Protein arginine methyltransferase 5 (PRMT5) is an emerging epigenetic enzyme that mainly represses transcription of target genes via symmetric dimethylation of arginine residues on histones H4R3, H3R8 and H2AR3. Accumulating evidence suggests that PRMT5 may function as an oncogene to drive cancer cell growth by epigenetic inactivation of several tumor suppressors. Here we provide evidence that PRMT5 promotes prostate cancer cell growth by epigenetically activating transcription of the androgen receptor (AR) in prostate cancer cells. Knockdown of PRMT5 or inhibition of PRMT5 by a specific inhibitor reduces the expression of AR and suppresses the growth of multiple AR-positive, but not AR-negative, prostate cancer cells. Significantly, knockdown of PRMT5 in AR-positive LNCaP cells completely suppresses the growth of xenograft tumors in mice. Molecular analysis reveals that PRMT5 binds to the proximate promoter region of the AR gene and contributes mainly to the enriched symmetric dimethylation of H4R3 in the same region. Mechanistically, PRMT5 is recruited to the AR promoter by its interaction with Sp1, the major transcription factor responsible for AR transcription, and forms a complex with Brg1, an ATP-dependent chromatin remodeler, on the proximate promoter region of the AR gene. Furthermore, PRMT5 expression in prostate cancer tissues is significantly higher than that in benign prostatic hyperplasia tissues, and PRMT5 expression correlates positively with AR expression at both the protein and mRNA levels. Taken together, our results identify PRMT5 as a novel epigenetic activator of AR in prostate cancer. Given that inhibiting AR transcriptional activity or androgen synthesis remains the major mechanism of action for most existing anti-androgen agents, our findings also raise an interesting possibility that targeting PRMT5 may represent a novel approach for prostate cancer treatment by eliminating AR expression.

We retrospectively analyzed the clinicopathologic characteristics and prognosis of 33 patients with diffuse proliferative lupus nephritis (class IV LN) complicated with thrombotic microangiopathy (TMA). Eighty-one percent of patients had renal dysfunction (mean Scr 3.1 ± 2.0 mg/dl), among whom 42.4% needed acute hemodialysis. Nephrotic proteinuria, gross hematuria and hypertension were presented in 57.6%, 24.2% and 93.9% of the patients. Microangiopathic hemolytic anemia, serum anti-dsDNA and anticardiolipin antibodies were found in 60.6%, 75.8% and 33.3% of the patients. Renal biopsy showed IV-G in 75.8%, class IV with class V in 21.2%, and IV-S in 1.23% of the patients. Glomerular segmental necrosis, microthrombi, crescents and arteriolar thrombosis were found in 51.5%, 69.7%, 60.6% and 60.7% of the patients, respectively. The follow up was 1 to 101 months (median 13 months). Only 50% of patients showed response to treatment. Three patients died, 10 developed end-stage renal failure (ESRF). The 5-year patient and renal survival rate was 69.2% and 46.7%, respectively. Major risks for ESRF included: a need for acute dialysis on admission, no response to the treatment and high renal chronic index. The results showed that class IV lupus nephritis with TMA has high mortality and low renal survival.

Cadmium, a heavy metal, is a toxic environmental and industrial pollutant. Exposure to cadmium can lead to the toxic effects in a variety of tissues, also including the brain. The present study investigated the effect of cadmium exposure on the histopathology of cerebral cortex in juvenile mice. Juvenile mice were randomly divided into control, low (1.87 mg/kg), medium (3.74 mg/kg), and high (7.48 mg/kg) dose groups. After cadmium exposure by drinking water for 10 days, the cerebral cortex was obtained for histopathology studies. The medium and high dose of cadmium, rather than low dose, could induce the histopathology alterations of cerebral cortex in a dose-dependent manner. In the high-dose group, microstructure significantly showed pia mater encephali divorcing from cerebral cortex layer, serious hyperemia of blood capillary in pia mater encephali and cerebral cortex, broadening vessel peripheral clearance, a large number of eosinophil leukocyte infiltrating around blood vessel, vacuolar degeneration in part granule cells, and obviously increasing apoptotic cells. Ultrastructure obviously displayed marginalized heterochromatin, incomplete or fused nuclear membranes, broadened perinuclear space, ambiguous mitochondria cristae, decreased synaptic cleft, and fused presynaptic and postsynaptic membrane. Our results revealed that cadmium at the middle and high dose could induce obvious microstructure and ultrastructure alterations of cerebral cortex in juvenile mice, which may be one important mechanism of cadmium neurotoxicity.

This study aimed to analyze the clinicopathological characteristics of familial SLE patients with lupus nephritis (LN). A total of 136 Chinese patients with lupus nephritis diagnosed by renal biopsy, including 34 familial patients and 102 sporadic cases, were recruited. Their demographic information, age of onset, disease duration, clinical features, laboratory data and histological manifestations were compared. The first-degree relatives (17 sibling cases and eight parent-offspring cases) of familial SLE patients were primarily affected. The prevalence of fever, rash and arthritis in familial subjects was higher than that in sporadic subjects. Familial patients had lower platelet counts and higher low-density lipoprotein. In familial patients, class V lupus nephritis was less common. After adjusted with the Benjamini and Hochberg procedure, however, fever was the only feature occurring significantly and more frequently in familial patients (58.8% vs 26.5%, P = 0.001). Moreover, SLEDAI and other clinicopathological features did not differ significantly between the two groups. Multivariate analysis showed that a higher prevalence of fever was an independent predictor of familial SLE. Most clinicopathological features in familial SLE patients were not significantly different from those in sporadic patients; the severity of LN in familial SLE patients was similar to that of sporadic cases. Thus, familial SLE may not be a different clinical entity.