Explore the vast range of titles available.

Human triple negative breast cancer cells, MDA-MB-231, show typical epithelial to mesenchymal transition associated with cancer progression. Mitochondria play a major role in cancer progression, including metastasis. Changes in mitochondrial architecture affect cellular migration, autophagy and apoptosis. Silibinin is reported to have anti-breast cancer effect. We here report that silibinin at lower concentrations (30–90 μM) inhibits epithelial to mesenchymal transition (EMT) of MDA-MB-231, by increasing the expression of epithelial marker, E-cadherin, and decreasing the expression of mesenchymal markers, N-cadherin and vimentin. Besides, silibinin inhibition of cell migration is associated with reduction in the protein expression of matrix metalloproteinases 2 and 9 (MMP2 and MMP9) and paxillin. In addition, silibinin treatment increases mitochondrial fusion through down-regulating the expression of mitochondrial fission-associated protein dynamin-related protein 1 (DRP1) and up-regulating the expression of mitochondrial fusion-associated proteins, optic atrophy 1, mitofusin 1 and mitofusin 2. Silibinin perturbed mitochondrial biogenesis via down-regulating the levels of mitochondrial biogenesis regulators including mitochondrial transcription factor A (TFAM), peroxisome proliferator-activated receptor gamma coactivator (PGC1) and nuclear respiratory factor (NRF2). Moreover, DRP1 knockdown or silibinin inhibited cell migration, and MFN1&2 knockdown restored it. Mitochondrial fusion contributes to silibinin’s negative effect on cell migration. Silibinin decreased reactive oxygen species (ROS) generation, leading to inhibition of the NLRP3 inflammasome activation. In addition, knockdown of mitofusin 1&2 (MFN 1&2) relieved silibinin-induced inhibition of NLRP3 inflammasome activation. Repression of ROS contributes to the inhibition of the expression of NLRP3, caspase-1 and IL-β proteins as well as of cell migration. Taken together, our study provides evidence that silibinin impairs mitochondrial dynamics and biogenesis, resulting in reduced migration and invasion of the MDA-MB-231 breast cancer cells.

This study investigates mist-assisted film cooling on a flat plate in a supersonic crossflow (mainstream Ma  = 2.0) through numerical simulations under the mist particle diameter of 5 μm. The cooling performance of cylindrical hole, merged hole and sister hole structure is systematically compared at the cooling jet Mach number ranging from 0.4 to 1.4 and mist concentration ranging from 0 to 5%. The effects of shock system, kidney vortex pair and mist particles distribution on film cooling performance are analyzed. Results demonstrate that increasing the cooling jet Mach number could intensify the shear layer effect, shock waves interaction and kidney vortices, promoting both the jet lift-off and mist particle lift-off phenomena, thus reducing the cooling performance enhancement obtained by the mists injection at the near-hole region. Increasing the mist concentration could primarily improve the cooling performance at the more downstream region where the cooling capacities of the air jets decay rapidly and more mist particles diffuse onto the wall surface. Results also indicate that proper management of vortex structures and expansion wave impingement location enable more effective mist transport to protect the wall surface. Among three configurations, sister holes demonstrate superior overall cooling performance in both air-only and mist-assisted conditions, particularly at a higher jet Mach number. Under Ma c  = 1.4 and 5% mist concentration, sister holes achieve a 40% enhancement and merged holes achieve a 16% enhancement in cooling effectiveness compared to cylindrical holes.

Besides motor disorder, cognitive dysfunction is also common in Parkinson’s disease (PD). Essentially no causal therapy for cognitive dysfunction of PD exists at present. In this study, a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD was used to analyze the neuroprotective potential of orally administered silibinin, a proverbial hepatoprotective flavonoid derived from the herb milk thistle (Silybum marianum). Results demonstrated that silibinin administration significantly attenuated MPTP-induced cognitive impairment in behavioral tests. Nissl staining results showed that MPTP injection significantly increases the loss of neurons in the hippocampus. However, these mice were protected by oral administration of silibinin, accompanying reduction in the cell apoptosis in the hippocampus. The hippocampal aggregates of α-synuclein (α-syn) appeared in MPTP-injected mice, but were significantly decreased by silibinin treatment. MPTP injection induced oxidative stress, as evidenced by increased malondialdehyde (MDA) and decreased superoxide dismutase (SOD). The oxidative stress was alleviated by silibinin treatment. Mitochondrial disorder including the decline of mitochondrial membrane potential (MMP) was another signature in the hippocampus of MPTP-treated mice, accompanying increased mitochondrial fission and decreased fusion. Silibinin administration restored these mitochondrial disorders, as expected for the protection against MPTP injury. These findings suggest that silibinin has a potential to be further developed as a therapeutic candidate for cognitive dysfunction in PD.

Recent advances in high throughput sequencing (HTS) of T cell receptors (TCRs) and in transcriptomic analysis, particularly at the single cell level, have opened the door to a new level of understanding of human immunology and immune-related diseases. In this article, we discuss the use of HTS of TCRs to discern the factors controlling human T cell repertoire development and how this approach can be used in combination with human immune system (HIS) mouse models to understand human repertoire selection in an unprecedented manner. An exceptionally high proportion of human T cells has alloreactive potential, which can best be understood as a consequence of the processes governing thymic selection. High throughput TCR sequencing has allowed assessment of the development, magnitude and nature of the human alloresponse at a new level and has provided a tool for tracking the fate of pre-transplant-defined donor- and host-reactive TCRs following transplantation. New insights into human allograft rejection and tolerance obtained with this method in combination with single cell transcriptional analyses are reviewed here.

In infrared radiation calculations, the k-distribution method effectively improves the computational efficiency of solving the radiative transfer equation for uniform paths and achieves accuracy comparable to the line-by-line method. However, when applied to highly non-uniform scenarios involving multiple thermodynamic states, such as the infrared radiation from aero-engine nozzles, the computational error increases significantly. This paper proposes a spectral mapping method for multiple thermodynamic states, which iteratively partitions the spectral intervals of the target gas into multiple comonotonic sub-intervals using particle swarm and clustering algorithms. This approach eliminates the blurring effect of traditional k-distribution methods in strongly non-uniform scenarios and enhances the computational accuracy. The study examines the impact of sub-interval partitioning strategies on the accuracy of the gas radiation model, explores the mechanism behind constructing comonotonicity within sub-intervals, and reveals how variations in the comonotonic vector and spectral point clustering strengthen sub-interval comonotonicity. The proposed spectral mapping method and optimization techniques are applied to gas radiation models in typical infrared bands, and the performance of the model is evaluated using results from representative one-dimensional test cases. The results demonstrate that the optimized spectral mapping method reduces the overall relative error of the gas radiation model from 63% to 7.3%, achieving a maximum improvement in computational accuracy of 88.5%.

Inflammasomes are supramolecular complexes that form in the cytosol in response to pathogen-associated and damage-associated stimuli, as well as other danger signals that perturb cellular homoeostasis, resulting in host defence responses in the form of cytokine release and programmed cell death (pyroptosis). Inflammasome activity is closely associated with numerous human disorders, including rare genetic syndromes of autoinflammation, cardiovascular diseases, neurodegeneration and cancer. In recent years, a range of inflammasome components and their functions have been discovered, contributing to our knowledge of the overall machinery. Here, we review the latest advances in inflammasome biology from the perspective of structural and mechanistic studies. We focus on the most well-studied components of the canonical inflammasome — NAIP–NLRC4, NLRP3, NLRP1, CARD8 and caspase-1 — as well as caspase-4, caspase-5 and caspase-11 of the noncanonical inflammasome, and the inflammasome effectors GSDMD and NINJ1. These structural studies reveal important insights into how inflammasomes are assembled and regulated, and how they elicit the release of IL-1 family cytokines and induce membrane rupture in pyroptosis.This Review highlights new insights into the biology of inflammasomes from the perspective of structural and mechanistic studies, revealing how the supramolecular complexes that activate inflammatory caspases are assembled and regulated, to induce cytokine maturation and release, as well as pyroptotic cell death.

Bruton's Tyrosine Kinase (BTK) and IL-2 Inducible T-cell Kinase (ITK) are enzymes responsible for the phosphorylation and activation of downstream effectors in the B-cell receptor (BCR) signaling and T cell receptor (TCR) signaling pathways, respectively. Ibrutinib is an FDA-approved potent inhibitor of both BTK and ITK that impairs B-cell and T-cell function. CD4 T cells and B cells are essential for the induction of chronic graft-versus-host disease (cGVHD). We evaluated these targets by testing the ability of Ibrutinib to prevent or ameliorate cGVHD, which is one of the major complications for patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). We found that Ibrutinib significantly alleviated cGVHD across four different mouse models, accompanied by increased long-term survival and reduced clinical score. The clinical improvements in Ibrutinib-treated recipients were associated with decreased serum-autoantibodies, costimulatory molecule activation, B-cell proliferation, and glomerulonephritis compared to vehicle controls. Ibrutinib was also able to alleviate the clinical manifestations in acute GVHD (aGVHD), where the recipients were given grafts with or without B cells, suggesting that an inhibitory effect of Ibrutinib on T cells contributes to a reduction in both aGVHD and cGVHD pathogenesis. An effective prophylactic regimen is still lacking to both reduce the incidence and severity of human cGVHD following allo-HSCT. Our study shows that Ibrutinib is an effective prophylaxis against several mouse models of cGVHD with minimal toxicity and could be a promising strategy to combat human cGVHD clinically.

Methionine (Met), an essential amino acid involved in antioxidant defense and immune regulation in all vertebrates, may play a critical role in modulating acute immune stress responses; however, whether methionine reduction or supplementation in broilers is more beneficial during acute immune challenge remains unclear. To address this gap, this study compared the effects of dietary methionine reduction and supplementation on growth performance, antioxidant status, immune responses, and methionine metabolism in broilers subjected to lipopolysaccharide (LPS) challenge. In total, 504 one-day-old male broilers were assigned to four treatment groups: control (CON, 0.55%, marked as 100%Met), lipopolysaccharide-challenged (LPS, 0.55%, marked as 100%Met), methionine-restricted with LPS challenge (MR + LPS, 0.35%, marked as 60%Met), and methionine-supplemented with LPS challenge (MS + LPS, 0.75%, marked as 140%Met) groups. The experiment lasted for 21 days. On days 17, 19, and 21, broilers in the LPS-stimulated groups received intraperitoneal injections of LPS at 1 mg/kg body weight. Methionine restriction increased the feed conversion ratio before challenge, whereas average daily gain decreased in both LPS and MS + LPS groups during the challenge. Serum alanine aminotransferase, aspartate transaminase, LPS, corticosterone, interleukin-1β, interleukin-6, tumor necrosis factor-α, and hepatic malondialdehyde levels were reduced in the MR + LPS group compared with the LPS group (p < 0.05), whereas interleukin-10, antioxidant enzyme activities, total antioxidant capacity, and hepatic expression of antioxidant- and sulfur-metabolism-related genes were increased (p < 0.05). These findings indicate that moderate methionine restriction during acute immune stress enhances antioxidant capacity, alleviates hepatic burden, and supports metabolic stability in broilers.

The diversity and composition of T-cell receptor (TCR) repertoire, which is the result of V, (D), and J gene recombination in TCR gene locus, has been found to be implicated in T-cell responses in autoimmunity, cancer, and organ transplantation. The correlation of T-cell repertoire with the pathogenesis of graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation remains largely undefined. Here, by utilizing high-throughput sequencing of the genes encoding TCRβ-chain, we comprehensively analyzed the profile of T-cell repertoire in recipient lymphoid and GVHD target organs after bone marrow transplantation (BMT) in mice. In lymphoid organs, TCR diversity was narrowed, accompanied with reduced numbers of unique clones while increased accumulation of dominant clones in allogeneic T cells compared to syngeneic T cells. In an individual allogeneic recipient, donor-derived TCR clones were highly overlapped among tissue sites, and the degree of overlapping was increasing from day 7 to 14 after allogeneic BMT. The top clones in peripheral blood, gut, liver, and lungs were highly mutually shared in an allogenic recipient, indicating that blood has the potential to predict dominant clones in these GVHD target organs. T cells in GVHD target organs from allogeneic recipients had fewer overlapped clones with pre-transplant donor T cells compared to those from syngeneic recipients. Importantly, the top 10 clones in allogeneic recipients were not detectable in pre-transplant donor T cells, indicating clonal expansion of rare rearrangements. Interestingly, even starting from the same pool of donor repertoires, T cells had very few overlapped clones between each allogeneic recipient who developed completely different dominant clones. We were only able to trace a single clone shared by three replicate allogeneic recipients within the top 500 clones. Although dominant clones were different among allogeneic recipients, V26 genes were consistently used more frequently by TCR clones in allogeneic than syngeneic recipients. This is the first study to extensively examine the feature of T-cell repertoire in multiple lymphoid and parenchyma organs, which establishes the association between T-cell activation and GVHD pathogenesis at the level of TCR clones. Immune repertoire sequencing-based methods may represent a novel personalized strategy to guide diagnosis and therapy in GVHD.