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Molecular Medicine (Cambridge, Mass.) Jun 2024L-theanine is a unique non-protein amino acid in tea that is widely used as a safe food additive. We investigated the cardioprotective effects and mechanisms of...
BACKGROUND
L-theanine is a unique non-protein amino acid in tea that is widely used as a safe food additive. We investigated the cardioprotective effects and mechanisms of L-theanine in myocardial ischemia-reperfusion injury (MIRI).
METHODS
The cardioprotective effects and mechanisms of L-theanine and the role of Janus Kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling were investigated in MIRI mice using measures of cardiac function, oxidative stress, and apoptosis.
RESULTS
Administration of L-theanine (10 mg/kg, once daily) suppressed the MIRI-induced increase in infarct size and serum creatine kinase and lactate dehydrogenase levels, as well as MIRI-induced cardiac apoptosis, as evidenced by an increase in Bcl-2 expression and a decrease in Bax/caspase-3 expression. Administration of L-theanine also decreased the levels of parameters reflecting oxidative stress, such as dihydroethidium, malondialdehyde, and nitric oxide, and increased the levels of parameters reflecting anti-oxidation, such as total antioxidant capacity (T-AOC), glutathione (GSH), and superoxide dismutase (SOD) in ischemic heart tissue. Further analysis showed that L-theanine administration suppressed the MIRI-induced decrease of phospho-JAK2 and phospho-STAT3 in ischemic heart tissue. Inhibition of JAK2 by AG490 (5 mg/kg, once daily) abolished the cardioprotective effect of L-theanine, suggesting that the JAK2/STAT3 signaling pathway may play an essential role in mediating the anti-I/R effect of L-theanine.
CONCLUSIONS
L-theanine administration suppresses cellular apoptosis and oxidative stress in part via the JAK2/STAT3 signaling pathway, thereby attenuating MIRI-induced cardiac injury. L-theanine could be developed as a potential drug to alleviate cardiac damage in MIRI.
Topics: Animals; Janus Kinase 2; STAT3 Transcription Factor; Oxidative Stress; Myocardial Reperfusion Injury; Apoptosis; Glutamates; Signal Transduction; Male; Mice; Cardiotonic Agents
PubMed: 38943069
DOI: 10.1186/s10020-024-00865-0 -
International Immunopharmacology Jun 2024Psoriasis, a chronic autoimmune skin disorder, causes rapid and excessive skin cell growth due to immune system dysfunction. Numerous studies have shown that flavonoids... (Review)
Review
Flavonoid compounds and their synergistic effects: Promising approaches for the prevention and treatment of psoriasis with emphasis on keratinocytes - A systematic and mechanistic review.
Psoriasis, a chronic autoimmune skin disorder, causes rapid and excessive skin cell growth due to immune system dysfunction. Numerous studies have shown that flavonoids have anti-psoriatic effects by modulating various molecular mechanisms involved in inflammation, cytokine production, keratinocyte proliferation, and more. This study reviewed experimental data reported in scientific literature and used network analysis to identify the potential biological roles of flavonoids' targets in treating psoriasis. 947 records from Web of Sciences, ScienceDirect database, Scopus, PubMed, and Cochrane library were reviewed without limitations until June 26, 2023. 66 articles were included in the systematic review. The ten genes with the highest scores, including interleukin (IL)-10, IL-12A, IL-1β, IL-6, Tumor necrosis factor-α (TNF-α), Janus kinase 2 (JAK 2), Jun N-terminal kinase (JUN), Proto-oncogene tyrosine-protein kinase Src (SRC), Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), and Signal transducer and activator of transcription 3 (STAT3), were identified as the hub genes. KEGG pathway analysis identified connections related to inflammation and autoimmune responses, which are key characteristics of psoriasis. IL-6, STAT3, and JUN's presence in both hub and enrichment genes suggests their important role in flavonoid's effect on psoriasis. This comprehensive study highlights how flavonoids can target biological processes in psoriasis, especially when combined for enhanced effectiveness.
PubMed: 38941673
DOI: 10.1016/j.intimp.2024.112561 -
The Nurse Practitioner Jun 2024Atopic dermatitis (AD), a chronic inflammatory, pruritic skin disorder, is seen primarily in the pediatric population but can be found among all age groups. The symptoms...
Atopic dermatitis (AD), a chronic inflammatory, pruritic skin disorder, is seen primarily in the pediatric population but can be found among all age groups. The symptoms of AD can cause embarrassment in patients and can interrupt daily activities and productivity, potentially resulting in avoidance of social situations. In addition to nonpharmacologic management, mainstay pharmacologic treatments for AD are topical medications including corticosteroids, calcineurin inhibitors, phosphodiesterase-4 inhibitors, and topical Janus kinase (JAK) inhibitors. Promising new drugs-oral JAK inhibitors and monoclonal antibodies-have emerged as new treatment options for moderate-to-severe AD.
Topics: Dermatitis, Atopic; Humans; Janus Kinase Inhibitors; Phosphodiesterase 4 Inhibitors; Adrenal Cortex Hormones; Calcineurin Inhibitors; Dermatologic Agents; Nurse Practitioners
PubMed: 38941080
DOI: 10.1097/01.NPR.0000000000000183 -
Sheng Li Xue Bao : [Acta Physiologica... Jun 2024Hemoglobinopathies are one of the most common single-gene genetic disorders globally, with approximately 1% to 5% of the global population carrying the mutated gene for... (Review)
Review
Hemoglobinopathies are one of the most common single-gene genetic disorders globally, with approximately 1% to 5% of the global population carrying the mutated gene for thalassemia. Thalassemia are classified into transfusion-dependent thalassemia and non-transfusion-dependent thalassemia based on the need for blood transfusion. Traditional treatment modalities include blood transfusion, splenectomy, hydroxyurea therapy, and iron chelation therapy, which are now widely used for clinical treatment and constitute the main methods recommended in the β-thalassemia treatment guidelines. However, there are multiple barriers and limitations to the application of these approaches, and there is an urgent need to explore new therapeutic approaches. With the in-depth study of the pathophysiological process of β-thalassemia, a deeper understanding of the pathogenesis of the disease has been gained. It has been demonstrated that the pathogenesis of thalassemia is closely related to ineffective erythropoiesis (IE), imbalance in the ratio of α/β-globin protein chains and iron overload. New therapeutic approaches are emerging for different pathogenic mechanisms. Among them, new drugs for the treatment of IE mainly include activin receptor II trap ligands, Janus kinase 2 inhibitors, pyruvate kinase activators, and glycine transporter protein 1 inhibitors. Correcting the imbalance in the hemoglobin chain is mainly due to emerging technologies such as bone marrow transplantation and gene editing. Measures in reducing iron overload are associated with inhibiting the activity of transferrin and hepcidin. These new approaches provide new ideas and options for the treatment and management of β-thalassemia.
Topics: beta-Thalassemia; Humans; Genetic Therapy; Blood Transfusion; Janus Kinase 2; Activin Receptors, Type II; Splenectomy; Gene Editing; Iron Chelating Agents; Bone Marrow Transplantation; Iron Overload; Erythropoiesis; Immunoglobulin Fc Fragments; Recombinant Fusion Proteins
PubMed: 38939943
DOI: No ID Found -
Research (Washington, D.C.) 2024Hepatocellular carcinoma (HCC) was characterized as being hypervascular. In the present study, we generated a single-cell spatial transcriptomic landscape of the...
Hepatocellular carcinoma (HCC) was characterized as being hypervascular. In the present study, we generated a single-cell spatial transcriptomic landscape of the vasculogenic etiology of HCC and illustrated overexpressed Golgi phosphoprotein 73 (GP73) HCC cells exerting cellular communication with vascular endothelial cells with high pro-angiogenesis potential via multiple receptor-ligand interactions in the process of tumor vascular development. Specifically, we uncovered an interactive GP73-mediated regulatory network coordinated with c-Myc, lactate, Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway, and endoplasmic reticulum stress (ERS) signals in HCC cells and elucidated its pro-angiogenic roles in vitro and in vivo. Mechanistically, we found that GP73, the pivotal hub gene, was activated by histone lactylation and c-Myc, which stimulated the phosphorylation of downstream STAT3 by directly binding STAT3 and simultaneously enhancing glucose-regulated protein 78 (GRP78)-induced ERS. STAT3 potentiates GP73-mediated pro-angiogenic functions. Clinically, serum GP73 levels were positively correlated with HCC response to anti-angiogenic regimens and were essential for a prognostic nomogram showing good predictive performance for determining 6-month and 1-year survival in patients with HCC treated with anti-angiogenic therapy. Taken together, the aforementioned data characterized the pro-angiogenic roles and mechanisms of a GP73-mediated network and proved that GP73 is a crucial tumor angiogenesis niche gene with favorable anti-angiogenic potential in the treatment of HCC.
PubMed: 38939041
DOI: 10.34133/research.0387 -
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