Comprehensive Investigation into the Impact of Degradation of Recycled Polyethylene and Recycled Polypropylene on the Thermo-Mechanical Characteristics and Thermal Stability of Blends.

The impact of degradation on plastics is a critical factor influencing their properties and behavior, particularly evident in polyethylene (PE) and polypropylene (PP) and their blends. However, the effect of photoaging and thermal degradation, specifically within recycled polyethylene (rPE) and recycled polypropylene (rPP), on the thermo-mechanical and thermostability aspects of these blends remains unexplored. To address this gap, a range of materials, including virgin polyethylene (vPE), recycled polyethylene (rPE), virgin polypropylene (vPP), recycled polypropylene (rPP), and their blends with different ratios, were comprehensively investigated. Through a systematic assessment encompassing variables such as melting flow index (MFI), functional groups, mechanical traits, crystallization behavior, microscopic morphology, and thermostability, it was found that thermo-oxidative degradation generated hydroxyl and carboxyl functional groups in rPE and rPP. Optimal mechanical properties were achieved with a 6:4 mass ratio of rPE to rPP, as validated by FTIR spectroscopy and microscopic morphology. By establishing the chemical model, the changes in the system with an rPE-rPP ratio of 6:4 and 8:2 were monitored by the molecular simulation method. When the rPE-rPP ratio was 6:4, the system's energy was lower, and the number of hydrogen bonds was higher, which also confirmed the above experimental results. Differential scanning calorimetry revealed an increased crystallization temperature in rPE, a reduced crystallization peak area in rPP, and a diminished crystallization capacity in rPE/rPP blends, with rPP exerting a pronounced influence. This study plays a pivotal role in enhancing recycling efficiency and reducing production costs for waste plastics, especially rPE and rPP-the primary components of plastic waste. By uncovering insights into the degradation effects and material behaviors, our research offers practical pathways for more sustainable waste management. This approach facilitates the optimal utilization of the respective performance characteristics of rPE and rPP, enabling the development of highly cost-effective rPE/rPP blend materials and promoting the efficient reuse of waste materials.

TMEM100 acts as a TAK1 receptor that prevents pathological cardiac hypertrophy progression.

Pathological cardiac hypertrophy is the primary cause of heart failure, yet its underlying mechanisms remain incompletely understood. Transmembrane protein 100 (TMEM100) plays a role in various disorders, such as nervous system disease, pain and tumorigenesis, but its function in pathological cardiac hypertrophy is still unknown. In this study, we observed that TMEM100 is upregulated in cardiac hypertrophy. Functional investigations have shown that adeno-associated virus 9 (AAV9) mediated-TMEM100 overexpression mice attenuates transverse aortic constriction (TAC)-induced cardiac hypertrophy, including cardiomyocyte enlargement, cardiac fibrosis, and impaired heart structure and function. We subsequently demonstrated that adenoviral TMEM100 (AdTMEM100) mitigates phenylephrine (PE)-induced cardiomyocyte hypertrophy and downregulates the expression of cardiac hypertrophic markers in vitro, whereas TMEM100 knockdown exacerbates cardiomyocyte hypertrophy. The RNA sequences of the AdTMEM100 group and control group revealed that TMEM100 was involved in oxidative stress and the MAPK signaling pathway after PE stimulation. Mechanistically, we revealed that the transmembrane domain of TMEM100 (amino acids 53-75 and 85-107) directly interacts with the C-terminal region of TAK1 (amino acids 1-300) and inhibits the phosphorylation of TAK1 and its downstream molecules JNK and p38. TAK1-binding-defective TMEM100 failed to inhibit the activation of the TAK1-JNK/p38 pathway. Finally, the application of a TAK1 inhibitor (iTAK1) revealed that TAK1 is necessary for TMEM100-mediated cardiac hypertrophy. In summary, TMEM100 protects against pathological cardiac hypertrophy through the TAK1-JNK/p38 pathway and may serve as a promising target for the treatment of cardiac hypertrophy.

Inhibition of GBP5 activates autophagy to alleviate inflammatory response in LPS-induced lung injury in mice.

BACKGROUND: Pulmonary emphysema is a condition that causes damage to the lung tissue over time. GBP5, as part of the guanylate-binding protein family, is dysregulated in mouse pulmonary emphysema. However, the role of GBP5 in lung inflammation in ARDS remains unveiled. METHODS: To investigate whether GBP5 regulates lung inflammation and autophagy regulation, the study employed a mouse ARDS model and MLE-12 cell culture. Vector transfection was performed for the genetic manipulation of GBP5. Then, RT-qPCR, WB and IHC staining were conducted to assess its transcriptional and expression levels. Histological features of the lung tissue were observed through HE staining. Moreover, ELISA was conducted to evaluate the secretion of inflammatory cytokines, autophagy was assessed by immunofluorescent staining, and MPO activity was determined using a commercial kit. RESULTS: Our study revealed that GBP5 expression was altered in mouse ARDS and LPS-induced MLE-12 cell models. Moreover, the suppression of GBP5 reduced lung inflammation induced by LPS in mice. Conversely, overexpression of GBP5 diminished the inhibitory impact of LPS on ARDS during autophagy, leading to increased inflammation. In the cell line of MLE-12, GBP5 exacerbates LPS-induced inflammation by blocking autophagy. CONCLUSION: The study suggests that GBP5 facilitates lung inflammation and autophagy regulation. Thus, GBP5 could be a potential therapeutic approach for improving ARDS treatment outcomes, but further research is required to validate these findings.

A Factor-Free Hydrogel with ROS Scavenging and Responsive Degradation for Enhanced Diabetic Bone Healing.

In view of the increased levels of reactive oxygen species (ROS) that disturb the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs), the repair of diabetic bone defects remains a great challenge. Herein, a factor-free hydrogel is reported with ROS scavenging and responsive degradation properties for enhanced diabetic bone healing. These hydrogels contain ROS-cleavable thioketal (TK) linkers and ultraviolet (UV)-responsive norbornene (NB) groups conjugated with 8-arm PEG macromers, which are formed via UV crosslinking-mediated gelation. Upon reacting with high levels of ROS in the bone defect microenvironment, ROS-cleavable TK linkers are destroyed, allowing the responsive degradation of hydrogels, which promotes the migration of BMSCs. Moreover, ROS levels are reduced through hydrogel-mediated ROS scavenging to reverse BMSC differentiation from adipogenic to osteogenic phenotype. As such, a favorable microenvironment is created after simultaneous ROS scavenging and hydrogel degradation, leading to the effective repair of bone defects in diabetic mouse models, even without the addition of growth factors. Thus, this study presents a responsive hydrogel platform that regulates ROS scavenging and stromal degradation in bone engineering.

Exploring the association of PM2.5 with lung cancer incidence under different climate zones and socioeconomic conditions from 2006 to 2016 in China.

Air pollution generated by urbanization and industrialization poses a significant negative impact on public health. Particularly, fine particulate matter (PM2.5) has become one of the leading causes of lung cancer mortality worldwide. The relationship between air pollutants and lung cancer has aroused global widespread concerns. Currently, the spatial agglomeration dynamic of lung cancer incidence (LCI) has been seldom discussed, and the spatial heterogeneity of lung cancer's influential factors has been ignored. Moreover, it is still unclear whether different socioeconomic levels and climate zones exhibit modification effects on the relationship between PM2.5 and LCI. In the present work, spatial autocorrelation was adopted to reveal the spatial aggregation dynamic of LCI, the emerging hot spot analysis was introduced to indicate the hot spot changes of LCI, and the geographically and temporally weighted regression (GTWR) model was used to determine the affecting factors of LCI and their spatial heterogeneity. Then, the modification effects of PM2.5 on the LCI under different socioeconomic levels and climatic zones were explored. Some findings were obtained. The LCI demonstrated a significant spatial autocorrelation, and the hot spots of LCI were mainly concentrated in eastern China. The affecting factors of LCI revealed an obvious spatial heterogeneity. PM2.5 concentration, nighttime light data, 2 m temperature, and 10 m u-component of wind represented significant positive effects on LCI, while education-related POI exhibited significant negative effects on LCI. The LCI in areas with low urbanization rates, low education levels, and extreme climate conditions was more easily affected by PM2.5 than in other areas. The results can provide a scientific basis for the prevention and control of lung cancer and related epidemics.

RNF13 protects against pathological cardiac hypertrophy through p62-NRF2 pathway.

Heart failure (HF) severely impairs human health because of its high incidence and mortality. Cardiac hypertrophy is the main cause of HF, while its underlying mechanism is not fully clear. As an E3 ubiquitin ligase, Ring finger protein 13 (RNF13) plays a crucial role in many disorders, such as liver immune, neurological disease and tumorigenesis, whereas the function of RNF13 in cardiac hypertrophy remains largely unknown. In the present study, we found that the protein expression of RNF13 is up-regulated in the transverse aortic constriction (TAC)-induced murine hypertrophic hearts and phenylephrine (PE)-induced cardiomyocyte hypertrophy. Functional investigations indicated that RNF13 global knockout mice accelerates the degree of TAC-induced cardiac hypertrophy, including cardiomyocyte enlargement, cardiac fibrosis and heart dysfunction. On the contrary, adeno-associated virus 9 (AAV9) mediated-RNF13 overexpression mice alleviated cardiac hypertrophy. Furthermore, we demonstrated that adenoviral RNF13 attenuates the PE-induced cardiomyocyte hypertrophy and down-regulates the expression of cardiac hypertrophic markers, while the opposite results were observed in the RNF13 knockdown group. The RNA-sequence of RNF13 knockout and wild type mice showed that RNF13 deficiency activates oxidative stress after TAC surgery. In terms of the mechanism, we found that RNF13 directly interacted with p62 and promoted the activation of downstream NRF2/HO-1 signaling. Finally, we proved that p62 knockdown can reverse the effect of RNF13 in cardiac hypertrophy. In conclusion, RNF13 protects against the cardiac hypertrophy via p62-NRF2 axis.

Interleukin-21 knockout reduces bone loss in ovariectomized mice by inhibiting osteoclastogenesis.

Estrogen deficiency accelerates osteoporosis in elderly women. However, the role of IL-21 in postmenopausal osteoporosis remains unclear. Female wild-type (WT) C57BL/6 and IL-21 knockout (KO) mice were used for ovariectomy (OVX). Here, IL-21 levels were significantly increased in the serum and bone tissues of WT-OVX mice. The trabecular bone space of the femur was significantly increased, and the bone mass was reduced in OVX mice, accompanied by a significant decrease in the maximum load, energy absorption, and elastic modulus indices. In contrast, IL-21 knockout effectively alleviated the effects of OVX on bone mass. Serum TRACP-5b and receptor activator of nuclear factor kappa B ligand (RANKL) levels and osteoclastogenesis were significantly higher in OVX mice than in sham mice, while serum TRACP-5b and RANKL levels and osteoclastogenesis were significantly decreased in IL-21 KO + OVX mice compared to WT + OVX mice. IL-21 knockdown reduces TRACP-5b, RANKL, and osteoclastogenesis, effectively preventing bone resorption and alleviating the progression of OVX-induced osteoporosis.

Supramolecular assemblies with spatio-temporal sequential drug delivery capability treat spinal cord injury via neuroprotection and immunoregulation.

Spinal cord injury (SCI) can result in irreversible motor and sensory deficits. However, up to data, clinical first-line drugs have ambiguous benefits and debilitating side effects, mainly due to the insufficient accumulation, poor physiological barrier penetration, and lack of spatio-temporal controlled release at lesion tissue. Herein, we proposed a supramolecular assemblies composed of hyperbranched polymer-formed core/shell structure through host-guest interactions. Such HPAA-BM@CD-HPG-C assemblies co-loaded with p38 inhibitor (SB203580) and insulin-like growth factor 1(IGF-1) are able to achieve time- and space-programmed sequential delivery benefiting from their cascaded responsiveness. The core-shell disassembly of HPAA-BM@CD-HPG-C occurs in acidic micro-environment around lesion, achieving preferentially the burst release of IGF-1 to protect survival neurons. Subsequently, the HPAA-BM cores containing SB203580 are endocytosed by the recruited macrophages and degraded by intracellular GSH, accelerating the release of SB203580 to promote the conversion from M1 to M2 macrophage. Hence, the successive synergy of neuroprotection and immunoregulation effects contribute to subsequent nerve repair and locomotor recovery as demonstrated in vitro and in vivo studies. Thus, our fabrication provides a strategy that multiple drugs co-delivery in a spatio-temporal selective manner adapting to the disease progression through self-cascaded disintegration, are expected to realize multidimensional precise treatment of SCI.

Endothelial Stat3 activation promotes osteoarthritis development.

The mechanism of the balance between subchondral angiogenesis and articular damage within osteoarthritis (OA) progression remains a mystery. However, the lack of specific drugs leads to limited clinical treatment options for OA, frequently failing to prevent eventual joint destruction in patients. Increasing evidence suggests that subchondral bone angiogenesis precedes cartilage injury, while proliferating endothelial cells (ECs) induce abnormal bone formation. Signal transducer and activator of transcription 3 (Stat3) is triggered by multiple cytokines in the OA microenvironment. Here, we observed elevated Stat3 activation in subchondral bone H-type vessels. Endothelial Stat3 activation will lead to stronger cell proliferation, migration and angiogenesis by simulating ECs in OA. In contrast, either Stat3 activation inhibition or knockdown of Stat3 expression could relieve such alterations. More interestingly, blocking Stat3 in ECs alleviated angiogenesis-mediated osteogenic differentiation and chondrocyte lesions. Stat3 inhibitor reversed surgically induced subchondral bone H-type vessel hyperplasia in vivo, significantly downregulating vessel volume and vessel number. Due to the reduced angiogenesis, subchondral bone deterioration and cartilage loss were alleviated. Overall, our data suggest that endothelial Stat3 activation is an essential trigger for OA development. Therefore, targeted Stat3 blockade is a novel promising therapeutic regimen for OA.

Novel biomimetic mesoporous silica nanoparticle system possessing targetability and immune synergy facilitates effective solid tumor immuno-chemotherapy.

New strategies that enhance both the targetability of chemotherapy drugs and the synergistic effects of chemotherapy and immunotherapy are urgently needed for efficacious solid tumor therapy. In this study, a novel biomimetic nanoparticle system possessing the properties of tumor targeting and immune synergy was designed to meet these requirements. Mesoporous silica nanoparticles loaded with the chemotherapeutic drug doxorubicin (DOX) were coated with cell membranes modified by glycosylphosphatidylinositol (GPI)-anchored anti-HER2 single chain variable fragment (scFv) and the GPI-anchored co-stimulatory molecule CD80 (to promote solid tumor-targeted chemotherapy and cooperated immunotherapy, respectively). The impact of the nanotherapeutic system on both tumor-targeted chemotherapy and cellular immune response was investigated through in vitro and in vivo experiments. The results show that the novel biomimetic therapeutic system effectively promoted antitumor efficiency in vitro and in vivo. In addition, this therapeutic system further enhanced antitumor capacity by increasing CD8+ T cell activation and cytokine production and reducing myeloid-derived suppressor cell (MDSC) levels in tumors.

Biased gene expression reveals the contribution of subgenome to altitude adaptation in allopolyploid Isoetes sinensis.

Allopolyploids are believed to inherit the genetic characteristics of its progenitors and exhibit stronger adaptability and vigor. The allotetraploid Isoetes sinensis was formed by the natural hybridization and polyploidization of two diploid progenitors, Isoetes taiwanensis and Isoetes yunguiensis, and was believed to have the potential to adapt to plateau environments. To explore the expression pattern of homoeologous genes and their contributions to altitude adaptation, we transplanted natural allotetraploid I. sinensis (TnTnYnYn) along the altitude gradient for a long-term, and harvested them in summer and winter, respectively. One year after transplanting, it still lived well, even in the extreme environment of the Qinghai-Tibet Plateau. Then, we performed high-throughput RNA sequencing to measure their gene expression level. A total of 7801 homoeologous genes were expressed, among which 5786 were identified as shared expression in different altitudes and seasons. We further found that altitude variations could change the subgenome bias trend of I. sinensis, but season could not. Moreover, the functions of uniquely expressed genes indicated that temperature might be an important restrictive factor during the adaptation process. Through the analysis of DEGs and uniquely expressed genes, we found that Y subgenome provided more contributions to high altitude adaptation than T subgenome. These adaptive traits to high altitude may be inherited from its plateau progenitor I. yunguiensis. Through weighted gene co-expression network analysis, pentatricopeptide repeats gene family and glycerophospholipid metabolism pathway were considered to play important roles in high-altitude adaptation. Totally, this study will enrich our understanding of allopolyploid in environmental adaptation.

Role of GALNT4 in protecting against cardiac hypertrophy through ASK1 signaling pathway.

Pathological myocardial hypertrophy is regulated by multiple pathways. However, its underlying pathogenesis has not been fully explored. The goal of this work was to elucidate the function of polypeptide N-acetylgalactosaminyltransferase 4 (GALNT4) in myocardial hypertrophy and its underlying mechanism of action. We illustrated that GALNT4 was upregulated in the models of hypertrophy. Two cardiac hypertrophy models were established through partial transection of the aorta in GALNT4-knockout (GALNT4-KO) mice and adeno-associated virus 9-GALNT4 (AAV9-GALNT4) mice. The GALNT4-KO mice demonstrated accelerated cardiac hypertrophy, dysfunction, and fibrosis, whereas the opposite phenotype was observed in AAV9-GALNT4 mice. Similarly, GALNT4 overexpression mitigated the degree of phenylephrine-induced cardiomyocyte hypertrophy in vitro whereas GALNT4 knockdown aggravated the hypertrophy. In terms of mechanism, GALNT4 deficiency increased the phosphorylation and activation of ASK1 and its downstream targets (JNK and p38), whereas GALNT4 overexpression inhibited activation of the ASK1 pathway. Furthermore, we demonstrated that GALNT4 can directly bind to ASK1 inhibiting its N-terminally mediated dimerization and the subsequent phosphorylation of ASK1. Finally, an ASK1 inhibitor (iASK1) was able to reverse the effects of GALNT4 in vitro. In summary, GALNT4 may serve as a new regulatory factor and therapeutic target by blocking the activation of the ASK1 signaling cascade.

Decreased circulating follicular regulatory T cells in patients with dilated cardiomyopathy.

Follicular regulatory T cells (Tfr) have critical functions in inflammatory and autoimmune disorders. The main purpose of the current work was to assess Tfr cell frequency in patients with dilated cardiomyopathy (DCM). Flow cytometry showed that, compared with normal controls, DCM cases showed markedly reduced Tfr cell rates and Tfr/Tfh ratios, but significantly increased follicular helper T cell (Tfh) rates. Correlation analysis showed that the Tfr rate in DCM patients was positively correlated with left ventricular ejection fraction (LVEF), and negatively correlated with N-terminal brain natriuretic peptide (NT-proBNP) levels. Lower Foxp3 and higher Bcl-6, ICOS, and PD-1 mRNA expression levels were found in patients with DCM. In addition, plasma interleukin (IL)-6, tumor necrosis factor (TNF)-α, and IL-21 levels were significantly increased in DCM cases. Moreover, IgG and IgG3 levels were also elevated in individuals with DCM. Correlation analysis showed that the Tfr rate in DCM patients was negatively correlated with IgG and IgG3, while the Tfh rate was positively correlated with IgG and IgG3. Changes in circulating Tfr levels may have a critical immunomodulatory function in DCM and may become a new therapeutic target for DCM.

METTL1-mediated m7G modification of Arg-TCT tRNA drives oncogenic transformation.

The emerging "epitranscriptomics" field is providing insights into the biological and pathological roles of different RNA modifications. The RNA methyltransferase METTL1 catalyzes N7-methylguanosine (m7G) modification of tRNAs. Here we find METTL1 is frequently amplified and overexpressed in cancers and is associated with poor patient survival. METTL1 depletion causes decreased abundance of m7G-modified tRNAs and altered cell cycle and inhibits oncogenicity. Conversely, METTL1 overexpression induces oncogenic cell transformation and cancer. Mechanistically, we find increased abundance of m7G-modified tRNAs, in particular Arg-TCT-4-1, and increased translation of mRNAs, including cell cycle regulators that are enriched in the corresponding AGA codon. Accordingly, Arg-TCT expression is elevated in many tumor types and is associated with patient survival, and strikingly, overexpression of this individual tRNA induces oncogenic transformation. Thus, METTL1-mediated tRNA modification drives oncogenic transformation through a remodeling of the mRNA "translatome" to increase expression of growth-promoting proteins and represents a promising anti-cancer target.

Shashen maidong decoction: the effect of TNF-α and IL-6 on lung cancer cachexia based on cancer toxicity theory.

OBJECTIVE: To study the curative effect of the traditional Chinese medicine (TCM) Shashen Maidong Decoction in treating lung cancer cachexia based on the cancer toxicity theory, and analyze its influence on patients' serum tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6). METHODS: From January 2018 to January 2019, 104 patients with primary lung cancer cachexia diagnosed and treated in our hospital's oncology department were selected and randomly divided into experimental group and control group, with 52 cases in each group. The control group received routine treatment and nutritional support, while the experimental group received Shashen Maidong Decoction plus. Indexes were compared and analyzed before and after 4 weeks of treatment, including TCM syndrome score, Patient-Generated Subjective Global Assessment (PG-SGA) score, Karnofsky score (KPS), albumin, prealbumin, TNF-α and IL-6 levels. RESULTS: (1) After treatment, both groups' PG-SGA score, KPS score and TCM syndrome score were better than those before treatment (P < 0.01), and the experimental group's PG-SGA score, KPS score and TCM syndrome score were higher than those of the control group (P < 0.01). (2) After treatment, both groups' serum albumin and prealbumin levels were higher than those before treatment (P < 0.05), and the experimental group's prealbumin level was higher than that in the control group (P < 0.05). (3) After treatment, both groups' serum levels of TNF-α and IL-6 were lower than those before treatment (P < 0.05), and the experimental group's levels of TNF-α and IL-6 were lower than those in the control group (P < 0.05). CONCLUSION: Based on the cancer toxicity theory, the application of Shashen Maidong Decoction in treating lung cancer cachexia has definite therapeutic effects and important clinical values. It can effectively alleviate patients' symptoms, improve nutritional status, and reduce body's inflammatory response.

In silico model for miRNA-mediated regulatory network in cancer.

Deregulation of gene expression is associated with the pathogenesis of numerous human diseases including cancer. Current data analyses on gene expression are mostly focused on differential gene/transcript expression in big data-driven studies. However, a poor connection to the proteome changes is a widespread problem in current data analyses. This is partly due to the complexity of gene regulatory pathways at the post-transcriptional level. In this study, we overcome these limitations and introduce a graph-based learning model, PTNet, which simulates the microRNAs (miRNAs) that regulate gene expression post-transcriptionally in silico. Our model does not require large-scale proteomics studies to measure the protein expression and can successfully predict the protein levels by considering the miRNA-mRNA interaction network, the mRNA expression, and the miRNA expression. Large-scale experiments on simulations and real cancer high-throughput datasets using PTNet validated that (i) the miRNA-mediated interaction network affects the abundance of corresponding proteins and (ii) the predicted protein expression has a higher correlation with the proteomics data (ground-truth) than the mRNA expression data. The classification performance also shows that the predicted protein expression has an improved prediction power on cancer outcomes compared to the prediction done by the mRNA expression data only or considering both mRNA and miRNA. Availability: PTNet toolbox is available at http://github.com/CompbioLabUCF/PTNet.

Silencing long intergenic non-protein coding RNA 00987 inhibits proliferation, migration, and invasion of osteosarcoma cells by sponging miR-376a-5p to regulate FNBP1 expression.

High expression of long intergenic non-protein coding RNA 987 (LINC00987) is strongly associated with low overall survival of osteosarcoma; however, its role in osteosarcoma remains unclear. This study explored the biological function and underlying mechanism of LINC00987 in osteosarcoma. In this study, LINC00987 expression in osteosarcoma cells was analyzed using Cancer Cell Line Encyclopedia and qRT-PCR. The proliferation and migration and invasion in osteosarcoma cells were evaluated using Cell Counting Kit-8 and Transwell assays, respectively. Bioinformatic analysis was used to predict the LINC00987-bound miRNAs and miR-376a-5p-bound mRNAs. Dual-luciferase reporter assays were used to assess the interaction between miR-376a-5p, LINC00987, and forming-binding protein 1 (FNBP1). FNBP1 expression was measured by western blotting. LINC00987 was found to be upregulated in osteosarcoma cells. LINC00987 silencing suppressed proliferation, migration, and invasion of osteosarcoma cells. Additionally, miR-376a-5p expression was downregulated in osteosarcoma cells. miR-376a-5p knockdown reversed the effect of LINC00987 silencing on the biological function of osteosarcoma cell. miR-376a-5p was found to target LINC00987 and FNBP1. FNBP1protein level was increased in osteosarcoma cells; however, it was inhibited by silencing LINC00987 and enhanced by silencing miR-376a-5p. In conclusions, this study suggests LINC00987 silencing inhibits osteosarcoma cell proliferation, migration, and invasion by sponging miR-376a-5p to regulate FNBP1 expression. LINC00987 as a potential therapeutic target for osteosarcoma.

Decreased circulating follicular regulatory T cells in patients with dilated cardiomyopathy

Follicular regulatory T cells (Tfr) have critical functions in inflammatory and autoimmune disorders. The main purpose of the current work was to assess Tfr cell frequency in patients with dilated cardiomyopathy (DCM). Flow cytometry showed that, compared with normal controls, DCM cases showed markedly reduced Tfr cell rates and Tfr/Tfh ratios, but significantly increased follicular helper T cell (Tfh) rates. Correlation analysis showed that the Tfr rate in DCM patients was positively correlated with left ventricular ejection fraction (LVEF), and negatively correlated with N-terminal brain natriuretic peptide (NT-proBNP) levels. Lower Foxp3 and higher Bcl-6, ICOS, and PD-1 mRNA expression levels were found in patients with DCM. In addition, plasma interleukin (IL)-6, tumor necrosis factor (TNF)-α, and IL-21 levels were significantly increased in DCM cases. Moreover, IgG and IgG3 levels were also elevated in individuals with DCM. Correlation analysis showed that the Tfr rate in DCM patients was negatively correlated with IgG and IgG3, while the Tfh rate was positively correlated with IgG and IgG3. Changes in circulating Tfr levels may have a critical immunomodulatory function in DCM and may become a new therapeutic target for DCM.

miR-34b/c regulates doxorubicin-induced myocardial cell injury through ITCH.

Objective: To determine the underlying mechanism of miR-34b/c in regulating doxorubicin (Dox)-induced myocardial cell injury.Methods: The viability of mouse myocardial cells HL-1 was detected by MTT assay. The apoptosis of HL-1 cells was detected by TUNEL assay. mRNA expressions of ITCH, TNF-α and IL-6 were measured by qRT-PCR. Protein levels of ITCH, NF-κB, TNF-α and IL-6 were measured by western blot. Dual luciferase assay was performed to detect the regulation of miR-34b/c on ITCH. Mouse model of cardiomyopathy was induced by intraperitoneal injection of Dox.Results: Dox reduced HL-1 cell viability and activated NF-κB pathway in HL-1 cells. miR-34b/c expressions were gradually up-regulated and ITCH expression was gradually down-regulated in Dox-treated HL-1 cells. miR-34b/c expression had negative correlation with the mRNA expression of ITCH. Besides, ITCH was a target of miR-34b/c. miR-34b/c mimic reduced cell viability, suppressed ITCH expression, increased TNF-α and IL-6 level, and promoted NF-κB expression in nucleus and cytoplasm of HL-1 cells. Whereas silencing miR-34 protected HL-1 cells through regulating ITCH. Finally, we demonstrated miR-34 antagomir-protected myocardial cells in mouse model of cardiomyopathy.Conclusion: miR-34b/c decreased HL-1 cell viability and promoted the secretion of proinflammatory cytokines in Dox-induced myocardial cells through ITCH/NF-κB pathway.

mRNA circularization by METTL3-eIF3h enhances translation and promotes oncogenesis.

N6-methyladenosine (m6A) modification of mRNA is emerging as an important regulator of gene expression that affects different developmental and biological processes, and altered m6A homeostasis is linked to cancer1-5. m6A modification is catalysed by METTL3 and enriched in the 3' untranslated region of a large subset of mRNAs at sites close to the stop codon5. METTL3 can promote translation but the mechanism and relevance of this process remain unknown1. Here we show that METTL3 enhances translation only when tethered to reporter mRNA at sites close to the stop codon, supporting a mechanism of mRNA looping for ribosome recycling and translational control. Electron microscopy reveals the topology of individual polyribosomes with single METTL3 foci in close proximity to 5' cap-binding proteins. We identify a direct physical and functional interaction between METTL3 and the eukaryotic translation initiation factor 3 subunit h (eIF3h). METTL3 promotes translation of a large subset of oncogenic mRNAs-including bromodomain-containing protein 4-that is also m6A-modified in human primary lung tumours. The METTL3-eIF3h interaction is required for enhanced translation, formation of densely packed polyribosomes and oncogenic transformation. METTL3 depletion inhibits tumorigenicity and sensitizes lung cancer cells to BRD4 inhibition. These findings uncover a mechanism of translation control that is based on mRNA looping and identify METTL3-eIF3h as a potential therapeutic target for patients with cancer.