Ent-eudesmane sesquiterpenoids with anti-neuroinflammatory activity from the marine-derived fungus Eutypella sp. F0219.

In this study, twenty-three ent-eudesmane sesquiterpenoids (1-23) including fifteen previously undescribed ones, named eutypelides A-O (1-15) were isolated from the marine-derived fungus Eutypella sp. F0219. Their planar structures and relative configurations were established by HR-ESIMS and extensive 1D and 2D NMR investigations. The absolute configurations of the previously undescribed compounds were determined by single-crystal X-ray diffraction analyses, modified Mosher's method, and ECD calculations. Structurally, eutypelide A (1) is a rare 1,10-seco-ent-eudesmane, whereas 2-15 are typically ent-eudesmanes with 6/6/-fused bicyclic carbon nucleus. The anti-neuroinflammatory activity of all isolated compounds (1-23) was accessed based on their ability to NO production in LPS-stimulated BV2 microglia cells. Compound 16 emerged as the most potent inhibitor. Further mechanistic investigation revealed that compound 16 modulated the inflammatory response by decreasing the protein levels of iNOS and increasing ARG 1 levels, thereby altering the iNOS/ARG 1 ratio and inhibiting macrophage polarization. qRT-PCR analysis showed that compound 16 reversed the LPS-induced upregulation of pro-inflammatory cytokines, including iNOS, TNF-α, IL-6, and IL-1ß, at both the transcriptional and translational levels. These effects were linked to the inhibition of the NF-κB pathway, a key regulator of inflammation. Our findings suggest that compound 16 may be a potential structure basis for developing neuroinflammation-related disease therapeutic agents.

Discovery of novel melatonin-mydroxyquinoline hybrids as multitarget strategies for Alzheimer's disease therapy.

Alzheimer's disease (AD) is a neurodegenerative disease that seriously affects human health, and current treatment strategies are far from meeting clinical needs. Inspired by multi-target drug design strategies, a series of novel natural products-based melatonin-hydroxyquinoline hybrids were designed and synthesized, targeting anti-oxidation and metal-chelating at the same time. Most of the compounds showed significant oxygen radical absorbance capacity and Aß1-42 aggregation inhibition. Moreover, the compounds possess good blood-brain barrier permeability. 6b and 6c have a good ability to alleviate oxidative stress induced by hydrogen peroxide. 6b and 6c possess metal-chelating properties with the chelation ratio being 2:1. Furthermore, 6b can significantly mitigate metal-induced Aß aggregation. This work may provide a new multi-target treatment strategy for Alzheimer's disease.

Taxonomic and functional ß-diversity patterns reveal stochastic assembly rules in microbial communities of seagrass beds.

Microorganisms are important members of seagrass bed ecosystems and play a crucial role in maintaining the health of seagrasses and the ecological functions of the ecosystem. In this study, we systematically quantified the assembly processes of microbial communities in fragmented seagrass beds and examined their correlation with environmental factors. Concurrently, we explored the relative contributions of species replacement and richness differences to the taxonomic and functional ß-diversity of microbial communities, investigated the potential interrelation between these components, and assessed the explanatory power of environmental factors. The results suggest that stochastic processes dominate community assembly. Taxonomic ß-diversity differences are governed by species replacement, while for functional ß-diversity, the contribution of richness differences slightly outweighs that of replacement processes. A weak but significant correlation (p < 0.05) exists between the two components of ß-diversity in taxonomy and functionality, with almost no observed significant correlation with environmental factors. This implies significant differences in taxonomy, but functional convergence and redundancy within microbial communities. Environmental factors are insufficient to explain the ß-diversity differences. In conclusion, the assembly of microbial communities in fragmented seagrass beds is governed by stochastic processes. The patterns of taxonomic and functional ß-diversity provide new insights and evidence for a better understanding of these stochastic assembly rules. This has important implications for the conservation and management of fragmented seagrass beds.

Marine fungus Aspergillus c1. sp metabolite activates the HSF1/PGC-1α axis, inducing a thermogenic program for treating obesity.

Background and aims: Obesity is one of the most prevalent diseases worldwide with less ideal approved agents in clinic. Activating the HSF1/PGC-1α axis in adipose tissues has been reported to induce thermogenesis in mice, which presents a promising therapeutic avenue for obesity treatment. The present study aimed to identified novel natural HSF1 activator and evaluated the therapeutic effects of the newly discovered compound on obesity-associated metabolic disorders and the molecular mechanisms of these effects. Methods: Our previous reported HSF1/PGC-1α activator screening system was used to identify novel natural HSF1 activator. The PGC-1α luciferase activity, immunoblot, protein nuclear-translocation, immunofluorescence, chromatin immunoprecipitation assays were used to evaluate the activity of compound HN-001 in activating HSF1. The experiments of mitochondrial number measurement, TG assay and imaging, cellular metabolic assay, gene assays, and CRISPR/Cas 9 were applied for investigating the metabolic effect of HN-001 in C3H10-T1/2 adipocytes. The in vivo anti-obesity efficacies and beneficial metabolic effects of HN-001 were evaluated by performing body and fat mass quantification, plasma chemical analysis, GTT, ITT, cold tolerance test, thermogenesis analysis. Results: HN-001 dose- and time-dependently activated HSF1 and induced HSF1 nuclear translocation, resulting in an enhancement in binding with the gene Pgc-1α. This improvement induced activation of adipose thermogenesis and enhancement of mitochondrial oxidation capacity, thus inhibiting adipocyte maturation. Deletion of HSF1 in adipocytes impaired mitochondrial oxidation and abolished the above beneficial metabolic effects of HN-001, including adipocyte browning induction, improvements in mitogenesis and oxidation capacity, and lipid-lowering ability. In mice, HN-001 treatment efficiently alleviated diet-induced obesity and metabolic disorders. These changes were associated with increased body temperature in mice and activation of the HSF1/PGC-1α axis in adipose tissues. UCP1 expression and mitochondrial biogenesis were increased in both white and brown adipose tissues of HN-001-treated mice. Conclusion: These data indicate that HN-001 may have therapeutic potential for obesity-related metabolic diseases by increasing the capacity of energy expenditure in adipose tissues through a mechanism involving the HSF1/PGC-1α axis, which shed new light on the development of novel anti-obesity agents derived from marine sources.

Identification of a natural PLA2 inhibitor from the marine fungus Aspergillus sp. c1 for MAFLD treatment that suppressed lipotoxicity by inhibiting the IRE-1α/XBP-1s axis and JNK signaling.

Lipotoxicity is a pivotal factor that initiates and exacerbates liver injury and is involved in the development of metabolic-associated fatty liver disease (MAFLD). However, there are few reported lipotoxicity inhibitors. Here, we identified a natural anti-lipotoxicity candidate, HN-001, from the marine fungus Aspergillus sp. C1. HN-001 dose- and time- dependently reversed palmitic acid (PA)-induced hepatocyte death. This protection was associated with IRE-1α-mediated XBP-1 splicing inhibition, which resulted in suppression of XBP-1s nuclear translocation and transcriptional regulation. Knockdown of XBP-1s attenuated lipotoxicity, but no additional ameliorative effect of HN-001 on lipotoxicity was observed in XBP-1s knockdown hepatocytes. Notably, the ER stress and lipotoxicity amelioration was associated with PLA2. Both HN-001 and the PLA2 inhibitor MAFP inhibited PLA2 activity, reduced lysophosphatidylcholine (LPC) level, subsequently ameliorated lipotoxicity. In contrast, overexpression of PLA2 caused exacerbation of lipotoxicity and weakened the anti-lipotoxic effects of HN-001. Additionally, HN-001 treatment suppressed the downstream pro-apoptotic JNK pathway. In vivo, chronic administration of HN-001 (i.p.) in mice alleviated all manifestations of MAFLD, including hepatic steatosis, liver injury, inflammation, and fibrogenesis. These effects were correlated with PLA2/IRE-1α/XBP-1s axis and JNK signaling suppression. These data indicate that HN-001 has therapeutic potential for MAFLD because it suppresses lipotoxicity, and provide a natural structural basis for developing anti-MAFLD candidates.

Assessment of greenhouse gases emissions and intensity from Chinese marine aquaculture in the past three decades.

Marine aquaculture is increasingly gaining importance as a source of food with high nutritional value. However, the expansion of aquaculture could be responsible for water contamination that influences the environmental quality of coastal ecosystems, and emissions of greenhouse gases (GHG) that affect global climate. China is the world's largest producer of marine aquaculture protein, which demands robust studies to assess the corresponding GHG emissions and intensity. To fill in this knowledge gap, the current study quantifies and analyzes GHG emissions and intensity (emission intensity is defined as GHG emissions per unit of production) from Chinese marine aquaculture (marine aquaculture production) over the past 30 years (1991-2020). The production of marine aquaculture comes from the China Fisheries Statistical Yearbooks. And the GHG emissions and intensity were calculated based on five sectors (commercial feed, trash fish, N2O, CH4, and energy) by Emission-Factor Approach. The results suggest that, excluding shellfish and algae, GHG emissions of ten coastal provinces (excluding Shanghai, Hong Kong, Taiwan, and Macau) increased from 2 Mt (109 kg) CO2-eq in 1991 to 25 Mt CO2-eq in 2020. In contrast, GHG emission intensity decreased in the same period from 7.33 (t CO2-eq/t production) to 6.34 (t CO2-eq/t production), indicating a progressive mitigation in GHG emissions per unit of product, hence sustainably satisfying a growing demand for food. As a result, China's marine aquaculture seems to be paving a promising way towards the neutrality of GHG emissions. In most provinces, GHG is on the rise, and only in Tianjin is on the decline in recent years. For the emissions intensity, the values of more than half provinces showed the downtrends. In addition, by considering the ratio of shellfish and algae, Chinese marine aquaculture can improve the net zero goal for GHG emissions of the sector. Finally, results also reveal for the first time the changes in taxonomic composition and spatial GHG emissions and intensity, providing new understanding and scientific bases to elaborate consistent mitigation strategies for an expanding global marine aquaculture.

A facile method for anti-cancer drug encapsulation into polymersomes with a core-satellite structure.

Polymersomes possess the self-assembly vesicular structure similar to liposomes. Although a variety of comparisons between polymersomes and liposomes in the aspects of physical properties, preparation and applications have been elaborated in many studies, few focus on their differences in drug encapsulation, delivery and release in vitro and in vivo. In the present work, we have provided a modified direct hydration method to encapsulate anti-cancer drug paclitaxel (PTX) into PEG-b-PCL constituted polymersomes (PTX@PS). In addition to advantages including narrow particle size distribution, high colloid stability and moderate drug-loading efficiency, we find that the loaded drug aggregate in small clusters and reside through the polymersome membrane, representing a unique core-satellite structure which might facilitate the sustained drug release. Compared with commercial liposomal PTX formulation (Lipusu®), PTX@PS exhibited superb tumor cell killing ability underlain by multiple pro-apoptotic mechanisms. Moreover, endocytic process of PTX@PS significantly inhibits drug transporter P-gp expression which could be largely activated by free drug diffusion. In glioma mice models, it has also confirmed that PTX@PS remarkably eradicate tumors, which renders polymersomes as a promising alternative to liposomes as drug carriers in clinic.

Reactive oxygen species-activated self-amplifying prodrug nanoagent for tumor-specific Cu-chelate chemotherapy and cascaded photodynamic therapy.

Disulfiram (DSF), an effective FDA-approved anti-alcoholism drug, shows potent antitumor activity by producing Cu(DTC)2, a chelate of its metabolite diethyldithiocarbamate (DTC) and copper. However, the rapid metabolism and unselective distribution of DSF and the insufficient endogenous copper severely restrict enough bioactive Cu(DTC)2 generation in tumor tissues to achieve satisfactory antitumor effect. Moreover, directly Cu(DTC)2 administration also suffers from serious systemic toxicity. Herein, a reactive oxygen species (ROS)-activatable self-amplifying prodrug nanoagent (HA-DQ@MOF) was developed for the stable co-delivery of DTC prodrug and Cu-quenched photosensitizer, aiming to achieve tumor-specific dual-activation of highly-toxic Cu(DTC)2-mediated chemotherapy and cascaded photodynamic therapy (PDT). The ROS-cleavable hyaluronic acid-conjugated DTC prodrug (HA-DQ) was decorated on Cu2+ and photosensitizer Zn-TCPP coordinated MOF (PDT-shielded state) to construct HA-DQ@MOF. HA-DQ@MOF could specifically activated in ROS-overexpressed tumor cells to rapidly release DTC, while remaining relatively stable in normal cells. The free DTC immediately grabbed Cu2+ from MOF to in situ generate highly-cytotoxic Cu(DTC)2 chelate, accompanied by MOF dissociation to restore the PDT effect of Zn-TCPP. Importantly, ROS produced by PDT could in turn trigger more DTC release, which further promoted Zn-TCPP liberation, forming a self-amplifying prodrug/photosensitizer activation positive feedback loop. Experimental results confirmed the dual-activated and combined tumor-killing effect of Cu(DTC)2-mediated chemotherapy and Zn-TCPP-based PDT with little systemic toxicity. This work provides a dual-activated "low toxic-to-toxic" transformable treatment pattern for tumor-specific chemo-photodynamic therapy.

Discovery of a Potent Glutathione Peroxidase 4 Inhibitor as a Selective Ferroptosis Inducer.

Potent and selective ferroptosis regulators promote an intensive understanding of the regulation and mechanisms underlying ferroptosis, which is highly associated with various diseases. In this study, through a stepwise structure optimization, a potent and selective ferroptosis inducer was developed targeting to inhibit glutathione peroxidase 4 (GPX4), and the structure-activity relationship (SAR) of these compounds was uncovered. Compound 26a exhibited outstanding GPX4 inhibitory activity with a percent inhibition up to 71.7% at 1.0 µM compared to 45.9% of RSL-3. At the cellular level, 26a could significantly induce lipid peroxide (LPO) increase and effectively induce ferroptosis with satisfactory selectivity (the value of 31.5). The morphological analysis confirmed the ferroptosis induced by 26a. Furthermore, 26a significantly restrained tumor growth in a mouse 4T1 xenograft model without obvious toxicity.

Phototriggered Self-Adaptive Functionalized MOC-Based Drug Delivery Platform Promises High Antitumor Efficacy.

Due to their great stability and special cavities, metal-organic cages (MOCs) are increasingly considered as promising nanocarriers for drug delivery. However, the size and surface dilemmas restrict their further biomedical applications. The ultrasmall size of MOCs facilitates tumor penetration but suffers from quick clearance and poor accumulation at the tumor site. Hydrophobicity of MOC surfaces improves internalization into tumor cells while causing low blood circulation time as well as poor biocompatibility. Therefore, it remains challenging for the MOC-based drug delivery nanoplatform to realize high therapeutic efficacy because it requires different or even opposite dimensions and surface characteristics in different steps of circulation, penetration, accumulation, and internalization processes. In this study, an unprecedented phototriggered self-adaptive platform (ZnPc@polySCage) is developed by integrating functionalized MOCs and a photodynamic therapy based reactive oxygen species responsive strategy to realize high-efficiency tumor-specific therapy. ZnPc@polySCage remains hydrophilic and stealthy during circulation, and retains its small original size for tumor penetration, while transforming to a larger size for effective accumulation and hydrophobic for enhanced internalization under laser irradiation in tumor tissue. With these essential transitions, ZnPc@polySCage demonstrates prominent antitumor effects. Overall, the work provides an advantageous strategy for functional MOC-based platforms and biomedical applications.

Reduction-responsive dehydroepiandrosterone prodrug nanoparticles loaded with camptothecin for cancer therapy by enhancing oxidation therapy and cell replication inhibition.

The pentose phosphate pathway (PPP) plays a critical role by providing ribulose-5-phosphate (Ru5P) and NADPH for nucleotide synthesis and reduction energy, respectively. Accordingly, blocking the PPP process may be an effective strategy for enhancing oxidation therapy and inhibiting cell replication. Here, we designed a novel reduction-responsive PEGylated prodrug and constructed nanoparticles PsD@CPT to simultaneously deliver a PPP blocker, dehydroepiandrosterone (DHEA), and chemotherapeutic camptothecin (CPT) to integrate amplification of oxidation therapy and enhance cell replication inhibition. Following cellular uptake, DHEA and CPT were released from PsD@CPT in the presence of high glutathione (GSH) levels. As expected, DHEA-mediated reduction level decreases and CPT-induced oxidation level increases synergistically, breaking the redox balance to aggravate cancer oxidative stress. In addition, suppressing nucleotide synthesis by DHEA through the reduction of Ru5P and blocking DNA replication by CPT further motivates a synergistic inhibition effect on tumor cell proliferation. The results showed that PsD@CPT featuring multimodal treatment has satisfactory antitumor activity both in vitro and in vivo. This study provides a new tumor treatment strategy, which combines the amplification of oxidative stress and enhancement of inhibition of cell proliferation based on inhibition of the PPP process.

Discovery of 4-Arylindolines Containing a Thiazole Moiety as Potential Antitumor Agents Inhibiting the Programmed Cell Death-1/Programmed Cell Death-Ligand 1 Interaction.

Through specific structural modification of a 4-phenylindoline precursor, new 4-arylindolines containing a thiazole moiety were developed and found to be promising modulators of the programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) axis. Compound A30 exhibited outstanding biochemical activity, with an IC50 of 11.2 nM in a homogeneous time-resolved fluorescence assay. In the cell-based assay, A30 significantly promoted IFN-γ secretion and rescued T-cell proliferation, which were inhibited by PD-1 activation. Furthermore, A30 showed favorable in vivo antitumor activity in a mouse 4T1 breast carcinoma model. Moreover, in mouse CT26 colon carcinoma models, A30 potently suppressed the growth of CT26/PD-L1 tumor but did not obviously affect the growth of CT26/vector tumor. The results of flow cytometry analysis indicated that A30 inhibited tumor growth by activating the immune microenvironment. We concluded that A30 is a new starting point for further development of PD-1/PD-L1 interaction inhibitors as antitumor agents.

[Identification of keystone predators in Haizhou Bay food web based on the revised SURF index]. / 基于改进的SURFæŒ‡æ•°ç”„é€‰æµ·å·žæ¹¾é±¼ç±»ç¾¤è½çš„å ³é”®æ•é£Ÿè€ .

Keystone predator species play an important role in regulating the number, richness and distribution of prey species. Based on the bottom trawl surveys in Haizhou Bay, keystone predator species in fish communities were identified by the revised SURF (supportive role to fishery ecosystems) index. Conger myriaster, Saurida elongata, Hexagrammos otakii, Chelidonichthys spinosus, and Larimichthys polyactis were the keystone predators in the fish community. They had high number of nodes degree, and were also the main predators of many species. Further, they had strong ability of clustering. The fluctuations of their density would have great impacts on ecosystem energy flow and food web structure. The method not only considered the feeding ratio between species, but also took the amount of catch and abundance of species as important factors in the identification of keystone predators. Compared with the traditional method, this method had great improvement and provided a new one for the identification of key predators. Our results showed that the strong inter-specific interactions played an important role in maintaining the structure and function of food webs. Protection of key predators would benefit the stability of biological communities and species diversity. Therefore, ecosystem-based fisheries management (EBFM) should give priority to the protection of key species. The important economic fish species, C. myriaster and L. polyactis, should be protected with high priority as they suffered from higher fishing pressure.

Design, synthesis and biological evaluation of new Axl kinase inhibitors containing 1,3,4-oxadiazole acetamide moiety as novel linker.

Using the principle of bioisosteric replacement, we present a structure-based design approach to obtain new Axl kinase inhibitors with significant activity at the kinase and cellular levels. Through a stepwise structure-activity relationships exploration, a series of 6,7-disubstituted quinoline derivatives, which contain 1,3,4-oxadiazol acetamide moiety as novel Linker, were ultimately synthesized with Axl as the primary target. Most of them exhibited moderate to excellent activity, with IC50 values ranging from 0.032 to 1.54 µM against the tested cell lines. Among them, the most promising compound 47e, as an Axl kinase inhibitor (IC50 = 10 nM), shows remarkable cytotoxicity against A549, HT-29, PC-3, MCF-7, H1975 and MDA-MB-231 cell lines. More importantly, 47e also shows a significant inhibitory effect on EGFR-TKI resistant NSCLC cell lines H1975/gefitinib. Meanwhile, this study provides a novel type of linker for Axl kinase inhibitors, namely 1,3,4-oxadiazol acetamide moiety, which is out of the scope of the "5- atoms role ".

Enhanced cancer therapy through synergetic photodynamic/immune checkpoint blockade mediated by a liposomal conjugate comprised of porphyrin and IDO inhibitor.

Cancer metastases is still a hurdle for good prognosis and live quality of breast cancer patients. Treatment strategies that can inhibit metastatic cancer while treating primary cancer are needed to improve the therapeutic effect of breast cancer. Methods: In this study, a dual functional drug conjugate comprised of protoporphyrin IX and NLG919, a potent indoleamine-2,3-dioxygenase (IDO) inhibitor, is designed to combine photodynamic therapy and immune checkpoint blockade to achieve both primary tumor and distant metastases inhibition. Liposomal delivery is applied to improve the biocompatibility and tumor accumulation of the drug conjugate (PpIX-NLG@Lipo). A series of in vitro and in vivo experiments were carried out to examine the PDT effect and IDO inhibition activity of PpIX-NLG@Lipo, and subsequently evaluate its anti-tumor capability in the bilateral 4T1 tumor-bearing mice. Results: The in vitro and in vivo experiments demonstrated that PpIX-NLG@Lipo possess strong ability of ROS generation to damage cancer cells directly through PDT. Meanwhile, PpIX-NLG@ Lipo can induce immunogenic cell death to elicit the host immune system. Furthermore, PpIX-NLG@Lipo interferes the activity of IDO, which can amplify PDT-induced immune responses, leading to an increasing amount of CD8+ T lymphocytes infiltrated into tumor site, finally achieve both primary and distant tumor inhibition. Conclusion: This work presents a novel conjugate approach to synergize photodynamic therapy and IDO blockade for enhanced cancer therapy through simultaneously inhibiting both primary and distant metastatic tumor.

Design, synthesis, and biological evaluation of novel substituted benzamide derivatives bearing a 1,2,3-triazole moiety as potent human dihydroorotate dehydrogenase inhibitors.

A novel series of substituted benzamide derivatives bearing a 1,2,3-triazole moiety were designed and synthesized by click chemistry. Human dihydroorotate dehydrogenase inhibition assay was used to evaluate the synthesized compounds as potent hDHODH inhibitors. Most compounds showed moderate to significant potency, accompanied with a suitable clogD7.4 value and compounds 4d, 4o, and 5j effectively inhibited the activity of hDHODH with IC50 values of 2.1, 2.1 and 1.5 µM, respectively. Compound 4o also effectively suppressed proliferation of the activated PBMCs. The study of structure-activity relationships also revealed that a suitable substitution on para-position of terminal phenyl ring was crucial for high activity. Together, the most promising compound 4o might serve as a novel hDHODH inhibitors for further investigation.