A rare case of pediatric recurrent rhabdomyolysis with compound heterogenous variants in the LPIN1.

BACKGROUND: Lipin-1, encoded by LPIN1 gene, serves as an enzyme and a transcriptional co-regulator to regulate lipid metabolism and mitochondrial respiratory chain. Autosomal recessive mutations in LPIN1 were recognized as one of the most common causes of pediatric recurrent rhabdomyolysis in western countries. However, to date, there were only a few cases reported in Asian group. This study aims to report the first pediatric case of recurrent rhabdomyolysis with a novel LPIN1 mutation in China mainland in order to raise the awareness of both pediatricians and patients. CASE PRESENTATIONS: Here we report a Chinese pediatric case of recurrent rhabdomyolysis with compound heterozygous variants (p.Arg388* and p.Arg810Cys) in the LPIN1 gene. The c.2428C > T was a novel missense variant involved Arg-to-Cys substitution at position 810 (p.Arg810Cys), located in the highly conserved region which predicted to be damaging by multiple algorithms. The patient manifested as cola-colored urine, muscle weakness and tenderness, as well as acute kidney injury with peak blood creatine kinase level 109,570 U/l in 19-month old. In his second episode of 9 years old, the symtoms were relatively milder with peak creatine kinase level 50,948 U/l. He enjoyed quite normal life between the bouts but slightly elevation of serum creatine kinase level during the fever or long-term exercises. Prolonged weight training combined with calorie deprivation were speculated to be the triggers of his illness. Prompt symptomatic therapy including fluid therapy and nutritional support was given and the patient recovered soon. CONCLUSIONS: LPIN1-related rhabdomyolysis is still quite new to physicians due to its seemly low-incidence especially in Asian countries. In the future, more active genetic test strategy and detailed prophylactic care education should be taken in patients with severe recurrent rhabdomyolysis, who are the high risk group of LPIN1 genetic defects.

[Corrigendum] IL­8 promotes proliferation and inhibition of apoptosis via STAT3/AKT/NF­κB pathway in prostate cancer.

After the publication of the above article, the authors have realized that the paper contained two errors concerning the address where the tissue samples were collected from and one of the subtitles in the Materials and methods section. First, on p. .9036, the Materials and methods section, "Tissue samples", in the first sentence it should have been stated that the tissues were collected from the Department of Urology, Nanjing Integrated Traditional Chinese and Western Medicine Hospital Affiliated with Nanjing University of Chinese Medicine (not the Gynecology Department, Children's Hospital of Nanjing Medical University). Secondly, the title of the third subsection of the Materials and methods should have read as "Treatment with IL­8 of prostate cancer cell lines" (not "panceatic"). The authors regret that these errors were allowed to remain in their paper, and apologize for any inconvenience caused. [the original article was published in Molecular Medicine Reports 16: 9035­9042, 2017; DOI: 10.3892/mmr.2017.7747].

IL­8 promotes proliferation and inhibition of apoptosis via STAT3/AKT/NF­κB pathway in prostate cancer.

Interleukin-8 (IL-8) possesses tumorigenic and proangiogenic properties, and is overexpressed in many human cancer types. However, only few studies have demonstrated the mechanisms of action of IL­8 regarding the ability to promote proliferation and to inhibit apoptosis in prostate cancer. Here, the aim of the present study was to investigate the effects of IL­8 on the prostate cancer cell line and determine possible mechanisms underlying its effect. In this study, IL­8 was shown to be significantly upregulated in prostate cancer compared with paired normal control tissues. The data showed that IL­8 exhibits direct oncogenicity, which significantly induced cell proliferation, invasion and attenuated apoptosis in prostate cancer cells via signal transducer and activator of transcription 3/protein kinase B/nuclear factor­κB signaling pathways. In conclusion, modulation of IL­8 expression or its associated signaling pathway may provide a novel working mechanism of IL­8 in prostate cancer, and a promising strategy for controlling the progression and metastasis of prostate cancer.

Activation of ERK1/2 by NADPH oxidase-originated reactive oxygen species mediates uric acid-induced mesangial cell proliferation.

Hyperuricemia is associated with kidney complications including glomerulosclerosis and mesangial cell (MC) proliferation by poorly understood mechanisms. The present study investigated the underlying mechanisms that mediate uric acid (UA)-induced MC proliferation. A rat MC line, HBZY-1, was treated with various concentrations of UA in the presence or absence of a specific extracellular-regulated protein kinase 1/2 (ERK1/2) inhibitor (U0126), apocynin. UA dose dependently stimulated MC proliferation as shown by increased DNA synthesis and number of cells in the S and G2 phases in parallel with the upregulation of cyclin A2 and cyclin D1. In addition, UA time dependently promoted MC proliferation and significantly increased phosphorylation of ERK1/2 but not c-Jun NH2-terminal kinase and p38 MAPK in MCs as assessed by immunoblotting. Inhibition of ERK1/2 signaling via U0126 markedly blocked UA-induced MC proliferation. More importantly, UA induced intracellular reactive oxygen species (ROS) production of MCs dose dependently, which was completely blocked by apocynin, a specific NADPH oxidase inhibitor. Toll-like receptor (TLR)2 and TLR4 signaling had no effect on NADPH-derived ROS and UA-induced MC proliferation. Interestingly, pretreatment with apocynin inhibited ERK1/2 activation, the upregulation of cyclin A2 and cyclin D1, and MC proliferation. In conclusion, UA-induced MC proliferation was mediated by NADPH/ROS/ERK1/2 signaling pathway. This novel finding not only reveals the mechanism of UA-induced MC cell proliferation but also provides some potential targets for future treatment of UA-related glomerular injury.

Over-expressing transient receptor potential cation channel 6 in podocytes induces cytoskeleton rearrangement through increases of intracellular Ca2+ and RhoA activation.

Transient receptor potential cation channel 6 (TRPC6) is one of the key molecules for filtration barrier function of podocytes. Over-expression of TRPC6 in podocytes is frequently found in acquired or inherited proteinuric kidney diseases, and animal model over-expression of TRPC6 may lead to proteinuria. To investigate the impact of TRPC6 over-expression in podocytes on its function and its relation to proteinuria in kidney diseases, we over-expressed TRPC6 in mouse podocytes by transient transfection of TRPC6 cDNA plasmid, and observed their changes in foot processes, intracellular F-actin distribution, nephrin and synaptopodin expression, electrophysiology, RhoA activity and intracellular Ca(2+). In podocytes over-expressing TRPC6, cell processes were reduced remarkably in association with the derangement of cytoskeleton demonstrated by the abnormal distribution of intracellular F-actin. These cells also displayed a higher increase of intracellular Ca(2+) ion to the TRPC6 agonist 1-oleoyl-acetyl-sn-glycerol and a higher current in the patch-clamp experiment, down-regulation of nephrin and synaptopodin expression and increase of activated RhoA. These changes could be rescued by the treatment of the cells with U73122 to block TRPC6 channel or BAPTA-AM to chelate intracellular Ca(2+) ion. Additionally, the podocytes over-expressing TRPC6 treated with RhoA inhibitor Y-27632 showed an improvement in F-actin arrangement in the cells and increase of nephrin and synaptopodin expression. From these results, we therefore propose that over-expression of TRPC6 in podocytes may be one of the fundamental changes relating to the dysfunction of the slit diaphragm and proteinuria. Podocytes over-expressing TRPC6 may lead to higher intracellular Ca(2+) ion concentration in the presence of stimuli. The increase of intracellular Ca(2+) down-regulates the expression of two important molecules, nephrin on slit diaphragm and synaptopodin in cytoskeleton, and stimulates RhoA activity, which in turn causes F-actin derangement and the decrease of foot processes.

Y-box protein 1 stimulates mesangial cell proliferation via activation of ERK1/2.

AIMS: To investigate the effects of Y-box protein 1 (YB-1) on the mitogen-activated protein kinase pathway to ascertain which signaling pathway is involved in YB-1-induced mesangial cell (MC) proliferation. METHODS: The rat MC line HBZY-1 was transfected with pcDNA3.1-YB-1. Cell proliferation was determined by [(3)H]thymidine incorporation, cell counting and cell-cycle analysis. The expression of cyclins was examined by real-time RT-PCR and immunoblotting analysis. Phosphorylation of c-Raf, MEK1/2, and ERK1/2 was detected by immunoblotting analysis. RESULTS: MCs transfected with YB-1 showed an increased DNA synthesis and number of cells in the S and G2 phases of the cell cycle. The expression of cyclins (cyclin A2, cyclin D1, cyclin E and p27) was increased, while p21 levels were decreased. The expression levels of phosphorylated c-Raf kinase, MEK1/2 and the ERK1/2 proteins were elevated in MCs transfected with YB-1. YB-1-stimulated cell proliferation was blocked by U0126, a specific inhibitor of ERK1/2. ERK1/2 regulated YB-1 expression in MCs stimulated with TGF-beta, an effect that was inhibited by U0126. CONCLUSIONS: YB-1 has an apparent stimulatory effect on c-Raf, MEK1/2, ERK1/2 and cell-cycle progression in MCs, after which activated ERK1/2 goes on to upregulate YB-1 expression and augment the proliferative effect of YB-1.