Nitric Oxide-Activated Bioorthogonal Codelivery Nanoassembly for In Situ Synthesis of Photothermal Agent for Precise and Safe Anticancer Treatment.

The development of bioorthogonal activation in drug release represents a promising avenue for precise and safe anticancer treatment. However, two significant limitations currently hinder their clinical application: i) the necessity for separate administration of the drug precursor and its corresponding activator, leading to poor drug accumulation and potential side effects; ii) the reliance on exogenous metal or organic activators for triggering bioorthogonal activation, which often exhibit low efficiency and systemic toxicity when extending to living animals. To overcome these limitations, a nitric oxide (NO)-mediated bioorthogonal codelivery nanoassembly, termed TTB-NH2@PArg, which comprises a precursor molecular (TTB-NH2) and amphipathic polyarginine (PArg) is developed. In TTB-NH2@PArg, PArg serves as both self-assembled nanocarrier for TTB-NH2 and a NO generator. In tumor microenvironment (TME), the TME-specific generation of NO acts as a gas activator, triggering in situ bioorthogonal bond formation that transforms TTB-NH2 into TTB-AZO. This tumor-specific generation of TTB-AZO not only serves as a potential photothermal agent for effective tumor inhibition but also induces fluorescence change that enables real-time monitoring of bioorthogonal activation. This study presents a drug codelivery approach that enables precise and safe control of bioorthogonal activation for anticancer treatment, improving cancer therapy efficacy while minimizing side effects.

Design, synthesis, and antitumor mechanism investigation of iridium(III) complexes conjugated with ibuprofen.

The design and synthesis of a series of metal complexes formed by non-steroidal anti-inflammatory drugs (NSAIDs) ibuprofen (IBP) and iridium(III), with the molecular formula [Ir(C^N)2bpy(4-CH2OIBP-4'-CH2OIBP)](PF6) (Ir-IBP-1, Ir-IBP-2) (C^N = 2-phenylpyridine (ppy, Ir-IBP-1), 2-(2-thienyl)pyridine (thpy, Ir-IBP-2)) was introduced in this article. Firstly, it was found that the anti-proliferative activity of these complexes was more effective than that of cisplatin. Further research showed that Ir-IBP-1 and Ir-IBP-2 can accumulate in intracellular mitochondria, thereby disrupting mitochondrial membrane potential (MMP), increasing intracellular reactive oxygen species (ROS), blocking the G2/M phase of the cell cycle, and inducing cell apoptosis. In terms of protein expression, the expression of COX-2, MMP-9, NLRP3 and Caspase-1 proteins can be downregulated, indicating their ability to anti-inflammatory and overcome immune evasion. Furthermore, Ir-IBP-1 and Ir-IBP-2 can induce immunogenic cell death (ICD) by triggering the release of cell surface calreticulin (CRT), high mobility group box 1 (HMGB1) and adenosine triphosphate (ATP). Overall, iridium(III)-IBP conjugates exhibit various anti-tumor mechanisms, including mitochondrial damage, cell cycle arrest, inflammatory suppression, and induction of ICD.

Smart Nanoassembly Enabling Activatable NIR Fluorescence and ROS Generation with Enhanced Tumor Penetration for Imaging-Guided Photodynamic Therapy.

Fluorescence imaging-guided photodynamic therapy (FIG-PDT) holds promise for cancer treatment, yet challenges persist in poor imaging quality, phototoxicity, and insufficient anti-tumor effect. Herein, a novel nanoplatform, LipoHPM, designed to address these challenges, is reported. This approach employs an acid-sensitive amine linker to connect a biotin-modified hydrophilic polymer (BiotinPEG) with a new hydrophobic photosensitizer (MBA), forming OFF-state BiotinPEG-MBA (PM) micelles via an aggregation-caused quenching (ACQ) effect. These micelles are then co-loaded with the tumor penetration enhancer hydralazine (HDZ) into pH-sensitive liposomes (LipoHPM). Leveraging the ACQ effect, LipoHPM is silent in both fluorescence and reactive oxygen species (ROS) generation during blood circulation but restores both properties upon disassembly. Following intravenous injection in tumor-bearing mice, LipoHPM actively targets tumor cells overexpressing biotin-receptors, contributing to enhanced tumor accumulation. Upon cellular internalization, LipoHPM disassembles within lysosomes, releasing HDZ to enhance tumor penetration and inhibit tumor metastasis. Concurrently, the micelles activate fluorescence for tumor imaging and boost the production of both type-I and type-II ROS for tumor eradication. Therefore, the smart LipoHPM synergistically integrates near-infrared emission, activatable tumor imaging, robust ROS generation, efficient anti-tumor and anti-metastasis activity, successfully overcoming limitations of conventional photosensitizers and establishing itself as a promising nanoplatform for potent FIG-PDT applications.

RNA Control via Redox-Responsive Acylation.

Incorporating stimuli-responsive components into RNA constructs provides precise spatiotemporal control over RNA structures and functions. Despite considerable advancements, the utilization of redox-responsive stimuli for the activation of caged RNAs remains scarce. In this context, we present a novel strategy that leverages post-synthetic acylation coupled with redox-responsive chemistry to exert control over RNA. To achieve this, we design and synthesize a series of acylating reagents specifically tailored for introducing disulfide-containing acyl adducts into the 2'-OH groups of RNA ("cloaking"). Our data reveal that these acyl moieties can be readily appended, effectively blocking RNA catalytic activity and folding. We also demonstrate the traceless release and reactivation of caged RNAs ("uncloaking") through reducing stimuli. By employing this strategy, RNA exhibits rapid cellular uptake, effective distribution and activation in the cytosol without lysosomal entrapment. We anticipate that our methodology will be accessible to laboratories engaged in RNA biology and holds promise as a versatile platform for RNA-based applications.

Changes in sensory characteristics, chemical composition and microbial succession during fermentation of ancient plants Pu-erh tea.

"Ancient tea plants" are defined as tea trees > 100 years old, or with a trunk diameter > 25 cm; their leaves are manufactured to high - quality, valuable ancient plants pu-erh tea (APPT). In this study, a fermentation of APPT were developed, and outstanding sweetness of APPT infusion was observed. During fermentation, the content of soluble sugars, theabrownins (p < 0.05), as well as 41 metabolites were increased [Variable importance in projection (VIP) > 1.0; p < 0.05 and Fold-change (FC) FC > 2]; While relative levels of 72 metabolites were decreased (VIP > 1.0, p < 0.05 and FC < 0.5. Staphylococcus, Achromobacter, Sphingomonas, Thermomyces, Rasamsonia, Blastobotrys, Aspergillus and Cladosporium were identified as dominant genera, and their relative levels were correlated with contents of characteristic components (p < 0.05). Together, changes in sensory characteristics, chemical composition and microbial succession during APPT fermentation were investigated, and advanced the formation mechanism of its unique quality.

A nomogram based on the expression level of angiopoietin-like 4 to predict the severity of community-acquired pneumonia.

BACKGROUND: The morbidity and mortality of community-acquired pneumonia (CAP) remain high among infectious diseases. It was reported that angiopoietin-like 4 (ANGPTL4) could be a diagnostic biomarker and a therapeutic target for pneumonia. This study aimed to develop a more objective, specific, accurate, and individualized scoring system to predict the severity of CAP. METHODS: Totally, 31 non-severe community-acquired pneumonia (nsCAP) patients and 14 severe community-acquired pneumonia (sCAP) patients were enrolled in this study. The CURB-65 and pneumonia severity index (PSI) scores were calculated from the clinical data. Serum ANGPTL4 level was measured by enzyme-linked immunosorbent assay (ELISA). After screening factors by univariate analysis and receiver operating characteristic (ROC) curve analysis, multivariate logistic regression analysis of ANGPTL4 expression level and other risk factors was performed, and a nomogram was developed to predict the severity of CAP. This nomogram was further internally validated by bootstrap resampling with 1000 replications through the area under the ROC curve (AUC), the calibration curve, and the decision curve analysis (DCA). Finally, the prediction performance of the new nomogram model, CURB-65 score, and PSI score was compared by AUC, net reclassification index (NRI), and integrated discrimination improvement (IDI). RESULTS: A nomogram for predicting the severity of CAP was developed using three factors (C-reactive protein (CRP), procalcitonin (PCT), and ANGPTL4). According to the internal validation, the nomogram showed a great discrimination capability with an AUC of 0.910. The Hosmer-Lemeshow test and the approximately fitting calibration curve suggested a satisfactory accuracy of prediction. The results of DCA exhibited a great net benefit. The AUC values of CURB-65 score, PSI score, and the new prediction model were 0.857, 0.912, and 0.940, respectively. NRI comparing the new model with CURB-65 score was found to be statistically significant (NRI = 0.834, P < 0.05). CONCLUSION: A robust model for predicting the severity of CAP was developed based on the serum ANGPTL4 level. This may provide new insights into accurate assessment of the severity of CAP and its targeted therapy, particularly in the early-stage of the disease.

A Nomogram for Early Diagnosis of Community-Acquired Pneumonia Based on Bronchoalveolar Lavage Fluid Metabolomics.

Purpose: There is a high disease burden associated with community-acquired pneumonia (CAP) around the world. A timely and correct diagnosis of CAP can facilitate early treatment and prevent illness progression. The present study aimed to find some novel biomarkers of CAP by metabolic analysis and construct a nomogram model for precise diagnosis and individualized treatment of CAP patients. Patients and Methods: 42 CAP patients and 20 controls were enrolled in this study. The metabolic profiles of bronchoalveolar lavage fluid (BALF) samples were identified by untargeted LC-MS/MS analysis. With a VIP score ≥ 1 in OPLS-DA analysis and P < 0.05, the significantly dysregulated metabolites were estimated as potential biomarkers of CAP, which were further included in the construction of the diagnostic prediction model along with laboratory inflammatory indexes via stepwise backward regression analysis. Discrimination, calibration, and clinical applicability of the nomogram were evaluated by the C-index, the calibration curve, and the decision curve analysis (DCA) estimated by bootstrap resampling. Results: The metabolic profiles differed obviously between CAP patients and healthy controls, as shown by PCA and OPLS-DA plots. Seven metabolites significantly dysregulated in CAP were established: dimethyl disulfide, oleic acid (d5), N-acetyl-a-neuraminic acid, pyrimidine, choline, LPC (12:0/0:0) and PA (20:4/2:0). Multivariate logistic regression revealed that the expression levels of PA (20:4/2:0), N-acetyl-a-neuraminic acid, and CRP were associated with CAP. After being validated by bootstrap resampling, this model showed satisfactory diagnostic performance. Conclusion: A novel nomogram prediction model containing metabolic potential biomarkers in BALF that was developed for the early diagnosis of CAP offers insights into the pathogenesis and host response in CAP.

Characterization of the Microbiome and Host's Metabolites of the Lower Respiratory Tract During Acute Community-Acquired Pneumonia Identifies Potential Novel Markers.

Purpose: Community-acquired pneumonia (CAP) is one of the most frequently encountered infectious diseases worldwide. Few studies have explored the microbial composition of the lower respiratory tract (LRT) and host metabolites of CAP. We analyzed the microbial composition of the LRT and levels of host metabolites to explore new biomarkers for CAP. Patients and Methods: Bronchoalveolar lavage fluid (BALF) was collected from 28 CAP patients and 20 healthy individuals. Following centrifugation, BALF pellets were used for amplicon sequencing of a variable region of the bacterial 16S rDNA gene to characterize the microbial composition. Non-targeted metabolomics was used to detect host's metabolites in the supernatant. Results: Compared with healthy individuals, the bacterial alpha diversity in the LRT of CAP patients was significantly lower in CAP patients (p<0.05). On the bacterial genus level, over 20 genera were detected with lower relative abundance (p<0.05), while the relative abundance of Ruminiclostridium-6 was significantly higher in CAP patients. The levels of the host metabolites dimethyldisulfide, choline, pyrimidine, oleic acid and N-acetyl-neuraminic acid were all increased in BALF of CAP patients (p<0.05), while concentrations of lysophosphatidylcholines (LPC (12:0/0:0)) and phosphatidic acid (PA (20:4/2:0)) were decreased (p<0.05). Furthermore, the relative abundance of Parvimonas, Treponema-2, Moraxella, Aggregatibacter, Filifactor, Fusobacterium, Lautropia and Neisseria negatively correlated with concentrations of oleic acid (p<0.05). A negative correlation between the relative abundance of Treponema-2, Moraxella, Filifactor, Fusobacterium and dimethyldisulfide concentrations was also observed (p<0.05). In contrast, the relative abundance of Treponema-2, Moraxella, Filifactor, and Fusobacterium was found to be positively associated with concentrations of LPC (12:0/0:0) and PA (20:4/2:0) (p<0.05). Conclusion: The composition of the LRT microbiome differed between healthy individuals and CAP patients. We propose that some respiratory microbial components and host metabolites are potentially novel diagnostic markers of CAP.

GPR174 knockdown enhances blood flow recovery in hindlimb ischemia mice model by upregulating AREG expression.

Regulatory T cells (Tregs) are critically involved in neovascularization, an important compensatory mechanism in peripheral artery disease. The contribution of G protein coupled receptor 174 (GPR174), which is a regulator of Treg function and development, in neovascularization remains elusive. Here, we show that genetic deletion of GPR174 in Tregs potentiated blood flow recovery in mice after hindlimb ischemia. GPR174 deficiency upregulates amphiregulin (AREG) expression in Tregs, thereby enhancing endothelial cell functions and reducing pro-inflammatory macrophage polarization and endothelial cell apoptosis. Mechanically, GPR174 regulates AREG expression by inhibiting the nuclear accumulation of early growth response protein 1 (EGR1) via Gαs/cAMP/PKA signal pathway activation. Collectively, these findings demonstrate that GPR174 negatively regulates angiogenesis and vascular remodeling in response to ischemic injury and that GPR174 may be a potential molecular target for therapeutic interventions of ischemic vascular diseases.

A novel long noncoding RNA AC092718.4 as a prognostic biomarker and promotes lung adenocarcinoma progression.

Long noncoding RNAs (lncRNAs) reportedly play critical roles in the pathogenesis of various cancers, including lung adenocarcinoma (LUAD). However, the expression level, clinical significance, and potential function of lncRNA-AC092718.4 in LUAD remain unclear. In this study, we found that AC092718.4 was highly expressed in LUAD and high expression of AC092718.4 was correlated with poor overall survival (OS) and disease-specific survival (DSS) in LUAD. Cox regression analysis confirmed that AC092718.4 was an independent factor for LUAD prognosis. Kyoto Encyclopedia of Genes and Genomes (KEGG) results showed that AC092718.4 was involved in the PI3K-Akt signaling pathway, Th17 cell differentiation, and cell apoptosis. AC092718.4 expression was correlated with immune cell infiltration. Finally, we found that the knockdown of AC092718.4 inhibited lung adenocarcinoma (LUAD) cell growth and promote cell apoptosis. Our findings confirmed that AC092718.4 may serve as a potential prognostic biomarker in LUAD.

Evaluating the role of algae in algal-bacterial granular sludge: Nutrient removal, microbial community and granular characteristics.

Algal-bacterial granular sludge (ABGS) and bacterial granular sludge (BGS, control group) were operated over 240 days to investigate the role of algae in treating synthetic municipal wastewater. The results showed that algae significantly improved the removal efficiency of total nitrogen (TN). The nitrogen removal load of ABGS was 2.6 mg-N/g-VSS/day (22.8 %, light) and 1.1 mg-N/g-VSS/day (9.6 %, dark) higher than that of BGS, respectively, which was attributed to algae enhanced NH3-N removal capacity in the anaerobic stage and increased the utilization efficiency of organics in denitrification. Algae increased the relative abundance of denitrifying bacteria, and ABGS (28.83 %) was higher than BGS (14.28 %). Moreover, the dominant phylum of algae was Chlorophyta (98.39 %), the chlorophyll-a was sustained at 1.28 ± 0.26 mg/g-VSS. Algae significantly increased the content of extracellular polymeric substances (EPS), and the increased polysaccharide came from the tightly bound EPS. This study expands the understanding of the role of algae in ABGS.

Joint effects of polycyclic aromatic hydrocarbons, smoking, and XPC polymorphisms on damage in exon 2 of KRAS gene among young coke oven workers.

Genetic polymorphisms may contribute to individual susceptibility to DNA damage induced by environmental exposure. In this study, we evaluate the effects of co-exposure to PAHs, smoking and XPC polymorphisms, alone or combined, on damage in exons. A total of 288 healthy male coke oven workers were enrolled into this study, and urinary 1-hydroxypyrene (1-OH-Pyr) was detected. Base modification in exons of KRAS and BRAF gene, and polymorphisms of XPC were determined in plasma by real-time PCR. We observed 1-OH-Pyr was positively related to damage in exon 2 of KRAS (KRAS-2) and in exon 15 of BRAF (BRAF-15), respectively, and KRAS-2 and BRAF-15 were significantly associated with increased 1-OH-Pyr. A stratified analysis found 1-OH-Pyr was significantly associated with KRAS-2 in both smokers and non-smokers, while 1-OH-Pyr was significantly associated with BRAF-15 only in smokers. Additionally, individuals carrying both rs2228001 G-allele (GG+GT) and rs3731055 GG homozygote (GG) genotype appeared to have more significant effect on KRAS-2. The high levels of 1-OH-Pyr were associated with KRAS-2 only in rs2228001 GG+GT genotype carriers and the high levels of 1-OH-Pyr were associated with KRAS-2 only in rs3731055 GG genotype carriers and the most severe KRAS-2 was observed among subjects carrying all four of the above risk factors. Our findings indicated the co-exposure effect of PAHs and smoking could increase the risk of KRAS-2 by a mechanism partly involving XPC polymorphisms.

Cardiac Resident Macrophage-Derived Legumain Improves Cardiac Repair by Promoting Clearance and Degradation of Apoptotic Cardiomyocytes After Myocardial Infarction.

BACKGROUND: Cardiac resident macrophages are self-maintaining and originate from embryonic hematopoiesis. After myocardial infarction, cardiac resident macrophages are responsible for the efficient clearance and degradation of apoptotic cardiomyocytes (efferocytosis). This process is required for inflammation resolution and tissue repair; however, the underlying molecular mechanisms remain unknown. Therefore, we aimed to identify the mechanisms of the continued clearance and degradation of phagolysosomal cargo by cardiac resident macrophages during myocardial infarction. METHODS: Multiple transgenic mice such as Lgmn-/-, LgmnF/F; LysMCre, LgmnF/F; Cx3cr1CreER, LgmnF/F; LyveCre, and cardiac macrophage Lgmn overexpression by adenovirus gene transfer were used to determine the functional significance of Lgmn in myocardial infarction. Immune cell filtration and inflammation were examined by flow cytometry and quantitative real-time polymerase chain reaction. Moreover, legumain (Lgmn) expression was analyzed by immunohistochemistry and quantitative real-time polymerase chain reaction in the cardiac tissues of patients with ischemic cardiomyopathy and healthy control subjects. RESULTS: We identified Lgmn as a gene specifically expressed by cardiac resident macrophages. Lgmn deficiency resulted in a considerable exacerbation in cardiac function, accompanied by the accumulation of apoptotic cardiomyocytes and a reduced index of in vivo efferocytosis in the border area. It also led to decreased cytosolic calcium attributable to defective intracellular calcium mobilization. Furthermore, the formation of LC3-II-dependent phagosome around secondary-encountered apoptotic cardiomyocytes was disabled. In addition, Lgmn deficiency increased infiltration of MHC-IIhigh CCR2+ macrophages and the enhanced recruitment of MHC-IIlow CCR2+ monocytes with downregulation of the anti-inflammatory mediators, interleukin-10, and transforming growth factor-ß and upregulationof the proinflammatory mediators interleukin-1ß, tumor necrosis factor-α, interleukin-6, and interferon-γ. CONCLUSIONS: Our results directly link efferocytosis to wound healing in the heart and identify Lgmn as a significant link between acute inflammation resolution and organ function.

Environmental eustress improves postinfarction cardiac repair via enhancing cardiac macrophage survival.

Macrophages play a vital role in cardiac repair following myocardial infarction (MI). An enriched environment (EE) is involved in the regulation of macrophage-related activities and disease progression; however, whether EE affects the phenotype and function of macrophages to improve postinfarction cardiac repair remains unknown. In this study, we found that EE improved cardiac function, decreased mortality, and ameliorated adverse ventricular remodeling in mice after MI, with these outcomes closely related to the increased survival of Ly6Clow macrophages and their CCR2-MHCIIlow subsets. EE increased the expression of brain-derived neurotrophic factor (BDNF) in the hypothalamus, leading to higher circulating levels of BDNF, which, in turn, regulated the cardiac macrophages. BDNF bound to tropomyosin receptor kinase B to activate downstream ERK1/2 and AKT pathways, promoting macrophage survival. These findings demonstrate that EE optimizes postinfarction cardiac repair and highlights the significance of EE as a previously unidentified strategy for impeding adverse ventricular remodeling.

Legumain Is an Endogenous Modulator of Integrin αvß3 Triggering Vascular Degeneration, Dissection, and Rupture.

BACKGROUND: The development of thoracic aortic dissection (TAD) is closely related to extracellular matrix degradation and vascular smooth muscle cell (VSMC) transformation from contractile to synthetic type. LGMN (legumain) degrades extracellular matrix components directly or by activating downstream signals. The role of LGMN in VSMC differentiation and the occurrence of TAD remains elusive. METHODS: Microarray datasets concerning vascular dissection or aneurysm were downloaded from the Gene Expression Omnibus database to screen differentially expressed genes. Four-week-old male Lgmn knockout mice (Lgmn-/-), macrophage-specific Lgmn knockout mice (LgmnF/F;LysMCre), and RR-11a-treated C57BL/6 mice were given BAPN (ß-aminopropionitrile monofumarate; 1 g/kg/d) in drinking water for 4 weeks for TAD modeling. RNA sequencing analysis was performed to recapitulate transcriptome profile changes. Cell interaction was examined in macrophage and VSMC coculture system. The reciprocity of macrophage-derived LGMN with integrin αvß3 in VSMCs was tested by coimmunoprecipitation assay and colocalization analyses. RESULTS: Microarray datasets from the Gene Expression Omnibus database indicated upregulated LGMN in aorta from patients with TAD and mice with angiotensin II-induced AAA. Elevated LGMN was evidenced in aorta and sera from patients with TAD and mice with BAPN-induced TAD. BAPN-induced TAD progression was significantly ameliorated in Lgmn-deficient or inhibited mice. Macrophage-specific deletion of Lgmn alleviated BAPN-induced extracellular matrix degradation. Unbiased profiler polymerase chain reaction array and Gene Ontology analysis displayed that LGMN regulated VSMC phenotype transformation. Macrophage-specific deletion of Lgmn ameliorated VSMC phenotypic switch in BAPN-treated mice. Macrophage-derived LGMN inhibited VSMC differentiation in vitro as assessed by macrophages and the VSMC coculture system. Macrophage-derived LGMN bound to integrin αvß3 in VSMCs and blocked integrin αvß3, thereby attenuating Rho GTPase activation, downregulating VSMC differentiation markers and eventually exacerbating TAD development. ROCK (Rho kinase) inhibitor Y-27632 reversed the protective role of LGMN depletion in vascular dissection. CONCLUSIONS: LGMN signaling may be a novel target for the prevention and treatment of TAD.

Effect of Cationic Charge Density on Transcytosis of Polyethylenimine.

The adsorption-mediated transcytosis (AMT) induced by the electrostatic interaction between the positively charged surface of carriers and negatively charged cell membrane is a new paradigm enabling nanomedicine's tumor extravasation and infiltration. However, little is known about the correlation between the carrier's charge density and its AMT-induced tumor infiltration efficiency. Herein, we investigate the effect of the cationic polymer's charge on the AMT-induced tumor penetration ability using in vitro multilayer tumor spheroids (MTSs). A cationic polymer, polyethylenimine (PEI), is amidized with acetic anhydride to obtain acetylated PEIs (AcPEIs) with different cationic charge densities. As the amidization ratio increases, the AcPEIs' cytotoxicity, zeta potential, and cell-binding affinity significantly decrease. Notably, not only does the weak cell binding (AcPEIs with high acetylation degrees) lead to slow endocytosis and inefficient transcytosis, so does the strong cell-binding PEI. The PEI with 24% acetylation (AcPEI24%) is found to have the highest transcytosis efficiency because its balanced cell-binding affinity triggers fast adsorption-mediated endocytosis. The subsequent Golgi apparatus/endoplasmic reticulum-mediated exocytosis via extracellular vesicles leads to highly effective transcellular delivery and tumor penetration in MTSs. Therefore, the drug carrier's surface cationic charge density critically influences its AMT-induced tumor penetration efficiency. This study provides mechanistic insights into the design of drug-delivery systems with active transcytosis for improved tumor penetration and enhanced therapeutic efficiency.

The interaction effects of FEN1 rs174538 polymorphism and polycyclic aromatic hydrocarbon exposure on damage in exon 19 and 21 of EGFR gene in coke oven workers.

Polycyclic aromatic hydrocarbon (PAH) exposure and genetic susceptibility were conductive to genotoxic effects including gene damage, which can increase mutational probability. We aimed to explore the dose-effect associations of PAH exposure with damage of exons of epidermal growth factor receptor (EGFR) and breast cancer susceptibility gene 1 (BRCA1), as well as their associations whether modified by Flap endonuclease 1 (FEN1) genotype. Two hundred eighty-eight coke oven male workers were recruited, and we detected the concentration of 1-hydroxypyrene (1-OH-pyr) as PAH exposure biomarker in urine and examined base modification in exons of EGFR and BRCA1 respectively, and genotyped FEN1 rs174538 polymorphism in plasma. We found that the damage indexes of exon 19 and 21 of EGFR (EGFR-19 and EGFR-21) were both significantly associated with increased urinary 1-OH-pyr (both Ptrend < 0.001). The levels of urinary 1-OH-pyr were both significantly associated with increased EGFR-19 and EGFR-21 in both smokers and nonsmokers (both P < 0.001). Additionally, we observed that the urinary 1-OH-pyr concentrations were linearly associated with both EGFR-19 and EGFR-21 only in rs174538 GA+AA genotype carriers (both P < 0.001). Moreover, FEN1rs rs174538 showed modifying effects on the associations of urinary 1-OH-pyr with EGFR-19 and EGFR-21 (both Pinteraction < 0.05). Our findings revealed the linear dose-effect association between exon damage of EGFR and PAH exposure and highlight differences in genetic contributions to exon damage and have the potential to identify at-risk subpopulations who are susceptible to adverse health effects induced by PAH exposure.

Enhanced tumour penetration and prolonged circulation in blood of polyzwitterion-drug conjugates with cell-membrane affinity.

Effective anticancer nanomedicines need to exhibit prolonged circulation in blood, to extravasate and accumulate in tumours, and to be taken up by tumour cells. These contrasting criteria for persistent circulation and cell-membrane affinity have often led to complex nanoparticle designs with hampered clinical translatability. Here, we show that conjugates of small-molecule anticancer drugs with the polyzwitterion poly(2-(N-oxide-N,N-diethylamino)ethyl methacrylate) have long blood-circulation half-lives and bind reversibly to cell membranes, owing to the negligible interaction of the polyzwitterion with proteins and its weak interaction with phospholipids. Adsorption of the polyzwitterion-drug conjugates to tumour endothelial cells and then to cancer cells favoured their transcytosis-mediated extravasation into tumour interstitium and infiltration into tumours, and led to the eradication of large tumours and patient-derived tumour xenografts in mice. The simplicity and potency of the polyzwitterion-drug conjugates should facilitate the design of translational anticancer nanomedicines.

Exploration of the Potential Mechanism of Calculus Bovis in Treatment of Primary Liver Cancer by Network Pharmacology.

AIM AND OBJECTIVE: Calculus Bovis (CB) has been employed to treat diseases for a long time. It has been identified to play significant anti-inflammatory and anti-tumor roles. However, the mechanism of treating primary liver cancer (PLC) remains to be revealed. This study aims to clarify the molecules and mechanisms of CB in treating PLC. MATERIALS AND METHODS: After oral bioavailability (OB) and drug-likeness (DL) screening, 15 small molecules were identified as the potential ingredients against PLC. Following this, related targets network constructions and pathways were applied to clarify the mechanism of CB in treating PLC. An in vitro experiment was carried out to identify the function of CB in treating PLC. RESULTS: Eleven compounds of CB were identified that play an anti-PLC role, including oleanolic acid, ergosterol, ursolic acid, etc. The potential targets which were observed include IL6, MAPK-8, VEGFA, Caspase-3, etc. Further analysis showed that the mechanism of CB in the treatment of PLC involved apoptosis-related pathways and immune-related pathways. CONCLUSION: In summary, the current study combines network pharmacology and in vitro experiments to reveal the mechanism of CB against PLC. We concluded that 11 ingredients of CB have an anti-PLC effect. Furthermore, CB plays a key role in treating PLC mainly by apoptosisrelated pathways and immune-related pathways. Our experiment verifies that CB promotes the apoptosis of SMMC-7721.

Active Transportation of Liposome Enhances Tumor Accumulation, Penetration, and Therapeutic Efficacy.

Liposomes are the first and mostly explored nanocarriers for cancer drug delivery, which have shown great promise in clinical applications, but their limited accumulation and penetration into the tumor interstitial space, significantly reduce the therapeutic efficacy. Here, a γ-glutamyltranspeptidase (GGT)-triggered charge-switchable approach is reported that can trigger the fast endocytosis and transcytosis of the liposome in tumor microenvironments to overcome the harsh biological barriers in tumor tissues. The active transporting liposomal nanocarrier (GCSDL) is prepared by surface modification with a glutathione (GSH) moiety and encapsulated with doxorubicin (DOX). When the GCSDL contacts with tumor vascular endothelial cells, the overexpressed GGT enzyme on cytomembrane catalyzes the hydrolysis of GSH to generate cationic primary amines. The cationic GCSDL triggers fast caveolae-mediated endocytosis and vesicle-mediated transcytosis, resulting in sequential transcytosis to augment its tumor accumulation and penetration. Along with continual intercellular transportation, GCSDL can release DOX throughout the tumor to induce cancer cell apoptosis, resulting in complete eradication of hepatocellular carcinoma and cessation of pancreatic ductal adenocarcinoma's progression. This study develops an efficient strategy to realize high tumor accumulation and deep penetration for the liposomal drug delivery system via active transcytosis.