An Emerging Role of Defective Copper Metabolism in Heart Disease

Copper is an essential trace metal element that significantly affects human physiology and pathology by regulating various important biological processes, including mitochondrial oxidative phosphorylation, iron mobilization, connective tissue crosslinking, antioxidant defense, melanin synthesis, blood clotting, and neuron peptide maturation. Increasing lines of evidence obtained from studies of cell culture, animals, and human genetics have demonstrated that dysregulation of copper metabolism causes heart disease, which is the leading cause of mortality in the US. Defects of copper homeostasis caused by perturbed regulation of copper chaperones or copper transporters or by copper deficiency resulted in various types of heart disease, including cardiac hypertrophy, heart failure, ischemic heart disease, and diabetes mellitus cardiomyopathy. This review aims to provide a timely summary of the effects of defective copper homeostasis on heart disease and discuss potential underlying molecular mechanisms.     

Role and mechanism of action of LAPTM4B in EGFR-mediated autophagy

LAPTM4B is upregulated in the majority of types of cancer and associated with cancer cell proliferation, survival and drug resistance, as well as poor patient prognosis. LAPTM4B knockdown inhibits autophagosome maturation in the context of metabolic stress. Autophagy is a homeostatic process that degrades and recycles intracellular components in response to metabolic stress. The function of autophagy is dual, as this process can either have a tumor suppressor or an oncogenic role. EGFR serves an important role in determining the tumor-suppressive or oncogenic roles of autophagy. EGFR family members regulate autophagy through various signaling pathways, including PI3K/AKT signaling. Notably, LAPTM4B also promotes cancer cell proliferation via the PI3K/AKT signaling pathway. In addition, LAPTM4B can enhance and prolong EGFR signal transduction by blocking active EGFR intraluminal sorting and lysosomal degradation. Thus, LAPTM4B may be associated with autophagy through EGFR signaling. The present review proposed that LAPTM4B participates in regulating autophagy through the EGFR pathway.     

Modified Nuss procedure with a novel steel bar in patients with pectus excavatum post-congenital heart surgery

 Open in a separate windowOBJECTIVESPectus excavatum (PE) can be secondary in patients who underwent sternotomy for cardiac surgery. Retrosternal adhesions increase the complexity and risk of traditional Nuss repair. Thus, we summarized the outcomes of our modified Nuss procedure using a newly designed bar.METHODSA retrospective analysis was performed on 35 patients who underwent modified PE repair after open heart surgery from January 2011 to July 2019. The surgery was performed using a novel bar with no need for intraoperative reshaping and rotation, assisted by thoracoscopy and subxiphoid incision when necessary.RESULTSThere were 19 males and 16 females with a median age of 5.3 years (interquartile range, 4.1–10.9) at PE repair. All patients underwent the modified procedure uneventfully with no death. The median operating time was 70 min. Twenty-nine (82.9%) patients required subxiphoid incision assistance. There was 1 case (2.8%) with unexpected sternotomy due to intraoperative bleeding. The median length of postoperative hospital stay was 4 days. During the median 3.5 years of follow-up, no bar dislocation was found and 30 (85.7%) patients had their bars removed with no recurrence recorded. After PE repair, the Haller index improved significantly (2.6 ± 0.4 vs 4.9 ± 1.3, P < 0.05) and further decreased till the time of bar removal (2.5 ± 0.4 vs 2.6 ± 0.4, P < 0.05). All patients were satisfied with the cosmetic outcome.CONCLUSIONSThe novel bar can be placed and removed easily with a low rate of adverse events. This modified Nuss procedure seems to be a safe, effective and convenient approach for the management of PE after cardiac surgery.     

拉西地平与小剂量双氢克尿噻联用治疗老年单纯收缩期高血压疗效观察

目的 观察拉西地平与小剂量双氢克尿噻联用治疗老年单纯收缩期高血压疗效及不良反应.方法 入选126例年龄≥60岁单纯收缩期高血压病患者随机分为三组.A组拉西地平4mg/d,双氢克尿噻12.5mg/d联用;B组拉西地平4mg/d;C组双氢克尿噻25mg/d;各组疗程均为4周.结果 A组显效34例(81%),有效6例(14%),无效2例(5%),总有效率95%;B组显效21例(50%),有效10例(24%),无效11例(26%),总有效率74%;C组显效13例(31%),有效13例(31%),无效16例(38%),总有效率67%.结论 拉西地平与小剂量双氢克尿噻联用治疗老年单纯收缩期高血压疗效显著,不良反应少.     

系统性硬化症相关间质性肺病的诊治现状和进展

【摘要】 系统性硬化症（SSc）是一种罕见的伴有内脏器官纤维化的慢性结缔组织病,其并发的间质性肺病（ILD）是SSc患者死亡的首要原因。SSc相关ILD发病隐匿,不及时治疗进展迅速,患者生存质量和生存率明显下降。本文综述SSc-ILD早期诊断方法和治疗时机,并对传统的免疫抑制剂和新近出现的靶向药物、造血干细胞移植、肺移植等治疗方法做出综述。     

High mobility group box-1-toll-like receptor 4-phosphatidylinositol 3-kinase/protein kinase B-mediated generation of matrix metalloproteinase-9 in the dorsal root ganglion promotes chemotherapy-induced peripheral neuropathy

Chemotherapy-induced peripheral neuropathy (CIPN) is a significant side effect of chemotherapeutics. The mechanisms of CIPN remain substantially unidentified, although inflammation-induced peripheral sensitization has been indicated as an important factor. Here, we aimed to illustrate the role of the matrix metalloproteinase (MMP)-9-related signaling pathway in the process of CIPN. Oxaliplatin (L-OHP) was administered to mice to establish the CIPN model. Gelatin zymography was used to measure MMP-9/2 activities. Western blotting and immunohistochemistry were used to measure the expression of high-mobility group box-1 (HMGB-1), calcitonin gene-related peptide and ionized calcium-binding adapter molecule 1. Mechanical withdrawal was measured by von Frey hairs testing. Raw 264.7 cells and SH-SY5Y cells were cultured to investigate cell signaling in vitro. Here, we report that L-OHP-induced mechanical pain in mice with significant MMP-9/2 activation in dorsal root ganglion (DRG) neurons. MMP-9 inhibition or knockout alleviated the occurrence of CIPN directly. MMP-9/2 were released from macrophages and neurons in the DRG via the HMGB-1-toll-like receptor 4 (TLR4)-phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) axis, because MMP-9/2 activities could be reduced by macrophage scavengers or PI3Kγ knockout in CIPN mice. The in vitro data revealed that induced MMP-9 activity by recombinant HMGB-1 could be abolished by TLR4, PI3K or Akt inhibitors. Finally, it was shown that N-acetyl-cysteine (NAC) could reduce MMP-9/2 activities and attenuate CIPN effectively and safely. The HMGB-1-TLR4-PI3K/Akt-MMP-9 axis is involved in the crosstalk between macrophages and neurons in the pathological process of CIPN in mice. Direct inhibition of MMP-9 by NAC may be a potential therapeutic regimen for CIPN treatment.