Inhibition Of Interleukin Research Articles

Antioxidant and Anti-Inflammatory Activity on LPS-Stimulated RAW 264.7 Macrophage Cells of White Mulberry (Morus alba L.) Leaf Extracts.

The white mulberry (Morus alba L.) is widely used as a medicinal plant in Asia. In this study, the bioactive compounds of ethanolic extracts of white mulberry leaves from the Sakon Nakhon and Buriram cultivars were evaluated. The ethanolic extracts of mulberry leaves from the Sakon Nakhon cultivar showed the highest total phenolic content of 49.68 mg GAE/g extract and antioxidant activities of 4.38 mg GAE/g extract, 4.53 mg TEAC/g extract, and 92.78 mg FeSO4/g extract using 2,2 diphenyl-1-picrylhydrazyl (DPPH), 2,20-azinobis-(3-ethylbenzothiazolin-6-sulfonic acid) (ABTS), and ferric reducing antioxidant power (FRAP) assays, respectively. The resveratrol and oxyresveratrol compounds in mulberry leaves were also investigated by high-performance liquid chromatography (HPLC). The mulberry leaf extracts from the Sakon Nakhon and Buriram cultivars showed oxyresveratrol contents of 1.20 ± 0.04 mg/g extract and 0.39 ± 0.02 mg/g extract, respectively, whereas resveratrol was not detected. It was also found that the potent anti-inflammatory properties of mulberry leaf extracts and its compounds, resveratrol and oxyresveratrol, suppressed the LPS-stimulated inflammatory responses in RAW 264.7 macrophage cells by significantly reducing nitric oxide production in a concentration-dependent manner. These compounds further inhibited interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) production and suppressed the mRNA and protein expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in LPS-stimulated RAW 264.7 macrophage cells. Therefore, it is established that mulberry leaf extract and its bioactive compounds contribute to its anti-inflammatory activity.

Bimekizumab efficacy and safety in patients with moderate to severe plaque psoriasis: Two-year interim results from the open-label extension of the randomized BE RADIANT phase 3b trial

Bimekizumab is a monoclonal IgG1 antibody that inhibits interleukin (IL)-17A/F. Bimekizumab is more efficacious than secukinumab over one year in the treatment of psoriasis. Evaluate safety and efficacy of bimekizumab through two years in patients with moderate to severe plaque psoriasis. The BE RADIANT phase 3b randomized controlled trial consisted of a 48-week double-blinded period, where patients received bimekizumab (320mg every 4 or 8 weeks) or secukinumab (300mg weekly to Week 4, then every 4 weeks), and an open-label extension (OLE). From Week 48, all patients received bimekizumab in the OLE. At Week 48, more patients achieved complete skin clearance (PASI100; modified non-responder imputation) with bimekizumab than secukinumab (74.8% vs 52.8%). PASI100 responses were maintained to Week 96 in continuous bimekizumab patients (70.8%); patients who switched from secukinumab to bimekizumab had increased rates at Week 96 (76.6%). The most common adverse events were: nasopharyngitis, oral candidiasis, urinary tract infection. Safety data were consistent with the known safety profile of bimekizumab. Limited racial diversity; overlap with COVID-19 pandemic. High PASI100 responses achieved with bimekizumab over 48 weeks were sustained through Week 96; secukinumab patients who switched to bimekizumab achieved similar response by Week 96.

Inhibition of Interleukin-17 in Patients with Oligoarticular Psoriatic Arthritis.

This study evaluated the efficacy of the interleukin-17A inhibitor secukinumab in patients with oligoarticular psoriatic arthritis (PsA). A total of 84 patients with oligoarticular PsA, defined as 1-4 tender joints and 1-4 swollen joints, were pooled from the FUTURE2-5 and MAXIMISE trials (NCT01752634, NCT01989468, NCT02294227, NCT02404350, and NCT02721966). Patients were grouped by treatment received at week12 (secukinumab 300mg, secukinumab 150mg, or placebo) and week52 (any secukinumab 300mg or any secukinumab 150mg). Efficacy was assessed by the proportion of patients achieving selected clinical outcomes. The predictors of Disease Activity index for Psoriatic Arthritis (DAPSA) responses at weeks12 and 52 were identified by logistic regression analysis. Secukinumab treatment resulted in greater achievement of DAPSA-based low disease activity (LDA), DAPSA-based remission (REM), DAPSA50, and DAPSA75 than placebo at week12, with improvements sustained or further increased through week52. LDA or REM was achieved at week52 by more than 90% of patients who received either secukinumab dose, although secukinumab 300mg resulted in the highest achievement of the stringent DAPSA75 and DAPSA REM outcomes. At week12, younger age was associated with DAPSA LDA or REM and DAPSA50, while lower baseline swollen joint count was associated with DAPSA REM. No predictors were identified at week52. The safety profile was consistent with the full study populations. Secukinumab demonstrated efficacy vs placebo across several outcome measures in patients with oligoarticular PsA at week12, with sustained or improved responses through week52.

Intranasal in situ gelling liquid crystal for delivery of resveratrol ameliorates memory and neuroinflammation in Alzheimer's disease

Alzheimer's disease (AD) is an illness that affects people aged 65 or older and affects around 6.5 million in the United States. Resveratrol is a chemical obtained from natural products and it exhibits biological activity based on inhibiting the formation, depolymerization of the amyloid, and decreasing neuroinflammation. Due to the insolubility of this compound; its incorporation in surfactant-based systems was proposed to design an intranasal formulation. A range of systems has been produced by mixing oleic acid, CETETH-20 and water. Polarised light microscopy (PLM), small angle x-ray scattering (SAXS) and transmission electron microscopy (TEM) confirm the initial liquid formulation (F) presented as microemulsion (ME). After dilution, the gelled systems were characterized as hexagonal mesophase and they showed feasibility proprieties. Pharmacological assays performed after intranasal administration showed the ability to improve learning and memory in animals, as well as remission of neuroinflammation via inhibition of interleukin.

Lifting the Lid on CAPS: Uncovering Genetic Anticipation in Cryopyrin-Associated Periodic Syndrome

Cryopyrin-associated periodic syndrome (CAPS) is a spectrum of autoinflammatory conditions comprising three subtypes: familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal onset multisystem inflammatory disease (NOMID).1 Symptoms include urticaria, fever, arthralgias, conjunctival injection, and headaches, which can occur spontaneously or during periods of cold/stress.2 Complications include permanent sensorineural hearing loss (SNHL), chronic aseptic meningitis, systemic amyloidosis, developmental delay, seizures, and chronic arthropathy.3 CAPS is treated with inhibition of interleukin (IL)-1 which can reduce symptoms and prevent progression of complications including hearing loss, CNS inflammation, and renal disease from amyloidosis.3,4.Here, we present a five-year-old boy who developed unexplained arthralgias, SNHL, increased intracranial pressure, atrophic retinal nerve fiber layer, and painful urticaria. Laboratory testing showed elevated inflammatory markers and neutrophil count. Genetic testing showed a heterozygous variant in the NLRP3 gene that was previously reported in a patient with NOMID. Interestingly, his mother had similar history of arthralgia, aseptic meningitis, SNHL, and recurrent aphthous ulcers, while his maternal grandmother had a history of SNHL and arthralgia. The mother and grandmother had similar elevations in inflammatory markers and neutrophils. Both were found to have the same variant in NLRP3 as the index patient and were diagnosed with CAPS/NOMID. The histories suggested a degree of genetic anticipation, for the child’s symptoms were most severe, while his mother had moderate symptoms and his grandmother was relatively mildly affected. Notably, neither the mother nor grandmother had signs of kidney disease to suggest amyloidosis. All three family members were started on canakinumab injections. The child’s arthralgias and mother’s symptoms improved, and flares have decreased in frequency. The grandmother has not yet received therapy long enough to assess for improved symptoms.CAPS is a group of autoinflammatory disorders with autosomal dominant inheritance, quality-of-life-limiting symptoms, and potential life-long complications. CAPS should be suspected and screened for in relatives of affected individuals. This familial case demonstrates a pattern of increased severity of CAPS symptoms with each subsequent generation from grandmother to grandchild suggestive of genetic anticipation. Early diagnosis and initiation of anti-IL-1 therapy is important to prevent progression and complications.

Withaferin A inhibits breast cancer-induced osteoclast differentiation.

Bone is the most prone to metastatic spread of breast cancer cells for each subtype of the disease. Bone metastasis-related complications including severe pain and pathological fractures affect patients' quality of life. Current treatment options including surgery, radiation, and bone-targeted therapies (e.g., bisphosphonates) are costly or have serious adverse effects such as renal toxicity and osteonecrosis of the jaws. Therefore, a safe, inexpensive, and efficacious agent for prevention of breast cancer bone metastasis is urgently needed. Our previously published RNA sequencing analysis revealed that many genes implicated in bone remodeling and breast cancer bone metastasis were significantly downregulated by treatment with withaferin A (WA), which is a promising cancer chemopreventive agent derived from a medicinal plant (Withania somnifera). The present study investigated whether WA inhibits breast cancer induction of osteoclast differentiation. At plasma achievable doses, WA treatment inhibited osteoclast differentiation (osteoclastogenesis) induced by three different subtypes of breast cancer cells (MCF-7, SK-BR-3, and MDA-MB-231). WA and the root extract of W. somnifera were equally effective for inhibition of breast cancer induction of osteoclast differentiation. This inhibition was accompanied by suppression of interleukin (IL)-6, IL-8, and receptor activator of nuclear factor-κB ligand, which are pivotal osteoclastogenic cytokines. The expression of runt-related transcription factor 2, nuclear factor-κB, and SOX9 transcription factors, which positively regulate osteoclastogenesis, was decreased in WA-treated breast cancer cells as revealed by confocal microscopy and/or immunoblotting. Taken together, these data suggest that WA could be a promising agent for prevention of breast cancer-induced bone metastasis.

IL-12 and IL-23 pathway inhibition in inflammatory bowel disease.

Interleukin-12 (IL-12) and interleukin-23 (IL-23), which belong to the IL-12 family of cytokines, have a key role in intestinal homeostasis and inflammation and are implicated in the pathogenesis of inflammatory bowel disease. Upon their secretion by antigen-presenting cells, they exert both pro-inflammatory and anti-inflammatory receptor-mediated effects. Anincreased understanding of these biological effects, particularly the pro-inflammatory effects mediated by IL-12 and IL-23, has led to the development of monoclonal antibodies that target a subunit common to IL-12 and IL-23 (p40; targeted by ustekinumab and briakinumab), or the IL-23-specific subunit (p19; targeted by risankizumab, guselkumab, brazikumab and mirikizumab). This Review provides a summary of the biology of the IL-12 family cytokines IL-12 and IL-23, discusses the role of these cytokines in intestinal homeostasis and inflammation, and highlights IL-12- and IL-23-directed drug development for the treatment of Crohn's disease and ulcerative colitis.

Lycium barbarum polysaccharide reduces lung cancer immunotherapy-related endocrine adverse reactions and improves prognosis via interleukin-2

This paper studies the mechanism of Lycium barbarum polysaccharide (LBP) in adverse reactions after immunotherapy. Five groups including model group, low-dose LBP group, middle-dose LBP group, high-dose LBP group, and interleukin-2 (IL-2) inhibitor group were set up. Adverse reactions after immunotherapy were observed through staining, blood collection and related experiments. IL-2 content was detected by ELISA, RT-qPCR and Western blot. The correlation coefficient between adverse reactions and prognosis was analyzed by Pearson software. LBP improved the diarrhea after immunotherapy and inhibition of IL-2 made the diarrhea more serious. Neutrophils around the hair follicles in the high-dose LBP group were less while they were more in model group where the hair follicles were blocked. The follicles in model group were more swelled while the follicles of high-dose LBP group had fewer swollen follicles. The degree of liver damage was inversely proportional to the concentration of LBP and the inhibition of IL-2 increased liver damage. The increased LBP promoted the improvement of immune function. LBP had a positive correlation with IL-2 level. The expression of IL-2 and E-cadherin increased with increased LBP concentration. Further analysis showed a negative correlation between diarrhea, ALT activity and AST activity and E-cadherin expression. Positive correlation between CD4+/CD8+ level and E-cadherin was observed. Conclusively, LBP could reduce adverse reactions after immunotherapy and promote IL-2 expression. IL-2 is related to immune function and its decrease causes more serious adverse reactions after immunotherapy. Thus, LBP can control IL-2 expression to reduce the adverse reactions after immunotherapy.

Efficacy and Safety of Secukinumab in Elderly Patients with Moderate to Severe Plaque-Type Psoriasis: Post-Hoc Analysis of the SUPREME Study.

Secukinumab is a fully human monoclonal antibody that inhibits interleukin (IL)-17A approved for the treatment of moderate to severe plaque psoriasis in adults and children. We compared the efficacy and safety of secukinumab in patients aged < 65 years (adult patients) versus patients aged ≥ 65 years (elderly patients) in a post-hoc analysis of the SUPREME study. Patients with moderate to severe plaque psoriasis received subcutaneous secukinumab 300 mg per week for the first 5 weeks, then 300 mg per month. We compared the following outcomes in patients aged ≥ 65 years vs < 65 years: baseline characteristics; PASI50/75/90/100 response rates (improvements ≥ 50%/75%/90%/100% in Psoriasis Area and Severity Index (PASI) from baseline); changes in Dermatology Life Quality Index (DLQI); Hospital Anxiety and Depression Scale (HAD-A, HAD-D) score changes; treatment-emergent adverse events (TEAEs). Secukinumab was slightly less effective in elderly patients than in adult patients (response rates at week 16: PASI90, 69.4% vs 80.9%, p = 0.4528; PASI100, 44.4% vs 56.7%, p = 0.8973). Elderly and adult patients showed a similar time course of changes in absolute PASI scores. Patients aged ≥ 65 years had a statistically significantly lower improvement in quality of life (mean DLQI reduction) than patients aged < 65 years at week 16 [-5.4 (±4.3) vs -8.8 (±6.9), p = 0.0065] and at week 24 [-5.3 (±4.4) vs -9.2 (±7.1), p = 0.0038]. Secukinumab treatment resulted in comparable mean reductions in anxiety and depression scores in both cohorts at 24 weeks [HAD-A, -1.3 (±3.3) vs -2.1 (±3.8), p = 0.9004; HAD-D, -1.0 (±3.3) vs -1.5 (±3.1), p = 0.4598]. The frequency of TEAEs in the two cohorts was similar (16.7% vs 14.6%, p = 0.7391). Secukinumab is a valid option for the management of moderate to severe psoriasis in elderly patients.

Anti-inflammatory effects of Gracilaria vermiculophylla Papenfuss extracts on Porphyromonas gingivalis stimulated RAW 264.7 cells

Seaweed Gracilaria vermiculophylla Papenfuss, commonly called ‘Worm wart weed’, is a red alga widely distributed in the coastal areas of several countries. Though G. vermiculophylla has been reported to have antioxidant and anti-inflammatory effects, such effects on periodontal diseases remain unclear. In this study, we investigated the anti-inflammatory effects of G. vermiculophylla on the production of inflammatory cytokines in Porphyromonas gingivalis induced RAW 264.7 cells. G. vermiculophylla found that RAW 264.7 cells had no cytotoxic effect on cell viability compared with untreated controls. In P. gingivalis stimulated RAW 264.7, G. vermiculophylla treatment reduced nitric oxide (NO) levels in a concentration-dependent manner by downregulating inducible nitric oxide synthase (iNOS) proteins. Reverse transcription-quantitative (RT-q) PCR inhibited interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α mRNA. Western blot analysis found that both inhibitor of kappa B alpha (IκBα) kinase (IKK) phosphorylation and IκBα degradation in P. gingivalis-stimulated RAW 264.7 was inhibited by G. vermiculophylla in a dose-dependent manner. In addition, G. vermiculophylla treatment reduced the nuclear translocation of nuclear factor (NF)-κB p65, suggesting that the anti-inflammatory effect of G. vermiculophylla is associated with the inhibition of NF-κB signaling pathways. These data suggest that G. vermiculophylla extract may have anti-inflammatory effects on periodontitis and can be used as a therapeutic agent to prevent periodontal disease.

Dual-Mechanism Glycolipidpeptide with High Antimicrobial Activity, Immunomodulatory Activity, and Potential Application for Combined Antibacterial Therapy.

Bacterial drug resistance is becoming increasingly serious, and it is urgent to develop effective antibacterial drugs. Antimicrobial peptides (AMPs), as potential candidates against bacteria, have a broad prospect for development. Herein, a series of AMPs with biological characteristics (net positive charge, amphiphilicity, and α-helix), an AXA motif recognized by membrane bound serine protease type I signal peptidases (SPase I), an FLPII motif to reduce hemolysis, and a monosaccharide motif to improve the stability and activity were designed and synthesized, and among which, the glycolipidpeptide GLP6 (glycosylated LP6 lipopeptide) had excellent antibacterial and immunomodulatory activity, good stability and biocompatibility, and excellent biofilm eradication and membrane penetrating activity. The positively charged spherical aggregates formed by self-assembly of GLP6 could encapsulate tetracycline (TC) to form GLP6@TC with a sustained-release effect, which could enhance the sensitivity of bacteria to the antibiotic and realize combined sterilization. The results of acute peritonitis and bacterial keratitis showed that GLP6@TC had a good combined antibacterial effect and the ability to inhibit interleukin-2 (IL-2), which could significantly reduce the inflammatory response while treating bacterial infection, and it had great potential for application. The results of computer molecular docking showed the AXA motif could effectively bind to SPase I, which was consistent with the results of biological experiments. In general, the study could provide a perspective for the design of AMPs and combined antibacterial therapy.

Dupilumab-associated cutaneous adverse events among adult patients with atopic dermatitis: A retrospective study.

Dupilumab, a monoclonal antibody inhibiting interleukin (IL) 4 and IL-13, is approved for the treatment of moderate to severe atopic dermatitis (AD) in children aged ≥6 years, adolescents, and adults. Both clinical trials and real-life data demonstrate its efficacy and safety. However, some cutaneous adverse events (cAEs) have been observed during real-world experiences. The authors' aim was to analyze the spectrum of cAEs in patients receiving dupilumab for the treatment of AD in a real-world setting. A retrospective review of electronic medical records was conducted for 916 patients (475 males and 541 females; mean age, 50.23 ± 19.66 years [range, 18-91 years]) who had received dupilumab for a minimum of 1month for the treatment of AD from December 2018 to November 2022 at the Department of Dermatology of University Federico II of Naples (Italy). The mean duration of dupilumab treatment was 27.31 ± 21.26 months. A total of 148 of 916 (16.15%) (90 males; mean age, 50.91 ± 15.34 years) patients reported other cAEs apart of AD flare; namely, facial redness (82 of 916; 8.95%), psoriasis (39 of 916; 4.25%), alopecia areata (11 of 916; 1.2%), skin peeling (11 of 916; 1.2%), parapsoriasis (three of 916; 0.32%), and vitiligo (two of 916; 0.21%). Thirty-one of 916 (3.38%) patients discontinued dupilumab because of cAEs (18 of 916; 1.96%) for facial redness, 10 of 916 (1.09%) for psoriasis, and three of 916 (0.32%) for parapsoriasis. In our population, most of the cAEs were mild and did not require discontinuation of dupilumab. These findings would enable dermatologists understand the cutaneous side effects of dupilumab better, resulting in improved treatment plan decisions in clinical practice.

Effect of Induction Therapy With Olamkicept vs Placebo on Clinical Response in Patients With Active Ulcerative Colitis

Olamkicept, a soluble gp130-Fc-fusion-protein, selectively inhibits interleukin 6 (IL-6) trans-signaling by binding the soluble IL-6 receptor/IL-6 complex. It has anti-inflammatory activities in inflammatory murine models without immune suppression. To assess the effect of olamkicept as induction therapy in patients with active ulcerative colitis. Randomized, double-blind, placebo-controlled phase 2 trial of olamkicept in 91 adults with active ulcerative colitis (full Mayo score ≥5, rectal bleeding score ≥1, endoscopy score ≥2) and an inadequate response to conventional therapy. The study was conducted at 22 clinical study sites in East Asia. Patients were recruited beginning in February 2018. Final follow-up occurred in December 2020. Eligible patients were randomized 1:1:1 to receive a biweekly intravenous infusion of olamkicept 600 mg (n = 30) or 300 mg (n = 31) or placebo (n = 30) for 12 weeks. The primary end point was clinical response at week 12 (defined as ≥3 and ≥30% decrease from baseline total Mayo score; range, 0-12 [worst] with ≥1 decrease and ≤1 in rectal bleeding [range, 0-3 {worst}]). There were 25 secondary efficacy outcomes, including clinical remission and mucosal healing at week 12. Ninety-one patients (mean age, 41 years; 25 women [27.5%]) were randomized; 79 (86.8%) completed the trial. At week 12, more patients receiving olamkicept 600 mg (17/29 [58.6%]) or 300 mg (13/30 [43.3%]) achieved clinical response than placebo (10/29 [34.5%]), with adjusted difference vs placebo of 26.6% (90% CI, 6.2% to 47.1%; P = .03) for 600 mg and 8.3% (90% CI, -12.6% to 29.1%; P = .52) for 300 mg. Among patients randomized to receive 600 mg olamkicept, 16 of 25 secondary outcomes were statistically significant compared with placebo. Among patients randomized to receive 300 mg, 6 of 25 secondary outcomes were statistically significant compared with placebo. Treatment-related adverse events occurred in 53.3% (16/30) of patients receiving 600 mg olamkicept, 58.1% (18/31) receiving 300 mg olamkicept, and 50% (15/30) receiving placebo. The most common drug-related adverse events were bilirubin presence in the urine, hyperuricemia, and increased aspartate aminotransferase levels, and all were more common in the olamkicept groups compared with placebo. Among patients with active ulcerative colitis, biweekly infusion of olamkicept 600 mg, but not 300 mg, resulted in a greater likelihood of clinical response at 12 weeks compared with placebo. Further research is needed for replication and to assess longer-term efficacy and safety. ClinicalTrials.gov Identifier: NCT03235752.

Anti-inflammatory Effect by Cloves Treatment in LPS-induced RAW264.7 Cells

Background: Cloves mean the dried flower bud harvested from a tree of Syzygium aromaticum L. (SA). Objectives: The current study was to identify the anti-inflammatory effects of SA on lipopolysaccharide (LPS) (0.2 µg/mL)-treated RAW264.7 cells. Materials and Methods: WST-8 cell proliferation assay kit (WST-8) and lactate dehydrogenase (LDH) assays were completed to observe cell proliferation and cytotoxicity effects of SA. Other biochemical analyses analyzed releases of nitric oxide (NO) and the production of dichlorofluorescin diacetate (DCF-DA). Besides, inflammation-related factors and Sirt1 were carried out through immunohistochemistry (IHC) and immunofluorescence (IF). Results: LPS exposure not only caused abnormal elevations of both NO and reactive oxygen species (ROS) secretions, but also markedly increased inflammation-related proteins including inducible NO synthase (iNOS), cluster of differentiation (CD) 14, and toll-like receptor (TLR) 4, and nuclear factor-κB (NF-κB). The above-listed alterations were notably attenuated by SA pretreatment in a dose-dependent manner. We further figured out that, SA particularly activated AMPKα/ Sirt1 signaling pathway. Furthermore, SA dramatically inhibited interleukin (IL)-1β production, which was mediated by NLR family Pyrin domain containing (NLRP) 3 mediated inflammasome signaling pathway. Conclusion: SA inhibits LPS-induced inflammation in RAW264.7 cells via the TRL4/CD14/NF-κB pathway and it can lead to the reduction of IL-1β release by the inhibition of NLRP3 inflammasome. Such an anti-inflammatory effect was closely related to AMPKα/Sirt1 activation. Taken together, the findings of this study support both the inhibition of NLRP3 inflammasome and activation of Sirt1 can alleviate inflammation.

Phosphoenolpyruvate regulates the Th17 transcriptional program and inhibits autoimmunity

Aerobic glycolysis, a metabolic pathway essential for effector Tcell survival and proliferation, regulates differentiation of autoimmune T helper (Th) 17 cells, but the mechanism underlying this regulation is largely unknown. Here, we identify a glycolytic intermediate metabolite, phosphoenolpyruvate (PEP), as a negative regulator of Th17 differentiation. PEP supplementation or inhibition of downstream glycolytic enzymes in differentiating Th17 cells increases intracellular PEP levels and inhibits interleukin (IL)-17A expression. PEP supplementation inhibits expression of signature molecules for Th17 and Th2 cells but does not significantly affect glycolysis, cell proliferation, or survival of T helper cells. Mechanistically, PEP binds to JunB and inhibits DNA binding of the JunB/basic leucine zipper transcription factor ATF-like (BATF)/interferon regulatory factor 4 (IRF4) complex, thereby modulating the Th17 transcriptional program. Furthermore, daily administration of PEP to mice inhibits generation of Th17 cells and ameliorates Th17-dependent autoimmune encephalomyelitis. These data demonstrate that PEP links aerobic glycolysis to the Th17 transcriptional program, suggesting the therapeutic potential of PEP for autoimmune diseases.

Role of IL-6/STAT3 Axis in Resistance to Cisplatin in Gastric Cancers.

Gastric cancer, the second most common cause of death worldwide, is characterized by poor prognosis and low responsiveness to chemotherapy. Indeed, multidrug resistance, based mainly on cellular and molecular factors, remains one of the most limiting factors of the current approach to gastric cancer (GC) therapy. We employed a comprehensive gene expression analysis through data mining of publicly available databases to assess the role of the signal transducer and activator of transcription 3 (STAT3) in gastric cancer drug efficiency. It has been proposed that gastric cancer cells are less sensitive to these drugs because they develop resistance to these agents through activating alternative signalling pathways responsible for overcoming pharmacological inhibition. Our study evaluated the hypothesis that activating STAT3 signalling in response to cisplatin reduces the reaction to the drug. Consistent with this hypothesis, inhibition of interleukin 6 (IL-6)/STAT3 in combination therapy with cisplatin prevented both STAT3 activation and more lethality than induction by a single agent. The data suggest that the IL-6/STAT3 axis block associated with cisplatin treatment may represent a strategy to overcome resistance.

Synergistic Inhibitory Effect of Lactobacillus Cell Lysates and Butyrate on Poly I:C-Induced IL-8 Production in Human Intestinal Epithelial Cells.

Postbiotics include cell lysates (CLs), enzymes, cell wall fragments, and heat-killed bacteria derived from probiotics. Although postbiotics are increasingly being considered for their potential health-promoting properties, the effects of postbiotics on virus-mediated inflammatory responses in the intestine have not been elucidated. Hence, the present study aimed to examine whether CLs of Lactipantibacillus plantarum (LP CL) and Lacticaseibacillus rhamnosus GG (LR CL) could inhibit virus-mediated inflammatory responses in the human intestinal epithelial cell line HT-29 in vitro. Pretreatment with LP CL and LR CL significantly inhibited interleukin (IL)-8 production, which was induced by poly I:C, a synthetic analog of double-stranded RNA (dsRNA) viruses, at the mRNA and protein levels in HT-29 cells. However, peptidoglycans and heat-killed L. plantarum and L. rhamnosus GG did not effectively inhibit IL-8 production. LP CL and LR CL attenuated the poly I:C-induced phosphorylation of ERK and JNK and the activation of NF-κB, suggesting that these CLs could inhibit poly I:C-induced IL-8 production by regulating intracellular signaling pathways in HT-29 cells. Furthermore, among the short-chain fatty acids, butyrate enhanced the inhibitory effect of CLs on poly I:C-induced IL-8 production at the mRNA and protein levels in HT-29 cells, while acetate and propionate did not. Taken together, these results suggest that both LP CL and LR CL could act as potent effector molecules that can inhibit virus-mediated inflammatory responses and confer synergistic inhibitory effects with butyrate in human intestinal epithelial cells.

Enhanced secretion of hepatocyte growth factor in human umbilical cord mesenchymal stem cells ameliorates pulmonary fibrosis induced by bleomycin in rats.

Umbilical cord mesenchymal stem cells (UCMSCs) are a reportedly promising choice in the treatment of irreversible pulmonary fibrosis and lethal interstitial lung disease with limited drug treatment options. In this study, we investigated the therapeutic efficacy of UCMSCs overexpressing hepatocyte growth factor (HGF), which is considered one of the main anti-fibrotic factors secreted by MSCs. Adenovirus vector carrying the HGF gene was transfected into UCMSCs to produce HGF-modified UCMSCs (HGF-UCMSCs). Transfection promoted the proliferation of UCMSCs and did not change the morphology, and differentiation ability, or biomarkers. Rats were injected with HGF-UCMSCs on days 7 and 11 after intratracheal administration of bleomycin (10mg/kg). We performed an analysis of histopathology and lung function to evaluate the anti-fibrotic effect. The results showed that HGF-UCMSCs decreased the Ashcroft scores in hematoxylin and eosin-stained sections, the percentage positive area in Masson trichrome-stained sections, and the hydroxyproline level in lungs. Forced expiratory volume in the first 300m/forced vital capacity was also improved by HGF-UCMSCs. To explore the possible therapeutic mechanism of HGF-UCMSCs, we detected inflammatory factors in the lungs and performed mRNA sequencing in UCMSCs and HGF-UCMSCs. The data indicated that inhibition of interleukin-17 in the lung may be related to the anti-fibrosis of HGF-UCMSCs, and overexpressed HGF probably played a primary role in the treatment. Collectively, our study findings suggested that the overexpression of HGF may improve the anti-fibrotic effect of UCMSCs through directly or indirectly interacting with interleukin-17-producing cells in fibrotic lungs.

Optogenetic Activation of Astrocytes Reduces Blood-Brain Barrier Disruption via IL-10 In Stroke.

Optogenetics has been used to regulate astrocyte activity and modulate neuronal function after brain injury. Activated astrocytes regulate blood-brain barrier functions and are thereby involved in brain repair. However, the effect and molecular mechanism of optogenetic-activated astrocytes on the change in barrier function in ischemic stroke remain obscure. In this study, adult male GFAP-ChR2-EYFP transgenic Sprague-Dawley rats were stimulated by optogenetics at 24, 36, 48, and 60 h after photothrombotic stroke to activate ipsilateral cortical astrocytes. The effects of activated astrocytes on barrier integrity and the underlying mechanisms were explored using immunostaining, western blotting, RT-qPCR, and shRNA interference. Neurobehavioral tests were performed to evaluate therapeutic efficacy. The results demonstrated that IgG leakage, gap formation of tight junction proteins, and matrix metallopeptidase 2 expression were reduced after optogenetic activation of astrocytes (p<0.05). Moreover, photo-stimulation of astrocytes protected neurons against apoptosis and improved neurobehavioral outcomes in stroke rats compared to controls (p<0.05). Notably, interleukin-10 expression in optogenetic-activated astrocytes significantly increased after ischemic stroke in rats. Inhibition of interleukin-10 in astrocytes compromised the protective effects of optogenetic-activated astrocytes (p<0.05). We found for the first time that interleukin-10 derived from optogenetic-activated astrocytes protected blood-brain barrier integrity by decreasing the activity of matrix metallopeptidase 2 and attenuated neuronal apoptosis, which provided a novel therapeutic approach and target in the acute stage of ischemic stroke.

Bimekizumab in patients with psoriatic arthritis, naive to biologic treatment: a randomised, double-blind, placebo-controlled, phase 3 trial (BE OPTIMAL)

Bimekizumab is a monoclonal IgG1 antibody that selectively inhibits interleukin (IL)-17A and IL-17F. We assessed the efficacy and safety of bimekizumab in patients with active psoriatic arthritis who were naive to biologic disease-modifying antirheumatic drugs (DMARDs). BE OPTIMAL was a 52-week, phase 3, multicentre, randomised, double-blind, placebo-controlled, active reference (adalimumab) trial done at 135 sites (hospitals, clinics, doctors' offices, and research centres) in 14 countries. Eligible patients were 18 years or older with a documented diagnosis of adult-onset psoriatic arthritis that met the Classification Criteria for Psoriatic Arthritis for at least 6 months before screening. Participants were randomly assigned with an interactive-voice and web-response system on the basis of a predetermined randomisation schedule (3:2:1, stratified by region and bone erosion number at baseline) to bimekizumab 160 mg every 4 weeks, placebo every 2 weeks, or the reference group (adalimumab 40 mg every 2 weeks), all administered subcutaneously. At week 16, patients randomly assigned to placebo switched to bimekizumab 160 mg every 4 weeks. The primary endpoint was the proportion of patients reaching 50% or greater improvement in American College of Rheumatology criteria (ACR50) at week 16 (non-responder imputation). Efficacy analyses included all patients who were randomly assigned (intention-to-treat population); the safety analysis set comprised patients who received one or more doses of treatment. Data are presented to week 24 (preplanned analysis). This trial is registered at ClinicalTrials.gov, NCT03895203. Between April 3, 2019, and Oct 25, 2021, 1163 patients were screened and 852 were randomly assigned to bimekizumab (n=431), placebo (n=281), and reference (adalimumab; n=140) groups. At week 16, significantly more patients receiving bimekizumab (189 [44%] of 431) reached ACR50 response versus placebo (28 [10%] of 281; odds ratio 7·1 [95% CI 4·6-10·9], p<0·0001; adalimumab 64 [46%] of 140). All secondary hierarchical endpoints were met. Treatment-emergent adverse events up to week 16 were reported in 258 [60%] of 431 patients receiving bimekizumab, 139 [49%] of 281 patients receiving placebo, and 83 [59%] of 140 patients receiving adalimumab. No deaths occurred. Bimekizumab treatment had superior improvements in joint, skin, and radiographic efficacy outcomes at week 16 compared with placebo in patients with psoriatic arthritis who were naive to biologic DMARDs. The safety profile of bimekizumab, including the occurrence of fungal infections, was consistent with previous phase 3 studies in patients with plaque psoriasis, and with IL-17A inhibitors. UCB Pharma.