In order to overcome the key challenge in improving both fabrication efficiency and their drug delivery capability of anti-cancer drug delivery systems (ACDDS), here polyacrylic acid (PAA) grafted dextran (Dex) nanohydrogels (NGs) with covalent crosslinked structure bearing redox sensitive disulfide crosslinking junctions (Dex-SS-PAA) were synthesized efficiently through a one-step self-assembly assisted methodology (SAA). The Dex-SS-PAA were subsequently conjugated with doxorubicin through an acid-labile hydrazone bond (Dex-SS-PAA-DOX). The in vitro drug release behavior, anti-cancer effects in vivo, and biosafety of the as-prepared acid- and redox-dual responsive biodegradable NGs were systematically investigated. The results revealed that the Dex-SS-PAA-DOX exhibited pH- and redox-controlled drug release, greatly reduced the toxicity of free DOX, while exhibiting a strong ability to inhibit the growth of MDA-MB-231 tumors. Our study demonstrated that the Dex-SS-PAA-DOX NGs are very promising candidates as ACDDS for anti-cancer therapeutics.

To investigate the role of interferon regulatory factor 5 (IRF5) in reversing polarization of lung macrophages during severe acute pancreatitis (SAP) in vitro.

Mechanical stress plays an important role in the initiation and progression of osteoarthritis. Studies show that excessive mechanical stress can directly damage the cartilage extracellular matrix and shift the balance in chondrocytes to favor catabolic activity over anabolism. However, the underlying mechanism remains unknown. MicroRNAs (miRNAs) are emerging as important regulators in osteoarthritis pathogenesis. We have found that mechanical loading up-regulated microRNA miR-365 in growth plate chondrocytes, which promotes chondrocyte differentiation. Here, we explored the role of the mechanical responsive microRNA miR-365 in pathogenesis of osteoarthritis (OA). We found that miR-365 was up-regulated by cyclic loading and IL-1β stimulation in articular chondrocytes through a mechanism that involved the transcription factor NF-κB. miR-365 expressed significant higher level in rat anterior cruciate ligament (ACL) surgery induced OA cartilage as well as human OA cartilage from primary OA patients and traumatic OA Patients. Overexpression of miR-365 in chondrocytes increases gene expression of matrix degrading enzyme matrix metallopeptidase 13 (MMP13) and collagen type X (Col X). The increase in miR-365 expression in OA cartilage and in response to IL-1 may contribute to the abnormal gene expression pattern characteristic of OA. Inhibition of miR-365 down-regulated IL-1β induced MMP13 and Col X gene expression. We further showed histone deacetylase 4 (HDAC4) is a direct target of miR-365, which mediates mechanical stress and inflammation in OA pathogenesis. Thus, miR-365 is a critical regulator of mechanical stress and pro-inflammatory responses, which contributes cartilage catabolism. Manipulation of the expression of miR-365 in articular chondrocytes by miR-365 inhibitor may be a potent therapeutic target for the prevention and treatment of osteoarthritis.

Zinc finger gene 217 (ZNF217) is a candidate gene of polycystic ovary syndrome (PCOS) which is vulnerable to ovarian hyperstimulation syndrome (OHSS). However, the relationship between ZNF217 and OHSS is largely unknown. Our study demonstrated that ZNF217 was mainly distributed in the granulosa cells of rat ovary. Significantly higher expression of ovarian ZNF217 was detected in OHSS rats, being consistent with serum 17β-estradiol concentration and ovarian aromatase. Moreover, OHSS rats also showed decreased ovarian TSP-1 mRNA, an acknowledged VEGF signaling suppressor. The same changes were detected in human granulosa cells and follicular fluid. Thus, the increased ZNF217 and decreased TSP-1 may participate in OHSS onset. In vitro experiment revealed that ZNF217 positively regulated E2 synthesis through promoting cAMP response element binding protein (CREB) and thereby CYP19A1 in KGN cells. Furthermore, ZNF217 negatively regulated TSP-1 in KGN cells while TSP-1 promoted claudin1 and inhibited nitric oxide (NO) in HUVECs and HAECs. Both of claudin1 and NO are responsible for the regulation of vascular permeability (VP). Therefore, we demonstrated that ZNF217 contributed to OHSS onset through promoting E2 synthesis and the increase of VP. Moreover, the increased ZNF217 and decreased TSP-1 provided new targets for the prevention or treatment of OHSS in the future.

Nanomedicine, which is the application of nanotechnology in medicine to make medical diagnosis and treatment more accurate, has great potential for precision medicine. Despite some improvements in nanomedicine, the lack of efficient and low-toxic vectors remains a major obstacle.

The complex preparation procedures and severe toxicities are two major obstacles facing the wide use of chimeric antigen receptor-modified T (CAR-T) cells in clinical cancer immunotherapy. The nanotechnology-based T cell temporary CAR modification may be a potential approach to solve these problems and make the CAR-T cell-based tumor therapy feasible and broadly applicable.

Serum amyloid A1 (SAA1) is an acute phase protein produced mainly by the liver to participate in immunomodulation in both sterile and non-sterile inflammation. However, non-hepatic tissues can also synthesize SAA1. It remains to be determined whether SAA1 synthesized locally in the placenta participates in parturition via eliciting inflammatory reactions. In this study, we investigated this issue by using human placenta and a mouse model. We found that SAA1 mRNA and protein were present in human placental villous trophoblasts, which was increased upon syncytialization as well as treatments with lipopolysaccharides (LPS), tumor necrosis factor-α (TNF-α), and cortisol. Moreover, significant increases in SAA1 abundance were observed in the placental tissue or in the maternal blood in spontaneous deliveries without infection at term and in preterm birth with histological chorioamnionitis. Serum amyloid A1 treatment significantly increased parturition-pertinent inflammatory gene expression including interleukin-1β (IL-1β), IL-8, TNF-α, and cyclooxygenase-2 (COX-2), along with increased PGF2α production in syncytiotrophoblasts. Mouse study showed that SAA1 was present in the placental junctional zone and yolk sac membrane, which was increased following intraperitoneal administration of LPS. Intraperitoneal injection of SAA1 not only induced preterm birth but also increased the abundance of IL-1β, TNF-α, and COX-2 in the mouse placenta. Conclusively, SAA1 can be synthesized in the human placenta, which is increased upon trophoblast syncytialization. Parturition is accompanied with increased SAA1 abundance in the placenta. Serum amyloid A1 may participate in parturition in the presence and absence of infection by inducing the expression of inflammatory genes in the placenta.

Ruminal methane (CH4) emissions from ruminants not only pollute the environment and exacerbate the greenhouse effect, but also cause animal energy losses and low production efficiency. Consequently, it is necessary to find ways of reducing methane emissions in ruminants. Studies have reported that feed additives such as nitrogen-containing compounds, probiotics, prebiotics, and plant extracts significantly reduce ruminant methane; however, systematic reviews of such studies are lacking. The present article summarizes research over the past five years on the effects of nitrogen-containing compounds, probiotics, probiotics, and plant extracts on methane emissions in ruminants. The paper could provide theoretical support and guide future research in animal production and global warming mitigation.

As the prototype of unconventional myosin motor family, myosin Va (MyoVa) transport cellular cargos along actin filaments in diverse cellular processes. The off-duty MyoVa adopts a closed and autoinhibited state, which can be relieved by cargo binding. The molecular mechanisms governing the autoinhibition and activation of MyoVa remain unclear. Here, we report the cryo-electron microscopy structure of the two full-length, closed MyoVa heavy chains in complex with 12 calmodulin light chains at 4.78-Å resolution. The MyoVa adopts a triangular structure with multiple intra- and interpolypeptide chain interactions in establishing the closed state with cargo binding and adenosine triphosphatase activity inhibited. Structural, biochemical, and cellular analyses uncover an asymmetric autoinhibition mechanism, in which the cargo-binding sites in the two MyoVa heavy chains are differently protected. Thus, specific and efficient MyoVa activation requires coincident binding of multiple cargo adaptors, revealing an intricate and elegant activity regulation of the motor in response to cargos.

Knowledge gaps that limit the development of therapies for polycystic ovary syndrome (PCOS) concern various environmental factors that impact clinical characteristics. Circadian dysrhythmia contributes to glycometabolic and reproductive hallmarks of PCOS. Here, we illustrated the amelioration of Limosilactobacillus reuteri (L. reuteri) on biorhythm disorder-ignited dyslipidemia of PCOS via a microbiota-metabolite-liver axis. A rat model of long-term (8 weeks) darkness treatment was used to mimic circadian dysrhythmia-induced PCOS. Hepatic transcriptomics certified by in vitro experiments demonstrated that increased hepatic galanin receptor 1 (GALR1) due to darkness exposure functioned as a critical upstream factor in the phosphoinositide 3-kinase (PI3K)/protein kinase B pathway to suppress nuclear receptors subfamily 1, group D, member 1 (NR1D1) and promoted sterol regulatory element binding protein 1 (SREBP1), inducing lipid accumulation in the liver. Further investigations figured out a restructured microbiome-metabolome network following L. reuteri administration to protect darkness rats against dyslipidemia. Notably, L. reuteri intervention resulted in the decrease of Clostridium sensu stricto 1 and Ruminococcaceae UCG-010 as well as gut microbiota-derived metabolite capric acid, which could further inhibit GALR1-NR1D1-SREBP1 pathway in the liver. In addition, GALR antagonist M40 reproduced similar ameliorative effects as L. reuteri to protect against dyslipidemia. While exogenous treatment of capric acid restrained the protective effects of L. reuteri in circadian disruption-induced PCOS through inhibiting GALR1-dependent hepatic lipid metabolism. These findings purport that L. reuteri could serve for circadian disruption-associated dyslipidemia. Manipulation of L. reuteri-capric acid-GALR1 axis paves way for clinical therapeutic strategies to prevent biorhythm disorder-ignited dyslipidemia in PCOS women.

Abundant evidence indicates a pivotal role of prostaglandin F2α (PGF2α) in human parturition. Both the fetal and maternal sides of the fetal membranes synthesize PGF2α. In addition to the synthesis of PGF2α from PGH2 by PGF synthase (PGFS), PGF2α can also be converted from PGE2 by carbonyl reductase 1 (CBR1). Here, we showed that there was concurrent increased production of cortisol and PGF2α in association with the elevation of CBR1 in human amnion obtained at term with labor versus term without labor. In cultured primary human amnion fibroblasts, cortisol (0.01-1μM) increased PGF2α production in a concentration-dependent manner, in parallel with elevation of CBR1 levels. Either siRNA-mediated knockdown of glucocorticoid receptor (GR) expression or GR antagonist RU486 attenuated the induction of CBR1 by cortisol. Chromatin immunoprecipitation (ChIP) showed an increased enrichment of both GR and RNA polymerase II to CBR1 promoter. Knockdown of CBR1 expression with siRNA or inhibition of CBR1 activity with rutin decreased both basal and cortisol-stimulated PGF2α production in human amnion fibroblasts. In conclusion, CBR1 may play a critical role in PGF2α synthesis in human amnion fibroblasts, and cortisol promotes the conversion of PGE2 into PGF2α via GR-mediated induction of CBR1 in human amnion fibroblasts. This stimulatory effect of cortisol on CBR1 expression may partly explain the concurrent increases of cortisol and PGF2α in human amnion tissue with labor, and these findings may account for the increased production of PGF2α in the fetal membranes prior to the onset of labor.

Calmodulin-like (CML) proteins are a class of important Ca2+ sensors in plants, which play vital roles in regulating plant growth and development and response to abiotic stress. Tea plant (Camellia sinensis L.) is the most popular non-alcoholic economic beverage crop around the world. However, the potential functions of CMLs in either tea plants growth or in the response to environmental stresses are still unclear. In the present study, five CsCML genes (CsCML16, CsCML18-1, CsCML18-2, CsCML38, and CsCML42) were isolated from tea plant, and functionally characterized. The CsCML genes showed diverse expression patterns in leaves, roots, old stems, immature stems and flowers of tea plants. To investigate the expression changes of the genes under various abiotic stresses and ABA treatment, time-course experiments were also performed, the results indicated that the expression levels of CsCML16, 18-2 and 42 were significantly induced under low temperature and salt condition, while CsCML38 was induced distinctly under drought stress and ABA treatment. Overall, CsCML genes showed diverse function in tea plant under various stimuli. These results will increase our knowledge of the significance of CsCML genes in tea plant in response to abiotic stresses and hormone treatments.

'Huangjinya' is an excellent albino tea germplasm cultivated in China because of its bright color and high amino acid content. It is light sensitive, with yellow leaves under intense light while green leaves under weak light. As well, the flavonoid and carotenoid levels increased after moderate shading treatment. However, the mechanism underlying this interesting phenomenon remains unclear. In this study, the transcriptome of 'Huangjinya' plants exposed to sunlight and shade were analyzed by high-throughput sequencing followed by de novo assembly. Shading 'Huangjinya' made its leaf color turn green. De novo assembly showed that the transcriptome of 'Huangjinya' leaves comprises of 127,253 unigenes, with an average length of 914 nt. Among the 81,128 functionally annotated unigenes, 207 differentially expressed genes were identified, including 110 up-regulated and 97 down-regulated genes under moderate shading compared to full light. Gene ontology (GO) indicated that the differentially expressed genes are mainly involved in protein and ion binding and oxidoreductase activity. Antioxidation-related pathways, including flavonoid and carotenoid biosynthesis, were highly enriched in these functions. Shading inhibited the expression of flavonoid biosynthesis-associated genes and induced carotenoid biosynthesis-related genes. This would suggest that decreased flavonoid biosynthetic gene expression coincides with increased flavonoids (e.g., catechin) content upon moderate shading, while carotenoid levels and biosynthetic gene expression are positively correlated in 'Huangjinya.' In conclusion, the leaf color changes in 'Huangjinya' are largely determined by the combined effects of flavonoid and carotenoid biosynthesis.

As the first-line drug for treatment of HER2-positive metastatic gastric cancer (GC), Herceptin exhibits significant therapeutic efficacy. However, acquired resistance of Herceptin limits the therapeutic benefit of gastric cancer patients, in which the molecular mechanisms remain to be further determined.

Insulin resistance (IR) contributes to ovarian dysfunctions in polycystic ovarian syndrome (PCOS) patients. Serum amyloid A1 (SAA1) is an acute phase protein produced primarily by the liver in response to inflammation. In addition to its role in inflammation, SAA1 may participate in IR development in peripheral tissues. Yet, expressional regulation of SAA1 in the ovary and its role in the pathogenesis of ovarian IR in PCOS remain elusive.

Lung adenocarcinoma is still cancer with the highest mortality. Hypoxia and immunity play an essential role in the occurrence and development of tumors. Therefore, this study is mainly to find new early diagnosis and prognosis markers and explore the relationship among the markers and immunity and hypoxia, to improve the prognosis of patients. Firstly, based on the clinical database in TCGA, we determined the most critical clinicopathological parameters affecting the prognosis of patients through a variety of analysis methods. According to pathological parameters, logistic most minor absolute contraction selection operator (lasso), univariate and multivariate regression analysis, the risk genes related to early prognosis were screened, and the risk model was established. Then, in different risk groups, GSEA and CIBERSORT algorithms were used to analyze the distribution and enrichment of the immune cells and hypoxia, to study the effects of early prognostic indicators on hypoxia and immunity. At the same time, we analyzed the different levels of risk genes in normal cells (BSEA-2B) and tumor cells (H1299, A549, PC9, and H1975). Finally, A549 and PC9 cells were induced by CoCl2 to establish a hypoxic environment, and the correlation between risk genes and HIF1A was analyzed. The risk model based on risk genes (CYP4B1, KRT6A, and FAM83A) was accurate and stable for the prognosis of patients. It is closely related to immunity and hypoxia. In BSEA-2B cells, the mRNA and protein expression of CYP4B1 was higher, while the expression of KRT6A and FAM83A was lower. Finally, we found that FAM83A and HIF1A showed a significant positive correlation when A549 and PC9 cells were exposed to hypoxia. The discovery of early diagnostic markers related to immunity, hypoxia, and prognosis, provides a new idea for early screening and prognostic treatment of lung adenocarcinoma.

Urban air pollution disproportionately harms communities of color and low-income communities in the U.S. Intraurban nitrogen dioxide (NO2) inequalities can be observed from space using the TROPOspheric Monitoring Instrument (TROPOMI). Past research has relied on time-averaged measurements, limiting our understanding of how neighborhood-level NO2 inequalities co-vary with urban air quality and climate. Here, we use fine-scale (250 m × 250 m) airborne NO2 remote sensing to demonstrate that daily TROPOMI observations resolve a major portion of census tract-scale NO2 inequalities in the New York City-Newark urbanized area. Spatiotemporally coincident TROPOMI and airborne inequalities are well correlated (r = 0.82-0.97), with slopes of 0.82-1.05 for relative and 0.76-0.96 for absolute inequalities for different groups. We calculate daily TROPOMI NO2 inequalities over May 2018-September 2021, reporting disparities of 25-38% with race, ethnicity, and/or household income. Mean daily inequalities agree with results based on TROPOMI measurements oversampled to 0.01° × 0.01° to within associated uncertainties. Individual and mean daily TROPOMI NO2 inequalities are largely insensitive to pixel size, at least when pixels are smaller than ∼60 km2, but are sensitive to low observational coverage. We statistically analyze daily NO2 inequalities, presenting empirical evidence of the systematic overburdening of communities of color and low-income neighborhoods with polluting sources, regulatory ozone co-benefits, and worsened NO2 inequalities and cumulative NO2 and urban heat burdens with climate change.

Intestinal inflammation is a vital precipitating factor of colorectal cancer (CRC), but the underlying mechanisms are still elusive. TANK-binding kinase 1 (TBK1) is a core enzyme downstream of several inflammatory signals. Recent studies brought the impacts of TBK1 in malignant disease to the forefront, we found aberrant TBK1 expression in CRC is correlated with CRC progression. TBK1 inhibition impaired CRC cell proliferation, migration, drug resistance and tumor growth. Bioinformatic analysis and experiments in vitro showed overexpressed TBK1 inhibited mTORC1 signaling activation in CRC along with elevated GLUT1 expression without inducing GLUT1 translation. TBK1 mediated mTORC1 inhibition induces intracellular autophagy, which in turn decreasing GLUT1 degradation. As a rescue, blocking of autophagosome and retromer respectively via autophagy-related gene 7 (ATG7) or TBC1 Domain Family Member 5 (TBC1D5) silence diminished the regulation of TBK1 to GLUT1. GLUT1 staining presented that TBK1 facilitated GLUT1 membrane translocation which subsequently enhanced glucose consumption. Inhibitor of TBK1 also decreased GLUT1 expression which potentiated drug-sensitivity of CRC cell. Collectively, TBK1 facilitates glucose consumption for supporting CRC progression via initiating mTORC1 inhibition induced autophagy which decreases GLUT1 degradation and increases GLUT1 membrane location. The adaptive signaling cascade between TBK1 and GLUT1 proposes a new strategy for CRC therapy.

The human amnion is an intrauterine tissue which is involved in the initiation of parturition. In-depth understanding of gene expression signatures of individual cell types in the amnion with respect to membrane rupture at parturition may help identify crucial initiators of parturition for the development of specific strategies to prevent preterm birth, a leading cause of perinatal mortality.

Amnion-derived prostaglandin E2 (PGE2) and cortisol are key to labor onset. Identification of a common transcription factor driving the expression of both cyclooxygenase-2 (COX-2) and 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1), the key enzymes in their production, may hold the key to the treatment of pre-term labor. Here, we have found that the CCAAT enhancer binding protein δ (C/EBPδ) is such a transcription factor which underlies the feed-forward induction of COX-2 and 11β-HSD1 expression by their own products PGE2 and cortisol in human amnion fibroblasts so that their production would be ensured in the amnion for the onset of labor. Moreover, the abundance of C/EBPδ in the amnion increases along with COX-2 and 11β-HSD1 at term and further increases at parturition. Knockout of C/EBPδ in mice delays the onset of labor further supporting the concept. In conclusion, C/EBPδ pathway may be speculated to serve as a potential pharmaceutical target in the amnion for treatment of pre-term labor.