A nano-platform combats the "attack" and "defense" of cytoskeleton to block cascading tumor metastasis.

The cytoskeleton facilitates tumor cells invasion into the bloodstream via vasculogenic mimicry (VM) for "attack", and protects cells against external threats through cytoskeletal remodeling and tunneling nanotubes (TNTs) for "defense". However, the existing strategies involving cytoskeleton are not sufficient to eliminate tumor metastasis due to mitochondrial energy supply, both within tumor cells and from outside microenvironment. Here, considering the close relationship between cytoskeleton and mitochondria both in location and function, we construct a nano-platform that combats the "attack" and "defense" of cytoskeleton in the cascading metastasis. The nano-platform is composed of KFCsk@LIP and KTMito@LIP for the cytoskeletal collapse and mitochondrial dysfunction. KFCsk@LIP prevents the initiation and circulation of cascading tumor metastasis, but arouses limited suppression in tumor cell proliferation. KTMito@LIP impairs mitochondria to trigger apoptosis and impede energy supply both from inside and outside, leading to an amplified effect for metastasis suppression. Further mechanisms studies reveal that the formation of VM and TNTs are seriously obstructed. Both in situ and circulating tumor cells are disabled. Subsequently, the broken metastasis cascade results in a remarkable anti-metastasis effect. Collectively, based on the nano-platform, the cytoskeletal collapse with synchronous mitochondrial dysfunction provides a potential therapeutic strategy for cascading tumor metastasis suppression.

The Effect of Copy Number Hemiplasy on Gene Family Evolution.

The evolution of gene families is complex, involving gene-level evolutionary events such as gene duplication, horizontal gene transfer, and gene loss (DTL), and other processes such as incomplete lineage sorting (ILS). Because of this, topological differences often exist between gene trees and species trees. A number of models have been recently developed to explain these discrepancies, the most realistic of which attempt to consider both gene-level events and ILS. When unified in a single model, the interaction between ILS and gene-level events can cause polymorphism in gene copy number, which we refer to as copy number hemiplasy (CNH). In this paper we extend the Wright-Fisher process to include duplications and losses over several species, and show that the probability of CNH for this process can be significant. We study how well two unified models - MLMSC (MultiLocus MultiSpecies Coalescent), which models CNH, and DLCoal (Duplication, Loss, and Coalescence), which does not - approximate the Wright-Fisher process with duplication and loss. We then study the effect of CNH on gene family evolution by comparing MLMSC and DLCoal. We generate comparable gene trees under both models, showing significant differences in various summary statistics; most importantly, CNH reduces the number of gene copies greatly. If this is not taken into account, the traditional method of estimating duplication rates (by counting the number of gene copies) becomes inaccurate. The simulated gene trees are also used for species tree inference with the summary methods ASTRAL and ASTRAL-Pro, demonstrating that their accuracy, based on CNH-unaware simulations calibrated on real data, may have been overestimated.

BRASSINOSTEROID-SIGNALING KINASE1 associates with and is required for cysteine protease RESPONSE TO DEHYDRATION 19-mediated disease resistance in Arabidopsis.

The receptor-like cytoplasmic kinase BRASSINOSTEROID-SIGNALING KINASE1 (BSK1) interacts with pattern recognition receptor (PRR) FLAGELLIN SENSING2 (FLS2) and positively regulates plant innate immunity in Arabidopsis thaliana. However, the molecular components involved in BSK1-mediated immune signaling remain largely unknown. To further explore the molecular mechanism underlying BSK1-mediated disease resistance, we screened two cysteine proteases, RESPONSE TO DEHYDRATION 19 (RD19) and RD19-LIKE 2 (RDL2), as BSK1-binding partners. Overexpression of RD19, but not RDL2, displayed an autoimmune phenotype, presenting programmed cell death and enhanced resistance to multiple pathogens. Interestingly, RD19-mediated immune activation depends on BSK1, as knockout of BSK1 in RD19-overexpressing plants rescued their autoimmunity and abolished the increased resistance. Furthermore, we found that BSK1 plays a positive role in maintaining RD19 protein abundance in Arabidopsis. Our results provide new insights into BSK1-mediated immune signaling and reveal a potential mechanism by which BSK1 stabilizes RD19 to promote effective immune output.

Double-enzyme active MnO2@BSA mediated lab-on-paper dual-modality aptasensor for di(2-ethylhexyl)phthalate.

Di(2-ethylhexyl)phthalate (DEHP), as an environmental endocrine disruptor, has adverse effects on eco-environments and health. Thus, it is crucial to highly sensitive on-site detect DEHP. Herein, a double-enzyme active MnO2@BSA mediated dual-modality photoelectrochemical (PEC)/colorimetric aptasensing platform with the cascaded sensitization structures of ZnIn2S4 and TiO2 as signal generators was engineered for rapid and ultrasensitive detection of DEHP using an all-in-one lab-on-paper analytical device. Benefitting from cascaded sensitization effect, the ZnIn2S4/TiO2 photosensitive structures-assembled polypyrrole paper electrode gave an enhanced photocurrent signal. The MnO2@BSA nanoparticles (NPs) with peroxidase-mimic and oxidase-mimic double-enzymatic activity induced multiple signal quenching effects and catalyzed color development. Specifically, the MnO2@BSA NPs acted as peroxidase mimetics to generate catalytic precipitates, which not only obstructed interfacial electron transfer but also served as electron acceptors to accept photogenerated electrons. Besides, the steric hindrance effect from MnO2@BSA NPs-loaded branchy polymeric DNA duplex structures further decreased photocurrent signal. The target recycling reaction caused the detachment of MnO2@BSA NPs to increase PEC signal, realizing the ultrasensitive detection of DEHP with a low detection limit of 27 fM. Ingeniously, the freed MnO2@BSA NPs flowed to colorimetric zone with the aid of fluid channels and acted as oxidase mimetics to induce color intensity enhancement, resulting in the rapid visual detection of DEHP. This work provided a prospective paradigm to develop field-based paper analytical tool for DEHP detection in aqueous environment.

Astragalus polysaccharide ameliorates CD8+ T cell dysfunction through STAT3/Gal-3/LAG3 pathway in inflammation-induced colorectal cancer.

Chronic inflammation can promote cancer development as observed in inflammation-induced colorectal cancer (CRC). However, the poor treatment outcomes emphasize the need for effective treatment. Astragalus polysaccharide (APS), a vital component of the natural drug Astragalus, has anti-tumor effects by inhibiting cancer cell proliferation and enhancing immune function. In this study, we found that APS effectively suppressed CRC development through activating CD8+ T cells and reversing its inhibitory state in the tumor microenvironment (TME) of AOM/DSS inflammation-induced CRC mice. Network pharmacology and clinical databases suggested that the STAT3/ Galectin-3(Gal-3)/LAG3 pathway might be APS's potential target for treating CRC and associated with CD8+ T cell dysfunction. In vivo experiments showed that APS significantly reduced phosphorylated STAT3 and Gal-3 levels in tumor cells, as well as LAG3 in CD8+ T cells. Co-culture experiments with MC38 and CD8+ T cells demonstrated that APS decreased the expression of co-inhibitory receptor LAG3 in CD8+ T cells by targeting STAT3/Gal-3 in MC38 cells. Mechanism investigations revealed that APS specifically improved CD8+ T cell function through modulation of the STAT3/Gal-3/LAG3 pathway to inhibit CRC development, providing insights for future clinical development of natural anti-tumor drugs and immunotherapies as a novel strategy combined with immune checkpoint inhibitors (ICIs).

NUA positively regulates plant immunity by coordination with ESD4 to deSUMOylate TPR1 in Arabidopsis.

Nuclear pore complex (NPC) is composed of multiple nucleoporins (Nups). A plethora of studies have highlighted the significance of NPC in plant immunity. However, the specific roles of individual Nups are poorly understood. NUCLEAR PORE ANCHOR (NUA) is a component of NPC. Loss of NUA leads to an increase in SUMO conjugates and pleiotropic developmental defects in Arabidopsis thaliana. Herein, we revealed that NUA is required for plant defense against multiple pathogens. NUCLEAR PORE ANCHOR associates with the transcriptional corepressor TOPLESS-RELATED1 (TPR1) and contributes to TPR1 deSUMOylation. Significantly, NUA-interacting protein EARLY IN SHORT DAYS 4 (ESD4), a SUMO protease, specifically deSUMOylates TPR1. It has been previously established that the SUMO E3 ligase SAP AND MIZ1 DOMAIN-CONTAINING LIGASE 1 (SIZ1)-mediated SUMOylation of TPR1 represses the immune-related function of TPR1. Consistent with this notion, the hyper-SUMOylated TPR1 in nua-3 leads to upregulated expression of TPR1 target genes and compromised TPR1-mediated disease resistance. Taken together, our work uncovers a mechanism by which NUA positively regulates plant defense responses by coordination with ESD4 to deSUMOylate TPR1. Our findings, together with previous studies, reveal a regulatory module in which SIZ1 and NUA/ESD4 control the homeostasis of TPR1 SUMOylation to maintain proper immune output.

Nomograms for the prediction of decannulation in patients with neurological injury: a study based on clinical practice.

BACKGROUND: Rational prediction of the probability of decannulation in tracheotomy patients is of great importance to clinicians and patients' families. This study aimed to develop a prediction model for decannulation in tracheotomized patients with neurological injury using routine clinical data and blood tests. METHODS: We developed a prediction model based on 186 tracheotomized patients, and data were collected from January 2018 to March 2021. The least absolute shrinkage and selection operator (LASSO) regression model was used to optimize feature selection for the decannulation risk model. The performance of the prediction model was evaluated in terms of discrimination, calibration, and clinical utility using measures such as C-index, calibration plot, and decision curve analysis (DCA). Internal validation was performed through bootstrapping validation. RESULTS: A total of 66.13% (123/186) of patients were decannulated. Predictors included in the prediction nomogram were age, gender, subtype of neurological injury, Glasgow Coma Scale (GCS) score, swallowing function, duration of tracheotomy, procalcitonin (PCT) level, white blood cell (WBC) count, and serum albumin (ALB) level. The predictive model showed good discrimination, with a C-index of 0.755 (95% confidence interval: 0.68-0.83). Internal validation also confirmed a satisfactory C-index of 0.690. The DCA indicated that the nomogram added substantial value in predicting decannulation risk for patients with threshold probabilities falling between >21% and <98% compared to the existing scheme. CONCLUSIONS: This predictive model serves as a valuable instrument for clinicians to quantitatively assess the probability of decannulation in patients with neurological injury, aiding in informed decision-making and patient management.

Gut microbiota-derived 12-ketolithocholic acid suppresses the IL-17A secretion from colonic group 3 innate lymphoid cells to prevent the acute exacerbation of ulcerative colitis.

Intestinal microbiota dysbiosis and metabolic disruption are well-known as the primary triggers of ulcerative colitis (UC). However, their role in regulating the group 3 innate lymphoid cells (ILC3s), which are essential for intestinal health, remains unexplored during the development of disease severity. Here, our results showed that the microbiota structure of patients with severe UC (SUCs) differed from those with mild UC (MiUCs), moderate UC (MoUCs), and healthy controls (HCs). Microbes producing secondary bile acids (SBAs) and SBAs decreased with the aggravation of UC, and a strong positive correlation existed between them. Next, fecal microbiota transfer was used to reproduce the human-derived microbiota in mice and decipher the microbiota-mediated inflammatory modulation during an increase in disease severity. Mice receiving SUC-derived microbiota exhibited enhancive inflammation, a lowered percentage of ILC3s, and the down-regulated expressions of bile acid receptors, including vitamin D receptor (VDR) and pregnane X receptor (PXR), in the colon. Similar to clinical results, SBA-producing microbes, deoxycholic acids (DCA), and 12-ketolithocholic acids (12-KLCA) were diminished in the intestine of these recipients. Finally, we compared the therapeutic potential of DCA and 12-KLCA in preventing colitis and the regulatory mechanisms mediated by ILC3s. 12-KLCA but not DCA represented a strong anti-inflammatory effect associated with the higher expression of VDR and the lower secretion of IL-17A from colonic ILC3s. Collectively, these findings provide new signatures for monitoring the acute deterioration of UC by targeting gut microbiota and bile acid metabolism and demonstrate the therapeutic and preventive potential of a novel microbiota-derived metabolite, 12-KLCA.

Protective effects of villi mesenchymal stem cells on human umbilical vein endothelial cells by inducing SPOCD1 expression in cases of gestational diabetes mellitus.

BACKGROUND: Gestational diabetes mellitus (GDM) is characterized by a lack of response to insulin in pregnancies, and often accompanied by severe complications. GDM is associated with structural and functional alterations, particularly endothelial dysfunction, in various tissues. This study is aimed to investigate the effect of placental mesenchymal stem cells (MSCs) on the endothelial biological function of human umbilical vein endothelial cells (HUVECs) and their molecular mechanisms. METHODS: Villi mesenchymal stem cells (VMSCs) were co-cultured with HUVECs, and transcriptomic analysis of differential genes was performed in HUVECs under high-glucose induction. Lentiviral transfection was performed to construct HUVECs with stable knockdown or overexpression of SPOCD1. The immunohistochemical assays were used to detect the expression of SPOCD1 in GDM patients. TUNEL fluorescence staining was applied for detection of the HUVEC apoptosis. ß galactosidase staining assay was performed to detect the cell senescence. Electron microscopy was used to detect the cell pyroptosis. qRT-PCR and western blot assays were conducted for identifying the mRNA & protein expressions of genes. RESULTS: VMSCs, when co-cultured with HUVECs, could inhibit the apoptosis, pyroptosis and senescence induced by high-glucose condition in HUVECs. Transcriptomic results showed an upregulation of SPOCD1 expression induced by VMSCs in HUVECs. Overexpression of SPOCD1 inhibited high-level glucose-induced apoptosis, pyroptosis and senescence in HUVECs via the ß-catenin pathway. CONCLUSION: VMSCs induce ß-catenin activation by upregulating the expression of SPOCD1 in HUVECs, which ultimately inhibits high-level glucose-induced apoptosis, pyroptosis and senescence in HUVECs. This observation provides potential therapeutic insight for future GDM treatment.

Triglyceride-glucose index and the risk of stroke in American adults: findings from the atherosclerosis risk in communities study.

OBJECTIVES: The associations between the triglyceride-glucose (TyG) index with subsequent stroke in American adults are unknown. The aim of this study was to determine the associations between baseline and trajectories of TyG index with subsequent stroke in American adults. METHODS: A total of 10,132 participants free of a history of stroke at baseline were included. We quantified the association of baseline and trajectories of TyG index with incident total stroke, ischemic stroke and intracerebral hemorrhage using Cox regression, restricted cubic splines and logistic regression analysis. RESULTS: There were 909 incident stroke cases over a median follow-up of 26.6 years. After adjustment for potential confounders, each unit increase in the TyG index was associated with a 32.1% higher risk of incident stroke. Compared with participants in the lowest quartile of the baseline TyG index, those in the highest quartile had a greater risk of incident stroke [HR (95% CI) 1.254 (1.014-1.552)]. Restricted cubic splines showed that the risk of stroke increased in participants with a higher TyG index, especially when the TyG index was > 8.6. Results were similar for incident ischemic stroke. Compared with participants in the lowest quartile of the baseline TyG index, those in the second quartile had a lower risk of intracerebral hemorrhage [HR (95% CI) 0.494 (0.262-0.931)]. Five discrete trajectories with stable TyG indexes at various levels at follow-up visits were identified, and parallel results were observed for the associations of trajectories of TyG index with outcomes. CONCLUSIONS: The TyG index independently predict stroke progression.

Bifunctional Strategy toward Constructing Perovskite/Upconversion Lab-on-Paper Photoelectrochemical Device for Sensitive Detection of Malathion.

Bifunctional nanocrystals which combine two kinds of materials into single nanoparticles hold great promise in photoelectrochemical (PEC) analysis, particularly for nanocrystals based on perovskite quantum dots (QDs) which generally exhibit excellent photoelectric activity yet poor stability and upconversion nanoparticles (UCNP) that normally suffer from negligible photoelectric activity. Therefore, to achieve good performance of the PEC bioassay platform, it is valuable to combine perovskite QDs with UCNP encapsulation and promote their advantages to form hybrid nanocrystals that are stable, NIR excitable, and photoelectric. Herein, the core-shell configuration of perovskite/upconversion CsPbBr2I@NaYF4:Yb,Tm (CPBI@UCNP) nanocrystals coupled with a NiMn-layered double hydroxide (NiMn-LDH)/CdS heterojunction to form a cascade sensitization structure was proposed to construct the lab-on-paper PEC device for ultrasensitive detection of malathion pesticides. Concretely, the bifunctional CPBI@UCNP nanocrystals that encapsulated CPBI QDs into UCNPs were employed as a nanoscale light source and sensitizer in the lab-on-paper system, which not only prevented the degradation of perovskite QDs but also overcame the negligible photoelectric performance of pristine UCNPs with the cooperation of photoactive CPBI QDs. The synergistic quenching effect, including fluorescence energy resonance transfer (FRET) and photoinduced electron transfer (PET), was created to realize enhanced PEC signal readout. Benefiting from the dynamic cascade sensitization structure of CPBI@UCNP/NiMn-LDH/CdS and synergistic quenching effect of FRET/PET, the ultrasensitive detection of malathion was achieved with high selectivity, reproducibility, and stability, which provided guidelines to employ perovskite/upconversion nanomaterials for lab-on-paper PEC analysis.

Visible Light and Microwave-Mediated Rapid Trapping and Release of Singlet Oxygen Using a Coordination Polymer.

Due to its high reactivity and oxidative strength, singlet oxygen (1 O2 ) is used in a variety of fields including organic synthesis, biomedicine, photodynamic therapy and materials science. Despite its importance, the controlled trapping and release of 1 O2 is extremely challenging. Herein, we describe a one-dimensional coordination polymer, CP1, which upon irradiation with visible light, transforms 3 O2 (triplet oxygen) to 1 O2 . CP1 consists of CdII centers bridged by 9,10-bis((E)-2-(pyridin-4-yl)vinyl)anthracene ligands which undergo a [4+2] cycloaddition reaction with 1 O2 , resulting in the generation of CP1-1 O2 . Using microwave irradiation, CP1-1 O2 displays efficient release of 1 O2 , over a period of 30 s. In addition, CP1 exhibits enhanced fluorescence and has an oxygen detection limit of 97.4 ppm. Theoretical calculations reveal that the fluorescence behaviour is dominated by unique through-space conjugation. In addition to describing a highly efficient approach for the trapping and controlled release of 1 O2 , using coordination polymers, this work also provides encouragement for the development of efficient fluorescent oxygen sensors.

Efficacy and Safety of Oral Anticoagulants in Older Adult Patients With Atrial Fibrillation: Pairwise and Network Meta-Analyses.

OBJECTIVE: To evaluate the efficacy and safety of oral anticoagulants for older adult patients with atrial fibrillation (AF). DESIGN: Pairwise and network meta-analyses. SETTING AND PARTICIPANTS: Patients with AF aged ≥75 years. METHODS: PubMed, Embase, and the Cochrane library were searched for published randomized controlled trials and adjusted observational studies evaluating the use of a non-vitamin K antagonist oral anticoagulants (NOACs), vitamin K antagonist, or antiplatelet drug for the prevention of stroke. The primary efficacy and safety outcomes were the composite of stroke and systemic embolism (SSE) and major bleedings. RESULTS: This study included 38 studies enrolling 1,022,908 older adult patients with AF. Results from pairwise meta-analyses showed that NOACs were superior to warfarin for all outcomes, except that dabigatran increased the risk of gastrointestinal (GI) bleedings. Aspirin was associated with a higher risk of SSE and ischemic stroke than warfarin or NOACs. Results of network meta-analyses indicated that apixaban significantly reduced the risk of SSE, major bleedings, and GI bleedings than warfarin, rivaroxaban, and dabigatran. Apixaban, edoxaban, rivaroxaban, and dabigatran reduced the risk of ischemic stroke and intracranial bleeding compared to warfarin. Dabigatran showed lower risk of all-cause mortality than warfarin and of intracranial bleeding than rivaroxaban. CONCLUSIONS AND IMPLICATIONS: NOACs are of at least equal efficacy, or even superior to warfarin. The safety profile of individual NOAC agents was significantly different, as apixaban performs better than the other oral anticoagulants in reducing major bleeding and GI bleeding, whereas dabigatran increased the risk of GI bleeding.

Potential benefits of spicy food consumption on cardiovascular outcomes in patients with diabetes: A cohort study of the China Kadoorie Biobank.

OBJECTIVES: Dietary capsaicin from spicy foods has potential benefits for those with cardiometabolic diseases (CMDs). However, to our knowledge there is no evidence linking spicy food consumption with cardiovascular outcomes in individuals with diabetes. The aim of this study was to explore the association between spicy food consumption and the incidence of major adverse cardiovascular events (MACEs) in individuals with diabetes from the CKB (China Kadoorie Biobank) study and to provide evidence-based dietary recommendations for those with CMDs. METHODS: This prospective study enrolled 26 163 patients from the CKB study who had diabetes without coronary heart disease, stroke, or cancer to our knowledge. Of the 26 163 patients enrolled, 17 326 never or rarely ate spicy food (non-spicy group), and 8837 ate spicy food ≥1 d/wk (spicy group). The primary outcomes were MACEs, including cardiac death, non-fatal myocardial infarction, and stroke. Cox proportional hazards models were used to estimate the hazard ratio (HR) of MACEs and their associated 95% confidence intervals (CIs). RESULTS: During a median follow-up of 8.5 y, MACEs occurred in 5465 participants (20.9%), with 3820 (22%) and 1645 (18.6%) cases occurring in the non-spicy and spicy groups, respectively. Spicy food consumption was independently associated with a decreased tendency for MACEs, with an adjusted HR of 0.94 (95% CI, 0.89-1.00; P = 0.041). Subgroup analysis showed consistency in the results that the regular spicy eating groups were associated with significantly lower incidence of MACEs than the non-spicy group. There was no statistical difference in the incidence of MACEs among the three different spicy eating frequency groups. CONCLUSION: This cohort study revealed that the consumption of spicy food was independently associated with a reduced incidence of adverse cardiovascular events in Chinese adults with diabetes, suggesting a beneficial effect on cardiovascular health. Further studies are needed to confirm the association between the consumption of different doses of spicy food and cardiovascular outcomes and the exact mechanism of action.

Phase Transition-Promoted Rapid Photomechanical Motions of Single Crystals of a Triene Coordination Polymer.

Molecular crystals with the ability to transform light energy into macroscopic mechanical motions are a promising class of materials with potential applications in actuating and photonic devices. In regard to such materials, coordination polymers that exhibit dynamic photomechanical motion, associated with a phase transition, are unknown. Herein, we report an intriguing photoactive, one-dimensional ZnII coordination polymer, 1, derived from 1,3,5-tri-4-pyridyl-1,2-ethenylbenzene and 3,5-difluorobenzoate. Single crystals of 1 under UV light irradiation exhibit rapid shrinking and bending, violent bursting-jumping, splitting, and cracking behavior. Single-crystal X-ray diffraction analysis and 1 H NMR spectroscopy reveal an unusual photoinduced phase transition involving a single-crystal-to-single-crystal [2+2] cycloaddition reaction that results in photomechanical responses. Interestingly, crystals of 1, which are triclinic with space group P 1 ‾ ${P\bar{1}}$ , are transformed into a higher symmetry, monoclinic cell with space group C2/c. This process represents a rare example of symmetry enhancement upon photoirradiation. The photomechanical activity is likely due to the sudden release of stress associated with strained molecular geometries and significant solid-state molecular movement arising from cleavage and formation of chemical bonds. A composite membrane fabricated from 1 and polyvinyl alcohol (PVA) also displays interesting photomechanical behavior under UV light illumination, indicating the material's potential as a photoactuator.

Photopolymerization-Driven Macroscopic Mechanical Motions of a Composite Film Containing a Vinyl Coordination Polymer.

We report a unique vinyl coordination polymer (CP), [Zn(4-Fb)2 (tkpvb)]n (1, 4-HFb=4-fluorobenzoic acid, tkpvb=1,2,4,5-tetrakis(4-pyridylvinyl)benzene) that undergoes a rare photopolymerization reaction to form a two-dimensional CP integrated with a one-dimensional linear organic polymer. Upon light irradiation at different wavelengths, 1 exhibits an unprecedented phenomenon of photoinduced nonlinear lattice expansion. 1 can be uniformly dispersed in polyvinyl alcohol (PVA) to form the composite film of 1-PVA. When this film is exposed to UV light, internal minute stresses within crystallites are released by lattice expansion, resulting in a variety of photopolymerization-driven macroscopic mechanical motions. The findings provide new insights into the conversion of small lattice expansions of CPs into macroscopic mechanical motions based on photopolymerization reactions, which can promote the development of CPs-based smart photoactuators in the burgeoning field of microrobotics.

Dachengqi Decoction alleviates intestinal inflammation in ovalbumin-induced asthma by reducing group 2 innate lymphoid cells in a microbiota-dependent manner.

Background and aim: Dachengqi Decoction (DCQD) as a classic traditional Chinese medicine has been reported to be effective in treating asthma, but its mechanism remains unknown. This study aimed to reveal the mechanisms of DCQD on the intestinal complications of asthma mediated by group 2 innate lymphoid cells (ILC2) and intestinal microbiota. Experimental procedure: Ovalbumin (OVA) was used to construct asthmatic murine models. IgE, cytokines (e.g., IL-4, IL-5), fecal water content, colonic length, histopathologic appearance, and gut microbiota were evaluated in asthmatic mice treated with DCQD. Finally, we administered DCQD to antibiotic-treated asthmatic mice to measure the ILC2 in the small intestine and colon. Results and conclusion: DCQD decreased pulmonary IgE, IL-4, and IL-5 levels in asthmatic mice. The fecal water content, the colonic length weight loss, and the epithelial damage of jejunum, ileum, and colon of asthmatic mice were ameliorated by DCQD. Meanwhile, DCQD greatly improved intestinal dysbiosis by enriching Allobaculum, Romboutsia and Turicibacter in the whole intestine, and Lactobacillus gasseri only in the colon. However, DCQD caused less abundant Faecalibaculum and Lactobacillus vaginalis in the small intestine of asthmatic mice. A higher ILC2 proportion in different gut segments of asthmatic mice was reversed by DCQD. Finally, significant correlations appeared between DCQD-mediated specific bacteria and cytokines (e.g., IL-4, IL-5) or ILC2. These findings indicate that DCQD alleviated the concurrent intestinal inflammation in OVA-induced asthma by decreasing the excessive accumulation of intestinal ILC2 in a microbiota-dependent manner across different gut locations.

Plasma homocysteine levels and risk of congestive heart failure or cardiomyopathy: A Mendelian randomization study.

Background: Although observational studies have demonstrated associations between elevated plasma homocysteine levels and the risk of cardiovascular diseases, controversy remains. Objective: This study investigated the causal association of plasma homocysteine levels with congestive heart failure and cardiomyopathy risk. Methods: We performed a two-sample Mendelian randomization (MR) study of congestive heart failure (n = 218,792), cardiomyopathy (n = 159,811), and non-ischemic cardiomyopathy (n = 187,152). Genetic summary data on the association of single-nucleotide polymorphisms with homocysteine were extracted from the most extensive genome-wide association study of 44,147 individuals. MR analyses, including the random-effect inverse variance-weighted (IVW) meta-analysis, weighted median, simple median, maximum likelihood, penalized weighted median, MR-PRESSO, and MR-Egger regression, were used to estimate the associations between the selected single-nucleotide polymorphisms and congestive heart failure or cardiomyopathy. Results: The MR analyses revealed no causal role of higher genetically predicted plasma homocysteine levels with congestive heart failure risk (random-effect IVW, odds ratio [OR] per standard deviation (SD) increase in homocysteine levels = 1.753, 95% confidence interval [CI] = 0.674-4.562, P = 0.250), cardiomyopathy (random-effect IVW, OR per SD increase in homocysteine levels = 0.805, 95% CI = 0.583 to 1.020, P = 0.189), or non-ischemic cardiomyopathy (random-effect IVW, OR per SD increase in homocysteine levels = 1.064, 95% CI = 0.927-1.222, P = 0.379). The results were consistent with other analytical methods and sensitivity analyses. Conclusion: Genetically predicted homocysteine level was not associated with congestive heart failure or cardiomyopathy risk. It is unlikely that homocysteine-lowering therapy decreases the incidence or improves the outcomes of congestive heart failure and cardiomyopathy.

Functional characterization and development of novel human kinase insert domain receptor chimeric antigen receptor T-cells for immunotherapy of non-small cell lung cancer.

CAR-T cell therapy, in which T cells are transfected or transduced with a chimeric antigen receptor (CAR), is a transformative type of cancer immunotherapy. Despite outstanding success in hematological malignancies, their efficacy against solid tumors has been limited. Here, we aimed to explore whether T cells modified by a CAR targeting the vascular endothelial growth factor 2 receptor/ kinase insert domain receptor (KDR) could destroy tumors and their vasculature. A second-generation KDR-CAR was constructed and transfected into T cells using lentivirus. The 3D structure of the CAR construct and target antigen was predicted. Moreover, in silico analysis, including molecular docking and molecular dynamics (MD) simulation, were used to evaluate the minimum energy of interaction and stability of the complex. The anti-cancer effect of KDR-specific CAR-T cells was tested with KDR-expressing and KDR overexpressing A549 cell line. The in-silico study suggested that this CAR construct could be effective for lung cancer therapy. We evaluated this using both in vitro and in vivo experiments. The KDR-CAR-T cells targeted and killed KDR-A549 with high efficiency by expressing IFN-γ and releasing granzyme B. The in vivo study showed that KDR-CAR-T cells dramatically inhibited the growth of lung cancer KDR-A549 xenografts in BALB/c-nu mice at day 10. The characterization of T cells modified by KDR-CAR by computational biology and wet-lab experiments suggested its applicability as a new treatment strategy for lung cancer and, potentially, for other vascularized solid tumors.

Qing-Xin-Jie-Yu Granule inhibits ferroptosis and stabilizes atherosclerotic plaques by regulating the GPX4/xCT signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Qing-Xin-Jie-Yu Granule (QXJYG) is an integrated traditional Chinese medicine formula used to treat atherosclerotic (AS) cardiovascular diseases. A randomized controlled trial found that QXJYG reduced cardiovascular events and experiments also verified that QXJYG attenuated AS by remodeling the intestinal flora. AIM OF THE STUDY: To determine whether QXJYG would attenuate AS and plaque vulnerability by regulating ferroptosis in high-fat diet-induced atherosclerotic ApoE-/- mice and to investigate the effects of QXJYG on macrophage ferroptosis in RAS-selective lethal 3 (RSL3)-induced J744A.1 cells. METHODS: AS models in ApoE-/- mice and RSL3-induced ferroptosis in J744A.1 cells were established to measure the protective and anti-ferroptotic effects of QXJYG in vivo and in vitro. The glutathione peroxidase 4 (GPX4)/cystine glutamate reverse transporter (xCT) signal pathway was examined by immunohistochemistry and western blotting. RESULTS: QXJYG attenuated AS progression and plaque vulnerability. Characteristic morphological changes of ferroptosis in the QXJYG-treated animals were rare. Total iron was significantly lower in the QXJYG group than in the model group (P < 0.05); QXJYG suppressed the lipid peroxidation (LPO) levels (malondialdehyde), enhanced the antioxidant capacity (superoxide dismutase and glutathione), and reduced inflammatory factors (interleukin [IL]-6, IL-1ß, tumor necrosis factor-α) associated with ferroptosis. Expression of GPX4/xCT in aorta tissues was remarkably increased in the QXJYG group. QXJYG inhibited ferroptosis in J744A.1 macrophages disturbed using RSL3. The Fe2+, LPO, and reactive oxygen species levels were lower in the QXJYG group than in the RSL3 group (P < 0.05). The QXJYG group showed higher expression of the GPX4/xCT signal pathway. CONCLUSION: QXJYG inhibits ferroptosis in vulnerable AS plaques partially via the GPX4/xCT signaling pathway.