Phosphofurin acidic cluster sorting protein 2 (PACS2) plays a vital role in maintaining cellular homeostasis by regulating protein trafficking between cellular membranes. This function impacts crucial processes like apoptosis, mitochondria-endoplasmic reticulum interaction, and subsequently Ca2+ flux, lipid biosynthesis, and autophagy. Missense mutations, particularly E209K and E211K, are linked to developmental and epileptic encephalopathy-66 (DEE66), known as PACS2 syndrome. Individuals with this syndrome exhibit neurodevelopmental delay, seizures, facial dysmorphism, hypotonia, and delayed motor skills.Understanding the impact of these missense mutations on molecular processes is crucial. Studies suggest that E209K mutation decreases phosphorylation, increases the survival time of protein, and modifies protein-protein interaction, consequently leading to disruption of calcium flux and lower resistance to apoptosis induction. Unfortunately, to date, only a limited number of research groups have investigated the effects of mutations in the PACS2 gene. Current research on PACS2 syndrome is hampered by the lack of suitable models. While in vitro models using transfected cell lines offer insights, they cannot fully capture the disease's complexity.To address this, utilizing cells from individuals with PACS2 syndrome, specifically induced pluripotent stem cells (iPSCs), holds promise for understanding phenotypic diversity and developing personalized therapies. However, iPSC models may not fully capture tissue-specific effects of the E209K/E211K mutation. In vivo studies using animal models, particularly mice, could overcome these limitations.This review summarizes current knowledge about PACS2 structure and functions, explores the cellular consequences of E209K and E211K mutations, and highlights the potential of iPSC and mouse models in advancing our understanding of PACS2 syndrome.
- MeSH
- Induced Pluripotent Stem Cells metabolism MeSH
- Humans MeSH
- Mutation, Missense * MeSH
- Mutation MeSH
- Vesicular Transport Proteins * genetics metabolism MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
Chronic intestinal inflammation significantly contributes to the development of colorectal cancer and remains a pertinent clinical challenge, necessitating novel therapeutic approaches. Indole-based microbial metabolite mimics Felix Kopp Kortagere 6 (FKK6), which is a ligand and agonist of the pregnane X receptor (PXR), was recently demonstrated to have PXR-dependent anti-inflammatory and protective effects in a mouse model of dextran sodium sulfate (DSS)-induced acute colitis. Here, we examined the therapeutic potential of FKK6 in a mouse model (C57BL/6 FVB humanized PXR mice) of colitis-associated colon cancer (CAC) induced by azoxymethane and DSS. FKK6 (2 mg/kg) displayed substantial antitumor activity, as revealed by reduced size and number of colon tumors, improved colon histopathology, and decreased expression of tumor markers (c-MYC, β-catenin, Ki-67, and cyclin D) in the colon. In addition, we carried out a chronic toxicity (30 days) assessment of FKK6 (1 mg/kg and 2 mg/kg) in C57BL/6 mice. Histological examination of tissues, biochemical blood analyses, and immunohistochemical staining for Ki-67 and γ-H2AX showed no difference between FKK6-treated and control mice. Comparative metabolomic analyses in mice exposed for 5 days to DSS and administered with FKK6 (0.4 mg/kg) revealed no significant effects on several classes of metabolites in the mouse fecal metabolome. Ames and micronucleus tests showed no genotoxic and mutagenic potential of FKK6 in vitro. In conclusion, anticancer effects of FKK6 in azoxymethane/DSS-induced CAC, together with FKK6 safety data from in vitro tests and in vivo chronic toxicity study, and comparative metabolomic study, are supportive of the potential therapeutic use of FKK6 in the treatment of CAC. SIGNIFICANCE STATEMENT: Microbial metabolite mimicry proposes that chemical mimics of microbial metabolites that serve to protect hosts against aberrant inflammation in the gut could serve as a new paradigm for the development of drugs targeting inflammatory bowel disease if, like the parent metabolite, is devoid of toxicity but more potent against the microbial metabolite receptor. We identified a chemical mimic of Felix Kopp Kortagere 6, and we propose that Felix Kopp Kortagere 6 is devoid of toxicity yet significantly reduces tumor formation in an azoxymethane-dextran sodium sulfate model of murine colitis-induced colon cancer.
- MeSH
- Azoxymethane toxicity MeSH
- Chronic Disease MeSH
- Indoles pharmacology therapeutic use MeSH
- Colitis drug therapy chemically induced metabolism pathology MeSH
- Colorectal Neoplasms * drug therapy metabolism pathology MeSH
- Disease Models, Animal * MeSH
- Molecular Mimicry MeSH
- Mice, Inbred C57BL * MeSH
- Mice MeSH
- Colitis-Associated Neoplasms pathology drug therapy metabolism MeSH
- Dextran Sulfate toxicity MeSH
- Inflammation drug therapy metabolism MeSH
- Animals MeSH
- Check Tag
- Male MeSH
- Mice MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
The extracellular matrix (ECM)-and its mechanobiology-regulates key cellular functions that drive tumor growth and development. Accordingly, mechanotherapy is emerging as an effective approach to treat fibrotic diseases such as cancer. Through restoring the ECM to healthy-like conditions, this treatment aims to improve tissue perfusion, facilitating the delivery of chemotherapies. In particular, the manipulation of ECM is gaining interest as a valuable strategy for developing innovative treatments based on nanoparticles (NPs). However, further progress is required; for instance, it is known that the presence of a dense ECM, which hampers the penetration of NPs, primarily impacts the efficacy of nanomedicines. Furthermore, most 2D in vitro studies fail to recapitulate the physiological deposition of matrix components. To address these issues, a comprehensive understanding of the interactions between the ECM and NPs is needed. This review focuses on the main features of the ECM and its complex interplay with NPs. Recent advances in mechanotherapy are discussed and insights are offered into how its combination with nanomedicine can help improve nanomaterials design and advance their clinical translation.
- MeSH
- Extracellular Matrix * metabolism MeSH
- Humans MeSH
- Neoplasms * therapy MeSH
- Nanoparticles * chemistry MeSH
- Nanomedicine * methods MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
In screening biocontrol strains with broad-spectrum and high-efficiency herbicidal activities, a strain with strong pathogenicity, HY-021, was isolated from the leaves of Rumex acetosa, which was identified as Botrytis fabiopsis based on morphology and molecular biology. The herbicidal activities of the fermentation filtrate of strain HY-021 against nine weeds, including Chenopodium album L., Elsholtzia densa Benth., Malva verticillata L. var. Crispa, Polygonum lapathifolium L., Amaranthus retroflexus L., Avena fatua L., Thlaspi arvense L., Polygonum aviculare L., and Galium spurium L., were determined in vitro and in vivo. The results showed that the pathogenicity of strain HY-021 to the different weeds in vitro was as follows: E. densa > A. retroflexus > P. aviculare > P. lapathifolium > M. verticillata > T. arvense > G. spurium > A. fatua > C. album. Seven days after inoculation with the HY-021 strain, the incidences in nine weeds were in the range of 32.9-87.23%, and the disease index values of the nine weeds were 41.73-94.57%. The pathogenic effects from high to low were A. retroflexus > E. densa > A. fatua > G. spurium > C. album > M. verticillata > T. arvense > P. aviculare > P. lapathifolium. The crop safety test showed that the biocontrol strain HY-021 was safe to V. faba, P. sativum, H. vulgare, and T. aestivum, but had a slight effect on B. napus. Scanning electron microscopy showed that the mycelium of strain HY-021 invaded the tissue through the stomata of C. album leaves, parasitized and reproduced in the tissue, and gradually destroyed the tissue. The results of this study provide a basis for the development and utilization of new and efficient microbial source herbicides.
- MeSH
- Pest Control, Biological * methods MeSH
- Biological Control Agents * MeSH
- Botrytis * isolation & purification physiology genetics pathogenicity MeSH
- Herbicides metabolism pharmacology MeSH
- Weed Control * methods MeSH
- Plant Leaves microbiology MeSH
- Plant Diseases * microbiology prevention & control MeSH
- Plant Weeds * microbiology MeSH
- Publication type
- Journal Article MeSH
- Geographicals
- China MeSH
Bacillus is well known for producing a wide range of compounds that inhibit microbial phytopathogens. From this perspective, we were interested in evaluating the biocontrol potential of 5 plant growth-promoting rhizobacteria Bacillus species (PGPR-Bacillus) on 21 microbial pectinolytic plant pathogens isolated from previous studies. Phytopathogenicity and in vivo biocontrol potential of PGPR curative and preventive treatments were investigated from this angle. Overall, the pathogenicity test on healthy tomato, zucchini, and mandarin showed low rot to no symptoms for all PGPR strain culture treatments. Conversely, zucchini pre-treated with PGPR strains B. circulans and B. cereus for 72 h showed no signs of soft rot and remained healthy when in vitro contaminated with phytopathogens (Neisseria cinerea and Pichia anomala). Additionally, the PGPR-Bacillus strains were shown to be effective in mitigating the symptoms of soft rot in tomatoes, zucchini, and oranges using in vivo curative treatment. It is true that the majority of pectinolytic phytopathogenic strains exhibited antibiotic resistance. In vivo tests revealed that PGPR-Bacillus cell culture was effective against plant pathogens. Thus, PGPR-Bacillus can be considered a potential biocontrol agent for pectinolytic plant pathogens.
- MeSH
- Antibiosis * MeSH
- Bacillus * physiology MeSH
- Pest Control, Biological * methods MeSH
- Biological Control Agents * MeSH
- Citrus microbiology growth & development MeSH
- Plant Diseases * microbiology prevention & control MeSH
- Pectins metabolism MeSH
- Soil Microbiology MeSH
- Solanum lycopersicum microbiology growth & development MeSH
- Plant Development MeSH
- Publication type
- Journal Article MeSH
Acute kidney injury (AKI) due to gentamicin nephrotoxicity is a significant concern in clinical medicine, particularly in patients receiving prolonged or high-dose gentamicin therapy. Gentamicin is an aminoglycoside antibiotic frequently used in the treatment of a range of bacterial infections. However, its use is associated with nephrotoxicity which can manifest as AKI. Due to this, it is crucial to diagnose promptly and manage treatment effectively. Ongoing studies are therefore focusing on non-protein-coding RNAs as potential biomarkers for AKI. Numerous microRNAs (miRNAs) have been implicated in gentamicin-induced nephrotoxicity and AKI. They participate in pathways associated with inflammation, cell death, and oxidative stress and each of these factors play critical roles in the development of gentamicin-induced kidney injury. Research studies have demonstrated changes in the expression levels of these miRNAs in response to gentamicin exposure both in vitro and in in vivo models, as well as in human clinical trials involving patients receiving gentamicin therapy. The dysregulation of these miRNAs correlates with the severity of kidney injury and may serve as sensitive biomarkers for early detection and monitoring of AKI induced by gentamicin.
- MeSH
- Acute Kidney Injury * chemically induced diagnosis MeSH
- Anti-Bacterial Agents * adverse effects MeSH
- Biomarkers * MeSH
- Gentamicins * adverse effects MeSH
- Humans MeSH
- MicroRNAs * MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
The forskolin-induced swelling assay (FIS) in patient-derived intestinal organoids (PDIOs), used to determine in vitro responsiveness to elexacaftor/tezacaftor/ivacaftor (ETI), showed variability in swelling among PDIOs obtained from people with CF (pwCF) carrying the same F508del/F508del CFTR genotype. We aimed to characterise the effect of ETI on the transcriptional activity of PDIOs-derived cells to understand the intracellular processes triggered by ETI and the differences in treatment response. Six high- and six low-responding PDIOs to ETI, derived from F508del/F508del pwCF, were incubated with or without ETI for 2 to 6 h. Gene expression was assessed using 3'-mRNA sequencing and modelled using negative binomial models. Incubation with ETI resulted in a significant upregulation of several biological processes: mostly related to chemokines and signalling, chemotaxis, and tissue development processes. No changes were observed in abundance of the CFTR transcripts or in CFTR-related gene sets and pathways. The genes and pathways associated with ETI did not overlap with those whose expression changed with time only. PDIOs with a high FIS response did not significantly differ in any interpretable gene from the FIS-low organoids. The changes in the PDIOs gene expression upon the exposure to ETI cannot explain differences in the magnitude of PDIOs FIS-measured response to ETI. In conclusion, on incubation with ETI, genes of the CFTR-related pathways do not change their transcriptional activity; instead, overexpression was observed in genes of inflammatory-like cytokine response and receptor activation pathways.
- MeSH
- Chloride Channel Agonists therapeutic use pharmacology MeSH
- Aminophenols * therapeutic use pharmacology MeSH
- Benzodioxoles * therapeutic use pharmacology MeSH
- Quinolones * pharmacology therapeutic use MeSH
- Cystic Fibrosis * genetics drug therapy MeSH
- Drug Combinations MeSH
- Indoles * pharmacology MeSH
- Humans MeSH
- Organoids * metabolism MeSH
- Cystic Fibrosis Transmembrane Conductance Regulator genetics MeSH
- Pyrazoles * pharmacology MeSH
- Pyridines pharmacology MeSH
- Pyrrolidines pharmacology MeSH
- Pyrroles pharmacology MeSH
- Gene Expression Profiling methods MeSH
- Intestines drug effects MeSH
- Transcriptome MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
PURPOSE: Docetaxel resistance is a significant obstacle in the treatment of prostate cancer (PCa), resulting in unfavorable patient prognoses. Intratumoral heterogeneity, often associated with epithelial-to-mesenchymal transition (EMT), has previously emerged as a phenomenon that facilitates adaptation to various stimuli, thus promoting cancer cell diversity and eventually resistance to chemotherapy, including docetaxel. Hence, understanding intratumoral heterogeneity is essential for better patient prognosis and the development of personalized treatment strategies. METHODS: To address this, we employed a high-throughput single-cell flow cytometry approach to identify a specific surface fingerprint associated with docetaxel-resistance in PCa cells and complemented it with proteomic analysis of extracellular vesicles. We further validated selected antigens using docetaxel-resistant patient-derived xenografts in vivo and probed primary PCa specimens to interrogate of their surface fingerprint. RESULTS: Our approaches revealed a 6-molecule surface fingerprint linked to docetaxel resistance in primary PCa specimens. We observed consistent overexpression of CD95 (FAS/APO-1), and SSEA-4 surface antigens in both in vitro and in vivo docetaxel-resistant models, which was also observed in a cell subpopulation of primary PCa tumors exhibiting EMT features. Furthermore, CD95, along with the essential enzymes involved in SSEA-4 synthesis, ST3GAL1, and ST3GAL2, displayed a significant increase in patients with PCa undergoing docetaxel-based therapy, correlating with poor survival outcomes. CONCLUSION: In summary, we demonstrate that the identified 6-molecule surface fingerprint associated with docetaxel resistance pre-exists in a subpopulation of primary PCa tumors before docetaxel treatment. Thus, this fingerprint warrants further validation as a promising predictive tool for docetaxel resistance in PCa patients prior to therapy initiation.
- MeSH
- Drug Resistance, Neoplasm * MeSH
- Docetaxel * pharmacology therapeutic use MeSH
- Epithelial-Mesenchymal Transition drug effects MeSH
- Humans MeSH
- Mice MeSH
- Cell Line, Tumor MeSH
- Prostatic Neoplasms * pathology drug therapy metabolism MeSH
- Antineoplastic Agents pharmacology therapeutic use MeSH
- Xenograft Model Antitumor Assays MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Atherosclerosis is a chronic inflammatory disease of the blood vessels caused by elevated levels of lipoproteins. The hyperlipoproteinemia triggers a series of cellular changes, particularly the activation of the macrophages, which play a crucial role in the development and progression of atherosclerosis. The presence of free cholesterol (FC) in lipoproteins may contribute to macrophage stimulation. However, the mechanisms linking the accumulation of FC in macrophages to their pro-inflammatory activation remain poorly understood. Our research found a positive correlation between the number of pro-inflammatory macrophages (CD14 + CD16 + CD36high) in visceral adipose tissue and the levels of LDL-C and cholesterol remnant particles in 56 healthy people. In contrast, the proportion of anti-inflammatory, alternatively activated macrophages (CD14 + CD16-CD163+) correlated negatively with HDL-C. Additionally, our in vitro study demonstrated that macrophages accumulating FC promoted a pro-inflammatory response, activating the TNF-α and chemokine CCL3 genes. Furthermore, the accumulation of FC in macrophages alters the surface receptors on macrophages (CD206 and CD16) and increases cellular granularity. Notably, the CD36 surface receptor and the ACAT and CD36 genes did not show a response. These results suggest a link between excessive FC accumulation and systemic inflammation to underlie the development of atherosclerosis.
- MeSH
- Macrophage Activation MeSH
- CD36 Antigens metabolism MeSH
- Atherosclerosis metabolism MeSH
- Antigens, CD metabolism MeSH
- Cholesterol * metabolism MeSH
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Macrophages * metabolism immunology drug effects MeSH
- Intra-Abdominal Fat metabolism MeSH
- Tumor Necrosis Factor-alpha metabolism genetics MeSH
- Inflammation * metabolism MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
Although chronic inflammation is implicated in the pathogenesis of diffuse large B-cell lymphoma (DLBCL), the mechanisms responsible are unknown. We demonstrate that the overexpression of the collagen receptor, DDR1, correlates with reduced expression of spindle checkpoint genes, with three transcriptional signatures of aneuploidy and with a higher frequency of copy number alterations, pointing to a potential role for DDR1 in the acquisition of aneuploidy in DLBCL. In support of this, we found that collagen treatment of primary germinal centre B cells transduced with DDR1, not only partially recapitulated the aberrant transcriptional programme of DLBCL but also downregulated the expression of CENPE, a mitotic spindle that has a crucial role in preventing chromosome mis-segregation. CENPE expression was also downregulated following DDR1 activation in two B-cell lymphoma lines and was lost in most DDR1-expressing primary tumours. Crucially, the inhibition of CENPE and the overexpression of a constitutively activated DDR1 were able to induce aneuploidy in vitro. Our findings identify a novel mechanistic link between DDR1 signalling and chromosome instability in B cells and provide novel insights into factors driving aneuploidy in DLBCL.
- MeSH
- Aneuploidy * MeSH
- B-Lymphocytes metabolism MeSH
- Chromosomal Instability * genetics MeSH
- Lymphoma, Large B-Cell, Diffuse * genetics pathology metabolism MeSH
- Collagen pharmacology MeSH
- Humans MeSH
- Cell Line, Tumor MeSH
- Discoidin Domain Receptor 1 * genetics metabolism MeSH
- Gene Expression Regulation, Neoplastic MeSH
- Signal Transduction MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
