Project description:For better use of cyclooxygenase dependent anti-inflammatory properties and mitochondrial activities of aspirin, new hydrophobic analogues of aspirin were developed and successfully encapsulated in polymeric nanoparticles (NPs). In vivo anti-inflammatory effects of these NPs using a mouse model demonstrated unique properties of an optimized aspirin analogue to inhibit production of pro-inflammatory and enrichment of anti-inflammatory cytokines.
Project description:OBJECTIVE:We previously identified CYR61 as a histone deacetylase 5 (HDAC-5)-repressed gene in systemic sclerosis (SSc; scleroderma) endothelial cells (ECs). When overexpressed, cysteine-rich angiogenic inducer 61 (CYR-61) promoted angiogenesis in SSc ECs. This study was undertaken to examine the role of CYR-61 in fibrosis and determine the mechanisms involved in CYR-61-mediated angiogenesis in SSc. METHODS:Dermal ECs and fibroblasts were isolated from biopsy specimens from healthy subjects and patients with SSc. CYR-61 level was determined by quantitative polymerase chain reaction, Western blotting, and enzyme-linked immunosorbent assay. CYR-61 was overexpressed using a CYR61 vector or knocked down using small interfering RNA, and functional and mechanistic studies were then conducted in fibroblasts and ECs. RESULTS:Lower CYR61 messenger RNA levels were observed in dermal fibroblasts and ECs from SSc patients than in those from healthy controls. In SSc fibroblasts, overexpression of CYR-61 led to significant reduction in the expression of profibrotic genes, including COL1A1 (P = 0.002) and ACTA2 (P = 0.04), and an increase in the expression of matrix-degrading genes, including MMP1 (P = 0.002) and MMP3 (P =0.004), and proangiogenic VEGF (P = 0.03). The antifibrotic effect of CYR-61 was further demonstrated by delay in wound healing, inhibition of gel contraction, inactivation of the transforming growth factor β pathway, and early superoxide production associated with senescence in SSc fibroblasts. In SSc ECs, overexpression of CYR-61 led to increased production of vascular endothelial cell growth factor. The proangiogenic effects of CYR-61 were mediated by signaling through αvβ3 receptors and downstream activation of AMP-activated protein kinase, AKT, and the endothelial cell nitric oxide synthase/nitric oxide pathway system. CONCLUSION:CYR-61, which is epigenetically regulated by HDAC-5, is a potent antifibrotic and proangiogenic mediator in SSc. Therapeutic intervention to promote CYR-61 activity or increase CYR-61 levels might be of benefit in SSc.
Project description:Diabetic nephropathy (DN) is clinically characterized by proteinuria and hypertension. Investigations suggest that matrix accumulation and inflammatory processes contribute to the pathological features of this progressive disease. This chapter reviews novel targeted approaches to the treatment of DN, with the goal of slowing the progression and improving renal function. Many studies support the use of agents that block the renin-angiotensin-aldosterone system in DN. Novel, oral agents that are promising in early clinical studies are agents such as pirfenidone and bardoxolone as they are associated with early improvement in renal function in patients with advanced diabetic kidney disease. Additionally, strategies that inhibit inflammatory cytokines, chemokines, adhesion molecules and mediators of the innate immune response may provide novel targets for the treatment of DN. Larger clinical studies are eagerly awaited to determine if new agents that specifically block kidney fibrosis and inflammation will delay, arrest and possibly reverse progressive renal failure.
Project description:BACKGROUND:Despite the growing epidemic of heart failure (HF), there is limited data available to systematically compare non-cardiac comorbidities in the young-old, old-old, and oldest-old patients hospitalized for HF. The precise differences will add valuable information for better management of HF in elderly patients. METHODS:A total of 1053 patients aged 65 years or older hospitalized with HF were included in this study. Patients were compared among three age groups: (1) young-old: 65 to 74 years, (2) old-old: 75 to 84 years, and (3) oldest-old: ?85 years. Clinical details of presentation, comorbidities, and prescribed medications were recorded. RESULTS:The mean age was 76.7 years and 12.7% were 85 years or older. Most elderly patients with HF (97.5%) had at least one of the non-cardiac comorbidities. The patterns of common non-cardiac comorbidities were different between the young-old and oldest-old group. The three most common non-cardiac comorbidities were anemia (53.6%), hyperlipidemia (45.9%), and diabetes (42.4%) in the young-old group, while anemia (73.1%), infection (58.2%), and chronic kidney disease (44.0%) in the oldest-old group. Polypharmacy was observed in 93.0% elderly patients with HF. Additionally, 29.2% patients were diagnosed with infection, and 67.0% patients were prescribed antibiotics. However, 60.4% patients were diagnosed with anemia with only 8.9% of them receiving iron repletion. CONCLUSIONS:Non-cardiac comorbidities are nearly universal in three groups but obviously differ by age, and inappropriate medications are very common in elderly patients with HF. Further treatment strategies should be focused on providing optimal medications for age-specific non-cardiac conditions.
Project description:Cadaver decomposition islands around animal carcasses can facilitate establishment of various plant life. Facultative scavengers have great potential for endozoochory, and often aggregate around carcasses. Hence, they may disperse plant seeds that they ingest across the landscape towards cadaver decomposition islands. Here, we demonstrate this novel mechanism along a gradient of wild tundra reindeer carcasses. First, we show that the spatial distribution of scavenger faeces (birds and foxes) was concentrated around carcasses. Second, faeces of the predominant scavengers (corvids) commonly contained viable seeds of crowberry, a keystone species of the alpine tundra with predominantly vegetative reproduction. We suggest that cadaver decomposition islands function as endpoints for directed endozoochory by scavengers. Such a mechanism could be especially beneficial for species that rely on small-scale disturbances in soil and vegetation, such as several Nordic berry-producing species with cryptic generative reproduction.
Project description:Here we present MS1 spectra of nontoxigenic and toxigenic BF cells membrane extract, complemented by MS/MS spectra of separate parent ions in positive and negative mode
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MS1 total spectra BFplus and BFminus in negative and positive mode
2015-09-04-pos-bminus-baselinel-1.d - MS1 acquisition spectre of sample BFminus in pos mode, sample acquisition started from 7.5 min of chromatogramm
2015-09-04-pos-bminus-picture-tertac-dla lockmass.d - MS1 acquisition spectre of sample BFminus in pos mode, tetracycline as internal standard was used,m/z 445
NAT-neg-6-plus.d - MS1 acquisition spectre of sample BFplus in neg mode
nat-plus-pos.d- MS1 acquisition spectre of sample BFplus in pos mode
NAT-neg-2-minus-1-10.d - MS1 acquisition spectre of sample BFminus in neg mode
Project description:Concurrent developments in anticancer nanotechnological treatments have been observed as the burden of cancer increases every year. The 21st century has seen a transformation in the study of medicine thanks to the advancement in the field of material science and nanomedicine. Improved drug delivery systems with proven efficacy and fewer side effects have been made possible. Nanoformulations with varied functions are being created using lipids, polymers, and inorganic and peptide-based nanomedicines. Therefore, thorough knowledge of these intelligent nanomedicines is crucial for developing very promising drug delivery systems. Polymeric micelles are often simple to make and have high solubilization characteristics; as a result, they seem to be a promising alternative to other nanosystems. Even though recent studies have provided an overview of polymeric micelles, here we included a discussion on the "intelligent" drug delivery from these systems. We also summarized the state-of-the-art and the most recent developments of polymeric micellar systems with respect to cancer treatments. Additionally, we gave significant attention to the clinical translation potential of polymeric micellar systems in the treatment of various cancers.
Project description:Background: A special health fund was established in Nigeria in 2014 and is known as the Basic Health Care Provision Fund (BHCPF). The fund is equivalent to at least 1% of the Consolidated Revenue of the Federation. The BHCPF will provide additional revenue to fund primary healthcare services and help Nigeria to achieve universal health coverage (UHC). This fund is to be matched with counterpart funds from states and local government areas (LGAs), and is expected to provide at least a basic benefit health package that will cover maternal and child health (MCH) services for pregnant women and under-five children. Objective: To determine the financial feasibility of using the BHCPF to provide a minimum benefit package to cover all pregnant women and under-five children in Nigeria. Methods: The study focused on three states in Nigeria: Imo, Kaduna, and Niger. The feasibility analysis was performed using 3 scenarios but the main analysis was Scenario 1, which was based on the funding of drugs and consumables only. All the costs and revenues were in 2015 levels. The standard costs of a minimum benefit package for the different states were multiplied by the number of target beneficiaries to determine the amount required for the year. Financial feasibility is determined by the excess or otherwise of revenue over costs. Findings: It was found that in the best case funding scenario of using 95% of the CRF with 25% counterpart funding from states and LGAs, the entire available funds were not adequate to cover the benefit package for all the pregnant women and under-five children in the three states. The funds were also inadequate to cover the target beneficiaries that live below the poverty line in two of the states. Conclusion: The BHCPF is a good step toward providing essential MCH services, but the current level of funding will not assure UHC for all the target beneficiaries. However, the available funds should be used immediately to target priority mothers and children such as vulnerable groups, whilst sourcing for additional funds to ensure universal coverage of MCH services.
Project description:INTRODUCTION:Idiopathic pulmonary fibrosis (IPF) is a progressive fibrosing interstitial lung disease of unknown aetiology and cure. Recent studies have reported a dysregulation of exosomal microRNAs (miRs) in the IPF context. However, the impact of IPF-related exosomal miRs on the progression of pulmonary fibrosis is unknown. METHODS:Two independent cohorts were enrolled at the ambulatory care polyclinic of Liège University. Exosomes from sputum were obtained from 19 patients with IPF and 23 healthy subjects (HSs) (cohort 1), and the ones from plasma derived from 14 patients with IPF and 14 HSs (cohort 2). Exosomal miR expression was performed by quantitative reverse transcription-PCR. The functional role of exosomal miRs was assessed in vitro by transfecting miR mimics in human alveolar epithelial cells and lung fibroblasts. RESULTS:Exosomal miR analysis showed that miR-142-3p was significantly upregulated in sputum and plasma of patients with IPF (8.06-fold, p<0.0001; 1.64 fold, p=0.008, respectively). Correlation analysis revealed a positive association between exosomal miR-142-3p and the percentage of macrophages from sputum of patients with IPF (r=0.576, p=0.012), suggesting macrophage origin of exosomal miR-142-3p upregulation. The overexpression of miR-142-3p in alveolar epithelial cells and lung fibroblasts was able to reduce the expression of transforming growth factor ? receptor 1 (TGF?-R1) and profibrotic genes. Furthermore, exosomes isolated from macrophages present antifibrotic properties due in part to the repression of TGF?-R1 by miR-142-3p transfer in target cells. DISCUSSION:Our results suggest that macrophage-derived exosomes may fight against pulmonary fibrosis progression via the delivery of antifibrotic miR-142-3?p to alveolar epithelial cells and lung fibroblasts.
Project description:Herein we present the synthesis of a polymeric prodrug nanomaterial capable of spontaneous, self-assembled nanoparticle formation and of the conjugation (encapsulation) of drugs with amino and/or carboxyl and/or hydroxyl groups via ester and/or amide linkage. Mitomycin C (MMC) a versatile drug with antibiotic, antibacterial and antineoplastic properties, was used to prove this concept. The in vitro drug release experiments showed a fast release for the pure MMC (k = 49.59 h-n); however, a significantly lower MMC dissolution rate (k = 2.25, 1.46, and 1.35 h-n) was obtained for the nanoparticles with increased cross-link density (3, 10, 21%). The successful modification and conjugation reactions were confirmed using FTIR and EDX measurements, while the mucoadhesive properties of the self-assembled particles synthesized in a simple one-pot reaction were proved by rheological measurement. The prepared biocompatible polymeric prodrugs are very promising and applicable as a drug delivery system (DDS) and useful in the area of cancer treatment.