The Inhibitory Effects of Pentacyclic Triterpenes from Loquat Leaf against Th17 Differentiation.

BACKGROUND: Loquat leaf is an herb that is commonly used in traditional Chinese medicine (TCM) for its anti-inflammatory properties. Numerous studies have demonstrated that Th17 cells play a fundamental role in mediating SLE pathological deterioration. In our study, we investigated the inhibitory effect of pentacyclic triterpenes from loquat leaf on T helper 17 (Th17) cells and the therapeutic efficacy of OA in Lupus nephritis (LN) development. METHODS: We isolated three pentacyclic triterpene compounds rom loquat leaf by bioassay-directed fractionation and separation method. There were methyl corosolate (MC), uvaol (UL), and oleanolic acid (OA) Firstly, we elucidated Retinoic acid receptor-related orphan receptor gamma t (RORγt) inhibitory activity of these three compounds in the cell-based assay and Th17 differentiation in vitro assay. Then, we used OA-treated pristine-induced LN mice to evaluate the therapeutic effects of OA in LN development. Anti-dsDNA level in serum was detected by enzyme-linked immunosorbent assay (ELISA), interleukin 17A (IL-17A) and interferon-γ (IFN-γ) expression in spleen cells by Flow cytometry (FCM), histomorphologic examination of kidneys were performed by periodic acid schiff (PAS) staining and immunofluorescence analysis. RESULTS: Pentacyclic triterpene compounds (MC, UL, OA) displayed inhibition of RORγt activity in cell-based assay and Th17 differentiation in vitro. Furthermore, our results also showed that OA could significantly decrease serum anti-dsDNA antibody levels, IL-17A and IFN-γ expression and alleviate renal pathological damage in OA-treated group mice than in the model group mice. CONCLUSION: These results demonstrated that OA can improve the clinical manifestation of LN, indicating potential application in SLE therapy.

NLRP3 Inflammasome Modulation by Melatonin Supplementation in Chronic Pristane-Induced Lupus Nephritis.

Lupus nephritis (LN) is a kidney inflammatory disease caused by systemic lupus erythematosus (SLE). NLRP3 inflammasome activation is implicated in LN pathogenesis, suggesting its potential targets for LN treatment. Melatonin, an endogenous indoleamine, is considered an important multitasking molecule that has been reported to have anti-inflammatory effects by inhibiting nuclear factor-kappa B (NF-κB)-mediated inflammatory responses in vivo. This molecule has also protective effects against the activation of the inflammasomes and, in particular, the NLRP3 inflammasome. Thus, this work evaluated the effect of melatonin on morphological alteration and NLRP3 inflammasome activation in LN pristane mouse models. To evaluate the melatonin effects in these mice, we studied the renal cytoarchitecture by means of morphological analyses and immunohistochemical expression of specific markers related to oxidative stress, inflammation and inflammasome activation. Our results showed that melatonin attenuates pristane-induced LN through restoring of morphology and attenuation of oxidative stress and inflammation through a pathway that inhibited activation of NLRP3 inflammasome signaling. Our data clearly demonstrate that melatonin has protective activity on lupus nephritis in these mice that is highly associated with its effect on enhancing the Nrf2 antioxidant signaling pathway and decreasing renal NLRP3 inflammasome activation.

Renal tubular acidosis type IV as a complication of lupus nephritis.

Renal tubular acidosis (RTA) is a rare complication of renal involvement of systemic lupus erythematosus (SLE). We describe a 24-year-old male with type IV lupus nephropathy as a presenting manifestation of SLE. He presented with improvement of renal function following induction therapy with three pulses of methylprednisolone and 500 mg biweekly pulses of cyclophosphamide. However, a week after the first pulse of cyclophosphamide, the patient presented with a significant increase in legs edema and severe hyperkalemia. Type IV RTA associated with hyporeninemic hypoaldosteronism was suspected in the presence of metabolic acidosis with a normal anion gap, severe hyperkalemia without worsening renal function, and urinary pH of 5. RTA was confirmed with a transtubular potassium concentration gradient of 2 and low levels of plasma aldosterone, renin, angiotensin II, and cortisol. Intravenous bicarbonate, high-dose furosemide, and fludrocortisone were administered with normalization of potassium levels and renal function.

Filter membrane-based automated therapeutic plasma exchange: a report of two cases from Nigeria.

These case reports demonstrated the diagnostic dilemma encountered in patients with systemic lupus erythematosus and thrombotic thrombocytopenic purpura particularly in settings with limited diagnostic facilities and laboratory support. The similarities in the diagnostic criteria for both conditions make clear distinction as well as management decisions difficult. We present the difficulties encountered with both the diagnosis and the management of these two patients that were managed in our facility.

Advances in the treatment of lupus nephritis.

Systemic lupus erythematosus (SLE) is an autoimmune disease that leads to the formation and deposition of immune complexes throughout the body, which are pathogenic for the disease. Different forms of glomerulonephritis can occur in patients with SLE and can contribute significantly to the associated morbidity and, ultimately, mortality from the disease. Over the past two decades, there have been significant strides in our understanding of the disease and in treatments that attempt to control the formation and deposition of anti-DNA auto-antibodies and immune complexes, as well as the subsequent inflammatory cascade mediated through various cellular and humoral pathways leading to progressive renal damage and end-stage renal disease. In this chapter, we review the current understanding of the pathogenesis and treatment of lupus nephritis in its various stages and discuss the experimental and human data regarding some of the potential newer forms of therapy. We discuss data regarding the use of steroids, azathioprine, cyclophosphamide, cyclosporine A, mycophenolate mofetil, gammaglobulin, plasmapheresis, LJP 394, flaxseed oil, bindarit, anti-CD40 ligand, and CTLA4Ig.

Factors associated with refractory renal disease in patients with systemic lupus erythematosus: the role of patient nonadherence.

OBJECTIVE: To assess the prevalence and underlying reasons for the development of chronic renal insufficiency (CRI) in patients with systemic lupus erythematosus (SLE) seen over a 3-year period in our lupus clinic, in particular to determine the frequency and types of patient-dependent factors that were associated with nonadherence when it occurred. METHODS: We determined the frequency and types of patient-dependent factors that were associated with the development of CRI in patients with SLE. CRI was defined as a serum creatinine level > or = 200 mumol/l for at least 6 months. RESULTS: Of the 462 patients followed at the lupus clinic between 1995 and 1998, 17 patients developed CRI. Patient-related factors were deemed to be the major reason for the development of CRI in 5 of these. Three of the 5 patients were nonwhite, and the 2 patients who were white were new immigrants. All 5 patients were reluctant to take high-dose corticosteroids because of potential adverse effects. Financial problems contributed to nonadherence in 2 cases. Two patients refused to continue steroids and immunosuppressive therapy and chose to use "alternative" medications as their sole therapy. Of these 5 patients, 3 are now on long-term renal replacement therapy, 1 has died, and 1 patient continues to be followed with a serum creatinine level of 250 mumol/l. CONCLUSION: There is a need for an educational program based on patients' cultural background in order to enhance patients' understanding of the aims, risks, and benefits of therapy in SLE.

Dietary omega-3 lipids delay the onset and progression of autoimmune lupus nephritis by inhibiting transforming growth factor beta mRNA and protein expression.

The present study was carried out to test whether transforming growth factor beta (TGF beta) plays a pathological role in the induction or progression of glomerulonephritis in a murine model of systemic lupus erythematosus (SLE), and whether dietary supplementation with fish oil (FO) can modulate the expression of TGF beta. Weanling female (NZB x NZW) F1 (B/W) mice were divided into three groups. One group was fed an unmanipulated diet (lab. chow; LC) and the other two groups were fed a nutritionally adequate semipurified diet supplemented with 10% CO or FO. Both water and food were provided ad libitum. Proteinuria and serum anti-dsDNA antibody levels were measured to assess disease progression. Mice were killed at 3.5 and 6.5 months of age and renal mRNA levels for TGF beta isoforms, fibronectin-1 (FN-1) and intercellular adhesion molecule-1 (ICAM-1) were studied by Northern blot analysis. TGF beta 1 protein levels were also examined in kidneys by Western blot analysis. Our results indicate that at 3.5 months of age, when urinary protein levels were undetectable and very low levels of anti-dsDNA were detected, no mRNA signal could be detected for TGF beta isoforms, ICAM-1 and FN-1 in either dietary group. However, at 6.5 months, the FO-fed mice, compared to LC and CO, had [1] greatly reduced proteinuria (LC: 2-3+, CO: 2-3+; FO: trace -1+) and serum anti-dsDNA antibodies; [2] improved survival (CO: 100% death (15/15) occurred by 8 months; FO: 50% were alive at 12 months (8/15) and [3] reduced renal TGF beta 1 mRNA and protein levels. TGF beta 2 and beta 3 were not significantly affected by FO diet. Similarly, lower levels of renal FN-1 and ICAM-1 mRNA were observed in FO fed mice. These data indicate that in B/W mice on a FO diet, prolonged survival and amelioration of renal disease may be attributed at least in part to lower levels of TGF beta 1 mRNA and protein in the kidneys.

[Image analysis for intercellular adhesion molecule-1 expression in MRI/lpr mice: effects of Chinese herb medicine].

To clarify the role of intercellular adhesion molecule-1 (ICAM-1) on pathogenesis of autoimmune lupus nephritis in MRL/lpr mice and the effects of Chinese herb medicine (stragalin), a computer image analysis system was used to study immunodepositions of ICAM-1, immunoglobulins and C3 in renal tissue sections of the mice. ICAM-1 was found in the mesangial area and deposited along the glomerular capillary walls in MRL/lpr mice. The distribution intensity of ICAM-1, immunoglobulins and C3 were significantly decreased after treatment with stragalin in form of decoction per os in the mice. We found that ICAM-1 might play an important role in pathogenesis of autoimmune lupus nephritis in MRL/lpr mice and Chinese herb medicine has some inhibition effects on immunodepositions in renal tissue of MRL/lpr mice.

Nefritis lúpica / Lupus nephritis

El conocimiento actual y nuestra propia experiencia sobre las alteraciones clínicas, inmunológicas y patológicas de la nefritis lúpica conduce a la formulación de las siguientes conclusiones: aproximadamente la mitad de los enfermos con LES desarrollaron en algún momento de su evolución evidencias clínicas de compromiso renal, el que fue la causa de muerte en un 40 por ciento de esos casos. La presencia de alteraciones de la función y el sedimento renal no es siempre indicativa del tipo histológico de lesión renal . Por lo tanto la biopsia renal es hasta el presente un método necesario para la detección y clasificación de la nefritis lúpica en sus distintos tipos: proliferativa difusa, proliferativa focal o membranosa. Esta identificación tiene implicancias pronósticas y terapéuticas; en esta como en otras series la forma difusa fue la de peor pronóstico. Sin embargo, en oportunidades la NLP focal puede evolucionar a NLP difusa. No hemos observado correlación entre el tipo y distribución de los depósitos de inmunoglobulinas y complemento por inmunofluorescencia directa con el tipo histológico de nefritis, sin embargo la intensidad de esos depósitos tuvo cierta relación con la actividad de la lesión renal. La investigación seriada de anticuerpos anti-DNA y de niveles de complemento sérico más que de valor diagnóstico de nefritis es de utilidad en el seguimiento de la misma como parámetro del grado de actividad. La detección de anticuerpos anti-DNA y/o hipocomplementemia en un enfermo con LES no son en nuestra experiencia, elementos suficientes que permitan vaticinar, como ha sido postulado, el desarrollo de nefritis y no justifican por lo tanto una conducta terapéutica más agresiva. El agregado de agentes citotóxicos al esquema terapéutico habitual con corticoesteroides de la nefritis lúpica, continúa siendo motivo de controversia.

Nefritis lúpica / Lupus nephritis

El conocimiento actual y nuestra propia experiencia sobre las alteraciones clínicas, inmunológicas y patológicas de la nefritis lúpica conduce a la formulación de las siguientes conclusiones: aproximadamente la mitad de los enfermos con LES desarrollaron en algún momento de su evolución evidencias clínicas de compromiso renal, el que fue la causa de muerte en un 40 por ciento de esos casos. La presencia de alteraciones de la función y el sedimento renal no es siempre indicativa del tipo histológico de lesión renal . Por lo tanto la biopsia renal es hasta el presente un método necesario para la detección y clasificación de la nefritis lúpica en sus distintos tipos: proliferativa difusa, proliferativa focal o membranosa. Esta identificación tiene implicancias pronósticas y terapéuticas; en esta como en otras series la forma difusa fue la de peor pronóstico. Sin embargo, en oportunidades la NLP focal puede evolucionar a NLP difusa. No hemos observado correlación entre el tipo y distribución de los depósitos de inmunoglobulinas y complemento por inmunofluorescencia directa con el tipo histológico de nefritis, sin embargo la intensidad de esos depósitos tuvo cierta relación con la actividad de la lesión renal. La investigación seriada de anticuerpos anti-DNA y de niveles de complemento sérico más que de valor diagnóstico de nefritis es de utilidad en el seguimiento de la misma como parámetro del grado de actividad. La detección de anticuerpos anti-DNA y/o hipocomplementemia en un enfermo con LES no son en nuestra experiencia, elementos suficientes que permitan vaticinar, como ha sido postulado, el desarrollo de nefritis y no justifican por lo tanto una conducta terapéutica más agresiva. El agregado de agentes citotóxicos al esquema terapéutico habitual con corticoesteroides de la nefritis lúpica, continúa siendo motivo de controversia. (AU)