lignans and Lupus-Nephritis

Using honokiol (HNK), a major anti-inflammatory bioactive compound in Magnolia officinalis, we show a potent therapeutic outcome against an accelerated, severe form of lupus nephritis (ASLN). The latter may follow infectious insults that act as environmental triggers in the patients. In the current study, an ASLN model in NZB/W F1 mice was treated with HNK by daily gavage after onset of the disease. We show that HNK ameliorated the ASLN by improving renal function, albuminuria, and renal pathology, especially reducing cellular crescents, neutrophil influx, fibrinoid necrosis in glomeruli, and glomerulonephritis activity scores. Meanwhile, HNK differentially regulated T cell functions, reduced serum anti-dsDNA autoantibodies, and inhibited NLRP3 inflammasome activation in the mice. The latter involved: (a) suppressed production of reactive oxygen species and NF-κB activation-mediated priming signal of the inflammasome, (b) reduced mitochondrial damage, and (c) enhanced sirtuin 1 (SIRT1)/autophagy axis activation. In conclusion, HNK represents a new drug candidate for acute, severe episodes of LN capable of alleviating renal lesions in ASLN mice by negatively regulating T cell functions and by enhancing SIRT1/autophagy axis-lessened NLRP3 inflammasome activation.

Topics: Animals; Anti-Inflammatory Agents; Autophagy; Biphenyl Compounds; Cells, Cultured; Female; Inflammasomes; Kidney; Lignans; Lupus Nephritis; Mice; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Reactive Oxygen Species; Sirtuin 1; T-Lymphocytes

Lupus nephritis (LN) is a common complication of systemic lupus erythematosus. The present study aimed to elucidate the protective effect of magnolol (MG) on the progression of LN, via inhibition of key signaling pathways. The results of the present study demonstrated that administration of MG caused inhibition of the activation of NACHT, LRR and PYD domains‑containing protein 3 and interleukin‑1β production. Histopathological analysis confirmed that the vehicle‑treated group exhibited characteristic glomerular disease, which was observed to be suppressed following the administration of MG; a marked decrease in glomerular and vascular lesions was observed compared with the vehicle control. This decrease was further demonstrated through analysis of kidney sections. The expression level of cell surface glycoprotein F4/80 was demonstrated to be markedly decreased in the MG‑treated mice compared with the vehicle control group. The MG‑treated mice exhibited a marked decrease in serum and renal tumor necrosis factor‑α expression levels.

Topics: Animals; Anti-Arrhythmia Agents; Antibodies, Antinuclear; Biopsy; Biphenyl Compounds; Cytokines; Disease Models, Animal; Female; Histocytochemistry; Inflammasomes; Inflammation Mediators; Lignans; Lupus Nephritis; Macrophages; Mice; Mice, Inbred MRL lpr; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Signal Transduction

Flaxseed has renoprotective effects in animal and human lupus nephritis. We have recently extracted the lignan precursor (secoisolariresinol diglucoside) (SDG) to determine if this more palatable derivative of flaxseed would exert renoprotection similar to the whole flaxseed in the aggressive MRL/lpr lupus mouse model.. 131 MRL/lpr mice were randomly assigned to saline gavage, 600, 1,200 and 4,800 microg lignan gavage groups. At 7 weeks, 6 animals underwent platelet aggregating factor (PAF) lethal challenge and 40 were studied with urine collection to determine the levels of secoisolariresinol, enterodiol and enterolactone in the gavaged animals. A baseline study of 10 saline gavaged animals took place at 6 weeks. 25 animals in the saline gavage, 600 and 1200 microg lignan groups were studied at 14 and 22 weeks for GFR, spleen lymphocyte S-phase and organ weight studies.. Metabolic studies indicated that secoisolariresinol is the major metabolite absorbed and the lowest lignan dose provides a lengthening in survival for the PAF lethal challenge. Body weight, fluid and water intake studies demonstrated that the lignan was well tolerated. Changes in proteinuria, GFR and renal size showed a time- and dose-dependent protection for the lignan precursor. Cervical lymph node size and spleen lymphocyte cells in the S-phase demonstrated modest dose-dependent reductions in the lignan gavaged groups.. SDG was converted in the gut to secoisolariresinol, which was absorbed and well tolerated by the MRL/lpr mice. Renoprotection was evidenced, in a dose-dependent fashion, by a significant delay in the onset of proteinuria with preservation in GFR and renal size. This study suggests that SDG may have a therapeutic role in lupus nephritis.

Topics: 4-Butyrolactone; Animals; Blood Coagulation Factors; Flax; Humans; Lignans; Lupus Nephritis; Mice; Phytotherapy; Platelet Activating Factor; Seeds