Network Pharmacology-Based Identification of Key Pharmacological Mechanism of Shen-qi-di-huang Decoction Acting on Uremia.

This study employs network pharmacology to uncover the pharmacological mechanisms underlying Shen-qi-di-huang decoction's efficacy in treating uremia. We identified a total of 927 differentially expressed genes (DEGs) through differential expression analysis and the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database and analysis platform, of which 607 were downregulated and 320 were upregulated. We also obtained the effective biological components and related target gene information of Chinese herbal medicines such as Renshen, Huangqi, shudihuang, Shanyao, Fuling, Mudanpi, and Shanzhuyu in Shen-qi-di-huang decoction and constructed a regulatory relationship network between molecular components and target genes in Shen-qi-di-huang decoction. We then constructed a protein-protein interaction (PPI) network of 15 targeted genes (RXRA, ND6, CYP1B1, SLPI, CDKN1A, RB1, HIF1A, MYC, HSPB1, IFNGR1, NQO1, IRF1, RASA1, PSMG1 and MAP2K4) using the STRING database and visualized the PPI network using the software Cytoscape. In addition, we revealed the key molecular functions of uremia through Gene Ontology (GO) enrichment analysis, mainly including neuron apoptotic process, cellular response to oxidative stress, regulation of neuron apoptotic process, neuron projection cytoplasm, RNA polymerase II transcription regulator complex, plasma membrane bounded cell projection cytoplasm, NADH and NADPH dehydrogenase (quinone) activity, protein kinase inhibitor and ubiquitin protein ligase binding, etc. Finally, we identified important biological pathways in uremia through Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, which mainly concentrated in Kaposi sarcoma-associated, small cell lung cancer, Gastric cancer, Hepatitis B and C, Hepatocellular carcinoma, Thyroid cancer, Bladder cancer, MAPK signaling pathway, ErbB signaling pathway, Th17 cell differentiation, HIF-1 signaling pathway, Thyroid hormone signaling pathway and Cell cycle, etc. Using integrated bioinformatical analysis, we elucidated key pharmacological mechanisms based on targeted genes, which was enable early identification of patients with uremia and would contribute to early clinical diagnosis and treatment of patients.

Assembling Artificial Photosynthetic Models in Water Using ß-Cyclodextrin-Conjugated Phthalocyanines as Building Blocks.

Two water-soluble zinc(II) phthalocyanines substituted with two or four permethylated ß-cyclodextrin (ß-CD) moieties at the α positions have been utilized as building blocks for the construction of artificial photosynthetic models in water. The hydrophilic and bulky ß-CD moieties not only can increase the water solubility of the phthalocyanine core and prevent its stacking in water but can also bind with a tetrasulfonated zinc(II) porphyrin (ZnTPPS) and/or sodium 2-anthraquinonesulfonate (AQ) in water through host-guest interactions. The binding interactions of these species have been studied spectroscopically, while the photoinduced processes of the resulting complexes have been investigated using steady-state and time-resolved spectroscopic methods. In the ternary complexes, the ZnTPPS units serve as light-harvesting antennas to capture the light energy and transfer it to the phthalocyanine core via efficient excitation energy transfer. The excited phthalocyanine is subsequently quenched by the electron-deficient AQ units through electron transfer. Femtosecond transient absorption spectroscopy provides clear evidence for the singlet-singlet energy transfer from the photo-excited ZnTPPS to the phthalocyanine core with a rate constant (kENT ) in the order of 109  s-1 . The population of phthalocyanine radical cations indicates the occurrence of electron transfer from the excited phthalocyanine to the AQ moieties, forming a charge-separated state.

Skullcapflavone II, a novel NQO1 inhibitor, alleviates aristolochic acid I-induced liver and kidney injury in mice.

Aristolochic acid I (AAI) is a well established nephrotoxin and human carcinogen. Cytosolic NAD(P)H quinone oxidoreductase 1 (NQO1) plays an important role in the nitro reduction of aristolochic acids, leading to production of aristoloactam and AA-DNA adduct. Application of a potent NQO1 inhibitor dicoumarol is limited by its life-threatening side effect as an anticoagulant and the subsequent hemorrhagic complications. As traditional medicines containing AAI remain available in the market, novel NQO1 inhibitors are urgently needed to attenuate the toxicity of AAI exposure. In this study, we employed comprehensive 2D NQO1 biochromatography to screen candidate compounds that could bind with NQO1 protein. Four compounds, i.e., skullcapflavone II (SFII), oroxylin A, wogonin and tectochrysin were screened out from Scutellaria baicalensis. Among them, SFII was the most promising NQO1 inhibitor with a binding affinity (KD = 4.198 µmol/L) and inhibitory activity (IC50 = 2.87 µmol/L). In human normal liver cell line (L02) and human renal proximal tubular epithelial cell line (HK-2), SFII significantly alleviated AAI-induced DNA damage and apoptosis. In adult mice, oral administration of SFII dose-dependently ameliorated AAI-induced renal fibrosis and dysfunction. In infant mice, oral administration of SFII suppressed AAI-induced hepatocellular carcinoma initiation. Moreover, administration of SFII did not affect the coagulation function in short term in adult mice. In conclusion, SFII has been identified as a novel NQO1 inhibitor that might impede the risk of AAI to kidney and liver without obvious side effect.

Aptasensors for the detection of infectious pathogens: design strategies and point-of-care testing.

The epidemic of infectious diseases caused by contagious pathogens is a life-threatening hazard to the entire human population worldwide. A timely and accurate diagnosis is the critical link in the fight against infectious diseases. Aptamer-based biosensors, the so-called aptasensors, employ nucleic acid aptamers as bio-receptors for the recognition of target pathogens of interest. This review focuses on the design strategies as well as state-of-the-art technologies of aptasensor-based diagnostics for infectious pathogens (mainly bacteria and viruses), covering the utilization of three major signal transducers, the employment of aptamers as recognition moieties, the construction of versatile biosensing platforms (mostly micro and nanomaterial-based), innovated reporting mechanisms, and signal enhancement approaches. Advanced point-of-care testing (POCT) for infectious disease diagnostics are also discussed highlighting some representative ready-to-use devices to address the urgent needs of currently prevalent coronavirus disease 2019 (COVID-19). Pressing issues in aptamer-based technology and some future perspectives of aptasensors are provided for the implementation of aptasensor-based diagnostics into practical application.

[Study on alleviating effect of Glycyrrhizae Radix et Rhizoma on Psoraleae Fructus-induced liver injury based on network pharmacology and cell experiments].

This study was designed to explore the alleviating effect and mechanism of Glycyrrhizae Radix et Rhizoma against Psora-leae Fructus-induced liver injury based on network pharmacology and cell experiments. The active components of Glycyrrhizae Radix et Rhizoma and Psoraleae Fructus were first retrieved from the Encyclopedia of Traditional Chinese Medicine(ETCM), Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP), Comparative Toxicogenomics Database(CTD), and literature and further screened by SwissADME. The obtained 25 potential toxic components of Psoraleae Fructus and 29 flavonoids in Glycyrrhizae Radix et Rhizoma were input into the SwissTargetPrediction for target predication. A total of 818 targets related to liver injury were screened out based on GeneCards and MalaCards, and 91 common targets of Psoraleae Fructus, Glycyrrhizae Radix et Rhizoma, and liver injury were obtained from Venny. STRING was applied for constructing the PPI network, and Metascape for analyzing the biological processes and signaling pathways that common targets participated in. Cytoscape was used to construct the component-target-disease network and component-target-pathway network for Glycyrrhizae Radix et Rhizoma against Psoraleae Fructus-induced liver injury. The predicted core targets were proto-oncogene tyrosine-protein kinase(SRC), phosphatidylinositol 4,5-bisphosphate 3-kinase subunit alpha(PIK3 CA), RAC-alpha serine/threonine-protein kinase(AKT1), etc, with PI3 K-AKT signaling pathway, MAPK signaling pathway, apoptosis, Toll-like receptor signaling pathway, and NF-κB signaling pathway mainly involved. Following the scree-ning of the main toxic and pharmacodynamic components, the pharmacodynamic effects were investigated by cell experiments. The results showed that licochalcone A was mainly responsible for alleviating coryfolin-induced liver injury, licochalcone B for coryfolin-and psoralidin-induced liver injury, and echinatin for corylifolinin-and bakuchiol-induced liver injury. The preliminary revealing of the alleviating effect of Glycyrrhizae Radix et Rhizoma on Psoraleae Fructus-induced liver injury and the prediction of related mechanisms will provide reference for further mechanism research and reasonable clinical compatibility.

[Comparison on distribution of 8 components from ethanol extract of Psoraleae Fructus between normal and lipopolysaccharide-induced model rats].

UPLC-TQ/MS was employed to determine the content of 8 main components(psoralen, isopsoralen, psoralenoside, isopsoralenoside, bavachin, psoralidin, corylin, and neobavaisoflavone) in tissues of normal and lipopolysaccharide(LPS)-induced model rats 0.5, 1, 2, 6, and 12 h after intragastric administration of 3.6 g·kg~(-1) ethanol extract of Psoraleae Fructus. The distribution characteristics of the 8 main components in the different tissues(liver, kidney, spleen, heart, and lung) were studied and compared. The results showed that the distribution behaviors of the components varied among different tissues. At different time points, the components presented wide and uneven distribution in the body. Liver and kidney had higher content of the components, followed by spleen, heart, and lung. In both normal and LPS-induced model rats, the content of the 8 main components was higher in liver and kidney and varied significantly among different tissues. The content of psoralen in the tissues of LPS-induced model rat was significantly higher than that of the normal group 12 h after administration. The reason may be that the modeling slowed down the absorption and distribution of psoralen. The LPS-induced model rats had higher content of psoralenoside and isopsoralenoside in the liver tissue than the normal rats, which indicated that the modeling increased the absorption and distribution of psoralenoside and isopsoralenoside in the liver tissue. Further, it is hypothesized that psoralenoside and isopsoralenoside may be toxic substances of Psoraleae Fructus-induced liver injury.

PGC-1α activates SIRT3 to modulate cell proliferation and glycolytic metabolism in breast cancer.

Breast cancer is the leading cause of death among women. PGC-1α plays an important role in the regulation of metabolic reprogramming in cancer cells. SIRT3 has significant implications for tumor growth. In this study, we explored the roles of PGC-1α and SIRT3 in cell proliferation and mitochondrial energy metabolism alterations in breast cancer cells. The expression patterns of PGC-1α and SIRT3 were examined using qRT-PCR and western blotting analysis. MCF-7 and MDA-MB-231 cells were infected with adenovirus to overexpress or knock down the expression of PGC-1α and SIRT3. Cell viability and apoptosis were analyzed by CCK-8 and flow cytometry, respectively. Hexokinase 2, pyruvate kinase activities, as well as NAD+/NADH ratio and ATP concentration, were assessed by commercial kits. Glucose consumption was measured using the glucose oxidase method and lactic acid concentration was detected by lactate dehydrogenase kit. Expression levels of PGC-1 and SIRT3 were much lower in breast cancer patients, compared with the normal controls. Overexpression of PGC-1α or SIRT3 both significantly promoted the apoptosis and inhibited the proliferation in MCF-7 and MDA-MB-231 cells. Additionally, PGC-1α or SIRT3 also induced the inhibition of glycolysis metabolism. Moreover, the expression of SIRT3 was positively regulated by PGC-1α. Silencing SIRT3 partly reversed the negative effects of PGC-1α on glycolytic metabolism. These findings demonstrated that PGC-1α/SIRT3 regulated cell proliferation and apoptosis of breast cancer through altering glycolysis, which may provide novel therapeutic strategies for breast cancer.

CYT387, a Novel JAK2 Inhibitor, Suppresses IL-13-Induced Epidermal Barrier Dysfunction Via miR-143 Targeting IL-13Rα1 and STAT3.

Atopic dermatitis (AD) is a chronic inflammatory skin disease influencing not only children but also adults. It is well-known that AD has a complex pathogenesis without effective therapy. Herein, we explored the function and mechanism of CYT387, a novel JAK2 inhibitor, on epidermal barrier damage. HaCaT cells exposed with high-concentration Ca2+ (1.8 mM) for 14 days were recruited for the model of keratinocytes (KC). The cell model of skin barrier damage was induced by IL-13, and KC markers such as filaggrin (FLG), loricrin (LOR), and involucrin (IVL) were detected to judge the success of the model. In this study, we found that miR-143 was lowly expressed whereas IL-13Rα1 was highly expressed in blood cells of patients with AD, indicating their negative correlation. Moreover, IL-13 treatment down-regulated miR-143 and up-regulated activated JAK2 and STAT3 phosphorylation, which was reversed by CYT387 administration. The dual-luciferase reporter assay verified that miR-143 could directly bind to 3'-UTR of IL-13Rα1, as well as STAT3. Furthermore, the function of CYT387 in the skin barrier damage induced by IL-13 was abolished by miR-143 inhibitor. Thus, CYT387 might alleviate IL-13-induced epidermal barrier damage via targeting IL-13Rα1 and STAT3 by miR-143 to repress inflammation. These findings revealed that the protective effects and the underlying mechanisms of CYT387 in AD, which provided evidence that miR-143 may be a novel therapeutic target for AD.

Alternaria tenuissima Causing Leaf Spot Disease on Amygdalus triloba in Xinjiang of China.

Amygdalus triloba (Rosaceae; previously Prunus triloba) is a deciduous, flowering shrub that is widely used in the greening and beautification of lawns, parks and courtyards in China. In late May 2019, a leaf spot disease of A. triloba was observed on approximately 35% of plants in the Xinjiang Alaer city (40˚33'20''N, 81˚17'19''E). The disease symptoms began as small, suborbicular, brown spots on the leaves. As the disease progressed, the spots enlarged and coalesced into large necrotic areas and resulted in premature defoliation. Leaf sections (5 x 5 mm) from infected leaves were surface - sterilized with 75% ethanol for 30 s and 0.1% HgCl2 for 1 min, rinsed three times in sterile distilled water and then incubated on potato dextrose agar (PDA). Fifteen fungal isolates showing similar morphological characteristics were obtained by single-spore isolation. On the PDA plates, all fungal colonies had a dark olive color with loose, cottony mycelium. On the potato carrot agar, the fungus formed unbranched spore chains, but occasionally formed one or two lateral branches. Conidiophores were short, hazel-colored, septae, arising singly, and measuring 15.1 to 61.8 × 1.8 to 4.2 µm (35.2 ± 1.4 × 2.3 ± 0.1 µm, n = 50). Mature conidia were ellipsoidal to ovoid with a short conical beak at the tip, light brown with zero to three longitudinal septa and one to five transverse septa, and measuring 19.3 to 30.8 × 7.2 to 12.5 µm (21.8 ± 0.3 × 9.5 ± 0.2 µm, n = 50). Based on the cultural and morphological traits, the pathogen was preliminary identified as Alternaria tenuissima (Simmons 2007). Genomic DNA was extracted from the representative isolate YALAR-1, and the internal transcribed spacer (ITS) region, the partial coding sequence of endopolygalacturonase (endoPG), the glyceradehyde -3- phosphate dehydrogenase (GAPDA), the partial region of the histone 3 (H3) genes were amplified using primers ITS1/ITS4 (White et al. 1990), PG2b/PG3a (Andrew et al. 2009), GDF1/GDR1 (Berbee et al. 1999) and H3-1a/H3-1b (Glass and Donaldson 1995), respectively. The amplicons were sequenced and deposited in GenBank [MT459807 (ITS), MT459808 (endoPG), MT459805 (GAPDA), MT459806 (H3)]. MegaBLAST analyses revealed that our ITS, endoPG, GAPDA, and H3 sequences were 99-100% identical to those of A. tenuissima isolates in GenBank [AF347032 (ITS), KP124026 (endoPG), AY278809 (GAPDA), KF997086 (H3)], confirming the identity of the pathogen as A. tenuissima. Pathogenicity tests were performed by inoculating the fungus onto healthy, mature leaves of A. triloba in the field. Twenty five leaves (five leaves/plant) were sprayed with spore suspensions (1 × 106 spores/ml) of each fungal pathogen, and the same number of leaves were sprayed with distilled water as controls. Inoculated and control leaves were covered with clear plastic bags for 3 days. The experiment was repeated three times. Twelve days after inoculation, the observed symptoms were similar to the original symptoms and the same fungal pathogen was reisolated from the inoculated leaves and identified as A. tenuissima based on morphological features and sequence analysis. The control leaves remained asymptomatic and no fungus was isolated from these leaves. Previously, a leaf spot of A. triloba caused by Alternaria brassicae was reported in Dalian, China (Xie et al. 2017). In order to control this disease effectively, further studies are needed on the biology and ecology of A. tenuissima and A. brassicae respectively. To our knowledge, this is the first report of A. tenuissima associated with leaf spot disease on A. triloba in China. In late September 2020, the diseased plant rate increased to 38% in Alaer city. If the disease control and prevention is neglected, the landscape of Alaer city will be affected seriously. So, in order to effectively control the spread of the disease, it is urgent now to study the sensitivity of pathogen to fungicide and carry out the field efficacy trials. References: Andrew, M., et al. 2009. Mycologia. 101:95. Berbee, M. L., et al. 1999. Mycologia. 91:964. Glass, N. L., and Donaldson, G. C. 1995. Appl. Environ. Microbiol. 61:1323. Simmons, E. G. 2007. Alternaria: An Identification Manual. CBS Fungal Biodiversity Centre, Utrecht, The Netherlands. White, T. J., et al. 1990. PCR Protocols: A Guide to Methods and Applications. Academic Press, San Diego, CA. Xie, Y., et al. 2017. Liaoning Agricultural Sciences. 6: 73.

Cardioprotective mechanisms of salvianic acid A sodium in rats with myocardial infarction based on proteome and transcriptome analysis.

Ischemic heart diseases (IHDs) cause great morbidity and mortality worldwide, necessitating effective treatment. Salvianic acid A sodium (SAAS) is an active compound derived from the well-known herbal medicine Danshen, which has been widely used for clinical treatment of cardiovascular diseases in China. This study aimed to confirm the cardioprotective effects of SAAS in rats with myocardial infarction and to investigate the underlying molecular mechanisms based on proteome and transcriptome profiling of myocardial tissue. The results showed that SAAS effectively protected against myocardial injury and improved cardiac function. The differentially expressed proteins and genes included important structural molecules, receptors, transcription factors, and cofactors. Functional enrichment analysis indicated that SAAS participated in the regulation of actin cytoskeleton, phagosome, focal adhesion, tight junction, apoptosis, MAPK signaling, and Wnt signaling pathways, which are closely related to cardiovascular diseases. SAAS may exert its cardioprotective effect by targeting multiple pathways at both the proteome and transcriptome levels. This study has provided not only new insights into the pathogenesis of myocardial infarction but also a road map of the cardioprotective molecular mechanisms of SAAS, which may provide pharmacological evidence to aid in its clinical application.

Assemblies of Boron Dipyrromethene/Porphyrin, Phthalocyanine, and C60 Moieties as Artificial Models of Photosynthesis: Synthesis, Supramolecular Interactions, and Photophysical Studies.

A series of light-harvesting conjugates based on a zinc(II) phthalocyanine core with either two or four boron dipyrromethene (BODIPY) or porphyrin units have been synthesized and characterized. The conjugation of BODIPY/porphyrin units can extend the absorptions of the phthalocyanine core to cover most of the visible region. Upon addition of an imidazole-substituted C60 (C60 Im), it can axially bind to the zinc(II) center of the phthalocyanine core through metal-ligand interactions. The resulting complexes form photosynthetic antenna-reaction center mimics in which the BODIPY/porphyrin units serve as the antennas to capture the light and transfer the energy to the phthalocyanine core by efficient excitation energy transfer. The excited phthalocyanine is then quenched by the axially bound C60 Im moiety by electron transfer, which has been supported by computational studies. The photoinduced processes of the assemblies have been studied in detail by various steady-state and time-resolved spectroscopic methods. By femtosecond transient absorption spectroscopic studies, the lifetimes of the charge-separated state of the bis(BODIPY) and bis(porphyrin) systems have been determined to be 3.2 and 4.0 ns, respectively.

Design, Synthesis, and Antifungal Activity of Novel Aryl-1,2,3-Triazole-ß-Carboline Hybrids.

The copper catalytic azide and terminal alkyne cycloaddition reaction, namely "click chemistry", gives a new and convenient way to create l,4-disubstitutd-l,2,3-triazoles. In this work, 2-pyrrolecarbaldiminato⁻Cu(II) complexes were established as efficient catalysts for the three-component 1,3-dipolar cycloaddition reaction of arylboronic acid and sodium azide (NaN3) with terminal alkynes in ethanol at room temperature to 50 °C, 1,4-disubstituted 1,2,3-triazoles were synthesized. Following the optimized protocol, two series of new aryl-1,2,3-triazole-ß-carboline hybrids have been designed and synthesized, and the chemical structures were characterized by ¹H NMR, 13C NMR, and high-resolution mass spectrometry (HRMS). All of the target compounds were evaluated in vitro for their antifungal activity against Rhizoctorzia solani, Fusarium oxysporum, Botrytis cinerea Pers., sunflower sclerotinia rot, and rape sclerotinia rot by mycelia growth inhibition assay at 50 µg/mL. The antifungal evaluation of the novel hybrids showed that, among the tested compounds, 5a, 5b, 5c, and 9b showed good antifungal activity against sunflower sclerotinia rot. Specifically, compound 9b also exhibited high broad-spectrum fungicidal against all the tested fungi with inhibition rates of 58.3%, 18.52%, 63.07%, 84.47%, and 81.23%. However, for F. oxysporum, all the target compounds showed no in vitro antifungal activities with an inhibition rate lower than 20%. These results provide an encouraging framework that could lead to the development of potent novel antifungal agents.

Target Identification of Kinase Inhibitor Alisertib (MLN8237) by Using DNA-Programmed Affinity Labeling.

Accurate identification of the molecular targets of bioactive small molecules is a highly important yet challenging task in biomedical research. Previously, a method named DPAL (DNA-programmed affinity labeling) for labeling and identifying the cellular targets of small molecules and nucleic acids was developed. Herein, DPAL is applied for the target identification of Alisertib (MLN8237), which is a highly specific aurora kinase A (AKA) inhibitor and a drug candidate being tested in clinical trials for cancer treatment. Apart from the well-established target of AKA, several potential new targets of MLN8237 were identified. Among them, p38 mitogen-activated protein kinase (p38) and laminin receptor (LAMR) were validated to be implicated in the anticancer activities of MLN8237. Interestingly, these new targets were not identified with non-DNA-based affinity probes. This work may facilitate an understanding of the molecular basis of the efficacy and side effects of MLN8237 as a clinical drug candidate. On the other hand, this work has also demonstrated that the method of DPAL could be a useful tool for target identification of bioactive small molecules.

Identification of a ligand for tumor necrosis factor receptor from Chinese herbs by combination of surface plasmon resonance biosensor and UPLC-MS.

Identification of bioactive compounds directly from complex herbal extracts is a key issue in the study of Chinese herbs. The present study describes the establishment and application of a sensitive, efficient, and convenient method based on surface plasmon resonance (SPR) biosensors for screening active ingredients targeting tumor necrosis factor receptor type 1 (TNF-R1) from Chinese herbs. Concentration-adjusted herbal extracts were subjected to SPR binding assay, and a remarkable response signal was observed in Rheum officinale extract. Then, the TNF-R1-bound ingredients were recovered, enriched, and analyzed by UPLC-QTOF/MS. As a result, physcion-8-O-ß-D-monoglucoside (PMG) was identified as a bioactive compound, and the affinity constant of PMG to TNF-R1 was determined by SPR affinity analysis (K D = 376 nM). Pharmacological assays revealed that PMG inhibited TNF-α-induced cytotoxicity and apoptosis in L929 cells via TNF-R1. Although PMG was a trace component in the chemical constituents of the R. officinale extract, it had considerable anti-inflammatory activities. It was found for the first time that PMG was a ligand for TNF receptor from herbal medicines. The proposed SPR-based screening method may prove to be an effective solution to analyzing bioactive components of Chinese herbs and other complex drug systems. Graphical abstract Scheme of the method based on SPR biosensor for screening and recovering active ingredients from complex herbal extracts and UPLC-MS for identifying them. Scheme of the method based on SPR biosensor for screening and recovering active ingredients from complex herbal extracts and UPLC-MS for identifying them.

Ferroptosis-Based Therapeutic Strategies toward Precision Medicine for Cancer.

Ferroptosis is a type of iron-dependent programmed cell death characterized by the dysregulation of iron metabolism and the accumulation of lipid peroxides. This nonapoptotic mode of cell death is implicated in various physiological and pathological processes. Recent findings have underscored its potential as an innovative strategy for cancer treatment, particularly against recalcitrant malignancies that are resistant to conventional therapies. This article focuses on ferroptosis-based therapeutic strategies for precision cancer treatment, covering the molecular mechanisms of ferroptosis, four major types of ferroptosis inducers and their inhibitory effects on diverse carcinomas, the detection of ferroptosis by fluorescent probes, and their implementation in image-guided therapy. These state-of-the-art tactics have manifested enhanced selectivity and efficacy against malignant carcinomas. Given that the administration of ferroptosis in cancer therapy is still at a burgeoning stage, some major challenges and future perspectives are discussed for the clinical translation of ferroptosis into precision cancer treatment.

A near-infrared emitting "off-on" fluorescent probe for bioimaging of Pd(â ¡) ions in living cells and mice.

BACKGROUND: The surging consumption of palladium in modern industry has given rise to its accumulation in the ecosystem, posing conspicuous toxicity to aquatic organisms and human health. The investigation of palladium in biological systems is highly demanded for the in-depth understanding of its dynamics and behaviors. Fluorescence imaging serves as a powerful approach to assess palladium species in biological systems, and currently most of the sensing probes are applicable to living cells. Effective tracking of palladium species in living organisms is challenging, which requires sufficient hydrophilicity and imaging depth of the probes. RESULTS: Based on an intramolecular charge transfer (ICT) mechanism, a distyryl boron dipyrromethene (BODIPY) derivative (DISBDP-Pd) has been prepared for the near-infrared (NIR) fluorescence imaging of Pd2+ ions. Two additional methoxy triethylene glycol (TEG) chains could serve as flexible and hydrophilic moieties to enhance the aqueous solubility and cell permeability of the extended conjugate. Solution studies revealed that DISBDP-Pd exhibited a NIR fluorescence enhancement signal exclusively to Pd2+ ions (detection limit as low as 0.85 ppb) with negligible interference from Pd0 species and other closely related metal ions. Computational calculations have been performed to rationalize the binding mode and the mechanism of action. Fluorescence imaging assays have been conducted on A549 human non-small cell lung carcinoma cells and mouse models. Exhibiting negligible cytotoxicity, DISBDP-Pd demonstrated concentration-related fluorescence enhancement signals in response to Pd2+ ions in living cells and mice. SIGNIFICANCE: DISBDP-Pd exhibits advantages over many small molecule palladium probes in terms of satisfactory aqueous solubility, high sensitivity and selectivity, and biocompatible NIR emission property, which are particularly favorable for the sensing application in biological environments. The design strategy of this probe can potentially be adopted for the functionalization of other BODIPY probes implemented for NIR fluorescence bioimaging.

Benzoylaconitine: A promising ACE2-targeted agonist for enhancing cardiac function in heart failure.

Benzoylaconitine is a natural product in the treatment of cardiovascular disease. However, its pharmacological effect, direct target protein, and molecular mechanisms for the treatment of heart failure are unclear. In this study, benzoylaconitine inhibited Ang II-induced cell hypertrophy and fibrosis in rat primary cardiomyocytes and rat fibroblasts, while attenuating cardiac function and cardiac remodeling in TAC mice. Using the limited proteolysis-mass spectrometry (LiP-MS) method, the angiotensin-converting enzyme 2 (ACE2) was confirmed as a direct binding target of benzoylaconitine for the treatment of heart failure. In ACE2-knockdown cells and ACE2-/- mice, benzoylaconitine failed to ameliorate cardiomyocyte hypertrophy, fibrosis, and heart failure. Online RNA-sequence analysis indicated p38/ERK-mediated mitochondrial reactive oxygen species (ROS) and nuclear factor kappa B (NF-κB) activation are the possible downstream molecular mechanisms for the effect of BAC-ACE2 interaction. Further studies in ACE2-knockdown cells and ACE2-/- mice suggested that benzoylaconitine targeted ACE2 to suppress p38/ERK-mediated mitochondrial ROS and NF-κB pathway activation. Our findings suggest that benzoylaconitine is a promising ACE2 agonist in regulating mitochondrial ROS release and inflammation activation to improve cardiac function in the treatment of heart failure.

A metabolomics approach reveals metabolic disturbance of human cholangiocarcinoma cells after parthenolide treatment.

ETHNOPHARMACOLOGICAL RELEVANCE: Tanacetum parthenium (L.) Schultz-Bip, commonly known as feverfew, has been traditionally used to treat fever, migraines, rheumatoid arthritis, and cancer. Parthenolide (PTL), the main bioactive ingredient isolated from the shoots of feverfew, is a sesquiterpene lactone with anti-inflammatory and antitumor properties. Previous studies showed that PTL exerts anticancer activity in various cancers, including hepatoma, cholangiocarcinoma, acute myeloid leukemia, breast, prostate, and colorectal cancer. However, the metabolic mechanism underlying the anticancer effect of PTL remains poorly understood. AIM OF THE STUDY: To explore the anticancer activity and underlying mechanism of PTL in human cholangiocarcinoma cells. MATERIAL AND METHODS: In this investigation, the effects and mechanisms of PTL on human cholangiocarcinoma cells were investigated via a liquid chromatography/mass spectrometry (LC/MS)-based metabolomics approach. First, cell proliferation and apoptosis were evaluated using cell counting kit-8 (CCK-8), flow cytometry analysis, and western blotting. Then, LC/MS-based metabolic profiling along with orthogonal partial least-squares discriminant analysis (OPLS-DA) has been constructed to distinguish the metabolic changes between the negative control group and the PTL-treated group in TFK1 cells. Next, enzyme-linked immunosorbent assay (ELISA) was applied to investigate the changes of metabolic enzymes associated with significantly alerted metabolites. Finally, the metabolic network related to key metabolic enzymes, metabolites, and metabolic pathways was established using MetaboAnalyst 5.0 and Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway Database. RESULTS: PTL treatment could induce the proliferation inhibition and apoptosis of TFK1 in a concentration-dependent manner. Forty-three potential biomarkers associated with the antitumor effect of PTL were identified, which primarily related to glutamine and glutamate metabolism, alanine, aspartate and glutamate metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, phenylalanine metabolism, arginine biosynthesis, arginine and proline metabolism, glutathione metabolism, nicotinate and nicotinamide metabolism, pyrimidine metabolism, fatty acid metabolism, phospholipid catabolism, and sphingolipid metabolism. Pathway analysis of upstream and downstream metabolites, we found three key metabolic enzymes, including glutaminase (GLS), γ-glutamyl transpeptidase (GGT), and carnitine palmitoyltransferase 1 (CPT1), which mainly involved in glutamine and glutamate metabolism, glutathione metabolism, and fatty acid metabolism. The changes of metabolic enzymes associated with significantly alerted metabolites were consistent with the levels of metabolites, and the metabolic network related to key metabolic enzymes, metabolites, and metabolic pathways was established. PTL may exert its antitumor effect against cholangiocarcinoma by disturbing metabolic pathways. Furthermore, we selected two positive control agents that are considered as first-line chemotherapy standards in cholangiocarcinoma therapy to verify the reliability and accuracy of our metabolomic study on PTL. CONCLUSION: This research enhanced our comprehension of the metabolic profiling and mechanism of PTL treatment on cholangiocarcinoma cells, which provided some references for further research into the anti-cancer mechanisms of other drugs.

[Pollution Characteristics and Risk Assessment of Antibiotics and Resistance Genes in Different Water Sources in the Wuhan Section of the Yangtze River].

The distribution characteristics, correlations, and potential ecological risks of 13 antibiotics and 10 antibiotic resistance genes (ARGs) in 16 water sources in Wuhan were analyzed using solid-phase extraction-ultra-high performance liquid chromatography-tandem mass spectrometry (SPE-UPLC-MS/MS) and real-time quantitative PCR technology. The distribution characteristics and correlations and potential ecological risks of antibiotics and resistance genes in this region were analyzed. The results showed that a total of nine antibiotics were detected in the 16 water source samples, and the concentration range was ND-177.36 ng·L-1. The concentration distribution presented as follows:Tributary Jushui River

Pyroptosis, Metabolism, and Oxidation in Tumorigenesis: Mechanisms and Therapeutic Implications.

Significance: Pyroptosis is a discovered programmed cell death that is mainly executed by the gasdermin protein family. Cell swelling and membrane perforation are observed when pyroptosis occurs, and is accompanied by the liberation of cell contents. Recent Advances: As the study of pyroptosis continues to progress, there is increasing evidence that pyroptosis influences the development of tumors. In addition, the relationship between pyroptosis and tumor is diverse for different tissues and cells. Critical Issues: In this review, we first introduce the research history and molecular mechanisms of pyroptosis. Then we specifically discuss the link between pyroptosis and metabolic and oxidation in tumorigenesis. In the subsequent sections, we focus on the induction of pyroptosis in cancer and its potential role as a promising target for cancer therapy, and discuss the implications of pyroptosis in tumor treatment. In addition, we further summarize the therapeutic value of pyroptosis in tumor treatment. Future Directions: A detailed understanding of the role played by pyroptosis in tumors will help us to further explore tumor formation and progression and provide ideas for the development of new pyroptosis-based therapeutic approaches for patients. Antioxid. Redox Signal. 39, 512-530.