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"Pogue, Robert"
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Polysaccharides—Naturally Occurring Immune Modulators
The prevention of disease and infection requires immune systems that operate effectively. This is accomplished by the elimination of infections and abnormal cells. Immune or biological therapy treats disease by either stimulating or inhibiting the immune system, dependent upon the circumstances. In plants, animals, and microbes, polysaccharides are abundant biomacromolecules. Due to the intricacy of their structure, polysaccharides may interact with and impact the immune response; hence, they play a crucial role in the treatment of several human illnesses. There is an urgent need for the identification of natural biomolecules that may prevent infection and treat chronic disease. This article addresses some of the naturally occurring polysaccharides of known therapeutic potential that have already been identified. This article also discusses extraction methods and immunological modulatory capabilities.
Journal Article
Advanced Therapies and Regulatory Framework in Different Areas of the Globe: Past, Present, and Future
The field of human medicine is in a constant state of evolution, developing and incorporating technological advances from diverse scientific fields. In recent years, cellular and gene therapies have come of age, challenging regulatory agencies to define the path for commercial registration. Approval necessarily demands robust evidence for safety and efficacy, but these exigencies must not be such that they render unviable the development and testing of the therapeutic agent. Furthermore, reimbursement strategies are required to guarantee commercial viability of these products, to avoid the risk that they will be removed from the market or become unavailable to most patients through lack of financial resources. To address such challenges, several countries have created strategies to manage advanced therapy products.
Based on official documents published by regulatory agencies worldwide, this review summarizes the current scenario in the United States, Europe, Brazil, Japan, South Korea, and China in this regard, discussing the harmonized and dissonant aspects of the regulatory framework in different regions of the world and exploring perspectives for the future.
The technical aspects of advanced therapies are increasingly complex, bringing challenges for high mass commercialization and demanding specific regulation. The regulatory framework of the analyzed regions is mainly recent and discordant, but many harmonizing initiatives were observed.
The comparative analysis of regulatory frameworks in different parts of the world is informative, as scientists must be aware of the rationale of regulators to assertively develop new technology and products that will be commercialized. The comparative analysis also provides insight into the main dissonances that must be addressed, fostering the harmonization of local regulatory frameworks. Many unanswered questions still lie ahead for the field of advanced therapies, and empirical evidence will be the most effective way to separate hype from hope and to establish the most sustainable mechanisms to regulate and finance such products in each part of the world.
Journal Article
Osteogenic Differentiation in Chitosan-Based Scaffolds via P28 and VEGF Delivery
Repairing large bone defects remains a significant clinical challenge due to the limitations of current treatments, including infection risk, donor site morbidity, and insufficient vascularization. The autograft is still the gold standard for large bone defects. In this study, we developed chitosan-based (CS-based) scaffolds, incorporating with hydroxyapatite (HAp) and fluorapatite (FAp) ceramics, fabricated by UV crosslinking and freeze-drying, and loaded with P28 peptide, alone or in combination with vascular endothelial growth factor (VEGF), to evaluate the effect of dual bioactive factor delivery. We hypothesized that CS-based scaffolds would optimize ceramic composition and co-delivery of P28 and VEGF, and can enhance early-stage osteogenic differentiation and support bone regeneration. The CS-based scaffolds were characterized by their physicochemical properties, including swelling behavior, mechanical strength, porosity, and in vitro degradation. Biological evaluations were performed including cell proliferation assays, ALP activity, ARS staining, and RT-qPCR, to assess osteogenic differentiation. The results showed that the scaffolds had high porosity, excellent swelling behavior, and degraded within 8 weeks. Dual delivery of P28 and VEGF significantly enhanced early osteogenic markers, indicating a complementary effect. These findings demonstrated that CS-based scaffolds with an optimized ceramic ratio and bioactive factor incorporation have the potential to facilitate bone regeneration.
Journal Article
Investigating the Promising P28 Peptide-Loaded Chitosan/Ceramic Bone Scaffolds for Bone Regeneration
Bone has the ability to heal itself; however, bone defects fail to heal once the damage exceeds a critical size. Bone regeneration remains a significant clinical challenge, with autograft considered the ideal bone graft material due to its sufficient porosity, osteogenic cells, and biological growth factors. However, limitations to bone grafting, such as limited bone stock and high resorption rates, have led to a great deal of research into developing bone graft substitutes. The P28 peptide is a small molecule bioactive biomimetic alternative to mimic the bone morphogenetic protein 2 (BMP-2). In this study, we investigated the potential of P28-loaded hybrid scaffolds to mimic the natural bone structure for enhancing the bone regeneration process. We hypothesized that the peptide-loaded scaffolds and nude scaffolds both have the potential to promote bone healing, and the bone healing process is accelerated by the release of the peptide. To verify our hypothesis, C2C12 cells were evaluated for the presence of calcium deposits by histological stain at 7 and 14 days in cultures with hybrid scaffolds. Total RNA was isolated from C2C12 cells cultured with hybrid scaffolds for 7 and 14 days to assess osteoblast differentiation. The project findings demonstrated that the hybrid scaffold could enhance osteoblast differentiation and significantly improve the therapeutic effects of the scaffold in bone regeneration.
Journal Article
Altered mRNA Splicing, Chondrocyte Gene Expression and Abnormal Skeletal Development due to SF3B4 Mutations in Rodriguez Acrofacial Dysostosis
The acrofacial dysostoses (AFD) are a genetically heterogeneous group of inherited disorders with craniofacial and limb abnormalities. Rodriguez syndrome is a severe, usually perinatal lethal AFD, characterized by severe retrognathia, oligodactyly and lower limb abnormalities. Rodriguez syndrome has been proposed to be a severe form of Nager syndrome, a non-lethal AFD that results from mutations in SF3B4, a component of the U2 small nuclear ribonucleoprotein particle (U2 snRNP). Furthermore, a case with a phenotype intermediate between Rodriguez and Nager syndromes has been shown to have an SF3B4 mutation. We identified heterozygosity for SF3B4 mutations in Rodriguez syndrome, confirming that the phenotype is a dominant disorder that is allelic with Nager syndrome. The mutations led to reduced SF3B4 synthesis and defects in mRNA splicing, primarily exon skipping. The mutations also led to reduced expression in growth plate chondrocytes of target genes, including the DLX5, DLX6, SOX9, and SOX6 transcription factor genes, which are known to be important for skeletal development. These data provide mechanistic insight toward understanding how SF3B4 mutations lead to the skeletal abnormalities observed in the acrofacial dysostoses.
Journal Article
Triangular Silver Nanoparticles Synthesis: Investigating Potential Application in Materials and Biosensing
Triangular silver nanoplates (TSNPs) exhibit unique optical and antimicrobial properties due to their shape, sharp edges, and vertices. In this study, TSNPs were incorporated into biopolymer blends (bacterial cellulose (BC) with polylactic acid (PLA), polycaprolactone (PCL), and polyhydroxybutyrate (PHB)). Antimicrobial activity of materials was tested against Escherichia coli ATCC 95922 and Staphylococcus aureus ATCC 25923 (106 CFU/mL). After incubation (24 h at 37 °C, 100 rpm), optical density was measured at 630 nm. In order to assess biosensing applications, specifically fibronectin (Fn) behavior, TSNPs were protected with gold (AuTSNP) and analyzed via sucrose sensitivity test and monitored by localized surface plasmon resonance (LSPR). Additionally, AuTSNPs were coated with polyethylene glycol (PEGAuTSNP). Fibronectin functionalization of PEGAuTSNPs and pH-conformation was monitored (FnPEGAuTSNP). Eventually, adequate Fn and anti-Fn antibody concentrations were determined. BC/PHB/TSNPs showed antimicrobial activity against E. coli and S. aureus with 80 and 95% of growth inhibition, respectively. The sucrose sensitivity test indicated that the LSPRλmax of the spectra is directly proportional to the sucrose concentration. LSPRλmax of Fn-PEGAuTSNPs at pH 7 and pH 4 were measured at 633 and 643 nm, respectively. A total of 5 µg of Fn was determined to be adequate concentration, while 0.212 mg/mL of anti-Fn antibody indicatied system saturation.
Journal Article
Comparative transcriptomic analysis indicates genes associated with local and systemic resistance to Colletotrichum graminicola in maize
The hemibiotrophic fungus
Colletotrichum graminicola
may cause severe damage to maize, affecting normal development of the plant and decreasing grain yield. In this context, understanding plant defense pathways at the inoculation site and systemically in uninoculated tissues can help in the development of genetic engineering of resistance against this pathogen. Previous work has discussed the molecular basis of maize -
C. graminicola
interaction. However, many genes involved in defense have not yet been exploited for lack of annotation in public databases. Here, changes in global gene expression were studied in root, male and female inflorescences of maize under local and systemic fungal infection treatments, respectively. RNA-Seq with qPCR was used to indicate genes involved in plant defense. We found that systemic acquired resistance induction in female inflorescences mainly involves accumulation of salicylic acid (SA)-inducible defense genes (
ZmNAC
,
ZmHSF
,
ZmWRKY
,
ZmbZIP
and
PR1
) and potential genes involved in chromatin modification. Furthermore, transcripts involved in jasmonic acid (JA) and ethylene (ET) signaling pathways were also accumulated and may participate in plant immunity. Moreover, several genes were functionally re-annotated based on domain signature, indicating novel candidates to be tested in strategies involving gene knockout and overexpression in plants.
Journal Article
The Combination of Synoeca-MP Antimicrobial Peptide with IDR-1018 Stimulates Proliferation, Migration, and the Expression of Pro-Regenerative Genes in Both Human Skin Cell Cultures and 3D Skin Equivalents
In skin lesions, the development of microbial infection affects the healing process, increasing morbidity and mortality rates in patients with severe burns, diabetic foot, and other types of skin injuries. Synoeca-MP is an antimicrobial peptide (AMP) that exhibits activity against several bacteria of clinical importance, but its cytotoxicity can represent a problem for its positioning as an effective antimicrobial compound. In contrast, the immunomodulatory peptide IDR-1018 presents low toxicity and a wide regenerative potential due to its ability to reduce apoptotic mRNA expression and promote skin cell proliferation. In the present study, we used human skin cells and a 3D skin equivalent models to analyze the potential of the IDR-1018 peptide to attenuate the cytotoxicity of synoeca-MP, as well as the influence of synoeca-MP/IDR-1018 combination on cell proliferation, regenerative processes, and wound repair. We found that the addition of IDR-1018 significantly improved the biological properties of synoeca-MP on skin cells without modifying its antibacterial activity against S. aureus. Likewise, in both melanocytes and keratinocytes, the treatment with synoeca-MP/IDR-1018 combination induces cell proliferation and migration, while in a 3D human skin equivalent model, it can accelerate wound reepithelization. Furthermore, treatment with this peptide combination generates an up-regulation in the expression of pro-regenerative genes in both monolayer cell cultures and in 3D skin equivalents. This data suggests that the synoeca-MP/IDR-1018 combination possesses a good profile of antimicrobial and pro-regenerative activity, opening the door to the development of new strategies for the treatment of skin lesions.
Journal Article