Chronic Inflammatory Conditions Research Articles

CGAS-STING signaling in cardiovascular diseases

Sterile inflammation, characterized by a persistent chronic inflammatory state, significantly contributes to the progression of various diseases such as autoimmune, metabolic, neurodegenerative, and cardiovascular disorders. Recent evidence has increasingly highlighted the intricate connection between inflammatory responses and cardiovascular diseases, underscoring the pivotal role of the Stimulator of Interferon Genes (STING). STING is crucial for the secretion of type I interferon (IFN) and proinflammatory cytokines in response to cytosolic nucleic acids, playing a vital role in the innate immune system. Specifically, research has underscored the STING pathway involvement in unregulated inflammations, where its aberrant activation leads to a surge in inflammatory events, enhanced IFN I responses, and cell death. The primary pathway triggering STING activation is the cyclic GMP-AMP synthase (cGAS) pathway. This review delves into recent findings on STING and the cGAS-STING pathways, focusing on their regulatory mechanisms and impact on cardiovascular diseases. It also discusses the latest advancements in identifying antagonists targeting cGAS and STING, and concludes by assessing the potential of cGAS or STING inhibitors as treatments for cardiovascular diseases.

SDH, a novel diarylheptane compound, alleviates dextran sulfate sodium (DSS)-induced colitis by reducing Th1/Th2/Th17 induction and regulating the gut microbiota in mice

Ulcerative colitis, a chronic inflammatory condition affecting the rectum and colon to varying degrees, is linked to a dysregulated immune response and the microbiota. Sodium (aS,9R)-3-hydroxy-16,17-dimethoxy-15-oxidotricyclo[12.3.1.12,6]nonadeca-1(18),2,4,6(19),14,16-hexene-9-yl sulfate hydrate (SDH) emerges as a novel diarylheptane compound aimed at treating inflammatory bowel diseases. However, the mechanisms by which SDH modulates these conditions remain largely unknown. In this study, we assessed SDH's impact on the clinical progression of dextran sodium sulfate (DSS)-induced ulcerative colitis. Our results demonstrated that SDH significantly mitigated the symptoms of DSS-induced colitis, reflected in reduced disease activity index scores, alleviation of weight loss, shortening of the colorectum, and reduction in spleen swelling. Notably, SDH decreased the proportion of Th1/Th2/Th17 cells and normalized inflammatory cytokine levels in the colon. Furthermore, SDH treatment modified the gut microbial composition in mice with colitis, notably decreasing Bacteroidetes and Proteobacteria populations while substantially increasing Firmicutes, Actinobacteria, and Patescibacteria. In conclusion, our findings suggest that SDH may protect the colon from DSS-induced colitis through the regulation of Th1/Th2/Th17 cells and gut microbiota, offering novel insights into SDH's therapeutic potential.

Comparison of the Efficacy of Clascoterone, Trifarotene, and Tazarotene for the Treatment of Acne: A Systematic Literature Review and Meta-Analysis.

Acne vulgaris, a chronic inflammatory condition, is associated with significant physical and psychosocial burden. Since 2019, three new topical agents for acne vulgaris have been approved in the USA and Canada. We performed a systematic review and meta-analysis to compare the efficacy between twice-daily clascoterone cream 1%, once-daily trifarotene 0.005% cream, and once-daily tazarotene 0.045% lotion for acne treatment. Randomized controlled trials (RCTs) comparing clascoterone, trifarotene, or tazarotene with vehicle in patients with moderate-to-severe acne were identified from a systematic literature review and included in a meta-analysis. Primary outcomes were percentage reduction in inflammatory and noninflammatory lesion count (ILC and NILC, respectively) and treatment success rate (≥ 2-grade improvement in Investigator's Global Assessment or Evaluator's Global Severity Score and a rating of clear or almost clear) at week 12. DerSimonian and Laird random-effects models with the inverse variance method were used to calculate the mean difference (MD) for percentage reduction in ILC and NILC, and odds ratios (ORs) for the rate of treatment success. Six Phase 3 RCTs were included in the meta-analysis. The analyses showed robust differences favoring the interventions for ILC (MD: - 11.5; 95% confidence interval [CI]: - 14.39, - 8.62), NILC (MD: - 12.25; 95% CI: - 15.21, - 9.29), and treatment success rate (OR: 2.14; 95% CI: 1.81, 2.53). No differences were observed between clascoterone, trifarotene, and tazarotene for ILC (MD: - 12.8, - 11.2, and - 10.1, respectively), NILC (MD: - 11.6, - 13.9, and - 12.8, respectively), or treatment success rate (OR: 2.9, 1.9, and 2.1, respectively (all P > 0.05). No significant differences in efficacy were observed between clascoterone, trifarotene, and tazarotene after 12weeks of treatment in patients with moderate-to-severe acne. Differences in application frequency and safety profile should also be taken into consideration when making treatment decisions.

Role of IL-33/ST2 Pathway in Inflammatory Bowel Disease: An Overview and Future Perspectives

Inflammatory bowel disease (IBD) represents a heterogenous and complex group of idiopathic chronic inflammatory conditions affecting the gastrointestinal tract and other extraintestinal systems with rising global incidences. The interplay of genetic predisposition and environmental factors contributes to its pathogenesis. Among the key cytokines implicated in IBD molecular alterations, IL-33 stands out for its multifaceted roles in both pathogenesis and repair mechanisms. IL-33, known for its action in initiating immune responses, is closely associated with Th2 immunity and is considered a potent inflammatory factor with dual functions, acting both as a pro-inflammatory cytokine and a transcriptional regulator. Primarily expressed by non-hematopoietic cells in the gastrointestinal tract, IL-33 interacts with its receptor, ST2, to modulate immune responses. In IBD, dysregulated IL-33 expression exacerbates mucosal inflammation, compromising barrier integrity and promoting tissue damage and fibrosis. Additionally, IL-33 plays a complex role in IBD-related colorectal cancer (CRC), affecting tumor progression and angiogenesis. This review summarizes the multifaceted roles of IL-33 in gastrointestinal health and disease, emphasizing its significance in the pathogenesis of IBD and CRC. Moreover, we thought it of interest to provide new insights into potential therapeutic avenues targeting IL-33 signaling for the management of these debilitating conditions.

BCG activation of trained immunity is associated with induction of cross reactive COVID-19 antibodies in a BCG vaccinated population

Background Pakistan is endemic to a diverse set of parasitic, mycobacterial and viral diseases. The recognition of BCG Trained Immunity (TI) led us to postulate that the continued presence of BCG-TI may play a protective role, previously reported for both infectious and noninfectious conditions. Most of the previous studies have addressed the issue of BCG-TI in the paediatric populations. This study addressed the key issue of maintenance of BCG-TI in a wider age range (adolescent and adults) to identify the strength and quality of the immune responses. Objective To assess the BCG-induced recall responses in healthy individuals by cytokines secreted from the TI network and its potential role in providing cross-protection against COVID-19 and other viral infections. Study design In this cross-sectional study, healthy young adults and adolescents (n = 20) were recruited from 16–40 years of age, with no prior history of TB treatment, autoimmune, or chronic inflammatory condition. Methods BCG-induced cytokine responses were assessed using prototypic markers for cells of the TI network [macrophages [M1 (TNFα, IFNγ), M2 (IL10)], NK (IL2), Gamma delta (γδ) T (IL17, IL4)] and SARS CoV2 IgG antibodies against RBD using short-term (12 hrs.) cultures assay. Results Significant differences were observed in the magnitude of recall responses to BCG with macrophage cytokines showing the highest mean levels of TNFα (9148 pg/ml) followed by IL10 (488 pg/ml) and IFNγ (355 pg/ml). The ratio of unstimulated vs.BCG-stimulated cytokines was 132 fold higher for TNFα, 40 fold fo r IL10, and 27 fold for IFNγ. Furthermore, SARS-CoV-2 antibodies were also detected in unstimulated plasma which showed cross reactivity with BCG. Conclusion The presence of cross reactive antibodies to SARS-CoV-2 and the relative ratio of pro- and anti-inflammatory cytokines secreted by activated TI cellular network may play a pivotal role in protection in the early stages of infection as observed during the COVID-19 pandemic in the younger age groups resulting in lower morbidity and mortality.

Considerations in Discoid Lupus: A Comprehensive Review

Discoid lupus erythematosus (DLE) is a chronic inflammatory skin condition that can lead to disfiguring scarring and pigmentary changes. This review article provides an overview of the epidemiology, pathogenesis, clinical manifestations, and treatment options for DLE. Special considerations in the management of DLE, including the role of photoprotection, topical and systemic therapies, and the importance of multidisciplinary care, are discussed. The impact of DLE on quality of life and psychosocial well-being is also addressed. A better understanding of the complexities of DLE can aid clinicians in providing comprehensive care to patients with this challenging condition.

Blood biomarkers of Alzheimer's disease in the community: Variation by chronic diseases and inflammatory status.

We explored the variations of blood biomarkers of Alzheimer's disease (AD) by chronic diseases and systemic inflammation. We explored the association of AD blood biomarkers with chronic diseases and systemic inflammation (interleukin-6 [IL-6]), in 2366 dementia-free participants of the Swedish National Study on Aging and Care-in Kungsholmen, using quantile regression models. A greater number of co-occurring chronic diseases was associated with higher concentrations of phosphorylated-tau 181 (p-tau181), total-tau (t-tau), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) (p<0.01). Anemia, kidney, cerebrovascular, and heart diseases were associated with variations in the levels of AD blood biomarkers. Participants in the highest (vs. lowest) interleukin-6 (IL-6) tertile had higher NfL concentration. Systemic inflammation amplified the associations between several chronic diseases and p-tau181, t-tau, NfL, and GFAP. In the community, the concentration of AD blood biomarkers varies in relation to medical conditions and systemic inflammation. Recognizing these influences is crucial for the accurate interpretation and clinical implementation of blood biomarkers. Participants with a complex clinical profile (i.e., multiple co-occurring diseases or specific disease combinations) display elevated levels of AD blood-biomarkers. Anemia, heart, cerebrovascular, and kidney diseases are associated with variations is the levels of AD blood biomarkers in cognitively intact older adults. Systemic inflammation amplifies the association between several chronic diseases and AD blood biomarkers.

The immune and microbial homeostasis determines the Candida-mast cells cross-talk in celiac disease.

Celiac disease (CD) is an autoimmune enteropathy resulting from an interaction between diet, genome, and immunity. Although many patients respond to a gluten-free diet, in a substantive number of individuals, the intestinal injury persists. Thus, other factors might amplify the ongoing inflammation. Candida albicans is a commensal fungus that is well adapted to the intestinal life. However, specific conditions increase Candida pathogenicity. The hypothesis that Candida may be a trigger in CD has been proposed after the observation of similarity between a fungal wall component and two CD-related gliadin T-cell epitopes. However, despite being implicated in intestinal disorders, Candida may also protect against immune pathologies highlighting a more intriguing role in the gut. Herein, we postulated that a state of chronic inflammation associated with microbial dysbiosis and leaky gut are favorable conditions that promote C. albicans pathogenicity eventually contributing to CD pathology via a mast cells (MC)-IL-9 axis. However, the restoration of immune and microbial homeostasis promotes a beneficial C. albicans-MC cross-talk favoring the attenuation of CD pathology to alleviate CD pathology and symptoms.

Amyloid, Crohn’s disease, and Alzheimer’s disease - are they linked?

Crohn’s disease (CD) is a chronic inflammatory disease that most frequently affects part of the distal ileum, but it may affect any part of the gastrointestinal tract. CD may also be related to systemic inflammation and extraintestinal manifestations. Alzheimer’s disease (AD) is the most common neurodegenerative disease, gradually worsening behavioral and cognitive functions. Despite the meaningful progress, both diseases are still incurable and have a not fully explained, heterogeneous pathomechanism that includes immunological, microbiological, genetic, and environmental factors. Recently, emerging evidence indicates that chronic inflammatory condition corresponds to an increased risk of neurodegenerative diseases, and intestinal inflammation, including CD, increases the risk of AD. Even though it is now known that CD increases the risk of AD, the exact pathways connecting these two seemingly unrelated diseases remain still unclear. One of the key postulates is the gut-brain axis. There is increasing evidence that the gut microbiota with its proteins, DNA, and metabolites influence several processes related to the etiology of AD, including β-amyloid abnormality, Tau phosphorylation, and neuroinflammation. Considering the role of microbiota in both CD and AD pathology, in this review, we want to shed light on bacterial amyloids and their potential to influence cerebral amyloid aggregation and neuroinflammation and provide an overview of the current literature on amyloids as a potential linker between AD and CD.

Identification of master regulator genes controlling pathogenic CD4+ T cell fate in inflammatory bowel disease through transcriptional network analysis

Inflammatory bowel diseases (IBD) are a group of chronic inflammatory conditions of the gastrointestinal tract associated with multiple pathogenic factors, including dysregulation of the immune response. Effector CD4+ T cells and regulatory CD4+ T cells (Treg) are central players in maintaining the balance between tolerance and inflammation. Interestingly, genetic modifications in these cells have been implicated in regulating the commitment of specific phenotypes and immune functions. However, the transcriptional program controlling the pathogenic behavior of T helper cells in IBD progression is still unknown. In this study, we aimed to find master transcription regulators controlling the pathogenic behavior of effector CD4+ T cells upon gut inflammation. To achieve this goal, we used an animal model of IBD induced by the transfer of naïve CD4+ T cells into recombination-activating gene 1 (Rag1) deficient mice, which are devoid of lymphocytes. As a control, a group of Rag1−/− mice received the transfer of the whole CD4+ T cells population, which includes both effector T cells and Treg. When gut inflammation progressed, we isolated CD4+ T cells from the colonic lamina propria and spleen tissue, and performed bulk RNA-seq. We identified differentially up- and down-regulated genes by comparing samples from both experimental groups. We found 532 differentially expressed genes (DEGs) in the colon and 30 DEGs in the spleen, mostly related to Th1 response, leukocyte migration, and response to cytokines in lamina propria T-cells. We integrated these data into Gene Regulatory Networks to identify Master Regulators, identifying four up-regulated master gene regulators (Lef1, Dnmt1, Mybl2, and Jup) and only one down-regulated master regulator (Foxo3). The altered expression of master regulators observed in the transcriptomic analysis was confirmed by qRT-PCR analysis and found an up-regulation of Lef1 and Mybl2, but without differences on Dnmt1, Jup, and Foxo3. These two master regulators have been involved in T cells function and cell cycle progression, respectively. We identified two master regulator genes associated with the pathogenic behavior of effector CD4+ T cells in an animal model of IBD. These findings provide two new potential molecular targets for treating IBD.

Ziziphus jujuba Miller Ethanol Extract Restores Disrupted Intestinal Barrier Function via Tight Junction Recovery and Reduces Inflammation

Inflammatory bowel disease (IBD) is a chronic inflammatory condition caused by the disruption of the intestinal barrier. The intestinal barrier is maintained by tight junctions (TJs), which sustain intestinal homeostasis and prevent pathogens from entering the microbiome and mucosal tissues. Ziziphus jujuba Miller (Z. jujuba) is a natural substance that has been used in traditional medicine as a therapy for a variety of diseases. However, in IBD, the efficacy of Z. jujuba is unknown. Therefore, we evaluated ZJB in Caco2 cells and a dextran sodium sulfate (DSS)-induced mouse model to demonstrate its efficacy in IBD. Z. jujuba extracts were prepared using 70% ethanol and were named ZJB. ZJB was found to be non-cytotoxic and to have excellent antioxidant effects. We confirmed its anti-inflammatory properties via the down-regulation of inflammatory factors, including inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). To evaluate the effects of ZJB on intestinal barrier function and TJ improvement, the trans-epithelial electrical resistance (TEER) and fluorescein isothiocyanate-dextran 4 kDa (FITC-Dextran 4) permeability were assessed. The TEER value increased by 61.389% and permeability decreased by 27.348% in the 200 μg/mL ZJB group compared with the 50 ng/mL IL-6 group after 24 h. Additionally, ZJB alleviated body weight loss, reduced the disease activity index (DAI) score, and induced colon shortening in 5% DSS-induced mice; inflammatory cytokines, tumor necrosis factor (TNF)-α, and interleukin (IL)-6 were down-regulated in the serum. TJ proteins, such as Zonula occludens (ZO)-1 and occludin, were up-regulated by ZJB in an impaired Caco2 mouse model. Additionally, according to the liquid chromatography results, in tandem with mass spectrometry (LC-MS/MS) analysis, seven active ingredients were detected in ZJB. In conclusion, ZJB down-regulated inflammatory factors, protected intestinal barrier function, and increased TJ proteins. It is thus a safe, natural substance with the potential to be used as a therapeutic agent in IBD treatment.

Particles in Exhaled Air (PExA): Clinical Uses and Future Implications

Access to distal airway samples to assess respiratory diseases is not straightforward and requires invasive procedures such as bronchoscopy and bronchoalveolar lavage. The particles in exhaled air (PExA) device provides a non-invasive means of assessing small airways; it captures distal airway particles (PEx) sized around 0.5–7 μm and contains particles of respiratory tract lining fluid (RTLF) that originate during airway closure and opening. The PExA device can count particles and measure particle mass according to their size. The PEx particles can be analysed for metabolites on various analytical platforms to quantitatively measure targeted and untargeted lung specific markers of inflammation. As such, the measurement of distal airway components may help to evaluate acute and chronic inflammatory conditions such as asthma, chronic obstructive pulmonary disease, acute respiratory distress syndrome, and more recently, acute viral infections such as COVID-19. PExA may provide an alternative to traditional methods of airway sampling, such as induced sputum, tracheal aspirate, or bronchoalveolar lavage. The measurement of specific biomarkers of airway inflammation obtained directly from the RTLF by PExA enables a more accurate and comprehensive understanding of pathophysiological changes at the molecular level in patients with acute and chronic lung diseases.

DNA Nanostructures Treat Inflammatory Bowel Disease through ROS Scavenging and Gut Microbiota Modulation

AbstractInflammatory bowel disease (IBD) encompasses a collection of chronic inflammatory conditions impacting the gastrointestinal tract, with a discernible global rise in prevalence and severity. The overabundance of reactive oxygen species (ROS) in the intestinal environment leads disruption of local redox homeostasis, and perturbation of the gut microbiota, exacerbating IBD. Consequently, mitigating excess ROS and preserving gut microbiota homeostasis have emerged as effective approaches for IBD management. In this study, a triangular DNA origami nanostructure loaded with siRNA targeting tumor necrosis factor α (siTNF‐αtDON) is introduced for this purpose. This nanostructure demonstrates efficacy in eliminating ROS within cells closely associated with IBD, diminishing inflammation, and ameliorating disorders in gut microbiota, as evidenced in an IBD mouse model. Furthermore, this investigation demonstrates the effects of siTNF‐αtDON on related inflammatory signaling pathways, including NF‐κB, MAPK/ERK and Keap1/Nrf2. Collectively, this study offers insights into the potential utilization of DNA nanostructures as antioxidants and gut microbiota modulators, presenting promising avenues for the IBD treatment.

MiR-148a-3p/SIRT7 Axis Relieves Inflammatory-Induced Endothelial Dysfunction

In endothelial cells, miR-148a-3p is involved in several pathological pathways, including chronic inflammatory conditions. However, the molecular mechanism of miR-148a-3p in endothelial inflammatory states is, to date, not fully elucidated. To this end, we investigated the involvement of miR-148a-3p in mitochondrial dysfunction and cell death pathways in human aortic endothelial cells (teloHAECs) treated with interleukin-6 (IL-6), a major driver of vascular dysfunction. The results showed that during IL6-activated inflammatory pathways, including increased protein levels of sirtuin 7 (SIRT7) (p &lt; 0.01), mitochondrial stress (p &lt; 0.001), and apoptosis (p &lt; 0.01), a decreased expression of miR-148a-3p was observed (p &lt; 0.01). The employment of a miR-148a mimic counteracted the IL-6-induced cytokine release (p &lt; 0.01) and apoptotic cell death (p &lt; 0.01), and ameliorated mitochondria redox homeostasis and respiration (p &lt; 0.01). The targeted relationship between miR-148a-3p and SIRT7 was predicted by a bioinformatics database analysis and validated via the dual-luciferase reporter assay. Mechanistically, miR-148a-3p targets the 3′ untranslated regions of SIRT7 mRNA, downregulating its expression (p &lt; 0.01). Herein, these in vitro results support the role of the miR-148a-3p/SIRT7 axis in counteracting mitochondrial damage and apoptosis during endothelial inflammation, unveiling a novel target for future strategies to prevent endothelial dysfunction.

Evaluation of the Protective and Healing Effects of Heracleum lasiopetalum Boiss on a Modified Acetic Acid-Induced Ulcerative Colitis Model in Rats

Background: Ulcerative colitis (UC), a chronic inflammatory condition of the colon with no definitive cure, necessitates the exploration of innovative therapies. Herbal remedies combined with conventional drugs may offer complementary benefits, enhancing treatment outcomes. Objectives: This study investigates the therapeutic effects of Heracleum lasiopetalum Boiss in a rat model of acetic acid-induced UC. Methods: Forty-eight adult female Wistar rats were randomly allocated to six groups (n = 8 per group) for each of two experiments. UC was induced by intracolonic administration of 1 ml of 4% acetic acid for 10 minutes. In the treatment groups, female rats received an oral gavage of 5%, 10%, and 40% aqueous plant extract, sulfasalazine (100 mg/kg), and distilled water for 6 days, starting 3 days after acetic acid administration. The protective groups received substances via oral gavage from 7 days before to 3 days after acetic acid administration. The extent of mucosal ulcers, hyperemia, inflammation, and mucosal bleeding was evaluated based on the Gerald Classification System Score (Macroscopic). Pathological assessment was conducted on prepared slides using the modified Wallace method (Microscopic). Changes in body and colon weight, along with food and water intake, were examined. Results: Significant changes in food intake were observed in both the extract and positive control treatment groups, exhibiting a notable difference compared to the negative control group (P &lt; 0.05). Body weight changes experienced a significant increase in the positive control treatment group compared to the negative control group (P &lt; 0.05), while no significant difference was evident between the extract and negative control treatment groups (P &gt; 0.05). In terms of water and food intake, as well as weight changes, no significant differences were detected among the various protective groups (P &gt; 0.05). Both microscopic and macroscopic examinations revealed a substantial enhancement in the colon of the extract and positive control treatment groups compared to the negative control group (P &lt; 0.05), with no significant difference observed between the protective groups (P &gt; 0.05). Conclusions: Heracleum lasiopetalum extract demonstrates a dose-dependent reduction in colon hyperemia, mucosal ulceration, inflammation, and fibrosis. This highlights its potential as a supplementary treatment option for UC, emphasizing the need for further investigation.

An Overview on Atopic Dermatitis, Oxidative Stress, and Psychological Stress: Possible Role of Nutraceuticals as an Additional Therapeutic Strategy.

Atopic dermatitis (AD) is a chronic inflammatory skin condition with a considerable impact on patients' quality of life. Its etiology is multifactorial and, among the predisposing factors, a role is played by oxidative stress. Pollution, recurrent infections, and psychological stress contribute to oxidative stress, amplifying the production of proinflammatory cytokines and worsening barrier damage. There are various oxidative stress mechanisms involved in the pathogenesis of AD. Moreover, AD often appears to be associated with psychological disorders such as alexithymia, depression, and anxiety due to severe itching and related insomnia, as well as social distress and isolation. The increasing incidence of AD requires the evaluation of additional therapeutic approaches in order to reduce the psychological burden of this condition. Our review aims to evaluate the role of some nutraceuticals in AD treatment and its related psychological comorbidities. The combination of some natural compounds (flavonoids, alkaloids, terpenes, isothiocyanates) with traditional AD treatments might be useful in improving the effectiveness of therapy, by reducing chronic inflammation and preventing flare-ups, and in promoting corticosteroid sparing. In addition, some of these nutraceuticals also appear to have a role in the treatment of psychological disorders, although the underlying oxidative stress mechanisms are different from those already known for AD.

Microbial Polysaccharides Extracted from Different Mature Muds of the Euganean Thermal District Show Similar Anti-Inflammatory Activity In Vivo.

The Euganean Thermal District, situated in North-East Italy, is one of Europe's largest and oldest thermal centres. The topical application of its therapeutic thermal muds is recognised by the Italian Health System as a beneficial treatment for patients suffering from arthro-rheumatic diseases. Polysaccharides produced by the mud microbiota have been recently identified as anti-inflammatory bioactive molecules. In this paper we analysed the efficacy of Microbial-Polysaccharides (M-PS) derived from mature muds obtained at different maturation temperatures, both within and outside the codified traditional mud maturation range. M-PSs were extracted from six mature muds produced by five spas of the Euganean Thermal District and investigated for their chemical properties, monosaccharide composition and in vivo anti-inflammatory potential, using the zebrafish model organism. Additionally, mature muds were characterized for their microbiota composition using Next-Generation Sequencing. The results showed that all M-PSs exhibit similar anti-inflammatory potential, referable to their comparable chemical composition. This consistency was observed despite changes in cyanobacteria populations, suggesting a possible role of the entire microbial community in shaping the properties of these biomolecules. These findings highlight the importance of scientific research in untangling the origins of the therapeutic efficacy of Euganean Thermal muds in the treatment of chronic inflammatory conditions.

Abstract PO3-19-02: White Button Mushroom and Biomarkers of Immune Cell and Inflammatory Responses in Obese Postmenopausal Women at High Risk of Breast Cancer

Abstract Background: White Button Mushroom (WBM), Agaricus bisporus, has anti-tumor and anti-inflammatory effects. Oral WBM mitigated the effects of a high fat diet on hepatic steatosis and insulin resistance in ovariectomized mice. A Phase I trial of WBM in men with prostate cancer demonstrated decreased myeloid derived suppressor cells (MDSC) in those with decreased PSA; MDSC have been linked to different cancers, including breast, and conditions of chronic inflammation. Design: This is a preliminary evidence trail in postmenopausal, obese women at high risk of breast cancer with a single intervention arm of 14g of WBM taken as 28 tablets daily for 3 months to assess effects on inflammation. Participants undergo a physical exam, measuring height, weight, and waist circumference, an optional fine needle aspiration (FNA) of breast tissue, a blood draw, a food frequency questionnaire and a 24-hour food recall at baseline and final visits. Participants are contacted monthly for tolerance and adherence. Blood samples and FNA adipose are used for metabolic measurements and processed for biomarkers of inflammation and immune response. Peripheral blood mononuclear cells (PBMC) will be used for RNA single-cell analysis to assess for immune cell profiles and expression with an interest in evaluating MDSC. Red blood cells will be assessed for fatty acid profiles. Eligibility: Postmenopausal, obese (BMI ≥30, Asian ≥25) women with high risk for breast cancer who can swallow pills are eligible. Patients are high risk if their relative risk of breast cancer is ≥2 times that of the general population; this includes women with a strong family history, a genetic mutation associated with hereditary breast cancer, a high-risk breast histology, Gail model 5-year risk &amp;gt;1.67, or a previous history of stage I-II breast cancer. Participants are excluded for an active malignancy within 5 years, ongoing active or preventative cancer treatment, or lab abnormalities of serum creatinine and total bilirubin &amp;gt;1.5 the upper limit of normal, hemoglobin of &amp;lt; 9.0 g/dL, platelets of &amp;lt; 100,000/mm3, or a total white blood cell count of &amp;lt; 3,500/mm3. Participants cannot be taking mushroom supplements, immunosuppressants, or non-steroidal anti-inflammatories. Specific Aims: This study aims to evaluate the effects of WBM on regulating immune response and inflammation in obese women at high risk for breast cancer. Our primary objective is the assessment of PBMC, specifically MDSC immune profiles before and after treatment. Our secondary objective is to evaluate changes in biomarkers of inflammation, immune cell profiles in breast adipose tissue, BMI, waist circumference, and metabolic biomarkers. Additionally, the study aims to assess tolerability of the WBM dose and effects on diet quality. Statistical Methods: 26 patients will provide 80% power to detect a change in %MDSC of -0.67, assuming a standard deviation of 1.15, and a 2-sided type I error of 5%. We will have similar power to evaluate changes in other immune subsets, inflammatory markers, metabolic markers, anthropometric measurements, and diet quality. FNA adipose tissue analysis will be used as a safety signal to evaluate the potential for unwanted inflammation with taking WBM. 13 patients with FNA will provide 80% power to detect a change of 85% of the standard deviation of the difference in the measure of biomarkers such as Interleukin-6 with a 2-sided type I error of 5%. As a safety signal, the signal will be reported without adjustment for multiple comparisons. Any conclusions based on such secondary endpoints will make note of the multiple comparison issue. Accrual: The accrual target is 26 evaluable patients with an estimated need to enroll 31. The study has enrolled 27 patients, 14 completed the study and 5 are currently on treatment. 8 participants were removed; 3 never started treatment, 1 was diagnosed with breast cancer, and 4 had other medical issues preventing continuation. Contact: Jessica Dzubnar, MD: jdzubnar@coh.org Citation Format: Jessica Dzubnar, Lisa Yee, Shiuan Chen. White Button Mushroom and Biomarkers of Immune Cell and Inflammatory Responses in Obese Postmenopausal Women at High Risk of Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-19-02.

Sacroiliitis in inflammatory bowel disease.

This review summarizes the recent evidence regarding the epidemiology of inflammatory bowel disease (IBD) associated sacroiliitis, including the prevalence, pathogenesis, role of imaging, and therapeutic challenges. Sacroiliitis is an underappreciated musculoskeletal manifestation of IBD, a chronic inflammatory condition of the gut affecting the younger population. Untreated sacroiliitis can lead to joint destruction and chronic pain, further adding to morbidity in IBD patients. Recent publications suggest sacroiliitis can be detected on abdominal imaging obtained in IBD patients to study bowel disease, but only a small fraction of these patients were seen by rheumatologists. Early detection of IBD-associated sacroiliitis could be achieved by utilization of clinical screening tools in IBD clinics, careful examination of existing computed tomography and MRI studies, and timely referral to rheumatologist for further evaluation and treatment. Current treatment approaches for IBD and sacroiliitis include several targeted biologic therapies, but IBD-associated sacroiliitis has limited options, as these therapies may not overlap in both conditions. With the advances in imaging, sacroiliitis is an increasingly recognized comorbidity in IBD patients. Future studies focusing on this unique patient population will expand our understanding of complex pathophysiology of IBD-associated sacroiliitis and lead to identification of novel targeted therapies for this condition.

Mesenteric adipose-derived exosomal TINAGL1 enhances intestinal fibrosis in Crohn's Disease via SMAD4

IntroductionCrohn's Disease (CD) is a chronic inflammatory condition characterized by intestinal fibrosis, severely impacting patient quality of life. The molecular mechanisms driving this fibrosis remain inadequately understood. Recent evidence implicates mesenteric adipose tissue (MAT) in CD pathogenesis, particularly through its exosome secretion, which may influence fibrogenic pathways. Understanding the role of MAT-derived exosomes is crucial for unraveling these molecular processes. ObjectivesThis study aims to elucidate the role of MAT-derived exosomes in CD-related intestinal fibrosis. We focus on investigating their molecular composition and the potential impact on fibrosis progression, with an emphasis on identifying novel therapeutic targets. MethodsWe induced chronic intestinal inflammation in mice using dinitrobenzene sulfonic acid (DNBS), simulating CD-like fibrosis. Exosomes were isolated from DNBS-treated mice (MG) and normal controls (NG) for characterization using electron microscopy and proteomic analysis. Additionally, human colonic fibroblasts were exposed to exosomes from CD patients and healthy individuals, with subsequent assessment of fibrogenesis through proteomic and RNA sequencing analyses. ResultsProteomic analyses revealed a significant activation of the TGF-β signaling pathway in MG-treated mice compared to controls, correlating with enhanced intestinal fibrosis. In vitro experiments demonstrated that colonic fibroblasts exposed to CD patient-derived exosomes exhibited increased fibrogenic activity. Protein docking and co-immunoprecipitation studies suggested a critical interaction between TINAGL1 and SMAD4, enhancing fibrosis. Importantly, in vivo experiments corroborated that recombinant TINAGL1 protein exacerbated DNBS-induced intestinal fibrosis. ConclusionOur findings highlight the pivotal role of MAT-derived exosomes, particularly those carrying TINAGL1, in the progression of intestinal fibrosis in CD. The involvement of the TGF-β signaling pathway, especially the SMAD4 protein, offers new insights into the molecular mechanisms of CD-related fibrosis and presents potential targets for therapeutic intervention.