60 research outputs found
Mycophenolate mofetil as maintenance therapy for proliferative lupus nephritis: a long-term observational prospective study
Epigenetic expansion of VHL-HIF signal output drives multiorgan metastasis in renal cancer.
Inactivation of the von Hippel-Lindau tumor suppressor gene, VHL, is an archetypical tumor-initiating event in clear cell renal carcinoma (ccRCC) that leads to the activation of hypoxia-inducible transcription factors (HIFs). However, VHL mutation status in ccRCC is not correlated with clinical outcome. Here we show that during ccRCC progression, cancer cells exploit diverse epigenetic alterations to empower a branch of the VHL-HIF pathway for metastasis, and the strength of this activation is associated with poor clinical outcome. By analyzing metastatic subpopulations of VHL-deficient ccRCC cells, we discovered an epigenetically altered VHL-HIF response that is specific to metastatic ccRCC. Focusing on the two most prominent pro-metastatic VHL-HIF target genes, we show that loss of Polycomb repressive complex 2 (PRC2)-dependent histone H3 Lys27 trimethylation (H3K27me3) activates HIF-driven chemokine (C-X-C motif) receptor 4 (CXCR4) expression in support of chemotactic cell invasion, whereas loss of DNA methylation enables HIF-driven cytohesin 1 interacting protein (CYTIP) expression to protect cancer cells from death cytokine signals. Thus, metastasis in ccRCC is based on an epigenetically expanded output of the tumor-initiating pathway
Potent and selective chemical probe of hypoxic signaling downstream of HIF-α hydroxylation via VHL inhibition
Chemical strategies to using small molecules to stimulate hypoxia inducible factors (HIFs) activity and trigger a hypoxic response under normoxic conditions, such as iron chelators and inhibitors of prolyl hydroxylase domain (PHD) enzymes, have broad-spectrum activities and off-target effects. Here we disclose VH298, a potent VHL inhibitor that stabilizes HIF-α and elicits a hypoxic response via a different mechanism, that is the blockade of the VHL:HIF-α protein-protein interaction downstream of HIF-α hydroxylation by PHD enzymes. We show that VH298 engages with high affinity and specificity with VHL as its only major cellular target, leading to selective on-target accumulation of hydroxylated HIF-α in a concentration- and time-dependent fashion in different cell lines, with subsequent upregulation of HIF-target genes at both mRNA and protein levels. VH298 represents a high-quality chemical probe of the HIF signalling cascade and an attractive starting point to the development of potential new therapeutics targeting hypoxia signalling
Lupus nephritis: treatment with mycophenolate mofetil
Objective. To evaluate the safety and efficacy of mycophenolate mofetil
(MMF) treatment in patients with lupus nephritis.
Methods. Eighteen patients with biopsy-proven lupus nephritis (17
females, one male; mean age 31.6 yr; mean lupus duration 92 months; mean
duration of nephritis 57 months; nine with focal proliferative
glomerulonephritis, three with diffuse proliferative glomerulonephritis,
six with membranous nephropathy) were included. With five exceptions,
all patients had been treated previously with cyclophosphamide and were
selected because of either toxicity or inadequate clinical response to
treatment. MMF was given at 2 g daily in combination with steroids for
up to 31months (mean 15.3 months). The side-effects of MMF were recorded
and efficacy was assessed as the renal function profile.
Results. Complete remission was observed in 10/18 patients and another
4/18 went into partial remission. Both creatinine clearance and
proteinuria were significantly improved during MMF treatment in patients
with the proliferative forms of nephritis. MMF demonstrated a
steroid-sparing effect in the whole population. Treatment failure was
recorded in 4/18 patients, all with membranous nephropathy. Two patients
developed gastrointestinal complaints and infectious meningitis occurred
in one patient.
Conclusion. MMF appears to be an efficacious and safe treatment in
patients with proliferative forms of lupus nephritis who do not respond
to or cannot tolerate conventional treatment. The efficacy of MMF in
lupus membranous nephropathy remains unclear
Inhibition of prolyl 4-hydroxylase decreases muscle fibrosis following chronic rotator cuff tear
Enhanced renoprotective effect of HIF-1α modified human adipose-derived stem cells on cisplatin-induced acute kidney injury in vivo
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