Impact of Glucagon-Like Peptide 1 Receptor Agonists on Biochemical Markers of the Initiation of Atherosclerotic Process.

Atherosclerosis stands out as one of the leading causes of global mortality. The inflammatory response against vascular wall components plays a pivotal role in the atherogenic process. The initiation of this process is notably driven by oxidized low-density lipoprotein (oxLDL) and a range of pro-inflammatory cytokines, with interleukin-1ß (Il-1ß) and tumor necrosis factor α (TNFα) emerging as particularly significant in the early stages of atherosclerotic plaque formation. In recent years, researchers worldwide have been diligently exploring innovative therapeutic approaches for metabolic diseases, recognizing their impact on the atherogenesis process. Our study aimed to investigate the influence of glucagon-like peptide 1 receptor agonists (GLP-1RA) on cytokine concentrations associated with the initiation of atherosclerotic plaque formation in a group of patients with type 2 diabetes and dyslipidemia. The study encompassed 50 subjects aged 41-81 (mean: 60.7), all diagnosed with type 2 diabetes, dyslipidemia and confirmed atherosclerosis based on B-mode ultrasound. Following a 180-day treatment with dulaglutide or semaglutide, we observed a statistically significant reduction in biochemical markers (oxLDL, TNFα and Il-1ß) associated with the initiation of the atherosclerotic process (p < 0.001) within our study group. In addition to the already acknowledged positive effects of GLP-1RA on the metabolic parameters of treated patients, these drugs demonstrated a notable reduction in proinflammatory cytokine concentrations and may constitute an important element of therapy aimed at reducing cardiovascular risk.

M1 polarization of macrophages promotes stress-induced hair loss via interleukin-18 and interleukin-1ß.

Stress-induced hair loss is a prevalent health concern, with mechanisms that remain unclear, and effective treatment options are not yet available. In this study, we investigated whether stress-induced hair loss was related to an imbalanced immune microenvironment. Screening the skin-infiltrated immune cells in a stressed mouse model, we discovered a significant increase in macrophages upon stress induction. Clearance of macrophages rescues mice from stress-induced hair shedding and depletion of hair follicle stem cells (HFSCs) in the skin, demonstrating the role of macrophages in triggering hair loss in response to stress. Further flow cytometry analysis revealed a significant increase in M1 phenotype macrophages in mice under stressed conditions. In searching for humoral factors mediating stress-induced macrophage polarization, we found that the hormone Norepinephrine (NE) was elevated in the blood of stressed mice. In addition, in-vivo and in-vitro studies confirm that NE can induce macrophage polarization toward M1 through the ß-adrenergic receptor, Adrb2. Transcriptome, enzyme-linked immunosorbent assay (ELISA), and western blot analyses reveal that the NLRP3/caspase-1 inflammasome signaling and its downstream effector interleukin 18 (IL-18) and interleukin 1 beta (IL-1ß) were significantly upregulated in the NE-treated macrophages. However, inhibition of the NE receptor Adrb2 with ICI118551 reversed the upregulation of NLRP3/caspase-1, IL-18, and IL-1ß. Indeed, IL-18 and IL-1ß treatments lead to apoptosis of HFSCs. More importantly, blocking IL-18 and IL-1ß signals reversed HFSCs depletion in skin organoid models and attenuated stress-induced hair shedding in mice. Taken together, this study demonstrates the role of the neural (stress)-endocrine (NE)-immune (M1 macrophages) axis in stress-induced hair shedding and suggestes that IL-18 or IL-1ß may be promising therapeutic targets.

No Observed Difference in Inflammatory and Coagulation Markers Following Diets Rich in n-6 Polyunsaturated Fat vs Monounsaturated Fat in Adults With Untreated Hypercholesterolemia: A Randomized Trial.

BACKGROUND: Inflammatory and prothrombotic responses are hallmark to the progression of cardiovascular disease and may be influenced by the type of dietary fat. Cottonseed oil (CSO) is rich in n-6 polyunsaturated fats and improves traditional cardiovascular disease risk factors such as cholesterol profiles. However, some clinicians are still hesitant to promote n-6 polyunsaturated fats consumption despite growing evidence suggesting they may not be independently pro-inflammatory. OBJECTIVE: To investigate the inflammatory and coagulation marker responses to an 8-week diet intervention rich in either CSO or olive oil (OO) (OO is rich in monounsaturated fat) in adults with untreated hypercholesterolemia. DESIGN: This was a secondary analysis of a parallel-arm randomized clinical trial with the main outcome of cholesterol measures. PARTICIPANTS/SETTING: Participants included in this analysis were 42 sedentary adults aged 30 to 75 years (62% women) in the Athens, GA, area, between May 2018 and June 2021, with untreated hypercholesterolemia or elevated blood lipids and body mass index >18.5. Hypercholesterolemia was defined as at least two blood lipid levels in a borderline undesirable/at risk range (total cholesterol level ≥180 mg/dL, low-density lipoprotein cholesterol level ≥110 mg/dL, high-density lipoprotein cholesterol level <50 mg/dL, or triglyceride level ≥130 mg/dL), or at least one in an undesirable range (total cholesterol level ≥240 mg/dL, low-density lipoprotein cholesterol level ≥160 mg/dL, high-density lipoprotein cholesterol level <40 mg/dL, or triglyceride level ≥200 mg/dL). INTERVENTION: Participants were randomly assigned to either the CSO or OO group in a partial outpatient feeding trial. Meals from the study provided approximately 60% of their energy needs with 30% of energy needs from either CSO or OO for 8 weeks. Participants fulfilled their remaining energy needs with meals of their choosing. MAIN OUTCOME MEASURES: Fasting plasma concentrations of inflammatory markers, including C-reactive protein, tumor necrosis factor-α, interleukin-6, and interleukin-1ß were measured at baseline and 8 weeks. Markers of coagulation potential, including plasminogen activator inhibitor-1, and tissue factor were measured at the same time points. STATISTICAL ANALYSES PERFORMED: Repeated measures linear mixed models were used with treatment and visit in the model for analyses of all biochemical markers. RESULTS: There were no significant differences in fasting C-reactive protein (P = 0.70), tumor necrosis factor-α (P = 0.98), interleukin-6 (P = 0.21), interleukin-1ß (P = 0.13), plasminogen activator inhibitor-1 (P = 0.29), or tissue factor (P = 0.29) between groups across the intervention. CONCLUSIONS: Inflammation and coagulation marker responses to diets rich in CSO vs OO were not significantly different between groups, and neither group showed changes in these markers in adults with untreated hypercholesterolemia. This provides additional evidence suggesting that dietary n-6 polyunsaturated fats may not promote inflammation compared with monounsaturated fatty acids, even in adults at increased risk for cardiovascular disease.

Interleukin-1ß triggers muscle-derived extracellular superoxide dismutase expression and protects muscles from doxorubicin-induced atrophy.

Doxorubicin, a conventional chemotherapeutic agent prescribed for cancer, causes skeletal muscle atrophy and adversely affects mobility and strength. Given that doxorubicin-induced muscle atrophy is attributable primarily to oxidative stress, its effects could be mitigated by antioxidant-focused therapies; however, these protective therapeutic targets remain ambiguous. The aim of this study was to demonstrate that doxorubicin triggers severe muscle atrophy via upregulation of oxidative stress (4-hydroxynonenal and malondialdehyde) and atrogenes (atrogin-1/MAFbx and muscle RING finger-1) in association with decreased expression of the antioxidant enzyme extracellular superoxide dismutase (EcSOD), in cultured C2C12 myotubes and mouse skeletal muscle. Supplementation with EcSOD recombinant protein elevated EcSOD levels on the cellular membrane of cultured myotubes, consequently inhibiting doxorubicin-induced oxidative stress and myotube atrophy. Furthermore, doxorubicin treatment reduced interleukin-1ß (IL-1ß) mRNA expression in cultured myotubes and skeletal muscle, whereas transient IL-1ß treatment increased EcSOD protein expression on the myotube membrane. Notably, transient IL-1ß treatment of cultured myotubes and local administration in mouse skeletal muscle attenuated doxorubicin-induced muscle atrophy, which was associated with increased EcSOD expression. Collectively, these findings reveal that the regulation of skeletal muscle EcSOD via maintenance of IL-1ß signalling is a potential therapeutic approach to counteract the muscle atrophy mediated by doxorubicin and oxidative stress. KEY POINTS: Doxorubicin, a commonly prescribed chemotherapeutic agent for patients with cancer, induces severe muscle atrophy owing to increased expression of oxidative stress; however, protective therapeutic targets are poorly understood. Doxorubicin induced muscle atrophy owing to increased expression of oxidative stress and atrogenes in association with decreased protein expression of extracellular superoxide dismutase (EcSOD) in cultured C2C12 myotubes and mouse skeletal muscle. Supplementation with EcSOD recombinant protein increased EcSOD levels on the cellular membrane of cultured myotubes, resulting in inhibition of doxorubicin-induced oxidative stress and myotube atrophy. Doxorubicin treatment decreased interleukin-1ß (IL-1ß) expression in cultured myotubes and skeletal muscle, whereas transient IL-1ß treatment in vivo and in vitro increased EcSOD protein expression and attenuated doxorubicin-induced muscle atrophy. These findings reveal that regulation of skeletal muscle EcSOD via maintenance of IL-1ß signalling is a possible therapeutic approach for muscle atrophy mediated by doxorubicin and oxidative stress.

The role of apoptosis in the pathogenesis of osteoarthritis.

PURPOSE: Apoptosis is an important physiological process, making a great difference to development and tissue homeostasis. Osteoarthritis (OA) is a chronic joint disease characterized by degeneration and destruction of articular cartilage and bone hyperplasia. This purpose of this study is to provide an updated review of the role of apoptosis in the pathogenesis of osteoarthritis. METHODS: A comprehensive review of the literature on osteoarthritis and apoptosis was performed, which mainly focused on the regulatory factors and signaling pathways associated with chondrocyte apoptosis in osteoarthritis and other pathogenic mechanisms involved in chondrocyte apoptosis. RESULTS: Inflammatory mediators such as reactive oxygen species (ROS), nitric oxide (NO), IL-1ß, tumor necrosis factor-α (TNF-α), and Fas are closely related to chondrocyte apoptosis. NF-κB signaling pathway, Wnt signaling pathway, and Notch signaling pathway activate proteins and gene targets that promote or inhibit the progression of osteoarthritis disease, including chondrocyte apoptosis and ECM degradation. Long non-coding RNAs (LncRNAs) and microRNAs (microRNAs) have gradually replaced single and localized research methods and become the main research approaches. In addition, the relationship between cellular senescence, autophagy, and apoptosis was also briefly explained. CONCLUSION: This review offers a better molecular delineation of apoptotic processes that may help in designing new therapeutic options for OA treatment.

The In Vitro Pro-inflammatory Functions of the SP/NK1R System in Prostate Cancer: a Focus on Nuclear Factor-Kappa B (NF-κB) and Its Pro-inflammatory Target Genes.

Prostate cancer is one of the main global health threats for men which is in close association with chronic inflammation. Neuropeptide substance P (SP), acting through neurokinin receptor (NK-1R), induces various pro-inflammatory responses which are strongly involved in the pathogenesis of several diseases as well as cancer. Therefore, we aimed to investigate the pro-inflammatory functions of the SP/NK1R complex in prostate cancer and the therapeutic effects of its inhibition by NK-1R antagonist, aprepitant, in vitro. MTT assay was conducted for the cytotoxicity assessment of aprepitant in prostate cancer cells. The protein expression levels were evaluated by Western blot assay. Quantitative real-time PCR (qRT-PCR) was applied to measure mRNA expression levels of pro-inflammatory cytokines. Concurrently, the protein concentrations of pro-inflammatory cytokines were also analyzed by enzyme-linked immunosorbent assay. We observed that SP increased the levels of pro-inflammatory cytokines (IL-1ß, IL-6, and TNF-α), while treatment with aprepitant reduced the effects of SP. We also indicated that SP increased the protein levels of nuclear factor-kappa B (NF-κB), as the main regulator of inflammatory processes, and also an NF-κB target gene, cyclooxygenase 2 (COX-2) in prostate cancer cells, while treatment with aprepitant reversed these effects. Taken together, our findings highlight the importance of the SP/NK1R system in the modulation of pro-inflammatory responses in prostate cancer cells and suggest that aprepitant may be developed as a novel anti-inflammatory agent for the management of cancer-associated inflammation.

Anti-Inflammatory and Analgesic Effects of Curcumin Nanoparticles Associated with Diclofenac Sodium in Experimental Acute Inflammation.

The present study evaluated the anti-inflammatory and analgesic effects of conventional curcumin (cC) and curcumin nanoparticles (nC) associated with diclofenac sodium (D) in experimental acute inflammation (AI) induced by carrageenan administration. Seven groups of eight randomly selected Wistar-Bratislava white rats were evaluated. One group was the control (C), and AI was induced in the other six groups. The AI group was treated with saline solution, the AID group was treated with D, the AIcC200 and AInC200 groups were treated with cC and nC, respectively, while AIcC200D and AInC200D were treated with cC and nC, respectively, both associated with D. Conventional curcumin, nC, and D were administered in a single dose of 200 mg/kg b.w. for cC and nC and 5 mg/kg b.w. for D. Association of cC or nC to D resulted in significant antinociceptive activity, and improved mechanical pressure stimulation and heat thresholds at 3, 5, 7 and 24 h (p < 0.03). The association of cC and nC with D (AIcC200D and AInC200D groups) showed significantly lower plasma and tissue levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1ß (IL-1ß) up to 2.5 times, with the best results in the group who received nC. Moreover, AInC200D presented the least severe histopathological changes with a reduced level of inflammation in the dermis and hypodermis. The combination of nC to D showed efficiency in reducing pain, inflammatory cytokines, and histological changes in acute inflammation.

Low Diversity and Instability of the Sinus Microbiota over Time in Adults with Cystic Fibrosis.

Chronic rhinosinusitis (CRS) is a common, yet underreported and understudied manifestation of upper respiratory disease in people with cystic fibrosis (CF). Recently developed standard of care guidelines for the management of CF CRS suggest treatment of upper airway disease may ameliorate lower airway disease. We sought to determine whether changes to sinus microbial community diversity and specific taxa known to cause CF lung disease are associated with increased respiratory disease and inflammation. We performed 16S rRNA gene sequencing, supplemented with cytokine analyses, microscopy, and bacterial culturing, on samples from the sinuses of 27 adults with CF CRS. At each study visit, participants underwent endoscopic paranasal sinus sampling and clinical evaluation. We identified key drivers of microbial community composition and evaluated relationships between diversity and taxa with disease outcomes and inflammation. Sinus community diversity was low, and the composition was unstable, with many participants exhibiting alternating dominance between Pseudomonas aeruginosa and staphylococci over time. Despite a tendency for dominance by these two taxa, communities were highly individualized and shifted composition during exacerbation of sinus disease symptoms. Exacerbations were also associated with communities dominated by Staphylococcus spp. Reduced microbial community diversity was linked to worse sinus disease and the inflammatory status of the sinuses (including increased interleukin-1ß [IL-1ß]). Increased IL-1ß was also linked to worse sinus endoscopic appearance, and other cytokines were linked to microbial community dynamics. Our work revealed previously unknown instability of sinus microbial communities and a link between inflammation, lack of microbial community diversity, and worse sinus disease. IMPORTANCE Together with prior sinus microbiota studies of adults with CF chronic rhinosinusitis, our study underscores similarities between sinus and lower respiratory tract microbial community structures in CF. We show how community structure tracks with inflammation and several disease measures. This work strongly suggests that clinical management of CRS could be leveraged to improve overall respiratory health in CF. Our work implicates elevated IL-1ß in reduced microbiota diversity and worse sinus disease in CF CRS, suggesting applications for existing therapies targeting IL-1ß. Finally, the widespread use of highly effective cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy has led to less frequent availability of spontaneous expectorated sputum for microbiological surveillance of lung infections. A better understanding of CF sinus microbiology could provide a much-needed alternative site for monitoring respiratory infection status by important CF pathogens.

Chaenomeles Fructus (CF), the Fruit of Chaenomeles sinensis Alleviates IL-1ß Induced Cartilage Degradation in Rat Articular Chondrocytes.

Osteoarthritis (OA) causes persistent pain, joint dysfunction, and physical disability. It is the most prevalent type of degenerative arthritis, affecting millions of people worldwide. OA is currently treated with a focus on pain relief, inflammation control, and artificial joint surgery. Hence, a therapeutic agent capable of preventing or delaying the progression of OA is needed. OA is strongly associated with the degeneration of the articular cartilage and changes in the ECM, which are primarily associated with a decrease in proteoglycan and collagen. In the progress of articular cartilage degradation, catabolic enzymes, such as matrix metalloproteinases (MMPs), are activated by IL-1ß stimulation. Given the tight relationship between IL-1ß and ECM (extra-cellular matrix) degradation, this study examined the effects of Chaenomeles Fructus (CF) on IL-1ß-induced OA in rat chondrocytes. The CF treatment reduced IL-1ß-induced MMP3/13 and ADAMTS-5 production at the mRNA and protein levels. Similarly, CF enhanced col2a and aggrecan accumulation and chondrocyte proliferation. CF inhibited NF-κB (nuclear factor kappa B) activation, nuclear translocation induced by IL-1ß, reactive oxygen species (ROS) production, and ERK phosphorylation. CF demonstrated anti-OA and articular regeneration effects on rat chondrocytes, thus, suggesting that CF is a viable and fundamental therapeutic option for OA.

Antiepileptic-drug tapering and seizure recurrence: Correlation with serum drug levels and biomarkers in persons with epilepsy.

OBJECTIVES: Antiepileptic-drug (AED) serum level and inflammatory biomarkers are primarily monitored/assessed during epilepsy treatment for effective seizure control; however, their correlation with seizure recurrence (SR) following AED-tapering has not been established, and this is being investigated in this study. MATERIALS AND METHODS: This prospective observational study enrolled persons with epilepsy (PWE) on AED monotherapy and going to start tapering after being seizure-free for ≥2 years. Data regarding seizure episodes, AED-treatment, and adverse events (using Liverpool Adverse Event profile [LAEP]-score) were recorded. Serum AED levels using high-performance liquid chromatography and biomarkers levels through enzyme-linked immunosorbent assay kits were estimated at AED-tapering commencement and at 6 months/SR time. RESULTS: Among 129 enrolled PWE (levetiracetam [n = 52], valproate [n = 34], carbamazepine [n = 29], and phenytoin [n = 14]), SR occurred in 23.3% during follow-up (range 12-44 months). PWE with subtherapeutic serum AED level at the onset of tapering had higher SR (P = 0.004) than those with therapeutic or higher levels. Levetiracetam-treated PWEs with SR have significantly low AED levels than PWE with no-SR (P < 0.001). PWE had significantly raised inflammatory biomarkers (interleukin [IL]-1 ß, tumor necrosis factor [TNF]-α, IL-6, and high-mobility group box protein 1) and decreased IL-10 than healthy control subjects. SR and no-SR groups did not differ significantly in inflammatory markers except for higher IL-1 ß and TNF-α levels in SR group (P = 0.001, 0.02, respectively). Improvement in LAEP score was observed in follow-up visits without any difference between SR and no-SR groups. CONCLUSION: Low serum AED levels (especially levetiracetam) and raised levels of TNF-α and IL-1 ß during tapering commencement had a higher association with SR following AED-tapering.

Genetic deficiency of nuclear factor of activated T cells 5 attenuates the development of osteoarthritis in mice.

OBJECTIVES: This study is aimed to investigate the role of nuclear factor of activated T cells 5 (NFAT5), originally known as the osmosensitive mammalian transcription factor, in the pathogenesis of osteoarthritis (OA) in mice. METHODS: OA was induced in male C57BL/6 (wild-type) and NFAT5 haplo-insufficient (NFAT5+/-) mice via destabilization of the medial meniscus (DMM) surgery. OA severity and synovial inflammation were histologically assessed. Expression of CCL2, inflammatory cytokines, cartilage degrading enzymes was determined in the knee joints and cultured chondrocytes from wild-type and NFAT5+/- mice. RESULTS: NFAT5 expression was significantly upregulated in the knee joint of a mouse after DMM surgery. NFAT5 deficiency decreased the severity of synovial inflammation and osteoarthritic changes in cartilage and subchondral bone. Moreover, NFAT5 deficiency also decreased the expression of CCL2, IL-1ß, MMP-13, ADMATS-5, and macrophage infiltration in the joint. In cultured chondrocytes, hyperosmolar or IL-1ß stimulation significantly enhanced the expression of NFAT5, CCL2, IL-1ß, IL-6, and MMP-13, and this effect was abolished in chondrocytes from NFAT5+/- mice. Hyperosmolarity or IL-1ß-induced NFAT5 and CCL2 downregulated by inhibiting p38 MAPK, JNK, and ERK pathways. CONCLUSIONS: Our results indicate that NFAT5 is a crucial regulator of OA pathogenesis by upregulating CCL2 expression and macrophage recruitment. In chondrocyte, NFAT5 plays an important role in the response to hyperosmolar or IL-1ß stimulation. Thus, NFAT5 could be an attractive therapeutic target for OA treatment.

Low deacetylation degree chitosan oligosaccharide protects against IL-1ß induced inflammation and enhances autophagy activity in human chondrocytes.

Osteoarthritis (OA) is a degenerative joint disease, which can lead to joint pain, stiffness, deformity and dysfunction, that seriously affects the quality of life in patients. At present, the treatments of OA mainly include early pharmacological treatment and late joint replacement. However, current pharmacological treatment has limited efficacy and undesired side effects. Chitosan oligosaccharide (COS) is a kind of nontoxic and biodegradable oligo-saccharide, which is composed of 2-20 glucosamine or N-acetylglucosamine linked by ß-1,4 glycosidic bond. Studies have shown that COS has significant biological properties like antimicrobial, anti-inflammatory, antioxidant, and anti-tumor, as well as immunoregulation ability. However, the effects of COS on OA have not been clarified. In this study, we explored the protective effects of COS with different degrees of deacetylation on chondrocytes stimulated by interleukin 1ß (IL-1ß) in vitro. The results showed that IL-1ß inhibited cell proliferation and promoted cell apoptosis. Besides that, IL-1ß increased the expression of the major chondro-degrading genes MMP13 and ADAMTS-5, while decreased the expression of COL2A and ACAN. COS with different degrees of deacetylation (HDACOS, MDACOS, LDACOS) had different effects on IL-1ß induced inflammation. LDACOS had the most obvious anti-inflammatory effects to inhibit the expression of MMP13 and ADAMTS-5 while promoted the expression of COL2A and ACAN. In addition, we found that the expression of autophagy-related gene Beclin-1 was up-regulated, and the ratio of LC3-II/LC3-I was increased in the LDACOS group. Furthermore, transmission electron microscopy (TEM) analysis showed that the number of intracellular autophagosomes increased significantly with the treatment of LDACOS. Based on our research, we suggested that LDACOS could inhibit chondrocytes inflammation and promote cell autophagy, and might be a protective drug for the treatment of OA.

Interleukin-1ß Protection Against Experimental Sepsis in Mice.

The inflammatory response involving interleukin-1ß (IL-1ß) has been thought to play an important role in the development of late-phase sepsis. However, in this study, we wanted to explore the possibility of using IL-1ß to improve the prognosis of sepsis by triggering local differentiation of bone marrow cells (BMCs) into regulatory dendritic cells (DCs) in vivo, thereby reversing the immune paralysis in late-phase sepsis. Sepsis mouse models were induced by cecal ligation and puncture (CLP) and lethal Escherichia coli O18 infection. Mice were injected intraperitoneally with IL-1ß after CLP and after the lethal infection. Septic BMCs and liver immune cells were isolated at 0, 3, 6, 9, and 14 days post-CLP. BMCs and liver cells isolated from septic mice treated with IL-1ß were adoptively transferred into CLP mice. GFP+-C57BL/6 parabiosis models were established. Serum IL-1ß levels were determined by enzyme-linked immunosorbent assay (ELISA) kit, and the number, ratio, and phenotype of immune cells were observed by flow cytometry. IL-1ß treatment improved the survival of sepsis and increased the numbers of BMCs and liver immune cells in septic mice. Moreover, IL-1ß stimulation increased the number and the percentage of CD11c-CD45RBhigh DCs in septic BM and liver. Adoptive transfer of septic BMCs, liver immune cells, and CD11c-CD45RBhigh DCs treated with IL-1ß into CLP mice attenuated sepsis. IL-1ß triggered the redistribution of CD11c-CD45RBhigh DCs as well as BMCs in parabiosis models. IL-1ß protects against sepsis by stimulating local proliferation and differentiation of BMCs into CD11c-CD45RBhigh DCs at immune organs and non-immune organs.

Pathogenesis, disease course, and prognosis of adult-onset Still's disease: an update and review.

OBJECTIVE: Adult-onset Still's disease (AOSD) is a rare but clinically well-known polygenic systemic autoinflammatory disease. In this review, we aim to present frontiers in the pathogenesis, clinical features, diagnosis, biomarkers, disease course, prognosis, and treatment in AOSD. DATA SOURCES: We retrieved information from the PubMed database up to July 2019, using various search terms and relevant words, including AOSD and Still's disease. STUDY SELECTION: We included data from peer-reviewed journals. Both basic and clinical studies were selected. RESULTS: Pathogenesis of AOSD involves genetic background, infectious triggers, and immunopathogenesis, mainly the activation of macrophages and neutrophils followed by a cytokine storm. Diagnosis and prognosis evaluation of AOSD is still challenging; therefore, there is an urgent need to identify better biomarkers. Biologic agents, including interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α antagonists in the treatment of AOSD, have good prospect. CONCLUSION: This review highlights the advances in pathogenesis, potential biomarkers, disease course, and treatment in AOSD.

Regulation of Inflammatory Response in Human Osteoarthritic Chondrocytes by Novel Herbal Small Molecules.

In this study, 34 Traditional Chinese Medicine (TCM) compounds were screened for potential anabolic and anti-inflammatory properties on human osteoarthritic (OA) chondrocytes. The anabolic effects were assessed by measuring the glycosaminoglycan (GAG) relative to the DNA content using a 3D pellet culture model. The most chondrogenic compounds were tested in an inflammatory model consisting of 3 days of treatment with cytokines (IL-1ß/TNF-α) with or without supplementation of TCM compounds. The anti-inflammatory effects were assessed transcriptionally, biochemically and histologically. From the 34 compounds, Vanilic acid (VA), Epimedin A (Epi A) and C (Epi C), 2''-O-rhamnosylicariside II (2-O-rhs II), Icariin, Psoralidin (PS), Protocatechuicaldehyde (PCA), 4-Hydroxybenzoic acid (4-HBA) and 5-Hydroxymethylfurfural (5-HMF) showed the most profound anabolic effects. After induction of inflammation, pro-inflammatory and catabolic genes were upregulated, and GAG/DNA was decreased. VA, Epi C, PS, PCA, 4-HBA and 5-HMF exhibited anti-catabolic and anti-inflammatory effects and prevented the up-regulation of pro-inflammatory markers including metalloproteinases and cyclooxygenase 2. After two weeks of treatment with TCM compounds, the GAG/DNA ratio was restored compared with the negative control group. Immunohistochemistry and Safranin-O staining confirmed superior amounts of cartilaginous matrix in treated pellets. In conclusion, VA, Epi C, PS, PCA, 4-HBA and 5-HMF showed promising anabolic and anti-inflammatory effects.

[The efficacy of recombinant interleukin-1ß in surgical treatment of acute ulcerative gastroduodenal bleedings.]

There was reported the results of the use of recombinant interleukin-1ß in basic conservative measures in the surgical treatment of acute gastroduodenal ulcer bleeding. Gastric ulcer were in 20 patients, duodenal ulcer in 84 patients and combined ulcers in 16 patients. According to А.А. Шалимов hospitalized patients with mild blood loss were 27, moderate degree - 62 and severe degree - 31 patients. According to J. Forrest, 29 showed active bleeding (F Ia, F Ib), in 67 - unstable hemostasis (F IIa, F IIb, F IIc) and in 24 - F III. Within the framework of differentiated individual-active tactics, patients were operated in emergency (21), urgent (38), delayed (35), and 26 people underwent early planned operations. Patients in the main group (63) after the operation, was included recombinant interleukin-1ß to the basic therapeutic measures additionally, taking into account the degree of blood loss and immune disorders. Patients of comparison group (57) before and after surgery received standard basic therapy without immunocorrection. In a comparative aspect, it has been proved that in postoperative period on the background of standard conservative measures, the use of recombinant interleukin-1ß positively influences elimination of the secondary immunodeficiency and cytokine imbalance significantly improves the results of surgical treatment.

Canakinumab in Children with Familial Mediterranean Fever: A Single-Center, Retrospective Analysis.

INTRODUCTION: Familial Mediterranean fever (FMF) is an autoinflammatory disease characterized by interleukin (IL)-1 overproduction. Colchicine is the mainstay drug in the treatment of FMF; however, a minority of patients do not respond despite the highest tolerated doses. We aimed to share our experience with canakinumab, a human monoclonal antibody against IL-1ß, in pediatric FMF patients. METHODS: This historical, single-cohort study retrospectively evaluated the disease characteristics, indications, and treatment responses of 14 pediatric FMF patients treated with canakinumab in our pediatric rheumatology department. RESULTS: The median age at onset and diagnosis of 14 FMF patients (9 females, 5 males), were 3.5 (range 0.5-10) years and 6 (range 3-16) years, respectively. Indications for canakinumab treatment were renal amyloidosis (n = 1), colchicine resistance (n = 11), and persistent arthritis (n = 2). Only two (14.3%) patients had colchicine intolerance. Complete response was obtained in 10/14 (71.5%) among all patients and 10/12 (86%) in patients with typical phenotype. The patient with chronic oligoarthritis had a complete response, whereas the patient with rheumatoid factor (RF)-positive polyarthritis demonstrated an initial partial response to canakinumab treatment. We found that attack frequency, proteinuria, and acute phase reactants, including erythrocyte sedimentation rate and C-reactive protein, were significantly decreased after canakinumab treatment in children with FMF. CONCLUSION: Canakinumab may be an effective treatment option for pediatric FMF patients with colchicine resistance, renal amyloidosis, and chronic oligoarthritis. Further studies are needed to clarify the efficacy of canakinumab in patients with a second disease, RF-positive polyarticular juvenile idiopathic arthritis.

Use of platelet-rich plasma to facilitate wound healing.

Platelet-rich plasma (PRP) is widely used nowadays in different fields of medicine, affecting physiological processes including tissue regeneration. The use of PRP in maxillofacial surgical interventions and its efficiency in the improvement of postoperative wound healing were analysed. Patients undergoing plastic and reconstructive surgeries in the maxillofacial region were recruited: 50 patients were enrolled into a control group (received no PPRP injection) and 50 patients were enrolled into a treatment group, where PRP was applied during the surgical procedure. Evaluation of treatment outcomes was carried out by determination of IL-1ß, TNFα, and IL-6 cytokines levels in the wound-drain fluid. The stages of wound healing were assessed by cytological analyses and ultrasound within a month period. The use of the PRP has substantially positive effects, contributing to the improvement of the healing process. In the treatment group, fibroblasts, macrophages, and collagen fibres appeared and their quantities increased earlier than when compared with control group patients. The concentration of IL-1ß and TNFα in wound fluid on day 1 and day 5 after operation was higher for the treatment group as opposed to the control group, which was linked to the influence of PRP on inflammatory and granulation phases of the healing process. An ultrasound examination showed less oedema and infiltration in the tissues around the wound of the treatment group.

Notch Shapes the Innate Immunophenotype in Breast Cancer.

Notch activation, which is associated with basal-like breast cancer (BLBC), normally directs tissue patterning, suggesting that it may shape the tumor microenvironment. Here, we show that Notch in tumor cells regulates the expression of two powerful proinflammatory cytokines, IL1ß and CCL2, and the recruitment of tumor-associated macrophages (TAM). Notch also regulates TGFß-mediated activation of tumor cells by TAMs, closing a Notch-dependent paracrine signaling loop between these two cell types. We use a mouse model in which Notch can be regulated in spontaneous mammary carcinoma to confirm that IL1ß and CCL2 production, and macrophage recruitment are Notch-dependent. In human disease, expression array analyses demonstrate a striking association between Notch activation, IL1ß and CCL2 production, macrophage infiltration, and BLBC. These findings place Notch at the nexus of a vicious cycle of macrophage infiltration and amplified cytokine secretion and provide immunotherapeutic opportunities in BLBC.Significance: BLBC is aggressive and has an unmet need for effective targeted treatment. Our data highlight immunotherapeutic opportunities in Notch-activated BLBC. Effective IL1ß and CCL2 antagonists are currently in clinical review to treat benign inflammatory disease, and their transition to the cancer clinic could have a rapid impact. Cancer Discov; 7(11); 1320-35. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 1201.

Papel da IL-17 na imunopatogênese de lesões periapicais experimentais / Role of IL-17 in the immunopathogenesis of experimental periapical lesions

A infecção dos sistemas de canais radiculares levará à consequente indução de uma lesão periapical, estando muitos mediadores inflamatórios envolvidos nesse processo. A IL-17 tem demonstrado impacto no processo de remodelação óssea, especialmente em casos de artrite, apresentando-se em altos níveis. Contudo, pouco se sabe a respeito do seu real papel na patogênese das periapicopatias. Neste estudo, procurou-se avaliar o papel da IL-17A na reabsorção óssea perirradicular, em infecções endodônticas experimentais em camundongos C57BL/6 e IL-17RA KO, bem como o efeito dessa infecção na artrite reumatóide experimental. Para se induzir a infecção endodôntica, cepas padrão de Porphyromonas gingivalis, Prevotella intermedia e Fusobacterium nucleatum foram inoculadas nos canais radiculares do primeiro molar superior esquerdo desses animais...