Network Pharmacology Based Elucidation of Molecular Mechanisms of Laoke Formula for Treatment of Advanced Non-Small Cell Lung Cancer.

OBJECTIVE: To explore the specific pharmacological molecular mechanisms of Laoke Formula (LK) on treating advanced non-small cell lung cancer (NSCLC) based on clinical application, network pharmacology and experimental validation. METHODS: Kaplan-Meier method and Cox regression analysis were used to evaluate the survival benefit of Chinese medicine (CM) treatment in 296 patients with NSCLC in Tianjin Medical University Cancer Institute and Hospital from January 2011 to December 2015. The compounds of LK were screened using the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform, and the corresponding targets were performed from Swiss Target Prediction. NSCLC-related targets were obtained from Therapeutic Target Database and Comparative Toxicogenomics Database. Key compounds and targets were identified from the compound-target-disease network and protein-protein interaction (PPI) network analysis, respectively. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analysis were used to predict the potential signaling pathways involved in the treatment of advanced NSCLC with LK. The binding affinities between key ingredients and targets were further verified using molecular docking. Finally, A549 cell proliferation and migration assay were used to evaluate the antitumor activity of LK. Western blot was used to further verify the expression of key target proteins related to the predicted pathways. RESULTS: Kaplan-Meier survival analysis showed that the overall survival of the CM group was longer than that of the non-CM group (36 months vs. 26 months), and COX regression analysis showed that LK treatment was an independent favorable prognostic factor (P=0.027). Next, 97 components and 86 potential targets were included in the network pharmacology, KEGG and GO analyses, and the results indicated that LK was associated with proliferation and apoptosis. Moreover, molecular docking revealed a good binding affinity between the key ingredients and targets. In vitro, A549 cell proliferation and migration assay showed that the biological inhibition effect was more obvious with the increase of LK concentration (P<0.05). And decreased expressions of nuclear factor κB1 (NF-κB1), epidermal growth factor receptor (EGFR) and AKT serine/threonine kinase 1 (AKT1) and increased expression of p53 (P<0.05) indicated the inhibitory effect of LK on NSCLC by Western blot. CONCLUSION: LK inhibits NSCLC by inhibiting EGFR/phosphoinositide 3-kinase (PI3K)/AKT signaling pathway, NFκB signaling pathway and inducing apoptosis, which provides evidence for the therapeutic mechanism of LK to increase overall survival in NSCLC patients.

Recent Advances in Organic Small-Molecule Fluorescent Probes Based on Dicyanoisophorone Derivatives.

Fluorescent probe technology holds great promise in the fields of environmental monitoring and clinical diagnosis due to its inherent advantages, including easy operation, reliable detection signals, fast analysis speed, and in situ imaging capabilities. In recent years, a wide range of fluorescent probes based on diverse fluorophores have been developed for the analysis and detection of various analytes, yielding significant achievement. Among these fluorophores, the dicyanoisophorone-based fluorophores have garnered significant attention. Dicyanoisoporone exhibits minimal fluorescence, yet possesses a robust electron-withdrawing capability, rendering it suitable for constructing of D-π-A structured fluorophores. Leveraging the intramolecular charge transfer (ICT) effect, such fluorophores exhibit near-infrared (NIR) fluorescence emission with a large Stokes shift, thereby offering remarkable advantages in the design and development of NIR fluorescence probes. This review article primarily focus on small-molecule dicyanoisoporone-based probes from the past two years, elucidating their design strategies, detection performances, and applications. Additionally, we summarize current challenges while predicting future directions to provide valuable references for developing novel and advanced fluorescence probes based on dicyanoisoporone derivatives.

Recent Advances in Organic Small-Molecule Fluorescent Probes for the Detection of Zinc Ions (Zn2+).

Zinc(II) ions (Zn2g) play crucial roles in the growth, propagation, and metabolism of animals, plants, and humans. Abnormal concentrations of Zn2+ in the environment and living organisms pose potential risks to environmental protection and human health. Therefore, it is imperative to develop rapid, reliable and in-situ detection methods for Zn2+ in both environmental and biological contexts. Furthermore, effective analytical methods are required for diagnosing diseases and understanding physiological metabolic mechanisms associated with Zn2+ concentration levels. Organic small-molecule fluorescent probes offer advantages such as fast, reliable, convenient, non-destructive detection capabilities and have significant application potential in Zn2+ detection and bioimaging; thus garnering extensive attention. Over the past two years alone, various organic small-molecule probes for Zn2+ based on different detection mechanisms and fluorophores have been rapidly developed. However, these probes still exhibit several limitations that need further resolution. In light of this context, we provide a comprehensive summary of the detection mechanisms, performance characteristics, and application scope of Zn2+ fluorescence probes since year 2022 while highlighting their advantages. We also propose solutions to address existing issues with these probes and outline future directions for their advancement. This review aims to serve as a valuable reference source offering insights into the development of advanced organic small-molecule-based fluorescence probes specifically designed for detecting Zn2+.

A Halloysite Nanotubes-based Probe for Efficient Fluorescence Detection and Adsorption Removal of Pb2+ in Water.

The detection and removal of Pb2+ is of utmost importance for environmental protection and human health due to its toxicity, persistent pollution, and bioaccumulation effects. To address the limitations associated with organic small molecule-based fluorescence probes such as poor water solubility and single functionality in detecting Pb2+, a fluorescence probe based on halloysite nanotubes was developed. This probe not only enables specific, rapid, and reliable detection of Pb2+ but also facilitates efficient removal of it from water. The development of this bifunctional fluorescent probe provides a valuable insight for designing more advanced probes targeting heavy metal ions.

Cationic fructan-based pH and intestinal flora dual stimulation nanoparticle with berberine for targeted therapy of IBD.

Inflammatory bowel disease (IBD) can cause intestinal microbial imbalance and aggravate intestinal inflammation. Mixed fructan is more easily fermented by colonic microorganisms and can be used as colonic drug delivery materials. Here, we constructed a mixed fructan based nanoparticle with dual targeted stimulation of pH and intestinal flora to effectively deliver berberine for the treatment of ulcerative colitis (UC). The complex of fructan based nanoparticle and berberine (BBRNPs) significantly ameliorated the inflammatory response of sodium dextran sulfate (DSS)-induced colitis in mice by inhibiting the activation of NF-κB/STAT-3 pathway and increasing tight junction protein expression in vivo. Importantly, BBRNPs improved the responsiveness of colitis microbiome and effectively regulated the relative homeostasis of harmful flora Enterobacteriaceae and Escherichia-shigolla, and beneficial flora Ruminococcaceae and Akkermansiaceae. This study provides a promising strategy for the effective treatment of UC and expands the application of branched fructan in pharmaceutics.

A Dicyanoisoflurone-based Near-infrared Fluorescence Probe for Highly Sensitive Detection of Hg2.

Due to its high toxicity, long durability, easy absorption by aquatic organisms, and significant bioaccumulation, Hg2+ has caused substantial environmental damage and posed serious threats to human health. Therefore, effective detection of Hg2+ is of utmost importance. In this study, a turn-on fluorescent probe based on dicyanoisoflurone was developed for the detection of Hg2+. The probe exhibited near-infrared fluorescence signal at 660 nm upon excitation by 440 nm UV light in a mixture of CH3CN and HEPES buffer (4:1, v/v, 10 mM, pH = 7.5), with selective binding to Hg2+ in a molar ratio of 1:1. This binding event was accompanied by a visible color change from light yellow to orange. By utilizing the enhanced fluorescence signal change, this probe enables highly sensitive analysis and detection of Hg2+ with excellent selectivity (association constant = 1.63 × 104 M- 1), large Stokes shift (220 nm), high sensitivity (detection limit as low as 5.6 nM), short reaction time (30 s), and a physiological pH range of 7.5-9.5. The probe was successfully employed for detecting of Hg2+ in real water and living cells.

Molecular Engineering to Achieve AIE-active Fluorophore with Near-infrared (NIR) Emission and Temperature-sensitive Property.

Near-infrared organic small molecule luminescent materials have the advantages of easy modification, high quantum efficiency, good biological affinity, and color adjustability; thus, have promising application prospects in the fields of photoelectric devices, sensitive detection, photodynamic therapy, and biomedical imaging. However, traditional organic luminescent molecules have the problems of short emission wavelength, aggregation-causing emission quenching, and low quantum yield. Herein, we successfully synthesized four D-π-A-D light-emitting molecules based on electron-withdrawing malonitrile group and different electron-donating arylamine groups. These compounds showed satisfactory solvatochromism, aggregation-induced emission, red and near-infrared fluorescence, high photoluminescence quantum efficiency and temperature response properties. This successful example of molecular engineering provides a valuable reference for the development of advanced NIR materials with AIE and temperature-sensitive properties.

Study on the Gas Release of 3D-Printed Furan Resin Sand Core during the Casting Process.

In sand casting, gas porosity is a common defect that can result in decreased strength, leakage, rough surfaces, or other problems. Although the forming mechanism is very complicated, gas release from sand cores is often a significant contributor to the formation of gas porosity defects. Therefore, studying the gas release behavior of sand cores is crucial to solving this problem. Current research on the gas release behavior of sand cores mainly focuses on parameters such as gas permeability and gas generation properties, through experimental measurement and numerical simulation methods. However, accurately reflecting the gas generation situation in the actual casting process is difficult, and there are certain limitations. To achieve the actual casting condition, a sand core was designed and enclosed inside a casting. The core print was extended to the sand mold surface, with two types of core prints: hollow and dense. Pressure and airflow speed sensors were installed on the exposed surface of the core print to investigate the burn-off of the binder of the 3D-printed furan resin quartz sand cores. The experimental results showed that the gas generation rate was high in the initial stage of the burn-off process. The gas pressure quickly reached its peak in the initial stage and then decreased rapidly. The exhaust speed of the dense type of core print was 1 m/s, lasting for 500 s. The pressure peak of the hollow-type sand core was 1.09 kPa, and the exhaust speed peak was 1.89 m/s. The binder can be sufficiently burned off for the location surrounding the casting and the crack-affected area, so the burnt sand appears white, while the burnt core appears black due to insufficient burning of the binder because of isolation from the air. The gas generated by the burnt resin sand in contact with air was 30.7% less than that generated by the burnt resin sand insulated from the air.

A dual-functional fluorescent probe based on kaolin nanosheets for the detection and separation of aluminum ions.

Aluminum ions (Al3+) are closely related to environmental protection and human health, thus the detection and separation of Al3+ is of great significance. In this study, a dual-functional fluorescent probe for the detection and separation of Al3+ was successfully developed by grafting fluorophore onto kaolin nanosheets. The probe has the characteristics of good dispersion without the involvement of organic solvents, excellent specificity, the low limit of detection (0.55 µM), and fast response time (10 min). And the recovery rates of Al3+ using this probe are in the range from 93.0% to 101.8%, and the corresponding relative standard deviations are in the range from 3.5% to 5.8%. Besides, it also can remove Al3+ in aqueous solution through adsorption, and the removal rates is in the range from 95.1% to 99.3% when the concentration of the probe is 0.4 mg/mL. The probe combines detection and separation functions, overcomes the defect that single-function materials can only be used for detection or separation, which has important significance and good application value.

Sevoflurane protects against intracerebral hemorrhage via microRNA-133b/FOXO4/BCL2 axis.

The application of Sevoflurane (Sev) in neurological diseases has been documented. We herein clarified the role of Sev in intracerebral hemorrhage (ICH). Through bioinformatics analysis, ICH-related microRNA (miRNA) was collected with microRNA-133b (miR-133b) chosen for the study subject. Then, the related downstream gene Forkhead box O4 (FOXO4) was identified. For in vivo assays, an ICH mouse model was established by autologous blood injection. For in vitro assays, hippocampal neurons were extracted from mouse brain tissues, and erythrocyte lysates were employed to simulate in vitro hemorrhage. Interaction between miR-133b and FOXO4 as well as between FOXO4 and BCL2 were assayed. We found decreased miR-133b in the brain tissue of ICH mice and erythrocyte lysate-treated hippocampal neurons. Sev treatment attenuated ICH and hippocampal neuronal apoptosis in mice by upregulating miR-133b. miR-133b targeted FOXO4 expression, and inhibition of FOXO4 attenuated hippocampal neuronal apoptosis by increasing BCL2 expression. Sev attenuated ICH in mice by increasing BCL2 expression through regulation of miR-133b-mediated FOXO4 expression. The findings highlighted the protective effect of Sev on ICH mice through the regulation of miR-133b-mediated FOXO4 expression.

A dicyanisophorone-based probe for dual sensing Zn2+ and Cd2+ by near-infrared fluorescence.

Zinc ions (Zn2+) and cadmium ions (Cd2+) are widely present in our production and life, which are closely related to human health and environmental protection. Hence, it is essential to detect their concentrations. Herein, we developed a convenient and reliable small-molecule fluorescent probe based on Schiff base of dicyanisophorone and 2-hydrazinopyridine. This probe can be able to selectively detect Zn2+ and Cd2+, showing the advantages of near-infrared emission (the maximum emission wavelength: 668 nm), good selectivity, high sensitivity (the detection limits: 0.21 µM and 0.31 µM, respectively) and rapid response (15 s). It has excellent potential for rapid testing and visual tracking of Zn2+ and Cd2+ in aqueous solution and living cells.

Tanshinone IIA promotes apoptosis by downregulating BCL2 and upregulating TP53 in triple-negative breast cancer.

Tanshinone IIA (Tan IIA) was mainly used for cardiovascular disease treatment. Recent studies have demonstrated the role of Tan IIA for tumor treatment, but its mechanism remains unclear. At the first, the inhibitory effect of Tan IIA on 4T1 breast cancer cells was determined by CCK8 and colony formation assay. Then, a 4T1 BALB/c model of breast cancer was established to evaluate the anti-cancer effect of Tan IIA in vivo. Flow cytometry analysis and the TUNEL test were used to detect cell apoptosis in vitro and in vivo, respectively. The related targets and mechanisms of Tan IIA were predicted through network-based systems biology. At last, molecular docking and the molecular biological techniques were used to evaluate the predicted targets. Tan IIA displayed encouraging inhibitory influences on 4T1 cells after incubation for 24 h and showed a half-maximal inhibitory concentration (IC50) of 49.78 µM after 48-h incubation. After 23 days of treatment, the relative tumor volumes in the Tan IIA group were 65.53% inhibited compared with the control group. Furthermore, Tan IIA induced 4T1 cell apoptosis both in vivo and in vitro. The possible targets of Tan IIA for TNBC treatment were predicted with network-based systems biology, and results showed that TP53, NF-κB, AKT, MYC, and BCL-2 were the hub targets. The mechanism against breast cancer may be based on the P53 signaling pathway, the PI3K/Akt pathway, the MAPK signaling pathway, and the mTOR signaling pathways. Molecular docking analysis reveals that Tan IIA has a high affinity for p53, Bcl-2, and NF-κB1; the binding energies were - 6.92, - 6.07, and - 6.28 kcal/mol, respectively. The predicted proteins were further validated using Western blotting. Increased expression of phosphorylated p53 and p53 and decreased expression of Bcl-2 were found in Tan IIA-treated 4T1 cells. Tan IIA is potentially effective for the treatment of 4T1 breast cancer, and the molecular mechanism may be through enhancing the activity of p53 and decreasing Bcl-2 to suppress proliferation and promote apoptosis.

[Retracted] MicroRNA­199a­3p inhibits ovarian cancer cell viability by targeting the oncogene YAP1.

Following the publication of the above article, the authors have submitted a request that it be retracted on account of the fact that, when requested to do so, the first author was unable to provide the original data for this article. The Editor of Molecular Medicine Reports has agreed with the request that this article be retracted. Note that all the authors agree with the decision to retract this article. The Editor and the authors regret any inconvenience that this retraction will cause to the readership of the Journal. [Molecular Medicine Reports 23: 237, 2021; DOI: 10.3892/mmr.2021.11876].

A near-infrared Fluorescent Probe Based on Dicyanisophorone for the Detection of Zinc Ions (Zn2+) in Water and Living Cells.

As one of the important metal ions, zinc ions (Zn2+) are widely involved in various physiological and pathological processes, and play fundamental roles in neurotransmission, cell metabolism and apoptosis. However, the convenient monitor of Zn2+ in environmental and biological samples remains challenging. In this study, a small molecule dicyanoisophorone-based schiff base incorporating with o-phenylenediamine was synthesized. It can rapidly combine with Zn2+ to emit significant near-infrared fluorescence (maximum emission wavelength: 660 nm), so it can be used as a probe to quantitatively detect Zn2+ in the range of 0-10 µM, with a detection limit as low as 4.8 nM, showing the probe has high sensitivity for Zn2+. And the probe has a fast response time to Zn2+ (less than 30 s) and a large Stoke-shift (179 nm). In addition, the high recovery rates in practical water samples, and the clear fluorescent images in living A549 cells were obtained, which are of great significance for the detection of Zn2+ in the environment and biosystem. Due to its simple operation, good selectivity and anti-interference ability, short detection time and high sensitivity, this probe has great application potential as a fast detection tool for Zn2+ in environmental water and biological samples.

Retraction Note: MicroRNA-199a-5p suppresses the cell growth of colorectal cancer by targeting oncogene Caprin1.

[This retracts the article DOI: 10.1007/s13205-020-02433-9.].

Effects of ultrasound-guided alveolar recruitment manoeuvres compared with sustained inflation or no recruitment manoeuvres on atelectasis in laparoscopic gynaecological surgery as assessed by ultrasonography: a randomized clinical trial.

BACKGROUND: The majority of patients may experience atelectasis under general anesthesia, and the Trendelenburg position and pneumoperitoneum can aggravate atelectasis during laparoscopic surgery, which promotes postoperative pulmonary complications. Lung recruitment manoeuvres have been proven to reduce perioperative atelectasis, but it remains controversial which method is optimal. Ultrasonic imaging can be conducive to confirming the effect of lung recruitment manoeuvres. The purpose of our study was to assess the effects of ultrasound-guided alveolar recruitment manoeuvres by ultrasonography on reducing perioperative atelectasis and to check whether the effects of recruitment manoeuvres under ultrasound guidance (visual and semiquantitative) on atelectasis are superior to sustained inflation recruitment manoeuvres (classical and widely used) in laparoscopic gynaecological surgery. METHODS: In this randomized, controlled, double-blinded study, women undergoing laparoscopic gynecological surgery were enrolled. Patients were randomly assigned to receive either lung ultrasound-guided alveolar recruitment manoeuvres (UD group), sustained inflation alveolar recruitment manoeuvres (SI group), or no RMs (C group) using a computer-generated table of random numbers. Lung ultrasonography was performed at four predefined time points. The primary outcome was the difference in lung ultrasound score (LUS) among groups at the end of surgery. RESULTS: Lung ultrasound scores in the UD group were significantly lower than those in both the SI group and the C group immediately after the end of surgery (7.67 ± 1.15 versus 9.70 ± 102, difference, -2.03 [95% confidence interval, -2.77 to -1.29], P < 0.001; 7.67 ± 1.15 versus 11.73 ± 1.96, difference, -4.07 [95% confidence interval, -4.81 to -3.33], P < 0.001;, respectively). The intergroup differences were sustained until 30 min after tracheal extubation (9.33 ± 0.96 versus 11.13 ± 0.97, difference, -1.80 [95% confidence interval, -2.42 to -1.18], P < 0.001; 9.33 ± 0.96 versus 10.77 ± 1.57, difference, -1.43 [95% confidence interval, -2.05 to -0.82], P < 0.001;, respectively). The SI group had a significantly lower LUS than the C group at the end of surgery (9.70 ± 1.02 versus 11.73 ± 1.96, difference, -2.03 [95% confidence interval, -2.77 to -1.29] P < 0.001), but the benefit did not persist 30 min after tracheal extubation. CONCLUSIONS: During general anesthesia, ultrasound-guided recruitment manoeuvres can reduce perioperative aeration loss and improve oxygenation. Furthermore, these effects of ultrasound-guided recruitment manoeuvres on atelectasis are superior to sustained inflation recruitment manoeuvres. TRIAL REGISTRATION: Chictr.org.cn, ChiCTR2100042731, Registered 27 January 2021, www.chictr.org.cn .

A Novel Strategy for Regulating mRNA's Degradation via Interfering the AUF1's Binding to mRNA.

The study on the mechanism and kinetics of mRNA degradation provides a new vision for chemical intervention on protein expression. The AU enrichment element (ARE) in mRNA 3'-UTR can be recognized and bound by the ARE binding protein (AU-rich Element factor (AUF1) to recruit RNase for degradation. In the present study, we proposed a novel strategy for expression regulation that interferes with the AUF1-RNA binding. A small-molecule compound, JNJ-7706621, was found to bind AUF1 protein and inhibit mRNA degradation by screening the commercial compound library. We discovered that JNJ-7706621 could inhibit the expression of AUF1 targeted gene IL8, an essential pro-inflammatory factor, by interfering with the mRNA homeostatic state. These studies provide innovative drug design strategies to regulate mRNA homeostasis.

Two near-infrared fluorescent probes based on dicyanoisfluorone for rapid monitoring of Zn2+and Pb2.

Zinc (Zn2+) and lead (Pb2+) ions in the environment have important effects on human health and environmental safety. Therefore, it is necessary to effectively detect them by a convenient and reliable analysis method. In this study, two near-infrared fluorescent probes for the fast determination of Zn2+and Pb2+were synthesized by a simple Schiff base reaction between the dicyanoisophorone skeleton and carbohydrazide derivatives. Among them, the probe with the thiophene-2-carbohydrazide group showed a selective fluorescence response to Zn2+and Pb2+with a maximum emission wavelength of 670 nm. And the detection limits of the probe for Zn2+and Pb2+were 1.59 nM and 1.65 nM, respectively. In contrast the probe modified by the furan-2-carbohydrazide group achieved quantitative detection of Zn2+, with a detection limit of 2.7 nM. These results were attributed to the fact that the probes bind to Zn2+and Pb2+in stoichiometric ratios of 1:1, blocking the intramolecular PET effect. Furthermore, these two probes can be recycled through the action of EDTA and have been successfully used to detect Zn2+and Pb2+in real water samples.

A near infrared fluorescent probe for detection and bioimaging of zinc ions and hypochlorous acid.

It is of great significance to monitor zinc ions (Zn2+) and hypochlorous acid (HClO) conveniently in disease diagnosis and environmental protection. Herein, we successfully prepared a near-infrared fluorescent probe based on dicyanoisophorone derivative and methyl hydrazate by Schiff base reaction for effective detection of Zn2+ and HClO. After binding with Zn2+ at a molar ratio of 1:1, the fluorescence intensity (λex = 482 nm, λem = 653 nm) of the probe was significantly enhanced, thus achieving quantitative detection and optical cell imaging of Zn2+. The complexation constant (K) of the probe with Zn2+ was 2.34 × 104 M-1. The response time of the probe for Zn2+ was less than 20 s and the detection limit was 15.3 nM. Moreover, this probe also showed a specific response to HClO. After interacting with HClO, the fluorescence intensity of the probe was increased significantly with a red shift of the emission wavelength from 670 nm to 705 nm (λex = 550 nm). The response time and the detection limit of probe for HClO were 4 min and 1.39 µM, respectively. The probe was successfully applied for visual bioimaging of Zn2+ and HClO inside living cells. The recoveries of Zn2+ and HClO using the probe in actual water samples were satisfactory.

Therapeutic targeting RORγ with natural product N-hydroxyapiosporamide for small cell lung cancer by reprogramming neuroendocrine fate.

Small cell lung cancer (SCLC) is an aggressive and exceptionally fatal disease. Unlike non- small cell lung cancer (NSCLC), no targetable genetic driver events have been identified in SCLC to date. Here, we investigate the function of RAR-related orphan receptor gamma (RORγ) and identified the anti-cancer activity of its natural inhibitor against SCLC and illustrate the underlying mechanism. We show that RORγ depletion affected cell growth both in 2-D cell proliferation and 3-D organoids formation. Natural marine product N-hydroxyapiosporamide (N-hydap) directly bound to RORγ and inhibited its transcriptional activity, leading to the blocking of transmission process of RORγ signaling. Gene expression profiling analysis revealed that N-hydap reprograms neuroendocrine fate via inhibiting RORγ activity in SCLC. Chromatin immunoprecipitation analysis showed that N-hydap strongly reduced RORγ occupancy and transcriptional activation-linked histone marks H3K27ac on the promoter and/or enhancer sites of neurogenesis markers gene including aurora kinase a (AURKA), delta like canonical Notch ligand 3 (DLL3) and tubulin beta 3 class III (TUBB3). Therapeutically, N-hydap exhibited a strong inhibitory effect on tumor growth and did not show significant toxicity in SCLC mice xenograft models. Taken together, RORγ could be an attractive target for SCLC and thus N-hydap can be a promising therapeutic drug candidate for SCLC by inhibiting the RORγ activation.