Hsa_circ_0008833 promotes COPD progression via inducing pyroptosis in bronchial epithelial cells.

Purpose: Chronic obstructive pulmonary disease (COPD) is a common respiratory disorder. Pyroptosis represents a distinctive form of inflammatory cell death that is mediated through the activation of Caspase-1 and inflammasomes. CircRNAs have emerged as a novel class of biomolecules with implications in various human diseases. This study aims to investigate the circRNAs profile of in COPD progression and identify pivotal circRNAs associated with the development of this disease. Methods: he expression profiles of circRNAs in peripheral blood mononuclear cells of COPD patients were assessed by circRNA microarray. Furthermore, flag-labeled vectors were constructed to assess the potential protein-coding capacity of has-circ-0008833. 16HBE cells were stably transfected with lentivirus approach, and cell proliferation and death were assessed to clarify the functional roles of has-circ-0008833 and its encoded protein circ-0008833aa. Additionally, western blot analysis was furthered performed to determine the level of Caspase-1, IL-18, IL-1ß, NLRP3, ASC, and cleaved GSDMD regulated by has-circ-0008833 and circ-0008833-57aa. Results: Initially, we screened the expression profiles of human circRNAs in peripheral blood mononuclear cells of COPD patients, and found that has-circ-0008833 exhibited a significant increase in COPD mononuclear cells. Subsequently, we demonstrated that has-circ-0008833 carried an open reading frame (ORF), which encoded a functional protein, referred to as circ-0008833-57aa. By employing gain-of-function approaches, our results suggested that both circ-0008833 and circ-0008833-57aa inhibited proliferation, but accelerated the rate of 16HBE cell death. Finally, we discovered that circ-0008833 and circ-0008833-57aa promoted the expression of Caspase-1, IL-18, IL-1ß, NLRP3, ASC, and cleaved GSDMD in 16HBE cells. Conclusions: Upregulation of circ-0008833 might promote COPD progression by inducing pyroptosis of bronchial epithelial cells through the encoding of a 57-amino acid peptide.

Salvianolic Acid B Alleviates Liver Injury by Regulating Lactate-Mediated Histone Lactylation in Macrophages.

Salvianolic acid B (Sal B) is the primary water-soluble bioactive constituent derived from the roots of Salvia miltiorrhiza Bunge. This research was designed to reveal the potential mechanism of Sal B anti-liver injury from the perspective of macrophages. In our lipopolysaccharide-induced M1 macrophage model, Sal B showed a clear dose-dependent gradient of inhibition of the macrophage trend of the M1 type. Moreover, Sal B downregulated the expression of lactate dehydrogenase A (LDHA), while the overexpression of LDHA impaired Sal B's effect of inhibiting the trend of macrophage M1 polarization. Additionally, this study revealed that Sal B exhibited inhibitory effects on the lactylation process of histone H3 lysine 18 (H3K18la). In a ChIP-qPCR analysis, Sal B was observed to drive a reduction in H3K18la levels in the promoter region of the LDHA, NLRP3, and IL-1ß genes. Furthermore, our in vivo experiments showed that Sal B has a good effect on alleviating CCl4-induced liver injury. An examination of liver tissues and the Kupffer cells isolated from those tissues proved that Sal B affects the M1 polarization of macrophages and the level of histone lactylation. Together, our data reveal that Sal B has a potential mechanism of inhibiting the histone lactylation of macrophages by downregulating the level of LDHA in the treatment of liver injury.

Smartphone-based microplate reader for high-throughput quantitation of disease markers in serum.

Herein, a smartphone-based portable reader with integrated optics for standard microtiter plates (96 wells) has been designed and demonstrated for high-throughput quantitation of validated biomarkers in serum. The customized optical attachment was simply constructed with a convex lens and a light source, by which the transmitted light through a 96-well microtiter plate was converged for imaging with a smartphone, so that accurate and wide-range reading of the plate can be achieved. More importantly, relying on the digitized colorimetric analysis of the obtained images, concentrations of various biomarkers can be determined directly using the customized mobile app. A set of validated biomarkers for inflammation and infection, C-reactive protein (CRP), serum amyloid A (SAA), and procalcitonin (PCT) have been quantitated with this new system; both the response ranges and limits of detection meet the requirement of clinical tests. The consistency with the results obtained using a commercial microplate reader proves its reliability and precision, augments its potential as a point-of-care diagnostic device for on-site testing or resource-limited settings.

The mechanisms of multidrug resistance of breast cancer and research progress on related reversal agents.

Chemotherapy is the mainstay in the treatment of breast cancer. However, many drugs that are commonly used in clinical practice have a high incidence of side effects and multidrug resistance (MDR), which is mainly caused by overexpression of drug transporters and related enzymes in breast cancer cells. In recent years, researchers have been working hard to find newer and safer drugs to overcome MDR in breast cancer. In this review, we provide the molecule mechanism of MDR in breast cancer, categorize potential lead compounds that inhibit single or multiple drug transporter proteins, as well as related enzymes. Additionally, we have summarized the structure-activity relationship (SAR) based on potential breast cancer MDR modulators with lower side effects. The development of novel approaches to suppress MDR is also addressed. These lead compounds hold great promise for exploring effective chemotherapy agents to overcome MDR, providing opportunities for curing breast cancer in the future.

Identification of Mycoplasma pneumoniae by DNA-modified gold nanomaterials in a colorimetric assay.

Mycoplasma pneumoniae is a highly infectious bacterium and the major cause of pneumonia especially in school-going children. Mycoplasma pneumoniae affects the respiratory tract, and 25% of patients experience health-related problems. It is important to have a suitable method to detect M. pneumoniae, and gold nanoparticle (GNP)-based colorimetric biosensing was used in this study to identify the specific target DNA for M. pneumoniae. The color of GNPs changes due to negatively charged GNPs in the presence of positively charged monovalent (Na+ ) ions from NaCl. This condition is reversed in the presence of a single-stranded oligonucleotide, as it attracts GNPs but not in the presence of double-stranded DNA. Single standard capture DNA was mixed with optimal target DNA that cannot be adsorbed by GNPs; under this condition, GNPs are not stabilized and aggregate at high ionic strength (from 100 mM). Without capture DNA, the GNPs that were stabilized by capture DNA (from 1 µM) became more stable under high ionic conditions and retaining their red color. The GNPs turned blue in the presence of target DNA at concentrations of 1 pM, and the GNPs retained a red color when there was no target in the solution. This method is useful for the simple, easy, and accurate identification of M. pneumoniae target DNA at higher discrimination and without involving sophisticated equipment, and this method provides a diagnostic for M. pneumoniae.

The Study of the Influence of IL5RA Variants on Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease (COPD) is a complex disease, and its pathogenesis is influenced by genetic factors. This study aimed to evaluate the role of IL5RA genetic variation in the risk of COPD. In this study, 498 patients with COPD and 498 normal controls were recruited. Subsequently, five SNPs (rs3804795, rs2290610, rs13097407, rs334782, and rs3856850) in the IL5RA gene were genotyped. Logistic analysis examined the association of five single nucleotide polymorphisms (SNPs) in IL5RA with the risk of COPD under various genetic models. Furthermore, the association between IL5RA and susceptibility to COPD was comprehensively analyzed with stratification based on age, sex, smoking, and alcohol consumption. Our study showed that IL5RA rs13097407 reduced susceptibility to COPD (OR = 0.43, p < 0.001, p (FDR)< 0.001). On the other hand, rs3856850 was associated with an increased risk of COPD (OR = 1.71, p = 0.002, p (FDR) = 0.002). Interestingly, the effect of IL5RA SNPs on susceptibility to COPD was found to be influenced by factors such as sex and smoking. IL5RA gene variants were significantly associated with susceptibility to COPD.

Anticancer activity of oleanolic acid and its derivatives modified at A-ring and C-28 position.

Oleanolic acid (OA) is a five-ring triterpenoid compound, which is widely present in plants. Due to a wide range of pharmacological activities, oleanolic acid has attracted more and more attention. However, oleanolic acid is insoluble in water and has low bioavailability, which limits its clinical application. In this review, we focus on summarizing the anti-cancer activity and mechanism of the A ring or C-28 carboxyl modified derivatives of OA since 2015, to determine the strength of its anti-cancer effectiveness and evaluate whether it could be used as a clinical anti-cancer drug.

The m6 A reader MhYTP2 regulates MdMLO19 mRNA stability and antioxidant genes translation efficiency conferring powdery mildew resistance in apple.

N6 -methyladenosine (m6 A) reader protein plays an important role in trichome morphology, developmental timing and morphogenesis in Arabidopsis. However, the function of m6 A readers in plant-microbe interaction remains unclear. Here, a Malus YTH-domain family protein MhYTP2 was initially characterized as an m6 A reader. MhYTP2 overexpression increased mRNA m6 A modification level and translation efficiency. The m6 A in the exon regions appeared to destabilize the mRNAs, whereas m6 A in the untranslated regions positively correlated with the associated mRNA abundance. MhYTP2 overexpression enhanced apple powdery mildew resistance, possibly by rapidly degrading the bound mRNAs of MdMLO19 and MdMLO19-X1 and improving the translation efficiency of the antioxidant genes. To conclude, the results shed light on the apple m6 A profile, the effect of MhYTP2 on m6 A profile, and the m6 A roles in MdMLO19 and MdMLO19-X1 mRNAs stability and glutamate dehydrogenase 1-like MdGDH1L mRNA translation efficiency.

Pd-Catalyzed Aerobic Intermolecular 1,2-Diamination of Conjugated Dienes: Regio- and Chemoselective Synthesis of Piperazines and 2-Piperazinones.

Dinitrogen heterocycles are among the most important molecular structures, and the synthesis of these types of structures through intermolecular 1,2-diamination of olefins is a direct and efficient method. However, the types of nitrogen sources are mostly derived from ureas or arylamines, and nitrogen sources from aliphatic amines are still limited due to their distinct electronic and steric effects. Herein, we report a palladium-catalyzed aerobic intermolecular 1,2-diamination of conjugated dienes, using ethanediamine and α-amino amide derivatives as nitrogen sources respectively, for the synthesis of piperazines and 2-piperazinones in good yields (up to 95 %) and with high regio- and chemoselectivities.

Recent Advances of Curcumin Derivatives in Breast Cancer.

Curcumin is a potential plant-derived drug for the treatment of breast cancer. Poor solubility and bioavailability are the main factors that limit its clinical application. Various structural modification strategies have been developed to improve the anti-breast cancer activity of curcumin. This review focuses on the difference of modification sites and heterocyclic/non-heterocyclic modifications to systematically summarize curcumin derivatives with better anti-breast cancer activity.

Brd4 participates in epigenetic regulation of the extinction of remote auditory fear memory.

BACKGROUND: Inaccurate fear memories can be maladaptive and potentially portrait a core symptomatic dimension of fear adaptive disorders such as post-traumatic stress disorder (PTSD), which is generally characterized by an intense and enduring memory for the traumatic events. Evidence exists in support of epigenetic regulation of fear behavior. Brd4, a member of the bromodomain and extra-terminal domain (BET) protein family, serves as a chromatin "reader" by binding to histones in acetylated lysine residues, and hence promotes transcriptional activities. However, less is known whether Brd4 participates in modulating cognitive activities especially memory formation and extinction. Here we provide evidence for a role of Brd4 in modulation of auditory fear memory. Auditory fear conditioning resulted in a biphasic Brd4 activation in the anterior cingulate cortex (ACC) and hippocampus of adult mice. Thus, Brd4 phosphorylation occurred 6 h and 3-14 days, respectively, after auditory fear conditioning. Systemic inhibition of Brd4 with a BET inhibitor, JQ1, impaired the extinction of remote (i.e., 14 days after conditioning) fear memory. Further, conditional Brd4 knockout in excitatory neurons of the forebrain impaired remote fear extinction as observed in the JQ1-treated mice. Herein, we identified that Brd4 is essential for extinction of remote fear in rodents. These results thus indicate that Brd4 potentially plays a role in the pathogenesis of PTSD.

Antitumor activity of tridentate pincer and related metal complexes.

Pincer complexes featuring tunable tridentate ligand frameworks are one of the most actively studied classes of metal-based complexes. Currently, growing attention is devoted to the cytotoxicity of pincer and related metal complexes. The antiproliferative activity of numerous pincer complexes has been reported. Pincer tridentate ligand scaffolds show different coordination modes and offer multiple options for directed structural modifications. This review summarizes the significant progress in the research studies of the antitumor activity of pincer and related platinum(ii), gold(iii), palladium(ii), copper(ii), iron(iii), ruthenium(ii), nickel(ii) and some other metal complexes, in order to provide a reference for designing novel metal coordination drug candidates with promising antitumor activity.

Synthesis and biological evaluation of resveratrol derivatives with anti-breast cancer activity.

Resveratrol is a natural phytoestrogen produced by plants to protect themselves from injury, UV irradiation, and fungal attack. The main active structure is E-resveratrol, which has many pharmacological activities. As the structure of resveratrol is similar to the natural estrogen 17ß-estradiol and the synthetic estrogen E-diethylstilbestrol, resveratrol is used in reducing the incidence of breast cancer. However, the therapeutic application of resveratrol is limited due to its low bioavailability. To improve its bioavailability and pharmacological activity, some resveratrol derivatives have been designed and synthesized by substitutions of methoxy, hydroxyl, and other functional groups or heterocyclic esterification either on the "A" or "B" ring, and double bonds were replaced by imine bonds and isometric heterocycles such as naphthyl and imidazole, or synthetic resveratrol oligomers. The structures, synthetic routes, and evaluation of the biological activities of these compounds are discussed. These are aimed at providing some references for the study of resveratrol derivatives in anti-breast cancer treatment.

Synthesis and antioxidant activity of curcumin analogs.

Numerous biological activities including antioxidant, antitumor, anti-inflammation, and antivirus of the natural product curcumin were reported. However, the clinical application of it was significantly limited by its instability, poor solubility, less body absorbing, and low bioavailability. This review focuses on the structure modification and antioxidant activity evaluation of curcumin. To study the structure-activity relationship (SAR), five series of curcumin analogs were synthesized and their antioxidant activity were evaluated in vitro. The results showed that electron-donating groups, especially the phenolic hydroxyl group are an essential component to improve the antioxidant activity.

P-stereogenic PNP pincer-Pd catalyzed intramolecular hydroamination of amino-1,3-dienes.

A new P-stereogenic PNP pincer-Pd complex was readily prepared from optically pure 2,6-bis[(boranato(tert-butyl)methylphosphino)methyl]pyridine. It was used in the asymmetric intramolecular hydroamination of amino-1,3-dienes, with the desired products being obtained in good yields and with excellent regioselectivities and up to moderate enantioselectivities. The absolute configuration of one of the hydroamination products was determined by X-ray crystallography studies. This simple and efficient procedure can be used for the synthesis of allyl-type chiral pyrrolidine derivatives.

Melatonin facilitates extinction, but not acquisition or expression, of conditional cued fear in rats.

BACKGROUND: Previous studies have shown that melatonin is involved in the processes that contribute to learning and memory. At present study, we tested the effects of exogenous melatonin (2.5 mg/kg) on the acquisition, expression and extinction of cued fear in rats. RESULTS: Results showed that a single afternoon administration 30 min before conditioning has no effect on the acquisition of cued fear. Compared to rats injected with vehicle, rats injected with melatonin 30 min before extinction training presented a significant lower freezing during both extinction training and extinction test phases, however, freezing response did not differ for the initial four trials during extinction training. Melatonin injected immediately after extinction training was ineffective on extinction learning. CONCLUSIONS: These results suggest that melatonin, at the dose applied in this study, facilitates the extinction of conditional cued fear without affecting its acquisition or expression, and melatonin facilitates cued fear extinction only when it is present during extinction training. These findings extend previous research on the melatonin effects on learning and memory and suggest that melatonin may serve as an agent for the treatment of anxiety disorders such as posttraumatic stress disorder (PTSD).

PGKD-Net: Prior-guided and Knowledge Diffusive Network for Choroid Segmentation.

The thickness of the choroid is considered to be an important indicator of clinical diagnosis. Therefore, accurate choroid segmentation in retinal OCT images is crucial for monitoring various ophthalmic diseases. However, this is still challenging due to the blurry boundaries and interference from other lesions. To address these issues, we propose a novel prior-guided and knowledge diffusive network (PGKD-Net) to fully utilize retinal structural information to highlight choroidal region features and boost segmentation performance. Specifically, it is composed of two parts: a Prior-mask Guided Network (PG-Net) for coarse segmentation and a Knowledge Diffusive Network (KD-Net) for fine segmentation. In addition, we design two novel feature enhancement modules, Multi-Scale Context Aggregation (MSCA) and Multi-Level Feature Fusion (MLFF). The MSCA module captures the long-distance dependencies between features from different receptive fields and improves the model's ability to learn global context. The MLFF module integrates the cascaded context knowledge learned from PG-Net to benefit fine-level segmentation. Comprehensive experiments are conducted to evaluate the performance of the proposed PGKD-Net. Experimental results show that our proposed method achieves superior segmentation accuracy over other state-of-the-art methods. Our code is made up publicly available at: https://github.com/yzh-hdu/choroid-segmentation.

Network Pharmacology and Experimental Verification Reveal the Regulatory Mechanism of Chuanbeimu in Treating Chronic Obstructive Pulmonary Disease.

Background: Chronic obstructive pulmonary disease (COPD) is a common respiratory disorder in pulmonology. Chuanbeimu (CBM) is a traditional Chinese medicinal herb for treating COPD and has been widely utilized in clinical practice. However, the mechanism of CBM in the treatment of COPD remains incompletely understood. This study aims to investigate the underlying therapeutic mechanism of CBM for COPD using network pharmacology and experimental approaches. Methods: Active ingredients and their targets were obtained from the Traditional Chinese Medicine Systems Pharmacology database. COPD-associated targets were retrieved from the GeneCards database. The common targets for CBM and COPD were identified through Venn diagram analysis. Protein-protein interaction (PPI) networks and disease-herb-ingredient-target networks were constructed. Subsequently, the results of the network pharmacology were validated by molecular docking and in vitro experiments. Results: Seven active ingredients and 32 potential targets for CBM were identified as closely associated with COPD. The results of the disease-herb-ingredient-target network and PPI network showed that peimisine emerged as the core ingredient, and SRC, ADRB2, MMP2, and NOS3 were the potential targets for CBM in treating COPD. Molecular docking analysis confirmed that peimisine exhibited high binding affinity with SRC, ADRB2, MMP2, and NOS3. In vitro experiments demonstrated that peimisine significantly upregulated the expression of ADRB2 and NOS3 and downregulated the expression of SRC and MMP2. Conclusion: These findings indicate that CBM may modulate the expression of SRC, ADRB2, MMP2, and NOS3, thereby exerting a protective effect against COPD.

Clustering analysis and prognostic model based on PI3K/AKT-related genes in pancreatic cancer.

Background: Pancreatic cancer is one of most aggressive malignancies with a dismal prognosis. Activation of PI3K/AKT signaling is instrumental in pancreatic cancer tumorigenesis. The aims of this study were to identify the molecular clustering, prognostic value, relationship with tumor immunity and targeting of PI3K/AKT-related genes (PARGs) in pancreatic cancer using bioinformatics. Methods: The GSEA website was searched for PARGs, and pancreatic cancer-related mRNA data and clinical profiles were obtained through TCGA downloads. Prognosis-related genes were identified by univariate Cox regression analysis, and samples were further clustered by unsupervised methods to identify significant differences in survival, clinical information and immune infiltration between categories. Next, a prognostic model was constructed using Lasso regression analysis. The model was well validated by univariate and multivariate Cox regression analyses, Kaplan-Meier survival analysis and ROC curves, and correlations between risk scores and patient pathological characteristics were identified. Finally, GSEA, drug prediction and immune checkpoint protein analyses were performed. Results: Pancreatic cancers were divided into Cluster 1 (C1) and Cluster 2 (C1) according to PARG mRNA expression. C1 exhibited longer overall survival (OS) and higher immune scores and CTLA4 expression, whereas C2 exhibited more abundant PD-L1. A 6-PARG-based prognostic model was constructed to divide pancreatic cancer patients into a high-risk score (HRS) group and a low-risk score (LRS) group, where the HRS group exhibited worse OS. The risk score was defined as an independent predictor of OS. The HRS group was significantly associated with pancreatic cancer metastasis, aggregation and immune score. Furthermore, the HRS group exhibited immunosuppression and was sensitive to radiotherapy and guitarbine chemotherapy. Multidrug sensitivity prediction analysis indicated that the HRS group may be sensitive to PI3K/AKT signaling inhibitors (PIK-93, GSK2126458, CAL-101 and rapamycin) and ATP concentration regulators (Thapsigargin). In addition, we confirmed the oncogenic effect of protein phosphatase 2 regulatory subunit B'' subunit alpha (PPP2R3A) in pancreatic cancer in vitro and in vivo. Conclusions: PARGs predict prognosis, tumor immune profile, radiotherapy and chemotherapy drug sensitivity and are potential predictive markers for pancreatic cancer treatment that can help clinicians make decisions and personalize treatment.

The m6A reader MhYTP2 regulates the stability of its target mRNAs contributing to low nitrogen tolerance in apple (Malus domestica).

Studies have shown that the m6A reader primarily affects genes expression by participating in the regulation of mRNA localization, splicing, degradation, translation, and other metabolic processes. Previously, we discovered that the apple (Malus domestica) m6A reader MhYTP2 bound with and destabilized m6A-modified MdMLO19 mRNA. In addition, it enhanced the translation efficiency of m6A-modified mRNA of MdGDH1L, encoding a glutamate dehydrogenase, which confers resistance to powdery mildew. In this study, we report the function of MhYTP2 in the regulation of resistance to low nitrogen (N). The overexpression of MhYTP2 enhances the resistance of apple to low N. We show that MhYTP2 binds with and stabilizes the mRNAs of MdALN, which participates in the allantoin catabolic process and cellular response to N starvation in apple; MdPIDL, which participates in root hair elongation; MdTTG1, which is involved in the differentiation process of trichomes; and MdATG8A, which is a core participant in the regulation of autophagy. In addition, MhYTP2 accelerates the degradation of MdRHD3 mRNA, which regulates root development. RNA immunoprecipitation-seq and electrophoretic mobility shift assays show that the mRNAs of MdALN, MdATG8A, MdPIDL, MdTTG1, and MdRHD3 are the direct targets of MhYTP2. Overexpressing or knocking down the above genes in MhYTP2 overexpressing plants dismisses the function of MhYTP2 under low N, suggesting the role of MhYTP2 is dependent on those genes. Together, these results demonstrate that MhYTP2 enhances the resistance of apple to N deficiency by affecting the stability of the bound mRNAs.