Association between triglyceride glucose index and severity of diabetic foot ulcers in type 2 diabetes mellitus.

BACKGROUND: Triglyceride glucose (TyG) index is a good surrogate biomarker to evaluate insulin resistance (IR). The study aimed to investigate whether the TyG index is related to the severity of diabetic foot ulcers (DFUs) in patients with type 2 diabetes mellitus (T2DM). METHODS: A total of 1059 T2DM patients were enrolled in this observational, retrospective, single-center study. TyG index was calculated as ln[fasting triglycerides (mg/dl) × fasting glucose (mg/ dl)/2]. The severity of DFUs was classified into mild-to-moderate DFUs (Wagner grade score < 3) and severe DFUs (Wagner grade score ≥ 3) based on Wagner classification. Patients were stratified according to the tertiles of TyG index. Logistic regression models were implemented to explore the association between TyG index and the severity of DFUs. Subgroup analyses were used to verify the reliability of results. RESULTS: Compared with the reference lowest TyG tertile (T1), the highest tertile (T3) was associated with 0.377-fold increased risk of prevalence of severe DFUs (odds ratio [OR] 1.377, 95% confidence interval [CI] 1.017-1.865) (P = 0.039). After adjusting for potential confounders, the multivariable-adjusted OR and 95% CI were 1.506 (1.079-2.103) (P = 0.016) in patients with highest tertile. Moreover, subgroup analyses indicated that the association was stronger among men, patients with age ≥ 65 years, duration of diabetes more than 10 years, or without PAD. CONCLUSIONS: Elevated TyG index is independently associated with severity of DFUs even after adjusting conventional confounders.

Self-stabilizing regulation of deubiquitinating enzymes in an enzymatic activity-dependent manner.

Deubiquitinating enzymes (DUBs) play important roles in many physiological and pathological processes by modulating the ubiquitination of their substrates. DUBs undergo post-translational modifications including ubiquitination. However, whether DUBs can reverse their own ubiquitination and regulate their own protein stability requires further investigation. To answer this question, we screened an expression library of DUBs and their enzymatic activity mutants and found that some DUBs regulated their own protein stability in an enzymatic activity- and homomeric interaction-dependent manner. Taking Ubiquitin-specific-processing protease 29 (USP29) as an example, we found that USP29 deubiquitinates itself and protects itself from proteasomal degradation. We also revealed that the N-terminal region of USP29 is critical for its protein stability. Taken together, our work demonstrates that at least some DUBs regulate their own ubiquitination and protein stability. Our findings provide novel molecular insight into the diverse regulation of DUBs.

The deubiquitinating enzyme OTUD1 antagonizes BH3-mimetic inhibitor induced cell death through regulating the stability of the MCL1 protein.

BACKGROUND: Myeloid cell leukaemia 1 (MCL1) is a pro-survival Bcl-2 family protein that plays important roles in cell survival, proliferation, differentiation and tumourigenesis. MCL1 is a fast-turnover protein that is degraded via an ubiquitination/proteasome-dependent mechanism. Although several E3 ligases have been discovered to promote the ubiquitination of MCL1, the deubiquitinating enzyme (DUB) that regulates its stability requires further investigation. METHODS: The immunoprecipitation was used to determine the interaction between OTUD1 and MCL1. The ubiquitination assays was performed to determine the regulation of MCL1 by OTUD1. The cell viability was used to determine the regulation of BH3-mimetic inhibitor induced cell death by OTUD1. The survival analysis was used to determine the relationship between OTUD1 expression levels and the survival rate of cancer patients. RESULTS: By screening a DUB expression library, we determined that the deubiquitinating enzyme OTUD1 regulates MCL1 protein stability in an enzymatic-activity dependent manner. OTUD1 interacts with MCL1 and promotes its deubiquitination. Knockdown of OTUD1 increases the sensitivity of tumour cells to the BH3-mimetic inhibitor ABT-263, while overexpression of OTUD1 increases tumour cell tolerance of ABT-263. Furthermore, bioinformatics analysis data reveal that OTUD1 is a negative prognostic factor for liver cancer, ovarian cancer and specific subtypes of breast and cervical cancer. CONCLUSIONS: The deubiquitinating enzyme OTUD1 antagonizes BH3-mimetic inhibitor induced cell death through regulating the stability of the MCL1 protein. Thus, OTUD1 could be considered as a therapeutic target for curing these cancers.