Tryptophan catabolism is a major metabolic pathway utilized by several professional and non-professional antigen presenting cells to maintain immunological tolerance. Here we report that 3-hydroxy-l-kynurenamine (3-HKA) is a biogenic amine produced via an alternative pathway of tryptophan metabolism. In vitro, 3-HKA has an anti-inflammatory profile by inhibiting the IFN-γ mediated STAT1/NF-κΒ pathway in both mouse and human dendritic cells (DCs) with a consequent decrease in the release of pro-inflammatory chemokines and cytokines, most notably TNF, IL-6, and IL12p70. 3-HKA has protective effects in an experimental mouse model of psoriasis by decreasing skin thickness, erythema, scaling and fissuring, reducing TNF, IL-1β, IFN-γ, and IL-17 production, and inhibiting generation of effector CD8+ T cells. Similarly, in a mouse model of nephrotoxic nephritis, besides reducing inflammatory cytokines, 3-HKA improves proteinuria and serum urea nitrogen, overall ameliorating immune-mediated glomerulonephritis and renal dysfunction. Overall, we propose that this biogenic amine is a crucial component of tryptophan-mediated immune tolerance.
Inflammatory Breast Cancer (IBC) is a highly aggressive malignancy with distinct clinical and histopathological features whose molecular basis is unresolved. Here we describe a human IBC cell line, A3250, that recapitulates key IBC features in a mouse xenograft model, including skin erythema, diffuse tumor growth, dermal lymphatic invasion, and extensive metastases. A3250 cells express very high levels of the CCL2 chemokine and induce tumors enriched in macrophages. CCL2 knockdown leads to a striking reduction in macrophage densities, tumor proliferation, skin erythema, and metastasis. These results establish IBC-derived CCL2 as a key factor driving macrophage expansion, and indirectly tumor growth, with transcriptomic analysis demonstrating the activation of multiple inflammatory pathways. Finally, primary human IBCs exhibit macrophage infiltration and an enriched macrophage RNA signature. Thus, this human IBC model provides insight into the distinctive biology of IBC, and highlights potential therapeutic approaches to this deadly disease.
Context Dietary patterns play a key role in mental health, depression, and mood state. However, the evidence concerning specific foods highly recommended for mental health, such as nuts, has not yet been synthesized. Objective The objective of this review was to synthesize the evidence for a relationship between higher levels of nut consumption, lower risk of depression, and better mood state in the general population. Data Sources The MEDLINE, Scopus, Cochrane Central, Web of Science, and PsycInfo databases were systematically searched from each database’s inception to March 2021. Data Extraction Randomized clinical trials (RCTs) and observational studies exploring the association between nut consumption, level of depression, and mood state in the general population were included. The quality of the studies was measured through the Joanna Briggs Institute tool (cross-sectional studies), the NIH Quality Assessment Tool (cohort studies), and the Cochrane Risk-of-Bias tool (RCTs). The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. Data Analysis A total of 10 studies involving 66 418 individuals were included, of which 3 were cross-sectional, 3 were cohort studies, and 4 were RCTs. In studies concerned with depression (n = 6 studies), a higher level of nut consumption was associated with a lower risk of depression in 2 cross-sectional studies and 1 cohort study, while a similar but nonsignificant association was found in another cohort and in two RCTs. In studies concerned with mood state (n = 4), 1 cohort study reported an association between higher nut consumption and significant improvement in mood state, whereas (nonsignificant) associations between higher nut consumption and increased negative feelings were reported in a cross-sectional study and two RCTs. Conclusion Despite the small number of studies and the limitations related to them, such as reverse causation bias, overall, the available literature suggests that higher nut consumption could be associated with a lower risk of depression, fewer depressive symptoms, and better mood state in the general population. Systematic Review Registration PROSPERO registration no. CRD42021241070.
Although prior research has synthesized the relationships between the Mediterranean diet (MD) and components of physical fitness (PF) in adults, they are limited and inconclusive. This study aimed to synthesize the associations between high (vs. low) MD adherence and PF levels along with each of its components (cardiorespiratory, motor, and musculoskeletal) in adulthood. We conducted a systematic search in five databases from inception to January 2022. Observational studies and randomized controlled trials (RCTs) were included. Pooled odds ratios (ORs) and effect sizes (Cohen's d index) with their 95% CIs were calculated using a random-effects model. A total of 30 studies (19 cross-sectional in young, middle-aged, and older adults, 10 prospective cohort in older adults, and one RCT in young adults) involving 36,807 individuals (mean age range: 20.9–86.3 years) were included. Pooled effect sizes showed a significant cross-sectional association between higher MD adherence scores (as a continuous variable) and overall PF (d = 0.45; 95% CI: 0.14, 0.75; I2 = 91.0%; n = 6). The pooled ORs from cross-sectional data showed that high adherence to MD was associated with higher cardiorespiratory fitness (OR = 2.26; 95% CI: 2.06, 2.47; I2 = 0%; n = 4), musculoskeletal fitness (OR = 1.26; 95% CI: 1.05, 1.47; I2 = 61.4%; n = 13), and overall PF (OR = 1.44; 95% CI: 1.20, 1.68; I2 = 83.2%; n = 17) than low adherence to MD (reference category = 1). Pooled ORs from prospective cohort studies (3–12-year follow-up) showed that high adherence to MD was associated with higher musculoskeletal fitness (OR = 1.20; 95% CI: 1.01, 1.38; I2 = 0%; n = 4) and overall PF (OR = 1.14; 95% CI: 1.02, 1.26; I2 = 9.7%; n = 7) than low adherence to MD (reference category = 1). Conversely, no significant association was observed between MD and motor fitness. High adherence to MD was associated with higher PF levels, a crucial marker of health status throughout adulthood.
e15050 Background: Avian paramyxoviruses (APMVs) are negative-sense, single-stranded RNA viruses, of which best known is APMV-1, commonly referred to as Newcastle disease virus (NDV). NDV has been extensively studied as an oncolytic virus (OV) and has been shown to be a promising viral agent for human cancer therapy. We identified APMV-4 as a novel OV from the APMV family, with several advantages over NDV and other classes of OVs. APMV-4 is selective for cancer cells, it is not a human pathogen, there is no pre-existing immunity to this virus in humans, and it can be engineered to deliver various therapeutics. Here, we investigated anti-tumor properties of APMV-4 in mouse tumor models, and the role of Vascular Endothelial Growth Factor-C (VEGF-C), a key lymphangiogenesis factor, on therapeutic effects of AMPV-4. Methods: Anti-tumor effects of OVs were assessed using B16F10 melanoma and CT26.WT colon carcinoma in syngeneic mouse models. Tumor cells were injected intradermally into the flank, and treatment commenced when tumors reached ̃50mm3. Viruses were injected intratumorally (107 PFU) every two days, for a total of four treatments. For studies of VEGF-C, B16F10 cells were transfected with VEGF-C or with an empty vector. Tumor regression and long-term survival were assessed. Mice in complete remission were re-challenged with tumor cells on the opposite side. High-dimensional immunophenotyping using Aurora Spectral flow cytometry was performed on tumor samples collected 12 hr after the 2nd treatment with OVs. Results: Intratumoral administration of APMV-4 extended survival, promoted tumor elimination and conferred protection against re-challenge in murine colon carcinoma and melanoma tumor models, and was more effective than NDV strain LaSota. Expression of VEGF-C in B16F10 melanoma enhanced anti-tumor effects of APMV-4 or NDV, resulting in complete remission in 100% and 86% of mice, respectively (n = 7). Mice remained tumor-free during the 90-day observation period, and following re-challenge remained tumor-free for more than a year. Protection from tumor development upon re-challenge was observed in 71% and 83% of mice treated with APMV-4 or NDV, respectively. Results are representative of two experiments. VEGF-C expression in tumors induced lymphangiogenesis, which correlated with high T-cell densities. Analysis of tumor immune cell composition by flow cytometry revealed multiple unique T-cell and NK-cell subsets associated with complete remission. Conclusions: These studies identify APMV-4 as a novel oncolytic agent with great therapeutic potential and VEGF-C as potent enhancer of anti-tumor immunity. High anti-tumor efficacy of APMV-4/VEGF-C monotherapy, that in preclinical models leads to tumor eradication, indicates great therapeutic and vaccine potential of APMV-4 when combined with VEGF-C.
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