Novel nano-carriers with N-formylmethionyl-leucyl-phenylalanine-modified liposomes improve effects of C16-angiopoietin 1 in acute animal model of multiple sclerosis.

Gradual loss of neuronal structure and function due to impaired blood-brain barrier (BBB) and neuroinflammation are important factors in multiple sclerosis (MS) progression. Our previous studies demonstrated that the C16 peptide and angiopoietin 1 (Ang-1) compound (C + A) could modulate inflammation and vascular protection in many models of MS. In this study, nanotechnology and a novel nanovector of the leukocyte chemotactic peptide N-formyl-methionyl-leucyl-phenylalanine (fMLP) were used to examine the effects of C + A on MS. The acute experimental autoimmune encephalomyelitis (EAE) model of MS was established in Lewis rats. The C + A compounds were conjugated to control nano-carriers and fMLP-nano-carriers and administered to animals by intravenous injection. The neuropathological changes in the brain cortex and spinal cord were examined using multiple approaches. The stimulation of vascular injection sites was examined using rabbits. The results showed that all C + A compounds (C + A alone, nano-carrier C + A, and fMLP-nano-carrier C + A) reduced neuronal inflammation, axonal demyelination, gliosis, neuronal apoptosis, vascular leakage, and BBB impairment induced by EAE. In addition, the C + A compounds had minimal side effects on liver and kidney functions. Furthermore, the fMLP-nano-carrier C + A compound had better effects compared to C + A alone and the nano-carrier C + A. This study indicated that the fMLP-nano-carrier C + A could attenuate inflammation-related pathological changes in EAE and may be a potential therapeutic strategy for the treatment of MS and EAE.

Co-Application of C16 and Ang-1 Improves the Effects of Levodopa in Parkinson Disease Treatment.

Background: Levodopa is regarded as a standard medication in Parkinson disease (PD) treatment. However, long-term administration of levodopa leads to levodopa-induced dyskinesia (LID), which can markedly affect patient quality of life. Previous studies have shown that neuroinflammation in the brain plays a role in LID and increases potential neuroinflammatory mediators associated with the side effects of levodopa. Objective: The treatment effect of C16 (a peptide that competitively binds integrin αvß3 and inhibits inflammatory cell infiltration) and angiopoietin-1 (Ang-1; a vascular endothelial growth factor vital for blood vessel protection), along with levodopa, was evaluated in a rodent model of PD. Methods: We administered a combination of C16 and Ang-1 in a rodent model of PD induced by MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). Seventy-five mice were randomly divided into five treatment groups: control, vehicle, levodopa, C16+Ang-1, and levodopa+C16+Ang-1. Behavioral, histological, and electrophysiological experiments were used to determine neuron function and recovery. Results: The results showed that C16+Ang-1 treatment alleviated neuroinflammation in the CNS and promoted the recovery effects of levodopa on neural function. Conclusion: Our study suggests that C16+Ang-1 can compensate for the shortcomings of levodopa, improve the CNS microenvironment, and ameliorate the effects of levodopa. This treatment strategy could be developed as a combinatorial therapeutic in the future.

Adjusting vascular permeability, leukocyte infiltration, and microglial cell activation to rescue dopaminergic neurons in rodent models of Parkinson's disease.

Animal studies have indicated that increased blood-brain barrier (BBB) permeability and inflammatory cell infiltration are involved during the progression of Parkinson's disease (PD). This study used C16, a peptide that competitively binds to integrin αvß3 and inhibits inflammatory cell infiltration, as well as angiopoietin-1 (Ang-1), an endothelial growth factor crucial for blood vessel protection, to reduce inflammation and improve the central nervous system (CNS) microenvironment in murine models of PD. The combination of C16 and Ang-1 yielded better results compared to the individual drugs alone in terms of reducing dopaminergic neuronal apoptosis, ameliorating cognitive impairment, and electrophysiological dysfunction, attenuating inflammation in the CNS microenvironment, and improving the functional disability in PD mice or rats. These results suggest neuroprotective and anti-inflammatory properties of the C16 peptide plus Ang-1 in PD.

Combined treatment with C16 peptide and angiopoietin-1 confers neuroprotection and reduces inflammation in 3-nitropropionic acid-induced dystonia mice.

Dystonia is a disorder associated with abnormalities in many brain regions including the basal ganglia and cerebellum. The toxin 3-Nitropropionic acid (3-NP) can induce neuropathologies in the mice striatum and nigra substance, including excitotoxicity, neuroinflammation, and extensive neuronal atrophy, characterized by progressive motor dysfunction, dystonia, and memory loss, mimicking those observed in humans. We established a mouse model of dystonia by administering 3-NP. Given the reported neuroprotective effects of the endothelial growth factor angiopoietin-1 (Ang-1) and the anti-inflammatory integrin αvß3 binding peptide C16, we performed this study to evaluate their combined effects on 3-NP striatal toxicity and their therapeutic potential with multiple methods using an in vivo mouse model. Sixty mice were equally and randomly divided into three groups: control, 3-NP treatment, and 3-NP+C16+Ang-1 treatment. Behavioral and electrophysiological tests were conducted and the effect of the combined C16+Ang-1 treatment on neural function recovery was determined. We found that C16+Ang-1 treatment alleviated 3-NP-induced behavioral, biochemical, and cellular alterations in the central nervous system and promoted function recovery by restoring vascular permeability and reducing inflammation in the micro-environment. In conclusion, our results confirmed the neuroprotective effect of combined C16+Ang-1 treatment and suggest their potential as a complementary therapeutic against 3-NP-induced dystonia.

Angiopoietin-1 and ανß3 integrin peptide promote the therapeutic effects of L-serine in an amyotrophic lateral sclerosis/Parkinsonism dementia complex model.

Amyotrophic lateral sclerosis (ALS) is an adult disorder of neurodegeneration that manifests as the destruction of upper and lower motor neurons. Beta-N-methylamino-L-alanine (L-BMAA), an amino acid not present in proteins, was found to cause intraneuronal protein misfolding and to induce ALS/Parkinsonism dementia complex (PDC), which presents symptoms analogous to those of Alzheimer's-like dementia and Parkinsonism. L-serine suppresses the erroneous incorporation of L-BMAA into proteins in the human nervous system. In this study, angiopoietin-1, an endothelial growth factor crucial for vascular development and angiogenesis, and the integrin αvß3 binding peptide C16, which inhibits inflammatory cell infiltration, were utilized to improve the local microenvironment within the central nervous system of an ALS/PDC rodent model by minimizing inflammation. Our results revealed that L-serine application yielded better effects than C16+ angiopoietin-1 treatment alone for alleviating apoptotic and autophagic changes and improving cognition and electrophysiological dysfunction, but not for improving the inflammatory micro-environment in the central nerve system, while further advances in attenuating the functional disability and pathological impairment induced by L-BMAA could be achieved by co-treatment with C16 and angiopoietin-1 in addition to L-serine. Therefore, C16+ angiopoietin-1 could be beneficial as a supplement to promote the effects of L-serine treatment.

Correlation of enhancement degree on contrast-enhanced ultrasound with histopathology of carotid plaques and serum high sensitive C-reactive protein levels in patients undergoing carotid endarterectomy.

This study was undertaken to investigate the correlation of the enhancement degree on contrast-enhanced ultrasound (CEUS) with the histopathology of carotid plaques and the serum high sensitive C-reactive protein (hs-CRP) levels in patients undergoing carotid endarterectomy (CEA). Carotid CEUS was performed preoperatively in 115 patients who would undergo CEA, and the enhancement degree of the carotid plaques was evaluated by both the visual semiquantitative analysis and the quantitative time-intensity curve analysis. Serum hs-CRP levels were detected using the particle-enhanced immunoturbidimetric assay also before the operation. Additionally, the carotid plaque samples were subjected to histopathological examination postoperatively. The density of neovessels and the number of macrophages in the plaques were assessed by immunohistochemistry. The results showed that among the 115 patients, grade 0 plaque contrast enhancement was noted in 35 patients, grade 1 in 48 patients and grade 2 in 32 patients. The degree of plaque enhancement, the density of neovessels, the number of macrophages, and the hs-CRP levels were highest in the grade 2 patients. Correlation analysis showed that the enhancement degree of the carotid plaques was closely related to the immunohistochemical parameters of the plaques and the serum hs-CRP levels. It was suggested that the carotid plaque enhancement on CEUS can be used to evaluate the vulnerability of carotid plaques.

Correlation of Enhancement Degree on Contrast-enhanced Ultrasound with Histopathology of Carotid Plaques and Serum High Sensitive C-Reactive Protein Levels in Patients Undergoing Carotid Endarterectomy / 华中科技大学学报（医学）（英德文版）

This study was undertaken to investigate the correlation of the enhancement degree on contrast-enhanced ultrasound (CEUS) with the histopathology of carotid plaques and the serum high sensitive C-reactive protein (hs-CRP) levels in patients undergoing carotid endarterectomy (CEA).Carotid CEUS was performed preoperatively in 115 patients who would undergo CEA,and the enhancement degree of the carotid plaques was evaluated by both the visual semiquantitative analysis and the quantitative time-intensity curve analysis.Serum hs-CRP levels were detected using the particle-enhanced immunoturbidimetric assay also before the operation.Additionally,the carotid plaque samples were subjected to histopathological examination postoperatively.The density of neovessels and the number of macrophages in the plaques were assessed by immunohistochemistry.The results showed that among the 115 patients,grade 0 plaque contrast enhancement was noted in 35 patients,grade 1 in 48 patients and grade 2 in 32 patients.The degree of plaque enhancement,the density ofneovessels,the number of macrophages,and the hs-CRP levels were highest in the grade 2 patients.Correlation analysis showed that the enhancement degree of the carotid plaques was closely related to the immunohistochemical parameters of the plaques and the serum hs-CRP levels.It was suggested that the carotid plaque enhancement on CEUS can be used to evaluate the vulnerability of carotid plaques.