Tripterygium wilfordii Hook F. (TwHF) based therapy has been proved as effective in treating rheumatoid arthritis (RA), yet the predictors to its response remains unclear. A two-stage trial was designed to identify and verify the baseline symptomatic predictors of this therapy. 167 patients with active RA were enrolled with a 24-week TwHF based therapy treatment and the symptomatic predictors were identified in an open trial; then in a randomized clinical trial (RCT) for verification, 218 RA patients were enrolled and classified into predictor positive (P+) and predictor negative (P−) group, and were randomly assigned to accept the TwHF based therapy and Methotrexate and Sulfasalazine combination therapy (M&S) for 24 weeks, respectively. Five predictors were identified (diuresis, excessive sweating, night sweats for positive; and yellow tongue-coating, thermalgia in the joints for negative). In the RCT, The ACR 20 responses were 82.61% in TwHF/P+ group, significantly higher than that in TwHF/P− group (P = 0.0001) and in M&S/P+ group (P < 0.05), but not higher than in M&S/P− group. Similar results were yielded in ACR 50 yet not in ACR 70 response. No significant differences were detected in safety profiles among groups. The identified predictors enable the TwHF based therapy more efficiently in treating RA subpopulations.
Transforming growth factor–β1 (TGFβ1) has been identified as a major pathogenic factor underlying the development of diabetic nephropathy (DN). However, the current strategy of antagonizing TGFβ1 has failed to demonstrate favorable outcomes in clinical trials. To identify a different therapeutic approach, we designed a mass spectrometry–based DNA-protein interaction screen to find transcriptional repressors that bind to the TGFB1 promoter and identified Yin Yang 1 (YY1) as a potent repressor of TGFB1. YY1 bound directly to TGFB1 promoter regions and repressed TGFB1 transcription in human renal mesangial cells. In mouse models, YY1 was elevated in mesangial cells during early diabetic renal lesions and decreased in later stages, and knockdown of renal YY1 aggravated, whereas overexpression of YY1 attenuated glomerulosclerosis. In addition, although their duration of diabetic course was comparable, patients with higher YY1 expression developed diabetic nephropathy more slowly compared to those who presented with lower YY1 expression. We found that a small molecule, eudesmin, suppressed TGFβ1 and other profibrotic factors by increasing YY1 expression in human renal mesangial cells and attenuated diabetic renal lesions in DN mouse models by increasing YY1 expression. These results suggest that YY1 is a potent transcriptional repressor of TGFB1 during the development of DN in diabetic mice and that small molecules targeting YY1 may serve as promising therapies for treating DN.
Highly efficient plasmon-driven catalysis and excellent surface-enhanced Raman spectroscopy (SERS) performance are proportional to the square of the local electromagnetic field (hot spot). However, a proven way to realize the enhancement in intensity and density of “hot spot” still needs to be investigated. Here, we report on multilayered Ag nanoparticle (Ag NP)/graphene coupled to an underlying Cu film system (MAgNP-CuF) which can be used as an effective SERS substrates realizing ultra-sensitive detection for toxic molecules and in situ monitoring the plasmon-driven reaction for p-nitrothiophenol (PNTP) to p,p′-dimercaptobenzene (DMAB) conversion. The mechanism of ultra-sensitive SERS response and catalytic reaction is investigated via Ag NP/graphene layer-dependent experiments combined with theoretical simulations. The research found that the intensity and density of “hot spot” can be effectively manipulated by the number of plasmonic layers, and the bottom Cu film could also reflect the scattered and excitation beam and would further enhance the Raman signals. Moreover, the MAgNP-CuF exhibits outstanding performance in stability and reproducibility. We believe that this concept of multilayered plasmonic structures would be widely used not only in the field of SERS but also in the wider research in photocatalysis.
The emergence of new drugs is a major feature of the treatment history of multiple myeloma (MM), which also reflects the current incurability of MM. As a unique member of cyclin dependent kinase (cdK) family, cdK5 participates in numerous tumorigenic or non-tumorigenic processes. The aim of this study is to investigate the effects of cdK5 on the viability of MM cells and bortezomib resistance using western blotting, immunohistochemistry, transient transfection, MTT assays, cell cycle analysis, apoptosis assays and a myeloma xenograft mouse model. The present study found that MM patients with high CDK5 expression in the bone marrow do not respond well to bortezomib, have higher DS stage and worse prognosis. Genetic and pharmacological (dinaciclib) inhibition of CDK5 triggers MM cell viability inhibition. Dinaciclib induces G2/M arrest and apoptosis of MM cells.In vivo experiments with myeloma xenograft mice indicate that dinaciclib significantly reduces the volume of tumors with good tolerance. Dinaciclib combined with bortezomib exerts a synergistic anti-myeloma activity accompanied by inhibiting the activation of the nuclear factor-κB pathway. This study demonstrates the important role of cdK5 in the pathogenesis, viability, prognosis and resistance to bortezomib of MM, laying a solid theoretical foundation for further clinical use of CDK5 inhibitors.
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