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The synthesis or derivation of a series of structural analogues based on natural products is a common strategy for discovering antitumor drugs. As a unique natural diterpene derived from Trigonostemon howii, 3,4-seco-sonderianol (1) exhibited moderate cytotoxic effects. To improve the activity, a new diterpene derivative (1b) with a mitochondrial targeting function was synthesized by coupling triphenylphosphine to compound 1. Compared to the parent molecule, the antitumor activity of 1b increased greatly. A series of mechanistic experiments revealed that compound 1b induced cancer cell apoptosis and inhibited cancer cell migration by targeting the mitochondria and regulating the STAT3 and FAK signaling pathways. Meanwhile, 1b was found to inhibit angiogenesis in a transgenic zebrafish model. It is worth noting that 1b also demonstrated excellent antitumor effects in zebrafish tumor xenotransplantation models. All the evidence supports that compound 1b targeting mitochondria has the potential to be a candidate for an antitumor drug.

Currently, the use of nanotechnology to repurpose traditional drugs has emerged as a promising strategy for cancer treatment. Quercetin (Qu), a chemotherapy molecule, has excellent antitumor activity, and IR780, a photosensitizer, possesses sound tumor phototherapy effects. However, both compounds have poor water solubility and other drawbacks that hinder their extensive clinical applications. To effectively utilize two molecules in the fight against cancer, a new multifunctional chemical-phototherapy nanoplatform with tumor target and glutathione (GSH) response was designed. By modifying hyaluronic acid (HA), the amphiphilic molecule carrying biotin and IR780 was obtained, which self-assembled to load the antitumor active molecule Qu, namely Qu@BHSI. In addition to addressing the hydrophobic issue of Qu and IR780, the prepared nanoparticles can rapidly release Qu with high concentrations of GSH present and generate heat and cytotoxic reactive oxygen species (ROS) under near-infrared light. The biological function research showed that Qu@BHSI nanoparticles had the ability to suppress the growth of A549 cells, induce cell apoptosis, stimulate ROS production in zebrafish, and inhibit angiogenesis in transgenic zebrafish. The construction of nanosystems provides new or alternative strategies and approaches for effectively repurposing classical drug molecules including photosensitizers and chemotherapy drugs.

Natural products are one of the essential sources of innovative drugs. Trigothysoid N, a natural daphnane diterpenoid obtained from Trigonostemon thyrsoideus, possessed the strong ability to inhibit the proliferation of A549 cells. Besides interrupting the cell cycle, the mechanism examination revealed that trigothysoid N can inhibit tumor proliferation and migration by targeting mitochondria, regulating the STAT3/FAK signal pathway, and suppressing angiogenesis. In addition to the possible mechanism, in vivo antitumor experiments were performed to explore the potential of trigothysoid N for treating non-small cell lung cancer (NSCLC). Collectively, these findings supported the great potential of trigothysoid N as a hopeful therapeutic agent against NSCLC.

Akebia quinata is a traditional medicinal plant distributed in East Asia and its fruits are applicated in food and pharmaceutical fields. Herein, a novel polysaccharide (AQP70-2A) with a molecular weight of 1.49 × 104 Da was isolated from the fruits of A. quinata. Results of the chemical and spectroscopic analysis indicated that AQP70-2A was an arabinofuranan with a backbone mainly consisting of → 5)-α-l-Araf-(1→, →3,5)-α-l-Araf-(1→, and → 2,3,5)-α-l-Araf-(1→, and it also contained two types of branch chains. At the cellular level, AQP70-2A did not show significant antitumor properties, while selenylation significantly made the inhibitory effect of this natural macromolecule on HepG2 cells to be increased. Furthermore, the zebrafish xenograft model confirmed that selenized polysaccharide Se-AQP70-2A effectively blocked hepatocellular carcinoma cells invasion and metastasis. Meanwhile, the inhibition of Se-AQP70-2A on development of intersegmental vessels revealed its antiangiogenic activity.

Cancer is one of the deadliest human diseases, causing high rates of illness and death. Lung cancer has the highest mortality rate among all malignancies worldwide. Effusanin B, a diterpenoid derived from Isodon serra, showed therapeutic potential in treating non-small-cell lung cancer (NSCLC). Further research on the mechanism indicated that effusanin B inhibited the proliferation and migration of A549 cells both in vivo and in vitro. The in vitro activity assay demonstrated that effusanin B exhibited significant anticancer activity. Effusanin B induced apoptosis, promoted cell cycle arrest, increased the production of reactive oxygen species (ROS), and altered the mitochondrial membrane potential (MMP). Based on mechanistic studies, effusanin B was found to inhibit the proliferation and migration of A549 cells by affecting the signal transducer and activator of transcription 3 (STAT3) and focal adhesion kinase (FAK) pathways. Moreover, effusanin B inhibited tumor growth and spread in a zebrafish xenograft model and demonstrated anti-angiogenic effects in a transgenic zebrafish model.

Aimed at discovering small molecules as anticancer drugs or lead compounds from plants, a lindenane-type sesquiterpene dimer, chlorahololide D, was isolated from Chloranthus holostegius. The literature review showed that there were few reports on the antitumor effects and mechanisms of chlorahololide D. Our biological assay suggested that chlorahololide D blocked the growth and triggered apoptosis of MCF-7 cells by stimulating the reactive oxygen species (ROS) levels and arresting the cell cycle at the G2 stage. Further mechanism exploration suggested that chlorahololide D regulated apoptosis-related proteins Bcl-2 and Bax. Moreover, chlorahololide D inhibited cell migration by regulating the FAK signaling pathway. In the zebrafish xenograft model, chlorahololide D was observed to suppress tumor proliferation and migration significantly. Considering the crucial function of angiogenesis in tumor development, the anti-angiogenesis of chlorahololide D was also investigated. All of the research preliminarily revealed that chlorahololide D could become an anti-breast cancer drug.

An unreported polysaccharide, PLP90-1B, was isolated from Paeonia lactiflora. Structural analysis showed that PLP90-1B contained arabinose and glucose, which was a highly-linear gluco-arabinan having a molecular weight of about 9.5 kDa. The backbone of PLP90-1B consisted of → 5)-α-l-Araf-(1→, →3,5)-α-l-Araf-(1→, →2,3,5)-α-l-Araf-(1→, and → 4)-α-d-Glcp-(1→, terminating with α-l-Araf. PLP90-1B was found to have anti-tumor activity by suppressing the proliferation and migration of HepG2 cells microinjected into the zebrafish. The further mechanism investigation revealed that the anti-tumor activity of PLP90-1B was closely related to immune regulation, which can improve phagocytic ability and enhance the release of NO and cytokines (IL-6, IL-1β, and TNF-α) in RAW264.7 cells. The immunopotentiation activity was further corroborated by zebrafish experiments. All these results exhibited that PLP90-1B may have the potential to become a potentially immune-mediated anti-tumor drug in the future.

Nanoparticles have been found to possess unique advantages in many fields, especially in the field of cancer treatment. Herein, based on the unique physical and chemical properties of natural polysaccharides, the polysaccharide from the edible and medicinal fruits of Chaenomeles speciosa was prepared, and the complex nanoparticles constructed by combining C. speciosa polysaccharide with selenium have been successfully developed by a chemical method. Monodisperse spherical nanoparticles with the particle size of 80.5 nm were characterized by various methods, which exhibited ideal size distribution and prominent stability under physiological conditions and alkaline conditions. Cellular studies demonstrated the nanoparticles significantly inhibited the growth of MCF-7 cells with an IC50 value of 8.37 ± 0.97 μg/mL through inducing the apoptosis and arresting the cell circle at S phase. Moreover, the zebrafish assays confirmed the antitumor effects of the nanoparticles, which suppressed the proliferation and migration of tumor and blocked the angiogenesis of transgenic zebrafish. Collectively, the results suggested that the nanoparticles may be considered as a candidate agent to treat breast cancer.

To discover phytochemicals as lead compounds for cancer treatment, cratoxylumxanthone C, a natural xanthone, was obtained from Cratoxylum cochinchinense (Lour.) Bl., for which there have been no reports on the biological effects against cancer. Our study revealed that cratoxylumxanthone C had significant anti-tumor activity by inducing apoptosis, augmenting cellular reactive oxygen species (ROS), and arresting cell circle. The mechanistic examination showed the inhibition of A549 cell proliferation and metastasis by cratoxylumxanthone C was coupled with the signal transducer and activator of transcription 3 (STAT3) and focal adhesion kinase (FAK) signaling pathways. Furthermore, the zebrafish models confirmed its significant in vivo anti-tumor activity, in which cratoxylumxanthone C inhibited tumor proliferation and metastasis and suppressed the angiogenesis. Comprehensively, these cellular and zebrafish experiments implied that cratoxylumxanthone C may have the potential to become an anti-tumor agent for lung cancer, especially non-small cell lung cancer (NSCLC).

Background: : P-glycoprotein mediated efflux leads to multidrug resistance of tumor cells, which is an important reason for chemotherapy failure. Thus inhibiting P-gp is an effective approach to reverse multidrug resistance. Purpose: : Swietephragmin D is a limonoid compound isolated from the fruits and leaves of Swietenia mahagoni (L.) Jacq.. The reversal efficiency of swietephragmin D was examined in this study. Methods: : Rhodamine 123 efflux assays were used to measure inhibition efficiency of swietephragmin D. Cytotoxicity assays were used to measure the reversal effect of swietephragmin D. Real-time PCR and ATPase assays were performed to explore the mechanisms of reversion. Results: : Swietephragmin D inhibited P-glycoprotein-induced efflux in a dose and time dependent manner. This compound inhibited P-glycoprotein more effectively than verapamil. The IC50 values of the multidrug resistant cells were reduces by swietephragmin D significantly. The transcription levels of ABCB1 (encoded P-glycoprotein) were not affected by swietephragmin D. However, the ATPase activity of P-glycoprotein was stimulated by swietephragmin D. Conclusion: : Swietephragmin D was a substrate of P-glycoprotein and inhibited P-gp mediated efflux. It did not interfere with expression of ABCB1. Thus swietephragmin D reversed multidrug resistance as a competitive inhibitor of P-glycoprotein.

α-Mangostin, a natural xanthone, was found to have anticancer effects, but these effects are not sufficient to be effective. To increase anticancer potential and selectivity, a triphenylphosphonium cation moiety (TPP) was introduced to α-mangostin to specifically target cancer cell mitochondria. Compared to the parent compound, the cytotoxicity of the synthesized compound 1b increased by one order of magnitude. Mechanistic analysis revealed that the anti-tumor effects were involved in the mitochondrial apoptotic pathway by prompting apoptosis and arresting the cell cycle at the G0/G1 phase, increasing the production of reactive oxygen species (ROS), and reducing mitochondrial membrane potential (Δψm). More notably, the antitumor activity of compound 1b was further confirmed by zebrafish models, which remarkably inhibited cancer cell proliferation and migration, as well as zebrafish angiogenesis. Taken together, our results for the first time indicated that TPP-linked 1b could lead to the development of new mitochondrion-targeting antitumor agents.

Casearlucin A, a diterpenoid obtained from Casearia graveolens, has been reported to possess strong cytotoxic activity. However, the in vivo anti-tumor effects and the action mechanism of casearlucin A remain poorly understood. Our study revealed that casearlucin A arrested cell cycle at G0/G1 stage and induced cell apoptosis in cell level. Additionally, casearlucin A inhibited HepG2 cell migration via regulating a few of metastasis-related proteins. Furthermore, it inhibited tumor angiogenesis in zebrafish in vivo. More importantly, casearlucin A significantly inhibited cell proliferation and migration in an in vivo zebrafish xenograft model. Collectively, these results are valuable for the further development and application of casearlucin A as an anticancer agent.

The data presented in this article are associated with the research article entitled “Bioactive Constituents Study of Pugionium cornutum L. Gaertn on Intestinal Motility” [1]. The aim of this data was to provide the 1D, 2D NMR and MS spectrum of novel bioactive compounds from P. cornutum. Keywords: Traditional Mongolian medicine, Pugionium cornutum L. Gaertn, Novel bioactive constituents, Thiohydantoin derivatives

Background: Plant natural products have many different biological activities but the precise mechanisms underlying these activities remain largely unknown. Hypericum longistylum has long been recorded in Chinese medicine as a cure for depression and related disorders, but how it repairs neural lineages has not been addressed. Methods: We extracted compounds from Hypericum longistylum and determined their effect on neural differentiation of embryonic stem cells (ESCs) in vitro by using the Pax6-GFP reporter system. The amount of serotonin released during differentiation was measured by HPLC. The tail suspension test and forced swimming test was performed for determining the effect of compounds on depression-like behaviors in mice. Results: We found that one of the phloroglucinol derivatives not only facilitated differentiation of neural progenitor cells, but also increased the efficiency of differentiation into serotonergic neurons. This compound also improved the behaviors of mice placed in a stressful environment and reduced signs of depression. Conclusions: This is the first use of Chinese herb derived-natural products to promote neurogenesis of ESCs, including the generation of serotonergic neurons, and the first attempt to identify the active compound in Hypericum longistylum responsible for its beneficial effects on depressive diseases. Keywords: Cell differentiation, Chemical modification, Depression, Chinese medicine, Neural differentiation, Serotonergic neuron

Tussilago farfara L. is a well-known herb plant and used widely in China, North Africa, and Europe. A phytochemical investigation to obtain new NO inhibitors resulted in the isolation of three new sesquiterpenes, one new phenolic derivative, and ten known compounds from the flower buds of T. farfara. Their structures were established on the basis of extensive analyses of nuclear magnetic resonance (NMR) spectroscopic data. All of the isolates exhibited inhibitory effects on LPS-induced NO production in BV-2 cells. The possible mechanism of NO inhibition was also investigated using molecular docking, which revealed the interactions of bioactive compounds with iNOS protein. The present study disclosed that flower buds of T. farfara have the potential to be developed into a functional food.

The root barks of perennial herb Dictamnus dasycarpus (Cortex Dictamni) were reported to be rich in anti-inflammation activity constituents, limonoids. Then, the investigation of anti-inflammation therapeutic limonoids from this plant was developed in the present study. Through the combination of various chromatographies isolation, six new limonoids, named dictamlimonol A (1), dictamlimonoside B (2), and dictamlimonols C–F (3–6), along with seven known ones (7–13), were obtained. Their structures were ascertained based on the extensive spectroscopic methods and ECD data analysis. Among them, compound 1 was the first 7,19-epoxy limonoid found in natural products. The anti-inflammatory effects of all limonoids were evaluated in lipopolysaccharide (LPS)-treated RAW 264.7 cell lines. Compounds 5, 7–11, and 13 were found to inhibit LPS-induced nitric oxide (NO) production. Moreover, dictamlimonol D (5), fraxinellone (11), and dasylactone A (13) were found to reduce the LPS-induced expressions of interleukin-6 (IL-6), tumor necrosis factor (TNF-α), inducible nitric oxide synthase (iNOS), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and cyclooxygenase-2 (COX-2) at the protein levels in a dose-dependent manner. These findings support that the administration of Cortex Dictamni may be beneficial for inflammation.

Hepatitis E virus (HEV) is one of the major causes of acute hepatitis worldwide. Here, we investigated the role of autophagy on HEV replication and demonstrated anti-HEV effects of japonicone V, a main constituent of the flowers of Inula japonica. Results showed that HEV infection induced autophagy in Huh7 cells. Chloroquine (CQ) and 3-methyladenine (3-MA), two autophagy inhibitors inhibited HEV replication. Moreover, japonicone V suppressed HEV replication and inhibited autophagy in the HEV infectious model. CQ had additive inhibitory effects with japonicone V on HEV replication, while rapamycin, an autophagy inducer, attenuated japonicone V-mediated inhibition of HEV replication. In addition, HEV infection inhibited the PI3K/AKT/mTOR pathway; however, this effect could be alleviated by japonicone V treatment. Collectively, our findings reveal that autophagy machinery is required for HEV replication; japonicone V inhibited HEV replication by targeting the virus-associated autophagy, at least in part, through inhibition of the PI3K/AKT/mTOR pathway.

Bioactive substances that promote neurite outgrowth and prevent neuronal degeneration are potentially useful for the medical treatment of Alzheimer's disease (AD). This study aimed to obtain bioactive compounds from the stems of the medicinal and edible plant Melicope pteleifolia that promote neurite outgrowth. A bioassay-guided phytochemical investigation led to the isolation of four new chroman derivatives, pteleifolones A–D (1–4), and nine known components, acronyculatin B (5), acronylin (6), marmesin (7), 5-methoxymarmesin (8), (+)-peucedanol (9), atanine (10), N-methylatanine (11), dictamnine (12), and evolitrine (13). Their structures were established by extensive nuclear magnetic resonance (NMR) spectroscopic data analysis. Most of these compounds promoted nerve growth factor (NGF)-mediated neurite outgrowth in PC12 cells. These chemical and biological results provide a basis for the further development and utilization of M. pteleifolia as a functional food.

Petasites japonicus (Sieb. & Zucc.) Maxim., belonging to the Compositae family, is a perennial herb and has been consumed as a wild vegetable. Our survey on the chemical composition of P. japonicus resulted in the isolation of two new and seventeen known sesquiterpenoids. Their structures were elucidated on the basis of nuclear magnetic resonance (NMR) spectroscopic data analysis, and the absolute configurations of the new compounds were established by comparison of the calculated and experimental electronic circular dichroism (ECD) spectra. Among these isolates, compound 1 was a sesquiterpene carrying a chlorine atom, 2 processed a rare 7,9-secobakkenolide skeleton, and compounds 4, 11–13, 15, 18, and 19 were obtained from this species for the first time. Most of these compounds showed promoting effects on neurite outgrowth from PC12 cells. These chemical and biological results provide a basis for further development and utilization of P. japonicus as a functional food.

Three new myrsinol diterpenes were isolated from the roots of Euphorbia prolifera. Their structures were elucidated as 2α-O-isobutyryl-3β,5α,7β,10,15β-penta-O-acetyl-14α-O-benzoyl-10,18-dihydromyrsinol (1), 2α-O-isobutyryl-3β-O-propion-yl-5α,7β,10,15β-tetra-O-acetyl-10,18-dihydromyrsinol (2), and 2α,14α-di-O-benzoyl-3β,5α,7β,10,15β-penta-O-acetyl-10,18-dihydromyrsinol (3) on the basis of spectroscopic data analyses (IR, ESI-MS, HR-ESI-MS, and 1D and 2D NMR). Their neuroprotective activities were evaluated and compounds 1 and 2 showed neuroprotective effects against MPP+-induced neuronal cell death in SH-SY5Y cells.