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Abstract Zinc (Zn) is an essential trace element that modulate innate and acquired immune responses, and its deficiency triggers lymphopenia. However, the precise mechanisms underlying zinc-mediated lymphocyte maintenance have not been well clarified. Here, we have successfully generated a zip6 -null mutant zebrafish line using TALENs. The Zip6 -null mutant zebrafish developed normally during gastrulation. Loss of zip6 in zebrafish resulted in significant T lymphocyte reduction and a decrease in intracellular Zn levels. And the zip6 deficiency increases caspase-related cell apoptosis in both zebrafish cells and human T cells. Our results suggest that ZIP6 plays a critical part in T cell development, and enhance our understanding of Zn homeostasis and immune system maintenance. Highlights • Generate a zip6 -null mutant zebrafish line using TALENs. • Loss of zip6 in zebrafish results in significant T lymphocyte reduction. • Zip6 deficiency increases caspase-related cell apoptosis. [ABSTRACT FROM AUTHOR]

An effective method for the selection of active compounds from cranberry based on counter-current fractionation and bioassay-guided separation was established. Cranberry extract showed potential α-glucosidase inhibitory activity. The active compounds were extracted by different solvents and enriched in water. The water extract was divided into eight fractions via high-speed counter-current chromatography to further track the active compounds. Results indicated that the α-glucosidase inhibitory activity of F7 was remarkable higher than the other fractions. Four compounds, including delphinidin-3-glucoside (D3G), cyanidin-3-glucoside, cyanidin-3-rutinoside, and pelargonidin-3-glucoside, were separated from F7 through column chromatography, and their structures were identified by high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry, 1H nuclear magnetic resonance (NMR), and 13C NMR. D3G showed the strongest α-glucosidase inhibitory activity among the compounds. Moreover, the interaction mechanism between α-glucosidase and D3G was clearly characterized and described by spectroscopic analyses and molecular docking. D3G could spontaneously bind with α-glucosidase to form complexes through hydrophobic interaction. The secondary structure of α-glucosidase changed in varying degrees after complexation with D3G. The α-helix and β-turn contents of α-glucosidase markedly decreased, whereas the irregular coil increased. These findings provide a new insight into the interaction between α-glucosidase and D3G. • Counter-current fractionation assisted bioassay-guided separation. • Four compoundswere separated from cranberry. • Delphinidin-3-glucoside (D3G) showed the strongest α-glucosidase inhibitory activity. • Interaction between α-glucosidase and D3G was studied. • Spectroscopy and molecular docking explored the interaction mechanism. [ABSTRACT FROM AUTHOR]

Flupyradifurone (FLU) has great application potential in agricultural production as a new generation of neonicotinoid insecticide after imidacloprid. Nevertheless, the toxic effects of FLU on non-target soil organisms remain unclear, resulting in considerable environmental risks. We evaluated the acute and subchronic toxicities of FLU to earthworms. The results of acute toxicity show that the median lethal concentration (LC 50) values (14 d) of FLU were 186.9773 mg kg−1 for adult earthworms and 157.6502 mg kg−1 for juveniles, respectively. The subchronic toxicity of FLU that focused on the activities of antioxidant and detoxication enzymes showed the superoxide dismutase (SOD), catalase (CAT), and glutathione-S transferase (GST) activities in earthworms increased while the peroxidase (POD) and acetylcholinesterase (AChE) activities decreased after exposure to FLU. Oxidative damage analyses revealed that the reactive oxygen species (ROS) level and malonaldehyde (MDA) content in earthworms were increased by FLU, resulting in DNA damage. Transcriptomics and RT-qPCR confirmed that FLU influenced the expression of genes related to antioxidant response and detoxification of earthworms. Ultimately detoxification metabolism, environmental information processing, cell processes, and immune system pathways are significantly enriched to respond jointly to FLU. Our study fills the gaps in the toxicity of FLU to earthworms, providing a basis for its risk assessment of soil ecosystems and non-target biological toxicity. [Display omitted] • Flupyradifurone (FLU) was low toxic to adult and juvenile earthworms from LC 50. • FLU led to oxidative stress, lipid and DNA damage to adult earthworms. • Transcriptomics revealed oxidative stress and detoxification mechanisms in earthworms. • Integrated biomarker response indicated FLU toxicity had dose and time effects. [ABSTRACT FROM AUTHOR]

[Display omitted] • Novel GNA derivatives were synthesized and screened for their antitumor activities. • Introduction of sulfoximines increased the antitumor activity of GNA derivatives. • 12 k with CF 3 group displayed the most pronounced anti-cancer efficacy. • 12 k triggered pyroptosis in cancer cells via the caspase-3/GSDME pathway. Gambogenic acid (GNA), a caged xanthone derived from Garcinia hanburyi , exhibits a wide range of anti-cancer properties. The caged skeleton of GNA serves as the fundamental pharmacophore responsible for its antitumor effects. However, limited exploration has focused on the structural modifications of GNA. This study endeavors to diversify the structure of GNA and enhance its anti-cancer efficacy. Sulfoximines, recognized as pivotal motifs in medicinal chemistry due to their outstanding properties, have featured in several anti-cancer drugs undergoing clinical trials. Accordingly, a series of 33 GNA derivatives combined with sulfoximines were synthesized and evaluated for their anti-cancer effects against MIAPaCa2, MDA-MB-231, and A549 cells in vitro. The activity screening led to the identification of compound 12 k , which exhibited the most potent anti-cancer effect. Mechanistic studies revealed that 12 k primarily induced pyroptosis in MIAPaCa2 and MDA-MB-231 cells by activating the caspase-3/gasdermin E (GSDME) pathway. These findings suggested that 12 k is a promising drug candidate in cancer therapy and highlighted the potential of sulfoximines as a valuable functional group in drug discovery. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) is a heterogeneous clonal hematopoietic malignancy with poor survival and frequent relapse. Recently, a posttranslational modification of proteins with small ubiquitin-like modifiers (SUMO) has been notably implicated in a wide spectrum of diseases, especially cancers. Ubc9, as the sole E2-conjugating enzyme in SUMOylation cascade, particularly has been associated with adverse clinical outcomes. 2-D08, a small molecular agent, functions by blocking the transfer of SUMO from the Ubc9 thioester to SUMO substrates without any effects on other individual steps in this process. However, both the effects and mechanisms of 2-D08 on AML cells are still unknown. In this study, we found that 2-D08 significantly suppressed cell viability and colony formation ability. Additionally, it induced mitochondrial-mediated apoptosis with dramatic accumulation of the reactive oxygen species (ROS), which could be almost completely rescued by the ROS scavenger N -acetylcysteine (NAC). Furthermore, we confirmed that the fatal accumulation of ROS was due to its aberrant generation instead of defective scavenging. In summary, our results suggest that 2-D08, as a specific SUMOylation inhibitor, induces ROS accumulation-mediated intrinsic apoptosis of AML cells possibly through deSUMOylation of NOX2. Therefore, 2-D08 might be a promising therapeutic agent for the treatment of AML in the future. Image 1 • 2-D08 inhibits the cell viability, colony formation ability and provokes apoptosis of AML cells. • 2-D08 induces the mitochondria-mediated apoptosis in AML cells. • Aberrant accumulation of ROS is required for 2-D08 induced apoptosis in AML cells. • NADPH oxidases up-regulation and NOX2 deSUMOylation might be key events in 2-D08 induced ROS accumulation in AML cells. [ABSTRACT FROM AUTHOR]

[Display omitted] • Total synthesis and structural elucidation of several PPAPs were achieved. • The biogenetic pathway of garcinol and its analogues was proposed. • The cytotoxicity was evaluated and the SARs were summarized. • The mechanism to induce apoptosis in BxPC3 cells was investigated. • Garcinol was found to induce pyroptosis and apoptosis simultaneously. Garcinol is a polyisoprenylated benzophenone isolated from Garcinia. It has been reported to have a variety of intriguing biological effects, including anticancer, anti-inflammatory, and antioxidant capabilities. The purpose of this research is to thoroughly evaluate garcinol and a series of its analogues in terms of synthesis, structural diversity, biosynthesis, and potential for preventing carcinoma cell proliferation. Garcinopicrobenzophenone and eugeniaphenone, which contain a unique cyclobutyl unit at C-5, were initially synthesized using the procedures utilized in the synthesis of garcinol. All the natural analogs of garcinol were produced at completion of the synthesis, and their structures and absolute configurations were clarified. Based on the synthesis, a possible biogenetic synthesis pathway towards cambogin, 13,14-didehydroxyisogarcinol via O -cyclization, and garcinopicrobenzophenone or eugeniaphenone via C -cyclization was proposed. The cytotoxicity of polyisoprenylated benzophenones produced in our group was tested, and the structure–activity relationship was summarized. The mechanism by which garcinol, cambogin, and 21′ induce apoptosis was studied. Cambogin and 21′ were shown to have a greater capacity to cause apoptosis in pancreatic cancer BXPC3 cells, and the suppression of BXPC3 cells by 21′ might be attributed to the target of STAT3 signaling. Garcinol could cause pyroptosis and apoptosis in pancreatic cancer cells at the same time, which was the first time that garcinol was identified as a possible chemotherapeutic agent that could significantly promote pyroptosis in cancer cells. [ABSTRACT FROM AUTHOR]

Ultrasound assisted aqueous two-phase extraction of polysaccharides from Lilium lancifolium Thunb was modeled by response surface methodology (RSM) and artificial neural network (ANN), and optimized using genetic algorithm coupled with ANN (GA-ANN). Statistical analysis showed that the models obtained by RSM and ANN could accurately predict the Lilium lancifolium Thunb polysaccharides (LLPs) yield. However, ANN prediction was more accurate than RSM. The optimum extraction parameters to achieve the highest LLPs yield (15.17 ± 0.21)% was obtained at the ultrasound power of 250 W, extraction temperature of 63 °C, liquid-to-solid ratio of 21 mL/g, and extraction time of 32 min. Subsequently, the crude LLPs were further purified via DEAE-52 and Sephadex G-100 chromatography to obtain a homogenous fraction (LLPs-2-SG, 421.41 kDa) that contained mannose, glucose, and galactose in a molar ratio of 10.52:23.06:7.19. The structure of LLPs-2-SG was characterized with UV–vis, FT–IR, AFM, and SEM. The findings provide a critical method for the extraction, separation and purification of polysaccharides from natural resources. • Ultrasound assisted aqueous two-phase extraction was proposed to extract LLT polysaccharides. • RSM and ANN were modeled to predict the LLPs yield. • GA-ANN was used to optimize extraction process for obtaining the maximum LLPs yield. • LLPs-2-SG contains three monosaccharides and does not contain a triple helix structure. [ABSTRACT FROM AUTHOR]