TIPE2 and PCNP expression abnormalities in peripheral blood mononuclear cells associated with disease activity in rheumatoid arthritis: a meta-analysis.

OBJECTIVE: Rheumatoid arthritis (RA) is a prevalent chronic autoimmune disease posing a considerable burden on both individuals and society. Tumor necrosis induced protein 8-like 2 (TIPE2), closely related to PEST-containing nuclear protein (PCNP) expression, is an immune-related protein potentially involved in the pathogenesis of autoimmune diseases. In this study, we aimed to assess differential expressions of TIPE2 and PCNP in peripheral blood mononuclear cells (PBMCs) between active and inactive RA patients. MATERIALS AND METHODS: Relevant studies were selected from Medline, Google Scholar, Web of Science, and China National Knowledge Infrastructure (CNKI). Only observational studies (irrespective of publication status, language, or blinding), which compared patients in high disease activity, irrespective of the sample size, with patients in low disease activity of RA were evaluated. RESULTS: Four studies were included with 248 patients, 138 in the active group and 110 in the inactive group. Three studies provided data on TIPE2 expression levels, where 106 patients were divided into the active group and 88 patients were divided into the inactive group. The pooled analysis revealed a statistically significant difference between the two groups (WMD: 5.60; 95% CI: 5.02-6.18). Two studies provided data on PCNP expression levels, where 64 patients were divided into the active group and 44 patients were divided into the inactive group. The pooled analysis revealed a statistically significant difference between the two groups (WMD: 7.76; 95% CI: 3.09-12.43). CONCLUSIONS: The expression levels of TIPE2 and PCNP are significantly increased in PBMCs of active RA patients.

CRM1 inhibition induces tumor cell cytotoxicity and impairs osteoclastogenesis in multiple myeloma: molecular mechanisms and therapeutic implications.

The key nuclear export protein CRM1/XPO1 may represent a promising novel therapeutic target in human multiple myeloma (MM). Here we showed that chromosome region maintenance 1 (CRM1) is highly expressed in patients with MM, plasma cell leukemia cells and increased in patient cells resistant to bortezomib treatment. CRM1 expression also correlates with increased lytic bone and shorter survival. Importantly, CRM1 knockdown inhibits MM cell viability. Novel, oral, irreversible selective inhibitors of nuclear export (SINEs) targeting CRM1 (KPT-185, KPT-330) induce cytotoxicity against MM cells (ED50<200 nM), alone and cocultured with bone marrow stromal cells (BMSCs) or osteoclasts (OC). SINEs trigger nuclear accumulation of multiple CRM1 cargo tumor suppressor proteins followed by growth arrest and apoptosis in MM cells. They further block c-myc, Mcl-1, and nuclear factor κB (NF-κB) activity. SINEs induce proteasome-dependent CRM1 protein degradation; concurrently, they upregulate CRM1, p53-targeted, apoptosis-related, anti-inflammatory and stress-related gene transcripts in MM cells. In SCID mice with diffuse human MM bone lesions, SINEs show strong anti-MM activity, inhibit MM-induced bone lysis and prolong survival. Moreover, SINEs directly impair osteoclastogenesis and bone resorption via blockade of RANKL-induced NF-κB and NFATc1, with minimal impact on osteoblasts and BMSCs. These results support clinical development of SINE CRM1 antagonists to improve patient outcome in MM.

The effects of berberine on the pharmacokinetics of cyclosporin A in healthy volunteers.

The effects of berberine (BBR) on the pharmacokinetics of ciclosporin A (CsA) were examined in healthy volunteers. Six healthy male volunteers were orally treated with 0.3 g BBR, twice daily for 10 days. Pharmacokinetic investigations on CsA at 6 mg/kg were done both before and at the end of the BBR treatment period. Another six healthy male volunteers were involved in the pharmacokinetic study with 3 mg CsA/kg, in which the subjects orally received the second single dose of 3 mg CsA/kg, followed by a single oral dose of 0.3 g BBR. The blood CsA concentrations were determined by fluorescence polarization immunoassay. In the pharmacokinetic study with 6 mg CsA/kg, BBR caused no significant changes in the pharmacokinetic parameters of CsA. However, in the trial with 3 mg CsA/kg, the average percentage increase in area under the blood concentration-time curve of CsA was 19.2% (P < 0.05) and the mean C12 increased to 123 microg/l from 104 microg/l (P < 0.05), without altering elimination half-life (t(1/2)), maximum blood drug concentration (Cmax), time to Cmax (tmax), apparent oral clearance (CL/F). The present results suggest that BBR can increase the oral bioavailability of CsA at the dosage of 3 mg/kg. The BBR-mediated increase in CsA bioavailability may be partly attributed to a decrease in liver and/or intestinal metabolism through the inhibition of CYP3A4 in the liver and/or gut wall. The BBR-induced increase in emptying time of stomach and small intestine might be another reason for the increase in CsA bioavailability. However, the speculation should be proved by further investigation.