The phosphatase DUSP2 controls the activity of the transcription activator STAT3 and regulates TH17 differentiation.

Deregulation of the TH17 subset of helper T cells is closely linked with immunological disorders and inflammatory diseases. However, the mechanism by which TH17 cells are regulated remains elusive. Here we found that the phosphatase DUSP2 (PAC1) negatively regulated the development of TH17 cells. DUSP2 was directly associated with the signal transducer and transcription activator STAT3 and attenuated its activity through dephosphorylation of STAT3 at Tyr705 and Ser727. DUSP2-deficient mice exhibited severe susceptibility to experimental colitis, with enhanced differentiation of TH17 cells and secretion of proinflammatory cytokines. In clinical patients with ulcerative colitis, DUSP2 was downregulated by DNA methylation and was not induced during T cell activation. Our data demonstrate that DUSP2 is a true STAT3 phosphatase that modulates the development of TH17 cells in the autoimmune response and inflammation.

Epigenetic regulation of HBV-specific tumor-infiltrating T cells in HBV-related HCC.

BACKGROUND AND AIMS: HBV shapes the T-cell immune responses in HBV-related HCC. T cells can be recruited to the nidus, but limited T cells participate specifically in response to the HBV-related tumor microenvironment and HBV antigens. How epigenomic programs regulate T-cell compartments in virus-specific immune processes is unclear. APPROACH AND RESULTS: We developed Ti-ATAC-seq. 2 to map the T-cell receptor repertoire, epigenomic, and transcriptomic landscape of αß T cells at both the bulk-cell and single-cell levels in 54 patients with HCC. We deeply investigated HBV-specific T cells and HBV-related T-cell subsets that specifically responded to HBV antigens and the HBV + tumor microenvironment, respectively, characterizing their T-cell receptor clonality and specificity and performing epigenomic profiling. A shared program comprising NFKB1/2-, Proto-Oncogene, NF-KB Sub unit, NFATC2-, and NR4A1-associated unique T-cell receptor-downstream core epigenomic and transcriptomic regulome commonly regulated the differentiation of HBV-specific regulatory T-cell (Treg) cells and CD8 + exhausted T cells; this program was also selectively enriched in the HBV-related Treg-CTLA4 and CD8-exhausted T cell-thymocyte selection associated high mobility subsets and drove greater clonal expansion in HBV-related Treg-CTLA4 subset. Overall, 54% of the effector and memory HBV-specific T cells are governed by transcription factor motifs of activator protein 1, NFE2, and BACH1/2, which have been reported to be associated with prolonged patient relapse-free survival. Moreover, HBV-related tumor-infiltrating Tregs correlated with both increased viral titer and poor prognosis in patients. CONCLUSIONS: This study provides insight into the cellular and molecular basis of the epigenomic programs that regulate the differentiation and generation of HBV-related T cells from viral infection and HBV + HCC unique immune exhaustion.

Antihypertensive treatment during pregnancy induces long-term changes in gut microbiota and the behaviors of the attention deficit hyperactivity disorder offspring.

The pathogenesis of attention-deficit/hyperactivity disorder (ADHD) has not been fully elucidated. Gestational hypertension could double the probability of ADHD in the offspring, while the initial bacterial communication between the mother and offspring has been associated with psychiatric disorders. Thus, we hypothesize that antihypertensive treatment during pregnancy may abate the impairments in neurodevelopment of the offspring. To test this hypothesis, we chose Captopril and Labetalol, to apply to pregnant spontaneously hypertensive rat (SHR) dams and examined the outcomes in the male offspring. Our data demonstrated that maternal treatment with Captopril and Labetalol had long-lasting changes in gut microbiota and behavioral alterations, including decreased hyperactivity and increased curiosity, spatial learning and memory in the male offspring. Increased diversity and composition were identified, and some ADHD related bacteria were found to have the same change in the gut microbiota of both the dam and offspring after the treatments. LC-MS/MS and immunohistochemistry assays suggested elevated expression of brain derived neurotrophic factor (BDNF) and dopamine in the prefrontal cortex and striatum of offspring exposed to Captopril/ Labetalol, which may account for the improvement of the offspring's psychiatric functions. Therefore, our results support the beneficial long-term effects of the intervention of gestational hypertension in the prevention of ADHD.

Anxiolytic effect of antidiabetic metformin is mediated by AMPK activation in mPFC inhibitory neurons.

Diabetic patients receiving the antidiabetic drug metformin have been observed to exhibit a lower prevalence of anxiety disorders, yet the precise mechanism behind this phenomenon is unclear. In our study, we found that anxiety induces a region-specific reduction in AMPK activity in the medial prefrontal cortex (mPFC). Concurrently, transgenic mice with brain-specific AMPK knockout displayed abnormal anxiety-like behaviors. Treatment with metformin or the overexpression of AMPK restored normal AMPK activity in the mPFC and mitigated social stress-induced anxiety-like behaviors. Furthermore, the specific genetic deletion of AMPK in the mPFC not only instigated anxiety in mice but also nullified the anxiolytic effects of metformin. Brain slice recordings revealed that GABAergic excitation and the resulting inhibitory inputs to mPFC pyramidal neurons were selectively diminished in stressed mice. This reduction led to an excitation-inhibition imbalance, which was effectively reversed by metformin treatment or AMPK overexpression. Moreover, the genetic deletion of AMPK in the mPFC resulted in a similar defect in GABAergic inhibitory transmission and a consequent hypo-inhibition of mPFC pyramidal neurons. We also generated a mouse model with AMPK knockout specific to GABAergic neurons. The anxiety-like behaviors in this transgenic mouse demonstrated the unique role of AMPK in the GABAergic system in relation to anxiety. Therefore, our findings suggest that the activation of AMPK in mPFC inhibitory neurons underlies the anxiolytic effects of metformin, highlighting the potential of this primary antidiabetic drug as a therapeutic option for treating anxiety disorders.

Nano-Cu Derived from a Copper Nitride Precatalyst for Reductive Coupling of Nitroaromatics to Azo Compounds.

The study of structural reconstruction is vital for the understanding of the real active sites in heterogeneous catalysis and guiding the improved catalyst design. Herein, we applied a copper nitride precatalyst in the nitroarene reductive coupling reaction and made a systematic investigation on the dynamic structural evolution behaviors and catalytic performance. This Cu3N precatalyst undergoes a rapid phase transition to nanostructured Cu with rich defective sites, which act as the actual catalytic sites for the coupling process. The nitride-derived defective Cu is very active and selective for azo formation, with 99.6% conversion of nitrobenzene and 97.1% selectivity to azobenzene obtained under mild reaction conditions. Density functional theory calculations suggest that the defective Cu sites play a role for the preferential adsorption of nitrosobenzene intermediates and significantly lowered the activation energy of the key coupling step. This work not only proposes a highly efficient noble-metal-free catalyst for nitroarenes coupling to valuable azo products but also may inspire more scientific interest in the study of the dynamic evolution of metal nitrides in different catalytic reactions.

Nature of Li2O2 and its relationship to the mechanisms of discharge/charge reactions of lithium-oxygen batteries.

Lithium-air batteries (LABs) are considered one of the most promising energy storage devices because of their large theoretical energy density. However, low cyclability caused by battery degradation prevents its practical use. Thus, to realize practical LABs, it is essential to improve cyclability significantly by understanding how the degradation processes proceed. Here, we used online mass spectrometry for real-time monitoring of gaseous products generated during charging of lithium-oxygen batteries (LOBs), which was operated with pure oxygen not air, with 1 M lithium bis(trifluoromethanesulfonyl)imide (LiTFSI) tetraethylene glycol dimethyl ether (TEGDME) electrolyte solution. Linear voltage sweep (LVS) and voltage step modes were employed for charge instead of constant current charge so that the energetics of the product formation during the charge process can be understood more quantitatively. The presence of two distinctly different types of Li2O2, one being decomposed in a wide range of relatively low cell voltages (2.8-4.16 V) (l-Li2O2) and the other being decomposed at higher cell voltages than ca. 4.16 V (h-Li2O2), was confirmed by both LVS and step experiments. H2O generation started when the O2 generation rate reached a first maximum and CO2 generation took place accompanied by the decomposition of h-Li2O2. Based on the above results and the effects of discharge time and the use of isotope oxygen during discharge on product distribution during charge, the generation mechanism of O2, H2O, and CO2 during charging is discussed in relation to the reactions during discharge.

Modulation of alveolar macrophage and mitochondrial fitness by medicinal plant-derived nanovesicles to mitigate acute lung injury and viral pneumonia.

Acute lung injury (ALI) is generally caused by severe respiratory infection and characterized by overexuberant inflammatory responses and inefficient pathogens-containing, the two major processes wherein alveolar macrophages (AMs) play a central role. Dysfunctional mitochondria have been linked with distorted macrophages and hence lung disorders, but few treatments are currently available to correct these defects. Plant-derive nanovesicles have gained significant attention because of their therapeutic potential, but the targeting cells and the underlying mechanism remain elusive. We herein prepared the nanovesicles from Artemisia annua, a well-known medicinal plant with multiple attributes involving anti-inflammatory, anti-infection, and metabolism-regulating properties. By applying three mice models of acute lung injury caused by bacterial endotoxin, influenza A virus (IAV) and SARS-CoV-2 pseudovirus respectively, we showed that Artemisia-derived nanovesicles (ADNVs) substantially alleviated lung immunopathology and raised the survival rate of challenged mice. Macrophage depletion and adoptive transfer studies confirmed the requirement of AMs for ADNVs effects. We identified that gamma-aminobutyric acid (GABA) enclosed in the vesicles is a major molecular effector mediating the regulatory roles of ADNVs. Specifically, GABA acts on macrophages through GABA receptors, promoting mitochondrial gene programming and bioenergy generation, reducing oxidative stress and inflammatory signals, thereby enhancing the adaptability of AMs to inflammation resolution. Collectively, this study identifies a promising nanotherapeutics for alleviating lung pathology, and elucidates a mechanism whereby the canonical neurotransmitter modifies AMs and mitochondria to resume tissue homeostasis, which may have broader implications for treating critical pulmonary diseases such as COVID-19.

The effect of lipid-lowering therapy on lipid-related residual risk factors: a prospective study.

BACKGROUND: Remnant cholesterol (RC) and nonhigh-density lipoprotein cholesterol (nonHDL-C) are key risk factors for atherosclerotic cardiovascular disease (ASCVD), with apolipoprotein B (apoB) and lipoprotein(a) [Lp(a)] also contributing to its residual risk. However, real-world population-based evidence regarding the impact of current clinical LDL-C-centric lipid-lowering therapy (LLT) on achieving RC and nonHDL-C goals, as well as on modifying residual CVD risk factors is limited. METHODS: This prospective observational study enrolled 897 CVD patients from September, 2020 to July, 2021. All participants had previously received low-/moderate-intensity LLT and were discharged with either low-/moderate-intensity LLT or high-intensity LLT. After a median follow-up of 3 months, changes in RC, nonHDL-C, and other biomarkers were assessed. Multivariate logistic regression was performed to analyze the impact of the LLT on goal attainment. RESULTS: Among all patients, 83.50% transitioned to high-intensity LLT from low or moderate. After follow-up, the high-intensity group saw significantly greater reductions in RC (-20.51% vs. -3.90%, P = 0.025), nonHDL-C (-25.12% vs. 0.00%, P < 0.001), apoB (-19.35% vs. -3.17%, P < 0.001), triglycerides (-17.82% vs. -6.62%, P < 0.001), and LDL-C and total cholesterol. Spearman correlation analysis revealed that LDL-C reduction from current LLT was strongly correlated with nonHDL-C reduction (r = 0.87, P < 0.001). Patients who received high-intensity LLT had significant improvements in attainment of RC (from 44.2% to 60.7%, χ² = 39.23, P < 0.001) and nonHDL-C (from 19.4% to 56.9%, χ² = 226.06, P < 0.001) goals. Furthermore, multivariate logistic regression showed that high-intensity LLT was a protective factor for RC [odds ratio (OR) = 0.66; 95% confidence intervals (CI), 0.45-0.97; P = 0.033] and nonHDL-C goal attainment (OR = 0.51; 95% CI, 0.34-0.75; P < 0.001), without a significant increase of adverse reactions. CONCLUSION: Current levels of clinically prescribed LDL-C-centric treatment can reduce RC and other lipid-related residual risk factors, but high-intensity LLT is better at achieving nonHDL-C and RC goals than low-/moderate-intensity LLT, with a good safety profile. More targeted RC treatments are still needed to reduce residual lipid risk further.

Omics analysis revealed the intestinal toxicity induced by aflatoxin B1 and aflatoxin M1.

Aflatoxin B1 (AFB1), a common mycotoxin, can occur in agricultural products. As a metabolite of AFB1, aflatoxin M1 (AFM1) mainly exist in dairy products. These two mycotoxins threaten human health, although it is unclear how they affect the function of the intestinal barrier. In this study, mice were exposed to AFB1 (0.3 mg/kg body b.w.) and AFM1(3.0 mg/kg b.w.) either individually or in combination for 28 days to explore the main differentially expressed proteins (DEPs) and the associated enriched pathways. These findings were preliminarily verified by the transcriptomic and proteomic analyses in differentiated Caco-2 cells. The results revealed that AFB1 and AFM1 exposure in mice disrupted the function of the intestinal barrier, and the combined toxicity was greater than that of each toxin alone. Further proteomic analysis in mice demonstrated that the mechanisms underlying these differences could be explained as follows: (i) lipid metabolism was enriched by AFB1-induced DEPs. (ii) protein export pathway was stimulated by AFM1-induced DEPs. (iii) cell metabolic ability was inhibited (as evidenced by changes in UDP-GT1, UDP-GT2, and Gatm6), apoptosis was induced (MAP4K3), and epithelial cell integrity was disrupted (Claudin7 and IQGAP2), resulting in more extensive intestinal damage after combined treatment. In conclusion, the hazardous impact of co-exposure to AFB1 and AFM1 from proteomic perspectives was demonstrated in the present study.

Small Molecule SHP2 Inhibitor LXQ-217 Affects Lung Cancer Cell Proliferation in Vitro and in Vivo.

BACKGROUND: SHP2 is highly expressed in a variety of cancer and has emerged as a potential target for cancer therapeutic agents. The identification of uncharged pTyr mimics is an important direction for the development of SHP2 orthosteric inhibitors. METHODS: Surface plasmon resonance analysis and cellular thermal shift assay were employed to verify the direct binding of LXQ-217 to SHP2. The inhibitory effect of LXQ-217 was characterized by linear Weaver-Burke enzyme kinetic analysis and BIOVIA Discovery Studio. The inhibition of tumor cell proliferation by LXQ-217 was characterized by cell viability assay, colony formation assays and hoechst 33258 staining. The inhibition of lung cancer proliferation in vivo was studied in nude mice after oral administration of LXQ-217. RESULTS: An electroneutral bromophenol derivative, LXQ-217, was identified as a competitive SHP2 inhibitor. LXQ-217 induced apoptosis and inhibited growth of human pulmonary epithelial cells by affecting the RAS-ERK and PI3 K-AKT signaling pathways. Long-term oral administration of LXQ-217 significantly inhibited the proliferation ability of lung cancer cells in nude mice. Moreover, mice administered LXQ-217 orally at high doses exhibited no mortality or significant changes in vital signs. CONCLUSIONS: Our findings on the uncharged orthosteric inhibitor provide a foundation for further development of a safe and effective anti-lung cancer drug.

Doping Ferrocene-Based Conjugated Microporous Polymers with 7,7,8,8-Tetracyanoquinodimethane for Efficient Photocatalytic CO2 Reduction.

The design and synthesis of organic photocatalysts remain a great challenge due to their strict structural constraints. However, this could be mitigated by achieving structural flexibility by constructing permanent porosity into the materials. Conjugated microporous polymers (CMPs) are an emerging class of porous materials with an amorphous, three-dimensional network structure, which makes it possible to integrate the elaborate functional groups to enhance photocatalytic performance. Here, we report the synthesis of a novel CMP, named TAPFc-TFPPy-CMP, constructed by 1,1'3,3'-tetra(4-aminophenyl)ferrocene (TAPFc) and 1,3,6,8-tetrakis(4-formylphenyl)pyrene (TFPPy) monomers. The integration of the p-type dopant 7,7,8,8-tetracyanoquinodimethane (TCNQ) into the TAPFc-TFPPy-CMP improved the light adsorption performance, leading to a decrease in the optical bandgap from 2.00 to 1.43 eV. The doped CMP (TCNQ@TAPFc-TFPPy-CMP) exhibited promising catalytic activity in photocatalytic CO2 reduction under visible light, yielding 546.8 µmol g-1 h-1 of CO with a selectivity of 96% and 5.2 µmol g-1 h-1 of CH4. This represented an 80% increase in the CO yield compared to the maternal TAPFc-TFPPy-CMP. The steady-state photoluminescence (PL) and fluorescence lifetime (FL) measurements reveal faster carrier separation and transport after the doping. This study provides guidance for the development of organic photocatalysts for the utilization of renewable energy.

Highly Efficient Capture of Volatile Iodine by Conjugated Microporous Polymers Constructed Using Planar 3- and 4-Connected Organic Monomers.

The effective capture and recovery of radioiodine species associated with nuclear fuel reprocessing is of significant importance in nuclear power plants. Porous materials have been proven to be one of the most effective adsorbents for the capture of radioiodine. In this work, we design and synthesize a series of conjugated microporous polymers (CMPs), namely, TPDA-TFPB CMP, TPDA-TATBA CMP, and TPDA-TECHO CMP, which are constructed based on a planar rectangular 4-connected organic monomer and three triangular 3-connected organic monomers, respectively. The resultant CMPs are characterized using various characterization techniques and used as effective adsorbents for iodine capture. Our experiments indicated that the CMPs exhibit excellent iodine adsorption capacities as high as 6.48, 6.25, and 6.37 g g-1 at 348 K and ambient pressure. The adsorption mechanism was further investigated and the strong chemical adsorption between the iodine and the imine/tertiary ammonia of the CMPs, 3D network structure with accessible hierarchical pores, uniform micromorphology, wide π-conjugated structure, and high-density Lewis-base sites synergistically contribute to their excellent iodine adsorption performance. Moreover, the CMPs demonstrated good recyclability. This work provides guidance for the construction of novel iodine adsorbent materials with high efficiency in the nuclear power field.

Polymer Nanoparticles with 2-HP-ß-Cyclodextrin for Enhanced Retention of Uptake into HCE-T Cells.

Triamcinolone acetonide (TA), a medium-potency synthetic glucocorticoid, is primarily employed to treat posterior ocular diseases using vitreous injection. This study aimed to design novel ocular nanoformulation drug delivery systems using PLGA carriers to overcome the ocular drug delivery barrier and facilitate effective delivery into the ocular tissues after topical administration. The surface of the PLGA nanodelivery system was made hydrophilic (2-HP-ß-CD) through an emulsified solvent volatilization method, followed by system characterization. The mechanism of cellular uptake across the corneal epithelial cell barrier used rhodamine B (Rh-B) to prepare fluorescent probes for delivery systems. The triamcinolone acetonide (TA)-loaded nanodelivery system was validated by in vitro release behavior, isolated corneal permeability, and in vivo atrial hydrodynamics. The results indicated that the fluorescent probes, viz., the Rh-B-(2-HP-ß-CD)/PLGA NPs and the drug-loaded TA-(2-HP-ß-CD)/PLGA NPs, were within 200 nm in size. Moreover, the system was homogeneous and stable. The in vitro transport mechanism across the epithelial barrier showed that the uptake of nanoparticles was time-dependent and that NPs were actively transported across the epithelial barrier. The in vitro release behavior of the TA-loaded nanodelivery systems revealed that (2-HP-ß-CD)/PLGA nanoparticles could prolong the drug release time to up to three times longer than the suspensions. The isolated corneal permeability demonstrated that TA-(2-HP-ß-CD)/PLGA NPs could extend the precorneal retention time and boost corneal permeability. Thus, they increased the cumulative release per unit area 7.99-fold at 8 h compared to the suspension. The pharmacokinetics within the aqueous humor showed that (2-HP-ß-CD)/PLGA nanoparticles could elevate the bioavailability of the drug, and its Cmax was 51.91 times higher than that of the triamcinolone acetonide aqueous solution. Therefore, (2-HP-ß-CD)/PLGA NPs can potentially elevate transmembrane uptake, promote corneal permeability, and improve the bioavailability of drugs inside the aqueous humor. This study provides a foundation for future research on transocular barrier nanoformulations for non-invasive drug delivery.

Using system biology and bioinformatics to identify the influences of COVID-19 co-infection with influenza virus on COPD.

Coronavirus disease 2019 (COVID-19) has speedily increased mortality globally. Although they are risk factors for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), less is known about the common molecular mechanisms behind COVID-19, influenza virus A (IAV), and chronic obstructive pulmonary disease (COPD). This research used bioinformatics and systems biology to find possible medications for treating COVID-19, IAV, and COPD via identifying differentially expressed genes (DEGs) from gene expression datasets (GSE171110, GSE76925, GSE106986, and GSE185576). A total of 78 DEGs were subjected to functional enrichment, pathway analysis, protein-protein interaction (PPI) network construct, hub gene extraction, and other potentially relevant disorders. Then, DEGs were discovered in networks including transcription factor (TF)-gene connections, protein-drug interactions, and DEG-microRNA (miRNA) coregulatory networks by using NetworkAnalyst. The top 12 hub genes were MPO, MMP9, CD8A, HP, ELANE, CD5, CR2, PLA2G7, PIK3R1, SLAMF1, PEX3, and TNFRSF17. We found that 44 TFs-genes, as well as 118 miRNAs, are directly linked to hub genes. Additionally, we searched the Drug Signatures Database (DSigDB) and identified 10 drugs that could potentially treat COVID-19, IAV, and COPD. Therefore, we evaluated the top 12 hub genes that could be promising DEGs for targeted therapy for SARS-CoV-2 and identified several prospective medications that may benefit COPD patients with COVID-19 and IAV co-infection.

Over expression of ubiquitin-conjugating enzyme E2O in bone marrow mesenchymal stromal cells partially attenuates acute myeloid leukaemia progression.

Bone marrow mesenchymal stromal cells (BM-MSCs) are implicated in the pathogenesis of acute myeloid leukaemia (AML). However, due to the high heterogeneity of AML the mechanism underlying the cross-talk between MSCs and leukaemia cells is not well understood. We found that mixed-lineage leukaemia-AF9 (MLL-AF9)-induced AML mice-derived MSCs had higher proliferative viability compared to wild-type mice-derived MSCs with ubiquitin-conjugating enzyme E2O (Ube2o) down-regulation. After overexpression of UBE2O in AML-derived MSCs, the growth capacity of MSCs was reduced with nuclear factor kappa B subunit 1 (NF-κB) pathway deactivation. In vitro co-culture assay revealed that UBE2O-overexpression MSCs suppressed the proliferation and promoted apoptosis of AML cells by direct contact. In vivo results revealed that the leukaemia burden was reduced and the overall survival of AML mice was prolonged, with decreased dissemination of leukaemia cells in BM, spleen, liver and peripheral blood. Additionally, subcutaneous tumorigenesis revealed that tumour growth was also suppressed in the UBE2O-overexpression MSCs group. In conclusion, UBE2O was expressed at a low level in MLL-AF9-induced AML mice-derived MSCs. Overexpression of UBE2O in MSCs suppressed their proliferation through NF-κB pathway deactivation, which resulted in AML suppression. Our study provides a theoretical basis for a BM microenvironment-based therapeutic strategy to control disease progression.

Advances of autoimmune rheumatic diseases related to malignant tumors.

BACKGROUND: Malignant neoplasms are a well-recognized global public health concern, with significant impacts on human health and quality of life. The interplay between tumors and autoimmune rheumatic diseases is complex, and the resulting tumor-associated rheumatic diseases represent a rare and intricate group of conditions that occur in the context of malignant tumors. In addition, various rheumatic diseases can arise as a consequence of oncology treatment. These diseases present with intricate clinical manifestations and pathological features, often rendering them challenging to diagnose and impacting patients' quality of life. Despite this, they have yet to be fully recognized. METHODS: This article presents a literature review of published original articles and review articles concerning paraneoplastic rheumatic syndromes and rheumatic diseases associated with cancer treatment. We conducted a comprehensive literature search in PubMed, Web of Science and Google Scholar databases, excluding duplicated and irrelevant studies. In cases of duplicated research, we selected articles with higher impact factors for the review. RESULTS: This review focuses on the clinical features, diagnosis, and treatment of paraneoplastic rheumatic diseases, as well as the pathogenesis of these diseases. Additionally, we summarize the autoimmune rheumatic diseases associated with cancer treatment. Ultimately, the goal of this review is to enhance recognition and improve the management of autoimmune rheumatic diseases related to tumors.

Medicinal plant-derived mtDNA via nanovesicles induces the cGAS-STING pathway to remold tumor-associated macrophages for tumor regression.

Plant-derived nanovesicles (PDNVs) have been proposed as a major mechanism for the inter-kingdom interaction and communication, but the effector components enclosed in the vesicles and the mechanisms involved are largely unknown. The plant Artemisia annua is known as an anti-malaria agent that also exhibits a wide range of biological activities including the immunoregulatory and anti-tumor properties with the mechanisms to be further addressed. Here, we isolated and purified the exosome-like particles from A. annua, which were characterized by nano-scaled and membrane-bound shape and hence termed artemisia-derived nanovesicles (ADNVs). Remarkably, the vesicles demonstrated to inhibit tumor growth and boost anti-tumor immunity in a mouse model of lung cancer, primarily through remolding the tumor microenvironment and reprogramming tumor-associated macrophages (TAMs). We identified plant-derived mitochondrial DNA (mtDNA), upon internalized into TAMs via the vesicles, as a major effector molecule to induce the cGAS-STING pathway driving the shift of pro-tumor macrophages to anti-tumor phenotype. Furthermore, our data showed that administration of ADNVs greatly improved the efficacy of PD-L1 inhibitor, a prototypic immune checkpoint inhibitor, in tumor-bearing mice. Together, the present study, for the first time, to our knowledge, unravels an inter-kingdom interaction wherein the medical plant-derived mtDNA, via the nanovesicles, induces the immunostimulatory signaling in mammalian immune cells for resetting anti-tumor immunity and promoting tumor eradication.

The coexistence of aflatoxin M1 and ochratoxin A induced intestinal barrier disruption via the regulation of key differentially expressed microRNAs and long non-coding RNAs in BALB/c mice.

Food safety can be seriously threatened by the existence of both aflatoxin M1 (AFM1) and ochratoxin A (OTA) in milk and corresponding products. The importance of intestine integrity in preserving human health is widely understood in vitro, but the fundamental processes by which AFM1 and OTA cause disruption of the intestinal barrier are as yet unknown, especially in vivo. Based on the analysis of the whole transcriptome of BALB/c mice, the competing endogenous RNA (ceRNA) regulation network was obtained in the current study. Each of 12 mice were separated into five treatments: saline solution treatment, 1.0% DMSO vehicle control treatment, 3.0 mg/kg b.w. individual AFM1 treatment (AFM1), 3.0 mg/kg b.w. individual OTA treatment (OTA), and combined mycotoxins treatment (AFM1 +OTA). The study period lasted 28 days. The jejunum tissue was collected for the histological assessment and whole transcriptome analysis, and the whole blood was collected, and determination of serum biochemical indicators. The phenotypic results demonstrated that AFM1 and OTA caused intestinal barrier disruption via an increased apoptosis level and decreased expression of tight junction (TJ) proteins. The ceRNA network demonstrated that AFM1 and OTA induced cell apoptosis through activating the expression of DUSP9 and suppressing the expression of PLA2G2D, which were regulated by differentially expressed microRNAs (DEmiRNAs) (miR-124-y, miR-194-z, miR-224-x, and miR-452-x) and differentially expressed long non-coding RNAs (DElncRNAs) (FUT8 and GPR31C). And AFM1 and OTA decreased TJ proteins via inhibiting the expression of PAK6, which was regulated by several important DEmiRNAs and DElncRNAs. These DE RNAs in intestinal integrity were involved in MAPK and Ras signaling pathway. Overall, our findings expand the current knowledge regarding the potential mechanisms of intestinal integrity disruption brought on by AFM1 and OTA in vivo.

Intrathyroid thymic carcinoma: A clinicopathological analysis of 22 cases.

OBJECTIVE: Intrathyroid thymic carcinoma (ITTC) is a rare malignancy. The current understanding of ITTC is inadequate, and there is no standard treatment for ITTC. In the present study, we aimed to explore the clinicopathological characteristics of ITTC and identify potential therapeutic targets. METHODS: The clinicopathological characteristics of 22 ITTC patients at our institution were reviewed. The expression of DNA mismatch repair (MMR) proteins and PD-L1 in ITTC were assessed by immunohistochemistry (IHC). RESULTS: All patients underwent surgery. There were nine females and 13 males, with a slight male predominance. Their ages ranged from 42 to 79 years (average, 54. 1 years). The diameters of the neck masses ranged from 10 to 100 mm (average, 39 mm). Ipsilateral lymph node (LN) dissection was performed in 18 patients: 12 demonstrated LN metastasis, six showed no LN metastasis, and no lymph nodes were dissected in four. One patient had liver metastasis. CK5/6, P63, CD5, and CD117 were expressed in all cases. All cases were negative for TTF1, PAX8, thyroglobulin, and BRAF V600E. DNA MMR protein expression was retained in all tested tumors, and EBV-encoded small RNA (EBER) in situ hybridization was consistently negative. The Ki67 proliferation index ranged from 10 to 70 %. All patients were followed-up for 14-134 months, four died, six were lost to follow-up, and the remaining patients survived without disease. The PD-L1 combined positive score ranged from 10 to 80 (average: 40). CONCLUSION: Our results confirm that CD5 and CD117 co-expression support a diagnosis of ITTC. All tumors in this cohort were DNA MMR-proficient and were not associated with Epstein-Barr virus (EBV) infection. A high CPS for PD-L1 suggests that immune checkpoint inhibitor therapy may be worthy of further exploration in patients with ITTC.

Strontium Chloride Improves Reproductive Function and Alters Gut Microbiota in Male Rats.

Strontium (Sr) is an essential trace element in the human body and plays an important role in regulating male reproductive health. Recent studies have shown that gut flora plays a key role in maintaining spermatogenesis, as well as testicular health, through the gut-testis axis. At present, it is unclear whether gut microbiota can mediate the effects of Sr on sperm quality, and what the underlying mechanisms may be. We investigated the effects of different concentrations of strontium chloride (SrCl2) solutions (0, 50, 100, and 200 mg/kg BW) on reproductive function and gut microbiota in male Wistar rats (6-8 weeks, 250 ± 20 g). All the animals were euthanized after 37 days of treatment. The Sr-50 group significantly increased sperm concentration, sperm motility, and sperm viability in rats. After Sr treatment, serum and testicular testosterone (T) and Sr levels increased in a dose-dependent manner with increasing Sr concentration. At the same time, we also found that testicular marker enzymes (ACP, LDH) and testosterone marker genes (StAR, 3ß-HSD, and Cyp11a1) increased significantly in varying degrees after Sr treatment, while serum NO levels decreased significantly in a dose-dependent manner. Further investigation of intestinal flora showed that SrCl2 affected the composition of gut microbiome, but did not affect the richness and diversity of gut microbiota. Sr treatment reduced the number of bacteria with negative effects on reproductive health, such as Bacteroidetes, Tenericutes, Romboutsia, Ruminococcaceae_UCG_014, Weissella, and Eubacterium_coprostanoligenes_group, and added bacteria with negative effects on reproductive health, such as Jeotgalicoccus. To further explore the Sr and the relationship between the gut microbiota, we conducted a Spearman correlation analysis, and the results showed that the gut microbiota was closely correlated with Sr content in serum and testicular tissue, sex hormone levels, and testicular marker enzymes. Additionally, gut microbiota can also regulate each other and jointly maintain the homeostasis of the body's internal environment. However, we found no significant correlation between intestinal flora and sperm quality in this study, which may be related to the small sample size of our 16S rDNA sequencing. In conclusion, the Sr-50 group significantly increased T levels and sperm quality, and improved the levels of testicular marker enzymes and testosterone marker genes in the rats. Sr treatment altered the gut flora of the rats. However, further analysis of the effects of gut microbiota in mediating the effects of SrCl2 on male reproductive function is needed. This study may improve the current understanding of the interaction between Sr, reproductive health, and gut microbiota, providing evidence for the development of Sr-rich foods and the prevention of male fertility decline.