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Endocrine Reviews Nov 2023Pregnancy-associated plasma protein-A (PAPP-A) was first identified in the early 1970s as a placental protein of unknown function, present at high concentrations in the... (Review)
Review
Pregnancy-associated plasma protein-A (PAPP-A) was first identified in the early 1970s as a placental protein of unknown function, present at high concentrations in the circulation of pregnant women. In the mid-to-late 1990s, PAPP-A was discovered to be a metzincin metalloproteinase, expressed by many nonplacental cells, that regulates local insulin-like growth factor (IGF) activity through cleavage of high-affinity IGF binding proteins (IGFBPs), in particular IGFBP-4. With PAPP-A as a cell surface-associated enzyme, the reduced affinity of the cleavage fragments results in increased IGF available to bind and activate IGF receptors in the pericellular environment. This proteolytic regulation of IGF activity is important, since the IGFs promote proliferation, differentiation, migration, and survival in various normal and cancer cells. Thus, there has been a steady growth in investigation of PAPP-A structure and function outside of pregnancy. This review provides historical perspective on the discovery of PAPP-A and its structure and cellular function, highlights key studies of the first 50 years in PAPP-A research, and introduces new findings from recent years.
Topics: Pregnancy; Humans; Female; Pregnancy-Associated Plasma Protein-A; Placenta; Metalloproteases; Cell Differentiation; Insulin-Like Growth Factor I
PubMed: 37267421
DOI: 10.1210/endrev/bnad017 -
Journal of Hazardous Materials Jan 2024Macrophages are essential for the maintenance of endothelial cell function. However, the potential impact and mechanisms of crosstalk between macrophages and endothelial...
Macrophages are essential for the maintenance of endothelial cell function. However, the potential impact and mechanisms of crosstalk between macrophages and endothelial cells during silicosis progression remain unexplored. To fill this knowledge gap, a mouse model of silicosis was established. Single cell sequencing, spatial transcriptome sequencing, western blotting, immunofluorescence staining, tube-forming and wound healing assays were used to explore the effects of silicon dioxide on macrophage-endothelial interactions. To investigate the mechanism of macrophage-mediated fibrosis, MMP12 was specifically inactivated using siRNA and pharmacological approaches, and macrophages were depleted using disodium chlorophosphite liposomes. Compared to the normal saline group, the silica dust group showed altered macrophage-endothelial interactions. Matrix metalloproteinase family member MMP12 was identified as a key mediator of the altered function of macrophage-endothelial interactions after silica exposure, which was accompanied by pro-inflammatory macrophage activation and fibrotic progression. By using ablation strategies, macrophage-derived MMP12 was shown to mediate endothelial cell dysfunction by accumulating on the extracellular matrix. During the inflammatory phase of silicosis, MMP12 secreted by pro-inflammatory macrophages caused decreased endothelial cell viability, reduced migration, decreased trans-endothelial resistance and increased permeability; while during the fibrotic phase, macrophage-derived MMP12 sustained endothelial cell injury through accumulation on the extracellular matrix.
Topics: Animals; Mice; Matrix Metalloproteinase 12; Endothelial Cells; Fibrosis; Macrophages; Silicosis; Silicon Dioxide
PubMed: 37816293
DOI: 10.1016/j.jhazmat.2023.132733 -
Nature Communications Oct 2023Cold stimulation dynamically remodels mitochondria in brown adipose tissue (BAT) to facilitate non-shivering thermogenesis in mammals, but what regulates mitochondrial...
Cold stimulation dynamically remodels mitochondria in brown adipose tissue (BAT) to facilitate non-shivering thermogenesis in mammals, but what regulates mitochondrial plasticity is poorly understood. Comparing mitochondrial proteomes in response to cold revealed FAM210A as a cold-inducible mitochondrial inner membrane protein. An adipocyte-specific constitutive knockout of Fam210a (Fam210a) disrupts mitochondrial cristae structure and diminishes the thermogenic activity of BAT, rendering the Fam210a mice vulnerable to lethal hypothermia under acute cold exposure. Induced knockout of Fam210a in adult adipocytes (Fam210a) does not affect steady-state mitochondrial structure under thermoneutrality, but impairs cold-induced mitochondrial remodeling, leading to progressive loss of cristae and reduction of mitochondrial density. Proteomics reveals an association between FAM210A and OPA1, whose cleavage governs cristae dynamics and mitochondrial remodeling. Mechanistically, FAM210A interacts with mitochondrial protease YME1L and modulates its activity toward OMA1 and OPA1 cleavage. These data establish FAM210A as a key regulator of mitochondrial cristae remodeling in BAT and shed light on the mechanism underlying mitochondrial plasticity in response to cold.
Topics: Animals; Mice; Adipocytes, Brown; Adipose Tissue, Brown; Cold Temperature; Hypothermia; Metalloendopeptidases; Mitochondria; Mitochondrial Membranes; Thermogenesis; Mitochondrial Proteins
PubMed: 37816711
DOI: 10.1038/s41467-023-41988-y -
Cell Aug 2023The endopeptidase ADAM10 is a critical catalyst for the regulated proteolysis of key drivers of mammalian development, physiology, and non-amyloidogenic cleavage of APP...
The endopeptidase ADAM10 is a critical catalyst for the regulated proteolysis of key drivers of mammalian development, physiology, and non-amyloidogenic cleavage of APP as the primary α-secretase. ADAM10 function requires the formation of a complex with a C8-tetraspanin protein, but how tetraspanin binding enables positioning of the enzyme active site for membrane-proximal cleavage remains unknown. We present here a cryo-EM structure of a vFab-ADAM10-Tspan15 complex, which shows that Tspan15 binding relieves ADAM10 autoinhibition and acts as a molecular measuring stick to position the enzyme active site about 20 Å from the plasma membrane for membrane-proximal substrate cleavage. Cell-based assays of N-cadherin shedding establish that the positioning of the active site by the interface between the ADAM10 catalytic domain and the bound tetraspanin influences selection of the preferred cleavage site. Together, these studies reveal the molecular mechanism underlying ADAM10 proteolysis at membrane-proximal sites and offer a roadmap for its modulation in disease.
Topics: Animals; ADAM10 Protein; Amyloid Precursor Protein Secretases; Mammals; Proteolysis; Tetraspanins; Humans
PubMed: 37516108
DOI: 10.1016/j.cell.2023.06.026 -
Journal of Cell Science Jan 2024Matrix metalloproteinases (MMPs) are a family of zinc-dependent proteinases that belong to the group of endopeptidases or matrixins. They are able to cleave a plethora... (Review)
Review
Matrix metalloproteinases (MMPs) are a family of zinc-dependent proteinases that belong to the group of endopeptidases or matrixins. They are able to cleave a plethora of substrates, including components of the extracellular matrix and cell-surface-associated proteins, as well as intracellular targets. Accordingly, MMPs play key roles in a variety of physiological and pathological processes, such as tissue homeostasis and cancer cell invasion. MMP activity is exquisitely regulated at several levels, including pro-domain removal, association with inhibitors, intracellular trafficking and transport via extracellular vesicles. Moreover, the regulation of MMP activity is currently being rediscovered for the development of respective therapies for the treatment of cancer, as well as infectious, inflammatory and neurological diseases. In this Cell Science at a Glance article and the accompanying poster, we present an overview of the current knowledge regarding the regulation of MMP activity, the intra- and extra-cellular trafficking pathways of these enzymes and their diverse groups of target proteins, as well as their impact on health and disease.
Topics: Endopeptidases; Extracellular Matrix; Extracellular Vesicles; Membrane Proteins; Matrix Metalloproteinases
PubMed: 38236162
DOI: 10.1242/jcs.261898 -
Journal of the Neurological Sciences Jan 2024Botulinum toxin (BoNT) was approved by the United States Food and Drug Administration (FDA) in 1989 for facial movement disorders and strabismus, but since that time its... (Review)
Review
Botulinum toxin (BoNT) was approved by the United States Food and Drug Administration (FDA) in 1989 for facial movement disorders and strabismus, but since that time its indications have been expanding beyond neurologic and ophthalmologic disorders. This article is a narrative review of the therapeutic use of BoNT in tremors, dystonia, sialorrhea, bladder and other autonomic symptoms, levodopa-induced dyskinesia and other problems occuring in the setting of parkinsonism. Though FDA approval is lacking for some of these indications, expert experiences have shown that BoNT is often beneficial in this group of patients.
Topics: United States; Humans; Botulinum Toxins; Parkinson Disease; Parkinsonian Disorders; Tremor; Dystonic Disorders; Botulinum Toxins, Type A
PubMed: 38056063
DOI: 10.1016/j.jns.2023.122810 -
Aesthetic Surgery Journal Aug 2023In aesthetic clinical practice, botulinum toxin type A (BoNT-A) is best known for its use as a neuromodulator for the treatment of dynamic facial lines; however, when...
Microtoxin for Improving Pore Size, Skin Laxity, Sebum Control, and Scars: A Roundtable on Integrating Intradermal Botulinum Toxin Type A Microdoses Into Clinical Practice.
BACKGROUND
In aesthetic clinical practice, botulinum toxin type A (BoNT-A) is best known for its use as a neuromodulator for the treatment of dynamic facial lines; however, when injected intradermally as microdroplets, BoNT-A can improve skin quality and overall skin appearance.
OBJECTIVES
To discuss key aspects of microtoxin use in clinical practice and provide expert guidance on utilization.
METHODS
As part of a continuing medical education lecture series and roundtable, the authors discussed key aspects of microtoxin patient selection, injection technique, and safety.
RESULTS
The experiences of expert faculty are shared here. Clinical experience is consistent with reported data. Microtoxin can be used to reduce pore size, sebum production, rosacea, acne, and fine lines, and to improve jawline and neck definition. Intradermal injection can also be employed for the improvement of transverse neck lines as well as for the safe prevention and management of scars and keloids.
CONCLUSIONS
Expanding the use of BoNT-A, a predictable, minimally invasive, and affordable treatment to address commonly encountered complaints is appealing. The authors have found that making patients aware of microtoxin as a treatment option results in an increased interest in and utilization of BoNT-A, and high satisfaction among appropriately selected patients.
Topics: Humans; Botulinum Toxins, Type A; Sebum; Skin; Injections, Intradermal; Keloid
PubMed: 36857534
DOI: 10.1093/asj/sjad044 -
Atlas of the Oral and Maxillofacial... Mar 2024
Review
Topics: Humans; Rhytidoplasty; Face; Botulinum Toxins, Type A; Rejuvenation; Hyaluronic Acid; Cosmetic Techniques; Skin Aging
PubMed: 38307633
DOI: 10.1016/j.cxom.2023.10.004 -
Toxicon : Official Journal of the... Aug 2023Many studies have shown that botulinum toxin (BoNT) can be an option to treat motor and non-motor symptoms in Parkinson's disease (PD) and parkinsonian syndromes. The... (Review)
Review
Many studies have shown that botulinum toxin (BoNT) can be an option to treat motor and non-motor symptoms in Parkinson's disease (PD) and parkinsonian syndromes. The advantages of BoNT compared to oral medications include localized action and low incidence of systemic side effects, which is important in treating neurodegenerative disease. Motor symptoms that can be treated with BoNT include blepharospasm, apraxia of eyelid opening, tremor, cervical dystonia and limb dystonia. Other indications with less evidence include camptocormia, freezing of gait and dyskinesia. Non-motor symptoms that may improve with BoNT include sialorrhea, pain, overreactive bladder, dysphagia and constipation. However, the current evidence for use of BoNT in parkinsonism is mostly based on open-label studies and there are few randomized, controlled trials. BoNT can be a valuable tool to treat certain symptoms of PD and parkinsonian syndromes to improve the patient's quality of life. However, many of the uses are not supported by high quality studies and further studies are needed to provide further evidence of efficacy, define the optimal injection protocols such as doses and muscle selection.
Topics: Humans; Botulinum Toxins; Botulinum Toxins, Type A; Gait Disorders, Neurologic; Neurodegenerative Diseases; Parkinson Disease; Parkinsonian Disorders; Quality of Life; Torticollis
PubMed: 37429465
DOI: 10.1016/j.toxicon.2023.107209 -
Toxins Oct 2023Ancient scientific manuscripts indicate that Dr [...].
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Topics: Botulinum Toxins; Neurotoxins
PubMed: 37888652
DOI: 10.3390/toxins15100621