Ruxolitinib Cream 1.5%: A Review in Non-Segmental Vitiligo.

Topical ruxolitinib 1.5% cream (Opzelura®), a Janus kinase (JAK) inhibitor, is the first treatment to be approved in several countries for use in patients aged ≥ 12 years with non-segmental vitiligo. In the identical phase III TRuE-V1 and TRuE-V2 trials, significantly more ruxolitinib cream recipients were able to achieve statistically significant and clinically meaningful facial and total body repigmentation, as well as reductions in vitiligo noticeability, compared with vehicle recipients. Efficacy was sustained in longer-term analyses to week 104 of treatment. Ruxolitinib 1.5% cream was generally tolerable in these trials; the most common treatment-related adverse events were acne, pruritus and exfoliation, all at the application site. As with orally administered JAK inhibitors, topical ruxolitinib carries boxed warnings in the USA for serious infections, mortality, malignancy, major adverse cardiovascular events (MACE) and thrombosis, although the incidences were low with topical application. Thus, topical ruxolitinib 1.5% cream is an effective and generally tolerable treatment option for patients aged ≥ 12 years with non-segmental vitiligo.

Non-segmental vitiligo is a chronic autoimmune disease where the skin throughout the body loses its pigmentation, and is usually managed with topical therapies, light therapy or surgery. Topical ruxolitinib 1.5% cream (Opzelura^®) is the first treatment approved in several countries for patients aged ≥ 12 years with non-segmental vitiligo. It inhibits Janus kinase (JAK) proteins, reducing the destruction of skin pigment-producing cells. In two clinical trials, significantly more ruxolitinib cream recipients achieved significant and meaningful skin repigmentation compared with patients who received a non-medicated cream; these results were sustained to week 104 of treatment. Ruxolitinib 1.5% cream was generally tolerable; the most common treatment-related adverse events were acne, itchiness and exfoliation, all at the application site. Topical ruxolitinib has special warnings in the USA for major adverse cardiovascular events (MACE), blood clots, serious infections, death and cancer (associated with the use of oral JAK inhibitors), although incidence rates for these adverse events were low in the clinical trials. Topical ruxolitinib 1.5% cream is an effective and generally tolerable treatment option for patients aged ≥ 12 years with non-segmental vitiligo.

Treatment of in vitro generated Langerhans cells with JAK-STAT inhibitor reduces their inflammatory potential.

Alopecia areata (AA) is a condition in which hair is lost in small regions or over the entire body. It has a prevalence of 1 in 1000 and has a great impact on psychological wellbeing. AA is generally considered an autoimmune disease in which a collapse of the immune privilege system of the hair follicle has shown to play an important role, potentially driven by interferon gamma (IFN-γ). The most prominent cells located in or around the hair follicle in AA are Langerhans cells, CD4+ or CD8+ T cells, macrophages and mast cells. Langerhans cells, specialized dendritic cells, are resident in the epidermis and are known to associate with hair follicles. Therefore, we aimed to develop in vitro generated Langerhans cells contributing as an in vitro model of disease. In vitro models provide insight into the behaviour of cells and are a valuable tool before being in need of an animal model or patient samples. For this, Langerhans-like cells were generated from CD14+ monocytes in the presence of GM-CSF and TGF-ß. After 10 days of cell culture, Langerhans-like cells express CD207 and CD1a but lack CD209 expression as well as Birbeck granules. Next, Langerhans-like cells were exposed to inflammatory conditions and the effect of different AA treatments was investigated. All treatments-diphencyprone contact immunotherapy, UV-B light therapy and JAK-STAT inhibition-affect the expression of costimulatory and skin-homing markers on Langerhans-like cells. Importantly, also the T cell stimulatory capacity of Langerhans-like cells was significantly reduced following treatment under inflammatory conditions. Noteworthy, JAK-STAT inhibition outperformed conventional AA treatments. In conclusion, our findings demonstrate that in vitro generated Langerhans-like cells can be used as a model of disease. Moreover, JAK-STAT inhibition may become a valuable new approach for the treatment of AA.

[Anti-inflammatory drugs : from old classical ones to biotherapies and JAK inhibitors]. / Les médicaments anti-inflammatoires : des anciens classiques aux biothérapies et inhibiteurs de JAK.

Anti-inflammatory medications are known since a long time and still remain among the most used drugs in clinical practice. They belong to a variety of pharmacological classes and act via very different biochemical mechanisms. Nonsteroid anti-inflammatory drugs, which are derived from acetylsalicylic acid, and cortisone with its multiple derivative molecules (glucocorticoids) remain the background therapy of diseases associated with inflammation, either acute or chronic. Some old molecules, known to exert an anti-inflammatory activity, still have specific indications, colchicine and methotrexate as examples. However, the greatest innovation of the last two decades results from the launch of biological therapies, starting with the use of anti-TNF? agents to move towards monoclonal antibodies targeting various pro-inflammatory interleukins (IL-1, IL-6, IL-5, IL-17, IL-23, …). Finally, small molecules acting as JANUS kinase inhibitors or tyrosine kinase 2 inhibitors open new alternatives in severe diseases that are resistant to other anti-inflammatory drugs. The interest for anti-inflammatory medications has been reinforced since the COVID-19 outbreak.

: Les anti-inflammatoires sont des médicaments connus de longue date et qui restent encore parmi les plus utilisés en pratique clinique. Ils appartiennent à diverses classes pharmacologiques et agissent via des mécanismes biochimiques très différents. Les anti-inflammatoires non stéroïdiens, issus des travaux concernant l'acide acétylsalicylique, et la cortisone avec ses multiples dérivés (glucocorticoïdes) restent la base du traitement des maladies caractérisées par une inflammation, qu'elle soit aiguë ou chronique. Certaines molécules anciennes, connues aussi pour leur action anti-inflammatoire, gardent une place dans des indications spécifiques, comme la colchicine et le méthotrexate. Mais la grande révolution des deux dernières décennies provient de la mise sur le marché des médicaments biologiques avec, d'abord, la percée des agents anti-TNF? pour évoluer vers des anticorps monoclonaux ciblant diverses interleukines pro-inflammatoires (IL-1, IL-6, IL-5, IL-17, IL-23, …). Enfin, de petites molécules, inhibitrices des JANUS kinases et de la tyrosine kinase 2, ouvrent également des alternatives dans des maladies sévères, résistantes aux autres agents anti-inflammatoires. L'intérêt pour les médicaments anti-inflammatoires a été ravivé depuis la pandémie COVID-19.

The Effect of Anti-rheumatic Drugs on the Skeleton.

The therapeutic armamentarium for rheumatoid arthritis has increased substantially over the last 20 years. Historically antirheumatic treatment was started late in the disease course and frequently included prolonged high-dose glucocorticoid treatment which was associated with accelerated generalised bone loss and increased vertebral and non-vertebral fracture risk. Newer biologic and targeted synthetic treatments and a combination of conventional synthetic DMARDs prevent accelerated systemic bone loss and may even allow repair of cortical bone erosions. Emerging data also gives new insight on the impact of long-term conventional synthetic DMARDs on bone health and fracture risk and highlights the need for ongoing studies for better understanding of "established therapeutics". An interesting new antirheumatic treatment effect is the potential of erosion repair with the use of biologic DMARDs and janus kinase inhibitors. Although several newer anti-rheumatic drugs seem to have favorable effects on bone mineral density in RA patients, these effects are modest and do not seem to influence the fracture risk thus far. We summarize recent developments and findings of the impact of anti-rheumatic treatments on localized and systemic bone integrity and health.

Targeting JAK/STAT signaling pathways in treatment of inflammatory bowel disease.

Janus kinase/signal transduction and transcriptional activator (JAK/STAT) signaling pathway is a transport hub for cytokine secretion and exerts its effects. The activation of JAK/STAT signaling pathway is essential for the regulation of inflammatory responses. Inappropriate activation or deletion of JAK/STAT signaling pathway is the initiator of the inflammatory response. JAK/STAT signaling pathway has been demonstrated to be involved in the process of innate and adaptive immune response to inflammatory bowel disease (IBD). In this review, we discuss the role of the JAK/STAT signaling pathway in the regulation of different cells in IBD, as well as new findings on the involvement of the JAK/STAT signaling pathway in the regulation of the intestinal immune response. The current status of JAK inhibitors in the treatment of IBD is summarized as well. This review highlights natural remedies that can serve as potential JAK inhibitors. These phytochemicals may be useful in the identification of precursor compounds in the process of designing and developing novel JAK inhibitors.

Integrated Human and Murine Clinical Study Establishes Clinical Efficacy of Ruxolitinib in Chronic Myelomonocytic Leukemia.

PURPOSE: Chronic myelomonocytic leukemia (CMML) is a rare leukemia characterized by peripheral monocytosis with no disease-modifying therapies. CMML cells are uniquely hypersensitive to granulocyte-macrophage colony-stimulating factor (GM-CSF) and robustly engraft in immunocompromised mice that secrete human cytokines. To leverage these unique biological features, we conducted an integrated human and murine study evaluating ruxolitinib, a JAK1/2 inhibitor that potently downregulates intracellular GM-CSF signaling. PATIENTS AND METHODS: A total of 50 patients with WHO-defined CMML were enrolled in this open-label, multi-institution phase I/II clinical study, with a ruxolitinib dose of 20 mg twice daily studied in phase II. In parallel, 49 patient-derived xenografts (PDX) derived from 13 study participants were generated and randomized to receive ruxolitinib or vehicle control. RESULTS: The most common grade 3/4 treatment-related toxicities observed were anemia (10%) and thrombocytopenia (6%). The clinical overall response rate was 38% by Myelodysplastic Syndrome/Myeloproliferative Neoplasm (MDS/MPN) International Working Group (IWG) criteria and 43% of patients with baseline splenomegaly achieved a spleen response. Profiling of cytokine levels and somatic mutations at baseline failed to identify predictive biomarkers. PDX models derived from screening samples of study participants recapitulated responses seen in humans, particularly spleen responses, and corroborated ruxolitinib's clinical efficacy in a randomized murine study not feasible in human trials. CONCLUSIONS: Ruxolitinib demonstrated clinical efficacy and an acceptable adverse event profile in patients with CMML, identifying a potential novel therapeutic in this rare malignancy. Furthermore, this study demonstrates proof of concept that PDX modeling can recapitulate responses of patients treated on clinical trial and represents a novel correlative study that corroborates clinical efficacy seen in humans.See related commentary by Shastri and Adrianzen-Herrera, p. 6069.

Role of intracellular signaling pathways and their inhibitors in the treatment of inflammation.

Inflammation is not only a defense mechanism of the innate immune system against invaders, but it is also involved in the pathogenesis of many diseases such as atherosclerosis, thrombosis, diabetes, epilepsy, and many neurodegenerative disorders. The World Health Organization (WHO) reports worldwide estimates of people (9.6% in males and 18.0% in females) aged over 60 years, suffering from symptomatic osteoarthritis, and around 339 million suffering from asthma. Other chronic inflammatory diseases, such as ulcerative colitis and Crohn's disease are also highly prevalent. The existing anti-inflammatory agents, both non-steroidal and steroidal, are highly effective; however, their prolonged use is marred by the severity of associated side effects. A holistic approach to ensure patient compliance requires understanding the pathophysiology of inflammation and exploring new targets for drug development. In this regard, various intracellular cell signaling pathways and their signaling molecules have been identified to be associated with inflammation. Therefore, chemical inhibitors of these pathways may be potential candidates for novel anti-inflammatory drug approaches. This review focuses on the anti-inflammatory effect of these inhibitors (for JAK/STAT, MAPK, and mTOR pathways) describing their mechanism of action through literature search, current patents, and molecules under clinical trials.

Small molecule TCS21311 can replace BMP7 and facilitate cell proliferation in in vitro expansion culture of nephron progenitor cells.

Several groups have developed in vitro expansion cultures for mouse metanephric nephron progenitor cells (NPCs) using cocktails of small molecules and growth factors including BMP7. However, the detailed mechanisms by which BMP7 acts in the NPC expansion remain to be elucidated. Here, by performing chemical screening for BMP substitutes, we identified a small molecule, TCS21311, that can replace BMP7 and revealed a novel inhibitory role of BMP7 in JAK3-STAT3 signaling in NPC expansion culture. Further, we found that TCS21311 facilitates the proliferation of mouse embryonic NPCs and human induced pluripotent stem cell-derived NPCs when added to the expansion culture. These results will contribute to understanding the mechanisms of action of BMP7 in NPC proliferation in vitro and in vivo and to the stable supply of NPCs for regenerative therapy, disease modeling and drug discovery for kidney diseases.

Impact of Janus Kinase Inhibition on the Treatment of Axial Spondyloarthropathies.

Many immune cells and effector molecules (e.g. cytokines, Interferons, growth factors) utilize different combinations of Janus kinase (JAK) and signal transducer and activator of transcription (STAT) molecules to transduce signals from the cell surface to the nucleus, where they regulate transcription. This pathway is basically involved in almost all inflammatory diseases and also in the interleukin (IL)-23/IL-17 cascade, which is an essential part of the pathogenesis of spondyloarthropathies (SpA). Upon evidence from in vitro and in vivo experiments indicating disease-modifying effects of JAK inhibition in inflammatory joint disease, numerous inhibitors of the JAK/STAT pathway (= JAKinibs) with different selectivity against the four members of the JAK family [JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2)] were developed. Trials in rheumatoid arthritis were successful with respect to efficacy and safety, and currently, three JAKinibs are approved for the treatment of rheumatoid arthritis in the European Union. Although new treatment options (anti-IL-23, anti-IL-17, and phosphodiesterase 4 inhibitors) have become available for spondyloarthritis and especially psoriatic arthritis (PsA) within the last years, most of them are biologics and do not address all disease manifestations equally. Therefore, multiple trials were initiated to evaluate JAKinibs in PsA and axial spondyloarthritis (axSpA). A trial of Tofacitinib (OPAL) was successful in PsA and has led to the inclusion of JAKinibs into the treatment algorithm. Currently many trials with JAKinibs are ongoing for PsA and axSpA, with one phase III trial of upadacitinib (selective JAK1 inhibitor) showing good therapeutic response in active radiographic axSpA.

Development of piperidinyl dipyrrrolopyridine-based dual inhibitors of Janus kinase and Bruton's tyrosine kinase: a potential therapeutic probability to deal with rheumatoid arthritis.

Rheumatoid arthritis is an autoimmune disorder causing joint deformity and work disability. Several drugs are available to deal with the disease including conventional drugs; biological drugs such as TNFα inhibitors, B cell-targeted drugs, T cell co-stimulation inhibitors, interleukin-6 inhibitors, and interleukin-1 inhibitors; and kinase inhibitory drugs. In spite of the broad spectrum of drugs available, the disease remains uncontrolled in a number of patients and there is a need for new drugs with better efficacy and universal response rate. The failure of the available drugs to control the disease can be owed to the complex pathogenesis with complementary pathways of disease progression. The blockade of one pathway cannot supersede pathogenesis through other complementary pathways. Janus kinase (JAK) and Bruton's tyrosine kinase (BTK) are the two important mediators of disease which control a number of signaling pathways involved in rheumatoid arthritis pathogenesis. In this study, using the computer-aided drug designing techniques (virtual screening, molecular docking, and molecular dynamics studies), we have designed piperidinyl dipyrrolopyridine-based dual inhibitors of Janus kinase and Bruton's tyrosine kinase. Dual JAK and BTK inhibitors seem promising to fight the complex pathogenesis of the disease at multiple fronts and can be the future drug for patients unresponsive to current remedies.

Emerging systemic drugs in the treatment of plaque psoriasis.

INTRODUCTION: Psoriasis is a common, chronic inflammatory skin condition that affects 2-3% of the US population and represents a large psychosocial burden for patients. Over the last decade, highly effective targeted therapies for psoriasis have been developed - namely, those targeting interleukin (IL)-17 and IL-23. The success of biologic agents targeting IL-17 and IL-23 underscores the importance of the IL-23/T helper (Th)17 cell axis in psoriasis pathogenesis. Oral small molecule drugs - such as Janus kinase (JAK) inhibitors, tyrosine kinase 2 (TYK2) inhibitors, and fumaric acid esters (FAEs) - are also being investigated for the treatment of psoriasis. AREAS COVERED: This article reviews systemic biologic and oral small molecule drugs currently undergoing clinical trials for the treatment of plaque psoriasis. EXPERT OPINION: Many patients with psoriasis have mild disease, and many with mild disease do not seek medical care for their condition. Many patients with mild disease could be adequately treated with topical treatments and phototherapy; however, adherence and feasibility have often been an issue with these treatment types. There seems to be limited room for development of novel biologics, as the existing ones are extraordinarily safe, effective, and convenient with few injections. Patients would prefer a safe, effective oral treatment; however, JAK inhibitors seem unlikely to fill this role completely.

Small molecule oral targeted therapies in ulcerative colitis.

The incidence and prevalence of ulcerative colitis are increasing globally. Although the exact cause and pathogenesis of this disease is unclear, research has led to a better understanding of the condition and to identification of new targets for therapy, which in turn has encouraged the development of new therapies. As well as biologic therapies, which have changed the way inflammatory bowel disease is managed, small molecules have been developed for the treatment of ulcerative colitis. These small molecule treatments are orally administered and are likely to bring a substantial shift in the way this chronic disease is treated. Oral therapies offer many advantages over infusion therapies, such as ease of use, increased acceptability by patients, and reduction of cost. This Review focuses not only on oral therapies that have been approved for use in ulcerative colitis, but also on those that are in development, providing a comprehensive overview for clinicians of available oral therapies and drugs that are likely to become available. We have also reviewed drugs that have shown promise in preclinical studies and could be effective future therapies.

Inhibition of JAK2/STAT3/SOCS3 signaling attenuates atherosclerosis in rabbit.

BACKGROUND: Previous studies have indicated that the JAK/STAT signaling pathway is involved in modulating arterial adventitia inflammation response. In this study, we designed experiments to further investigate the effect of JAK2/STAT3/SOCS3 signaling in rabbit atherosclerosis process. METHODS: Atherosclerosis was induced in the abdominal arteries of rabbits by balloon injury of the aorta supplemented by the atherogenic diet. Simultaneously, in the process of atherosclerosis, animals underwent either ruxolitinib treatment or not for 12 weeks. At the end of the experimental period, all rabbits were sacrificed. The plaque areas in abdominal artery, the lipid burden of plaque and the calcium burden of plaque were detected by H&E staining, Oil Red O staining and Alizarin Red staining, respectively. In addition, rabbit plasma lipids and inflammatory cytokines were measured by biochemical test kits or ELISA kits. Finally, the expression and phosphorylation levels of JAK2/STAT3/SOCS3 pathway-related proteins were detected by RT-qPCR, western blot and immunohistochemistry assays. RESULTS: H&E staining and CT scan analysis showed that rabbit atherosclerosis model was constructed successfully. Ruxolitinib, an inhibitor of the Janus kinase 2 (JAK2), substantially reduced the area of atherosclerotic plaques in rabbits treated with high fat diet and balloon injury of the aorta. Moreover, ruxolitinib significantly decreased IL-6, IL-1ß, IFN-γ and TNF-α, but increased IL-10 and IL-17 levels in plasma of atherosclerotic rabbits. Additionally, ruxolitinib reduced plasma TC, TG and LDL-C contents and AIP value, while enhanced HDL-C level in atherosclerotic rabbits. Furthermore, we found that JAK2 and STAT3 phosphorylation were up-regulated in rabbits with atherosclerosis when compared with those of the control group, followed by the expression of SOCS3 was also increased due to the activation of JAK2 and STAT3. Interestingly, ruxolitinib could inactivate JAK2 and STAT3 pathway and decrease SOCS3 expression. CONCLUSION: Taken together, the inhibition of JAK2/STAT3/SOCS3 signaling pathway may be a novel method for the clinical treatment of artery atherosclerosis.

Biologic Therapy in Crohn's Disease-What We Have Learnt So Far.

Crohn's disease (CD) is an autoimmune disorder from the group of inflammatory bowel diseases. The etiology of CD is not clear; currently, the interaction between the genetic, immunological and environmental factors is assumed as the cause of the disease. Partial knowledge of those factors has led to the development of drugs, which control the clinical symptoms and improve the overall condition of the infected; the main objective of the modern therapeutic strategies is the induction and maintenance of remission. Among the wide range of available treatments, older generation molecules: mesalazine, corticosteroids and thiopurine derivatives as well as biological drugs and biosimilars can be distinguished. Moreover, some novel biologics and small molecule drugs have shown potential in CD clinical trials, providing safe and effective results. This article provides an overview of the achievements in the field of biologic therapy, its efficacy and safety with an indication of future directions in CD treatment.

Genkwanin ameliorates adjuvant-induced arthritis in rats through inhibiting JAK/STAT and NF-κB signaling pathways.

BACKGROUND: Genkwanin is a flavone isolated from the traditional Chinese herb Daphne genkwa. Our previous work proved that four flavonoids (including genkwanin) isolated from D. genkwa (FFD) significantly improved the symptoms of arthritis in rat models. Recent studies have revealed that genkwanin exhibited anti-inflammatory and immunomodulatory activities, both of which were closely related to the pathology of rheumatoid arthritis (RA). Therefore, studying the anti-RA effects and mechanisms of genkwanin may give us insight into FFD's therapeutic effects on RA. PURPOSE: This study aimed to investigate the anti-rheumatoid arthritis activity of genkwanin on adjuvant-induced arthritis (AIA) model in rats and explore the underlying mechanisms. METHODS: The anti-rheumatoid arthritis activity of genkwanin was evaluated on AIA rat model by determining the paw swelling degrees and arthritis index scores, along with histopathological analysis of joint tissues. The serum cytokine levels were measured by ELISA method, and serum NO levels were measured by Griess method. The expression and phosphorylation levels of proteins in JAK/STAT and NF-κB signaling pathways were determined by western blot analysis and immunohistochemistry analysis. RESULTS: Genkwanin significantly decreased the paw swelling and arthritis index in AIA rats and also decreased the inflammation and bone destruction in joint tissues. The serum TNF-α, IL-6, and NO concentrations were markedly reduced while the IL-10 concentration was markedly increased with the treatment of genkwanin. Genkwanin inhibited the activation of JAK/STAT and NF-κB signaling pathways in synovial tissues of AIA rats. CONCLUSION: Genkwanin exerted anti-rheumatoid arthritis effects on AIA rats through inhibiting the activation of JAK/STAT and NF-κB signaling pathways. The results obtained in this work lead us to suggest that Genkwanin could play a crucial role on the previously demonstrated anti-rheumatoid arthritis activity of flavonoid extract of D. genkwa (namely FFD).

Centipedegrass extracts regulate LPS-mediated aberrant immune responses by inhibiting Janus kinase.

BACKGROUND: Centipedegrass extract (CGE) is rich in several polyphenolic compounds including C-glycosylflavonoids, such as maysin and its derivatives, and exerts antioxidant, anti-adipogenic and anticancer effects. However, the effect of CGE on the immune system is unclear. PURPOSE: CGE might inhibit NO production induced by lipopolysaccharide (LPS). In this study, we propose a molecular mechanism for regulation of aberrant immune responses by CGE in LPS-stimulated RAW264.7 cells. STUDY DESIGN: We will preparation of Centipedegrass extract and purify partially in rich of maysin and its derivatives. And examine the effect of the CGE on immune system using LPS-induced RAW cells and animals. METHODS: LPS-induced nitric oxide (NO) and interleukin-6 levels were measured by enzyme-linked immunosorbent assay. The mRNA and protein levels of immune mediators were analyzed by reverse-transcription polymerase chain reaction and immunoblotting, respectively. RESULTS: CGE inhibited LPS-induced NO production in a concentration-dependent manner by suppressing inducible nitric oxide synthase (iNOS) expression in LPS-stimulated cells; this effect was mediated by inhibition of the JAK/STAT pathway. However, CGE did not regulate the expression of other factors, including phosphorylated p38, c-jun N-terminal kinase, or extracellular signal-regulated kinase 1/2. In addition, CGE increased T cells percentage in peripheral blood after oral administration. CONCLUSION: These results indicate that CGE suppresses LPS-induced production of NO and expression of iNOS by directly inhibiting JAK2 kinase activity and enhancing effects on the immune system in mice.

On the Mechanism of Action of Anti-Inflammatory Activity of Hypericin: An In Silico Study Pointing to the Relevance of Janus Kinases Inhibition.

St. John's Wort (Hypericum perforatum L.) flowers are commonly used in ethnomedical preparations with promising outcomes to treat inflammation both per os and by topical application. However, the underlying molecular mechanisms need to be described toward a rational, evidence-based, and reproducible use. For this purpose, the aptitude of the prominent Hypericum metabolite hypericin was assessed, along with that of its main congeners, to behave as an inhibitor of janus kinase 1, a relevant enzyme in inflammatory response. It was used a molecular modeling approach relying on docking simulations, pharmacophoric modeling, and molecular dynamics to estimate the capability of molecules to interact and persist within the enzyme pocket. Our results highlighted the capability of hypericin, and some of its analogues and metabolites, to behave as ATP-competitive inhibitor providing: (i) a likely mechanistic elucidation of anti-inflammatory activity of H. perforatum extracts containing hypericin and related compounds; and (ii) a rational-based prioritization of H. perforatum components to further characterize their actual effectiveness as anti-inflammatory agents.

Essential oil of Artemisia argyi suppresses inflammatory responses by inhibiting JAK/STATs activation.

ETHNOPHARMACOLOGICAL RELEVANCE: Artemisia argyi is a herbal medicine traditionally used in Asia for the treatment of bronchitis, dermatitis and arthritis. Recent studies revealed the anti-inflammatory effect of essential oil in this plant. However, the mechanisms underlying the therapeutic potential have not been well elucidated. The present study is aimed to verify its anti-inflammatory effect and investigate the probable mechanisms. MATERIALS AND METHODS: The essential oil from Artemisia argyi (AAEO) was initially tested against LPS-induced production of inflammatory mediators and cytokines in RAW264.7 macrophages. Protein and mRNA expressions of iNOS and COX-2 were determined by Western blotting and RT-PCR analysis, respectively. The effects on the activation of MAPK/NF-κB/AP-1 and JAK/STATs pathway were also investigated by western blot. Meanwhile, in vivo anti-inflammatory effect was examined by histologic and immunohistochemical analysis in TPA-induced mouse ear edema model. RESULTS: The results of in vitro experiments showed that AAEO dose-dependently suppressed the release of pro-inflammatory mediators (NO, PGE2 and ROS) and cytokines (TNF-α, IL-6, IFN-ß and MCP-1) in LPS-induced RAW264.7 macrophages. It down-regulated iNOS and COX-2 protein and mRNA expression but did not affect the activity of these two enzymes. AAEO significantly inhibited the phosphorylation of JAK2 and STAT1/3, but not the activation of MAPK and NF-κB cascades. In animal model, oral administration of AAEO significantly attenuated TPA-induced mouse ear edema and decreased the protein level of COX-2. CONCLUSION: AAEO suppresses inflammatory responses via down-regulation of the JAK/STATs signaling and ROS scavenging, which could contribute, at least in part, to the anti-inflammatory effect of AAEO.

Psoralen with ultraviolet A-induced apoptosis of cutaneous lymphoma cell lines is augmented by type I interferons via the JAK1-STAT1 pathway.

BACKGROUND: Photochemotherapy with psoralen and ultraviolet A (PUVA), with or without adjuvant interferon-α (IFN-α), is a first-line therapy for early-stage mycosis fungoides and other forms of cutaneous T-cell lymphoma (CTCL). However, the mechanism by which PUVA with IFN-α work in CTCL is poorly understood. PURPOSE: To develop a model to investigate the mechanisms of PUVA and PUVA with IFN-α in CTCL cells. METHODS: An in vitro model to study the molecular mechanisms of PUVA was created using two different CTCL cell lines, MyLa, which has functional p53, and HuT-78, in which p53 is inactivated due to a homozygous nonsense mutation. RESULTS: PUVA caused G2/M cell cycle block and apoptosis of MyLa and HuT-78 accompanied by increase in the expression of the mitochondrial pro-apoptotic genes Bax, BAK, and PUMA and a downregulation in anti-apoptotic Bcl-2. p53 was induced and c-Myc was repressed by PUVA, but neither were essential for PUVA-induced apoptosis. IFN-α augmented PUVA-induced apoptosis via the JAK1 pathway, and this activity could be inhibited by ruxolitinib. CONCLUSION: PUVA induces p53-independent apoptosis in CTCL cell lines, and this process is augmented by type I interferons via the JAK1 pathway.