The spike protein of SARS-CoV-2 induces endothelial inflammation through integrin α5β1 and NF-κB signaling

Vascular endothelial cells (ECs) form a critical interface between blood and tissues that maintains whole-body homeostasis. In COVID-19, disruption of the EC barrier results in edema, vascular inflammation, and coagulation, hallmarks of this severe disease. However, the mechanisms by which ECs are dysregulated in COVID-19 are unclear. Here, we show that the spike protein of SARS-CoV-2 alone activates the EC inflammatory phenotype in a manner dependent on integrin ⍺5β1 signaling. Incubation of human umbilical vein ECs with whole spike protein, its receptor-binding domain, or the integrin-binding tripeptide RGD induced the nuclear translocation of NF-κB and subsequent expression of leukocyte adhesion molecules (VCAM1 and ICAM1), coagulation factors (TF and FVIII), proinflammatory cytokines (TNFα, IL-1β, and IL-6), and ACE2, as well as the adhesion of peripheral blood leukocytes and hyperpermeability of the EC monolayer. In addition, inhibitors of integrin ⍺5β1 activation prevented these effects. Furthermore, these vascular effects occur in vivo, as revealed by the intravenous administration of spike, which increased expression of ICAM1, VCAM1, CD45, TNFα, IL-1β, and IL-6 in the lung, liver, kidney, and eye, and the intravitreal injection of spike, which disrupted the barrier function of retinal capillaries. We suggest that the spike protein, through its RGD motif in the receptor-binding domain, binds to integrin ⍺5β1 in ECs to activate the NF-κB target gene expression programs responsible for vascular leakage and leukocyte adhesion. These findings uncover a new direct action of SARS-CoV-2 on EC dysfunction and introduce integrin ⍺5β1 as a promising target for treating vascular inflammation in COVID-19.     

Fibronectin type III domain‐containing 5 improves aging‐related cardiac dysfunction in mice

Aging is an important risk factor for cardiovascular diseases, and aging‐related cardiac dysfunction serves as a major determinant of morbidity and mortality in elderly populations. Our previous study has identified fibronectin type III domain‐containing 5 (FNDC5) and its cleaved form, irisin, as the cardioprotectant against doxorubicin‐induced cardiomyopathy. Herein, aging or matched young mice were overexpressed with FNDC5 by adeno‐associated virus serotype 9 (AAV9) vectors, or subcutaneously infused with irisin to uncover the role of FNDC5 in aging‐related cardiac dysfunction. To verify the involvement of nucleotide‐binding oligomerization domain‐like receptor with a pyrin domain 3 (NLRP3) and AMP‐activated protein kinase α (AMPKα), Nlrp3 or Ampkα2 global knockout mice were used. Besides, young mice were injected with AAV9‐FNDC5 and maintained for 12 months to determine the preventive effect of FNDC5. Moreover, neonatal rat cardiomyocytes were stimulated with tumor necrosis factor‐α (TNF‐α) to examine the role of FNDC5 in vitro. We found that FNDC5 was downregulated in aging hearts. Cardiac‐specific overexpression of FNDC5 or irisin infusion significantly suppressed NLRP3 inflammasome and cardiac inflammation, thereby attenuating aging‐related cardiac remodeling and dysfunction. In addition, irisin treatment also inhibited cellular senescence in TNF‐α‐stimulated cardiomyocytes in vitro. Mechanistically, FNDC5 activated AMPKα through blocking the lysosomal degradation of glucagon‐like peptide‐1 receptor. More importantly, FNDC5 gene transfer in early life could delay the onset of cardiac dysfunction during aging process. We prove that FNDC5 improves aging‐related cardiac dysfunction by activating AMPKα, and it might be a promising therapeutic target to support cardiovascular health in elderly populations.     

Dissection of Targeting Molecular Mechanisms of Aristolochic Acid-induced Nephrotoxicity via a Combined Deconvolution Strategy of Chemoproteomics and Metabolomics

Aristolochic acid (AA), mainly derived from herbal Aristolochia and Asarum plants, was listed as a human carcinogen class I in 2002. Aristolochic acid nephropathy (AAN) is a rapidly progressive tubulointerstitial nephritis and urothelial cancer caused by AA. However, the targeting molecular mechanisms of AAs-induced nephrotoxicity are largely unclear. This study aims to dissect targeting molecular mechanisms of AA-induced nephrotoxicity. Activity-based protein profiling (ABPP) in combination with cellular thermal shift assay (CETSA) was performed to identify the AAs binding target proteins. Our data indicated that several key enzymes in the metabolic process and mitochondrial respiration including IDH2 and MDH2 (Krebs cycle), PKM and LDH (aerobic respiration), FASN (fatty acid beta-oxidation), HK2 (glucose metabolism), and ATP synthase were identified as directly binding targets of AAs. Metabolomics and oxygen consumption rate (OCR) experiments further confirmed that AAs targeting proteins disrupted metabolic biosynthesis processes and impaired mitochondrial functions. Ultimately, AAs induced renal cells apoptosis by disturbing various biological processes. Cumulatively, AAs may directly bind to key proteins involved in the metabolic process and mitochondrial homeostasis, and finally induce aristolochic acid nephropathy. Our findings provide novel insight into underlying mechanisms of AAs-induced kidney toxicity, which may help to develop therapeutic strategies for AAN.     

Function and dysfunction of CD4+ T cells in the immune response to melanoma

A major difficulty for tumor immunotherapy derives from the phenomenon that the encounter of the immune system with an antigen does not necessarily result in activation, but may also be followed by the induction of tolerance either by anergy or physical deletion. It is well established that the immune system becomes alerted only in the face of danger, i.e. upon ligand recognition in the context of increased expression of costimulatory molecules, adhesion molecules, and MHC molecules on antigen-presenting cells (APC). The pivotal role of CD4⁺ T lymphocytes in this process has been established. However, encounter of CD4⁺ T cells with either MHC class II-expressing melanoma cells or certain tumor antigen-presenting APC has been reported to induce antigen-specific tolerance. Thus, as more is learned about the molecular regulation of immune responses and the role of CD4⁺ T cells in particular, additional strategies to block inhibitory pathways of T-cell activation will be developed. Such strategies are likely to be based on a modulation of the context in which antigen is encountered by the immune system, e.g. in situ cytokine therapy, induction of costimulatory molecules or the simulation of `danger' signals. Received: 20 March 1999 / Accepted: 3 May 1999     

Protective role of scutellarin on LPS induced – Acute lung injury and regulation of apoptosis,oxidative stress and reduction of mitochondrial dysfunction

Lung fluid accumulation was determined using wet/dry lung mass ratio. Rats subjected to LPS-induced acute lung injury (2.8 ± 0.33, P < 0.05) presented with a significantly higher wet to dry lung weight ration ratio than sham rats (1.6 ± 0.23, P < 0.05). These results demonstrate that acutely inured rats'' lungs were oedematous. On the other hand, treatment with scutellarin alone and in combination with a JNK inhibitor, SP600125, both significantly attenuated pulmonary edema as shown via reduced wet/dry lung mass ratios (1.7 ± 0.09 and 1.8 ± 0.23; P < 0.05, respectively). These results showed that the interventions were effective against LPS-induced edema of the lungs. However, the difference between treatment groups'' weight ratios was not statistically significant (P > 0.05). In the sham control rats, the levels of ROS and SOD production were maintained at a low and at a high concentration, respectively (P < 0.05). However, following LPS infusion, the ROS levels skyrocketed while that of SOD decreased significantly relative to the control rats (P < 0.05). Furthermore, we noted that pre-treatment with scutellarin reduced the ROS levels in LPS-injured rats while the SOD was increased to near control levels (P < 0.05). Moreover, the combined effect of scutellarin and JNK inhibitor SP600125 on the levels of ROS and the SOD activity followed a similar trend to that of scutellarin alone albeit with a lower magnitude of change. Our results also showed that the combinatorial treatment was not significantly different from scutellarin alone in terms of influence on the levels of ROS production and SOD activity (P > 0.05). The effect of Scutellarin on broncho-alveolar lavage fluid (BALF) cytokine secretion The expression of interleukins-1β, −18 and −6 in the broncho-alveolar lavage fluid were significantly upregulated by LPS infusion (P < 0.05). The rise was, however, attenuated via pre-treatment with scutellarin only or in conjunction with SP600125, a JNK inhibitor (all P < 0.05). On the contrary, we observed that LPS injection caused a reduction of interlekins −4 and −10 secreted in the BALF. Pre-treatment with scutellarin alone (P < 0.05) and not in combination with SP600125 or SP600125 was able to significantly reverse this noted down-regulation (all P > 0.05).     

与突触可塑性相关的神经振荡和信息流研究

作为一种有节律的神经活动,神经振荡现象发生在所有的神经系统中,例如大脑皮层、海马、皮层下神经核团以及感觉器官.本综述首先给出了已有的研究结果,即基于theta和gamma频段的同步神经振荡揭示了认知过程的起源与本质,如学习与记忆.然后介绍了关于神经振荡分析的新技术和算法,如表征神经元突触可塑性的神经信息流方向指数,并例...     

缺血/缺氧对自发性高血压大鼠肠系膜动脉血管舒缩功能的影响及其可能机制

高血压引起的脑卒中、冠心病等严重并发症的发生,均与组织缺血/缺氧导致的动脉血管痉挛有关。为了研究高血压大鼠肠系膜血管缺血/缺氧后的功能学改变,本研究采用三气培养箱模拟缺血/缺氧条件处理自发性高血压大鼠(spontaneously hypertensive rats,SHR)肠系膜动脉血管环,运用敏感的肌张力描记技术测定血管环对不同血管活性物质的反应性。结果显示:与WKY组大鼠相比,SHR组大鼠肠系膜动脉血管对收缩剂KCl和苯肾上腺素(phenylephrine,PE)的反应性明显提高,对内皮依赖的血管舒张剂乙酰胆碱(acetylcholine,ACh)的反应性显著降低;而与SHR组和急性缺血/缺氧对照(WKY+H)组相比较,高血压合并急性缺血/缺氧(SHR+H)组对KCl和PE的收缩反应显著性增加,对ACh的舒张反应明显降低。N-硝基-L-精氨酸甲酯(L-NAME)存在时,SHR+H组和SHR组血管环对ACh的舒张反应没有明显变化,而WKY组血管对ACh的舒张反应显著降低。与SHR组相比,SHR+H组CaCl2诱导的钙依赖性收缩曲线明显左移。在无钙K-H液中,SHR+H组PE和咖啡因(caffeine)诱导的...     

COVID‐19 and olfactory dysfunction: A possible associative approach towards neurodegenerative diseases

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), the agent of novel coronavirus 2019 (COVID‐19), has kept the globe in disquiets due to its severe life‐threatening conditions. The most common symptoms of COVID‐19 are fever, sore throat, and shortness of breath. According to the anecdotal reports from the health care workers, it has been suggested that the virus could reach the brain and can cause anosmia, hyposmia, hypogeusia, and hypopsia. Once the SARS‐CoV‐2 has entered the central nervous system (CNS), it can either exit in an inactive form in the tissues or may lead to neuroinflammation. Here, we aim to discuss the chronic infection of the olfactory bulb region of the brain by SARS‐CoV‐2 and how this could affect the nearby residing neurons in the host. We further review the probable cellular mechanism and activation of the microglia 1 phenotype possibly leading to various neurodegenerative disorders. In conclusion, SARS‐CoV‐2 might probably infect the olfactory bulb neuron enervating the nasal epithelium accessing the CNS and might cause neurodegenerative diseases in the future.     

Can mild cognitive impairment and Alzheimer’s disease be diagnosed by monitoring a miRNA triad in the blood?

Objectively diagnosing age‐related cognitive impairment (ACI), mild cognitive impairment (MCI), and early‐stage Alzheimer''s disease (AD) is a difficult task, as most cognitive impairment is clinically established via questionnaires, history, and physical examinations. A recent study has suggested that monitoring a miRNA triad, miR‐181a‐5p, miR‐146a‐5p, and miR‐148a‐3p can identify ACI and its progression to MCI and AD (Islam et al., EMBO Mol Med. 13: e14997, 2021). This commentary deliberates findings from this article, such as elevated levels of the miRNA triad in the brain impairing neural plasticity and cognitive function, the efficiency of measuring the miRNA triad in the circulating blood diagnosing MCI and AD, and the promise for improving cognitive function in MCI and AD by inhibiting this miRNA triad. Additional studies required prior to employing this miRNA triad in clinical practice are also discussed.     

海马位置细胞对空间信息的处理

海马位置细胞接收各种来源的空间信息后,可对这些信息进行加工处理,在海马内形成认知地图或加强联合皮层内细胞集群的突触联系以形成对空间位置的永久记忆。海马内的空间信息输出后,在伏核（nucleus accumbens,NAC）。内与其它来源的信息进行整合,最终通过运动环路形成目标指向性行为。