Reductive Dimerization of Alkenes and Allenes Enabled by Photochemically Activated Zinc-Zinc Bonded Compounds.

Metal radicals have shown versatile reactivity in modern synthetic chemistry. However, the use of zinc radicals for molecular synthesis has been barely explored. Here, we show that a transient zinc radical can be formed through photoactivation of a zinc-zinc bonded compound, which is able to mediate the selective dimerization of alkenes and allenes. Treatment of dizinc compounds [L2Zn2] [L = CH3C(2,6-iPr2C6H3N)CHC(CH3)(NCH2CH2PR2); R = Ph (LPh) or iPr (LiPr)] with a diverse array of aromatic alkenes under UV irradiation (365 nm) facilely afforded the head-to-head coupling products, i.e., 1,4-dizinciobutanes in high yields. In addition, arylallenes could also be selectively dimerized by the dizinc compound to give 2,5-dizincyl-functionalized 1,5-hexadienes under the same conditions. Control reactions of [LPh2Zn2] in the presence of UV irradiation isolated a zinc phenyl complex and a trimeric zinc phosphide complex resulting from C-P bond cleavage at the tridentate ligand. Reactions of photoactivated dizinc compounds with organic spin traps, i.e., 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) and 2,2'-bipyridine (2,2'-bpy), successfully isolated zinc radical trapping products [LZnOTEMP] and [LPhZn(2,2'-bpy)·-], respectively. The profile of alkene dimerization was elucidated by density functional theory calculations, which confirmed that a transient zinc radical [LZn·] was initially generated through homolytic Zn-Zn bond cleavage via photoactivation followed by single-electron transfer and radical dimerization. The unique selectivity of the current reaction was also studied computationally.

Effect of dietary koumine on the immune and antioxidant status of carp (Cyprinus carpio) after Aeromonas hydrophila infection.

Koumine (KM) has anxiolytic, anti-inflammatory and growth-promoting effects in pigs and sheep. Based on the growth-promoting and immunological effects of koumine, the present study was conducted on Cyprinus carpio (C. carpio) with four KM concentrations: 0 mg/kg, 0.2 mg/kg, 2 mg/kg, and 20 mg/kg for 10 weeks, followed by a 1-week Aeromonas hydrophila (A. hydrophila) infection experiment. The effect of KM on the immunity of A. hydrophila infected carp was analyzed by histopathology, biochemical assay, and qRT-PCR to assess the feasibility of KM in aquaculture. The results showed that the presence of KM alleviated pathogen damage to carp tissues. At 2 mg/kg and 20 mg/kg concentrations of KM successively and significantly elevated (p < 0.05) the SOD activities in the intestinal tract, hepatopancreas and kidney of carp. The expression levels of hepatopancreatic antioxidant genes Nrf2 and IGF-1 were significantly up-regulated in the same group (p < 0.05), while the expression levels of immune genes IL-8 and IL-10 were down-regulated. In summary, KM at concentrations of 2 mg/kg and 20 mg/kg could regulate the expression of antioxidant and immune genes in various tissues in an orderly and rapid manner, and significantly improve the antioxidant and immune abilities of carp, which is conducive to the improvement of the resilience of carp.

GSTZ1-1 Deficiency Activates NRF2/IGF1R Axis in HCC via Accumulation of Oncometabolite Succinylacetone.

The IGF1R signaling is important in the malignant progression of cancer. However, overexpression of IGF1R has not been properly assessed in HCC. Here, we revealed that GSTZ1-1, the enzyme in phenylalanine/tyrosine catabolism, is downregulated in HCC, and its expression was negatively correlated with IGF1R. Mechanistically, GSTZ1-1 deficiency led to succinylacetone accumulation, alkylation modification of KEAP1, and NRF2 activation, thus promoting IGF1R transcription by recruiting SP1 to its promoter. Moreover, inhibition of IGF1R or NRF2 significantly inhibited tumor-promoting effects of GSTZ1 knockout in vivo. These findings establish succinylacetone as an oncometabolite, and GSTZ1-1 as an important tumor suppressor by inhibiting NRF2/IGF1R axis in HCC. Targeting NRF2 or IGF1R may be a promising treatment approach for this subset HCC.

Koumine induces apoptosis in Cyprinus carpio liver cells by regulating JAK-STAT and p53 signaling pathways.

Koumine is an alkaloid with significant anti-anxiety, anticancer cell proliferation, and analgesic activities, and our previous studies have shown that koumine can be used as an immunostimulant in aquaculture, but the molecular mechanism of its effect remains unclear. We fed a basal diet with 0, 0.2, 2, and 20 mg/kg koumine to C. carpio for 10 weeks, and comprehensive studies of the histological and biochemical parameters and transcriptomes of the four groups were performed. Histological results indicated that the number of apoptotic cells in the liver increased with increasing koumine concentration. Compared with those of the control group, the malondialdehyde, superoxide dismutase, catalase, acid phosphatase, alkaline phosphatase, and lactate dehydrogenase levels of the treatment group increased to varying degrees. In total, 100.11 GB of clean data, 4774 DEGs, and 138 differentially expressed genes were obtained from the transcriptome data. Differentially expressed genes were classified into 187 signalling pathways, and the circadian rhythm signalling pathway, the JAK-STAT signalling pathway, the p53 signalling pathway and the PPAR signalling pathway were the top enriched pathways. The qRT-PCR results confirmed that the key genes ifnar1, socs3l, epoa, ghra, cMyc, mcl-1, shisa4, and gtse1 involved in balancing cell proliferation and apoptosis were enriched in these pathways. We discovered that the JAK-STAT and p53 pathways are important targets of koumine. Such information contributes to a better understanding of the potential mechanism by which koumine regulates hepatic immunity as well as to lays the theoretical foundation for its application.

Excitation Wavelength-Dependent Fluorescence of a Lanthanide Organic Metal Halide Cluster for Anti-Counterfeiting Applications.

The achievement of significant photoluminescence (PL) in lanthanide ions (Ln3+ ) has primarily relied on host sensitization, where energy is transferred from the excited host material to the Ln3+ ions. However, this luminous mechanism involves only one optical antenna, namely the host material, which limits the accessibility of excitation wavelength-dependent (Ex-De) PL. Consequently, the wider application of Ln3+ ions in light-emitting devices is hindered. In this study, we present an organic-inorganic compound, (DMA)4 LnCl7 (DMA+ =[CH3 NH2 CH3 ]+ , Ln3+ =Ce3+ , Tb3+ ), which serves as an independent host lattice material for efficient Ex-De emission by doping it with trivalent antimony (Sb3+ ). The pristine (DMA)4 LnCl7 compounds exhibit high luminescence, maintaining the characteristic sharp emission bands of Ln3+ and demonstrating a high PL quantum yield of 90-100 %. Upon Sb3+ doping, the compound exhibits noticeable Ex-De emission with switchable colors. Through a detailed spectral study, we observe that the prominent energy transfer process observed in traditional host-sensitized systems is absent in these materials. Instead, they exhibit two independent emission centers from Ln3+ and Sb3+ , each displaying distinct features in luminous color and radiative lifetime. These findings open up new possibilities for designing Ex-De emitters based on Ln3+ ions.

Highly Luminescent One-Dimensional Organic-Inorganic Hybrid Double-Perovskite-Inspired Materials for Single-Component Warm White-Light-Emitting Diodes.

Double perovskites (DPs) are one of the most promising candidates for developing white light-emitting diodes (WLEDs) owing to their intrinsic broadband emission from self-trapped excitons (STEs). Translation of three-dimensional (3D) DPs to one-dimensional (1D) analogues, which could break the octahedral tolerance factor limit, is so far remaining unexplored. Herein, by employing a fluorinated organic cation, we report a series of highly luminescent 1D DP-inspired materials, (DFPD)2 MI InBr6 (DFPD=4,4-difluoropiperidinium, MI =K+ and Rb+ ). Highly efficient warm-white photoluminescence quantum yield of 92 % is achieved by doping 0.3 % Sb3+ in (DFPD)2 KInBr6 . Furthermore, single-component warm-WLEDs fabricated with (DFPD)2 KInBr6 :Sb yield a luminance of 300 cd/m2 , which is one of the best-performing lead-free metal-halides WLEDs reported so far. Our study expands the scope of In-based metal-halides from 3D to 1D, which exhibit superior optical performances and broad application prospects.

Effects of partial replacement of dietary flour meal with seaweed polysaccharides on the resistance to ammonia stress in the intestine of hybrid snakehead (Channa maculatus ♀ × Channa argus ♂).

The purpose of this study was to evaluate the effects of partial replacement of dietary flour meal with seaweed polysaccharides on survival rate, histology, intestinal oxidative stress levels, and expression of immune-related genes in hybrid snakeheads under acute ammonia stress. Four experimental diets were set: (C) basal diet with 0% of seaweed polysaccharides as the control group, (MR) basal diet with 10% of seaweed polysaccharides, (HR) basal diet with 15% of seaweed polysaccharides, (HF) basal diet with 10% of fish oil. After 60 days of feeding, fish fed with the diet of C group were sampled as the control group, and other fish were exposed to ammonia nitrogen for 48 h. Two concentrations of total ammonia nitrogen (TAN) were used in this study: 120 mg/L TAN (low concentration exposure group), and 1200 mg/L TAN (high concentration exposure group). After exposure to ammonia nitrogen for 48 h, fish were sampled. The results indicated that adding seaweed polysaccharides to the diet could improve the survival rate of hybrid snakeheads under high concentration of ammonia stress. Histopathological analysis demonstrated multiple abnormalities in gills and intestines after exposure to two concentrations of TAN. The activities of superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), and lactate dehydrogenase (LDH) were all increased in the MR group under two concentrations of TAN stress. The mRNA abundance of immune-related genes in fish intestinal tissues was significantly induced or inhibited. These results suggested that partial replacement of dietary flour meal with seaweed polysaccharides improved the ability of hybrid snakeheads to resist ammonia stress.

Effects of Dietary Koumine on Growth Performance, Intestinal Morphology, Microbiota, and Intestinal Transcriptional Responses of Cyprinus carpio.

Gelsemium elegans Benth. (GEB) is a traditional medicinal plant in China, and acts as a growth promoter in pigs and goats. Koumine (KM) is the most abundant alkaloid in GEB and produces analgesic, anti-cancer, and immunomodulatory effects. KM can be used as an aquatic immune stimulant, but its growth-promoting effects and transcriptional mechanisms have not been investigated. Diets containing KM at 0, 0.2, 2, and 20 mg/kg were fed to Cyprinus carpio for 71 days to investigate its effects on growth performance, intestinal morphology, microflora, biochemical indicators, and transcriptional mechanisms. Cyprinus carpio fed with KM as the growth promoter, and the number of intestinal crypts and intestinal microbial populations were influenced by KM concentration. KM increased the abundance of colonies of Afipia, Phyllobacterium, Mesorhizobium, and Labrys, which were associated with compound decomposition and proliferation, and decreased the abundance of colonies of pathogenic bacteria Methylobacterium-Methylorubrum. A total of 376 differentially-expressed genes (DEGs) among the four experimental groups were enriched for transforming growth factor-ß1 and small mother against decapentaplegic (TGF-ß1/Smad), mitogen-activated protein kinase (MAPK), and janus kinases and signal transducers and activators of transcription (Jak/Stat) signaling pathways. In particular, tgfbr1, acvr1l, rreb-1, stat5b, smad4, cbp, and c-fos were up-regulated and positively correlated with KM dose. KM had a growth-promoting effect that was related to cell proliferation driven by the TGF-ß1/Smad, MAPK, and Jak/Stat signaling pathways. KM at 0.2 mg/kg optimized the growth performance of C. carpio, while higher concentrations of KM (2 and 20 mg/kg) may induce apoptosis without significantly damaging the fish intestinal structure. Therefore, KM at low concentration has great potential for development as an aquatic growth promotion additive.

Gonadal Transcriptome Analysis and Sequence Characterization of Sex-Related Genes in Cranoglanis bouderius.

In China, the Cranoglanis bouderius is classified as a national class II-protected animal. The development of C. bouderius populations has been affected by a variety of factors over the past few decades, with severe declines occurring. Considering the likelihood of continued population declines of the C. bouderius in the future, it is critical to investigate the currently unknown characteristics of gonadal differentiation and sex-related genes for C. bouderius conservation. In this study, the Illumina sequencing platform was used to sequence the gonadal transcriptome of the C. bouderius to identify the pathways and genes related to gonadal development and analyze the expression differences in the gonads. A total of 12,002 DEGs were identified, with 7220 being significantly expressed in the ovary and 4782 being significantly expressed in the testis. According to the functional enrichment results, the cell cycle, RNA transport, apoptosis, Wnt signaling pathway, p53 signaling pathway, and prolactin signaling pathway play important roles in sex development in the C. bouderius. Furthermore, the sequence characterization and evolutionary analysis revealed that AMH, DAX1, NANOS1, and AR of the C. bouderius are highly conserved. Specifically, the qRT-PCR results from various tissues showed significant differences in AMH, DAX1, NANOS1, and AR expression levels in the gonads of both sexes of C. bouderius. These analyses indicated that AMH, DAX1, NANOS1, and AR may play important roles in the differentiation and development of C. bouderius gonads. To our best knowledge, this study is the first to analyze the C. bouderius gonadal transcriptome and identify the structures of sex-related genes, laying the foundation for future research.

Metformin alleviates allergic airway inflammation and increases Treg cells in obese asthma.

Obesity increases the morbidity and severity of asthma, with poor sensitivity to corticosteroid treatment. Metformin has potential effects on improving asthma airway inflammation. Regulatory T cells (Tregs) play a key role in suppressing the immunoreaction to allergens. We built an obese asthmatic mouse model by administering a high-fat diet (HFD) and ovalbumin (OVA) sensitization, with daily metformin treatment. We measured the body weight and airway inflammatory status by histological analysis, qRT-PCR, and ELISA. The percentage of Tregs was measured by flow cytometry. Obese asthmatic mice displayed more severe airway inflammation and more significant changes in inflammatory cytokines. Metformin reversed the obese situation and alleviated the airway inflammation and remodelling with increased Tregs and related transcript factors. The anti-inflammatory function of metformin may be mediated by increasing Tregs.

A dosage-effect assessment of acute toxicology tests of microplastic exposure in filter-feeding fish.

Abundant microplastics was found in aquatic ecosystem and aquatic organisms, which raised many concerns in public. Silver carp (Hypophthalmichthys molitrix), a species filter-feeding planktivorous fish, feed on particle between 4 and 85 µm in size, and the respiratory process works together with feeding mechanism when filtering plankton from water. The aim of this study was to assess the physiological response of silver carp exposed to 5 µm polystyrene microspheres during 48 h of exposure followed by 48 h of depuration through the gill histology, and oxidative stress biomarkers in intestine. The results revealed that microplastics can pass through the whole digestive tract of silver carp and be excreted by feces. Low microplastic concentration (80 µg/L) induced oxidative stress and up-regulation of TUB84 and HSP70 gene in intestine, and silver carp have ability to recover after the exposure to microplastic was removed. High microplastic concentration (800 µg/L) definitely cause significant damage to gills and intestines, in this situation, far beyond the possibility of fish own repair, and even when the threaten removed, silver carp can't recovery soon. Our studies assessed the dosage-effect relationship with physiological stress on silver carp when exposure to microplastics.

miR-142-5p and miR-130a-3p regulate pulmonary macrophage polarization and asthma airway remodeling.

Macrophages are key regulators of the development and progression of asthma, facilitating deleterious airway remodeling in affected patients. Immune cell function is tightly regulated by microRNAs (miRNAs), but how these miRNAs impact macrophage-mediated airway remodeling in the context of asthma remains to be determined. In this study, we utilized an ovalbumin (OVA)-based murine model of asthma to evaluate the importance of miRNAs within these macrophages. We found that macrophages from mice that had been sensitized with and exposed to OVA expressed higher levels of M2-like phenotypic markers and exhibited significantly altered expression of both miR-142-5p and miR-130a-3p. When these isolated pulmonary macrophages were cultured in vitro, we determined that transfecting them with miR-142-5p antisense oligonucleotide (ASO) or miR-130a-3p mimics was sufficient to inhibit the ability of interleukin-4 to induce M2 cytokine production. We additionally confirmed the in vivo relevance of these miRNAs in a Ccr2-/- murine model system mimicking asthma. Specifically, we determined that transfecting monocytes with miR-142-5p ASO and/or miR-130a-3p mimics was sufficient to disrupt the ability of these cells to promote airway remodeling. As such, these findings reveal that miR-142-5p and miR-130a-3p dysregulation are important factors governing the polarization of macrophages and associated airway remodeling in OVA-sensitized mice.

Effects of different combinations of koumine and gelsemine on growth performance, intestinal health, and transcriptome of Cyprinus carpio.

Koumine (KM) and gelsemine (GS) have shown significant benefits in livestock production, but their potential in aquaculture remains largely unexplored. This study examined the impact of different KM and GS combinations as feed additives on C. carpio (90 fish per group, initial weight 1.95 ± 0.08 g). KM and GS were introduced in ratios of 2:2 (mg/kg), 2:1 (mg/kg), and 2:0.67 (mg/kg) over a 10-week aquaculture experiment. The results demonstrate that the 2:1 (mg/kg) group increases the villus length, muscular layer thickness, crude protein, and crude fat content. Regarding fatty acid content, KM and GS enhance the levels of various fatty acids, including the total saturated fatty acid and total monounsaturated fatty acid. Additionally, KM and GS improve the composition and function of the intestinal microbiota. The 2:1 (mg/kg) group significantly elevates the enzymatic activities of SOD, MDA, CAT and upregulates the expression of immune-related genes such as toll-like receptor 2, transforming growth factor ß, and glutathione S-transferase. Transcriptomic analysis suggests that KM and GS may have potential benefits for nutrient utilization and immune regulation in C. carpio. In summary, this study provides valuable insights into the use of KM and GS as feed additives in aquaculture.

Species-specific effects of microplastics on juvenile fishes.

Microplastics contamination have been extensively reported in aquatic ecosystem and organisms. It is wildly acknowledged that the ingestion, accumulation and elimination of microplastics in fishes are species-specific, which mainly depending on the feeding behavior. This study aimed to investigate the effects of microplastics on the morphology and inflammatory response in intestines of fishes with different feeding types. Largemouth bass (carnivorous fish), grass carp (herbivorous fish) and Jian carp (omnivorous fish) were used as organism model. The contributing concentration and size of microplastics were explored as well as the response time and legacy effect in fishes. Two different sizes of polystyrene microplastics (80 nm and 8 µm) were set at three concentrations. And samples were analyzed at different exposure times and depuration times. Histological analysis indicated that multiple abnormalities in intestines were presented in three species fishes after acute exposure microplastics. The mRNA abundance of immune-related genes in the intestine tissues of fishes were significantly fluctuant. There were differential expressions of genes coping with differential sizes and concentrations of microplastics exposure in different fishes. The reason for the difference effects of microplastics on fishes was still unclear but could be due to the difference in the structure and function of the digestive system. These results provided a theoretical basis to further analysis of the mechanism of fish intestinal pathology caused by microplastics.

An effect assessment of microplastics and nanoplastics interacting with androstenedione on mosquitofish (Gambusia affinis).

An increasing number of microplastics have been detected in aquatic environments, causing various damage to organisms. The size of microplastics affects the toxicity once they enter the organisms. Meanwhile, there is an increasing variety of Endocrine-disrupting chemicals (EDCs) present in aquatic environments. Androstenedione (AED) is a typical EDC. In this study, we used polystyrene microspheres of 80 nm (NPs) and 8 µm (MPs) as materials to simulate environmental contaminants in the aquatic environment with AED. We used female mosquitofish (Gambusia affinis) as the research object to investigate the effects of microplastics on fish in waters containing AED. We compared different sizes of particles accumulation in some tissues of fish and variation of enzyme activities (SOD, LDH, CAT), and the content of MDA in the gut. MPs, NPs, and AED combined exposure test investigated mRNA profiles of immune-related genes (IL-1ß, IL-6, IL-8, IL-10) and hormone receptor genes (ARα, ARß, ERα, ERß) in the liver of fish. Our results indicated that MPs emerged in various tissues (gill, gut, and liver) of mosquitofish. Besides, NPs and MPs caused enteric abnormal enzyme activity after 48 h of exposure, which was particularly pronounced in the MPs-AED group. MPs induced significant upregulation of inflammatory factors and gonadal factor genes after 96 h of exposure, which was more pronounced when co-exposed with AED. In conclusion, NPs and MPs caused mechanisms of immune damage and inflammatory response. MPs were found to be more likely to cause adverse reactions than NPs, and these responses were enhanced by the combined effects of AED. This study demonstrated that AED can exacerbate the negative effects of MPs and NPs on mosquitofish. It provided an important basis for the effective assessment of MPs and NPs on bioaccumulation and biochemical status of mosquitofish. Additionally, it serves as a foundation to investigate the interactive effects of microplastics and EDCs in living organisms.

Replacing starch with resistant starch (Laminaria japonica) improves water quality, nitrogen and phosphorus budget and microbial community in hybrid snakehead (Channa maculata ♀ × Channa argus ♂).

It is essential to increase the use of carbohydrates as an energy source and improve protein synthesis and utilization to reduce ammonia nitrogen emissions. A 60-day cultural experiment was conducted to assess the impact of resistant starch (kelp meal, Laminaria japonica) replacing starch on water quality, nitrogen and phosphorus budget and microbial community of hybrid snakehead. Approximately 1350 experimental fish (11.4 ± 0.15 g) were randomly divided into control group (C, 20% starch) and four resistant starch groups: low replacement group (LR, 15% starch), medium replacement group (MR, 10% starch), high replacement group (HR, 5% starch) and full replacement group (FR, 0% starch). The crude protein and crude fat content of hybrid snakehead fish fed with the FR diet had the most significant improvement (P < 0.05). However, resistant starch also increased the effectiveness of nitrogen and phosphorus utilization in hybrid snakeheads, which decreased the proportion of total nitrogen and total phosphorus in tail water. The minimum nitrogen and phosphorus emission rate was when the starch level was 6.1%. Denitrifying microbes including Gemmobacter, Rhodobacter, Emticicia and Bosea have become much more prevalent in group FR (P < 0.05). In general, replacing starch with resistant starch can enhance the rate at which nitrogen and phosphorus are used in feeding, lessening water pollution and altering environmental microbial composition. PRACTITIONER POINTS: Resistant starch (RS) improves whole fish nutritional content. Resistant starch improves dietary nitrogen and phosphorus utilization. Resistant starch acts as a carbon source and encourages the colonization of denitrifying bacteria in water.

Integrated transcriptome, metabolome and phytohormone analysis reveals developmental differences between the first and secondary flowering in Castanea mollissima.

Introduction: Chestnut (Castanea mollissima BL.) is an important woody grain, and its flower formation has a significant impact on fruit yield and quality. Some chestnut species in northern China re-flower in the late summer. On the one hand, the second flowering consumes a lot of nutrients in the tree, weakening the tree and thus affecting flowering in the following year. On the other hand, the number of female flowers on a single bearing branch during the second flowering is significantly higher than that of the first flowering, which can bear fruit in bunches. Therefore, these can be used to study the sex differentiation of chestnut. Methods: In this study, the transcriptomes, metabolomes, and phytohormones of male and female chestnut flowers were determined during spring and late summer. We aimed to understand the developmental differences between the first and secondary flowering stages in chestnuts. We analysed the reasons why the number of female flowers is higher in the secondary flowering than in the first flowering and found ways to increase the number of female flowers or decrease the number of male flowers in chestnuts. Results: Transcriptome analysis of male and female flowers in different developmental seasons revealed that EREBP-like mainly affected the development of secondary female flowers and HSP20 mainly affected the development of secondary male flowers. KEGG enrichment analysis showed that 147 common differentially-regulated genes were mainly enriched from circadian rhythm-plant, carotenoid biosynthesis, phenylpropanoid biosynthesis, and plant hormone signal transduction pathways. Metabolome analysis showed that the main differentially accumulated metabolites in female flowers were flavonoids and phenolic acids, whereas the main differentially accumulated metabolites in male flowers were lipids, flavonoids, and phenolic acids. These genes and their metabolites are positively correlated with secondary flower formation. Phytohormone analysis showed that abscisic and salicylic acids were negatively correlated with secondary flower formation. MYB305, a candidate gene for sex differentiation in chestnuts, promoted the synthesis of flavonoid substances and thus increased the number of female flowers. Discussion: We constructed a regulatory network for secondary flower development in chestnuts, which provides a theoretical basis for the reproductive development mechanism of chestnuts. This study has important practical implications for improving chestnut yield and quality.

Signaling metabolite succinylacetone activates HIF-1α and promotes angiogenesis in GSTZ1-deficient hepatocellular carcinoma.

Aberrant angiogenesis in hepatocellular carcinoma (HCC) is associated with tumor growth, progression, and local or distant metastasis. Hypoxia-inducible factor 1α (HIF-1α) is a transcription factor that plays a major role in regulating angiogenesis during adaptation of tumor cells to nutrient-deprived microenvironments. Genetic defects in Krebs cycle enzymes, such as succinate dehydrogenase and fumarate hydratase, result in elevation of oncometabolites succinate and fumarate, thereby increasing HIF-1α stability and activating the HIF-1α signaling pathway. However, whether other metabolites regulate HIF-1α stability remains unclear. Here, we reported that deficiency of the enzyme in phenylalanine/tyrosine catabolism, glutathione S-transferase zeta 1 (GSTZ1), led to accumulation of succinylacetone, which was structurally similar to α-ketoglutarate. Succinylacetone competed with α-ketoglutarate for prolyl hydroxylase domain 2 (PHD2) binding and inhibited PHD2 activity, preventing hydroxylation of HIF-1α, thus resulting in its stabilization and consequent expression of vascular endothelial growth factor (VEGF). Our findings suggest that GSTZ1 may serve as an important tumor suppressor owing to its ability to inhibit the HIF-1α/VEGFA axis in HCC. Moreover, we explored the therapeutic potential of HIF-1α inhibitor combined with anti-programmed cell death ligand 1 therapy to effectively prevent HCC angiogenesis and tumorigenesis in Gstz1-knockout mice, suggesting a potentially actionable strategy for HCC treatment.

Single and combined effects of microplastics and cadmium on juvenile grass carp (Ctenopharyngodon idellus).

Microplastics (MPs) have received extensive attention as a new type of environmental pollutants with potential ecological risks. However, there are still few studies on the physiological stress response of aquatic organisms under the interaction of MPs and heavy metals. In this study, grass carp (Ctenopharyngodon idellus) were chosen as experimental fish and were exposed to 5 µm polystyrene microplastics (PS - MPs, 700 µg/L) and cadmium (Cd, 100 µg/L) individually or in combination. The results indicated that the presence of Cd didn't affect the accumulation of MPs in the intestines of grass carp. On the contrary, the concentration of Cd in the intestines of grass carp was higher in the MPs - Cd combined exposure group than in the Cd alone exposure group. Histological analysis revealed multiple abnormalities in the intestines after acute exposure, and the damage in the MPs - Cd combined exposure group was particularly severe. After 24 h of exposure, the expression of pro-inflammatory cytokines was significantly up-regulated in all exposed groups. However, after 48 h of exposure, the expression of inflammatory cytokines was significantly down-regulated, which may be related to intestinal damage. Our results deepen the significance of toxicological studies of MPs exposure, highlight their interaction with heavy metal toxicants, and provide important data for assessing the risk of MPs and heavy metals to grass carp.

Effects of substitution and conjugation on ESIPT behavior of Schiff base derivatives.

The excited-state proton transfer (ESIPT) behavior of organic fluorophores has been of great interest due to their unique photophysical properties. In this work, we have focused on the excited state kinetic behavior of four Schiff base organic molecules (i.e. CPMP, CPMMP, CPMDP, and CPMN) in acetonitrile solvents. The electron-donating of substituents and conjugation effects on the photophysical properties and ESIPT process of the Schiff base derivatives are investigated by theoretical methods. The results show that the hydrogen bonds are all enhanced in the excited states, which could provide the impetus for the ESIPT process. To further reveal the reaction process of ESIPT, we have scanned the potential energy curves of the ESIPT process and compared the potential barriers. It is found that the stronger the substituents give electrons and the conjugation effects the more favorable the excited state proton transfer (ESIPT). In the meantime, this study paves the way for the development of new Schiff base materials based on ESIPT.