Tuning Fe3O4 for sustainable cathodic heterogeneous electro-Fenton catalysis by acetylated chitosan.

Peroxidase-like catalysts are safe and low-cost candidates to tackle the dilemma in constructing sustainable cathodic heterogeneous electro-Fenton (CHEF) catalysts for water purification, but the elusive structure-property relationship of enzyme-like catalysts constitutes a pressing challenge for the advancement of CHEF processes in practically relevant water and wastewater treatment. Herein, we probe the origins of catalytic efficiency in the CHEF process by artificially tailoring the peroxidase-like activity of Fe3O4 through a series of acetylated chitosan-based hydrogels, which serve as ecofriendly alternatives to traditional carbon shells. The optimized acetylated chitosan wrapping Fe3O4 hydrogel on the cathode shows an impressive activity and stability in CHEF process, overcoming the complicated and environmentally unfavored procedures in the electro-Fenton-related processes. Structural characterizations and theoretical calculations reveal that the amide group in chitosan can modulate the intrinsic redox capacity of surficial Fe sites on Fe3O4 toward CHEF catalysis via the neutral hydrogen bond. This work provides a sustainable path and molecule-level insight for the rational design of high-efficiency CHEF catalysts and beyond.

Genomic Anatomy of Homozygous XX Females and YY Males Reveals Early Evolutionary Trajectory of Sex-determining Gene and Sex Chromosomes in Silurus Fishes.

Sex chromosomes display remarkable diversity and variability among vertebrates. Compared with research on the X/Y and Z/W chromosomes, which have long evolutionary histories in mammals and birds, studies on the sex chromosomes at early evolutionary stages are limited. Here, we precisely assembled the genomes of homozygous XX female and YY male Lanzhou catfish (Silurus lanzhouensis) derived from an artificial gynogenetic family and a self-fertilized family, respectively. Chromosome 24 (Chr24) was identified as the sex chromosome based on resequencing data. Comparative analysis of the X and Y chromosomes showed an approximate 320 kb Y-specific region with a Y-specific duplicate of anti-Mullerian hormone type II receptor (amhr2y), which is consistent with findings in 2 other Silurus species but on different chromosomes (Chr24 of Silurus meridionalis and Chr5 of Silurus asotus). Deficiency of amhr2y resulted in male-to-female sex reversal, indicating that amhr2y plays a male-determining role in S. lanzhouensis. Phylogenetic analysis and comparative genomics revealed that the common sex-determining gene amhr2y was initially translocated to Chr24 of the Silurus ancestor along with the expansion of transposable elements. Chr24 was maintained as the sex chromosome in S. meridionalis and S. lanzhouensis, whereas a sex-determining region transition triggered sex chromosome turnover from Chr24 to Chr5 in S. asotus. Additionally, gene duplication, translocation, and degeneration were observed in the Y-specific regions of Silurus species. These findings present a clear case for the early evolutionary trajectory of sex chromosomes, including sex-determining gene origin, repeat sequence expansion, gene gathering and degeneration in sex-determining region, and sex chromosome turnover.

UBC9-mediated SUMOylation of Lamin B1 enhances DNA-damage-induced nuclear DNA leakage and autophagy after spinal cord injury.

Recent studies have shown that nucleophagy can mitigate DNA damage by selectively degrading nuclear components protruding from the nucleus. However, little is known about the role of nucleophagy in neurons after spinal cord injury (SCI). Western blot analysis and immunofluorescence were performed to evaluate the nucleophagy after nuclear DNA damage and leakage in SCI neurons in vivo and NSC34 expression in primary neurons cultured with oxygen-glucose deprivation (OGD) in vitro, as well as the interaction and colocalization of autophagy protein LC3 with nuclear lamina protein Lamin B1. The effect of UBC9, a Small ubiquitin-related modifier (SUMO) E2 ligase, on Lamin B1 SUMOylation and nucleophagy was examined by siRNA transfection or 2-D08 (a small-molecule inhibitor of UBC9), immunoprecipitation, and immunofluorescence. In SCI and OGD injured NSC34 or primary cultured neurons, neuronal nuclear DNA damage induced the SUMOylation of Lamin B1, which was required by the nuclear Lamina accumulation of UBC9. Furthermore, LC3/Atg8, an autophagy-related protein, directly bound to SUMOylated Lamin B1, and delivered Lamin B1 to the lysosome. Knockdown or suppression of UBC9 with siRNA or 2-D08 inhibited SUMOylation of Lamin B1 and subsequent nucleophagy and protected against neuronal death. Upon neuronal DNA damage and leakage after SCI, SUMOylation of Lamin B1 is induced by nuclear Lamina accumulation of UBC9. Furthermore, it promotes LC3-Lamin B1 interaction to trigger nucleophagy that protects against neuronal DNA damage.

Interleukin-17A educated hepatic stellate cells promote hepatocellular carcinoma occurrence through fibroblast activation protein expression.

BACKGROUND: Liver cancer is typified by a complex inflammatory tumor microenvironment, where an array of cytokines and stromal cells orchestrate a milieu that significantly influences tumorigenesis. Interleukin-17A (IL-17A), a pivotal pro-inflammatory cytokine predominantly secreted by Th17 cells, is known to play a substantial role in the etiology and progression of liver cancer. However, the precise mechanism by which IL-17A engages with hepatic stellate cells (HSCs) to facilitate the development of hepatocellular carcinoma (HCC) remains to be fully elucidated. This investigation seeks to unravel the interplay between IL-17A and HSCs in the context of HCC. METHODS: An HCC model was established in male Sprague-Dawley rats using diethylnitrosamine to explore the roles of IL-17A and HSCs in HCC pathogenesis. In vivo overexpression of Il17a was achieved using adeno-associated virus. A suite of molecular techniques, including RT-qPCR, enzyme-linked immunosorbent assays, Western blotting, cell counting kit-8 assays and colony formation assays, was employed for in vitro analyses. RESULTS: The study findings indicate that IL-17A is a key mediator in HCC promotion, primarily through the activation of hepatic progenitor cells (HPCs). This pro-tumorigenic influence appears to be mediated by HSCs, rather than through a direct effect on HPCs. Notably, IL-17A-induced expression of fibroblast activation protein (FAP) in HSCs emerged as a critical factor in HCC progression. Silencing Fap in IL-17A-stimulated HSCs was observed to reverse the HCC-promoting effects of HSCs. CONCLUSIONS: The collective evidence from this study implicates the IL-17A/FAP signaling axis within HSCs as a contributor to HCC development by enhancing HPC activation. These findings bolster the potential of IL-17A as a diagnostic and preventative target for HCC, offering new avenues for therapeutic intervention.

A Review of Metal-Organic Frameworks Derived Hollow-Structured Photocatalysts: Synthesis and Applications.

Photocatalysis is a most important approach to addressing global energy shortages and environmental issues due to its environmentally friendly and sustainable properties. The key to realizing efficient photocatalysis relies on developing appropriate catalysts with high efficiency and chemical stability. Among various photocatalysts, Metal-organic frameworks (MOFs)-derived hollow-structured materials have drawn increased attention in photocatalysis based on advantages like more active sites, strong light absorption, efficient transfer of pho-induced charges, excellent stability, high electrical conductivity, and better biocompatibility. Specifically, MOFs-derived hollow-structured materials are widely utilized in photocatalytic CO2 reduction (CO2RR), hydrogen evolution (HER), nitrogen fixation (NRR), degradation, and other reactions. This review starts with the development story of MOFs, the commonly adopted synthesis strategies of MOFs-derived hollow materials, and the latest research progress in various photocatalytic applications are also introduced in detail. Ultimately, the challenges of MOFs-derived hollow-structured materials in practical photocatalytic applications are also prospected. This review holds great potential for developing more applicable and efficient MOFs-derived hollow-structured photocatalysts.

Azaphilone pigments from the marine-derived Penicillium sclerotium UJNMF 0503 and their neuroprotective potential against H2O2-induced cell apoptosis through modulating PI3K/Akt pathway.

Azaphilones represent a particular group of fascinating pigments from fungal source, with easier industrialization and lower cost than the traditional plant-derived pigments, and they also display a wide range of pharmacological activities. Herein, 28 azaphilone analogs, including 12 new ones, were obtained from the fermentation culture of a marine fungus Penicillium sclerotium UJNMF 0503. Their structures were elucidated by MS, NMR and ECD analyses, together with NMR and ECD calculations and biogenetic considerations. Among them, compounds 1 and 2 feature an unusual natural benzo[d][1,3]dioxepine ring embedded with an orthoformate unit, while 3 and 4 represent the first azaphilone examples incorporating a novel rearranged 5/6 bicyclic core and a tetrahydropyran ring on the side chain, respectively. Our bioassays revealed that half of the isolates exhibited neuroprotective potential against H2O2-induced injury on RSC96 cells, while compound 13 displayed the best rescuing capacity toward the cell viability by blocking cellular apoptosis, which was likely achieved by upregulating the PI3K/Akt signaling pathway.

Longitudinal and time-to-event modeling for the survival of advanced pancreatic ductal adenocarcinoma patients.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers especially at advanced stage. In order to analyze the dynamics of potential prognostic biomarkers and further quantify their relationships with the overall survival (OS) of advanced PDAC patients, we herein developed a parametric time-to-event (TTE) model integrated with longitudinal submodels. Data from 104 patients receiving standard chemotherapies were retrospectively collected for model development, and other 54 patients were enrolled as external validation. The longitudinal submodels were developed with the time-course data of sum of longest diameters (SLD) of tumors, serum albumin (ALB) and body weight (BW) using nonlinear mixed effect models. The model-derived metrics including model parameters and individual predictions at different time points were further analyzed in the TTE model, together with other baseline information of patients. A linear growth-exponential shrinkage model was employed to describe the dynamics of SLD, while logistic models were used to fit the relationship of time prior to death with ALB and BW. The TTE model estimated the ALB and BW changes at the 9th week after chemotherapies as well as the baseline CA19-9 level that showed most significant impact on the OS, and the model-based simulations could provide individual survival rate predictions for patients with different prognostic factors. This study quantitatively demonstrates the importance of physical status and baseline disease for the OS of advanced PDAC patients, and highlights that timely nutrition support would be helpful to improve the prognosis.

APP mediates tau uptake and its overexpression leads to the exacerbated tau pathology.

Alzheimer's disease (AD), as the most common type of dementia, has two pathological hallmarks, extracellular senile plaques composed of ß-amyloid peptides and intracellular neurofibrillary tangles containing phosphorylated-tau protein. Amyloid precursor protein (APP) and tau each play central roles in AD, although how APP and tau interact and synergize in the disease process is largely unknown. Here, we showed that soluble tau interacts with the N-terminal of APP in vitro in cell-free and cell culture systems, which can be further confirmed in vivo in the brain of 3XTg-AD mouse. In addition, APP is involved in the cellular uptake of tau through endocytosis. APP knockdown or N-terminal APP-specific antagonist 6KApoEp can prevent tau uptake in vitro, resulting in an extracellular tau accumulation in cultured neuronal cells. Interestingly, in APP/PS1 transgenic mouse brain, the overexpression of APP exacerbated tau propagation. Moreover, in the human tau transgenic mouse brain, overexpression of APP promotes tau phosphorylation, which is significantly remediated by 6KapoEp. All these results demonstrate the important role of APP in the tauopathy of AD. Targeting the pathological interaction of N-terminal APP with tau may provide an important therapeutic strategy for AD.

Four Tremulanes and Two Pyroglutamate-Containing Dipeptides from the Mangrove Endophytic Fungus Phaeosphaeriopsis sp. P11.

Four new tremulane sesquiterpenes, named phaeosphaerienols A-D (1-4), and two new pyroglutamate-containing dipeptides, named phaeosphaeratides A-B (5-6), were isolated from the mangrove endophytic fungus Phaeosphaeriopsis sp. P11, together with a new 2-furancarboxylic acid derivative (7). Structurally, pheaosphaerienols A-C (1-3) are rare tremulanes containing a 1,10-epoxide moiety. The structures of these compounds were established by extensive NMR spectroscopic data, single-crystal X-ray diffraction analysis, and Marfey's derivatization method. All the isolates were evaluated for their cytotoxic, antibacterial, and DPPH free radical scavenging effects. However, none of the compounds exhibited obvious activities.

Anti-inflammatory Polyketides from an Endophytic Fungus Chaetomium sp. UJN-EF006 of Vaccinium bracteatum.

Seven new polyketides including three chromone derivatives (1-3) and four linear ones incorporating a tetrahydrofuran ring (4-7), along with three known compounds (8-10), were obtained from the fermentation of an endophytic fungus (Chaetomium sp. UJN-EF006) isolated from the leaves of Vaccinium bracteatum. The structures of these fungal metabolites have been elucidated by spectroscopic means including MS, NMR and electronic circular dichroism. A preliminary anti-inflammatory screening with the lipopolysaccharide (LPS) induced RAW264.7 cell model revealed moderate NO production inhibitory activity for compounds 1 and 4. In addition, the expression of three LPS-induced inflammatory factors IL-6, iNOS and COX-2 was also blocked by 1 and 4.

Bioactive neolignan, iridoid and flavonoid glycosides from the leaves of Vaccinium bracteatum.

Two neolignan glycosides including a new one (1), along with seven iridoid glycosides (3 - 9) and nine flavonoid glycosides (10 - 18), were isolated from the leaves of Vaccinium bracteatum. Their structures were established mainly on the basis of 1D/2D NMR and ESIMS analyses, as well as comparison to known compounds in the literature. The structure of 1 with absolute stereochemistry was also confirmed by chemical degradation and ECD calculation. Selective compounds showed antiradical activity against ABTS and/or DPPH. Moreover, several isolates also suppressed the production of ROS in RAW264.7 cells and exerted neuroprotective effect toward PC12 cells.

[Expressions of zinc homeostasis proteins, GPR39 and ANO1 mRNA in the sperm of asthenozoospermia patients and their clinical significance].

OBJECTIVE: To explore the expressions of zinc homeostasis-related proteins, G protein-coupled receptor 39 (GPR39) and ANO1 mRNA in the sperm of patients with asthenozoospermia (AS), and analyze their correlation with sperm motility. METHODS: We collected semen samples from 82 male subjects with PR+NP < 40%, PR < 32% and sperm concentration > 15×106/ml (the AS group, n = 40) or PR+NP ≥ 40%, PR ≥ 32% and sperm concentration > 15×106/ml (the normal control group, n = 42). We analyzed the routine semen parameters and measured the zinc content in the seminal plasma using the computer-assisted sperm analysis system, detected the expressions of zinc transporters (ZIP13, ZIP8 and ZNT10), metallothioneins (MT1G, MT1 and MTF), GPR39, and calcium-dependent chloride channel protein (ANO1) in the sperm by real-time quantitative PCR (RT qPCR), examined free zinc distribution in the sperm by laser confocal microscopy, and determined the expressions of GPR39 and MT1 proteins in the sperm by immunofluorescence staining, followed by Spearman rank correlation analysis of their correlation with semen parameters. RESULTS: There was no statistically significant difference in the zinc concentration in the seminal plasma between the AS and normal control groups (P>0.05). Compared with the controls, the AS patients showed a significantly reduced free zinc level (P<0.05), relative expressions of MT1G, MTF, ZIP13, GPR39 and ANO1 mRNA (P<0.05), and that of the GPR39 protein in the AS group (P<0.05). No statistically significant differences were observed in the relative expression levels of ZIP8, ZNT10 and MT1 mRNA between the two groups (P>0.05). The relative expression levels of GPR39, ANO1, MT1G and MTF mRNA were positively correlated with sperm motility and the percentage of progressively motile sperm (P<0.05). CONCLUSION: The expressions of zinc homeostasis proteins (MT1G, MTF and ZIP13), GPR39 and ANO1 mRNA are downregulated in the sperm of asthenozoospermia patients, and positively correlated with sperm motility.

Precisely Tuning Band Gaps of Hexabenzocoronene-Based MOFs Toward Enhanced Photocatalysis.

Precise adjusting the band gaps in metal-organic frameworks (MOFs) is crucial for improving their visible-light absorption capacity during photocatalysis, presenting both a formidable challenge and a charming opportunity. This present study employed a symmetry-reduction strategy to pre-design six novel 4-connected ligands with systematic substituents (-NO2, -H, -tBu, -OCH3, -OH and -NH2) and synthesized the corresponding pillared-layer Zr-MOFs (NKM-668) retaining the hexaphenylbenzene fragment. Subsequently, the NKM-668 MOFs were transformed into large-π-conjugated hexabenzocoronene-based MOFs (pNKM-668) via the Scholl reaction. These twelve MOFs exhibited broad and tunable band gaps over 1.41 eV (ranging from 3.25 eV to 1.84 eV), and the photocatalytic CO2 conversion rate raised by 33.2-fold. This study not only enriches the type of hexaphenylbenzene-based MOFs, but also paves the way for nanographene-containing MOFs in the further application of photocatalysis.

Dynamic Bond-Directed Synthesis of Stable Mesoporous Metal-Organic Frameworks under Room Temperature.

Stable metal-organic frameworks (MOFs) with mesopores (2-50 nm) are promising platforms for immobilizing nanosized functional compounds, such as metal-oxo clusters, metal-sulfide quantum dots, and coordination complexes. However, these species easily decompose under acidic conditions or high temperatures, hindering their in situ encapsulation in stable MOFs, which are usually synthesized under harsh conditions involving excess acid modulators and high temperatures. Herein, we report a route for the room-temperature and acid-modulator-free synthesis of stable mesoporous MOFs and MOF catalysts with acid-sensitive species encapsulated: (1) we initially construct a MOF template by connecting stable Zr6 clusters with labile Cu-bipyridyl moieties; (2) Cu-bipyridyl moieties are subsequently exchanged by organic linkers to afford a stable version of Zr-MOFs; (3) acid-sensitive species, including polyoxometalates (POMs), CdSeS/ZnS quantum dots, and Cu-coordination cages, can be encapsulated in situ into the MOFs during step 1. The room-temperature synthesis allows the isolation of mesoporous MOFs with 8-connected Zr6 clusters and reo topology as kinetic products, which are inaccessible by traditional solvothermal synthesis. Furthermore, acid-sensitive species remain stable, active, and locked within the frameworks during MOF synthesis. We observed high catalytic activity for VX degradation by the POM@Zr-MOF catalysts as a result of the synergy between redox-active POMs and Lewis-acidic Zr sites. The dynamic bond-directed method will accelerate the discovery of large-pore stable MOFs and offer a mild route to avoid the decomposition of catalysts during MOF synthesis.

Monitoring the Activation of Open Metal Sites in [FexM3-x(µ3-O)] Cluster-Based Metal-Organic Frameworks by Single-Crystal X-ray Diffraction.

While trinuclear [FexM3-x(µ3-O)] cluster-based metal-organic frameworks (MOFs) have found wide applications in gas storage and catalysis, it is still challenging to identify the structure of open metal sites obtained through proper activations and understand their influence on the adsorption and catalytic properties. Herein, we use in situ variable-temperature single-crystal X-ray diffraction to monitor the structural evolution of [FexM3-x(µ3-O)]-based MOFs (PCN-250, M = Ni2+, Co2+, Zn2+, Mg2+) upon thermal activation and provide the snapshots of metal sites at different temperatures. The exposure of open Fe3+ sites was observed along with the transformation of Fe3+ coordination geometries from octahedron to square pyramid. Furthermore, the effect of divalent metals in heterometallic PCN-250 was studied for the purpose of reducing the activation temperature and increasing the number of open metal sites. The metal site structures were corroborated by X-ray absorption and infrared spectroscopy. These results will not only guide the pretreatment of [FexM3-x(µ3-O)]-based MOFs but also corroborate spectral and computational studies on these materials.

Synergistic effect of kanamycin and amikacin with setomimycin on biofilm formation inhibition of Listeria monocytogenes.

Listeria monocytogenes, a foodborne pathogen that causes listeriosis with high fatality rate, exhibits multidrug resistance (MDR) known to be progressively increasing. Alternative antibacterial strategies are in high demand for treating this well-known pathogen. Anti-biofilm and anti-virulence strategies are being explored as novel approaches to treat bacterial infections. In this study, one rare antibacterial named setomimycin was isolated from Streptomyces cyaneochromogenes, which showed potent antibacterial activity against L. monocytogenes. Next, the inhibition of biofilm formation and listeriolysin O (LLO) production against L. monocytogenes were investigated at sub-minimal inhibitory concentrations (sub-MICs) of setomimycin alone or combined with kanamycin and amikacin. Crystal violet staining confirmed that setomimycin combining with kanamycin or amikacin could dramatically reduce biofilm formation against L. monocytogenes at sub-MICs, which was further evaluated by scanning electron microscopy (SEM) and confocal laser scanning microscopy (CLSM). In the meantime, sub-MICs of setomimycin could significantly suppress the secretion of LLO. Furthermore, the transcription of genes associated with biofilms and main virulence factors, such as LLO, flagellum, and metalloprotease, were suppressed by setomimycin at sub-MICs. Hence, the study provided a deep insight into setomimycin as an alternative antibacterial agent against L. monocytogenes.

An integrated PK/PD model investigating the impact of tumor size and systemic safety on animal survival in SW1990 pancreatic cancer xenograft.

Survival is one of the most important endpoints in cancer therapy, and parametric survival analysis could comprehensively reveal the overall result of disease progression, drug efficacy, toxicity as well as their interactions. In this study we investigated the efficacy and toxicity of dexamethasone (DEX) combined with gemcitabine (GEM) in pancreatic cancer xenograft. Nude mice bearing SW1990 pancreatic cancer cells derived tumor were treated with DEX (4 mg/kg, i.g.) and GEM (15 mg/kg, i.v.) alone or in combination repeatedly (QD, Q3D, Q7D) until the death of animal or the end of study. Tumor volumes and net body weight (NBW) were assessed every other day. Taking NBW as a systemic safety indicator, an integrated pharmacokinetic/pharmacodynamic (PK/PD) model was developed to quantitatively describe the impact of tumor size and systemic safety on animal survival. The PK/PD models with time course data for tumor size and NBW were established, respectively, in a sequential manner; a parametric time-to-event (TTE) model was also developed based on the longitudinal PK/PD models to describe the survival results of the SW1990 tumor-bearing mice. These models were evaluated and externally validated. Only the mice with good tumor growth inhibition and relatively stable NBW had an improved survival result after DEX and GEM combination therapy, and the simulations based on the parametric TTE model showed that NBW played more important role in animals' survival compared with tumor size. The established model in this study demonstrates that tumor size was not always the most important reason for cancer-related death, and parametric survival analysis together with safety issues was also important in the evaluation of oncology therapies in preclinical studies.

Combining network pharmacology and experimental verification to reveal the mechanism of Chaigui granules in the treatment of depression through PI3K/Akt/mTOR signaling pathways.

INTRODUCTION: Chaigui granules are a novel manufactured traditional Chinese antidepressant medicine, which is originated from the ancient classical prescription of Xiaoyaosan. It ameliorated depression-like behavior and concomitant symptoms in animal models. But its antidepressant mechanism is still unclear. Therefore, network pharmacology and molecular biology were used to explore underlying antidepressant mechanism in this study. METHODS: Firstly, network pharmacology was used to screen main active ingredients and potential targets in the treatment of depression with Chaigui granules, and to perform pathway enrichment analysis. Secondly, chronic and unpredictable mild stress-induced depression model rats were used, and behavioral tests were used to evaluate the antidepressant effect of Chaigui granules. Finally, the core targets and key pathways predicted by network pharmacology were validated by qRT-PCR and Western blot to determine the relevant gene and protein expression levels in rat hippocampus. RESULTS: The results of network pharmacology indicated that the PI3K/Akt signaling pathway may play a key role in antidepressant of Chaigui granules. The results of animal experiments showed that Chaigui granules significantly modulated behavioral indicators. Subsequently, the upregulation of relative mRNA levels of mTOR, Akt and PI3K and downregulation of GSK-3ß and FoxO3a were observed in rat hippocampus by molecular biology diagnosis. In addition, the decreased expression of Akt and mTOR in CUMS rats hippocampus was significantly reversed, and the expression levels of GSK-3ß and FoxO3a were upregulated. CONCLUSIONS: Based on the results of network pharmacology and animal experiment validation, Chaigui granules may reverse CUMS-induced depression-like behavior in rats through PI3K/Akt/mTOR signaling pathway.

Indole Diterpenes from Mangrove Sediment-Derived Fungus Penicillium sp. UJNMF0740 Protect PC12 Cells against 6-OHDA-Induced Neurotoxicity via Regulating the PI3K/Akt Pathway.

In our chemical investigation into Penicillium sp. UJNMF0740 derived from mangrove sediment, fourteen indole diterpene analogs, including four new ones, are purified by multiple chromatographic separation methods, with their structures being elucidated by the analyses of NMR, HR-ESIMS, and ECD data. The antibacterial and neuroprotective effects of these isolates were examined, and only compounds 6 and 9 exhibited weak antibacterial activity, while compounds 5, 8, and 10 showed protective effects against the injury of PC12 cells induced by 6-hydroxydopamine (6-OHDA). Additionally, compound 5 could suppress the apoptosis and production of reactive oxygen species (ROS) in 6-OHDA-stimulated PC12 cells as well as trigger the phosphorylation of PI3K and Akt. Taken together, our work enriches the structural diversity of indole diterpenes and hints that compounds of this skeleton can repress the 6-OHDA-induced apoptosis of PC12 cells via regulating the PI3K/Akt signaling pathway, which provides evidence for the future utilization of this fascinating class of molecules as potential neuroprotective agents.

Stable Isotope-Resolved Metabolomics Studies on Corticosteroid-Induced PC12 Cells: A Strategy for Evaluating Glucose Catabolism in an in Vitro Model of Depression.

Depression is a common psychopathological state or mood disorder syndrome. The serious risks to human life and the inadequacy of the existing antidepressant drugs have driven us to understand the pathogenesis of depression from a new perspective. Our research group has found disturbances in glucose catabolism in both depression and nephrotic syndrome. What are the specific metabolic pathways and specificities of glucose catabolism disorders caused by depression? To address the above scientific questions, we creatively combined traditional metabolomics technology with stable isotope-resolved metabolomics to research the glucose catabolism of the corticosterone-induced PC12 cell damage model and the adriamycin-induced glomerular podocyte damage model. The results showed an increased flux of pyruvate metabolism in depression. The increased flux of pyruvate metabolism led to an activation of gluconeogenesis in depression. The disturbed upstream metabolism of succinate caused the tricarboxylic acid cycle (TCA cycle) to be blocked in depression. In addition, there were metabolic disturbances in the purine metabolism and pentose phosphate pathways in depression. Compared with nephrotic syndrome, pyruvate metabolism, the TCA cycle, and gluconeogenesis metabolism in depression were specific. The metabolic pathways researched above are likely to be important targets for the efficacy of antidepressants.