Intelligent Devices Harnessing Underwater Superoleophobic and Underoil Superhydrophobic Quartz Sands for the Separation of Diverse Stratified and Emulsified Water-Oil Mixtures.

To achieve the green, sustainable, and controllable recovery of oil-water resources and to address the limited functionality of single superwet materials in oil-water separation, this study reports a multifunctional oil-water separation strategy by compositing the underwater superoleophobic and underoil superhydrophobic materials (HS). The underwater superoleophobic quartz sands with an oil contact angle of 152.68° were prepared by adjusting the particle size. This material demonstrated a water flux of 4688 L m-2 h-1 and a low-density oil and water mixture separation efficiency of 98.6%, which remained above 97.9% over 50 cycles. It was effective in separating oil-in-water emulsions with a separation efficiency of >99%. For HS, quartz sands were modified with dodecyltrimethoxysilane. The optimized HS-4 exhibited superhydrophobic properties with a water contact angle of 157.06°. It achieved an oil flux of 5775 L m-2 h-1 and a water and dichloromethane mixture separation efficiency of 98.4%. Additionally, they exhibited significant potential in the separation of water-in-oil emulsions. Furthermore, by placing the underwater superoleophobic and underoil superhydrophobic units at the bottom of the filter, we achieved cyclic separation of high-density oil and water mixtures, low-density oil and water mixtures, water-in-oil emulsions, and oil-in-water emulsions. The separation efficiency consistently exceeded 96.5% over 10 cycles. In addition, the oil-water separation mechanism of underwater oleophobic and underoil hydrophobic materials was demonstrated by the relative concentration distribution of water and oil with molecular dynamics simulations. This intelligent oil-water separation method marks a significant advancement in the sustainable separation of diverse oil-water mixtures.

Diagnostic performance of radiomics for predicting osteoporosis in adults: a systematic review and meta-analysis.

This study aimed to assess the diagnostic accuracy of radiomics for predicting osteoporosis and the quality of radiomic studies. The study protocol was prospectively registered on PROSPERO (CRD42023425058). We searched PubMed, EMBASE, Web of Science, and Cochrane Library databases from inception to June 1, 2023, for eligible articles that applied radiomic techniques to diagnosing osteoporosis or abnormal bone mass. Quality and risk of bias of the included studies were evaluated with radiomics quality score (RQS), METhodological RadiomICs Score (METRICS), and Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tools. The data analysis utilized the R program with mada, metafor, and meta packages. Ten retrospective studies with 5926 participants were included in the systematic review and meta-analysis. The overall risk of bias and applicability concerns for each domain of the studies were rated as low, except for one study which was considered to have a high risk of flow and time bias. The mean METRICS score was 70.1% (range 49.6-83.2%). There was moderate heterogeneity across studies and meta-regression identified sources of heterogeneity in the data, including imaging modality, feature selection method, and classifier. The pooled diagnostic odds ratio (DOR) under the bivariate random effects model across the studies was 57.22 (95% CI 27.62-118.52). The pooled sensitivity and specificity were 87% (95% CI 81-92%) and 87% (95% CI 77-93%), respectively. The area under the summary receiver operating characteristic curve (AUC) of the radiomic models was 0.94 (range 0.8 to 0.98). The results supported that the radiomic techniques had good accuracy in diagnosing osteoporosis or abnormal bone mass. The application of radiomics in osteoporosis diagnosis needs to be further confirmed by more prospective studies with rigorous adherence to existing guidelines and multicenter validation.

Therapeutic potential of a prominent dihydroxyflavanone pinocembrin for osteolytic bone disease: In vitro and in vivo evidence.

Background/objective: As the pivotal cellular mediators of bone resorption and pathological bone remodeling, osteoclasts have emerged as a prominent target for anti-resorptive interventions. Pinocembrin (PIN), a predominant flavonoid found in damiana, honey, fingerroot, and propolis, has been recognized for its potential therapeutic effects in osteolysis. The purpose of our project is to investigate the potential of PIN to prevent bone resorption in ovariectomized (OVX) mice by suppressing osteoclast production through its underlying mechanisms. Methods: The study commenced by employing protein-ligand molecular docking to ascertain the specific interaction between PIN and nuclear factor-κB (NF-κB) ligand (RANKL). Subsequently, PIN was introduced to bone marrow macrophages (BMMs) under the stimulation of RANKL. The impact of PIN on osteoclastic activity was assessed through the utilization of a positive TRAcP staining kit and a hydroxyapatite resorption assay. Furthermore, the study investigated the generation of reactive oxygen species (ROS) in osteoclasts induced by RANKL using H2DCFDA. To delve deeper into the underlying mechanisms, molecular cascades triggered by RANKL, including NF-κB, ROS, calcium oscillations, and NFATc1-mediated signaling pathways, were explored using Luciferase gene report, western blot analysis, and quantitative real-time polymerase chain reaction. Moreover, an estrogen-deficient osteoporosis murine model was established to evaluate the therapeutic effects of PIN in vivo. Results: In this study, we elucidated the profound inhibitory effects of PIN on osteoclastogenesis and bone resorption, achieved through repression of NF-κB and NFATc1-mediated signaling pathways. Notably, PIN also exhibited potent anti-oxidative properties by mitigating RANKL-induced ROS generation and augmenting activities of ROS-scavenging enzymes, ultimately leading to a reduction in intracellular ROS levels. Moreover, PIN effectively abrogated the expression of osteoclast-specific marker genes (Acp5, Cathepsin K, Atp6v0d2, Nfatc1, c-fos, and Mmp9), further underscoring its inhibitory impact on osteoclast differentiation and function. Additionally, employing an in vivo mouse model, we demonstrated that PIN effectively prevented osteoclast-induced bone loss resultant from estrogen deficiency. Conclusion: Our findings highlight the potent inhibitory effects of PIN on osteoclastogenesis, bone resorption, and RANKL-induced signaling pathways, thereby establishing PIN as a promising therapeutic candidate for the prevention and management of osteolytic bone diseases. The translational potential of this article: PIN serves as a promising therapeutic agent for the prevention and management of osteolytic bone diseases and holds promise for future clinical applications in addressing conditions characterized by excessive bone resorption. PIN is a natural compound found in various sources, including damiana, honey, fingerroot, and propolis. Its widespread availability and potential for therapeutic use make it an attractive candidate for further investigation and development as a clinical intervention.

Spindle apparatus coiled-coil protein 1 (SPDL1) serves as a novel prognostic biomarker in triple-negative breast cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) has a poor prognosis, an ineffective diagnosis, and a high degree of aggressiveness. Therefore, novel therapeutic targets for TNBC urgently need to be identified. METHODS: Through a series of bioinformatics analyses, including analysis of differential gene expression, protein-protein interaction (PPI) network, univariate cox regression, immune infiltration, pathway enrichment, etc, as well as auxiliary immunohistochemistry (IHC) and protein quantitativae analysis, to explore prognostic marker for TNBC. RESULTS: In TNBC tissues, we found that SPDL1 (CCDC99) was considerably overexpressed at both the mRNA and protein levels compared to that in normal and non-TNBC tissues. Additionally, we found that SPDL1-high expression was strongly linked to poor prognosis in TNBC patients. Excessive SPDL1 expression was positively correlated with tumor growth and strongly linked to the cell cycle, DNA replication, and the p53 signaling pathway. In addition, CIBERSORT analysis revealed that SPDL1 can affect the tumor immune microenvironment (TME) in TNBC, encourage the development of TNBC and act as a potential prognostic biomarker for TNBC. Patients with SPDL1-high expression were more sensitive to AZD8055. Notably, we discovered that SPDL1 is highly expressed in the majority of malignancies and may have an impact on the pancancer prognosis. CONCLUSIONS: SPDL1 can serve as a novel prognostic marker for TNBC and pancancer patients.

Metal-Free Activation of Molecular Oxygen by 9-Fluorenone-Based Porous Organic Polymers for Selective Aerobic Oxidation.

Oxygen activation is a critical step in heterogeneous oxidative processes, particularly in catalytic, electrolytic, and pharmaceutical applications. Among the various catalysts available for photocatalytic O2 activation, homogeneous aryl ketones are at the forefront. To avoid the degradation and deactivation of aryl ketones, 9-fluorenone-based porous organic polymers were designed and regulated by doping them with co-monomers. The obtained heterogeneous photocatalyst showed good performance in O2 activation, and its performance was better than that of homogeneous 9-fluorenone. The obtained heterogeneous photocatalyst showed good reusability. We believe that the presented method and findings represent an important step toward designing catalysts tailored for specific tasks.

Hydrogenation of levulinic acid to γ-valerolactone over hydrophobic Ru@HCP catalysts.

This study introduces an efficient strategy for promoting the synthesis of γ-valerolactone (GVL) via levulinic acid (LA) hydrogenation. A series of hyper-crosslinked porous polymer (HCP) supported Ru catalysts with different monomers were prepared. The wettabilities were controlled by the surface functional groups. The hydrophobic catalysts showed much higher activity than the hydrophilic ones in the hydrogenation of LA to GVL, highly possible due to the substrate enrichment. Further insight showed that the reaction proceeded through the 4-HVA route. These results illustrated the importance of surface wettability in bio-based molecule upgrading, which is beneficial for catalyst design.

A novel Glycyrrhiza glabra extract liquiritin targeting NFATc1 activity and ROS levels to counteract ovariectomy-induced osteoporosis and bone loss in murine model.

Osteoporosis, a prevalent osteolytic condition worldwide, necessitates effective strategies to inhibit excessive bone resorption by curbing osteoclast hyperactivation. Liquiritin (LIQ), an flavanone derivative employed in acute lung injury and rheumatoid arthritis treatment, possesses an unclear role in addressing excessive bone resorption. In this investigation, we found that LIQ demonstrates the ability to inhibit osteoclast formation and the bone-resorbing activity induced by RANKL. At a specific concentration, LIQ significantly attenuated NF-κB-Luc activity induced by RANKL and curtailed NF-κB activation in RANKL-stimulated RAW264.7 cells, resulting in reduced IκB-α breakdown and diminished nuclear NF-κB levels. Furthermore, LIQ markedly inhibited RANKL-induced NFATc1 activation, as evidenced by diminished NFATc1 luciferase activity, reduced NFATc1 mRNA levels, and decreased nuclear NFATc1 protein levels. Subsequent experiments demonstrated that LIQ effectively restrained the RANKL-induced elevation of intracellular calcium as well as reactive oxygen species. Additionally, LIQ exhibited a downregulating effect on the expression of osteoclast-specific genes, which include Acp5, Cathepsin K, Atp6v0d2, Nfatc1, c-Fos, and Mmp9. Notably, our findings revealed the potential of LIQ to counteract decreased bone density in mice that underwent ovariectomy. Collectively, the data indicate that LIQ impedes osteoclast formation triggered by RANKL and the subsequent reduction in bone mass by mitigating ROS levels and suppressing the Ca2+/MAPK-NFATc1 signaling pathway, suggesting its promising candidacy as a therapeutic agent for RANKL-mediated osteoporosis.

Prediction of musculoskeletal pain after the first intravenous zoledronic acid injection in patients with primary osteoporosis: development and evaluation of a new nomogram.

OBJECTIVE: To construct a new prediction nomogram to predict the risk of musculoskeletal pain in patients with primary osteoporosis who receive zoledronic acid intravenously for the first time. METHOD: Clinical data of 368 patients with primary osteoporosis who received the first intravenous injection of zoledronic acid in our hospital from December 2019 to December 2022 were studied. Patients were divided into a musculoskeletal pain group (n = 258) and a non-musculoskeletal pain group (n = 110) based on the presence or absence of musculoskeletal pain 3 days after injection. Statistically significant predictors were screened by logistic regression analysis and the minimum absolute contraction and selection operator (LASSO) to construct a nomogram. The nomogram was evaluated by the receiver operating characteristic (ROC) curve, the calibration curve, the C-index, and the decision curve analysis (DCA) and verified in a validation cohort. RESULTS: The independent predictors of the nomogram were age, serum 25-hydroxyvitamin D, NSAIDs, prior Vitamin D intake, and BMI. The area under the ROC curve (AUC) was 0.980 (95% CI, 0.915-0.987), showing excellent predictive performance. The nomogram c index was 0.980, and the nomogram c index for internal verification remained high at 0.979. Moreover, calibration curves show that the nomogram has good consistency. Finally, the DCA showed that the net benefit of the nomogram was 0.20-0.49. CONCLUSION: Musculoskeletal pain is a common symptom of APR in OP patients treated with intravenous zoledronic acid. Risk factors for musculoskeletal pain after zoledronic acid injection in OP patients were: non-use of NSAIDs, youth (<80 years old), serum 25 (OH) D<30ng /mL, no prior intake of vitamin D, BMI<24 kg /m2. A nomogram constructed from the above predictors can be used to predict musculoskeletal pain after the first zoledronic acid injection.

Operational and Intervention Effects of Targeted Tuina in Lumbar Intervertebral Disc Degeneration Model Rabbits.

Tui Na or massage therapy alleviates symptoms related to intervertebral disc degeneration (IDD). However, precise, repeatable, standardized instructions for Tuina manipulation are lacking. This study establishes IDD model rabbits induced by fibrous ring puncture, creates targeted Tuina stimulation protocols at the acupuncture points in the lumbar region, and describes in detail the operation methods and requirements of kneading, pointing, and flicking. New Zealand male white rabbits (n = 15) were selected and randomly divided into a blank group, a model group, and a Tuina group. The rabbits in the model group and the Tuina group were molded by fibrous ring puncture; the rabbits in the model group were only immobilized on the operating table without treatment. In contrast, the Tuina group used the "8N/10N, 30 cycles/min" prescription for kneading, pointing, and flicking to perform the intervention, using tactile sensory aids to monitor and regulate the intensity of the Tuina operation. Imaging diagnosis and pathological tests were used to assess the effect of Tuina in rabbits, and the results showed improved imaging features and significantly lowered pathology scores of lumbar disc degeneration in the Tuina group compared to the model group (P < 0.01). Targeted Tuina in the lumbar region may be beneficial in the alleviation of lumbar disc degeneration, but further verification is needed. By regularly performing Tuina and recording the mechanical information involved enables reproducible manipulation prescriptions and helps to observe the basic features of the underlying mechanism of Tuina for IDD.

Thyroid-Related Hormones Changes Predict Changes in Anthropometric Measures and Incidence of Obesity in Chinese Euthyroid Persons.

The purpose of this study was to investigate the correlation of thyroid-related hormones changes within the reference range with the changes in anthropometric measures and incidence of obesity. The study included 4850 subjects with normal thyroid-related hormones at baseline and at follow-up. We evaluated the relationship of changes in thyroid-related biomarkers with anthropometric measures changes and incidence of obesity. In euthyroid persons, changes in serum thyroid stimulating hormone (TSH), free triiodothyronine (FT3), and free thyroxine (FT4) concentrations and FT3/FT4 ratio were independent predictors of changes in body mass index (BMI) and waist circumference (WC) in men, changes in serum FT3 and FT4 concentrations and FT3/FT4 ratio were independent predictors of changes in BMI and WC in women. Every single unit increment in ΔFT3/FT4 was accompanied by a 7.144 and 7.572 times risk of having obesity in men and women, respectively. Every single unit decrement in ΔFT4 was accompanied by a 21.0% and 26.9% lower risk of having obesity in men and women, respectively. In conclusion, in euthyroid individuals, changes in thyroid-related hormones were associated with anthropometric measures changes and incidence of obesity.

Mitochondria in cancer stem cells: Achilles heel or hard armor.

Previous studies have shown that mitochondria play core roles in not only cancer stem cell (CSC) metabolism but also the regulation of CSC stemness maintenance and differentiation, which are key regulators of cancer progression and therapeutic resistance. Therefore, an in-depth study of the regulatory mechanism of mitochondria in CSCs is expected to provide a new target for cancer therapy. This article mainly introduces the roles played by mitochondria and related mechanisms in CSC stemness maintenance, metabolic transformation, and chemoresistance. The discussion mainly focuses on the following aspects: mitochondrial morphological structure, subcellular localization, mitochondrial DNA, mitochondrial metabolism, and mitophagy. The manuscript also describes the recent clinical research progress on mitochondria-targeted drugs and discusses the basic principles of their targeted strategies. Indeed, an understanding of the application of mitochondria in the regulation of CSCs will promote the development of novel CSC-targeted strategies, thereby significantly improving the long-term survival rate of patients with cancer.

Retinal vein changes after treatment with aflibercept and PRP in high-risk proliferative diabetic retinopathy.

Objective: The objective of the study was to investigate the effectiveness of aflibercept and panretinal photocoagulation (PRP) in the treatment of proliferative diabetic retinopathy (PDR). Methods: A retrospective analysis was performed on 59 patients (59 eyes) with high-risk PDR who were treated with aflibercept and PRP between January 2018 and December 2019. The best corrected visual acuity (BCVA), central foveal thickness (CFT), and retinal vein diameter post-treatment were compared to those before the treatment. Results: The best corrected visual acuity (BCVA) at 6 months (0.49 ± 0.14 logMAR), 12 months (0.54 ± 0.15 logMAR), 18 months (0.48 ± 0.15 logMAR), and 24 months (0.51 ± 0.15 logMAR) post-treatment were superior to the pre-treatment measurement (0.65 ± 0.18 logMAR). The central foveal thickness (CFT) at 6 months (310.67 ± 52.53 µm), 12 months (295.98 ± 45.65 µm), 18 months (282.56 ± 43.57 µm), and 24 months (281.53 ± 51.16 µm) post-treatment were lower than the pre-treatment measurement (456.53 ± 51.49 µm); the retinal vein diameter at 12 months (310.13 ± 24.60 µm), 18 months (309.50 ± 31.58 µm), and 24 months (317.00 ± 27.54 µm) post-treatment were lower than the pre-treatment measurement (361.81 ± 30.26 µm). Conclusion: Aflibercept intravitreal injection and panretinal photocoagulation may morphologically reverse retinal vein diameter and venous beading in high-risk proliferative diabetic retinopathy.

The prelimbic cortex regulates itch processing by controlling attentional bias.

Itch is a complex and unpleasant sensory experience. Recent studies have begun to investigate the neural mechanisms underlying the modulation of sensory and emotional components of itch in the brain. However, the key brain regions and neural mechanism involved in modulating the attentional processing of itch remain elusive. Here, we showed that the prelimbic cortex (PrL) is associated with itch processing and that the manipulation of itch-responsive neurons in the PrL significantly disrupted itch-induced scratching. Interestingly, we found that increasing attentional bias toward a distracting stimulus could disturb itch processing. We also demonstrated the existence of a population of attention-related neurons in the PrL that drive attentional bias to regulate itch processing. Importantly, itch-responsive neurons and attention-related neurons significantly overlapped in the PrL and were mutually interchangeable in the regulation of itch processing at the cellular activity level. Our results revealed that the PrL regulates itch processing by controlling attentional bias.

Water-Tree Characteristics and Its Mechanical Mechanism of Crosslinked Polyethylene Grafted with Polar-Group Molecules.

In order to restrain electric-stress impacts of water micro-droplets in insulation defects under alternating current (AC) electric fields in crosslinked polyethylene (XLPE) material, the present study represents chemical graft modifications of introducing chloroacetic acid allyl ester (CAAE) and maleic anhydride (MAH) individually as two specific polar-group molecules into XLPE material with peroxide melting approach. The accelerated water-tree aging experiments are implemented by means of a water-blade electrode to measure the improved water resistance and the affording mechanism of the graft-modified XLPE material in reference to benchmark XLPE. Melting−crystallization process, dynamic viscoelasticity and stress-strain characteristics are tested utilizing differential scanning calorimeter (DSC), dynamic thermomechanical analyzer (DMA) and electronic tension machine, respectively. Water-tree morphology is observed for various aging times to evaluate dimension characteristics in water-tree developing processes. Monte Carlo molecular simulations are performed to calculate free-energy, thermodynamic phase diagram, interaction parameter and mixing energy of binary mixing systems consisting of CAAE or MAH and water molecules to evaluate their thermodynamic miscibility. Water-tree experiments indicate that water-tree resistance to XLPE can be significantly improved by grafting CAAE or MAH, as indicated by reducing the characteristic length of water-trees from 120 to 80 µm. Heterogeneous nucleation centers of polyethylene crystallization are rendered by the grafted polar-group molecules to ameliorate crystalline microstructures, as manifested by crystallinity increment from 33.5 to 36.2, which favors improving water-tree resistance and mechanical performances. The highly hydrophilic nature of CAAE can evidently inhibit water molecules from aggregating into water micro-droplets in amorphous regions between crystal lamellae, thus acquiring a significant promotion in water-tree resistance of CAAE-modified XLPE. In contrast, the grafted MAH molecules can enhance van der Waals forces between polyethylene molecular chains in amorphous regions much greater than the grafted CAAE and simultaneously act as more efficient crystallization nucleation centers to ameliorate crystalline microstructures of XLPE, resulting in a greater improvement (relaxation peak magnitude increases by >10%) of mechanical toughness in amorphous phase, which primarily accounts for water-tree resistance promotion.

Magnetic Force Probe Characterizations of Nanoscaled Ferromagnetic Domains: Finite-Element Magnetostatic Simulations.

Microscopic characterization of magnetic nanomaterials by magnetic probe interacting with ferromagnetic nano-domains is proposed according to finite-element magnetostatic field simulations. Magnetic forces detected by microscopic probe are systematically investigated on magnetic moment orientation, magnetization intensity and geometry of ferromagnetic nano-domains, and especially on permanent magnetic coating thickness and tilting angle of probe, to provide a theoretical basis for developing magnetic force microscopy. Magnetic force direction is primarily determined by magnetic moment orientation of nanosample, and the tip curvature dominates magnetic force intensity that is meanwhile positively correlated with nanosample magnetization and probe magnetic coating thickness. Nanosample should reach a critical thickness determined by its transverse diameter to be capable of accurately detecting the magnetic properties of ferromagnetic nanomaterials. Magnetic force signal relies on probe inclination when the sample magnetic moment is along probe tilting direction, which, however, is not disturbed by probe inclination when sample magnetic moment is perpendicular to probe tilting plane. Within the geometry of satisfying a critical size requirement, the magnetic force can successfully image the ferromagnetic nano-domains by characterizing their sizes and magnetic moment orientations. The present study is expected to provide effective analyzing schemes and theoretical evidences for magnetic force microscopy of characterizing magnetic structures in ferromagnetic nanomaterials.

Itch-specific neurons in the ventrolateral orbital cortex selectively modulate the itch processing.

Itch is a cutaneous sensation that is critical in driving scratching behavior. The long-standing question of whether there are specific neurons for itch modulation inside the brain remains unanswered. Here, we report a subpopulation of itch-specific neurons in the ventrolateral orbital cortex (VLO) that is distinct from the pain-related neurons. Using a Tet-Off cellular labeling system, we showed that local inhibition or activation of these itch-specific neurons in the VLO significantly suppressed or enhanced itch-induced scratching, respectively, whereas the intervention did not significantly affect pain. Conversely, suppression or activation of pain-specific neurons in the VLO significantly affected pain but not itch. Moreover, fiber photometry and immunofluorescence verified that these itch- and pain-specific neurons are distinct in their functional activity and histological location. In addition, the downstream targets of itch- and pain-specific neurons were different. Together, the present study uncovers an important subpopulation of neurons in the VLO that specifically modulates itch processing.

Experiment and Numerical Simulation of Damage Progression in Transparent Sandwich Structure under Impact Load.

Crack initiation and propagation is a long-standing difficulty in solid mechanics, especially for elastic brittle materials. A new type of transparent sandwich structure, with a magnesium-aluminum spinel ceramic glass as the outer structure, was proposed in this paper. Its dynamic response was studied by high-speed impact experiments and numerical simulations of peridynamics under impact loads, simultaneously. In the experiments, a light gas cannon was used to load the projectile to 180 m/s, and the front impacted the transparent sandwich structure. In the numerical simulations, the discontinuous Galerkin peridynamics method was adopted to investigate the dynamic response of the transparent sandwich structure. We found that both the impact experiments and the numerical simulations could reproduce the crack propagation process of the transparent sandwich structure. The radial cracks and circumferential cracks of the ceramic glass layer and the inorganic glass layer were easy to capture. Compared with the experiments, the numerical simulations could easily observe the damage failure of every layer and the splashing of specific fragments of the transparent sandwich structure. The ceramic glass layer and the inorganic glass layer absorbed the most energy in the impact process, which is an important manifestation of the impact resistance of the transparent sandwich structure.

Corrigendum: Sevoflurane Alleviates Myocardial Ischemia Reperfusion Injury by Inhibiting P2X7-NLRP3 Mediated Pyroptosis.

[This corrects the article DOI: 10.3389/fmolb.2021.768594.].

An aldehyde dehydrogenase 1A3 inhibitor attenuates the metastasis of human colorectal cancer.

Metastasis is the leading cause of death for patients with colorectal cancer (CRC). The development of therapeutic regimens that selectively inhibit the biological processes involved in CRC cell dissemination is important. We used multiple Affymetrix DNA microarray hybridization datasets to identify genes related to metastasis and have significant prognostic value for patients with CRC. Quantitative real-time PCR, immunofluorescent and immunohistochemical staining were used to evaluate mRNA and protein expression. The function of aldehyde dehydrogenase 1A3 (ALDH1A3) in invasion was assessed by performing transwell assays and animal experiments. Real-time PCR, luciferase reporter assays, and western blotting were used to identify the genes regulated by ALDH1A3. Molecular docking, MTS assays, cellular thermal shift assays, isothermal titration calorimetry, microscale thermophoresis, and enzymatic activity assays were used to screen and verify the efficacy of the ALDH1A3-specific inhibitor YD1701 (dibenzo-30-crown10-ether). Finally, subcutaneous or orthotopic xenograft models were established to investigate the therapeutic potential of YD1701. Human ALDH1A3 was identified to correlate with a metastatic phenotype in CRC cells and a poor patient prognosis. Moreover, ALDH1A3 upregulated the expression of ZEB1 and SNAI2 by inhibiting miR-200 family members. The ALDH1A3-specific inhibitor YD1701 was screened, attenuated the invasion of CRC cells in vitro, and prolonged the survival of mice bearing subcutaneous or orthotopic xenografts. Our results show that ALDH1A3 promotes invasion and metastasis via the miR-200-ZEB1/SANI2 axis and is thus a plausible marker for predicting CRC progression. Inhibiting ALDH1A3 with the identified compound YD1701 might represent an effective therapeutic approach to prevent the metastasis of CRC.