Treatment of castration-resistant prostate cancer (CRPC) remains challenging due to the development of drug resistance. The Warburg effect describes the ability of cancer cells to consume larger amounts of glucose compared to normal tissues. We identified derivatives of natural 1,4-naphthoquinones to be active in CRPC and further synthetically modified them via glucose conjugation to increase selectivity by Warburg effect targeting. Mechanisms of action were examined by quantitative proteomics followed by bioinformatical analysis and target validation. Four synthesized molecules revealed the highest selectivity towards human CRPC cells, which correlated with higher GLUT-1 activity and expression. The compounds were able to induce pro-apoptotic signs and to inhibit the pro-survival processes and mechanisms of drug resistance (i.e., AR-signaling and autophagy). Proteome analysis suggested a disruption of the mitochondria/oxidative phosphorylation, which was validated by further functional analysis: thus, mitochondria depolarization, elevated levels of cytotoxic ROS, an increase of Bax/Bcl-2 ratio as well as release of mitochondrial AIF and cytochrome C to cytoplasm were observed. In conclusion, glucose-conjugated 1,4-naphthoquinones show potent activity and selectivity in human CRPC exerted via mitochondrial targeting. The compounds can overcome drug resistance against current standard therapies and suppress pro-survival mechanisms. This unique combination of properties makes them new promising candidates for the treatment of CRPC.

Broccoli sprouts are an excellent source of health-promoting phytochemicals such as vitamins, glucosinolates, and phenolics. The study aimed to investigate in vitro antioxidant, antiproliferative, apoptotic, and antibacterial activities of broccoli sprouts. Five-day-old sprouts extracted by 70% ethanol showed significant antioxidant activities, analyzed to be 68.8 μmol Trolox equivalent (TE)/g dry weight by 2,2'-azino-bis-3-ethylbenzothiazoline-6-sulphonic (ABTS) assay, 91% scavenging by 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay, 1.81 absorbance by reducing power assay, and high phenolic contents by high-performance liquid chromatography (HPLC). Thereafter, sprout extract indicated considerable antiproliferative activities towards A549 (lung carcinoma cells), HepG2 (hepatocellular carcinoma cells), and Caco-2 (colorectal adenocarcinoma cells) using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, with IC50 values of 0.117, 0.168 and 0.189 mg/mL for 48 h, respectively. Furthermore, flow cytometry confirmed that Caco-2 cells underwent apoptosis by an increase of cell percentage in subG1 phase to 31.3%, and a loss of mitochondrial membrane potential to 19.3% after 48 h of treatment. Afterward, the extract exhibited notable antibacterial capacities against Bacillus subtilis and Salmonella Typhimurium with minimum inhibition concentration (MIC) values of 0.39 and 0.78 mg/mL, appropriately, along with abilities against Staphylococcus aureus and Escherichia coli with an MIC value of 1.56 mg/mL. Thus, broccoli sprouts were confirmed as a potential food source for consumers' selection and functional food industry.

The green synthesis of nanoparticles (NPs) is currently under worldwide investigation as an eco-friendly alternative to traditional routes (NPs): the absence of toxic solvents and catalysts make it suitable in the design of promising nanomaterials for nanomedicine applications. In this work, we used the extracts collected from leaves of two cultivars (Leccino and Carolea) belonging to the species Olea Europaea, to synthesize silver NPs (AgNPs) in different pH conditions and low temperature. NPs underwent full morphological characterization with the aim to define a suitable protocol to obtain a monodispersed population of AgNPs. Afterwards, to validate the reproducibility of the mentioned synthetic procedure, we moved on to another Mediterranean plant, the Laurus Nobilis. Interestingly, the NPs obtained using the two olive cultivars produced NPs with different shape and size, strictly depending on the cultivar selected and pH. Furthermore, the potential ability to inhibit the growth of two woman cancer cells (breast adenocarcinoma cells, MCF-7 and human cervical epithelioid carcinoma, HeLa) were assessed for these AgNPs, as well as their capability to mitigate the bacteria concentration in samples of contaminated well water. Our results showed that toxicity was stronger when MCF-7 and Hela cells were exposed to AgNPs derived from Carolea obtained at pH 7 presenting irregular shape; on the other hand, greater antibacterial effect was revealed using AgNPs obtained at pH 8 (smaller and monodispersed) on well water, enriched with bacteria and coliforms.

MicroRNAs (miRNAs) are small, single-stranded RNA sequences that regulate gene expression on a post-transcriptional level. In the last few decades, various trials have investigated the diagnostic and therapeutic potential of miRNAs in several disease entities. Here, we provide a review of the available evidence on miRNAs in inflammatory heart diseases (myocarditis, endocarditis, and pericarditis) and sepsis-induced cardiac dysfunction.

Whereas a majority of monogenean flatworms are ectoparasitic, i.e., parasitize on external surfaces (mainly gills) of their fish hosts, Enterogyrus species (subfamily Ancyrocephalinae) are mesoparasitic, i.e., parasitize in the stomach of the host. As there are numerous drastic differences between these two environments (including lower oxygen availability), we hypothesized that this life-history innovation might have produced adaptive pressures on the energy metabolism, which is partially encoded by the mitochondrial genome (OXPHOS). To test this hypothesis, we sequenced mitochondrial genomes of two Ancyrocephalinae species: mesoparasitic E. malmbergi and ectoparasitic Ancyrocephalus mogurndae. The mitogenomic architecture of E. malmbergi is mostly standard for monogeneans, but that of A. mogurndae exhibits some unique features: missing trnL2 gene, very low AT content (60%), a non-canonical start codon of the nad2 gene, and exceptionally long tandem-repeats in the non-coding region (253 bp). Phylogenetic analyses produced paraphyletic Ancyrocephalinae (with embedded Dactylogyrinae), but with low support values. Selective pressure (PAML and HYPHY) and protein structure analyses all found evidence for adaptive evolution in cox2 and cox3 genes of the mesoparasitic E. malmbergi. These findings tentatively support our hypothesis of adaptive evolution driven by life-history innovations in the mitogenome of this species. However, as only one stomach-inhabiting mesoparasitic monogenean was available for this analysis, our findings should be corroborated on a larger number of mesoparasitic monogeneans and by physiological studies.

(1) Background: The human gut microbiota at early life is shaped by numerous factors, especially factors from mothers, which have huge influence on infants' gut microbiotas. The aim of this study was to investigate the effect of maternal adherence to Chinese traditional postpartum practices of "doing the month" on the development of infant gut microbiota at 6-month postpartum. (2) Methods: A cohort of 62 Chinese women at late pregnancy was recruited from a tertiary general hospital in a central region of China. The participants and their babies were followed up to 6 months postpartum. Finally, 50 mother-infant dyads were enrolled in the study. Women's adherence to the traditional postpartum practices was measured by adherence to doing the month practices (ADP). Infant fecal samples were collected at six months of age and were analyzed using 16S rRNA V3 and V4 gene region sequences. (3) Results: Ruminococcus gnavus was significantly less abundant in infants whose mothers had a better adherence to the traditional postpartum practices of "doing the month." Infants receiving Clostridium-butyricum during the first month after delivery had a significant dominance of Escherichia/Shigella. (4) Conclusions: Adherence to the traditional postpartum practices of "doing the month" can impact an infant's gut microbiota at 6 months of age. Infants receiving probiotics during the first month after delivery had a significant dominance of opportunistic pathogens.

Complete restoring of functional connectivity between neurons or target tissue after traumatic lesions is still an unmet medical need. Using models of nerve axotomy and compression, we investigated the effect of autophagy induction by genetic and pharmacological manipulation on motor nerve regeneration. ATG5 or NAD+-dependent deacetylase sirtuin-1 (SIRT1) overexpression on spinal motoneurons stimulates mTOR-independent autophagy and facilitates a growth-competent state improving motor axonal regeneration with better electromyographic records after nerve transection and suture. In agreement with this, using organotypic spinal cord cultures and the human cell line SH-SY5Y, we observed that the activation of SIRT1 and autophagy by NeuroHeal increased neurite outgrowth and length extension and that this was mediated by downstream HIF1a. To conclude, SIRT1/Hifα-dependent autophagy confers a more pro-regenerative phenotype to motoneurons after peripheral nerve injury. Altogether, we provide evidence showing that autophagy induction by SIRT1/Hifα activation or NeuroHeal treatment is a novel therapeutic option for improving motor nerve regeneration and functional recovery after injury.

Polymyositis (PM) and dermatomyositis (DM) are both classified as idiopathic inflammatory myopathies. They share a few common characteristics such as inflammation and muscle weakness. Previous studies have indicated that these diseases present aspects of an auto-immune disorder; however, their exact pathogenesis is still unclear. In this study, three gene expression datasets (PM: 7, DM: 50, Control: 13) available in public databases were used to conduct meta-analysis. We then conducted expression quantitative trait loci analysis to detect the variant sites that may contribute to the pathogenesis of PM and DM. Six-hundred differentially expressed genes were identified in the meta-analysis (false discovery rate (FDR) < 0.01), among which 317 genes were up-regulated and 283 were down-regulated in the disease group compared with those in the healthy control group. The up-regulated genes were significantly enriched in interferon-signaling pathways in protein secretion, and/or in unfolded-protein response. We detected 10 single nucleotide polymorphisms (SNPs) which could potentially play key roles in driving the PM and DM. Along with previously reported genes, we identified 4 novel genes and 10 SNP-variant regions which could be used as candidates for potential drug targets or biomarkers for PM and DM.

A series of 34 1,2,3-triazole-naphthoquinone conjugates were synthesized via copper-catalyzed cycloaddition (CuAAC). They were evaluated for their in vitro antimalarial activity against chloroquine-sensitive strains of Plasmodium falciparum and against three different tumor cell lines (SKBr-3, MCF-7, HEL). The most active antimalarial compounds showed a low antiproliferative activity. Simplified analogues were also obtained and some structure-activity relationships were outlined. The best activity was obtained by compounds 3s and 3j, having IC50 of 0.8 and 1.2 μM, respectively. Molecular dockings were also carried on Plasmodium falciparum enzyme dihydroorotate dehydrogenase (PfDHODH) in order to rationalize the results.

The growing market demand for plant raw materials with improved biological value promotes the extensive search for new elicitors and biostimulants. Gellan gum derivatives may enhance plant growth and development, but have never been used under stress conditions. Perilla (Perilla frutescens, Lamiaceae) is a source of valuable bioproducts for the pharmaceutical, cosmetic, and food industries. However, there is not much information on the use of biostimulators in perilla cultivation. In this work we investigated the effects of oligo-gellan and salt (100 mM NaCl) on the yield and quality of red perilla (P. frutescens var. crispa f. purpurea) leaves. Plants grown under stress showed inhibited growth, smaller biomass, their leaves contained less nitrogen, phosphorus, potassium, total polyphenol and total anthocyanins, and accumulated considerably more sodium than control plants. Treatment with oligo-gellan under non-saline conditions stimulated plant growth and the fresh weight content of the above-ground parts, enhanced the accumulation of nitrogen, potassium, magnesium and total polyphenols, and increased antioxidant activity as assessed by DPPH and ABTS assays. Oligo-gellan applied under saline conditions clearly alleviated the stress effects by limiting the loss of biomass, macronutrients, and total polyphenols. Additionally, plants pretreated with oligo-gellan and then exposed to 100 mM NaCl accumulated less sodium, produced greater amounts of photosynthetic pigments, and had greater antioxidant activity than NaCl-stressed plants. Irrespective of the experimental treatment, 50% extract effectively inhibited growth of Escherichia coli and Staphylococcus aureus. Both microorganisms were the least affected by 25% extract obtained from plants untreated with either NaCl or oligo-gellan. In conclusion, oligo-gellan promoted plant growth and enhanced the quality of red perilla leaves and efficiently alleviated the negative effects of salt stress.

Naked mole-rats are long-lived animals that show unusual resistance to hypoxia, cancer and ageing. Protein deimination is an irreversible post-translational modification caused by the peptidylarginine deiminase (PAD) family of enzymes, which convert arginine into citrulline in target proteins. Protein deimination can cause structural and functional protein changes, facilitating protein moonlighting, but also leading to neo-epitope generation and effects on gene regulation. Furthermore, PADs have been found to regulate cellular release of extracellular vesicles (EVs), which are lipid-vesicles released from cells as part of cellular communication. EVs carry protein and genetic cargo and are indicative biomarkers that can be isolated from most body fluids. This study was aimed at profiling deiminated proteins in plasma and EVs of naked mole-rat. Key immune and metabolic proteins were identified to be post-translationally deiminated, with 65 proteins specific for plasma, while 42 proteins were identified to be deiminated in EVs only. Using protein-protein interaction network analysis, deiminated plasma proteins were found to belong to KEEG (Kyoto Encyclopedia of Genes and Genomes) pathways of immunity, infection, cholesterol and drug metabolism, while deiminated proteins in EVs were also linked to KEEG pathways of HIF-1 signalling and glycolysis. The mole-rat EV profiles showed a poly-dispersed population of 50-300 nm, similar to observations of human plasma. Furthermore, the EVs were assessed for three key microRNAs involved in cancer, inflammation and hypoxia. The identification of post-translational deimination of critical immunological and metabolic markers contributes to the current understanding of protein moonlighting functions, via post-translational changes, in the longevity and cancer resistance of naked mole-rats.

Our objective was to identify and characterize the types of vocalization other than meowing (VOM) in two contexts, a pleasant and an aversive situation, and to study the effect of the sex of the animal. A total of 74 cats (32 tom cats and 42 queens) living in the city of Curitiba, Brazil, participated in the study; in total, 68 (29 tom cats and 39 queens) were divided into two groups according to the stimulus they were exposed to: either a pleasant situation (PS), when they were offered a snack, or an aversive situation (AS), with the simulation of a car transport event. The other six animals (three tom cats and three queens) participated in both situations. Only the PS group presented VOM; of the 40 PS animals, 14 presented VOM, mostly acknowledgment or trill and squeak. No correlation was observed between vocalization and cat sex (p = 0.08; Pearson's Chi-Square). Results show that VOM is exclusively associated with positive situations, suggesting that these vocalizations may be relevant for understanding the valence of cat emotional state. Further studies are warranted to advance knowledge on other VOMs and on the generalization of our findings to other situations.

Centriolar satellites are non-membrane cytoplasmic granules that deliver proteins to centrosome during centrosome biogenesis and ciliogenesis. Centriolar satellites are highly dynamic during cell cycle or ciliogenesis and how they are regulated remains largely unknown. We report here that sorting nexin 17 (SNX17) regulates the homeostasis of a subset of centriolar satellite proteins including PCM1, CEP131, and OFD1 during serum-starvation-induced ciliogenesis. Mechanistically, SNX17 recruits the deubiquitinating enzyme USP9X to antagonize the mindbomb 1 (MIB1)-induced ubiquitination and degradation of PCM1. SNX17 deficiency leads to enhanced degradation of USP9X as well as PCM1 and disrupts ciliogenesis upon serum starvation. On the other hand, SNX17 is dispensable for the homeostasis of PCM1 and USP9X in serum-containing media. These findings reveal a SNX17/USP9X mediated pathway essential for the homeostasis of centriolar satellites under serum starvation, and provide insight into the mechanism of USP9X in ciliogenesis, which may lead to a better understating of USP9X-deficiency-related human diseases such as X-linked mental retardation and neurodegenerative diseases.

Freezing-thawing procedures and in vitro culture conditions are considered as a source of stress associated with increased reactive oxygen species (ROS) generation, leading to a damaged cell aerobic metabolism and consequently to oxidative stress. In the present study, we sought to investigate whether vitamin E (Vit E) or reduced glutathione (GSH) enhances sperm production by decreasing ROS accumulation during in vitro maturation of prepubertal mice testes. Testes of prepubertal mice were cryopreserved using a freezing medium supplemented or not supplemented with Vit E and were cultured after thawing. In presence of Rol alone in culture medium, frozen-thawed (F-T) testicular tissues exhibited a higher ROS accumulation than fresh tissue during in vitro culture. However, Vit E supplementation in freezing, thawing, and culture media significantly decreased cytoplasmic ROS accumulation in F-T testicular tissue during in vitro maturation when compared with F-T testicular tissue cultured in the presence of Rol alone, whereas GSH supplementation in culture medium significantly increased ROS accumulation associated with cytolysis and tissue disintegration. Vit E but not GSH promoted a better in vitro sperm production and was a suitable ROS scavenger and effective molecule to improve the yield of in vitro spermatogenesis from F-T prepubertal mice testes. The prevention of oxidative stress in the cytoplasmic compartment should be regarded as a potential strategy for improving testicular tissue viability and functionality during the freeze-thaw procedure and in vitro maturation.

In this study, we investigated whether the curcuminoids, CLEFMA and EF24, improved cisplatin efficacy and reduced cisplatin ototoxicity. We used the lung cancer cell line, A549, to determine the effects of the curcuminoids and cisplatin on cell viability and several apoptotic signaling mechanisms. Cellular viability was measured using the MTT assay. A scratch assay was used to measure cell migration and fluorescent spectrophotometry to measure reactive oxygen species (ROS) production. Western blots and luminescence assays were used to measure the expression and activity of apoptosis-inducing factor (AIF), caspases-3/7, -8, -9, and -12, c-Jun N-terminal kinases (JNK), mitogen-activated protein kinase (MAPK), and proto-oncogene tyrosine-protein kinase (Src). A zebrafish model was used to evaluate auditory effects. Cisplatin, the curcuminoids, and their combinations had similar effects on cell viability (IC50 values: 2-16 μM) and AIF, caspase-12, JNK, MAPK, and Src expression, while caspase-3/7, -8, and -9 activity was unchanged or decreased. Cisplatin increased ROS yield (1.2-fold), and curcuminoid and combination treatments reduced ROS (0.75-0.85-fold). Combination treatments reduced A549 migration (0.51-0.53-fold). Both curcuminoids reduced auditory threshold shifts induced by cisplatin. In summary, cisplatin and the curcuminoids might cause cell death through AIF and caspase-12. The curcuminoids may potentiate cisplatin's effect against A549 migration, but may counteract cisplatin's effect to increase ROS production. The curcuminoids might also prevent cisplatin ototoxicity.

Three major forms of the nicotinic agonist toxin anabaseine (cyclic iminium, cyclic imine and the monocationic open-chain ammonium-ketone) co-exist in almost equal concentrations at physiological pH. We asked the question: Which of these forms is pharmacologically active? First, we investigated the pH dependence of anabaseine inhibition of [3H]-methylcarbamylcholine binding at rat brain α4β2 nicotinic acetylcholine receptors (nAChRs). These experiments indicated that one or both monocationic forms interact with the orthosteric binding site for ACh. However, since they occur at equal concentrations near physiological pH, we employed another approach, preparing a stable analog of each form and examining its agonist activities and binding affinities at several vertebrate brain and neuromuscular nAChRs. Only 2-(3-pyridyl)-1,4,5,6-tetrahydropyrimidine monohydrogen chloride (PTHP), the cyclic iminium analog, displayed nAChR potencies and binding affinities similar to anabaseine. The cyclic imine analog 2,3'-bipyridyl and the open-chain ammonium-ketone analog 5-methylamino-1-(3-pyridyl)-1-pentanone (MAPP), displayed ≤1% of the activity predicted if the one form was solely active. The lower potency of weakly basic 2,3'-bipyridyl can be explained by the presence of a small concentration of its monocationic form. Since the open chain ammonium-ketone monocationic form of anabaseine has some structural similarity to the neurotransmitter GABA, we also tested the ability of anabaseine and its 1,2-dehydropyrrolidinyl analog myosmine to activate a mammalian GABAA receptor, but no activity was detected. We conclude that the monocationic cyclic iminium is the form which avidly binds and activates vertebrate nAChRs.

Due to the increasing sewage sludge production in the world and problems with its disposal, an application of sludge to the soil appears to be a suitable solution considering its fertilizer properties and ability to improve the soil physical conditions. On the other hand, the sludge may also contain undesirable and toxic substances. Since soil microorganisms are sensitive to environmental changes, they can be used as indicators of soil quality. In this study, we used sewage sludge (SS) from two municipal wastewater treatment plants (SS-A and SS-B) in the dose of 5 t/ha and 15 t/ha in order to determine possible changes in the fungal community diversity, especially arbuscular mycorrhizal fungi (AMF), in the rhizosphere of Arundo donax L. Rhizosphere samples were collected in summer and autumn for two consecutive years and the fungal diversity was examined using terminal restriction fragment length polymorphism and 18S rDNA sequencing. Fungal alpha diversity was more affected by SS-A than SS-B probably due to the higher heavy metal content. However, based on principal component analysis and ANOSIM, significant changes in overall fungal diversity were not observed. Simultaneously, 18S rDNA sequencing showed that more various fungal taxa were detected in the sample with sewage sludge than in the control. Glomus sp. as a representative of AMF was the most represented. Moreover, Funneliformis in both samples and Rhizophagus in control with Septoglomus in the sludge sample were other representatives of AMF. Our results indicate that the short-term sewage sludge application into the soil does not cause a shift in the fungal community composition.

One of the most significant therapeutic challenges in the treatment of ovarian cancer is the development of recurrent platinum-resistant disease. Cancer stem cells (CSCs) are postulated to contribute to recurrent and platinum-resistant ovarian cancer (OvCa). Drugs that selectively target CSCs may augment the standard of care cytotoxics and have the potential to prevent and/or delay recurrence. Increased reliance on metabolic pathway modulation in CSCs relative to non-CSCs offers a possible therapeutic opportunity. We demonstrate that treatment with the metabolic inhibitor CPI-613 (devimistat, an inhibitor of tricarboxylic acid (TCA) cycle) in vitro decreases CD133+ and CD117+ cell frequency relative to untreated OvCa cells, with negligible impact on non-CSC cell viability. Additionally, sphere-forming capacity and tumorigenicity in vivo are reduced in the CPI-613 treated cells. Collectively, these results suggest that treatment with CPI-613 negatively impacts the ovarian CSC population. Furthermore, CPI-613 impeded the unintended enrichment of CSC following olaparib or carboplatin/paclitaxel treatment. Collectively, our results suggest that CPI-613 preferentially targets ovarian CSCs and could be a candidate to augment current treatment strategies to extend either progression-free or overall survival of OvCa.

Hepatocellular carcinoma (HCC) pathogenesis involves the alteration of multiple liver-specific metabolic pathways. We systematically profiled cancer- and liver-related classes of metabolites in HCC and adjacent liver tissues and applied supervised machine learning to compare their potential yield for HCC biomarkers.

Worldwide, depression and bipolar disorder affect a large and growing number of people. However, current pharmacotherapy options remain limited. Despite adequate treatment, many patients continue to have subsyndromal symptoms, which predict relapse in bipolar illness and often result in functional impairments. Aspirin, a common nonsteroidal anti-inflammatory drug (NSAID), has purported beneficial effects on mood symptoms, showing protective effects against depression in early cohort studies. This systematic review thus aimed to investigate the role of aspirin in mood disorders. Using the keywords (aspirin or acetylsalicy* or asa) and (mood or depress* or bipolar or mania or suicid*), a comprehensive search of PubMed, EMBASE, Medline, PsycINFO, Clinical Trials Register of the Cochrane Collaboration Depression, Anxiety and Neurosis Group (CCDANTR), Clinicaltrials.gov and Google Scholar databases found 13,952 papers published in English between 1 January 1988 and 1 May 2019. A total of six clinical studies were reviewed. There were two randomized, placebo-controlled, double-blind trials and populations drawn from two main cohort studies (i.e., the Geelong Osteoporosis Study and the Osteoarthritis Initiative study). Using a random-effects model, the pooled hazard ratio of the three cohort studies was 0.624 (95% confidence interval: 0.0503 to 1.198, p = 0.033), supporting a reduced risk of depression with aspirin exposure. Overall, the dropout rates were low, and aspirin appears to be well-tolerated with minimal risk of affective switch. In terms of methodological quality, most studies had a generally low risk of bias. Low-dose aspirin (80 to 100 mg/day) is safe, well-tolerated and potentially efficacious for improving depressive symptoms in both unipolar and bipolar depression. Due to its ability to modulate neuroinflammation and central nervous system processes, aspirin may also have valuable neuroprotective and pro-cognitive effects that deserve further exploration. Further randomized, controlled trials involving the adjunctive use of aspirin should be encouraged to confirm its therapeutic benefits.