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MSphere Oct 2023A crucial phase in the life cycle of tick-borne pathogens is the time spent colonizing and persisting within the arthropod. Tick immunity is emerging as a key force...
A crucial phase in the life cycle of tick-borne pathogens is the time spent colonizing and persisting within the arthropod. Tick immunity is emerging as a key force shaping how transmissible pathogens interact with the vector. How pathogens remain in the tick despite immunological pressure remains unknown. In persistently infected , we found that (causative agent of Lyme disease) and (causative agent of granulocytic anaplasmosis) activate a cellular stress pathway mediated by the endoplasmic reticulum receptor PKR-like ER kinase (PERK) and the central regulatory molecule eIF2α. Disabling the PERK pathway through pharmacological inhibition and RNA interference (RNAi) significantly decreased microbial numbers. RNAi of the PERK pathway not only reduced the number of and colonizing larvae after a bloodmeal but also significantly reduced the number of bacteria that survive the molt. An investigation into PERK pathway-regulated targets revealed that and induce activity of the antioxidant response regulator, nuclear factor erythroid 2-related factor 2 (Nrf2). Tick cells deficient for expression or PERK signaling showed accumulation of reactive oxygen and nitrogen species in addition to reduced microbial survival. Supplementation with antioxidants rescued the microbicidal phenotype caused by blocking the PERK pathway. Altogether, our study demonstrates that the PERK pathway is activated by transmissible microbes and facilitates persistence in the arthropod by potentiating an Nrf2-regulated antioxidant environment. IMPORTANCE Recent advances demonstrate that the tick immune system recognizes and limits the pathogens they transmit. Innate immune mediators such as antimicrobial peptides and reactive oxygen/nitrogen species are produced and restrict microbial survival. It is currently unclear how pathogens remain in the tick, despite this immune assault. We found that an antioxidant response controlled by the PERK branch of the unfolded protein response is activated in ticks that are persistently infected with (Lyme disease) or (granulocytic anaplasmosis). The PERK pathway induces the antioxidant response transcription factor, Nrf2, which coordinates a gene network that ultimately neutralizes reactive oxygen and nitrogen species. Interfering with this signaling cascade in ticks causes a significant decline in pathogen numbers. Given that innate immune products can cause collateral damage to host tissues, we speculate that this is an arthropod-driven response aimed at minimizing damage to "self" that also inadvertently benefits the pathogen. Collectively, our findings shed light on the mechanistic push and pull between tick immunity and pathogen persistence within the arthropod vector.
Topics: Animals; Anaplasmosis; Antioxidants; NF-E2-Related Factor 2; Ixodes; Lyme Disease; Borrelia burgdorferi; Anaplasma phagocytophilum; Nitrogen; Oxygen
PubMed: 37733353
DOI: 10.1128/msphere.00321-23 -
Molecular and Cellular Endocrinology May 2024A significant advance has been made, especially during the last two decades, in the knowledge of the effects on crustacean species of pollutants proven to be endocrine... (Review)
Review
A significant advance has been made, especially during the last two decades, in the knowledge of the effects on crustacean species of pollutants proven to be endocrine disruptors in vertebrates. Such effects have been also interpreted in the light of recent studies on crustacean endocrinology. Year after year, the increased number of reports refer to the effects of endocrine disruptors on several processes hormonally controlled. This review is aimed at summarizing and discussing the effects of several kinds of endocrine disruptors on the hormonal control of reproduction (including gonadal growth, sexual differentiation, and offspring development), molting, and intermediate metabolism of crustaceans. A final discussion about the state of the art, as well as the perspective of this toxicological research line is given.
Topics: Animals; Endocrine Disruptors; Endocrine System; Crustacea; Reproduction; Environmental Pollutants
PubMed: 38365065
DOI: 10.1016/j.mce.2024.112189 -
Pesticide Biochemistry and Physiology Nov 2023Due to chemical and photochemical stability, triazophos has been frequently detected in rivers and oceans over the years with extensive use for pest control in...
Due to chemical and photochemical stability, triazophos has been frequently detected in rivers and oceans over the years with extensive use for pest control in agriculture, and it has become a worldwide ecological concern to the aquatic environment. Until now, fewer data are available regarding the potential long-term adverse effects of triazophos on aquatic invertebrates, which plays an essential role in aquatic food webs, as a key group for water ecosystems. In this experiment, the F- and F progenies of Daphnia magna were recovered when daphnias (F) exposure to triazophos at environmental-related concentrations (0.1 and 1.0 μg/L) for 21 d; and the indexes related to phenotypic traits, reproduction and gene expression were measured in tested animals. The results showed that heart rate and total number of neonates in exposed F-daphnias were significantly lower than those of control group, and the detoxification genes (HR96 and P-gp) were up-regulated while genes related reproduction (Vtg) and molting (Nvd and Shd) were significantly down-regulated. The heart rate and individual size of F-daphnias (<24 h) were significantly reduced in the treatment group. After 21-d recovery, the heart rate and expression of HR96, P-gp, Vtg, Nvd and Shd were declined in F-daphnias. There was no obvious difference of morphological traits and heart rate between treatment and control in F-daphnias (<24 h). In summary, daphnias (F) exposure to triazophos with environmental dose could raise toxic effects on its offspring (F), which is mainly manifested by reduced heart rate, the accumulated number and individual size of offspring and decreased expression of genes related to molting and reproduction.
Topics: Animals; Daphnia; Ecosystem; Water Pollutants, Chemical; Reproduction
PubMed: 37945248
DOI: 10.1016/j.pestbp.2023.105607 -
ACS Applied Bio Materials Dec 2023l-asparaginase (ASNase), an enzyme that catalyzes the hydrolysis of l-asparagine into l-aspartic acid, is frequently used as a medication for acute lymphoblastic...
l-asparaginase (ASNase), an enzyme that catalyzes the hydrolysis of l-asparagine into l-aspartic acid, is frequently used as a medication for acute lymphoblastic leukemia (ALL). However, when derived from bacterial sources, this enzyme can elicit side effects, including allergic or hypersensitivity reactions, owing to immune responses. Here, we describe the synthesis of polyoxazoline-conjugated ASNase (POx-ASNase) and investigate its enzyme activity, anticancer efficacy, immunogenicity, and retention in the bloodstream. The water-soluble POx was coupled with surface lysine residues of ASNase using a bifunctional cross-linker. The average number of polymers bound to each enzyme was determined as 10. Although the enzymatic activity of POx-ASNase decreased to 56% of that of native ASNase, its temperature and pH dependencies remained unaltered. Remarkably, the lyophilized powder form of POx-ASNase retained its catalytic ability for 24 months. POx-ASNase demonstrated nearly identical anticancer efficacy compared to naked ASNase against leukemia and lymphoma cells (MOLT-4, CLBL-1, and K562) while displaying no cytotoxicity toward normal cells. Animal experiments conducted using rats revealed that the POx decoration suppressed the generation of anti-ASNase IgM and IgG antibodies with no detection of anti-POx antibodies. The half-life within the bloodstream extended to 34 h, representing a 17-fold increase compared to unmodified ASNase. These findings suggest that POx-ASNase serves as an anticancer therapeutic agent, characterized by the absence of antibody production and notably extended circulation persistence.
Topics: Animals; Rats; Asparaginase; Antibody Formation; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Antineoplastic Agents; Asparagine
PubMed: 38047730
DOI: 10.1021/acsabm.3c00888 -
Insect Molecular Biology Aug 2023The nuclear receptor (NR) superfamily is one of the largest groups of transcription factors in living organisms. Oestrogen related receptor (ERR) is a class of nuclear...
The nuclear receptor (NR) superfamily is one of the largest groups of transcription factors in living organisms. Oestrogen related receptor (ERR) is a class of nuclear receptors closely related to oestrogen receptors (ERs). In this study, the Nilaparvata lugens (N. lugens) ERR2 (NlERR2) was cloned, and the expression of NlERR2 was detected by qRT-PCR to explore the distribution of NlERR2 during development and in different tissues. Using RNAi and qRT-PCR, the interaction between NlERR2 and related genes of the 20-hydroxyecdysone (20E) and juvenile hormone (JH) signalling pathways was studied. The results showed that topical application of 20E and juvenile hormone III (JHIII) affected the expression of NlERR2, and NlERR2 could affect the expression of genes related to 20E and JH signalling pathways. Furthermore, NlERR2 and JH/20E hormone signalling-related genes affect moulting and ovarian development. NlERR2 and NlE93/NlKr-h1 affect the transcriptional expression of Vg-related genes. In summary, NlERR2 is related to hormone signalling pathways, which is also related to the expression of Vg and Vg related genes. Brown planthopper is one of the most important rice pests. This study provides an important basis for mining new targets for pest control.
Topics: Female; Animals; Molting; Insect Proteins; Ovary; Receptors, Cytoplasmic and Nuclear; Hormones; Hemiptera
PubMed: 36861367
DOI: 10.1111/imb.12837 -
Naunyn-Schmiedeberg's Archives of... Jun 2024TNF-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily that is capable of apoptosis induction selectively in tumor cells. Although TRAIL has...
TNF-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily that is capable of apoptosis induction selectively in tumor cells. Although TRAIL has been harnessed in numerous clinical trials, resistance to TRAIL-induced apoptosis is a major challenge ahead of this therapy in various cancer models as well as in leukemia. Since histone deacetylases (HDACs) are known to affect drug resistance in malignant cells, the present study aimed to evaluate the potential of fisetin for sensitization of MOLT-4 and K-562 leukemic cells to TRAIL-induced apoptosis. The MOLT-4 and K-562 cells were treated with increasing concentrations of fisetin and its impact on the growth inhibition and apoptosis induction of TRAIL were evaluated by MTT and Annexin V/7-AAD assays. The impact of fisetin on the mRNA and protein expression levels of apoptosis regulatory genes such as BIRC2/c-IAP1, CFLAR/cFLIP, CASP3, CASP7, CASPP9, TNFRSF10A/DR4, TNFRSF10B/DR5, and BID were examined by PCR array, qRT-PCR, and flow cytometry. Pre-treatment of MOLT-4 and K-562 cells with fisetin reduced the IC50 of TRAIL in growth inhibition along with an improvement in apoptosis induction by TRAIL. The expression of the BIRC2 gene encoding antiapoptotic protein c-IAP1 downregulated in the fisetin-treated cells while the expressions of TNFRSF10A and TNFRSF10B encoding TRAIL death receptors increased. Fisetin demonstrated a potential for alleviating the TRAIL resistance by modulating the apoptosis regulatory factors and improving the expressions of TRAIL receptors that could facilitate the application of TRAIL in cancer therapies.
PubMed: 38918236
DOI: 10.1007/s00210-024-03101-y -
Microorganisms Sep 2023Investigations of bacterial communities are on the rise both in human and veterinary medicine. Their role in health maintenance and pathogenic mechanisms is in the...
Investigations of bacterial communities are on the rise both in human and veterinary medicine. Their role in health maintenance and pathogenic mechanisms is in the limelight of infectious, metabolic, and cancer research. Among the most considered, gut bacterial communities take the cake. Their part in animals was assessed mainly to improve animal production, public health, and pet management. In this regard, canaries deserve attention, being a popular pet and source of economic income for bird-keepers, for whom breeding represents a pivotal point. Thus, the present work aimed to follow gut bacterial communities' evolution along on whole reproductive cycle of 12 healthy female canaries. Feces were collected during parental care, molting, and resting phase, and submitted for 16S rRNA sequencing. Data were analyzed and a substantial presence of along all the phases, and a relevant shift of microbiota during molting and rest due to an abrupt decrease of the Vermiphilaceae family were detected. Although the meaning of such change is not clear, future research may highlight unforeseen scenarios. Moreover, may be deemed for normal bacteria flora restoration in debilitated birds, perhaps improving their health and productivity.
PubMed: 37764133
DOI: 10.3390/microorganisms11092289 -
Future Medicinal Chemistry Sep 2023Histone deacetylases (HDACs) play a vital role in the epigenetic regulation of transcription and expression. HDAC1 overexpression is seen in many cancers. The authors...
Histone deacetylases (HDACs) play a vital role in the epigenetic regulation of transcription and expression. HDAC1 overexpression is seen in many cancers. The authors synthesized and evaluated 27 novel coumarin-based amide derivatives for HDAC1 inhibitory activity. The compounds were screened at the US National Cancer Institute, and and were selected for five-dose assays. Compound showed GI values of 0.294 and 0.264 μM against MOLT-4 and LOX-IMVI, respectively; whereas had GI values of 0.189 and 0.263 μM, respectively. Both derivatives showed better activity than entinostat and suberoylanilide hydroxamic acid. Compound exhibited an IC value of 1.00 μM on ACHN cells. Coumarin derivatives exhibited promising HDAC1 inhibitory potential and warrant future development as anticancer agents.
Topics: Amides; Coumarins; Epigenesis, Genetic; Cell Line, Tumor; Histone Deacetylase Inhibitors; Cell Proliferation; Hydroxamic Acids; Drug Design; Antineoplastic Agents; Structure-Activity Relationship; Drug Screening Assays, Antitumor; Neoplasms
PubMed: 37732405
DOI: 10.4155/fmc-2023-0105 -
Archives of Insect Biochemistry and... Apr 2024Kissing bugs do not respond to host cues when recently molted and only exhibit robust host-seeking several days after ecdysis. Behavioral plasticity has peripheral...
Kissing bugs do not respond to host cues when recently molted and only exhibit robust host-seeking several days after ecdysis. Behavioral plasticity has peripheral correlates in antennal gene expression changes through the week after ecdysis. The mechanisms regulating these peripheral changes are still unknown, but neuropeptide, G-protein coupled receptor, nuclear receptor, and takeout genes likely modulate peripheral sensory physiology. We evaluated their expression in antennal transcriptomes along the first week postecdysis of Rhodnius prolixus 5th instar larvae. Besides, we performed clustering and co-expression analyses to reveal relationships between neuromodulatory (NM) and sensory genes. Significant changes in transcript abundance were detected for 50 NM genes. We identified 73 sensory-related and NM genes that were assigned to nine clusters. According to their expression patterns, clusters were classified into four groups: two including genes up or downregulated immediately after ecdysis; and two with genes with expression altered at day 2. Several NM genes together with sensory genes belong to the first group, suggesting functional interactions. Co-expression network analysis revealed a set of genes that seem to connect with sensory system maturation. Significant expression changes in NM components were described in the antennae of R. prolixus after ecdysis, suggesting that a local NM system acts on antennal physiology. These changes may modify the sensitivity of kissing bugs to host cues during this maturation interval.
Topics: Animals; Rhodnius; Neuropeptides; Transcriptome; Triatoma; Molting
PubMed: 38597092
DOI: 10.1002/arch.22106 -
Philosophical Transactions of the Royal... Jan 2024is a natural parasite of wild rats and most laboratory mouse strains are also fully permissive. The infection can be divided into three distinct phases: the tissue... (Review)
Review
is a natural parasite of wild rats and most laboratory mouse strains are also fully permissive. The infection can be divided into three distinct phases: the tissue migration of the infective third stage larvae during the first two days, the early intestinal establishment of parasites molting to adults on days three to six and the later intestinal parasitic phase until the end of infection. Immunocompetent mice terminate the infection after one month and are semi-resistant to a second infection. Employing the powerful tools of mouse immunology has facilitated a detailed analysis of the initiation, execution and regulation of the immune response to . Here we review the information collected to date on the protective immune response to migrating larvae in tissues and to adult parasites in the intestine. We show that depending on the phase of infection, a site-specific portfolio of immune effector mechanisms is required for infection control. In addition, we summarize the strategies employed by to evade the immune system and survive long enough in its host to replicate despite an effective immune response. Selected murine studies using the closely related will be discussed. This article is part of the Theo Murphy meeting issue ': omics to worm-free populations'.
Topics: Mice; Rats; Animals; Strongyloides ratti; Strongyloidiasis; Intestines; Larva; Immunity
PubMed: 38008111
DOI: 10.1098/rstb.2022.0440