Effect of tea polyphenols on intestinal barrier and immune function in weaned lambs

IntroductionThe purpose of this study was to explore the effects of tea polyphenols on growth performance, cytokine content, intestinal antioxidant status and intestinal barrier function of lambs, in order to provide reference for intestinal health of ruminants.MethodsThirty weaned lambs (average initial weight 9.32 ± 1.72 kg) were randomly divided into five groups with six lambs in each group. The control group did not add anything but the basic diet mainly composed of Pennisetum and Corn, and the other four groups added 2, 4, 6 g/kg tea polyphenols and 50 mg/kg chlortetracycline to the basic diet, respectively. The experiment lasted for 42 days.ResultsDietary tea polyphenols improved the growth and stress response and reduced intestinal permeability of lambs (p > 0.05), while CTC did not affect the final lamb weight (p > 0.05). Both tea phenols and CTC significantly reduced inflammatory factors and enhanced the immune system (p > 0.05). Dietary tea polyphenols increased villus height, villus height/crypt depth, secretory immunoglobulin A (p > 0.05), and antioxidant enzymes, while decreasing MDA and apoptosis in the intestine (p > 0.05). However, compared with other groups, the content of T-AOC in jejunum did not change significantly (p > 0.05). Tea polyphenols also increased claudin-1 levels in the duodenum, jejunum, and ileum more than CTC (p > 0.05). CTC had a limited effect on the mRNA expression of Occludin and ZO-1, while tea polyphenols increased these in both the duodenum and ileum (p > 0.05).ConclusionThis study demonstrated that tea polyphenols can effectively improve the intestinal barrier of weaned lambs, and that they have anti-inflammatory and antioxidant effects similar to those of antibiotics. Thus, tea polyphenols could be used to replace antibiotics in ensuring safety of livestock products and in achieving the sustainable development of modern animal husbandry

Galectin-9 as an indicator of functional limitations and radiographic joint damage in patients with rheumatoid arthritis

BackgroundPrevious studies have revealed that Galectin-9 (Gal-9) acts as an apoptosis modulator in autoimmunity and rheumatic inflammation. In the present study, we investigated the potential role of Gal-9 as a biomarker in patients with rheumatoid arthritis (RA), especially as an indicator of functional limitations and radiographic joint damage.MethodsA total of 146 patients with RA and 52 age- and sex-matched healthy controls were included in this study. Clinical data including disease activity, physical function, and radiographic joint damage were assessed. Functional limitation was defined as the Stanford Health Assessment Questionnaire (HAQ) disability index >1. Subjects with joint erosion >0 or joint space narrowing >0 were considered to have radiographic joint damage. Serum Gal-9 levels were detected by an enzyme-linked immunosorbent assay. Univariate and multivariate logistic regression analysis were used to evaluate the association between Gal-9 and high disease activity and functional limitations, and a prediction model was established to construct predictive nomograms.ResultsSerum levels of Gal-9 were significantly increased in patients with RA compared to those in healthy controls (median 13.1 ng/mL vs. 7.6 ng/mL). Patients with RA who were older (>65 years), had a longer disease duration (>5 years), longer morning stiffness (>60mins), elevated serum erythrocyte sedimentation rate and C-reactive protein, and difficult-to-treat RA had significantly higher Gal-9 levels than those in the corresponding control subgroups (all p <0.05). Patients with RA were divided into two subgroups according to the cut-off value of Gal-9 of 11.6 ng/mL. Patients with RA with Gal-9 >11.6 ng/mL had a significantly higher core clinical disease activity index, HAQ scores, Sharp/van der Heijde modified Sharp scores, as well as a higher percentage of advanced joint damage (all p<0.05) than patients with Gal-9 ≤11.6 ng/mL. Accordingly, patients with RA presenting either functional limitations or radiographic joint damage had significantly higher serum Gal-9 levels than those without (both p <0.05). Furthermore, multivariate logistic regression analysis showed that a serum level of Gal-9 >11.6 ng/mL was an independent risk factor for high disease activity (OR=3.138, 95% CI 1.150–8.567, p=0.026) and presence of functional limitations (OR=2.455, 95% CI 1.017–5.926, p=0.046), respectively.ConclusionGal-9 could be considered as a potential indicator in patients with RA, especially with respect to functional limitations and joint damage

Magnetic Manganese Oxide Sweetgum-Ball Nanospheres with Large Mesopores Regulate Tumor Microenvironments for Enhanced Tumor Nanotheranostics.

An important objective of cancer nanomedicine is to improve the delivery efficacy of functional agents to solid tumors for effective cancer imaging and therapy. Stimulus-responsive nanoplatforms can target and regulate the tumor microenvironment (TME) for the optimization of cancer theranostics. Here, we developed magnetic manganese oxide sweetgum-ball nanospheres (MMOSs) with large mesopores as tools for improved cancer theranostics. MMOSs contain magnetic iron oxide nanoparticles and mesoporous manganese oxide (MnO2) nanosheets, which are assembled into gumball-like structures on magnetic iron oxides. The large mesopores of MMOSs are suited for cargo loading with chlorin e6 (Ce6) and doxorubicin (DOX), thus producing so-called CD@MMOSs. The core of magnetic iron oxides could achieve magnetic targeting of tumors under a magnetic field (0.25 mT), and the targeted CD@MMOSs may decompose under TME conditions, thereby releasing loaded cargo molecules and reacting with endogenous hydrogen peroxide (H2O2) to generate oxygen (O2) and manganese (II) ions (Mn2+). Investigation in vivo in tumor-bearing mice models showed that the CD@MMOS nanoplatforms achieved TME-responsive cargo release, which might be applied in chemotherapy and photodynamic therapy. A remarkable in vivo synergy of diagnostic and therapeutic functionalities was achieved by the decomposition of CD@MMOSs and coadministration with chemo-photodynamic therapy of tumors using the magnetic targeting mechanism. Thus, the result of this study demonstrates the feasibility of smart nanotheranostics to achieve tumor-specific enhanced combination therapy

Aloperine Suppresses Cancer Progression by Interacting with VPS4A to Inhibit Autophagosome-lysosome Fusion in NSCLC.

Aloperine (ALO), a quinolizidine-type alkaloid isolated from a natural Chinese herb, has shown promising antitumor effects. Nevertheless, its common mechanism of action and specific target remain elusive. Here, it is demonstrated that ALO inhibits the proliferation and migration of non-small cell lung cancer cell lines in vitro and the tumor development in several mouse tumor models in vivo. Mechanistically, ALO inhibits the fusion of autophagosomes with lysosomes and the autophagic flux, leading to the accumulation of sequestosome-1 (SQSTM1) and production of reactive oxygen species (ROS), thereby inducing tumor cell apoptosis and preventing tumor growth. Knockdown of SQSTM1 in cells inhibits ROS production and reverses ALO-induced cell apoptosis. Furthermore, VPS4A is identified as a direct target of ALO, and the amino acids F153 and D263 of VPS4A are confirmed as the binding sites for ALO. Knockout of VPS4A in H1299 cells demonstrates a similar biological effect as ALO treatment. Additionally, ALO enhances the efficacy of the anti-PD-L1/TGF-β bispecific antibody in inhibiting LLC-derived subcutaneous tumor models. Thus, ALO is first identified as a novel late-stage autophagy inhibitor that triggers tumor cell death by targeting VPS4A

Pediatric-inspired regimen for adolescent and adult patients with Philadelphia chromosome-negative acute lymphoblastic leukemia: a prospective study from China

Several international centers have used and reported pediatric-inspired regimens for adolescent and adult patients with Philadelphia chromosome-negative acute lymphoblastic leukemia (Ph- ALL). However, there is a lack of prospective data on the Chinese population. Herein, we performed a prospective study with a pediatric-inspired regimen (IH-2014 regimen) in treating adolescent and adult Ph- ALL patients in our center. From 2014 to 2021, a total of 415 patients aged between 14 and 65 years (median age, 27) were included in this study. After a median follow-up of 40.8 months, the 5-year overall survival, disease-free survival, and event-free survival rates were 53.8%, 51.1% and 45.0%, respectively. The regimen was generally well tolerated and safe, and the overall chemotherapy-related mortality was 3.6%. Age ≥ 40 years and persistent detectable minimal residual disease (MRD) post-induction were independent prognostic factors. Traditional risk factors for adult patients combined with MRD post-induction exhibit predictive significance for survival and relapse, which is helpful in the selection of subsequent treatment. Patients with high risk factors who can achieve deep MRD response after induction do not derive benefit from allogeneic hematopoietic stem cell transplantation

Perturbed myoepithelial cell differentiation in BRCA mutation carriers and in ductal carcinoma in situ.

Myoepithelial cells play key roles in normal mammary gland development and in limiting pre-invasive to invasive breast tumor progression, yet their differentiation and perturbation in ductal carcinoma in situ (DCIS) are poorly understood. Here, we investigated myoepithelial cells in normal breast tissues of BRCA1 and BRCA2 germline mutation carriers and in non-carrier controls, and in sporadic DCIS. We found that in the normal breast of non-carriers, myoepithelial cells frequently co-express the p63 and TCF7 transcription factors and that p63 and TCF7 show overlapping chromatin peaks associated with differentiated myoepithelium-specific genes. In contrast, in normal breast tissues of BRCA1 mutation carriers the frequency of p63+TCF7+ myoepithelial cells is significantly decreased and p63 and TCF7 chromatin peaks do not overlap. These myoepithelial perturbations in normal breast tissues of BRCA1 germline mutation carriers may play a role in their higher risk of breast cancer. The fraction of p63+TCF7+ myoepithelial cells is also significantly decreased in DCIS, which may be associated with invasive progression

The Current State of Nanoparticle-Induced Macrophage Polarization and Reprogramming Research

Macrophages are vital regulators of the host defense in organisms. In response to different local microenvironments, resting macrophages (M0) can be polarized into different phenotypes, pro-inflammatory (M1) or anti-inflammatory (M2), and perform different roles in different physiological or pathological conditions. Polarized macrophages can also be further reprogrammed by reversing their phenotype according to the changed milieu. Macrophage polarization and reprogramming play essential roles in maintaining the steady state of the immune system and are involved in the processes of many diseases. As foreign substances, nanoparticles (NPs) mainly target macrophages after entering the body. NPs can perturb the polarization and reprogramming of macrophages, affect their immunological function and, therefore, affect the pathological process of disease. Optimally-designed NPs for the modulation of macrophage polarization and reprogramming might provide new solutions for treating diseases. Systematically investigating how NPs affect macrophage polarization is crucial for understanding the regulatory effects of NPs on immune cells in vivo. In this review, macrophage polarization by NPs is summarized and discussed