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Recent evidence has uncovered an important role of Rab7 in regulating mitochondrial morphology and function. Missense mutation(s) of Rab7 underlies the pathogenesis of Charcot Marie Tooth 2B (CMT2B) peripheral neuropathy. Herein, we investigated how mitochondrial morphology and function were impacted by the CMT2B associated Rab7V162M mutation in fibroblasts from human CMT2B patients as well as in a knockin mouse model. In contrast to recently published results from studies of using heterologous overexpression systems, our results have demonstrated significant mitochondrial fragmentation in fibroblasts of both human CMT2B patients and CMT2B mouse embryonic fibroblasts (MEFs). Furthermore, we have shown that mitochondria were fragmented and axonal mitochondrial movement was dysregulated in primary cultured E18 dorsal root ganglion (DRG) sensory neurons, but not in E18 hippocampal and cortical primary neurons. We also show that inhibitors to either the mitochondrial fission protein Drp1 or to the nucleotide binding to Rab7 normalized the mitochondrial deficits in both MEFs and E18 cultured DRG neurons. Our study has revealed, for the first time, that expression of CMT2B Rab7 mutation at physiological level enhances Drp1 activity to promote mitochondrial fission, that may potentially underlie selective vulnerability of peripheral sensory neurons in CMT2B pathogenesis.

Background and Aim: The collaborative care (CC) is emerging as an effective method in treating patients with multimorbidity, but evidence whether this model is effective for people with comorbid depression and diabetes is unclear. This study aimed to investigate whether CC could improve depression outcomes and HbA1c in patients with depressive symptoms and diabetes, and assess its effects on Quality of Life (QoL).Method: The author searched Embase, Scopus, PubMed, Cochrane, PsycINFO and CINAHL to identify randomized controlled trials (RCTs) and cluster RCTs published up to October 21, 2020. Studies were required to assess CC in patients with depressive symptoms and diabetes. The primary outcomes were depression treatment response rate and HbA1c and secondary outcome was Quality of Life (QoL). Available individual patient data was collected from all eligible studies. Studies were independently screened by two reviewers and critically appraised using the Cochrane Risk of Bias tool. This study conducted a systematic review and meta-analysis, and the fixed effects and random effects model were used to pool Relative Risks (RRs) and Standard Mean Differences (SMDs).Results: Our research identified 7906 articles, and finally 12 RCTs were included. Study sample sizes ranged from 58 to 417. The total follow-up period ranged from 12 weeks to 24 months. At follow-up, depression treatment response rate had a significant increase (RR = 1·31, 95% CI 1·23 to 1·39, I2 = 0%) in CC patients compared to controls. There was no statistically significant difference in HbA1c between CC group and the control group (SMD = 0·15, 95% CI -0·35 to 0·65, I2 = 97·6%). Overall QoL at follow-up was greater (SMD = 0·12, 95% CI 0·03 to 0·21, I2 = 54·2%) in CC patients compared to controls but the difference was minor.Conclusion: This systematic review and meta-analysis supported the effectiveness of CC in reducing depression and improving QoL in people with comorbid depression and diabetes.

Aim Toll-like receptors (TLRs) participate in several physiological and pathological processes of transplantation, including inflammation and allograft rejection, but the expression of TLRs and their ligands remains undetermined in small-for-size graft transplantation. Methods A non-arterialized partial liver transplantation model was used. The expression of TLR2 and TLR4 mRNA and protein, CD14 and Myeloid Differentiation-2 (MD-2) mRNA, as well as TLR2 and TLR4 exogenous ligands (endotoxin) and endogenous ligands [heat shock protein (HSP) 60 and 70] were assessed. The signaling pathways induced by TLR2 and TLR4 were also assessed. Results In small-for-size liver graft, the expression of mRNA and protein of TLR2 and TLR4, CD14 and MD-2 mRNA, as well as endogenous ligands of TLR2 and TLR4 such as HSP60 and HSP70 was quickly and significantly increased after reperfusion, and reached a peak at 3 h after reperfusion. The levels of exogenous ligands (endotoxin) were increased and reached a peak at 6 h after reperfusion. The appearance of TLR2 and TLR4 mRNA was accompanied by increased HSP 60 and 70 mRNA within 24 h after reperfusion. In the small-for-size group, the peak levels of TLRs and their endogenous ligands appeared earlier than those in the full size group; the peak levels of TLRs and their endogenous and exogenous ligands were higher than those in the full size group. Conclusion TLR2 and TLR4, as well as their endogenous and exogenous ligands were activated in small-for-size liver graft transplantation.

Objective In small-for-size liver transplantation, portal hypertension aggravates endotoxin from the gut which accelerates the activation of inducible nitric oxide synthase (iNOS). However, there is little knowledge as to the effects of iNOS inhibitors on small-for-size graft damage. Our study was designed to investigate the role of an iNOS inhibitor both with and without lipopolysaccharide (LPS) treatment in ischemia–reperfusion injury of small-for-size liver transplantation. Methods Subjecting Sprague–Dawley rats to small-for-size grafts liver transplantation, we investigated the time course of changes in hepatic expression of iNOS and endothelial nitric oxide synthase (eNOS). Meantime, we also investigated the effects of iNOS inhibitor, both with and without LPS treatment, at 6 h after reperfusion. Results While iNOS mRNA expression reached a peak at 3 h, the highest protein level occurred at 6 h after reperfusion. Aminoguanidine (AG) significantly inhibited mRNA and protein expressions of iNOS, but not that of eNOS. However, LPS accelerated activation of iNOS, but suppressed the expression of eNOS. Meanwhile, compared with the untreated group, those treated with AG or LPS experienced worsened liver function and tissue damage, promoting neutrophil infiltration in the liver tissue. The difference between the LPS group and the LPS + AG group was found to be significant. In addition, AG and LPS treatments up-regulated the protein expression of ICAM-1 and NF-κB p65. Conclusion In a small-for-size model of rat liver transplantation, regardless of LPS treatment, the inhibitor of iNOS, AG, attenuated iNOS expression, but worsened liver function and tissue damage. The subsequent increased neutrophil infiltration in liver tissue may be associated with up-regulation of ICAM-1 and NF-κB expressions.