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ID PMID Title PublicationDate abstract
33432580 Immune complexome analysis reveals the presence of immune complexes and identifies disease 2021 May Sjögren's syndrome (SS) is a chronic autoimmune disease that mainly damages the salivary and lacrimal glands. Immune complex (IC) formation triggers local inflammation through IC deposition and decreased antigen function. Some ICs can leak from the lesion and into the saliva, but no salivary ICs have been reported to date. We used immune complexome analysis to comprehensively identify antigens incorporated into IC (IC-antigens) in saliva samples from patients with SS (n = 9) or with xerostomia (n = 7). Neutrophil defensin 1 (67%), small proline-rich protein 2D (67%), myeloperoxidase (44%), neutrophil elastase (44%), cathepsin G (33%), nuclear mitotic apparatus 1 (33%) and phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit gamma (33%) were identified as new IC-antigens specifically and frequently detected in the saliva of SS patients. Of these, neutrophil defensin 1, myeloperoxidase, neutrophil elastase and cathepsin G are neutrophil intracellular proteins, which suggests that repeated destruction of neutrophils due to abnormal autoimmunity may be involved in the pathogenesis of SS. We also analyzed serum samples from three SS patients. There was little overlap of IC-antigens between two of the samples (fewer than 30% of the IC-antigens in the saliva samples), suggesting that many ICs are formed locally and independently of the circulation. In addition, we found that four SS-specific salivary antigens show sequence homology with several proteins of oral microbiomes but no antigen has homology with Epstein-Barr virus proteins. The homology between some IC-antigens and oral microbiome proteins may indicate the impact of oral infection on local autoimmunity through molecular mimicry theory.
33777025 Deep Phenotyping of CD11c(+) B Cells in Systemic Autoimmunity and Controls. 2021 Circulating CD11c(+) B cells are a key phenomenon in certain types of autoimmunity but have also been described in the context of regular immune responses (i.e., infections, vaccination). Using mass cytometry to profile 46 different markers on individual immune cells, we systematically initially confirmed the presence of increased CD11c(+) B cells in the blood of systemic lupus erythematosus (SLE) patients. Notably, significant differences in the expression of CD21, CD27, and CD38 became apparent between CD11c(-) and CD11c(+) B cells. We observed direct correlation of the frequency of CD21(-)CD27(-) B cells and CD21(-)CD38(-) B cells with CD11c(+) B cells, which were most pronounced in SLE compared to primary Sjögren's syndrome patients (pSS) and healthy donors (HD). Thus, CD11c(+) B cells resided mainly within memory subsets and were enriched in CD27(-)IgD(-), CD21(-)CD27(-), and CD21(-)CD38(-) B cell phenotypes. CD11c(+) B cells from all donor groups (SLE, pSS, and HD) showed enhanced CD69, Ki-67, CD45RO, CD45RA, and CD19 expression, whereas the membrane expression of CXCR5 and CD21 were diminished. Notably, SLE CD11c(+) B cells showed enhanced expression of the checkpoint molecules CD86, PD1, PDL1, CD137, VISTA, and CTLA-4 compared to HD. The substantial increase of CD11c(+) B cells with a CD21(-) phenotype co-expressing distinct activation and checkpoint markers, points to a quantitative increased alternate (extrafollicular) B cell activation route possibly related to abnormal immune regulation as seen under the striking inflammatory conditions of SLE which shows a characteristic PD-1/PD-L1 upregulation.
34087868 Intrathecal drug delivery to treat intractable neuropathic pain following Sjögren's syndr 2021 Jun 4 RATIONALE: Transverse myelitis (TM) is a spinal cord inflammatory myelopathy that causes motor/sensory loss and urinary retention below the level of the affected spinal cord. Although a few case reports have described the control of neuropathic pain in patients with TM via spinal cord stimulation, no documented case regarding the control of severe allodynia following TM via intrathecal pump has been described. PATIENT CONCERNS: A 37-year-old woman was referred to a pain clinic for severe intractable pain below the T5 level followed by Sjögren's syndrome-induced TM. DIAGNOSES: A neurological examination revealed paresthesia and allodynia below the T5 level. The sensory evaluation was limited by extreme pain and jerking movements. The muscle strength of both lower limbs was grade 3. INTERVENTIONS: Intrathecal pump was inserted into the left lower abdomen. Catheter tip was placed at the midline of the T8 level. OUTCOMES: The numeric rating scale (NRS) for pain score decreased from 10 to 5. Functional Independence Measure score increased from 67 before implantation to 92 at the time of discharge, while the patient's Barthel score increased from 31 to 46. LESSONS: Neuropathic pain due to Sjögren's syndrome-related TM could be controlled effectively using the intrathecal morphine pump.
33202089 Predicting Resolvin D1 Pharmacokinetics in Humans with Physiologically-Based Pharmacokinet 2021 Mar Sjögren's syndrome (SS) is an autoimmune disease with no effective treatment options. Resolvin D1 (RvD1) belongs to a class of lipid-based specialized pro-resolving mediators that showed efficacy in preclinical models of SS. We developed a physiologically-based pharmacokinetic (PBPK) model of RvD1 in mice and optimized the model using plasma and salivary gland pharmacokinetic (PK) studies performed in NOD/ShiLtJ mice with SS-like features. The predictive performance of the PBPK model was also evaluated with two external datasets from the literature reporting RvD1 PKs. The PBPK model adequately captured the observed concentrations of RvD1 administered at different doses and in different species. The PKs of RvD1 in virtual humans were predicted using the verified PBPK model at various doses (0.01-10 mg/kg). The first-in-human predictions of RvD1 will be useful for the clinical trial design and translation of RvD1 as an effective treatment strategy for SS.
33932514 A comprehensive strategy to clarify the pharmacodynamic constituents and mechanism of Wu-t 2021 Jul 15 ETHNOPHARMACOLOGICAL RELEVANCE: As a traditional Chinese medicine (TCM) formula, Wu-tou decoction has been used for treating rheumatoid arthritis (RA) for more than a thousand years. Identifying pharmacodynamic constituents (PCs) of WTD and exploring their in vivo process are very meaningful for promoting the modernization of TCM. However, the pathological state might change this process. AIM OF THE STUDY: Hence, it is necessary and significant to compare the process in vivo of drugs both in normal and disease state and clarify their action mechanism. MATERIALS AND METHODS: Taking Wu-tou decoction (WTD) as the research object, a comprehensive strategy based on liquid chromatography coupled with mass spectrometry (LC-MS) was developed to identify PCs, clarify and compare their absorption and distribution in normal and model rats, and then explore the potential mechanism of TCM. Firstly, the PCs in WTD were identified. Then, the pharmacokinetics (PK) and tissue distribution of these ingredients were studied. Finally, the constituents with the difference between normal and model rats were selected for target network pharmacological analysis to clarify the mechanism. RESULTS: A total of 27 PCs of WTD were identified. The absorption and distribution of 20 PCs were successfully analyzed. In the disease state, the absorption and distribution of all these components were improved to have better treatment effects. The results of target network pharmacological analysis indicated that PTGS1, PTGS2, ABCB1, SLC6A4, CHRM2, ESR1, ESR2, CDK2, TNF and IL-6 are 10 key targets for WTD against RA. The regulatory effects of WTD on the expression of PTGS2 and TNF were further verified. Pathway enrichment analysis showed that the key mechanism of WTD against RA is to reduce inflammation and regulate the immune response. CONCLUSION: These results indicated that this strategy could better understand the in vivo process and mechanism of WTD under the pathological state. Furthermore, this strategy is also appropriate for other TCM.
35056105 Jakinibs of All Trades: Inhibiting Cytokine Signaling in Immune-Mediated Pathologies. 2021 Dec 30 Over the last 25 years, inhibition of Janus kinases (JAKs) has been pursued as a modality for treating various immune and inflammatory disorders. While the clinical development of JAK inhibitors (jakinibs) began with the investigation of their use in allogeneic transplantation, their widest successful application came in autoimmune and allergic diseases. Multiple molecules have now been approved for diseases ranging from rheumatoid and juvenile arthritis to ulcerative colitis, atopic dermatitis, graft-versus-host-disease (GVHD) and other inflammatory pathologies in 80 countries around the world. Moreover, two jakinibs have also shown surprising efficacy in the treatment of hospitalized coronavirus disease-19 (COVID-19) patients, indicating additional roles for jakinibs in infectious diseases, cytokine storms and other hyperinflammatory syndromes. Jakinibs, as a class of pharmaceutics, continue to expand in clinical applications and with the development of more selective JAK-targeting and organ-selective delivery. Importantly, jakinib safety and pharmacokinetics have been investigated alongside clinical development, further cementing the potential benefits and limits of jakinib use. This review covers jakinibs that are approved or are under late phase investigation, focusing on clinical applications, pharmacokinetic and safety profiles, and future opportunities and challenges.
33252843 Association of serum CXCL12 levels with arthropathy in patients with systemic sclerosis. 2021 Feb AIM: Systemic sclerosis (SSc) is an autoimmune connective tissue disease, in which extensive fibrotic change and vasculopathy affect the skin and various internal organs. It also involves the joints, causing stiffness, arthralgia, and arthritis. Although arthropathy is commonly observed in SSc, its underlying mechanism remains unknown. CXCL12, also known as stromal cell derived factor 1, is associated with inflammation, mesenchymal cell recruitment, angiogenesis, and collagen production, and is implicated in the development of various joint diseases. To assess the potential contribution of CXCL12 to SSc development, we investigated the clinical association of serum CXCL12 levels in patients with SSc. METHOD: We conducted a cross-sectional analysis of 68 patients with SSc and 20 healthy controls recruited in a single center over 9 years. Serum CXCL12 levels were measured by enzyme-linked immunosorbent assay. RESULTS: Serum CXCL12 levels were significantly higher in patients with SSc than in healthy controls (median 1554.0 pg/mL, 25th-75th centiles 1313.0-1914.0 pg/mL vs 967.4 pg/mL, 608.8-1271.0 pg/mL, P < 0.001). Patients with SSc with elevated CXCL12 levels had significantly more cases of arthropathy than those with normal CXCL12 levels (85.7% vs 25.0%, P = 0.01). Furthermore, patients with SSc with elevated CXCL12 levels showed an increased trend in the prevalence of limited range of motion of the finger joints compared with those with normal CXCL12 levels (60.0% vs 18.6%, P =0 .07). Moreover, serum CXCL12 levels were significantly correlated with the titers of rheumatoid factor in patients with SSc (r = .41, P = 0.001). CONCLUSION: Elevated serum CXCL12 levels may be related to the development of SSc arthropathy.
34964027 Clinical Impact of the ABO Blood Type in Patients with Rheumatic Diseases: Is there a Link 2021 Sep OBJECTIVES: Several studies have shown associations of ABO and Rh blood groups with various diseases; however, the relationship of ABO and Rh blood groups with rheumatic diseases are scarce. The aim of the present study was to examine whether there is an association between ABO and Rh blood groups and the types of rheumatic diseases. METHOD: In this multi-centre cross-sectional study, sociodemographic data, type of rheumatic disease, and type ABO and Rh blood groups were examined for patients with different rheumatic diseases. RESULTS: A total of 304 patients; 207 (68.1%) were diagnosed with rheumatoid arthritis, and 40 (13.2%) had systemic lupus erythematosus. The patients were assessed for blood types; 37.8% patients had A type, 27.6% had B type, 19.1% had O type, and 15.4% had AB type. The Rh (+) blood group was more prevalent (89.1%) than Rh (-). Blood group A was more prevalent in patients with rheumatic disease, followed by B, O, and AB respectively, although there was no significant difference in the distribution of ABO groups among rheumatic diseases. Female gender, smoking, and anti-cyclic citrullinated peptide are significantly different between the blood groups within rheumatic diseases. CONCLUSION: The A and Rh (+) blood groups were more commonly observed in patients with rheumatic diseases. There was lack of association between types of rheumatic diseases and ABO blood groups. The study provides knowledge for the interaction between ABO blood groups and several risk factors related to rheumatic diseases and may serve a guide for future clinical studies.
34934338 Monitoring and Managing Cardiovascular Risk in Immune Mediated Inflammatory Diseases. 2021 Cardiovascular disease (CVD) is common in immune-mediated inflammatory diseases (IMIDs) and it is predominately attributed to the interplay between chronic inflammation and traditional CVD risk factors. CVD has significant impact on the survival of patients with IMIDs as it is associated with increased morbidity and mortality. Despite recommendations for monitoring and managing CVD in patients with IMIDs, the individual CVD risk assessment remains problematic as CVD risk calculators for the general population consistently underestimate the risk in patients with IMIDs. Application of new technologies utilizing artificial intelligence techniques have shown promising potential for tailoring predictive medicine to the individual patient, but further validation of their role in clinical decision-making is warranted. In the meantime, individuals with IMIDs should be encouraged to adopt behavioral interventions targeting at modifiable lifestyle CVD risk factors, whereas rheumatologists need to be well aware of the unfavorable effects of antirheumatic medication on various CVD risk factors and outcomes. In the current paper, we aim to provide an overview of current and emerging strategies for mitigating CVD risk in patients with IMIDs, based on a practical approach.
34792672 Deubiquitylating enzymes: potential target in autoimmune diseases. 2021 Dec The ubiquitin-proteasome pathway is responsible for the turnover of different cellular proteins, such as transport proteins, presentation of antigens to the immune system, control of the cell cycle, and activities that promote cancer. The enzymes which remove ubiquitin, deubiquitylating enzymes (DUBs), play a critical role in central and peripheral immune tolerance to prevent the development of autoimmune diseases and thus present a potential therapeutic target for the treatment of autoimmune diseases. DUBs function by removing ubiquitin(s) from target protein and block ubiquitin chain elongation. The addition and removal of ubiquitin molecules have a significant impact on immune responses. DUBs and E3 ligases both specifically cleave target protein and modulate protein activity and expression. The balance between ubiquitylation and deubiquitylation modulates protein levels and also protein interactions. Dysregulation of the ubiquitin-proteasome pathway results in the development of various autoimmune diseases such as inflammatory bowel diseases (IBD), psoriasis, multiple sclerosis (MS), systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). This review summarizes the current understanding of ubiquitination in autoimmune diseases and focuses on various DUBs responsible for the progression of autoimmune diseases.
34784069 High-dose vitamin C therapy for symptomatic deficiency in a patient with myasthenia gravis 2021 Nov 16 Vitamin C (ascorbic acid) is an essential water-soluble antioxidant, and deficiency (ie, plasma level <11 μmol/L) can result in scurvy. People at the highest risk for vitamin C deficiency (ie, scurvy) are those with inadequate intake, such as patients with alcohol abuse disorder, malnutrition, psychiatric disorders, restrictive eating habits, and food insecurity, as well as those with malabsorptive syndromes. We present a case of a 26-year-old woman with Crohn's colitis, myasthenia gravis, and juvenile rheumatoid arthritis who presented with frequent bruising, epistaxis, and excessive bleeding from small cuts and who was found to be deficient in vitamin C. Plasma levels initially normalized with oral vitamin C supplementation, but bleeding symptoms eventually returned despite high-dose oral supplementation with 2000 mg daily. She ultimately required routine intravenous supplementation in the home setting for the normalization of levels and the resolution of symptoms. Case reports of vitamin C deficiency typically involve patients with an inadequate intake of vitamin C-containing foods or inadequate absorption. In contrast, our patient reported a regular intake of vitamin C-containing foods, in addition to oral supplementation, but continued to have difficulty maintaining normal vitamin C levels. Scurvy should be considered for any patient with symptoms of bleeding, petechiae, or ecchymosis and, although it can typically be treated with oral vitamin C, intravenous repletion may be necessary in some cases.
34766146 UPLC-MS/MS-based plasma lipidomics reveal a distinctive signature in systemic lupus erythe 2021 Jun Global lipidomics is of considerable utility for exploring altered lipid profiles and unique diagnostic biomarkers in diseases. We aim to apply ultra-performance liquid chromatography-tandem mass spectrometry to characterize the lipidomics profile in systemic lupus erythematosus (SLE) patients and explore the underlying pathogenic pathways using the lipidomics approach. Plasma samples from 18 SLE patients, 20 rheumatoid arthritis (RA) patients, and 20 healthy controls (HC) were collected. A total of 467 lipids molecular features were annotated from each sample. Orthogonal partial least square-discriminant analysis, K-mean clustering analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis indicated disrupted lipid metabolism in SLE patients, especially in phospholipid, glycerol, and sphingolipid metabolism. The area under curve (AUC) of lipid metabolism biomarkers was better than SLE inflammation markers that ordinarily used in the clinic. Proposed model of monoglyceride (MG) (16:0), MG (18:0), phosphatidylethanolamine (PE) (18:3-16:0), PE (16:0-20:4), and phosphatidylcholine (PC) (O-16:2-18:3) yielded AUC 1.000 (95% CI, 1.000-1.000), specificity 100% and sensitivity 100% in the diagnosis of SLE from HC. A panel of three lipids molecular PC (18:3-18:1), PE (20:3-18:0), PE (16:0-20:4) permitted to accurately diagnosis of SLE from RA, with AUC 0.921 (95% CI, 0.828-1.000), 70% specificity, and 100% sensitivity. The plasma lipidomics signatures could serve as an efficient and accurate tool for early diagnosis and provide unprecedented insight into the pathogenesis of SLE.
34613654 Recent Advances on Carbon Monoxide Releasing Molecules for Antibacterial Applications. 2021 Dec 14 Carbon monoxide (CO) has been known as an endogenous signaling molecule in addition to an air pollutant. It plays a critical role in many physiological and pathological processes. Therefore, CO has been recognized as a potent therapeutic agent for the treatment of numerous diseases such as cancers, rheumatoid arthritis, and so on. Instead of direct CO inhalation, two main categories of CO-releasing molecules (CORMs) (i. e., metal carbonyls and nonmetallic CO donors) have been developed to safely and locally deliver CO to target tissues. In this minireview, we summarize the recent achievements of CORMs on antibacterial applications. It appears that the antibacterial activity of CORMs is different from CO gas, which is tightly correlated to not only the types of CORMs applied but also the tested bacterial strains. In some circumstances, the antibacterial mechanisms are debated and need to be clarified. We hope more attention can be paid to this emerging field and new antibacterial agents with a low risk of drug resistance can be developed.
34357328 Metabolomics in Bone Research. 2021 Jul 1 Identifying the changes in endogenous metabolites in response to intrinsic and extrinsic factors has excellent potential to obtain an understanding of cells, biofluids, tissues, or organisms' functions and interactions with the environment. The advantages provided by the metabolomics strategy have promoted studies in bone research fields, including an understanding of bone cell behaviors, diagnosis and prognosis of diseases, and the development of treatment methods such as implanted biomaterials. This review article summarizes the metabolism changes during osteogenesis, osteoclastogenesis, and immunoregulation in hard tissue. The second section of this review is dedicated to describing and discussing metabolite changes in the most relevant bone diseases: osteoporosis, bone injuries, rheumatoid arthritis, and osteosarcoma. We consolidated the most recent finding of the metabolites and metabolite pathways affected by various bone disorders. This collection can serve as a basis for future metabolomics-driven bone research studies to select the most relevant metabolites and metabolic pathways. Additionally, we summarize recent metabolic studies on metabolomics for the development of bone disease treatment including biomaterials for bone engineering. With this article, we aim to provide a comprehensive summary of metabolomics in bone research, which can be helpful for interdisciplinary researchers, including material engineers, biologists, and clinicians.
34336512 Maternal and Perinatal Outcomes of Pregnancy in Women With Autoimmune Disorder. 2021 Jun Objective Pregnancy with an autoimmune disorder is faced with several risks for mother and fetus. The aim of the present study is to analyze the course and outcome of pregnancy in women with autoimmune disorders (AIDs). Methods A retrospective cohort study was conducted at a tertiary care teaching hospital. The hospital records of 153 pregnancies with autoimmune disorders and 1095 low-risk pregnant women who served as controls were reviewed. An adverse perinatal outcome was defined as the presence of any obstetric complications, including preeclampsia, eclampsia, abruption, antepartum hemorrhage (APH), prematurity, fetal growth restriction (FGR), intrauterine death (IUD), intrapartum event, mode of delivery, birth weight, neonatal intensive care unit (NICU) stay, or disease-specific neonatal complications. For all statistical tests with two-tailed probability, p<0.05 was considered statistically significant. Results A high incidence of adverse perinatal outcomes was observed in all women with AIDs when compared with age-matched controls. The highest incidence of adverse perinatal outcomes was observed in women with Takayasu's arteritis. The incidence of abortions was more in women with antiphospholipid antibody syndrome (APS) and Grave's disease (22.2% and 33.3%, respectively). The incidence of prematurity, fetal growth restriction (FGR), and low birth weight were highest in women with systemic lupus erythematosus (SLE). Pregnancy with myasthenia gravis and rheumatoid arthritis did not have any significant adverse impact on pregnancy outcomes. Conclusion We found a strong association between autoimmune disorders and obstetric complications. The multidisciplinary team approach and pre-pregnancy optimization of the disease improve maternal and fetal outcomes.
34277495 Whipple's disease: a fatal mimic. 2021 Whipple's Disease, a rare diagnosis caused by the slow-growing bacterium Tropheryma whipplei, most often presents with the classically described signs of malabsorption due to gastrointestinal colonization. However, it can also have signs and symptoms that clinically overlap with rheumatic diseases, potentially resulting in misdiagnosis. Furthermore, treatment with modern potent biologic immunosuppressive agents and classic disease modifying anti-rheumatic drugs (DMARDs) can lead to serious exacerbation of undiagnosed infections. We present the case of a middle-aged woman with long term complaints of arthalgias, who was diagnosed with seronegative rheumatoid arthritis and subsequently treated for almost 7 years with such immunosuppressive therapies. The patient's disease course included chronic diarrhea that abruptly intensified and culminated in fatal hypovolemic shock/sepsis. A diagnosis of WD was made by autopsy examination, wherein several organ systems were found to be heavily involved by Tropheryma whipplei organisms, and their identification was confirmed with histochemical and molecular evaluation. Notably, most bacterial organisms were located deeply in the submucosa/muscularis of affected organs, a practical reminder to practicing pathologists that challenges the classic histopathologic description of Whipple disease as an infiltration of predominantly lamina propria, and the potential for sampling bias in typically superficial endoscopic biopsies during routine procedures.
34157797 Sulfatase 1 and sulfatase 2 as novel regulators of macrophage antigen presentation and pha 2021 Oct BACKGRUOUND: Sulfation of heparan sulfate proteoglycans (HSPGs) is critical for the binding and signaling of ligands that mediate inflammation. Extracellular 6-O-endosulfatases regulate posttranslational sulfation levels and patterns of HSPGs. In this study, extracellular 6-O-endosulfatases, sulfatase (Sulf)-1 and Sulf-2, were evaluated for their expression and function in inflammatory cells and tissues. METHODS: Harvested human peripheral blood mononuclear cells were treated with phytohemagglutinin and lipopolysaccharide, and murine peritoneal macrophages were stimulated with interleukin (IL)-1β for the evaluation of Sulf-1 and Sulf-2 expression. Sulf expression in inflammatory cells was examined in the human rheumatoid arthritis (RA) synovium by immunofluorescence staining. The antigen presentation and phagocytic activities of macrophages were compared according to the expression state of Sulfs. Sulfs-knockdown macrophages and Sulfs-overexpressing macrophages were generated using small interfering RNAs and pcDNA3.1 plasmids for Sulf-1 and Sulf-2, respectively. RESULTS: Lymphocytes and monocytes showed weak Sulf expression, which remained unaffected by IL-1β. However, peritoneal macrophages showed increased expression of Sulfs upon stimulation with IL-1β. In human RA synovium, two-colored double immunofluorescent staining of Sulfs and CD68 revealed active upregulation of Sulfs in macrophages of inflamed tissues, but not in lymphocytes of lymphoid follicles. Macrophages are professional antigen-presenting cells. The antigen presentation and phagocytic activities of macrophages were dependent on the level of Sulf expression, suppressed in Sulfs-knockdown macrophages, and enhanced in Sulfs-overexpressing macrophages. CONCLUSION: The results demonstrate that upregulation of Sulfs in macrophages occurs in response to inflammation, and Sulfs actively regulate the antigen presentation and phagocytic activities of macrophages as novel immune regulators.
34100601 Macrolide Inspired Macrocycles as Modulators of the IL-17A/IL-17RA Interaction. 2021 Jun 24 Interleukin 17 (IL-17) cytokines promote inflammatory pathophysiology in many autoimmune diseases, including psoriasis, multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease. Such broad involvement of IL-17 in various autoimmune diseases makes it an ideal target for drug discovery. Psoriasis is a chronic inflammatory disease characterized by numerous defective components of the immune system. Significantly higher levels of IL-17A have been noticed in lesions of psoriatic patients, if compared to non-lesion parts. Therefore, this paper is focused on the macrolide inspired macrocycles as potential IL-17A/IL-17RA modulators and covers the molecular design, synthesis, and in vitro profiling. Macrocycles are designed to diversify and enrich chemical space through different ring sizes and a variety of three-dimensional shapes. Inhibitors in the nM range were identified in both target-based and phenotypic assays. In vitro ADME as well as in vivo PK properties are reported.
34093208 The Research Progress of Exosomes in Osteoarthritis, With Particular Emphasis on the Media 2021 Osteoarthritis (OA) is a kind of degenerative disease, which is caused by many factors such as aging, obesity, strain, trauma, congenital joint abnormalities, joint deformities. Exosomes are mainly derived from the invagination of intracellular lysosomes, which are released into the extracellular matrix after fusion of the outer membrane of multi vesicles with the cell membrane. Exosomes mediate intercellular communication and regulate the biological activity of receptor cells by carrying non-coding RNA, long noncoding RNAs (lncRNAs), microRNAs (miRNAs), proteins and lipids. Evidences show that exosomes are involved in the pathogenesis of OA. In view of the important roles of exosomes in OA, this paper systematically reviewed the roles of exosomes in the pathogenesis of OA, including the roles of exosomes in OA diagnosis, the regulatory mechanisms of exosomes in the pathogenesis, and the intervention roles of exosomes in the treatment of OA. Reviewing the roles of exosomes in OA will help to clarify the pathogenesis of OA and explore new diagnostic biomarkers and therapeutic targets.
34084534 Exophiala dermatitidis pneumonia with bronchiectasis required prolonged voriconazole treat 2021 Jun Exophiala dermatitidis is a black fungus that rarely causes respiratory infection. We report a case of E. dermatitidis pneumonia with bronchiectasis that relapsed after 11 months of voriconazole (VRCZ) treatment in a rheumatoid arthritis (RA) patient with bronchiectasis. A 65-year-old woman with RA and abnormal findings on chest radiography was referred for assessment of chronic cough and increased sputum production. She underwent bronchoscopy, and E. dermatitidis was identified from bronchoalveolar lavage fluid (BALF). Exophiala dermatitidis chronic lower respiratory tract infection and pneumonia were diagnosed. Although her condition improved after 11 months of VRCZ treatment, chest computed tomography (CT) images showed worsening at five months after the cessation of VRCZ treatment and E. dermatitidis was again detected in BALF. Re-administration of VRCZ for two years improved symptoms and chest CT images, and her condition is currently stable. In patients with bronchiectasis, E. dermatitidis pneumonia might require prolonged antifungal treatment.