HDAC1 Promotes Mitochondrial Pathway Apoptosis and Inhibits the Endoplasmic Reticulum Stress Response in High Glucose-Treated Schwann Cells via Decreased U4 Spliceosomal RNA.

Dysfunction of Schwann cells, including cell apoptosis, autophagy inhibition, dedifferentiation, and pyroptosis, is a pivotal pathogenic factor in induced diabetic peripheral neuropathy (DPN). Histone deacetylases (HDACs) are an important family of proteins that epigenetically regulate gene transcription by affecting chromatin dynamics. Here, we explored the effect of HDAC1 on high glucose-cultured Schwann cells. HDAC1 expression was increased in diabetic mice and high glucose-cultured RSC96 cells, accompanied by cell apoptosis. High glucose also increased the mitochondrial pathway apoptosis-related Bax/Bcl-2 and cleaved caspase-9/caspase-9 ratios and decreased endoplasmic reticulum response-related GRP78, CHOP, and ATF4 expression in RSC96 cells (P < 0.05). Furthermore, overexpression of HDAC1 increased the ratios of Bax/Bcl-2, cleaved caspase-9/caspase-9, and cleaved caspase-3 and reduced the levels of GRP78, CHOP, and ATF4 in RSC96 cells (P < 0.05). In contrast, knockdown of HDAC1 inhibited high glucose-promoted mitochondrial pathway apoptosis and suppressed the endoplasmic reticulum response. Moreover, RNA sequencing revealed that U4 spliceosomal RNA was significantly reduced in HDAC1-overexpressing RSC96 cells. Silencing of U4 spliceosomal RNA led to an increase in Bax/Bcl-2 and cleaved caspase-9 and a decrease in CHOP and ATF4. Conversely, overexpression of U4 spliceosomal RNA blocked HDAC1-promoted mitochondrial pathway apoptosis and inhibited the endoplasmic reticulum response. In addition, alternative splicing analysis of HDAC1-overexpressing RSC96 cells showed that significantly differential intron retention (IR) of Rpl21, Cdc34, and Mtmr11 might be dominant downstream targets that mediate U4 deficiency-induced Schwann cell dysfunction. Taken together, these findings indicate that HDAC1 promotes mitochondrial pathway-mediated apoptosis and inhibits the endoplasmic reticulum stress response in high glucose-cultured Schwann cells by decreasing the U4 spliceosomal RNA/IR of Rpl21, Cdc34, and Mtmr11.

Optimising recovery after perineal trauma: Implementation of an evidence-based patient-centred care and clinical practice guideline.

BACKGROUND: Perineal trauma and pain can affect the quality of life of women who experience vaginal birth. AIM: To investigate the effect of perineal care and pain management on women's postpartum recovery. METHODS: This was a Quasi-experimental study. In Phase 1 women were treated using our old postnatal perineal care management guideline. In Phase 2 an updated guideline was introduced (regular administration of icepacks and analgesia during the first 24-48 h postpartum). During Phase 1, pregnant women planning a vaginal birth completed a baseline questionnaire. Those who sustained perineal trauma completed a survey at 24-48 h, seven days and 12 weeks after birth. In Phase 2 we continued recruiting participants, using the same procedure, and investigated the efficacy of pain relief approaches using the new guideline. RESULTS: In Phase 1, 111 women (Group 1), and Phase 2, 146 women (Group 2) were recruited. No statistically significant differences were found between the two groups in terms of the women's pain catastrophising, their partner's responses to pain behaviours, or birth outcomes. At 24-48 h and seven days postpartum, women in Group 2 were less likely than women in Group 1 to be bothered by back or perineal pain, headache, sleeping difficulties and dizziness (p < 0.05). More women in Group 2 received regular paracetamol and perineal icepacks during their hospital stay, with less use of oxycodone in Group 2 than Group 1. CONCLUSION: The implementation of the guideline's recommendations was associated with decrease back and perineal pain, headache, sleeping difficulties and dizziness during the first seven days postpartum.

Quantitative Proteomics Characterization of the Effect and Mechanism of Trichostatin A on the Hippocampus of Type II Diabetic Mice.

Diabetic encephalopathy (DE) is one of the complications of diabetes mellitus with mild-to-moderate cognitive impairment. Trichostatin A (TSA) has been revealed to show protective effect on central nervous systems in Alzheimer's disease (AD) and hypoxic-ischemic brain injury. However, the effect and molecular mechanism of TSA on cognitive function of DE are unknown. Here, we demonstrated that cognitive function was damaged in diabetic mice versus normal mice and treatment with TSA improved cognitive function in diabetic mice. Proteomic analysis of the hippocampus revealed 174 differentially expressed proteins in diabetic mice compared with normal mice. TSA treatment reversed the expression levels of 111 differentially expressed proteins grouped into functional clusters, including the longevity regulating pathway, the insulin signaling pathway, peroxisomes, protein processing in the endoplasmic reticulum, and ribosomes. Furthermore, protein-protein interaction network analysis of TSA-reversed proteins revealed that UBA52, CAT, RPL29, RPL35A, CANX, RPL37, and PRKAA2 were the main hub proteins. Multiple KEGG pathway-enriched CAT and PRKAA2 levels were significantly decreased in the hippocampus of diabetic mice versus normal mice, which was reversed by TSA administration. Finally, screening for potential similar or ancillary drugs for TSA treatment indicated that HDAC inhibitors ISOX, apicidin, and panobinostat were the most promising similar drugs, and the PI3K inhibitor GSK-1059615, the Aurora kinase inhibitor alisertib, and the nucleophosmin inhibitor avrainvillamide-analog-6 were the most promising ancillary drugs. In conclusion, our study revealed that CAT and PRKAA2 were the key proteins involved in the improvement of DE after TSA treatment. ISOX, apicidin, and panobinostat were promising similar drugs and that GSK-1059615, alisertib, and avrainvillamide-analog-6 were promising ancillary drugs to TSA in the treatment of DE.

Hybrid Bipedal Locomotion Based on Reinforcement Learning and Heuristics.

Locomotion control has long been vital to legged robots. Agile locomotion can be implemented through either model-based controller or reinforcement learning. It is proven that robust controllers can be obtained through model-based methods and learning-based policies have advantages in generalization. This paper proposed a hybrid framework of locomotion controller that combines deep reinforcement learning and simple heuristic policy and assigns them to different activation phases, which provides guidance for adaptive training without producing conflicts between heuristic knowledge and learned policies. The training in simulation follows a step-by-step stochastic curriculum to guarantee success. Domain randomization during training and assistive extra feedback loops on real robot are also adopted to smooth the transition to the real world. Comparison experiments are carried out on both simulated and real Wukong-IV humanoid robots, and the proposed hybrid approach matches the canonical end-to-end approaches with higher rate of success, faster converging speed, and 60% less tracking error in velocity tracking tasks.

Lycorine improves peripheral nerve function by promoting Schwann cell autophagy via AMPK pathway activation and MMP9 downregulation in diabetic peripheral neuropathy.

Diabetic peripheral neuropathy (DPN) is the most common complication of diabetes mellitus and no effective therapy is approved. Here, lycorine, a natural alkaloid, was identified as a potential drug for DPN by the bioinformatics analysis of GEO datasets and Connectivity Map database. Lycorine administration improved peripheral nerve function and autophagy-associated proteins of diabetic mice. Again, in vitro high glucose-cultured rat Schwann cells (RSC96) showed enhanced autophagosome marker LC3-II with the treatment of lycorine. Additionally, beclin-1 and Atg3 were decreased in high glucose-stimulated RSC96 cells, which were reversed by lycorine treatment. Furthermore, DPN-associated differentially expressed genes (DEGs) from GEO datasets and lycorine-drug targets from PubChem and PharmMapper were visually analyzed and revealed that MMP9 was both DPN-associated DEGs and lycorine-drug target. Functional enrichment analysis of MMP9-relevant genes showed that cell energy metabolism was involved. Moreover, lycorine reduced high glucose-enhanced MMP9 expression in RSC96 cells. Overexpression of MMP9 attenuated lycorine-induced the expression of beclin-1, Atg3 and LC3-II in high glucose-cultured RSC96 cells. In addition, AMPK pathway activation was confirmed in lycorine-treated high glucose-cultured RSC96 cells. Then AMPK pathway inhibition attenuated lycorine-reduced MMP9 expression in high glucose-treated RSC96 cells. Molecular docking analysis revealed that lycorine bound the domain of AMPK containing Thr 172 site, which affected AMPK (Thr 172) phosphorylation. Finally, AMPK pathway activation and MMP9 downregulation were also revealed in the sciatic nerves of diabetic mice administrated with lycorine. Taken together, lycorine was advised to promote Schwann cell autophagy via AMPK pathway activation and MMP9 downregulation-induced LC3-II transformation in diabetic peripheral neuropathy.