Features Of Inflammation Research Articles

Transcriptome analysis of cardiac endothelial cells after myocardial infarction reveals temporal changes and long-term deficits.

Endothelial cells (ECs) have essential roles in cardiac tissue repair after myocardial infarction (MI). To establish stage-specific and long-term effects of the ischemic injury on cardiac ECs, we analyzed their transcriptome at landmark time points after MI in mice. We found that early EC response at Day 2 post-MI centered on metabolic changes, acquisition of proinflammatory phenotypes, initiation of the S phase of cell cycle, and activation of stress-response pathways, followed by progression to mitosis (M/G2 phase) and acquisition of proangiogenic and mesenchymal properties during scar formation at Day 7. In contrast, genes involved in vascular physiology and maintenance of vascular tone were suppressed. Importantly, ECs did not return to pre-injury phenotypes after repair has been completed but maintained inflammatory, fibrotic and thrombotic characteristics and lost circadian rhythmicity. We discovered that the highest induced transcript is the mammalian-specific Sh2d5 gene that promoted migration and invasion of ECs through Rac1 GTPase. Our results revealed a synchronized, temporal activation of disease phenotypes, metabolic pathways, and proliferation in quiescent ECs after MI, indicating that precisely-timed interventions are necessary to optimize cardiac tissue repair and improve outcomes. Furthermore, long-term effects of acute ischemic injury on ECs may contribute to vascular dysfunction and development of heart failure.

Anguilla anguilla vs Contracaecum rudolphii: Granuloma allows host tolerance and parasite survival

High survival of the nematode Contracaecum rudolphii in European eel, Anguilla anguilla L. despite an extensive recruitment of immune cells in granulomas is described. A total of 39 eel specimens captured in Canneviè lagoon (Northern Adriatic Sea, Italy) was obtained from local fishermen. The fish were examined for the presence of endoparasitic helminths. Twenty-six eels (67%) harbored third-stage larvae (L3) of Contracaecum rudolphii A and the intensity of infection ranged from 1 to 100 parasites per fish (mean 11.4). A total of 296 larvae were counted and 293 were alive and encysted in the serosa (primarily on external surface of the rectum) as conspicuous granulomas, appearing as white nodules. Histological sections showed a granuloma formed around an individual larva and consisted of three concentric cell layers, containing numerous mast cells (MCs), fibroblasts, macrophages, and epithelioid cells. Encysted larvae were also present in other layers of the intestinal wall, including the mucosa, where recruitment of macrophage aggregates in lamina propria was documented. Immunohistochemical investigations, applying eight antibodies raised against immune cell markers, revealed histamine and serotonin in MCs and inducible-nitric oxide synthase and toll-like receptor-2 in macrophages surrounding the parasite larvae. The study indicates that this innate cellular response in the eel has a chronic inflammatory character and keeps the nematode larvae arrested in a state allowing both host tolerance and parasite survival. The European eel serves as prey for birds and the high survival of C. rudolphii A larvae in the eel indicates that this fish species is a good paratenic host for the parasite allowing completion of its life cycle in birds.

Langerhans cell histiocytosis: NACHO update on progress, chaos, and opportunity on the path to rational cures.

Langerhans cell histiocytosis (LCH) is a myeloid neoplastic disorder characterized by lesions with CD1a-positive/Langerin (CD207)-positive histiocytes and inflammatory infiltrate that can cause local tissue damage and systemic inflammation. Clinical presentations range from single lesions with minimal impact to life-threatening disseminated disease. Therapy for systemic LCH has been established through serial trials empirically testing different chemotherapy agents and durations of therapy. However, fewer than 50% of patients who have disseminated disease are cured with the current standard-of-care vinblastine/prednisone/(mercaptopurine), and treatment failure is associated with long-term morbidity, including the risk of LCH-associated neurodegeneration. Historically, the nature of LCH-whether a reactive condition versus a neoplastic/malignant condition-was uncertain. Over the past 15 years, seminal discoveries have broadly defined LCH pathogenesis; specifically, activating mitogen-activated protein kinase pathway mutations (most frequently, BRAFV600E) in myeloid precursors drive lesion formation. LCH therefore is a clonal neoplastic disorder, although secondary inflammatory features contribute to the disease. These paradigm-changing insights offer a promise of rational cures for patients based on individual mutations, clonal reservoirs, and extent of disease. However, the pace of clinical trial development behind lags the kinetics of translational discovery. In this review, the authors discuss the current understanding of LCH biology, clinical characteristics, therapeutic strategies, and opportunities to improve outcomes for every patient through coordinated agent prioritization and clinical trial efforts.

Diagnosis, management and therapeutic options for eosinophilic esophagitis.

Eosinophilic esophagitis is a chronic and commonly evolving condition leading to relevant and potentially irreversible burden in terms of tissue damage and related functional impairment, thus significantly impacting on quality of life. The aim of the present review is to summarize the recent advances in terms of diagnostic work-up and pharmacological and nonpharmacological management of the disease, under the broader perspective of type 2 inflammation. Two major novelties have prompted an innovative approach to EoE. In terms of diagnosis, it has been proposed to dissect the disease heterogeneity in three endotypes, independent from tissue eosinophil number: EoEe1, characterized by normal appearing oesophagus; EoEe2, associated with type 2 inflammation and steroid-refractoriness; EoEe3, whose features include adult onset, a more fibro-stenotic aspect and loss of epithelial gene expression. Concerning treatment, two recently licensed drugs for EoE, oro-dispersible budesonide and dupilumab represent the first treatment options specifically developed for EoE and addressing EoE-related peculiar pathobiological features. In the era of precision medicine, managing EoE according to a phenotype-driven approach might be helpful in defining the best treatment options in the different disease forms or stages. In addition, exploring the coexistence or the previous occurrence of other type 2 conditions may suggest the opportunity to specifically target type 2 inflammation through biologic therapy. The complex EoE pathobiology combining inflammatory and functional features, both at organ and systemic level, requires a multidimensional approach relying on the strict integration of gastroenterologists and allergist-immunologists.

The impact and inflammatory characteristics of SARS-CoV-2 infection during ovarian stimulation on the outcomes of assisted reproductive treatment.

Despite the global prevalence of coronavirus disease 2019 (COVID-19), limited research has been conducted on the effects of SARS-CoV-2 infection on human reproduction. The aims of this study were to investigate the impact of SARS-CoV-2 infection during controlled ovarian stimulation (COS) on the outcomes of assisted reproductive treatment (ART) and the cytokine status of patients. This retrospective cohort study included 202 couples who received ART treatment, 101 couples infected with SARS-CoV-2 during COS and 101 matched uninfected couples. The parameters of ovarian stimulation and pregnancy outcomes were compared between the two groups. The All-Human Inflammation Array Q3 kit was utilized to measure cytokine levels in both blood and follicular fluid. No difference was found in the number of good-quality embryos (3.3 ± 3.1 vs. 3.0 ± 2.2, P = 0.553) between the infected and uninfected groups. Among couples who received fresh embryo transfers, no difference was observed in clinical pregnancy rate (53.3% vs. 51.5%, P = 0.907). The rates of fertilization, implantation, miscarriage, ectopic pregnancy and live birth were also comparable between the two groups. After adjustments were made for confounders, regression models indicated that the quality of embryos (B = 0.16, P = 0.605) and clinical pregnancy rate (P = 0.206) remained unaffected by SARS-CoV-2 infection. The serum levels of MCP-1, TIMP-1, I-309, TNF-RI and TNF-RII were increased, while that of eotaxin-2 was decreased in COVID-19 patients. No significant difference was found in the levels of cytokines in follicular fluid between the two groups. Asymptomatic or mild COVID-19 during COS had no adverse effects on ART outcomes. Although mild inflammation was present in the serum, it was not detected in the follicular fluid of these patients. The subsequent immune response needs further investigation.

Association between pro-inflammatory diet and abdominal pain: cross-sectional and case-control study from UK biobank and NHANES 2017-2020.

There is a close association between diet and abdominal pain; however, relationship between inflammatory diet and characteristics of abdominal pain has not been characterized yet. This study analyzed baseline data from the UK Biobank, 3-item DHQ-Abdominal Pain Questionnaire (DHQ-3Q), which including abdominal pain in the past 3 months, severity of abdominal pain, and frequency of abdominal pain, and data from the National Health and Nutrition Examination Survey (NHANES) from 2017 to 2020. Energy-adjusted Dietary Inflammatory Index (E-DII), constructed based on 26 or 27 nutrients, was analyzed using continuous or categorical methods. Logistic regression and restricted cubic spline analyses examined the association between E-DII and abdominal pain. In UK Biobank, compared to participants in the lowest quintile of E-DII, the adjusted ORs for the highest quintile were 1.12 (95% CI 1.02-1.24; P = .022), 1.05 (95% CI 1.00-1.09; P = .030), 1.26 (95% CI 1.17-1.36; P < .001), and 1.10 (95% CI 1.00-1.20; P = .044) for chronic abdominal pain, abdominal pain in the past three months, severity of abdominal pain, and frequency of abdominal pain, respectively. In NHANES, compared to participants in the lowest quintile of E-DII, the adjusted ORs for the highest quintile were 1.46 (95% CI 1.20-1.77;P < .001), 1.75 (95% CI 1.20-2.60; P = .005), 1.45 (95% CI 1.14-1.87; P = .003), and 1.18 (95% CI 0.82-1.72; P = .380) for abdominal pain in the past year, upper left abdominal pain, upper middle abdominal pain, and upper right abdominal pain. Additionally, there was a nonlinear correlation between E-DII score and DHQ-3Q (P nonlinear <.001). Following a pro-inflammatory diet is linked to a higher likelihood of experiencing abdominal pain, as well as increased severity and frequency of such pain. Therefore, further longitudinal studies are necessary to investigate this relationship.

Rapamycin suppresses rheumatoid arthritis fibroblast synovial cell proliferation and induces apoptosis via the AKT/mTORC1 pathway

AbstractBackgroundRheumatoid arthritis (RA) is an autoimmune disease characterized by the overproliferation of synovial fibroblast‐like synoviocytes (FLSs) in the lining, leading to chronic inflammation and progressive joint damage. RA pathogenesis involves lymphocyte infiltration, increased synovial cell proliferation, and impaired cell death. This study investigated the effects of rapamycin on RA‐FLSs and explored the underlying molecular mechanisms.MethodsThe optimal drug concentration and time for rapamycin administration were determined using a cell counting kit‐8 assay. The concentration of rapamycin varied from 1 to 25 nmol/L. The mRNA expression levels of protein kinase B (AKT), mammalian target of rapamycin (mTOR), B cell lymphoma 2 (Bcl‐2), and Bcl‐2‐associated X protein (Bax) were quantified by real‐time polymerase chain reaction. Protein expression (p‐AKT, AKT, p‐mTOR, mTOR, pS6 kinase [S6K], S6K, p‐4E‐binding protein 1 [4EBP1], 4EBP1, Bcl‐2, Bax, caspase 3, caspase 9, cyclin‐dependent kinase 2 [CDK2], and CD1) were detected by Western blotting analysis.ResultsRapamycin suppresses RA‐FLS proliferation and induces apoptosis in a dose‐dependent manner. Rapamycin significantly elevated the protein expression of Bax (p &lt; 0.01), caspase 3 (p &lt; 0.05), and caspase 9 (p &lt; 0.001), and downregulated Bcl‐2 expression (p &lt; 0.01). Rapamycin increased Bax mRNA expression (p &lt; 0.01) and decreased Bcl‐2 (p &lt; 0.05), AKT (p &lt; 0.05), and mTOR (p &lt; 0.05) expression. Additionally, there was a marked reduction in the expression levels of p‐AKT(Ser473) (p &lt; 0.01), p‐mTOR (Ser2448) (p &lt; 0.01), p‐S6K1 (p &lt; 0.01), and p‐4EBP1, CDK2, and CD1 (p &lt; 0.01).ConclusionsRapamycin effectively inhibited proliferation and induced apoptosis of RA‐FLSs by targeting the AKT/mTORC1 pathway. These findings underscore the potential of rapamycin as a therapeutic candidate for addressing the dysregulated proliferation and inflammatory characteristics of RA. Further clinical investigations are required to validate its application in the management of RA.

Pulsed Radiofrequency Electromagnetic Fields as Modulators of Inflammation and Wound Healing in Primary Dermal Fibroblasts of Ulcers.

Venous leg ulcers are one of the most common nonhealing conditions and represent an important clinical problem. The application of pulsed radiofrequency electromagnetic fields (PRF-EMFs), already applied for pain, inflammation, and new tissue formation, can represent a promising approach for venous leg ulcer amelioration. This study aims to evaluate the effect of PRF-EMF exposure on the inflammatory, antioxidant, cell proliferation, and wound healing characteristics of human primary dermal fibroblasts collected from venous leg ulcer patients. The cells' proliferative and migratory abilities were evaluated by means of a BrdU assay and scratch assay, respectively. The inflammatory response was investigated through TNFα, TGFβ, COX2, IL6, and IL1β gene expression analysis and PGE2 and IL1β production, while the antioxidant activity was tested by measuring GSH, GSSG, tGSH, and GR levels. This study emphasizes the ability of PRF-EMFs to modulate the TGFβ, COX2, IL6, IL1β, and TNFα gene expression in exposed ulcers. Moreover, it confirms the improvement of the proliferative index and wound healing ability presented by PRF-EMFs. In conclusion, exposure to PRF-EMFs can represent a strategy to help tissue repair, regulating mediators involved in the wound healing process.

Ruxolitinib Improves Immune-Dysregulation Features but not Epigenetic Abnormality in a Patient with STAT1 GOF

PurposePatients with STAT1 gain-of-function (GOF) mutations often exhibit autoimmune features. The JAK1/2 inhibitor ruxolitinib can be administered to alleviate autoimmune symptoms; however, it is unclear how immune cells are molecularly changed by ruxolitinib treatment. Then, we aimed to investigate the trnscriptional and epigenetic status of immune cells before and after ruxolitinib treatment in a patient with STAT1 GOF.MethodsA patient with a heterozygous STAT1 GOF variant (p.Ala267Val), exhibiting autoimmune features, was treated with ruxolitinib, and peripheral blood mononuclear cells (PBMCs) were longitudinally collected. PBMCs were transcriptionally analyzed by single-cell cellular indexing of the transcriptomes and epitopes by sequencing (CITE-seq), and epigenetically analyzed by assay of transposase-accessible chromatin sequencing (ATAC-seq).ResultsCITE-seq analysis revealed that before treatment, the patient’s PBMCs exhibited aberrantly activated inflammatory features, especially IFN-related features. In particular, monocytes showed high expression levels of a subset of IFN-stimulated genes (ISGs). Ruxolitinib treatment substantially downregulated aberrantly overexpressed ISGs, and improved autoimmune features. However, epigenetic analysis demonstrated that genetic regions of ISGs—e.g., STAT1, IRF1, MX1, and OAS1—were highly accessible even after ruxolitinib treatment. When ruxolitinib was temporarily discontinued, the patient’s autoimmune features were aggravated, which is in line with sustained epigenetic abnormality.ConclusionsIn a patient with STAT1 GOF, ruxolitinib treatment improved autoimmune features and downregulated aberrantly overexpressed ISGs, but did not correct epigenetic abnormality of ISGs.

BIOLOGICAL MODEL OF LUNG CANCER COMBINATION AND TUBERCULOSIS: DEVELOPMENT FOR PRECLINICAL STUDY OF RATIONAL COMBINATIONS OF TARGETED ANTITUMOR AND ANTITUBERCULOSIS THERAPY

Introduction. Lung cancer occupies a leading position in the structure of mortality from cancer. Chronic inflammation characteristic of tuberculosis increases the risk of lung cancer. Currently, more and more information is emerging confirming the cause-and-effect relationship between tuberculosis and cancer. The need to develop recommendations for public health regarding screening and treatment of tuberculosis in the tumor process determines the relevance of experimental studies on biological models of the combination of cancer and tuberculosis.. Aim. Creation а biological model of the combination of lung cancer and tuberculosis for preclinical study of rational combinations of antitumor and antituberculosis therapy. Material and methods: The biological model was implemented on C57BL/6 mice at the age of two months. Lewis epidermoid lung carcinoma was used to reproduce the tumor process. Modeling of tuberculosis was carried out using the reference strain Mycobacterium Tuberculosis H37RV. During the study, the following groups were formed: “intact mice” (healthy, uninfected with the Mycobacterium Tuberculosis (MBT) H37Rv strain without tumor cell transplantation); “control of MBT infection” (animals infected with Mycobacterium Tuberculosis strain H37Rv), “tumor control” (animals that were transplanted with epidermoid Lewis lung carcinoma) and “main group” (animals that were transplanted with epidermoid Lewis lung carcinoma simultaneously with MBT infection). Results. During the experiment, several models for creating the combined pathology of lung cancer and tuberculosis were identified. In the first (simultaneous infection and tumor inoculation), carcinoma developed more slowly in infected animals than in the tumor control group, and lung damage occurred with a predominance of the tuberculous process over the tumor process. The second (staged infection) also showed minimal metastatic manifestations with pronounced secondary changes in the primary tumor node. Analysis of the choice of model showed that the model with simultaneous infection and tumor inoculation most adequately ensures the development of the tumor process and tuberculosis infection, which allows maintaining the viability of the animal, fully developing the tumor process with metastasis to the lungs and obtaining the development of morphologically verified pulmonary tuberculosis.

Multi-System-Level Analysis Reveals Differential Expression of Stress Response-Associated Genes in Inflammatory Solar Lentigo.

Although the pathogenesis of solar lentigo (SL) involves chronic ultraviolet (UV) exposure, cellular senescence, and upregulated melanogenesis, underlying molecular-level mechanisms associated with SL remain unclear. The aim of this study was to investigate the gene regulatory mechanisms intimately linked to inflammation in SL. Skin samples from patients with SL with or without histological inflammatory features were obtained. RNA-seq data from the samples were analyzed via multiple analysis approaches, including exploration of core inflammatory gene alterations, identifying functional pathways at both transcription and protein levels, comparison of inflammatory module (gene clusters) activation levels, and analyzing correlations between modules. These analyses disclosed specific core genes implicated in oxidative stress, especially the upregulation of nuclear factor kappa B in the inflammatory SLs, while genes associated with protective mechanisms, such as SLC6A9, were highly expressed in the non-inflammatory SLs. For inflammatory modules, Extracellular Immunity and Mitochondrial Innate Immunity were exclusively upregulated in the inflammatory SL. Analysis of protein-protein interactions revealed the significance of CXCR3 upregulation in the pathogenesis of inflammatory SL. In conclusion, the upregulation of stress response-associated genes and inflammatory pathways in response to UV-induced oxidative stress implies their involvement in the pathogenesis of inflammatory SL.

Is Meibomian Gland Dysfunction One Disease? Heterogeneity Among Phenotypes.

The purpose of this study was to examine ocular surface symptoms, tear metrics, and tear cytokines by Meibomian gland dysfunction (MGD) features. Symptom questionnaires and an ocular surface evaluation were performed on 40 individuals with varied MGD signs (Meibomian gland [MG] plugging, eyelid vascularity, meibum quality, and MG dropout). Tear proteins were extracted off Schirmer strips and analyzed for 23 human inflammation-related proteins. Statistical analysis was performed to examine associations between dry eye metrics inflammatory proteins and MGD features. The study involved 40 South Florida veterans with a mean age of 61 ± 13 years; most individuals were male (95%), White (31%), and non-Hispanic (85%). MGD features differentially related to dry eye signs. Eyelid vascularity, meibum quality, and MG dropout, but not MG plugging, correlated with higher corneal staining and lower tear production. MGD features also differentially related to tear cytokines. Eyelid vascularity most closely related to inflammation with significant correlations for interferon-gamma-γ (r = 0.36, P = 0.02), interleukin-4 (IL-4) (r = 0.43, P = 0.006), IL-17A (r = 0.42, P = 0.007), matrix metalloproteinase-2 (r = 0.39, P = 0.01), C-X-C motif chemokine ligand 5 (Regulated upon Activation, Normal T-Cell Expressed and presumably Secreted [RANTES]) (r = 0.32, P = 0.04), and tumor necrosis factor α (r = 0.36, P = 0.02). The other 3 MGD signs were less related to inflammation. Multivariable models revealed IL-4 to be most closely related to eyelid vascularity (standardized β = 0.39, P < 0.0001). Eyelid vascularity was the MGD sign most closely related to inflammatory cytokines, suggesting that different MGD features may be driven by different pathophysiological mechanisms.

Blood periostin/procalcitonin index and glomerular filtration rate in various types of bronchial asthma

Introduction. The possibility of co-existence of chronic kidney disease (CKD) and bronchial asthma (BA) was shown earlier and we found that the mechanisms of the CKD development differ depending on the variant of the disease (allergic and nonallergic). New biomarkers of the activity of allergic (periostin) and infectious (procalcitonin) inflammation in BA have appeared. Evidence of the involvement of the periostin in the pathogenesis of the CKD was obtained, and an increase in the level of procalcitoninin CKD was also found. The purpose of the study is to evaluate the possible influence of periostin and procalcitonin on progression of creatinine clearance decrease regarding different BA phenotypes. Methods. 19 patients with BA (13 patients with an allergic variant, 6 patients with a nonallergic variant of the disease) were examined.The determination of blood periostin and blood procalcitonin was carried out by ELISA. The periostin/procalciton index was calculated, the resulting dimensionless value was subject to logarithming on the basis of 10. Results. It was found that the levels of periostin differ depending on the BA variant. With an allergic variant, the level of periostin is significantly higher than in nonallergic variant. The level of procalcitonin is much higher in a nonallergic variant of the disease, although the levels of this protein are on average within normal values in both variants of the disease. The glomerular filtration rate in the examined group of patients as a whole is within normal values. Factor analysis revealed that factor 1 reflects the relationship of the component characterizing the biomarkers of infectious inflammation (procalcitonin, ESR) with a negative factor load for bronchial asthma and the glomerular filtration rate with a positive factor load. The component of such an integral indicator as the periostin/procalcitonin index has the highest factor load; factor 2 reflects the negative impact of both biomarkers on the glomerular filtration rate; factor 3 reflects the characteristics of the eosinophilic IgE-mediated inflammation in bronchial asthma. Conclusion. Periostin and procalcitonin as biomarkers of allergic and infectious inflammation possibly influence the glomerular filtration rate in different variants of bronchial asthma. The activity of each biomarker may vary depending on BA type (allergic or nonallergic).

Hodgkin Lymphoma-related Inflammatory Modification-displayed Castleman Disease-like Histological Features and Positron Emission Tomography/Computed Tomography Usefulness for the Differential Diagnosis.

Hodgkin lymphoma (HL) and idiopathic multicentric Castleman disease (iMCD) are markedly different conditions. However, in some cases, histological similarities caused by elevated cytokines, including interleukin-6, can lead to a misdiagnosis of HL as Castleman disease (CD). We herein report a patient with HL who had been diagnosed with CD by an expert panel and for whom an additional biopsy was useful for determining the correct diagnosis. Furthermore, we analyzed the positron emission tomography/computed tomography findings at the diagnosis and found that the maximum standardized uptake value was useful for distinguishing HL from iMCD.

Mapping cutaneous field carcinogenesis of nonmelanoma skin cancer using mesoscopic imaging of pro-inflammation cues.

Nonmelanoma skin cancers remain the most widely diagnosed types of cancers globally. Thus, for optimal patient management, it has become imperative that we focus our efforts on the detection and monitoring of cutaneous field carcinogenesis. The concept of field cancerization (or field carcinogenesis), introduced by Slaughter in 1953 in the context of oral cancer, suggests that invasive cancer may emerge from a molecularly and genetically altered field affecting a substantial area of underlying tissue including the skin. A carcinogenic field alteration, present in precancerous tissue over a relatively large area, is not easily detected by routine visualization. Conventional dermoscopy and microscopy imaging are often limited in assessing the entire carcinogenic landscape. Recent efforts have suggested the use of noninvasive mesoscopic (between microscopic and macroscopic) optical imaging methods that can detect chronic inflammatory features to identify pre-cancerous and cancerous angiogenic changes in tissue microenvironments. This concise review covers major types of mesoscopic optical imaging modalities capable of assessing pro-inflammatory cues by quantifying blood haemoglobin parameters and hemodynamics. Importantly, these imaging modalities demonstrate the ability to detect angiogenesis and inflammation associated with actinically damaged skin. Representative experimental preclinical and human clinical studies using these imaging methods provide biological and clinical relevance to cutaneous field carcinogenesis in altered tissue microenvironments in the apparently normal epidermis and dermis. Overall, mesoscopic optical imaging modalities assessing chronic inflammatory hyperemia can enhance the understanding of cutaneous field carcinogenesis, offer a window of intervention and monitoring for actinic keratoses and nonmelanoma skin cancers and maximise currently available treatment options.

Effects of intra-articular injection of platelet-rich plasma on the inflammatory process and histopathological characteristics of cartilage and synovium in animals with osteoarthritis: a systematic review with meta-analysis

BackgroundOsteoarthritis (OA) affects the entire joint, causing structural changes in articular cartilage, subchondral bone, ligaments, capsule, synovial membrane, and periarticular muscles that afflicts millions of people globally, leading to persistent pain and diminished quality of life. The intra-articular use of platelet-rich plasma (PRP) is gaining recognition as a secure therapeutic approach due to its potential regenerative capabilities. However, there is controversial clinical data regarding efficacy of PRP for OA treatment. In this context, gathering scientific evidence on the effects of PRP in treating OA in animal models could provide valuable insights into understanding its impact on aspects like cartilage health, synovial tissue integrity, and the inflammatory process in affected joints. Thus, the objective of this study was to assess the effects of PRP injections on inflammation and histopathological aspects of cartilage and synovium in animal models of OA through a comprehensive systematic review with meta-analysis.MethodsA electronic search was conducted on Medline, Embase, Web of Science, The Cochrane Library, LILACS, and SciELO databases for relevant articles published until June 2022. A random-effects meta-analysis was employed to synthesize evidence on the histological characteristics of cartilage and synovium, as well as the inflammatory process. The GRADE approach was utilized to categorize the quality of evidence, and methodological quality was assessed using SYRCLE’s RoB tool.ResultsTwenty-one studies were included in the review, with twelve of them incorporated into the meta-analysis. PRP treatment demonstrated superior outcomes compared to the control group in terms of cartilage histology (very low quality; p = 0.0002), synovium histology (very low quality; p < 0.0001), and reductions in proinflammatory markers, including IL-1 (low quality; p = 0.002), IL-6 (very low quality; p < 0.00001), and TNF-α (very low; p < 0.00001). However, PRP treatment did not yield a significant impact on PDGF-A levels (very low quality; p = 0.81).ConclusionPRP appears capable of reducing proinflammatory markers (IL-1, IL-6, TNF-α) and mitigating cartilage and synovium damage in animals with OA. However, the levels of evidence of these findings are low to very low. Therefore, more rigorous studies with larger samples are needed to improve the quality of evidence.PROSPERO registrationCRD42022250314

ПРОТИВОМИКРОБНАЯ ТЕРАПИЯ ПРИ РИНОСИНУСОГЕННЫХ ОСЛОЖНЕНИЯХ: ВЗГЛЯД КЛИНИЧЕСКОГО ФАРМАКОЛОГА

Rhinosinusogenic orbital (RSOC) and intracranial complications (RSIC) remain relevant for physicians of various specialties due to high risks of unfavorable outcomes. The key to successful medical care of patients with complicated forms of nasal and paranasal sinus pathology is not only untimely diagnosis and surgical sanation of the primary focus of infection, but also properly selected systemic antimicrobial therapy (SPMT), the choice of which is based on local data on the structure of pathogens and their sensitivity to antibacterial drugs. As a result of retrospective analysis of medical records of 266 completed cases of complicated forms of rhinosinusitis in adult patients for the period from 2010 to 2023, the peculiarities of the course of RSOC and RSIC, the microbial landscape in this pathology, the nature and extent of SPMT were studied. It was revealed that in the structure of the complicated course of RSOC occupy the leading positions. Secondary meningitis prevailed among RSIC, accounting for (92.6%). Clearly expressed changes of inflammatory character on the part of the general blood analysis and integral hematologic indices were characteristic for RSIC and purulent-inflammatory complications of the eyes. Staphylococcus spp. prevailed in the structure of etiologic factors in RSOC, while polymorphism of the isolated microflora was observed in RSIC (Staphylococcus spp., Streptococcus spp., Enterobacterales, Acinetobacter spp., Enterococcus spp., anaerobes, Candida spp., Mucor spp). Analysis of antibiograms revealed that the most problematic in terms of the choice of SPMT were representatives of the order Enterobacterales, Acinetobacter spp., in some established ones - Enterococcus spp., among the pathogens of mycosis - Mucor spp. 3-generation cephalosporins prevailed in the structure of empirical SPMT, and to a lesser extent inhibitor-protected aminopenicillins. However, the severity of the patients' condition, especially in case of RSIC, the results of microbiologic examination dictated the need to switch to "observation" antibiotics (meropenem, cefepime). Timely diagnosis, clear tactics of medical care, including the choice of effective SPMT led to favorable outcomes in 98.8% of patients.

Abstract 5459: Inflammatory gene-based subtyping of osteosarcoma patients reveals the association of inflammation in tumor microenvironment with better survival

Abstract Introduction:Inflammation has a significant impact on the tumor microenvironment (TME) of osteosarcoma (OS). Nevertheless, due to the high heterogenecity and variable inflammatory characteristics among OS patients, it is still unclear which inflammatory factors or immune/stroma cell types are crucially associated with OS prognosis. Therefore, it is essential to explore the immune infiltration pattern and the related core inflammatory genes in OS. Method:We combined bulk RNA-seq data of 88 osteosarcoma (OS) patients from the TARGET database and single cell RNA-seq data in GSE152048 from the NCBI Gene Expression Omnibus. Firstly, we calculated the inflammatory gene expression matrix of bulk RNA-seq data by combining 80 inflammatory gene sets (3427 genes in total) from the MSigDB using the gene set variation analysis (GSVA). Secondly, consensus clustering was executed to evaluate the stability of clustering for the above matrix. Furthermore, the overall survival and differential expression analyses were used to screen for core inflammatory genes. Immune infiltration patterns among groups were profiled with CIBERSORT. Finally, we employed the scRNA-seq series to evaluate cell-level information to identify the survival-associated cell subpopulations using the Seurat package. The t-SNE was used for dimensionality reduction and cluster identification. Results:88 osteosarcoma (OS) patients were clustered into two distinct groups according to the consensus clustering of our formed GSVA inflammatory gene expression matrix. Group 1 (43 patients) exhibited evident inflammation features, while Group 2 (45 patients) displayed limited inflammation features. Patients from Group 1 had significantly better overall survival than those from Group 2. The difference in immune infiltration pattern of two groups were examined using bulk RNA-seq data. Group 1 showed a higher population of macrophages and CD8+ T cells compared to Group 2, implying high inflammatory features might lead to a better immune activation of TME in patients. To explore the factors and cell types that contributes to restricted immune infiltration and activation in OS TME, scRNA-seq data of 11 OS patient tissues were analyzed. Consistently with bulk RNA seq analysis, the 338 up-regulated genes from Group 1 were mainly expressed in immune cells including macrophages and myeloid cells. Interestingly, the 64 up-regulated genes from Group 2 were found nearly uniformly expressed in two type of non-immune cells: myoblasts and chondroblastic cells. Conclusion:Inflammatory gene-based subtyping of osteosarcoma (OS) patients reveals that the inflammation in TME led by myeloid-derived immune cells including macrophage is associated with better prognosis. Furthermore, myoblasts and chondroblastic cells might contribute to the limited inflammation response in OS TME. Citation Format: Liu Yang, Yalan Sheng, Shuangying Qiao, Desheng Hu, Debajyoti Chowdhury, Hiu Fung Yip, Zheng Chen, Yun He, Aiping Lu, Fangfei Li. Inflammatory gene-based subtyping of osteosarcoma patients reveals the association of inflammation in tumor microenvironment with better survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5459.

Abstract 4048: Comparative effects of SOS1 inhibitor with IL-6 blockade and their combination on Kras mutant lung cancer

Abstract Despite recent advances in treatment, lung adenocarcinoma (LUAD), particularly harboring Kras mutations, is still the leading cause of cancer mortality. We and others have previously shown that Kras mutant LUAD development and progression is associated with intrinsic inflammatory characteristics driven by epithelial NF-κB activation, increased levels of IL-6 (which is transcriptionally regulated by NF-κB), and activation of the IL-6-responsive transcription factor STAT3. We further demonstrated that IL-6 blockade suppresses lung tumorigenesis by reducing tumor-associated immunosuppressive myeloid populations and induction of a T cell-mediated anti-tumor response. The recent discovery of a novel SOS1-targeting compound (BI-3406) that selectively inhibits the KRAS-SOS1 interaction and leads to anti-proliferative activity has opened up the possibility to more efficiently inhibit Kras mutant lung cancer. Accordingly, in this study we used a mouse model of KRAS mutant LUAD (CC-LR) to compare the therapeutic effects of BI-3406, IL-6 blockade, and MEK inhibitor (trametinib). We also tested whether inhibiting IL-6 driven pro-tumor immune response would provide a synergistic/additive response and increase the tumor inhibitory effect of either BI-3406 or Trametinib. Eight cohorts of 14-week-old female mice were treated with either anti-IL-6 antibody, trametinib, or BI-3406, or their combinations for 4 weeks, and their tumor burden was compared at the end of study. We observed a significant reduction in tumor multiplicity and tumor area in response to all monotherapies, with the highest effect in the trametinib treated cohort. Neither combination therapy led to decreased tumor burden over either of the monotherapy regimens in our model. However, we observed an increase in T helper 1 and CD8 T expressing IFNγ cell populations in the cohort treated with Trametinib and anti-IL-6 Ab combination. In addition, using qPCR analysis of RNA extracted from the whole lung we found a higher expression of IFNγ along with a reduced expression of IL-10 in the cohort treated with BI-3406 and anti-IL-6 Ab combination. This suggests that these combinations may have the potential to improve the anti-tumor immune responses. Hence, we conclude that further adjustment of the treatment regimen (doses, interval, duration) may allow to obtain improved anti-tumor efficacy with these combinations. Overall, this study provides a new research perspective for the improvement of currently available treatment modalities for patients with Kras mutant lung cancer that could be further explored preclinically. Citation Format: Katherine E. Larsen, Maria J. Arredondo Sancristobal, Melody Zarghooni, Avantika Krishna, Maria T. Grimaldo, Nastaran Karimi, Arnav Gaitonde, Michael J. Clowers, Seyed Javad Moghaddam. Comparative effects of SOS1 inhibitor with IL-6 blockade and their combination on Kras mutant lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4048.

Se Alleviated Pb-Caused Neurotoxicity in Chickens: SPS2-GPx1-GSH-IL-2/IL-17-NO Pathway, Selenoprotein Suppression, Oxidative Stress, and Inflammatory Injury.

Lead (Pb), a heavy metal environmental pollutant, poses a threat to the health of humans and birds. Inflammation is one of the most common pathological phenomena in the case of illness and poisoning. However, the underlying mechanisms of inflammation remain unclear. The cerebellum and the thalamus are important parts of the nervous system. To date, there have been no reports of Pb inducing inflammation in animal cerebellums or thalami. Selenium (Se) can relieve Pb poisoning. Therefore, we aimed to explore the mechanism by which Se alleviates Pb toxicity to the cerebellums and thalami of chickens by establishing a chicken Pb or/and Se treatment model. Our results demonstrated that exposure to Pb caused inflammatory damage in cerebellums and thalami, evidenced by the characteristics of inflammation, the decrease in anti-inflammatory factors (interleukin (IL)-2 and interferon-γ (INF-γ)), and the increase in pro-inflammatory factors (IL-4, IL-6, IL-12β, IL-17, and nitric oxide (NO)). Moreover, we found that the IL-2/IL-17-NO pathway took part in Pb-caused inflammatory injury. The above findings were reversed by the supplementation of dietary Se, meaning that Se relieved inflammatory damage caused by Pb via the IL-2/IL-17-NO pathway. In addition, an up-regulated oxidative index malondialdehyde (MDA) and two down-regulated antioxidant indices (glutathione (GSH) and total antioxidant capacity (TAC)) were recorded after the chickens received Pb stimulation, indicating that excess Pb caused an oxidant/antioxidant imbalance and oxidative stress, and the oxidative stress mediated inflammatory damage via the GSH-IL-2 axis. Interestingly, exposure to Pb inhibited four glutathione peroxidase (GPx) family members (GPx1, GPx2, GPx3, and GPx4), three deiodinase (Dio) family members (Dio1, Dio2, and Dio3), and fifteen other selenoproteins (selenophosphate synthetase 2 (SPS2), selenoprotein (Sel)H, SelI, SelK, SelM, SelO, SelP1, SelPb, SelS, SelT, SelU, and selenoprotein (Sep)n1, Sepw1, Sepx1, and Sep15), suggesting that Pb reduced antioxidant capacity and resulted in oxidative stress involving the SPS2-GPx1-GSH pathway. Se supplementation, as expected, reversed the changes mentioned above, indicating that Se supplementation improved antioxidant capacity and mitigated oxidative stress in chickens. For the first time, we discovered that the SPS2-GPx1-GSH-IL-2/IL-17-NO pathway is involved in the complex inflammatory damage mechanism caused by Pb in chickens. In conclusion, this study demonstrated that Se relieved Pb-induced oxidative stress and inflammatory damage via the SPS2-GPx1-GSH-IL-2/IL-17-NO pathway in the chicken nervous system. This study offers novel insights into environmental pollutant-caused animal poisoning and provides a novel theoretical basis for the detoxification effect of Se against oxidative stress and inflammation caused by toxic pollutants.