Synthetic protein circuits for programmable control of mammalian cell death.

Natural cell death pathways such as apoptosis and pyroptosis play dual roles: they eliminate harmful cells and modulate the immune system by dampening or stimulating inflammation. Synthetic protein circuits capable of triggering specific death programs in target cells could similarly remove harmful cells while appropriately modulating immune responses. However, cells actively influence their death modes in response to natural signals, making it challenging to control death modes. Here, we introduce naturally inspired "synpoptosis" circuits that proteolytically regulate engineered executioner proteins and mammalian cell death. These circuits direct cell death modes, respond to combinations of protease inputs, and selectively eliminate target cells. Furthermore, synpoptosis circuits can be transmitted intercellularly, offering a foundation for engineering synthetic killer cells that induce desired death programs in target cells without self-destruction. Together, these results lay the groundwork for programmable control of mammalian cell death.

Heteryunine A, an amidated tryptophan-catechin-spiroketal hybrid with antifibrotic activity from Heterosmilax yunnanensis.

An unprecedented spiro-C-glycoside adduct, heteryunine A (1), along with two uncommon alkaloids featuring a 2,3-diketopiperazine skeleton, heterpyrazines A (2) and B (3), were discovered in the roots of Heterosmilax yunnanensis. The detailed spectroscopic analysis helped to clarify the planar structures of these compounds. Compound 1, containing 7 chiral centers, features a catechin fused with a spiroketal and connects with a tryptophan derivative by a CC bond. Its complex absolute configuration was elucidated by rotating frame overhauser enhancement spectroscopy (ROESY), specific rotation, and the 13C nuclear magnetic resonance (NMR) and electronic circular dichroism (ECD) calculation. The possible biosynthetic routes for 1 were deduced. Compounds 1 and 2 showed significant antifibrotic effects and further research revealed that they inhibited the activation, migration and proliferation of hepatic stellate cells (HSCs) through suppressing the activity of Ras homolog family member A (RhoA).

Fourteen new 2-benzylbenzofuran glycosides with cardioprotective activity from Heterosmilax yunnanensis.

Fourteen new 2-benzylbenzofuran O-glycosides (1-13, 15) and one new key precursor, diarylacetone (14) were isolated from the roots of Heterosmilax yunnanensis Gagnep, which all have characteristic 2,3,4-O-trisubstituted benzyl. Their structures were elucidated by 1D and 2D NMR, HRESIMS, UV and IR. The isolated compounds were assessed for their cardioprotective activities and compounds 1, 3 and 6 could significantly improve cardiomyocytes viability. Moreover, the mechanistic study revealed that these three compounds could significantly decrease intracellular ROS levels and maintain mitochondrial homeostasis upon hypoxia inducement. Consequently, 1, 3 and 6 might serve as potential lead compounds to prevent myocardial ischemia.

Genetically proxied antidiabetic drugs targets and stroke risk.

BACKGROUND: Previous studies have assessed the association between antidiabetic drugs and stroke risk, but the results are inconsistent. Mendelian randomization (MR) was used to assess effects of antidiabetic drugs on stroke risk. METHODS: We selected blood glucose-lowering variants in genes encoding antidiabetic drugs targets from genome-wide association studies (GWAS). A two-sample MR and Colocalization analyses were applied to examine associations between antidiabetic drugs and the risk of stroke. For antidiabetic agents that had effect on stroke risk, an independent blood glucose GWAS summary data was used for further verification. RESULTS: Genetic proxies for sulfonylureas targets were associated with reduced risk of any stroke (OR=0.062, 95% CI 0.013-0.295, P=4.65×10－4) and any ischemic stroke (OR=0.055, 95% CI 0.010-0.289, P=6.25×10－4), but not with intracranial hemorrhage. Colocalization supported shared casual variants for blood glucose with any stroke and any ischemic stroke within the encoding genes for sulfonylureas targets (KCNJ11 and ABCC8) (posterior probability>0.7). Furthermore, genetic variants in the targets of insulin/insulin analogues, glucagon-like peptide-1 analogues, thiazolidinediones, and metformin were not associated with the risk of any stroke, any ischemic stroke and intracranial hemorrhage. The association was consistent in the analysis of sulfonylureas with stroke risk using an independent blood glucose GWAS summary data. CONCLUSIONS: Our findings showed that genetic proxies for sulfonylureas targets by lowering blood glucose were associated with a lower risk of any stroke and any ischemic stroke. The study might be of great significance to guide the selection of glucose-lowering drugs in individuals at high risk of stroke.

Modulating photothermal properties by integration of fined Fe-Co in confined carbon layer of SiO2 nanosphere for pollutant degradation and solar water evaporation.

Environmental governance by photothermal materials especially for the separation of organic pollutants and regeneration of freshwater afford growing attention owing to their special solar-to-heat properties. Here, we construct a special functional nanosphere composed of an internal silica core coated by a thin carbon layer encapsulated plasmonic bimetallic FeCo2O4 spinel (SiO2@CoFe/C) by a facile self-assembled approach and tuned calcination. Through combining the advantage of bimetallic Fe-Co and carbon layer, this obtained nanosphere affords improved multiple environmental governing functions including peroxymonosulfate (PMS) activation to degrade pollutants and photothermal interfacial solar water evaporation. Impressively, fined bimetal (FeCo) species (20 nm) acted as main catalytic substance were distributed on the N-doping carbon thin layer, which favors electron transfer and reactive accessibility of active metals. The increasing treatment temperature of catalysts caused the optimization of the surface active metal species and tuning catalytic properties in the AOPs. Besides, the incorporation of Co in the SiO2@CoFe/C-700 could enable the improved PMS activation efficiency compared to SiO2@Fe/C-700 and the mixed SiO2@Co/C-700 and SiO2@Fe/C-700, hinting a synergetic promotion effect. The bimetal coupled catalyst SiO2@CoFe/C-700 affords enhanced photothermal properties compared to SiO2@Co/C-700. Furthermore, photothermal catalytic PMS activation using optimal SiO2@CoFe/C-700 was further explored in addressing stubborn pollutants including oxytetracycline, sulfamethoxazole, 2, 4-dichlorophenol, and phenol. The free radical quenching control suggests that both the sulfate radical, hydroxyl radical, superoxide radical, and singlet oxygen species are involved in the degradation, while the hydroxyl radical and singlet oxygen play a dominant role. Furthermore, the implementation of a solar-driven interfacial water evaporation model using SiO2@CoFe/C-700 was further studied to obtain freshwater regeneration (1.26 kg m-2 h-1, 76.81% efficiency), indicating the comprehensive ability of the constructed nanocomposites for treating complicated environmental pollution including organics removal and freshwater regeneration.

Assessing the association between white matter lesions and Parkinson's disease.

BACKGROUND: The association between white matter (WM) lesions and Parkinson's disease (PD) was not fully established. We therefore applied Mendelian randomization (MR) analyses to identify the causal effect between white matter lesions and PD. METHODS: We performed a bidirectional two-sample Mendelian randomization (MR) study to investigate the association between three WM phenotypes-white matter hyperintensities (WMH, N = 18,381), fractional anisotropy (FA, N = 17,673), and mean diffusivity (MD, N = 17,467)-with PD (N = 482,730) using summary statistics from genome-wide association studies (GWAS). The inverse variance weighted (IVW), weighted median, MR-Egger, and MR-PRESSO methods were used to evaluate the causal estimate. RESULTS: Significant evidence was suggested that higher MD was associated with a higher PD risk (OR = 1.049, 95% CI = 1.018-1.081, p = 0.022) when the outlier was removed using MR-PRESSO method. Moreover, genetically predicted PD was associated with a lower WMH load (IVW ß = - 0.047, 95% CI = - 0.085 to - 0.009, p = 0.016) and a higher FA (ß = 0.185, 95% CI = 0.021-0.349, p = 0.027). No evidence of pleiotropy was found using MR-Egger intercept. CONCLUSION: Our findings provided genetic support that white matter microstructural integrity lesions might increase the risk of PD. However, genetically predicted PD was potentially associated with a lower load of white matter lesions.

Evaluating the causal association between microRNAs and amyotrophic lateral sclerosis.

BACKGROUND: Currently, miRNAs are involved in the development of amyotrophic lateral sclerosis (ALS), and identifying circulating miRNAs that are causally associated with ALS risk as biomarkers is imperative. METHODS: We performed a two-sample Mendelian randomization study to evaluate the causal relationship between miRNAs and ALS. Our analysis was conducted using summary statistics from miRNA expression quantitative loci (eQTL) data of the Framingham Heart Study and ALS genome-wide association studies data. Another independent miRNA data was used to further validate. RESULTS: We identified eight unique miRNAs that were causally associated with ALS risk. Using expression data of miRNAs from an independent study, we validated three high-confidence miRNAs, namely hsa-miR-27b-3p, hsa-miR-139-5p, and hsa-miR-152-3p, which might have a potential causal effect on ALS risk. CONCLUSION: We suggested that higher levels of hsa-miR-27b-3p and hsa-miR-139-5p had protective effects on ALS, whereas higher levels of hsa-miR-152-3p might act as a risk factor for ALS. The analytical framework presented in this study helps to understand the role of miRNAs in the development of ALS and to identify the biomarkers for ALS risk.

Exploring Interfacial Hydrolysis of Artificial Neutral Lipid Monolayer and Bilayer Catalyzed by Phospholipase C.

Phospholipase C (PLC) represents an important type of enzymes with the feature of hydrolyzing phospholipids at the position of the glycerophosphate bond, among which PLC extracted from Bacillus cereus (BC-PLC) has been extensively studied owing to its similarity to hitherto poorly characterized mammalian analogues. This study focuses on investigating the interfacial hydrolysis mechanism of phosphatidylcholine (PC) monolayer and bilayer membranes catalyzed by BC-PLC using sum frequency generation vibrational spectroscopy (SFG-VS) and laser scanning confocal microscopy (LSCM). We found that, upon interfacial hydrolysis, BC-PLC was adsorbed onto the lipid interface and catalyzed the lipolysis with no net orientation, as evidenced by the silent amide I band, indicating that ordered PLC alignment was not a prerequisite for the enzyme activity, which is very different from what we have reported for phospholipase A1 (PLA1) and phospholipase A2 (PLA2) [Kai, S. Phys. Chem. Chem. Phys. 2018, 20(1), 63-67; Wang, F. Langmuir 2019, 35(39), 12831-12838; Zhang, F. Langmuir 2020, 36(11), 2946-2953]. For the PC monolayer, one of the two hydrolysates, phosphocholine, desorbed from the interface into the aqueous phase, while the other one, diacylglycerol (DG), stayed well packed with high order at the interface. For the PC bilayer, phosphocholine dispersed into the aqueous phase too, similar to the monolayer case; however, DG, presumably formed clusters with the unreacted lipid substrates and desorbed from the interface. With respect to both the monolayer and bilayer cases, mechanistic schematics were presented to illustrate the different interfacial hydrolysis processes. Therefore, this model experimental study in vitro provides significant molecular-level insights and contributes necessary knowledge to reveal the lipolysis kinetics with respect to PLC and lipid membranes with monolayer and bilayer structures.

C/EBPß enhances immunosuppression activity of myeloid-derived suppressor cells by a P300-mediated acetylation modification.

OBJECTIVE: Myeloid-derived suppressor cells (MDSCs) are a major immunosuppressive population in the tumor microenvironment,inhibiting anti-tumor immune response and exerting pro-tumorigenic effect. CCAAT/enhancer-binding protein beta (C/EBPß), a key transcription factor indispensable for myelopoiesis, plays a fundamental role in regulating expansion and activation of MDSCs. Lysine acetylation can regulate functions of transcription factors. However, the role of C/EBPß acetylation modification in MDSCs has not been reported. MATERIALS AND METHODS: MDSCs derived from the spleens of tumor-bearing mice (TB-SP-MDSCs) were isolated by immunomagnetic beads. Bone marrow derived MDSCs were induced by IL-6 and GM-CSF. Western-blot was used to detect the expression of P300 and co-immunoprecipitation (CO-IP) was used to detect the C/EBPß acetylation in MDSCs. Inhibitor C646 was used to specificly inhibit P300 activity. RESULTS: In this study, we found that C/EBPß was acetylated by acetyltransferase P300 in MDSCs. A P300-mediated C/EBPß acetylation enhanced C/EBPß transactivation activity on arginase 1 (Arg-1) gene promoter. Inhibition of P300 activity downregulated the inhibitory effects of MDSCs in vitro and attenuated pro-tumorigenic effects of MDSCs in vivo. Additionally, IL-6 from tumor microenvironment could upregulate the expression of P300 and enhance C/EBPß acetylation in MDSCs. CONCLUSION: In general, a P300-mediated C/EBPß acetylation enhanced C/EBPß transactivation activity on Arg-1 promoter, thus promoting immunosuppressive function of MDSCs. In view of the critical role of P300 in regulating MDSCs, P300 might be a potential target of anti-tumor immunotherapy.

A novel GALC gene mutation associated with adult-onset Krabbe disease: a case report.

To analyze the clinical, imaging, and genetic characteristics of a patient diagnosed with adult-onset Krabbe disease (KD). Clinical and imaging features of the patient were retrospectively reviewed. The patient, a 40-year-old female, presented adult-onset spastic paraplegia. Brain magnetic resonance imaging (MRI) showed white matter hyperintensities along bilateral optic radiations. Colorimetry of galactocerebrosidase enzyme activity showed low enzyme levels. A heterozygous missense mutation: c.1658G>A (p.G553E) and c.1901T>C (p.L634S) was identified in the GALC gene by whole exome sequencing, and was verified by Sanger sequencing. KD should be considered when patients presented adult-onset spastic paraplegia with classical MRI imaging features. Mutation c.1658G>A (p.G553E) was novel in GALC gene and broaden the mutation spectrum.

The efficacy and toxicity of angiogenesis inhibitors for ovarian cancer: a meta-analysis of randomized controlled trials.

PURPOSE: To evaluate the efficacy and toxicity of angiogenesis inhibitors for the treatment of ovarian cancer patients, we conducted a meta-analysis of the published literature on this subject. METHODS: In this meta-analysis, we searched PubMed, EMBASE, Web of Science, and Cochrane Library databases for randomized controlled trials (RCTs). The literature search was performed up to August 12, 2019. The risk of bias of the included studies was evaluated using The Cochrane Collaboration's tool, and the statistical analyses were performed using RevMan 5.3 software. The sensitivity analysis was performed with Stata 12.0 software. RESULTS: 22 RCTs with 11,254 patients were included. Our meta-analysis demonstrates that angiogenesis inhibitors therapy can significantly improve progression-free survival (PFS) (hazard ratio [HR] 0.71, 95% CI 0.63-0.79, I2 = 80%, P < 0.00001) and overall survival (OS) (HR 0.95, 95% CI 0.90-0.99, I2 = 0%, P = 0.03) in ovarian cancer patients. The subgroups results suggest differences in the benefit in OS in first-line treatment (HR 1.00, 95% CI 0.93-1.08, I2 = 0%, P = 0.90) compared with treatment at relapse (HR 0.87, 95% CI 0.81-0.95, I2 = 0%, P = 0.0008). The PFS improved both in first-line treatment (HR 0.87, 95% CI 0.79-0.95, I2 = 60%, P = 0.003) and recurrent treatment (HR 0.60, 95% CI 0.53-0.67, I2 = 57% P < 0.0001) patients. The PFS and OS in recurrent group were prolonged both in the platinum-resistant group(PFS: HR 0.50, 95% CI 0.42-0.60, I2 = 0%, P < 0.00001; OS: HR 0.76, 95% CI 0.62-0.93, I2 = 0%, P = 0.007) and the platinum-sensitive group (PFS: HR 0.58, 95% CI 0.49-0.69, I2 = 64%, P < 0.00001; OS: HR 0.88, 95% CI 0.79-0.99, I2 = 0%, P = 0.03). However, this therapy is associated with a higher risk of common adverse events of grade ≥ 3 (risk ratio [RR]: 1.12; 95% CI 1.07-1.17; I2 = 0%, P = 0.68) such as arterial thromboembolic disease, ascites, diarrhea, gastrointestinal perforations, headache, hemorrhagic, hypertension, hypokalemia, leucopenia, pain, proteinuria, thrombocytopenia, and thrombosis or embolism. CONCLUSION: This meta-analysis suggests angiogenesis inhibitors may significantly improve PFS and OS of ovarian cancer patients and increase the incidence of common adverse events.

Iridium-Catalyzed Regio- and Enantioselective Borylation of Unbiased Methylene C(sp3 )-H Bonds at the Position ß to a Nitrogen Center.

Reported herein is the pyrazole-directed iridium-catalyzed enantioselective borylation of unbiased methylene C-H bonds at the position ß to a nitrogen center. The combination of a chiral bidentate boryl ligand, iridium precursor, and pyrazole directing group was responsible for the high regio- and enantioselectivity observed. The method tolerated a vast array of functional groups to afford the corresponding C(sp3 )-H functionalization products with good to excellent enantioselectivity.

Clinical Analysis of Patients with Primary Blepharospasm: A Report of 100 Cases in China.

PURPOSE: This study explored the clinical characteristics, diagnosis and treatments of primary blepharospasm. METHODS: In this retrospective analysis, 100 patients with blepharospasm were enrolled. Data were collected from medical records and face-to-face interviews with patients and their families. RESULTS: The age of onset was 56.4 ± 2.7 (range, 32-76 years). The duration between onset and accurate diagnosis was 38.7 ± 36.0 months (range, 2-120 months). Dry eyes occurred in 54% of the patients. The initial diagnostic accuracy was 10%. Dry eye syndrome, conjunctivitis/keratitis and myasthenia gravis caused the most confusion in the differential diagnosis. Regular botulinum toxin type A injections improved both eyelid spasms and subjective ocular symptoms in all patients. CONCLUSIONS: Regular botulinum toxin type A injections improved both eyelid spasms and subjective ocular symptoms in blepharospasm patients. The differentiation of primary blepharospasm differentiation from dry eye syndrome, conjunctivitis/keratitis and myasthenia gravis must be improved.

Causal association between obstructive sleep apnea and amyotrophic lateral sclerosis: a Mendelian randomization study.

Background: Obstructive sleep apnea (OSA) had a high prevalence in the population. Whether OSA increases the risk of amyotrophic lateral sclerosis (ALS) is unknown. Our aim was to clarify this issue using two-sample Mendelian randomization (MR) analysis in a large cohort. Methods: Two-sample MR was used to evaluate the potential causality between OSA and ALS by selecting single-nucleotide polymorphisms (SNPs) as instrumental variables (IVs) from genome-wide association studies (GWAS). The inverse-variance weighted (IVW) method was chosen as the primary method to estimate causal association. Weighted median, weighted mode and simple mode methods were used as sensitivity analyses to ensure the robustness of the results. Results: In MR analysis, IVW mode showed genetic liability to OSA was found to be significantly associated with a higher ALS risk (OR, 1.220; 95% confidence interval, 1.031-1.443; p = 0.021). No evidence of heterogeneity and horizontal pleiotropy were suggested. Conclusion: We found potential evidence for a causal effect of OSA on an increased risk of ALS.

miRNA circuit modules for precise, tunable control of gene expression.

The ability to express transgenes at specified levels is critical for understanding cellular behaviors, and for applications in gene and cell therapy. Transfection, viral vectors, and other gene delivery methods produce varying protein expression levels, with limited quantitative control, while targeted knock-in and stable selection are inefficient and slow. Active compensation mechanisms can improve precision, but the need for additional proteins or lack of tunability have prevented their widespread use. Here, we introduce a toolkit of compact, synthetic miRNA-based circuit modules that provide precise, tunable control of transgenes across diverse cell types. These circuits, termed DIMMERs (Dosage-Invariant miRNA-Mediated Expression Regulators) use multivalent miRNA regulatory interactions within an incoherent feed-forward loop architecture to achieve nearly uniform protein expression over more than two orders of magnitude variation in underlying gene dosages or transcription rates. They also allow coarse and fine control of expression, and are portable, functioning across diverse cell types. In addition, a heuristic miRNA design algorithm enables the creation of orthogonal circuit variants that independently control multiple genes in the same cell. These circuits allowed dramatically improved CRISPR imaging, and super-resolution imaging of EGFR receptors with transient transfections. The toolbox provided here should allow precise, tunable, dosage-invariant expression for research, gene therapy, and other biotechnology applications.

Developing a novel immune infiltration-associated mitophagy prediction model for amyotrophic lateral sclerosis using bioinformatics strategies.

Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, which leads to muscle weakness and eventual paralysis. Numerous studies have indicated that mitophagy and immune inflammation have a significant impact on the onset and advancement of ALS. Nevertheless, the possible diagnostic and prognostic significance of mitophagy-related genes associated with immune infiltration in ALS is uncertain. The purpose of this study is to create a predictive model for ALS using genes linked with mitophagy-associated immune infiltration. Methods: ALS gene expression profiles were downloaded from the Gene Expression Omnibus (GEO) database. Univariate Cox analysis and machine learning methods were applied to analyze mitophagy-associated genes and develop a prognostic risk score model. Subsequently, functional and immune infiltration analyses were conducted to study the biological attributes and immune cell enrichment in individuals with ALS. Additionally, validation of identified feature genes in the prediction model was performed using ALS mouse models and ALS patients. Results: In this study, a comprehensive analysis revealed the identification of 22 mitophagy-related differential expression genes and 40 prognostic genes. Additionally, an 18-gene prognostic signature was identified with machine learning, which was utilized to construct a prognostic risk score model. Functional enrichment analysis demonstrated the enrichment of various pathways, including oxidative phosphorylation, unfolded proteins, KRAS, and mTOR signaling pathways, as well as other immune-related pathways. The analysis of immune infiltration revealed notable distinctions in certain congenital immune cells and adaptive immune cells between the low-risk and high-risk groups, particularly concerning the T lymphocyte subgroup. ALS mouse models and ALS clinical samples demonstrated consistent expression levels of four mitophagy-related immune infiltration genes (BCKDHA, JTB, KYNU, and GTF2H5) with the results of bioinformatics analysis. Conclusion: This study has successfully devised and verified a pioneering prognostic predictive risk score for ALS, utilizing eighteen mitophagy-related genes. Furthermore, the findings indicate that four of these genes exhibit promising roles in the context of ALS prognostic.

Synthetic dosage-compensating miRNA circuits allow precision gene therapy for Rett syndrome.

A longstanding challenge in gene therapy is expressing a dosage-sensitive gene within a tight therapeutic window. For example, loss of MECP2 function causes Rett syndrome, while its duplication causes MECP2 duplication syndrome. Viral gene delivery methods generate variable numbers of gene copies in individual cells, creating a need for gene dosage-invariant expression systems. Here, we introduce a compact miRNA-based, incoherent feed-forward loop circuit that achieves precise control of Mecp2 expression in cells and brains, and improves outcomes in an AAV-based mouse model of Rett syndrome gene therapy. Single molecule analysis of endogenous and ectopic Mecp2 mRNA revealed precise, sustained expression across a broad range of gene dosages. Delivered systemically in a brain-targeting AAV capsid, the circuit strongly suppressed Rett behavioral symptoms for over 24 weeks, outperforming an unregulated gene therapy. These results demonstrate that synthetic miRNA-based regulatory circuits can enable precise in vivo expression to improve the safety and efficacy of gene therapy.

A CuCo Bimetal Confined Hollow SiC Hybrid Photothermal Nanoreactor for the Integration of Pollutant Mineralization and Solar-Powered Water Evaporation.

Growing attention has been paid to the rational treatment of antibiotics-bearing medical wastewater. However, the complexity of polluted wastewater makes the later comprehensive treatment difficult only by the Advanced Oxidation Process technique. Therefore, the coupled water treatment techniques including contaminant mineralization and regeneration of cleanwater become very attractive. A bimetallic functional hollow nanoreactor defined as (Co@SiO2/Cu-X) was successfully constructed by coating a Cu-doped silica layer on the metal-organic framework (ZIF-67) followed by programmed calcination in nitrogen. The nanoreactor was endowed with a hollow configuration composed of mesoporous N-doping C-Silica hybrid shell encapsulated ultrafine Cu and Co metallic species. Such a configuration allows for the efficient diffusion and open reaction space of big contaminant molecules. The catalytic synergy of exposed Co-Cu bimetals and the easy accessibility of electron-rich contaminants by polar N doping sites triggered surface affinity make the optimal Co@SiO2/Cu-6 afford an excellent catalytic norfloxacin mineralization activity (7 min, kabs=0.744 min-1) compared to Cu-free Co@SiO2-6 (kabs=0.493 min-1) and Co-6 (kabs=0.378 min-1) Benefiting from the above unique advantages, Co@SiO2/Cu-6 show excellent removal performance in degrading different pollutants (carbamazepine, oxytetracycline, tetracycline, and bisphenol A) and persistent recycled stability in removing NFX. In addition, by virtue of the excellent photothermal properties, interfacial solar water evaporation application by Co@SiO2/Cu-6 was further explored to reach the regeneration of cleanwater (1.595 kg m-2 h-1, 97.51 %). The integration of pollutant mineralization and solar water evaporation by creating the monolith evaporation by anchoring the Co@SiO2/Cu-6 onto the tailored melamine sponge allows the regeneration of cleanwater (1.6 kg⋅m-2⋅h-1) and synchronous pollutant removal (NFX, 95 %, 60 min), which provides potential possibility the treatment of complicated wastewater.

Discovery of Natural Ah Receptor Antagonists from Salvia miltiorrhiza Bunge and Synthesis of Analogs for Tumor Immunotherapy.

IDO/TDO/Kyn/AhR signaling plays a crucial role in regulating innate and adaptive immunity, and targeting Ah receptor (AhR) inhibition can potentially redirect immune cells toward an antitumoral phenotype. Therefore, AhR is an attractive drug target for novel small molecule cancer immunotherapies. In this study, natural products tanshinolic A-D (1-4), the first adducts composed of ortho-naphthoquinone-type tanshinone and phenolic acid featuring a unique 1,4-benzodioxan hemiacetal structure, were isolated and characterized from the roots of Salvia miltiorrhiza Bunge. Luciferase reporter gene assay revealed that these adducts exhibited significant AhR inhibitory activity. A linear strategy was developed to construct a cis-3,4-disubstituted 1,4-benzodioxan hemiacetal structure. Encouragingly, in both in vitro and in vivo experiments, (±)-13e demonstrated the ability to inhibit tumor cell proliferation, promote INF-γ secretion in CD8+ T cells, and inhibit PD-1/PD-L1 signal transduction, which could exert tumor inhibition properties by inhibiting AhR activity, positioning it as a promising candidate for tumor immunotherapy.

Bromodomain-containing protein 9 activates proliferation and epithelial-mesenchymal transition of colorectal cancer via the estrogen pathway in vivo and in vitro.

Background: Bromodomain-containing protein 9 (BRD9) has been reported to be upregulated in multiple malignancies and facilitate cancer progression. However, there is a paucity of data relating to its expression and biological role in colorectal cancer (CRC). Therefore, this current study examined the prognostic role of BRD9 in CRC and the underlying mechanisms involved. Methods: Real-time polymerase chain reaction (PCR) and Western blotting were used to examine the expression of BRD9 in paired fresh CRC and para-tumor tissues from colectomy patients (n=31). Immunohistochemistry (IHC) was performed to assess BRD9 expression in 524 paraffin-embedded archived CRC samples. The clinical variables are including age, sex, carcinoembryonic antigen (CEA), location of tumor, T stage, N stage, and TNM classification. The effect of BRD9 on the prognosis of CRC patients was explored by Kaplan-Meier and Cox regression analyses. Cell counting kit 8 (CCK-8), clone formation assay, transwell assay, and flow cytometry were used to determine CRC cell proliferation, migration, invasion, and apoptosis, respectively. Xenograft models in nude mice were established to investigate the role of the BRD9 in vivo. Results: BRD9 mRNA and protein expression levels were significantly upregulated in CRC cells compared to normal colorectal epithelial cells (P<0.001). IHC analysis of 524 paraffin-embedded archived CRC tissues showed that high BRD9 expression was significantly associated with TNM classifications, CEA, and lymphatic invasion (P<0.01). Univariate and multivariate analyses indicated that BRD9 [hazard ratio (HR): 3.04, 95% confidence interval (CI): 1.78-5.20; P<0.01] expression and sex (HR: 6.39, 95% CI: 3.94-10.37; P<0.01) were independent prognostic factors for overall survival in the entire cohort. Overexpressing BRD9 promoted CRC cell proliferation, while silencing BRD9 inhibited the proliferation of CRC cells. Furthermore, we showed that BRD9 silencing significantly inhibited epithelial-mesenchymal transition (EMT) via the estrogen pathway. Finally, we demonstrated that silencing BRD9 significantly inhibited the proliferation and tumorigenicity of SW480 and HCT116 cells in vitro and in vivo in nude mice (P<0.05). Conclusions: This study demonstrated that BRD9 high could be an independent prognostic risk factor for CRC. Furthermore, the BRD9/estrogen pathway may contribute to the proliferation of CRC cells and EMT, suggesting that BRD9 may be a novel molecular target in the therapeutic treatment of CRC.