Highlights • PDGF-C promotes blood vessel growth and maturation. • PDGF-C is a potent survival factor for different types of neurons. • The expression and function of PDGF-C and its receptors differ ...from those of VEGF. • PDGF-C may represent a new paradigm of neurovascular interaction and crosstalk.
RATIONALE:Multiple sclerosis (MS) and its mouse model, experimental autoimmune encephalomyelitis (EAE), are inflammatory disorders of the central nervous system (CNS). The function of platelets in ...inflammatory and autoimmune pathologies is thus far poorly defined.
OBJECTIVE:We addressed the role of platelets in mediating CNS inflammation in EAE.
METHODS AND RESULTS:We found that platelets were present in human MS lesions as well as in the CNS of mice subjected to EAE but not in the CNS from control nondiseased mice. Platelet depletion at the effector-inflammatory phase of EAE in mice resulted in significantly ameliorated disease development and progression. EAE suppression on platelet depletion was associated with reduced recruitment of leukocytes to the inflamed CNS, as assessed by intravital microscopy, and with a blunted inflammatory response. The platelet-specific receptor glycoprotein Ibα (GPIbα) promotes both platelet adhesion and inflammatory actions of platelets and targeting of GPIbα attenuated EAE in mice. Moreover, targeting another platelet adhesion receptor, glycoprotein IIb/IIIa (GPIIb/IIIa), also reduced EAE severity in mice.
CONCLUSIONS:Platelets contribute to the pathogenesis of EAE by promoting CNS inflammation. Targeting platelets may therefore represent an important new therapeutic approach for MS treatment.
VEGF-B, a homolog of VEGF discovered a long time ago, has not been considered an important target in antiangiogenic therapy. Instead, it has received little attention from the field. In this study, ...using different animal models and multiple types of vascular cells, we revealed that although VEGF-B is dispensable for blood vessel growth, it is critical for their survival. Importantly, the survival effect of VEGF-B is not only on vascular endothelial cells, but also on pericytes, smooth muscle cells, and vascular stem/progenitor cells. In vivo, VEGF-B targeting inhibited both choroidal and retinal neovascularization. Mechanistically, we found that the vascular survival effect of VEGF-B is achieved by regulating the expression of many vascular prosurvival genes via both NP-1 and VEGFR-1. Our work thus indicates that the function of VEGF-B in the vascular system is to act as a "survival," rather than an "angiogenic" factor and that VEGF-B inhibition may offer new therapeutic opportunities to treat neovascular diseases.
Enhanced platelet-derived growth factor (PDGF) signaling in glioma drives its development and progression. In this study, we define a unique role for stroma-derived PDGF signaling in maintaining ...tumor homeostasis within the glioma microenvironment. Large numbers of PDGF receptor-α (PDGFRα)-expressing stromal cells derived from oligodendrocytes progenitor cells (OPC) were discovered at the invasive front of high-grade gliomas, in which they exhibited a unique perivascular distribution. In PDGFRα-deficient host mice, in which orthotopic Gl261 tumors displayed reduced outgrowth, we found that tumor-associated blood vessels displayed smaller lumens and normalized vascular morphology, with tumors in host animals injected with the vascular imaging agent gadolinium also being enhanced less avidly by MRI. Notably, glioma-associated OPC promoted endothelial sprouting and tubule formation, in part by abrogating the inhibitory effect that perivascular astrocytes exert on vascular endothelial conjunctions. Stromal-derived PDGF-CC was crucial for the recruitment and activation of OPC, insofar as mice genetically deficient in PDGF-CC phenocopied the glioma/vascular defects observed in PDGFRα-deficient mice. Clinically, we showed that higher levels of PDGF-CC in glioma specimens were associated with more rapid disease recurrence and poorer overall survival. Our findings define a PDGFRα/PDGF-CC signaling axis within the glioma stromal microenvironment that contributes to vascular remodeling and aberrant tumor angiogenesis in the brain.
Azithromycin is used as an alternative medicine in patients with syphilis who are intolerant to penicillin. Nevertheless, the report of treatment failure of azithromycin for patients with syphilis ...has raised concerns in China in the past years. In this study, 178 patients with early syphilis, who were treated in sexually transmitted infections clinics in four cities in Guangxi Zhuang Autonomous Region were enrolled to investigate the regional prevalence of Treponema pallidum strain resistant to azithromycin. Nested PCR was performed to amplify the 23S ribosomal RNA (23SrRNA) gene. The point mutation of A2058G in 23SrRNA, which confers Treponema pallidum resistance to azithromycin, was measured by endonuclease digestion of PCR amplification products using MboII. A2058G point mutation was detected in 91.0% (162/178; 95% CI, 86.8%, 95.2%) of the specimens, but no difference in prevalence of azithromycin resistance was found between the patients who had taken antibiotics before enrollment and the patients who had not (91.8% vs. 89.4%), nor between the patients with and without past sexually transmitted infections (87.1% vs. 93.1%). We concluded that azithromycin may not be suitable for syphilis as a treatment option in Guangxi Zhuang Autonomous Region because of the extremely high prevalence of resistance in the general syphilis population.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Ocular neovascularization is a devastating pathology of numerous ocular diseases and is a major cause of blindness. Caveolin-1 (Cav-1) plays important roles in the vascular system. However, little is ...known regarding its function and mechanisms in ocular neovascularization. Here, using comprehensive model systems and a cell permeable peptide of Cav-1, cavtratin, we show that Cav-1 is a critical player in ocular neovascularization. The genetic deletion of Cav-1 exacerbated and cavtratin administration inhibited choroidal and retinal neovascularization. Importantly, combined administration of cavtratin and anti–VEGF-A inhibited neovascularization more effectively than monotherapy, suggesting the existence of other pathways inhibited by cavtratin in addition to VEGF-A. Indeed, we found that cavtratin suppressed multiple critical components of pathological angiogenesis, including inflammation, permeability, PDGF-B and endothelial nitric oxide synthase expression (eNOS). Mechanistically, we show that cavtratin inhibits CNV and the survival and migration of microglia and macrophages via JNK. Together, our data demonstrate the unique advantages of cavtratin in antiangiogenic therapy to treat neovascular diseases.
Amblyopia is a common eye disease characterized by impaired best-corrected visual acuity. It starts in early childhood and leads to permanent vision reduction if left untreated. Even though many ...young patients with amblyopia are well treated in clinical practice, the underlying mechanism remains to be elucidated, which limits not only our understanding of this disease but also the therapeutic approach. To investigate the molecular mechanism of amblyopia, primate and rodent models of monocular-deprived amblyopia were created for mRNA screening and confirmation. We obtained 818 differentially expressed genes from the dorsal lateral geniculate nucleus (dLGN) of a primate model of amblyopia. After Gene Ontology and kyoto encyclopedia of genes and genomes (KEGG) enrichment analyses, the main enriched pathways were related to neural development. Interestingly, a particular neurotransmitter pathway, the dopaminergic pathway, was identified. The downregulation of dopamine receptor D1 (
DRD1
) was confirmed in both monkey and mouse samples. Furthermore, the immunofluorescence staining indicated that DRD1 expression was downregulated in both ventrolateral region of the contralateral dLGN and the dorsomedial region of the ipsilateral dLGN in the mouse model. The regions with downregulated expression of DRD1 were the downstream targets of the visual projection from the amblyopic eye. This study suggested that the downregulation of DRD1 in the LGN may be a cause for amblyopia. This may also be a reason for the failure of some clinical cases of levodopa combined with carbidopa applied to amblyopes.
Sumoylation is a post-translational modification that was originally thought to only target nuclear proteins. Evidence has emerged, however, that the role of sumoylation is much more diverse: three ...plasma membrane proteins belonging to different protein families (glucose transporters, K+ channels and metabotropic glutamate receptors) have been shown to be sumoylated. In addition, sumoylation of transcription factors, such as myocyte enhancer factor 2 (MEF2), was found to regulate synapse formation. A major role of sumoylation in other systems is to modify protein–protein interactions, and because protein interactions are particularly elaborate in the nervous system and crucial for synapse formation and function, sumoylation could constitute a major regulatory mechanism in neurons. In this review, we evaluate the available data and discuss possible roles for sumoylation in the regulation of crucial neurobiological processes, such as neuronal development and synaptic transmission.
Aim:
To investigate the incidence and clinical features of primary iris and ciliary body cysts in Chinese primary angle closure disease (PACD). Patients were evaluated by measuring and analyzing the ...cysts with an ultrasound biomicroscope (UBM).
Methods:
The data of patients diagnosed with PACD were reviewed. Demographic data were collected, and the cyst number, size, location, and trabecular-iris angle (TIA) were measured, with the size including the longest diameter (LD) and its corresponding vertical diameter (CVD).
Results:
A total of 1,334 cases (2,317 eyes) were reviewed, and 409 cysts were found in 131 cases (168 eyes), with an average of 2.43 ± 3.14 cysts per eye. The ages of the patients with cysts ranged from 25 to 80 years, with an average age of 55.24 ± 12.22 years. The detection rate was 7.3%, and the majority of cysts were located in the iridociliary sulcus. Among the 131 patients, 94 had monocular cysts, while binocular cysts occurred in 37 patients. The locations of the cysts in both eyes were mainly in the inferior and temporal quadrants (42.5 and 34.0%, respectively). The cysts were mainly of medium size (49.9%), followed by small cysts (33.3%), large cysts (14.7%) and giant cysts (2.2%). The average LD was 0.68 ± 0.33 mm, and the average CVD was 0.45 ± 0.23 mm. There were no statistically significant differences in the TIA between the cyst area and unaffected area.
Conclusions:
The incidence of cysts is 7.3% in the PACD population. The cysts are mainly monocular, medium in size, and located in the iridociliary sulcus. Additionally, the cysts were located mainly in the inferior and temporal quadrants. These cysts have little effect on the anterior chamber angle.
The importance of identifying VEGF-independent pathways in pathological angiogenesis is increasingly recognized as a result of the emerging drug resistance to anti-VEGF therapies. PDGF-CC is the ...third member of the PDGF family discovered after more than two decades of studies on PDGF-AA and PDGF-BB. The biological function of PDGF-CC and the underlying cellular and molecular mechanisms remain largely unexplored. Here, using different animal models, we report that PDGF-CC inhibition by neutralizing antibody, shRNA, or genetic deletion suppressed both choroidal and retinal neovascularization. Importantly, we revealed that PDGF-CC targeting acted not only on multiple cell types important for pathological angiogenesis, such as vascular mural and endothelial cells, macrophages, choroidal fibroblasts and retinal pigment epithelial cells, but also on the expression of other important angiogenic genes, such as PDGF-BB and PDGF receptors. At a molecular level, we found that PDGF-CC regulated glycogen synthase kinase (GSK)—3β phosphorylation and expression both in vitro and in vivo. Activation of GSK3β impaired PDGF-CC—induced angiogenesis, and inhibition of GSK3β abolished the antiangiogenic effect of PDGF-CC blockade. Thus, we identified PDGF-CC as an important candidate target gene for antiangiogenic therapy, and PDGF-CC inhibition may be of therapeutic value in treating neovascular diseases.
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