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Frontiers in Immunology 2024The new topical formula is urgent needed to meet clinical needs for majority mild patients with psoriasis. Deucravacitinib exerts outstanding anti-psoriatic capacity as...
Reactive oxygen species-responsive supramolecular deucravacitinib self-assembly polymer micelles alleviate psoriatic skin inflammation by reducing mitochondrial oxidative stress.
INTRODUCTION
The new topical formula is urgent needed to meet clinical needs for majority mild patients with psoriasis. Deucravacitinib exerts outstanding anti-psoriatic capacity as an oral TYK2 inhibitor; however, single therapy is insufficient to target the complicated psoriatic skin, including excessive reactive oxygen species (ROS) and persistent inflammation. To address this need, engineered smart nano-therapeutics hold potential for the topical delivery of deucravacitinib.
METHODS
hydrophobic Deucravacitinib was loaded into polyethylene glycol block-polypropylene sulphide (PEG-b-PPS) for transdermal delivery in the treatment of psoriasis. The oxidative stress model of HaCaT psoriasis was established by TNF-α and IL-17A . JC-1 assay, DCFH-DA staining and mtDNA copy number were utilized to assess mitochondrial function. 0.75% Carbopol934 was incorporated into SPMs to produce hydrogels and Rhb was labeled to monitor penetration by Immunofluorescence. , we established IMQ-induced psoriatic model to evaluate therapeutic effect of Car@Deu@PEPS.
RESULTS
Deu@PEPS exerted anti-psoriatic effects by restoring mitochondrial DNA copy number and mitochondrial membrane potential in HaCaT. , Car@Deu@PEPS supramolecular micelle hydrogels had longer retention time in the dermis in the IMQ-induced ROS microenvironment. Topical application of Car@Deu@PEPS significantly restored the normal epidermal architecture of psoriatic skin with abrogation of splenomegaly in the IMQ-induced psoriatic dermatitis model. Car@Deu@PEPS inhibited STAT3 signaling cascade with a corresponding decrease in the levels of the differentiation and proliferative markers Keratin 17 and Cyclin D1, respectively. Meanwhile, Car@Deu@PEPS alleviated IMQ-induced ROS generation and subsequent NLRP3 inflammasome-mediated pyroptosis.
CONCLUSION
Deu@PEPS exerts prominent anti-inflammatory and anti-oxidative effects, which may offers a more patient-acceptable therapy with fewer adverse effects compared with oral deucravacitinib.
Topics: Reactive Oxygen Species; Psoriasis; Humans; Oxidative Stress; Mitochondria; Micelles; Animals; Mice; Skin; Polymers; HaCaT Cells; Administration, Cutaneous; Male
PubMed: 38799436
DOI: 10.3389/fimmu.2024.1407782 -
Cureus Apr 2024Infectious mononucleosis (IM) is a clinical disease caused by the Epstein-Barr virus (EBV). Common presenting symptoms include sore throat, lymph node enlargement,...
Infectious mononucleosis (IM) is a clinical disease caused by the Epstein-Barr virus (EBV). Common presenting symptoms include sore throat, lymph node enlargement, fever, and malaise. Although severe upper airway obstruction is uncommon, it is a potentially fatal complication that requires immediate intervention. We describe the case of an 18-year-old Hispanic man who presented with a progressive sore throat and difficulty speaking, requiring endotracheal intubation for airway protection. CT images showed diffuse swelling of Waldeyer's tonsillar ring, multiple enlarged lymphadenopathies, and splenomegaly. Acute EBV infection was confirmed considering clinical presentation and using the heterophile antibody, anti-nuclear and anti-viral capsid antigens, and quantitative PCR. The patient was managed with ventilatory support, empirical antibiotic therapy, and systemic corticosteroids, achieving a positive outcome. Our case illustrates the use of corticosteroids in managing severe upper airway obstruction complicating IM.
PubMed: 38779228
DOI: 10.7759/cureus.58735 -
Disease Models & Mechanisms May 2024Hyperinflammatory disease is associated with an aberrant immune response resulting in cytokine storm. One such instance of hyperinflammatory disease is known as...
Hyperinflammatory disease is associated with an aberrant immune response resulting in cytokine storm. One such instance of hyperinflammatory disease is known as macrophage activation syndrome (MAS). The pathology of MAS can be characterised by significantly elevated serum levels of interleukin (IL)-18 and interferon (IFN)-γ. Given the role for IL-18 in MAS, we sought to establish the role of inflammasomes in the disease process. Using a murine model of CpG-DNA induced MAS, we discovered that the expression of the NLRP3 inflammasome was increased and correlated with IL-18 production. Inhibition of the NLRP3 inflammasome, or downstream caspase-1, prevented MAS-mediated upregulation of plasma IL-18 but interestingly did not alleviate key features of hyperinflammatory disease including hyperferritinaemia and splenomegaly. Furthermore IL-1 receptor blockade with IL-1Ra did not prevent the development of CpG-induced MAS, despite being clinically effective in the treatment of MAS. These data demonstrate that in the development of MAS, the NLRP3 inflammasome was essential for the elevation in plasma IL-18, a key cytokine in clinical cases of MAS, but was not a driving factor in the pathogenesis of CpG-induced MAS.
PubMed: 38775430
DOI: 10.1242/dmm.050762 -
Therapeutics and Clinical Risk... 2024Lymphoproliferation is defined by lymphadenopathy, splenomegaly, hepatomegaly, or lymphocytic organ and tissue infiltration. The most common etiologies of... (Review)
Review
The Etiologic Landscape of Lymphoproliferation in Childhood: Proposal for a Diagnostic Approach Exploring from Infections to Inborn Errors of Immunity and Metabolic Diseases.
Lymphoproliferation is defined by lymphadenopathy, splenomegaly, hepatomegaly, or lymphocytic organ and tissue infiltration. The most common etiologies of lymphoproliferation are represented by infectious diseases and lymphoid malignancies. However, it is increasingly recognized that lymphoproliferative features can be the presenting sign of rare conditions, including inborn errors of immunity (IEI) and inborn errors of metabolism (IEM). Among IEI, lymphoproliferation is frequently observed in autoimmune lymphoproliferative syndrome (ALPS) and related disorders, common variable immunodeficiency (CVID), activated phosphoinositide 3-kinase δ syndrome, and Epstein-Barr virus (EBV)-related disorders. Gaucher disease and Niemann-Pick disease are the most common IEMs that can present with isolated lymphoproliferative features. Notably, other rare conditions, such as sarcoidosis, Castleman disease, systemic autoimmune diseases, and autoinflammatory disorders, should be considered in the differential diagnosis of patients with persistent lymphoproliferation when infectious and malignant diseases have been reasonably ruled out. The clinical features of lymphoproliferative diseases, as well as the associated clinical findings and data deriving from imaging and first-level laboratory investigations, could significantly help in providing the correct diagnostic suspicion for the underlying etiology. This paper reviews the most relevant diseases associated with lymphoproliferation, including infectious diseases, hematological malignancies, IEI, and IEM. Moreover, some practical indications to orient the initial diagnostic process are provided, and two diagnostic algorithms are proposed for the first-level assessment and the approach to persistent lymphoproliferation, respectively.
PubMed: 38770035
DOI: 10.2147/TCRM.S462996 -
Cureus Apr 2024Congenital dyserythropoietic anemias (CDAs) are rare hereditary disorders, of which type II CDA is the most common. Mutations in the gene located on chromosome 20...
Congenital dyserythropoietic anemias (CDAs) are rare hereditary disorders, of which type II CDA is the most common. Mutations in the gene located on chromosome 20 result in this autosomal recessive disorder. In this case report, we present a case of CDA II with unique biopsy findings being detected via genetic testing. A female aged 30 years presented with major complaints of pallor weakness and easy fatiguability since childhood. The patient gave a history of 25 units of blood transfusion, the majority of which were transfused during pregnancy, followed by regular transfusions thereafter. On examination, all her vitals were in the normal range. Pallor, frontal bossing, and malocclusion of teeth were noted. Her laboratory workup showed the following: hemoglobin (Hb): 3.7 g/dl; mean corpuscular volume: 83 fl; mean corpuscular Hb: 29 g/dl; mean corpuscular Hb concentration: 34.9 g/dl; red cell distribution width: 30.4%; reticulocyte count (RC): 6.2%; corrected RC: 1.3%; lactate dehydrogenase: 441 IU/L; direct Coombs test/indirect Coombs test: negative; serum iron: 242 microgram/dl; transferrin saturation: 96.08%; ferritin: 1,880 ng/ml; and normal high-performance liquid chromatography and eosin-5'-maleimide binding test. The peripheral blood film showed normocytic normochromic anemia with anisopoikilocytosis in the form of a few spherocytes. No immature cells were seen. After obtaining the patient's consent, we performed a hereditary hemolytic anemia gene analysis test, which showed homozygous missense variation in exon 12 of the gene. The bone marrow examination showed hyperplasia in the erythroid series with dyserythropoiesis, and surprisingly, myelofibrosis grade I-II (WHO 2017) was also observed on biopsy. Patients with CDA type II generally present with variable degrees of anemia along with pallor, icterus, splenomegaly, gallstones, and iron overload. In our case, the diagnosis of CDA type II was made at an adult age. Also, evidence of myelofibrosis was noted in our case, making it worth reporting. The use of a hereditary hemolytic anemia gene analysis panel test came as a rescue for its exact diagnosis. This case report emphasizes the role of molecular genetic testing for early and accurate diagnosis, which, in turn, could help in appropriate treatment planning and proper genetic counseling. The prevalence of CDA type II is still vaguely known; hence, extensive workup of persistent anemias and proper follow-up would be beneficial.
PubMed: 38765414
DOI: 10.7759/cureus.58515 -
Transplantation Proceedings May 2024A 21-year-old woman diagnosed with cystic fibrosis developed cirrhosis, exocrine pancreatic insufficiency, and insulin-dependent diabetes mellitus. The patient qualified...
BACKGROUND
A 21-year-old woman diagnosed with cystic fibrosis developed cirrhosis, exocrine pancreatic insufficiency, and insulin-dependent diabetes mellitus. The patient qualified for double organ liver-pancreas transplantation beyond typical indications. The respiratory symptoms of cystic fibrosis were moderate and well-treated. The patient was endangered mainly by liver insufficiency and recurrent hypoglycemia, which was due to the treatment of diabetes with high doses of insulin. Computed tomography showed mild bronchiectasis, cirrhotic liver, splenomegaly, and atrophy of the pancreas. Pseudomonas aeruginosa colonized the upper respiratory tract. Gastrointestinal complications were sufficient for the patient to be qualified for combined liver-pancreas transplantation.
METHODS
First, a standard hepatectomy was performed. The liver was transplanted orthotopically. Subsequently, the team performed pancreas transplantation through a separate incision. The donor's duodenum was anastomosed to the recipient's jejunum, close to the ligament of Treitz.
RESULTS
No serious complications were noted during the postoperative period. Transplanted organs started functioning without delay. The patient was discharged after 6 weeks in general good condition. Twenty months later, the patient felt well, and the grafts kept functioning properly.
CONCLUSION
Combined liver-pancreas transplantation in patients with CF restores exocrine and endocrine pancreatic function and minimizes the risk of life-threatening complications associated with liver insufficiency. Improvement of life quality coincides with the possibility of discontinuing insulin and pancreatic enzyme supplementation. The combination of liver and pancreas transplantation may prevent advanced pulmonary complications, extend the prognosis of survival, and improve the long-term life quality.
Topics: Humans; Cystic Fibrosis; Pancreas Transplantation; Female; Liver Transplantation; Young Adult; Diabetes Mellitus, Type 1; Exocrine Pancreatic Insufficiency; Treatment Outcome
PubMed: 38749862
DOI: 10.1016/j.transproceed.2024.03.034 -
SAGE Open Medical Case Reports 2024Acute coronary syndrome is commonly associated with traditional cardiovascular risk factors such as smoking, hypertension, diabetes, and hyperlipidemia. Myocardial...
Acute coronary syndrome is commonly associated with traditional cardiovascular risk factors such as smoking, hypertension, diabetes, and hyperlipidemia. Myocardial infarction in a young person presents a significant challenge because its etiology is least likely associated with atherosclerosis. Polycythemia vera refers to one of the rare causes of myocardial infarction, which involves enhanced erythrocyte levels, leukocytosis, thrombocytosis, splenomegaly, and a greater chance of vascular occlusion due to clotting in coronary arteries. A 22-year-old male from Pakistan, Asia without typical risk factors, presented with severe chest pain. Electrocardiography indicated acute inferior wall myocardial infarction, and streptokinase was administered. Subsequent investigations confirmed polycythemia vera. Treatment with hydroxyurea and aspirin was initiated, whereas normal coronary arteries in CT coronary angiogram were observed. This case highlights polycythemia vera's rare role in young individuals' heart attacks without known risk factors, emphasizing the need for early detection and specialized treatments involving hematologists to prevent future thrombotic episodes.
PubMed: 38741603
DOI: 10.1177/2050313X241253741 -
Journal of Infection in Developing... Apr 2024Hepatitis B virus (HBV) infection is a global epidemic that can lead to several liver diseases, seriously affecting people's health. This study aimed to investigate the...
INTRODUCTION
Hepatitis B virus (HBV) infection is a global epidemic that can lead to several liver diseases, seriously affecting people's health. This study aimed to investigate the clinical potential of serum β-klotho (KLB) as a promising biomarker in HBV-related liver diseases.
METHODOLOGY
This study enrolled 30 patients with chronic hepatitis B (CHB), 35 with HBV-related cirrhosis, 66 with HBV-related hepatocellular carcinoma (HCC), and 48 healthy individuals. ELISA measured the levels of serum KLB in the four groups. We then compared the differences in serum KLB levels among the groups and analyzed the relationship between serum KLB and routine clinical parameters.
RESULTS
The concentrations of serum KLB levels were increased sequentially among the healthy subjects, the HBV-related CHB group, the HBV-related cirrhosis group, and the HBV-related HCC group (p < 0.05). Expression of KLB was positively correlated with alpha-fetoprotein (AFP), total bilirubin, direct bilirubin, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl-transferase, alkaline phosphatase, total bile acid, serum markers for liver fibrosis, ascites, cirrhosis, splenomegaly, and model for end-stage liver disease sodium, while negatively correlated with platelet count, albumin, and prothrombin activity (p < 0.05). In addition, serum KLB has better sensitivity in diagnosing HCC than AFP, and serum KLB combined with AFP has higher sensitivity and specificity than AFP alone in diagnosing HCC.
CONCLUSIONS
Serum KLB level is associated with the severity of HBV-related liver diseases and has important diagnostic value for HCC. Therefore, it could be a predictive biomarker for monitoring disease progression.
Topics: Humans; Male; Female; Biomarkers; Middle Aged; Adult; Hepatitis B, Chronic; Klotho Proteins; Carcinoma, Hepatocellular; Glucuronidase; Liver Neoplasms; Liver Cirrhosis; Disease Progression; Enzyme-Linked Immunosorbent Assay; Aged
PubMed: 38728647
DOI: 10.3855/jidc.17870 -
PloS One 2024Human T-cell leukemia virus type I (HTLV-I) is an oncogenic virus whose infection can cause diverse diseases, most notably adult T-cell leukemia/lymphoma (ATL or ATLL),...
Human T-cell leukemia virus type I (HTLV-I) is an oncogenic virus whose infection can cause diverse diseases, most notably adult T-cell leukemia/lymphoma (ATL or ATLL), an aggressive and fatal malignancy of CD4 T cells. The oncogenic ability of HTLV-I is mostly attributed to the viral transcriptional transactivator Tax. Tax alone is sufficient to induce specific tumors in mice depending on the promotor used to drive Tax expression, thereby being used to understand HTLV-I tumorigenesis and model the tumor types developed in Tax transgenic mice. Tax exerts its oncogenic role predominantly by activating the cellular transcription factor NF-κB. Here, we report that genetic deletion of NF-κB1, the prototypic member of the NF-κB family, promotes adrenal medullary tumors but suppresses neurofibromas in mice with transgenic Tax driven by the HTLV-I Long Terminal Repeat (LTR) promoter. The adrenal tumors are derived from macrophages. Neoplastic macrophages also infiltrate the spleen and lymph nodes, causing splenomegaly and lymphadenopathy in mice. Nevertheless, the findings could be human relevant, because macrophages are important target cells of HTLV-I infection and serve as a virus reservoir in vivo. Moreover, the spleen, lymph nodes and adrenal glands are the most common sites of tumor cell infiltration in HTLV-I-infected patients. These data provide new mechanistic insights into the complex interaction between Tax and NF-κB, therefore improving our understanding of HTLV-I oncogenic pathogenesis. They also expand our knowledge and establish a new animal model of macrophage neoplasms and adrenal tumors.
Topics: Animals; Humans; Mice; Adrenal Gland Neoplasms; Gene Products, tax; Human T-lymphotropic virus 1; Macrophages; Mice, Transgenic; NF-kappa B p50 Subunit; Terminal Repeat Sequences
PubMed: 38722890
DOI: 10.1371/journal.pone.0303138