Inhibition of Fap Promotes Cardiac Repair by Stabilizing BNP.

BACKGROUND: Myocardial infarction (MI) elicits cardiac fibroblast activation and extracellular matrix (ECM) deposition to maintain the structural integrity of the heart. Recent studies demonstrate that Fap (fibroblast activation protein)-a prolyl-specific serine protease-is an important marker of activated cardiac fibroblasts after MI. METHODS: Left ventricle and plasma samples from patients and healthy donors were used to analyze the expression level of FAP and its prognostic value. Echocardiography and histological analysis of heart sections were used to analyze cardiac functions, scar formation, ECM deposition and angiogenesis after MI. RNA-Sequencing, biochemical analysis, cardiac fibroblasts (CFs) and endothelial cells co-culture were used to reveal the molecular and cellular mechanisms by which Fap regulates angiogenesis. RESULTS: We found that Fap is upregulated in patient cardiac fibroblasts after cardiac injuries, while plasma Fap is downregulated and functions as a prognostic marker for cardiac repair. Genetic or pharmacological inhibition of Fap in mice significantly improved cardiac function after MI. Histological and transcriptomic analyses showed that Fap inhibition leads to increased angiogenesis in the peri-infarct zone, which promotes ECM deposition and alignment by cardiac fibroblasts and prevents their overactivation, thereby limiting scar expansion. Mechanistically, we found that BNP (brain natriuretic peptide) is a novel substrate of Fap that mediates postischemic angiogenesis. Fap degrades BNP to inhibit vascular endothelial cell migration and tube formation. Pharmacological inhibition of Fap in Nppb (encoding pre-proBNP) or Npr1 (encoding the BNP receptor)-deficient mice showed no cardioprotective effects, suggesting that BNP is a physiological substrate of Fap. CONCLUSIONS: This study identifies Fap as a negative regulator of cardiac repair and a potential drug target to treat MI. Inhibition of Fap stabilizes BNP to promote angiogenesis and cardiac repair.

Transdermal Microneedles Alleviated Rheumatoid Arthritis by Inducing Immune Tolerance via Skin-Resident Antigen Presenting Cells.

Restoring immune tolerance is the ultimate goal for rheumatoid arthritis (RA) treatment. The most reported oral or intravenous injection routes for the immunization of autoantigens cause gastrointestinal side effects, low patient compliance, and unsatisfied immune tolerance induction. Herein, the use of a transdermal microneedle patch is for the first time investigated to codeliver CII peptide autoantigen and rapamycin for reversing immune disorders of RA. The immunized microneedles efficiently recruit antigen-presenting cells particularly Langerhans cells, and induce tolerogenic dendritic cells at the administration skin site. The tolerogenic dendritic cells further homing to lymph nodes to activate systemic Treg cell differentiation, which upregulates the expression of anti-inflammatory mediators while inhibiting the polarization of Th1/2 and Th17 T cell phenotypes and the expression of inflammatory profiles. As a result, the optimized microneedles nearly completely eliminate RA symptoms and inflammatory infiltrations. Furthermore, it is demonstrated that a low dose of rapamycin is crucial for the successful induction of immune tolerance. The results indicate that a rationally designed microneedle patch is a promising strategy for immune balance restoration with increased immune tolerance induction efficiency and patient compliance.

RUNX1, FUS, and ELAVL1-induced circPTPN22 promote gastric cancer cell proliferation, migration, and invasion through miR-6788-5p/PAK1 axis-mediated autophagy.

BACKGROUND: An increasing number of studies have demonstrated the association of circular RNAs (circRNAs) with the pathological processes of various diseases and their involvement in the onset and progression of multiple cancers. Nevertheless, the functional roles and underlying mechanisms of circRNAs in the autophagy regulation of gastric cancer (GC) have not been fully elucidated. METHODS: We used transmission electron microscopy and the mRFP-GFP-LC3 dual fluorescent autophagy indicator to investigate autophagy regulation. The cell counting kit-8 assay, colony formation assay, 5-ethynyl-2'-deoxyuridine incorporation assay, Transwell assay, and Western blot assay were conducted to confirm circPTPN22's influence on GC progression. Dual luciferase reporter assays validated the binding between circPTPN22 and miR-6788-5p, as well as miR-6788-5p and p21-activated kinase-1 (PAK1). Functional rescue experiments assessed whether circPTPN22 modulates PAK1 expression by competitively binding miR-6788-5p, affecting autophagy and other biological processes in GC cells. We investigated the impact of circPTPN22 on in vivo GC tumors using a nude mouse xenograft model. Bioinformatics tools predicted upstream regulatory transcription factors and binding proteins of circPTPN22, while chromatin immunoprecipitation and ribonucleoprotein immunoprecipitation assays confirmed the binding status. RESULTS: Upregulation of circPTPN22 in GC has been shown to inhibit autophagy and promote cell proliferation, migration, and invasion. Mechanistically, circPTPN22 directly binds to miR-6788-5p, subsequently regulating the expression of PAK1, which activates protein kinase B (Akt) and extracellular signal-regulated kinase (Erk) phosphorylation. This modulation ultimately affects autophagy levels in GC cells. Additionally, runt-related transcription factor 1 (RUNX1) negatively regulates circPTPN22 expression, while RNA-binding proteins such as FUS (fused in sarcoma) and ELAVL1 (recombinant ELAV-like protein 1) positively regulate its expression. Inhibition of the autophagy pathway can increase FUS expression, further upregulating circPTPN22 in GC cells, thereby exacerbating the progression of GC. CONCLUSION: Under the regulation of the transcription factor RUNX1 and RNA-binding proteins FUS and ELAVL1, circPTPN22 activates the phosphorylation of Akt and Erk through the miR-6788-5p/PAK1 axis, thereby modulating autophagy in GC cells. Inhibition of autophagy increases FUS, which in turn upregulates circPTPN22, forming a positive feedback loop that ultimately accelerates the progression of GC.

Clinical application and detection techniques of liquid biopsy in gastric cancer.

Gastric cancer (GC) is one of the most common tumors worldwide and the leading cause of tumor-related mortality. Endoscopy and serological tumor marker testing are currently the main methods of GC screening, and treatment relies on surgical resection or chemotherapy. However, traditional examination and treatment methods are more harmful to patients and less sensitive and accurate. A minimally invasive method to respond to GC early screening, prognosis monitoring, treatment efficacy, and drug resistance situations is urgently needed. As a result, liquid biopsy techniques have received much attention in the clinical application of GC. The non-invasive liquid biopsy technique requires fewer samples, is reproducible, and can guide individualized patient treatment by monitoring patients' molecular-level changes in real-time. In this review, we introduced the clinical applications of circulating tumor cells, circulating free DNA, circulating tumor DNA, non-coding RNAs, exosomes, and proteins, which are the primary markers in liquid biopsy technology in GC. We also discuss the current limitations and future trends of liquid biopsy technology as applied to early clinical biopsy technology.

Plasma GAS6 predicts mortality risk in acute heart failure patients: insights from the DRAGON-HF trial.

BACKGROUND: Growth arrest-specific 6 (GAS6) is a vitamin K-dependent protein related to inflammation, fibrosis, as well as platelet function. Genetic ablation of GAS6 in mice protects against cardiac hypertrophy and dysfunction. Nonetheless, the association between plasma GAS6 levels and acute heart failure (AHF) patients is still unknown. METHODS: We measured plasma GAS6 concentrations in 1039 patients with AHF who were enrolled in the DRAGON-HF trial (NCT03727828). Mean follow-up of the study was 889 days. The primary endpoint is all-cause death. RESULTS: In total, there were 195 primary endpoints of all-cause death and 135 secondary endpoints of cardiovascular death during the mean follow-up duration of 889 days. The higher levels of GAS6 were associated with higher rates of all-cause and cardiovascular death (P < 0.05). Baseline plasma GAS6 levels were still strongly correlated with clinical outcomes in different models after adjustment for clinical factors and N-terminal pro-brain natriuretic peptide (NT-proBNP, P < 0.05). GAS6 could further distinguish the risks of clinical outcomes based on NT-proBNP measurement. CONCLUSION: Elevated plasma GAS6 levels were associated with an increased risk of all-cause and cardiovascular death in patients with AHF. Trial registration NCT03727828 (DRAGON-HF trial) clinicaltrials.gov.

280 mT static magnetic field promotes the growth of postpartum condylar cartilage.

PURPOSE: Functional appliances made of permanent magnets have been used in jaw orthopedic treatment. However, whether the static magnetic field (SMF) generated by permanent magnets promotes the developmental sequence of condylar cartilage and thus promotes the growth of the mandible remains to be studied. The aim of this study was to investigate the effects of 280 mT SMF on postnatal condylar chondrogenesis and endochondral ossification and the roles of FLRT3, FGF2 and BMP2 signaling in this chondrodevelopmental sequences. METHODS: Forty-eight rats were assigned to two groups (control and SMF). The condyles were collected at the specified time points. The histomorphological changes in the condyle were observed by histological staining. The expression of proteins related to the proliferation and differentiation of the condylar cartilage and the changes in subchondral bone microstructure were analyzed by immunohistochemical staining and micro-CT scanning. FLRT3, FGF2, and BMP2 expression was detected by immunofluorescence staining. RESULTS: Under SMF stimulation, the cartilage of young rats grew longitudinally and laterally, and the thickness of the cartilage became thinner as it grew. The SMF promoted the proliferation and differentiation of condylar chondrocytes and endochondral ossification and increased subchondral bone mineral density, and BMP2 signaling was involved. Moreover, under SMF loading, the increased expression of FGF2 and FLRT3 were involved in regulating cartilage morphogenesis and growth. In late development, the decreased expression of FGF2/FLRT3 and the increased expression of BMP2 promoted endochondral ossification. The SMF accelerated this opposite expression trend. CONCLUSION: FGF2/FLRT3 and BMP2 signals are involved in the regulatory effect of SMF exposure on chondrogenesis and endochondral ossification, which provides a theoretical basis for the clinical use of magnetic appliances to promote condylar growth.

m6A-modified circRNAs: detections, mechanisms, and prospects in cancers.

Circular RNAs (circRNAs) have become a research hotspot in recent years with their universality, diversity, stability, conservativeness, and spatiotemporal specificity. N6-methyladenosine (m6A), the most abundant modification in the eukaryotic cells, is engaged in the pathophysiological processes of various diseases. An increasing amount of evidence has suggested that m6A modification is common in circRNAs and is associated with their biological functions. This review summarizes the effects of m6A modification on circRNAs and their regulation mechanisms in cancers, providing some suggestions of m6A-modified circRNAs in cancer therapy.

B(C6F5)3-Catalyzed α,ß-Difunctionalization and C-N Bond Cleavage of Saturated Amines with Benzo[c]isoxazoles: Access to Quinoline Derivatives.

Herein, we disclose a strategy to realize α,ß-difunctionalization and C-N bond cleavage of saturated amines with benzo[c]isoxazoles via a B(C6F5)3-catalyzed consecutive hydrogen-borrowing and [4 + 2] cycloaddition followed by a C-N bond cleavage process. In general, the reactions proceed efficiently in the absence of any oxidant and metal catalyst to afford a broad range of quinoline derivatives starting from easily accessible substrates in an atom-economical manner.

Childhood adversity patterns differentially cluster with mental disorders and socioeconomic indicators in a large Swiss community sample.

BACKGROUND: Exposure to childhood adversities (CHAD) has been found to be strongly associated with individuals' mental health and social development. Recently, it has been suggested that certain CHAD patterns exist in the population, which are more closely related to individuals' later mental health than the simple summation of adversities. The current study aims 1) to establish CHAD patterns based on self-reported child abuse and family dysfunction and 2) to assess their associations with mental disorders and sociodemographic indicators reported in adulthood. METHODS: Data used in this cross-sectional study were derived from the representative CoLaus/PsyCoLaus population-based cohort (N = 5111, 35 to 88 years). Latent class analysis was conducted for the identification of CHAD patterns, while their associations with mental disorders and socioeconomic achievements (e. g. education and income) were investigated using correspondence analysis. RESULTS: Four CHAD patterns emerged. While the majority (70.7%) of the sample showed an overall low adversity pattern (c1), 13.6% had not been raised by both of their biological parents due to divorce or being placed in foster home (c2), 11.0% had been raised by conflictive / dysfunctional / abusive parents (c3), and 4.7% showed high overall adversities (c4). Patterns c3 and c4 were most strongly associated with various mental disorders, especially c3 with internalizing anxiety disorders, while c2 was closely related to lower educational achievement. CONCLUSIONS: Four CHAD patterns characterised by varying levels of child abuse and family dysfunction existed in this community sample. They yielded distinct associations with mental disorders and socioeconomic indicators.

Highly enhanced heterogeneous photo-Fenton process for tetracycline degradation by Fe/SCN Fenton-like catalyst.

To suppress the electron-hole recombination and enhance the electron transfer on carbon nitride, an Fe-doped porous carbon nitride catalyst (Fe/SCN) was synthesized via supramolecular self-assembly method and applied in heterogeneous Fenton activation for efficient tetracycline (TC) degradation. Various characterizations revealed that the catalyst exhibited excellent visible light capture performance and electron transfer capacity. The highest degradation efficiency and mineralization rate of TC (10 mg L-1) were achieved under neutral condition (90.3% and 61.2%, respectively) with the leaching of Fe less than 14 µg L-1. Free radical quenching experiments and spin-resonance spectroscopy characterizations revealed the dominating role of OH in TC degradation, and density functional theory calculation confirmed the formation of Fe-NX and revealed the interaction between Fe sites and H2O2. Three possible pathways of TC degradation were proposed, and the biological inhibition test revealed the potential of Fe/SCN/H2O2 system to reduce environmental risks caused by TC. This work provides a new insight into the design of metal-doped heterogeneous Fenton catalyst for the efficient degradation of antibiotic contaminants in water.

Comparison of seven in silico tools for evaluating of daphnia and fish acute toxicity: case study on Chinese Priority Controlled Chemicals and new chemicals.

BACKGROUND: A number of predictive models for aquatic toxicity are available, however, the accuracy and extent of easy to use of these in silico tools in risk assessment still need further studied. This study evaluated the performance of seven in silico tools to daphnia and fish: ECOSAR, T.E.S.T., Danish QSAR Database, VEGA, KATE, Read Across and Trent Analysis. 37 Priority Controlled Chemicals in China (PCCs) and 92 New Chemicals (NCs) were used as validation dataset. RESULTS: In the quantitative evaluation to PCCs with the criteria of 10-fold difference between experimental value and estimated value, the accuracies of VEGA is the highest among all of the models, both in prediction of daphnia and fish acute toxicity, with accuracies of 100% and 90% after considering AD, respectively. The performance of KATE, ECOSAR and T.E.S.T. is similar, with accuracies are slightly lower than VEGA. The accuracy of Danish Q.D. is the lowest among the above tools with which QSAR is the main mechanism. The performance of Read Across and Trent Analysis is lowest among all of the tested in silico tools. The predictive ability of models to NCs was lower than that of PCCs possibly because never appeared in training set of the models, and ECOSAR perform best than other in silico tools. CONCLUSION: QSAR based in silico tools had the greater prediction accuracy than category approach (Read Across and Trent Analysis) in predicting the acute toxicity of daphnia and fish. Category approach (Read Across and Trent Analysis) requires expert knowledge to be utilized effectively. ECOSAR performs well in both PCCs and NCs, and the application shoud be promoted in both risk assessment and priority activities. We suggest that distribution of multiple data and water solubility should be considered when developing in silico models. Both more intelligent in silico tools and testing are necessary to identify hazards of Chemicals.

CircRNAs and their regulatory roles in cancers.

Circular RNAs (circRNAs), a novel type of non-coding RNAs (ncRNAs), have a covalently closed circular structure resulting from pre-mRNA back splicing via spliceosome and ribozymes. They can be classified differently in accordance with different criteria. As circRNAs are abundant, conserved, and stable, they can be used as diagnostic markers in various diseases and targets to develop new therapies. There are various functions of circRNAs, including sponge for miR/proteins, role of scaffolds, templates for translation, and regulators of mRNA translation and stability. Without m7G cap and poly-A tail, circRNAs can still be degraded in several ways, including RNase L, Ago-dependent, and Ago-independent degradation. Increasing evidence indicates that circRNAs can be modified by N-6 methylation (m6A) in many aspects such as biogenesis, nuclear export, translation, and degradation. In addition, they have been proved to play a regulatory role in the progression of various cancers. Recently, methods of detecting circRNAs with high sensitivity and specificity have also been reported. This review presents a detailed overview of circRNAs regarding biogenesis, biomarker, functions, degradation, and dynamic modification as well as their regulatory roles in various cancers. It's particularly summarized in detail in the biogenesis of circRNAs, regulation of circRNAs by m6A modification and mechanisms by which circRNAs affect tumor progression respectively. Moreover, existing circRNA detection methods and their characteristics are also mentioned.

As a biomarker for gastric cancer, circPTPN22 regulates the progression of gastric cancer through the EMT pathway.

BACKGROUND: Gastric cancer (GC) is one of the most common cancers in the world. Due to the lack of specific symptoms, more than 80% of patients are diagnosed as the advanced stage with a high mortality rate, so the early diagnosis of GC is incredibly essential. Circular RNAs (CircRNAs) are a kind of endogenous non-coding RNA with stable structure, the long half-life, and tumor specificity. It can be used as a diagnostic marker for tumors. METHOD: Using circRNA sequencing technology screened three pairs of GC and adjacent tissues, and circRNAs with significant expression differences were screened out. The circular structure and characteristics of circPTPN22 were determined by RT-qPCR, agarose gel electrophoresis, Sanger sequencing, RNase R, and actinomycin D assays. Cell Counting Kit-8, colony formation, Transwell, Wound healing, tumor formation in mice and western blotting assays were used to detect the effects of circPTPN22 on the proliferation, invasion, migration, tumor growth of GC cells in vitro and protein expression. RESULT: CircPTPN22 is up-regulated and positively correlated with metastasis in GC tissues, cells, and plasma. RT-qPCR results showed that circPTPN22 had good diagnostic efficacy and could be used to predict the prognosis of GC patients. In vitro and vivo experiments showed that the downregulation of circPTPN22 could inhibit cell proliferation, migration, and invasion through the epithelial-mesenchymal transformation (EMT) pathway. CircPTPN22 may regulate GC progression through the competitive binding of miRNAs. CONCLUSION: CircPTPN22 can be used as a potential diagnostic and prognostic marker for GC and can inhibit cell proliferation and metastasis through the competitive binding of miRNA to inhibit the EMT pathway.

miR-199 family contributes to regulation of sonic hedgehog expression during craniofacial development.

BACKGROUND: The frontonasal ectodermal zone (FEZ) is a signaling center that regulates patterned development of the upper jaw, and Sonic hedgehog (SHH) mediates FEZ activity. Induction of SHH expression in the FEZ results from SHH-dependent signals from the brain and neural crest cells. Given the role of miRNAs in modulating gene expression, we investigated the extent to which miRNAs regulate SHH expression and FEZ signaling. RESULTS: In the FEZ, the miR-199 family appears to be regulated by SHH-dependent signals from the brain; expression of this family increased from HH18 to HH22, and upon activation of SHH signaling in the brain. However, the miR-199 family is more broadly expressed in the mesenchyme of the frontonasal process and adjacent neuroepithelium. Downregulating the miR-199 genes expanded SHH expression in the FEZ, resulting in wider faces, while upregulating miR-199 genes resulted in decreased SHH expression and narrow faces. Hypoxia inducible factor 1 alpha (HIF1A) and mitogen-activated protein kinase kinase kinase 4 (MAP3K4) appear to be potential targets of miR-199b. Reduction of MAP3K4 altered beak development but increased apoptosis, while reducing HIF1A reduced expression of SHH in the FEZ and produced malformations independent of apoptosis. CONCLUSIONS: Our results demonstrate that this miRNA family appears to participate in regulating SHH expression in the FEZ; however, specific molecular mechanisms remain unknown.

Synthesis and evaluation of cationic flocculant P(DAC-PAPTAC-AM) for flocculation of coal chemical wastewater.

In this study, a high-efficiency cationic flocculant, P(DAC-MAPTAC-AM), was successfully prepared using UV-induced polymerization technology. The monomer Acrylamide (AM): Acryloxyethyl Trimethyl ammonium chloride (DAC): methacrylamido propyl trimethyl ammonium chloride (MAPTAC) ratio, monomer concentration, photoinitiator concentration, urea content, and cationic monomer DAC:MAPTAC ratio, light time, and power of high-pressure mercury lamp were studied. The characteristic groups, characteristic diffraction peaks, and characteristic proton peaks of P(DAC-MAPTAC-AM) were confirmed by fourier transform infrared spectroscopy (FTIR), X-Ray diffraction (XRD), 1H nuclear magnetic resonance spectrometer (1H NMR), and scanning electron microscopy (SEM). The effects of dosage, pH value, and velocity gradient (G) value on the removal efficiencies of turbidity, COD, ammonia nitrogen, and total phenol by poly aluminum ferric chloride (PAFC), P(DAC-MAPTAC-AM), and PAFC/P(DAC-MAPTAC-AM) in the flocculation treatment of coal chemical wastewater were investigated. Results showed that the optimal conditions for the flocculation of coal chemical wastewater using P(DAC-MAPTAC-AM) alone are as follows: dosage of 8-12 mg/L, G value of 100-250 s - 1, and pH value of 4-8. The optimal dosage of PAFC is 90-150 mg/L with a pH of 2-12. The optimal dosage for PAFC/P(DAC-MAPTAC-AM) is as follows: PAFC dosage of 90-150 mg/L, P(DAC-MAPTAC-AM) dosage of 8-12 mg/L, and pH range of 2-6. When P(DAC-MAPTAC-AM) was used alone, the optimal removal efficiencies of turbidity, COD, ammonia nitrogen, and total phenol were 81.0%, 35.0%, 75.0%, and 80.3%, respectively. PAFC has good tolerance to wastewater pH and good pH buffering. Thus, the flocculation treatment of coal chemical wastewater using the PAFC/P(DAC-MAPTAC-AM) compound also exhibits excellent resistance and buffering capacity.

Static magnetic fields accelerate osteogenesis by regulating FLRT/BMP pathway.

OBJECTIVES: Static magnetic fields (SMF) have been proved to enhance osteogenic differentiation in mesenchymal stem cells (MSCs). However, the effect of SMF on mandibular condylar chondrocytes (MCCs) are less investigated, which contributes to the vertical formation of mandible. The purpose of the present study was to identify whether SMF accelerate the osteogenesis on mature condylar cartilage and explore the potential regulatory mechanism. METHODS: In this study, we presented a 280 mT SMF stimulation set-up to investigate the genomic effects of SMF exposure on MCCs differentiation and osteoblast-related factor secretion in vitro. Induced by Oricell™ for osteogenesis, MCCs from primary SD Rat were stimulated with or without SMF for cell culture. Cell proliferation was determined by CCK-8. The enhanced osteogenetic capacity of the SMF stimulated MCCs was identified by Alizarin red staining (ARS). Additionally, the effects of SMF on the expression of transmembrane protein marker (FLRT3), terminal differentiation markers (BMP2), and transcription factors (Smad1/5/8) were quantified by Western blot and immunofluorescence analysis. RESULTS: Compared with the control group, SMF decreased the proliferation of MCCs (p < 0.05) after 14 days osteogenesis-specific induction. The mineral synthesis of MCCs was upregulated by SMF (p < 0.0001). The expression of BMP2, Smad1/5/8 showed decrease trends while the protein level of FLRT3 acted in contrary manner (p < 0.05). CONCLUSIONS: Our findings emphasized the ability of osteogenesis positively respond to SMF stimulation by exhibiting enhanced differentiation via FLRT/BMP signaling.

Identification and characterization of CircRNAs involved in the regulation of wheat root length.

BACKGROUND: Recent studies indicate that circular RNAs (circRNAs) may play important roles in the regulation of plant growth and development. Plant roots are the main organs of nutrient and water uptake. However, whether circRNAs involved in the regulation of plant root growth remains to be elucidated. METHODS: LH9, XN979 and YN29 are three Chinese wheat varieties with contrasting root lengths. Here, the root circRNA expression profiles of LH9, XN979 and YN29 were examined by using high-throughput sequencing technology. RESULTS: Thirty-three and twenty-two differentially expressed circRNAs (DECs) were identified in the YN29-LH9 comparison and YN29-XN979 comparison, respectively. Among them, ten DECs coexisted in both comparisons. As the roots of both LH9 and XN979 were significantly larger and deeper than YN29, the ten DECs coexisting in the two comparisons were highly likely to be involved in the regulation of wheat root length. Moreover, three of the ten DECs have potential miRNA binding sites. Real-time PCR analysis showed that the expression levels of the potential binding miRNAs exhibited significant differences between the long root plants and the short root plants. CONCLUSIONS: The expression levels of some circRNAs exhibited significant differences in wheat varieties with contrasting root phenotypes. Ten DECs involved in the regulation of wheat root length were successfully identified in which three of them have potential miRNAs binding sites. The expression levels of putative circRNA-binding miRNAs were correlated with their corresponding circRNAs. Our results provide new clues for studying the potential roles of circRNAs in the regulation of wheat root length.

Comprehensive analysis of long noncoding RNAs and mRNAs expression profiles and functional networks during chondrogenic differentiation of murine ATDC5 cells.

Chondrogenic differentiation is a coordinated biological process orchestrated by various cell signaling pathways, involving complex pathways regulated at both transcriptional and post-transcriptional levels. Long noncoding RNAs (lncRNAs) are emerging as important regulators in the modulation of multiple cell processes. However, the potential roles of lncRNAs and their regulatory mechanisms in chondrogenic differentiation remain largely unclear. In this study, microarray was performed to detect the expression profiles of lncRNAs and messenger RNAs (mRNAs) during chondrogenic differentiation of murine chondrogenic cell line ATDC5. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed to explore their functions. Coding-noncoding co-expression (CNC) and competing endogenous RNA (ceRNA) networks were also constructed with bioinformatics methods. The results revealed that 1009 lncRNAs and 1206 mRNAs were differentially regulated during chondrogenic differentiation. GO and KEGG pathway analysis indicated that the principal functions of the transcripts were associated with system development and extracellular matrix-receptor interaction, TGF-ß signaling, and PI3K-Akt signaling pathways. The CNC network showed that lncRNA AK136902 was positively correlated with prostaglandin F receptor (FP). The ceRNA network covered 3 lncRNAs, 121 miRNAs and 241 edges. The upregulated lncRNA AK136902, AK016344, and ENSMUST00000180767 might promote chondrogenic differentiation by acting as ceRNAs. Knockdown of lncRNA AK136902 could inhibit the mRNA expression of FP and other chondrogenic related genes, including Aggrecan and Col2a1 during chondrogenic differentiation. Our results provide a new perspective on the modulation of lncRNAs during chondrogenic differentiation.

Antihyperlipidemic Effect, Identification and Isolation of the Lipophilic Components from Artemisia integrifolia.

Artemisia integrifolia L (Compositae) is a medicinal and edible plant. To investigate its antihyperlipidemic effect, a crude lipophilic extract and the composing compounds were isolated and fractioned from the petroleum ether extract of aerial parts of A. integrifolia using column chromatography on silica gel. The anti-hyperlipidemia effect was studied in a rat model of acute hyperlipidemia, which was induced by triton WR-1339. A new compound, integrinol (4), together with nine known compounds, namely chamazulene (1), acetylenes (E)-2 (2), acetylenes (E)-3 (3), eugenol (5), palmitic acid (6), oleic acid (7), linoleic acid (8), linolenic acid (9) and 12,13-epoxylinolenic acid were isolated from the crude lipophilic extract of A. integrifolia. The LD50 value of the crude extract was more than 4g/kg. In Triton WR-1339-induced acute hyperlipidemia model, the crude lipophilic extract (200 mg/kg) significantly reduced total cholesterol (TC) by 70% (p ≤ 0.01) and triglycerides (TGs) by 94% (p ≤ 0.001). The fractioned compounds, such as chamazulene (1), acetylene-2 (2), and linolenic acid (9), used at 4 mg/kg dose, also significantly decreased the concentrations of TC (32%, 33% and 64%, respectively) and TGs (48%, 33% and 93%, respectively). These compounds (i.e., chamazulene, acetylenes (E)-2, and linolenic acid) were considered to be responsible for the bioactive antihyperlipidemic effect. In conclusion, the crude lipid extract of Artemisia integrifolia L could be used as a potential treatment to avert hyperlipidemia. Further studies to confirm these results in other models of hyperlipidemia (e.g., diet-induced obesity) are warranted.

Antibiotic ivermectin selectively induces apoptosis in chronic myeloid leukemia through inducing mitochondrial dysfunction and oxidative stress.

Mitochondria has been a promising target in blood cancer given their unique dependencies on mitochondrial functions compared to normal hematopoietic cells. In line with this concept, we show that an anthelminthic drug ivermectin selectively kills chronic myeloid leukemia (CML) cells via inducing mitochondrial dysfunctions and oxidative stress. Ivermectin is significantly more effective in inducing caspase-dependent apoptosis in CML cell line K562 and primary CML CD34 than normal bone marrow (NBM) CD34 cells. Ivermectin also augments in vitro and in vivo efficacy of standard CML tyrosine kinase inhibitors. Mechanistically, ivermectin inhibits respiratory complex I activity and suppresses mitochondrial respiration in K562 and CML CD34 cells. Interestingly, we demonstrate that mitochondrial respiration are lower in NBM CD34 compared to malignant CD34 cells. In addition, ivermectin also induces mitochondrial dysfunctions in NBM CD34 cells in a similar manner as in CML CD34 cells whereas NBM CD34 cells are significantly less sensitive to ivermectin than CML CD34 cells. These suggest that NBM CD34 cells are more tolerable to mitochondrial dysfunctions than CML CD34 cells. Consistently, ivermectin induces higher levels of oxidative stress and damage in CML than normal counterparts. Antioxidant NAC rescues ivermectin's effects, confirming oxidative stress as the mechanism of its action in CML. Our work provides the fundamental evidence to repurpose ivermectin for CML treatment. Our work also highlights the therapeutic value of targeting mitochondria respiration in CML.