G Protein-Coupled Receptor Kinase 2 as Novel Therapeutic Target in Fibrotic Diseases

G protein-coupled receptor kinase 2 (GRK2), an important subtype of GRKs, specifically phosphorylates agonist-activated G protein-coupled receptors (GPCRs). Besides, current research confirms that it participates in multiple regulation of diverse cells via a non-phosphorylated pathway, including interacting with various non-receptor substrates and binding partners. Fibrosis is a common pathophysiological phenomenon in the repair process of many tissues due to various pathogenic factors such as inflammation, injury, drugs, etc. The characteristics of fibrosis are the activation of fibroblasts leading to myofibroblast proliferation and differentiation, subsequent aggerate excessive deposition of extracellular matrix (ECM). Then, a positive feedback loop is occurred between tissue stiffness caused by ECM and fibroblasts, ultimately resulting in distortion of organ architecture and function. At present, GRK2, which has been described as a multifunctional protein, regulates copious signaling pathways under pathophysiological conditions correlated with fibrotic diseases. Along with GRK2-mediated regulation, there are diverse effects on the growth and apoptosis of different cells, inflammatory response and deposition of ECM, which are essential in organ fibrosis progression. This review is to highlight the relationship between GRK2 and fibrotic diseases based on recent research. It is becoming more convincing that GRK2 could be considered as a potential therapeutic target in many fibrotic diseases.

DNA Damage Repair in Brain Tumor Immunotherapy

With the gradual understanding of tumor development, many tumor therapies have been invented and applied in clinical work, and immunotherapy has been widely concerned as an emerging hot topic in the last decade. It is worth noting that immunotherapy is nowadays applied under too harsh conditions, and many tumors are defined as “cold tumors” that are not sensitive to immunotherapy, and brain tumors are typical of them. However, there is much evidence that suggests a link between DNA damage repair mechanisms and immunotherapy. This may be a breakthrough for the application of immunotherapy in brain tumors. Therefore, in this review, first, we will describe the common pathways of DNA damage repair. Second, we will focus on immunotherapy and analyze the mechanisms of DNA damage repair involved in the immune process. Third, we will review biomarkers that have been or may be used to evaluate immunotherapy for brain tumors, such as TAMs, RPA, and other molecules that may provide a precursor assessment for the rational implementation of immunotherapy for brain tumors. Finally, we will discuss the rational combination of immunotherapy with other therapeutic approaches that have an impact on the DNA damage repair process in order to open new pathways for the application of immunotherapy in brain tumors, to maximize the effect of immunotherapy on DNA damage repair mechanisms, and to provide ideas and guidance for immunotherapy in brain tumors.

Reconstructed Brain Like Neural Network R-KFDNN

Through the neural system damage and repair process of human brain, we can construct the complex deep learning and training of the repair process such as the damage of brain like high-dimensional flexible neural network system or the local loss of data, so as to prevent the dimensional disaster caused by the local loss of high-dimensional data. How to recover and extract feature information when the damaged neural system (flexible neural network) has amnesia or local loss of stored information. Information extraction generally exists in the distribution table of the generation sequence of the key group of the higher dimension or the lower dimension to find the core data stored in the brain. The generation sequence of key group exists in a hidden time tangent cluster. Brain like slice data processing runs on different levels, different dimensions, different tangent clusters and cotangent clusters. The key group in the brain can be regarded as the distribution table of memory fragments. Memory parsing has mirror reflection and is accompanied by the loss of local random data. In the compact compressed time tangent cluster, it freely switches to the high-dimensional information field, and the parsed key is buried in the information.

Mussels repair shell damage despite limitations imposed by ocean acidification

Bivalves frequently withstand shell boring attempts by predatory gastropods that result in shell damage that must be quickly repaired to ensure survival. While the processes that underlie larval shell development have been extensively studied within the context of ocean acidification (OA), it remains unclear whether shell repair is impaired by elevated pCO2. To better understand the stereotypical shell repair process, we monitored mussels (Mytilus edulis) with sublethal shell damage within both field and laboratory conditions to characterize the deposition rate, mineral composition, and structural integrity of repaired shell. These results were then compared with a laboratory experiment wherein mussels (Mytilus trossulus) repaired shell damage in one of seven pCO2 treatments (400–2500 µatm). Shell repair proceeded through four distinct stages; shell damage was first covered with an organic film, then mineralized over the course of weeks, acquiring the appearance of nacre after 8 weeks. OA did not impact the ability of mussels to close drill holes, nor the strength or density of the repaired shell after 10-weeks, as measured through mechanical testing and µCT analysis. However, as mussels progressed through each repair stage, significant interactions between pCO2, the length of exposure to treatment conditions, and the strength, inorganic content, and physiological condition of mussels within OA treatments were observed. These results suggest that, while OA may not prevent mussels from repairing shell damage, sustained exposure to elevated pCO2 may induce physiological stress responses that impose energetic constraints on the shell repair process.

THE USE OF IONTOPHORESIS WITH HYALURONIC ACID ASSOCIATED WITH GOLD NANOPARTICLES ACCELERATES WOUND HEALING IN RATS

This study aimed to investigate the effects of iontophoresis with HA associated to GNPs solution in an epithelial lesion model. Fifty Wistar rats (n=10/group) were randomly assigned to the following groups: epithelial lesion (EL); (EL+MIC); (EL+MIC+HA); (EL+MIC+GNPs); (EL+MIC+HA-GNPs). The animals induced to an epithelial lesion and treatment started 24 hours after injury with microcurrents (300µA) containing gel with HA (0.9%) and/or GNPs (30mg/Kg) in the electrodes (1mL) for seven days. The animals were sacrificed 12 hours after the last treatment application. Results demonstrated a reduction in the levels of pro-inflammatory cytokines (IFNϒ, IL-1β, TNFα, IL6) in the group in which the therapies were combined; an increase in the levels of anti-inflammatory cytokines (IL-4, IL-10) and growth factors (FGF, TGFβ) in EL+MIC+HA and EL+MIC+HA-GNPs groups. As for dichlorofluorescein (DCF) and nitrite levels, decreased in the combined therapy group when compared to the control group, as well as the oxidative damage (carbonyl and sulfhydryl). In antioxidant defense, there was an increase in glutathione (GSH) and a decrease in superoxide dismutase (SOD) in the combination therapy group. Histological analysis showed a reduction in the inflammatory infiltrate in groups treated with MIC and in the combination therapy group. An increase in contraction of the wound area was obtained in all treated groups when compared to the control group, proving that the proposed therapies are effective in the process of epithelial healing. The results of this study demonstrated that the associated therapies favor the tissue repair process more significantly compared to the isolated therapies.

Material Priority Engineered Metal-Polyphenol Networks: Mechanism And Platform For Multifunctionalities

Engineering the surface of materials with desired multifunctionalities is an effective way to fight against multiple adverse factors during the tissue repair process. Recently, metal-polyphenol networks (MPNs) have gained increasing attention because of their rapid and simple deposition process onto various substrates (silicon, quartz, gold and polypropylene sheets, etc.). However, the coating mechanism has not been clarified, and multifunctionalized MPNs remain unexplored. Herein, the flavonoid polyphenol procyanidin (PC) was selected to form PC-MPN coatings with Fe3+, and assembly parameters, including pH, molar ratio between PC and Fe3+, and material priority during coating formation, were thoroughly evaluated. We found that the material priority (addition sequence of PC and Fe3+) had a great influence on the thickness of the formed PC-MPNs. Various surface techniques (e.g., ultraviolet-visible spectrophotometry, quartz crystal microbalance, X-ray photoelectron spectroscopy, atomic force microscopy, and scanning electron microscopy) were used to investigate the formation mechanism of PC-MPNs, and PC-MPNs were further engineered for multifunctionalities (fastening cellular attachment in the early stage, promoting long-term cellular proliferation, antioxidation and antibacterial activity). We believe that these findings could further reveal the coating formation mechanism of MPNs and guide the future design of MPN coatings with multifunctionalities, thereby greatly broadening their application prospects, such as in sensors, environments, drug delivery, and tissue engineering.

Effect of Topical PTH 1-34 Functionalized to Biogran® in the Process of Alveolar Repair in Rats Submitted to Orchiectomy

(1) Background: There are many therapies for osteoporosis control and bone maintenance; anabolic drugs such as teriparatide and bone grafts help in the repair process and stimulate bone formation. Thus, the aim of the present study was to evaluate the behavior of repaired bone in the presence of PTH (teriparatide) associated with Biogran® (biomaterial) through a sonochemical procedure after extraction in rats. (2) Methods: The insertion of Biogran® with PTH in the alveolus was performed 30 days after incisor extraction. Euthanasia occurred after 60 days. (3) Results: The use of local treatment of PTH loaded with Biogran® in healthy rats promoted good results for micro-CT, with an increase in percentage and bone volume, number and trabecular separation and less total porosity. Greater immunostaining for Wnt, β-Catenin and osteocalcin proteins and lower expression for Thrombospondin-Related Adhesive Protein (TRAP), which shows an increase in the number of osteoblasts and inhibition of osteoclast action. However, the treated orchiectomized groups did not obtain such expressive results. (4) Conclusion: The use of Biogran® with PTH improved alveolar repair in rats. However, new researches with more efficient doses must be studied to collaborate effectively with the formation of a quality bone after the orchiectomy.

Reconstructed Brain Like Neural Network R-KFDNN

Through the neural system damage and repair process of human brain, we can construct the complex deep learning and training of the repair process such as the damage of brain like high-dimensional flexible neural network system or the local loss of data, so as to prevent the dimensional disaster caused by the local loss of high-dimensional data. How to recover and extract feature information when the damaged neural system (flexible neural network) has amnesia or local loss of stored information. Information extraction generally exists in the distribution table of the generation sequence of the key group of the higher dimension or the lower dimension to find the core data stored in the brain. The generation sequence of key group exists in a hidden time tangent cluster. Brain like slice data processing runs on different levels, different dimensions, different tangent clusters and cotangent clusters. The key group in the brain can be regarded as the distribution table of memory fragments. Memory parsing has mirror reflection and is accompanied by the loss of local random data. In the compact compressed time tangent cluster, it freely switches to the high-dimensional information field, and the parsed key is buried in the information.