Stimuli-responsive polymeric systems containing special responsive moieties can undergo alteration of chemical structures and physical properties in response to external stimulus. We synthesized a hybrid amphiphilic block copolymer containing methoxy polyethylene glycol (MePEG), methacrylate isobutyl polyhedral oligomeric silsesquioxane (MAPOSS) and 2-(diisopropylamino)ethyl methacrylate (DPA) named MePEG-b-P(MAPOSS-co-DPA) via atom transfer radical polymerization (ATRP). Spherical micelles with a core-shell structure were obtained by a self-assembly process based on MePEG-b-P(MAPOSS-co-DPA), which showed a pH-responsive property. The influence of hydrophobic chain length on the self-assembly behavior was also studied. The pyrene release properties of micelles and their ability of antifouling were further studied.

Bile acids (BAs) are key mediators of the glycemic control after bariatric surgeries. Cholecystectomy modifies the kinetics of BAs, and whether this procedure influences the BAs pool and its metabolic response to bariatric surgeries is not known. We used targeted and untargeted metabolomics to assess whether cholecystectomy influenced plasma and fecal BAs fluctuations and the systemic metabolomic profile after Roux-en-Y gastric bypass (RYGB). Women with obesity and type 2 diabetes were included. Sample collections and clinical evaluations were performed before and 3 months after RYGB. RYGB influenced 9 fecal and 3 plasma BAs in patients with cholecystectomy (p ≤ 0.05). Comparisons between patients with and without cholecystectomy revealed different concentrations of 4 fecal and 5 plasma BAs (p ≤ 0.05). Cholecystectomy impacted the global metabolomics responses to RYGB, and patients who underwent the gallbladder removal also lacked some significant improvements in clinical markers, primarily the lipid profile. By affecting the BAs concentrations, cholecystectomy seems to alter the systemic metabolic response to RYGB. Therefore, cholecystectomy may act as a bias in assessments of the metabolic effects of bariatric surgeries and their relationships with clinical outcomes.

Many commercially available glucagon products for treatment of severe hypoglycaemia require cumbersome reconstitution and potentially intimidating injection during an emergency. Nasal glucagon (NG) is a novel drug-device combination product consisting of a single-use dosing device that delivers glucagon dry powder through nasal administration. The present study assessed whether 3 mg NG was non-inferior to 1 mg intramuscular glucagon (IMG) in adults with type 1 diabetes.

The search for biomarkers associated with obesity-related diseases is ongoing, but it is not clear whether plasma and serum can be used interchangeably in this process. Here we used high-throughput screening to analyze 358 proteins and 76 lipids, selected because of their relevance to obesity-associated diseases, in plasma and serum from age- and sex-matched lean and obese humans. Most of the proteins/lipids had similar concentrations in plasma and serum, but a subset showed significant differences. Notably, a key marker of cardiovascular disease PAI-1 showed a difference in concentration between the obese and lean groups only in plasma. Furthermore, some biomarkers showed poor correlations between plasma and serum, including PCSK9, an important regulator of cholesterol homeostasis. Collectively, our results show that the choice of biofluid may impact study outcome when screening for obesity-related biomarkers and we identify several markers where this will be the case.

Notwithstanding the remarkable progress in the clinical treatment of ischemic disease, proangiogenic drugs mostly suffer from their abnormal angiogenesis and potential cancer risk, and currently, no off-the-shelf biomaterials can efficiently induce angiogenesis. Here, we reported that a semisynthetic sulfated chitosan (SCS) readily engaged anti-inflammatory macrophages and increased its secretion of endogenous vascular endothelial growth factor (VEGF) to induce angiogenesis in ischemia via a VEGF-VEGFR2 signaling pathway. The depletion of host macrophages abrogated VEGF secretion and vascularization in implants, and the inhibition of VEGF or VEGFR2 signaling also disrupted the macrophage-associated angiogenesis. In addition, in a macrophage-inhibited mouse model, SCS efficiently helped to recover the endogenous levels of VEGF and the number of CD31hiEmcnhi vessels in ischemia. Thus, both sulfated group and pentasaccharide sequence in SCS played an important role in directing the therapeutic angiogenesis, indicating that this highly bioactive biomaterial can be harnessed to treat ischemic disease.

Cadmium is a toxic metal widely found in workplaces and plant soil because of extensive industrialization. Wheat is an important source of food generated from plant soil. The different responses of wheat against different omic levels of cadmium have been observed and widely studied worldwide. With the development of high-throughput sequencing, micro-level biological research has extended to the microRNA level. In this study, high-cadmium-accumulating wheat cultivars (Annong9267) and low-cadmium-accumulating wheat cultivars (Qian 102032) were used as experimental models. The two cultivars were treated by Cd for 2 h to explore the microRNA profiles in root and leaf tissues through small RNA sequencing. Important small RNAs, such as tae-miR9663-5p and tae-miR6201, and potential small RNA-mediated mechanisms associated with cadmium accumulation were identified by summarizing specific microRNA profiling patterns and their respective target genes. At the wheat roots and leaves, differentially expressed small RNAs related to cadmium accumulation in different plant tissues (roots or leaves) were identified, and functional enrichment analyses on target genes of differentially expressed miRNAs in low- and high-cadmium-accumulating wheat cultivars in different plant tissues (roots or leaves) obtained some known mature miRNAs and new miRNAs. The identified miRNA will be regarded as a potential screening biomarker for low-cadmium-accumulating wheat.

Mouse knockouts facilitate the study ofgene functions. Often, multiple abnormal phenotypes are induced when a gene is inactivated. The International Mouse Phenotyping Consortium (IMPC) has generated thousands of mouse knockouts and catalogued their phenotype data. We have acquired metabolomics data from 220 plasma samples from 30 unique mouse gene knockouts and corresponding wildtype mice from the IMPC. To acquire comprehensive metabolomics data, we have used liquid chromatography (LC) combined with mass spectrometry (MS) for detecting polar and lipophilic compounds in an untargeted approach. We have also used targeted methods to measure bile acids, steroids and oxylipins. In addition, we have used gas chromatography GC-TOFMS for measuring primary metabolites. The metabolomics dataset reports 832 unique structurally identified metabolites from 124 chemical classes as determined by ChemRICH software. The GCMS and LCMS raw data files, intermediate and finalized data matrices, R-Scripts, annotation databases, and extracted ion chromatograms are provided in this data descriptor. The dataset can be used for subsequent studies to link genetic variants with molecular mechanisms and phenotypes.

Terpenoid metabolism plays vital roles in stress defense and the environmental adaptation of monocot crops. Here, we describe the identification of the terpene synthase (TPS) gene family of the panicoid food and bioenergy model crop foxtail millet (Setaria italica). The diploid S. italica genome contains 32 TPS genes, 17 of which were biochemically characterized in this study. Unlike other thus far investigated grasses, S. italica contains TPSs producing all three ent-, (+)- and syn-copalyl pyrophosphate stereoisomers that naturally occur as central building blocks in the biosynthesis of distinct monocot diterpenoids. Conversion of these intermediates by the promiscuous TPS SiTPS8 yielded different diterpenoid scaffolds. Additionally, a cytochrome P450 monooxygenase (CYP99A17), which genomically clustered with SiTPS8, catalyzes the C19 hydroxylation of SiTPS8 products to generate the corresponding diterpene alcohols. The presence of syntenic orthologs to about 19% of the S. italica TPSs in related grasses supports a common ancestry of selected pathway branches. Among the identified enzyme products, abietadien-19-ol, syn-pimara-7,15-dien-19-ol and germacrene-d-4-ol were detectable in planta, and gene expression analysis of the biosynthetic TPSs showed distinct and, albeit moderately, inducible expression patterns in response to biotic and abiotic stress. In vitro growth-inhibiting activity of abietadien-19-ol and syn-pimara-7,15-dien-19-ol against Fusarium verticillioides and Fusarium subglutinans may indicate pathogen defensive functions, whereas the low antifungal efficacy of tested sesquiterpenoids supports other bioactivities. Together, these findings expand the known chemical space of monocot terpenoid metabolism to enable further investigations of terpenoid-mediated stress resilience in these agriculturally important species.

Fetal growth restriction (FGR) increases the risk for perinatal complications and predisposes the infant to diabetes and cardiovascular disease later in life. No treatment for FGR is available, and the underlying pathophysiology remains poorly understood. Increased IGFBP-1 phosphorylation has been implicated as an important mechanism by which fetal growth is reduced. However, to what extent circulating IGFBP-1 is phosphorylated in FGR is unknown, and the molecular mechanisms linking FGR to IGFBP-1 phosphorylation have not been established. We used umbilical cord plasma of appropriate for gestational age (AGA) and growth-restricted human fetuses and determined IGFBP-1 and IGF-I concentrations (ELISA) and site-specific IGFBP-1 phosphorylation (Western blotting using IGFBP-1 phospho-site specific antibodies). In addition, we used a baboon model of FGR produced by 30% maternal nutrient restriction and determined mammalian target of rapamycin (mTOR)C1 activity, CK2 expression/activity, IGFBP-1 expression and phosphorylation, and IGF-I levels in baboon fetal liver by Western blot, enzymatic assay, and ELISA. HepG2 cells and primary fetal baboon hepatocytes were used to explore mechanistic links between mTORC1 signaling and IGFBP-1 phosphorylation. IGFBP-1 was hyperphosphorylated at Ser101, Ser119, and Ser169 in umbilical plasma of human FGR fetuses. IGFBP-1 was also hyperphosphorylated at Ser101, Ser119, and Ser169 in the liver of growth-restricted baboon fetus. mTOR signaling was markedly inhibited, whereas expression and activity of CK2 was increased in growth-restricted baboon fetal liver in vivo. Using HepG2 cells and primary fetal baboon hepatocytes, we established a mechanistic link between mTOR inhibition, CK2 activation, IGFBP-1 hyperphosphorylation, and decreased IGF-I-induced IGF-I receptor autophosphorylation. We provide clear evidence for IGFBP-1 hyperphosphorylation in FGR and identified an mTOR and CK2-mediated mechanism for regulation of IGF-I bioavailability. Our findings are consistent with the model that inhibition of mTOR in the fetal liver, resulting in increased CK2 activity and IGFBP-1 hyperphosphorylation, constitutes a novel mechanistic link between nutrient deprivation and restricted fetal growth.

We have previously shown trichloroethylene (TCE) induced occupational medicamentosa-like dermatitis due to TCE (OMLDT) with immune liver injury, and kallikrein-kinin system (KKS) activation as a probably mechanism underlying the immune damage. Bradykinin (BK) is an important active component of KKS system function, but the specific role of BK in the immune liver injury has never been examined. The present study aimed to explore the important role of BK and mechanisms of action in immune liver injury induced by TCE. TCE sensitization significantly increased the expression of BK receptor (B2R) in the liver. Compared to blank and vehicle control group, TCE sensitization positive mice developed exacerbated liver injury evidenced by elevated AST, ALT levels and hepatocyte damage. TCE sensitization also stimulated MAPK and STAT3 activation in liver tissue. B2R antagonist HOE140 ameliorated these changes. Kupffer cells (KCs) of the liver were also activated following TCE sensitization; both CD68+ KCs and CD16/CD32+ M1 type KCs were increased in TCE positive group. Further experiments isolated the KCs from the liver in each group and showed that TCE sensitization resulted activation of MAPK signal pathway which in turn caused release of the pro-inflammatory cytokines, IL-1β, IL-6, TNF-α, in KCs; the antagonist HOE140 again decreased these changes in KCs. These results uncover a novel role of BK and B2R cross-talk in KCs activation in TCE sensitized mice, mediated by pro-inflammatory cytokine release via MAPK and STAT3 activation, contributing to the immune liver injury.

Ferula assafoetida is a medicinal plant of the Apiaceae family that has traditionally been used for its therapeutic value. Particularly, terpenoid and phenylpropanoid metabolites, major components of the root-derived oleo-gum-resin, exhibit anti-inflammatory and cytotoxic activities, thus offering a resource for potential therapeutic lead compounds. However, genes and enzymes for terpenoid and coumarin-type phenylpropanoid metabolism have thus far remained uncharacterized in F. assafoetida Comparative de novo transcriptome analysis of roots, leaves, stems, and flowers was combined with computational annotation to identify candidate genes with probable roles in terpenoid and coumarin biosynthesis. Gene network analysis showed a high abundance of predicted terpenoid- and phenylpropanoid-metabolic pathway genes in flowers. These findings offer a deeper insight into natural product biosynthesis in F. assafoetida and provide genomic resources for exploiting the medicinal potential of this rare plant.

Emerging evidence indicates that microRNAs, a class of small and well-conserved noncoding RNAs, participate in many physiological and pathological processes. RNase III endonuclease DICER is one of the key enzymes for microRNA biogenesis. Here, we found that DICER was downregulated in tumor samples of colorectal cancer (CRC) patients at both mRNA and protein levels. Importantly, intestinal epithelial cell (IEC)-specific deletion of Dicer mice got more tumors after azoxymethane and dextran sulfate sodium (DSS) administration. Interestingly, IEC-specific deletion of Dicer led to severe chronic inflammation and epithelium layer remodeling in mice with or without DSS administration. Microarray analysis of 3 paired Dicer deletion CRC cell lines showed that miR-324-5p was one of the most significantly decreased miRNAs. In the intestinal epithelium of IEC-specific deletion of Dicer mice, miR-324-5p was also found to be markedly reduced. Mechanistically, miR-324-5p directly bound to the 3'untranslated regions (3'UTRs) of HMG-box containing 3 (HMGXB3) and WAS protein family member 2 (WASF-2), two key proteins participated in cell motility and cytoskeleton remodeling, to suppress their expressions. Intraperitoneal injection of miR-324-5p AgomiR (an agonist of miR-324-5p) curtailed chronic inflammation and cytoskeleton remodeling of colorectal epithelium and restored intestinal barrier function in IEC-specific deletion of Dicer mice induced by DSS. Therefore, our study reveals a key role of a DICER/miR-324-5p/HMGXB3/WASF-2 axis in tumorigenesis of CRC by regulation of cytoskeleton remodeling and maintaining integrity of intestinal barriers.

In this study, soft hydrogel crawlers with remote magnetic-responsive motility in confined spaces have been developed. Inspired by the motion of maggots, the hydrogel crawlers can reversibly contract and elongate their body controlled by repeatedly switching on/off an alternating magnetic field. Based on the cyclic deformation, the hydrogel crawlers can move peristaltically in a confined space that is coated with asymmetric micro-patterns. The dependence of the hydrogel motility on the pattern structures and lubrication is characterized using experimental measurements. Such a hydrogel system pioneers the study of active motile systems in porous media and has the potential to impact the fields of targeted drug delivery and active actuators.

Ubiquitination is a basic post-translational modification for cellular homeostasis, and members of the conjugating enzyme (E2) family are the key components of the ubiquitin-proteasome system. However, the role of E2 family in colorectal cancer (CRC) is largely unknown. Our study aimed to investigate the role of Ube2v1, one of the ubiquitin-conjugating E2 enzyme variant proteins (Ube2v) but without the conserved cysteine residue required for the catalytic activity of E2s, in CRC.

There are 51 tributaries in the middle reaches of the Yarlung Zangbo River (YZR), and the confluences of 87% of the tributaries west of Jiacha Gorge are high-angle or perpendicular, reflecting the anomalous development of these tributaries. In this paper, field investigation and digital elevation model (DEM) methods were used to analyse the causes of this anomalous phenomenon, and it was found that there was a watershed in the area of the Jiacha Gorge. The palaeo-YZR west of the Jiacha Gorge flowed westward before the early Pleistocene into the Zada, Zhongba, Jilong and Gamba-Dingri palaeolakes, which featured a large amount of total accommodation space in the western Qinghai-Tibet Plateau; thus, this river was a continental river. With the intensification of the collision between the Indian plate and the Eurasian plate, the Qinghai-Tibet Plateau experienced rapid uplift and formed a landscape with high elevations in the west and lower elevations in the east, promoting the headward erosion of the eastward-flowing river. During the early Pleistocene, the river east of the Jiacha Gorge crossed the watershed and captured the palaeo-YZR, causing a reversal in the flow direction of the palaeo-YZR.

Sleeping habits may greatly impact the prevalence of functional dyspepsia (FD). This study examined relationships between aspects of sleep impairment and FD.

Altered lipid metabolism is a hallmark of cancer. p73, a p53 family member, regulates cellular processes and is expressed as multiple isoforms. However, the role of p73 in regulating lipid metabolism is not well-characterized. Previously, we found that loss of p73 exon 12 (E12) leads to an isoform switch from p73α to p73α1, the latter of which has strong tumor suppressive activity. In this study, comprehensive untargeted metabolomics was performed to determine whether p73α1 alters lipid metabolism in non-small cell lung carcinoma cells. RNA-seq and molecular biology approaches were combined to identify lipid metabolism genes altered upon loss of E12 and identify a direct target of p73α1. We found that loss of E12 leads to decreased levels of phosphatidylcholines, and this was due to decreased expression of genes involved in phosphatidylcholine synthesis. Additionally, we found that E12-knockout cells had increased levels of phosphatidylcholines containing saturated fatty acids (FAs) and decreased levels of phosphatidylcholines containing monounsaturated fatty acids (MUFAs). We then found that p73α1 inhibits cancer cell viability through direct transcriptional suppression of Stearoyl-CoA Desaturase-1 (SCD1), which converts saturated FAs to MUFAs. Finally, we showed that p73α1-mediated suppression of SCD1 leads to increased ratios of saturated FAs to MUFAs.

Background. Work-related musculoskeletal disorders (MSDs) are a group of painful disorders of muscles, tendons, and nerves, such as neck and shoulder MSD. This study was designed to use miniscalpel-needle (MSN) technique as an intervention for work-related MSDs. Methods. Thirty-one patients with work-related MSDs and 28 healthy subjects were enrolled as controls in this study. The MSD symptoms of each patient were assessed by visual analog scale (VAS) and neck disability index (NDI). Blood samples were collected from control subjects and MSD patients before and after treatment. Serum levels of C-reactive protein (CRP) and tumor necrosis factor (TNF) were measured using ELISA. Results. Prior to MSN treatment, serum levels of CRP and TNF were significantly higher in the MSD patients than the healthy controls. Serum CRP levels correlated with VAS and NDI scores, and serum TNF levels correlated with NDI scores. Compared to pretreatment, VAS and NDI scores were significantly lower in MSD patients after MSN treatment, while serum CRP and TNF levels were significantly lower compared with the healthy control levels. Conclusions. Our results indicate that MSN may be an effective intervention for work-related MSDs and be associated with lower serum levels of inflammatory biomarkers.

Nur77, an orphan member of the nuclear receptor superfamily, plays critical roles in inflammation and immunity. However, the role of Nur77 in tumor microenvironment remains elusive. Results showed that deletion of Nur77 strikingly enhanced tumor metastasis compared to WT mice. Additionally, compared to the conditioned media derived from Nur77+/+ peritoneal macrophages (CM1), the conditioned media derived from Nur77-/- peritoneal macrophages (CM2) significantly promoted the EMT of cancer cells, and greatly enhanced the migratory and invasive abilities of cancer cells. Moreover, studies using TNF-α blocking antibody demonstrated that pro-inflammatory cytokine TNF-α was indispensable in supporting CM2-induced EMT to drive cancer cells migration and invasion. Furthermore, we found that Nur77 promoted the expression of CSF-1R, a novel downstream target gene of Nur77, and subsequently enhanced the migration of inflammatory cells. Notably, infiltration of inflammatory cells in the tumors of Nur77-/- mice was markedly abrogated compared to Nur77+/+ mice. Collectively, these results revealed that host Nur77 expression was pivotal in antitumor immune response, and in inhibiting tumor metastasis.

The mechanisms and key factors involved in tumor environments for lung metastasis of CRC are still unclear. Here, using clinical samples from lung metastases of CRC patients, we found that intestinal immune network for IgA production was significantly dysregulated in lung metastases of CRC. Single-cell RNA sequencing discovered a subtype of B cells positive for Erbin, one member of the leucine-rich repeat and PDZ domain (LAP) family, was involved in the lung metastases. Erbin deletion in B cells suppressed lung metastasis of CRC in vivo. And, deletion of Erbin in B cells enhanced the killing effects of CD8+ T cells on tumor cells. Mechanistically, Erbin knockout attenuated TGFβ-mediated suppression of migration of CXCR5+ IgA+ cells and STAT6-mediated PD1 expression. Our study uncovered a key role of Erbin in regulating PD1+ IgA+ B cells in lung metastasis of CRC. Targeting Erbin as well as combined use of neutralizing B cells and antibodies neutralizing PD1 suppresses lung metastasis of CRC in mice, suggesting the potential option for treatment of lung metastasis of CRC.