Search Results (1,808)

New EA-sulfonamides and indazole-sulfonamides were synthesized, characterized, and evaluated for their anticancer activities. The target compound structures were elucidated using various spectroscopic techniques such as NMR-{¹H and ¹³C}, infrared spectroscopy, and high-resolution mass spectrometry. The anticancer activities of the novel compounds were evaluated against four human cancer cell lines, namely A-549, MCF-7, Hs-683, and SK-MEL-28 as well as the normal cell line HaCaT, using 5-fluorouracil and etoposide as reference drugs. Among the tested compounds, 9, 10, and 13 exhibited potent anticancer activities which are better than or similar to the reference compounds 5-fluorouracil and etoposide, against the A-549, MCF-7, and Hs-683 cancer cell lines, with IC₅₀ values ranging from 0.1 to 1 μM. Molecular docking studies of compounds 9, 10, and 13 showed a strong binding with selected protein kinase targets, which are linked to the tested cancer types. Furthermore, the analysis of the molecular dynamics simulation results demonstrated that compound 9 exhibits significant stability when bound to both JAK3 and ROCK1 kinases. This new compound has the potential to be developed as a novel therapeutic agent against various cancers. Full article

Treatment-resistant asthma remains an unresolved clinical problem and a challenge for current medical science. Consequently, there is a growing and urgent need to develop novel or alternative therapeutic options for the treatment of asthma. The research problem raised in this study was to assess and compare mycophenolate mofetil (MMF), an inhibitor of inosine monophosphate dehydrogenase, and tofacitinib (TFB), a Janus kinase inhibitor, for anti-asthmatic properties, and consequently to determine whether these agents may have potential as alternative options for treatment of allergic asthma. For this purpose, we assessed the effect of administration of MMF and TFB on the development of a mouse model of allergic airway inflammation (AAI) and accompanying CD4⁺ (cluster of differentiation 4) T-cell immune response in the lung-draining mediastinal lymph nodes (MLNs) and lungs, i.e., in the inductive and effector sites, respectively, of the immune response underlying the development of allergic asthma. The results from a histopathological scoring system demonstrated that the administration of MMF and TFB did not prevent or abolish ovalbumin-induced AAI, but strongly attenuated its severity. The pulmonary function tests revealed that the treatment with MMF and TFB significantly reduced methacholine-induced bronchoconstriction. These results indicate that the treatment with TFB and MMF attenuated the development of ovalbumin-induced AAI. The magnitude of the anti-asthmatic effect was comparable between both agents. The study revealed that the impairment of the clonal expansion of effector CD4⁺ T cells in the MLNs is a critical event in the mechanism underlying the anti-asthmatic effect of MMF and TFB. Apart from this, the findings of the study strongly suggest that the suppression of the interleukin-33/suppression of tumorigenicity-2 signaling pathway may constitute an additional mechanism responsible for producing this effect. In turn, the results indicate that the anti-asthmatic action induced by the studied agents is not mediated by the generation of forkhead box protein 3-expressing CD4⁺ regulatory T cells. Clinical implication of the results: the results suggest that MMF and TFB may exert anti-asthmatic action, and thus they may be considered therapeutic options for the treatment of allergic asthma cases resistant to conventional/existing treatment. Full article

Fowl adenovirus serotype 4 (FAdV-4) outbreaks have caused significant economic losses in the Chinese poultry industry since 2015. The relationships among viral structural proteins in infected hosts are relatively unknown. To explore the role of different parts of the fiber-1 protein in FAdV-4-infected hosts, we truncated fiber-1 into fiber-1-Δ1 (73–205 aa) and fiber-1-Δ2 (211–412 aa), constructed pEF1α-HA-fiber-1-Δ1 and pEF1α-HA-fiber-1-Δ2 and then transfected them into leghorn male hepatocyte (LMH) cells. After FAdV-4 infection, the roles of fiber-1-Δ1 and fiber-1-Δ2 in the replication of FAdV-4 were investigated, and transcriptome sequencing was performed. The results showed that the fiber-1-Δ1 and fiber-1-Δ2 proteins were the shaft and knob domains, respectively, of fiber-1, with molecular weights of 21.4 kDa and 29.6 kDa, respectively. The fiber-1-Δ1 and fiber-1-Δ2 proteins were mainly localized in the cytoplasm of LMH cells. Fiber-1-Δ2 has a greater ability to inhibit FAdV-4 replication than fiber-1-Δ1, and 933 differentially expressed genes (DEGs) were detected between the fiber-1-Δ1 and fiber-1-Δ2 groups. Functional analysis revealed these DEGs in a variety of biological functions and pathways, such as the phosphoinositide 3-kinase–protein kinase b (PI3K–Akt) signaling pathway, the mitogen-activated protein kinase (MAPK) signaling pathway, cytokine–cytokine receptor interactions, Toll-like receptors (TLRs), the Janus tyrosine kinase–signal transducer and activator of transcription (Jak–STAT) signaling pathway, the nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) signaling pathway, and other innate immune pathways. The mRNA expression levels of type I interferons (IFN-α and INF-β) and proinflammatory cytokines (IL-1β, IL-6 and IL-8) were significantly increased in cells overexpressing the fiber-1-Δ2 protein. These results demonstrate the role of the knob domain of the fiber-1 (fiber-1-Δ2) protein in FAdV-4 infection and provide a theoretical basis for analyzing the function of the fiber-1 protein of FAdV-4. Full article

Atopic dermatitis is one of the most common inflammatory skin diseases, with an increasing incidence among both children and adults. The recurrent nature, often with the persistence of symptoms, and the polymorphism of the response to current therapies have led to increased research in the therapeutic area dedicated to this condition. The understanding of pathophysiological pathways has contributed to the development of innovative therapies, including biological therapies, JAK inhibitors, but also emerging technologies like nanotechnology-based drug delivery systems. These innovations promise enhanced efficacy, reduced side effects, and improved patient outcomes. The ongoing exploration of novel vehicles, formulations, and natural biopolymers, along with cutting-edge therapeutic agents like tapinarof and mesenchymal stem cells, highlights the potential for an even more precise and personalized management of AD in the future. Despite these advances, challenges persist, particularly in ensuring the long-term safety, accessibility, and broader application of these therapies, necessitating continued research and development. Full article

Therapeutically, the Janus kinase (Jak) 1/Jak2 inhibitor baricitinib reduces the pathology of rheumatoid arthritis and may also reduce pain. Here, we investigated whether baricitinib directly affects joint nociceptors. We recorded action potentials from nociceptive C- and A∂-fibers of the normal and inflamed knee joint in anesthetized rats to monitor their responses to innocuous and noxious joint rotation. In isolated and cultured dorsal root ganglion (DRG) neurons, we examined Stat3 activation using Western blots and monitored excitability using patch-clamp recordings. Intra-articular injection of baricitinib did not alter C- and A∂-fiber responses to innocuous and noxious rotations of the normal knee but reduced C-fiber responses to these stimuli in inflamed joints. Baricitinib prevented the increase in C-fiber responses to joint rotation evoked by interleukin (IL)-6 plus soluble interleukin-6 receptor (sIL-6R) but not the increase evoked by TNF. In DRG neurons, baricitinib blocked Stat3 activation by hyper-IL-6, and baricitinib or the Stat3 inhibitor Sta21 prevented induction of hyperexcitability by IL-6 plus sIL-6R. Thus, neuronal Jaks are involved in the generation of C-fiber hyperexcitability induced by inflammation and IL-6. Pain reduction by baricitinib may result, at least in part, from direct effects on joint nociceptors. Full article

Adenomyosis is a benign gynecological condition characterized by the proliferation of the endometrial stroma and glands into the myometrium, uterine volume enlargement, and peripheral smooth muscle hypertrophy. The typical clinical symptoms include chronic pelvic pain, abnormal uterine bleeding, and subfertility, all of which significantly impact quality of life. There are no effective prevention or treatment strategies for adenomyosis, partly due to a limited understanding of the pathological mechanisms underlying the initiation and progression of the disease. Given that signaling pathways play a crucial role in the development of adenomyosis, a better understanding of these signaling pathways is essential for identifying therapeutic targets and advancing drug development. The occurrence and progression of adenomyosis are closely linked to various underlying pathophysiological mechanisms, including proliferation, migration, invasion, fibrosis, angiogenesis, inflammation, oxidative stress, immune response, and epigenetic changes. This review summarizes the signaling pathways and targets associated with the pathogenesis of adenomyosis, including CXCL/CXCR, NLRP3, NF-κB, TGF-β/smad, VEGF, Hippo/YAP, PI3K/Akt/mTOR, JAK/STAT, and other relevant pathways. In addition, it identifies promising future targets for the development of adenomyosis treatment, such as m6A, GSK3β, sphks, etc. Full article

Background and Objectives: Autism is a developmental disability characterized by impairment of motor functions and social communication together with the development of repetitive or stereotyped behaviors. Neither the exact etiology or the curative treatment of autism are yet completely explored. The goals of this study were to evaluate the possible effects of perindopril on a rat model of autism and to elucidate the possible molecular mechanisms that may contribute to these effects. Materials and Methods: In a rat model of sodium valproate (VPA)-induced autism, the effect of postnatal administration of different doses of perindopril on growth and motor development, social and repetitive behaviors, sirtuin-1, oxidative stress and inflammatory markers, PI3K/Akt/GSK-3β pathway, JAK2/STAT3 axis, and PPAR-gamma signaling in the hippocampal tissues were investigated. The histopathological and electron microscopic changes elicited by administration of the different treatments were also investigated. Results: Perindopril dose-dependently combatted the effects of prenatal exposure to VPA on growth and maturation, motor development, and social and repetitive behaviors. In addition, the different doses of perindopril ameliorated the effects of prenatal exposure to VPA on sirtuin-1, oxidative stress and inflammatory markers, PI3K/Akt/GSK-3β pathway, JAK2/STAT3 axis, and PPAR-gamma signaling. These effects had a mitigating impact on VPA-induced histopathological and electron microscopic changes in the hippocampal tissues. Conclusions: Perindopril may emerge as a promising agent for amelioration of the pathologic changes of autism spectrum disorders. Full article

The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway is highly conserved and essential for numerous biological functions triggered by extracellular signals, including cell proliferation, metabolism, immune response, and inflammation. Defects in STATs, either loss-of-function or gain-of-function defects, lead to a broad spectrum of clinical phenotypes in humans, including a wide range of infectious complications. The susceptibility to pathogens can stem from defects in immune cells within the hematopoietic compartment, impaired barrier functions of non-hematopoietic compartment, or a combination of both, depending on the specific STAT defect as well as the pathogen exposure history. Effective management involves antimicrobial prophylaxis tailored to the patient’s infection risk and improving disease control with targeted therapies and/or hematopoietic cell transplantation. Full article

Phytochemical investigations of Melia azedarach fruits have led to the isolation of a novel tirucallane triterpenoid (1), four new limonoids (2–5), and four known limonoids (6–9). Their structures were clarified by comprehensive spectroscopic and spectrometric analyses. The anti-inflammatory activities of isolated compounds were assessed in vitro. Compound 2 exhibited the most potent anti-inflammatory effect, with an IC₅₀ value of 22.04 μM. Additionally, compound 2 attenuated LPS-induced reactive oxygen species (ROS) production and reduced the levels of inflammatory mediators IL-6 and TNF-α. A mechanistic study revealed that limonoid 2 suppresses the expression of iNOS and JAK2 and is implicated in the modulation of the NF-κB signaling cascade, which reveals its anti-inflammatory actions. Full article

Ongoing outbreaks and often rapid spread of infections caused by coronaviruses, influenza, Nipah, Dengue, Marburg, monkeypox, and other viruses are a concern for health authorities in most countries. Therefore, the search for and study of new antiviral compounds are in great demand today. Since almost all viruses with pandemic potential have immunotoxic properties of various origins, particular attention is paid to the search and development of immunomodulatory drugs. We have synthesised a new compound related to indole-3-carboxylic acid derivatives (hereinafter referred to as the XXV) that has antiviral and interferon-inducing activity. The purpose of this work is to study the effect of the XXV on the stimulation of the expression of toll-like receptor genes, interferons, and immunoregulatory cytokines in a macrophage-like cell model. In this study, real-time PCR methods were used to obtain data on the transcriptional activity of genes in macrophage-like cells. Stimulation of the genes of toll-like receptors TLR2, TLR3, TLR4, TLR7, TLR8, and TLR9 was detected. A high-fold increase in stimulation (from 6.5 to 16,000) of the expression of the TLR3 and TLR4 genes was detected after 4 h of exposure to the XXV. Increased activity of interferon (IFNA1, IFNA2, IFNB1, IFNK, and IFNλ1) genes with simultaneous stimulation of the expression of interferon receptor (IFNAR1 and IFNAR2) genes and signalling molecule (JAK1 and ISG15) genes was detected. Increased fold stimulation of the expression of the cytokine genes IL6, TNFA, IL12A, and IL12B was also observed. Thus, it is shown that the XXV is an activator of TLR genes of innate immunity, which trigger signalling mechanisms of pathogen “recognition” and lead to stimulation of the expression of genes of proinflammatory cytokines and interferons. Full article

Background/Objectives/Methods: Atopic dermatitis (AD) impacts various aspects of patients’ lives including personal life, psychological aspects/disturbances (e.g., depression, anxiety, or even suicidal thoughts), school, and work-related activities, including career advancement. The aim of this narrative review is to present the latest information available on how to best approach AD patient management, as well as decisions regarding standard/advanced systemic therapy, by gathering evidence from the relevant medical literature (PubMed and other prominent medical databases). Results: Thus, AD patient management and decisions regarding advanced/systemic therapy are complex, requiring the consideration of multiple disease-related factors: age; disease severity; patient medical history and comorbidities; previous topical therapy use and any adverse reactions; treatment efficacy concerns; patient preferences, expectations and fears; pregnancy planning; ability and willingness to adhere to the treatment regimen; impact on related risks; and any associated psychological or psychiatric issues. Current guidelines and systematic reviews support the safety and efficacy of systemic therapy including conventional drugs (cyclosporine, methotrexate, and azathioprine), biologics (dupilumab and tralokinumab), and JAK inhibitors (baricitinib, upadacitinib, and abrocitinib) recommended for treating moderate and severe AD. Recently, additional biologics have been evaluated in clinical trials, including lebrikizumab, nemolizumab, eblasakimab, and OX40/OX40L, among others. Conclusions: The most recently suggested approach to treating AD patients suggests focusing on therapy that targets and achieves minimal disease activity (MDA), where therapy decisions are informed by both the patient and the clinician. Available data also indicate the importance of a personalized, stepwise, and multidisciplinary approach. This type of approach promotes patient compliance, satisfaction with therapy, and increased engagement, which all lead to better patient outcomes. Full article

Background/Objectives: In connection with previous work on V-shaped polycyclic thiazolo[5,4-f]quinazolin-9-one and [5,4-f]quinazoline derivatives that can modulate the activity of various kinases, the synthesis of straight thiazole-fused [4,5-g] or [5,4-g]quinazolin-8-ones and quinazoline derivatives hitherto undescribed was envisioned. Methods: An innovative protocol allowed to obtain the target structures. The synthesis of inverted thiazolo[4,5-h] and [5,4-h]quinazolin-8-one derivatives was also explored with the aim of comparing biological results. The compounds obtained were tested against a representative panel of eight mammalian protein kinases of human origin: CDK9/CyclinT, Haspin, Pim-1, GSK-3β, CK-1ε, JAK3, CLK1 and DYRK1A. Results and Conclusions: The results obtained show that the novel linear thiazoloquinazolines are not kinase inhibitors. The cytotoxicity of these newly synthesized compounds was assessed against seven representative tumor cell lines (human cancers: Huh7-D12, Caco-2, HCT-116, MCF-7, MDA-MB-231, MDA-MB-468 and PC-3). The majority of these novel molecules proved capable of inhibiting the growth of the tested cells. The 7-Benzyl-8-oxo-7,8-dihydrothiazolo[5,4-g]quinazolinones 5b and 6b are the most potent, with IC₅₀ values in the micromolar range. None of these compounds showed toxicity against normal cells. A larger program of investigations will be launched to investigate the real potential interest of such compounds in anticancer applications. Full article

Background: Current drug therapy for myelofibrosis does not alter the natural course of the disease or prolong survival, and allogeneic stem cell transplantation is the only curative treatment modality. For over a decade, the Janus kinase (JAK) inhibitor ruxolitinib has been the standard of care. More recently, newer-generation JAK inhibitors have joined the ranks of accepted treatment options. Objectives: The primary goal of treatment is to reduce spleen size and minimize disease-related symptoms. Prognostic scoring systems are used to designate patients as being at lower or higher risk. For transplant-eligible patients, transplant is offered to those with a bridge of a JAK inhibitor; patients who are not eligible for transplant are usually offered long-term therapy with a JAK inhibitor. Limited disease-modifying activity, dose-limiting cytopenias, and other adverse effects have contributed to discontinuation of JAK inhibitor treatment. Conclusions: Novel JAK inhibitors and combination approaches are currently being explored to overcome these shortcomings. Further research will be essential to establish optimal therapeutic approaches in first-line and subsequent treatments. Full article

Avoidance of an immune response is critical to completion of the human papillomavirus (HPV) life cycle, which occurs in the stratified epithelium and is linked to epithelial differentiation. We previously demonstrated that high-risk HPVs use apoptotic caspases to suppress an antiviral innate immune response during the productive phase of the life cycle. We found that caspase-8 and caspase-3 suppress a type I IFN-β and type III IFN-λ response by disabling the MDA5/MAVS double-stranded RNA (dsRNA) sensing pathway, indicating that immunogenic RNAs increase upon differentiation in HPV+ cells. In this study, we demonstrate that caspase inhibition results in aberrant transcription of a subset of endogenous retroviruses (ERVs) that have been shown to activate an IFN response through dsRNA-sensing pathways. We show that the increase in ERV transcription is accompanied by an enrichment in dsRNA formation. Additionally, we demonstrate that the robust increase in ERV expression requires activation of the JAK/STAT-signaling pathway, indicating that this subset of ERVs is IFN-inducible. Overall, these results suggest a model by which caspase activity blocks the reactivation of ERVs through the JAK/STAT pathway, protecting HPV+ cells from an increase in immunogenic dsRNAs that otherwise would trigger an IFN response that inhibits productive viral replication. Full article

Background/Objectives: Polymyalgia Rheumatica (PMR) is an inflammatory condition that primarily affects individuals aged 50 and older, especially in Western countries. Although glucocorticoids are the cornerstone of PMR treatment, these drugs are associated with side effects, making it advisable to use them for the shortest duration possible. However, tapering or discontinuation of glucocorticoids often leads to disease relapses. In this review, we focus on the traditional management of PMR, as well as the potential for therapies that may reduce glucocorticoid use. Special attention is given to the efficacy of biologic agents in PMR management. Methods: A literature review, primarily based on articles published in PubMed, was conducted. In addition to discussing various glucocorticoids and conventional disease-modifying drugs used for the management of isolated PMR, this review specifically focused on the information reported regarding new therapies, with particular emphasis on biologic agents. Results: Prednisone or prednisolone at a dose ranging between 12.5 and 25 mg/day is the agreed-upon treatment for PMR. Due to the side effects associated with prolonged glucocorticoid use and the high frequency of relapses when glucocorticoids are tapered, glucocorticoid-sparing agents have emerged as tools in the management of PMR. Methotrexate has traditionally been the conventional disease-modifying antirheumatic drug (DMARD) unanimously recommended for use in PMR. Other conventional DMARDs, such as leflunomide, have shown promising results but require further study. The use of biologic agents has marked a significant step forward in the management of PMR. While anti-TNF agents failed to provide beneficial effects in isolated PMR, anti-IL-6 receptor agents, such as tocilizumab and sarilumab, have demonstrated efficacy in reducing relapse frequency, lowering the cumulative glucocorticoid burden, and achieving long-term remission of the disease. Other biologic agents, many of which have been used in giant cell arteritis, as well as Janus kinase (JAK) inhibitors, are currently under investigation. Conclusions: Glucocorticoids are the primary treatment for isolated PMR but are associated with comorbidities, especially in patients with pre-existing conditions or frequent relapses. Glucocorticoid-sparing agents, such as methotrexate and biologics, in particular tocilizumab and sarilumab, offer alternatives, improving symptoms and reducing glucocorticoid use. While biologic agents reduce long-term side effects and help achieve disease remission, their use must consider potential side effects and higher costs compared to traditional therapies. Full article