Identification of a novel Calpain-2-SRC feed-back loop as necessity for ß-Catenin accumulation and signaling activation in hepatocellular carcinoma.

Rapid progression is the major cause of the poor prognosis of hepatocellular carcinoma (HCC); however, the underlying mechanism remained unclear. Here, we found Calpain-2 (CAPN2), a well-established protease that accelerates tumor progression in several malignancies, is overexpressed in HCC and acts as an independent predictor for poor outcomes. Furthermore, CAPN2 promoted the proliferation and invasion of HCC, and showed a positive correlation with the levels of invasion-related markers. Mechanistically, a novel CAPN2-SRC positive regulatory loop was identified upstream of ß-catenin to prevent its ubiquitination and degradation, and subsequently promoted HCC progression: CAPN2 could proteolyze PTP1B to form a truncation of approximately 42 kDa with increased phosphatase activity, resulting in reduced SRC Y530 phosphorylation and increased SRC kinase activity; meanwhile, CAPN2 itself was a bone fide substrate of SRC that was primarily phosphorylated at Y625 by SRC and exhibited increased proteolysis activity upon phosphorylation. Interestingly, the CAPN2-SRC loop could not only restrain most of cytoplasmic ß-catenin degradation by inhibiting GSK3ß pathway, but also prevented TRIM33-induced nuclear ß-catenin degradation even in ß-catenin-mutant cells. Present study identified a CAPN2-SRC positive loop responsible for intracellular ß-catenin accumulation and signaling activation, and targeting CAPN2 protease activity might be a promising approach for preventing HCC progression.

Evaluation of individualized treatment of nonproliferative diabetic retinopathy: a multicenter, randomized, parallel-controlled study.

OBJECTIVE: To evaluate the differences in the efficacy of stationary treatment and individualized treatment for patients with nonproliferative diabetic retinopathy (NPDR). METHODS: This study was a randomized, controlled, multicenter clinical trial. Participants with NPDR were randomized into the stationary treatment group or the individualized treatment group. The stationary treatment group was given the basic treatment and Qiming granules, and the individualized treatment group was given the basic treatment, Qiming granules, and individualized Chinese herbal medicines over a 12-week period. The individualized therapeutic formula was also changed over time to adjust to the changes in the clinical presentation of the patient. We conducted observations of fundus retinal exudation and hemorrhage, visual acuity, Traditional Chinese Medicine symptom scores and other indicators. RESULTS: A total of 140 participants with NPDR were randomized into the stationary treatment group or the individualized treatment group, and 132 participants completed this study. Following the 12-week treatment, significant improvements in both primary and secondary outcomes were observed in the stationary and individualized treatment groups. No remarkable difference in the primary outcomes between the two groups was observed. However, there was a significant difference in the Traditional Chinese Medicine symptom scores (18 ± 7 vs 15 ± 6; P < 0.05). There were no severe adverse effects. CONCLUSION: Compared with stationary treatment, individualized treatment is more effective at relieving the Traditional Chinese Medicine symptoms and improving vision and fundus lesions at 12 weeks post treatment.

Rhodium-Catalyzed ortho-Selective Carbene C-H Insertion of Unprotected Phenols Directed by a Transient Oxonium Ylide Intermediate.

ortho-Selective carbene C-H insertion of unprotected phenols is achieved with dimethyl diazomalonate under the catalysis of [Rh(COD)Cl]2. After the C-H insertion, subsequent cyclization and electrophilic addition of another carbene molecule affords tris-carboxylate-substituted 2-benzofuranones as the final reaction products. The enantioselective variant has been developed with the use of chiral diene ligands. Mechanistic experiments indicate that a transient oxonium ylide directing group might be responsible for the regiocontrol at the C-H activation step.