NSC828779 Alleviates Renal Tubulointerstitial Lesions Involving Interleukin-36 Signaling in Mice.

Renal tubulointerstitial lesions (TILs), a common pathologic hallmark of chronic kidney disease that evolves to end-stage renal disease, is characterized by progressive inflammation and pronounced fibrosis of the kidney. However, current therapeutic approaches to treat these lesions remain largely ineffectual. Previously, we demonstrated that elevated IL-36α levels in human renal tissue and urine are implicated in impaired renal function, and IL-36 signaling enhances activation of NLRP3 inflammasome in a mouse model of TILs.

Cf-02, a novel benzamide-linked small molecule, blunts NF-κB activation and NLRP3 inflammasome assembly and improves acute onset of accelerated and severe lupus nephritis in mice.

In the present study, acute onset of severe lupus nephritis was successfully treated in mice using a new, benzamide-linked, small molecule that targets immune modulation and the NLRP3 inflammasome. Specifically, 6-(2,4-difluorophenyl)-3-(3-(trifluoromethyl)phenyl)-2H-benzo[e][1,3]oxazine-2,4(3H)-dione (Cf-02) (a) reduced serum levels of IgG anti-dsDNA, IL-1β, IL-6, and TNF-α, (b) inhibited activation of dendritic cells and differentially regulated T cell functions, and (c) suppressed the NF-κB/NLRP3 inflammasome axis, targeting priming and activating signals of the inflammasome. Moreover, treatment with Cf-02 significantly inhibited secretion of IL-1β in lipopolysaccharide-stimulated macrophages, but this effect was abolished by autophagy induction.

LCC18, a benzamide-linked small molecule, ameliorates IgA nephropathy in mice.

IgA nephropathy (IgAN), an immune complex-mediated process and the most common primary glomerulonephritis, can progress to end-stage renal disease in up to 40% of patients. Accordingly, a therapeutic strategy targeting a specific molecular pathway is urgently warranted. Aided by structure characterisation and target identification, we predicted that a novel ring-fused 6-(2,4-difluorophenyl)-3-(3-(trifluoromethyl)phenyl)-2H-benzo[e][1,3]oxazine-2,4(3H)-dione (LCC18) targets the NLRP3 inflammasome, which participates in IgAN pathogenesis.

Tris DBA ameliorates IgA nephropathy by blunting the activating signal of NLRP3 inflammasome through SIRT1- and SIRT3-mediated autophagy induction.

Tris (dibenzylideneacetone) dipalladium (Tris DBA), a small-molecule palladium complex, can inhibit cell growth and proliferation in pancreatic cancer, lymphocytic leukaemia and multiple myeloma. Given that this compound is particularly active against B-cell malignancies, we have been suggested that it can alleviate immune complexes (ICs)-mediated conditions, especially IgA nephropathy (IgAN). The therapeutic effects of Tris DBA on glomerular cell proliferation and renal inflammation and mechanism of action were examined in a mouse model of IgAN.

Accelerated, severe lupus nephritis benefits from treatment with honokiol by immunoregulation and differentially regulating NF-κB/NLRP3 inflammasome and sirtuin 1/autophagy axis.

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.

IgA Nephropathy Benefits from Compound K Treatment by Inhibiting NF-κB/NLRP3 Inflammasome and Enhancing Autophagy and SIRT1.

IgA nephropathy (IgAN), the most common primary glomerular disorder, has a relatively poor prognosis yet lacks a pathogenesis-based treatment. Compound K (CK) is a major absorbable intestinal bacterial metabolite of ginsenosides, which are bioactive components of ginseng. The present study revealed promising therapeutic effects of CK in two complementary IgAN models: a passively induced one developed by repeated injections of IgA immune complexes and a spontaneously occurring model of spontaneous grouped ddY mice.

Tris DBA Ameliorates Accelerated and Severe Lupus Nephritis in Mice by Activating Regulatory T Cells and Autophagy and Inhibiting the NLRP3 Inflammasome.

Tris (dibenzylideneacetone) dipalladium (Tris DBA), a small-molecule palladium complex, has been shown to inhibit cell growth and proliferation in pancreatic cancer, lymphocytic leukemia, and multiple myeloma. In the current study, we examined the therapeutic effects of Tris DBA on glomerular cell proliferation, renal inflammation, and immune cells. Treatment of accelerated and severe lupus nephritis (ASLN) mice with Tris DBA resulted in improved renal function, albuminuria, and pathology, including measurements of glomerular cell proliferation, cellular crescents, neutrophils, fibrinoid necrosis, and tubulointerstitial inflammation in the kidneys as well as scoring for glomerulonephritis activity.

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.