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Physiological and Biochemical Zoology :... 2023AbstractSeasonality in infectious disease prevalence is predominantly attributed to changes in exogenous risk factors. For vectored pathogens, high abundance, activity,...
AbstractSeasonality in infectious disease prevalence is predominantly attributed to changes in exogenous risk factors. For vectored pathogens, high abundance, activity, and/or diversity of vectors can exacerbate disease risk for hosts. Conversely, many host defenses, particularly immune responses, are seasonally variable. Seasonality in host defenses has been attributed, in part, to the proximate (i.e., metabolic) and ultimate (i.e., reproductive fitness) costs of defense. In this study, our goal was to discern whether any seasonality is observable in how a common avian host, the house sparrow (), copes with a common zoonotic arbovirus, the West Nile virus (WNV), when hosts are studied under controlled conditions. We hypothesized that if host biorhythms play a role in vector-borne disease seasonality, birds would be most vulnerable to WNV when breeding and/or molting (i.e., when other costly physiological activities are underway) and thus most transmissive of WNV at these times of year (unless birds died from infection). Overall, the results only partly supported our hypothesis. Birds were most transmissive of WNV in fall (after their molt is complete and when WNV is most prevalent in the environment), but WNV resistance, WNV tolerance, and WNV-dependent mortality did not vary among seasons. These results collectively imply that natural arboviral cycles could be partially underpinned by endogenous physiological changes in hosts. However, other disease systems warrant study, as this result could be specific to the nonnative and highly commensal nature of the house sparrow or a consequence of the relative recency of the arrival of WNV to the United States.
Topics: Animals; West Nile virus; West Nile Fever; Bird Diseases; Sparrows
PubMed: 37713719
DOI: 10.1086/725888 -
Marine Environmental Research Oct 2023Nanoplastics (NPs) and heavy metals are typical marine pollutants, affecting the gut microbiota composition and molting rate of marine organisms. Currently, there is a...
Nanoplastics (NPs) and heavy metals are typical marine pollutants, affecting the gut microbiota composition and molting rate of marine organisms. Currently, there is a lack of research on the toxicological effects of combined exposure to horseshoe crabs. In this study, we investigated the effects of NPs and copper on the expression of molt-related genes and gut microbiome in juvenile tri-spine horseshoe crabs Tachypleus tridentatus by exposing them to NPs (100 nm, 10 particles L) and/or Cu (10 μgL) in seawater for 21 days. Compared with the control group, the relative mRNA expression of ecdysone receptor (EcR), retinoid x receptor (RXR), calmodulin-A-like isoform X1 (CaM X1), and heat shock 70 kDa protein (Hsp70) were significantly increased under the combined stress of NPs and Cu. There were no significant differences in the diversity and abundance indices of the gut microbial population of horseshoe crabs between the NPs and/or Cu groups and the control group. According to linear discriminant analysis, Oleobacillus was the most abundant microorganism in the NPs and Cu stress groups. These results indicate that exposure to either NPs stress alone or combined NPs and Cu stress can promote the expression levels of juvenile molting genes. NPs exposure has a greater impact on the gut microbial community structure of juvenile horseshoe crabs compared to Cu exposure. This study is helpful for predicting the growth and development of horseshoe crabs under complex environmental pollution.
Topics: Animals; Horseshoe Crabs; Copper; Gastrointestinal Microbiome; Microplastics; Molting
PubMed: 37587001
DOI: 10.1016/j.marenvres.2023.106128 -
Environmental Science and Pollution... Dec 2023In Daphnia magna, 20-hydroecdysone (20E) is the main molting hormone and its metabolism is of interest to identify new biomarkers of exposure to contaminants. The...
In Daphnia magna, 20-hydroecdysone (20E) is the main molting hormone and its metabolism is of interest to identify new biomarkers of exposure to contaminants. The present study aimed to (i) assess baseline levels of 20E and transcription levels of four related-genes (shade, neverland, ultraspiracle, and ecdysteroid receptor); and (ii) evaluate effects in D. magna after 21 days of exposure to fenarimol (anti-ecdysteroid) and a mixture of gemfibrozil and clofibric acid (lipid-lowering drugs) at sublethal concentrations. Endpoints included transcription of the target genes and quantification of 20E, mortality, and reproduction of daphnids. Baseline results showed that average responses were relatively similar and did not vary more than 2-fold. However, intra-day variation was generally high and could be explained by sampling individuals with slightly different stages of their development. Exposure tests indicated a significant decrease in daphnid reproduction following chronic exposure to a concentration of 565 μg/L of fenarimol. However, no difference was observed between the control and exposed groups for any of the investigated genes, nor for the levels of 20E after 21 days of exposure. Following exposition to gemfibrozil and clofibric acid at 1 μg/L, no changes were observed for the measured parameters. These results suggest that changes in transcription levels of the target genes and concentrations of 20E may not be sensitive endpoints that can be used as biomarkers of sublethal exposure to the target compounds in D. magna. Measuring multiple time points instead of a single measure as well as additional molecular endpoints obtained from transcriptomic and metabolomic studies could afford more insights on the changes occurring in exposed daphnids to lipid-altering compounds and identify efficient biomarkers of sublethal exposure.
Topics: Humans; Animals; Ecdysterone; Molting; Gemfibrozil; Reproduction; Biomarkers; Clofibric Acid; Daphnia; Water Pollutants, Chemical
PubMed: 38010540
DOI: 10.1007/s11356-023-31087-2 -
Pharmaceuticals (Basel, Switzerland) Mar 2024Inappropriate expression of histone deacetylase (HDAC-6) and deregulation of the phosphatidylinositol 3-kinase (PI3K) signalling pathway are common aberrations observed...
Inappropriate expression of histone deacetylase (HDAC-6) and deregulation of the phosphatidylinositol 3-kinase (PI3K) signalling pathway are common aberrations observed in cancers. LASSBio-2208, has been previously described as a dual inhibitor in the nanomolar range of HDAC-6 and PI3Kα and is three times more potent in inhibiting HDAC-6. In this paper we described the cytotoxic and antiproliferative potency of LASSBio-2208 on different tumour cell lines, its possible synergism effect in association with PI3K and HDAC-6 inhibitors, and its drug metabolism and pharmacokinetics (DMPK) in vitro profile. Our studies have demonstrated that LASSBio-2208 has moderate cytotoxic potency on breast cancer cell line MCF-7 (IC = 23 µM), human leukaemia cell line CCRF-CEM (IC = 8.54 µM) and T lymphoblast cell line MOLT-4 (IC = 7.15 µM), with no cytotoxic effect on human peripheral blood mononuclear cells (hPBMC). In addition, it has a good antiproliferative effect on MCF-7 cells (IC = 5.44 µM), low absorption by parallel artificial membrane permeability-gastrointestinal tract (PAMPA-GIT) and low permeation by parallel artificial membrane permeability-blood-brain barrier (BBB) (PAMPA-BBB), exhibiting high metabolic stability in rat plasma. Moreover, LASSBio-2208 exhibited synergism when combined with getadolisib and tubastatin A, using the concentrations corresponding to their CC values on MOLT-4 and CCRF-CEM cells.
PubMed: 38543175
DOI: 10.3390/ph17030389 -
Frontiers in Pharmacology 2023Leukemias are a common cancer in adults and children. While existing treatments are effective, they are associated with severe side-effects compounded by the emergence...
Leukemias are a common cancer in adults and children. While existing treatments are effective, they are associated with severe side-effects compounded by the emergence of drug resistance. This necessitates the need to develop new drugs and phytopharmaceuticals offer a largely untapped source. Oleoresins produced by plants in the genus have been used for centuries in traditional medicine and recent work suggests they may exhibit anti-cancer activity. However, the underlying mechanisms remain unclear and most existing research focusses on ; just one of many species in the genus. To address these limitations, we elucidated the anti-cancer potential and associated mechanisms of action of . A methanolic solvent extraction method was optimised. The effect of methanolic extracts of on leukaemia (K562, MOLT-4 and CCRF-CEM) and normal (PBMC) cell line viability was assessed using MTT assay and flow cytometry. Cell morphology, apoptosis (Annexin-V/propidium iodide), mitochondrial membrane potential (Rhodamine-123) and the cell cycle (propidium iodide) were evaluated using flow cytometry. Regulatory protein expression was quantified using Western Blot. Methanolic extracts of oleoresin reduced the viability of K562, MOLT-4 and CCRF-CEM cell lines with selectivity indexes of between 1.75 and 2.68. Extracts increased the proportion of cells in late apoptosis by 285.4% ± 51.6%. Mitochondrial membrane potential was decreased by 41% ± 2% and the expression of cleaved caspase-3, -7, and -9 was increased by 5.7, 3.3, and 1.5-fold respectively. Extracts increased the proportion of cells in G and G phase by 867.8% ± 122.9% and 14.0 ± 5.5 and decreased those in S phase and G/M by 63.4% ± 2.0% and 57.6% ± 5.3%. Expression of CDK2, CDK6, cyclin D1, and cyclin D3 were decreased by 2.8, 4.9, 3.9, and 2.5-fold. We are the first to report that methanolic extracts of are selectively cytotoxic against three leukemia cell lines. Cytotoxic mechanisms likely include activation of the intrinsic apoptotic pathway and cell cycle arrest through downregulation of CDK2, CDK6, cyclin D1, and cyclin D3. Our findings suggest that may be an important source of novel chemotherapeutic drugs and justifies further investigation.
PubMed: 38155908
DOI: 10.3389/fphar.2023.1282239 -
BMC Complementary Medicine and Therapies May 2024Cepharanthin alone or in combination with glucocorticoid (GC) has been used to treat chronic immune thrombocytopenia (ITP) since the 1990s. Cepharanthine (CEP) is one of...
Cepharanthine synergistically promotes methylprednisolone pharmacodynamics against human peripheral blood mononuclear cells possibly via regulation of P-glycoprotein/glucocorticoid receptor translocation.
BACKGROUND
Cepharanthin alone or in combination with glucocorticoid (GC) has been used to treat chronic immune thrombocytopenia (ITP) since the 1990s. Cepharanthine (CEP) is one of the main active components of Cepharanthin. The purpose of this study was to investigate the effects of CEP on GC pharmacodynamics on immune cells and analyse the possible action mechanism of their interactions.
METHODS
Peripheral blood mononuclear cells (PBMCs), T lymphocytic leukemia MOLT-4 cells and daunorubicin resistant MOLT-4 cells (MOLT-4/DNR) were used to evaluate the pharmacodynamics and molecular mechanisms. Drug pharmacodynamics was evaluated by WST-8 assay. P-glycoprotein function was examined by rhodamine 123 assay. CD4CD25Foxp3 regulatory T cells and Th1/Th2/Th17 cytokines were detected by flow cytometry. P-glycoprotein expression and GC receptor translocation were examined by Western blot.
RESULTS
CEP synergistically increased methylprednisolone (MP) efficacy with the suppressive effect on the cell viability of PBMCs. 0.3 and 1 μM of CEP significantly inhibited P-glycoprotein efflux function of CD4 cells, CD8 cells, and lymphocytes (P<0.05). 0.03~3 μM of CEP also inhibited the P-glycoprotein efflux function in MOLT-4/DNR cells in a concentration-dependent manner (P<0.001). However, 0.03~3 μM of CEP did not influence P-glycoprotein expression. 0.03~0.3 μM of CEP significantly increased the GC receptor distribution from the cytoplasm to the nucleus in a concentration-dependent manner in MOLT-4/DNR cells. The combination did not influence the frequency of CD4, CD4CD25 and CD4CD25Foxp3 T cells or the secretion of Th1/Th2/Th17 cytokines from PBMCs. In contrast, CEP alone at 1 μM decreased the percentage of CD4 T cell significantly (P<0.01). It also inhibited the secretion of IL-6, IL-10, IL-17, TNF-α, and IFN-γ.
CONCLUSIONS
CEP synergistically promoted MP pharmacodynamics to decrease the cell viability of the mitogen-activated PBMCs, possibly via inhibiting P-glycoprotein function and potentiating GC receptor translocation. The present study provides new evidence of the therapeutic effect of Cepharanthin alone or in combination with GC for the management of chronic ITP.
Topics: Humans; Benzylisoquinolines; Leukocytes, Mononuclear; ATP Binding Cassette Transporter, Subfamily B, Member 1; Methylprednisolone; Receptors, Glucocorticoid; Drug Synergism; Benzodioxoles
PubMed: 38734604
DOI: 10.1186/s12906-024-04489-z -
BMC Genomics Jun 2024A growing number of studies have demonstrated that the polar regions have the potential to be a significant repository of microbial resources and a potential source of...
BACKGROUND
A growing number of studies have demonstrated that the polar regions have the potential to be a significant repository of microbial resources and a potential source of active ingredients. Genome mining strategy plays a key role in the discovery of bioactive secondary metabolites (SMs) from microorganisms. This work highlighted deciphering the biosynthetic potential of an Arctic marine-derived strain Aspergillus sydowii MNP-2 by a combination of whole genome analysis and antiSMASH as well as feature-based molecular networking (MN) in the Global Natural Products Social Molecular Networking (GNPS).
RESULTS
In this study, a high-quality whole genome sequence of an Arctic marine strain MNP-2, with a size of 34.9 Mb was successfully obtained. Its total number of genes predicted by BRAKER software was 13,218, and that of non-coding RNAs (rRNA, sRNA, snRNA, and tRNA) predicted by using INFERNAL software was 204. AntiSMASH results indicated that strain MNP-2 harbors 56 biosynthetic gene clusters (BGCs), including 18 NRPS/NRPS-like gene clusters, 10 PKS/PKS-like gene clusters, 8 terpene synthse gene clusters, 5 indole synthase gene clusters, 10 hybrid gene clusters, and 5 fungal-RiPP gene clusters. Metabolic analyses of strain MNP-2 grown on various media using GNPS networking revealed its great potential for the biosynthesis of bioactive SMs containing a variety of heterocyclic and bridge-ring structures. For example, compound G-8 exhibited a potent anti-HIV effect with an IC value of 7.2 nM and an EC value of 0.9 nM. Compound G-6 had excellent in vitro cytotoxicities against the K562, MCF-7, Hela, DU145, U1975, SGC-7901, A549, MOLT-4, and HL60 cell lines, with IC values ranging from 0.10 to 3.3 µM, and showed significant anti-viral (H1N1 and H3N2) activities with IC values of 15.9 and 30.0 µM, respectively.
CONCLUSIONS
These findings definitely improve our knowledge about the molecular biology of genus A. sydowii and would effectively unveil the biosynthetic potential of strain MNP-2 using genomics and metabolomics techniques.
Topics: Aspergillus; Arctic Regions; Humans; Multigene Family; Biological Products; Aquatic Organisms; Cell Line, Tumor; Biosynthetic Pathways; Secondary Metabolism; Genome, Fungal
PubMed: 38886660
DOI: 10.1186/s12864-024-10501-0 -
Acta Tropica Oct 2023Canine filariasis is caused by nematodes from the family Onchocercidae, which is transmitted by arthropod vectors. The disease is commonly found in Southeast Asia and...
Canine filariasis is caused by nematodes from the family Onchocercidae, which is transmitted by arthropod vectors. The disease is commonly found in Southeast Asia and exists worldwide. Some filarial nematodes are associated with intracellular bacteria of the genus Wolbachia, which plays an important role in embryogenesis, molting, and the long-term survival of adult worms. This study aims to characterize Wolbachia sp. and determine the association between Wolbachia and canine filarial nematode species in Thailand. A total of 46 dog blood samples that were naturally infected with filarial nematodes were obtained to identify filarial nematode species by Giemsa stained under a light microscope and confirmed using the molecular technique. In order to characterize Wolbachia sp., the nested PCR assay targeting the 16S rRNA gene showed that all samples of Dirofilaria immitis and fifteen samples of Candidatus Dirofilaria hongkongensis were grouped into Wolbachia supergroup C. In addition, all samples of Brugia spp. and five samples of Candidatus Dirofilaria hongkongensis were classified into Wolbachia supergroup D. The genetic diversity analysis conducted using the 16S rRNA gene revealed a similar result when analyzed through phylogenetic tree analysis. This is the first genetic diversity study of Wolbachia of Candidatus Dirofilaria hongkongensis in infected dogs in Thailand.
Topics: Animals; Dogs; Wolbachia; RNA, Ribosomal, 16S; Phylogeny; Dirofilariasis; Dirofilaria immitis; Dirofilaria; Filarioidea; Heart Diseases; Genetic Variation; Dog Diseases
PubMed: 37567493
DOI: 10.1016/j.actatropica.2023.107000 -
Current Medical Science Feb 2024YAP1 plays a dual role as an oncogene and tumor suppressor gene in several tumors; differentiating between these roles may depend on the YAP1 phosphorylation pattern....
OBJECTIVE
YAP1 plays a dual role as an oncogene and tumor suppressor gene in several tumors; differentiating between these roles may depend on the YAP1 phosphorylation pattern. The specific function of YAP1 in B cell acute lymphoblastic leukemia (B-ALL), however, is currently unclear. Thus, in the present study, the role of YAP1 in B-ALL was investigated using relevant cell lines and patient datasets.
METHODS
The effects of shRNA-mediated knockdown on YAP1 and LATS1 levels in the NALM6 and MOLT-4 cell lines were examined using Western blotting, quantitative real-time polymerase chain reaction, flow cytometry, immunostaining, and nude mouse subcutaneous tumorigenesis experiments. Gene expression levels of Hippo pathway-related molecules before and after verteporfin (VP) treatment were compared using RNA-Seq to identify significant Hippo pathway-related genes in NALM6 cells.
RESULTS
Patients with ALL showing high YAP1 expression and low YAP1-Ser127 phosphorylation levels had worse prognoses than those with low YAP1 protein expression and high YAP1-Ser127 phosphorylation levels. YAP1-Ser127 phosphorylation levels were lower in NALM6 cells than in MOLT-4 and control cells; YAP1 was distributed in the nuclei in NALM6 cells. Knockdown of YAP1 inhibited MOLT-4 and NALM6 cell proliferation and arrested the NALM6 cell cycle in the G0/G1 phase. Before and after VP treatment, the expression of the upstream gene LATS1 was upregulated; its overexpression promoted YAP1-Ser127 phosphorylation. Further, YAP1 was distributed in the plasma.
CONCLUSION
LATS1 may downregulate YAP1-Ser127 phosphorylation and maintain B-ALL cell function; thus, VP, which targets this axis, may serve as a new therapeutic method for improving the outcomes for B-ALL patients.
Topics: Animals; Mice; Humans; Phosphorylation; Signal Transduction; Adaptor Proteins, Signal Transducing; Transcription Factors; YAP-Signaling Proteins; Protein Serine-Threonine Kinases; Carcinogenesis
PubMed: 38277019
DOI: 10.1007/s11596-023-2821-7 -
Biochemical and Biophysical Research... Oct 2023T-cell acute lymphoblastic leukemia is characterized by its fast progression rate and high complications. TRAIL can be used to trigger apoptosis in cancer cells with...
INTRODUCTION
T-cell acute lymphoblastic leukemia is characterized by its fast progression rate and high complications. TRAIL can be used to trigger apoptosis in cancer cells with minimal effects on normal cells, but most of cancer cells develop resistance to this agent through various mechanisms. HDAC inhibitors like SAHA can be used to make cancer cells more susceptible to TRAIL-induced apoptosis. In this study, this hypothesis was tested on MOLT-4 cancer cell line.
MATERIALS AND METHODS
The cells were divided into six groups including the control group, TRAIL 50 nM, TRAIL 100 nM, SAHA 2 μM, SAHA 2 μM + TRAIL 50 nM, and SAHA 2 μM + TRAIL 100 nM. Apoptosis was evaluated by flowcytometry after 24, 48 and 72 h. The expression levels of c-flip, DR4, DR5, CHOP, NF-κB, STAT3, Akt, and PI3K genes were investigated by quantitative real-time PCR. Data were analyzed using two-way variance analysis with Tukey's and Dunnett's multiple comparisons tests, and statistical significance was defined as having a p-value less than 0.05.
RESULTS
Groups exposed to the combination of SAHA with TRAIL demonstrated the maximum apoptosis in MOLT-4 cells by increasing the expression of DR4, DR5, and CHOP and decreasing the expression of c-flip, STAT3, PI3k, Akt, and NF-kB genes.
CONCLUSION
It can be concluded that SAHA increases the sensitivity of MOLT-4 cells to TRAIL-mediated apoptosis, which can be used as a strategy to overcome resistance to TRAIL in leukemic patients.
Topics: Humans; Proto-Oncogene Proteins c-akt; Apoptosis; Cell Line; Flow Cytometry; NF-kappa B; Phosphatidylinositol 3-Kinases; Neoplasms
PubMed: 37480688
DOI: 10.1016/j.bbrc.2023.05.115