GPX4-Regulated Ferroptosis Mediates S100-Induced Experimental Autoimmune Hepatitis Associated with the Nrf2/HO-1 Signaling Pathway

Autoimmune hepatitis (AIH) is an inflammatory autoimmune disease of the liver. Oxidative stress triggered by reactive oxygen radicals is a common pathophysiological basis for the pathogenesis of many liver diseases, and ferroptosis is associated with the toxic accumulation of reactive oxygen species. The signaling transduction pathways responsible for iron processing and lipid-peroxidation mechanisms are believed to drive ferroptosis. However, the specific mechanisms regulating ferroptosis remain unclear. The aims of this investigation were to identify the possible effector functions of ferroptosis, based on glutathione peroxidase 4 (GPX4) regulation in an S100-induced autoimmune hepatitis mouse model and hepatocyte injury models. The S100 liver antigen-induced AIH mouse model was used to detect ferroptotic biomarkers using western blotting. Upregulated levels of cyclooxygenase2 (COX2) and Acyl-Coenzyme A synthase long-chain family member 4 (ACSL4) were observed in the S100-induced AIH model group, while levels of GPX4 and ferritin heavy chain 1 (FTH1) were downregulated ( P < 0.05 ). The expression profiles of COX2, ACSL4, GPX4, and FTH1 were restored following the administration of ferrostatin-1. In addition, Nrf2 and HO-1 levels in the S100-induced AIH model mice after treatment with ferrostatin-1 were downregulated compared to the nonferrostatin-1-treated S100-induced AIH model mice ( P < 0.05 ). Moreover, COX2 and ACSL4 levels were significantly upregulated, with significant FTH1 downregulation, in the AIH model mice when liver-specific GPX4 was silenced using AAV8 constructs. These data indicate that inhibition of ferroptosis significantly ameliorated the influence of AIH on the Nuclear factor E2-related factor 2 (Nrf2)/Heme oxygenase-1 (HO-1) signaling pathway, and that ferroptosis may act as an initiator or intermediate mediator leading to AIH.

A Computational Modeling Framework to Analyze Synovial-Tissue Based Drug Targets and Diagnostic Biomarkers in Rheumatoid Arthritis

Rheumatoid Arthritis (RA) is an inflammatory autoimmune disease that affects 23 million people worldwide. It is a clinically heterogeneous disorder characterized by the attack of inflammatory chemicals on the synovial tissue that lines joints. It is advantageous to develop effective, targeted treatments and identify specific diagnostic biomarkers for RA before extensive joint degradation, bone erosion, and cartilage destruction. Current modes of RA treatments have alleviated and notably halted the progression of RA. Despite this, not many patients reach low disease activity status after treatment, and a significant number of patients fail to respond to medication due to drug non-specificity. While the reasons for these rates remain unknown, the cellular and molecular signatures present in the synovial tissue for RA patients likely play a role in the varied treatment response. Thus, a drug that particularly targets specific genes and networks may have a significant effect in halting the progression of RA. This study evaluates and proposes potential drug targets through in silico mathematical modeling of various pathways of interest in RA. To understand how drugs interact with genes, we built a mathematical model with 30 two-gene and three-gene network interactions and analyzed the effect of 92 different perturbations to rate constants. We determined that inhibition of the LCK-CD4, VAV1-CD4, and MLT-ROR pathways could potentially serve as drug targets. We also found that increased activity of the DEC2-IL1β and the NF-κB-interleukin pathway and the decreased activity of the TNF-α-REV-ERB pathway could serve as diagnostic biomarkers.

In-silico Molecular Docking of Coumarin and Naphthalene Derivatives from Pyrenacantha volubilis with the Pathological Mediators of Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease which mainly targets synovial membrane during its disease pathogenesis. Available therapeutic drugs for the treatment of RA provide only symptomatic relief and are associated with severe side effects. Herbal plants comprise many active biological compounds that cure the disease with minimal adverse effects. Pyrenacantha volubilis is a climber and member of Icacinaceae family. Gas chromatography- mass spectrometry (GC-MS) analysis of ethanolic extracts of leaves of Pyrenacantha volubilis (EEPV) reveals the presence of 2-isopropyl-5-methylcyclohexyl 3-(1-(4- chlorophenyl)-3-oxobutyl)-coumarin-4-yl carbonate and 1-naphthalenepropanol, alpha-ethyldecahydro-5- (hydroxymethyl)-alpha,5,8A-trimethyl-2-methyl phytoconstitutents. Hence these compounds were docked with various pathological mediators of RA using Autodock 4.2. The docking results unveils that these compounds had better binding energy against inflammatory, oxidative stress and receptor for advanced glycation end products (RAGE) mediators that plays a pivotal role in the progression of RA. However, this study warrants further in- vitro and in-vivo studies to be carried out to establish the anti-inflammatory and anti-arthritic activity of selected phytoconstitutents.

Phototherapies in the management of an ulcerative lip lesion in a patient taking multiple medications for rheumatoid arthritis

The treatment of rheumatoid arthritis (RA), an inflammatory autoimmune disease of chronic nature, consists of medications, exercises, patient education on the disease, and rest. Unfortunately, many drugs used for RA have been recently recognized to induce oral manifestations due to either immunosuppression or antiproliferative effects. Thus, the present study reports a case of a patient who was receiving multiple medications (methotrexate, leflunomide, and sodium risedronate) for RA and developed an extensive lip ulcerative lesion not responsive to previous treatments. The lesion management was performed using only a combination of photobiomodulation therapy (PBMT) and antimicrobial photodynamic therapy (aPDT), totalizing three laser sessions. Within 4 days, the patient no longer complained of pain and the lesion presented an advanced healing aspect. According to the current case, the combination of PBMT and aPDT seems to be a suitable alternative for the management of oral lesions in patients taking medications for RA.

A Tale of Two Immune Cells in Rheumatoid Arthritis: The Crosstalk Between Macrophages and T Cells in the Synovium

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease. Joint inflammation of RA is closely related to infiltration of immune cells, synovium hyperplasia, and superfluous secretion of proinflammatory cytokines, which lead to cartilage degradation and bone erosion. The joint synovium of RA patients contains a variety of immune cellular types, among which monocytes/macrophages and T cells are two essential cellular components. Monocytes/macrophages can recruit and promote the differentiation of T cells into inflammatory phenotypes in RA synovium. Similarly, different subtypes of T cells can recruit monocytes/macrophages and promote osteoblast differentiation and production of inflammatory cytokines. In this review, we will discuss how T cell-monocyte/macrophage interactions promote the development of RA, which will provide new perspectives on RA pathogenesis and the development of targeted therapy.

A Swiss Health Care Professionals’ Perspective on the Meaning of Interprofessional Collaboration in Health Care of People with MS—A Focus Group Study

Multiple sclerosis (MS) is a chronic, inflammatory autoimmune disease of the central nervous system mainly of adults ranging from 20 to 45 years of age. The risk of developing MS is 50% higher in women than in men. Most people with MS (PwMS) experience a spectrum of symptoms such as spasticity, continence dysfunctions, fatigue, or neurobehavioral manifestations. Due to the complexity of MS and the variety of patient-centered needs, a comprehensive approach of interprofessional collaboration (IPC) of multiple health care professionals (HCP) is necessary. The aim of this qualitative study was to explore the meaning of IPC in the comprehensive care of PwMS from a HCP perspective. Focus groups (FG) with HCP were conducted, recorded, and transcribed verbatim. The sample contained HCP from three MS clinics in different phases of care and rehabilitation. Four main categories emerged: (a) experience with IPC, (b) relevant aspects for IPC in patients’ treatment, (c) differences in in- and outpatient settings, and (d) influence of patient perspective. IPC plays a crucial role in HCP perspective when treating PwMS, which can benefit from an IPC therapeutic approach because HCP work together in a patient-centered way. The inpatient setting of HCP strongly supports the implementation of IPC. This prerequisite does not exist in outpatient settings.

Extended Inflammation Parameters (EIP) as Markers of Immune System Cell Activation in Psoriasis

Psoriasis is an inflammatory, autoimmune disease that affects approximately 2% of the population. The inflammation in psoriasis can be systemic, so despite a predominantly cutaneous manifestation, it also affects the internal organs. The diagnosis and monitoring of the disease are based on the clinical picture. To assess the disorders of other organs, additional tests need to be performed. Recently, the examination of blood morphology has been enriched with modern haematological parameters, i.e., Extended Inflammation Parameters (EIP), which include RE-LYMPH (activated lymphocytes), AS-LYMPH (antibody-producing B lymphocytes), and NEUT-RI and NEUT-GI (activated neutrophils). In the study, higher values of new haematological parameters were observed in individuals with psoriasis than in healthy controls. A higher EIP value was noted in the group of individuals with plaque psoriasis than in the group of individuals with psoriatic arthritis. Implementation of these parameters into routine laboratory analysis will likely make it possible to estimate the severity of the inflammation and improve its assessment.

Potential role of bioactive lipids in rheumatoid arthritis

: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease, which involves a pathological inflammatory response against articular cartilage in multiple joints throughout the body. It is a complex disorder associated with comorbidities such as depression, lymphoma, osteoporosis and cardiovascular disease (CVD), which significantly deteriorate patients’ quality of life and prognosis. This has ignited a large initiative to elucidate the physiopathology of RA, aiming to identify new therapeutic targets and approaches in its multidisciplinary management. Recently, various lipid bioactive products have been proposed to have an essential role in this process; including eicosanoids, specialized pro-resolving mediators, phospholipids/sphingolipids, and endocannabinoids. Dietary interventions using omega-3 polyunsaturated fatty acids or treatment with synthetic endocannabinoids agonists have been shown to significantly ameliorate RA symptoms. Indeed, the modulation of lipid metabolism may be crucial in the pathophysiology and treatment of autoimmune diseases.

The Preparation of a Novel Poly(Lactic Acid)-Based Sustained H2S Releasing Microsphere for Rheumatoid Arthritis Alleviation

Rheumatoid arthritis (RA) is a chronic, inflammatory autoimmune disease that mainly erodes joints and surrounding tissues, and if it is not treated in time, it can cause joint deformities and loss of function. S-propargyl-cysteine (SPRC) is an excellent endogenous hydrogen sulfide donor which can relieve the symptoms of RA through the promotion of H2S release via the CSE/H2S pathway in vivo. However, the instant release of H2S in vivo could potentially limit its further clinical use. To solve this problem, in this study, a SPRC-loaded poly(lactic acid) (PLA) microsphere (SPRC@PLA) was prepared, which could release SPRC in vitro in a sustained manner, and further promote sustained in vivo H2S release. Furthermore, its therapeutical effect on RA in rats was also studied. A spherical-like SPRC@PLA was successfully prepared with a diameter of approximately 31.61 μm, yielding rate of 50.66%, loading efficiency of 6.10% and encapsulation efficiency of 52.71%. The SPRC@PLA showed significant prolonged in vitro SPRC release, to 4 days, and additionally, an in vivo H2S release around 3 days could also be observed. In addition, a better therapeutical effect and prolonged administration interval toward RA rats was also observed in the SPRC@PLA group.

Paediatric multiple sclerosis: a case report of missed and dismissed diagnosis

Multiple Sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system (CNS). Up to 10 % of MS patients have onset in paediatric age group. Although the clinical profile of MS appears similar to that seen in adults, several features may differ and specific issues arise in children. Here, we reported a 12-year old girl who presented with 3-year history of episodes of seizures and facial nerve palsy and finally fatigue and cognitive impairment were noted and interfered with her academic performance. Because of the presumed atypical clinical presentations, the diagnosis was missed then dismissed despite neuroimaging features and CSF immunological findings that were highly suggestive of MS. Later, evolution of the disease by neuroimaging helped confirming the diagnosis and directed toward the delayed therapy.