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Clinically, most prostate cancer (PCa) patients inevitably progress to castration‐resistant prostate cancer (CRPC) with poor prognosis after androgen deprivation therapy (ADT), including abiraterone, the drug of choice for ADT. Therefore, it is necessary to explore the resistance mechanism of abiraterone in depth. Genome‐wide CRISPR/Cas9 knockout technology was used to screen CRPC cell line 22Rv1 for abiraterone‐resistant genes. Combined with bioinformatics, a key gene with high expression and poor prognosis in CRPC patients was screened. Then, the effects of target gene on abiraterone‐resistant 22Rv1 cell function were explored by silencing and overexpression. Further, a natural product with potential targeting effect was identified and validated by molecular docking and protein expression. Molecular dynamics simulations revealed potential mechanism for the natural product affecting target protein expression. Finally, the combined anti‐CRPC effects of the natural product and abiraterone were validated by cellular and in vivo experiments. Five common resistance genes (KCNJ3, COL2A1, PPP1CA, MDH2 and EXOSC5) were identified successfully, among which high PPP1CA expression had the worst prognosis for disease‐free survival. Moreover, PPP1CA was highly expressed in abiraterone‐resistant 22Rv1 cells. Silencing PPP1CA increased cell sensitivity to abiraterone while promoting apoptosis and inhibiting clone formation. Overexpressing PPP1CA exerted the opposite effects. Molecular docking revealed the binding mode of the natural product nodularin‐R to PPP1CA with a dose‐dependent manner for inhibition. Mechanistically, nodularin‐R attenuates the interaction between PPP1CA and USP11 (deubiquitinating enzyme), potentially promoting PPP1CA degradation. Additionally, combination of 2.72 μM nodularin‐R and 54.5 μM abiraterone synergistically inhibited the resistant 22Rv1 cell function. In vivo experiments also revealed that combination therapy significantly inhibited tumour growth and reduced inducible expression of PPP1CA. PPP1CA is a key driver for abiraterone resistance, and nodularin‐R enhances the anti‐CRPC effects of abiraterone by inhibiting PPP1CA.

The impacts of climate change on cyanobacterial harmful algal blooms (cHABs) are paramount, promoting the widespread distribution, intensity, and toxicity of these phenomena in major freshwater bodies across the globe. Microcystins (MCs) and nodularins (NODs) are monocyclic peptides that produce hepatotoxic effects in living organisms. Despite efforts in understanding their molecular toxicological mechanisms, we do not fully have a grasp on the human health impacts associated with these toxins derived from freshwater cHABs. We seek to provide a current update on the toxicity and epidemiology of MCs and NODs, integrating key evidence from in vitro, in vivo, and epidemiological studies. The primary objective of this work is to understand the human health impacts of MC and NOD-producing cHABs.

Cyanobacteria are photoautotrophic organisms which occur in aquatic and terrestrial environments. They have the potential to produce toxins which pose a threat to human and animal health. This review covers the global distribution of the common cyanotoxins and related poisoning cases. A total of 468 selected articles on toxic cyanobacteria, dating from the earliest records until 2018, were reviewed. Most of the articles were published after 2000 (72%; 337 out of 468), which is consistent with the recent growth in interest in the analysis, toxinology and ecotoxicology of cyanotoxins. Animal and/or human poisoning cases were described in more than a third of the overall publications (38%; 177 out of 468). The reviewed publications showed that there were 1118 recorded identifications of major cyanotoxins in 869 freshwater ecosystems from 66 countries throughout the world. Microcystins were the most often recorded cyanotoxins worldwide (63%; 699 out of 1118), followed by cylindrospermopsin (10%; 107 out of 1118), anatoxins (9%; 100 out of 1118), and saxitoxins (8%; 93 out of 1118). Nodularins were the most rarely recorded cyanotoxins (2%; 19 out of 1118); however, there were also reports where cyanotoxins were not analysed or specified (9%; 100 out of 1118). The most commonly found toxic cyanobacterial genera were Microcystis spp. (669 reports), Anabaena spp. (397 reports), Aphanizomenon spp. (100 reports), Planktothrix spp. (98 reports), and Oscillatoria spp. (75 reports). Furthermore, there were 183 recorded cyanotoxin poisonings of humans and/or animals. Out of all toxic cyanobacterial blooms reviewed in this paper, the highest percentage of associated poisonings was found in North and Central America (39%; 69 cases out of 179), then Europe (20%; 35 out of 179), Australia including New Zealand (15%; 27 out of 179), and Africa (11%; 20 out of 179), while the lowest percentage was related to Asia (8%; 14 cases out of 179) and South America (8%; 14 cases out of 179). Events where only animals were known to have been affected were 63% (114 out of 182), whereas 32% (58 out of 182) of the investigated events involved only humans. A historical overview of human and animal poisoning episodes associated with cyanobacterial blooms is presented. Further, geographical data on the occurrence of cyanotoxins and related poisonings based on the available literature are shown. Some countries (mainly European) have done very intensive research on the occurrence of toxic cyanobacteria and cyanotoxins, and reported related ecotoxicological observations, while in some countries the lack of data is apparent. The true global extent of cyanotoxins and associated poisonings is likely to be greater than found in the available literature, and it can be assumed that ecotoxicological and hygienic problems caused by toxic cyanobacteria may occur in more environments.

Lichens are symbiotic associations between fungi and photosynthetic algae or cyanobacteria. Microcystins are potent toxins that are responsible for the poisoning of both humans and animals. These toxins are mainly associated with aquatic cyanobacterial blooms, but here we show that the cyanobacterial symbionts of terrestrial lichens from all over the world commonly produce microcystins. We screened 803 lichen specimens from five different continents for cyanobacterial toxins by amplifying a part of the gene cluster encoding the enzyme complex responsible for microcystin production and detecting toxins directly from lichen thalli. We found either the biosynthetic genes for making microcystins or the toxin itself in 12% of all analyzed lichen specimens. A plethora of different microcystins was found with over 50 chemical variants, and many of the variants detected have only rarely been reported from free-living cyanobacteria. In addition, high amounts of nodularin, up to 60 μg g–1, were detected from some lichen thalli. This microcystin analog and potent hepatotoxin has previously been known only from the aquatic bloom-forming genus NODULARIA: Our results demonstrate that the production of cyanobacterial hepatotoxins in lichen symbiosis is a global phenomenon and occurs in many different lichen lineages. The very high genetic diversity of the mcyE gene and the chemical diversity of microcystins suggest that lichen symbioses may have been an important environment for diversification of these cyanobacteria.

Nodularin (NOD) is a potent toxin produced by Nodularia spumigena cyanobacteria. Usually, NOD co-exists with other microcystins in environmental waters, a class of cyanotoxins secreted by certain cyanobacteria species, which makes identification difficult in the case of mixed toxins. Herein we report a complete theoretical DFT-vibrational Raman characterization of NOD along with the experimental drop-coating deposition Raman (DCDR) technique. In addition, we used the vibrational characterization to probe SERS analysis of NOD using colloidal silver nanoparticles (AgNPs), commercial nanopatterned substrates with periodic inverted pyramids (KlariteTM substrate), hydrophobic Tienta® SpecTrimTM slides, and in-house fabricated periodic nanotrenches by nanoimprint lithography (NIL). The 532 nm excitation source provided more well-defined bands even at LOD levels, as well as the best performance in terms of SERS intensity. This was reflected by the results obtained with the KlariteTM substrate and the silver-based colloidal system, which were the most promising detection approaches, providing the lowest limits of detection. A detection limit of 8.4 × 10−8 M was achieved for NOD in solution by using AgNPs. Theoretical computation of the complex vibrational modes of NOD was used for the first time to unambiguously assign all the specific vibrational Raman bands.

Recently, there has been a rise in freshwater harmful algal blooms (HABs) globally, as well as increasing aquaculture practices. HABs can produce cyanotoxins, many of which are hepatotoxins. An ultra-performance liquid chromatography tandem mass spectrometry method was developed and validated for nine cyanotoxins across three classes including six microcystins, nodularin, cylindrospermopsin and anatoxin-a. The method was used to analyse free cyanotoxin(s) in muscle ( n  = 34), liver ( n  = 17) and egg ( n  = 9) tissue samples of 34 fish sourced from aquaculture farms in Southeast Asia. Conjugated microcystin was analysed by Lemieux oxidation to ascertain the total amount of microcystin present in muscle. Some tilapia accumulated free microcystin-LR in the muscle tissue at a mean of 15.45 μg/kg dry weight (dw), with total microcystin levels detected at a mean level of 110.1 μg/kg dw, indicating that the amount of conjugated or masked microcystin present in the fish muscle accounted for 85% of the total. Higher levels of cyanotoxin were detected in the livers, with approximately 60% of those tested being positive for microcystin-LR and microcystin-LF, along with cylindrospermopsin. Two fish from one of the aquaculture farms contained cylindrospermopsin in the eggs; the first time this has been reported. The estimated daily intake for free and total microcystins in fish muscle tissue was 2 and 14 times higher, respectively, than the tolerable daily intake value. This survey presents the requirement for further monitoring of cyanotoxins, including masked microcystins, in aquaculture farming in these regions and beyond, along with the implementation of guidelines to safeguard human health. Graphical abstract ᅟ

In this paper, an LC-MS/MS method for the simultaneous identification and quantification of cyanotoxins with hydrophilic and lipophilic properties in edible bivalves is presented. The method includes 17 cyanotoxins comprising 13 microcystins (MCs), nodularin (NOD), anatoxin-a (ATX-a), homoanatoxin (h-ATX) and cylindrospermopsin (CYN). A benefit to the presented method is the possibility for the MS detection of MC-LR-[Dha7] and MC-LR-[Asp3] as separately identified and MS-resolved MRM signals, two congeners which were earlier detected together. The performance of the method was evaluated by in-house validation using spiked mussel samples in the quantification range of 3.12–200 µg/kg. The method was found to be linear over the full calibration range for all included cyanotoxins except CYN for which a quadratic regression was used. The method showed limitations for MC-LF (R2 = 0.94), MC-LA (R2 ≤ 0.98) and MC-LW (R2 ≤ 0.98). The recoveries for ATX-a, h-ATX, CYN, NOD, MC-LF and MC-LW were lower than desired (<70%), but stable. Despite the given limitations, the validation results showed that the method was specific and robust for the investigated parameters. The results demonstrate the suitability of the method to be applied as a reliable monitoring tool for the presented group of cyanotoxins, as well as highlight the compromises that need to be included if multi-toxin methods are to be used for the analysis of cyanotoxins with a broader range of chemical properties. Furthermore, the method was used to analyze 13 samples of mussels (Mytilus edulis) and oysters (Magallana gigas) collected in the 2020–2022 summers along the coast of Bohuslän (Sweden). A complementary qualitative analysis for the presence of cyanotoxins in phytoplankton samples collected from marine waters around southern Sweden was performed with the method. Nodularin was identified in all samples and quantified in bivalve samples in the range of 7–397 µg/kg. Toxins produced by cyanobacteria are not included in the European Union regulatory monitoring of bivalves; thus, the results presented in this study can be useful in providing the basis for future work including cyanotoxins within the frame of regulatory monitoring to increase seafood safety.

The Drinking Water Directive (EU) 2020/2184 includes the parameter microcystin LR, a cyanotoxin, which drinking water producers need to analyze if the water source has potential for cyanobacterial blooms. In light of the increasing occurrences of cyanobacterial blooms worldwide and given that more than 50 percent of the drinking water in Sweden is produced from surface water, both fresh and brackish, the need for improved knowledge about cyanotoxin occurrence and cyanobacterial diversity has increased. In this study, a total of 98 cyanobacterial blooms were sampled in 2016–2017 and identified based on their toxin production and taxonomical compositions. The surface water samples from freshwater lakes throughout Sweden including brackish water from eight east coast locations along the Baltic Sea were analyzed for their toxin content with LC-MS/MS and taxonomic composition with 16S rRNA amplicon sequencing. Both the extracellular and the total toxin content were analyzed. Microcystin’s prevalence was highest with presence in 82% of blooms, of which as a free toxin in 39% of blooms. Saxitoxins were found in 36% of blooms in which the congener decarbamoylsaxitoxin (dcSTX) was detected for the first time in Swedish surface waters at four sampling sites. Anatoxins were most rarely detected, followed by cylindrospermopsin, which were found in 6% and 10% of samples, respectively. As expected, nodularin was detected in samples collected from the Baltic Sea only. The cyanobacterial operational taxonomic units (OTUs) with the highest abundance and prevalence could be annotated to Aphanizomenon NIES-81 and the second most profuse cyanobacterial taxon to Microcystis PCC 7914. In addition, two correlations were found, one between Aphanizomenon NIES-81 and saxitoxins and another between Microcystis PCC 7914 and microcystins. This study is of value to drinking water management and scientists involved in recognizing and controlling toxic cyanobacteria blooms.

Nodularin (NOD) and cylindrospermopsin (CYN) are hepatotoxic cyanotoxins that are present in numerous ecosystems where bloom episodes occur. In this review, the different effects of both of these cyanotoxins on the different ontogenic stages of various fish species were summarised to clarify the state-of-the-art scientific knowledge on this topic. It is clear that fish that are exposed to NOD and CYN were negatively impacted in every studied ontogenic stage. Indeed, these cyanotoxins can accumulate in various organs of fish, leading to deleterious effects on the physiology. This review highlights the fact that all of the previously published studies on the topic have focused only on the short-term effects of a given cyanotoxin on fish. However, during cyanobacterial blooms, fish can be exposed chronically to a variety of toxic compounds with which the fish interact, leading to stronger effects than those observed with a single toxin tested over a short timeframe. Thus, it is essential to conduct additional studies to better understand the actual toxic effects of cyanobacterial blooms on fish populations over medium- and long-term time scales.

Future sustainability of freshwater resources is seriously threatened due to the presence of harmful cyanobacterial blooms, and yet, the number, extent, and distribution of most cyanobacterial toxins—including “emerging” toxins and other bioactive compounds—are poorly understood. We measured 15 cyanobacterial compounds—including four microcystins (MC), saxitoxin (SXT), cylindrospermopsin (CYL), anatoxin-a (ATX) and homo-anatoxin-a (hATX), two anabaenopeptins (Apt), three cyanopeptolins (Cpt), microginin (Mgn), and nodularin (NOD)—in six freshwater lakes that regularly experience noxious cHABs. MC, a human liver toxin, was present in all six lakes and was detected in 80% of all samples. Similarly, Apt, Cpt, and Mgn were detected in all lakes in roughly 86%, 50%, and 35% of all samples, respectively. Despite being a notable brackish water toxin, NOD was detected in the two shallowest lakes—Wingra (4.3 m) and Koshkonong (2.1 m). All compounds were highly variable temporally, and spatially. Metabolite profiles were significantly different between lakes suggesting lake characteristics influenced the cyanobacterial community and/or metabolite production. Understanding how cyanobacterial toxins are distributed across eutrophic lakes may shed light onto the ecological function of these metabolites, provide valuable information for their remediation and removal, and aid in the protection of public health.