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ID PMID Title PublicationDate abstract
33744307 Paternal Exposure to Immunosuppressive and/or Biologic Agents and Birth Outcomes in Patien 2021 Jul BACKGROUND & AIMS: We conducted a retrospective cohort study to inform the safety of exposure to immunosuppressive and/or biologic agents around conception in expectant fathers with immune-mediated inflammatory diseases (IMIDs) on birth outcomes. METHODS: Using a deidentified administrative claims database (OptumLabs Data Warehouse), we identified 7453 expectant fathers with IMIDs (inflammatory bowel diseases, rheumatoid arthritis, psoriasis/psoriatic arthritis, and ankylosing spondylitis) linked to newborns with periconception medication exposure between 38 and 60 weeks before the newborn birth date (34-58 weeks prior for preterm newborns) and neonatal follow-up for 3 months after the birth date. Through logistic regression adjusting for paternal age and race (and, in a subset, for maternal age, race, presence of IMIDs, and nonsingleton births), we compared the risk of major congenital malformations (primary outcome) and preterm birth and low birth weight in fathers exposed to thiopurines (n = 461), methotrexate (n = 171), tumor necrosis factor (TNF) α antagonists (n = 1082), or non-TNF-targeting biologic agents (n = 132) vs fathers not exposed to any of these medications (n = 5607). RESULTS: As compared to unexposed fathers (3.4% prevalence of major congenital malformations), exposure to thiopurines (relative risk [RR], 1.12; 95% confidence interval [CI], 0.66-1.76), methotrexate (RR, 0.67; 95% CI, 0.21-1.55), TNF-α antagonists (RR, 1.14; 95% CI, 0.81-1.57), and non-TNF-targeting biologic agents (RR, 1.75; 95% CI, 0.80-3.24) was not associated with increased risk of major congenital malformations. No association was observed between paternal medication exposure and risk of preterm birth or low birth weight. Results were stable on subanalyses of linked father-mother-newborn triads. CONCLUSIONS: In a large cohort study of 7453 expectant fathers with IMIDs, exposure to immunosuppressive or biologic agents around conception was not associated with increased risk of adverse birth outcomes.
33685523 Serum chitinase-3-like 1 protein is a useful biomarker to assess disease activity in ANCA- 2021 Mar 8 BACKGROUND: To investigate whether serum chitinase-3-like 1 protein (YKL-40) is associated with disease activity in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). METHODS: ELISA was performed in serum samples from AAV patients who were enrolled in our prospective observational cohort to estimate levels of YKL-40. Birmingham vasculitis activity score (BVAS) (version 3), five factor score (FFS), and short form-36 (SF-36), as well as clinical and laboratory data were collected. Kidney expression of YKL-40 was assessed by immunohistochemical staining using renal biopsy tissues from ANCA-associated glomerulonephritis patients (AAGN). Severe AAV and FFS were defined as BVAS ≥ 12 and FFS ≥ 2, and the correlations between laboratory variables, BVAS, FFS, and SF-36 score were assessed using linear regression analysis. The optimal cut-off of serum YKL-40 for severe AAV and high FFS was calculated using the receiver operator characteristic curve analysis. RESULTS: Of the included 60 patients, 32 (53.3%), 17 (28.3%), and 11 (18.3%) were classified as microscopic polyangiitis, granulomatosis with polyangiitis, and eosinophilic granulomatosis with polyangiitis. The median BVAS and FFS were 7.0 and 1.0, whereas the mean SF-36 physical and mental component scores were 50.5 and 58.3. Serum YKL-40 level was higher in patients with severe AAV and high FFS compared to those without (p = 0.007 and p < 0.001); multivariable linear regression analysis revealed that serum YKL-40 was independently associated with BVAS, FFS, and SF-36 scores. On kidney tissues obtained from AAGN patients, strong cytoplasmic staining of YKL-40 was found in cells present in inflammatory lesions. In addition, AAV patients had higher levels of serum YKL-40 compared to those with systemic lupus erythematosus, rheumatoid arthritis, osteoarthritis, and healthy control. The proportion of patients having severe AAV and high FFS was significantly higher in those with serum YKL-40 > 221.3 ng/mL and > 227.1 ng/mL than those without (relative risk 2.852 and 7.000). In 12 patients with serial YKL-40 testing, 11 patients (91.7%) exhibited a reduction in serum YKL-40 levels following a decrease in disease activity (p < 0.001). CONCLUSION: Our findings suggest that serum YKL-40 may be a clinically useful biomarker to assess AAV disease activity. TRIAL REGISTRATION: Retrospectively registered.
35008719 Implantation of Various Cell-Free Matrixes Does Not Contribute to the Restoration of Hyali 2021 Dec 28 Articular cartilage is a highly organized tissue that has a limited ability to heal. Tissue engineering is actively exploited for joint tissue reconstruction in numerous cases of articular cartilage degeneration associated with trauma, arthrosis, rheumatoid arthritis, and osteoarthritis. However, the optimal scaffolds for cartilage repair are not yet identified. Here we have directly compared five various scaffolds, namely collagen-I membrane, collagen-II membrane, decellularized cartilage, a cellulose-based implant, and commercially available Chondro-Gide(®) (Geistlich Pharma AG, Wolhusen, Switzerland) collagen membrane. The scaffolds were implanted in osteochondral full-thickness defects, formed on adult Wistar rats using a hand-held cutter with a diameter of 2.0 mm and a depth of up to the subchondral bone. The congruence of the articular surface was almost fully restored by decellularized cartilage and collagen type II-based scaffold. The most vivid restoration was observed 4 months after the implantation. The formation of hyaline cartilage was not detected in any of the groups. Despite cellular infiltration into scaffolds being observed in each group except cellulose, neither chondrocytes nor chondro-progenitors were detected. We concluded that for restoration of hyaline cartilage, scaffolds have to be combined either with cellular therapy or morphogens promoting chondrogenic differentiation.
34922462 Immunogenicity profile in African green monkeys of a vaccine candidate based on a mutated 2021 Dec 18 BACKGROUND: Interleukin (IL)-15 is a proinflammatory T-cell growth factor overexpressed in several autoimmune diseases such as rheumatoid arthritis. Our initial strategy to neutralize the increased levels of IL-15 consisted in a vaccine candidate based on the recombinant modified human IL-15 (mhIL-15) mixed with the alum adjuvant. A previous study in non-human primates Macaca fascicularis has shown that vaccination induces neutralizing antibodies against native IL-15, without affecting animal behavior, clinical status, or the percentage of IL-15-dependent cell populations. However, the mhIL-15 used as an antigen was active in the IL-2-dependent cytotoxic T-cell line CTLL-2, which could hinder its therapeutic application. The current article evaluated the immunogenicity in African green monkeys of a vaccine candidate based on IL-15 mutant D8SQ108S, an inactive form of human IL-15. RESULTS: IL-15 D8SQ108S was inactive in the CTLL-2 bioassay but was able to competitively inhibit the biological activity of human IL-15. Immunization with 200 µg of IL-15 mutant combined with alum elicited anti-IL-15 IgG antibodies after the second and third immunizations. The median values of anti-IL-15 antibody titers were slightly higher than those generated in animals immunized with 200 µg of mhIL-15. The highest antibody titers were induced after the third immunization in monkeys vaccinated with 350 µg of IL-15 D8SQ108S. In addition, sera from immunized animals inhibited the biological activity of human IL-15 in CTLL-2 cells. The maximum neutralizing effect was observed after the third immunization in sera of monkeys vaccinated with the highest dose of the IL-15 mutant. These sera also inhibited the proliferative activity of simian IL-15 in the CTLL-2 bioassay and did not affect the IL-2-induced proliferation of the aforementioned T-cell line. Finally, it was observed that vaccination neither affects the animal behavior nor the general clinical parameters of immunized monkeys. CONCLUSION: Immunization with inactive IL-15 D8SQ108S mixed with alum generated neutralizing antibodies specific for human IL-15 in African green monkeys. Based on this fact, the current vaccine candidate could be more effective than the one based on biologically active mhIL-15 for treating autoimmune disorders involving an uncontrolled overproduction of IL-15.
34768006 [Management of HPV-induced cervical lesions in immunosuppressed patients - Review of the 2022 Jan INTRODUCTION: Current French recommendations for the management of cervical lesions related to human papilloma virus (HPV) infection are limited to general population. Patients who are immunocompromised appear to be at increased risk of induced HPV lesions. The objective of this review is to summarize the various existing data about risk of induced HPV lesions in immunocompromised patients to specify the management. METHODS: The Medline database was searched through the Pubmed portal, as well as the recommendations of various international learned societies. RESULTS: Situations with an increased risk are regardless of treatment: Human Immunodeficiency Virus (HIV) infection, transplants, lupus. Patients with chronic inflammatory bowel disease (IBD) and rheumatoid arthritis are at increased risk only when immunosuppressive therapy is required. Screening for dysplasic intraepithelial lesions in HIV+ patients should be more sustained than in the general population. Due to lack of data, recommendations for other conditions have been extrapolated from the management of HIV+ patients. HPV vaccination is effective in these populations, particularly at times when the immune system is the most effective. DISCUSSION: Identified immunocompromised populations are at higher risk of induced HPV lesions due to an incomplete immune response and should be screened on a sustained basis. In addition, HPV vaccination should be encouraged.
34745114 Intranuclear Delivery of HIF-1α-TMD Alleviates EAE via Functional Conversion of TH17 Cell 2021 T helper 17 (TH17) cells are involved in several autoimmune diseases such as multiple sclerosis (MS) and rheumatoid arthritis (RA). In addition to retinoic acid receptor-related orphan nuclear receptor gamma t (ROR-γt), hypoxia-inducible factor-1α (HIF-1α) is essential for the differentiation and inflammatory function of TH17 cells. To investigate the roles of HIF-1α in the functional regulation of TH17 cells under the normal physiological condition without genetic modification, the nucleus-transducible form of transcription modulation domain (TMD) of HIF-1α (ntHIF-1α-TMD) was generated by conjugating HIF-1α-TMD to Hph-1 protein transduction domain (PTD). ntHIF-1α-TMD was effectively delivered into the nucleus of T cells without cellular cytotoxicity. ntHIF-1α-TMD significantly blocked the differentiation of naïve T cells into TH17 cells in a dose-dependent manner via IL-17A and ROR-γt expression inhibition. However, T-cell activation events such as induction of CD69, CD25, and IL-2 and the differentiation potential of naïve T cells into TH1, TH2, or Treg cells were not affected by ntHIF-1α-TMD. Interestingly, TH17 cells differentiated from naïve T cells in the presence of ntHIF-1α-TMD showed a substantial level of suppressive activity toward the activated T cells, and the increase of Foxp3 and IL-10 expression was detected in these TH17 cells. When mRNA expression pattern was compared between TH17 cells and ntHIF-1α-TMD-treated TH17 cells, the expression of the genes involved in the differentiation and functions of TH17 cells was downregulated, and that of the genes necessary for immune-suppressive functions of Treg cells was upregulated. When the mice with experimental autoimmune encephalomyelitis (EAE) were treated with ntHIF-1α-TMD with anti-IL-17A mAb as a positive control, the therapeutic efficacy of ntHIF-1α-TMD in vivo was comparable with that of anti-IL-17A mAb, and ntHIF-1α-TMD-mediated therapeutic effect was contributed by the functional conversion of TH17 cells into immune-suppressive T cells. The results in this study demonstrate that ntHIF-1α-TMD can be a new therapeutic reagent for the treatment of various autoimmune diseases in which TH17 cells are dominant and pathogenic T cells.
34719401 Progressive fibrosing interstitial lung disease: prevalence and clinical outcome. 2021 Oct 31 BACKGROUND: The progressive fibrosing (PF) phenotype of interstitial lung disease (ILD) is characterised by worsening respiratory symptoms, lung function, and extent of fibrosis on high-resolution computed tomography. We aimed to investigate the prevalence and clinical outcomes of PF-ILD in a real-world cohort and assess the prognostic significance of the PF-ILD diagnostic criteria. METHODS: Clinical data of patients with fibrosing ILD other than idiopathic pulmonary fibrosis (IPF) consecutively diagnosed at a single centre were retrospectively reviewed. A PF phenotype was defined based on the criteria used in the INBUILD trial. RESULTS: The median follow-up duration was 62.7 months. Of the total of 396 patients, the mean age was 58.1 years, 39.9% were men, and rheumatoid arthritis-ILD was the most common (42.4%). A PF phenotype was identified in 135 patients (34.1%). The PF-ILD group showed lower forced vital capacity and total lung capacity (TLC) than the non-PF-ILD group. The PF-ILD group also showed poorer survival (median survival, 91.2 months vs. not reached; P < 0.001) than the non-PF-ILD group. In multivariable Cox analysis adjusted for age, DL(CO), HRCT pattern, and specific diagnosis, PF phenotype was independent prognostic factor (hazard ratio, 3.053; P < 0.001) in patients with fibrosing ILD. Each criterion of PF-ILD showed similar survival outcomes. CONCLUSIONS: Our results showed that approximately 34% of patients with non-IPF fibrosing ILD showed a progressive phenotype and a poor outcome similar to that of IPF, regardless of the diagnostic criteria used.
34717693 Incidence and risk factors associated with human albumin administration following total jo 2021 Oct 30 BACKGROUND: Enhanced recovery after surgery (ERAS) program advocates implementation of perioperative goal-directed fluid therapy and reduced application of colloidal fluids. It should be used reasonably selectively in high-risk patients despite the clear efficacy of human albumin (HA). Therefore, it is vital to identify the risk factors for the use of HA. This study aims to determine the incidence and risk factors of HA administration in patients undergoing total hip or knee arthroplasty (THA, TKA). METHODS: We identified patients undergoing THA or TKA in multiple institutions from 2014 to 2016 and collected patient demographics and perioperative variables. The criterion of HA administration was defined as a postoperative albumin level < 32 g/L or 32 to 35 g/L for at-risk patients. We compared 14 variables between patients who received HA administration and those who did not after stratification by the preoperative albumin (pre-ALB) level. Multivariable regressions identified the independent risk factors associated with HA administration. RESULTS: In total, 958 (20.3%) of 4713 patients undergoing THA and 410 (9.7%) of 4248 patients undergoing TKA received HA administration. In addition to pre-ALB < 35 g/L, preoperative anemia (odds ratio [OR] 2.12, P = 0.001; OR 1.39, P < 0.001) and drain use (OR 3.33, P = 0.001; OR 4.25, P < 0.001) were also independent risk factors for HA administration after THA regardless pre-ALB < 35 g/L or not, and patients undergoing TKA diagnosed of rheumatoid arthritis or ankylosing spondylitis tended to receive HA administration regardless pre-ALB < 35 g/L or not (OR 3.67, P = 0.002; OR 2.06, P < 0.001). CONCLUSIONS: The incidence of HA administration was high in patients undergoing THA or TKA, and several variables were risk factors for HA administration. This finding may aid surgeons in preoperatively identifying patients requiring HA administration and optimizing perioperative managements.
34688465 Tripterygium wilfordii multiglycoside-induced hepatotoxicity via inflammation and apoptosi 2021 Oct Tripterygium wilfordii multiglycoside (GTW) is a commonly used compound for the treatment of rheumatoid arthritis (RA) and immune diseases in clinical practice. However, it can induce liver injury and the mechanism of hepatotoxicity is still not clear. This study was designed to investigate GTW-induced hepatotoxicity in zebrafish larvae and explore the mechanism involved. The 72 hpf (hours post fertilization) zebrafish larvae were administered with different concentrations of GTW for three days and their mortality, malformation rate, morphological changes in the liver, transaminase levels, and histopathological changes in the liver of zebrafish larvae were detected. The reverse transcription-polymerase chain reaction (RT-PCR) was used to examine the levels of microRNA-122 (miR-122) and genes related to inflammation, apoptosis, cell proliferation and liver function. The results showed that GTW increased the mortality of zebrafish larvae, while significant malformations and liver damage occurred. The main manifestations were elevated levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), significant liver atrophy, vacuoles in liver tissue, sparse cytoplasm, and unclear hepatocyte contours. RT-PCR results showed that the expression of miR-122 significantly decreased by GTW; the mRNA levels of inflammation-related genes il1β, il6, tnfα, il10, cox2 and ptges significantly increased; the mRNA level of tgfβ significantly decreased; the mRNA levels of apoptosis-related genes, caspase-8 and caspase-9, significantly increased; the mRNA level of bcl2 significantly decreased; the mRNA levels of cell proliferation-related genes, top2α and uhrf1, significantly reduced; the mRNA levels of liver function-related genes, alr and cyp3c1, significantly increased; and the mRNA level of cyp3a65 significantly decreased. In zebrafish, GTW can cause increased inflammation, enhanced apoptosis, decreased cell proliferation, and abnormal expression of liver function-related genes, leading to abnormal liver structure and function and resulting in hepatotoxicity.
34655404 Mycofabrication of AgONPs derived from Aspergillus terreus FC36AY1 and its potent antimicr 2021 Dec BACKGROUND: There is an emergency need for the natural therapeutic agents to treat arious life threatening diseases such as cardio- vascular disease, Rheumatoid arthritis and cancer. Among these diseases, cancer is found to be the second life threatening disease; in this view the present study focused to synthesize the silver oxide nanoparticles (AgONPs) from endophytic fungus. METHODS: The endophytic fungus was isolated from a medicinal tree Aegle marmelos (Vilva tree) and the potential strain was screened through antagonistic activity. The endophytic fungus was identified through microscopic (Lactophenol cotton blue staining and spore morphology in culture media) and Internal Transcribed Spacer (ITS) 1, ITS 4 and 18S rRNA amplification. The endophyte was cultured for the synthesis of AgONPs and the synthesized NPs were characterized through UV- Vis, FT- IR, EDX, XRD and SEM. The synthesized AgONPs were determined for antimicrobial, antioxidant and anti- angiogenic activity. RESULTS: About 35 pigmented endophytic fungi were isolated, screened for antagonistic activity against 12 pathogens and antioxidant activity through DPPH radical scavenging assay; among the isolates, FC36AY1 explored the highest activity and the strain FC36AY1 was identified as Aspergillus terreus. The AgONPs were synthesized from the strain FC36AY1 and characterized for its confirmation, functional groups, nanostructures with unit cell dimensions, size and shape, presence of elements through UV-Vis spectrophotometry, FT-IR, XRD, SEM with EDX analysis. The myco-generated AgONPs manifested their antimicrobial and antioxidant properties with maximum activity at minimum concentration. Moreover, the inhibition of angiogenesis by the AgONPs in Hen's Egg Test on the Chorio-Allantoic Membrane analysis were tested on the eggs of Chittagong breed evinced at significant bioactivity least concentration at 0.1 µg/mL. CONCLUSIONS: Thus, the results of this study revealed that the fungal mediated AgONPs can be exploited as potential in biomedical applications.
34635393 RORγt protein modifications and IL-17-mediated inflammation. 2021 Nov RORγt, the master transcription factor for cytokine interleukin (IL)-17, is expressed explicitly in Th17 cells, γδT cells, and type 3 innate lymphoid cells in mice and humans. Since dysregulated IL-17 expression is strongly linked to several human inflammatory diseases, the RORγt-IL-17 axis has been the focus of intense research. Recently, several studies have shown that RORγt is modified by multiple post-translational mechanisms, including ubiquitination, acetylation, SUMOylation, and phosphorylation. This review discusses how post-translational modifications modulate RORγt function and its turnover to regulate IL-17-driven inflammation. Broad knowledge of these pathways is crucial for a clear understanding of the pathogenic role of RORγt(+)IL-17(+) cells and for the development of putative therapeutic strategies to target IL-17-driven diseases such as multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, and inflammatory bowel disease.
34595860 Incidence and Reappraisal of Known Risk Factors Associated with Carpal Tunnel Syndrome: A 2021 Oct BACKGROUND AND PURPOSE: Previous studies have revealed various risk factors for carpal tunnel syndrome (CTS), but few large-scale studies have been conducted. We used data from the 11-year, longitudinal, nationwide population-based National Health Insurance Service-National Health Screening cohort to identify the actual risk factors for CTS. METHODS: We collected patients with CTS newly diagnosed using electrodiagnostic studies while excluding radiculopathy, plexopathy, or polyneuropathy, which can be confused with CTS. The crude and standardized incidence rates of CTS were calculated. Univariate and multivariate Cox analyses and the incidence of CTS were used to identify the risk factors for newly diagnosed CTS. RESULTS: The standardized incidence was 130.8/100,000 person-years based on the World Health Organization World Standard Population as a reference. Multivariate Cox analysis identified that the risk factors for CTS were being middle-aged, female, and obese, and having rheumatoid arthritis and Raynaud's syndrome, whereas gout and hypothyroidism were not risk factors. Diabetes and end-stage renal disease did not show a significant hazard ratio, although it is implicit that the durations of these diseases affect the development of CTS. CONCLUSIONS: This study calculated the incidence of CTS and reappraised the associated risk factors found in previous studies. This information will be helpful for determining the pathophysiology of CTS, and hence aid the establishment of effective new public health policies.
34594157 Natural Killer T (NKT) Cells and Periodontitis: Potential Regulatory Role of NKT10 Cells. 2021 Natural killer T (NKT) cells constitute a unique subset of T lymphocytes characterized by specifically interacting with antigenic glycolipids conjugated to the CD1d receptor on antigen-presenting cells. Functionally, NKT cells are capable of performing either effector or suppressor immune responses, depending on their production of proinflammatory or anti-inflammatory cytokines, respectively. Effector NKT cells are subdivided into three subsets, termed NKT1, NKT2, and NKT17, based on the cytokines they produce and their similarity to the cytokine profile produced by Th1, Th2, and Th17 lymphocytes, respectively. Recently, a new subgroup of NKT cells termed NKT10 has been described, which cooperates and interacts with other immune cells to promote immunoregulatory responses. Although the tissue-specific functions of NKT cells have not been fully elucidated, their activity has been associated with the pathogenesis of different inflammatory diseases with immunopathogenic similarities to periodontitis, including osteolytic pathologies such as rheumatoid arthritis and osteoporosis. In the present review, we revise and discuss the pathogenic characteristics of NKT cells in these diseases and their role in the pathogenesis of periodontitis; particularly, we analyze the potential regulatory role of the IL-10-producing NKT10 cells.
34049183 The role of oral microbiome in respiratory health and diseases. 2021 Aug The oral cavity (mouth) has various microbial habitats, including, teeth, gingival sulcus, gingiva, tongue, inner cheek, hard palate, and soft palate. The human oral cavity houses the second most diverse microbiome in the body harboring over 700 bacterial species. The fine-tuned equilibrium of the oral microbiome ecosystem maintains oral health. Oral dysbiosis caused by food habits and poor oral hygiene leads to various oral diseases such as periodontitis, caries, gingivitis, and oral cancer. Recent advances in technology have revealed the correlation between the oral microbiome and systemic diseases such as pulmonary diseases, cardiovascular diseases, rheumatoid arthritis, Alzheimer's disease, and other metabolic diseases. Since the oral cavity directly connects with the upper respiratory tract, the oral microbiome has easier access to the respiratory system compared to other organ systems. Direct aspiration of oral microflora in the respiratory system and oral dysbiosis-induced host immune reaction and inflammation are mainly responsible for various pulmonary complications. Numbers of literature have reported the correlation between oral diseases and pulmonary diseases, suggesting the possible role of the oral microbiome in respiratory diseases such as chronic obstructive pulmonary diseases, pneumonia, lung cancer, etc. This paper reviews the current evidence in establishing a link between the oral microbiome and pulmonary diseases. We also discuss future research directions focusing on the oral microbiome to unravel novel therapeutic approaches that could prevent or treat the various pulmonary complications.
34025650 Anti-TNF-α agents Modulate SARS-CoV-2 Receptors and Increase the Risk of Infection Throug 2021 Although millions of patients with underlining conditions are treated primarily with anti-TNF-α agents, little is known about the safety of this standard therapy during the coronavirus disease-2019 (COVID-19) pandemic. In this study, we investigated the effect of anti-TNF-α monoclonal antibodies on the cellular entry mechanism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and increasing the risk of COVID-19 development. We focused on the expression of angiotensin-converting enzyme II (ACE2), type II transmembrane serine proteases (TMPRSS2)/TNF-α converting enzyme (TACE) ratio. We also investigated the involvement of Notch-1 signaling and its downstream influence on IL-6, myeloid cell leukemia sequence-1(MCL-1) in the anti-TNF-α mode of action and increased the susceptibility to Mycobacterium avium subspecies paratuberculosis (MAP) infection. Surprisingly, anti-TNF-α downregulated ACE2 expression by 0.46-fold and increased TMPRSS2/TACE ratio by 44% in THP-1 macrophages. Treatment of macrophages with rIL-6 also downregulated ACE2 and increased TMPRSS2/TACE ratio by 54%. Interestingly, anti-TNF-α treatment upregulated Notch-1, IL-6, and MCL-1 by 1.3, 1.2, and 1.9-fold, respectively, and increased viability and burden of MAP infection in macrophages. Blocking Notch signaling doubled ACE2 expression, decreased TMPRSS2/TACE ratio by 38%, and reduced MAP viability by 56%. In a small group of patients, ACE2 level was significantly lower in the plasma from rheumatoid arthritis (RA) patients on anti-TNF-α treatment compared to healthy control. The data in this critical study demonstrated that through Notch-1/IL-6 signaling, anti-TNF-α agents decreased ACE2 expression and shedding through TMPRSS2/TACE modulation and increased the susceptibility to infection. Overall, this study warns against anti-TNF-α therapy in some patients with underlining inflammatory conditions during the COVID-19 pandemic. The findings should impact current guidelines regarding treatment decisions of patients on anti-TNF-α during the COVID-19 pandemic.
34020044 The association between vitamin D and acute rejection in human kidney transplantation: A s 2021 Aug BACKGROUND: Vitamin D (VitD) deficiency is associated with several diseases such as multiple sclerosis, rheumatoid arthritis, respiratory infection, and so forth. In the field of transplantation (kidney transplantation), some studies reported that patients with VitD deficiency are of increased chance of acute rejection, but other studies did not show such a chance. On the other hand, since VitD is a modulatory factor and can reduce the inflammatory response, understanding the exact role of it in transplantation may contribute to tolerance condition in these patients. METHODS: The electronic databases, including PubMed, Scopus, Embase, ProQuest, Web of Science, and Google Scholar, were searched for eligible studies. In general, 14 studies with a total of 4770 patients were included in this meta-analysis. Regarding the methodological heterogeneity, we selected a random-effects combination model. Moreover, OR was chosen as an effect size for this study. RESULTS: After the combination of 14 studies, we showed that patients in the VitD-deficient group had an 82% increased chance of acute rejection compared with patients in the VitD-sufficient group, and this effect was significant (OR 1.82; 95% confidence interval [CI] [1.29, 2.56]; I(2) = 52.3%). This result was significant, and, regarding the narrow CI, it can be a conclusive result. Study quality and gender variables were the main sources of inconsistent results in the primary studies. Moreover, using meta-regression, we showed that VitD deficiency (independent from the estimated glomerular filtration rate (eGFR) of patients) increased the chance of acute rejection. CONCLUSION: The normal VitD status of patients a few days before and after transplantation can reduce the chance of acute rejection.
33711047 Association between dementia and systemic rheumatic disease: A nationwide population-based 2021 OBJECTIVES: Systemic rheumatic disease is characterized by autoimmunity and systemic inflammation and affects multiple organs. Few studies have investigated whether autoimmune diseases increase the risk of dementia. Herein, we evaluate the relationship between systemic rheumatic disease and dementia through a population-based study using the Korean National Health Insurance Service (NHIS) claims database. METHODS: We conducted a nationwide population-based study using the Korean NHIS database, consisting of individuals who submitted medical claims from 2002-2013. Dementia was defined as having an acetylcholinesterase inhibitors (AChEIs) prescription along with symptoms satisfying the Alzhemier's disease (AD) International Classification of Diseases (ICD)-10 codes (F00 or G30), or vascular dementia (VaD; ICD-10 or F01) criteria. Control subjects were matched to the dementia patients by age and sex. The study group was limited to those diagnosed with rheumatic disease at least 6 months prior to diagnosis of dementia. Rheumatic disease was defined by the following ICD-10 codes: Rheumatoid arthritis (RA: M05), Sjögren's syndrome (SS: M35), systemic lupus erythematosus (SLE: M32), and Behcet's disease (BD: M35.2). RESULTS: Of the 6,028 dementia patients, 261 (4.3%) had RA, 108 (1.6%) had SS, 12 (0.2%) had SLE, and 6 (0.1%) had BD. SLE history was significantly higher in dementia patients (0.2%) than in controls (0.1%) and was associated with dementia (odds ratio [OR], 2.48; 95% confidence interval [CI], 1.19-5.15). In subgroup analysis, SLE significantly increased dementia risk, regardless of dementia type (AD: OR, 2.29; 95% CI, 1.06-4.91; VaD: OR, 4.54; 95% CI, 1.36-15.14). However, these associations were not sustained in the mild CCI or elderly group. CONCLUSION: SLE was independently associated with a higher risk of dementia, including AD and VaD when compared to the control group, even after adjustment. SLE patients (<65 years old) are a high-risk group for early vascular dementia and require screening for early detection and active prevention.
33629254 CIGB-258, a peptide derived from human heat-shock protein 60, decreases hyperinflammation 2021 May Hyperinflammation distinguishes COVID-19 patients who develop a slight disease or none, from those progressing to severe and critical conditions. CIGB-258 is a therapeutic option for the latter group of patients. This drug is an altered peptide ligand (APL) derived from the cellular stress protein 60 (HSP60). In preclinical models, this peptide developed anti-inflammatory effects and increased regulatory T cell (Treg) activity. Results from a phase I clinical trial with rheumatoid arthritis (RA) patients indicated that CIGB-258 was safe and reduced inflammation. The aim of this study was to examine specific biomarkers associated with hyperinflammation, some cytokines linked to the cytokine storm granzyme B and perforin in a cohort of COVID-19 patients treated with this peptide. All critically ill patients were under invasive mechanical ventilation and received the intravenous administration of 1 or 2 mg of CIGB-258 every 12 h. Seriously ill patients were treated with oxygen therapy receiving 1 mg of CIGB-258 every 12 h and all patients recovered from their severe condition. Biomarker levels associated with hyperinflammation, such as interleukin (IL)-6, IL-10, tumor necrosis factor (TNF-α), granzyme B, and perforin, significantly decreased during treatment. Furthermore, we studied the ability of CIGB-258 to induce Tregs in COVID-19 patients and found that Tregs were induced in all patients studied. Altogether, these results support the therapeutic potential of CIGB-258 for diseases associated with hyperinflammation. Clinical trial registry: RPCEC00000313.
33614031 The complex interplay between endoplasmic reticulum stress and the NLRP3 inflammasome: a p 2021 Inflammation is the result of a complex network of cellular and molecular interactions and mechanisms that facilitate immune protection against intrinsic and extrinsic stimuli, particularly pathogens, to maintain homeostasis and promote tissue healing. However, dysregulation in the immune system elicits excess/abnormal inflammation resulting in unintended tissue damage and causes major inflammatory diseases including asthma, chronic obstructive pulmonary disease, atherosclerosis, inflammatory bowel diseases, sarcoidosis and rheumatoid arthritis. It is now widely accepted that both endoplasmic reticulum (ER) stress and inflammasomes play critical roles in activating inflammatory signalling cascades. Notably, evidence is mounting for the involvement of ER stress in exacerbating inflammasome-induced inflammatory cascades, which may provide a new axis for therapeutic targeting in a range of inflammatory disorders. Here, we comprehensively review the roles, mechanisms and interactions of both ER stress and inflammasomes, as well as their interconnected relationships in inflammatory signalling cascades. We also discuss novel therapeutic strategies that are being developed to treat ER stress- and inflammasome-related inflammatory disorders.
33589796 NOD-like receptors in autoimmune diseases. 2021 Nov Autoimmune diseases are chronic immune diseases characterized by dysregulation of immune system, which ultimately results in a disruption in self-antigen tolerance. Cumulative data show that nucleotide-binding and oligomerization domain (NOD)-like receptors (NLRs) play essential roles in various autoimmune diseases, such as inflammatory bowel disease (IBD), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), psoriasis, multiple sclerosis (MS), etc. NLR proteins, consisting of a C-terminal leucine-rich repeat (LRR), a central nucleotide-binding domain, and an N-terminal effector domain, form a group of pattern recognition receptors (PRRs) that mediate the immune response by specifically recognizing cellular pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) and triggering numerous signaling pathways, including RIP2 kinase, caspase-1, nuclear factor kappa B (NF-κB), mitogen-activated protein kinase (MAPK) and so on. Based on their N-terminal domain, NLRs are divided into five subfamilies: NLRA, NLRB, NLRC, NLRP, and NLRX1. In this review, we briefly describe the structures and signaling pathways of NLRs, summarize the recent progress on NLR signaling in the occurrence and development of autoimmune diseases, as well as highlight numerous natural products and synthetic compounds targeting NLRs for the treatment of autoimmune diseases.