Overexpression of Kdr in adult endocardium induces endocardial neovascularization and improves heart function after myocardial infarction

Dear Editor, Coronary artery disease is a leading cause of mortality and morbidity worldwide.Blockade of effective blood flow to heart muscles results in cardi...     

Genome-wide CRISPR screen identifies synthetic lethality between DOCK1 inhibition and metformin in liver cancer

Metformin is currently a strong candidate anti-tumor agent in multiple cancers. However, its anti-tumor effectiveness varies among different cancers or subpopulations, potentially due to tumor heterogeneity. It thus remains unclear which hepatocellular carcinoma (HCC) patient subpopulation(s) can benefit from metformin treatment. Here, through a genome-wide CRISPR-Cas9-based knockout screen, we find that DOCK1 levels determine the anti-tumor effects of metformin and that DOCK1 is a synthetic lethal target of metformin in HCC. Mechanistically, metformin promotes DOCK1 phosphorylation, which activates RAC1 to facilitate cell survival, leading to metformin resistance. The DOCK1-selective inhibitor, TBOPP, potentiates anti-tumor activity by metformin in vitro in liver cancer cell lines and patient-derived HCC organoids, and in vivo in xenografted liver cancer cells and immunocompetent mouse liver cancer models. Notably, metformin improves overall survival of HCC patients with low DOCK1 levels but not among patients with high DOCK1 expression. This study shows that metformin effectiveness depends on DOCK1 levels and that combining metformin with DOCK1 inhibition may provide a promising personalized therapeutic strategy for metformin-resistant HCC patients.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13238-022-00906-6.     

Binding of the erlin1/2 complex to the third intralumenal loop of IP3R1 triggers its ubiquitin-proteasomal degradation

Long-term activation of inositol 1,4,5-trisphosphate receptors (IP₃Rs) leads to their degradation by the ubiquitin–proteasome pathway. The first and rate-limiting step in this process is thought to be the association of conformationally active IP₃Rs with the erlin1/2 complex, an endoplasmic reticulum–located oligomer of erlin1 and erlin2 that recruits the E3 ubiquitin ligase RNF170, but the molecular determinants of this interaction remain unknown. Here, through mutation of IP₃R1, we show that the erlin1/2 complex interacts with the IP₃R1 intralumenal loop 3 (IL3), the loop between transmembrane (TM) helices 5 and 6, and in particular, with a region close to TM5, since mutation of amino acids D-2471 and R-2472 can specifically block erlin1/2 complex association. Surprisingly, we found that additional mutations in IL3 immediately adjacent to TM5 (e.g., D2465N) almost completely abolish IP₃R1 Ca²⁺ channel activity, indicating that the integrity of this region is critical to IP₃R1 function. Finally, we demonstrate that inhibition of the ubiquitin-activating enzyme UBE1 by the small-molecule inhibitor TAK-243 completely blocked IP₃R1 ubiquitination and degradation without altering erlin1/2 complex association, confirming that association of the erlin1/2 complex is the primary event that initiates IP₃R1 processing and that IP₃R1 ubiquitination mediates IP₃R1 degradation. Overall, these data localize the erlin1/2 complex–binding site on IP₃R1 to IL3 and show that the region immediately adjacent to TM5 is key to the events that facilitate channel opening.     

LRG‐1 promotes fat graft survival through the RAB31‐mediated inhibition of hypoxia‐induced apoptosis

Autologous adipose tissue is an ideal soft tissue filling material, and its biocompatibility is better than that of artificial tissue substitutes, foreign bodies and heterogeneous materials. Although autologous fat transplantation has many advantages, the low retention rate of adipose tissue limits its clinical application. Here, we identified a secretory glycoprotein, leucine‐rich‐alpha‐2‐glycoprotein 1 (LRG‐1), that could promote fat graft survival through RAB31‐mediated inhibition of hypoxia‐induced apoptosis. We showed that LRG‐1 injection significantly increased the maintenance of fat volume and weight compared with the control. In addition, higher fat integrity, more viable adipocytes and fewer apoptotic cells were observed in the LRG‐1‐treated groups. Furthermore, we discovered that LRG‐1 could reduce the ADSC apoptosis induced by hypoxic conditions. The mechanism underlying the LRG‐1‐mediated suppression of the ADSC apoptosis induced by hypoxia was mediated by the upregulation of RAB31 expression. Using LRG‐1 for fat grafts may prove to be clinically successful for increasing the retention rate of transplanted fat.     

姜品种叶片形态学研究

用光镜和电镜对姜(Zingiber officinale Rosc.)20个品种的叶表皮细胞、气孔器进行了观察,对叶形指数进行了研究。结果表明,姜叶片表皮细胞的形状主要有正六边形、长六边形和不规则六边形3种类型。气孔器均为平列型,气孔器的宽度为21.5-31.0μm,气孔器指数为1.75-8.22,叶形指数在品种间有较大差异。表皮的这些特征为确定品种间亲缘关系提供了依据。     

Hemin with Peroxidase Activity Can Inhibit the Oxidative Damage Induced by Ultraviolet A

Excessive reactive oxygen species (ROS), a highly reactive substance that contains oxygen, induced by ultraviolet A (UVA) cause oxidative damage to skin. We confirmed that hemin can catalyze the reaction of tyrosine (Tyr) and hydrogen peroxide (H₂O₂). Catalysis was found to effectively reduce or eliminate oxidative damage to cells induced by H₂O₂ or UVA. The scavenging effects of hemin for other free-radical ROS were also evaluated through pyrogallol autoxidation, 1,1-diphenyl-2-picrylhydrazyl radical (DPPH·)-scavenging assays, and phenanthroline–Fe²⁺ assays. The results show that a mixture of hemin and tyrosine exhibits strong scavenging activities for H₂O₂, superoxide anion (O₂⁻·), DPPH·, and the hydroxyl radical (·OH). Furthermore, the inhibition of oxidative damage to human skin keratinocyte (HaCaT) cells induced by H₂O₂ or UVA was evaluated. The results show that catalysis can significantly reduce the ratio of cell apoptosis and death and inhibit the release of lactate dehydrogenase (LDH), as well as accumulation of malondialdehyde (MDA). Furthermore, the resistance to apoptosis was found to be enhanced. These results show that the mixture of hemin and tyrosine has a significantly protective effect against oxidative damage to HaCaT cells caused by UVA, suggesting it as a protective agent for combating UVA damage.     

长期高饱和、高不饱和脂肪酸饮食诱导胰岛素抵抗大鼠肾动脉舒张和收缩功能的变化

本文旨在探讨长期高饱和、高不饱和脂肪酸饮食诱导胰岛素抵抗（insulin resistance,IR）大鼠。肾动脉舒张和收缩功能的变化。成年Wistar大鼠随机分为对照组、高饱和脂肪酸组和高不饱和脂肪酸组,每组14只。喂养6个月后,用高胰岛素正常葡萄糖钳夹技术的葡萄糖输注率（glucose infusion rate,GIR）评价IR;用尾套法测定大鼠血压,同时比较三组大鼠的体重、血清甘油三酯、游离脂肪酸、胰岛素、空腹血糖和NO代谢产物NO2-／NO3-。大鼠处死后,取肾动脉放入生理盐溶液中,观察血管对各种因子的舒、缩反应。结果显示,喂养6个月后,与对照组大鼠比较,高饱和脂肪酸组和高不饱和脂肪酸组大鼠均出现血压升高、血清甘油三酯升高和胰岛素敏感性降低;体重、空腹血糖、胰岛素和游离脂肪酸均升高（P〈0．01）：而两高脂组间体重、空腹血糖、胰岛素和游离脂肪酸无显著性差异。高饱和脂肪酸组大鼠肾动脉对ACh的内皮依赖性最大舒张反应（Rmax）最低,其次为高不饱和脂肪酸组和对照组：对照组与两高脂组有显著性差异（P〈0．01）,而两高脂组间无显著性差异。血管经L-Arg孵育后,两高脂组肾动脉对ACh的内皮依赖性Rmax均比孵育前增加,经N^ω-吐硝基-L-精氨酸（N^ω-nitro-L-arginine,L-NNA）及美蓝（methyleneblue,MB）孵育后,两高脂组Rmax均比孵育前降低（P〈0．05,P〈0．01）;对照组各孵育液之间无显著性差异（P：〈0．05）。肾动脉对硝普钠的非内皮依赖性Rmax及对去甲肾上腺素的收缩反应,三组间无显著性差异（P〈0．05）。相关分析结果显示,肾动脉对ACh的内皮依赖性Rmax与收缩压、甘油三酯呈明显负相关,与NO2-／NO3-和GIR呈明显正相关,游离脂肪酸与N02-／NO3-呈明显负相关。结果提示,高饱和及高不饱和脂肪酸饮食均可引起高血压及与之密切相关的内皮依赖性血管舒张功能减弱、高脂血症和IR,高脂诱导内皮依赖性血管舒张功能减弱与L-Arg-NO-cGMP通路受损有关。     

A rapid real-time recombinase polymerase amplification assay for diagnosis of acute hepatopancreatic necrosis disease in shrimp

Acute hepatopancreatic necrosis disease(AHPND)is an emerging disease in the shrimp farming industry with a high mortality rate that causes serious economic loss...