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Redox Biology Dec 2015Lipoxygenases (LOXs) are dioxygenases that catalyze the formation of corresponding hydroperoxides from polyunsaturated fatty acids such as linoleic acid and arachidonic... (Review)
Review
Lipoxygenases (LOXs) are dioxygenases that catalyze the formation of corresponding hydroperoxides from polyunsaturated fatty acids such as linoleic acid and arachidonic acid. LOX enzymes are expressed in immune, epithelial, and tumor cells that display a variety of physiological functions, including inflammation, skin disorder, and tumorigenesis. In the humans and mice, six LOX isoforms have been known. 15-LOX, a prototypical enzyme originally found in reticulocytes shares the similarity of amino acid sequence as well as the biochemical property to plant LOX enzymes. 15-LOX-2, which is expressed in epithelial cells and leukocytes, has different substrate specificity in the humans and mice, therefore, the role of them in mammals has not been established. 12-LOX is an isoform expressed in epithelial cells and myeloid cells including platelets. Many mutations in this isoform are found in epithelial cancers, suggesting a potential link between 12-LOX and tumorigenesis. 12R-LOX can be found in the epithelial cells of the skin. Defects in this gene result in ichthyosis, a cutaneous disorder characterized by pathophysiologically dried skin due to abnormal loss of water from its epithelial cell layer. Similarly, eLOX-3, which is also expressed in the skin epithelial cells acting downstream 12R-LOX, is another causative factor for ichthyosis. 5-LOX is a distinct isoform playing an important role in asthma and inflammation. This isoform causes the constriction of bronchioles in response to cysteinyl leukotrienes such as LTC4, thus leading to asthma. It also induces neutrophilic inflammation by its recruitment in response to LTB4. Importantly, 5-LOX activity is strictly regulated by 5-LOX activating protein (FLAP) though the distribution of 5-LOX in the nucleus. Currently, pharmacological drugs targeting FLAP are actively developing. This review summarized these functions of LOX enzymes under pathophysiological conditions in mammals.
Topics: 5-Lipoxygenase-Activating Proteins; Animals; Anti-Asthmatic Agents; Arachidonate 12-Lipoxygenase; Arachidonate 15-Lipoxygenase; Asthma; Clinical Trials as Topic; Gene Expression; Humans; Ichthyosis; Indoles; Lipoxygenase; Mice; Neoplasms; Pentanoic Acids
PubMed: 26298204
DOI: 10.1016/j.redox.2015.08.006 -
The Journal of Investigative Dermatology Sep 2017We designed and validated a Visual Index for Ichthyosis Severity for scale and erythema that provides (1) written descriptions of the features characteristic of each...
We designed and validated a Visual Index for Ichthyosis Severity for scale and erythema that provides (1) written descriptions of the features characteristic of each level of severity, (2) visual standards for four body sites, and (3) two distinct standards to account for different types of scale. We tested the Visual Index for Ichthyosis Severity for reliability and reproducibility using two different settings: one that utilized scoring of 60 test photographs by 10 dermatologists, and one with in-person evaluations on 85 subjects by 12 dermatologists at the Foundation for Ichthyosis and Related Skin Types conference. The validation process revealed high reliability and reproducibility for both scale and erythema. The interrater and intrarater intraclass correlation coefficients for scale were consistently near or greater than 0.7 in both settings. By contrast, the interrater reliability for erythema was higher during in-person validation compared with validation on test photographs. Our analysis indicates that the Visual Index for Ichthyosis Severity performs better in person than with photographs, an important consideration in the design of clinical trials. Power analysis predicts that a 1-point difference on this 5-step scale would be detectable with 12 subjects in each of two defined groups. This index provides a tool for clinical phenotyping and assessment of therapeutic response for many disorders of keratinization.
Topics: Adult; Biopsy, Needle; Cohort Studies; Female; Humans; Ichthyosis; Immunohistochemistry; Male; Middle Aged; Observer Variation; Photography; Severity of Illness Index
PubMed: 28596001
DOI: 10.1016/j.jid.2017.04.037 -
PLoS Genetics Sep 2015Netherton Syndrome (NS) is a rare and severe autosomal recessive skin disease which can be life-threatening in infants. The disease is characterized by extensive skin...
Netherton Syndrome (NS) is a rare and severe autosomal recessive skin disease which can be life-threatening in infants. The disease is characterized by extensive skin desquamation, inflammation, allergic manifestations and hair shaft defects. NS is caused by loss-of-function mutations in SPINK5 encoding the LEKTI serine protease inhibitor. LEKTI deficiency results in unopposed activities of kallikrein-related peptidases (KLKs) and aberrantly increased proteolysis in the epidermis. Spink5⁻/⁻ mice recapitulate the NS phenotype, display enhanced epidermal Klk5 and Klk7 protease activities and die within a few hours after birth because of a severe skin barrier defect. However the contribution of these various proteases in the physiopathology remains to be determined. In this study, we developed a new murine model in which Klk5 and Spink5 were both knocked out to assess whether Klk5 deletion is sufficient to reverse the NS phenotype in Spink5⁻/⁻ mice. By repeated intercrossing between Klk5⁻/⁻ mice with Spink5⁻/⁻ mice, we generated Spink5⁻/⁻Klk5⁻/⁻ animals. We showed that Klk5 knock-out in Lekti-deficient newborn mice rescues neonatal lethality, reverses the severe skin barrier defect, restores epidermal structure and prevents skin inflammation. Specifically, using in situ zymography and specific protease substrates, we showed that Klk5 knockout reduced epidermal proteolytic activity, particularly its downstream targets proteases KLK7, KLK14 and ELA2. By immunostaining, western blot, histology and electron microscopy analyses, we provide evidence that desmosomes and corneodesmosomes remain intact and that epidermal differentiation is restored in Spink5⁻/⁻Klk5⁻/⁻. Quantitative RT-PCR analyses and immunostainings revealed absence of inflammation and allergy in Spink5⁻/⁻Klk5⁻/⁻ skin. Notably, Il-1β, Il17A and Tslp levels were normalized. Our results provide in vivo evidence that KLK5 knockout is sufficient to reverse NS-like symptoms manifested in Spink5⁻/⁻ skin. These findings illustrate the crucial role of protease regulation in skin homeostasis and inflammation, and establish KLK5 inhibition as a major therapeutic target for NS.
Topics: Animals; Cell Differentiation; Kallikreins; Mice; Mice, Knockout; Netherton Syndrome; Skin Diseases
PubMed: 26390218
DOI: 10.1371/journal.pgen.1005389 -
BMJ Case Reports Jul 2021A 7-year-old girl born to consanguineous parents, had recurrent erythroderma since birth; she presented with intractable pruritus, scaling, dry skin and eczematous...
A 7-year-old girl born to consanguineous parents, had recurrent erythroderma since birth; she presented with intractable pruritus, scaling, dry skin and eczematous lesions, associated to fingers and toes onychogryphosis, along with refractory otitis. The hair was sparse and brittle, the simple light microscopic examination of hair shaft revealed a pathognomonic Bamboo aspect (trichorrehxis invaginata) and ear swab culture revealed as otitis agent. Due to the lack of genetic routine testing, children with recalcitrant erythroderma and otitis, along with hair shaft abnormalities, need to be evaluated for Netherton syndrome.
Topics: Candida parapsilosis; Child; Female; Hair; Humans; Ichthyosiform Erythroderma, Congenital; Netherton Syndrome; Otomycosis
PubMed: 34285026
DOI: 10.1136/bcr-2021-243260 -
Anais Brasileiros de Dermatologia 2021A 55-year-old male presented with an eight-month history of erythematous papules and plaques with demarcated areas of spared skin on his trunk, upper extremities, neck,...
A 55-year-old male presented with an eight-month history of erythematous papules and plaques with demarcated areas of spared skin on his trunk, upper extremities, neck, and face. Grover's disease is a rare, acquired disorder of unknown origin, which is classically characterized by the appearance of erythematous papules on the upper trunk that are usually transient. As in the present case, there are reports of atypical disease, with facial involvement, pityriasis rubra pilaris-like lesions, and a more chronic course.
Topics: Acantholysis; Humans; Ichthyosis; Male; Middle Aged; Pityriasis Rubra Pilaris; Skin
PubMed: 33589293
DOI: 10.1016/j.abd.2020.06.011 -
Journal of Neuroinflammation Dec 2022Dendritic cells (DCs) are the most potent professional antigen-presenting cells (APCs), which play a pivotal role in inducing either inflammatory or tolerogenic response... (Review)
Review
Dendritic cells (DCs) are the most potent professional antigen-presenting cells (APCs), which play a pivotal role in inducing either inflammatory or tolerogenic response based on their subtypes and environmental signals. Emerging evidence indicates that DCs are critical for initiation and progression of autoimmune diseases, including multiple sclerosis (MS). Current disease-modifying therapies (DMT) for MS can significantly affect DCs' functions. However, the study on the impact of DMT on DCs is rare, unlike T and B lymphocytes that are the most commonly discussed targets of these therapies. Induction of tolerogenic DCs (tolDCs) with powerful therapeutic potential has been well-established to combat autoimmune responses in laboratory models and early clinical trials. In contrast to in vitro tolDC induction, in vivo elicitation by specifically targeting multiple cell-surface receptors has shown greater promise with more advantages. Here, we summarize the role of DCs in governing immune tolerance and in the process of initiating and perpetuating MS as well as the effects of current DMT drugs on DCs. We then highlight the most promising cell-surface receptors expressed on DCs currently being explored as the viable pharmacological targets through antigen delivery to generate tolDCs in vivo.
Topics: Humans; Multiple Sclerosis; Dendritic Cells; Immune Tolerance; Autoimmune Diseases; Ichthyosiform Erythroderma, Congenital
PubMed: 36510261
DOI: 10.1186/s12974-022-02663-z -
Medecine Sciences : M/S Nov 2018Calcium (Ca) is an essential regulator for a large number of cellular functions in various tissues and organs, and small disturbances of Ca homeostasis can severely...
Calcium (Ca) is an essential regulator for a large number of cellular functions in various tissues and organs, and small disturbances of Ca homeostasis can severely compromise normal physiology. Intracellular Ca balance is mainly controlled by the reticular Ca sensor STIM1 and the plasma membrane Ca channel ORAI1 through a mechanism known as store-operated Ca entry (SOCE). Gain-of-function mutations in STIM1 or ORAI1 cause excessive extracellular Ca influx, resulting in tubular aggregate myopathy (TAM) and Stormorken syndrome (STRMK). Both disorders are spectra of the same disease and involve muscle weakness, miosis, thrombocytopenia, hyposplenism, ichthyosis, dyslexia, and short stature. Here we summarize the clinical and histological characteristics of both disorders, provide an overview on the genetic causes, and recapitulate the current knowledge on the pathomechanisms leading to the multi-systemic phenotype of tubular aggregate myopathy and Stormorken syndrome.
Topics: Biopsy; Blood Platelet Disorders; Calcium; Dyslexia; Erythrocytes, Abnormal; Genotype; Humans; Ichthyosis; Migraine Disorders; Miosis; Muscle Fatigue; Muscles; Mutation; Myopathies, Structural, Congenital; Neoplasm Proteins; ORAI1 Protein; Phenotype; Spleen; Stromal Interaction Molecule 1
PubMed: 30418142
DOI: 10.1051/medsci/201834s208 -
Journal of Thrombosis and Haemostasis :... Sep 2019
Topics: Awards and Prizes; Blood Platelet Disorders; Dyslexia; Education, Medical; Erythrocytes, Abnormal; Hematology; History, 20th Century; History, 21st Century; Ichthyosis; Migraine Disorders; Military Medicine; Miosis; Muscle Fatigue; Norway; Research; Spleen; Veterinary Medicine
PubMed: 31479185
DOI: 10.1111/jth.14585 -
Genes Mar 2023Autosomal recessive congenital ichthyosis (ARCI) is a non-syndromic congenital disorder of cornification characterized by abnormal scaling of the skin. The three major...
Autosomal recessive congenital ichthyosis (ARCI) is a non-syndromic congenital disorder of cornification characterized by abnormal scaling of the skin. The three major phenotypes are lamellar ichthyosis, congenital ichthyosiform erythroderma, and harlequin ichthyosis. ARCI is caused by biallelic mutations in , , , , , , , , , and . The most severe form of ARCI, harlequin ichthyosis, is caused by mutations in . Mutations in this gene can also lead to congenital ichthyosiform erythroderma or lamellar ichthyosis. We present a large cohort of 64 patients affected with ARCI carrying biallelic mutations in . Our study comprises 34 novel mutations in , expanding the mutational spectrum of -associated ARCI up to 217 mutations. Within these we found the possible mutational hotspots c.4541G>A, p.(Arg1514His) and c.4139A>G, p.(Asn1380Ser). A correlation of the phenotype with the effect of the genetic mutation on protein function is demonstrated. Loss-of-function mutations on both alleles generally result in harlequin ichthyosis, whereas biallelic missense mutations mainly lead to CIE or LI.
Topics: Humans; Ichthyosis, Lamellar; Genes, Recessive; Mutation; Ichthyosiform Erythroderma, Congenital; Genetic Association Studies; ATP-Binding Cassette Transporters; Acyltransferases; Phospholipases
PubMed: 36980989
DOI: 10.3390/genes14030717 -
Paediatric Anaesthesia Dec 2020Sjögren-Larsson syndrome is a rare inherited neurocutaneous disorder characterized by congenital ichthyosis, spasticity, intellectual disability, seizures, and...
BACKGROUND
Sjögren-Larsson syndrome is a rare inherited neurocutaneous disorder characterized by congenital ichthyosis, spasticity, intellectual disability, seizures, and ophthalmologic changes. Most individuals with Sjögren-Larsson syndrome live well into adulthood and often require surgical intervention to manage their symptomatology.
AIMS
The aim of this work was to review the clinical aspects of Sjögren-Larsson syndrome, highlight the unique anesthetic considerations associated with this disease, and provide practical recommendations about anesthetic management.
METHODS
A retrospective case review from February 2013 to October 2019 was performed based on subject participation in a Sjögren-Larsson syndrome longitudinal study at the University of Nebraska Medical Center. Anesthetic and surgical records were reviewed for the following data: age, sex, relevant comorbid conditions, anesthetic induction and maintenance agents, intravenous and oral analgesics, muscle relaxants, and anesthetic-related complications.
RESULTS
Fourteen patients with Sjögren-Larsson syndrome undergoing 48 anesthetic events were identified. A variety of anesthetic techniques was utilized. No serious adverse events were encountered. The most common clinical observations were related to the ichthyosis seen in Sjögren-Larsson syndrome, which led to difficulty in adherence of electrocardiogram leads and intravenous catheter dressings.
CONCLUSIONS
We found that anesthesia can be safely administered in patients with Sjögren-Larsson syndrome. Providers should be aware of anesthetic management issues in Sjögren-Larsson syndrome including challenges placing and securing lines and monitors secondary to the ichthyosis.
Topics: Adult; Anesthetics; Humans; Intellectual Disability; Longitudinal Studies; Retrospective Studies; Sjogren-Larsson Syndrome
PubMed: 33037729
DOI: 10.1111/pan.14034