Since it was first described in 1968, immunoglobulin (Ig)A nephropathy (IgAN) has become the most commonly diagnosed form of primary glomerular disease worldwide. A number of reports have shown that toll‑like receptor 9 (TLR9) and B‑cell activating factor (BAFF) may be associated with IgAN; however, sufficient evidence has not yet to be delivered. In the present study, serum levels of BAFF as well as TLR9 mRNA and protein levels in peripheral blood mononuclear cells (PBMCs) were assessed. Expression of TLR9 mRNA in PBMCs was examined by quantitative polymerase chain reaction and the TLR9 protein was determined by western blot analysis. The levels of serum BAFF and IgA1 were determined by specific ELISA. Serum levels of BAFF and IgA1 as well as levels of TLR9 mRNA and protein in PMBCs were significantly higher in patients with IgAN compared with patients with minimal glomerular abnormalities (P<0.05, P<0.01, P<0.01 and P<0.01, respectively) and normal controls (P<0.01, P<0.01, P<0.05 and P<0.01, respectively). A correlation and regression analysis was performed to determine the pathogenesis of IgAN. In patients with IgAN, serum levels of BAFF were positively correlated with IgA1 levels (rp, 0.515; P<0.01) and mesangial IgA deposition density (rp, 0.746; P<0.01). Expression levels of TLR9 protein in PBMCs of IgAN patients were positively correlated with levels of serum BAFF (rp, 0.444; P<0.05) and IgA1 (rp, 0.633; P<0.01). These results suggested that overexpression of TLR9 mRNA and protein in PBMCs and elevated levels of serum BAFF may be associated with overexpression of serum IgA1, and, furthermore, may have a role in the development of IgAN.

Nitroalkene derivatives of linoleic acid (nitrolinoleic acid; LNO2) and nitro-oleic acid (OA-NO2) are endogenous lipid products with potent anti-inflammatory properties. The present study was undertaken to evaluate the therapeutic potential of OA-NO2 in a mouse model of renal ischemia-reperfusion (I/R) injury. B6129SF2/J mice were subjected to bilateral renal ischemia for 30 min, followed by 24 h of reperfusion. Fifty minutes after ischemia, mice received intraperitoneal (ip) injections of OA-NO2 (500 microg/kg; I/R OA-NO2), vehicle for OA-NO2 (i.e., 0.8 ml/kg ethanol; I/R veh), or oleic acid (500 microg/kg; I/R OA) every 6 h during the 24-h recovery period. A sham-operated group was not subjected to ischemia and received 0.8 ml/kg ethanol ip every 6 h during the 24-h recovery period (sham veh). While plasma urea and creatinine were elevated (P<0.05) in I/R veh vs. sham veh mice, the severity was less (P<0.05) in I/R OA-NO2 animals. Indices of histological damage, polymorphonucleocyte infiltration, together with expression of intracellular adhesion molecule-1, interleukin-1beta, and tumor necrosis factor-alpha, p47(phox), and gp91(phox) were greater in I/R veh vs. sham veh mice, but were attenuated (P<0.05) in I/R OA-NO2 animals. Because indices of renal dysfunction were similar between I/R veh and I/R OA mice (P>0.05), but less (P<0.05) in I/R OA-NO2 animals compared with both groups, protection from bilateral renal ischemia is afforded by the nitrated but not free form of oleic acid. Together, delayed administration of nitrated fatty acid OA-NO2 attenuates renal I/R injury in the mouse likely via inhibition of the inflammatory response.

Heat shock factor 1 (HSF1) is associated with tissue-specific tumorigenesis in a number of mouse models, and has been used a as prognostic marker of cancer types, including breast and prostatic cancer. However, its role in human hepatocellular carcinoma (HCC) is not well understood. Using immunoblotting and immunohistochemical staining, it was identified that HSF1 and its serine (S) 326 phosphorylation, a biomarker of HSF1 activation, are significantly upregulated in human HCC tissues and HCC cell lines compared with their normal counterparts. Cohort analyses indicated that upregulation of the expression of HSF1 and its phospho-S326 is significantly correlated with HCC progression, invasion and patient survival prognosis (P<0.001); however, not in the presence of a hepatitis B virus infection and the expression of alpha-fetoprotein and carcinoembryonic antigen. Knockdown of HSF1 with shRNA induced the protein expression of tumor suppressor retinoblastoma protein, resulting in attenuated plc/prf5 cell growth and colony formation in vitro. Taken together, these data markedly support that HSF1 is a potential prognostic marker and therapeutic target for the treatment of HCC.

Hsf4b, a key regulator of postnatal lens development, is subjected to posttranslational modifications including phosphorylation. However, the phosphorylation sites in Hsf4b and their biological effects on the transcription activity of Hsf4b are poorly understood. Here we examined 17 potential phosphorylation residues in Hsf4b with alanine-scanning assays and found that a T472A mutation diminished Hsf4b-mediated expression of Hsp25 and alphaB-crystallin. In contrast, the phosphomimetic mutation of T472D enhanced their expression. Further investigation demonstrated that Hsf4b could interact with nuclear-transporter importin beta-1 and Hsc70 via amino acids 246-320 and 320-493, respectively. T472A mutation reduced Hsf4bs interaction with importin beta-1, while enhancing its interaction with Hsc7O, resulting in Hsf4b cytosolic re-localization, protein instability and transcription activity attenuation. At the upstream, MEK6 was found to interact with Hsf4b and enhance Hsf4b's nuclear translocation and transcription activity, probably by phosphorylation at sites such as T472. Taken together, our results suggest that phosphotylation of Hsf4b at T472 by protein kinases such as MEI(6 regulates Hsf4b interaction with the importin V I -Hsc7O complex, resulting in blockade of its nuclear translocation and transcriptional activity of Hsf4b.