World J Gastroenterol. 2024 Jul 21;30(27):3336-3355. doi: 10.3748/wjg.v30.i27.3336.

ABSTRACT

BACKGROUND: Colorectal polyps that develop via the conventional adenoma-carcinoma sequence [e.g., tubular adenoma (TA)] often progress to malignancy and are closely associated with changes in the composition of the gut microbiome. There is limited research concerning the microbial functions and gut microbiomes associated with colorectal polyps that arise through the serrated polyp pathway, such as hyperplastic polyps (HP). Exploration of microbiome alterations associated with HP and TA would improve the understanding of mechanisms by which specific microbes and their metabolic pathways contribute to colorectal carcinogenesis.

AIM: To investigate gut microbiome signatures, microbial associations, and microbial functions in HP and TA patients.

METHODS: Full-length 16S rRNA sequencing was used to characterize the gut microbiome in stool samples from control participants without polyps [control group (CT), n = 40], patients with HP (n = 52), and patients with TA (n = 60). Significant differences in gut microbiome composition and functional mechanisms were identified between the CT group and patients with HP or TA. Analytical techniques in this study included differential abundance analysis, co-occurrence network analysis, and differential pathway analysis.

RESULTS: Colorectal cancer (CRC)-associated bacteria, including Streptococcus gallolyticus (S. gallolyticus), Bacteroides fragilis, and Clostridium symbiosum, were identified as characteristic microbial species in TA patients. Mediterraneibacter gnavus, associated with dysbiosis and gastrointestinal diseases, was significantly differentially abundant in the HP and TA groups. Functional pathway analysis revealed that HP patients exhibited enrichment in the sulfur oxidation pathway exclusively, whereas TA patients showed dominance in pathways related to secondary metabolite biosynthesis (e.g., mevalonate); S. gallolyticus was a major contributor. Co-occurrence network and dynamic network analyses revealed co-occurrence of dysbiosis-associated bacteria in HP patients, whereas TA patients exhibited co-occurrence of CRC-associated bacteria. Furthermore, the co-occurrence of SCFA-producing bacteria was lower in TA patients than HP patients.

CONCLUSION: This study revealed distinct gut microbiome signatures associated with pathways of colorectal polyp development, providing insights concerning the roles of microbial species, functional pathways, and microbial interactions in colorectal carcinogenesis.

PMID:39086748 | PMC:PMC11287419 | DOI:10.3748/wjg.v30.i27.3336

Front Microbiol. 2024 Jul 17;15:1437572. doi: 10.3389/fmicb.2024.1437572. eCollection 2024.

ABSTRACT

INTRODUCTION: The oral trichomonad Trichomonas tenax is increasingly appreciated as a likely contributor to periodontitis, a chronic inflammatory disease induced by dysbiotic microbiota, in humans and domestic animals and is strongly associated with its worst prognosis. Our current understanding of the molecular basis of T. tenax interactions with host cells and the microbiota of the oral cavity are still rather limited. One laboratory strain of T. tenax (Hs-4:NIH/ATCC 30207) can be grown axenically and two draft genome assemblies have been published for that strain, although the structural and functional annotation of these genomes is not available.

METHODS: GenSAS and Galaxy were used to annotate two publicly available draft genomes for T. tenax, with a focus on protein-coding genes. A custom pipeline was used to annotate the CAZymes for T. tenax and the human sexually transmitted parasite Trichomonas vaginalis, the most well-characterized trichomonad. A combination of bioinformatics analyses was used to screen for homologs of T. vaginalis virulence and colonization factors within the T. tenax annotated proteins.

RESULTS: Our annotation of the two T. tenax draft genome sequences and their comparison with T. vaginalis proteins provide evidence for several candidate virulence factors. These include candidate surface proteins, secreted proteins and enzymes mediating potential interactions with host cells and/or members of the oral microbiota. The CAZymes annotation identified a broad range of glycoside hydrolase (GH) families, with the majority of these being shared between the two Trichomonas species.

DISCUSSION: The presence of candidate T. tenax virulence genes supports the hypothesis that this species is associated with periodontitis through direct and indirect mechanisms. Notably, several GH proteins could represent potential new virulence factors for both Trichomonas species. These data support a model where T. tenax interactions with host cells and members of the oral microbiota could synergistically contribute to the damaging inflammation characteristic of periodontitis, supporting a causal link between T. tenax and periodontitis.

PMID:39086644 | PMC:PMC11288935 | DOI:10.3389/fmicb.2024.1437572

Front Immunol. 2024 Jul 17;15:1398990. doi: 10.3389/fimmu.2024.1398990. eCollection 2024.

ABSTRACT

BACKGROUND: More and more evidence supports the association between myocardial infarction (MI) and osteoarthritis (OA). The purpose of this study is to explore the shared biomarkers and pathogenesis of MI complicated with OA by systems biology.

METHODS: Gene expression profiles of MI and OA were downloaded from the Gene Expression Omnibus (GEO) database. The Weighted Gene Co-Expression Network Analysis (WGCNA) and differentially expressed genes (DEGs) analysis were used to identify the common DEGs. The shared genes related to diseases were screened by three public databases, and the protein-protein interaction (PPI) network was built. GO and KEGG enrichment analyses were performed on the two parts of the genes respectively. The hub genes were intersected and verified by Least absolute shrinkage and selection operator (LASSO) analysis, receiver operating characteristic (ROC) curves, and single-cell RNA sequencing analysis. Finally, the hub genes differentially expressed in primary cardiomyocytes and chondrocytes were verified by RT-qPCR. The immune cell infiltration analysis, subtypes analysis, and transcription factors (TFs) prediction were carried out.

RESULTS: In this study, 23 common DEGs were obtained by WGCNA and DEGs analysis. In addition, 199 common genes were acquired from three public databases by PPI. Inflammation and immunity may be the common pathogenic mechanisms, and the MAPK signaling pathway may play a key role in both disorders. DUSP1, FOS, and THBS1 were identified as shared biomarkers, which is entirely consistent with the results of single-cell RNA sequencing analysis, and furher confirmed by RT-qPCR. Immune infiltration analysis illustrated that many types of immune cells were closely associated with MI and OA. Two potential subtypes were identified in both datasets. Furthermore, FOXC1 may be the crucial TF, and the relationship of TFs-hub genes-immune cells was visualized by the Sankey diagram, which could help discover the pathogenesis between MI and OA.

CONCLUSION: In summary, this study first revealed 3 (DUSP1, FOS, and THBS1) novel shared biomarkers and signaling pathways underlying both MI and OA. Additionally, immune cells and key TFs related to 3 hub genes were examined to further clarify the regulation mechanism. Our study provides new insights into shared molecular mechanisms between MI and OA.

PMID:39086489 | PMC:PMC11288954 | DOI:10.3389/fimmu.2024.1398990

Cancer Res. 2024 Aug 1;84(15):2397-2399. doi: 10.1158/0008-5472.CAN-24-1506.

ABSTRACT

Over the past three decades, high-throughput phenotypic cancer cell line screens have revealed unanticipated small-molecule activities and illuminated connections between tumor genotypes and anticancer efficacy. Founded in 1984, the National Cancer Institute's "NCI60" screen laid the conceptual groundwork for the contemporary landscape of phenotypic drug discovery. NCI60 first operated as a primary bioactivity screen, but molecular characterization of the NCI60 cell line panel and development of a small-molecule sensitivity pattern recognition algorithm (called "COMPARE") have enabled subsequent studies into drug mechanisms of action and biomarker identification. In this issue of Cancer Research, Kunkel and colleagues report an updated version of the NCI60 screen, dubbed "HTS384" NCI60, that better aligns with current cell proliferation assay standards and has higher throughput. Changes include the use of a 384-well plate format, automated laboratory equipment, 3 days of compound exposure, and a CellTiter-Glo luminescent endpoint. To confirm that data from the HTS384 and classic NCI60 screen are comparable, the authors tested a library of 1,003 anticancer agents using both protocols and applied COMPARE to analyze patterns of cell line sensitivities. More than three dozen groups of targeted therapies showed high comparability between screens. Modernization of NCI60, and closer integration with other large-scale pharmacogenomic screens and molecular feature sets, will help this public screening service remain pertinent for cancer drug discovery efforts for years to come. See related article by Kunkel et al., p. 2403.

PMID:39086314 | DOI:10.1158/0008-5472.CAN-24-1506

Analyst. 2024 Aug 1. doi: 10.1039/d4an00602j. Online ahead of print.

ABSTRACT

This study presents the development and validation of an innovative microfluidic liver-on-a-chip device utilizing gravity-driven perfusion for the evaluation of drug hepatotoxicity. This research involved the construction of a hydrogel-based coculture chip that integrates liver parenchymal and stellate cells within a tri-channel configuration. The assembly and operation of the liver-on-a-chip and its accompanying custom rocker were straightforward. The cells in the chip maintained high viability and continuously synthesized liver albumin over extended culture durations. Acetaminophen (APAP), a hepatic injury-inducing drug, was utilized as a positive control in hepatic toxicity assays on the chip. The liver chip exhibited hepatotoxic responses comparable to those observed in 2D models. Furthermore, in this study we evaluated the effects of two plant-derived natural compounds, aristolochic acid I (AA) and its analog aristolactam AII (AL), in both 2D cell models and the liver-on-a-chip system. AA, known for its hepatorenal toxicity, was observed to cause hepatotoxicity in both the 2D models and on the chip. The flow cytometry and mRNA sequencing results confirmed the propensity of these compounds to induce liver cell apoptosis. Notably, AL, previously considered nontoxic, provoked a significant decrease in the hepatic functionality marker albumin exclusively in the liver chip but not in 2D models, indicating the liver chip's enhanced sensitivity to toxic substances. In summary, this pumpless liver-on-a-chip is a simple yet powerful tool for drug hepatotoxicity studies.

PMID:39086194 | DOI:10.1039/d4an00602j

Kidney Int. 2024 Jul 29:S0085-2538(24)00525-8. doi: 10.1016/j.kint.2024.07.011. Online ahead of print.

ABSTRACT

Medial vascular calcification in chronic kidney disease (CKD) involves pro-inflammatory pathways induced by hyperphosphatemia. Several interleukin 6 family members have been associated with pro-calcific effects in vascular smooth muscle cells (VSMCs) and are considered as therapeutic targets. Therefore, we investigated the role of leukemia inhibitory factor (LIF) during VSMC calcification. LIF expression was found to be increased following phosphate exposure of VSMCs. LIF supplementation aggravated, while silencing of endogenous LIF or LIF receptor (LIFR) ameliorated the pro-calcific effects of phosphate in VSMCs. The soluble LIFR mediated antagonistic effects towards LIF and reduced VSMC calcification. Mechanistically, LIF induced phosphorylation of the non-receptor tyrosine-protein kinase 2 (TYK2) and signal transducer and activator of transcription-3 (STAT3) in VSMCs. TYK2 inhibition by deucravacitinib, a selective, allosteric oral immunosuppressant used in psoriasis treatment, not only blunted the effects of LIF, but also interfered with the pro-calcific effects induced by phosphate. Conversely, TYK2 overexpression aggravated VSMC calcification. Ex vivo calcification of mouse aortic rings was ameliorated by Tyk2 pharmacological inhibition and genetic deficiency. Cholecalciferol-induced vascular calcification in mice was improved by Tyk2 inhibition and in the Tyk2-deficient mice. Similarly, calcification was ameliorated in Abcc6/Tyk2-deficient mice after adenine/high phosphorus-induced CKD. Thus, our observations indicate a role for LIF in CKD-associated vascular calcification. Hence, the effects of LIF identify a central pro-calcific role of TYK2 signaling, which may be a future target to reduce the burden of vascular calcification in CKD.

PMID:39084258 | DOI:10.1016/j.kint.2024.07.011

Kidney Int. 2024 Jul 29:S0085-2538(24)00527-1. doi: 10.1016/j.kint.2024.06.023. Online ahead of print.

ABSTRACT

IgA nephropathy (IgAN) is the most common type of glomerulonephritis that frequently progresses to kidney failure. However, the molecular pathogenesis underlying IgAN remains largely unknown. Here, we investigated the role of galectin-3 (Gal-3), a galactoside-binding protein in IgAN pathogenesis and showed that Gal-3 expression by the kidney was significantly enhanced in patients with IgAN. In both TEPC-15 hybridoma-derived IgA-induced, passive, and spontaneous "grouped" ddY IgAN models, Gal-3 expression was clearly increased with disease severity in the glomeruli, peri-glomerular regions, and some kidney tubules. Gal-3 knockout (KO) in the passive IgAN model had significantly improved proteinuria, kidney function and reduced severity of kidney pathology, including neutrophil infiltration and decreased differentiation of Th17 cells from kidney-draining lymph nodes, despite increased percentages of regulatory T cells. Gal-3 KO also inhibited the NLRP3 inflammasome, yet it enhanced autophagy and improved kidney inflammation and fibrosis. Moreover, administration of 6-de-O-sulfated, N-acetylated low-molecular-weight heparin, a competitive Gal-3 binding inhibitor, restored kidney function and improved kidney lesions in passive IgAN mice. Thus, our results suggest that Gal-3 is critically involved in IgAN pathogenesis by activating the NLRP3 inflammasome and promoting Th17 cell differentiation. Hence, targeting Gal-3 action may represent a new therapeutic strategy for treatment of this kidney disease.

PMID:39084257 | DOI:10.1016/j.kint.2024.06.023

Cell Mol Life Sci. 2024 Aug 1;81(1):327. doi: 10.1007/s00018-024-05378-x.

ABSTRACT

Dysregulation of mucosal immune system has been proposed to be critical in the pathogenesis of inflammatory bowel diseases (IBDs). Regulatory T cells (Tregs) play an important role in regulating immune responses. Tregs are involved in maintaining intestinal homeostasis and exerting suppressive function in colitis. Our previous studies showed that a novel forkhead box protein P3 (Foxp3) negative Tregs (Treg-of-B cells), induced by culturing naïve CD4+ T cells with B cells, could protect against colitis and downregulate T helper (Th) 1 and Th17 cell cytokines in T cell-mediated colitis. In the present study, we aimed to induce Treg-of-B cells in the CD8+ T-cell population and investigate their characteristics and immunomodulatory functions. Our results showed that CD8+ Treg-of-B cells expressed Treg-associated markers, including lymphocyte-activation gene-3 (LAG3), inducible co-stimulator (ICOS), programmed death-1 (PD-1), cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), tumor necrosis factor receptor superfamily member-4 (TNFRSF4, OX40), and tumor necrosis factor receptor superfamily member-18 (TNFRSF18, GITR), but did not express Foxp3. CD8+ Treg-of-B cells produced higher concentration of inhibitory cytokine interleukin (IL)-10, and expressed higher levels of cytotoxic factor granzyme B and perforin after stimulation, compared to those of CD8+CD25- T cells. Moreover, CD8+ Treg-of-B cells suppressed T cell proliferation in vitro and alleviated colonic inflammation in chronic dextran sulfate sodium (DSS)-induced colitis. In conclusion, our study identified a novel subpopulation of CD8+ Tregs with suppressive effects through cell contact. These CD8+ Treg-of-B cells might have therapeutic potential for IBDs.

PMID:39085655 | DOI:10.1007/s00018-024-05378-x

J Comp Physiol B. 2024 Jul 31. doi: 10.1007/s00360-024-01575-z. Online ahead of print.

ABSTRACT

Coastal marine environments are characterized by daily, seasonal and long-term changes in both O2 and CO2, driven by local biotic and abiotic factors. The neuroepithelial cells (NECs) of fish are thought to be the putative chemoreceptors for sensing oxygen and CO2, and, thus, NECs play a key role in detecting these environmental changes. However, the role of NECs as chemosensors in marine fish remains largely understudied. In this study, the NECs of marine threespine sticklebacks (Gasterosteus aculeatus) were characterized using immunohistochemistry. We then determined if there were changes in NEC size and density, and in gill morphology in response to either mild (10 kPa) or moderate (6.8 kPa) hypoxia and two levels of elevated CO2 (1,500 and 3,000 µatm). We found that the NECs of stickleback contained synaptic vesicles and were innervated, and were 50-300% larger and 2 to 4 times more abundant than in other similar sized freshwater fishes. NEC size and density were largely unaffected by exposure to hypoxia, but there was a 50% decrease in interlamellar cell mass (ILCM) in response to mild and moderate hypoxia. NECs increased in size, but not abundance in response to elevated CO2. Moreover, fish exposed to moderate or elevated CO2 had 53-78% larger ILCMs compared to control fish. Our results demonstrated that adult marine sticklebacks have NECs that can respond to environmentally relevant pCO2 and likely hypoxia, which highlights the importance of NECs in marine fishes under the heterogeneity of environmental conditions in coastal areas.

PMID:39085643 | DOI:10.1007/s00360-024-01575-z

Nature. 2024 Jul 31. doi: 10.1038/s41586-024-07778-2. Online ahead of print.

ABSTRACT

The global retreat of glaciers is dramatically altering mountain and high-latitude landscapes, with new ecosystems developing from apparently barren substrates1-4. The study of these emerging ecosystems is critical to understanding how climate change interacts with microhabitat and biotic communities and determines the future of ice-free terrains1,5. Here, using a comprehensive characterization of ecosystems (soil properties, microclimate, productivity and biodiversity by environmental DNA metabarcoding6) across 46 proglacial landscapes worldwide, we found that all the environmental properties change with time since glaciers retreated, and that temperature modulates the accumulation of soil nutrients. The richness of bacteria, fungi, plants and animals increases with time since deglaciation, but their temporal patterns differ. Microorganisms colonized most rapidly in the first decades after glacier retreat, whereas most macroorganisms took longer. Increased habitat suitability, growing complexity of biotic interactions and temporal colonization all contribute to the increase in biodiversity over time. These processes also modify community composition for all the groups of organisms. Plant communities show positive links with all other biodiversity components and have a key role in ecosystem development. These unifying patterns provide new insights into the early dynamics of deglaciated terrains and highlight the need for integrated surveillance of their multiple environmental properties5.

PMID:39085613 | DOI:10.1038/s41586-024-07778-2

Sci Rep. 2024 Aug 1;14(1):17757. doi: 10.1038/s41598-024-68470-z.

ABSTRACT

Chronic kidney disease (CKD) impacts about 1 in 7 adults in the United States, but African Americans (AAs) carry a disproportionately higher burden of disease. Epigenetic modifications, such as DNA methylation at cytosine-phosphate-guanine (CpG) sites, have been linked to kidney function and may have clinical utility in predicting the risk of CKD. Given the dynamic relationship between the epigenome, environment, and disease, AAs may be especially sensitive to environment-driven methylation alterations. Moreover, risk models incorporating CpG methylation have been shown to predict disease across multiple racial groups. In this study, we developed a methylation risk score (MRS) for CKD in cohorts of AAs. We selected nine CpG sites that were previously reported to be associated with estimated glomerular filtration rate (eGFR) in epigenome-wide association studies to construct a MRS in the Hypertension Genetic Epidemiology Network (HyperGEN). In logistic mixed models, the MRS was significantly associated with prevalent CKD and was robust to multiple sensitivity analyses, including CKD risk factors. There was modest replication in validation cohorts. In summary, we demonstrated that an eGFR-based CpG score is an independent predictor of prevalent CKD, suggesting that MRS should be further investigated for clinical utility in evaluating CKD risk and progression.

PMID:39085340 | DOI:10.1038/s41598-024-68470-z

NPJ Biofilms Microbiomes. 2024 Jul 31;10(1):65. doi: 10.1038/s41522-024-00531-7.

ABSTRACT

Insect gut microbiomes play a crucial role in the insect development and are shaped, among other factors, by the specialized insect diet habits as well as the morphological structure of the gut. Rose chafers (Pachnoda spp.; Coleoptera: Scarabaeidae) have a highly differentiated gut characterized by a pronounced hindgut dilation which resembles a miniaturized rumen. Specifically, the species Pachnoda marginata has not been previously studied in detail in terms of microbial ecology. Here, we show a fine scale study of the highly compartmentalized gut of P. marginata by using amplicon and metagenomic sequencing to shed light on the bacterial, archaeal and fungal communities thriving in each section of the gut. We found a microbial gradient along the gut from aerobic (foregut) to strictly anaerobic communities (hindgut). In addition, we have characterized interesting biological activities and metabolic pathways of gut microbial communities related to cellulose degradation, methane production and sulfate reduction. Taken together, our results reveal the highly diverse microbial community and the potential of P. marginata gut as a source of industrially relevant microbial diversity.

PMID:39085298 | DOI:10.1038/s41522-024-00531-7

NPJ Sci Food. 2024 Jul 31;8(1):48. doi: 10.1038/s41538-024-00290-x.

ABSTRACT

Securing a sustainable global food supply for a growing population requires a shift toward a more plant-based diet. The application of plant-based proteins is therefore increasing, but unpleasant off-flavors complicate their use. Here, we screened 97 microorganisms for their potential to remove off-flavors in a process with limiting amounts of fermentable sugar. This allowed the production of a more neutral-tasting, purified food ingredient while limiting microbial growth and the production of typical fermentation end products. We demonstrate that various lactic acid bacteria (LAB) and yeasts remove "green" aldehydes and ketones. This conversion can be carried out in less than one hour in almond, pea, potato, and oat proteins. Heterofermentative LAB was best at aldehyde and ketone neutralization with minimum de novo formation of microbial volatiles such as ethylacetate (sweet, fruity) or alpha-diketones (butter- and cheese-like). While sensory properties were improved, changes in protein solubility, emulsification, foaming, and in vitro digestibility were limited.

PMID:39085288 | DOI:10.1038/s41538-024-00290-x

Nat Commun. 2024 Jul 31;15(1):6450. doi: 10.1038/s41467-024-50958-x.

NO ABSTRACT

PMID:39085258 | DOI:10.1038/s41467-024-50958-x

NPJ Biofilms Microbiomes. 2024 Aug 1;10(1):66. doi: 10.1038/s41522-024-00538-0.

ABSTRACT

The clinical course of COVID-19 is variable and often unpredictable. To test the hypothesis that disease progression and inflammatory responses associate with alterations in the microbiome and metabolome, we analyzed metagenome, metabolome, cytokine, and transcriptome profiles of repeated samples from hospitalized COVID-19 patients and uninfected controls, and leveraged clinical information and post-hoc confounder analysis. Severe COVID-19 was associated with a depletion of beneficial intestinal microbes, whereas oropharyngeal microbiota disturbance was mainly linked to antibiotic use. COVID-19 severity was also associated with enhanced plasma concentrations of kynurenine and reduced levels of several other tryptophan metabolites, lysophosphatidylcholines, and secondary bile acids. Moreover, reduced concentrations of various tryptophan metabolites were associated with depletion of Faecalibacterium, and tryptophan decrease and kynurenine increase were linked to enhanced production of inflammatory cytokines. Collectively, our study identifies correlated microbiome and metabolome alterations as a potential contributor to inflammatory dysregulation in severe COVID-19.

PMID:39085233 | DOI:10.1038/s41522-024-00538-0

Sci Transl Med. 2024 Jul 31;16(758):eadg7915. doi: 10.1126/scitranslmed.adg7915. Epub 2024 Jul 31.

ABSTRACT

Richter's transformation (RT) is a progression of chronic lymphocytic leukemia (CLL) to aggressive lymphoma. MGA (Max gene associated), a functional MYC suppressor, is mutated at 3% in CLL and 36% in RT. However, genetic models and molecular mechanisms of MGA deletion that drive CLL to RT remain elusive. We established an RT mouse model by knockout of Mga in the Sf3b1/Mdr CLL model using CRISPR-Cas9 to determine the role of Mga in RT. Murine RT cells exhibited mitochondrial aberrations with elevated oxidative phosphorylation (OXPHOS). Through RNA sequencing and functional characterization, we identified Nme1 (nucleoside diphosphate kinase) as an Mga target, which drives RT by modulating OXPHOS. Given that NME1 is also a known MYC target without targetable compounds, we found that concurrent inhibition of MYC and electron transport chain complex II substantially prolongs the survival of RT mice in vivo. Our results suggest that the Mga-Nme1 axis drives murine CLL-to-RT transition via modulating OXPHOS, highlighting a potential therapeutic avenue for RT.

PMID:39083585 | DOI:10.1126/scitranslmed.adg7915

Mol Biol Cell. 2024 Jul 31:mbcE24030122. doi: 10.1091/mbc.E24-03-0122. Online ahead of print.

ABSTRACT

Adaptation to environmental stress requires coordination between stress-defense programs and cell cycle progression. The immediate response to many stressors has been well characterized, but how cells survive in challenging environments long-term is unknown. Here, we investigate the role of the stress-activated phosphatase calcineurin (CN) in adaptation to chronic CaCl2 stress in Saccharomyces cerevisiae. We find that prolonged exposure to CaCl2 impairs mitochondrial function and demonstrate that cells respond to this stressor using two CN-dependent mechanisms - one that requires the downstream transcription factor Crz1 and another that is Crz1-independent. Our data indicate that CN maintains cellular fitness by promoting cell cycle progression and preventing CaCl2-induced cell death. When Crz1 is present, transient CN activation suppresses cell death and promotes adaptation despite high levels of mitochondrial loss. However, in the absence of Crz1, prolonged activation of CN prevents mitochondrial loss and further cell death by upregulating glutathione (GSH) biosynthesis genes thereby mitigating damage from reactive oxygen species. These findings illustrate how cells maintain long-term fitness during chronic stress and suggest that CN promotes adaptation in challenging environments by multiple mechanisms.

PMID:39083354 | DOI:10.1091/mbc.E24-03-0122

Mol Cancer Res. 2024 Jul 31. doi: 10.1158/1541-7786.MCR-24-0151. Online ahead of print.

ABSTRACT

Patients with class I V600EBRAF-mutant (MT) colorectal cancer (CRC) have a poor prognosis and their response to combined anti-BRAF/EGFR inhibition remains limited. There is clearly an unmet need in further understanding the biology of V600EBRAFMT CRC. We have used differential gene expression of BRAFWT and MT CRC cells to identify pathways underpinning BRAFMT CRC. We tested a panel of molecularly/genetically subtyped CRC cells for their sensitivity to the Unfolded Protein Response (UPR) activator BOLD-100. To identify novel combination strategies for BOLD-100, we performed RNA sequencing and high-throughput drug screening. Pathway enrichment analysis identified that the UPR and DNA repair pathways were significantly enriched in BRAFMT CRC. We found that oncogenic BRAF plays a crucial role in mediating response to BOLD-100. Using a systems biology approach, we identified V600EBRAFMT-dependent activation of the replication stress response kinase ATR as a key mediator of resistance to BOLD-100. Further analysis identified acute increases in BRAFMT-dependent-reactive oxygen species (ROS) levels following treatment with BOLD-100 that was demonstrated to promote ATR/CHK1 activation and apoptosis. Furthermore, activation of ROS/ATR/CHK1 following BOLD-100 was found to be mediated through the AHR transcription factor and CYP1A1. Importantly, pharmacological blockade of this resistance pathway with ATR inhibitors synergistically increased BOLD-100-induced apoptosis and growth inhibition in BRAFMT models. These results unveil possible novel therapeutic opportunity for BRAFMT CRC. Implications: BOLD-100 induces BRAFMT-dependent replication stress, and targeted strategies against replication stress (eg. by using ATR inhibitors) in combination with BOLD-100 may serve as a potential novel therapeutic strategy for clinically aggressive BRAFMT CRC.

PMID:39083088 | DOI:10.1158/1541-7786.MCR-24-0151

Proteomics Clin Appl. 2024 Jul 31:e202300115. doi: 10.1002/prca.202300115. Online ahead of print.

ABSTRACT

PURPOSE: Merozoites are the only extracellular form of blood stage parasites, making it a worthwhile target. Multiple invasins that are stored in the merozoite apical organelles, are secreted just prior to invasion, and mediates its interaction with RBC. A comprehensive identification of all these secreted invasins is lacking and this study addresses that gap.

EXPERIMENTAL DESIGN: Pf3D7 merozoites were enriched and triggered to discharge apical organelle contents by exposure to ionic conditions mimicking that of blood plasma. The secreted proteins were separated from cellular contents and both the fractions were subjected to proteomic analysis. Also, the identified secreted proteins were subjected to GO, PPI network analysis, and AI-based in silico approach to understand their vaccine candidacy.

RESULTS: A total of 63 proteins were identified in the secretory fraction with membrane and apical organellar localization. This includes various MSPs, micronemal EBAs and rhoptry bulb proteins, which play a crucial role in initial and late merozoite attachment, and majority of them qualified as vaccine candidates.

CONCLUSION AND CLINICAL RELEVANCE: We, for the first time, report the secretory repertoire of merozoite and its status for vaccine candidacy. This information can be utilized to develop better invasion blocking multisubunit vaccines, comprising of immunological epitopes from several secreted invasins.

PMID:39082488 | DOI:10.1002/prca.202300115

Front Microbiol. 2024 Jul 16;15:1371292. doi: 10.3389/fmicb.2024.1371292. eCollection 2024.

ABSTRACT

In the past three decades, dietary and lifestyle changes worldwide have resulted in a global increase in the prevalence of obesity in both adults and children. Known to be highly influenced by genetic, environmental and lifestyle factors, obesity is characterized by a low-grade chronic inflammation that contributes to the development of other metabolic diseases such as diabetes and cardiovascular disease. Recently, the gut microbiome has been added as a cause/contributor to the development of obesity. As differences in the microbiome between obese and normoweight individuals have been observed, we set out to determine whether infants harbor an obesogenic microbiome early on and whether the pre-pregnancy status of the mother (obese or normoweight) is correlated to their infant's microbiome composition. Using shotgun sequencing, we analyzed stool samples throughout the first year of life from infants born to obese (n = 23 participants, m = 104 samples) and normoweight (n = 23 participants, m = 99 samples) mothers. We found that the infants' microbiome diversity at taxonomic and functional levels was significantly influenced by time (ANOVA p < 0.001) but not by the mother's pre-pregnancy status. Overall, no deterministic succession of taxa or functions was observed. However, infants born to obese mothers were found to have a significantly higher Bacillota/Bacteroidota ratio (p = 0.02) at six months, were significantly depleted from six months old of the well-established obesity biomarkers Akkermansia municiphila and Faecalibacterium prausnitzii (p < 0.01), and were at one week old, significantly enriched in pathways such as the UDP-N-acetyl-D-glucosamine biosynthesis II (p = 0.02) involved in leptin production, suggesting perhaps that there may exist some underlying mechanisms that dictate the development of an obesogenic microbiota early on.

PMID:39081889 | PMC:PMC11287775 | DOI:10.3389/fmicb.2024.1371292