Proteome of thymus and spleen reveals that 10-hydroxydec-2-enoic acid could enhance immunity in mice.

Objectives: 10-hydroxydec-2-enoic acid (10-HDA), a unique component of royal jelly existing only in nature, has the potential to promote human health. Knowledge of 10-HDA in regulating immuno-activity, however, is lacking. The aim of our work is to gain a novel understanding of 10-HDA in promoting immunity.Methods: Immuno-suppressed mice were generated by cyclophosphamide injection, After 10-HDA supplementation to the mice to rescue their immunity, the proteomes of the thymus and spleen were analyzed.Results: The weight of the body, thymus, and spleen in cyclophosphamide-induced mice recovered by 10-HDA indicate its potential role in immuno-organ protection. In the thymus, the enhanced activity of pathways associated with DNA/RNA/protein activities may be critical for T-lymphocyte proliferation/differentiation, and cytotoxicity. In the spleen, the induced pathways involved in DNA/RNA/protein activities, and cell proliferative stimulation suggest their vital role in B-lymphocyte affinity maturation, antigen presentation, and macrophage activity. The up-regulated proteins highly connected in networks modulated by 10-HDA indicate that the mice may evolve tactics to respond to immuno-organ impairment by activating critical physiological processes.Conclusion: Our data constitute a proof-of-concept that 10-HDA is a potential agent to improve immunity in the thymus and spleen and offer a new venue for applying natural products to the therapy for hypoimmunity.

Immunomodulatory and Immunosuppressive Roles of 1α,25(OH)2D3 in Autoimmune Diseases.

Autoimmune diseases are pathological conditions characterized by abnormal responses, accompanied by autoantibodies to self-molecules. The role of vitamin D in autoimmune diseases has increased significantly in the recent past from its functions in calcium and phosphate homoeostasis, and it is now involved in the regulations and proliferations of Th1 and Th17 lymphocyte. 1α,25(OH)2D3 is very important in ameliorations of inflammatory disorders arising from autoimmune diseases, but the mechanism by which this is performed is still a bone of contentions. This review aimed to highlight the existing facts about the roles of Vitamin D in the treatment and management of autoimmune diseases. An extensive online literature search was conducted using PubMed, MEDLINE and Scopus. Accumulated bodies of research evidence are available which demonstrates that Vitamin D has a very important part to play in the regulation of immune responses in autoimmune diseases. Some of the authors suggested that Vitamin D3 carry-out its immunosuppressive and immune modulatory action, through its actions on antigen-presenting cells and activated T and B cells with the help of Vitamin D receptors present on the each of these cells. Vitamin D supplementation assists in autoimmune disorders by making qualitative and quantitative changes in the immune system (downregulation of Th1 and upregulations of Th2 cells). This resulted in the body to be more tolerant of self and less likely to mount autoimmune responses.

Is B Cell-Targeted Therapy Effective in Systemic Lupus Erythematosus?

In the past decade we have witnessed a dramatic change in the management of autoimmune diseases, such as rheumatoid arthritis, due to the development of new biologic drugs designed to target key mediators in the autoimmune process. However, the development of similar target-specific drugs for the management of SLE has not been as successful. The B cell has long been considered central to the pathogenesis of SLE and has been regarded as an important target for biologic drugs. Several B cell-targeted drugs have been developed and although the mechanisms seem promising, most of the studies published to date have failed to achieve their primary endpoints, leading to an ongoing debate regarding the role of B cell therapy in SLE. The present report discusses the pros and cons of B cell-targeted therapy in SLE, reviews the clinical studies, and offers possible explanations forthe discrepancies between randomized control studies and real-life experience.

Diterpenoids with Immunosuppressive Activities from Cinnamomum cassia.

Three new diterpenoids with unprecedented carbon skeletons, cinncassiols F (1) and G (2) and 16-O-ß-D-glucopyranosyl-19-deoxycinncassiol G (3), a new isoryanodane diterpenoid, 18-hydroxyperseanol (4), six known isoryanodane diterpenoids, 5-10, and a known ryanodane diterpenoid, 11, were isolated from the stem bark of Cinnamomum cassia. Compound 1 possesses an 11,13:12,13-diepoxy-6,11-epoxy:12,13-disecoisoryanodane diterpenoid skeleton bearing ketal and hemiketal functionalities, whereas compounds 2 and 3 feature an 11,12-secoisoryanodane diterpenoid skeleton with an 11,6-lactone moiety. The structures of the four new diterpenoids, 1-4, and their absolute configurations were established using HRESIMS, NMR, ECD, single-crystal X-ray diffraction, and chemical methods. Compounds 2 and 11 significantly inhibited the proliferation of murine T cells induced by ConA.

Concise review: combining human leukocyte antigen G and mesenchymal stem cells for immunosuppressant biotherapy.

Both human leukocyte antigen G (HLA-G) and multipotential mesenchymal stem/stromal cells (MSCs) exhibit immunomodulatory functions. In allogeneic tranplantation, the risks of acute and chronic rejection are still high despite improvement in immunosuppressive treatments, and the induction of a state of tolerance to alloantigens is not achieved. Immunomodulatory properties of MSCs and HLA-G in human allogeneic tranplantation to induce tolerance appears attractive and promising. Interestingly, we and others have demonstrated that MSCs can express HLA-G. In this review, we focus on the expression of HLA-G by MSCs and discuss how to ensure and improve the immunomodulatory properties of MSCs by selectively targeting MSCs expressing HLA-G (MSCs(HLA-G+)). We also discuss the possible uses of MSCs(HLA-G+) for therapeutic purposes, notably, to overcome acute and chronic immune rejection in solid-organ allogeneic transplantation in humans. Since MSCs are phenotypically and functionally heterogeneous, it is of primary interest to have specific markers ensuring that they have strong immunosuppressive potential and HLA-G may be a valuable candidate.

T-cell-replete HLA-haploidentical hematopoietic transplantation for hematologic malignancies using post-transplantation cyclophosphamide results in outcomes equivalent to those of contemporaneous HLA-matched related and unrelated donor transplantation.

PURPOSE: T-cell-replete grafts from haploidentical donors using post-transplantation cyclophosphamide may represent a solution for patients who require allogeneic hematopoietic cell transplantation (alloHCT) but lack a conventional donor. We compared outcomes of alloHCT using haploidentical donors with those of transplantation using conventional HLA-matched sibling donors (MRDs) and HLA-matched unrelated donors (MUDs). PATIENTS AND METHODS: Outcomes of 271 consecutive patients undergoing T-cell-replete first alloHCT for hematologic malignancies performed contemporaneously at a single center (53 using haploidentical donors; 117, MRDs; 101, MUDs) were compared. Overall and disease-free survival (DFS) were adjusted for effects of significant patient-, disease-, and transplantation-related covariates using a stratified Cox model. RESULTS: Patient characteristics were similar between the three donor groups. For patients undergoing MRD, MUD, and haploidentical transplantation, 24-month cumulative incidences of nonrelapse mortality were 13%, 16%, and 7% and of relapse were 34%, 34%, and 33%, respectively (P not significant [NS]). Cumulative incidences of grades 3 to 4 acute graft-versus-host disease (GVHD) at 6 months were 8%, 11%, and 11%, respectively (P NS); extensive chronic GVHD occurred in 54%, 54%, and 38% of patients, respectively (P < .05 for those undergoing haploidentical donor v MRD or MUD transplantation). Adjusted 24-month probabilities of survival were 76%, 67%, and 64% and of DFS were 53%, 52%, and 60%, respectively; these were not significantly different among the three donor groups. CONCLUSION: Haploidentical transplantation performed using T-cell-replete grafts and post-transplantation cyclophosphamide achieves outcomes equivalent to those of contemporaneous transplantation performed using MRDs and MUDs. Such transplantation represents a valid alternative for patients who lack a conventional donor.

Microencapsulated drug delivery: a new approach to pro-inflammatory cytokine inhibition.

CONTEXT: This article reviews the use of albumin microcapsules 3-4 µm in size containing cytokine inhibiting drugs which include neutralizing antibodies to TNF and IL1, CNI-1493, antisense oligonucleotides to TNF and NF-kappaB, and the antioxidant catalase. OBJECTIVE: Describe the effects, cellular uptake and distribution of microencapsulated drugs and the effect in both a peritonitis model of infection and a model of adjuvant-induced arthritis. METHODS: The studies performed by our group are reviewed, the only such studies available. RESULTS: Microencapsulation of these compounds produced high intracellular drug concentrations due to rapid uptake by phagocytic cells, including endothelial cells, without toxicity. All compounds produced excellent inhibition of TNF and IL1 resulting in improved animal survival in a peritonitis model of septic shock and inflammation in an arthritis model. CONCLUSION: Albumin microencapsulated pro-inflammatory cytokine inhibiting compounds are superior to equivalent concentration of these compounds administered in solution form.

Activity of an Intralipid formulation of nystatin in murine systemic candidiasis.

Since nystatin (NYT) is used only topically owing to its toxicity upon systemic administration, a study was initiated aiming to develop a formulation of NYT that could be used systemically against invasive mycoses. The present research is a continuation of previous in vitro investigation of the antifungal effect of nystatin-Intralipid (NYT-IL) against Candida, exploring its in vivo activity. NYT-IL was tested in murine systemic candidiasis induced in naïve as well as cyclophosphamide-immunosuppressed female ICR mice. The infection was assessed by survival rate (SR), mean survival time (MST) and qualitative and quantitative fungal organ colonisation. Mice were treated by intravenous administration of various doses of NYT-IL for 5 consecutive days starting either 24h or 48 h after the initiation of infection. The experiments showed that NYT-IL is therapeutically effective in the murine candidiasis model. NYT-IL was found to be less toxic in vivo than NYT and therefore higher doses of NYT-IL could be used. The efficacy of NYT-IL was expressed in treated naïve and immunosuppressed mice by increased SR, prolonged MST and reduced fungal organ colonisation. Early initiation of treatment increased efficacy. In summary, the Intralipid formulation of NYT can be administered parenterally and is effective against systemic experimental Candida infection.

Monitoring the status of T-cell activation in a microfluidic system.

Leukocyte adhesion to the endothelium through surface molecules such as E-selectin and intercellular adhesion molecule-1 (ICAM-1) is a critical cellular event reflecting the physiological status of both cell types. Here we present a microfluidic system that can not only easily monitor the interaction between leukocytes and endothelial cells under physiological conditions, but also screen drug candidates for potential modulation of this interaction. Shear stress, which is an important factor for the binding of activated T cells to tumor necrosis factor-alpha (TNF-α)-treated human umbilical vein endothelial cells (HUVECs), was easily controlled by adjusting the flow rate in the microfluidic system. Whole blood of patients with systemic lupus erythematosus (SLE) who have auto-reactive T cells were infused into the activated HUVECs which subsequently showed a higher level of binding compared to a control blood sample from a person without SLE. When these autoreactive T cells were treated with immunosuppressors tacrolimus and cyclosporin A, the binding of the T cells to HUVECs was dramatically decreased. Therefore, this microfluidic system is capable of differentiating the physiological status of T cells or endothelial cells representing different disease conditions, as well as being useful for the identification of novel reagents that modulate the functions of leukocytes or endothelial cells.

Medicinal plants as immunosuppressive agents in traditional Iranian medicine.

Immunomodulation using medicinal plants provides an alternative to conventional chemotherapy for several diseases, especially when suppression of inflammation is desired. The "Canon of Medicine", the epochal work of Avicenna, the great Persian scientist of the middle ages, provides comprehensive information about medicinal plants which used to cure inflammatory illnesses in traditional Iranian medicine. Taking into consideration that the mechanisms of damage in these illnesses are mediated by immune responses, it is reasonable to assume that the plants used for such diseases may suppress the immune responses and the resultant inflammation. In Iran, because of great diversity of climate and geographical conditions, numerous varieties of plants grow and at least 1000 species are recorded as medicinal plants. Many of these plants such as Punica granatum, Glycyrrhiza glabra, Foeniculum vulgare and Polygonum species prescribed by ancient Iranian physicians have been shown to possess anti-inflammatory and immunomodulatory effects. In recent literature, different species of native medicinal plants such as Stachys obtusicrena, Salvia mirzayanii, Echium amoenum, Dracocephalum kotschyi and Linum persicum have been shown to have appreciable anti-inflammatory and immunomodulatory effects including inhibitory effects on lymphocyte activation, suppression of cellular and humoral immunity and induction of apoptosis. This review focuses on plants that are used in Iranian traditional medicine and have been reported to act as immunoinhibitory agents.

Successful long-term outcome of ABO-incompatible liver transplantation using antigen-specific immunoadsorption columns.

ABO-incompatible (ABO-I) liver transplantation has been performed essentially in patients with acute liver failure awaiting an urgent liver transplantation. Early results with ABO-I liver transplantation were disappointing with a very low graft survival rate (20-50%). The main risk is the occurrence of severe humoral and cellular rejection, vascular thrombosis, and biliary complications. In order to avoid humoral rejection and improve graft survival, total plasma exchange in combination with an intense immunosuppressive regimen has been proposed to decrease hemagglutinin titers in ABO-I liver grafts. In some centers, this regimen was associated with splenectomy, phototherapy, and portal or arterial intrahepatic infusion therapy; however, as these patients are at high risk of sepsis, a selective approach using antigen-specific immunoadsorption with immunoadsorbent columns has been successfully proposed for ABO-I living donor kidney transplantation. Few cases have been reported following liver transplantation. We report our recent experience with three adult patients (two patients with acute liver failure, and one with severe cirrhosis and hepatic encephalopathy) transplanted in an emergency situation with an ABO-I liver graft and managed with the use of GlycoSorb ABO immunoadsorbent columns and a quadruple immunosuppressive regimen with preservation of the spleen. Eight sessions were performed in the three patients. Antigen-specific immunoadsorption greatly lowered the anti-A hemagglutinin titers. None of the three patients developed acute humoral or cellular rejection. Two patients are alive at 1.5 and 3 years follow-up with a normally functioning graft. The third patient died with a functioning graft, one month after the transplantation, from septic complications.

Therapeutic control of B cell activation via recruitment of Fcgamma receptor IIb (CD32B) inhibitory function with a novel bispecific antibody scaffold.

OBJECTIVE: To exploit the physiologic Fcgamma receptor IIb (CD32B) inhibitory coupling mechanism to control B cell activation by constructing a novel bispecific diabody scaffold, termed a dual-affinity retargeting (DART) molecule, for therapeutic applications. METHODS: DART molecules were constructed by pairing an Fv region from a monoclonal antibody (mAb) directed against CD32B with an Fv region from a mAb directed against CD79B, the beta-chain of the invariant signal-transducing dimer of the B cell receptor complex. DART molecules were characterized physicochemically and for their ability to simultaneously bind the target receptors in vitro and in intact cells. The ability of the DART molecules to negatively control B cell activation was determined by calcium mobilization, by tyrosine phosphorylation of signaling molecules, and by proliferation and Ig secretion assays. A DART molecule specific for the mouse ortholog of CD32B and CD79B was also constructed and tested for its ability to inhibit B cell proliferation in vitro and to control disease severity in a collagen-induced arthritis (CIA) model. RESULTS: DART molecules were able to specifically bind and coligate their target molecules on the surface of B cells and demonstrated a preferential simultaneous binding to both receptors on the same cell. DART molecules triggered the CD32B-mediated inhibitory signaling pathway in activated B cells, which translated into inhibition of B cell proliferation and Ig secretion. A DART molecule directed against the mouse orthologs was effective in inhibiting the development of CIA in DBA/1 mice. CONCLUSION: This innovative bispecific antibody scaffold that simultaneously engages activating and inhibitory receptors enables novel therapeutic approaches for the treatment of rheumatoid arthritis and potentially other autoimmune and inflammatory diseases in humans.

The novel calcineurin inhibitor CN585 has potent immunosuppressive properties in stimulated human T cells.

The Ca2+/calmodulin-dependent protein phosphatase calcineurin is a key mediator in antigen-specific T cell activation. Thus, inhibitors of calcineurin, such as cyclosporin A or FK506, can block T cell activation and are used as immunosuppressive drugs to prevent graft-versus-host reactions and autoimmune diseases. In this study we describe the identification of 2,6- diaryl-substituted pyrimidine derivatives as a new class of calcineurin inhibitors, obtained by screening of a substance library. By rational design of the parent compound we have attained the derivative 6-(3,4-dichloro-phenyl)-4-(N,N-dimethylaminoethylthio)-2-phenyl-pyrimidine (CN585) that noncompetitively and reversibly inhibits calcineurin activity with a K(i) value of 3.8 mum. This derivative specifically inhibits calcineurin without affecting other Ser/Thr protein phosphatases or peptidyl prolyl cis/trans isomerases. CN585 shows potent immunosuppressive effects by inhibiting NFAT nuclear translocation and transactivation, cytokine production, and T cell proliferation. Moreover, the calcineurin inhibitor exhibits no cytotoxicity in the effective concentration range. Therefore, calcineurin inhibition by CN585 may represent a novel promising strategy for immune intervention.

Geranylated flavonoids from the roots of Campylotropis hirtella and their immunosuppressive activities.

In an effort to identify new immunosuppressive agents from natural sources, 12 new geranylated flavonoids, 5,7,4'-trihydroxy-3'-[7-hydroxy-3,7-dimethyl-2(E)-octenyl]isoflavone (1), a racemate of 5,7,2',4'-tetrahydroxy-3'-[7-hydroxy-3,7-dimethyl-2(E)-octenyl]isoflavanone (2), 2''(S)-5,7-dihydroxy-[2''-methyl-2''-(4-methyl-3-pentenyl)pyrano]-5'',6'':3',4'-isoflavone (3), (2''S,3''R,4''S)-5,7,3'',4''-tetrahydroxy[2''-methyl-2''-(4-methyl-3-pentenyl)pyrano]-5'',6'':3',4'-isoflavone (4), a racemate of 3'-geranyl-5,7,2',4'-tetrahydroxyisoflavanone (5), a racemate of 3'-geranyl-4'-methoxy-5,7,2'-trihydroxyisoflavanone (6), 3'-geranyl-5,7,4',5'-tetrahydroxyisoflavone (8), 3'-geranyl-5,7,2',5'-tetrahydroxyisoflavone (9), 3'-geranyl-4'-methoxy-5,7,2'-trihydroxyisoflavone (10), 2(R),3(R)-3'-geranyl-2,3-trans-5,7,4'-trihydroxyflavonol (12), (2R,3R)-6-methyl-3'-geranyl-2,3-trans-5,7,4'-trihydroxyflavonol (13), and 5,7-dihydroxy-4'-O-geranylisoflavone (14), were isolated from the roots of Campylotropis hirtella (Franch.) Schindl. together with three previously described flavonoids. Their structures were elucidated by spectroscopic measurements, including two-dimensional nuclear magnetic resonance (NMR) techniques. The immunosuppressive effects of these compounds were assessed using mitogen-induced splenocyte proliferation, and the cytotoxicity of the compounds was also examined. The IC50 values of the compounds were found to be in the range of 1.49-61.23 microM for T lymphocyte suppression and 1.16-73.07 microM for B lymphocyte suppression. An analysis of their structure-activity relationships revealed that an isoflavonoid carbon skeleton with a C10 substituent at the C3' position was necessary for the activity. As many of the compounds exhibited good immunosuppressive activities, they may be promising as novel immunosuppressive agents.

Developmental and peri-postnatal study in cynomolgus monkeys with belimumab, a monoclonal antibody directed against B-lymphocyte stimulator.

Belimumab is a fully human monoclonal antibody antagonist for soluble B-lymphocyte stimulator, and is a potential therapeutic for various autoimmune disorders. To support clinical use, belimumab was administered intravenously to pregnant cynomolgus monkeys every 2 weeks throughout gestation at dosages of 5 and 150 mg/kg. Fetuses were delivered by C-section on Gestation Day 150 from one-half of the mothers, and evaluated for teratologic effects (external, visceral, skeletal, and heart), pharmacodynamics (PD) and toxicokinetics (TK). Remaining mothers delivered their infants naturally, enabling extensive assessment of PD and TK during a 1-year postnatal period. Effects attributed to belimumab were limited to the expected pharmacology, primarily decreased numbers of B-lymphocytes in peripheral blood of mothers and infants, and in fetal lymphoid tissues. Infants demonstrated full recovery upon cessation of exposure. In conclusion, belimumab was well tolerated at pharmacologically active dose levels in pregnant cynomolgus monkeys and their infants after exposure throughout pregnancy.

A microbial polysaccharide reduces the severity of rheumatoid arthritis by influencing Th17 differentiation and proinflammatory cytokines production.

Rheumatoid arthritis (RA) is a chronic and debilitating autoimmune disease characterized by chronic joint inflammation with subsequent cartilage and bone destruction. RA is emerging as a model of IL-17-driven autoimmune inflammatory disease. IL-17 is a marker for Th17 cells, with its master regulator being the retinoic acid receptor-related orphan receptor (RORgammat) regulated by STAT3 signaling. Glucuronoxylomannan (GXM), a polysaccharide representing the main component of the capsular material of the opportunistic yeast Cryptococcus neoformans, exhibits potent immunosuppressive properties both in vitro and in vivo. The present study investigates the effects of GXM treatment on the progression of collagen-induced arthritis. GXM suppressed clinical signs of collagen-induced arthritis and blocked joint erosion progression. This effect was mediated by down-regulation of key cytokines involved in the pathogenesis of RA such as TNF-alpha and IL-1beta, and up-regulation of the inhibitory cytokine IL-10. Moreover, a reduction of IL-6 and TGF-beta, which inhibit Th17 differentiation with consequent decreased IL-17 production at the local and systemic level, was observed. The effect of GXM on Th17 differentiation mirrored the reduction in STAT3 activation and inhibition of RORgammat synthesis. Consequently, this work highlights the beneficial properties of an efficacious compound that could eventually be destined to the clinic.

Treatment of experimental periodontal disease by photodynamic therapy in immunosuppressed rats.

BACKGROUND AND OBJECTIVE: The aim of this study was to compare photodynamic therapy (PDT) as an adjunctive treatment of induced periodontitis with scaling and root planing (SRP) in dexamethasone-inhibited rats. MATERIAL AND METHODS: The animals were divided into two groups: ND (n=90), saline solution treatment; D (n=90), dexamethasone treatment. In the ND and D Groups, periodontal disease was ligature-induced at the first mandibular molar. After 7 days, the ligature was removed and all animals received SRP and were divided according to the following treatments: SRP, saline solution; Toluidine Blue-O (TBO), phenothiazinium dye; and PDT, TBO and laser irradiation. Ten animals in each treatment were killed at 7, 15 and 30 days. The radiographic and histometric values were statistically analysed. RESULTS: In the ND and D Groups, radiographic analysis showed less bone loss in animals treated by PDT in all the experimental periods than SRP and TBO at 15 days (p<0.05). After a histometric analysis was carried out in the ND and D groups, the animals treated by PDT showed less bone loss in all periods than SRP and TBO after 15 days (p<0.05). CONCLUSIONS: The PDT was an effective adjunctive treatment of induced periodontitis compared with SRP in dexamethasone-inhibited rats.

Immunomodulatory activity of isoflavones isolated from Iris germanica (Iridaceae) on T-lymphocytes and cytokines.

The immunomodulatory activities of two isoflavones, 5,7-dihydroxy-6,4'-dimethoxyisoflavone (irisolidone) (1) and 5,4'-dihydroxy-6,7-methylenedioxyisoflavone (irilone) (2) isolated from Iris germanica (Iridaceae) is reported. Their influence on production of T-lymphocytes (CD4+ and CD8+ cells) and T-cell cytokines, namely Th1: IL-2, IFN-gamma and Th2: IL-4 and IL-5 in a dose-dependent manner was studied by flow cytometric method in Balb/c mice. Oral administration of drugs at doses of 0.1-0.8 mg/kg per oral dose showed 1 to possess stimulatory activity on T-cells and Th1 cytokine production, while as 2 acted as an immunosuppressant for both cells and cytokines. The methylated products of 1 and 2 showed a similar trend to that of their parent compounds but their activity was drastically decreased revealing the importance of free phenolic groups for their immunomodulating activities.

Short-term effects of high-dose zoledronic acid treatment on bone mineralization density distribution after orthotopic liver transplantation.

Patients with "hepatic" bone disease exhibit increased fracture incidence. The effects on bone material properties, their changes due to orthotopic liver transplantation (OLT), as well as zolendronate (ZOL) treatment have not yet been investigated. We studied bone mineralization density distribution (BMDD) in paired transiliacal biopsies (at and 6 months after OLT) from patients (control CON n = 18, treatment group ZOL n = 21, the latter treated with i.v. ZOL at doses of 4 mg/month) for how bone at the material level was affected by the "hepatic" disease in general, as well as by OLT and ZOL in particular. (1) BMDD parameters at baseline reflected disturbed bone matrix mineralization in "hepatic" bone disease combined with low turnover. Trabecular bone displayed a decrease in mean and most frequent calcium concentration (Ca(MEAN) -2.9% and Ca(PEAK) -2.8%, respectively; both P < 0.001), increased heterogeneity of mineralization (Ca(WIDTH) +12.2%, P = 0.01), and increased percentage of bone areas with low mineralization (Ca(LOW) +32.4%, P = 0.02) compared to normal; however, there were no differences compared to cortical bone. (2) Six months after OLT, ZOL-treated trabecular bone displayed reduced Ca(LOW) (-32.0%, P = 0.047), cortical bone increased Ca(MEAN) (+4.2%, P = 0.009), increased Ca(PEAK) (+3.3%, P = 0.040), and decreased Ca(LOW) (-55.7, P = 0.038) compared to CON and increased Ca(MEAN) compared to baseline (+1.9, P = 0.032) without any signs of hyper- or defective mineralization. These changes as consequence of the antiresorptive action of ZOL visible already after 6 months result in beneficial effects on bone matrix mineralization, likely contributing to the significant decrease in fracture incidence observed in these patients 2 years post transplantation.

Sodium tanshinone IIA sulfonate protects mice from ConA-induced hepatitis via inhibiting NF-kappaB and IFN-gamma/STAT1 pathways.

INTRODUCTION: Sodium tanshinone IIA sulfonate (STS) is a water-soluble derivative of tanshinone IIA, the main pharmacologically active component of Salvia miltiorrhiza. The aim of this study was to investigate the effect of STS on concanavalin A (ConA)-induced hepatitis (CIH) in mice, an experimental model of immune-mediated liver injury. RESULTS: C57BL/6 mice pretreated with STS released much less alanine transaminase into plasma in response to ConA challenge and had reduced inflammatory infiltration and hepatocyte apoptosis in the liver compared with control mice pretreated with vehicle solutions. Thus, STS protected mice from CIH. In STS-pretreated mice induced with CIH, we found abrogated tumor necrosis factor-alpha and interferon (IFN)-gamma production. Moreover, mRNA expressions of IFN-inducible protein-10 and macrophage inflammatory protein-1alpha in these mice were decreased. The mechanism of anti-inflammatory effects of STS may be attributed to its modulation of crucial inflammatory signaling pathways, including NF-kappaB and IFN-gamma/STAT1. CONCLUSION: In conclusion, STS was capable of protecting mice from immune-mediated liver injury in vivo, and the protection was associated with its suppressive effect on the production of important inflammatory mediators through modulating NF-kappaB and IFN-gamma/STAT1 signaling pathways.