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Scientific Reports Jan 2023Wound healing is a well-organized dynamic process involving coordinated consecutive phases: homeostasis, inflammation, proliferation and resolution. Fibroblasts play...
Wound healing is a well-organized dynamic process involving coordinated consecutive phases: homeostasis, inflammation, proliferation and resolution. Fibroblasts play major roles in skin wound healing such as in wound contraction and release of growth factors which are of importance in angiogenesis and tissue remodeling. Abnormal fibroblast phenotypes have been identified in patients with chronic wounds. In this work, we analyzed scRNA-seq datasets of normal and wounded skin from mice at day 4 post-wound to investigate fibroblast heterogeneity during the proliferative phase of wound healing. Compositional analysis revealed a specific subset of fibroblast (cluster 3) that primarily increased in wounded skin (14%) compared to normal skin (3.9%). This subset was characterized by a gene signature marked by the plasma membrane proteins Sfrp2 + Sfrp4 + Sfrp1 + and the transcription factors Ebf1 + Prrx1 + Maged1 + . Differential gene expression and enrichment analysis identified epithelial to mesenchymal transition (EMT) and angiogenesis to be upregulated in the emerging subset of fibroblasts of the wounded skin. Using two other datasets for murine wounded skin confirmed the increase in cluster 3-like fibroblasts at days 2, 7 and 14 post-wounding with a peak at day 7. By performing a similarity check between the differential gene expression profile between wounded and normal skin for this emerging fibroblast subset with drug signature from the ConnectivityMap database, we identified drugs capable of mimicking the observed gene expression change in fibroblasts during wound healing. TTNPB, verteprofin and nicotinic acid were identified as candidate drugs capable of inducing fibroblast gene expression profile necessary for wound healing. On the other hand, methocarbamol, ifosfamide and penbutolol were recognized to antagonize the identified fibroblast differential expression profile during wound healing which might cause delay in wound healing. Taken together, analysis of murine transcriptomic skin wound healing datasets suggested a subset of fibroblasts capable of inducing EMT and further inferred drugs that might be tested as potential candidates to induce wound closure.
Topics: Mice; Animals; Skin; Epithelial-Mesenchymal Transition; Wound Healing; Transcription Factors; Fibroblasts; Neoplasm Proteins
PubMed: 36650180
DOI: 10.1038/s41598-022-27152-4 -
Genome Medicine Oct 2021In spite of many years of research, our understanding of the molecular bases of Alzheimer's disease (AD) is still incomplete, and the medical treatments available mainly...
BACKGROUND
In spite of many years of research, our understanding of the molecular bases of Alzheimer's disease (AD) is still incomplete, and the medical treatments available mainly target the disease symptoms and are hardly effective. Indeed, the modulation of a single target (e.g., β-secretase) has proven to be insufficient to significantly alter the physiopathology of the disease, and we should therefore move from gene-centric to systemic therapeutic strategies, where AD-related changes are modulated globally.
METHODS
Here we present the complete characterization of three murine models of AD at different stages of the disease (i.e., onset, progression and advanced). We combined the cognitive assessment of these mice with histological analyses and full transcriptional and protein quantification profiling of the hippocampus. Additionally, we derived specific Aβ-related molecular AD signatures and looked for drugs able to globally revert them.
RESULTS
We found that AD models show accelerated aging and that factors specifically associated with Aβ pathology are involved. We discovered a few proteins whose abundance increases with AD progression, while the corresponding transcript levels remain stable, and showed that at least two of them (i.e., lfit3 and Syt11) co-localize with Aβ plaques in the brain. Finally, we found two NSAIDs (dexketoprofen and etodolac) and two anti-hypertensives (penbutolol and bendroflumethiazide) that overturn the cognitive impairment in AD mice while reducing Aβ plaques in the hippocampus and partially restoring the physiological levels of AD signature genes to wild-type levels.
CONCLUSIONS
The characterization of three AD mouse models at different disease stages provides an unprecedented view of AD pathology and how this differs from physiological aging. Moreover, our computational strategy to chemically revert AD signatures has shown that NSAID and anti-hypertensive drugs may still have an opportunity as anti-AD agents, challenging previous reports.
Topics: Aging; Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Cognitive Dysfunction; Disease Models, Animal; Drug Discovery; Female; Gene Expression Regulation, Neoplastic; Gene Knock-In Techniques; Humans; Mice; Mice, Inbred C57BL; Mice, Transgenic; Plaque, Amyloid; Proteomics; Transcriptome
PubMed: 34702310
DOI: 10.1186/s13073-021-00983-y -
Spectrochimica Acta. Part A, Molecular... Feb 2021In this paper, a highly fluorescent water-soluble CdTe quantum dots (CdTe QDs) stabilized with thioglycolic acid (TGA) were synthesized for the quantitative and...
In this paper, a highly fluorescent water-soluble CdTe quantum dots (CdTe QDs) stabilized with thioglycolic acid (TGA) were synthesized for the quantitative and selective determination of salbutamol (SAL). When ten different of 2.09 × 10 mol L alpha-2 adrenoceptor agonist were added to 4.38 × 10 mol LCdTe QDs solution, the fluorescence signal of the CdTe QDs quenched obviously by SAL with 57.32% and 0.815% - 7.00% for other nine kinds of veterinary medicine, such as tulobuterol, fenoterol, phenylethanamine A, simatero, penbutolol, clenbuterol, ractopamine, terbutaline and clorprenaline. The result shows that the CdTe QDs is highly sensitive sensor for SAL. The quenching mechanism has been investigated by absorption spectroscopy and K at different temperatures, and shew a static quenching process than dynamic quenching. Under the optimal conditions, respectively the straight line equation (F/F = 0.1491 × 10 C + 1.3078) was found between the relative fluorescence intensity and the concentration of SAL was in the range of 6.27 × 10 to 2.09 × 10 mol L, and the limit of detection was 4.2 × 10 mol L. The proposed method has been applied to the determination of SAL in pig urine samples.
Topics: Albuterol; Animals; Cadmium Compounds; Fluorescent Dyes; Quantum Dots; Spectrometry, Fluorescence; Swine; Tellurium; Thioglycolates
PubMed: 33166780
DOI: 10.1016/j.saa.2020.119107 -
Current Pharmaceutical Biotechnology Jan 2024Aerogels are the 3D network of organic, inorganic, composite, layered, or hybrid-type materials that are used to increase the solubility of Class 1 (low solubility and...
Aerogels are the 3D network of organic, inorganic, composite, layered, or hybrid-type materials that are used to increase the solubility of Class 1 (low solubility and high permeability) and Class 4 (poor solubility and low permeability) molecules. This approach improves systemic drug absorption due to the alveoli's broad surface area, thin epithelial layer, and high vascularization. Local therapies are more effective and have fewer side effects than systemic distribution because inhalation treatment targets the specific location and raises drug concentration in the lungs. The present manuscript aims to explore various aspects of aerogel formulations for pulmonary targeted delivery of active pharmaceutical agents. The manuscript also discusses the safety, efficacy, and regulatory aspects of aerogel formulations. According to projections, the global respiratory drug market is growing 4-6% annually, with short-term development potential. The proliferation of literature on pulmonary medicine delivery, especially in recent years, shows increased interest. Aerogels come in various technologies and compositions, but any aerogel used in a biological system must be constructed of a material that is biocompatible and, ideally, biodegradable. Aerogels are made via "supercritical processing". After many liquid phase iterations using organic solvents, supercritical extraction, and drying are performed. Moreover, the sol-gel polymerization process makes inorganic aerogels from TMOS or TEOS, the less hazardous silane. The resulting aerogels were shown to be mostly loaded with pharmaceutically active chemicals, such as furosemide-sodium, penbutolol-hemisulfate, and methylprednisolone. For biotechnology, pharmaceutical sciences, biosensors, and diagnostics, these aerogels have mostly been researched. Although aerogels are made of many different materials and methods, any aerogel utilized in a biological system needs to be made of a substance that is both biocompatible and, preferably, biodegradable. In conclusion, aerogel-based pulmonary drug delivery systems can be used in biomedicine and non-biomedicine applications for improved sustainability, mechanical properties, biodegradability, and biocompatibility. This covers scaffolds, aerogels, and nanoparticles. Furthermore, biopolymers have been described, including cellulose nanocrystals (CNC) and MXenes. A safety regulatory database is necessary to offer direction on the commercialization potential of aerogelbased formulations. After that, enormous efforts are discovered to be performed to synthesize an effective aerogel, particularly to shorten the drying period, which ultimately modifies the efficacy. As a result, there is an urgent need to enhance the performance going forward.
PubMed: 38251702
DOI: 10.2174/0113892010275613231120031855