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CNS Neuroscience & Therapeutics Feb 2024Widely used second-generation antipsychotics are associated with adverse metabolic effects, contributing to increased cardiovascular mortality. To develop strategies to...
AIM
Widely used second-generation antipsychotics are associated with adverse metabolic effects, contributing to increased cardiovascular mortality. To develop strategies to prevent or treat adverse metabolic effects, preclinical models have a clear role in uncovering underlying molecular mechanisms. However, with few exceptions, preclinical studies have been performed in healthy animals, neglecting the contribution of dysmetabolic features inherent to psychotic disorders.
METHODS
In this study, methylazoxymethanol acetate (MAM) was prenatally administered to pregnant Sprague-Dawley rats at gestational day 17 to induce a well-validated neurodevelopmental model of schizophrenia mimicking its assumed pathogenesis with persistent phenotype. Against this background, the dysmetabolic effects of acute treatment with olanzapine and haloperidol were examined in female rats.
RESULTS
Prenatally MAM-exposed animals exhibited several metabolic features, including lipid disturbances. Half of the MAM rats exposed to olanzapine had pronounced serum lipid profile alteration compared to non-MAM controls, interpreted as a reflection of a delicate MAM-induced metabolic balance disrupted by olanzapine. In accordance with the drugs' clinical metabolic profiles, olanzapine-associated dysmetabolic effects were more pronounced than haloperidol-associated dysmetabolic effects in non-MAM rats and rats exposed to MAM.
CONCLUSION
Our results demonstrate metabolic vulnerability in female prenatally MAM-exposed rats, indicating that findings from healthy animals likely provide an underestimated impression of metabolic dysfunction associated with antipsychotics. In the context of metabolic disturbances, neurodevelopmental models possess a relevant background, and the search for adequate animal models should receive more attention within the field of experimental psychopharmacology.
Topics: Pregnancy; Rats; Female; Animals; Haloperidol; Methylazoxymethanol Acetate; Olanzapine; Rats, Sprague-Dawley; Antipsychotic Agents; Lipids; Disease Models, Animal
PubMed: 38421095
DOI: 10.1111/cns.14565 -
Cell Reports Mar 2024The radioresistant signature of colorectal cancer (CRC) hampers the clinical utility of radiotherapy. Here, we find that fecal microbiota transplantation (FMT)...
The radioresistant signature of colorectal cancer (CRC) hampers the clinical utility of radiotherapy. Here, we find that fecal microbiota transplantation (FMT) potentiates the tumoricidal effects of radiation and degrades the intertwined adverse events in azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced CRC mice. FMT cumulates Roseburia intestinalis (R. intestinalis) in the gastrointestinal tract. Oral gavage of R. intestinalis assembles at the CRC site and synthetizes butyrate, sensitizing CRC to radiation and alleviating intestinal toxicity in primary and CRC hepatic metastasis mouse models. R. intestinalis-derived butyrate activates OR51E1, a G-protein-coupled receptor overexpressing in patients with rectal cancer, facilitating radiogenic autophagy in CRC cells. OR51E1 shows a positive correlation with RALB in clinical rectal cancer tissues and CRC mouse model. Blockage of OR51E1/RALB signaling restrains butyrate-elicited autophagy in irradiated CRC cells. Our findings highlight that the gut commensal bacteria R. intestinalis motivates radiation-induced autophagy to accelerate CRC cell death through the butyrate/OR51E1/RALB axis and provide a promising radiosensitizer for CRC in a pre-clinical setting.
Topics: Humans; Animals; Mice; Butyrates; Clostridiales; Azoxymethane; Colorectal Neoplasms; Rectal Neoplasms; Dextran Sulfate; Disease Models, Animal; Mice, Inbred C57BL; Receptors, G-Protein-Coupled
PubMed: 38412097
DOI: 10.1016/j.celrep.2024.113846 -
BioRxiv : the Preprint Server For... Feb 2024Colorectal cancer (CRC) is a major public health concern and disproportionately impacts racial/ethnic minority populations in the US. Animal models are helpful in...
Colorectal cancer (CRC) is a major public health concern and disproportionately impacts racial/ethnic minority populations in the US. Animal models are helpful in examining human health disparities because many stress-induced human health conditions can be recapitulated using mouse models. Azoxymethane (AOM)/ dextran sodium sulfate (DSS) treatment can be used to model colitis-associated cancers. While colitis-associated cancers account for only 2% of colon cancers, the AOM/DSS model is useful for examining links between inflammation, immunity, and colon cancer. Mice were housed in enriched and impoverished environments for 1-month prior to behavioral testing. Following behavioral testing the mice were subjected to the AOM/DSS model. While our analysis revealed no significant behavioral variances between the impoverished and enriched housing conditions, we found significant effects in tumorigenesis. Enriched mice had fewer tumors and smaller tumor volumes compared to impoverished mice. African Americans are at higher risk for early onset colorectal cancers in part due to social economic status. Furthermore, housing conditions and environment may reflect social economic status. Research aimed at understanding links between social economic status and colorectal cancer progression is important for eliminating disparities in health outcomes.
PubMed: 38405737
DOI: 10.1101/2024.02.13.580099 -
Cardiovascular Research May 2024Heart failure (HF) and cancer are the leading causes of death worldwide. Epidemiological studies revealed that HF patients are prone to develop cancer. Preclinical...
AIMS
Heart failure (HF) and cancer are the leading causes of death worldwide. Epidemiological studies revealed that HF patients are prone to develop cancer. Preclinical studies provided some insights into this connection, but the exact mechanisms remain elusive. In colorectal cancer (CRC), gut microbial dysbiosis is linked to cancer progression and recent studies have shown that HF patients display microbial dysbiosis. This current study focussed on the effects of HF-induced microbial dysbiosis on colonic tumour formation.
METHODS AND RESULTS
C57BL/6J mice were subjected to myocardial infarction (MI), with sham surgery as control. After six weeks faeces were collected, processed for 16 s rRNA sequencing, and pooled for faecal microbiota transplantation. CRC tumour growth was provoked in germ-free mice by treating them with Azoxymethane/Dextran sodium sulphate. The CRC mice were transplanted with faeces from MI or sham mice. MI-induced HF resulted in microbial dysbiosis, characterized by a decreased α-diversity and microbial alterations on the genus level, several of which have been associated with CRC. We then performed faecal microbiota transplantation with faeces from HF mice in CRC mice, which resulted in a higher endoscopic disease score and an increase in the number of tumours in CRC mice.
CONCLUSION
We demonstrated that MI-induced HF contributes to colonic tumour formation by altering the gut microbiota composition, providing a mechanistic explanation for the observed association between HF and increased risk for cancer. Targeting the microbiome may present as a tool to mitigate HF-associated co-morbidities, especially cancer.
Topics: Animals; Dysbiosis; Mice, Inbred C57BL; Gastrointestinal Microbiome; Fecal Microbiota Transplantation; Disease Models, Animal; Myocardial Infarction; Heart Failure; Male; Colon; Ribotyping; Colonic Neoplasms; Bacteria; Feces; Host-Pathogen Interactions
PubMed: 38400709
DOI: 10.1093/cvr/cvae038 -
Animal Models and Experimental Medicine Feb 2024Nuclear receptor-binding SET domain 2 (NSD2) is a histone methyltransferase, that catalyzes dimethylation of lysine 36 of histone 3 (H3K36me2) and is associated with...
BACKGROUND
Nuclear receptor-binding SET domain 2 (NSD2) is a histone methyltransferase, that catalyzes dimethylation of lysine 36 of histone 3 (H3K36me2) and is associated with active transcription of a series of genes. NSD2 is overexpressed in multiple types of solid human tumors and has been proven to be related to unfavorable prognosis in several types of tumors.
METHODS
We established a mouse model in which the NSD2 gene was conditionally knocked out in intestinal epithelial cells. We used azoxymethane and dextran sodium sulfate to chemically induce murine colorectal cancer. The development of colorectal tumors were investigated using post-necropsy quantification, immunohistochemistry, and enzyme-linked immunosorbent assay (ELISA).
RESULTS
Compared with wild-type (WT) control mice, NSD2 -Vil1-Cre mice exhibited significantly decreased tumor numbers, histopathological changes, and cytokine expression in colorectal tumors.
CONCLUSIONS
Conditional knockout of NSD2 in intestinal epithelial cells significantly inhibits colorectal cancer progression.
PubMed: 38400589
DOI: 10.1002/ame2.12392 -
Acta Neuropathologica Communications Feb 2024
Topics: Humans; Mutagens; Guam; Methylazoxymethanol Acetate; Mutagenesis; Amyotrophic Lateral Sclerosis
PubMed: 38383591
DOI: 10.1186/s40478-024-01725-y -
Heliyon Feb 2024Natural killer (NK) cells constitute an active and potent anti-tumor effector population against multiple malignancies. NK cells exploit tumoricidal machinery to...
Natural killer (NK) cells constitute an active and potent anti-tumor effector population against multiple malignancies. NK cells exploit tumoricidal machinery to restrain colorectal carcinoma (CRC) expansion and invasion. Nonetheless, it is becoming increasingly evident that functional exhaustion considerably compromises the potency of NK cells in patients with CRC. To elucidate the factors that impair NK cell function in the context of CRC, we determined the role of zinc finger protein 335 (ZFP335) in modulating NK cell activity in mouse CRC induced by azoxymethane and dextran sulfate sodium. ZFP335 was profoundly decreased in NK cells in mesenteric lymph nodes of CRC-bearing mice. ZFP335 was especially diminished in NK cells that were both phenotypically and functionally exhausted. Besides, effective ZFP335 knockdown markedly undermined NK cell proliferation, tumoricidal protein production, degranulation, and cytotoxic efficacy on malignant cells, strongly suggesting that ZFP335 reinforces NK cell function. Importantly, ZFP335 knockdown lowered the expression of Janus kinase 1 (JAK1) and Janus kinase 3 (JAK3), both of which play crucial roles in NK cell homeostasis and activation. Collectively, ZFP335 down-regulation is essential for NK cell exhaustion in mesenteric lymph nodes of mice with CRC. We discovered a new ZFP335-JAK1/3 signaling pathway that modulates NK cell exhaustion.
PubMed: 38375265
DOI: 10.1016/j.heliyon.2024.e25721 -
Frontiers in Oncology 2023The pro-inflammatory cytokine interleukin-23 (IL-23) has been implicated in colorectal cancer (CRC). Yet, the cell-specific contributions of IL-23 receptor (IL-23R)...
INTRODUCTION
The pro-inflammatory cytokine interleukin-23 (IL-23) has been implicated in colorectal cancer (CRC). Yet, the cell-specific contributions of IL-23 receptor (IL-23R) signaling in CRC remain unknown. One of the cell types that highly expresses IL-23R are colonic regulatory T cells (Treg cells). The aim of this study was to define the contribution of Treg cell-specific IL-23R signaling in sporadic and inflammation-associated CRC.
METHODS
In mice, the role of IL-23R in Treg cells in colitis-associated cancer (CAC) was investigated using azoxymethane/dextran sodium sulphate in wild-type Treg cell reporter mice (WT, ), and mice harboring a Treg cell-specific deletion of IL-23 ( ). The role of IL-23R signaling in Treg cells in sporadic CRC was examined utilizing orthotopic injection of the syngeneic colon cancer cell line MC-38 submucosally into the colon/rectum of mice. The function of macrophages was studied using clodronate. Finally, single-cell RNA-seq of a previously published dataset in human sporadic cancer was reanalyzed to corroborate these findings.
RESULTS
In CAC, mice had increased tumor size and increased dysplasia compared to WT mice that was associated with decreased tumor-infiltrating macrophages. In the sporadic cancer model, mice had increased survival and decreased tumor size compared to WT mice. Additionally, MC-38 tumors of mice exhibited a higher frequency of pro-inflammatory macrophages and IL-17 producing CD4 T cells. The decreased tumor size in mice was macrophage-dependent. These data suggest that loss of IL-23R signaling in Treg cells permits IL-17 production by CD4 T cells that in turn promotes pro-inflammatory macrophages to clear tumors. Finally, analysis of TCGA data and single-cell RNA-seq analysis of a previously published dataset in human sporadic cancer, revealed that was highly expressed in CRC compared to other cancers and specifically in tumor-associated Treg cells.
CONCLUSION
Inflammation in colorectal carcinogenesis differs with respect to the contribution of IL-23R signaling in regulatory T cells.
PubMed: 38375204
DOI: 10.3389/fonc.2023.1276743 -
Journal of Translational Medicine Feb 2024Adenomatous polyps (APs) with inflammation are risk factors for colorectal cancer. However, the role of inflammation-related gut microbiota in promoting the progression...
BACKGROUND
Adenomatous polyps (APs) with inflammation are risk factors for colorectal cancer. However, the role of inflammation-related gut microbiota in promoting the progression of APs is unknown.
METHODS
Sequencing of the 16S rRNA gene was conducted to identify characteristic bacteria in AP tissues and normal mucosa. Then, the roles of inflammation-related bacteria were clarified by Spearman correlation analysis. Furthermore, colorectal HT-29 cells, normal colon NCM460 cells, and azoxymethane-treated mice were used to investigate the effects of the characteristic bacteria on progression of APs.
RESULTS
The expression levels of inflammation-related markers (diamine oxidase, D-lactate, C-reactive protein, tumor necrosis factor-α, interleukin-6 and interleukin-1β) were increased, whereas the expression levels of anti-inflammatory factors (interleukin-4 and interleukin-10) were significantly decreased in AP patients as compared to healthy controls. Solobacterium moorei (S. moorei) was enriched in AP tissues and fecal samples, and significantly positively correlated with serum inflammation-related markers. In vitro, S. moorei preferentially attached to HT-29 cells and stimulated cell proliferation and production of pro-inflammatory factors. In vivo, the incidence of intestinal dysplasia was significantly increased in the S. moorei group. Gavage of mice with S. moorei upregulated production of pro-inflammatory factors, suppressed proliferation of CD4 and CD8cells, and disrupted the integrity of the intestinal barrier, thereby accelerating progression of APs.
CONCLUSIONS
S. moorei accelerated the progression of AP in mice via activation of the NF-κB signaling pathway, chronic low-grade inflammation, and intestinal barrier disruption. Targeted reduction of S. moorei presents a potential strategy to prevent the progression of APs.
Topics: Humans; Animals; Mice; RNA, Ribosomal, 16S; Firmicutes; Inflammation; Adenomatous Polyps
PubMed: 38368407
DOI: 10.1186/s12967-024-04977-3 -
Scientific Reports Feb 2024This study investigated the sex-specific correlation between obesity and colorectal cancer emphasizing a more pronounced association in males. Estrogen, chromosomal...
This study investigated the sex-specific correlation between obesity and colorectal cancer emphasizing a more pronounced association in males. Estrogen, chromosomal genes, and gut bacteria were assessed in C57BL6/J male, female and ovariectomized (OVX) female mice, subjected to either a low-fat diet (LFD) or high-fat diet (HFD) for 14 weeks. Induction of colon tumor involved azoxymethane (10 mg/kg) administration, followed by three cycles of dextran sulfate sodium. Male mice on HFD exhibited higher final body weight and increased colon tumors compared to females. Colonic mucin 2 expression was significantly higher in females. HFD-modulated differentially expressed genes numbered 290 for males, 64 for females, and 137 for OVX females. Only one up-regulated gene (Gfra3) overlapped between females and OVX females, while two down-regulated genes (Thrsp and Gbp11) overlapped between males and OVX females. Genes up-regulated by HFD in males were linked to cytokine-cytokine interaction, HIF-1 signaling pathway, central carbon metabolism in cancer. Sex-specific changes in gut microbial composition in response to HFD were observed. These findings suggest a male-specific vulnerability to HFD-induced colon tumor formation, implicating key genes and colonic bacteria in colon tumorigenesis.
Topics: Female; Male; Animals; Mice; Sex Characteristics; Obesity; Colonic Neoplasms; Diet, High-Fat; Cytokines; Microbiota; Gene Expression; Mice, Inbred C57BL
PubMed: 38347027
DOI: 10.1038/s41598-024-53861-z