Intermittent hypoxia exacerbates anxiety in high-fat diet-induced diabetic mice by inhibiting TREM2-regulated IFNAR1 signaling.

BACKGROUND: Type 2 diabetes mellitus (T2DM) and obstructive sleep apnea (OSA) are mutual risk factors, with both conditions inducing cognitive impairment and anxiety. However, whether OSA exacerbates cognitive impairment and anxiety in patients with T2DM remains unclear. Moreover, TREM2 upregulation has been suggested to play a protective role in attenuating microglia activation and improving synaptic function in T2DM mice. The aim of this study was to explore the regulatory mechanisms of TREM2 and the cognitive and anxiety-like behavioral changes in mice with OSA combined with T2DM. METHODS: A T2DM with OSA model was developed by treating mice with a 60% kcal high-fat diet (HFD) combined with intermittent hypoxia (IH). Spatial learning memory capacity and anxiety in mice were investigated. Neuronal damage in the brain was determined by the quantity of synapses density, the number and morphology of brain microglia, and pro-inflammatory factors. For mechanism exploration, an in vitro model of T2DM combined with OSA was generated by co-treating microglia with high glucose (HG) and IH. Regulation of TREM2 on IFNAR1-STAT1 pathway was determined by RNA sequencing and qRT-PCR. RESULTS: Our results showed that HFD mice exhibited significant cognitive dysfunction and anxiety-like behavior, accompanied by significant synaptic loss. Furthermore, significant activation of brain microglia and enhanced microglial phagocytosis of synapses were observed. Moreover, IH was found to significantly aggravate anxiety in the HFD mice. The mechanism of HG treatment may potentially involve the promotion of TREM2 upregulation, which in turn attenuates the proinflammatory microglia by inhibiting the IFNAR1-STAT1 pathway. Conversely, a significant reduction in TREM2 in IH-co-treated HFD mice and HG-treated microglia resulted in the further activation of the IFNAR1-STAT1 pathway and consequently increased proinflammatory microglial activation. CONCLUSIONS: HFD upregulated the IFNAR1-STAT1 pathway and induced proinflammatory microglia, leading to synaptic damage and causing anxiety and cognitive deficits. The upregulated TREM2 inT2DM mice brain exerted a negative regulation of the IFNAR1-STAT1 pathway. Mice with T2DM combined with OSA exacerbated anxiety via the downregulation of TREM2, causing heightened IFNAR1-STAT1 pathway activation and consequently increasing proinflammatory microglia.

Pathway integration and annotation: building a puzzle with non-matching pieces and no reference picture.

Biological pathways are a broadly used formalism for representing and interpreting the cascade of biochemical reactions underlying cellular and biological mechanisms. Pathway representation provides an ontological link among biomolecules such as RNA, DNA, small molecules, proteins, protein complexes, hormones and genes. Frequently, pathway annotations are used to identify mechanisms linked to genes within affected biological contexts. This important role and the simplicity and elegance in representing complex interactions led to an explosion of pathway representations and databases. Unfortunately, the lack of overlap across databases results in inconsistent enrichment analysis results, unless databases are integrated. However, due to absence of consensus, guidelines or gold standards in pathway definition and representation, integration of data across pathway databases is not straightforward. Despite multiple attempts to provide consolidated pathways, highly related, redundant, poorly overlapping or ambiguous pathways continue to render pathways analysis inconsistent and hard to interpret. Ontology-based integration will promote unbiased, comprehensive yet streamlined analysis of experiments, and will reduce the number of enriched pathways when performing pathway enrichment analysis. Moreover, appropriate and consolidated pathways provide better training data for pathway prediction algorithms. In this manuscript, we describe the current methods for pathway consolidation, their strengths and pitfalls, and highlight directions for future improvements to this research area.

Traumatic MicroRNAs: Deconvolving the Signal After Severe Traumatic Brain Injury.

History of traumatic brain injury (TBI) represents a significant risk factor for development of dementia and neurodegenerative disorders in later life. While histopathological sequelae and neurological diagnostics of TBI are well defined, the molecular events linking the post-TBI signaling and neurodegenerative cascades remain unknown. It is not only due to the brain's inaccessibility to direct molecular analysis but also due to the lack of well-defined and highly informative peripheral biomarkers. MicroRNAs (miRNAs) in blood are promising candidates to address this gap. Using integrative bioinformatics pipeline including miRNA:target identification, pathway enrichment, and protein-protein interactions analysis we identified set of genes, interacting proteins, and pathways that are connected to previously reported peripheral miRNAs, deregulated following severe traumatic brain injury (sTBI) in humans. This meta-analysis revealed a spectrum of genes closely related to critical biological processes, such as neuroregeneration including axon guidance and neurite outgrowth, neurotransmission, inflammation, proliferation, apoptosis, cell adhesion, and response to DNA damage. More importantly, we have identified molecular pathways associated with neurodegenerative conditions, including Alzheimer's and Parkinson's diseases, based on purely peripheral markers. The pathway signature after acute sTBI is similar to the one observed in chronic neurodegenerative conditions, which implicates a link between the post-sTBI signaling and neurodegeneration. Identified key hub interacting proteins represent a group of novel candidates for potential therapeutic targets or biomarkers.

Enrichment of biofertilizer-type hydrogen-oxidizing bacteria on urea containing Cu(II).

With the utilization of pesticides and fertilizers (e.g. urea), the presence of nitrogen and heavy metals (e.g. copper) can enter and pollute the environment. Biofertilizers can be used to replace chemical fertilizers to increase crop yields and reduce environmental stress. The utilization of hydrogen-oxidizing bacteria (HOB) to be biofertilizers has recently attracted more attention. However, the enrichment of HOB on urea and the effect of copper are undetermined. HOB were successfully enriched using urea in this investigation. The average urea conversion rate (AUCR) was 180.08 mgN/L/d with a hydraulic retention time of 10 h. Microbial community (R1) was dominated by Hydrogenophaga (83.92%), a biofertilizer-type HOB. After addition of 5.47 mg/L Cu2+, the AUCR was decreased by 16%-151.18 mgN/L/d, and the growth of HOB was inhibited by 48%. Meanwhile, inhibition was also reflected by the increase of polysaccharide content (20.27 ± 0.57 to 33.45 ± 2.53 mg/gVSS) and protein content (106.19 ± 19.39 to 125.14 ± 24.73 mg/gVSS) of extracellular polymeric substances in the HOB. The resulting microbial community (R2) was changed to Azospiralium-dominated flora (91.33%). Both enriched microbial communities (R1 and R2) exhibited the abilities of ACC degradation and phosphate solubilization. This study demonstrates that employing urea can directly enrich biofertilizer-type HOB and copper-tolerant HOB can be obtained in a 5.47 mg/L Cu2+ environment. The results provide potential methods to obtain biofertilizer from copper-containing urea wastewater via HOB.

Safety enhancement of improved hydrodissection for microwave ablation in secondary hyperparathyroidism.

OBJECTIVE: To study the safety of improved hydrodissection based on the periparathyroidal fascial space during microwave ablation (MWA) for secondary hyperparathyroidism (SHPT). MATERIALS AND METHODS: Data from 337 patients (162 males and 175 females; mean age, 50.8 ± 12.8 [range, 16-84] years) who underwent MWA for SHPT were retrospectively reviewed. Among them, 177 patients underwent traditional hydrodissection (traditional group) and 160 patients underwent improved hydrodissection based on periparathyroidal fascial spaces (improved group). Safety enhancement was analyzed by comparing the complications between the two groups. The characteristics of the hydrodissected fascial spaces, complications, and the follow-up results were recorded. The baseline data, clinical parameters, laboratory indices and characteristics of SHPT lesions were analyzed to assess the risk factors associated with hoarseness. RESULTS: Hydrodissection was successfully performed in all the enrolled patients according to the protocol. Six periparathyroid fascial spaces were hydrodissected, depending on the location of the SHPT lesions. The incidence of hoarseness due to recurrent laryngeal nerve injury, the most common complication of thermal ablation for SHPT lesions, was lower in the improved group than in the traditional group (6.9% vs. 13.0%, p = 0.044). The median hoarseness recovery time in the improved group was shorter than that in the traditional group (2 vs. 6 months, p < 0.001). There was no difference in technical efficiency between the two groups (improved group vs. traditional group: 75.0% vs. 70.6%; p > 0.05). CONCLUSIONS: Compared with traditional hydrodissection, improved hydrodissection based on periparathyroidal fascial spaces could enhance safety during MWA for SHPT.

(-)-Epicatechin gallate prevents inflammatory response in hypoxia-activated microglia and cerebral edema by inhibiting NF-κB signaling.

High-altitude cerebral edema (HACE), a potentially lethal disease, is associated with a time-dependent exposure to altitude-related hypobaric hypoxia (HH) and has reportedly been associated with microglia hyperactivation. Catechins are substances with good antioxidant properties, among which (-)-epigallocatechin gallate (EGCG) may play a neuroprotective role through the inhibition of microglia overactivation; however, the function of its analog- (-)-epicatechin gallate (ECG)-requires further elucidation. The aim of the present study was to investigate whether ECG prevented HACE by inhibiting HH-activated microglia. Primary microglia exposed to lipopolysaccharide (LPS)/ATP were co-treated with EGCG, ECG, and (-)-epigallocatechin, and ECG and EGCG exerted significant anti-inflammatory and neuroprotective effects. ECG inhibited the NF-κB pathway to prevent the activation of microglia induced by 1% O2. In addition, ECG ameliorated the increase in brain water content and aquaporin 4 expression induced by HH in mice. ECG also reduced the number of Iba1+ microglia in the brain, the release of proinflammatory factors, and the recruitment of microglia to blood vessels in HH-exposed mice. The outcomes of the present study revealed that ECG alleviated hypoxic hyperactivated microglia, reduced the neuroinflammation and blood-brain barrier permeability, and prevented HACE by inhibiting NF-κB signaling.

Intermolecular interactions, photocatalysis and THz-TDS interrelationships for lanthanide phosphine oxide complexes based on {PW12}.

A series of rare earth complexes containing (α-PW12O40)3- and PO ligand are synthesized by water bath in 70 °C, [Ln(OPPh3)4(H2O)3](PW12O40)·4CH3CN (Ln = La, Pr, Nd, Sm, Gd, Tb, Ho 1-7) (OPPh3 = Triphenylphosphine oxide, {PW12} = phosphotungstic acid). The precise structures are confirmed by X-ray single crystal diffraction and the result shows all complexes are isostructural. Complexes 1-7 are fully characterized by PXRD, FT-IR, TGA, UV diffuse reflectance spectra and terahertz time-domain spectroscopy (THz-TDS). Complex 3 exhibits the highest photocatalytic degradation efficiency for methylene blue (MB) in this series of complexes. The experimental results showed that the photodegradation efficiency can remain constant at the level of 95% after five consecutive cycles. The photocatalytic reaction kinetics and mechanism of complexes were investigated. Additionally, complexes also exhibit photocatalytic hydrogen evolution activity. THz-TDS was used to characterize the complexes and its raw materials, the characteristic peaks of OPPh3 (broad peak at 1.20 THz) and phosphotungstic acid (sharp peaks at 0.23, 0.32 THz) were obtained.

Facile high yield, excellent catalytic performance of polyoxometalate-based lanthanide phosphine oxide complexes: Syntheses, structures, photocatalysis and THz spectra.

Water pollution, which continuously threatens human health and the sustainable development of society, has become a major concern. Photocatalytic degradation is an effective strategy to remove organic dyes from wastewater. For this strategy, it is crucial to select the appropriate catalyst. Using triphenylphosphine oxide (OPPh3) as the ligand, phosphomolybdic acid as the anion template, three new lanthanide complexes [Ln(OPPh3)4(H2O)3](PMo12O40)∙4C2H5OH (1-3) (Ln = Sm, Gd, Tb) were synthesized. The raw materials for the reaction are cheap and readily available. The convenient synthesis method is environmentally friendly, with high yield (70%-80%). Complexes 1-3 are all seven-coordinated mononuclear structures centered on lanthanide ions, [PMo12O40]3- anions and solvent molecules are not coordinated with metal ions. These mononuclear structures eventually form complicated 3D supramolecular structures through hydrogen bonds, Mo-O … π or C-H … π weak interactions. Complexes 1-3 photocatalytic degradation of MB have high removal rates, as catalysts have enough stability to be reused, and can be used as excellent catalysts for the degradation of dye molecules in sewage. Among them, the removal rate of MB by photodegradation of complex 2 was highest (99.50%). In addition, the effects of different initial concentrations of MB solution and different types of organic dyes on the photocatalysis experiment were investigated. The photocatalytic reaction mechanism of complexes 1-3 was also studied. Due to the similar structures of complexes 1-3, they have almost the same THz absorption spectra with different absorption intensity, which may be attributed to the difference of the number of weak interactions. Therefore, terahertz spectroscopy can be used as a sensitive method to distinguish and determine small differences between lanthanide-organic complexes. This is the first time that this spectrum has been used to characterize lanthanide phosphine oxide complexes modified by [PMo12O40]3-.

A Review of Crystalline Multibridged Cyclophane Cages: Synthesis, Their Conformational Behavior, and Properties.

This paper reviews the most stable conformation of crystalline three-dimensional cyclophane (CP) achieved by self-assembling based on changing the type of aromatic compound or regulating the type and number of bridging groups. [3n]cyclophanes (CPs) were reported to form supramolecular compounds with bind organic, inorganic anions, or neutral molecules selectively. [3n]cyclophanes ([3n]CPs) have stronger donor capability relative to compound [2n]cyclophanes ([2n]CPs), and it is expected to be a new type of electron donor for the progress of fresh electron conductive materials. The synthesis, conformational behavior, and properties of crystalline multi-bridge rings are summarized and discussed.

[Structural Design and Finite Element Analysis of New Type Posterior Integral Glaucoma Valve].

The treatment of refractory Glaucoma is a difficult problem in clinical ophthalmology. For refractory glaucoma patients with hyphema, shallow anterior chamber, anterior conglutination of peripheral chamber angle, corneal endothelium dystrophy or decompensated, at present, there is no effective treatment. In order to solve this problem, a new type posterior integral glaucoma valve with IOP control device was designed using medical titanium alloy, and the valve model was established by Abaqus software, and the stiffness and preload of the valve were analyzed by finite element method. The results showed that the opening and closing of the valve were controlled automatically by the pressure difference between the front and back of the valve, and the opening and flow rate of the valve increase dynamically with the increase of intraocular pressure, and finally reached the set ideal IOP value of steady state.

Modelling the effects of the contaminated environments on tuberculosis in Jiangsu, China.

Tuberculosis (TB) is still an important public health issue in Jiangsu province, China. In this study, based on the TB transmission routes and the statistical data of TB cases, we formulate a novel TB epidemic model accounting for the effects of the contaminated environments on TB transmission dynamics. The value of this study lies in two aspects. Mathematically, we define the basic reproduction number, R0, and prove that R0 can be used to govern the threshold dynamics of the model. Epidemiologically, we find that the annual average R0 is 1.13,>1 and TB in Jiangsu is an endemic disease. Therefore, in order to control the TB in Jiangsu efficiently, we must decrease the virus shedding rate or increase the recovery rates, and increase the environmental clearance rate.

Responses of microbial function, biomass and heterotrophic respiration, and organic carbon in fir plantation soil to successive nitrogen and phosphorus fertilization.

Carbon dioxide (CO2) emissions from forest ecosystems originate largely from soil respiration, and microbial heterotrophic respiration plays a critical role in determining organic carbon (C) stock. This study investigated the impacts of successive nitrogen (N) and phosphorus (P) fertilization after 9 years on soil organic C stock; CO2 emission; and microbial biomass, community, and function in a Chinese fir plantation. The annual fertilization rates were (1) CK, control without N or P fertilization; (2) N50, 50 kg N ha-1; (3) N100, 100 kg N ha-1; (4) P50, 50 kg P ha-1; (5) N50P50, 50 kg N ha-1 + 50 kg P ha-1; and (6) N100P50, 100 kg N ha-1 + 50 kg P ha-1. The N100P50 treatment had the highest cumulative soil CO2 emissions, but the CK treatment had the lowest cumulative soil CO2 emissions among all treatments. The declines of soil organic C (SOC) after successive 9-year fertilization were in the order of 100 kg N ha-1 year-1 > 50 kg N ha-1 year-1 > CK. Compared to the CK treatment, successive N fertilization significantly changed soil microbial communities at different application rates and increased the relative gene abundances of glycoside hydrolases, glycosyl transferases, carbohydrate-binding modules, and polysaccharide lyases at 100 kg N ha-1 year-1. Relative to P fertilization alone (50 kg P ha-1 year-1), combined N and P fertilization significantly altered the soil microbial community structure and favored more active soil microbial metabolism. Microbial community and metabolism changes caused by N fertilization could have enhanced CO2 emission from heterotrophic respiration and eventually led to the decrease in organic C stock in the forest plantation soil. KEY POINTS: • N fertilization, alone or with P, favored more active microbial metabolism genes. • 100 kg N ha-1 fertilization significantly changed microbial community and function. • N fertilization led to a "domino effect" on the decrease of soil C stock.

Extracellular Matrix Injury of Kidney Allografts in Antibody-Mediated Rejection: A Proteomics Study.

BACKGROUND: Antibody-mediated rejection (AMR) accounts for >50% of kidney allograft loss. Donor-specific antibodies (DSA) against HLA and non-HLA antigens in the glomeruli and the tubulointerstitium cause AMR while inflammatory cytokines such as TNFα trigger graft injury. The mechanisms governing cell-specific injury in AMR remain unclear. METHODS: Unbiased proteomic analysis of laser-captured and microdissected glomeruli and tubulointerstitium was performed on 30 for-cause kidney biopsy specimens with early AMR, acute cellular rejection (ACR), or acute tubular necrosis (ATN). RESULTS: A total of 107 of 2026 glomerular and 112 of 2399 tubulointerstitial proteins was significantly differentially expressed in AMR versus ACR; 112 of 2026 glomerular and 181 of 2399 tubulointerstitial proteins were significantly dysregulated in AMR versus ATN (P<0.05). Basement membrane and extracellular matrix (ECM) proteins were significantly decreased in both AMR compartments. Glomerular and tubulointerstitial laminin subunit γ-1 (LAMC1) expression decreased in AMR, as did glomerular nephrin (NPHS1) and receptor-type tyrosine-phosphatase O (PTPRO). The proteomic analysis revealed upregulated galectin-1, which is an immunomodulatory protein linked to the ECM, in AMR glomeruli. Anti-HLA class I antibodies significantly increased cathepsin-V (CTSV) expression and galectin-1 expression and secretion in human glomerular endothelial cells. CTSV had been predicted to cleave ECM proteins in the AMR glomeruli. Glutathione S-transferase ω-1, an ECM-modifying enzyme, was significantly increased in the AMR tubulointerstitium and in TNFα-treated proximal tubular epithelial cells. CONCLUSIONS: Basement membranes are often remodeled in chronic AMR. Proteomic analysis performed on laser-captured and microdissected glomeruli and tubulointerstitium identified early ECM remodeling, which may represent a new therapeutic opportunity.

Novel Perbutyrylated Glucose Derivatives of (-)-Epigallocatechin-3-Gallate Inhibit Cancer Cells Proliferation by Decreasing Phosphorylation of the EGFR: Synthesis, Cytotoxicity, and Molecular Docking.

Lung cancer is one of the most commonly occurring cancer mortality worldwide. The epidermal growth factor receptor (EGFR) plays an important role in cellular functions and has become the new promising target. Natural products and their derivatives with various structures, unique biological activities, and specific selectivity have served as lead compounds for EGFR. D-glucose and EGCG were used as starting materials. A series of glucoside derivatives of EGCG (7-12) were synthesized and evaluated for their in vitro anticancer activity against five human cancer cell lines, including HL-60, SMMC-7721, A-549, MCF-7, and SW480. In addition, we investigated the structure-activity relationship and physicochemical property-activity relationship of EGCG derivatives. Compounds 11 and 12 showed better growth inhibition than others in four cancer cell lines (HL-60, SMMC-7721, A-549, and MCF), with IC50 values in the range of 22.90-37.87 µM. Compounds 11 and 12 decreased phosphorylation of EGFR and downstream signaling protein, which also have more hydrophobic interactions than EGCG by docking study. The most active compounds 11 and 12, both having perbutyrylated glucose residue, we found that perbutyrylation of the glucose residue leads to increased cytotoxic activity and suggested that their potential as anticancer agents for further development.

Two Nanometer-Sized High-Nuclearity Homometallic Bromide Clusters (M26Br38)12- (M = Cu, Ag): Syntheses, Crystal Structures, and Efficient Adsorption Properties.

The spontaneous formation of discrete spherical nanosized molecules is ubiquitous in nature; however, the actual structural imitation of such high-symmetry polyhedra from the edge sharing of regular polygons has still proved to be elusive. Herein, two high-nuclearity metal clusters, namely (TTB)4·M26Br38 (M = Cu (1), Ag (2), TTB·Br3 = 1, 3, 5-tris(triethylammoniomethyl)benzene tribromide), have been rationally and solvothermally synthesized and structurally characterized. Single-crystal X-ray analysis confirmed that 1 has I4̅3m symmetry with a (Cu25Br34)12- anion shell enwrapping a CuBr4 tetrahedron and 2 has I4̅3m symmetry with a [Ag26Br34]12- anion shell enwrapping a Br4 pyramid. The diffuse-reflectance UV-vis measurements showed that both compounds possess proper semiconductor behaviors with tunable band gaps of 1.87 eV for 1 and 1.90 eV for 2. Interestingly, all the samples feature distinct adsorption speed and compound 1 shows good adsorption activity for methyl orange (MO) under the same reaction conditions. The effects of pH, temperature, and cyclicity on dye adsorption, together with the thermal stabilities and luminescence properties of the compounds, were also studied. From the cyclic adsorption of compound 1 to the anionic dye MO, it was found that the adsorption of MO was good over three cycles, and the third adsorption rate was still 93.90%.

Successive mineral nitrogen or phosphorus fertilization alone significantly altered bacterial community rather than bacterial biomass in plantation soil.

Bacteria play determining roles in forest soil environment and contribute to essential functions in the cycling of nitrogen (N) and phosphorus (P). Understanding the effects of different fertilizer applications, especially successive fertilization, on soil properties and bacterial community could reveal the impacts of fertilization on forest soil ecology and shed light on the nutrient cycling in forest system. This study aimed to evaluate the impacts of successive mineral N (NH4NO3) and P (NaH2PO4) fertilization at different rates, alone or together, on soil bacterial biomass and communities at 0-5, 5-10, and 10-20 cm. Compared with the control, N fertilization decreased soil pH, but P alone or with N fertilization had negligibly negative impacts on soil pH. Different mineral fertilizer applications, alone or together, showed no significant effects on soil organic matter contents, relative to the control treatment. Bacterial biomass remained stable to different fertilizations but decreased with sampling depths. Sole N or P fertilization, rather than combined fertilizations, significantly changed soil bacterial community structures. Our results demonstrated that mineral N or P fertilization alone significantly affected bacterial community structures rather than biomass in the plantation soils. KEY POINTS: • Impacts of successive mineral fertilization on soil bacteria were determined. • Mineral fertilization showed negligible impacts on bacterial biomass. • N additions stimulated Chloroflexi relative abundances. • Mineral N or P fertilization significantly altered bacterial community structure.

Hybrid and Endovascular Treatment of Pulmonary Sequestration: Two Case Reports and Literature Review.

Pulmonary sequestration is an uncommon congenital pulmonary anomaly associated with aberrant systemic arteries which usually originate from the thoracic aorta or abdominal aorta. Traditionally, surgical resection and ligation of the feeding vessels are the gold standard treatments of the disease. Endovascular intervention and hybrid operation are promising treatment options. However, the case reports with endovascular and hybrid treatment are sparse to our knowledge. We presented 2 symptomatic adult patients with pulmonary sequestration successfully treated by hybrid operation and transcatheter embolization, respectively. Besides, we reviewed 37 previously reported cases of pulmonary sequestration treated by endovascular or hybrid treatment.

TGF-ß1 stimulates epithelial-mesenchymal transition and cancer-associated myoepithelial cell during the progression from in situ to invasive breast cancer.

BACKGROUND: The progression of ductal carcinoma in situ (DCIS) into invasive ductal carcinoma (IDC) is prevented by normal breast myoepithelial cells. Studies have suggested that EMT-associated genes were enriched in IDC in contrast to DCIS. This paper explored the relationship and potential mechanism between myoepithelial cells and EMT-associated genes in facilitating the transformation from DCIS to breast cancer. METHODS: EMT markers and myoepithelial phenotypic markers in IDC, DCIS, and healthy breast tissue were characterized using immunohistochemical assay. Both in vivo and in vitro models were created to mimic the various cell-cell interactions in the development of invasive breast cancer. RESULTS: We found that EMT markers were more abundant in invasive carcinomas than DCIS and adjacent normal breast tissue. Meanwhile, TGF-ß1 regulated the morphology of MCF-7 (epithelial cells substitute) migration and EMT markers during the transformation from DCIS to invasive breast cancer. Additionally, TGF-ß1 also regulated invasion, migration and cytokines secretion of MDA-MB-231 (myoepithelial cells substitute) and epithelial cells when co-cultured with MCF-7 both in vitro and in vivo. CONCLUSIONS: In conclusion, these findings demonstrated that both EMT phenotypes and cancer-associated myoepithelial cells may have an impact on the development of invasive breast cancer.

Efficient Extraction of Anti-Inflammatory Active Ingredients from Schefflera octophylla Leaves Using Ionic Liquid-Based Ultrasonic-Assisted Extraction Coupled with HPLC.

Schefflera octophylla (Lour.) Harms, a kind of traditional Chinese medicine (TCM), is commonly used for anti-inflammatory, analgesic, rheumatism, fever, and hemostasis therapy. In our previous studies, two major triterpenoids were isolated and identified from leaves of S. octophylla, and evaluated for their inhibitory effects on lipopolysaccharide (LPS)-induced nitric oxide production in RAW264.7 cells; both of them displayed significant anti-inflammatory activities at their noncytotoxic concentrations. Therefore, it is very useful to establish an efficient and green extraction method to isolated the two major triterpenoids from leaves of S. octophylla. In this paper, ionic liquid based ultrasonic-assisted extraction (ILUAE) was successfully applied to extract the two major triterpenoids from leaves of S. octophylla. Four single factors (ionic liquids (ILs) concentration, solid-liquid ratio, centrifugal speed, mesh number), with a greater impact on extraction rate, were selected from a variety of influencing factors, and the optimal conditions were obtained by Box-Behnken response surface methodology (RSM). Under optimal conditions, the total extraction yield and extraction rate of two triterpenoids were 288.03 mg/g and 28.80%, respectively, which was 6.80% higher than that of 70% Ethanol (220 mg/g and 22%, respectively).

AR-PDEF pathway promotes tumour proliferation and upregulates MYC-mediated gene transcription by promoting MAD1 degradation in ER-negative breast cancer.

BACKGROUND: Androgen receptor (AR) is expressed in 60%~ 70% oestrogen receptor (ER)-negative breast cancer (BC) cases and promotes the growth of this cancer subtype. Expression of prostate-derived Ets factor (PDEF), a transcription factor, is highly restricted to epithelial cells in hormone-regulated tissues. MYC and its negative regulator MAD1 play an important role in BC progression. Previously, we found that PDEF expression is strongly correlated with AR expression. However, the relationship between AR and PDEF and the function of PDEF in ER-negative BC proliferation are unclear. METHODS: AR and PDEF expression in ER-negative BC tissues and cell lines was determined by performing immunohistochemistry or western blotting. Protein expression levels and location were analysed by performing western blotting, RT-qPCR and immunofluorescence staining. Co-immunoprecipitation and chromatin immunoprecipitation assays were performed to validate the regulation of AR-PDEF-MAD1-MYC axis. Moreover, the effect of AR and PDEF on BC progression was investigated both in vitro and in vivo. RESULTS: We found that PDEF was overexpressed in ER-negative BC tissues and cell lines and appeared to function as an oncogene. PDEF expression levels were strongly correlated with AR expression in ER-negative BC, and PDEF transcription was positively regulated by AR. PDEF upregulated MYC-mediated gene transcription by promoting MAD1 degradation in ER-negative BC. Finally, we found that compared with the inhibition of AR expression alone, simultaneous inhibition of AR and PDEF expression further suppressed tumour proliferation both in vitro and in vivo. CONCLUSIONS: Our data highlight the role of the AR-PDEF-MAD1-MYC axis in BC progression and suggest that PDEF can be used as a new clinical therapeutic target for treating ER-negative BC.