The Ocean's Pharmacy: Health Discoveries in Marine Algae.

Non-communicable diseases (NCDs) represent a global health challenge, constituting a major cause of mortality and disease burden in the 21st century. Addressing the prevention and management of NCDs is crucial for improving global public health, emphasizing the need for comprehensive strategies, early interventions, and innovative therapeutic approaches to mitigate their far-reaching consequences. Marine organisms, mainly algae, produce diverse marine natural products with significant therapeutic potential. Harnessing the largely untapped potential of algae could revolutionize drug development and contribute to combating NCDs, marking a crucial step toward natural and targeted therapeutic approaches. This review examines bioactive extracts, compounds, and commercial products derived from macro- and microalgae, exploring their protective properties against oxidative stress, inflammation, cardiovascular, gastrointestinal, metabolic diseases, and cancer across in vitro, cell-based, in vivo, and clinical studies. Most research focuses on macroalgae, demonstrating antioxidant, anti-inflammatory, cardioprotective, gut health modulation, metabolic health promotion, and anti-cancer effects. Microalgae products also exhibit anti-inflammatory, cardioprotective, and anti-cancer properties. Although studies mainly investigated extracts and fractions, isolated compounds from algae have also been explored. Notably, polysaccharides, phlorotannins, carotenoids, and terpenes emerge as prominent compounds, collectively representing 42.4% of the investigated compounds.

Shedding Light on the Hidden Benefit of Porphyridium cruentum Culture.

Microalgae can represent a reliable source of natural compounds with different activities. Here, we evaluated the antioxidant and anti-inflammatory activity of sulfated exopolysaccharides (s-EPSs) and phycoerythrin (PE), two molecules naturally produced by the red marine microalga Porphyridium cruentum (CCALA415). In vitro and cell-based assays were performed to assess the biological activities of these compounds. The s-EPSs, owing to the presence of sulfate groups, showed biocompatibility on immortalized eukaryotic cell lines and a high antioxidant activity on cell-based systems. PE showed powerful antioxidant activity both in vitro and on cell-based systems, but purification is mandatory for its safe use. Finally, both molecules showed anti-inflammatory activity comparable to that of ibuprofen and helped tissue regeneration. Thus, the isolated molecules from microalgae represent an excellent source of antioxidants to be used in different fields.

Spatio-temporal evaluation of macro, meso and microplastics in surface waters, bottom and beach sediments of two embayments in Niterói, RJ, Brazil.

This study evaluated in the dry and rainy periods, the anthropogenic influence and the hydrodynamics in the distribution of plastic items in surface waters and bottom and beach sediments of the Jurujuba (Guanabara Bay, low and medium hydrodynamic) and Itaipu (oceanic region, high hydrodynamics) embayments; places of cultivation and extraction of mussels. Microplastics were 83% of the wastes collected, with a higher average concentration (138.41 items.kg-1) in beach sediments. High density polyethylene (HDPE) (38%), polypropylene (21%), and styrene (10%) were the most frequent polymers. There was no difference between the water and bottom sediment samples in the different embayments, in the studied periods, different from that observed in the beach sediment samples, with higher concentrations in the rainy season in Jurujuba. The results suggest that beach sediments are the best compartment to understand the dynamics of the distribution of plastic waste over time.

Prevalence of contamination by intestinal parasites in vegetables (Lactuca sativa L. and Coriandrum sativum L.) sold in markets in Belém, northern Brazil.

BACKGROUND: Previous studies have recorded a high prevalence of intestinal parasites in lettuce (Lactuca sativa L.) and coriander (Coriandrum sativum L.) destined for human consumption. This study determined the prevalence of contamination by intestinal parasites in these two plants sold in two street markets and two supermarkets in the city of Belém, northern Brazil. RESULTS: A total of 200 plant samples were analyzed (100 of each species). The samples were collected randomly between August and October 2018, examined by the spontaneous sedimentation method with two washes, and stored for 24 h. The analysis found that 89% (89/100) of the lettuce samples and 86% (86/100) of the coriander samples were contaminated. Polyparasitism was more frequent in lettuce, but monoparasitism predominated in the coriander. A total of 226 intestinal parasites were found in the lettuce, with a predominance of non-pathogenic parasites in the supermarket samples and more pathogenic parasites in the samples from street markets. In the coriander samples, 172 intestinal parasites were identified, with a predominance of pathogenic parasites in samples from both types of market. In the case of the protozoans, the most prevalent species was Endolimax nana, followed by Blastocystis hominis, in both vegetables. In the helminths, hookworms predominated in the lettuce, and Trichuris trichiura in the coriander. CONCLUSIONS: These results highlight the need for the monitoring of parasite contamination in vegetables destined for human consumption. Public health initiatives should include educational campaigns on the importance of disinfecting vegetables prior to consumption. © 2020 Society of Chemical Industry.

HBO1 is required for the maintenance of leukaemia stem cells.

Acute myeloid leukaemia (AML) is a heterogeneous disease characterized by transcriptional dysregulation that results in a block in differentiation and increased malignant self-renewal. Various epigenetic therapies aimed at reversing these hallmarks of AML have progressed into clinical trials, but most show only modest efficacy owing to an inability to effectively eradicate leukaemia stem cells (LSCs)1. Here, to specifically identify novel dependencies in LSCs, we screened a bespoke library of small hairpin RNAs that target chromatin regulators in a unique ex vivo mouse model of LSCs. We identify the MYST acetyltransferase HBO1 (also known as KAT7 or MYST2) and several known members of the HBO1 protein complex as critical regulators of LSC maintenance. Using CRISPR domain screening and quantitative mass spectrometry, we identified the histone acetyltransferase domain of HBO1 as being essential in the acetylation of histone H3 at K14. H3 acetylated at K14 (H3K14ac) facilitates the processivity of RNA polymerase II to maintain the high expression of key genes (including Hoxa9 and Hoxa10) that help to sustain the functional properties of LSCs. To leverage this dependency therapeutically, we developed a highly potent small-molecule inhibitor of HBO1 and demonstrate its mode of activity as a competitive analogue of acetyl-CoA. Inhibition of HBO1 phenocopied our genetic data and showed efficacy in a broad range of human cell lines and primary AML cells from patients. These biological, structural and chemical insights into a therapeutic target in AML will enable the clinical translation of these findings.

Inhibitors of histone acetyltransferases KAT6A/B induce senescence and arrest tumour growth.

Acetylation of histones by lysine acetyltransferases (KATs) is essential for chromatin organization and function1. Among the genes coding for the MYST family of KATs (KAT5-KAT8) are the oncogenes KAT6A (also known as MOZ) and KAT6B (also known as MORF and QKF)2,3. KAT6A has essential roles in normal haematopoietic stem cells4-6 and is the target of recurrent chromosomal translocations, causing acute myeloid leukaemia7,8. Similarly, chromosomal translocations in KAT6B have been identified in diverse cancers8. KAT6A suppresses cellular senescence through the regulation of suppressors of the CDKN2A locus9,10, a function that requires its KAT activity10. Loss of one allele of KAT6A extends the median survival of mice with MYC-induced lymphoma from 105 to 413 days11. These findings suggest that inhibition of KAT6A and KAT6B may provide a therapeutic benefit in cancer. Here we present highly potent, selective inhibitors of KAT6A and KAT6B, denoted WM-8014 and WM-1119. Biochemical and structural studies demonstrate that these compounds are reversible competitors of acetyl coenzyme A and inhibit MYST-catalysed histone acetylation. WM-8014 and WM-1119 induce cell cycle exit and cellular senescence without causing DNA damage. Senescence is INK4A/ARF-dependent and is accompanied by changes in gene expression that are typical of loss of KAT6A function. WM-8014 potentiates oncogene-induced senescence in vitro and in a zebrafish model of hepatocellular carcinoma. WM-1119, which has increased bioavailability, arrests the progression of lymphoma in mice. We anticipate that this class of inhibitors will help to accelerate the development of therapeutics that target gene transcription regulated by histone acetylation.

Marine debris on beaches of Arraial do Cabo, RJ, Brazil: An important coastal tourist destination.

Arraial do Cabo, RJ, Brazil, is known as the diving capital due to its clear waters and great biodiversity, a consequence of the upwelling phenomenon. This feature attracts tourists tripling their population during holidays, causing increase in the amount of debris on beaches and waters endangering marine biodiversity. To evaluate the amount of solid waste found on beaches in two different holiday period, eight people in each beach collected macrodebris (≥2 cm) in a transect covering an 20 m wide area, during 20 min, in winter/2015 and summer/2017. The materials were weighed, quantified and characterized. In the summer, when the number of tourists is greater, a larger total amount of waste in units were found. Plastic and cigarette butts were the most abundant. The results show that the city does not have adequate planning to receive a large amount of tourists, being vulnerable to socioeconomic and environmental damages.

The influence of the intensity of use, rainfall and location in the amount of marine debris in four beaches in Niteroi, Brazil: Sossego, Camboinhas, Charitas and Flechas.

The presence of marine debris in coastal and oceanic regions is a worldwide and growing problem and own to different factors. In order to check the influence of some of these factors in the amount of debris in these areas, we quantified and identified marine debris found on sand of four beaches in the city of Niterói, RJ during dry and rainy seasons; two in oceanic region and two in Guanabara Bay, and observed the intensity of use of them by people. Our results showed that intensity of use and intensity of rain had influence in the presence and amount of solid waste collected. Environmental education campaigns and improvements in basic sanitation are extremely necessary to prevent the pollution of aquatic environments and get improvements on waste management in the cities of Niterói, RJ.

Evaluation of microplastics in Jurujuba Cove, Niterói, RJ, Brazil, an area of mussels farming.

Once non-biodegradable, microplastics remain on the environment absorbing toxic hydrophobic compounds making them a risk to biodiversity when ingested or filtered by organisms and entering in the food chain. To evaluate the potential of the contamination by microplastics in mussels cultivated in Jurujuba Cove, Niterói, RJ, waters of three stations were collected during a rain and dry seasons using a plankton net and later filtered. Microplastics were quantified and characterized morphologically and chemically. The results showed a high concentration of microplastics in both seasons with diversity of colors, types and sizes. Synthetic polymers were present in all samples. The presence of microplastics was probably due to a high and constant load of effluent that this area receives and to the mussel farming activity that use many plastic materials. Areas with high concentrations of microplastics could not be used for mussel cultivation due to the risk of contamination to consumers.

Discovery and SAR of novel pyrazolo[1,5-a]pyrimidines as inhibitors of CDK9.

The serine-threonine kinase CDK9 is a target of emerging interest for the development of anti-cancer drugs. There are multiple lines of evidence linking CDK9 activity to cancer, including the essential role this kinase plays in transcriptional regulation through phosphorylation of the C-terminal domain (CTD) of RNA polymerase II. Indeed, inhibition of CDK9 has been shown to result in a reduction of short-lived proteins such as the pro-survival protein Mcl-1 in malignant cells leading to the induction of apoptosis. In this work we report our initial studies towards the discovery of selective CDK9 inhibitors, starting from the known multi-kinase inhibitor PIK-75 which possesses potent CDK9 activity. Our series is based on a pyrazolo[1,5-a]pyrimidine nucleus and, importantly, the resultant lead compound 18b is devoid of the structural liabilities present in PIK-75 and possesses greater selectivity.

Spatial-temporal analysis of marine debris on beaches of Niterói, RJ, Brazil: Itaipu and Itacoatiara.

In many areas of the world, studies of marine debris are conducted with an emphasis on analyzing their composition, quantification and distribution on sandy beaches. However, in Brazil, studies are still restricted to some areas of the coast, and the quantities and the spatial and temporal patterns are unknown. To enhance the marine debris information in these areas, we selected the Itaipu and Itacoatiara beaches in Niterói, RJ, to collect, quantify and qualify the solid residues present in their sands. We collected 12 samples and recorded 118.39 kg of residues in Itaipu and 62.94 kg in Itacoatiara. At both beaches, the largest portion of debris was located on the upper part of the beach. Several debris items were related to food and drink consumption on the beaches, which indicated the contribution of beach users to pollution. Most of the debris was plastic. The greatest amount of debris was found at Itaipu in January and February and at Itacoatiara in January and March, months related to both the holiday season and abundant rainfall. The results demonstrated the necessity to implement an Environmental Education project for these areas to reduce its degradation.

Characterization of the novel broad-spectrum kinase inhibitor CTx-0294885 as an affinity reagent for mass spectrometry-based kinome profiling.

Kinase enrichment utilizing broad-spectrum kinase inhibitors enables the identification of large proportions of the expressed kinome by mass spectrometry. However, the existing inhibitors are still inadequate in covering the entire kinome. Here, we identified a novel bisanilino pyrimidine, CTx-0294885, exhibiting inhibitory activity against a broad range of kinases in vitro, and further developed it into a Sepharose-supported kinase capture reagent. Use of a quantitative proteomics approach confirmed the selectivity of CTx-0294885-bound beads for kinase enrichment. Large-scale CTx-0294885-based affinity purification followed by LC-MS/MS led to the identification of 235 protein kinases from MDA-MB-231 cells, including all members of the AKT family that had not been previously detected by other broad-spectrum kinase inhibitors. Addition of CTx-0294885 to a mixture of three kinase inhibitors commonly used for kinase-enrichment increased the number of kinase identifications to 261, representing the largest kinome coverage from a single cell line reported to date. Coupling phosphopeptide enrichment with affinity purification using the four inhibitors enabled the identification of 799 high-confidence phosphosites on 183 kinases, ∼10% of which were localized to the activation loop, and included previously unreported phosphosites on BMP2K, MELK, HIPK2, and PRKDC. Therefore, CTx-0294885 represents a powerful new reagent for analysis of kinome signaling networks that may facilitate development of targeted therapeutic strategies. Proteomics data have been deposited to the ProteomeXchange Consortium ( http://proteomecentral.proteomexchange.org ) via the PRIDE partner repository with the data set identifier PXD000239.

The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity.

The systematic translation of cancer genomic data into knowledge of tumour biology and therapeutic possibilities remains challenging. Such efforts should be greatly aided by robust preclinical model systems that reflect the genomic diversity of human cancers and for which detailed genetic and pharmacological annotation is available. Here we describe the Cancer Cell Line Encyclopedia (CCLE): a compilation of gene expression, chromosomal copy number and massively parallel sequencing data from 947 human cancer cell lines. When coupled with pharmacological profiles for 24 anticancer drugs across 479 of the cell lines, this collection allowed identification of genetic, lineage, and gene-expression-based predictors of drug sensitivity. In addition to known predictors, we found that plasma cell lineage correlated with sensitivity to IGF1 receptor inhibitors; AHR expression was associated with MEK inhibitor efficacy in NRAS-mutant lines; and SLFN11 expression predicted sensitivity to topoisomerase inhibitors. Together, our results indicate that large, annotated cell-line collections may help to enable preclinical stratification schemata for anticancer agents. The generation of genetic predictions of drug response in the preclinical setting and their incorporation into cancer clinical trial design could speed the emergence of 'personalized' therapeutic regimens.

Care management and the transition of older adults from a skilled nursing facility back into the community.

After hospitalization, many older adults require skilled nursing care. Although some patients receive services at home, others are admitted to a skilled nursing facility. In the current fragmented health care system, hospitals are financially incentivized to discharge frail older adults to a facility for postacute care as soon as possible. Similarly, many skilled nursing facilities are incentivized to extend the posthospitalization period of care and to transition the patient to custodial nursing home care. The resulting overuse of institution-based skilled nursing care may be associated with various adverse medical social and financial consequences. Care management interventions for more efficient and effective skilled nursing facility use must consider the determinants involved in the decisions to admit and maintain patients in skilled nursing facilities. As we await health care reform efforts that will address these barriers, opportunities already exist for care managers to improve the current postacute transition processes.

Sez-6 proteins affect dendritic arborization patterns and excitability of cortical pyramidal neurons.

Development of appropriate dendritic arbors is crucial for neuronal information transfer. We show, using seizure-related gene 6 (sez-6) null mutant mice, that Sez-6 is required for normal dendritic arborization of cortical neurons. Deep-layer pyramidal neurons in the somatosensory cortex of sez-6 null mice exhibit an excess of short dendrites, and cultured cortical neurons lacking Sez-6 display excessive neurite branching. Overexpression of individual Sez-6 isoforms in knockout neurons reveals opposing actions of membrane-bound and secreted Sez-6 proteins, with membrane-bound Sez-6 exerting an antibranching effect under both basal and depolarizing conditions. Layer V pyramidal neurons in knockout brain slices show reduced excitatory postsynaptic responses and a reduced dendritic spine density, reflected by diminished punctate staining for postsynaptic density 95 (PSD-95). In behavioral tests, the sez-6 null mice display specific exploratory, motor, and cognitive deficits. In conclusion, cell-surface protein complexes involving Sez-6 help to sculpt the dendritic arbor, in turn enhancing synaptic connectivity.

Automated analysis of neurite branching in cultured cortical neurons using HCA-Vision.

Manual neuron tracing is a very labor-intensive task. In the drug screening context, the sheer number of images to process means that this approach is unrealistic. Moreover, the lack of reproducibility, objectivity, and auditing capability of manual tracing is limiting even in the context of smaller studies. We have developed fast, sensitive, and reliable algorithms for the purpose of detecting and analyzing neurites in cell cultures, and we have integrated them in software called HCA-Vision, suitable for the research environment. We validate the software on images of cortical neurons by comparing results obtained using HCA-Vision with those obtained using an established semi-automated tracing solution (NeuronJ). The effect of the Sez-6 deletion was characterized in detail. Sez-6 null neurons exhibited a significant increase in neurite branching, although the neurite field area was unchanged due to a reduction in mean branch length. HCA-Vision delivered considerable speed benefits and reliable traces.

Abnormalities of the RB1 pathway in ovarian serous papillary carcinoma as determined by overexpression of the p16(INK4A) protein.

Dysfunction of proteins involved in the G1 to S transition of the cell cycle, such as p16(INK4A) and RB1, is common in many cancer types. A screen of p16 protein expression was performed in benign, borderline, and invasive ovarian tumors, together with endometrial cancers, aligned on a tissue microarray. We observed frequent p16 overexpression in serous papillary carcinomas of ovarian and endometrial origin. An extended cohort of ovarian serous papillary carcinomas was examined to further evaluate the frequency of p16 overexpression. Strong, uniform staining in the majority of cancer cells occurred commonly in invasive serous papillary ovarian cancers, particularly in grade 3 carcinomas. RB1 protein expression abnormalities were rare. Our data indicate that abnormalities in the retinoblastoma pathway, as determined by p16 overexpression, are common in serous papillary carcinomas and are probably an early event.

Complex CGH alterations on chromosome arm 8p at candidate tumor suppressor gene loci in breast cancer cell lines.

Loss of genetic material from chromosome arm 8p occurs frequently in human breast carcinomas, consistent with this region of the genome harboring one or more tumor suppressor genes (TSGs). We used the complementary techniques of microsatellite-based LOH, high-density FISH, and conventional CGH on 6 breast cancer cell lines (MCF7, SKBR3, T47D, MDA MB453, BT549, and BT474) to investigate the molecular cytogenetic changes occurring on chromosome 8 during tumorigenesis, with particular emphasis on 6 potential TSGs on 8p. We identified multiple alterations of chromosome 8, including partial or complete deletion of 8p or 8q, duplication of 8q, and isochromosome 8q. The detailed FISH analysis showed several complex rearrangements of 8p with differing breakpoints of varying proximity to the genes of interest. High rates of LOH were observed at markers adjacent to or within PCM1, DUSP4/MKP2, NKX3A, and DLC1, supporting their status as candidate TSGs. Due to the complex ploidy status of these cell lines, relative loss of 8p material detected by CGH did not always correlate with microsatellite-based LOH results. These results extend our understanding of the mechanisms accompanying the dysregulation of candidate tumor suppressor loci on chromosome arm 8p, and identify appropriate cellular systems for further investigation of their biological properties.

Tissue microarrays: a practical guide.

Tissue microarrays are a recent innovation in the field of pathology. They were originally designed as a high-throughput approach for researchers to assess the expression of interesting candidate disease-related genes or gene products simultaneously on hundreds of tissue samples. However, their use is becoming more widespread in routine pathology, for example for quality assurance and for the optimisation of diagnostic reagents such as monoclonal antibodies and gene probes. Several molecular and conventional pathological techniques can be performed on a single tissue array, thereby enabling morphology, DNA, RNA and protein targets to be analysed on sequential sections through multiple tissue samples. Moreover, compared with full-face tissue sections, tissue microarrays are a cost- and time-efficient, effective approach to analysing biomarker expression on a large number of samples. Whilst tissue microarrays are available from commercial sources, many pathology laboratories prefer to make in-house arrays from their often extensive pathology archive to facilitate the correlation of their findings with clinical parameters. The technical skills necessary to produce tissue arrays are well within the capacity of most laboratories. However, several pitfalls to successful array production exist. The present article describes the applications of this technique and details practical points for optimal tissue array production.