Targeting Tumor Necrosis Factor Research Articles

Development of a specialty medication clinical dashboard to improve tumor necrosis factor-α inhibitor safety and adherence monitoring.

To describe the development of a pilot specialty medication clinical dashboard targeting tumor necrosis factor (TNF)-α inhibitor therapy. This was a quality improvement project conducted between August 2019 and April 2020. The dashboard was designed with collaboration between clinical pharmacists and specialty providers in rheumatology, gastroenterology, and dermatology. Data was queried from the Veterans Affairs Corporate Data Warehouse. Patients with an active prescription or intravenous order for a TNF-α inhibitor were included. Dashboard flag criteria focused on TNF-α inhibitor safety and adherence monitoring. Flag results from the dashboard were characterized from data captured at a single time point. For 431 patients on TNF-α inhibitor treatment at the institution, 304 flags corresponding to 223 unique patients (51.7%) were identified on the dashboard: 3% of patients had a new infection, 9% had overdue monitoring laboratory tests, 5% had a critical laboratory result, 2% were on 2 biologic agents, 27% were overdue for a refill, 6% had an emergency department visit, and 2% had an inpatient admission. No patients were flagged for heart failure exacerbation or new malignancy. Seventeen percent of patients were prescribed high-dose etanercept or adalimumab, representing a potential annual cost savings of $302,497 if 50% of these patients had their dose successfully reduced to labeled dosing. Opportunities for pharmacist intervention utilizing the dashboard were identified and characterized through chart review of flagged patients. Pharmacists have the opportunity to improve safety and adherence for TNF-α inhibitor therapy through use of a specialty medication clinical dashboard. The dashboard should be used in conjunction with collaborative practice protocols.

Molecular Docking Analysis of Ficus religiosa Active Compound with Anti-Inflammatory Activity by Targeting Tumour Necrosis Factor Alpha and Vascular Endothelial Growth Factor Receptor in Diabetic Wound Healing

BACKGROUND: Diabetes mellitus contributes to the delayed healing of wounds causes disturbance of inflammatory cytokine. Tumour necrosis factor alpha (TNF-alpha) and Vascular Endothelial Growth Factor Receptor (VEGFR) both have a role in the persistent inflammation associated with diabetic wounds. Ficus religiosa has developed a reputation as a traditional wound healer among some java people in Indonesia. AIM: Our study aims to discover the molecular interaction between the active constituents of F. religiosa with TNF-alpha and VEGFR. MATERIALS AND METHODS: This research was conducted in computerized molecular docking using Protein database, Pymol, Discovery studio, and Pyrex software. A thorough literature search was conducted to identify the potential compound and molecular target for diabetic wounds. Analysis of its anti-inflammatory properties was also carried out using a passonline webserver. Pharmacokinetic analysis was performed using the Lipinski Rule of Five websites and the PreADMET website. RESULTS: Each of the study’s active compounds has a good pharmacokinetic profile. The predictions of the compound’s structure indicate that it has a strong anti-inflammatory impact. Lupenyl acetate and Lanosterol bind more strongly to the TNF-alpha than the natural ligand, but Piperine binds more strongly to VEGFR. CONCLUSIONS: Lupenyl acetate, Lanosterol, and Piperine compounds have anti-inflammatory effects through inhibition of TNF-alpha and VEGFR. In addition, this compound has potential to become a drug because it has good pharmacokinetics. Future studies are required to determine the effectiveness and toxicity of Lupenyl acetate, Lanosterol, and Piperine as potential treatment in diabetic wounds.

A Review of the Totality of Evidence for the Development and Approval of ABP710 (AVSOLA), an Infliximab Biosimilar.

ABP 710 (AVSOLA®) is a biosimilar to infliximab reference product (RP), a monoclonal antibody targeting tumor necrosis factor alpha (TNFα). It is approved in the USA and Canada for all the same indications as infliximab RP. Approval of ABP 710 was based on the totality of evidence (TOE) generated using a stepwise approach to assess its similarity with infliximab RP with regard to analytical (structural and functional) characteristics, pharmacokinetic parameters, and clinical efficacy and safety. ABP 710 was shown to be analytically similar to infliximab RP including in amino acid sequence, primary peptide structure, and glycan mapping and purity. ABP 710 was also demonstrated to be similar to infliximab RP with regard to functional characterization including in vitro binding, effector functions, and signaling pathways important for the mechanisms of action for clinical efficacy in multiple indications of immune-mediated inflammatory disorders including inflammatory bowel disease (IBD), especially binding to both soluble and membrane-bound TNFα. Pharmacokinetic similarity of ABP 710 with infliximab RP was demonstrated in healthy volunteers following a single 5 mg/kg intravenous dose. Comparative clinical efficacy of ABP 710 with infliximab RP was demonstrated in patients with rheumatoid arthritis. Safety and immunogenicity were also demonstrated to be similar for both ABP 710 and the RP. Overall, the TOE supported the conclusion that ABP 710 is highly similar to infliximab RP and supported scientific justification for extrapolation to all approved indications of infliximab RP, including IBD.

MicroRNA-20-1 and microRNA-101a Suppress the NF-κB-Mediated Inflammation Production by Targeting TRAF6 in Miiuy Croaker.

Upon recognition of pathogen components by pattern recognition receptors, cells could be activated to produce inflammatory cytokines and type I interferons. The inflammation is tightly modulated by the host to prevent inappropriate inflammatory responses. MicroRNAs (miRNAs) are noncoding small RNAs that can inhibit gene expression and participate in various biological functions, including maintaining a balanced immune response in the host. To maintain the balance of the immune response, these pathways are closely regulated by the host to prevent inappropriate reactions of the cells. However, in lower vertebrates, the miRNA-mediated inflammatory response regulatory networks remain largely unknown. Here, we report that two miRNAs, i.e., miR-20-1 and miR-101a, were identified as negative regulators in teleost inflammatory responses. Initially, we found that both miR-20-1 and miR-101a dramatically increased after lipopolysaccharide (LPS) stimulation and Vibrio harveyi infection. Upregulated miR-20-1 and miR-101a inhibited LPS-induced inflammatory cytokine production by targeting tumor necrosis factor receptor-associated factor 6 (TRAF6), thus avoiding excessive inflammation. Moreover, miR-20-1 and miR-101a regulate the inflammatory responses through the TRAF6-mediated NF-κB signaling pathway. Collectively, these data indicate that miR-20-1 and miR-101a act as negative regulators by regulating the TRAF6-mediated NF-κB signaling pathway and participate in host antibacterial immune responses, which will provide new insights into the intricate networks of the host-pathogen interactions in the lower vertebrates.

Selectively targeting myeloid-derived suppressor cells through TRAIL receptor 2 to enhance the efficacy of CAR T cell therapy for treatment of breast cancer

BackgroundSuccessful targeting of solid tumors such as breast cancer (BC) using chimeric antigen receptor (CAR) T cells has proven challenging, largely attributed to the immunosuppressive tumor microenvironment (TME). Myeloid-derived suppressor...

Альтернативні методи у веденні прееклампсії. Аналітичний огляд

There are many alternative drugs for the prevention and treatment of preeclampsia in the new research. This drugs can effect on the underlying pathophysiology of the disease: oxidative stress, antiangiogenic factors, as well as angiotensin, nitric oxide and various parts of the inflammatory process. Thus, they affect the disease of the placenta or endothelium. The proposed treatments are currently undergoing preclinical and clinical trials. Pravastatin was of the greatest interest among all the proposed therapeutic agents. It has pleiotropic effect, i.e. affects multiple molecular targets against preeclampsia. Proton pump inhibitors, metformin, and sulfasalazine are other drugs that have preclinical evidence of multiple molecular actions that may address the pathophysiology of preeclampsia. Currently, these molecules are also in clinical trials. Many natural compounds for the treatment of preeclampsia, such as plant extracts and trace elements, are being researched to identify the potential in anti-inflammatory or antioxidant activity. Monoclonal antibodies are another direction is new molecular-oriented strategies. They are targeting tumor necrosis factor alpha, placental growth factor and short interfering RNA technology to inhibit the expression of soluble fms-like tyrosine kinase-1 or angiotensinogen. Folic acid, nitric oxide donors (such as L-arginine), recombinant antithrombin III, and immunogenic digoxin antigen and melatonin are other treatment approaches that have been tested in humans (ranging from single-group studies to phase III trials that have been completed or are ongoing). The series of cases demonstrated that removal of circulating soluble fms-like tyrosine kinase-1 can help stabilize the disease and prolong pregnancy. Monoclonal antibodies such as eculizumab (a complement inhibitor) may have therapeutic potential. Thus, the identified alternative drugs in the treatment and prevention of preeclampsia create the potential to improve maternal health and pregnancy. No conflict of interests was declared by the author. Key words: preeclampsia, pregnancy, pravastatin, metformin, sulfalazine

MicroRNA-602 prevents the development of inflammatory bowel diseases in a microbiota-dependent manner.

Inflammatory bowel diseases (IBD) are a group of chronic disorders occurring in the intestinal tract. Previous studies demonstrated that genetics and microbiota play critical roles in the pathogenesis of IBD. Discoveries of genes that may regulate the homeostasis of gut microbiota and pathogenesis of IBD have the potential to provide new therapeutic targets for IBD treatment. The results suggested that the expression level of microRNA (miR)-602 is negatively related to the development of IBD, and that miR-602 overexpression in mice may prevent inflammation and intestinal barrier injuries in dextran sulfate sodium (DSS)-induced IBD mice. It was also found that the microbiota is important for miR-602-mediated prevention of IBD, as the inhibitory effect of miR-602 was lost when the microbiota was depleted using antibiotics. Furthermore, co-housing or adoptive transfer of microbiota from miR-602 could attenuate the pathogenesis of IBD. In addition, it was demonstrated that miR-602 could target tumor necrosis factor receptor-associated factor 6 (TRAF6) in intestinal epithelial cells. Collectively, the present results suggest that miR-602 plays a protective role in DSS-induced IBD by targeting TRAF6 in a microbiota-dependent manner.

Efficacy, safety, and drug survival of IL-23, IL-17, and TNF-alpha inhibitors for psoriasis treatment: a retrospective study

Background Real-life studies in psoriasis are lacking. Many monoclonal antibodies targeting tumor-necrosis factor (TNF)-alpha, interleukin 17, and 23 are approved drugs for psoriasis treatment. Objectives To compare the short and long-term efficacy, safety, and drug survival of anti TNF-alpha, anti-IL-17, and anti-IL-23 in a large case series. Methods Psoriasis area severity index (PASI) and retention rates for adalimumab, secukinumab, guselkumab, ixekizumab, and brodalumab were analised. Results A total of 263 patients were randomly selected among the five drugs register of the patients attending the Psoriasis Unit at the Turin University Hospital. The mean PASI at baseline was 14.3. Ixekizumab showed a significantly higher efficacy profile compared to other drugs in terms of PASI90 and PASI100 at week 12, 24, and week 48 even when adjusted for other confounding factors. This superiority was not followed by an expected higher drug survival. On the contrary, secukinumab was the only drug that showed a higher drug survival among bio-naïve patients.

Body mass index, HbA1c and serum C-reactive protein are predictors of secondary failure in infliximab continuance for Japanese psoriasis patients: A hospital-based retrospective case-control study.

Biologics has had a great impact on psoriasis treatment as well as the life of psoriasis patients. Infliximab (IFX), one of the biologics targeting tumor necrosis factor (TNF), is the first of the biologics introduced to Japanese psoriasis patients. Many patients had benefits of IFX from initial applications and sustained remission of skin lesions and arthritis. Some, however, fall into so-called secondary failure, in which patients become less responsive to IFX when the treatment is repeated. The mechanism of secondary failure and the background of patients with secondary failure have not been completely elucidated. To address this issue, we retrospectively evaluated psoriasis patients treated with IFX in our department. In this retrospective, single-center, case-control study based on the clinical record, a total of 34 patients were enrolled. We excluded 7 patients who discontinued IFX because of adverse events of IFX. We divided other 27 patients into two groups; 16 patients who kept using IFX (Continuance group); and 11 patients who switched to other treatments (Discontinuance group). Among various clinical features, body mass index (BMI), HbA1c, and serum CRP level were significantly higher in the Discontinuance group than the Continuance group. The results indicated that these three clinical features of BMI, HbA1c and serum CRP level before treatment are the predictors of successful IFX treatment and suggest that improvement of metabolic conditions contributes to avoiding secondary failure and discontinuance of IFX.

Noncanonical NF-κB Signaling Upregulation in Inflammatory Bowel Disease Patients is Associated With Loss of Response to Anti-TNF Agents.

Objectives: Targeting tumor necrosis factor (TNF) with biologic agents, such as infliximab and adalimumab, is a widely used and effective therapeutic strategy in inflammatory bowel disease (IBD). Unfortunately, a significant number of patients fail to respond or lose response over time to these agents. Previous studies have defined multiple complex roles for canonical NF-κB signaling in the pathogenesis of IBD. However, preliminary evidence suggests that the lesser defined noncanonical NF-κB signaling pathway also contributes to disease pathogenesis and response to anti-TNF agents. The objective of this study was to evaluate this hypothesis in Crohn’s disease (CD) and ulcerative colitis (UC) patients. Design: A total of 27 subjects with IBD (19 with CD and 8 with UC) and 15 control subjects were tested. Clinical criteria, patient history, and endoscopic disease activity were factors used to categorize patients and define therapeutic response. Biopsy specimens were collected during colonoscopy and expression was determined for 88 target genes known to be associated with noncanonical NF-κB signaling and IBD. Results: Noncanonical NF-κB signaling was significantly upregulated in IBD patients and was associated with increased gastrointestinal inflammation, epithelial cell death, lymphocyte migration, and Nod-like receptor signaling. Furthermore, noncanonical NF-κB signaling was further upregulated in patients unresponsive to anti-TNF agents and was suppressed in responsive patients. MAP3K14, NFKB2, CCL19, CXCL12, and CXCL13 were significantly dysregulated, as were genes that encode pathway regulators, such as CYLD, NLRP12, and BIRC2/3. Conclusion: Our study identifies a previously uncharacterized role for the understudied noncanonical NF-κB signaling pathway in the pathogenesis of IBD and anti-TNF therapy responsiveness. The genes and pathways identified may ultimately prove useful in IBD management and could potentially be used as biomarkers of drug response.

AB0549 PREDICTIVE FACTORS FOR SWITCHING IN PATIENTS WITH PSORIATIC ARTHRITIS UNDERGOING ANTI-TNFα, ANTI-IL12/23 OR ANTI-IL17 DRUGS: A FIFTEEN-YEAR MONOCENTRIC REAL-LIFE STUDY

Background:Biological Disease-Modifying Anti-Rheumatic Drugs (bDMARDs) targeting Tumor Necrosis Factor (TNF) alpha, Interleukin (IL) 12/23 and IL17, have been approved for Psoriatic Arthritis (PsA) treatment, in this chronological order.Objectives:The aims of our study were to evaluate 1) predictors of first bDMARD failure, including mechanism of action 2) factors associated to failure of multiple (>=2) therapies.Methods:Consecutive patients attending our Rheumatology Unit, classified as PsA according to CASPAR criteria and beginning treatment with bDMARDs in the period 2004-2020, were enrolled. Disease characteristics, previous/ongoing treatments, comorbidities and follow-up duration were recorded. Demographic, clinical and laboratory data, disease-activity and functional indexes [including Disease Activity in PSoriatic Arthritis (DAPSA), PASI (Psoriasis Area and Severity Index) and Health Assessment Questionnaire (HAQ)], were recorded at baseline and yearly and were compared between switchers (>=1 switch/swap) and non-switchers. Date and reason for switching were collected. Effectiveness was evaluated over-time with descriptive statistics. A multivariable Cox-Proportional-Hazard (PH) model was built to evaluate the influence of mechanism of action (anti-TNFalpha/anti-IL12/23/anti-IL17) and of negative prognostic factors for drug response on time to first bDMARD discontinuation. Furthermore, a multivariable logistic regression model was built to assess the association between negative prognostic factors for drug response (independent variables) and failure of>=2 bDMARDs (“multifailure”, outcome). Kaplan-Meier curves were used to assess differences in time-to-first bDMARD discontinuation according to the targeted cytokine. P values <=0.05 were considered significant. Infections and adverse events were recorded.Results:Our study included 264 patients, 117 (44.32%) females, mean age 56±12 years, mean PsA duration 15±3 years;117 (44.32%) switched bDMARDs at least once. Switchers were mostly females, with higher PASI and worse HAQ at baseline (Figure 1). Mean time-to-first bDMARD discontinuation was 72 months; 2-year and 5-year retention rate was 75% and 60%, respectively. Survival curves for anti-TNFalpha/anti-IL12/23/anti-IL17 were similar (log-rak test=0.83;p=0.66). Main reasons for switching were inefficacy (79) and adverse events (38). The Cox PH model showed that female sex was independently associated to a higher risk of first bDMARD discontinuation (HR=2.39; 95%CI:1.50-3.81), while initiating therapy before 2015 was protective (HR=0.40; 95%CI:0.22-0.73). Other independent variables, including mechanism of action (HR=0.76; 95%CI:0.30-1.74 for anti-IL17; HR=0.53; 95%CI 0.15-1.86 for anti-IL12/23; reference: anti-TNFalpha), age (HR=1.00; 95%CI:0.99-1.03), baseline DAPSA (HR=0.98; 95%CI:0.96-1.00), PASI (HR=0.95; 95%CI:0.86-1.04), HAQ (HR=1.29; 95%CI:0.91-1.83), Body Mass Index BMI (HR=1.02; 95%CI:0.98-1.07) and comorbidities (HR=1.10; 95%CI:0.92-1.31) were not associated to the outcome. In the logistic regression model, only female sex was significantly associated to failure of>=2 therapies (OR=1.99, 95%CI:1.07-3.69); bDMARD mechanism of action, age, and initiating therapy before 2015 were instead not independently associated.Conclusion:Survival rate was good for anti-TNFalpha and other bDMARDs. Female sex was a predictor of first bDMARD discontinuation, unlike mechanism of action, comorbidities and BMI.Figure 1.Disclosure of Interests:Mariagrazia Lorenzin: None declared., Augusta Ortolan: None declared., Giacomo Cozzi: None declared., Antonia Calligaro: None declared., Maria Favaro: None declared., Teresa Del Ross: None declared., Andrea Doria Grant/research support from: AD has received honoraria and speaker fees from Novartis, Abbvie, Pfizer, MSD, Janssen., Roberta Ramonda Grant/research support from: RR has received honoraria and speaker fees from Novartis, Abbvie, Pfizer, MSD, Janssen.

Managing Osteoporosis and Joint Damage in Patients with Rheumatoid Arthritis: An Overview.

In rheumatoid arthritis, a representative systemic autoimmune disease, immune abnormality and accompanying persistent synovitis cause bone and cartilage destruction and systemic osteoporosis. Biologics targeting tumor necrosis factor, which plays a central role in the inflammatory process, and Janus kinase inhibitors have been introduced in the treatment of rheumatoid arthritis, making clinical remission a realistic treatment goal. These drugs can prevent structural damage to bone and cartilage. In addition, osteoporosis, caused by factors such as menopause, aging, immobility, and glucocorticoid use, can be treated with bisphosphonates and the anti-receptor activator of the nuclear factor-κB ligand antibody. An imbalance in the immune system in rheumatoid arthritis induces an imbalance in bone metabolism. However, osteoporosis and bone and cartilage destruction occur through totally different mechanisms. Understanding the mechanisms underlying osteoporosis and joint destruction in rheumatoid arthritis leads to improved care and the development of new treatments.

Variability of rituximab and tocilizumab trough concentrations in patients with rheumatoid arthritis.

Patients with rheumatoid arthritis (RA) are eligible for treatment with therapeutic monoclonal antibodies (mAbs) that target tumor necrosis factor α (TNFα), as well as others, such as rituximab (RTX) and tocilizumab (TCZ). Although pharmacokinetic variability and the link between concentration-clinical response of anti-TNFα mAbs have been well-described, little is known about RTX and TCZ. We aimed to evaluate the variability of RTX and TCZ serum concentrations in RA patients treated in second-line and the relationship between RTX/TCZ concentrations and the clinical response. Serum mAb trough concentrations of RA patients treated with RTX (n=35) or TCZ (n=46) were determined at week 24 by liquid chromatography-tandem mass spectrometry. The clinical response was assessed at week 24 by the change in the disease activity score in the 28 joints-erythrocyte sedimentation rate from baseline (ΔDAS28-Erythrocyte Sedimentation Rate) and according to the European League Against Rheumatism (EULAR) recommendations. RTX and TCZ trough concentrations were highly variable, with a coefficient of variation of 171.3% for RTX (median [10th-90th percentiles]: <1.0µg/mL [<1.0-5.1]) and 132.6% for TCZ (median [10th-90th percentiles]: 5.4µg/mL [<1.0-27.8]). Univariate analysis did not identify any determinants of such variability, except cotreatment with methotrexate, which was associated with lower RTX concentrations (P=0.03). The response to treatment was not related to the RTX or TCZ trough concentration. RTX and TCZ trough concentrations at 24weeks were highly variable in RA patients treated in the second line, without any link concentration-clinical response having been demonstrated.

Targeting tumour necrosis factor to ameliorate viral pneumonia.

Pneumonia is a serious complication associated with inflammation of the lungs due to infection with viral pathogens. Seasonal and pandemic influenza viruses, variola virus (agent of smallpox) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; agent of COVID-19) are some leading examples. Viral pneumonia is triggered by excessive inflammation associated with dysregulated cytokine production, termed 'cytokine storm'. Several cytokines have been implicated but tumour necrosis factor (TNF) plays a critical role in driving lung inflammation, severe lung pathology and death. Despite this, the exact role TNF plays in the aetiology and pathogenesis of virus infection-induced respiratory complications is not well understood. In this review, we discuss the pathological and immunomodulatory roles of TNF in contributing to immunopathology and resolution of lung inflammation, respectively, in mouse models of influenza- and smallpox (mousepox)-induced pneumonia. We review studies that have investigated dampening of inflammation on the outcome of severe influenza and orthopoxvirus infections. Most studies on the influenza model have evaluated the efficacy of treatment with anti-inflammatory drugs, including anti-TNF agents, in animal models on the day of viral infection. We question the merits of those studies as they are not transferable to the clinic given that individuals generally present at a hospital only after the onset of disease symptoms and not on the day of infection. We propose that research should be directed at determining whether dampening lung inflammation after the onset of disease symptoms will reduce morbidity and mortality. Such a treatment strategy will be more relevant clinically.

Treatments of inflammatory bowel disease toward personalized medicine.

Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), is a chronic inflammatory disease characterized by intestinal inflammation and epithelial injury. For the treatment of IBD, 5-aminosalicylic acids, corticosteroids, immunomodulators, and biologic agents targeting tumor necrosis factor (TNF)-α, α4β7-integrin, and interleukin (IL)-12/23 have been widely used. Especially, anti-TNF-α antibodies are the first biologic agents that presently remain at the forefront. However, 10-30% of patients resist biologic agents, including anti-TNF-α agents (primary non-responder; PNR), and 20-50% of primary responders develop treatment resistance within one year (secondary loss of response; SLR). Nonetheless, the etiologies of PNR and SLR are not clearly understood, and predictors of response to biologic agents are also not defined yet. Numerous studies are being performed to discover prediction markers of the response to biologic agents, and this review will introduce currently available therapeutic options for IBD, biologics under investigation, and recent studies exploring various predictive factors related to PNR and SLR.

Hepatoprotective effect of forsythiaside a against acetaminophen-induced liver injury in zebrafish: Coupling network pharmacology with biochemical pharmacology

Ethnopharmacological relevanceForsythiae Fructus, the dried fruit of Forsythia suspensa (Thunb.) Vahl, is a commonly used traditional Chinese medicine and possesses various pharmacological activities, including anti-inflammation, anti-oxidant and liver protection. Aim of the studyAlthough acetaminophen (APAP) has been frequently used for its antipyretic and analgesic effects, it leads to liver injury at an overdose or long-term medication. Forsythiaside A (FA), the principal active component of Forsythiae Fructus, exerts prominent antioxidant, anti-inflammatory and hepatoprotective effects. However, the protective property and underlying mechanism of FA against APAP challenge have not yet been elucidated. Therefore, we aimed to explore the hepatoprotective effect and action mechanism of FA against APAP-induced liver injury in zebrafish. Materials and methodsIn this study, liver-specific transgenic zebrafish larvae (lfabp: EGFP) were used to investigate the protective effect of FA against overdose APAP exposure. The liver phenotype, morphological and biochemical assessments were carried out to evaluate the hepatoprotective effect of FA. Network pharmacology and molecular docking study were conducted to analyze the potential targets of FA in the treatment of APAP-induced liver injury. Finally, the mechanism of action was verified by reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR). ResultsThe liver phenotype, morphological and biochemical assessments indicated that FA could mitigate APAP-triggered liver injury. Network pharmacology and molecular docking analysis indicated that the protective effect of FA might be related to the regulation of targets tumor necrosis factor (TNF), matrix metallopeptidase 9 (MMP9), matrix metallopeptidase 2 (MMP2), and phosphatidylinositol 3-kinase (PI3K). PCR results confirmed that FA could reverse the progressive alterations of genes involving in extracellular matrix remolding and PI3K/AKT-mediated apoptosis signaling pathway. ConclusionsOur results indicated that FA could mitigate APAP-induced liver injury through modulating the remolding of extracellular matrix and PI3K/AKT-mediated apoptosis.

Protective Effect of miR-193a-5p and miR-320-5p on Caerulein-Induced Injury in AR42J Cells

Acute pancreatitis is a common inflammatory disease. MicroRNAs have been implicated in the pathogenesis of acute pancreatitis. The purpose of this study was to investigate the precise roles of miR-193a-5p and miR-320-5p in AP. The levels of miR-193a-5p, miR-320-5p and tumor necrosis factor receptor-associated factor 3 were detected by quantitative real-time polymerase chain reaction. Cell apoptosis was determined using flow cytometry. Enzyme-linked immunosorbent assay was performed to measure TNF-α, IL-6, IL-1β and IL-8 production, amylase activity, and malondialdehyde content. Targeted relationship between miR-193a-5p or miR-320-5p and TRAF3 was confirmed by the dual-luciferase reporter and RNA immunoprecipitation assays. Our data showed that miR-193a-5p and miR-320-5p were down-regulated in acute pancreatitis serum and caerulein-treated AR42J cells. The increased expression of miR-193a-5p or miR-320-5p alleviated caerulein-induced cell injury in AR42J cells. Tumor necrosis factor receptor-associated factor 3 was a direct target of miR-193a-5p and miR-320-5p in AR42J cells. Moreover, miR-193a-5p and miR-320-5p regulated caerulein-induced AR42J cells injury through targeting tumor necrosis factor receptor-associated factor 3. The present findings demonstrated that miR-193a-5p and miR-320-5p protected AR42J cells against caerulein-induced cell injury by targeting tumor necrosis factor receptor-associated factor 3, highlighting their roles as potential therapeutic targets for acute pancreatitis treatment.

DNA Copy Number Variation Associated with Anti-tumour Necrosis Factor Drug Response and Paradoxical Psoriasiform Reactions in Patients with Moderate-to-severe Psoriasis.

Biological drugs targeting tumour necrosis factor are effective for psoriasis. However, 30–50% of patients do not respond to these drugs and may even develop paradoxical psoriasiform reactions. This study searched for DNA copy number variations that could predict anti-tumour necrotic factor drug response or the appearance of antitumour necrotic factor induced psoriasiform reactions. Peripheral blood samples were collected from 70 patients with anti-tumour necrotic factor drug-treated moderate-to-severe plaque psoriasis. Samples were analysed with an Illumina 450K methylation microarray. Copy number variations were obtained from raw methylation data using conumee and Chip Analysis Methylation Pipeline (ChAMP) R packages. One copy number variation was found, harbouring one gene (CPM) that was significantly associated with adalimumab response (Bonferroni-adjusted p-value < 0.05). Moreover, one copy number variation was identified harbouring 3 genes (ARNT2, LOC101929586 and MIR5572) related to the development of paradoxical psoriasiform reactions. In conclusion, this study has identified DNA copy number variations that could be good candidate markers to predict response to adalimumab and the development of anti-tumour necrotic factor paradoxical psoriasiform reactions.

Efficient treatment of a preclinical inflammatory bowel disease model with engineered bacteria

We developed an orally administered, engineered, bacterium-based, RNA interference-mediated therapeutic method to significantly reduce the symptoms in the most frequently used animal model of inflammatory bowel disease. This bacterium-mediated RNA interference strategy was based on the genomically stable, non-pathogenic E. coli MDS42 strain, which was engineered to constitutively produce invasin and the listeriolysin O cytolysin. These proteins enabled the bacteria first to invade the colon epithelium and then degrade in the phagosome. This allowed the delivery of a plasmid encoding small hairpin RNA (shRNA) targeting tumor necrosis factor (TNF) into the cytoplasm of the target cells. The expression levels of TNF and other cytokines significantly decreased upon this treatment in dextran sulfate sodium (DSS)-induced colitis, and the degree of inflammation was significantly reduced. With further safety modifications this method could serve as a safe and side effect-free alternative to biologicals targeting TNF or other inflammatory mediators.

Management of Patients with Psoriatic Arthritis – Analysis and Discussion of the Main Points of the EULAR Recommendations 2019

Updated recommendations of the European League Against Rheumatism (EULAR) on the pharmacological management of psoriatic arthritis (PsA) 2019 were presented in May 2020. The recommendations are compiled in accordance with the standardized EULAR operating procedures, a systematic review of the literature, followed by a consensus meeting of 28 international members of the task force for guideline development.Updated recommendations include 6 general principles and 12 recommendations. General principles relate to the nature of PsA and the diversity of both musculoskeletal and non-musculoskeletal manifestations; emphasizes the need for joint decision-making by the patient and the doctor. The recommendations represent treatment strategies for pharmacological therapy. Nonsteroidal anti-inflammatory drugs and local injections of glucocorticoids are offered as initial therapy; for patients with arthritis and poor prognostic factors, such as polyarthritis or monoarthritis/oligoarthritis, accompanied by dactylitis or joint damage, it is recommended that the usual synthetic disease-modifying antirheumatic drugs (DMARD) be started quickly. If the treatment objective is not achieved using this strategy, biological DMARD (bDMARD) should be initiated, targeting tumor necrosis factor (TNF), interleukin (IL)-17A, or IL-12/23 taking into account skin lesions. If axial disease predominates, an TNF inhibitor or an IL-17A inhibitor should be started as a first-line DMARD.The use of Janus kinase inhibitors is considered primarily after the ineffectiveness of bDMARD. Inhibition of phosphodiesterase-4 is proposed for patients who are not suitable for other drugs, usually in the context of a mild disease. The switching of drugs and dose tapering in the phase of sustained remission are considered. This guideline provides an updated consensus on the pharmacological treatment of PsA based on a combination of evidence and expert opinion.