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FEBS Open Bio Jul 2024Glucose is essential for energy metabolism, and its usage can determine other cellular functions, depending on the cell type. In some pathological conditions, cells are...
Glucose is essential for energy metabolism, and its usage can determine other cellular functions, depending on the cell type. In some pathological conditions, cells are exposed to high concentrations of glucose for extended periods. In this study, we investigated metabolic, oxidative stress, and cellular senescence pathways in human bronchial epithelial cells (HBECs) cultured in media with physiologically low (5 mm) and high (12.5 mm) glucose concentrations. HBECs exposed to 12.5 mm glucose showed increased glucose routing toward the pentose phosphate pathway, lactate synthesis, and glycogen, but not triglyceride synthesis. These metabolic shifts were not associated with changes in cell proliferation rates, oxidative stress, or cellular senescence pathways. Since hyperglycemia is associated with fibrosis in the lung, we asked whether HBECS could activate fibroblasts. Primary human lung fibroblasts cultured in media conditioned by 12.5 mm glucose-exposed HBECs showed a 1.3-fold increase in the gene expression of COL1A1 and COL1A2, along with twofold increased protein levels of smooth muscle cell actin and 2.4-fold of COL1A1. Consistently, HBECs cultured with 12.5 mm glucose secreted proteins associated with inflammation and fibrosis, such as interleukins IL-1β, IL-10, and IL-13, CC chemokine ligands CCL2 and CCL24, and with extracellular matrix remodeling, such as metalloproteinases (MMP)-1, MMP-3, MMP-9, and MMP-13 and tissue inhibitors of MMPs (TIMP)-1 and -2. This study shows that HBECs undergo metabolic reprogramming and increase the secretion of profibrotic mediators following exposure to high concentrations of glucose, and it contributes to the understanding of the metabolic crosstalk of neighboring cells in diabetes-associated pulmonary fibrosis.
PubMed: 38952051
DOI: 10.1002/2211-5463.13852 -
Drug Development Research Aug 2024Chromone-based compounds have established cytotoxic, antiproliferative, antimetastatic, and antiangiogenic effects on various cancer cell types via modulating different...
Chromone-based compounds have established cytotoxic, antiproliferative, antimetastatic, and antiangiogenic effects on various cancer cell types via modulating different molecular targets. Herein, 17 novel chromone-2-carboxamide derivatives were synthesized and evaluated for their in vitro anticancer activity against 15 human cancer cell lines. Among the tested cell lines, MDA-MB-231, the triple-negative breast cancer cell line, was found to be the most sensitive, where the N-(2-furylmethylene) (15) and the α-methylated N-benzyl (17) derivatives demonstrated the highest growth inhibition with GI values of 14.8 and 17.1 μM, respectively. In vitro mechanistic studies confirmed the significant roles of compounds 15 and 17 in the induction of apoptosis and suppression of EGFR, FGFR3, and VEGF protein levels in MDA-MB-231 cancer cells. Moreover, compound 15 exerted cell cycle arrest at both the G0-G1 and G2-M phases. The in vivo efficacy of compound 15 as an antitumor agent was further investigated in female mice bearing Solid Ehrlich Carcinoma. Notably, administration of compound 15 resulted in a marked decrease in both tumor weight and volume, accompanied by improvements in biochemical, hematological, histological, and immunohistochemical parameters that verified the repression of both angiogenesis and inflammation as additional Anticancer mechanisms. Moreover, the binding interactions of compounds 15 and 17 within the binding sites of all three target receptors (EGFR, FGFR3, and VEGF) were clearly illustrated using molecular docking.
Topics: Humans; ErbB Receptors; Female; Animals; Triple Negative Breast Neoplasms; Vascular Endothelial Growth Factor A; Cell Line, Tumor; Antineoplastic Agents; Receptor, Fibroblast Growth Factor, Type 3; Mice; Molecular Docking Simulation; Chromones; Drug Design; Apoptosis; Cell Proliferation
PubMed: 38952003
DOI: 10.1002/ddr.22228 -
Biotechnology and Applied Biochemistry Jul 2024Alveolar ridge resorption following tooth extraction poses significant challenges for future dental restorations. This study investigated the efficacy of fish...
Alveolar ridge resorption following tooth extraction poses significant challenges for future dental restorations. This study investigated the efficacy of fish scale-derived hydroxyapatite (FSHA) as a socket preservation graft material to maintain alveolar bone volume and architecture. FSHA was extracted from *Labeo rohita* fish scales and characterized using Fourier transform infrared (FTIR) analysis. In vitro, biocompatibility and osteogenic potential were assessed using Saos-2 human osteosarcoma cells. Cell viability, migration, and proliferation were evaluated using MTT and scratch assays. In vivo performance was assessed in a rat model, and FSHA was compared to a commercial xenograft (Osseograft) and ungrafted controls. Histological analysis was performed at 8-week post-implantation to quantify new bone formation. FTIR confirmed the purity and homogeneity of FSHA. In vitro, FSHA enhanced Saos-2 viability, migration, and proliferation compared to controls. In vivo, FSHA demonstrated superior bone regeneration compared to Osseograft and ungrafted sites, with balanced graft resorption and new bone formation. Histological analysis revealed an active incorporation of FSHA into new bone, with minimal gaps and ongoing remodeling. Approximately 50%-60% of FSHA was resorbed by 8 weeks, closely matching the rate of new bone deposition. FSHA stimulated more bone formation in the apical socket region than in coronal areas. In conclusion, FSHA is a promising biomaterial for alveolar ridge preservation, exhibiting excellent biocompatibility, osteogenic potential, and balanced resorption. Its ability to promote robust bone regeneration highlights its potential as an effective alternative to currently used graft materials in socket preservation procedures.
PubMed: 38951991
DOI: 10.1002/bab.2627 -
Microbiome Jul 2024Endometrial cancer is a multifactorial disease with inflammatory, metabolic and potentially microbial cues involved in disease pathogenesis. The endometrial cancer...
BACKGROUND
Endometrial cancer is a multifactorial disease with inflammatory, metabolic and potentially microbial cues involved in disease pathogenesis. The endometrial cancer microbiome has been poorly characterised so far and studies have often overestimated bacterial biomass due to lack of integration of appropriate contamination controls. There is also a scarcity of evidence on the functionality of microbial microenvironments in endometrial cancer. This work addresses that knowledge gap by interrogating the genuine, contamination-free microbial signatures in the female genital tract and rectum of women with endometrial cancer and the mechanistic role of microbiome on carcinogenic processes.
RESULTS
Here we sampled different regions of the reproductive tract (vagina, cervix, endometrium, fallopian tubes and ovaries) and rectum of 61 patients (37 endometrial cancer; 24 benign controls). We performed 16S rRNA gene sequencing of the V1-V2 hypervariable regions and qPCR of the 16S rRNA gene to qualitatively and quantitatively assess microbial communities and used 3D benign and endometrial cancer organoids to evaluate the effect of microbial products of L. crispatus, which was found depleted in endometrial cancer patients following primary analysis, on endometrial cell proliferation and inflammation. We found that the upper genital tract of a subset of women with and without endometrial cancer harbour microbiota quantitatively and compositionally distinguishable from background contaminants. Endometrial cancer was associated with reduced cervicovaginal and rectal bacterial load together with depletion of Lactobacillus species relative abundance, including L. crispatus, increased bacterial diversity and enrichment of Porphyromonas, Prevotella, Peptoniphilus and Anaerococcus in the lower genital tract and endometrium. Treatment of benign and malignant endometrial organoids with L. crispatus conditioned media exerted an anti-proliferative effect at high concentrations but had minimal impact on cytokine and chemokine profiles.
CONCLUSIONS
Our findings provide evidence that the upper female reproductive tract of some women contains detectable levels of bacteria, the composition of which is associated with endometrial cancer. Whether this is a cause or consequence of cancer pathophysiology and what is the functional significance of this finding remain to be elucidated to guide future screening tools and microbiome-based therapeutics. Video Abstract.
Topics: Humans; Female; Endometrial Neoplasms; RNA, Ribosomal, 16S; Microbiota; Middle Aged; Bacteria; Endometrium; Aged; Rectum; Vagina; Adult
PubMed: 38951935
DOI: 10.1186/s40168-024-01821-0 -
Cancer Cell International Jun 2024Malignant Pleural Mesothelioma (MPM) is a rare malignancy with a poor prognosis. Current therapies are unsatisfactory and novel cures are urgently needed. In a previous...
BACKGROUND
Malignant Pleural Mesothelioma (MPM) is a rare malignancy with a poor prognosis. Current therapies are unsatisfactory and novel cures are urgently needed. In a previous drug screening, we identified thonzonium bromide (TB) as one of the most active compounds against MPM cells. Since the biological effects of TB are poorly known, in this work we departed from some hints of previous studies and investigated several hypotheses. Moreover, we evaluated the efficacy of TB in an in vivo xenograft rodent model.
METHODS
In vitro assessment was made on five MPM (Mero-14, Mero-25, Ren, NCI-H28, MSTO-211H) and one SV40-immortalized mesothelial cell line (MeT-5A). We evaluated TB ability to affect proliferation, apoptosis, mitochondrial functions and metabolism, and the mevalonate pathway. In vivo assay was carried out on MPM-xenograft NOD-SCID mice (4 mg/kg delivered intraperitoneally, twice a week for 4 weeks) and the overall survival was analysed with Kaplan-Meier curves.
RESULTS
After TB treatment, we observed the suppression of ERK 1/2 phosphorylation, the increase of BAX expression and p38 phosphorylation. TB affected Ca homeostasis in both mitochondrial and cytosolic compartments, it regulated the mitochondrial functioning, respiration, and ATP production as well as the mevalonate pathway. The in vivo study showed an increased overall survival for TB treated group vs. vehicle control group (P = 0.0076).
CONCLUSIONS
Both in vitro and in vivo results confirmed the effect of TB on MPM and unravelled novel targets with translational potential.
PubMed: 38951927
DOI: 10.1186/s12935-024-03400-7 -
Breast Cancer Research : BCR Jun 2024HER3, a member of the EGFR receptor family, plays a central role in driving oncogenic cell proliferation in breast cancer. Novel HER3 therapeutics are showing promising...
PURPOSE
HER3, a member of the EGFR receptor family, plays a central role in driving oncogenic cell proliferation in breast cancer. Novel HER3 therapeutics are showing promising results while recently developed HER3 PET imaging modalities aid in predicting and assessing early treatment response. However, baseline HER3 expression, as well as changes in expression while on neoadjuvant therapy, have not been well-characterized. We conducted a prospective clinical study, pre- and post-neoadjuvant/systemic therapy, in patients with newly diagnosed breast cancer to determine HER3 expression, and to identify possible resistance mechanisms maintained through the HER3 receptor.
EXPERIMENTAL DESIGN
The study was conducted between May 25, 2018 and October 12, 2019. Thirty-four patients with newly diagnosed breast cancer of any subtype (ER ± , PR ± , HER2 ±) were enrolled in the study. Two core biopsy specimens were obtained from each patient at the time of diagnosis. Four patients underwent a second research biopsy following initiation of neoadjuvant/systemic therapy or systemic therapy which we define as neoadjuvant therapy. Molecular characterization of HER3 and downstream signaling nodes of the PI3K/AKT and MAPK pathways pre- and post-initiation of therapy was performed. Transcriptional validation of finings was performed in an external dataset (GSE122630).
RESULTS
Variable baseline HER3 expression was found in newly diagnosed breast cancer and correlated positively with pAKT across subtypes (r = 0.45). In patients receiving neoadjuvant/systemic therapy, changes in HER3 expression were variable. In a hormone receptor-positive (ER +/PR +/HER2-) patient, there was a statistically significant increase in HER3 expression post neoadjuvant therapy, while there was no significant change in HER3 expression in a ER +/PR +/HER2+ patient. However, both of these patients showed increased downstream signaling in the PI3K/AKT pathway. One subject with ER +/PR -/HER2- breast cancer and another subject with ER +/PR +/HER2 + breast cancer showed decreased HER3 expression. Transcriptomic findings, revealed an immune suppressive environment in patients with decreased HER3 expression post therapy.
CONCLUSION
This study demonstrates variable HER3 expression across breast cancer subtypes. HER3 expression can be assessed early, post-neoadjuvant therapy, providing valuable insight into cancer biology and potentially serving as a prognostic biomarker. Clinical translation of neoadjuvant therapy assessment can be achieved using HER3 PET imaging, offering real-time information on tumor biology and guiding personalized treatment for breast cancer patients.
Topics: Humans; Female; Breast Neoplasms; Neoadjuvant Therapy; Middle Aged; Receptor, ErbB-3; Prospective Studies; Adult; Aged; Biomarkers, Tumor; Receptor, ErbB-2; Receptors, Estrogen; Gene Expression Regulation, Neoplastic; Signal Transduction; Positron-Emission Tomography
PubMed: 38951909
DOI: 10.1186/s13058-024-01859-w -
Journal of Translational Medicine Jul 2024Triple-negative breast cancer (TNBC) is a recurrent, heterogeneous, and invasive form of breast cancer. The treatment of TNBC patients with paclitaxel and fluorouracil...
BACKGROUND
Triple-negative breast cancer (TNBC) is a recurrent, heterogeneous, and invasive form of breast cancer. The treatment of TNBC patients with paclitaxel and fluorouracil in a sequential manner has shown promising outcomes. However, it is challenging to deliver these chemotherapeutic agents sequentially to TNBC tumors. We aim to explore a precision therapy strategy for TNBC through the sequential delivery of paclitaxel and fluorouracil.
METHODS
We developed a dual chemo-loaded aptamer with redox-sensitive caged paclitaxel for rapid release and non-cleavable caged fluorouracil for slow release. The binding affinity to the target protein was validated using Enzyme-linked oligonucleotide assays and Surface plasmon resonance assays. The targeting and internalization abilities into tumors were confirmed using Flow cytometry assays and Confocal microscopy assays. The inhibitory effects on TNBC progression were evaluated by pharmacological studies in vitro and in vivo.
RESULTS
Various redox-responsive aptamer-paclitaxel conjugates were synthesized. Among them, AS1411-paclitaxel conjugate with a thioether linker (ASP) exhibited high anti-proliferation ability against TNBC cells, and its targeting ability was further improved through fluorouracil modification. The fluorouracil modified AS1411-paclitaxel conjugate with a thioether linker (FASP) exhibited effective targeting of TNBC cells and significantly improved the inhibitory effects on TNBC progression in vitro and in vivo.
CONCLUSIONS
This study successfully developed fluorouracil-modified AS1411-paclitaxel conjugates with a thioether linker for targeted combination chemotherapy in TNBC. These conjugates demonstrated efficient recognition of TNBC cells, enabling targeted delivery and controlled release of paclitaxel and fluorouracil. This approach resulted in synergistic antitumor effects and reduced toxicity in vivo. However, challenges related to stability, immunogenicity, and scalability need to be further investigated for future translational applications.
Topics: Triple Negative Breast Neoplasms; Aptamers, Nucleotide; Humans; Paclitaxel; Nucleolin; Cell Line, Tumor; Animals; Female; Fluorouracil; Drug Liberation; RNA-Binding Proteins; Delayed-Action Preparations; Phosphoproteins; Oligodeoxyribonucleotides; Antineoplastic Combined Chemotherapy Protocols; Mice, Nude; Xenograft Model Antitumor Assays; Cell Proliferation; Oxidation-Reduction; Mice, Inbred BALB C
PubMed: 38951906
DOI: 10.1186/s12967-024-05429-8 -
Journal of Nanobiotechnology Jul 2024Diabetic wounds present significant challenges, specifically in terms of bacterial infection and delayed healing. Therefore, it is crucial to address local bacterial...
BACKGROUND
Diabetic wounds present significant challenges, specifically in terms of bacterial infection and delayed healing. Therefore, it is crucial to address local bacterial issues and promote accelerated wound healing. In this investigation, we utilized electrospinning to fabricate microgel/nanofiber membranes encapsulating MXene-encapsulated microgels and chitosan/gelatin polymers.
RESULTS
The film dressing facilitates programmed photothermal therapy (PPT) and mild photothermal therapy (MPTT) under near-infrared (NIR), showcasing swift and extensive antibacterial and biofilm-disrupting capabilities. The PPT effect achieves prompt sterilization within 5 min at 52 °C and disperses mature biofilm within 10 min. Concurrently, by adjusting the NIR power to induce local mild heating (42 °C), the dressing stimulates fibroblast proliferation and migration, significantly enhancing vascularization. Moreover, in vivo experimentation successfully validates the film dressing, underscoring its immense potential in addressing the intricacies of diabetic wounds.
CONCLUSIONS
The MXene microgel-loaded nanofiber dressing employs temperature-coordinated photothermal therapy, effectively amalgamating the advantageous features of high-temperature sterilization and low-temperature promotion of wound healing. It exhibits rapid, broad-spectrum antibacterial and biofilm-disrupting capabilities, exceptional biocompatibility, and noteworthy effects on promoting cell proliferation and vascularization. These results affirm the efficacy of our nanofiber dressing, highlighting its significant potential in addressing the challenge of diabetic wounds struggling to heal due to infection.
Topics: Wound Healing; Nanofibers; Photothermal Therapy; Animals; Bandages; Anti-Bacterial Agents; Mice; Biofilms; Chitosan; Male; Diabetes Mellitus, Experimental; Temperature; Rats; Infrared Rays; Cell Proliferation; Rats, Sprague-Dawley; Humans; Wound Infection
PubMed: 38951903
DOI: 10.1186/s12951-024-02621-2 -
Cancer & Metabolism Jun 2024Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease without meaningful therapeutic options beyond the first salvage therapy. Targeting PDAC metabolism...
BACKGROUND
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease without meaningful therapeutic options beyond the first salvage therapy. Targeting PDAC metabolism through amino acid restriction has emerged as a promising new strategy, with asparaginases, enzymes that deplete plasma glutamine and asparagine, reaching clinical trials. In this study, we investigated the anti-PDAC activity of the asparaginase formulation Pegcrisantaspase (PegC) alone and in combination with standard-of-care chemotherapeutics.
METHODS
Using mouse and human PDAC cell lines, we assessed the impact of PegC on cell proliferation, cell death, and cell cycle progression. We further characterized the in vitro effect of PegC on protein synthesis as well as the generation of reactive oxygen species and levels of glutathione, a major cellular antioxidant. Additional cell line studies examined the effect of the combination of PegC with standard-of-care chemotherapeutics. In vivo, the tolerability and efficacy of PegC, as well as the impact on plasma amino acid levels, was assessed using the C57BL/6-derived KPC syngeneic mouse model.
RESULTS
Here we report that PegC demonstrated potent anti-proliferative activity in a panel of human and murine PDAC cell lines. This decrease in proliferation was accompanied by inhibited protein synthesis and decreased levels of glutathione. In vivo, PegC was tolerable and effectively reduced plasma levels of glutamine and asparagine, leading to a statistically significant inhibition of tumor growth in a syngeneic mouse model of PDAC. There was no observable in vitro or in vivo benefit to combining PegC with standard-of-care chemotherapeutics, including oxaliplatin, irinotecan, 5-fluorouracil, paclitaxel, and gemcitabine. Notably, PegC treatment increased tumor expression of asparagine and serine biosynthetic enzymes.
CONCLUSIONS
Taken together, our results demonstrate the potential therapeutic use of PegC in PDAC and highlight the importance of identifying candidates for combination regimens that could improve cytotoxicity and/or reduce the induction of resistance pathways.
PubMed: 38951899
DOI: 10.1186/s40170-024-00346-2 -
Journal of Nanobiotechnology Jul 2024The characteristic features of the rheumatoid arthritis (RA) microenvironment are synovial inflammation and hyperplasia. Therefore, there is a growing interest in...
Graphene oxide quantum dots-loaded sinomenine hydrochloride nanocomplexes for effective treatment of rheumatoid arthritis via inducing macrophage repolarization and arresting abnormal proliferation of fibroblast-like synoviocytes.
The characteristic features of the rheumatoid arthritis (RA) microenvironment are synovial inflammation and hyperplasia. Therefore, there is a growing interest in developing a suitable therapeutic strategy for RA that targets the synovial macrophages and fibroblast-like synoviocytes (FLSs). In this study, we used graphene oxide quantum dots (GOQDs) for loading anti-arthritic sinomenine hydrochloride (SIN). By combining with hyaluronic acid (HA)-inserted hybrid membrane (RFM), we successfully constructed a new nanodrug system named HA@RFM@GP@SIN NPs for target therapy of inflammatory articular lesions. Mechanistic studies showed that this nanomedicine system was effective against RA by facilitating the transition of M1 to M2 macrophages and inhibiting the abnormal proliferation of FLSs in vitro. In vivo therapeutic potential investigation demonstrated its effects on macrophage polarization and synovial hyperplasia, ultimately preventing cartilage destruction and bone erosion in the preclinical models of adjuvant-induced arthritis and collagen-induced arthritis in rats. Metabolomics indicated that the anti-arthritic effects of HA@RFM@GP@SIN NPs were mainly associated with the regulation of steroid hormone biosynthesis, ovarian steroidogenesis, tryptophan metabolism, and tyrosine metabolism. More notably, transcriptomic analyses revealed that HA@RFM@GP@SIN NPs suppressed the cell cycle pathway while inducing the cell apoptosis pathway. Furthermore, protein validation revealed that HA@RFM@GP@SIN NPs disrupted the excessive growth of RAFLS by interfering with the PI3K/Akt/SGK/FoxO signaling cascade, resulting in a decline in cyclin B1 expression and the arrest of the G2 phase. Additionally, considering the favorable biocompatibility and biosafety, these multifunctional nanoparticles offer a promising therapeutic approach for patients with RA.
Topics: Morphinans; Animals; Quantum Dots; Arthritis, Rheumatoid; Synoviocytes; Graphite; Cell Proliferation; Rats; Macrophages; Fibroblasts; Male; Arthritis, Experimental; Rats, Sprague-Dawley; Mice; Humans; RAW 264.7 Cells; Hyaluronic Acid
PubMed: 38951875
DOI: 10.1186/s12951-024-02645-8