Exploring the mechanism of 6-Methoxydihydrosanguinarine in the treatment of lung adenocarcinoma based on network pharmacology, molecular docking and experimental investigation.

BACKGROUND: 6-Methoxydihydrosanguinarine (6-MDS) has shown promising potential in fighting against a variety of malignancies. Yet, its anti­lung adenocarcinoma (LUAD) effect and the underlying mechanism remain largely unexplored. This study sought to explore the targets and the probable mechanism of 6-MDS in LUAD through network pharmacology and experimental validation. METHODS: The proliferative activity of human LUAD cell line A549 was evaluated by Cell Counting Kit-8 (CCK8) assay. LUAD related targets, potential targets of 6-MDS were obtained from databases. Venn plot analysis were performed on 6-MDS target genes and LUAD related genes to obtain potential target genes for 6-MDS treatment of LUAD. The Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database was utilized to perform a protein-protein interaction (PPI) analysis, which was then visualized by Cytoscape. The hub genes in the network were singled out by CytoHubba. Metascape was employed for GO and KEGG enrichment analyses. molecular docking was carried out using AutoDock Vina 4.2 software. Gene expression levels, overall survival of hub genes were validated by the GEPIA database. Protein expression levels, promotor methylation levels of hub genes were confirmed by the UALCAN database. Timer database was used for evaluating the association between the expression of hub genes and the abundance of infiltrating immune cells. Furthermore, correlation analysis of hub genes expression with immune subtypes of LUAD were performed by using the TISIDB database. Finally, the results of network pharmacology analysis were validated by qPCR. RESULTS: Experiments in vitro revealed that 6-MDS significantly reduced tumor growth. A total of 33 potential targets of 6-MDS in LUAD were obtained by crossing the LUAD related targets with 6-MDS targets. Utilizing CytoHubba, a network analysis tool, the top 10 genes with the highest centrality measures were pinpointed, including MMP9, CDK1, TYMS, CCNA2, ERBB2, CHEK1, KIF11, AURKB, PLK1 and TTK. Analysis of KEGG enrichment hinted that these 10 hub genes were located in the cell cycle signaling pathway, suggesting that 6-MDS may mainly inhibit the occurrence of LUAD by affecting the cell cycle. Molecular docking analysis revealed that the binding energies between 6-MDS and the hub proteins were all higher than - 6 kcal/Mol with the exception of AURKB, indicating that the 9 targets had strong binding ability with 6-MDS.These results were corroborated through assessments of mRNA expression levels, protein expression levels, overall survival analysis, promotor methylation level, immune subtypes andimmune infiltration. Furthermore, qPCR results indicated that 6-MDS can significantly decreased the mRNA levels of CDK1, CHEK1, KIF11, PLK1 and TTK. CONCLUSIONS: According to our findings, it appears that 6-MDS could possibly serve as a promising option for the treatment of LUAD. Further investigations in live animal models are necessary to confirm its potential in fighting cancer and to delve into the mechanisms at play.

Comparing Neuromuscular Blockade Measurement Between Upper Arm (TOF Cuff®) and Eyelid (TOF Scan®) Using Mivacurium during General Anesthesia.

BACKGROUND Mivacurium is a non-depolarizing neuromuscular blocking agent. TOF-Cuff® is a device that monitors intraoperative neuromuscular blockade and blood pressure. TOF-Scan® measures muscle relaxation status of an anaesthetized patient. This study included 36 patients aged 18 to 75 years presenting for elective surgery, to compare neuromuscular blockade measured using the TOF-Cuff of the upper arm and the TOF-Scan of the facial corrugator supercilii muscle during general anesthesia and following administration of mivacurium. MATERIAL AND METHODS Train-of-four (TOF) values were obtained every 30 s before intubation and successively every 5 min until extubation. RESULTS The median onset time for TOF-Cuff was longer than for TOF-Scan (210 s vs 90 s, P<0.00001). Multiplying the time to relaxation (according to TOF-Scan) by 1 to 8, respectively, provided concordance with the TOF-Cuff result for the following cumulative percentages of patients: 5.5%, 38.9%, 58.3%, 77.8%, 83.3%, 86.1%, 88.9%, and 91.7%. Analogue values for time to recovery from the last dose were 11.1%, 63.9%, 83.3%, 86.1%, 86.1%, 88.9%, 88.9%, and 91.7%. The proportion of patients who still had TOFratio=0 in the assessment performed at min 15 did not differ significantly between these 2 methods (P=0.088). Both TOF-Scan and TOF-Cuff showed a false-negative result in patients with clinical symptoms of preterm recovery; the numerical difference favored TOF-Cuff (1.6% vs 2.1%) but without statistical significance (P=0.2235). CONCLUSIONS When measurement on the limb is not possible, TOF-Scan on the eyelid can be an alternative for TOF-Cuff on the upper arm, if the time to relaxation is multiplied by at least 8, which is enough for 90% of patients.

Discovery of novel diaryl substituted isoquinolin-1(2H)-one derivatives as hypoxia-inducible factor-1 signaling inhibitors for the treatment of rheumatoid arthritis.

Since synovial hypoxic microenvironment significantly promotes the pathological progress of rheumatoid arthritis (RA), hypoxia-inducible factor 1 (HIF-1) has been emerged as a promising target for the development of novel therapeutic agents for RA treatment. In this study, we designed and synthesized a series of diaryl substituted isoquinolin-1(2H)-one derivatives as HIF-1 signaling inhibitors using scaffold-hopping strategy. By modifying the substituents on N-atom and 6-position of isoquinolin-1-one, we discovered compound 17q with the most potent activities against HIF-1 (IC50 = 0.55 µM) in a hypoxia-reactive element (HRE) luciferase reporter assay. Further pharmacological studies revealed that 17q concentration-dependently blocked hypoxia-induced HIF-1α protein accumulation, reduced inflammation response, inhibited cellular invasiveness and promoted VHL-dependent HIF-1α degradation in human RA synovial cell line. Moreover, 17q improved the pathological injury of ankle joints, decreased angiogenesis and attenuated inflammation response in the adjuvant-induced arthritis (AIA) rat model, indicating the promising therapeutic potential of compound 17q as an effective HIF-1 inhibitor for RA therapy.

Design, Synthesis, and Investigation of the Pharmacokinetics and Anticancer Activities of Indenoisoquinoline Derivatives That Stabilize the G-Quadruplex in the MYC Promoter and Inhibit Topoisomerase I.

G-quadruplexes are noncanonical four-stranded DNA secondary structures. MYC is a master oncogene and the G-quadruplex formed in the MYC promoter functions as a transcriptional silencer and can be stabilized by small molecules. We have previously revealed a novel mechanism of action for indenoisoquinoline anticancer drugs, dual-downregulation of MYC and inhibition of topoisomerase I. Herein, we report the design and synthesis of novel 7-aza-8,9-methylenedioxyindenoisoquinolines based on desirable substituents and π-π stacking interactions. These compounds stabilize the MYC promoter G-quadruplex, significantly lower MYC levels in cancer cells, and inhibit topoisomerase I. MYC targeting was demonstrated by differential activities in Raji vs CA-46 cells and cytotoxicity in MYC-dependent cell lines. Cytotoxicities in the NCI-60 panel of human cancer cell lines were investigated. Favorable pharmacokinetics were established, and in vivo anticancer activities were demonstrated in xenograft mouse models. Furthermore, favorable brain penetration, brain pharmacokinetics, and anticancer activity in an orthotopic glioblastoma mouse model were demonstrated.

Naphthylisoquinoline alkaloids: novel agents against the causative pathogens of eumycetoma and actinomycetoma-en route to broad-spectrum antimycetomal drugs.

Mycetoma is a devastating neglected tropical infection of the subcutaneous tissues. It is caused by fungal and bacterial pathogens recognized as eumycetoma and actinomycetoma, respectively. Mycetoma treatment involves diagnosing the causative microorganism as a prerequisite to prescribing a proper medication. Current therapy of fungal eumycetoma causative agents, such as Madurella mycetomatis, consists of long-term antifungal medication with itraconazole followed by surgery, yet with usually unsatisfactory clinical outcomes. Actinomycetoma, on the contrary, usually responds to treatment with co-trimoxazole and amikacin. Therefore, there is a pressing need to discover novel broad-spectrum antimicrobial agents to circumvent the time-consuming and costly diagnosis. Using the resazurin assay, a series of 23 naphthylisoquinoline (NIQ) alkaloids and related naphthoquinones were subjected to in vitro screening against two fungal strains of M. mycetomatis and three bacterial strains of Actinomadura madurae and A. syzygii. Seven NIQs, mostly dimers, showed promising in vitro activities against at least one strain of the mycetoma-causative pathogens, while the naphthoquinones did not show any activity. A synthetic NIQ dimer, 8,8'''-O,O-dimethylmichellamine A (18), inhibited all tested fungal and bacterial strains (IC50 = 2.81-12.07 µg/mL). One of the dimeric NIQs, michellamine B (14), inhibited a strain of M. mycetomatis and significantly enhanced the survival rate of Galleria mellonella larvae infected with M. mycetomatis at concentrations of 1 and 4 µg/mL, without being toxic to the uninfected larvae. As a result, broad-spectrum dimeric NIQs like 14 and 18 with antimicrobial activity are considered hit compounds that could be worth further optimization to develop novel lead antimycetomal agents.

1H NMR guided isolation of 3-arylisoquinoline alkaloids from Hypecoum erectum L. and their anti-inflammation activity.

Nine 3-arylisoquinoline alkaloids including five undescribed ones, hypectumines A-E (1-5), were isolated from the whole herb of Hypecoum erectum L. with the guidance of 1H-NMR. Their structures were established by a combination of 1D, 2D NMR, and HRESIMS spectrometry. Among them, hypectumines A and B possessed rare urea moieties while hypectumines C and D were characterized by 3-(methylamino)propanoic acid scaffolds. Biological assay demonstrated that alkaloids hypectumine B and 2,3-dimethoxy-N-formylcorydamine had anti-inflammatory effects by inhibiting NO production on LPS-induced RAW264.7 cells with IC50 values of 24.4 and 44.2 µM, respectively. Furthermore, hypectumine B could reduce the expression of pro-inflammatory cytokines TNF-α and IL-6, suggesting it might be a potential candidate for treating inflammatory disease.

New Pyridyl and Dihydroisoquinoline Alkaloids Isolated from the Chevron Nemertean Amphiporus angulatus.

Nemertean worms contain toxins that are used to paralyze their prey and to deter potential predators. Hoplonemerteans often contain pyridyl alkaloids like anabaseine that act through nicotinic acetylcholine receptors and crustacean chemoreceptors. The chemical reactivity of anabaseine, the first nemertean alkaloid to be identified, has been exploited to make drug candidates selective for alpha7 subtype nAChRs. GTS-21, a drug candidate based on the anabaseine scaffold, has pro-cognitive and anti-inflammatory actions in animal models. The circumpolar chevron hoplonemertean Amphiporus angulatus contains a multitude of pyridyl compounds with neurotoxic, anti-feeding, and anti-fouling activities. Here, we report the isolation and structural identification of five new compounds, doubling the number of pyridyl alkaloids known to occur in this species. One compound is an isomer of the tobacco alkaloid anatabine, another is a unique dihydroisoquinoline, and three are analogs of the tetrapyridyl nemertelline. The structural characteristics of these ten compounds suggest several possible pathways for their biosynthesis.

Effects of a dietary isoquinoline alkaloids blend on gut antioxidant capacity and gut barrier of young broilers.

Extensive mechanistic evidence to support the beneficial function of dietary phytobiotic applications for broiler performance, gut function and health is highly warranted. In particular, for isoquinoline alkaloids (IQ) the underlying mechanisms related to critical gut homeostasis components such as cytoprotection and gut barrier are scarce, especially for young broilers at the starter growth stage (d1-10). The aim of this study was to investigate the effect of a standardized blend of IQs on the relative gene expression of critical biomarkers relevant for antioxidant response and barrier function along the intestine of young broilers at the end of starter growth phase. For this purpose, 182 one-day-old Ross 308 broilers were allocated in 2 treatments with 7 replicates of 13 broilers each: control diet-no other additions (NC), and control diet containing a standardized blend of IQs at 200 mg/kg of diet (M) for the starter growth period (1-10d). The results revealed that the IQs blend significantly upregulated (P < 0.05) the expression of genes related to antioxidant response in all intestinal segments. Moreover, the IQs blend enhanced (P < 0.05) gut barrier components primarily at duodenal level. In conclusion, the blend of IQs beneficially affected critical pathway components relevant for the gut antioxidant capacity and barrier along the intestine of young broilers.

Design, synthesis, and biological evaluation of novel benzo[6,7]indolo[3,4-c]isoquinolines as anticancer agents with topoisomerase I inhibition.

A novel series of benzo[6,7]indolo[3,4-c]isoquinolines 3a-3f was designed by scaffold hopping of topoisomerase I inhibitor benzo[g][1]benzopyrano[4,3-b]indol-6(13H)-ones (BBPIs), which were developed by structural modification of the natural marine product lamellarin. The unconventional pentacycle was constructed by Bischler-Napieralski-type condensation of amide 11 and subsequent intramolecular Heck reaction. In vitro anticancer activity of the synthesized benzo[6,7]indolo[3,4-c]isoquinolines was evaluated on a panel of 39 human cancer cell lines (JFCR39). Among the compounds tested, N-(3-morpholinopropyl) derivative 3e showed the most potent antiproliferative activity, with a mean GI50 value of 39 nM. This compound inhibited topoisomerase I activity by stabilizing the enzyme-DNA complex.

Bioactivity and mechanism of action of sanguinarine and its derivatives in the past 10 years.

Sanguinarine is a quaternary ammonium benzophenanthine alkaloid found in traditional herbs such as Chelidonium, Corydalis, Sanguinarum, and Borovula. It has been proven to possess broad-spectrum biological activities, such as antitumor, anti-inflammatory, antiosteoporosis, neuroprotective, and antipathogenic microorganism activities. In this paper, recent progress on the biological activity and mechanism of action of sanguinarine and its derivatives over the past ten years is reviewed. The results showed that the biological activities of hematarginine and its derivatives are related mainly to the JAK/STAT, PI3K/Akt/mTOR, NF-κB, TGF-ß, MAPK and Wnt/ß-catenin signaling pathways. The limitations of using sanguinarine in clinical application are also discussed, and the research prospects of this subject are outlined. In general, sanguinarine, a natural medicine, has many pharmacological effects, but its toxicity and safety in clinical application still need to be further studied. This review provides useful information for the development of sanguinarine-based bioactive agents.

Cycloplatinated (II) Complex Based on Isoquinoline Alkaloid Elicits Ferritinophagy-Dependent Ferroptosis in Triple-Negative Breast Cancer Cells.

The development and optimization of metal-based anticancer drugs with novel cytotoxic mechanisms have emerged as key strategies to overcome chemotherapeutic resistance and side effects. Agents that simultaneously induce ferroptosis and autophagic death have received extensive attention as potential modalities for cancer therapy. However, only a limited set of drugs or treatment modalities can synergistically induce ferroptosis and autophagic tumor cell death. In this work, we designed and synthesized four new cycloplatinated (II) complexes harboring an isoquinoline alkaloid C∧N ligand. On screening the in vitro activity of these agents, we found that Pt-3 exhibited greater selectivity of cytotoxicity, decreased resistance factors, and improved anticancer activity compared to cisplatin. Furthermore, Pt-3, which we demonstrate can initiate potent ferritinophagy-dependent ferroptosis, exhibits less toxic and better therapeutic activity than cisplatin in vivo. Our results identify Pt-3 as a promising candidate or paradigm for further drug development in cancer treatment.

Biologically active isoquinoline alkaloids covering 2019-2022.

Isoquinoline alkaloids are an important class of natural products that are abundant in the plant kingdom and exhibit a wide range of structural diversity and biological activities. With the deepening of research in recent years, more and more isoquinoline alkaloids have been isolated and identified and proved to contain a variety of biological activities and pharmacological effects. In this review, we introduce the research progress of isoquinoline alkaloids from 2019 to 2022, mainly in the part of biological activities, including antitumor, antimicrobial, antidiabetic, antiviral, anti-inflammatory, antioxidant, neuroprotective, hepatoprotective, analgesic, and other activities. This study provides a clear direction for the rational development and utilization of isoquinoline alkaloids, suggesting that these alkaloids have great potential in the field of drug research.

Variability of Isoquinoline Alkaloid Profiles and Anticholinesterase Activities with Binding-Mode Predictions of Glaucium flavum Population.

In this study, phytochemical and biological activity studies supported by docking were carried out on a species of the genus Glaucium, a repository of isoquinoline alkaloids. The GC-MS (Gas Chromatography-Mass Spectrometry) method is used to characterize the isoquinoline alkaloids of Glaucium flavum Crantz. (Papaveraceae). G. flavum was collected from seven different regions of Türkiye (Antalya, Urla-Izmir, Mordogan-Izmir, Mugla, Assos-Canakkale, Karabiga-Canakkale, Giresun) and totally 17 compounds were detected by GC-MS. Glaucine was found to be the major constituent in the sample collected from Mugla, whereas isocorydine was recorded to be the principal alkaloid in other samples. Further fractionation studies on G. flavum collected from Antalya province in Southwestern Türkiye, yielded five major alkaloids (isocorydine 1, dihydrosanguinarine 2, glaucine 3, dehydroglaucine 4, protopine 5) which were characterized by spectroscopic methods. Anticholinesterase activities of the extracts and isolated alkaloids were also tested by in vitro Ellman method. The isolated compounds were also analyzed by a molecular docking technique to determine the binding orientations in the gorge of the active site of acetylcholinesterase (AChE) and a homology model of butyrylcholinesterase (BuChE). This is the first comparative investigation of the phytochemical composition and biodiversity of Glaucium flavum species growing in Türkiye.

Duvelisib: A comprehensive profile.

Duvelisib (DUV) is chemically named as (S)-3-(1-((9H-Purin-6-yl)amino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one. It is a novel drug with a small molecular weight and characterized by dual phosphoinositide-3-kinase (PI3K)- and PI3K-inhibitory activity. The Food and Drug Administration (FDA) recently approved DUV for the management of small lymphocytic lymphoma (SLL) and relapsed or refractory chronic lymphocytic leukemia (CLL) in adult patients. DUV is marketed under the brand name of Copiktra® (Verastem, Inc., Needham, MA, USA). This chapter provides a critical extensive review of the literature, the description of DUV in terms of its names, formulae, elemental composition, appearance, and use in the treatment of CLL, SLL, and follicular lymphoma. The chapter also describes the methods for preparation of DUV, its physical-chemical properties, analytical methods for its determination, pharmacological properties, and dosing information.

Discovery of Novel Isoquinoline Analogues as Dual Tubulin Polymerization/V-ATPase Inhibitors with Immunogenic Cell Death Induction.

Cancer immunotherapy has revolutionized clinical advances in a variety of cancers. Due to the low immunogenicity of the tumor, only a few patients can benefit from it. Specific microtubule inhibitors can effectively induce immunogenic cell death and improve immunogenicity of the tumor. A series of isoquinoline derivatives based on the natural products podophyllotoxin and diphyllin were designed and synthesized. Among them, F10 showed robust antiproliferation activity against four human cancer cell lines, and it was verified that F10 exerted antiproliferative activity by inhibiting tubulin and V-ATPase. Further studies indicated that F10 is able to induce immunogenic cell death in addition to apoptosis. Meanwhile, F10 inhibited tumor growth in an RM-1 homograft model with enhanced T lymphocyte infiltration. These results suggest that F10 may be a promising lead compound for the development of a new generation of microtubule drugs.

Activation of Intestinal HIF2α Ameliorates Iron-Refractory Anemia.

In clinics, hepcidin levels are elevated in various anemia-related conditions, particularly in iron-refractory anemia and in high inflammatory states that suppress iron absorption, which remains an urgent unmet medical need. To identify effective treatment options for various types of iron-refractory anemia, the potential effect of hypoxia and pharmacologically-mimetic drug FG-4592 (Roxadustat) are evaluated, a hypoxia-inducible factor (HIF)-prolyl hydroxylase (PHD) inhibitor, on mouse models of iron-refractory iron-deficiency anemia (IRIDA), anemia of inflammation and 5-fluorouracil-induced chemotherapy-related anemia. The potent protective effects of both hypoxia and FG-4592 on IRIDA as well as other 2 tested mouse cohorts are found. Mechanistically, it is demonstrated that hypoxia or FG-4592 could stabilize duodenal Hif2α, leading to the activation of Fpn transcription regardless of hepcidin levels, which in turn results in increased intestinal iron absorption and the amelioration of hepcidin-activated anemias. Moreover, duodenal Hif2α overexpression fully rescues phenotypes of Tmprss6 knockout mice, and Hif2α knockout in the gut significantly delays the recovery from 5-fluorouracil-induced anemia, which can not be rescued by FG-4592 treatment. Taken together, the findings of this study provide compelling evidence that targeting intestinal hypoxia-related pathways can serve as a potential therapeutic strategy for treating a broad spectrum of anemia, especially iron refractory anemia.

Neopetrotaurines A-C, Isoquinoline Alkaloids with an Unprecedented Taurine Bridge from the Sponge Neopetrosia sp.

Neopetrotaurines A-C (1-3), unusual alkaloids possessing two isoquinoline-derived moieties that are linked via a unique taurine bridge, were isolated from a Neopetrosia sp. marine sponge. These new compounds have proton-deficient structural scaffolds that are difficult to unambiguously assign using only conventional 2- and 3-bond 1H-13C and 1H-15N heteronuclear correlation data. Thus, the application of LR-HSQMBC and HMBC NMR experiments optimized to detect 4- and 5-bond long-range 1H-13C heteronuclear correlations facilitated the structure elucidation of these unusual taurine-bridged marine metabolites. Neopetrotaurines A-C (1-3) showed significant inhibition of transcription driven by the oncogenic fusion protein PAX3-FOXO1, which is associated with alveolar rhabdomyosarcoma, and cytotoxic activity against PAX3-FOXO1-positive cell lines.

Selective induction of Rab9-dependent alternative mitophagy using a synthetic derivative of isoquinoline alleviates mitochondrial dysfunction and cognitive deficits in Alzheimer's disease models.

Rationale: Promotion of mitophagy is considered a promising strategy for the treatment of neurodegenerative diseases including Alzheimer's disease (AD). The development of mitophagy-specific inducers with low toxicity and defined molecular mechanisms is essential for the clinical application of mitophagy-based therapy. The aim of this study was to investigate the potential of a novel small-molecule mitophagy inducer, ALT001, as a treatment for AD. Methods: ALT001 was developed through chemical optimization of an isoquinolium scaffold, which was identified from a chemical library screening using a mitophagy reporter system. In vitro and in vivo experiments were conducted to evaluate the potential of ALT001 as a mitophagy-targeting therapeutic agent and to investigate the molecular mechanisms underlying ALT001-induced mitophagy. The therapeutic effect of ALT001 was assessed in SH-SY5Y cells expressing mutant APP and mouse models of AD (5×FAD and PS2APP) by analyzing mitochondrial dysfunction and cognitive defects. Results: ALT001 specifically induces mitophagy both in vitro and in vivo but is nontoxic to mitochondria. Interestingly, we found that ALT001 induces mitophagy through the ULK1-Rab9-dependent alternative mitophagy pathway independent of canonical mitophagy pathway regulators such as ATG7 and PINK1. Importantly, ALT001 reverses mitochondrial dysfunction in SH-SY5Y cells expressing mutant APP in a mitophagy-dependent manner. ALT001 induces alternative mitophagy in mice and restores the decreased mitophagy level in a 5×FAD AD model mouse. In addition, ALT001 reverses mitochondrial dysfunction and cognitive defects in the PS2APP and 5×FAD AD mouse models. AAV-mediated silencing of Rab9 in the hippocampus further confirmed that ALT001 exerts its therapeutic effect through alternative mitophagy. Conclusion: Our results highlight the therapeutic potential of ALT001 for AD via alleviation of mitochondrial dysfunction and indicate the usefulness of the ULK1-Rab9 alternative mitophagy pathway as a therapeutic target.

Identification of novel 3-aryl-1-aminoisoquinolines-based KRASG12C inhibitors: Rational drug design and expedient construction by CH functionalization/annulation.

Developing a synthetic methodology to expediently construct a specific drug scaffold with the desired biological activity remains challenging. Herein, we describe a work on rational application of a synthetic methodology in the synthesis of KRASG12C inhibitors. Novel KRASG12C inhibitors were initially designed with 1-amino-3-aryl isoquinoline scaffold using structure-based drug design strategy. A ruthenium-catalyzed direct monoCH functionalization/annulation cascade reaction of amidines and sulfoxonium ylides was then developed with high versatility of substrates and good tolerance for polar functional groups. By using this reaction, the target compounds 1-amino-3-aryl isoquinolines were facilely prepared. Further in vitro tests led to identification of two novel lead compounds with KRASG12C inhibitory activity.

Liensinine alleviates LPS-induced acute lung injury by blocking autophagic flux via PI3K/AKT/mTOR signaling pathway.

Acute lung injury (ALI) is a major pathological problem characterized by severe inflammatory reactions and is a critical disease with high clinical morbidity and mortality. Liensinine, a major isoquinoline alkaloid, is extracted from the green embryos of mature Nelumbonaceae seeds. It has been reported to have an inhibitory effect on tumors. However, the effects of liensinine on ALI have not been reported to-date. The aim of this study was to explore the inhibitory effects of liensinine on lipopolysaccharide (LPS)-induced ALI and its possible mechanism. We found that liensinine significantly reduced LPS-induced ALI and reduced the production of inflammatory factors IL-6, IL-8, and TNF-α. In addition, liensinine blocked autophagic flux and increased the number of autophagosomes by upregulating LC3-II/I and p62 protein levels. More importantly, pretreatment with the early stages autophagy inhibitor 3-Methyladenine (3-MA) can reverse the inhibitory effects of liensinine on the secretion of inflammatory factors in ALI. The PI3K/AKT/mTOR pathway is involved in LPS-induced autophagy regulated by liensinine in ALI. In summary, this study suggests that liensinine inhibits the production of inflammatory factors in LPS-induced ALI by regulating autophagy via the PI3K/AKT/mTOR pathway, which may provide a new therapeutic strategy to alleviate ALI.