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Cells May 2020The metalloproteinase (MP) family of zinc-dependent proteases, including matrix metalloproteinases (MMPs), a disintegrin and metalloproteases (ADAMs), and a disintegrin... (Review)
Review
The metalloproteinase (MP) family of zinc-dependent proteases, including matrix metalloproteinases (MMPs), a disintegrin and metalloproteases (ADAMs), and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs) plays a crucial role in the extracellular matrix (ECM) remodeling and degradation activities. A wide range of substrates of the MP family includes ECM components, chemokines, cell receptors, and growth factors. Metalloproteinases activities are tightly regulated by proteolytic activation and inhibition via their natural inhibitors, tissue inhibitors of metalloproteinases (TIMPs), and the imbalance of the activation and inhibition is responsible in progression or inhibition of several diseases, e.g., cancer, neurological disorders, and cardiovascular diseases. We provide an overview of the structure, function, and the multifaceted role of MMPs, ADAMs, and TIMPs in several diseases via their cellular functions such as proteolysis of other cell signaling factors, degradation and remodeling of the ECM, and other essential protease-independent interactions in the ECM. The significance of MP inhibitors targeting specific MMP or ADAMs with high selectivity is also discussed. Recent advances and techniques used in developing novel MP inhibitors and MP responsive drug delivery tools are also reviewed.
Topics: Animals; Clinical Trials as Topic; Disease; Extracellular Matrix; Humans; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Signal Transduction
PubMed: 32466129
DOI: 10.3390/cells9051313 -
Cells Nov 2021As one of the largest organelles in eukaryotic cells, the endoplasmic reticulum (ER) plays a vital role in the synthesis, folding, and assembly of secretory and membrane... (Review)
Review
As one of the largest organelles in eukaryotic cells, the endoplasmic reticulum (ER) plays a vital role in the synthesis, folding, and assembly of secretory and membrane proteins. To maintain its homeostasis, the ER is equipped with an elaborate network of protein folding chaperones and multiple quality control pathways whose cooperative actions safeguard the fidelity of protein biogenesis. However, due to genetic abnormalities, the error-prone nature of protein folding and assembly, and/or defects or limited capacities of the protein quality control systems, nascent proteins may become misfolded and fail to exit the ER. If not cleared efficiently, the progressive accumulation of misfolded proteins within the ER may result in the formation of toxic protein aggregates, leading to the so-called "ER storage diseases". In this review, we first summarize our current understanding of the protein folding and quality control networks in the ER, including chaperones, unfolded protein response (UPR), ER-associated protein degradation (ERAD), and ER-selective autophagy (ER-phagy). We then survey recent research progress on a few ER storage diseases, with a focus on the role of ER quality control in the disease etiology, followed by a discussion on outstanding questions and emerging concepts in the field.
Topics: Animals; Disease; Endoplasmic Reticulum; Endoplasmic Reticulum-Associated Degradation; Humans; Protein Aggregates; Protein Folding; Unfolded Protein Response
PubMed: 34943844
DOI: 10.3390/cells10123337 -
Molecular Systems Biology Jan 2021A better understanding of the molecular mechanisms underlying disease is key for expediting the development of novel therapeutic interventions. Disease mechanisms are... (Review)
Review
A better understanding of the molecular mechanisms underlying disease is key for expediting the development of novel therapeutic interventions. Disease mechanisms are often mediated by interactions between proteins. Insights into the physical rewiring of protein-protein interactions in response to mutations, pathological conditions, or pathogen infection can advance our understanding of disease etiology, progression, and pathogenesis and can lead to the identification of potential druggable targets. Advances in quantitative mass spectrometry (MS)-based approaches have allowed unbiased mapping of these disease-mediated changes in protein-protein interactions on a global scale. Here, we review MS techniques that have been instrumental for the identification of protein-protein interactions at a system-level, and we discuss the challenges associated with these methodologies as well as novel MS advancements that aim to address these challenges. An overview of examples from diverse disease contexts illustrates the potential of MS-based protein-protein interaction mapping approaches for revealing disease mechanisms, pinpointing new therapeutic targets, and eventually moving toward personalized applications.
Topics: Disease; Gene Regulatory Networks; Humans; Mass Spectrometry; Protein Interaction Mapping
PubMed: 33434350
DOI: 10.15252/msb.20188792 -
Tissue Engineering. Part C, Methods Nov 2019Cell-cell adhesion complexes are macromolecular adhesive organelles that integrate cells into tissues. This mechanochemical coupling in cell-cell adhesion is required... (Review)
Review
Cell-cell adhesion complexes are macromolecular adhesive organelles that integrate cells into tissues. This mechanochemical coupling in cell-cell adhesion is required for a large number of cell behaviors, and perturbations of the cell-cell adhesion structure or related mechanotransduction pathways can lead to critical pathological conditions such as skin and heart diseases, arthritis, and cancer. Mechanical stretching has been a widely used method to stimulate the mechanotransduction process originating from the cell-cell adhesion and cell-extracellular matrix (ECM) complexes. These studies aimed to reveal the biophysical processes governing cell proliferation, wound healing, gene expression regulation, and cell differentiation in various tissues, including cardiac, muscle, vascular, and bone. This review explores techniques in mechanical stretching in two-dimensional settings with different stretching regimens on different cell types. The mechanotransduction responses from these different cell types will be discussed with an emphasis on their biophysical transformations during mechanical stretching and the cross talk between the cell-cell and cell-ECM adhesion complexes. Therapeutic aspects of mechanical stretching are reviewed considering these cellular responses after the application of mechanical forces, with a focus on wound healing and tissue regeneration. Impact Statement Mechanical stretching has been proposed as a therapeutic option for tissue regeneration and wound healing. It has been accepted that mechanotransduction processes elicited by mechanical stretching govern cellular response and behavior, and these studies have predominantly focused on the cell-extracellular matrix (ECM) sites. This review serves the mechanobiology community by shifting the focus of mechanical stretching effects from cell-ECM adhesions to the less examined cell-cell adhesions, which we believe play an equally important role in orchestrating the response pathways.
Topics: Adherens Junctions; Animals; Cell Adhesion; Desmosomes; Disease; Humans; Regeneration; Stress, Mechanical
PubMed: 31407627
DOI: 10.1089/ten.TEC.2019.0098 -
International Journal of Molecular... Sep 2023Telomeres play pivotal roles in processes closely related to somatic senescence and aging, making them a compelling target for interventions aimed at combating aging and...
Telomeres play pivotal roles in processes closely related to somatic senescence and aging, making them a compelling target for interventions aimed at combating aging and age-related pathologies. Ginsenoside, a natural compound, has emerged as a potential remedy for promoting healthy aging, yet how it protects telomeres remains incompletely understood. Here, we show that treatment of F1 can effectively restore the level of TRF2, thereby preserving telomere integrity. This restoration leads to inhibition of the DNA damage response and improvements in mitochondrial function and, ultimately, delays in cellular senescence. Conversely, depletion of TRF2 causes mitochondrial dysfunction, accompanied by increased oxidative stress, autophagy inhibition, insufficient energy metabolism, and the onset of cellular senescence. These observations underscore the critical role of TRF2 in maintaining telomere integrity and direct association with the initiation of cellular senescence. We conduct a further analysis, suggesting F1 could bind in proximity to the TRF2 heterodimer interface, potentially enhancing dimerization stability. These findings suggest that F1 may be a promising natural remedy for anti-aging, and restoring TRF2 could potentially prevent telomere-dependent diseases commonly associated with the aging process.
Topics: Humans; Ginsenosides; Cellular Senescence; Preservation, Biological; Syndrome
PubMed: 37762556
DOI: 10.3390/ijms241814241 -
Cells Apr 2020Extracellular vesicles (EV) are secretory membranous elements used by cells to transport proteins, lipids, mRNAs, and microRNAs (miRNAs). While their existence has been... (Review)
Review
Extracellular vesicles (EV) are secretory membranous elements used by cells to transport proteins, lipids, mRNAs, and microRNAs (miRNAs). While their existence has been known for many years, only recently has research begun to identify their function in intercellular communication and gene regulation. Importantly, cells have the ability to selectively sort miRNA into EVs for secretion to nearby or distant targets. These mechanisms broadly include RNA-binding proteins such as hnRNPA2B1 and Argonaute-2, but also membranous proteins involved in EV biogenesis such as Caveolin-1 and Neural Sphingomyelinase 2. Moreover, certain disease states have also identified dysregulated EV-miRNA content, shedding light on the potential role of selective sorting in pathogenesis. These pathologies include chronic lung disease, immune response, neuroinflammation, diabetes mellitus, cancer, and heart disease. In this review, we will overview the mechanisms whereby cells selectively sort miRNA into EVs and also outline disease states where EV-miRNAs become dysregulated.
Topics: Animals; Disease; Extracellular Vesicles; Humans; Membrane Proteins; MicroRNAs; Models, Biological; RNA-Binding Proteins
PubMed: 32331346
DOI: 10.3390/cells9041044 -
Pharmaceutics May 2023Microneedles are a well-known transdermal or transdermal drug delivery system. Different from intramuscular injection, intravenous injection, etc., the microneedle... (Review)
Review
Microneedles are a well-known transdermal or transdermal drug delivery system. Different from intramuscular injection, intravenous injection, etc., the microneedle delivery system provides unique characteristics for immunotherapy administration. Microneedles can deliver immunotherapeutic agents to the epidermis and dermis, where immune cells are abundant, unlike conventional vaccine systems. Furthermore, microneedle devices can be designed to respond to certain endogenous or exogenous stimuli including pH, reactive oxygen species (ROS), enzyme, light, temperature, or mechanical force, thereby allowing controlled release of active compounds in the epidermis and dermis. In this way, multifunctional or stimuli-responsive microneedles for immunotherapy could enhance the efficacy of immune responses to prevent or mitigate disease progression and lessen systemic adverse effects on healthy tissues and organs. Since microneedles are a promising drug delivery system for accurate delivery and controlled drug release, this review focuses on the progress of using reactive microneedles for immunotherapy, especially for tumors. Limitations of current microneedle system are summarized, and the controllable administration and targeting of reactive microneedle systems are examined.
PubMed: 37242649
DOI: 10.3390/pharmaceutics15051407 -
Frontiers in Public Health 2022COVID-19 is a major threat to public safety, and emergency public health measures to protect lives (e.g., lockdown, social distancing) have caused widespread disruption.... (Review)
Review
COVID-19 is a major threat to public safety, and emergency public health measures to protect lives (e.g., lockdown, social distancing) have caused widespread disruption. While these measures are necessary to prevent catastrophic trauma and grief, many people are experiencing heightened stress and fear. Public health measures, risks of COVID-19 and stress responses compound existing inequities in our community. First Nations communities are particularly at risk due to historical trauma, ongoing socio-economic deprivation, and lack of trust in government authorities as a result of colonization. The objective of this study was to review evidence for trauma-informed public health emergency responses to inform development of a culturally-responsive trauma-informed public health emergency framework for First Nations communities. We searched relevant databases from 1/1/2000 to 13/11/2020 inclusive, which identified 40 primary studies (and eight associated references) for inclusion in this review. Extracted data were subjected to framework and thematic synthesis. No studies reported evaluations of a trauma-informed public health emergency response. However, included studies highlighted key elements of a "trauma-informed lens," which may help to consider implications, reduce risks and foster a sense of security, wellbeing, self- and collective-efficacy, hope and resilience for First Nations communities during COVID-19. We identified key elements for minimizing the impact of compounding trauma on First Nations communities, including: a commitment to equity and human rights, cultural responsiveness, good communication, and positive leadership. The six principles guiding trauma-informed culturally-responsive public health emergency frameworks included: (i) safety, (ii) empowerment, (iii) holistic support, (iv) connectedness and collaboration, (v) compassion and caring, and (vi) trust and transparency in multi-level responses, well-functioning social systems, and provision of basic services. These findings will be discussed with First Nations public health experts, together with data on the experiences of First Nations families and communities during COVID-19, to develop a trauma-integrated public health emergency response framework or "lens" to minimize compounding trauma for First Nations communities.
Topics: Humans; Communicable Disease Control; COVID-19; Native Hawaiian or Other Pacific Islander; Public Health
PubMed: 36568798
DOI: 10.3389/fpubh.2022.1006513 -
Biomedicine & Pharmacotherapy =... Mar 2021Heat shock proteins (HSPs) are key players to restore cell homeostasis and act as chaperones by assisting the folding and assembly of newly synthesized proteins and... (Review)
Review
Heat shock proteins (HSPs) are key players to restore cell homeostasis and act as chaperones by assisting the folding and assembly of newly synthesized proteins and preventing protein aggregation. Recently, evidence has been accumulating that HSPs have been proven to have other functions except for the classical molecular chaperoning in that they play an important role in a wider range of fibrotic diseases via modulating cytokine induction and inflammation response, including lung fibrosis, liver fibrosis, and idiopathic pulmonary fibrosis. The recruitment of inflammatory cells, a large number of secretion of pro-fibrotic cytokines such as transforming growth factor-β1 (TGF-β1) and increased apoptosis, oxidative stress, and proteasomal system degradation are all events occurring during fibrogenesis, which might be associated with HSPs. However, their role on fibrotic process is not yet fully understood. In this review, we discuss new discoveries regarding the involvement of HSPs in the regulation of organ and tissue fibrosis, and note recent findings suggesting that HSPs may be a promising therapeutic target for improving the current frustrating outcome of fibrotic disorders.
Topics: Animals; Disease; Epithelial-Mesenchymal Transition; Extracellular Matrix; Fibrosis; Heat-Shock Proteins; Humans; Signal Transduction
PubMed: 33383375
DOI: 10.1016/j.biopha.2020.111067 -
Cells Sep 2021Neutrophils are key cells of the innate immune system. It is now understood that this leukocyte population is diverse in both the basal composition and functional... (Review)
Review
Neutrophils are key cells of the innate immune system. It is now understood that this leukocyte population is diverse in both the basal composition and functional plasticity. Underlying this plasticity is a post-translational framework for rapidly achieving early activation states, but also a transcriptional capacity that is becoming increasingly recognized by immunologists. Growing interest in the contribution of neutrophils to health and disease has resulted in more efforts to describe their transcriptional activity. Whilst initial efforts focused predominantly on understanding the existing biology, investigations with advanced methods such as single cell RNA sequencing to understand interactions of the entire immune system are revealing higher flexibility in neutrophil transcription than previously thought possible and multiple transition states. It is now apparent that neutrophils utilise many forms of RNA in the regulation of their function. This review collates current knowledge on the nuclei structure and gene expression activity of human neutrophils across homeostasis and disease, before highlighting knowledge gaps that are research priority areas.
Topics: Animals; Disease; Gene Expression Regulation; Homeostasis; Humans; Immunity, Innate; Neutrophils; Signal Transduction; Transcriptome
PubMed: 34572056
DOI: 10.3390/cells10092406