Search

Mycolactone is a complex macrolide toxin produced by Mycobacterium ulcerans, the causative agent of Buruli ulcer. The aim of this paper is to review the chemistry, biosynthetic, and synthetic pathways of mycolactone A/B to help develop an understanding of the mode of action of these polyketides as well as their therapeutic potential. The synthetic work has largely been driven by the desire to afford researchers enough (≥100 mg) of the pure toxins for systematic biological studies toward understanding their very high biological activities. The review focuses on pioneering studies of Kishi which elaborate first-, second-, and third-generation approaches to the synthesis of mycolactones A/B. The three generations focused on the construction of the key intermediates required for the mycolactone synthesis. Synthesis of the first generation involves assignment of the relative and absolute stereochemistry of the mycolactones A and B. This was accomplished by employing a linear series of 17 chemical steps (1.3% overall yield) using the mycolactone core. The second generation significantly improved the first generation in three ways: (1) by optimizing the selection of protecting groups; (2) by removing needless protecting group adjustments; and (3) by enhancing the stereoselectivity and overall synthetic efficiency. Though the synthetic route to the mycolactone core was longer than the first generation, the overall yield was significantly higher (8.8%). The third-generation total synthesis was specifically aimed at an efficient, scalable, stereoselective, and shorter synthesis of mycolactone. The synthesis of the mycolactone core was achieved in 14 linear chemical steps with 19% overall yield. Furthermore, a modular synthetic approach where diverse analogues of mycolactone A/B were synthesized via a cascade of catalytic and/or asymmetric reactions as well as several Pd-catalyzed key steps coupled with hydroboration reactions were reviewed. In addition, the review discusses how mycolactone is employed in the diagnosis of Buruli ulcer with emphasis on detection methods of mass spectrometry, immunological assays, RNA aptamer techniques, and fluorescent-thin layer chromatography (f-TLC) methods as diagnostic tools. We examined studies of the structure–activity relationship (SAR) of various analogues of mycolactone. The paper highlights the multiple biological consequences associated with mycolactone such as skin ulceration, host immunomodulation, and analgesia. These effects are attributed to various proposed mechanisms of actions including Wiskott–Aldrich Syndrome protein (WASP)/neural Wiskott–Aldrich Syndrome protein (N-WASP) inhibition, Sec61 translocon inhibition, angiotensin II type 2 receptor (AT2R) inhibition, and inhibition of mTOR. The possible application of novel mycolactone analogues produced based on SAR investigations as therapeutic agents for the treatment of inflammatory disorders and inflammatory pain are discussed. Additionally, their therapeutic potential as anti-viral and anti-cancer agents have also been addressed. [ABSTRACT FROM AUTHOR]

Objectives: B7 homolog 3 protein (B7-H3, also known as CD276) is a member of the B7 family that has been found to be associated with the growth and progression of a variety of tumors, but no pan-cancer evaluations of CD276 have been performed so far. In this study, we aimed to perform a pan-cancer analysis of the oncogenic role of CD276 in human tumors; Methods: We used a series of databases to perform a pan-cancer analysis of CD276, including the expression level of CD276 in pan-cancer and its relationship to tumor progression, patient survival duration, the immune cell infiltration within the tumor, and the potential signaling pathways and molecular mechanisms associated with CD276; Results: We found that CD276 was a potential biomarker for the prognosis of most cancers. The high expression of CD276 was associated with tumor progression, leading to poor survival. Notably, the up-regulation of CD276 expression in tumors increased the tumor infiltration of cancer-associated fibroblasts (CAFs) and myeloid-derived suppressor cells (MDSCs) and decreased the CD8+ T cells; Conclusions: Our study demonstrates that CD276 might promote tumor progression via the promotion of an immunosuppressive microenvironment. [ABSTRACT FROM AUTHOR]

This study develops a prognostic model to predict metastasis and prognosis in colorectal cancer liver metastases by identifying distinct macrophage subsets. Using scRNA-seq data from primary colorectal cancer and liver metastases, we dissected the cellular landscape to find unique macrophage subpopulations, particularly EEF1G + macrophages, which were prevalent in liver metastases. The study leveraged data from GSE231559, TCGA, and GEO databases to construct an 8-gene risk model named EMGS, based on the EEF1G + macrophage gene signature. Patients were divided into high-risk and low-risk groups using the median EMGS score, with the high-risk group showing significantly worse survival. This group also demonstrated upregulated pathways associated with tumor progression, such as epithelial-mesenchymal transition and angiogenesis, and downregulated metabolic pathways. Moreover, the high-risk group presented an immunosuppressive microenvironment, with a higher TIDE score indicating lower effectiveness of immunotherapy. The study identifies potential drugs targeting the high-risk group, suggesting therapeutic avenues to improve survival. Conclusively, the EMGS score identifies colorectal cancer patients at high risk of liver metastases, highlighting the role of specific macrophage subsets in tumor progression and providing a basis for personalized treatment strategies. [ABSTRACT FROM AUTHOR]

Simple Summary: Canine immune-mediated polyarthritis is a common disease that affects young dogs. This study aims at assessing whether leflunomide as add-on treatment to steroids would reduce the rate of relapse and improve survival in dogs with the disease. However, the results of this study suggest that there was no difference in outcomes between dogs that received or did not receive the drug as an add-on therapy. This could provide another step in understanding the nature of immune-mediated diseases and assist practicing veterinarians in making informed decisions about the most appropriate treatment for these conditions. Immune-mediated polyarthritis (IMPA) has a relatively high relapse rate compared to other immune-mediated diseases. Leflunomide is frequently used to treat dogs with IMPA in conjunction with prednisolone. This retrospective cohort study aimed to evaluate the therapeutic efficacy of leflunomide as an adjunctive therapy to prednisolone in reducing relapse and mortality rates in dogs diagnosed with IMPA in Australia. The medical records of client-owned dogs diagnosed with IMPA at a specialist referral hospital in Southeast Queensland from 2017 to 2024 were reviewed. A total of 93 dogs were included in this study, divided into two groups based on the treatment received: Group PRED, consisting of 53 dogs treated with prednisolone as the sole immunosuppressive agent, and Group L+PRED, consisting of 40 dogs that received leflunomide as adjunctive therapy alongside prednisolone. Data collected included breed, age, weight, sex, serum C-reactive protein concentration, results of synovial fluid analysis and microbial culture, treatment protocol, relapse rates and time to relapse, and mortality rates. There was no difference in relapse or mortality rates, time to relapse, nor time to discontinue prednisolone between the PRED and L+PRED groups. The L+PRED group had higher body weights and lower prednisolone dose rate at discharge compared to those in the PRED group. This study demonstrated that the use of leflunomide as an adjunctive therapy to prednisolone for the treatment of dogs with IMPA had no improved outcomes, reduced relapse rates, or shortening in the duration of prednisolone therapy when compared to dogs receiving prednisolone monotherapy. [ABSTRACT FROM AUTHOR]

The tumor microenvironment (TME) is a diverse milieu of cells including cancerous and non-cancerous cells such as fibroblasts, pericytes, endothelial cells and immune cells. The intricate cellular interactions within the TME hold a central role in shaping the dynamics of cancer progression, influencing pivotal aspects such as tumor initiation, growth, invasion, response to therapeutic interventions, and the emergence of drug resistance. In immunologically 'cold' tumors, the TME is marked by a scarcity of infiltrating immune cells, limited antigen presentation in the absence of potent immune-stimulating signals, and an abundance of immunosuppressive factors. While strategies targeting the TME as a therapeutic avenue in 'cold' tumors have emerged, there is a pressing need for novel approaches that faithfully replicate the complex cellular and non-cellular interactions in order to develop targeted therapies that can effectively stimulate immune responses and improve therapeutic outcomes in patients. Microfluidic devices offer distinct advantages over traditional in vitro 3D co-culture models and in vivo animal models, as they better recapitulate key characteristics of the TME and allow for precise, controlled insights into the dynamic interplay between various immune, stromal and cancerous cell types at any timepoint. This review aims to underscore the pivotal role of microfluidic systems in advancing our understanding of the TME and presents current microfluidic model systems that aim to dissect tumor-stromal, tumor-immune and immune-stromal cellular interactions in various 'cold' tumors. Understanding the intricacies of the TME in 'cold' tumors is crucial for devising effective targeted therapies to reinvigorate immune responses and overcome the challenges of current immunotherapy approaches.

Objective: The aim of this study was to investigate the phenotypes, predictive factors, and treatment approach of Behçet's patients with vascular involvement. Material and Method: This retrospective study analyzed 123 patients with Behçet's disease, 28 of whom had vascular involvement, and were followed up in our center. The study presented the vascular involvement patterns of the patients along with their clinical characteristics and comorbid conditions. The drugs usage by the patients were analyzed based on the first line and current medications, duration of medical therapy, and drug retention rate. Results: In Behçet's patients with vascular involvement, the male sex ratio was statistically higher compared to those without vascular involvement (60.7% vs 37.9%; OR=2.82 (1.17-6.77); p=0.018). The frequencies of Behçet's clinical manifestations, smoking, and comorbidities were similar in both groups. The most common subtype of vascular Behçet's is deep vein thrombosis (18; 64.2%), followed by superficial thrombophlebitis (5; 17.8%), neurovascular involvement (5; 17.8%), cardio-aortic (2; 7.1%) and pulmonary arterial (2; 7.1%). Azathioprine, glucocorticoids, and cyclophosphamide are the most preferred immunosuppressives in vasculo-Behçet's. Anticoagulant therapy was initiated in 67.8% (19; 28) of the patients at the first vascular event. Conclusion: The study presented that male gender predicts vascular involvement in Behçet's disease, with deep vein thrombosis being the most common vascular subtype. Although immunosuppressive drugs represent the cornerstone of treatment for vasculo-Behçet's disease, most patients had also received anticoagulant therapy following the initial attack. [ABSTRACT FROM AUTHOR]

Purpose: To report the trends of immunosuppressive drug use for non-infectious uveitis and explore their relationship with industry payments. Methods: A retrospective review of ophthalmologists reimbursed by Medicare for the administration of adalimumab (ADA), repository corticotropin (RCI), methotrexate (MTX), and mycophenolate mofetil (MMF) between 2014 and 2018. Results: A total of 316 ophthalmologists were reimbursed by Medicare for 1567 ADA, 465 RCI, 1752 MTX, and 12 333 MMF administrations. The number and dollar amount of industry payments were positively associated with ADA and RCI use (P < 0.001). From 2014 to 2018, there was a positive trend in the proportion of ADA (P = 0.007) and RCI (P = 0.007) used and negative trend in the proportion of MMF (P = 0.025) used. Conclusion: From 2014 to 2018, the use of ADA and RCI increased while MMF decreased and MTX remained stable. There was a positive association between ADA and RCI use and physician–industry interactions. A causal relationship is not determined. [ABSTRACT FROM AUTHOR]

Recent studies have highlighted the potential of Mesenchymal Stem Cells (MSCs) as an alternative treatment for Alopecia Areata (AA) due to their immunosuppressive properties. While MSCs have shown promise in cell experiments, their effectiveness in vivo remains uncertain. This study aims to validate local administration of MSC therapy's efficacy in AA treatment through animal experiments. AA was induced through Interferon-gamma (IFN-γ) administration in mice, and MSC treatment (MSCT)'s effects were assessed visually and through tissue analysis. The MSC-treated group showed more hair regrowth compared to the control (CTL) group. MSCT notably reduced local inflammatory cytokines (JAK1, JAK2, STAT1, STAT3, IFN-γR, IL-1β, IL-16, IL-17α, and IL-18) in AA-induced mice's skin, but systemic cytokine levels remained unchanged. Furthermore, MSC treatment normalized the expression of Wnt/β-catenin signaling pathway genes (LEF1 and β-catenin) and growth factors (FGF7 and FGF2), which are crucial for hair cycle regulation. This study lays the groundwork for further exploring MSCs as a potential treatment for AA, but more research is needed to fully understand their therapeutic potential. [ABSTRACT FROM AUTHOR]

Background/Aim: Oral squamous cell carcinoma (OSCC) presents a significant health challenge, requiring effective treatments. Magnolol, a compound with potential anticancer properties, warrants investigation in OSCC treatment. Here, we aimed to assess the efficacy of magnolol in inhibiting progression of OSCC and to explore the underlying mechanisms of its action. Materials and Methods: We evaluated the effect of magnolol on tumor progression using the MOC1- bearing orthotopic model. We examined its impact on pathology and toxicity through hematoxylin and eosin (H&E) staining, immunohistochemistry (IHC), and biochemical analysis. We also investigated the immunoregulatory effects of magnolol in the MOC1-bearing model using flow cytometry. Results: At high doses, magnolol significantly reduced tumor volume (p<0.0001 for comparisons between treated with magnolol and untreated groups) and weight loss by 70% in vivo. It also induced caspase-dependent apoptosis, evidenced by 2.42-, 2-, and 2.2- fold increases in the expression of caspase-3, -8, and -9, respectively, in mouse tumors treated with high 60 mg/kg of magnolol compared to untreated (p<0.0001 for all comparisons). Magnolol demonstrated no toxicity, maintaining body weight and normal biochemical parameters, including liver and kidney function. Pathological evaluations showed no adverse effects on organs in all treatment groups. Moreover, high doses of magnolol enhanced natural killer cells (by 3%), dendritic cells (20-25%), and cytotoxic T cells (20-40%) while reducing myeloid-derived suppressor cells and regulatory T cells by 1.5 times. Conclusion: Magnolol demonstrates potential as a therapeutic agent for OSCC, offering antitumor efficacy and immunomodulatory benefits. [ABSTRACT FROM AUTHOR]

Recent advances in immunotherapy represent a breakthrough in solid tumor treatment but the existing data indicate that immunotherapy is not effective in improving the survival time of patients with glioblastoma. The tumor microenvironment (TME) exerts a series of inhibitory effects on immune effector cells, which limits the clinical application of immunotherapy. Growing evidence shows that phosphate and tension homology deleted on chromosome ten (PTEN) plays an essential role in TME immunosuppression of glioblastoma. Emerging evidence also indicates that targeting PTEN can improve the antitumor immunity in TME and enhance the immunotherapy effect, highlighting the potential of PTEN as a promising therapeutic target. This review summarizes the function and specific upstream and downstream targets of PTEN-associated immune cells in glioblastoma TME, providing potential drug targets and therapeutic options for glioblastoma. [ABSTRACT FROM AUTHOR]

Glucagon-like peptide-1 receptor agonists (GLP-1RAs), such as semaglutide (Ozempic®), have emerged as effective treatments for diabetes and weight management. However, recent evidence indicates that GLP-1R signalling influences various tissues, including the immune system. Notably, GLP-1 has a short half-life (< 5 minutes) and exists in the picomolar range, while GLP-1RAs like semaglutide have extended half-lives of several days and are administered at supraphysiological doses. This review explores the potential impact of these medications on vaccine efficacy. We examine evidence suggesting that GLP-1RAs may attenuate vaccine responses through direct effects on immune cells and modulation of other tissues. Additionally, we discuss how GLP-1R signalling may create a tolerogenic environment, potentially reducing vaccine immunogenicity. Given the widespread use of GLP-1RAs, it is crucial to understand their impact on immune responses and the translational implications for vaccination outcomes. [Display omitted] • GLP-1RAs play a key role in managing diabetes and assisting weight loss. • Immune cells also express GLP-1R and are also affected by GLP-1RAs. • Various immune cells exhibit tolerogenic/anti-inflammatory responses to GLP-1RAs. • Signalling cascades downstream of GLP-1R direct immune-attenuating cAMP signalling. • GLP-1RAs impact vaccine efficacy through both immune and non-immune mechanisms. [ABSTRACT FROM AUTHOR]

Abstract Management of immune thrombocytopenia (ITP) in dogs and cats is evolving, but there are no evidence‐based guidelines to assist clinicians with treatment decisions. Likewise, the overall goals for treatment of ITP have not been established. Immunosuppressive doses of glucocorticoids are the first line treatment, but optimal treatment regimens beyond glucocorticoids remain uncertain. Additional options include secondary immunosuppressive drugs such as azathioprine, modified cyclosporine, and mycophenolate mofetil, usually selected based on clinician preference. Vincristine, human IV immunoglobulin (hIVIg), and transfusion of platelet or red blood cell–containing products are often used in more severe cases. Splenectomy and thrombopoietin receptor agonists are usually reserved for refractory cases, but when and in which patient these modalities should be employed is under debate. To develop evidence‐based guidelines for individualized treatment of ITP patients, we asked 20 Population Intervention Comparison Outcome (PICO) format questions. These were addressed by 17 evidence evaluators using a literature pool of 288 articles identified by a structured search strategy. Evidence evaluators, using panel‐designed templates and data extraction tools, summarized evidence and created guideline recommendations. These were integrated by treatment domain chairs and then refined by iterative Delphi survey review to reach consensus on the final guidelines. In addition, 19 non‐PICO questions covering scenarios in which evidence was lacking or of low quality were answered by expert opinion using iterative Delphi surveys with panelist integration and refinement. Commentary was solicited from multiple relevant professional organizations before finalizing the consensus. The rigorous consensus process identified few comparative treatment studies, highlighting many areas of ITP treatment requiring additional studies. This statement is a companion manuscript to the ACVIM Consensus Statement on the Diagnosis of Immune Thrombocytopenia in Dogs and Cats.

Abstract This study investigated the impact of novel copper ionophores on the prognosis of clear cell renal cell carcinoma (ccRCC) and the tumor microenvironment (TME). The differential expression of 10 cuproptosis and 40 TME-pathway-related genes were measured in 531 tumor samples and 71 adjacent kidney samples in The Cancer Genome Atlas database. A risk score model was constructed with LASSO cox to predict the prognosis of ccRCC patients. Forest plot and function enrichment were used to study the biological function of the key genes in depth. The study found that the risk score model accurately predicted the prognosis of ccRCC patients. Patients with high scores had higher immune responses with a higher proportion of anti-tumor lymphocytes and a lower proportion of immunosuppressive M2-like macrophages. However, the high-score group also exhibited a higher proportion of T follicular helper cells and regulatory T cells. These results suggest that cuproptosis-based therapy may be worth further investigation for the treatment of ccRCC and TME. Subsequently, by using RNAi, we established the stable depletion models of FDX1 and PDHB in ccRCC cell lines 786-O and ACHN. Through CCK8, colony formation, and Transwell assays, we observed that the knockdown of FDX1 and PDHB could significantly reduce the capabilities of proliferation and migration in ccRCC cells. In conclusion, this study illuminates the potential effectiveness of copper ionophores in the treatment of ccRCC, with higher risk scores correlating with better TME immune responses. It sets the stage for future cuproptosis-based therapy research in ccRCC and other cancers, focusing on copper’s role in TME.

PurposeMethodsResultsConclusionThe prognostic importance of vitreous cells (VC) in patients with Behçet syndrome (BS) is unknown. We aimed to determine the frequency of developing posterior uveitis (PU) and any additional risk factors associated with the development of PU in BS patients with VC at diagnosis.The charts of 572 consecutive BS patients who were registered between 2010 and 2012 were reviewed. Among the patients with a follow-up of ≥2 years, we included 110 patients with VC in one or both eyes and 147 patients without any eye findings in both eyes at baseline and compared them for the development of PU.Among the 110 included patients with VC, 61 had VC in both eyes, 34 had VC in only one eye, and 15 had VC in one eye and PU in the other eye. There was anterior uveitis (AU) in addition to VC in the same eye in 13 patients at baseline. PU developed in 24 (22%) of these patients during a mean follow-up of 1.9 ± 1.1 years. This was significantly more frequent than the 147 patients without any eye findings at baseline, among whom there were only 2 patients who developed PU (p < 0.001). Multivariate logistic regression analysis showed that having AU in addition to VC in the same eye (OR, 5.03, 95% CI; 1.37–18.47) was an independent risk factor for the development of PU in patients with VC.Careful follow-up is required for patients with VC at diagnosis, since 22% developed PU within 2 years. [ABSTRACT FROM AUTHOR]

This study investigated the impact of novel copper ionophores on the prognosis of clear cell renal cell carcinoma (ccRCC) and the tumor microenvironment (TME). The differential expression of 10 cuproptosis and 40 TME-pathway-related genes were measured in 531 tumor samples and 71 adjacent kidney samples in The Cancer Genome Atlas database. A risk score model was constructed with LASSO cox to predict the prognosis of ccRCC patients. Forest plot and function enrichment were used to study the biological function of the key genes in depth. The study found that the risk score model accurately predicted the prognosis of ccRCC patients. Patients with high scores had higher immune responses with a higher proportion of anti-tumor lymphocytes and a lower proportion of immunosuppressive M2-like macrophages. However, the high-score group also exhibited a higher proportion of T follicular helper cells and regulatory T cells. These results suggest that cuproptosis-based therapy may be worth further investigation for the treatment of ccRCC and TME. Subsequently, by using RNAi, we established the stable depletion models of FDX1 and PDHB in ccRCC cell lines 786-O and ACHN. Through CCK8, colony formation, and Transwell assays, we observed that the knockdown of FDX1 and PDHB could significantly reduce the capabilities of proliferation and migration in ccRCC cells. In conclusion, this study illuminates the potential effectiveness of copper ionophores in the treatment of ccRCC, with higher risk scores correlating with better TME immune responses. It sets the stage for future cuproptosis-based therapy research in ccRCC and other cancers, focusing on copper's role in TME. [ABSTRACT FROM AUTHOR]

Objective: To investigate the relationship between serum aproliferation inducing ligand (APRIL), monocyte chemoattractant protein-1 (MCP-1), CD4+/CD8+ ratio and immunosuppressive therapy efficacy in patients with idiopathic membranous nephropathy (IMN). Methods: 167 IMN patients who received immunosuppressive therapy in Loudi Hospital Affiliated to South China University from January 2020 to March 2022 were selected as the research objects. The levels of serum APRIL and MCP-1 before treatment were detected by enzyme-linked immunosorbent assay (ELISA), CD4+ and CD8+ were detected by flow cytometry, and the ratio of CD4+/CD8+ was calculated. Patients were divided into effective group (n=126) and ineffective group (n=41) according to the curative effect after treatment, the serum APRIL, MCP-1 and CD4+/CD8+ ratio were compared between two groups. The influencing factors of the efficacy of immunosuppressive therapy for IMN were analyzed by Logistic regression model, the predictive value of serum APRIL, MCP-1 and CD4+/CD8+ ratio for ineffective immunosuppressive therapy was analyzed by receiver operating characteristic (ROC) curve. Results: The serum APRIL, MCP-1 and CD4+/CD8+ ratio in ineffective group were higher than those in effective group (P<0.05). Univariate analysis showed that, the efficacy of immunosuppressive therapy in IMN patients was related to pathological stage, 24 h urine protein, serum creatinine (Scr), cystatin C (CysC), and glomerular filtration rate (GFR) (P<0.05). Multivariate Logistic regression analysis showed that, elevated serum APRI, MCP-1, CD4+/CD8+ ratio and pathological stage III and IV were independent risk factors for ineffective immunosuppressive therapy for IMN (P<0.05). The area under the curve (AUC) of serum APRIL, MCP-1, CD4+/CD8+ ratio and combined detection for predicting ineffective immunosuppressive therapy in IMN patients were 0.815, 0.811, 0.749 and 0.939 respectively, the predictive value of combined detection was better than that of each index alone. Conclusion: The increase of serum APRIL, MCP-1 and CD4+/CD8+ ratio are independent risk factors for the ineffective treatment of IMN immunosuppressive agents, the combine detection of the three indicators has a high predictive value for the efficacy of IMN immunosuppressive agents. [ABSTRACT FROM AUTHOR]

Management of immune thrombocytopenia (ITP) in dogs and cats is evolving, but there are no evidence‐based guidelines to assist clinicians with treatment decisions. Likewise, the overall goals for treatment of ITP have not been established. Immunosuppressive doses of glucocorticoids are the first line treatment, but optimal treatment regimens beyond glucocorticoids remain uncertain. Additional options include secondary immunosuppressive drugs such as azathioprine, modified cyclosporine, and mycophenolate mofetil, usually selected based on clinician preference. Vincristine, human IV immunoglobulin (hIVIg), and transfusion of platelet or red blood cell–containing products are often used in more severe cases. Splenectomy and thrombopoietin receptor agonists are usually reserved for refractory cases, but when and in which patient these modalities should be employed is under debate. To develop evidence‐based guidelines for individualized treatment of ITP patients, we asked 20 Population Intervention Comparison Outcome (PICO) format questions. These were addressed by 17 evidence evaluators using a literature pool of 288 articles identified by a structured search strategy. Evidence evaluators, using panel‐designed templates and data extraction tools, summarized evidence and created guideline recommendations. These were integrated by treatment domain chairs and then refined by iterative Delphi survey review to reach consensus on the final guidelines. In addition, 19 non‐PICO questions covering scenarios in which evidence was lacking or of low quality were answered by expert opinion using iterative Delphi surveys with panelist integration and refinement. Commentary was solicited from multiple relevant professional organizations before finalizing the consensus. The rigorous consensus process identified few comparative treatment studies, highlighting many areas of ITP treatment requiring additional studies. This statement is a companion manuscript to the ACVIM Consensus Statement on the Diagnosis of Immune Thrombocytopenia in Dogs and Cats. [ABSTRACT FROM AUTHOR]

Programmed death ligand 1 (PD-L1) is a co-inhibitory molecule expressed on the surface of various cell types and known for its suppressive effect on T cells through its interaction with PD-1. Neutrophils also express PD-L1, and its expression is elevated in specific situations; however, the immunobiological role of PD-L1+ neutrophils has not been fully characterized. Here, we report that PD-L1-expressing neutrophils increased in methicillin-resistant Staphylococcus aureus (MRSA) infection are highly functional in bacterial elimination and supporting inflammatory resolution. The frequency of PD-L1+ neutrophils was dramatically increased in MRSA-infected mice, and this population exhibited enhanced activity in bacterial elimination compared to PD-L1- neutrophils. The administration of PD-L1 monoclonal antibody did not impair PD-L1+ neutrophil function, suggesting that PD-L1 expression itself does not influence neutrophil activity. However, PD-1/PD-L1 blockade significantly delayed liver inflammation resolution in MRSA-infected mice, as indicated by their increased plasma alanine transaminase (ALT) levels and frequencies of inflammatory leukocytes in the liver, implying that neutrophil PD-L1 suppresses the inflammatory response of these cells during the acute phase of MRSA infection. Our results reveal that elevated PD-L1 expression can be a marker for the enhanced anti-bacterial function of neutrophils. Moreover, PD-L1+ neutrophils are an indispensable population attenuating inflammatory leukocyte activities, assisting in a smooth transition into the resolution phase in MRSA infection. [ABSTRACT FROM AUTHOR]

Abstract Background Immunotherapy brings new hope to patients with advanced gastric cancer. However, liver metastases can reduce the efficacy of immunotherapy in patients. Tumor-associated macrophages (TAMs) may be the cause of this reduction in efficacy. SPP1 + TAMs are considered to have immunosuppressive properties. We aimed to investigate the involvement of SPP1 + TAMs in the metastasis of gastric cancer. Methods The single-cell transcriptome was combined with batched BULK datasets for analysis. Animal models were used to verify the analysis results. Results We reveal the interaction of SPP1 + TAMs with CD8 + exhausted T cells in metastatic cancer. Among these interactions, GDF15-TGFBR2 may play a key immunosuppressive role. We constructed an LR score to quantify interactions based on ligands and receptors. The LR score is highly correlated with various immune features and clinical molecular subtypes. The LR score may also guide the prediction of the efficacy of immunotherapy and prognosis. Conclusions The crosstalk between SPP1 + TAMs and CD8 + exhausted T cells plays a key immunosuppressive role in the gastric metastatic cancer microenvironment. Graphical Abstract

Mycolactone is a complex macrolide toxin produced by Mycobacterium ulcerans, the causative agent of Buruli ulcer. The aim of this paper is to review the chemistry, biosynthetic, and synthetic pathways of mycolactone A/B to help develop an understanding of the mode of action of these polyketides as well as their therapeutic potential. The synthetic work has largely been driven by the desire to afford researchers enough (≥100 mg) of the pure toxins for systematic biological studies toward understanding their very high biological activities. The review focuses on pioneering studies of Kishi which elaborate first-, second-, and third-generation approaches to the synthesis of mycolactones A/B. The three generations focused on the construction of the key intermediates required for the mycolactone synthesis. Synthesis of the first generation involves assignment of the relative and absolute stereochemistry of the mycolactones A and B. This was accomplished by employing a linear series of 17 chemical steps (1.3% overall yield) using the mycolactone core. The second generation significantly improved the first generation in three ways: (1) by optimizing the selection of protecting groups; (2) by removing needless protecting group adjustments; and (3) by enhancing the stereoselectivity and overall synthetic efficiency. Though the synthetic route to the mycolactone core was longer than the first generation, the overall yield was significantly higher (8.8%). The third-generation total synthesis was specifically aimed at an efficient, scalable, stereoselective, and shorter synthesis of mycolactone. The synthesis of the mycolactone core was achieved in 14 linear chemical steps with 19% overall yield. Furthermore, a modular synthetic approach where diverse analogues of mycolactone A/B were synthesized via a cascade of catalytic and/or asymmetric reactions as well as several Pd-catalyzed key steps coupled with hydroboration reactions were reviewed. In addition, the review discusses how mycolactone is employed in the diagnosis of Buruli ulcer with emphasis on detection methods of mass spectrometry, immunological assays, RNA aptamer techniques, and fluorescent-thin layer chromatography (f-TLC) methods as diagnostic tools. We examined studies of the structure–activity relationship (SAR) of various analogues of mycolactone. The paper highlights the multiple biological consequences associated with mycolactone such as skin ulceration, host immunomodulation, and analgesia. These effects are attributed to various proposed mechanisms of actions including Wiskott–Aldrich Syndrome protein (WASP)/neural Wiskott–Aldrich Syndrome protein (N-WASP) inhibition, Sec61 translocon inhibition, angiotensin II type 2 receptor (AT2R) inhibition, and inhibition of mTOR. The possible application of novel mycolactone analogues produced based on SAR investigations as therapeutic agents for the treatment of inflammatory disorders and inflammatory pain are discussed. Additionally, their therapeutic potential as anti-viral and anti-cancer agents have also been addressed.

In recent years, the tumor microenvironment （TME） has garnered significant attention from scientists. It is a complex system composed of tumor cells, cancer-associated fibroblasts （CAFs）, immune cells, blood vessels, extracellular matrix, surrounding supportive tissues and their metabolic environment. Two fundamental characteristics of this system are immune escape and metabolic changes （the shift from aerobic to anaerobic metabolism of glucose, leading to lactate production）. Although lactate has traditionally been considered a metabolic "waste" product in the TME, it is now widely recognized that the increase in lactate and the acidification of the tumor microenvironment play key roles in tumor development and progression, including immune escape, tissue invasion/tumor metastasis, angiogenesis and tumor drug resistance. Therefore, studying the regulatory mechanisms of lactate metabolism, immune suppression, angiogenesis, and tumor drug resistance in the TME can provide a theoretical basis and practical evidence for new therapeutic strategies targeting the TME. [ABSTRACT FROM AUTHOR]

Peripheral nerve damage is a critical disorder causing disability of locomotion. The aim of the study was to clarify the effects of testosterone and tacrolimus on the gastrocnemius muscle following sciatic injury. The study was done on 20 rats (n = 5 in each group) whose left sciatic nerve was crushed for 10 s. The sham group (S) of animals received no medicine; the testosterone group (Tes) received testosterone (5 mg/kg, s.c.); the tacrolimus group (Tac): received tacrolimus (5 mg/kg, p.o.); the testosterone and tacrolimus group (Tes+Tac) received testosterone (5 mg/kg, s.c.) and tacrolimus (5 mg/kg, p.o.) daily for four weeks. The gastrocnemius was assessed by gross observation of the plantar surface of paws; the pelvic limb mass muscle and the muscle diameter ratio of the left pelvic limb to the right one by ultrasonography. The gastrocnemius muscle index (GMI) of the left and right pelvic limb, muscle colour, and pathologic changes were also studied. Pathology study of the gastrocnemius included fatty infiltration, muscle atrophy, presence of inflammatory cells and fibrosis formation. Heel redness and swelling were seen in group Tac. No significant difference was found in the GMI between the Tes and S groups (P > 0.01); its value was higher than in the Tes+Tac and Tac groups (P < 0.01). One rat in group Tes had fatty infiltration grade II. Inflammatory cells were grade I in group Tes but fibrosis formation was grade I in group Tes+Tac. Our results show that tacrolimus and testosterone administration may shorten sciatic nerve regeneration time. Testosterone may diminish gastrocnemius muscle atrophy after sciatic nerve crush. [ABSTRACT FROM AUTHOR]

Aframomum melegueta K Schum (A. melegueta), an herbaceous plant renowned for its medicinal seeds, was investigated for its potential immunomodulatory effects in vitro and in vivo using ethanolic and methanolic extracts. The immunomodulatory effect was evaluated by measuring antibody titers using the agglutination technique, while anti-inflammatory activity was assessed in a carrageenan-induced mouse paw edema model. In vitro immunomodulatory activity was measured by lysozyme release from neutrophils. Additionally, white blood cell counts were analyzed post-extracts treatment. The MTT assay was employed to determine cytotoxicity, and the biochemical parameters of liver toxicity were evaluated. Remarkably, both extracts exhibited a dose-dependent reduction in paw edema (p < 0.001), with the most significant reduction observed at 1 g/kg (78.13 and 74.27% for ethanolic and methanolic extracts, respectively). Neutrophil degranulation was significantly inhibited in a dose-dependent manner (p < 0.003), reaching maximal inhibition at 100 μg/mg (60.78 and 39.7% for ethanolic and methanolic extracts, respectively). In comparison to the control group, both antibody production and white blood cell counts were reduced. Neither of the extracts showcased any cytotoxicity or toxicity. These findings suggest that A. melegueta extracts exhibit immunosuppressive and anti-inflammatory activities due to the presence of various biomolecules. [ABSTRACT FROM AUTHOR]

Chicken infectious anemia virus (CIAV), Marek's disease virus (MDV), reticuloendotheliosis virus (REV), and avian leukosis virus (ALV) are immunosuppressive pathogens of concern for poultry. To investigate the prevalence of immunosuppressive pathogens in diseased chickens and the interactions between different viral infections, 768 tissue samples collected from diseased chickens in Jiangsu Province, China were analyzed for CIAV, MDV, REV, and ALV using polymerase chain reaction. The detection rate of these four immunosuppressive pathogens was 55.99%, and the detection rates of CIAV, MDV, REV, and ALV were 29.95, 23.05, 9.90 and 23.44%, respectively. The detection rates of coinfection, dual infection, triple infection, and quadruple infection were 23.57, 17.45, 5.47 and 0.65%, respectively. The most common dual and triple infections were CIAV + ALV (detection rate: 5.08%) and CIAV + MDV + ALV (detection rate: 2.60%). The infection of chicken flocks with immunosuppressive pathogens in Jiangsu Province showed a decreasing trend from 2016 to 2022. There was a synergistic association between CIAV and REV or CIAV and ALV (P<0.01). Therefore, infections and co-infections with immunosuppressive pathogens are prevalent in chicken flocks in Jiangsu Province, China, and CIAV plays a critical role in coinfection, providing an important guide for the future control of these diseases. [ABSTRACT FROM AUTHOR]

Primary hyperparathyroidism (PHPT) is an endocrinological disease that affects systemic inflammation. This study is aimed to investigate the preoperative and postoperative effect of PHPT on systemic inflammation. A total of 203 patients who were successfully operated for PHPT and 98 healthy controls were included in the study. The blood tests of the patients in the last month preoperatively and in the postoperative 6th month were compared. In addition, preoperative and postoperative tests were compared with the healthy control group. When the preoperative neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), and systemic inflammation index (SII) values of the patients who were operated for parathyroid adenoma were compared with the control group (p values were < 0.05, 0.01, 0.19, < 0.05), the NLR, PLR, and SII values were significantly lower in the patient group with parathyroid adenoma than in the control group. When the preoperative and postoperative 6th month NLR, PLR, LMR, and SII values of the patients were compared (p values: 0.026, 0.56, 0.023, 0.016, respectively), there was a significant increase in NLR and SII values after excision, while a significant decrease was observed in the LMR value. When the postoperative 6th month NLR, PLR, LMR, SII values were compared with the healthy control group (p values: 0.22, 0.29, 0.19, 0.29, respectively), no significant difference was observed between all values. We found that the immune system was suppressed in PHPT and this returned to normal levels after a successful surgery. [ABSTRACT FROM AUTHOR]

Objective: The study aimed to examine the demographic, clinical and therapeutic characteristics of people with neuromyelitis optica spectrum disorders (NMOSD, pwNMOSD) during the coronavirus disease 2019 (COVID‐19) pandemic. Methods: This was an observational study of pwNMOSD at a tertiary care clinic. Data on COVID‐19 infection were collected between 11 March 2020 and 30 April 2022. Data on COVID‐19 symptoms, severity and death rate were analyzed. Results: We observed 16 confirmed COVID‐19 cases and three suspected cases. Three (15.8%) patients had severe infections, whereas 16 (84.2%) had mild conditions. Only one person was admitted to the hospital due to pneumonia. COVID‐19 re‐infection was reported by three patients. No pwNMOSD died as a result of COVID‐19 disease. Cough was the most frequently reported symptom. The incidence of COVID‐19 infection in our cohort was 21.1%. Immunosuppressants were taken by 57.9% of pwNMOSD with COVID‐19, and by 84.5% of pwNMOSD without COVID‐19. Conclusions: Due to the small sample size, there was no predominant difference in infection between infected and uninfected patients with or without immunosuppressant drugs. However, given that immunosuppressants are a risk for infection, patient decision‐making in their selection is important. [ABSTRACT FROM AUTHOR]

Lymphatic metastasis is the main metastatic route for colorectal cancer, which increases the risk of cancer recurrence and distant metastasis. The properties of the lymph node metastatic colorectal cancer (LNM-CRC) cells are poorly understood, and effective therapies are still lacking. Here, we found that hypoxia-induced fibroblast activation protein alpha (FAP α) expression in LNM-CRC cells. Gain- or loss-function experiments demonstrated that FAP α enhanced tumor cell migration, invasion, epithelial–mesenchymal transition, stemness, and lymphangiogenesis via activation of the STAT3 pathway. In addition, FAP α in tumor cells induced extracellular matrix remodeling and established an immunosuppressive environment via recruiting regulatory T cells, to promote colorectal cancer lymph node metastasis (CRCLNM). Z-GP-DAVLBH, a FAP α -activated prodrug, inhibited CRCLNM by targeting FAP α -positive LNM-CRC cells. Our study highlights the role of FAP α in tumor cells in CRCLNM and provides a potential therapeutic target and promising strategy for CRCLNM. FAP α exhibits selective expression in lymph node metastatic colorectal cancer cells, facilitating colorectal cancer lymph node metastasis, which can be effectively inhibited by FAP α -activated prodrug Z-GP-DAVLBH. [Display omitted] [ABSTRACT FROM AUTHOR]

Osteosarcoma (OS) is the most common primary bone malignancy and has a high propensity for local invasion and metastasis. The tumour microenvironment of OS is infiltrated by a large number of immune cells, which play a crucial role in its progression and prognosis. Mast cells are important innate immune cells in the tumour stroma and exhibit different phenotypes in diverse tumour microenvironments. However, the underlying mechanisms of mast cell accumulation and the phenotypic characteristics of mast cells in OS remain poorly understood. In this article, we found for the first time that mast cell accumulation in osteosarcoma tissue was modulated by the CXCL6-CXCR2 axis and that the number of infiltrating mast cells was significantly greater in tumour tissues than in adjacent nontumour tissues. These tumour-infiltrating mast cells express high levels of the immunosuppressive molecule PD-L2, and survival analyses revealed that patients in the PD-L2+ high-expression group had a worse prognosis. In vitro, mast cells were induced to express PD-L2 in a time- and dose-dependent manner using OS tissue culture supernatants to mimic the tumour microenvironment. Mechanistic studies revealed that tumour cell-derived G-CSF significantly induced mast cell PD-L2 expression by activating STAT3. Importantly, mast cells overexpressing PD-L2 inhibit tumour-specific CD8+ T-cell proliferation and tumour-killing cytokine secretion, which is reversed by blocking PD-L2 on mast cells. Therefore, our findings provide new insight into the immunosuppressive and tumorigenic roles of mast cells, as well as a novel mechanism by which PD-L2-expressing mast cells mediate immune tolerance.

Background and aims5-aminosalicylates (5-ASA) are frequently used in the management of Crohn's disease (CD). We used a de-identified administrative claims database to compare patterns and outcomes of continuing versus stopping 5-ASA in patients with CD who escalated to anti-metabolite monotherapy.MethodsPatients with CD on 5-ASA who were new users of anti-metabolite monotherapy and followed for at least 12 months from OptumLabs® Data Warehouse. Three patterns of 5-ASA use were identified: stopped 5-ASA, short-term 5-ASA (use for  6 months after starting anti-metabolites). Outcomes (need for corticosteroids, risk of CD-related hospitalization and/or surgery, treatment escalation to biologic therapy) were compared using Cox proportional hazard analysis adjusting for key covariates, with a 12-month immortal time period.ResultsOf 3036 patients with CD who were new-users of anti-metabolite monotherapy, 667 (21.9%), 626 (20.6%), and 1743 (57.4%) stopped 5-ASA, used 5-ASA transiently or persistently, respectively. Compared to patients who stopped 5-ASA after starting anti-metabolites, persistent 5-ASA use was associated with a higher risk of corticosteroid use (HR, 1.24 [1.08-1.42]), without an increase in risk of CD-related hospitalization (HR, 1.21 [0.98-1.49]), CD-related surgery (HR, 1.28 [0.90-1.80]) or treatment escalation (HR, 0.85 [0.62-1.20]). Sensitivity analyses using a 3-month window after initiation of anti-metabolites to classify patients as continuing vs. stopping 5-ASA showed similar results. Residual confounding by disease severity could not be excluded.Conclusion5-ASAs are frequently continued long-term even after escalation to anti-metabolite therapy in patients with CD but offer no clinical benefit over stopping 5-ASA.

Cancer immunotherapy has gained momentum for treating malignant tumors over the past decade. Checkpoint blockade and chimeric antigen receptor cell therapy (CAR-T) have shown considerable potency against liquid and solid cancers. However, the tumor microenvironment (TME) is highly immunosuppressive and hampers the effect of currently available cancer immunotherapies on overall treatment outcomes. Advancements in the design and engineering of nanomaterials have opened new avenues to modulate the TME. Progress in the current nanocomposite technology can overcome immunosuppression and trigger robust immunotherapeutic responses by integrating synergistic functions of different molecules. We will review recent advancements in nanomedical applications and discuss specifically designed nanocomposites modulating the TME for cancer immunotherapy. In addition, we provide information on the current landscape of clinical-stage nanocomposites for cancer immunotherapy.

Immunotherapy has rejuvenated cancer therapy, especially after anti-PD-(L)1 came onto the scene. Among the many therapeutic options, therapeutic cancer vaccines are one of the most essential players. Although great progress has been made in research on tumor antigen vaccines, few phase III trials have shown clinical benefits. One of the reasons lies in obstruction from the tumor microenvironment (TME). Meanwhile, the therapeutic cancer vaccine reshapes the TME in an ambivalent way, leading to immune stimulation or immune escape. In this review, we summarize recent progress on the interaction between therapeutic cancer vaccines and the TME. With respect to vaccine resistance, innate immunosuppressive TME components and acquired resistance caused by vaccination are both involved. Understanding the underlying mechanism of this crosstalk provides insight into the treatment of cancer by directly targeting the TME or synergizing with other therapeutics.

Introduction: Tuberculosis is one of the most common infections that lead to death,; incidence of tuberculosis is higher in individuals with immune system deficiency. Candidates for receiving immunosuppressive drugs should be examined for the presence of latent tuberculosis, so that if this test is positive, appropriate treatment and prophylaxis measures for tuberculosis can be carried out for them. The purpose of this study was to screen patients who are candidates for receiving immunosuppressive drugs in terms of tuberculosis. Methods: This cross-sectional study was conducted on the patients who were candidates for injectable immunosuppressive drugs hospitalized in Shahid Sadoughi Hospital between 2019 to 2020. Tuberculin skin test (TST) was taken from all eligible patients by the infection control unit of the hospital. Statistical analysis was done by SPSS V16. The P value less than 0.05 was considered statistically significant. Results: Participants were divided into three groups: healthy (TST=0-4), suspected (TST=5-9) and infected with tuberculosis (TST≥10); the frequency in the three groups was 83 (23.9%), 164 respectively. (47.3%) and 100 (28.8%). There was a significant relationship between the reason for referral to receive immunosuppressive drugs and the results of the TST test (P=0.003). Conclusion: If the patients with rheumatology, dermatology disorders and kidney transplant candidates receive immunosuppressive drugs, they are at high risk of primary tuberculosis infection and activation of latent tuberculosis, and it is necessary for health workers to pay more attention to this issue. Corresponding Author:Zohreh Akhoundimeybodi Orcid: 0000-0003-1250-6845 You can search for this author in PubMed Google Scholar Profile

Abstract Background Cancer cells express immunosuppressive molecules, such as programmed death ligands (PD-L)1 and PD-L2, enabling evasion from the host’s immune system. Cancer cells synthesize and secrete acetylcholine (ACh), acting as an autocrine or paracrine hormone to promote their proliferation, differentiation, and migration. Methods We correlated the expression of PD-L1, PD-L2, cholinergic muscarinic receptor 3 (M3R), alpha 7 nicotinic receptor (α7nAChR), and choline acetyltransferase (ChAT) in colorectal cancer (CRC) tissues with the stage of disease, gender, age, risk, and patient survival. The effects of a muscarinic receptor blocker, atropine, and a selective M3R blocker, 4-DAMP, on the expression of immunosuppressive and cholinergic markers were evaluated in human CRC (LIM-2405, HT-29) cells. Results Increased expression of PD-L1, M3R, and ChAT at stages III-IV was associated with a high risk of CRC and poor survival outcomes independent of patients’ gender and age. α7nAChR and PD-L2 were not changed at any CRC stages. Atropine and 4-DAMP suppressed the proliferation and migration of human CRC cells, induced apoptosis, and decreased PD-L1, PD-L2, and M3R expression in CRC cells via inhibition of EGFR and phosphorylation of ERK. Conclusions The expression of immunosuppressive and cholinergic markers may increase the risk of recurrence of CRC. These markers might be used in determining prognosis and treatment regimens for CRC patients. Blocking cholinergic signaling may be a potential therapeutic for CRC through anti-proliferation and anti-migration via inhibition of EGFR and phosphorylation of ERK. These effects allow the immune system to recognize and eliminate cancer cells.

Abstract Cell proliferation and function require nutrients, energy, and biosynthesis activity to duplicate repertoires for each daughter. It is therefore not surprising that tumor microenvironment (TME) metabolic reprogramming primarily orchestrates the interaction between tumor and immune cells. Tumor metabolic reprogramming affords bioenergetic, signaling intermediates, and biosynthesis requirements for both malignant and immune cells. Different immune cell subsets are recruited into the TME, and these manifestations have distinct effects on tumor progression and therapeutic outcomes, especially the mutual contribution of glycolysis and cholesterol metabolism. In particularly, glycolysis-cholesterol metabolic axis interconnection plays a critical role in the TME modulation, and their changes in tumor metabolism appear to be a double-edged sword in regulating various immune cell responses and immunotherapy efficacy. Hence, we discussed the signature manifestation of the glycolysis-cholesterol metabolic axis and its pivotal role in tumor immune regulation. We also highlight how hypothetical combinations of immunotherapy and glycolysis/cholesterol-related metabolic interventions unleash the potential of anti-tumor immunotherapies, as well as developing more effective personalized treatment strategies.

Abstract Background Immunosuppression is a significant factor contributing to the poor prognosis of cancer. S100P, a member of the S100 protein family, has been implicated in various cancers. However, its role in the tumor microenvironment (TME) of pancreatic cancer remains unclear. This study aimed to investigate the potential impact of S100P on TME characteristics in patients with pancreatic cancer. Methods Multiple data (including microarray, RNA-Seq, and scRNA-Seq) were obtained from public databases. The expression pattern of S100P was comprehensively evaluated in RNA-Seq data and validated in four different microarray datasets. Prognostic value was assessed through Kaplan-Meier plotter and Cox regression analyses. Immune infiltration levels were determined using the ESTIMATE and ssGSEA algorithms and validated at the single-cell level. Spearman correlation test was used to examine the correlation between S100P expression and immune checkpoint genes, and tumor mutation burden (TMB). DNA methylation analysis was performed to investigate the change in mRNA expression. Reverse transcription PCR (RT-PCR) and immunohistochemical (IHC) were utilized to validate the expression using five cell lines and 60 pancreatic cancer tissues. Results This study found that S100P was differentially expressed in pancreatic cancer and was associated with poor prognosis (P

Abstract Background The efficacy of human umbilical cord mesenchymal stem cell (hUC-MSC) transplantation in treating systemic lupus erythematosus (SLE) has been confirmed by small-scale clinical trials. However, these trials focused on severe or refractory SLE, while few studies focused on mild SLE. Therefore, this study focused on the therapeutic effects of hUC-MSC transplantation in early-stage or mild MRL/lpr lupus model mice. Methods Commercially available hUC-MSCs were transplanted into 8-week-old MRL/lpr mice by tail vein injection. Flow cytometry was used to analyze B cells and their subsets in the peripheral blood. Further, plasma inflammatory factors, autoantibodies, and plasma biochemical indices were detected using protein chip technology and ELISA kits. In addition, pathological staining and immunofluorescence were performed to detect kidney injury in mice. Results hUC-MSC transplantation did not affect the mice’s body weight, and both middle and high dose hUC-MSC transplantation (MD and HD group) actually reduced spleen weight. hUC-MSC transplantation significantly decreased the proportion of plasmablasts (PB), IgG1− PB, IgG1+ PB, IgG1+ memory B (MB) cells, IgG1+ DN MB, and IgG1+ SP MB cells. The hUC-MSC transplantation had significantly reduced plasma levels of inflammatory factors, such as TNF-α, IFN-γ, IL-6, and IL-13. Pathological staining showed that the infiltration of glomerular inflammatory cells was significantly reduced and that the level of glomerular fibrosis was significantly alleviated in hUC-MSC-transplanted mice. Immunofluorescence assays showed that the deposition of IgG and IgM antibodies in the kidneys of hUC-MSC-transplanted mice was significantly lower than in the control. Conclusion hUC-MSC transplantation could inhibit the proliferation and differentiation of peripheral blood B cells in the early-stage of MRL/lpr mice, thereby alleviating the plasma inflammatory environment in mice, leading to kidney injury remission. The study provides a new and feasible strategy for SLE treatment.

The tumor microenvironment (TME) is a diverse milieu of cells including cancerous and non-cancerous cells such as fibroblasts, pericytes, endothelial cells and immune cells. The intricate cellular interactions within the TME hold a central role in shaping the dynamics of cancer progression, influencing pivotal aspects such as tumor initiation, growth, invasion, response to therapeutic interventions, and the emergence of drug resistance. In immunologically ‘cold’ tumors, the TME is marked by a scarcity of infiltrating immune cells, limited antigen presentation in the absence of potent immune-stimulating signals, and an abundance of immunosuppressive factors. While strategies targeting the TME as a therapeutic avenue in ‘cold’ tumors have emerged, there is a pressing need for novel approaches that faithfully replicate the complex cellular and non-cellular interactions in order to develop targeted therapies that can effectively stimulate immune responses and improve therapeutic outcomes in patients. Microfluidic devices offer distinct advantages over traditional in vitro 3D co-culture models and in vivo animal models, as they better recapitulate key characteristics of the TME and allow for precise, controlled insights into the dynamic interplay between various immune, stromal and cancerous cell types at any timepoint. This review aims to underscore the pivotal role of microfluidic systems in advancing our understanding of the TME and presents current microfluidic model systems that aim to dissect tumor-stromal, tumor-immune and immune-stromal cellular interactions in various ‘cold’ tumors. Understanding the intricacies of the TME in ‘cold’ tumors is crucial for devising effective targeted therapies to reinvigorate immune responses and overcome the challenges of current immunotherapy approaches.

Sinomenine, an isoquinoline alkaloid extracted from the roots and stems of Sinomenium acutum, has been extensively studied for its derivatives as bioactive agents. This review concentrates on the research advancements in the biological activities and action mechanisms of sinomenine-related compounds until November 2023. The findings indicate a broad spectrum of pharmacological effects, including antitumor, anti-inflammation, neuroprotection, and immunosuppressive properties. These compounds are notably effective against breast, lung, liver, and prostate cancers, exhibiting IC50 values of approximately 121.4 nM against PC-3 and DU-145 cells, primarily through the PI3K/Akt/mTOR, NF-κB, MAPK, and JAK/STAT signaling pathways. Additionally, they manifest anti-inflammatory and analgesic effects predominantly via the NF-κB, MAPK, and Nrf2 signaling pathways. Utilized in treating rheumatic arthritis, these alkaloids also play a significant role in cardiovascular and cerebrovascular protection, as well as organ protection through the NF-κB, Nrf2, MAPK, and PI3K/Akt/mTOR signaling pathways. This review concludes with perspectives and insights on this topic, highlighting the potential of sinomenine-related compounds in clinical applications and the development of medications derived from natural products. [ABSTRACT FROM AUTHOR]

Coffee is a kind of daily beverage, and its correlation with cardiovascular disease and atherosclerosis is still debatable. The aim of this study is to investigate the effects of Amstirdam coffee extract (ACE) on lipoprotein-associated phospholipase A2 (Lp-PLA2) and the inflammatory response in atherosclerosis mouse models. The study used 25 Swiss male mice for five groups (n = 5): healthy mice fed a normal diet (N); mice fed a high-fat, high-fructose diet (HFFD); mice fed HFFD and treated with ACE at doses of 104 (D1), 520 (D2), and 5200 mg/kg BW (D3). The levels of Lp-PLA2, regulatory T cells (Tregs) (CD4+CD25+CD62L+, CD4+CD25+IL-10+, CD4+CD25+TGF-+), IL-10 (CD4+IL-10+), and TGF-B (CD4+TGF+) were analyzed using a flow cytometer. Histological analysis of the mouse aorta was done by hematoxylin and eosin (HE) staining. This study indicated a significant increase in total cholesterol (TC), triglyceride (TG), LDL, and Lp-PLA2 levels in the HFFD group. HFFD also reduced HDL, IL-10, and TGF produced by CD4 and Tregs compared with the normal group. ACE at all doses significantly reduced Lp-PLA2 levels compared with the HFFD group (p < 0.05). Interestingly, the administration of 520 mg/kg BW ACE (D2) increased the production of IL-10 significantly compared to other doses (p < 0.05). The D3 group possessed a high TGF- production and Treg expression level significantly different between groups (p < 0.05). Foam cells were mostly found in the aorta of the HFFD group compared to the normal and ACE treatment groups. This study suggested that ACE could reduce Lp-PLA2 enzyme activity and foam cell formation through the immunosuppressive activity of IL-10 and TGF cytokines. [ABSTRACT FROM AUTHOR]

This study introduces a new method of targeting acidosis (low pH) within the tumor microenvironment (TME) through the use of cathodic electrochemical reactions (CER). Low pH is oncogenic by supporting immunosuppression. Electrochemical reactions create local pH effects when a current passes through an electrolytic substrate such as biological tissue. Electrolysis has been used with electroporation (destabilization of the lipid bilayer via an applied electric potential) to increase cell death areas. However, the regulated increase of pH through only the cathode electrode has been ignored as a possible method to alleviate TME acidosis, which could provide substantial immunotherapeutic benefits. Here, we show through ex vivo modeling that CERs can intentionally elevate pH to an anti-tumor level and that increased alkalinity promotes activation of naïve macrophages. This study shows the potential of CERs to improve acidity within the TME and that it has the potential to be paired with existing electric field-based cancer therapies or as a stand-alone therapy. [ABSTRACT FROM AUTHOR]

Introduction: Liver recipients to adhere to immunosuppressive therapy and cope with their health problems after liver transplantation are very important. Sexual dysfunction is common in transplant patients; however, previous studies mostly focused on male organ recipients. This study aimed to examine the adherence to immunosuppressive therapy, perceived spousal support, and sexual dysfunction in female liver recipients. Methods: This is a descriptive study and included a total of 184 female liver recipients. Data collection was done at three different transplant centers. Data were collected using a personal information form, the Immunosuppressant Therapy Adherence Scale, the Arizona Sexual Experience Scale, and the Spouse Support Scale and analyzed using descriptive statistical methods, regression analysis, and Pearson correlation analysis. Results: The mean age of female liver recipients was 41.03 ± 6.77 years, 69.6% of them were married, and 60.3% had moderate income. Due to immunosuppressive drugs, 51.1% of them had gastrointestinal issues, 38.6% had diabetes mellitus and endocrine issues. In addition, 50% and 30.4% of them had full and moderate adherence to immunosuppressive therapy, respectively. In this study, it was determined that as the social support perception of female liver recipients increased, sexual life improved (p < 0.05). Conclusions: As adherence to immunosuppressive therapy in female liver recipients increased, their sexual dysfunctions increased. There was a correlation between sexual dysfunction and spousal support in female liver recipients. Policy Implications: This study emphasized the effect of immunosuppressive drugs on sexual dysfunctions in female liver recipients, therefore recommends that female liver recipients with sexual dysfunction be referred to psychotherapeutic practices. [ABSTRACT FROM AUTHOR]

The first description of Pyoderma gangrenosum (PG) was made about a century ago. It is difficult to understand the aetiology, pathophysiology, and therapy of PG. This disease is believed to be caused by a systemic inflammatory response to neutrophil chemotaxis and faulty innate immune system control. Nearly fifty percent of the cases have underlying systemic symptoms. Significant improvements in PG management have been made over the years. The main goals of treatment are to reduce inflammation and speed up the healing of the PG wound. Even though the most recent medicines show promise, they are found on isolated case reports. The majority of patients are typically managed with topical treatment and local wound care, while resistant cases necessitate immunosuppressive medications. More progress can be made with improvements in technology in deciphering this complex disease and getting a greater understanding of the condition. The present standard therapies for refractory PG are not well supported by studies. In refractory PG, corticosteroids and cyclosporine have historically been administered. Tumour necrosis factor inhibitors are becoming a viable option; nonetheless, this requires careful research and upkeep. This review intended to describe the current trends in managing the PG. Several next-generation treatment options including the conventional therapies introduced to treat PG. We encompass the advantages and disadvantages of new treatments for PG. [ABSTRACT FROM AUTHOR]

Heterogeneity is a critical basis for understanding how the tumor microenvironment (TME) contributes to tumor progression. However, an understanding of the specific characteristics and functions of TME subtypes (subTMEs) in the progression of cancer is required for further investigations into single-cell resolutions. Here, we analyzed single-cell RNA sequencing data of 250 clinical samples with more than 200,000 cells analyzed in each cancer datum. Based on the construction of an intercellular infiltration model and unsupervised clustering analysis, four, three, three, and four subTMEs were revealed in breast, colorectal, esophageal, and pancreatic cancer, respectively. Among the subTMEs, the immune-suppressive subTME (subTME-IS) and matrix remodeling with malignant cells subTME (subTME-MRM) were highly enriched in tumors, whereas the immune cell infiltration subTME (subTME-ICI) and precancerous state of epithelial cells subTME (subTME-PSE) were less in tumors, compared with paracancerous tissues. We detected and compared genes encoding cytokines, chemokines, cytotoxic mediators, PD1, and PD-L1. The results showed that these genes were specifically overexpressed in different cell types, and, compared with normal tissues, they were upregulated in tumor-derived cells. In addition, compared with other subTMEs, the expression levels of PDCD1 and TGFB1 were higher in subTME-IS. The Cox proportional risk regression model was further constructed to identify possible prognostic markers in each subTME across four cancer types. Cell-cell interaction analysis revealed the distinguishing features in molecular pairs among different subTMEs. Notably, ligand–receptor gene pairs, including COL1A1-SDC1, COL6A2-SDC1, COL6A3-SDC1, and COL4A1-ITGA2 between stromal and tumor cells, associated with tumor invasion phenotypes, poor patient prognoses, and tumor advanced progression, were revealed in subTME-MRM. C5AR1-RPS19, LGALS9-HAVCR2, and SPP1-PTGER4 between macrophages and CD8+ T cells, associated with CD8+ T-cell dysfunction, immunosuppressive status, and tumor advanced progression, were revealed in subTME-IS. The spatial co-location information of cellular and molecular interactions was further verified by spatial transcriptome data from colorectal cancer clinical samples. Overall, our study revealed the heterogeneity within the TME, highlighting the potential pro-invasion and pro-immunosuppressive functions and cellular infiltration characteristics of specific subTMEs, and also identified the key cellular and molecular interactions that might be associated with the survival, invasion, immune escape, and classification of cancer patients across four cancer types. [ABSTRACT FROM AUTHOR]