Synthesis of 2,3-Dialkyl-5-hydroxybenzofurans via a One-pot, Three-step Reaction Sequence of 2-Monosubstituted 1,3-Diketones and 1,4-Benzoquinones.

An economical one-pot, three-step reaction sequence of readily available 2-monosubstituted 1,3-diketones and 1,4-benzoquinones has been explored for the facile access of 2,3-dialkyl-5-hydroxybenzofurans. By using cheap K2CO3 and conc. HCl as the reaction promoters, the reaction occurs smoothly via sequential Michael addition, aromatization, retro-Claisen, deacylation, hemiketalization, and dehydration processes under mild conditions in a practical manner. Additionally, an interesting phenomenon was observed during the derivatization studies, where the dihydroquinoline was converted into tetrahydroquinoline and quinoline products, respectively, via a disproportionation process.

HLA-G in asthma and its potential as an effective therapeutic agent.

OBJECTIVE: Asthma is a heterogeneous disease. Severity of asthma and sensitivity to medications vary across asthma subtypes. Human leukocyte antigen (HLA)-G has a wide range of functions in normal and pathological physiology. Due to its powerful immune function, HLA-G participates in the pathogenesis of different asthma phenotypes by regulating the activity and function of various immune cells. The mechanism of HLA-G in asthma is not fully clear, and there is no consensus on its mechanism in asthma. Further studies are needed to explore the role of HLA-G in different phenotypes of human asthma. METHODS: Observational study. RESULTS: HLA-G is an important immunomodulatory factor in asthma. Studies have found different levels of HLA-G in patients with different asthma subtypes and healthy controls, but other studies have come to the opposite conclusion. CONCLUSION: We speculate that further study on the mechanism of HLA-G in asthma pheno-types may explain some of the contradictions in current studies. Findings should provide information regarding the potential of HLA-G as a novel target for asthma diagnosis and treatment.

JUN activation modulates chromatin accessibility to drive TNFα-induced mesenchymal transition in glioblastoma.

Chromatin dynamics as well as genetic evolution underlies the adaptability of tumour cells to environmental cues. Three subtypes of tumour cells have been identified in glioblastoma, one of the commonest malignant brain tumours in adults. During tumour progression or under therapeutic pressure, the non-mesenchymal subtypes may progress to the mesenchymal subtype, leading to unfavourable prognosis. However, the molecular mechanisms for this transition remain poorly understood. Here taking a TNFα-induced cellular model, we profile the chromatin accessibility dynamics during mesenchymal transition. Moreover, we identify the JUN family as one of the key driving transcription factors for the gained chromatin accessibility. Accordingly, inhibition of JUN phosphorylation and therefore its transcription activity successfully impedes TNFα-induced chromatin remodelling and mesenchymal transition. In line with these findings based on experimental models, JUN activity is positively correlated with mesenchymal features in clinical glioblastoma specimens. Together, this study unveils a deregulated transcription regulatory network in glioblastoma progression and hopefully provides a rationale for anti-glioblastoma therapy.

Roles of sirtuin family members in chronic obstructive pulmonary disease.

The globally increasing annual incidence of chronic obstructive pulmonary disease (COPD), a common chronic disease, poses a serious risk to public health. Although the exact mechanism underlying the pathogenesis of COPD remains unclear, a large number of studies have shown that its pathophysiology and disease course are closely related to oxidative stress, inflammation, apoptosis, autophagy, and aging. The key players involved in COPD include the sirtuin family of NAD-dependent deacetylases that comprise seven members (SIRT1-7) in mammals. Sirtuins play an important role in metabolic diseases, cell cycle control, proliferation, apoptosis, and senescence. Owing to differences in subcellular localization, sirtuins exhibit anisotropy. In this narrative review, we discuss the roles and molecular pathways of each member of the sirtuin family involved in COPD to provide novel insights into the prevention and treatment of COPD and how sirtuins may serve as adjuvants for COPD treatment.

Abnormal expression of TGFBR2, EGF, LRP10, and IQGAP1 is involved in the pathogenesis of coronary artery disease.

Coronary artery disease (CAD) is the most common cardiovascular disease worldwide. In this study, we investigated the pathogenesis of CAD. We downloaded the GSE98583 dataset, including 12 CAD samples and 6 normal samples, from the Gene Expression Omnibus (GEO) database and screened differentially expressed genes (DEGs) in CAD versus normal samples. Next, we performed functional enrichment analysis, protein-protein interaction (PPI) network, and functional module analyses to explore potential functions and regulatory functions of identified DEGs. Next, transcription factors (TFs) and microRNAs (miRNAs) targeting DEGs were predicted. In total, 456 DEGs were identified in CAD and normal samples, including 175 upregulated and 281 downregulated genes. These genes were enriched in the intestinal immune network for immunoglobulin A production and the mitogen-activated protein kinase signaling pathway (e.g., TGFBR2 and EGF). The PPI network contained 212 genes, and HIST1H2BJ, HIST1H2AC, EGF, and EP300 were hub genes with degrees higher than 10. Four significant modules were identified from the PPI network, with genes in the modules mainly enriched in the inflammatory response, protein ubiquitination involved in ubiquitin-dependent protein catabolic processes, protein transport, and mitochondrial translational elongation, respectively. Two TFs (E2F1 and FOXK1) and five miRNAs (miR-122A, miR-516-5P, miR-507, miR-342, and miR-520F) were predicted to target 112 DEGs. miR-122A reportedly targets both LRP10 and IQGAP1 in the TF-miRNA target regulatory network. The abnormal expression of TGFBR2, EGF, LRP10, and IQGAP1 may be implicated in CAD pathogenesis. Our study provides targets and potential regulators for investigating CAD pathogenesis.

Rapid monitoring of reclaimed farmland effects in coal mining subsidence area using a multi-spectral UAV platform.

In eastern China, coal mining has damaged a large amount of farmland, posing a great threat to food security. Backfilling with coal waste, fly ash, and sediments from rivers is an effective method to restore farmland. This study was conducted at the reclaimed area (RA) and the undisturbed area (UA) in Shandong Province, China. Soil and plant analyzer development (SPAD) of corn was selected as an indicator of crop growth. Multi-spectral data was obtained by the unmanned aerial vehicle equipped with a camera. By analyzing the correlation between SPAD and spectral bands, the common vegetation index is improved. Different regression methods were used to construct the SPAD inversion model. The distribution of corn SPAD was monitored to objectively evaluate reclamation technology. The results are as follows: (1) the vegetation index improved using the red-edge band has a higher correlation with SPAD, and the largest coefficient of determination (R2) value is 0.779; (2) the optimum inversion model for both jointing stage (R2 = 0.676) and milky stage (R2 = 0.661) is the linear regression model; the optimum model for both tasseling stage (R2 = 0.809) and filling stage (R2 = 0.830) is the partial least squares regression model; (3) the SPAD inversion map of RA and UA obtained by the optimum model shows that the corn grown in RA is slightly better than in UA. This study realized the rapid and efficient monitoring of the reclamation effects based on multi-spectral imagery and verified the feasibility of backfilling reclamation with Yellow River sediment in coal mining subsidence areas.

Physiological functions of urea transporter B.

Urea transporters (UTs) are membrane proteins in the urea transporter protein A (UT-A) and urea transporter protein B (UT-B) families. UT-B is mainly expressed in endothelial cell membrane of the renal medulla and in other tissues, including the brain, heart, pancreas, colon, bladder, bone marrow, and cochlea. UT-B is responsible for the maintenance of urea concentration, male reproductive function, blood pressure, bone metabolism, and brain astrocyte and cardiac functions. Its deficiency and dysfunction contribute to the pathogenesis of many diseases. Actually, UT-B deficiency increases the sensitivity of bladder epithelial cells to apoptosis triggers in mice and UT-B-null mice develop II-III atrioventricular block and depression. The expression of UT-B in the rumen of cow and sheep may participate in digestive function. However, there is no systemic review to discuss the UT-B functions. Here, we update research approaches to understanding the functions of UT-B.

TRAIL signals through the ubiquitin ligase MID1 to promote pulmonary fibrosis.

BACKGROUND: Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) has previously been demonstrated to play a pro-inflammatory role in allergic airways disease and COPD through the upregulation of the E3 ubiquitin ligase MID1 and the subsequent deactivation of protein phosphatase 2A (PP2A). METHODS: Biopsies were taken from eight IPF patients presenting to the Second Affiliated Hospital of Jilin University, China between January 2013 and February 2014 with control samples obtained from resected lung cancers. Serum TRAIL, MID1 protein and PP2A activity in biopsies, and patients' lung function were measured. Wild type and TRAIL deficient Tnfsf10-/- BALB/c mice were administered bleomycin to induce fibrosis and some groups were treated with the FTY720 analogue AAL(s) to activate PP2A. Mouse fibroblasts were treated with recombinant TRAIL and fibrotic responses were assessed. RESULTS: TRAIL in serum and MID1 protein levels in biopsies from IPF patients were increased compared to controls. MID1 levels were inversely associated while PP2A activity levels correlated with DLco. Tnfsf10-/- and mice treated with the PP2A activator AAL(s) were largely protected against bleomycin-induced reductions in lung function and fibrotic changes. Addition of recombinant TRAIL to mouse fibroblasts in-vitro increased collagen production which was reversed by PP2A activation with AAL(s). CONCLUSION: TRAIL signalling through MID1 deactivates PP2A and promotes fibrosis with corresponding lung function decline. This may provide novel therapeutic targets for IPF.

The relationship between microRNAs and the STAT3-related signaling pathway in cancer.

MicroRNAs are non-coding RNAs that regulate gene expression by targeting messenger RNA molecules in 3' untranslated region. Mounting evidence indicates that microRNAs regulate several factors to influence various biological activities that are related to carcinogenesis, including signal transducer and activator of transcription 3, which is a transcription factor that also acts as an oncogene. MicroRNAs influence signal transducer and activator of transcription 3 either by directly targeting or via other pathway components upstream or downstream of signal transducer and activator of transcription 3 such as Janus kinases, members of the suppressor of cytokine signaling family, and other genes that regulate cell proliferation, apoptosis, migration, invasion, and epithelial-mesenchymal transition. However, signal transducer and activator of transcription 3 activation changes the pattern of expression of microRNAs and mediates tumorigenesis. Moreover, the relationship between signal transducer and activator of transcription 3 and microRNAs varies among different kinds of cancers. A specific microRNA may act as an oncogene or tumor suppressor in different cancers, and microRNAs also directly or indirectly regulate signal transducer and activator of transcription 3 via pathways in the same cancers. In this review, we focus on the reciprocal regulation and roles of microRNAs and signal transducer and activator of transcription 3 in cancer, as well as describe current research progress on this relationship. A better understanding of this relationship may facilitate in the identification of targets for clinical therapeutics.

Interluekin-35 in Asthma and Its Potential as an Effective Therapeutic Agent.

Interleukin- (IL-) 35 is a member of the IL-12 cytokine family and a heterodimeric protein formed by Epstein-Barr-induced gene 3 (EBI3) and IL-12p35. Emerging evidence shows that IL-35 is a key player in the regulation of cellular communication, differentiation, and inflammation. Altered IL-35 expression has been found in disease conditions such as cancer, rheumatoid arthritis, and, more recently, asthma. In cancer, IL-35 is involved in the regulation of tumorigenesis, cancer progression, and metastasis. In rheumatoid arthritis, IL-35 acts as a negative regulator of inflammation. Similarly, IL-35 also appears to suppress allergic inflammation in asthma. In an in vivo murine model of asthma, transfer of adenovirus-mediated IL-35 markedly reduced the degree of airway hyperresponsiveness (AHR) and inflammatory cell infiltration. Many studies have shown the involvement of IL-35 in a number of aspects of allergic inflammation, such as eosinophil and neutrophil recruitment as well as inhibition of inflammatory mediators of the Th2 subtype. However, the exact molecular mechanisms underlying the role of IL-35 in human asthma have yet to be fully elucidated. This review describes the current evidence regarding the role of IL-35 in the pathophysiology of asthma and evaluates the potential of IL-35 as a biomarker for airway inflammation and a therapeutic target for the treatment of asthma.

Overexpression of RBM5 induces autophagy in human lung adenocarcinoma cells.

BACKGROUND: Dysfunctions in autophagy and apoptosis are closely interacted and play an important role in cancer development. RNA binding motif 5 (RBM5) is a tumor suppressor gene, which inhibits tumor cells' growth and enhances chemosensitivity through inducing apoptosis in our previous studies. In this study, we investigated the relationship between RBM5 overexpression and autophagy in human lung adenocarcinoma cells. METHODS: Human lung adenocarcinoma cancer (A549) cells were cultured in vitro and were transiently transfected with a RBM5 expressing plasmid (GV287-RBM5) or plasmid with scrambled control sequence. RBM5 expression was determined by semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) and Western blot. Intracellular LC-3 I/II, Beclin-1, lysosome associated membrane protein-1 (LAMP1), Bcl-2, and NF-κB/p65 protein levels were detected by Western blot. Chemical staining with monodansylcadaverine (MDC) and acridine orange (AO) was applied to detect acidic vesicular organelles (AVOs). The ultrastructure changes were observed under transmission electron microscope (TEM). Then, transplanted tumor models of A549 cells on BALB/c nude mice were established and treated with the recombinant plasmids carried by attenuated Salmonella to induce RBM5 overexpression in tumor tissues. RBM5, LC-3, LAMP1, and Beclin1 expression was determined by immunohistochemistry staining in plasmids-treated A549 xenografts. RESULTS: Our study demonstrated that overexpression of RBM5 caused an increase in the autophagy-related proteins including LC3-I, LC3-II, LC3-II/LC3-I ratio, Beclin1, and LAMP1 in A549 cells. A large number of autophagosomes with double-membrane structure and AVOs were detected in the cytoplasm of A549 cells transfected with GV287-RBM5 at 24 h. We observed that the protein level of NF-κB/P65 was increased and the protein level of Bcl-2 decreased by RBM5 overexpression. Furthermore, treatment with an autophagy inhibitor, 3-MA, enhanced RBM5-induced cell death and chemosensitivity in A549 cells. Furthermore, we successfully established the lung adenocarcinoma animal model using A549 cells. Overexpression of RBM5 enhanced the LC-3, LAMP1, and Beclin1 expression in the A549 xenografts. CONCLUSIONS: Our findings showed for the first time that RBM5 overexpression induced autophagy in human lung adenocarcinoma cells, which might be driven by upregulation of Beclin1, NF-κB/P65, and downregulation of Bcl-2. RBM5-enhanced autophagy acts in a cytoprotective way and inhibition of autophagy may improve the anti-tumor efficacy of RBM5 in lung cancer.

Impairment of rumen biohydrogenation and bacteria of the Butyrivibrio group in the rumen of goats through a 20:5 n-3 (EPA) rich supplement.

BACKGROUND: Marine products can inhibit biohydrogenation in the rumen, but the mechanism is not clear. This study investigated a 20:5 n-3 rich supplement effects on rumen biohydrogenation, microbial change and fermentation characteristics in goats. RESULTS: The supplementation decreased 18:0 proportions in rumen fatty acids (P < 0.001), while it increased cis-9, trans-11 conjugated linoleic acid (CLA) (P < 0.001) and trans-10, cis-12 CLA proportions (P < 0.001). The supplement reduced the number of Butyrivibrio spp. and B. proteoclasticus (P < 0.01). Denaturing gradient gel electrophoresis redundancy analysis indicated that some species, mainly from the rumen of goats receiving the 2.5 and 5.0 g d(-1) supplement, were positively correlated with cis-9, trans-11 CLA proportions; some species, mainly from the rumen of control goats, were positively correlated with 18:0 proportions. The supplement reduced the NH3 -N concentrations and acetate molar proportions in the rumen (P < 0.05), but increased propionate and butyrate molar proportions (P < 0.01), and had no effect on total volatile fatty acid concentration. CONCLUSION: The supplement rich in 20:5 n-3 reduced the biohydrogenation of 18-carbon unsaturated fatty acids with a significant reduction of the 18:0 proportion and this was coupled with the suppression of the abundance of biohydrogenating bacteria and unknown bacteria.

Synthesis and biological evaluation of 3-phenyl-3-aryl carboxamido propanoic acid derivatives as small molecule inhibitors of retinoic acid 4-hydroxylase (CYP26A1).

All-trans-retinoic acid (ATRA), the biologically active metabolite of vitamin A, is used medicinally for the treatment of hyperproliferative diseases and cancers. However, it is easily metabolized. In this study, the leading compound S8 was found based on virtual screening. To improve the activity of the leading compound S8, a series of novel S8 derivatives were designed, synthesized and evaluated for their in vitro biological activities. All of the prepared compounds showed that substituting the 5-chloro-3-methyl-1-phenyl-1H-pyrazole group for the 2-tertbutyl-5-methylfuran scaffold led to a clear increase in the biological activity. The most promising compound 32, with a CYP26A1 IC50 value of 1.36µM (compared to liarozole (IC50=2.45µM) and S8 (IC50=3.21µM)) displayed strong inhibitory and differentiation activity against HL60 cells. In addition, the study focused on the effect of ß-phenylalanine, which forms the coordination bond with the heme of CYP26A1. These studies suggest that the compound 32 can be used as an appropriate candidate for future development.

Decoding heterogeneous and coordinated tissue architecture in glioblastoma using spatial transcriptomics.

Glioblastoma multiforme (GBM) is one of the most lethal brain tumors, characterized by profound heterogeneity. While single-cell transcriptomic studies have revealed extensive intra-tumor heterogeneity, shed light on intra-tumor diversity, spatial intricacies remain largely unexplored. Leveraging clinical GBM specimens, this study employs spatial transcriptomics technology to delve into gene expression heterogeneity. Our investigation unveils a significant enrichment of tissue stem cell signature in regions bordering necrosis and the peritumoral area, positively correlated with the mesenchymal subtype signature. Moreover, upregulated genes in these regions are linked with extracellular matrix (ECM)-receptor interaction, proteoglycans, as well as vascular endothelial growth factor (VEGF) and angiopoietin-Tie (ANGPT) signaling pathways. In contrast, signatures related to glycogen metabolism and oxidative phosphorylation show no relevance to pathological zoning, whereas creatine metabolism signature is notably exclusive to vascular-enriched areas. These spatial profiles not only offer valuable references but also pave the way for future in-depth functional and mechanistic investigations into GBM progression.

Asymmetric Retro-Claisen Reaction Catalyzed by Chiral Aza-Bisoxazoline-Zn(II) Complex: Enantioselective Synthesis of α-Arylated Ketones.

An asymmetric retro-Claisen reaction of α-monosubstituted ß-diketones and quinones (or quinone imine) has been developed under the catalysis of a chiral aza-bisoxazoline-Zn(II) complex. The reaction proceeds via a sequence of conjugate addition, arylation, hemiketal anion-initiated C-C bond cleavage, and enantioselective protonation of enolate to provide various functionalized α-arylated ketones bearing a tertiary stereogenic center with high enantioselectivities. Notably, biologically important benzofuran and γ-butyrolactone derivatives could be synthesized by application of the developed protocol.

Potential role of irisin in lung diseases and advances in research.

Irisin, a myokine, is secreted by the movement of skeletal muscles. It plays an important role in metabolic homeostasis, insulin resistance, anti-inflammation, oxidative stress, and bone metabolism. Several studies have reported that irisin-related signaling pathways play a critical role in the treatment of various diseases, including obesity, cardiovascular disease, diabetes, and neurodegenerative disorders. Recently, the potential role of irisin in lung diseases, including chronic obstructive pulmonary disease, acute lung injury, lung cancer, and their associated complications, has received increasing attention. This article aims to explore the role of irisin in lung diseases, primarily focusing on the underlying molecular mechanisms, which may serve as a marker for the diagnosis as well as a potential target for the treatment of lung diseases, thus providing new strategies for their treatment.

Triethylamine-Promoted Henry Reaction/Elimination of HNO2/Cyclization Sequence of Functionalized Nitroalkanes and 2-Oxoaldehydes: Diversity-Oriented Synthesis of Oxacycles.

The triethylamine-promoted cascade Henry reaction/elimination of HNO2/cyclization reaction of 2-oxoaldehydes with nitroalkanes bearing various remote functionalities is described. Both chiral and achiral nitroalkanes were applicable to this protocol, leading to a variety of oxacycles, such as chromenes, chromanes, cyclic hemiacetals, and polycyclic acetals. An unexpected regioselective photooxygenation occurred without sensitizer during derivatization to convert a derived diene product into a dioxetane by reaction with singlet oxygen, which provided chromen-2-one and benzaldehyde after fragmentation.

Asymmetric iminium ion-catalyzed conjugate addition of 2-hydroxycinnamaldehydes and 2-oxocarboxylic esters: synthesis of chiral polysubstituted bridged bicyclic ketals.

A highly regio-, chemo-, and stereoselective cascade process initiated by enantioselective iminium-catalyzed conjugate addition of 2-hydroxycinnamaldehydes and 2-oxocarboxylic esters is presented. Normal cinnamaldehydes are not reactive under the same reaction conditions. Bridged bicyclic ketals rather than acetals bearing stereocenters on both the bridge carbon and bridgehead ketal carbon are synthesized.

Brønsted-Acid-Catalyzed In Situ Formation of Acyclic Tertiary Enamides and Its Application to the Preparation of Diverse Nitrogen-Containing Heterocyclic Compounds.

A Brønsted acid-catalyzed cascade process, involving in situ formation of acyclic tertiary enamides and intramolecular Michael reaction, is developed for the synthesis of functionalized cyclic tertiary enamides. Based on the dual reactivities of the enamide moiety, several reaction sequences were realized by using rationally designed substrates, leading to biologically relevant nitrogen-containing heterocyclic compounds with diverse structural skeletons in a concise and diastereocontrolled manner.

Enantioselective Michael Addition/Cyclization/Desymmetrization Sequence of Prochiral Cyclic Hemiacetals and Nitroolefins: Synthesis of Chiral Oxygen-Bridged Bicyclic Compounds.

The organocatalytic enantioselective Michael addition of functionalized prochiral cyclic hemiacetals and nitroolefins has been developed under cooperative enamine and hydrogen bond catalysis. The obtained chiral hemiacetal intermediates could be used in the subsequent diastereocontrolled cyclization/desymmetrization divergent process to access (1) 9-oxabicyclo[3.3.1]nonane or 8-oxabicyclo[3.2.1]octane frameworks via oxocarbenium ion-mediated Friedel-Crafts cyclization, and (2) 2,9-dioxabicyclo[3.3.1]nonane frameworks via intramolecular nucleophilic cyclization. Experimental results suggest that there is neighboring group participation controlling the diastereoselectivities of the desymmetrization process.