Vasoprotective effect of PDGF-CC mediated by HMOX1 rescues retinal degeneration

Blood vessel degeneration is critically involved in nearly all types of degenerative diseases. Therefore strategies to enhance blood vessel protection and survival are highly needed. In this study, using different animal models and cultured cells, we show that PDGF-CC is a potent vascular protective and survival factor. PDGF-CC deficiency by genetic deletion exacerbated blood vessel regression/degeneration in various animal models. Importantly, treatment with PDGF-CC protein not only increased the survival of retinal blood vessels in a model of oxygen-induced blood vessel regression but also markedly rescued retinal and blood vessel degeneration in a disease model of retinitis pigmentosa. Mechanistically, we revealed that heme oxygenase-1 (HMOX1) activity is critically required for the vascular protective/survival effect of PDGF-CC, because blockade of HMOX1 completely abolished the protective effect of PDGF-CC in vitro and in vivo. We further found that both PDGF receptors, PDGFR-β and PDGFR-α, are required for the vasoprotective effect of PDGF-CC. Thus our data show that PDGF-CC plays a pivotal role in maintaining blood vessel survival and may be of therapeutic value in treating various types of degenerative diseases.Blood vessel degeneration and regression are vital pathologies in numerous human diseases and are associated with nearly all types of degenerative diseases, such as retinitis pigmentosa (RP), diabetic retinopathy, age-related macular degeneration, Alzheimer’s disease, Parkinson''s disease, and amyotrophic lateral sclerosis (1–3). RP is a retinal degenerative disorder in which blood vessel degeneration contributes significantly to retinal atrophy, ultimately leading to loss of vision. In addition, recent studies have shown that prolonged treatment with antiangiogenic drugs may cause tissue degeneration (4–6). Given the increasing incidence of many degenerative diseases in an aging population and the rapidly growing clinical use of antiangiogenic drugs, there is an urgent need for strategies promoting blood vessel survival and protection. Because the pathological process of vascular degeneration involves complex mechanisms (7), treating such diseases remains challenging. Identifying effective vascular protective factors and the underlying mechanisms therefore is highly warranted.The PDGF family plays important roles in the vascular system (8–11). PDGF-CC was the third of the four PDGF family members discovered (12, 13), long after the finding of PDGF-AA and PDGF-BB. PDGF-CC is highly expressed in the vascular system (8, 14) and is produced as a secreted homodimer that binds to and activates the PDGF receptors PDGFR-α and PDGFR-β (12, 15). PDGF-CC is a critical survival/protective factor for neuronal cells (8, 9, 16) and macrophages (17) and has been shown to be a potent angiogenic factor (10, 15, 18–20). However, whether PDGF-CC plays a role in the survival/regression of blood vessels remains unknown thus far.In this study we used different animal models and cultured cells and investigated the potential effect of PDGF-CC on blood vessel survival. We found that PDGF-CC is a potent vasoprotective factor that rescues blood vessels from degeneration/regression under developmental and pathological conditions. Mechanistically, we show that heme oxygenase-1 (HMOX1), a potent antioxidative and anti-inflammatory factor, is required for the vasoprotective effect of PDGF-CC. Our data indicate that PDGF-CC may be of therapeutic use in treating different types of degenerative diseases in which blood vessel survival is impaired.     

PILRα and PILRβ have a siglec fold and provide the basis of binding to sialic acid

Paired immunoglobulin-like type 2 receptor α (PILRα) and β (PILRβ) belong to the PILR family and are related to innate immune regulation in various species. Despite their high sequence identity, PILRα and PILRβ are shown to have variant sialic acid (SA) binding avidities. To explore the molecular basis of this interaction, we solved the crystal structures of PILRα and PILRβ at resolutions of 1.6 Å and 2.2 Å, respectively. Both molecules adopt a typical siglec fold but use a hydrophobic bond to substitute the siglec-specific disulfide linkage for protein stabilization. We further used HSV-1 glycoprotein B (gB) as a representative molecule to study the PILR–SA interaction. Deploying site-directed mutagenesis, we demonstrated that three residues (Y2, R95, and W108) presented on the surface of PILRα form the SA binding site equivalent to those in siglecs but are arranged in a unique linear mode. PILRβ differs from PILRα in one of these three residues (L108), explaining its inability to engage gB. Mutation of L108 to tryptophan in PILRβ restored the gB-binding capacity. We further solved the structure of this PILRβ mutant complexed with SA, which reveals the atomic details mediating PILR/SA recognition. In comparison with the free PILR structures, amino acid Y2 oriented variantly in the complex structure, thereby disrupting the linear arrangement of PILR residues Y2, R95, and W108. In conclusion, our study provides significant implications for the PILR–SA interaction and paves the way for understanding PILR-related ligand binding.There are two members in the paired immunoglobulin-like type 2 receptor (PILR) family: PILRα and PILRβ (1). Both are expressed as a monomeric transmembrane protein with a single V-set Ig-like (IgV) extracellular domain (2). In the cytoplasmic tail, PILRα bears two immunoreceptor tyrosine-based inhibitory motifs that deliver inhibitory signals by recruiting SHP-1 and SHP-2, whereas PILRβ binds to the DAP-12 molecule bearing a tyrosine-based activation motif (ITAM) for transduction of activating signals (3). Several studies in mice showed that the former is always related to the inhibition of the immune system, whereas the latter plays pivotal roles in activating natural killer (NK) cells and dendritic cells (DCs) and is involved in the mass production of inflammatory factors during infection (4). In addition, a recent report also demonstrated that PILRα could function to regulate neutrophil infiltration via activation of integrins during inflammation (5). Reminiscent of these immune-modulation functions, both receptors are largely expressed on cells of the immune system, especially those of the myeloid lineage such as monocytes, DCs, and macrophages (6, 7). PILRβ is also abundantly expressed on NK cells (6).To exert their regulatory functions, the PILR receptors require engagement of specific ligands via their extracellular domains. Mouse CD99 is the only identified ligand for PILRβ to date (8). However, a set of host molecules, including mouse CD99 (8), PILR-associating neural protein (9), neuronal differentiation and proliferation factor-1 (NPDC1) (7), and collectin-12 (7), can recognize PILRα, implicating important roles of PILRα in diverse processes. In addition to the natural host ligands, PILRα is also hijacked by some viruses, such as HSV-1 (10) and porcine pseudorabies virus (11), for cell entry. The viral surface glycoprotein B (gB) is shown to recognize PILRα and mediate the virus infection (10, 11). Elucidation of the mechanisms underlying these ligand–receptor interactions is important in understanding PILR-involved physiological processes. Current knowledge on these interactions, however, only indicates the involvement of sialic acid (SA) moieties residing on the ligand surface in PILR engagement (7, 8, 12). This character drew parallels between PILRs and siglecs, a family of SA-binding Ig-type lectins (13). Nevertheless, PILRs, unlike siglec molecules, are of low SA-binding avidity and fail to bind to single SA sugars in a glycan microarray (14). The molecular basis of the PILR–SA interaction is an interesting, yet unresolved, issue.In this study, we first solved both PILRα and PILRβ structures, demonstrating that they have siglec-like folds but maintain protein stability by hydrophobic interactions, different from siglecs, which have disulfide bonds. We also developed a Biacore-based assay for quantitative calculations of the PILR–SA interaction based on HSV-1 gB protein. A triresidue motif consisting of Y2, R95, and W108 was identified as a key SA-binding site in PILRα, and a W108L substitution in the motif was shown to be responsible for the inability of PILRβ to interact with gB. We further reported a complex structure of SA bound to a PILRβ L108W mutant protein, thereby presenting the atomic details mediating the PILR–SA interaction.     

A facile preparation method for new two-component supramolecular hydrogels and their performances in adsorption,catalysis, and stimuli-response

In this study, we prepared a novel multifunctional two-component supramolecular hydrogel (T-G hydrogel) via two organic molecules in ethanol/water mixed solvents. In addition, we prepared gold nanoparticle/T-G (AuNPs/T-G) composite hydrogels using T-G hydrogel as a template for stabilizing AuNPs by adding HAuCl₄ and NaBH₄ during the heating and cooling process of T-G hydrogels. The morphology and microstructure of the as-prepared hydrogels were characterized using SEM, TEM, XRD, and FT-IR. The hydrogels prepared by solutions that contained different ethanol/water volume ratios exhibited different microstructures, such as sheets, strips, and rods. The obtained T-G hydrogels exhibited a sensitive response to pH changes in the process of sol–gel transformation and showed good adsorption properties for model organic dyes. In the presence of NaBH₄, the obtained AuNP/T-G composite hydrogels exhibited the excellent catalytic performance for 4-nitrophenol (4-NP) degradation. Thus, the current research provides new clues in developing new multifunctional two-component supramolecular gel materials and exhibits potential applications for wastewater treatment.

New two-component supramolecular hydrogels were prepared via a self-assembly process, demonstrating potential applications in adsorption and catalysis as well as sensor materials.     

Successful recovery of recurrence of positive SARS-CoV-2 RNA in COVID-19 patient with systemic lupus erythematosus: a case report and review

Clinical Rheumatology - COVID-19 has become a global concern. A large number of reports have explained the clinical characteristics and treatment strategies of COVID-19, but the characteristics and...     

Protective effect of D-pinitol on the experimental spinal cord injury in rats

Metabolic Brain Disease - Spinal cord injury (SCI) is the major cause of the spinal damage affecting motor and sensory function. Thus, the present study was conducted to investigate the effect of...     

瞬时受体电位通道A1和瞬时受体电位通道M8在冷过敏中的作用

背景 冷过敏是炎性痛和神经病理性疼痛的一个常见症状,其内在机制尚不清楚. 目的 阐明瞬时受体电位通道A1 （transient receptor potential cation channel,subfamily A,member 1,TRPA1）和瞬时受体电位通道M8（transient receptor potential melastatin 8,TRPM8）参与冷过敏的机制. 内容 综述TRPA1和TRPM8的分子结构和门控机制及其在有害的冷、炎性痛和神经病理性疼痛的冷过敏形成、维持中的作用等方面的研究. 趋向 深入研究TRPA1和TRPM8在冷过敏发生中的作用,有助于阐明冷过敏的机制,并为开发拮抗剂提供理论依据.     

日间手术中心复合局部麻醉下腰骶部筋膜脂肪疝的治疗

目的：探讨分析日间手术中心（ambulatory surgery center,ASC）复合局部麻醉下腰骶部筋膜脂肪疝的手术治疗体会。方法回顾性分析2012年10月至2013年7月,佛山市第一人民医院ASC接收手术治疗腰骶部筋膜脂肪疝患者33例的临床资料。手术方式：疝囊口扩大＋内容物切除术。麻醉方式：复方利多卡因乳膏表面麻醉＋哌卡因局部浸润麻醉。结果本组患者均在复合局部麻醉下顺利完成手术治疗,术中、术后无手术相关并发症发生。术后随访6个月,手术疗效价：优良率为93．94％。结论 ACS复合局部麻醉下手术治疗腰骶部筋膜脂肪疝疗效确切、安全可靠,减少了患者在院时间,节省了医疗成本。     

The exponential function transforms the Abbreviated Injury Scale,which both improves accuracy and simplifies scoring

Purpose

We present here the exponential function which transforms the Abbreviated Injury Scale (AIS). It is called the Exponential Injury Severity Score (EISS), and significantly outperforms the venerable but dated New Injury Severity Score (NISS) and Injury Severity Score (ISS) as a predictor of mortality.

Methods

The EISS is defined as a change of AIS values by raising each AIS severity score (1–6) by 3 taking a power of AIS minus 2 and then summing the three most severe injuries (i.e., highest AIS), regardless of body regions. EISS values were calculated for every patient in two large independent data sets: 3,911 and 4,129 patients treated during a 6-year period at the Class A tertiary hospitals in China. The power of the EISS to predict mortality was then compared with previously calculated NISS values for the same patients in each of the two data sets.

Results

We found that the EISS is more predictive of survival [Zhejiang: area under the receiver operating characteristic curve (AUC): NISS = 0.932, EISS = 0.949, P = 0.0115; Liaoning: AUC: NISS = 0.924, EISS = 0.942, P = 0.0139]. Moreover, the EISS provides a better fit throughout its entire range of prediction (Hosmer–Lemeshow statistic for Zhejiang: NISS = 21.86, P = 0.0027, EISS = 13.52, P = 0.0604; Liaoning: NISS = 23.27, P = 0.0015, EISS = 15.55, P = 0.0164).

Conclusions

The EISS may be used as the standard summary measure of human trauma.     

中药浴联合穴位按摩佐治小儿发热效果观察

目的观察中药浴联合穴位按摩辅助治疗小儿外感发热的临床效果。方法将174例急性上呼吸道感染致发热患儿随机分为对照组(88例)和观察组(86例),对照组在常规治疗的基础上,给予温水洗浴;观察组采用中药洗浴联合穴位按摩。结果两组患儿洗浴前后体温、解热时间比较,差异有统计学意义(P0.05,P0.01)。结论两种辅助治疗小儿发热的方法均有效,中药药浴联合穴位按摩治疗的临床效果优于温水洗浴。