SERD-NHC-Au(I) complexes for dual targeting ER and TrxR to induce ICD in breast cancer.

The development of selective estrogen receptor degraders (SERDs) has brought new ideas for the clinical treatment of ER-positive advanced breast cancer. The successful application of combinational therapy inspired the exploration of other targets to prevent breast cancer progression. Thioredoxin reductase (TrxR) is an important enzyme that can regulate redox balance in cells and it was considered as a potential target for anticancer treatment. In this study, we firstly combine a clinical SERD candidate--G1T48 (NCT03455270), with a TrxR inhibitor--N-heterocyclic carbene gold(I) [NHC-Au(I)] to form dual targeting complexes that can regulate both signaling pathways. The most efficacious complex 23 exhibited significant antiproliferative profile through degrading ER and inhibiting TrxR activity. Interestingly, it can induce immunogenic cell death (ICD) caused by ROS. This is the first evidence to elucidate the role of ER/TrxR-ROS-ICD axis in ER positive breast cancer and this research may inspire new drug development with novel mechanisms. The in vivo xenograft study demonstrated that complex 23 had excellent antiproliferative activity toward MCF-7 cells in mice model.

Lc-pPG-612-OmpU-CTB: A promising oral vaccine for protecting Carassius auratus against Vibrio mimicus infection.

Vibrio mimicus (V. mimicus) is known to cause severe bacterial diseases with high mortality rates in fish, resulting in significant economic losses in the global aquaculture industry. Therefore, the objective of this study was to develop a safe and effective vaccine for protecting Carassius auratus (C. auratus) against V. mimicus infection. Recombinant Lactobacillus casei (L. casei) strains, Lc-pPG-612-OmpU and Lc-pPG-612-OmpU-CTB (surface-displayed), were constructed using a L. casei strain (ATCC 393) as an antigen delivery carrier and the cholera toxin B subunit (CTB) as an adjuvant. The two recombinant strains of L. casei were administered to C. auratus via oral immunization, and the protective efficacy of the oral vaccines was assessed. The results demonstrated that oral immunization with the two strains significantly increased the levels of nonspecific immune indicators in C. auratus, including alkaline phosphatase (AKP), lysozyme (LYS), acid phosphatase (ACP), complement 3 (C3), complement 4 (C4), lectin, and superoxide dismutase (SOD). Moreover, the experiment groups exhibited significant increases in specific immunoglobulin M (IgM) antibodies against OmpU, as well as the transcription of immune-related genes (ie., IL-1ß, TNF-α, IL-10, and TGF-ß), when compared to the control groups. Following infection of C. auratus with V. mimicus, the mortality rate of the recombinant L. casei-treated fish was observed to be lower compared to the control group. This finding suggests that recombinant L. casei demonstrates effective protection against V. mimicus infection in C. auratus. Furthermore, the addition of the immune adjuvant CTB was found to induce a more robust adaptive and innate immune response in C. auratus, resulting in reduced mortality after infection with V. mimicus.

Recent development of gold(I) and gold(III) complexes as therapeutic agents for cancer diseases.

Metal complexes have demonstrated significant antitumor activities and platinum complexes are well established in the clinical application of cancer chemotherapy. However, the platinum-based treatment of different types of cancers is massively hampered by severe side effects and resistance development. Consequently, the development of novel metal-based drugs with different mechanism of action and pharmaceutical profile attracts modern medicinal chemists to design and synthesize novel metal-based agents. Among non-platinum anticancer drugs, gold complexes have gained considerable attention due to their significant antiproliferative potency and efficacy. In most situations, the gold complexes exhibit anticancer activities by targeting thioredoxin reductase (TrxR) or other thiol-rich proteins and enzymes and trigger cell death via reactive oxygen species (ROS). Interestingly, gold complexes were recently reported to elicit biochemical hallmarks of immunogenic cell death (ICD) as an ICD inducer. In this review, the recent progress of gold(I) and gold(III) complexes is comprehensively summarized, and their activities and mechanism of action are documented.

Detection and genetic characterization of Toxoplasma gondii in market-sold mussels (Mytilus edulis) in certain provinces of China.

Mussels, randomly collected from fish markets in China, were analyzed by a semi-nested PCR to detect B1 gene of Toxoplasma gondii. Out of the 2215 samples, fifty-five (2.48%) were detected T. gondii-positive. The prevalence in Shandong province, Liaoning province and Zhejiang province were 2.51%, 2.26% and 2.69%, respectively. T. gondii oocysts were more frequently detected in digestive glands (1.04%) and haemolymph (1.49%) when compared with gills (0.23%). Of the 55 positive DNA, only two samples showed complete genotype at 11 locus and were authenticated as ToxoDB Genotype #9. To our knowledge, the present study is the first to confirm the presence of T. gondii in market-sold mussels in China. The findings point to the risk of humans acquiring T. gondii infection by consuming mussels bought in the aquatic product market.

Determination of melamine in aquaculture feed samples based on molecularly imprinted solid-phase extraction.

This research highlights the application of highly efficient molecularly imprinted solid-phase extraction for the preconcentration and analysis of melamine in aquaculture feed samples. Melamine-imprinted polymers were synthesized employing methacrylic acid and ethylene glycol dimethacrylate as functional monomer and cross-linker, respectively. The characteristics of obtained polymers were evaluated by scanning electron microscopy, Fourier transform infrared spectroscopy and binding experiments. The imprinted polymers showed an excellent adsorption ability for melamine and were applied as special solid-phase extraction sorbents for the selective cleanup of melamine. An off-line molecularly imprinted solid-phase extraction procedure was developed for the separation and enrichment of melamine from aquaculture feed samples prior to high-performance liquid chromatography analysis. Optimum molecularly imprinted solid-phase extraction conditions led to recoveries of the target in spiked feed samples in the range 84.6-96.6% and the relative standard deviation less than 3.38% (n = 3). The aquaculture feed sample was determined, and there was no melamine found. The results showed that the molecularly imprinted solid-phase extraction protocols permitted the sensitive, uncomplicated and inexpensive separation and pre-treatment of melamine in aquaculture feed samples.

Discovery of novel quinoline scaffold selective estrogen receptor degraders (SERDs) for treatment of ER positive breast cancer with enhanced antiproliferative bioactivity through immunogenic cell death (ICD) effects.

Combination therapy proven to be an effective therapeutic approach for estrogen receptor (ER)-positive breast cancer. Currently, cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are combined with aromatase inhibitors (AIs) or selective estrogen receptor degraders (SERDs) as first-line therapy for advanced ER-positive breast cancer. Herein, a new family of quinoline scaffold SERDs was synthesized and evaluated in MCF-7 cells. Among them, compounds 18j and 24d exhibited remarkable MCF-7 inhibition, both alone and in combination with ribociclib (CDK4/6 inhibitor), in vitro and in vivo. Meanwhile, compounds 18j and 24d effectively degraded ER and inhibited ER downstream signaling pathways. Interestingly, compounds 18j and 24d induced endoplasmic reticulum stress (ERS) and triggered immunogenic cell death (ICD) via damage-associated molecular patterns (DAMPs) in MCF-7 cells. These findings highlight the immune-related and enhanced antiproliferative effects of oral SERDs in ER positive breast cancer treatment.

Unveiling the pathogenic and multidrug-resistant profiles of Vibrio alfacsensis: A potential identified threat in turbot (Scophthalmus maximus) aquaculture.

Vibrio alfacsensis is traditionally seen as an environmental symbiont within its genus, with no detailedly documented pathogenicity in marine aquaculture to date. This study delves into the largely unexplored pathogenic potential and emerging antibiotic resistance of V. alfacsensis. The VA-1 strain, isolated from recirculating aquaculture system (RAS) effluent of cultured turbot (Scophthalmus maximus), underwent comprehensive analysis including biochemical identification, antibiotic susceptibility testing and reinfection trials. The results confirmed VA-1's pathogenicity and significant multiple antibiotic resistance. VA-1 could induce systemic infection in turbot, with symptoms like kidney enlargement, exhibiting virulence comparable to known Vibrio pathogens, with an LD50 around 2.36 × 106 CFU/fish. VA-1's remarkable resistance phenotype (14/22) suggested potential for genetic exchange and resistance factor acquisition in aquaculture environments. Phylogenetic analysis based on 16S rDNA sequences and whole-genome sequencing has firmly placed VA-1 within the V. alfacsensis clade, while genome-wide analysis highlights its similarity and diversity in relation to strains from across the globe. VA-1 contained numerous replicons, indicating the possibility for the spread of resistance and virulence genes. This study suggests V. alfacsensis may acquire and transfer pathogenic and resistant traits through horizontal gene transfer, a likelihood intensified by changing environmental and aquaculture conditions, highlighting the need for vigilant pathogen monitoring and new non-antibiotic treatments.

Diversities and Shifts of Microbial Communities Associated with Farmed Oysters (Crassostrea gigas) and Their Surrounding Environments in Laoshan Bay Marine Ranching, China.

Pacific oysters (Crassostrea gigas) are widely cultured in Chinese marine ranching with high economic value. However, mass death of farmed oysters has occurred frequently in recent years because of diseases and environmental disturbance (e.g., high temperatures). In order to analyze the potential relationships between microorganisms and the death of farmed oysters, we compared the dynamics of bacterial and protist communities in oysters at different growth phases using high-throughput sequencing. The results showed that the microbial communities in farmed oysters significantly changed and were markedly different from microbes in natural oysters and the surrounding environments. The number of biomarker taxa among farmed oysters and their surrounding environments decreased gradually with the growth of oysters. During the mass death of farmed oysters, the microbial communities' abundance of ecological function genes changed, and the correlations among microorganisms disappeared. These results enrich our understanding of the dynamics of microbial communities in farmed oysters at different growth phases, illustrating the characteristics of interactions among microorganisms during the mass death of farmed oysters. Our study is beneficial to promote the healthy aquaculture of oysters.

The effects of flow field on the succession of the microbial community on artificial reefs.

The flow field is one of the most important external conditions affecting the development of biofouling community on artificial reefs (ARs), especially the microbial community. In this article, we investigated the temporal dynamics of microbial communities between the stoss side and the lee side of ARs. The results showed that the composition and structure of microbial and macrobenthic communities between the stoss side and the lee side both presented obvious temporal variations. Microbial diversity and richness were higher on the stoss side than that on the lee side. There was a greater impact on bacterial and archaeal communities on temporal scale compared to that on micro-spatial scale, which was not suitable for the fungal community. The organism biomass, abundance and coverage of macrobenthic community on the lee side were higher than those on the stoss side, and the microbial diversity on the stoss side increased significantly with the organism coverage.

Research Progress on Bioactive Metal Complexes against ER-Positive Advanced Breast Cancer.

Breast cancer is the most prevalent cancer in women and represents a serious disease that is harmful to life and health. In 1977, with the approval of tamoxifen, endocrine therapy has become the main clinical treatment for ER-positive (ER+) breast cancer. Although patients initially respond well to endocrine therapies, drug resistance often emerges and side effects can be challenging. To overcome drug resistance, the exploration for new drugs is a priority. Metal complexes have demonstrated significant antitumor activities, and platinum complexes are widely used in the clinic against various cancers, including breast cancer. In this Perspective, the first section describes the classification and mechanism of endocrine therapy drugs for ER+ breast cancer, and the second section summarizes research since 2000 into metal complexes with activity toward ER+ breast cancer. Finally, we discuss the opportunities, challenges, and future directions for metal complexes in the treatment of ER+ breast cancer.

Weissella confusa N17 Derived from Loach (Misgurnus anguillicaudatus) Exhibits Promising for Further Applications in Loach Aquaculture.

The application of probiotics, in aquaculture, is becoming increasingly widespread and have had positive application effects. However, reports of loach-derived probiotics are quite limited. In this study, two representative strains of lactic acid bacteria with excellent traits, namely, Weissella confusa N17 and Lactobacillus saniviri N19, were screened from the intestine of healthy loaches. W. confusa N17 and L. saniviri N19 could inhibit different common various pathogenic bacteria, especially Aeromonas spp., and were sensitive to the most common antibiotics. The survival rate of the two strains exceeded 50% after 4 h of incubation in 10% loach bile. Moreover, the two strains showed significant tolerance to trypsin. Their autoaggregation capacity and hydrophobicity were greater than 30%. In addition, the aggregation ability of both strains was higher than 30% for both A. veronii TH0426 and A. hydrophila TPS. The two strains had a high biofilm-forming ability and strong adhesion to epithelioma papulosum cyprini (EPC) cells. Scanning electron microscopy results showed that the culture supernatants of the two strains had a significantly destructive effect on A. veronii TH0426 and A. hydrophila TPS. Overall, the traits of W. confusa N17 were better than those of L. saniviri N19. Genome sequencing and analysis demonstrated a lack of virulence factor-related or drug resistance-related genes in genome N17. The diet supplemented with the W. confusa N17 strain significantly improved the resistance of loaches to A. veronii infection, and the protection rate reached 57.1%. Therefore, W. confusa N17 exhibits promising for further applications in loach aquaculture.

Response mechanism of meiofaunal communities to multi-type of artificial reef habitats from the perspective of high-throughput sequencing technology.

Multiple types of artificial reefs have been widely deployed in the coast of northern Yellow Sea, which can enhance fishery resources, restore coastal habitats and improve the marine environment. Meiofauna plays important ecological roles in marine ecosystem, but the response mechanism of meiofaunal community to different types of artificial reef is still poorly understood. In this study, we characterized the meiofaunal communities of concrete artificial reef habitat (CAR), rocky artificial reef habitat (RAR), ship artificial reef habitat (SAR) and adjacent natural habitat (NH) using 18S rRNA gene high-throughput sequencing technology, and explored the relationship of community-environment. The results showed that the diversity and community structure of meiofauna differed significantly on both spatial and temporal scales. Spatial differences were mainly contributed to the flow field effects and biological effects generated by artificial habitats, while temporal differences were driven by temperature (T) and dissolved oxygen (DO). The dominant taxa of meiofauna included arthropods, annelids, platyhelminths and nematodes. Platyhelminths were mainly positively influenced by artificial habitats but annelids were the opposite. Co-occurrence network analysis revealed that NH was more sensitive to environmental change than artificial habitat, while the performance of CAR and SAR were more stable. These results indicated that meiofauna can respond accordingly to different types of artificial habitats, and could be superimposed over the normal seasonal effects. The current study could provide fundamental data for understanding the response mechanism of meiofaunal community to different types of artificial habitats and a reference for assessments of the impact of artificial reefs on the marine environment.

Distribution of nitrogen (N) and phosphorus (P) in seasonal low-oxygen marine ranching in northern Yellow Sea, China.

Seasonal low-oxygen in marine ranching in the northern Yellow Sea has been one of the major environmental problems in coastal waters in recent years. Nitrogen (N) and phosphorus (P) are important nutrients, which are susceptible to the concentration of dissolved oxygen (DO). This article studied the effects of low-oxygen on nutrients represented by N and P fractions in marine ranching in the northern Yellow Sea. The results showed that there were significant layer differences in temperature and salinity during the low-oxygen period. In the seawater, the nutrient distribution in the death disaster zone of sea cucumbers and the non-disaster zone was similar, and DO had a strong positive correlation with dissolved inorganic nitrogen (DIN). In the sediment, significant regional differences existed in nutrient concentration, and the concentration of total phosphorus (TP) decreased significantly with the increase in DO content. The results showed that the sources and sinks of nitrogen and phosphorus nutrients were inconsistent in this zone, and migration and transformation of the existing form of nitrogen with the seasonal changes in the water environment was a main factor for N distribution. This study extended the understanding of the effects of seasonal low-oxygen on N and P.

Design, synthesis and biological evaluation of fluorinated selective estrogen receptor degraders (FSERDs) --- A promising strategy for advanced ER positive breast cancer.

Although endocrine therapies involving pharmaceuticals, such as tamoxifen and aromatase inhibitors, had initially demonstrated good responses in patients with estrogen receptor-positive (ER+) breast cancer, they often led to drug resistance. ER plays a vital role in the progression of metastatic diseases. Fulvestrant, a first generation selective estrogen receptor degrader (SERD), can effectively downregulate the ER protein and inhibit its downstream signaling pathways. However, as the drug needs to be intramuscularly injected, its widespread use is limited owing to poor patient compliance. Herein, we described a novel class of orally bioavailable fluorine-substituted SERDs that exhibit improved pharmacokinetic profiles. We substituted the hydroxyl group of clinical SERD candidate 6 with a fluorine atom to diminish phase II metabolism. The subsequent structure-activity relationship (SAR) investigation identified 22h and 27b, which can effectively degrade ER in a dose-dependent manner and exhibit considerable antiproliferative potency and efficacy in vitro and in vivo. The excellent pharmacokinetic profiles of 27b render it promising candidate of clinically useful oral SERD.

Comparison studies of epiphytic microbial communities on four macroalgae and their rocky substrates.

Macroalgae and their rocky substrates both support diverse and abundant microbiota, performing essential ecological functions in marine ecosystem. However, the differences in the epiphytic microbial communities on macroalgae and rocky substrate are still poorly understood. In this study, the epiphytic microbial communities on four macroalgae (Corallina officinalis, Rhodomela confervoides, Sargassum thunbergii, and Ulva linza) and their rocky substrates from Weihai coast zone were characterized using high-throughput sequencing technology. The results showed that the alpha diversity indices were greater in rocky substrates than that in macroalgae. The microbial similarities among macroalgae and rocky substrate groups tended to decrease from the high taxonomic ranks to lower ranks, only 22.69% of the total amplicon sequence variants (ASVs) were shared between them. The functional analysis revealed that the microbiotas were mainly involved in metabolic activities. This study would provide the theoretical foundation for macroalgal cultivation and algal reef applications.

Seasonal variations and co-occurrence networks of bacterial communities in the water and sediment of artificial habitat in Laoshan Bay, China.

Marine bacteria in the seawater and seafloor are essential parts of Earth's biodiversity, as they are critical participants of the global energy flow and the material cycles. However, their spatial-temporal variations and potential interactions among varied biotopes in artificial habitat are poorly understood. In this study, we profiled the variations of bacterial communities among seasons and areas in the water and sediment of artificial reefs using 16S rRNA gene sequencing, and analyzed the potential interaction patterns among microorganisms. Distinct bacterial community structures in the two biotopes were exhibited. The Shannon diversity and the richness of phyla in the sediment were higher, while the differences among the four seasons were more evident in the water samples. The seasonal variations of bacterial communities in the water were more distinct, while significant variations among four areas were only observed in the sediment. Correlation analysis revealed that nitrite and mud content were the most important factors influencing the abundant OTUs in the water and sediment, respectively. Potential interactions and keystone species were identified based on the three co-occurrence networks. Results showed that the correlations among bacterial communities in the sediment were lower than in the water. Besides, the abundance of the top five abundant species and five keystone species had different changing patterns among four seasons and four areas. These results enriched our understanding of the microbial structures, dynamics, and interactions of microbial communities in artificial habitats, which could provide new insights into planning, constructing and managing these special habitats in the future.

Response mechanism of microbial community to seasonal hypoxia in marine ranching.

Seasonal hypoxia, as an increasingly recognized environmental issue, frequently occurred in marine ranching from northern Yellow Sea, China. Although microorganisms play an important ecological role in marine ecosystems, but little is known on the response mechanism of microbial community to seasonal hypoxia in marine ranching. A total of 132 seawater samples and 47 sediment samples were collected from the marine ranching, both in the death disaster zone of sea cucumbers and the non-disaster zone, and in different months. 16S rRNA gene high-throughput sequencing was used to explore the microbial community and its influencing factors. The results showed that the stratification in community composition and dissolved oxygen content appeared in August. The Alpha diversity in seawater was higher in summer than in winter, and significant differences in Beta diversity appeared between the death disaster zone of sea cucumbers and the non-disaster zone in sediments. In addition, environmental effects explained more of the variation in bacterial community composition in seawater as compared with spatial effects did, whereas, sedimentary bacterial communities were more closely related to spatial effects. The present results could provide fundamental data for understanding the response mechanism of the microbial community to seasonal hypoxia in marine ranching and are of great significance for the management and protection of marine ranching.

Evaluation of artificial reef habitats as reconstruction or enhancement tools of benthic fish communities in northern Yellow Sea.

Artificial reefs have been widely deployed in the northern Yellow Sea. However, the differences in the ecological benefits on different types of artificial reef habitats are still poorly understood. In this study, the temporal and spatial differences on benthic fish communities were evaluated among concrete artificial reef habitat (CAR), rocky artificial reef habitat (RAR), ship artificial reef habitat (SAR) around Xiaoshi Island in northern Yellow Sea. The results indicated that all three types of artificial reef habitats can enhance the diversity variables of benthic fish communities, and fish abundance, species richness and Shannon-Wiener index of CAR were generally better than the other two. CAR and RAR hosted similar community composition of benthic fish, and all types of habitats showed significant differences in community composition between winter-spring and summer-autumn. Environmental factors, especially water temperature, can also affect the community composition by affecting the migration of temperature-preferred species. Overall, the enhancement effects of artificial habitats on fisheries productivity varied with fish species and reef types. This study will help to understand the ecological effects of different types of artificial reefs in northern Yellow Sea, and then could give an insight for scientific construction of artificial reefs in this region.

Comparative Analysis of the Ecological Succession of Microbial Communities on Two Artificial Reef Materials.

Concrete and wood are commonly used to manufacture artificial reefs (ARs) worldwide for marine resource enhancement and habitat restoration. Although microbial biofilms play an important role in marine ecosystems, the microbial communities that colonize concrete and wooden ARs and their temporal succession have rarely been studied. In this study, the temporal succession of the microbial communities on concrete and wooden AR blocks and the driving factors were investigated. The composition of the microbial communities underwent successive shifts over time: among the six dominant phyla, the relative abundances of Proteobacteria, Cyanobacteria and Gracilibacteria significantly decreased in wood, as did that of Cyanobacteria in concrete. Operational taxonomic units (OTU) richness and Shannon index were significantly higher in concrete than in wood. Non-metric multidimensional scaling ordination placed the microbial communities in two distinct clusters corresponding to the two substrate materials. The macrobenthic compositions of concrete and wood were broadly similar and shifted over time, especially in the first five weeks. The Shannon index of the microbial communities in concrete and wood increased significantly with the organism coverage. The results provide fundamental data on microbial community succession during the initial deployment of ARs and contribute to understanding the ecological effects of ARs.

Comparative analysis of microbial communities between water and sediment in Laoshan Bay marine ranching with varied aquaculture activities.

We profiled and compared the bacterial and protist community compositions and dynamics in the Laoshan Bay marine ranching involving varied aquaculture activities. The dominant species, differential species and community compositions among the five aquaculture areas, two habitats and two periods were significantly different. The relationships between microbial communities and environmental factors were analyzed. We found that microbial communities in the water were more sensitive to the environmental changes than sediment, and the responses of bacterial and protist communities to the disturbances were varied. To meet the challenges of higher aquaculture density, the proportion of the positive correlations among co-occurrence networks in the water increased markedly from July to November; while the positive proportion in the sediment was stable. Potential ecological interactions and keystone taxa between bacteria and protists were studied. These results advanced our understanding of how mariculture stressors affect microbial communities in marine ranching.