The role of cellular senescence-related genes in Asthma: Insights from bioinformatics and animal experiments.

BACKGROUND: Asthma is a heterogeneous chronic respiratory disease, affecting about 10% of the global population. Cellular senescence is a multifaceted phenomenon defined as the irreversible halt of the cell cycle, commonly referred to as the senescence-associated secretory phenotype. Recent studies suggest that cellular senescence may play a role in asthma. This study aims to dissect the role and biological mechanisms of CSRGs in asthma, enhancing our understanding of the progression of asthma. METHODS: The study utilized the GSE147878 dataset, employing methods like WGCNA, Differential analysis, Cibersort, GO, KEGG, unsupervised clustering, and GSVA to explore CSRGs functions and immune cell patterns in asthma. Machine learning identified key diagnostic genes, validated externally with the GSE165934 dataset and through qRT-PCR and WB experiments in animal models. RESULT: From the GSE147878 dataset, 24 CSRGs were identified, highlighting their role in immune and inflammatory processes in asthma. Differences in CD4 naive T cells and activated dendritic cells between asthma and control groups underscored CSRGs' role in immune regulation. Cluster analysis revealed two distinct asthma patient groups with unique immune microenvironments. Machine learning identified five genes, leading to a TF-miRNA-mRNA network and singling out RHOA and RBM39 as key diagnostic genes, which were experimentally validated. Finally, a nomogram was created based on these genes. CONCLUSION: This study, utilizing bioinformatics and animal experiments, identified RHOA and RBM39 as key diagnostic genes for asthma, providing new insights into the potential role and biological mechanisms of CSRGs in asthma.

MiR-182/Sestrin2 affects the function of asthmatic airway smooth muscle cells by the AMPK/mTOR pathway.

Background and Objectives: Asthma is a chronic inflammatory airway disease and brings heavy economic and spiritual burdens to patients' families and the society. Airway smooth muscle cells (ASMCs) afect the development of asthma by secreting cytokines, growth factors, and prostates. The stress-inducing protein, Sestrin2, plays a vital role in antioxidant defense. The aim of this study is to investigate the role of Sestrin2 in asthma and its corresponding molecular mechanism. Materials and Methods: Airway remodeling was induced by construction of asthma rat model. Primary ASMCs were isolated through combining tissue block adherence and enzymatic digestion and identified by immunofluorescence staining. Gene expression was measured by quantitative real-time PCR (qPCR) and western blot (WB) experiments. Cell viability, proliferation, migration, and calcium flow of ASMCs were measured by Cell Counting Kit-8 (CCK-8), 5-ethynyl-deoxyuridine (EdU), Transwell, and Fluo-3AM, respectively. The binding of miR-182 and Sestrin2 3'-untranslated region (3'-UTR) was measured by luciferase reporter system and RNA-binding protein immunoprecipitation (RIP) analysis. Results: Sestrin2 expression was upregulated in asthma rat model and cell model. Overexpression of Sestrin2 enhanced the growth, migration, and calcium flow, and inversely, repression of Sestrin2 was reduced in ASMCs from the asthma group. MiR-182, one of the microRNAs (miRNAs) that possesses the potential to regulate Sestrin2, was downregulated in ASMCs from the asthma group. Further experiments revealed that Sestrin2 was inhibited by miR-182 and that overexpression of Sestrin2 reversed the miR-182-induced inhibition of the cellular progression of ASMCs from the asthma group. This study further investigated the downstream signaling pathway of Sestrin2 and found that increased expression of Sestrin2 activated 5'-adenosine monophosphate-activated protein kinase (AMPK), leading to the inactivation of mammalian target of rapamycin (mTOR) and thus promoting the growth, migration, and calcium flow of ASMCs from the asthma group. Conclusion: This study investigated the role of Sestrin2 for the first time and further dissected the regulatory factor of Sestrin2, ultimately elucidating the downstream signaling pathway of Sestrin2 in asthma, providing a novel pathway, and improving the understanding of the development and progression of asthma.

Soil phosphorus form affects the advantages that arbuscular mycorrhizal fungi confer on the invasive plant species, Solidago canadensis, over its congener.

Interactions between plants and arbuscular mycorrhizal fungi (AMF) are strongly affected by soil phosphorus (P) availability. However, how P forms impact rhizosphere AMF diversity, community composition, and the co-occurrence network associated with native and invasive plants, and whether these changes in turn influence the invasiveness of alien species remain unclear. In this work, we performed a greenhouse experiment with the invasive species Solidago canadensis and its native congener S. decurrens to investigate how different forms of P altered the AMF community and evaluate how these changes were linked with the growth advantage of S. canadensis relative to S. decurrens. Plants were subjected to five different P treatments: no P addition (control), simple inorganic P (sodium dihydrogen phosphate, NaP), complex inorganic P (hydroxyapatite, CaP), simple organic P (adenosine monophosphate, AMP) and complex organic P (myo-inositol hexakisphosphate, PA). Overall, invasive S. canadensis grew larger than native S. decurrens across all P treatments, and this growth advantage was strengthened when these species were grown in CaP and AMP treatments. The two Solidago species harbored divergent AMF communities, and soil P treatments significantly shifted AMF community composition. In particular, the differences in AMF diversity, community composition, topological features and keystone taxa of the co-occurrence networks between S. canadensis and S. decurrens were amplified when the dominant form of soil P was altered. Despite significant correlations between AMF alpha diversity, community structure, co-occurrence network composition and plant performance, we found that alpha diversity and keystone taxa of the AMF co-occurrence networks were the primary factors influencing plant growth and the growth advantage of invasive S. canadensis between soil P treatments. These results suggest that AMF could confer invasive plants with greater advantages over native congeners, depending on the forms of P in the soil, and emphasize the important roles of multiple AMF traits in plant invasion.

Physicochemical, functional, and digestive characteristics of tea seed cake protein obtained by ultrafiltration.

To make full use of tea seed cake protein (TSCP), this study investigated the physicochemical and functional properties of TSCP, including the TSCP extract and three ultrafiltration fractions TSCP-1 (Mw > 10 kDa), TSCP-2 (3.5 kDa < Mw < 10 kDa), and TSCP-3 (Mw < 3.5 kDa). After ultrafiltration, the content, thermal stability, and surface hydrophobicity of TSCP were increased, and the molecular weight distribution and structure of TSCP showed significant differences. In terms of functionality, each fraction showed its advantages. Specifically, compared with the others, TSCP had better solubility and foaming properties, and TSCP-1 had significantly higher oil absorption capacity, and TSCP-2 had better water absorption capacity and emulsifying properties, and TSCP-3 can flow more easily (p < 0.05). In terms of nutritional value, the content of essential amino acids in all samples was sufficient. The degree of hydrolysis of TSCP was highest (80.98 ± 1.50%), and ultrafiltration decreased digestibility. These results indicated that ultrafiltration effectively improved the structure and functional properties of TSCP, and the obtained fractions can be applied to different scenarios. Practical Application: Tea seed cakes are rich in protein and usually regarded as byproducts during oil processing. Because of its good functional properties, tea seed cake proteins obtained by ultrafiltration have the potential to be used as ingredients for food.

Effect of the BMPR-II-SMAD3/MRTF pathway on proliferation and migration of ASMCs and the mechanism in asthma.

BACKGROUND: A variety of smooth muscle-specific genes and proteins, including SMAD3, BMPR-II, and MRTF, are involved in airway remodeling in asthma. As a receptor of bone morphogenetic protein (BMP) signaling, BMPR-II has important roles in airway remodeling in asthma. However, the underlying mechanism of BMPR-II in airway smooth muscle cells (ASMCs) in asthma remains incomplete. METHODS: Wistar rats were intraperitoneally injected with ovalbumin antigen suspension and aluminium hydroxide and, stimulated with ovalbumin nebulized inhalation to constructed asthma model. Primary ASMCs were isolated with collagenase I and identified by testing the α-SMA expression. Quantitative polymerase chain reaction (qPCR) and western blot assay were employed to detect the gene expression. CCK8, Transwell and Fluo-4 A assays were introduced to measure the cell viability, migration and intracellular Ca2+. Co-Immunoprecipitation (Co-IP) assay was applied to test the interaction among proteins. RESULTS: First, we observed significant increases in BMPR-II in asthmatic rat model and ASMCs at both the mRNA and protein levels. Second, we observed that silencing of siBMPR-II inhibited proliferation, migratory capacity and intracellular Ca2+ concentration in ASMCs. Furthermore, our study demonstrated that siBMPR-II inhibited the Smad3 expression and overexpression promoted the bioactivity of ASMCs. In addition, this study showed that p-Smad3 could interacted with MRTF and siMRTF inhibits the bioactivity of ASMCs. Finally, our results revealed BMPR-II-SMAD3/MRTF pathway affected the bioactivity of ASMCs. CONCLUSIONS: This study indicates that the BMPR-II-SMAD3/MRTF signaling pathway is involved in the process of ASMCs remodeling, providing novel avenues for the identification of new therapeutic modalities.

The piRNA pathway is essential for generating functional oocytes in golden hamsters.

Piwi-interacting RNAs (piRNAs) are predominantly expressed in germ cells and function in gametogenesis in various species. However, Piwi-deficient female mice are fertile and mouse oocytes express a panel of small RNAs that do not appear to be widely representative of mammals. Thus, the function of piRNAs in mammalian oogenesis remains largely unclear. Here, we generated Piwil1- and Mov10l1-deficient golden hamsters and found that all female and male mutants were sterile, with severe defects in embryogenesis and spermatogenesis, respectively. In Piwil1-deficient female hamsters, the oocytes and embryos displayed aberrant transposon accumulation and extensive transcriptomic dysregulation, and the embryos were arrested at the two-cell stage with impaired zygotic genome activation. Moreover, PIWIL1-piRNAs exert a non-redundant function in silencing endogenous retroviruses in the oocytes and embryos. Together, our findings demonstrate that piRNAs are indispensable for generating functional germ cells in golden hamsters and show the value of this model species for piRNA studies in gametogenesis, especially those related to female infertility.

Phytic Acid-Based FeCo Bimetallic Metal-Organic Gels for Electrocatalytic Oxygen Evolution Reaction.

Electrocatalysts have been developed to improve the efficiency of gas release for oxygen evolution reaction (OER), and finding a simple and efficient method for efficient electrocatalysts has inspired research enthusiasm. Herein, we report bimetallic metal-organic gels derived from phytic acid (PA) and mixed transition metal ions to explore their performance in electrocatalytic oxygen evolution reaction. PA is a natural phosphorus-rich organic compound, which can be obtained from plant seeds and grains. PA reacts with bimetallic ions (Fe3+ and Co2+ ) in a facile one-pot synthesis under mild conditions to form PA-FeCo bimetallic gels, and the corresponding aerogels are further partially reduced with NaBH4 to improve the electrocatalytic activity. Mixed valence states of Fe(II)/Fe(III) and Co(III)/Co(II) are present in the materials. Excellent OER performance in terms of overpotential (257 mV at 20 mA cm-2 ) and Tafel slope (36 mV dec-1 ) is achieved in an alkaline electrolyte. This reduction method is superior to the pyrolysis method by well maintaining the gel morphology structure. This strategy is conducive to the further improvement of the performance of metal-organic electrocatalysts, and provides guidance for the subsequent application of metal-organic gel electrocatalysts.

Metagenomic Next-Generation Sequencing Can Clinch Diagnosis of Non-Tuberculous Mycobacterial Infections: A Case Report.

Non-tuberculou Mycobacteria (NTM) is ubiquitous in the environment and is conditional pathogen. Due to NTM and Mycobacterium tuberculosis belong to the genus Mycobacterium, their pathogenic mechanisms and clinical manifestations are similar. Therefore, NTM can cause tuberculosis-like lesions and lead to misdiagnosis. Early diagnosis and treatment greatly improve prognosis. However, traditional pathogenic microorganism detection has limitations, and it is difficult to accurately identify strains in clinical practice. Here, we report a 65-year-old man with NTM who presented with recurrent fever and cough. Computed tomography of the chest revealed a lung infection. The previous improper diagnosis and treatment did not improve his condition. With the aid of metagenomic next-generation sequencing, the pathogen was identified as Mycobacterium avium complex. Subsequently, he received accurate treatment and made significant improvements in clinical and radiology.

Self-Foaming Metal-Organic Gels Based on Phytic Acid and Their Mechanical, Moldable, and Load-Bearing Properties.

A catalogue of metal-organic gels are synthesized from phytic acid (PA) and a diversity of metal ions (Fe3+ , Cr3+ , Al3+ , Ce3+ , Y3+ , Co2+ , Ni2+ , Mn2+ , Cu2+ , Zn2+ , Mg2+ ) upon heating at 80 °C. PA-M gels have various morphologies, including irregular granular (PA-Fe, PA-Al, PA-Ce, PA-Cr, PA-Ni, PA-Co), spongy (PA-Y), and hollow tremella-like (PA-Cu) morphologies. Interestingly for PA-Fe-1 : 4 (PA:Fe3+ =1 : 4) a large amount of gas is generated during the gelation process leading to a self-foaming gel. The PA-Fe-1 : 4 self-foaming gel shows reversible gel-sol phase transition. The gel is unusually weakened and transformed into a sol at room temperature, and the sol is reversed to gelation when heated again at 80 °C. PA-Fe-1 : 4 gel also shows shapeable and load-bearing properties, and it can bear up to 200 times of its weight, depending on the gas amount fixed in the foam gel and the aging time. This work provides a catalogue of self-foaming supramolecular gels with tunable properties based on naturally abundant resources.

Zirconium-based metal-organic framework gels for selective luminescence sensing.

Metal-organic gelation represents a promising approach to fabricate functional nanomaterials. Herein a series of Zr-carboxylate gels are synthesized from rigid pyrene, porphyrin and tetraphenyl ethylene-derived tetracarboxylate linkers, namely Zr-TBAPy (H4TBAPy = 1,3,6,8-tetrakis(4-carboxylphenyl)pyrene), Zr-TCPE (H4TCPE = 1,1,2,2-tetra(4-carboxylphenyl)ethylene), and Zr-TCPP (H4TCPP = 5,10,15,20-tetrakis(4-carboxyphenyl)porphyrin). The gels are aggregated from metal-organic framework (MOF) nanoparticles. Zr-TBAPy gel consists of NU-901 nanoparticles, and Zr-TCPP gel consists of PCN-224 nanoparticles. The xerogels show high surface areas up to 1203 m2 g-1. MOF gel films are also anchored on the butterfly wing template to yield Zr-MOF/B composites. Zr-TBAPy and Zr-TCPE gels are luminescent for solution-phase sensing and vapour-phase sensing of volatile organic compounds, and exhibit a significant luminescence quenching effect for electron-deficient analytes. Arising from the high porosity and good dispersion of luminescent MOF gels, rapid and effective vapour-sensing of nitrobenzene and 2-nitrotoluene within 30 s has been achieved via Zr-TBAPy film or Zr-TBAPy/B.

Hierarchical Gelation of a Pd12L24 Metal-Organic Cage Regulated by Cholesteryl Groups.

The creation of supramolecular assemblies by assembly of structurally simple components via supramolecular interactions provides an opportunity to develop functional materials with hierarchical complexibility. Herein, we report an assembly approach to supramolecular gels based on metal-organic cages with tunable hierarchical structures and properties. A Pd12L24 cage (L is cholesteryl-functionalized 3,5-bis(4-pyridyl)benzene) bearing 24 cholesteryl groups is used as a supramolecular building unit and molecular platform for functionalization with tunable functional behaviors. The Pd12L24 cage motifs spontaneously self-assemble into gels where orthogonal metal-organic coordination and cholesteryl-cholesteryl interactions are involved in the gelation. The Pd12L24 cage exhibits a reversible transition between solution and aggregated gel states in response to temperature. The gelation and the mechanical property are rarely regulated by deuterated solvents and tetramethylsilane. The mechanical property of the gel materials is tunable by varying the content of cholesteryl groups of Pd12L24. Functional moieties (e.g., luminescent TPE group) can be introduced on the cage, and the luminescent property changes while the structure is maintained. The Pd12L24 gel shows visible anion-responsive behaviors arising from the hierarchical structure.

Nifuroxazide prompts antitumor immune response of TCL-loaded DC in mice with orthotopically-implanted hepatocarcinoma.

Hepatocellular carcinoma (HCC) is a highly aggressive malignancy with a poor prognosis and high mortality. At present, vaccination with tumor cell lysate (TCL) loaded dendritic cells (DC) has been shown to be an effective therapy against HCC. However, the ability of promoting the specific T cell immune response is rather weak, influencing the antitumor response. Thus, it is necessary to find a strategy to improve the antitumor effect of TCL-loaded DC. Activation of signal transducer and activator of transcription 3 (STAT3) significantly inhibits antitumor immune response and DC maturity. Nifuroxazide, an antidiarrheal agent, has been proved to directly inhibit STAT3 activation. Thus, we investigated whether nifuroxazide could improve the antitumor immune response in mice vaccinated with TCL-loaded DC. The study provides the theoretical and experimental basis for developing an effective adjuvant for DC vaccine to treat HCC. Our results showed that the administration of nifuroxazide and DC-loaded TCL could significantly improve the survival rate, inhibit the tumor growth, and prompt the antitumor immune responses in mice with orthotopically implanted hepatocarcinomas, thus, possibly providing a new combination strategy to treat HCC.

Combined nifuroxazide and SAT05f therapy reduces graft-versus-host disease after experimental allogeneic bone marrow transplantation.

Acute graft-versus-host disease (aGvHD) is the major barrier to the broader use of allogenetic hematopoietic stem cells. However, currently these are no highly specific and efficient drugs. Monotherapy is not sufficient and more efficient and safe therapeutic regimen are urgent need. Studies demonstrated TLR9 and Stat3 signal pathways are critical for antigen-presenting cell maturation and T-cell activation, which are important mediators in aGvHD. Specific block these two critical signal pathways using their inhibitors SAT05f and nifuroxazide may be the novel strategies for aGvHD therapy. The results showed combined therapy significantly decreased the severity of aGvHD and prolonged the survival rate. Furthermore, after treatment, the activation of CD4+ effect T cells was reduced, whereas Treg cells was increased, and the cytokine release was inhibited. In conclusion, combined therapy of nifuroxazide with SAT05f may be potential for the prevention or treatment of aGvHD, providing theoretic and experimental basis.

Regulator of G-protein signaling 5 protects cardiomyocytes against apoptosis during in vitro cardiac ischemia-reperfusion in mice by inhibiting both JNK1/2 and P38 signaling pathways.

Ischemic heart disease is one of the most common diseases in modern society. Ischemic myocardium can be salvaged by vascular recanalization therapy, but its benefit is attenuated by injury that can occur during reperfusion. And apoptotic cell death plays an important part in myocardial ischemia-reperfusion (IR) injury. Regulator of G-protein signaling 5 (RGS5), highly expressed in different cell types of the human adult heart, is a guanosine triphosphatase-activating protein to inhibit many signaling pathways such as c-Jun NH2-terminal kinase 1/2 (JNK1/2) and p38 which promote cardiac IR-induced apoptosis. However the role of RGS5 in cardiac IR-induced apoptosis remains unclear. An in vitro IR model was applied to the isolated hearts of wild type mice (WT), RGS5-transgenic mice (TG), and RGS5-knockout mice (KO). Our results revealed that compared with either WT or KO mice, TG mice showed inhibition of cardiomyocyte apoptosis as indicated by a greater increase of B cell lymphoma/lewkmia-2 (Bcl-2), and an obvious reduction in the positive expression of the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL), Bcl-2 Associated X protein (Bax), and active caspase-3. Moreover, the inhibition of both JNK1/2 and p38 signaling markedly reversed IR-induced cardiomyocyte apoptosis in RGS5-KO mice. These studies show that RGS5 protects cardiomyocytes against apoptosis during IR through inhibiting both JNK1/2 and p38 signaling pathways.

MiR-155 Knockout in Fibroblasts Improves Cardiac Remodeling by Targeting Tumor Protein p53-Inducible Nuclear Protein 1.

Cardiac remodeling caused by acute myocardial infarction (AMI) represents a major challenge for heart failure research. MiR-155 has been identified as a key mediator of cardiac inflammation and hypertrophy. In this study, we investigate the role of miR-155 in cardiac remodeling induced by AMI. We demonstrate that miR-155 expressed in cardiac fibroblasts is a potent contributor to cardiac remodeling. We reveal that in vivo, miR-155 knockout improves left ventricular function, reduces infarct size, and attenuates collagen deposition, whereas overexpression of miR-155 produces the opposite effects. MiR-155 knockout also inhibits cardiac fibroblast proliferation and differentiation into myofibroblasts. In addition, downregulation of tumor protein p53-inducible nuclear protein 1 (TP53INP1) by small interfering RNA reverses the effects of miR-155 knockout on cardiac fibroblasts. Our data reveal that knockout of miR-155 in cardiac fibroblasts improves cardiac remodeling by targeting TP53INP1, which may be a novel treatment strategy for cardiac remodeling.

Development of a live attenuated vaccine candidate against duck Tembusu viral disease.

Duck Tembusu virus (DTMUV) is a newly emerging pathogenic flavivirus that is causing massive economic loss in the Chinese duck industry. To obtain a live vaccine candidate against the disease, the DTMUV isolate FX2010 was passaged serially in chicken embryo fibroblasts (CEFs). Characterization of FX2010-180P revealed that it was unable to replicate efficiently in chicken embryonated eggs, nor intranasally infect mice or shelducks at high doses of 5.5log10 tissue culture infectious doses (TCID50). FX2010-180P did not induce clinical symptoms, or pathological lesions in ducks at a dose of 5.5log10TCID50. The attenuation of FX2010-180P was due to 19 amino acid changes and 15 synonymous mutations. Importantly, FX2010-180P elicited good immune responses in ducks inoculated at low doses (3.5log10TCID50) and provided complete protection against challenge with a virulent strain. These results indicate that FX2010-180P is a promising candidate live vaccine for prevention of duck Tembusu viral disease.