Gradient three-dimensional current collector with lithiophilic nanolayer regulation for efficient lithium metal anode construction.

Metallic lithium (Li) is highly desirable for Li battery anodes due to its unique advantages. However, the growth of Li dendrites poses challenges for commercialization. To address this issue, researchers have proposed various three-dimensional (3D) current collectors. In this study, the selective modification of a 3D Cu foam scaffold with lithiophilic elements was explored to induce controlled Li deposition. The Cu foam was selectively modified with Ag and Sn to create uniform Cu foam (U-Cu) and gradient lithiophilic Cu foam (G-Cu) structures. Density Functional Theory (DFT) calculations revealed that Ag exhibited a stronger binding energy with Li compared to Sn, indicating superior Li induction capabilities. Electrochemical testing demonstrated that the half cell with the G-Cu@Ag electrode exhibited excellent cycling stability, maintaining 550 cycles with an average Coulombic efficiency (CE) of 97.35%. This performance surpassed that of both Cu foam and G-Cu@Sn. The gradient modification of the current collectors improved the utilization of the 3D scaffold and prevented Li accumulation at the top of the scaffold. Overall, the selective modification of the 3D Cu foam scaffold with lithiophilic elements, particularly Ag, offers promising prospects for mitigating Li dendrite growth and enhancing the performance of Li batteries.

Research on different compound combinations of Realgar-Indigo naturalis formula to reverse acute promyelocytic leukemia arsenic resistance by regulating autophagy through mTOR pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: In China, the Chinese patent drug Realgar-Indigo naturalis Formula (RIF) is utilized for the therapy of acute promyelocytic leukemia (APL). Comprising four traditional Chinese herb-Realgar, Indigo naturalis, Salvia miltiorrhiza, and Pseudostellaria heterophylla-it notably includes tetra-arsenic tetra-sulfide, indirubin, tanshinone IIa, and total saponins of Radix Pseudostellariae as its primary active components. Due to its arsenic content, RIF distinctly contributes to the therapy for APL. However, the challenge of arsenic resistance in APL patients complicates the clinical use of arsenic agents. Interestingly, RIF demonstrates a high remission rate in APL patients, suggesting that its efficacy is not significantly compromised by arsenic resistance. Yet, the current state of research on RIF's ability to reverse arsenic resistance remains unclear. AIM OF THE STUDY: To investigate the mechanism of different combinations of the compound of RIF in reversing arsenic resistance in APL. MATERIALS AND METHODS: The present study utilized the arsenic-resistant HL60-PMLA216V-RARα cell line to investigate the effects of various RIF compounds, namely tetra-arsenic tetra-sulfide (A), indirubin (I), tanshinone IIa (T), and total saponins of Radix Pseudostellariae (S). The assessment of cell viability, observation of cell morphology, and evaluation of cell apoptosis were performed. Furthermore, the mitochondrial membrane potential, changes in the levels of PMLA216V-RARα, apoptosis-related factors, and the PI3K/AKT/mTOR pathway were examined, along with autophagy in all experimental groups. Meanwhile, we observed the changes about autophagy after blocking the PI3K or mTOR pathway. RESULTS: Tanshinone IIa, indirubin and total saponins of Radix Pseudostellariae could enhance the effect of tetra-arsenic tetra-sulfide down-regulating PMLA216V-RARα, and the mechanism was suggested to be related to inhibiting mTOR pathway to activate autophagy. CONCLUSIONS: We illustrated that the synergistic effect of different compound combinations of RIF can regulate autophagy through the mTOR pathway, enhance cell apoptosis, and degrade arsenic-resistant PMLA216V-RARα.

Effects of traditional Chinese exercises on cardiac rehabilitation in patients with myocardial infarction: a meta-analysis of randomized controlled trials.

Objective: Traditional Chinese exercises (TCE) are excellent cardiac rehabilitation (CR) training that can effectively improve cardiorespiratory fitness. However, there is no published meta-analysis of TCE on CR in patients with myocardial infarction (MI). Therefore, this study aimed to provide a comprehensive evaluation from multiple perspectives. Methods: This meta-analysis is based on the Cochrane Handbook of Systematic Reviews. Eight databases were searched from the date of database construction to March 15, 2023. Two investigators independently screened the literature and assessed their quality. The meta-analysis was performed with RevMan5.4 software. Results: A total of 21 articles involving 1,890 patients were included. N-terminal pro-brain natriuretic peptide (NT-proBNP) in the TCE group were lower than the control group (MD = -96.34, 95%CI: -140.69 ∼-51.98, P < 0.00001, I2 = 96%), the left ventricular ejection fraction (LVEF) in the TCE group was higher than the control group (MD = 4.58, 95%CI: 3.28-5.88, P < 0.00001, I2 = 79%), the left ventricular end diastolic dimension (LVDD) in TCE group was lower than the control group (MD = -3.83, 95%CI: -5.27 ∼-2.38, P < 0.00001, I2 = 94%), the left ventricular end systolic diameter (LVESD) in TCE group was lower than the control group (MD = -2.17, 95%CI: -4.10 ∼-0.24, P < 0.00001, I2 = 96%), The 6-minute walk test (6MWT) in the TCE group was higher than the control group (MD = 69.60, 95%CI: 34.59-104.60, P < 0.00001, I2 = 99%), the oxygen uptake (VO2) in the TCE group was higher than the control group (MD = 4.38, 95%CI: 2.25-6.51, P < 0.00001, I2 = 94%), the 36-item short form survey (SF-36) in the TCE group was higher than the control group (MD = 13.34, 95%CI: 9.25-17.42, P = 0.008, I2 = 75%), the Hamilton Anxiety Scale (HAMA) in the TCE group was lower than the control group (MD = -4.34, 95%CI: -5.18 ∼-3.50, P = 1.00, I2 = 0%), the Hamilton Depression Scale (HAMD) in the TCE group was lower than the control group (MD = -3.48, 95%CI: -5.35 ∼-1.61, P = 0.0002, I2 = 88%), the incidence of major adverse cardiac events (MACEs) in the TCE group was lower than the control group (RR = 0.31, 95%CI: 0.20-0.47, P = 0.52, I2 = 0%). Subgroup analysis revealed differences in TCE types could be a potential source of heterogeneity. Conclusion: MI patients who used TCE have not only notable improvements in cardiopulmonary function, physical function, quality of life, and emotions but also reduced the incidence of MACEs. Tai Chi might be more efficient than Ba Duan Jin. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023408675.

Identification of SLC2A3 as a prognostic indicator correlated with the NF-κB/EMT axis and immune response in head and neck squamous cell carcinoma.

SLC2A3 is an important member of the glucose transporter superfamily. It has been recently suggested that upregulation of SLC2A3 is associated with poor survival and acts as a prognostic marker in a variety of tumors. Unfortunately, the prognostic role of SLC2A3 in head and neck squamous cell carcinoma (HNSC) is less known. In the present study, we analyzed SLC2A3 expression in HNSC and its correlation with prognosis using TCGA and GEO databases. The results showed that SLC2A3 mRNA expression was higher in HNSC compared with adjacent normal tissues, which was validated with our 9 pairs of HNSC specimens. Moreover, high SLC2A3 expression predicted poor prognosis in HNSC patients. Mechanistically, GSEA revealed that high expression of SLC2A3 was enriched in epithelial-mesenchymal transition (EMT) and NF-κB signaling. In HNSC cell lines, SLC2A3 knockdown inhibited cell proliferation and migration. In addition, NF-κB P65 and EMT-related gene expression was suppressed upon SLC2A3 knockdown, indicating that SLC2A3 may play a preeminent role in the progression of HNSC through the NF-κB/EMT axis. Meanwhile, the expression of SLC2A3 was negatively correlated with immune cells, suggesting that SLC2A3 may be involved in the immune response in HNSC. The correlation between SLC2A3 expression and drug sensitivity was further assessed. In conclusion, our study demonstrated that SLC2A3 could predict the prognosis of HNSC patients and mediate the progression of HNSC via the NF-κB/EMT axis and immune responses.

Repurposing CRISPR/Cas to Discover SARS-CoV-2 Detecting and Neutralizing Aptamers.

RNA aptamers provide useful biological probes and therapeutic agents. New methodologies to screen RNA aptamers will be valuable by complementing the traditional Systematic Evolution of Ligands by Exponential Enrichment (SELEX). Meanwhile, repurposing clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR associated systems (Cas) has expanded their utility far beyond their native nuclease function. Here, CRISmers, a CRISPR/Cas-based novel screening system for RNA aptamers based on binding to a chosen protein of interest in a cellular context, is presented. Using CRISmers, aptamers are identified specifically targeting the receptor binding domain (RBD) of the spike glycoprotein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Two aptamer leads enable sensitive detection and potent neutralization of SARS-CoV-2 Delta and Omicron variants in vitro. Intranasal administration of one aptamer, further modified with 2'-fluoro pyrimidines (2'-F), 2'-O-methyl purines (2'-O), and conjugation with both cholesterol and polyethylene glycol of 40 kDa (PEG40K), achieves effective prophylactic and therapeutic antiviral activity against live Omicron BA.2 variants in vivo. The study concludes by demonstrating the robustness, consistency, and potential broad utility of CRISmers using two newly identified aptamers but switching CRISPR, selection marker, and host species.

Development of a Nomogram That Predicts the Risk of Coronary Heart Disease in Patients With Hyperlipidemia.

BACKGROUND: Hyperlipidemia is one of the independent risk factors for the onset of coronary heart disease (CHD), and our aim is to construct a coronary risk prediction model for patients with hyperlipidemia based on carotid ultrasound in combination with other risk factors. METHODS: The nomogram risk prediction model is based on a retrospective study on 820 patients with hyperlipidemia. The predictive accuracy and discriminative ability of the nomogram were determined by receiver operating characteristic (ROC) curves and calibration curves. The results were validated using bootstrap resampling and a prospective study on 39 patients with hyperlipidemia accepted at consenting institutions from 2021 to 2022. RESULT: In the modeling cohort, 820 patients were included. A total of 33 variables were included in univariate logistic regression. On multivariate analysis of the modeling cohort, independent factors for survival were sex, age, hypertension, plaque score, LVEF, PLT, and HbAlc, which were all selected into the nomogram. The calibration curve for probability of survival showed good agreement between prediction by nomogram and actual observation. The area under the curve (AUC) of the nomogram model was 0.881 (95% CI 0.858∼0.905), with a sensitivity of 79% and a specificity of 81.7%. In the validation cohort, the AUC was 0.75, 95% CI (0.602∼0.906). The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy of this model were 54.16%, 80%, 81.25%, 52.17% and 64.1%. This model showed a good fitting and calibration and positive net benefits in decision curve analysis. CONCLUSION: A nomogram model for CHD risk in patients with hyperlipidemia was developed and validated using 7 predictors, which may have potential application value in clinical risk assessment, decision-making, and individualized treatment associated with CHD.

Integrated transcriptomic and volatilomic profiles to explore the potential mechanism of aroma formation in Toona sinensis.

As an important quality determinant of Toona sinensis, the unique aroma largely impacts the purchasing behavior of consumers. However, the underlying formation mechanism of the characteristic aroma of T. sinensis remains poorly understood. In this work, integrative volatile/nonvolatile compounds profiling and RNA sequencing were used to characterize six T. sinensis cultivars. Volatile sulfur compounds (VSCs) and terpenoids were the main volatile organic compounds (VOCs) in T. sinensis, accounting for 36.95-67.27% and 17.75-31.36% of the total VOC content, respectively. Notably, the VOCs originated from terpenoid biosynthesis, and the degradation of unsaturated fatty acids (UFAs) played important roles in reconciling the irritating odor of VSCs. The above differential metabolic profiles are the main sources of the specific aroma of different T. sinensis cultivars. Furthermore, 13 volatile organic compounds were identified as potential biomarkers to distinguish these T. sinensis cultivars by chemometric analysis. Based on the analysis of transcriptomic datasets, the potential biosynthetic pathways of the key VSCs were firstly confirmed in T. sinensis. It was found that 1-propenylsulfenic acid is a crucial precursor in the formation of characteristic VSCs in T. sinensis. Additionally, two potential mechanisms were proposed to explain the differences of the key VSCs among six T. sinensis cultivars. These results provide theoretical guidance for improving the aroma quality of T. sinensis.

An Amperometric Biomedical Sensor for the Determination of Homocysteine Using Gold Nanoparticles and Acetylene Black-Dihexadecyl Phosphate-Modified Glassy Carbon Electrode.

A novel nanocomposite film composed of gold nanoparticles and acetylene black-dihexadecyl phosphate was fabricated and modified on the surface of a glassy carbon electrode through a simple and controllable dropping and electropolymerization method. The nanocomposite film electrode showed a good electrocatalytic response to the oxidation of homocysteine and can work as an amperometric biomedical sensor for homocysteine. With the aid of scanning electron microscopy, energy dispersive X-ray technology and electrochemical impedance spectroscopy, the sensing interface was characterized, and the sensing mechanism was discussed. Under optimal conditions, the oxidation peak current of homocysteine was linearly increased with its concentration in the range of 3.0 µmol/L~1.0 mmol/L, and a sensitivity of 18 nA/(µmol/L) was obtained. Furthermore, the detection limit was determined as 0.6 µmol/L, and the response time was detected as 3 s. Applying the nanocomposite film electrode for monitoring the homocysteine in human blood serum, the results were satisfactory.

PD-L1 Aptamer-Functionalized Metal-Organic Framework Nanoparticles for Robust Photo-Immunotherapy against Cancer with Enhanced Safety.

Immune checkpoint blockade has become a paradigm-shifting treatment modality to combat cancer, while conventional administration of immune checkpoint inhibitors, such as anti-PD-L1 antibody (α-PD-L1), often shows unsatisfactory immune responses and lead to severe immune-related adverse effects (irAEs). Herein, we develop a PD-L1 aptamer-based spherical nucleic acids (SNAs), which consists of oxaliplatin (OXA) encapsulated in a metal-organic framework nanoparticle core and a dense shell of aptPD-L1 (denoted as M@O-A). Upon light irradiation, this nanosystem enables concurrent photodynamic therapy (PDT), chemotherapy, and enhanced immunotherapy in one shot to inhibit both primary colorectal tumors and untreated distant tumors in mice. Notably, M@O-A shows scarcely any systemic immunotoxicity in a clinical irAEs-mimic transgenic mouse model. Collectively, this study presents a novel strategy for priming robust photo-immunotherapy against cancer with enhanced safety.

Integrated volatilomic profiles and chemometrics provide new insights into the spatial distribution and aroma differences of volatile compounds in seven Toona sinensis cultivars.

As a popular vegetable, the unique and pleasant aroma is the key quality characteristic of Toona sinensis. To explore the sources and differences of aroma, the volatilomic profiling in the leaves and shoots of seven T. sinensis cultivars were investigated by chemometric analysis. The results indicated that aroma differences of each cultivar can be distinguished by W5S, W1S, W1W and W2S sensors during E-nose analysis. More than two thirds of all volatile organic compounds (VOCs) were derived from the leaves of most cultivars, except for Ximu toon. Notably, 2-mercapto-3,4-dimethyl-2,3-dihydrothiophene, 3,4-dimethyl thiophene, methyl thiirane, isocaryophyllene and hexanal were the major VOCs in both the leaves and shoots of T. sinensis. By constructing a weighted correlation network model, 5 modules and 11 hub VOCs were identified in the leaf samples of all cultivars. The data indicate that differential intracellular metabolic responses are responsible for the aroma formation of seven T. sinensis cultivars.

Different software processing affects the peak picking and metabolic pathway recognition of metabolomics data.

In untargeted liquid chromatography‒mass spectrometry (LC‒MS) metabolomics studies, data preprocessing and metabolic pathway recognition are crucial for screening important pathways that are disturbed by diseases or restored by drugs. Here, we collected high-resolution mass spectrometry data of serum samples from 221 coronary heart disease (CHD) patients under two different chromatographic columns (BEH amide and C18 column) and evaluated the three commonly used software programs (XCMS, Progenesis QI, MarkerView) from four aspects (including signal drift, peak number, metabolite annotation and metabolic pathway enrichment). The results showed that the data preprocessed by the three software programs have different degrees of signal drift, but the StatTarget could improve the data quality to meet the data analysis requirement after correction. In addition, XCMS surpassed other software in detection of real chromatographic peaks and Progenesis QI was the best performer in terms of the number of metabolite annotation. XCMS and Progenesis QI showed different performance in pathway enrichment. However, metabolic pathways based on the combination of XCMS and Progenesis QI had a high coincidence with Progenesis QI. In addition, we also reported that C18 and amide columns were highly complementary and have great potential for cooperation in the context of metabolic pathways. In this study, the effects of different chromatographic columns and software pretreatments on metabolomics data were evaluated based on clinical large cohort samples, which will provide a reference for the metabolomics of clinical samples and guide subsequent mechanistic research.

Effects of Buyang Huanwu Decoction on Intestinal Barrier, Intestinal Flora, and Trimethylamine Oxide in Rats with Heart Failure.

OBJECTIVE: To explore the mechanisms of Buyang Huanwu Decoction (BYHWD) modulating the gut microbiome and trimethylamine oxide (TAMO) to exert cardioprotective effects. METHODS: Ligation of the left anterior descending coronary artery was performed in rats to induce heart failure (HF). Except for the sham-operation group (n=10), 36 operation-induced models were randomized into 3 groups using a random number table (n=12 in each group): the model group, the BYHWD group (15.02 g/kg BYHWD), and the positive group (4.99 g/kg metoprolol succinate). After 4-week treatment (once daily by gavage), echocardiography was applied to evaluate the cardiac function and the Tei index (the ratio of ventricular isovolumic contraction time (IVCT) and isovolumic diastolic time (IVRT) to ejection time (ET)) was calculated; hematoxylin-eosin (HE) staining was observed to characterize the pathology of the myocardium and small intestinal villi. D-lactic acid was detected by an enzyme-linked immunosorbent assay (ELISA). Expressions of occludin, claudin-1, and zonula occludens (ZO-1) were detected by Western blot. 16S ribosomal ribonucleic acid (16S rRNA) sequencing was used to explore the changes in the intestinal flora. TMAO was detected via liquid chromatography-tandem mass spectrometry (LC-MS/MS). RESULTS: In the echocardiography, the Tei index was considerably lower in the positive and BYHWD groups compared with the model group (P<0.05). Besides, BYHWD improved the pathology of myocardium and small intestine of HF rats and lowered the D-lactic acid content in the serum, when compared with the model group (P<0.05). BYHWD also improved the expression of occludin and claudin-1 (P<0.05); in the gut microbiota analysis, BYHWD slowed down modifications in the structure distribution of gut microbiota and regulated the diversity of intestinal flora in HF rats. The content of TMAO in the serum was significantly lowered by BYWHT compared with the model group (P<0.05). CONCLUSION: BYHWD may delay progression of HF by enhancing the intestinal barrier structure, and regulating intestinal flora and TAMO.

Combining Transcriptomics and Polyphenol Profiling to Provide Insights into Phenolics Transformation of the Fermented Chinese Jujube.

As an important medicine homologous food, Chinese jujube is rich in nutrition and medicinal value. To enhance the bioactive compounds level of Chinese jujube products, three kinds of fungi strains (Rhizopus oryzae, Aspergillus niger and Monascus purpureus) were firstly selected to evaluate their effects on total soluble phenolic compounds (TSPC) and total soluble flavonoids compounds (TSFC) contents during liquid state fermentation of Chinese jujube. As the best strain, the highest contents of TSPC and TSFC could increase by 102.1% (26.02 mg GAE/g DW) and 722.8% (18.76 mg RE/g DW) under M. purpureus fermentation when compared to the unfermented sample, respectively. Qualitative and quantitative analysis of individual polyphenol compounds indicated that proto-catechuic acid, p-hydroxybenzoic acid and chlorogenic acid showed the highest level in the fer-mented Chinese jujube at the 7th day, which was enhanced by 16.72-, 14.05- and 6.03-fold when compared to the control, respectively. Combining with RNA sequencing, function annotation of CAZymes database and polyphenol profiling, three potential transformation pathways of poly-phenol compounds were proposed in the fermented Chinese jujube by M. purpureus, such as the conversion of insoluble bound phenolic acids, rutin and anthocyanin degradation. These findings would be beneficial for better understanding of the biotransformation mechanism of polyphenol compounds in fungi fermentation.

Enzymatically Controlled Nanoflares for Specific Molecular Recognition and Biosensing.

In situ sensing of physiological and pathological species in cancer cells is of great importance to unravel their molecular and cellular processes. However, the biosensing with conventional probes is often limited by the undesired on-target off-tumor interference. Here, we report a novel strategy to design enzymatically controlled nanoflares for sensing and imaging molecular targets in tumor cells. The triggerable nanoflare was designed via rational engineering of structure-switching aptamers with the incorporation of an enzyme-activatable site and further conjugation on gold nanoparticles. The nanoflare sensors did not respond to target molecules in normal cells, but they could be catalytically activated by specific enzymes in cancer cells, thereby enabling cancer-specific sensing and imaging in vitro and in vivo with improved tumor specificity. Considering that diverse aptamers were selected, we expect that this strategy would facilitate the precise detection of a broad range of targets in tumors and may promote the development of smart probes for cancer diagnosis.

Bioactive neolignans and lignans from the roots of Paeonia lactiflora.

Two new neolignans and one new lignan (1-3) were obtained from the roots of Paeonia lactiflora. Their structures were unambiguously elucidated based on extensive spectroscopic analysis, single-crystal X-ray crystallography, and the calculated and experimental electronic circular dichroism (ECD) spectra. Compound 1 was a racemic mixture and successfully resolved into the anticipated enantiomers via chiral-phase HPLC. Compound 3 demonstrated moderate inhibitory activity against human carboxylesterase 2A1 (hCES2A1) with an IC50 value of 7.28 ± 0.94 µmol·-1.

Automatic Colorectal Cancer Screening Using Deep Learning in Spatial Light Interference Microscopy Data.

The surgical pathology workflow currently adopted by clinics uses staining to reveal tissue architecture within thin sections. A trained pathologist then conducts a visual examination of these slices and, since the investigation is based on an empirical assessment, a certain amount of subjectivity is unavoidable. Furthermore, the reliance on external contrast agents such as hematoxylin and eosin (H&E), albeit being well-established methods, makes it difficult to standardize color balance, staining strength, and imaging conditions, hindering automated computational analysis. In response to these challenges, we applied spatial light interference microscopy (SLIM), a label-free method that generates contrast based on intrinsic tissue refractive index signatures. Thus, we reduce human bias and make imaging data comparable across instruments and clinics. We applied a mask R-CNN deep learning algorithm to the SLIM data to achieve an automated colorectal cancer screening procedure, i.e., classifying normal vs. cancerous specimens. Our results, obtained on a tissue microarray consisting of specimens from 132 patients, resulted in 91% accuracy for gland detection, 99.71% accuracy in gland-level classification, and 97% accuracy in core-level classification. A SLIM tissue scanner accompanied by an application-specific deep learning algorithm may become a valuable clinical tool, enabling faster and more accurate assessments by pathologists.

Near-Infrared Light-Activatable Spherical Nucleic Acids for Conditional Control of Protein Activity.

Optical control of protein activity represents a promising strategy for precise modulation of biological processes. We report rationally designed, aptamer-based spherical nucleic acids (SNAs) capable of noninvasive and programmable regulation of target protein activity by deep-tissue-penetrable near-infrared (NIR) light. The photoresponsive SNAs are constructed by integrating activatable aptamer modules onto the surface of upconversion nanoparticles. The SNAs remain inert but can be remotely reverted by NIR light irradiation to capture the target protein and thus function as an enzyme inhibitor, while introduction of antidote DNA could further reverse their inhibition functions. Furthermore, we demonstrate the potential of the SNAs as controllable anticoagulants for the NIR light-triggered regulation of thrombin function. Ultimately, the availability of diverse aptamers would allow the design to regulate the activities of various proteins in a programmable manner.

A new ALK inhibitor overcomes resistance to first- and second-generation inhibitors in NSCLC.

More than 60% of nonsmall cell lung cancer (NSCLC) patients show a positive response to the first ALK inhibitor, crizotinib, which has been used as the standard treatment for newly diagnosed patients with ALK rearrangement. However, most patients inevitably develop crizotinib resistance due to acquired secondary mutations in the ALK kinase domain, such as the gatekeeper mutation L1196M and the most refractory mutation, G1202R. Here, we develop XMU-MP-5 as a new-generation ALK inhibitor to overcome crizotinib resistance mutations, including L1196M and G1202R. XMU-MP-5 blocks ALK signaling pathways and inhibits the proliferation of cells harboring either wild-type or mutant EML4-ALK in vitro and suppresses tumor growth in xenograft mouse models in vivo. Structural analysis provides insights into the mode of action of XMU-MP-5. In addition, XMU-MP-5 induces significant regression of lung tumors in two genetically engineered mouse (GEM) models, further demonstrating its pharmacological efficacy and potential for clinical application. These preclinical data support XMU-MP-5 as a novel selective ALK inhibitor with high potency and selectivity. XMU-MP-5 holds great promise as a new therapeutic against clinically relevant secondary ALK mutations.

Alkannin Inhibits the Development of Ovarian Cancer by Affecting miR-4461.

BACKGROUND: Previous studies have shown that alkannin has anticancer, anti-inflammatory, and antibacterial effects. However, the effect of alkannin in the development of ovarian cancer (OC) remains unknown. Therefore, this study aims to elucidate the function of alkannin in OC progression. METHODS: RT-qPCR and western blot analysis were used to measure mRNA and protein expression. Cell viability and metastasis were detected by the CCK-8 assay, flow cytometry analysis, and transwell assay. RESULTS: Alkannin had no cytotoxicity toward normal ovarian cells, but alkannin can inhibit cell proliferation and induce apoptosis in OC cells. In addition, alkannin inhibited cell migration and invasion and blocked EMT in OC. Besides, upregulation of miR-4461 was found in OC tissues and cells, which was regulated by alkannin. More importantly, miR-4461 can inverse the effects of alkannin on cell viability and metastasis in OC cells. CONCLUSION: Alkannin restrains cell viability, metastasis, and EMT in OC by downregulating miR-4461 expression.

Anti-anaphylactic potential of benzoylpaeoniflorin through inhibiting HDC and MAPKs from Paeonia lactiflora.

Guided by cell-based anti-anaphylactic assay, eighteen cage-like monoterpenoid glycosides (1-18) were obtained from the bioactive fraction of P. lactiflora extract. Among these, compounds 1, 5, 6, 11, 12, 15, and 17 significantly reduced the release rate of ß-HEX and HIS without or with less cytotoxicity. Furthermore, the most potent inhibitor benzoylpaeoniflorin (5) was selected as the prioritized compound for the study of action of mechanism, and its anti-anaphylactic activity was medicated by dual-inhibiting HDC and MAPK signal pathway. Moreover, molecular docking simulation explained that benzoylpaeoniflorin (5) blocked the conversion of L-histidine to HIS by occupying the HDC active site. Finally, in vivo on PCA using BALB/c mice, benzoylpaeoniflorin (5) suppressed the IgE-mediated PCA reaction in antigen-challenged mice. These findings indicated that cage-like monoterpenoid glycosides, especially benzoylpaeoniflorin (5), mainly contribute to the anti-anaphylactic activity of P. lactiflora by dual-inhibiting HDC and MAPK signal pathway. Therefore, benzoylpaeoniflorin (5) may be considered as a novel drug candidate for the treatment of anaphylactic diseases.