The ubiquitin-proteasome system is a major pathway for protein degradation, so that proteasome is now considered as an important target for drug discovery. Bortezomib, the first US FDA-approved proteasome inhibitor now used as a front-line treatment for multiple myeloma. To better understand the effects of bortezomib in cancer treatment, we carried out a review based on 32 published clinical trials to determine whether bortezomib will benefit patients with solid tumors. Information of complete response, partial response, stable disease and objective response rate was collected to assess clinical outcomes. A lack of therapeutic effects was observed when bortezomib was used as a single agent. Meanwhile, when bortezomib treatment was combined with other agents, bortezomib offered no statistically significant response versus these agents alone. High-quality studies are required to better understand the clinically effects of bortezomib and the development of a new generation of proteasome inhibitors is absolutely necessary.

The transition of antimicrobial peptides (AMPs) from the laboratory to market has been severely hindered by their instability toward proteases in biological systems. In the present study, we synthesized derivatives of the cationic AMP Pep05 (KRLFKKLLKYLRKF) by substituting L -amino acid residues with D - and unnatural amino acids, such as D- lysine, D- arginine, L- 2,4-diaminobutanoic acid (Dab), L- 2,3-diaminopropionic acid (Dap), L- homoarginine, 4-aminobutanoic acid (Aib), and L- thienylalanine, and evaluated their antimicrobial activities, toxicities, and stabilities toward trypsin, plasma proteases, and secreted bacterial proteases. In addition to measuring changes in the concentration of the intact peptides, LC-MS was used to identify the degradation products of the modified AMPs in the presence of trypsin and plasma proteases to determine degradation pathways and examine whether the amino acid substitutions afforded improved proteolytic resistance. The results revealed that both D- and unnatural amino acids enhanced the stabilities of the peptides toward proteases. The derivative DP06, in which all of the L- lysine and L- arginine residues were replaced by D -amino acids, displayed remarkable stability and mild toxicity in vitro but only slight activity and severe toxicity in vivo , indicating a significant difference between the in vivo and in vitro results. Unexpectedly, we found that the incorporation of a single Aib residue at the N-terminus of compound UP09 afforded remarkably enhanced plasma stability and improved activity in vivo . Hence, this derivative may represent a candidate AMP for further optimization, providing a new strategy for the design of novel AMPs with improved bioavailability.

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Objectives Podocyte injury is a prediction marker of diabetic nephropathy (DN), and AKT/mTOR pathway–mediated inhibition of autophagy is widely reported to contribute to podocyte damage. Recent study stated that sperm‐associated antigen 5 (SPAG5) activated AKT/mTOR signalling in bladder urothelial carcinoma, indicating SPAG5 might regulate autophagy and play a role in podocyte damage. Materials and methods Apoptosis and autophagy of human podocytes (HPCs) were detected by flow cytometry and immunofluorescence (IF). Gene level was assessed by Western blot and RT‐qPCR. Molecular interactions were determined by pulldown, RNA immunoprecipitation (RIP), co‐immunoprecipitation (co‐IP), chromatin immunoprecipitation (ChIP) and luciferase reporter assays. Results SPAG5 mRNA and protein levels were upregulated under high glucose treatment in HPCs. Silencing SPAG5 reversed the increase of apoptosis and decrease of autophagy in high glucose–treated HPCs. Later, we found a long non‐coding RNA (lncRNA) SPAG5 antisense RNA1 (SPAG5‐AS1) as a neighbour gene to SPAG5. Mechanistically, YY1 transcriptionally upregulated SPAG5‐AS1 and SPAG5 in high glucose–treated podocytes. SPAG5‐AS1 acted as a competitive endogenous RNA (ceRNA) to regulate miR‐769‐5p/YY1 axis and induce SPAG5. SPAG5‐AS1 interacted with ubiquitin‐specific peptidase 14 (USP14) and leads to de‐ubiquitination and stabilization of SPAG5 protein. Conclusions This study revealed that SPAG5‐AS1 inhibited autophagy and aggravated apoptosis of podocytes via SPAG5/AKT/mTOR pathway, indicating SPAG5‐AS1/SPAG5 as a potential target for the alleviation of podocyte injury and offering new thoughts for the treatments of DN.