Bifunctional resin-supported nanosized zero-valent iron (N–S-ZVI) composite was developed by combining the oxidation properties of nZVI/O2 with adsorption features of iron oxides and anion-exchange ...resin N–S. In batch culture experiments, N–S and the N–S-ZVI composite were examined for As(III) and As(V). The results reveal that ZVI in the composite played a key role in enhancing As(III) removal. The N–S-ZVI composites could oxidize more toxic As(III) to less toxic As(V) with high efficiency under ambient conditions without the need of noble metals. At the same time, the oxidized As(V) could be effectively removed by adsorption onto the surface of composites. The mechanisms for the oxidation of As(III) to As(V) and the simultaneous removal of As(V) are proposed. In order to investigate the potential performance of N–S-ZVI in practical use, the effects of solution pH and coexisting anions on arsenite removal and on fixed-bed column treatment of simulated waters were studied. All the results indicated that the bifunctional composites have a great potential for As(III) removal from contaminated waters.
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•N–S-ZVI nanocomposite could result in effective As(III) removal from water.•Simultaneous adsorption and oxidation was proposed for As(III) removal.•Effect of pH and competitive ions on As(III) removal was examined.
To probe the role of host chemistry in formation and properties of the inside nano-zero valent iron (nZVI), we encapsulated nZVI within porous polystyrene resins functionalized with –CH
2Cl and –CH
...2N
+(CH
3)
3 respectively and obtained two hybrid nZVIs denoted Cl–S–ZVI and N–S–ZVI. 14.5% (in Fe mass) of nZVI particles were distributed in N–S within a ring-like region (about 0.10 mm in thickness) of size around ∼5 nm, whereas only 4.0% of nZVI particles were entrapped near the outer surface of Cl–S of size > 20 nm. –CH
2N
+(CH
3)
3 is more favorable than –CH
2Cl to inhibit nZVI dissolution into Fe
2+ ions under acidic pH (3.0–5.5). 97.2% of nitrate was converted into ammonium when introducing 0.12 g N–S–ZVI into 50 mL 50 mg N/L nitrate solution, while that for Cl–S–ZVI was 79.8% under identical Fe/N molar ratio. Under pH = 2 of the effectiveness of nZVI was 88.8% for nitrate reduction, whereas that for Cl–S–ZVI was only 14.6% under similar conditions. Nitrate reduction by N–S–ZVI exhibits relatively slower kinetics than Cl–S–ZVI, which may be related to different nZVI distribution of both composites. The coexisting chloride and sulfate co-ions are favorable for the reactivity enhancement of N–S–ZVI whereas slightly unfavorable for Cl–S–ZVI. The results demonstrated that support chemistry plays a significant role in formation and reactivity of the encapsulated nZVI, and may shed new light on design and fabrication of hybrid nZVIs for environmental remediation.
► nZVI was controllably immobilized within two polymeric hosts. ► Host surface chemistry greatly affects nZVI size and efficiency. ► Chloride and sulfate impose considerably effect on both hybrids for nitrate reduction. ► Effect of host surface chemistry should be considered for fabrication of similar nanocomposites.
Gregatin A (1) is a fungal polyketide featuring an alkylated furanone core, but the biosynthetic mechanism to furnish the intriguing molecular skeleton has yet to be elucidated. Herein, we have ...identified the biosynthetic gene cluster of gregatin A (1) in Penicillium sp. sh18 and investigated the mechanism that produces the intriguing structure of 1 by in vivo and in vitro reconstitution of its biosynthesis. Our study established the biosynthetic route leading to 1 and illuminated that 1 is generated by the fusion of two different polyketide chains, which are, amazingly, synthesized by a single polyketide synthase GrgA with the aid of a trans-acting enoylreductase GrgB. Chain fusion, as well as chain hydrolysis, is catalyzed by an α/β hydrolase, GrgF, hybridizing the C11 and C4 carbon chains by Claisen condensation. Finally, structural analysis and mutational experiments using GrgF provided insight into how the enzyme facilitates the unusual chain-fusing reaction. In unraveling a new biosynthetic strategy involving a bifunctional PKS and a polyketide fusing enzyme, our study expands our knowledge concerning fungal polyketide biosynthesis.
The long non-coding RNA colorectal neoplasia differentially expressed (CRNDE) contributes to the proliferation and migration of tumors. However, its molecular mechanism underlying gastric cancer ...remains unknown. In the present study, we investigated whether CRNDE was involved in the development of colorectal cancer via the binding of microRNA (miR)-217 with transcription factor 7-like 2 (TCF7L2) to enhance the Wnt signaling pathway.
Quantitative polymerase chain reaction was used to detect CRNDE, miR-217 and TCF7L2 in colorectal cancer tissues and cells. The CCK-8 assay, wound healing assay, and Transwell assay were used to detect cell proliferation, migration and invasion, respectively. Western blotting and luciferase activity assays were used to identify CRNDE and TCF7L2 as one of the direct targets of miR-217. The activity of the Wnt/β-catenin signaling pathway was analyzed by the TOPflash assay, and the subcellular localization of β-catenin and TCF7L2 was analyzed by western blotting and confocal microscopy.
In this study, we found that high expression of CRNDE is negatively correlated with low expression of miR-217 in colorectal cancer tissue and colorectal cancer cells. The dual luciferase reporter analysis showed that miR-217 is bound to CRNDE and TCF7L2 and negatively regulate their expression. CRNDE down-regulation inhibited the cell proliferation, migration and invasion in vitro and in vivo and the inhibitions were both completely blocked after miR-217 inhibition or TCF7L2 overexpression. Finally, TOPflash analysis showed that the activity of Wnt/β-catenin signaling is inhibited by CRNDE down-regulation and rescued by TCF7L2 over-expression. Consistently immunostaining and western blotting analysis showed that the expression of b-catenin and TCF7L2 in the nucleus was significantly decreased by CRNDE down-regulation and was rescued by TCF7L2 over-expression.
The present study suggest that CRNDE involves in the cell proliferation, migration and invasion of colorectal cancer cells via increasing the expression of TCF7L2 and activity of Wnt/β-catenin signaling through binding miR-217 competitively.
An important pathway for biochar to alter the availability of soil phosphorus (P) is to change P sorption characteristics of the soil. The aim of this study was to understand the mechanisms of ...biochar effects on P sorption in acid upland red soils in the presence of different concentrations of exogenous P. Rice straw biochar (RSB) was prepared and applied at rates of 0, 1%, 3%, and 5% (w/w) to three red soils (MZ1, MZ2, and QY1) differing in initial pH (pH = 4.31, 4.82, and 5.68, respectively). The P sorption characteristics of these red soils were described using the Langmuir and Temkin equations and their relationships with soil basic physicochemical properties were analyzed. Furthermore, a representative red soil (MZ2) was selected to analyze the zeta potential of soil colloids and the chemical properties of sorption equilibrium solution, in order to understand their relationships with P sorption characteristics. Results showed that within a certain range of P concentration in the equilibrium solution, the amount of P sorbed by the three red soils decreased and the corresponding amount of P desorbed increased with increasing amendment rate of RSB. RSB showed the greatest effect on P desorption characteristics of MZ2 soil in the presence of higher exogenous P concentration. With increasing RSB amendment rate, the maximum P sorption of MZ1 soil decreased, while those of MZ2 and QY1 soils increased after an initial decrease. Phosphate sorption equilibrium constant and maximum P buffer capacity of each soil first increased and then decreased. However, a single physicochemical property could not interpret complex changes in multi-factors that jointly determine the P sorption characteristics of red soils. In the case of MZ2 soil, RSB amendment shifted the zeta potential of soil colloids to the negative direction; this decreased the positive charge and increased the negative charge on the soil surface, thus reducing P sorption in the MZ2 soil. In the presence of the same concentration of exogenous P, RSB amendment altered the pH, dissolved organic C (DOC), humification index (HIX), and maximum fluorescence intensity (Fmax) in the sorption equilibrium solution. In most cases, the amount of P sorbed by the MZ2 soil was negatively correlated with the pH value, DOC concentration, HIX value, and Fmax value of humic-like dissolved organic matter (DOM), and positively correlated with the Fmax value of protein-like DOM (P < 0.05 or P < 0.01). The relative fractional distribution of the contents for humic-like and protein-like DOM might determine the difference in the P sorption characteristics of MZ2 soil. In conclusion, different amendment rates of RSB affected the release of phosphate from soil surfaces into the solution by altering basic physicochemical and electrochemical properties of red soils and chemical properties of sorption equilibrium solution.
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•Three acid red soils were amended with rice straw biochar (RSB) at different rates.•RSB amendment decreased P sorption by altering soil physicochemical properties.•The increase in humic-like fluorescent dissolved organic matter decreased P sorption.•RSB amendment affected P release from soil surfaces into solution by multi-factors.
Resistance is the major cause of treatment failure and disease progression in non-small cell lung cancer (NSCLC). There is evidence that hypoxia is a key microenvironmental stress associated with ...resistance to cisplatin, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), and immunotherapy in solid NSCLCs. Numerous studies have contributed to delineating the mechanisms underlying drug resistance in NSCLC; nevertheless, the mechanisms involved in the resistance associated with hypoxia-induced molecular metabolic adaptations in the microenvironment of NSCLC remain unclear. Studies have highlighted the importance of posttranslational regulation of molecular mediators in the control of mitochondrial function in response to hypoxia-induced metabolic adaptations. Hypoxia can upregulate the expression of sirtuin 1 (SIRT1) in a hypoxia-inducible factor (HIF)-dependent manner. SIRT1 is a stress-dependent metabolic sensor that can deacetylate some key transcriptional factors in both metabolism dependent and independent metabolic pathways such as HIF-1α, peroxisome proliferator-activated receptor gamma (PPAR-γ), and PPAR-gamma coactivator 1-alpha (PGC-1α) to affect mitochondrial function and biogenesis, which has a role in hypoxia-induced chemoresistance in NSCLC. Moreover, SIRT1 and HIF-1α can regulate both innate and adaptive immune responses through metabolism-dependent and -independent ways. The objective of this review is to delineate a possible SIRT1/PGC-1α/PPAR-γ signaling-related molecular metabolic mechanism underlying hypoxia-induced chemotherapy resistance in the NSCLC microenvironment. Targeting hypoxia-related metabolic adaptation may be an attractive therapeutic strategy for overcoming chemoresistance in NSCLC.
Background and objective:
Sacituzumab govitecan (SG), the first antibody-drug conjugate targeting human trophoblast cell-surface antigen 2 (Trop-2), has been approved by the Food and Drug ...Administration (FDA) for the treatment of advanced or metastatic breast cancer and urothelial cancer. However, there is currently a dearth of information regarding the safety profiles of SG in a large sample cohort. The objective of the present study is to investigate SG-related adverse events (AEs) in real-world settings leveraging the FDA Adverse Event Reporting System (FAERS) database to guide the safety management of clinical medication.
Methods:
The FAERS database was retrospectively queried to extract reports associated with SG from April 2020 to March 2023. To identify and evaluate potential AEs in patients receiving SG, various disproportionality analyses such as reporting odds ratio (ROR), the proportional reporting ratio (PRR), the Bayesian confidence propagation neural network (BCPNN), and the multi-item gamma Poisson shrinker (MGPS) were employed.
Results:
Overall, 2069 reports of SG as the “primary suspect” were identified. Noteworthy, SG was significantly associated with an increased risk of blood lymphatic system disorders (ROR, 7.18; 95% CI, 6.58–7.84) and hepatobiliary disorders (ROR, 2.68; 95% CI, 2.17–3.30) at the System Organ Class (SOC) level. Meanwhile, 61 significant disproportionality preferred terms (PTs) simultaneously complied with all four algorithms were adopted. Therein, anemia, thrombocytopenia, neutropenia, leukopenia, diarrhea, asthenia, alopecia, and electrolyte imbalance were consistent with the common AEs described in the clinical trials and specification of SG. Furthermore, unexpected significant AEs include colitis (ROR, 12.09; 95% CI, 9.1–16.08), heart rate increased (ROR, 5.11; 95% CI, 3.84–6.79), sepsis (ROR, 4.77; 95% CI, 3.59–6.34), cholestasis (ROR, 6.28; 95% CI, 3.48–11.36), blood bilirubin increased (ROR, 4.65; 95% CI, 2.42–8.94) and meningitis (ROR, 7.23; 95% CI, 2.71–19.29) were also be detected. The median time to onset of SG-related AEs was 14 interquartile range (IQR), 7–52 days, with the majority occurring within the initial month of SG treatment.
Conclusion:
Our study validates the commonly known AEs and also found some potentially emerging safety issues related to SG in real-world clinical practice, which could provide valuable vigilance evidence for clinicians and pharmacists to manage the safety issues of SG.
The aim of this study was to investigate the potential risk of drug-induced liver injury (DILI) caused by the CDK4/6 inhibitors (CDK4/6is abemaciclib, ribociclib, and palbociclib by comprehensively ...analyzing the FDA Adverse Event Reporting System (FAERS) database. Moreover, potential toxicological mechanisms of CDK4/6is-related liver injury were explored via drug-gene network analysis.
In this retrospective observational study, we collected reports of DILI associated with CDK4/6i use from the FAERS dated January 2014 to March 2023. We conducted disproportionality analyses using the reporting odds ratio (ROR) with a 95% confidence interval (CI). Pathway enrichment analysis and drug-gene network analyses were subsequently performed to determine the potential mechanisms underlying CDK4/6i-induced liver injury.
We found positive signals for DILI with ribociclib (ROR = 2.60) and abemaciclib (ROR = 2.37). DILIs associated with liver-related investigations, signs, and symptoms were confirmed in all three reports of CDK4/6is. Moreover, ascites was identified as an unlisted hepatic adverse effect of palbociclib. We isolated 189 interactive target genes linking CDK4/6 inhibitors to hepatic injury. Several key genes, such as STAT3, HSP90AA1, and EP300, were revealed via protein-protein analysis, emphasizing their central roles within the network. KEGG pathway enrichment of these genes highlighted multiple pathways.
Our study revealed variations in hepatobiliary toxicity among the different CDK4/6 inhibitors, with ribociclib showing the highest risk of liver injury, followed by abemaciclib, while palbociclib appeared relatively safe. Our findings emphasize the need for cautious use of CDK4/6 inhibitors, and regular liver function monitoring is recommended for long-term CDK4/6 inhibitor use.
The phenotypic transformation from differentiated to dedifferentiated vascular smooth muscle cells (VSMCs) plays a crucial role in VSMC proliferation and vascular remodeling in many cardiovascular ...diseases including hypertension. Nesfatin-1, a multifunctional adipocytokine, is critically involved in the regulation of blood pressure. However, it is still largely unexplored whether nesfatin-1 is a potential candidate in VSMC phenotypic switch and proliferation in hypertension. Experiments were carried out in Wistar-Kyoto rats (WKY), spontaneously hypertensive rats (SHR), human VSMCs and primary rat aortic VSMCs. We showed that the expression of nesfatin-1 was upregulated in media layer of the aorta in SHR and SHR-derived VSMCs. Nesfatin-1 promoted VSMC phenotypic transformation, accelerated cell cycle progression and proliferation. Knockdown of nesfatin-1 inhibited the VSMC phenotype switch from a contractile to a synthetic state, attenuated cell cycle progression and retarded VSMC proliferation in SHR-derived VSMCs. Moreover, nesfatin-1-activated PI3K/Akt/mTOR signaling was abolished by JAK/STAT inhibitor WP1066, and the increased phosphorylation levels of JAK2/STAT3 in response to nesfatin-1 were suppressed by inhibition of PI3K/Akt/mTOR in VSMCs. Pharmacological blockade of the forming feedback loop between PI3K/Akt/mTOR and JAK2/STAT3 prevented the proliferation of nesfatin-1-incubated VSMCs and primary VSMCs from SHR. Chronic intraperitoneal injection of nesfatin-1 caused severe hypertension and cardiovascular remodeling in normal rats. In contrast, silencing of nesfatin-1 gene ameliorated hypertension, phenotype switching, and vascular remodeling in the aorta of SHR. Therefore, our data identified nesfatin-1 as a key modulator in hypertension and vascular remodeling by facilitating VSMC phenotypic switching and proliferation.
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•Nesfatin-1 promoted VSMC phenotypic transformation, cell cycle progression and proliferation.•PI3K/Akt/mTOR and JAK2/STAT formed a mutual transactivation loop in VSMCs response to nesfatin-1.•Chronic peripheral nesfatin-1 administration caused severe hypertension and cardiovascular remodeling in rats.•Silencing of nesfatin-1 gene ameliorated hypertension, phenotype switching, and vascular remodeling in the aorta of SHR.
Salusin-β is abundantly expressed in many organs and tissues including heart, blood vessels, brain and kidneys. Recent studies have identified salusin-β as a bioactive peptide that contributes to ...various diseases, such as atherosclerosis, hypertension, diabetes and metabolic syndrome. However, the role of salusin-β in the pathogenesis of acute kidney injury (AKI) is largely unclear. In the present study, we investigated the roles of salusin-β in cisplatin or lipopolysaccharide (LPS)-induced renal injury. Herein, we found that salusin-β expression was upregulated in both renal tubular cells and kidney tissues induced by both cisplatin and LPS. In vitro, silencing of salusin-β diminished, whereas overexpression of salusin-β exaggerated the increased PKC phosphorylation, oxidative stress, histone γH2AX expression, p53 activation and apoptosis in either cisplatin or LPS-challenged renal tubular cells. More importantly, salusin-β overexpression-induced tubular cell apoptosis were abolished by using the PKC inhibitor Go 6976, reactive oxygen species (ROS) scavenger NAC, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor apocynin (Apo) or p53 inhibitor Pifithrin-α. In animals, blockade of salusin-β alleviated PKC phosphorylation, ROS accumulation, DNA damage, and p53 activation as well as renal dysfunction in mice after administration of cisplatin or LPS. Taken together, these results suggest that overexpressed salusin-β is deleterious in AKI by activation of the PKC/ROS signaling pathway, thereby priming renal tubular cells for apoptosis and death.
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•Both cisplatin and LPS elevated the renal levels of endogenous salusin-β in mice.•Treatment with neutralizing the salusin-β antibody ameliorated renal dysfunction and tubular cell DNA damage and apoptosis.•Deletion of salusin-β alleviated, while overexpression of salusin-β aggravated tubular epithelial cell DNA damage and apoptosis.•Salusin-β contributed to tubular cell DNA damage and apoptosis through the PKC/ROS signaling pathway.
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