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Frontiers in Immunology 2024Human respiratory viruses are the most prevalent cause of disease in humans, with the highly infectious RSV being the leading cause of infant bronchiolitis and viral...
Human respiratory viruses are the most prevalent cause of disease in humans, with the highly infectious RSV being the leading cause of infant bronchiolitis and viral pneumonia. Responses to type I IFNs are the primary defense against viral infection. However, RSV proteins have been shown to antagonize type I IFN-mediated antiviral innate immunity, specifically dampening intracellular IFN signaling. Respiratory epithelial cells are the main target for RSV infection. In this study, we found RSV-NS1 interfered with the IFN-α JAK/STAT signaling pathway of epithelial cells. RSV-NS1 expression significantly enhanced IFN-α-mediated phosphorylation of STAT1, but not pSTAT2; and neither STAT1 nor STAT2 total protein levels were affected by RSV-NS1. However, expression of RSV-NS1 significantly reduced ISRE and GAS promoter activity and anti-viral IRG expression. Further mechanistic studies demonstrated RSV-NS1 bound STAT1, with protein modeling indicating a possible interaction site between STAT1 and RSV-NS1. Nuclear translocation of STAT1 was reduced in the presence of RSV-NS1. Additionally, STAT1's interaction with the nuclear transport adapter protein, KPNA1, was also reduced, suggesting a mechanism by which RSV blocks STAT1 nuclear translocation. Indeed, reducing STAT1's access to the nucleus may explain RSV's suppression of IFN JAK/STAT promoter activation and antiviral gene induction. Taken together these results describe a novel mechanism by which RSV controls antiviral IFN-α JAK/STAT responses, which enhances our understanding of RSV's respiratory disease progression.
Topics: STAT1 Transcription Factor; Humans; Signal Transduction; Interferon-alpha; Respiratory Syncytial Virus, Human; Viral Nonstructural Proteins; Respiratory Syncytial Virus Infections; Janus Kinases; Cell Nucleus; Phosphorylation; Active Transport, Cell Nucleus; Cell Line
PubMed: 38938568
DOI: 10.3389/fimmu.2024.1395809 -
Journal of Controlled Release :... Jun 2024Alopecia areata affects over 140 million people worldwide and causes severe psychological distress. The Janus kinase (JAK) inhibitor, tofacitinib, shows significant...
Alopecia areata affects over 140 million people worldwide and causes severe psychological distress. The Janus kinase (JAK) inhibitor, tofacitinib, shows significant potential in therapeutic applications for treating alopecia areata; however, the systemic adverse effects of oral administration and low absorption rate at the target site limit its application. Hence, to address this issue, we designed topical formulations of tofacitinib-loaded cationic lipid nanoparticles (TFB-cNLPs) with particle sizes of approximately 200 nm. TFB-cNLPs promoted percutaneous absorption and hair follicle targeting in an ex vivo pig ear model. TFB-cNLP decreased IFN-γ-induced alopecia areata symptoms in an in vitro follicle model by blocking the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway. It also reduced the number of CD8NKG2DT cells in a C3H mouse model of alopecia areata in vivo, thereby inhibiting the progression of alopecia areata and reversing hair loss. These findings suggest that TFB-cNLP enhanced hair follicle targeting and has the potential for topical treatment or prevention of alopecia areata.
PubMed: 38936744
DOI: 10.1016/j.jconrel.2024.06.060 -
International Journal of Biological... Jun 2024Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is an disease characterized by pulmonary edema and widespread inflammation, leading to a notably high...
Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is an disease characterized by pulmonary edema and widespread inflammation, leading to a notably high mortality rate. The dysregulation of both pro-inflammatory and anti-inflammatory systems, results in cytokine storm (CS), is intricately associated with the development of ALI/ARDS. Tetrastigma hemsleyanum polysaccharide (THP) exerts remarkable anti-inflammatory and immunomodulatory effects against the disease, although its precise role in pathogenesis remains unclear. In the present study, an ALI/ARDS model was established using bacterial lipopolysaccharides. THP administration via aerosol inhalation significantly mitigated lung injury, reduced the number of inflammatory cells, and ameliorated glycerophospholipid metabolism. Furthermore, specific CS-related pathways were investigated by examining the synergy between tumor necrosis factor-α and interferon-γ used to establish CS models. The results indicated that THP effectively decreased inflammatory damage and cell death. The RNA sequencing revealed the involvement of the Janus kinase (JAK) 2-signal transducers and activators of transcription (STAT) signaling pathway in exerting the mentioned effects. Additionally, THP inhibited the activation of the JAK-STAT pathway, thereby alleviating the CS both in vivo and in vitro. Overall, THP exhibited marked therapeutic potential against ALI/ARDS and CS, primarily by targeting the IFN-γ-JAK2/STAT signaling pathway.
PubMed: 38936586
DOI: 10.1016/j.ijbiomac.2024.133427 -
Military Medicine Jun 2024The article presents a clinical case of peculiarities of clinical manifestations, diagnostic and therapeutic approaches of undiagnosed chronic myeloproliferative...
A Clinical Case of Timely Diagnosis and Successful Treatment of Budd-Chiari Syndrome With Fulminant Cytolysis in the Setting of a First-time Diagnosed Myeloproliferative Disease.
The article presents a clinical case of peculiarities of clinical manifestations, diagnostic and therapeutic approaches of undiagnosed chronic myeloproliferative disease, on the background of which Budd-Chiari syndrome (BCS) developed. The results of clinical course, examination, and treatment of a patient with BCS as a manifestation of the hidden course of primary myelofibrosis with the presence of somatic mutation (V617F) in Janus-tyrosine kinase-2 (JAK2) gene in myeloid cells are presented. Standard clinical and laboratory examinations, and cytomorphologic and histologic examination of bone marrow were used. The diagnosis of BCS was confirmed by ultrasound (US) Doppler examination of the portal system vessels. Symptomatic therapy resulted in insignificant positive results. The analysis of this clinical case showed that the development of BCS was due to a chronic myeloproliferative disease that was not diagnosed before the development of thrombosis. Hepatic vein thrombosis was accompanied by the development of fulminant cytolytic syndrome. Along with symptomatic therapy, patient K., female, 32 years old, underwent transjugular intrahepatic portosystemic shunting 1 month after the first symptoms of BCS appeared, which contributed to a significant clinical effect. Seven years after the installation of 4 transjugular intrahepatic portosystemic shunts, the patient's condition remains satisfactory. The uniqueness of this clinical case lies in the presence of 2 serious diseases at the same time: myeloproliferative pathology (primary myelofibrosis) JAK2-positive variant and BCS. Timely diagnosis of both hematological diseases and their complication in the form of hepatic vein thrombosis with fulminant cytolytic syndrome allowed timely prescription of adequate treatment with a good clinical response.
PubMed: 38935394
DOI: 10.1093/milmed/usae331 -
Clinical and Translational... Jun 2024Patients with inflammatory bowel disease (IBD) are predisposed to the reactivation of viral infections such as cytomegalo virus (CMV). Clinical discrimination of disease...
INTRODUCTION
Patients with inflammatory bowel disease (IBD) are predisposed to the reactivation of viral infections such as cytomegalo virus (CMV). Clinical discrimination of disease flares and colonic CMV reactivation is difficult in patients with established diagnosis of IBD and there are no reliable non-invasive diagnostic tools yet. Further, the influence of novel therapeutics including biologicals and Janus kinase (JAK) inhibitors on the risk of CMV colitis is unclear. The goal of this study was to identify risk factors and clinical determinants of CMV colitis that could serve as minimally invasive markers both for active CMV colitis and relapse.
METHODS
To this end, a retrospective analysis of 376 patients with suspected or confirmed CMV colitis 2016-2023 was performed.
RESULTS
Previous administration of systemic steroids increased the odds of CMV colitis to OR 4.6. Biologicals did not change the incidence of CMV colitis but decreased the OR of a relapse to 0.13. Clinical parameters such as severely bloody diarrhea, intense microscopic ulcerative damage and decreased serum tryptophan correlated with detection of CMV. Importantly, persistent decrease of tryptophan was observed in patients with CMV relapse. Further, tryptophan degradation via the kynurenine pathway was increased in CMV positive patients.
CONCLUSIONS
Taken together, we identify decreased serum tryptophan as a novel potential minimally invasive marker to aid identification of IBD patients with active CMV colitis and at high-risk for relapse.
PubMed: 38934504
DOI: 10.14309/ctg.0000000000000731 -
Nutrients Jun 2024Adenovirus (HAdV) can cause severe respiratory infections in children and immunocompromised patients. There is a lack of specific therapeutic drugs for HAdV infection,...
Adenovirus (HAdV) can cause severe respiratory infections in children and immunocompromised patients. There is a lack of specific therapeutic drugs for HAdV infection, and the study of anti-adenoviral drugs has far-reaching clinical implications. Elemental selenium can play a specific role as an antioxidant in the human immune cycle by non-specifically binding to the amino acid methionine in body proteins. Methods: The antiviral mechanism of selenomethionine was explored by measuring cell membrane status, intracellular DNA status, cytokine secretion, mitochondrial membrane potential, and ROS production. Conclusions: Selenomethionine improved the regulation of ROS-mediated apoptosis by modulating the expression of Jak1/2, STAT3, and BCL-XL, which led to the inhibition of apoptosis. It is anticipated that selenomethionine will offer a new anti-adenoviral therapeutic alternative.
Topics: Humans; Selenomethionine; Apoptosis; Signal Transduction; Reactive Oxygen Species; STAT3 Transcription Factor; Janus Kinases; Antiviral Agents; Membrane Potential, Mitochondrial; A549 Cells
PubMed: 38931321
DOI: 10.3390/nu16121966 -
Journal of Clinical Medicine Jun 2024: To date, the literature concerning real-world data on the retention rate and safety of Janus kinase inhibitors (JAKis) is limited. To retrospectively evaluate the...
: To date, the literature concerning real-world data on the retention rate and safety of Janus kinase inhibitors (JAKis) is limited. To retrospectively evaluate the overall drug retention rate (DRR) of different JAKis in a monocentric cohort of patients with rheumatoid arthritis (RA). : Patients diagnosed with RA and treated with JAKis who were evaluated at our outpatient clinic from March 2017 to December 2023 were included in the study. Demographic, clinical characteristics, and comorbidities were recorded. The DRR was evaluated as the time to drug discontinuation, and baseline predictors of drug discontinuation were investigated through Cox regression after adjusting for baseline confounders. : The global DRR for JAKis was 51.3%. The DRR was 37.5% for tofacitinib, 46.6% for baricitinib, 69.4% for upadacitinib, and 53.5% for filgotinib. Considering all JAKis, the only significant predictor of drug discontinuation was the use of JAKis as a first-line treatment (HR 95% CI [0.25 (0.13-0.46)]. When considering each JAKi individually, a longer disease duration predicted TOF discontinuation (HR95% CI [1.05 (1.01-1.09)], while seropositivity protected against TOF being withdrawn (HR95% CI [0.41 (0.17-0.97)]. No independent predictors emerged for other JAKis. : the use of JAKis as a first-line treatment as well as disease duration and serology may impact the DRR of JAKis, which may inform tailored treatment strategies in clinical practice.
PubMed: 38930022
DOI: 10.3390/jcm13123494 -
Diagnostics (Basel, Switzerland) Jun 2024Vernal keratoconjunctivitis is a persistent allergic ocular disease predominantly mediated by the T-helper 2 lymphocyte-associated immune response. The standard...
Vernal keratoconjunctivitis is a persistent allergic ocular disease predominantly mediated by the T-helper 2 lymphocyte-associated immune response. The standard therapeutic approaches for vernal keratoconjunctivitis include topical corticosteroids and immunosuppressive eye drops. However, managing vernal keratoconjunctivitis with only topical treatments becomes challenging during seasonally exacerbated periods. Systemic treatments such as oral corticosteroids or cyclosporine may be alternative options. Recently, dupilumab's efficacy in refractory vernal keratoconjunctivitis treatment has been documented. Here, we report a case of refractory vernal keratoconjunctivitis coexisting with atopic dermatitis that rapidly improved after upadacitinib administration. An 18-year-old Japanese woman presented with atopic dermatitis, vernal keratoconjunctivitis, and hay fever. In winter, the patient experienced widespread erythema and escalated itching, leading to significant discomfort and insomnia. Owing to the difficulty in maintaining her current regimen, upadacitinib (15 mg), a Janus kinase inhibitor was initiated. After upadacitinib administration, the treatment-resistant vernal keratoconjunctivitis and erythema improved. Upadacitinib is beneficial in severe cases of atopic dermatitis. Consequently, in our case, upadacitinib may offer therapeutic benefits for refractory vernal conjunctivitis by improving the T-helper 1/2 type immune response, autoimmunity, and oxidative stress. To our knowledge, this is the first report suggesting the potential utility of upadacitinib in managing severe vernal conjunctivitis.
PubMed: 38928687
DOI: 10.3390/diagnostics14121272 -
Biomolecules Jun 2024Diabetes imposes a huge burden worldwide. Islet transplantation is an alternative therapy for diabetes. However, tacrolimus, a kind of immunosuppressant after organ...
Diabetes imposes a huge burden worldwide. Islet transplantation is an alternative therapy for diabetes. However, tacrolimus, a kind of immunosuppressant after organ transplantation, is closely related to post-transplant diabetes mellitus. Mesenchymal stem cells (MSCs) have attracted interest for their potential to alleviate diabetes. In vivo experiments revealed that human menstrual blood-derived stem cells (MenSCs) treatment improved tacrolimus-induced blood glucose, body weight, and glucose tolerance disorders in mice. RNA sequencing was used to analyze the potential therapeutic targets of MenSCs. In this study, we illustrated that cystathionine β-synthase (CBS) contributed to tacrolimus -induced islet dysfunction. Using β-cell lines (MIN6, β-TC-6), we demonstrated that MenSCs ameliorated tacrolimus-induced islet dysfunction in vitro. Moreover, MenSC reduced the tacrolimus-induced elevation of CBS levels and significantly enhanced the viability, anti-apoptotic ability, glucose-stimulated insulin secretion (GSIS), and glycolytic flux of β-cells. We further revealed that MenSCs exerted their therapeutic effects by inhibiting CBS expression to activate the IL6/JAK2/STAT3 pathway. In conclusion, we showed that MenSCs may be a potential strategy to improve tacrolimus-induced islet dysfunction.
Topics: Humans; STAT3 Transcription Factor; Tacrolimus; Interleukin-6; Animals; Mice; Female; Cystathionine beta-Synthase; Islets of Langerhans; Janus Kinase 2; Insulin-Secreting Cells; Menstruation; Mesenchymal Stem Cells; Signal Transduction; Insulin Secretion; Cell Line
PubMed: 38927074
DOI: 10.3390/biom14060671 -
Zhongguo Shi Yan Xue Ye Xue Za Zhi Jun 2024To investigate the effects of the serine/threonine kinase family member 1 () gene on the proliferation and apoptosis of acute myeloid leukemia (AML) U937 cells, and the...
OBJECTIVE
To investigate the effects of the serine/threonine kinase family member 1 () gene on the proliferation and apoptosis of acute myeloid leukemia (AML) U937 cells, and the regulation effect on Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway.
METHODS
Bone marrow mononuclear cells from newly diagnosed adult AML patients and patients with iron deficiency anemia were collected and mRNA expression was detected by RT-qPCR. AML cell line U937 cells were divided into U937 group (U937 cells were cultured normally), Si-PIM1 group (U937 cells were transfected with low expression adenovirus vector containing mRNA), Si-NC group (U937 cells were transfected with low expression adenovirus vector without mRNA), coumermycin A1 (CoA1) group (JAK2 activator CoA1 was added to U937 cells at a concentration of 20 μmol/L), and Si-PIM1+CoA1 group (U937 cells were transfected with adenoviral vector containing low expression of mRNA and added with CoA1 at a concentration of 20 μmol/L). After culture for 24 h, the expressions of mRNA and protein, JAK2/STAT3 pathway, cell cycle and apoptosis-related proteins in U937 cells were detected by RT-qPCR and Western blot, the cell proliferation activity was detected by MTT assay, and flow cytometry was used to detect cell cycle changes and apoptosis rate.
RESULTS
The mRNA expression level in bone marrow mononuclear cells in AML patients was higher than that in patients with iron deficiency anemia ( < 0.05). Compared with U937 group, mRNA and protein, phosphorylated JAK2 (p-JAK2)/JAK2, phosphorylated STAT3 (p-STAT3)/STAT3, Cyclin D1, cyclin-dependent kinase 2 (CDK2) protein, cell proliferation activity, S phase and G /M phase proportions were decreased in Si-PIM1 group (all < 0.05), while p27, Caspase-3 protein, G/G phase proportion and apoptosis rate were increased (all < 0.05). However, the changes of above indicators in CoA1 group were just opposite to those in Si-PIM1 group, indicating that CoA1 could reverse the effect of Si-PIM1 on U937 cells. There were no significant differences in above indexes of U937 cells between U937 group, Si-PIM1+CoA1 group and Si-NC group ( >0.05).
CONCLUSION
Knockdown of gene expression can inhibit U937 cell proliferation and promote apoptosis, in order to alleviate ALM process, which may be related to the inhibition of JAK2/STAT3 pathway activation.
Topics: Humans; Janus Kinase 2; Proto-Oncogene Proteins c-pim-1; STAT3 Transcription Factor; Cell Proliferation; Apoptosis; Signal Transduction; Leukemia, Myeloid, Acute; U937 Cells
PubMed: 38926951
DOI: 10.19746/j.cnki.issn.1009-2137.2024.03.003