Pulmonary delivery of the broad-spectrum matrix metalloproteinase inhibitor marimastat diminishes multiwalled carbon nanotube-induced circulating bioactivity without reducing pulmonary inflammation

Background Multiwalled carbon nanotubes (MWCNT) are an increasingly utilized engineered nanomaterial that pose the potential for significant risk of exposure-related health outcomes. The mechanism(s) underlying MWCNT-induced toxicity to extrapulmonary sites are still being defined. MWCNT-induced serum-borne bioactivity appears to dysregulate systemic endothelial cell function. The serum compositional changes after MWCNT exposure have been identified as a surge of fragmented endogenous peptides, likely derived from matrix metalloproteinase (MMP) activity. In the present study, we utilize a broad-spectrum MMP inhibitor, Marimastat, along with a previously described oropharyngeal aspiration model of MWCNT administration to investigate the role of MMPs in MWCNT-derived serum peptide generation and endothelial bioactivity. Results C57BL/6 mice were treated with Marimastat or vehicle by oropharyngeal aspiration 1 h prior to MWCNT treatment. Pulmonary neutrophil infiltration and total bronchoalveolar lavage fluid protein increased independent of MMP blockade. The lung cytokine profile similarly increased following MWCNT exposure for major inflammatory markers (IL-1β, IL-6, and TNF-α), with minimal impact from MMP inhibition. However, serum peptidomic analysis revealed differential peptide compositional profiles, with MMP blockade abrogating MWCNT-derived serum peptide fragments. The serum, in turn, exhibited differential potency in terms of inflammatory bioactivity when incubated with primary murine cerebrovascular endothelial cells. Serum from MWCNT-treated mice led to inflammatory responses in endothelial cells that were significantly blunted with serum from Marimastat-treated mice. Conclusions Thus, MWCNT exposure induced pulmonary inflammation that was largely independent of MMP activity but generated circulating bioactive peptides through predominantly MMP-dependent pathways. This MWCNT-induced lung-derived bioactivity caused pathological consequences of endothelial inflammation and barrier disruption.

Serum Peptide Immunoglobulin G Autoantibody Response in Patients with Different Central Nervous System Inflammatory Demyelinating Disorders

Previous efforts to discover new surrogate markers for the central nervous system (CNS) inflammatory demyelinating disorders have shown inconsistent results; moreover, supporting evidence is scarce. The present study investigated the IgG autoantibody responses to various viral and autoantibodies-related peptides proposed to be related to CNS inflammatory demyelinating disorders using the peptide microarray method. We customized a peptide microarray containing more than 2440 immobilized peptides representing human and viral autoantigens. Using this, we tested the sera of patients with neuromyelitis optica spectrum disorders (NMOSD seropositive, n = 6; NMOSD seronegative, n = 5), multiple sclerosis (MS, n = 5), and myelin-oligodendrocyte glycoprotein antibody-associated disease (MOGAD, n = 6), as well as healthy controls (HC, n = 5) and compared various peptide immunoglobulin G (IgG) responses between the groups. Among the statistically significant peptides based on the pairwise comparisons of IgG responses in each disease group to HC, cytomegalovirus (CMV)-related peptides were most clearly distinguishable among the study groups. In particular, the most significant differences in IgG response were observed for HC vs. MS and HC vs. seronegative NMOSD (p = 0.064). Relatively higher IgG responses to CMV-related peptides were observed in patients with MS and NMOSD based on analysis of the customized peptide microarray.

Role of Matrix Metalloproteinases in Multiwalled Carbon Nanotube-mediated Pulmonary and Systemic Inflammatory Activation

Background: Multiwalled carbon nanotubes (MWCNT) are an increasingly utilized engineered nanomaterial that pose the potential for significant risk of exposure-related health outcomes. The mechanism(s) underlying MWCNT-induced toxicity to extrapulmonary sites are still being defined. MWCNT-induced serum-borne bioactivity appears to dysregulate systemic endothelial cell function. The serum compositional changes after MWCNT exposure have been identified as a surge of fragmented endogenous peptides, likely derived from matrix metalloproteinase (MMP) activity. In the present study, we utilize a broad-spectrum MMP inhibitor, Marimastat, along with a previously described oropharyngeal aspiration model of MWCNT administration to investigate the role of MMPs in MWCNT-derived serum peptide generation and endothelial bioactivity. Results: C57BL/6 mice were treated with Marimastat or vehicle by oropharyngeal aspiration 1h prior to MWCNT treatment. Pulmonary neutrophil infiltration and total bronchoalveolar lavage fluid protein increased in a dose-dependent manner, independent of MMP blockade. The lung cytokine profile similarly increased following MWCNT exposure for major inflammatory markers (IL-1β, IL-6, and TNFα), with minimal impact from MMP inhibition. However, serum peptidomic analysis revealed differential peptide compositional profiles, with MMP blockade abrogating MWCNT-derived serum peptide fragments. The serum, in turn, exhibited differential potency in terms of inflammatory bioactivity when incubated with primary murine cerebrovascular endothelial cells. Serum from MWCNT-treated mice led to inflammatory responses in endothelial cells that were significantly blunted with serum from Marimastat-treated mice. Conclusion: Thus, MWCNT exposure induced pulmonary inflammation that was largely independent of MMP activity, but generated circulating bioactive peptides through predominantly MMP-dependent pathways. This MWCNT-induced lung-derived bioactivity caused pathological consequences of endothelial inflammation and barrier disruption.

Serum peptide fraction of patients with myocardial infarction and various forms of angina

Today, there is a growing worldwide trend of coronary heart disease, which is the most common cause of death among the working population. Along with the development of effective drugs, no less acute is the question of improving the means of diagnosing coronary heart disease, as well as means of monitoring the course of the disease and the effectiveness of its treatment. Given that angina is often the first clinical manifestation of coronary heart disease, it is important to study and identify early markers of this pathological condition. A promising direction in this context may be the study of the dynamics of changes in the peptide profile in the bloodstream of patients with various forms of angina and myocardial infarction, the second most important manifestation of coronary heart disease. The results showed that myocardial infarction, as well as various forms of angina, is accompanied by the accumulation in the bloodstream of patients of proteins and peptides. Chromatographic separation of peptide fractions obtained from the serum of patients of different experimental groups was performed. It was found that in the bloodstream of patients with myocardial infarction and various forms of angina, there were not only quantitative changes in the peptide pool, but also the accumulation of peptides that are atypical for the physiological state of the organism. On the one hand, such peptides may have effector properties and be involved in inhibiting the progression of the pathological condition and contributed to the normalization of homeostasis. On the other hand, the circulation of such peptides in the bloodstream may pose a potential threat of triggering non-specific mechanisms aimed at intensifying the pathological process. Further research is needed to confirm one of this hypothesis.

Practice pattern and use of serum peptide formulation in patients with alopecia: results of an opinion survey among dermatologists in India

<p>To evaluate practice pattern and preference for use of serum peptide formulation by dermatologists for the treatment of alopecia. Dermatologists in India were administered a questionnaire consisting of questions related to number of patients with alopecia seen every week, investigations, prevalence of nutritional deficiencies and use of serum peptide formulation in telogen effluvium (TE) and androgenetic alopecia (AGA). The responses were analysed as number and percentages. Out of 124 dermatologists, 38 (31%) reported that they see 11-15 patients with TE every week and 31 (25%) reported seeing 11-15 patients of AGA per week. According to 51 (41%) dermatologists, 40-60% patients with hair loss have some nutritional deficiency and 95 (77%) reported that iron deficiency profile, thyroid stimulating hormone (TSH), vitamin B1 and vitamin D level estimation is necessary in patients with TE. A total of 86 (69%) dermatologists preferred serum peptide formulation in patients with TE and AGA. Ninety nine (80%) and 75 (60%) dermatologists reported “very good” or “good” efficacy of serum peptide in TE and AGA respectively. Ninety nine (80%) dermatologists said, gender is not an important criterion for choosing a serum peptide in hair fall. For aesthetics related parameters, Folliserum (Abbott Health care Pvt Ltd) was rated as “Very good” and “Good” by 66 (53%) and 38 (31%) dermatologists respectively. According to dermatologists in India, nutritional deficiency is common in patients with alopecia. Majority of the survey participants rated Folliserum as “Very good” or “Good” for its efficacy and aesthetic parameters. </p>

Study on the Diagnosis of Gastric Cancer by Magnetic Beads Extraction and Mass Spectrometry

Objective. This study constructed a model for the early diagnosis of gastric cancer by comparing the serum peptides profiles of patients with advanced gastric cancer and healthy people. And that model may be the potential to be applied for the efficacy evaluation and recurrence monitoring in gastric cancer. Methods. Serums of 30 healthy people and 30 advanced gastric cancer patients were matched by age and gender were collected. The serum peptide spectrum was obtained by MB-WCX concentration and MALDI-TOF MS analysis. Based on the analysis of the efficiency of differential peptides in the diagnosis of gastric cancer, we first established a model for the diagnosis of gastric cancer based on differential peptides and then carried out external verification. The diagnostic reliability of this model was further tested by compared with carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9). Results. In this present study, we found the expression of two peptide peaks with a molecular weight of 2863 Da and 2953 Da were significantly increased in gastric cancer serum, while the expression of two peptide peaks with a molecular weight of 1945 Da and 2082 Da were significantly decreased. Depending on the characteristics of peptide expression, we constructed a diagnostic model, we compared the sensitivity and specificity of the model established by 2953 Da/1945 Da, and found this model is significantly higher than CEA and CA19-9. Conclusion. There were some differences in serum peptides profiles between patients with advanced gastric cancer and healthy people. The serum peptide diagnostic models based on 2953 Da and 1945 Da have high diagnostic efficiency for advanced gastric cancer. Our result indicated that this model was well worth further validation for clinical diagnosis.

Novel serum peptide model revealed by MALDI-TOF-MS and its diagnostic value in early bladder cancer

Background: Bladder cancer is the ninth most common cancer worldwide and has high morbidity and mortality. We aimed to search for potential serum peptide biomarkers and establish a diagnostic model for early bladder cancer. Methods: A total of 67 bladder cancer patients and 64 healthy volunteers were randomly divided into a training set and testing set 1. There were 30 hematuria patients used as testing set 2. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry based on weak cation exchange magnetic beads was used to obtain and analyze the serum peptide profiles between bladder cancer patients and healthy volunteers in the training set. Serum peptide diagnostic model through a k-nearest neighbor algorithm, was established and validated, and significantly differentially expressed protein biomarkers were ultimately identified. Results: We constructed a diagnostic model containing five peptides (m/z 1954.9, m/z 2081.0, m/z 3938.3, m/z 3946.5, and m/z 4268.8). In the training set, the area under the curve (AUC) value of the five-peptide model was 0.923, and the sensitivity and specificity was 93.75% and 96.77%, respectively. In testing set 1, the sensitivity and specificity was 91.43% and 90.91%, respectively, and the specificity of testing set 2 was 73.33%. For early-stage bladder cancer, the sensitivity and specificity was 92.31% and 93.75%, respectively; the sensitivity of early low-grade bladder cancer was 90.00%; and the AUC value was 0.944. Conclusion: The five-peptide diagnostic model established in this study had high sensitivity and specificity, especially in the diagnosis of early bladder cancer, and could differentiate between healthy volunteers and hematuria patients.