammatory injury is a major common pathway.

Berberine ameliorates experimental diabetes-induced renal inflammation and fibronectin by inhibiting the activation of RhoA/ROCK signaling.

The accumulation of glomerular extracellular matrix proteins, especially fibronectin (FN), is a critical pathological characteristic of diabetic renal fibrosis. Inflammation mediated by nuclear factor-κB (NF-κB) plays a critical role in the pathogenesis of diabetic nephropathy (DN). RhoA/ROCK signaling is responsible for FN accumulation and NF-κB activation. Berberine (BBR) treatment significantly inhibited renal inflammation and thus improved renal damage in diabetes. Here, we study whether BBR inhibits FN accumulation and NF-κB activation by inhibiting RhoA/ROCK signaling and the underlying mechanisms involved. Results showed that BBR effectively inhibited RhoA/ROCK signaling activation in diabetic rat kidneys and high glucose-induced glomerular mesangial cells (GMCs) and simultaneously down-regulated NF-κB activity, which was accompanied by reduced intercellular adhesionmolecule-1, transforming growth factor-beta 1 and FN overproduction. Furthermore, we observed that BBR abrogated high glucose-mediated reactive oxygen species generation in GMCs. BBR and N-acetylcysteine inhibited RhoA/ROCK signaling activation in high glucose-exposed GMCs. Collectively, our data suggest that the renoprotective effect of BBR on DN partly depends on RhoA/ROCK inhibition. The anti-oxidative stress effect of BBR is responsible for RhoA/ROCK inhibition in DN.

[Experience in phytotherapy in nephrolithiasis patients after extracorporeal shock-wave lithotripsy].

Our study of efficacy of Prolit-septo phytotherapy following extracorporeal shock-wave lithotripsy (ESWLT) in patients with nephrolithiasis has demonstrated that Prolit-septo noticeably reduces the time of evacuation from the urinary tract of the destructed stone fragments as well as renal colic incidence and renal inflammation exacerbation.

[Clinical observation on treatment of anaphylactic purpura nephritis by traditional Chinese herbs and Western medicine].

OBJECTIVE: To compare the clinical efficacy of Chinese traditional herbs (CTH) alone or combined with Western medicine (conventional treatment plus different doses of prednisone) in treating anaphylactic purpura nephritis (APN). METHODS: Clinical data of 232 patients with APN were collected and analyzed. They were assigned to four groups. Patients in Group A1 were treated with CTH; in Group A2 were treated initially with Western medicine but turned midway to CTH; in Group B1 and B2 treated with CTH combined with conventional Western medicine and plus low or high dose of prednisone respectively. The comprehensive clinical efficacy on symptoms, physical signs, routine urine examination, blood creatinine and urea nitrogen, as well as the treatment duration and long-term effect in the four groups were observed. RESULTS: There was no significant difference in the comprehensive clinical effects among the four groups (P > 0.05). However, the treatment duration was significantly shorter in Group A1 and B1 than in the other two groups (P < 0.01). Follow-up study on patients in similar duration showed similar reoccurrence rate among groups (P > 0.05). CONCLUSION: Chinese herbs has definite effects on APN with the treatment course shorter than that of other treatments, the optimal protocol for treatment of APN is applying Chinese herbs alone or combined with conventional Western medicine plus low dose prednisone. It is necessary to conduct a follow-up study even though the patients have been cured.

Therapy for children with henoch-schonlein purpura nephritis: a systematic review.

Although severe kidney involvement in children with Henoch-Shonlein purpura (HSP) is rarer than that in adults, morbidity should not be underevaluated and follow-up is mandatory. Some drugs are introduced as well-defined treatment options, others can be promising therapeutic alternatives. Therapy of HSP nephritis in children can range from simply steroids to combined immunosuppressant treatments. The prophylactic treatment for renal complication of patients with HSP has been sometimes suggested, but with conflicting results and ultimately not clearly proven. The treatment of overt HSP nephritis includes steroids and other immunosuppressant drugs. Methylprednisolone pulse therapy and prednisone per os are tested drugs. These steroids could be used in combination with other immunosuppressant drugs, such as cyclosporin A and cyclophosphamide. Unfortunately, of these two drugs, only cyclophosphamide is demonstrated as effective in a recent randomized controlled trial. However, since there are insufficient data and unstructured study designs, ACE-I, azathioprine, mycophenolate mofetil, and urokinase need to be more tested in childhood HSP nephritis. In addition to drugs, other techniques are used to treat the severe form of nephritis. Of these, in a multicenter study, plasmapheresis demonstrated efficacy in delaying the progression of kidney disease. However, no convincing studies have been made to date concerning either intravenous immunoglobulin, factor XIII administration, antioxidant vitamin E, and fish oil to treat HSP nephritis.

[Clinical study on treatment of childhood Henoch-Schonlein purpura nephritis with colquhounia root tablet].

OBJECTIVE: To study the effect of Colquhounia root tablet (CRT) in treating childhood Henoch-Schonlein purpura nephritis (HSPN) and compared with tripterygium wilfordii multiglycoside tablet (TWMGT). METHODS: Eighty-two children with HSPN were divided into the CRT group and the control group. To patients of nephritic type, treatment with CRT and TWMGT was applied separately, but to those of nephrotic type, the treatment was given together with prednisone. Therapeutic effect and changes of related indexes, including urinary protein, retinal-binding protein (RBP), N-acetyl-beta-glucosaminidase (NAG), were observed after patients received treatment for 6 months. RESULTS: The complete remission (CR) rate and partial remission (PR) rate in patients of nephritic type in the treated group was 58.8% and 41.2% respectively, while those in the control group was 20.8% and 66.7% respectively, and the ineffective rate being 12.5%. Comparison of the therapeutic effect between the two groups showed significant difference (P < 0.05). Although the CR rate in patients of nephrotic type in the treated group was higher than that in the control group, the difference was insignificant (P > 0.05). The urinary levels of protein, RBP and NAG lowered in both groups, but level of urinary protein in the treated group of nephritic type after 6 months of treatment was significantly lower than that in the control group (P < 0.05). CONCLUSION: CRT shows obvious effect in improving childhood HSPN of nephritic type, nephrotic type and attenuating the tubulointerstitial lesions, compared with TWMGT, CRT is more effective in lowering proteinuria and better in total effective rate.

Antioxidant intervention blunts renal injury in experimental renovascular disease.

Atherosclerotic renovascular disease (RVD) amplifies damage in a stenotic kidney by inducing pro-inflammatory mechanisms and disrupting tissue remodeling. Oxidative stress is increased in RVD, but its direct contribution to renal injury has not been fully established. The authors hypothesized that chronic antioxidant intervention in RVD would improve renal function and attenuate tissue injury. Single-kidney hemodynamics and function at baseline and during vasoactive challenge were quantified using electron-beam computed tomography in pigs after 12 wk of experimental RVD (simulated by concurrent hypercholesterolemia and renal artery stenosis, n = 7), RVD daily supplemented with antioxidant vitamins C (1 g), and E (100 IU/kg) (RVD+Vitamins, n = 7), or controls (normal, n = 7). Renal tissue was studied ex vivo using Western blot analysis and immunohistochemistry. Basal renal blood flow (RBF) and glomerular filtration rate (GFR) were similarly decreased in the stenotic kidney of both RVD groups. RBF and GFR response to acetylcholine was blunted in RVD, but significantly improved in RVD+Vitamins (P < 0.05 versus RVD). RVD+Vitamins also showed increased renal expression of endothelial nitric oxide synthase (eNOS) and decreased expression of NAD(P)H-oxidase, nitrotyrosine, inducible-NOS, and NF-kappaB, suggesting decreased superoxide abundance and inflammation. Furthermore, decreased expression of pro-fibrotic factors in RVD+Vitamins was accompanied by augmented expression of extracellular (matrix metalloproteinase-2) and intracellular (ubiquitin) protein degradation systems, resulting in significantly attenuated glomerulosclerosis and renal fibrosis. In conclusion, chronic antioxidant intervention in early experimental RVD improved renal functional responses, enhanced tissue remodeling, and decreased structural injury. This study supports critical pathogenic contribution of increased oxidative stress to renal injury and scarring in RVD and suggests a role for antioxidant strategies in preserving the atherosclerotic and ischemic kidney.

[Effect of danshao granule on serum superoxide dismutase activity and malonyldialdehyde content in children with Henoch-Schonlein purpura nephritis].

OBJECTIVE: To explore the effect and mechanism of Danshao Granule (DSG) in treating Henoch-Schonlein purpura nephritis (HSPN) in children. METHODS: The 63 patients with HSPN were randomly divided into two groups. The 32 patients in the treated group were treated with DSG and the 31 patients in the control group were treated with Tripterygium polyglycosides tablet and composite Salviae tablet. The therapeutic course for both groups was one month. The skin purpura, macroscopic hematuria, hypertension and edema subsidence time, 24 hrs urinary protein content, serum levels of immunoglobulins (IgA, IgG, IgM), superoxide dismutase (SOD) activity and malonyldialdehyde (MDA) content were observed before and after treatment. RESULTS: Therapeutic effect in the treated group was better than that in the control group in curing skin purpura and macroscopic hematuria (P < 0.05). The 24 hrs urinary protein content and serum levels of IgA, SOD and MDA were improved after treatment in both groups significantly (P < 0.01). However, the improvement of 24 hrs urinary protein, serum SOD and MDA in the treated group was more significant than that in the control group respectively (P < 0.05). CONCLUSION: DSG can alleviate the injury of free radicals in organism, so it is an ideal remedy for treatment of HSPN.

Carcinogenic aristolochic acids upon activation by DT-diaphorase form adducts found in DNA of patients with Chinese herbs nephropathy.

Aristolochic acid (AA), a naturally occurring nephrotoxin and rodent carcinogen, has recently been associated with the development of urothelial cancer in humans. Understanding which enzymes are involved in AA activation and/or detoxication is important in the assessment of an individual susceptibility to this natural carcinogen. We examined the ability of enzymes of rat renal and hepatic cytosolic fractions to activate AA to metabolites forming DNA adducts by the nuclease P1-enhanced version of the (32)P-postlabeling assay. Cytosolic fractions of both these organs generated AA-DNA adduct patterns reproducing those found in renal tissues from humans exposed to AA. 7-(Deoxyadenosin-N(6)-yl)aristolactam I, 7-(deoxyguanosin-N(2)-yl)aristolactam I and 7-(deoxyadenosin-N(6)-yl)aristolactam II were identified as AA-DNA adducts formed from AAI and 7-(deoxyguanosin-N(2)-yl)aristolactam II and 7-(deoxyadenosin-N(6)-yl)aristolactam II were generated from AAII by hepatic cytosol. Qualitatively the same AA-DNA adduct patterns were observed, although at lower levels, upon incubation of AAs with renal cytosol. To define the role of cytosolic reductases in the reductive activation of AA, we investigated the modulation of AA-DNA adduct formation by cofactors, specific inducers or selective inhibitors of the cytosolic reductases, DT-diaphorase, xanthine oxidase (XO) and aldehyde oxidase. The role of the enzymes in AA activation was also investigated by correlating the DT-diaphorase- and XO-dependent catalytic activities in cytosolic sample with the levels of AA-DNA adducts formed by the same cytosolic sample. On the basis of these studies, we attribute most of the cytosolic activation of AA to DT-diaphorase, although a role of cytosolic XO cannot be ruled out. With purified DT-diaphorase, the participation of this enzyme in the formation of AA-DNA adducts was confirmed. The binding orientation of AAI in the active site of DT-diaphorase was predicted by computer modeling based on published X-ray structures. The results presented here are the first report demonstrating a reductive activation of carcinogenic AAs by DT-diaphorase.

Antiviral and immunomodulatory effects of desferrioxamine in cytomegalovirus-infected rat liver allografts with rejection.

BACKGROUND: Cytomegalovirus (CMV) infection is associated with acute and chronic allograft rejection. We have recently shown that rat CMV increases portal inflammation and bile duct destruction in a model of rat liver allograft rejection. Desferrioxamine (DFO), an iron chelator and antioxidant, has recently been demonstrated to have antiviral as well as immunomodulatory effects in vitro. We therefore investigated whether DFO inhibits (a) CMV infection and (b) graft destruction in our rat model. METHOD: One day after liver transplantation, PVG (RT1c) into BN(RT1n), the rats were infected with rat CMV (RCMV, Maastricht strain; 10(5) plaque-forming units i.p.). The effects of 100 mg/kg body weight and 200 mg/kg body weight DFO were examined. RESULTS: In the untreated group, the grafts were uniformly RCMV culture-positive. In the group receiving 200 mg/kg DFO, RCMV replication was effectively inhibited. Inflammatory response in the graft, and especially the number of macrophages, was significantly reduced by DFO. Portal inflammation and bile duct destruction were also significantly reduced. In the untreated group, the bile duct epithelial cells were found to be strongly positive for tumor necrosis factor-alpha and this expression was clearly decreased by DFO. In addition, DFO significantly inhibited vascular cell adhesion molecule-1 expression on sinusoidal endothelial cells. CONCLUSIONS: Our in vivo transplant study strongly supports the inhibitory effects of metal chelators on CMV infection and their possible usefulness in the treatment of CMV-induced pathogenic changes.

Mortality risks associated with specific clinical manifestations of systemic lupus erythematosus.

BACKGROUND: Mortality in patients with systemic lupus erythematosus (SLE) is often related to disease in particular organ systems. We examined the risks of mortality associated with 8 clinical manifestations of SLE and determined whether these risks differed among patients with different sociodemographic characteristics. METHODS: Using life table analysis, we determined the associations of hemolytic anemia, leukopenia, thrombocytopenia, arthritis, serositis, nephritis, psychosis, and seizures with both all-cause mortality and SLE-related mortality in a cohort of 408 patients. RESULTS: Over a median duration of follow-up of 11 years, 144 patients died; 78 deaths (54%) were SLE related. In univariate analyses, the presence of hemolytic anemia, serositis, nephritis, psychosis, and seizures was associated with greater all-cause mortality, while the presence of arthritis was protective. In multivariate analyses that controlled for patient demographic characteristics, nephritis (relative risk, 2.34) and seizures (relative risk, 1.77) were associated with poorer overall survival. Nephritis and seizures, along with thrombocytopenia, were also associated with greater SLE-related mortality, while leukopenia was protective. The risk of death in association with these clinical manifestations did not differ among patient age, sex, race, or socioeconomic subgroups. CONCLUSIONS: The presence of nephritis and seizures each increased the risk of death in patients with SLE approximately 2-fold. Thrombocytopenia also increased the risk of SLE-related mortality, while leukopenia was protective.