-
Cells Nov 2023This review on acne transcriptomics allows for deeper insights into the pathogenesis of acne and isotretinoin's mode of action. Puberty-induced insulin-like growth... (Review)
Review
This review on acne transcriptomics allows for deeper insights into the pathogenesis of acne and isotretinoin's mode of action. Puberty-induced insulin-like growth factor 1 (IGF-1), insulin and androgen signaling activate the kinase AKT and mechanistic target of rapamycin complex 1 (mTORC1). A Western diet (hyperglycemic carbohydrates and milk/dairy products) also co-stimulates AKT/mTORC1 signaling. The AKT-mediated phosphorylation of nuclear FoxO1 and FoxO3 results in their extrusion into the cytoplasm, a critical switch which enhances the transactivation of lipogenic and proinflammatory transcription factors, including androgen receptor (AR), sterol regulatory element-binding transcription factor 1 (SREBF1), peroxisome proliferator-activated receptor γ (PPARγ) and signal transducer and activator of transcription 3 (STAT3), but reduces the FoxO1-dependent expression of GATA binding protein 6 (GATA6), the key transcription factor for infundibular keratinocyte homeostasis. The AKT-mediated phosphorylation of the p53-binding protein MDM2 promotes the degradation of p53. In contrast, isotretinoin enhances the expression of p53, FoxO1 and FoxO3 in the sebaceous glands of acne patients. The overexpression of these proapoptotic transcription factors explains isotretinoin's desirable sebum-suppressive effect via the induction of sebocyte apoptosis and the depletion of BLIMP1(+) sebocyte progenitor cells; it also explains its adverse effects, including teratogenicity (neural crest cell apoptosis), a reduced ovarian reserve (granulosa cell apoptosis), the risk of depression (the apoptosis of hypothalamic neurons), VLDL hyperlipidemia, intracranial hypertension and dry skin.
Topics: Humans; Isotretinoin; Proto-Oncogene Proteins c-akt; Tumor Suppressor Protein p53; Transcriptome; Acne Vulgaris; Mechanistic Target of Rapamycin Complex 1; Transcription Factors
PubMed: 37998335
DOI: 10.3390/cells12222600 -
Cureus Sep 2023Hypothyroidism means an underactive thyroid gland. This leads to a decrease in the functioning of the thyroid gland. It is a very common endocrine disorder that causes... (Review)
Review
Hypothyroidism means an underactive thyroid gland. This leads to a decrease in the functioning of the thyroid gland. It is a very common endocrine disorder that causes under-secretion of thyroid hormones, mainly thyroxine (T4) and triiodothyronine (T3). It affects people of every age group but is more commonly found in women and older people. The symptoms of hypothyroidism can go unnoticed, may not be specific, and may overlap with other conditions, which makes it harder to diagnose it in some cases. Common symptoms include fatigue, weight gain, increased sensitivity to cold (cold intolerance), irregular bowel movements (constipation), and dry skin (xeroderma). These conditions are mostly the result of a low metabolic rate in the body. Weight gain occurs due to a decrease in fat-burning rate and cold intolerance due to a decrease in heat production by the body. This condition can be caused by a variety of factors, including autoimmune diseases, radiation therapy, thyroid gland removal surgeries, and certain medications. The diagnosis of hypothyroidism is based on laboratory tests that measure the levels of thyroid hormones (T3 and T4) in the blood. Treatment typically involves lifelong hormone replacement therapy with synthetic thyroid hormone replacement medication, such as levothyroxine, to help regulate hormone levels in the body. People with hypothyroidism may need to have their medication dosage adjusted over time. If hypothyroidism is left untreated, it can lead to severe complications like mental retardation, delayed milestones, etc., in infants and heart failure, infertility, myxedema coma, etc., in adults. With appropriate treatment, the symptoms of hypothyroidism can be effectively managed, and most people with the condition can lead normal, healthy lives. Lifestyle modifications like eating healthy food and exercising regularly can help manage the symptoms and improve the quality of life.
PubMed: 37908940
DOI: 10.7759/cureus.46241 -
The Journal of Allergy and Clinical... Oct 2023Gain-of-function variants of JAK1 drive a rare immune dysregulation syndrome associated with atopic dermatitis, allergy, and eosinophilia.
BACKGROUND
Gain-of-function variants of JAK1 drive a rare immune dysregulation syndrome associated with atopic dermatitis, allergy, and eosinophilia.
OBJECTIVES
This study sought to describe the clinical and immunological characteristics associated with a new gain-of-function variant of JAK1 and report the therapeutic efficacy of Janus kinase (JAK) inhibition.
METHODS
The investigators identified a family affected by JAK1-associated autoinflammatory disease and performed clinical assessment and immunological monitoring on 9 patients. JAK1 signaling was studied by flow and mass cytometry in patients' cells at basal state or after immune stimulation. A molecular disease signature in the blood was studied at the transcriptomic level. Patients were treated with 1 of 2 JAK inhibitors: either baricitinib or upadacitinib. Clinical, cellular, and molecular response were evaluated over a 2-year period.
RESULTS
Affected individuals displayed a syndromic disease with prominent allergy including atopic dermatitis, ichthyosis, arthralgia, chronic diarrhea, disseminated calcifying fibrous tumors, and elevated whole blood histamine levels. A variant of JAK1 localized in the pseudokinase domain was identified in all 9 affected, tested patients. Hyper-phosphorylation of STAT3 was found in 5 of 6 patients tested. Treatment of patients' cells with baricitinib controlled most of the atypical hyper-phosphorylation of STAT3. Administration of baricitinib to patients led to rapid improvement of the disease in all adults and was associated with reduction of systemic inflammation.
CONCLUSIONS
Patients with this new JAK1 gain-of-function pathogenic variant displayed very high levels of blood histamine and showed a variable combination of atopy with articular and gastrointestinal manifestations as well as calcifying fibrous tumors. The disease, which appears to be linked to STAT3 hyperactivation, was well controlled under treatment by JAK inhibitors in adult patients.
Topics: Adult; Humans; Janus Kinase Inhibitors; Dermatitis, Atopic; Histamine; Neoplasms; Janus Kinase 1
PubMed: 37343845
DOI: 10.1016/j.jaci.2023.06.004