Phototheranostics have emerged and flourished as a promising pattern for cancer theranostics owing to their precise photoinduced diagnosis and therapeutic to meet the demands of precision medicine. ...The diagnosis information and therapeutic effect are directly determined by the fluorescence imaging ability and photothermal conversion efficiency (PCE) of phototheranostic agents. Hence, how to balance the competitive radiative and nonradiative processes of phototheranostic agents is the key factor to evaluate the phototheranostic effect. Herein, molecules named ICRs with high photostaibility are rationally designed, exhibiting fluorescence emission in the second near‐infrared window (NIR‐II, 1000–1700 nm) and high PCE, which are related to the strong donor–acceptor (D–A) interaction and high reorganization energy Noteworthily, ICR‐Qu with stronger D–A interaction and a large‐sized conjugated unit encapsulated in nanoparticles exhibits high PCE (81.1%). In addition, ICR‐QuNPs are used for fluorescence imaging (FLI), photoacoustic imaging (PAI), and photothermal imaging (PTI) to guide deep‐tissue photonic hyperthermia, achieving precise removal and inhibition of breast cancer. Furthermore, combined with α‐PD‐1, ICR‐QuNPs show huge potential to be a facile and efficient tool for photo‐immunotherapy. More importantly, this study not only reports an “all‐in‐one” polymethine‐based phototheranostic agent, but also sheds light on the exploration of versatile organic molecules for future practical applications.
Polymethine dyes with second near‐infrared emission and photoacoustic imaging capability are synthesized by the electronic‐donor group regulation strategy, which demonstrates high photothermal conversion efficiency (PCE = 81.1%) as an antitumor stategy in vivo and in vitro under the multimodal imaging guidance; theoretical calculation reveals the structure regulation mechanism for the polymethine‐based phototheranostic agent to achieve an excellent PCE.
3-Hydroxypropionic acid (3HP), an important three carbon (C3) chemical, is designated as one of the top platform chemicals with an urgent need for improved industrial production. Halomonas ...bluephagenesis shows the potential as a chassis for competitive bioproduction of various chemicals due to its ability to grow under an open, unsterile and continuous process. Here, we report the strategy for producing 3HP and its copolymer poly(3-hydroxybutyrate-co-3-hydroxypropionate) (P3HB3HP) by the development of H. bluephagenesis. The transcriptome analysis reveals its 3HP degradation and synthesis pathways involving endogenous synthetic enzymes from 1,3-propanediol. Combing the optimized expression of aldehyde dehydrogenase (AldD
), an engineered H. bluephagenesis strain of whose 3HP degradation pathway is deleted and that overexpresses alcohol dehydrogenases (AdhP) on its genome under a balanced redox state, is constructed with an enhanced 1.3-propanediol-dependent 3HP biosynthetic pathway to produce 154 g L
of 3HP with a yield and productivity of 0.93 g g
1,3-propanediol and 2.4 g L
h
, respectively. Moreover, the strain could also accumulate 60% poly(3-hydroxybutyrate-co-32-45% 3-hydroxypropionate) in the dry cell mass, demonstrating to be a suitable chassis for hyperproduction of 3HP and P3HB3HP.
Anaplastic lymphoma kinase (ALK) activation has been associated with many types of human cancer. Significant efforts have been devoted to the development of ALK inhibitors to antagonize the kinase ...activity of ALK. Four ALK inhibitors have been approved by the FDA to date for treating patients with ALK-positive non-small cell lung cancers (NSCLC). However, drug resistance has been observed in the majority of patients treated with these inhibitors. New therapeutic strategies (e.g., compounds with novel mechanisms of action) are needed to overcome the drug resistance issue. The emerging PROTAC (Proteolysis Targeting Chimera) technology has been successfully applied to selective degradation of multiple protein targets, but not ALK. Since ALK protein levels are not important for viability in mammals, ALK PROTACs could lead to novel therapeutics with minimal toxicity. Here we report the design, synthesis and biological evaluation of novel PROTACs (degraders) of ALK. MS4077 (5) and MS4078 (6) potently decreased cellular levels of oncogenic active ALK fusion proteins in a concentration- and time-dependent manner in SU-DHL-1 lymphoma and NCI-H2228 lung cancer cells. The ALK protein degradation induced by compounds 5 and 6 was cereblon and proteasome dependent. In addition, compounds 5 and 6 potently inhibited proliferation of SU-DHL-1 cells. Furthermore, compound 6 displayed good plasma exposure in a mouse pharmacokinetic study, thus is suitable for in vivo efficacy studies. We also developed MS4748 (7) and MS4740 (8), very close analogs of 5 and 6 respectively, which are incapable to degrade the ALK fusion proteins, as negative controls. Compounds 5–8 are valuable chemical tools for investigating effects of ALK pharmacological degradation. Our study paved the way for developing the next generation of ALK PROTACs.
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•We discovered novel ALK PROTACs (MS4077 and MS4078) and their close analogs as negative controls.•MS4077 and MS4078 potently reduced cellular ALK protein levels in a cereblon and proteasome dependent manner.•MS4077 and MS4078 potently inhibited cellular ALK signaling.•MS4077 and MS4078 effectively inhibited cancer cell proliferation.•MS4078 displayed good plasma exposure in mice, thus is suitable for in vivo efficacy studies.
Contamination of agricultural soil by heavy metals has become a global issue concerning food security and human health risk. In this study, a soil investigation was conducted to evaluate metals ...accumulation, potential ecological and health risks as well as to identify sources of metals in paddy soils in Hanzhong City, which is located in a sedimentary basin. Ninety-two (92) surface soil samples (bulk soil) and their corresponding rice samples, 21 irrigation water samples, and 18 fertilizer samples were collected from two typical counties and quantified for the heavy metals (i.e., As, Cd, Cu, Hg, Pb, and Zn) concentrations. The results showed that As, Cd, and Zn were the main contaminants in soils in the studied area. Additionally, elevated Hg content in soils might also pose risks to the local ecosystem. Cadmium and As demonstrated high mobility, and their average contents in rice grains were slightly higher than the permissible threshold (0.20 mg kg−1). Moreover, Pb, As, and Cd intake via rice consumption might result in potential risks to local residents. Metal distribution revealed that pollution in the studied area is non-homogeneous, and agricultural activities (As, Cu, and Cd), transportation emission (Cu and Pb), coal combustion (Hg and As), and smelting activities (Zn, Pb, and Cu) were ascertained as the potential sources based on the Positive matrix factorization (PMF) analysis results.
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•Metal contents in 92 soil and rice, 22 water, and 18 fertilizer samples were determined.•Cd and As were the main pollutants in soils, and soil Hg may pose risks to local ecosystem.•Average Cd and As contents in rice grains slightly exceeded the permissive limits.•Daily intake of Pb, As, and Cd might pose risks to local residents health.•Five sources were identified as main contributors to the elevated metals in paddy soils.
Organic molecules with second near‐infrared (NIR‐II, 1000–1700 nm) emission have significant advantages over NIR‐I (600–900 nm) dyes, and have been widely used as phototheranostic agents (PTAs) and ...fluorescent probes. However, the two biggest challenges for such reagents are improving photothermal conversion efficiency (PCE), and simplifying tedious synthetic procedures. Herein, different from the traditional NIR skeleton, for the first time, it develops two novel dibenzofulvene‐based NIR‐II emission PTAs via D‐π‐A concept with high PCEs through two simple synthetic steps. The increased intramolecular charge transfer effect and extended π‐conjugation effectively red‐shift their emissions to the NIR‐II region. In addition, the introduction of molecular rotors/vibrators and the formation of π–π stacking prompt the two PTAs to exhibit high PCEs. Notably, FE‐IDMN nanoparticles (FE‐IDMN NPs) achieve an exciting PCE of 82.6%, higher than most reported photothermal agents with NIR‐II emission. FE‐IDMN NPs also possess good colloidal, pH, and photothermal stabilities, as well as excellent photoacoustic response, which is further successfully applied for NIR‐II fluorescence/photoacoustic/photothermal imaging‐guided photothermal therapy. This work provides a simple strategy for constructing new D‐π‐A PTAs with low molecular weight, NIR‐II emission, and high PCE for cancer therapy.
A novel low‐molecular‐weight dibenzofulvene‐based D‐π‐A phototheranostic agent (PTA) with NIR‐II emission and high PCE is developed by the strategies of enhancing D‐A strength, introducing molecular rotors/vibrators, and facilitating intermolecular π–π stacking. The PTA is successfully applied in the multi‐modal imaging (NIR‐II fluorescence/photoacoustic/photothermal imaging)‐guided photothermal therapy.
Metal oxide-biochar composites have been used for removing pollutants from aqueous systems. In this work, optimized MgO-impregnated porous biochar was prepared using an integrated ...adsorption-pyrolysis method for absorption of phosphate, ammonium and organic matter (humate). Results revealed that the MgO-biochar was comprised of nano-sized MgO flakes and nanotube-like porous carbon. Mg content had significant effects on the development of the nanotube-like porous carbon structure in MgO impregnated biochar and its adsorption capacity for phosphate, ammonium and humate. The adsorption isotherms fitted by Langmuir model illustrated that the optimized adsorbent, 20% Mg-biochar, exhibited maximum adsorption capabilities of more than 398 mg/g for phosphate, 22 mg/g for ammonium, and 247 mg/g for humate, respectively. The phosphate adsorption fitted the pseudo-second-order kinetic model, while ammonium and humate adsorption were best described by the intra-particle diffusion model. The existence of Cl−, NO3−, SO42−, K+, Na+ and Ca2+ ions had no significant impacts on humate adsorption, but the presence of SO42− and Ca2+ affected the phosphate adsorption, and the presence of K+, Na+ and Ca2+ ions inhibited ammonium adsorption. Characterization of adsorbents by X-ray diffraction (XRD), field-emission scanning electron microscopy (SEM), and Fourier transform infrared spectroscopy (FTIR) before and after treating swine wastewater revealed that struvite crystallization, electrostatic attraction, and π–π interactions contributed to the adsorption of phosphate, ammonium and humate. The results demonstrated that the optimized MgO-biochar could be employed as an effective adsorbent for the simultaneous removal and recovery of phosphate, ammonium and organic substances from nutrient-rich livestock wastewaters.
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•Mg introduction enhanced biochar’s affinities for phosphate and organic matter.•MgO-impregnated biochar was optimized at 20% Mg content for pollutant sorption.•More than 398 mg phosphate, 22 mg ammonium and 247 mg humate captured by per gram sorbent.•MgO-biochar decontamination of swine wastewater involved multi-mechanisms.
Adipose-derived stem cells (ASCs) can be applied extensively in the clinic because they can be easily isolated and cause less donor-site morbidity; however, their application can be complicated by ...patient-specific factors, such as age and harvest site. In this study, we systematically evaluated the effects of age on the quantity and quality of human adipose-derived mesenchymal stem cells (hASCs) isolated from excised chest subcutaneous adipose tissue and investigated the underlying molecular mechanism. hASCs were isolated from donors of 3 different age-groups (i.e., child, young adult, and elderly). hASCs are available from individuals across all age-groups and maintain mesenchymal stem cell (MSC) characteristics. However, the increased age of the donors was found to have a significant negative effect on hASCs frequency base on colony-forming unit fibroblasts assay. Moreover, there is a decline in both stromal vascular fraction (SVF) cell yield and the proliferation rate of hASCs with increasing age, although this relationship is not significant. Aging increases cellular senescence, which is manifested as an increase in SA-β-gal-positive cells, increased mitochondrial-specific reactive oxygen species (ROS) production, and the expression of p21 in the elderly. Further, advancing age was found to have a significant negative effect on the adipogenic and osteogenic differentiation potentials of hASCs, particularly at the early and mid-stages of induction, suggesting a slower response to the inducing factors of hASCs from elderly donors. Finally, impaired migration ability was also observed in the elderly group and was determined to be associated with decreased expression of chemokine receptors, such as CXCR4 and CXCR7. Taken together, these results suggest that, while hASCs from different age populations are phenotypically similar, they present major differences at the functional level. When considering potential applications of hASCs in cell-based therapeutic strategies, the negative influence of age on hASC differentiation potential and migration abilities should be taken seriously.
Solid insulators applying functionally graded material (d-FGM) have spatially non-uniform dielectric properties. The d-FGM insulator is effective on insulation performance improvement without ...complicating the structure; however, the fabrication of such insulators remains a challenge. To investigate the feasibility of 3D printing technology on d-FGM, we designed and fabricated a conductivity non-uniform insulator and tested its surface flashover characteristics. First, a modified genetic algorithm is employed to design the conductivity distribution in the non-uniform insulator. The designed insulator is then fabricated using a 3D printing process named fused deposition modeling (FDM), in which we verified the applicability of 3D printing materials on electrical insulation. Finally, compared to the uniform insulator, the surface flashover voltages of non-uniform insulators were improved by 23% in SF 6 and 20% in vacuum. From above, we envision potential application feasibility for 3D printing of d-FGM in practical insulation design.
Abstract
Mesenchymal stem cells (MSCs) are a new therapeutic strategy for inflammatory bowel disease (IBD), and their efficacy has been widely recognized. However, there are still some challenges in ...cell therapy, including stable cell passage, laboratory conditions for cell culture, high-cost burden, and poor transplantation. The conditioned medium (CM) of MSCs is considered be an excellent alternative to cell transplantation, but the paracrine group in MSC-CM is limited in variety and low in concentration, which cannot meet the therapeutic needs of injured tissues and needs to be optimized. Pretreatment with low concentration of hydrogen peroxide (H
2
O
2
) can not only protect cells from oxidative damage, but also play a role similar to growth factors and regulate the physiological function of stem cells, to obtain an improved conditioned medium. To determine the optimal protocol for pretreatment of MSCs with H
2
O
2
, and to study the efficacy and potential mechanism of MSC-CM pretreated with H
2
O
2
on Dextran Sulfate Sodium (DSS)-induced acute experimental colitis. MSCs were exposed to different concentrations of H
2
O
2
, and the optimal H
2
O
2
pretreatment conditions were determined by evaluating their critical cell functional properties. H
2
O
2
-pretreated MSC-CM was transplanted into experimental mouse colitis by enema at 2, 4, and 6 days in modeling, and the changes of colonic tissue structure, the levels of inflammation and oxidative stress, the molecular changes of Nrf2/Keap1/ARE axis, and the related indicators of apoptosis in colonic epithelial cells were observed in each group. In vitro, Pretreated MSCs with 25 μM H
2
O
2
significantly enhanced cell proliferation, migration, and survival, but had no effect on apoptosis. In vivo, MSC-CM treatment decreased apoptosis and extracellular matrix deposition, and maintained the mechanical barrier and permeability of colonic epithelial cells in experimental mouse colitis. Mechanistically, H
2
O
2
-pretreated MSC-CM against reactive oxygen species (ROS) production and MDA generation, accompanied by increases in components of the enzymatic antioxidant system includes SOD, CAT, GSH-PX, and T-AOC, which is through the up-regulation of the Nrf2, HO-1, and NQO-1 antioxidant genes. Our data confirmed that 25 μM H
2
O
2
pretreated MSC-CM treatment could effectively improve intestinal mucosal repair in experimental colitis, which may be achieved by activating Nrf2/Keap1/ARE pathway.
Astrocytic morphological plasticity and its modulation of adjacent neuronal activity are largely determined by astrocytic volume regulation, in which glial fibrillary acidic protein (GFAP), aquaporin ...4 (AQP4), and potassium channels including inwardly rectifying K+ channel 4.1 (Kir4.1) are essential. However, associations of astrocyte‐dominant Kir4.1 with other molecules in astrocytic volume regulation and the subsequent influence on neuronal activity remain unclear. Here, we report our study on these issues using primary cultures of rat pups' hypothalamic astrocytes and male adult rat brain slices. In astrocyte culture, hyposmotic challenge (HOC) significantly decreased GFAP monomer expression and astrocytic volume at 1.5 min and increased Kir4.1 expression and inwardly rectifying currents (IRCs) at 10 min. BaCl2 (100 μmol/l) suppressed the HOC‐increased IRCs, which was simulated by VU0134992 (2 μmol/l), a Kir4.1 blocker. Preincubation of the astrocyte culture with TGN‐020 (10 μmol/l, a specific AQP4 blocker) made the HOC‐increased Kir4.1 currents insignificant. In hypothalamic brain slices, HOC initially decreased and then increased the firing rate of vasopressin (VP) neurons in the supraoptic nucleus. In the presence of BaCl2 or VU0134992, HOC‐elicited rebound increase in VP neuronal activity was blocked. GFAP was molecularly associated with Kir4.1, which was increased by HOC at 20 min; this increase was blocked by BaCl2. These results suggest that HOC‐evoked astrocytic retraction or decrease in the volume and length of its processes is associated with increased Kir4.1 activity. Kir4.1 involvement in HOC‐elicited astrocytic retraction is associated with AQP4 activity and GFAP plasticity, which together determines the rebound excitation of VP neurons.
Main Points
Inwardly rectifying K+ channel 4.1 (Kir4.1) plays a key role in the regulatory volume decrease (RVD).
RVD and its effect on the rebound activation of vasopressin neurons rely on the activity of Kir4.1.
Kir4.1 activity depends on aquaporin 4 activity and associates with glial fibrillary acidic protein plasticity.
Kir4.1 is a key target to regulate the activity of vasopressin neurons under hypotonicity.
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