Search Results (148)

Diabetic wounds are a devastating complication that cause chronic pain, recurrent infections, and limb amputations due to impaired healing. Despite advances in wound care, existing therapies often fail to address the underlying molecular dysregulation, highlighting the need for innovative and safe therapeutic approaches. Among these, D-amino acids such as D-tryptophan (D-Trp) have emerged as key regulators of cellular processes; however, their therapeutic potential in diabetic wounds remains largely unexplored. Here, we investigate the therapeutic potential of D-Trp in streptozotocin (STZ)-induced diabetic mice, comparing it with phosphate-buffered saline (PBS) controls and vascular endothelial growth factor (VEGF) as a positive control. Wound healing, inflammation, and histopathology were assessed. Protein and gene expression were analyzed via Western blot and RT-qPCR, respectively. Biolayer interferometry (BLI) measured the binding of D-Trp to hypoxia-inducible factor-1α (HIF-1α). D-Trp accelerated wound healing by modulating extracellular matrix (ECM) remodeling, signaling, and apoptosis. It upregulated matrix metalloproteinases (MMP1, MMP3, MMP-9), Janus kinase 2 (JAK2), and mitogen-activated protein kinase (MAPK) proteins while reducing pro-inflammatory cytokines (tumor necrosis factor-α [TNF-α], interleukin-1β [IL-1β], IL-6). D-Trp also suppressed caspase-3 and enhanced angiogenesis through HIF-1α activation. These findings suggest that D-Trp promotes healing by boosting ECM turnover, reducing inflammation, and activating MAPK/JAK pathways. Thus, D-Trp is a promising therapeutic for diabetic wounds. Full article

Janus kinase 2 (JAK2) inhibitors have gained regulatory approval for treating various human diseases. While the JAK2/signal tranducer and activator of transcription 3 (STAT3) pathway plays a role in tumorigenesis, JAK2/STAT3 inhibitors have shown limited therapeutic efficacy in triple-negative breast cancer (TNBC). In this study, we assessed the antiproliferative effects of clinically approved JAK2 inhibitors in TNBC cell lines (MDA-MB-231 and HS578T) using the MTT assay. Among the four JAK2 inhibitors evaluated (fedratinib, cerdulatinib, peficitinib, and filgotinib), fedratinib significantly inhibited the proliferation of TNBC cells with IC₅₀ values below 2 μM. Fedratinib also demonstrated superior efficacy in inhibiting long-term colony formation compared to other JAK2 inhibitors. Western blot analyses showed that fedratinib uniquely inhibits the phosphoinositide 3-kinase (PI3K)/AKT pathway and moderately affects the MAP kinase/ERK kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway, in addition to targeting JAK2/STAT3 signaling. Moreover, fedratinib distinctly decreased MYC and cyclin D1 protein levels while inducing poly (ADP-ribose) polymerase (PARP) cleavage and apoptotic cell death more effectively than other JAK2 inhibitors. We next investigated the effects of simultaneously inhibiting JAK2/STAT3 together with the MEK/ERK or PI3K/AKT pathways, as well as the impact of triple pathway inhibition. Notably, combining ceduratinib with either cobimetinib (MEK inhibitor) and ipatasertib (AKT inhibitor) or trametinib (MEK inhibitor) and alpelisib (PI3K inhibitor) mimicked the effects of fedratinib on the cell proliferation, MYC and cyclin D1 suppression, and pro-apoptotic protein induction. These finding suggest that JAK2 inhibition enhances the anticancer effects of concurrent MEK/ERK and PI3K/AKT pathway inhibition, while JAK2 inhibition alone shows minimal efficacy in TNBC cells. Full article

Ferulic acid (FA), a hydroxycinnamic acid derivative, is a key bioactive component in traditional medicinal plants including Angelica sinensis and Asafoetida. Accumulating evidence supports its therapeutic efficacy in inflammatory disorders, such as rheumatoid arthritis (RA) and ulcerative colitis (UC). FA exerts anti-inflammatory effects through (1) the regulation of inflammatory cytokine levels; (2) modulation of signaling pathways such as nuclear factor kappa B (NF-κB), mitogen-activated protein kinase (MAPK), and janus kinase/signal transducer and activator of transcription (JAK/STAT); (3) amelioration of oxidative stress; and (4) regulation of immune cell homeostasis. At the pharmacokinetic level, studies show that FA is rapidly absorbed but exhibits low bioavailability, mainly due to the influence of metabolic pathways and food matrix characteristics. This review systematically summarizes the literature on the anti-inflammatory effects of FA, covering molecular mechanisms, pharmacokinetic characteristics, and application scenarios. Preclinical studies show that FA has low toxicity and good safety, demonstrating potential for development as a novel anti-inflammatory drug. However, its clinical translation is hindered by bottlenecks such as low bioavailability and insufficient human clinical data. Future research should prioritize developing novel drug delivery systems and conducting large-scale clinical trials to facilitate its clinical translation. Full article

The pandemic of Coronavirus Disease 2019 has triggered a worldwide public health emergency. Its pathogen, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has developed multiple strategies for effectively evading the host immune defenses, including inhibition of interferon (IFN) signaling. Several viral proteins of SARS-CoV-2 are believed to interfere with IFN signaling. In this study, we found that the SARS-CoV-2 accessory protein ORF7a considerably impaired IFN-activated Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling via suppression of the nuclear translocation of IFN-stimulated gene factor 3 (ISGF3) and the activation of STAT2. ORF7a dampened STAT2 activation without altering the expression and phosphorylation of Janus kinases (JAKs). A co-immunoprecipitation (co-IP) assay was performed to gather ORF7a protein, but it failed to precipitate STAT2. Interestingly, mass spectrometry and immunoblotting analyses of the ORF7a co-IP product revealed that ORF7a interacted with an RNA-binding protein, heterogeneous nuclear ribonucleoprotein A2B1 (HNRNPA2B1), and HNRNPA2B1 was related to the inhibitory effect of ORF7a on STAT2 phosphorylation. Moreover, examination of ORF7a deletion constructs revealed that the C-terminal region of ORF7a (amino acids 96 to 122) is crucial for suppressing IFN-induced JAK/STAT signaling activation. In conclusion, we discovered that SARS-CoV-2 ORF7a antagonizes type I IFN-activated JAK/STAT signaling by interacting with HNRNPA2B1, and the C-terminal region of ORF7a is responsible for its inhibitory effect. Full article

Atopic dermatitis (AD) is a chronic inflammatory skin disorder marked by intricate interplay among skin barrier dysfunction, immune dysregulation, and microbial dysbiosis. While therapeutic advancements targeting T helper 2 (Th2) cytokines, such as interleukin (IL)-4 and IL-13, and the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway have yielded promising outcomes, a significant proportion of patients still experience inadequate relief, particularly from persistent pruritus. Achieving minimal disease activity remains an unmet clinical priority and a cornerstone of effective AD management. This review provides an in-depth analysis of current therapeutic approaches and integrates findings from recent biologic studies, with a particular focus on innovative strategies under active investigation. These approaches include targeting components of the innate immune system, such as thymic stromal lymphopoietin (TSLP) and IL-1 family cytokines; the adaptive immune system, including OX40-OX40L interactions and Th17- and Th22-related cytokines; and mechanisms associated with pruritus, such as IL-31, histamine receptors, and neurokinin 1 receptor. Emerging insights underscore the transformative potential of personalized therapeutic regimens tailored to the distinct endotypes and severity of AD. Advances in deciphering the pathogenesis of AD are unlocking unprecedented opportunities for precision medicine, offering renewed hope for improved outcomes in this multifaceted and heterogeneous condition. Full article

Myeloproliferative neoplasms (MPNs) are a group of rare blood cancers characterized by the excessive production of blood cells in the bone marrow. These disorders arise from acquired genetic driver mutations, with or without underlying genetic predispositions, resulting in the uncontrolled production of red blood cells, white blood cells, or platelets. The excessive cell production and abnormal signaling from driver mutations cause chronic inflammation and a higher risk of blood clots and vascular complications. The primary goals of MPN treatment are to induce remission, improve quality of life and survival, as well as to reduce the risk of complications such as thrombosis, vascular events, and leukemic transformation. This review provides a comprehensive update on the diagnosis and therapeutic advancements in major MPN subtypes, including chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, and primary myelofibrosis. It examines these complex diseases from a molecular and evolutionary perspective, highlighting key clinical trials’ long-term follow-up and therapies targeting driver mutations that have transformed treatment strategies. Additionally, several important advancements in addressing challenges such as anemia in myelofibrosis, along with promising emerging therapies, are also discussed. Full article

Background and Objectives: Philadelphia (Ph)-negative myeloproliferative neoplasms can exhibit defects in Janus kinase 2 (JAK2), Calreticulin (CalR), and MPL genes. It is possible that the presence of other driver mutations may influence diagnosis and prognosis in patients who do not have a JAK2 gene mutation. The purpose of this study was to assess the frequency of CalR and MPL gene mutations and the clinical effects of these mutations in JAK2 gene-unmutated MPN patients from a single center. Materials and Methods: We examined 46 patients (ET/PMF: 34/12) diagnosed with MPNs regarding their genetic conditions, diagnoses, and complications. Results: CalR Type 1 gene mutation was detected in 26.1% of cases, CalR Type 2 gene mutation in 13.0%, MPL-L gene mutation in 2.2%, and MPL-K gene mutation in 6.5%. In total, 56.5% of patients were triple-negative. The presence of CalR Type 1 and Type 2 mutations was significantly more prevalent in patients with essential thrombocytosis (ET), although the difference did not reach statistical significance (p = 0.51, p = 0.57). In contrast, MPL mutations were only observed in patients with primary myelofibrosis (PMF). Conclusions: We found no correlation between thrombosis, leukemic transformation, and driver mutations. MPL gene mutation was present in only myelofibrosis patients, and CALR gene mutation was present in one of the three cases of leukemic transformation. The triple-negative group had a lower survival rate, but this difference was not statistically significant (110.3 months vs. 121.4 months, respectively, p = 0.53). However, the sample size was quite small. Our limited observations suggest a possible trend that requires confirmation. Full article

Interleukin-6 (IL-6) is a pleiotropic cytokine with critical roles in immune regulation, inflammation, and haematopoiesis. While its functions in host defence and tissue repair are well established, accumulating evidence suggests that IL-6 also can directly and indirectly modulate megakaryocyte and platelet biology. This review examines the mechanistic basis supporting IL-6-mediated platelet hyper-responsiveness, in addition to its effect on megakaryopoiesis and thrombopoiesis in thromboinflammatory disease states. We discuss how IL-6-mediated trans-signalling may sensitizes platelets to activation, and that this may be exclusive to glycoprotein VI (GPVI) stimulation due to Janus kinase (JAK)–signal transducer 2 crosstalk, in addition to other mechanisms that may contribute to priming platelets. We further highlight clinical evidence linking IL-6 to thrombotic complications in cardiovascular disease and infection (e.g., COVID-19 and sepsis). Given the emerging interest in IL-6-targeting therapies as anti-inflammatory and anti-thrombotic agents, a thorough understanding of how IL-6 can drive platelet responsiveness is crucial. Full article

Pesticides are essential in agriculture for protecting crops and boosting productivity, but their widespread use may pose significant health risks. Farmworkers face direct exposure through skin contact and inhalation, which may lead to hormonal imbalances, neurological disorders, and elevated cancer risks. Moreover, pesticide residues in food and water may affect surrounding communities. One of the lesser investigated issues is immunotoxicity, mostly because the chronic effects of compound exposure are very complex to study. As a case study, this work utilized pharmacophore modeling and virtual screening to identify pesticides that may inhibit Janus kinases (JAK1, JAK2, JAK3) and tyrosine kinase 2 (TYK2), which are pivotal in immune response regulation, and are associated with cancer development and increased infection susceptibility. We identified 64 potential pesticide candidates, 22 of which have previously been detected in the human body, as confirmed by the Human Metabolome Database. These results underscore the critical need for further research into potential immunotoxic and chronic impacts of the respective pesticides on human health. Full article

The Janus kinase 2 (JAK2) protein fulfills an important role in hematopoiesis via the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, as it provides the genetic driver of BCR::ABL1-negative myeloproliferative neoplasms (MPNs), which are clinically manifested as polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). The most common cause of MPNs is the mutation of JAK2 V617F in the JAK2 gene, which results in increased cell proliferation. However, both the pathogenesis and treatment regimen of BCR::ABL1-negative MPNs remain poorly understood. The aim of the present study was to establish K562 cell lines with a point mutation in exon 14 (JAK2p.V617F) using CRISPR/Cas9 technology. The modified JAK2 V617F cell lines were examined for the gene mutation using droplet digital PCR (DDPCR), and the presence of the mutation was confirmed by DNA sequencing. Modified cells were characterized by measuring JAK2 gene expression and the extent of cell proliferation. Interferon α2a (IFN-α2a) and arsenic trioxide were also administered to the cells to explore their potential effects. The JAK2 V617F-mutated cells were found to exhibit a higher level of JAK2 gene expression compared with the wild type. Interestingly, a significant increase in the proliferation rate was observed with the modified cells compared with the wild type cells (p < 0.001), as assessed from the JAK2 gene expression levels. Furthermore, the treatments with IFN-α2a and arsenic trioxide led to the preferential suppression of the cell proliferation rate of the K562 expressing mutant JAK2 cells compared with the wild type cells, and this suppression occurred in a dose-dependent manner(p < 0.01). Moreover, the modified cells were able to differentiate into megakaryocyte-like cells following stimulation with phorbol 12 myristate 13 acetate (PMA). Taken together, the results of the present study have shown that the CRISPR/Cas9-modified JAK2 V617F model may be used as a disease model in the search of novel therapies for MPNs. Full article

(1) Background: Rheumatoid arthritis (RA) is a chronic inflammatory condition known for its symptoms of joint damage and cartilage breakdown. Current treatments frequently result in adverse effects and show restricted efficacy in the long term. Dendropanax morbiferus, a plant recognized for its bioactive properties, demonstrates promise in the treatment of inflammatory conditions. The objective of this study was to examine the therapeutic properties of Dendropanax morbiferus Lév. water extract (DMWE) in RA through the utilization of in vitro and in vivo models. (2) Methods: Ultra-high-performance liquid chromatography (UPLC) analysis was used to identify bioactive compounds in DMWE. Antioxidant activity was evaluated using 1,1-diphenyl-2-picrylhydrazyl (DPPH) and 2,2-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS) radical-scavenging assays. The in vitro experiments involved the treatment of CHON-001 cells with DMWE in order to assess its impacts on inflammation and matrix metalloproteinase (MMP) expression. The impact of DMWE on the Janus Kinase 2 (JAK2) and Signal Transducer and Activator of Transcription (STAT) signaling pathways was also assessed. RA was induced in Balb/c mice who were subsequently treated with varying doses of DMWE to assess its impact on joint morphology, edema, and body weight. (3) Results: DMWE demonstrated substantial antioxidant activity and hindered the expression of MMP-2 and MMP-8 in chondrocytes treated with IL-1β. It additionally inhibited the JAK2/STAT pathway and diminished inflammatory responses. Treatment with DMWE in living organisms led to a decrease in joint swelling, improved weight regains, and maintained joint structure, with higher doses exhibiting effects similar to those of the positive control, dexamethasone (Dexa). (4) Conclusions: DMWE was found to have excellent in vitro antioxidant and anti-inflammatory activities. In an RA-induced mouse model, DMWE-3 (500 mg/kg BW) was found to effectively treat RA by reducing the concentration of pro-inflammatory factors and preventing joint deformation. Full article

Janus kinase 2 (JAK2) is an important intracellular mediator of cytokine signaling. Mutations in the JAK2 gene are associated with myeloproliferative neoplasms (MPNs) such as polycythemia vera (PV) and essential thrombocythemia (ET), while aberrant JAK2 activity is also associated with a number of immune diseases. The acquired somatic mutation JAK2 V617F (95% of cases of PV and in 55–60% of cases of ET), which constitutively activates the JAK2, is the most common molecular event in MPN. The development of specific JAK2 inhibitors is therefore of considerable clinical importance. Ruxolitinib is a JAK inhibitor recently approved by the FDA/EMA and effective in relieving symptoms in patients with MPN. Ruxolitinib binds to the JAK2 last domain, namely JH1; its action on the dynamics of the domain is still only partially known. Using Molecular Dynamics simulations, we have analyzed the JH1 domain in four different states as follows: (i) alone, (ii) with one phosphorylation, (iii) adding Ruxolitinib, and (iv) with five phosphorylations and Ruxolitinib. The ligand induces a dynamic behavior similar to the inactive form of JH1, with a less flexible state than the phosphorylated active form of JH1. This study highlights the inhibitory effect of Ruxolitinib on the JH1 domain, demonstrating the importance of dynamics in regulating JH1 activation. Full article

Background: Alopecia areata is an autoimmune disorder that causes hair loss in clumps about the size and shape of a quarter. The estimated prevalence of the disorder is approximately 1 in 1000 people, with a lifetime risk of approximately 2 percent. One of the systemic therapies for alopecia areata consists of the use of glucocorticoids or immunosuppressants. Methods: Baricitinib (BCT) is a Janus kinase (JAK) 1 and 2 selective inhibitor used as an immunosuppressant drug. In this study, three olive oil BCT formulations (Oil A, Oil B, and Oil C, which differ in their content in squalene, tocopherol, tyrosol, and hydroxytyrosol) have been developed for topical delivery. The formulations were physicochemically characterized and the in vitro drug release and ex vivo permeation through human skin tissues were assessed. Results: The results showed nearly identical viscosity across all three formulations, exhibiting Newtonian behavior. The mathematical modeling used to describe the drug release profiles was the one-site binding hyperbola for all formulations. Oil-based formulations showed a slow BCT penetration into human skin. Skin integrity remained intact during the experiments, with no signs of irritation or alterations observed. In addition, all the formulations proved their efficacy in vivo. Conclusions: Among the formulations, Oil A demonstrated the highest ability retention capacity (Q_r = 1875 ± 124.32 ng/cm²) in the skin, making it an excellent candidate for further investigation in the treatment of alopecia areata. Full article

Deucravacitinib is an allosteric, selective tyrosine kinase 2 (TYK2) inhibitor that has demonstrated significant efficacy in the treatment of psoriasis. TYK2, a member of the Janus kinase (JAK) family, plays a critical role in intracellular signaling pathways for pro-inflammatory cytokines. Unlike traditional JAK inhibitors, which target active domains, deucravacitinib selectively binds to the pseudokinase domain of TYK2. This binding induces a conformational change that locks the enzyme in an inactive state, ensuring superior selectivity for TYK2 over JAK 1/2/3. This unique mechanism specifically inhibits key pro-inflammatory cytokines, including IL-12, IL-23, and type I interferons, critical in the pathogenesis of psoriasis and other immune-mediated diseases. As a result, deucravacitinib represents a promising option for targeted therapy in immune-mediated diseases and may reduce adverse events commonly associated with broader immunosuppressive treatments. Furthermore, its oral administration offers a convenient alternative to injectable biologics, potentially improving patient adherence and treatment satisfaction. This review highlights recent studies suggesting that deucravacitinib may also have therapeutic benefits in psoriatic arthritis, palmoplantar pustulosis, systemic lupus erythematosus, Sjogren’s disease, and inflammatory bowel disease. Given its expanding therapeutic potential, deucravacitinib may provide a safer and more effective alternative to current therapies, offering a tailored approach to treatment. Full article

Background: Tumor metastasis and poor drug efficacy are two of the most common causes of therapeutic failure in cancer patients. The underlying molecular mechanism requires further exploration, and novel effective curative strategies are urgently needed. Nature is a rich source of novel drugs, and Lycorine hydrochloride (Lyc.HCL) is a natural alkaloid with tremendous therapeutic potential. However, the molecular mechanisms of its antitumor activity are still unknown. In the current study, we investigated the effects and mechanisms of Lyc.HCL against esophageal squamous cell carcinomas (ESCCs), which pose serious threats to human life. Methods: An MTS assay and a clone formation assay were used to assess the viability of ESCC cell lines after Lyc.HCL treatment in vitro. Apoptosis and cell cycle regulation were analyzed using flow cytometry. Wound healing and Transwell assays were used to analyze cell migration, while invasion was analyzed using the Matrigel Transwell assay. We detected the expression of tripartite motif-containing 22 (TRIM22) through immunohistochemistry and Western blotting. A docking experiment was performed to explore the targets of Lyc.HCL. The expression levels of Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/extracellular signal-regulated kinase (Erk) pathway components were detected through Western blotting. A rescue experiment was performed to determine the potential role of TRIM22. In addition, we explored the in vivo anti-ESCC effects and mechanism of Lyc.HCL by using it to treat tumor-bearing mice. Results: The Lyc.HCL treatment was found to inhibit esophageal squamous cell carcinoma cell proliferation both in vitro and in vivo by blocking the cell cycle at the G2 phase, inhibiting cell migration and invasion. We found that the TRIM22 protein was highly expressed in ESCCs but not in normal esophageal tissue. Lyc.HCL directly targeted TRIM22, decreasing the expression of TRIM22 and the JAK2/STAT3 and Erk signaling pathways, both in vitro and in vivo. Using animal experiments, we observed that the depletion of TRIM22 delayed tumor growth, but this effect was significantly reversed upon TRIM22 overexpression. Conclusions: Taken together, these findings demonstrate that Lyc.HCL can effectively suppress ESCC both in vitro and in vivo by targeting TRIM22 and regulating the JAK2/STAT3 and Erk pathways. These results suggest that Lyc.HCL may serve as a potential novel therapeutic for ESCC, with TRIM22 emerging as a promising target for treatment. Full article