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Respiratory Research Jun 2024Pulmonary fibrosis (PF) represents the pathologic end stage of several interstitial lung diseases (ILDs) associated with high morbidity and mortality rates. However,...
BACKGROUND
Pulmonary fibrosis (PF) represents the pathologic end stage of several interstitial lung diseases (ILDs) associated with high morbidity and mortality rates. However, current treatments can only delay disease progression rather than provide a cure. The role of inflammation in PF progression is well-established, but new insights into immune regulation are fundamental for developing more efficient therapies. c-MET signaling has been implicated in the migratory capacity and effector functions of immune cells. Nevertheless, the role of this signaling pathway in the context of PF-associated lung diseases remains unexplored.
METHODS
To determine the influence of c-MET in immune cells in the progression of pulmonary fibrosis, we used a conditional deletion of c-Met in immune cells. To induce pulmonary fibrosis mice were administered with bleomycin (BLM) intratracheally. Over the course of 21 days, mice were assessed for weight change, and after euthanasia at different timepoints, bronchoalveolar lavage fluid cells and lung tissue were assessed for inflammation and fibrosis. Furthermore, c-MET expression was assessed in cryobiopsy sections, bronchoalveolar lavage fluid cells samples and single cell RNA-sequencing dataset from human patients with distinct interstitial lung diseases.
RESULTS
c-MET expression was induced in lung immune cells, specifically in T cells, interstitial macrophages, and neutrophils, during the inflammatory phase of BLM-induced PF mouse model. Deletion of c-Met in immune cells correlated with earlier weight recovery and improved survival of BLM-treated mice. Moreover, the deletion of c-Met in immune cells was associated with early recruitment of the immune cell populations, normally found to express c-MET, leading to a subsequent attenuation of the cytotoxic and proinflammatory environment. Consequently, the less extensive inflammatory response, possibly coupled with tissue repair, culminated in less exacerbated fibrotic lesions. Furthermore, c-MET expression was up-regulated in lung T cells from patients with fibrosing ILD, suggesting a potential involvement of c-MET in the development of fibrosing disease.
CONCLUSIONS
These results highlight the critical contribution of c-MET signaling in immune cells to their enhanced uncontrolled recruitment and activation toward a proinflammatory and profibrotic phenotype, leading to the exacerbation of lung injury and consequent development of fibrosis.
Topics: Animals; Pulmonary Fibrosis; Mice; Proto-Oncogene Proteins c-met; Pneumonia; Mice, Inbred C57BL; Humans; Bleomycin; Mice, Knockout; Male; Female; Lung; Disease Models, Animal
PubMed: 38909206
DOI: 10.1186/s12931-024-02884-1 -
BMC Oral Health Jun 2024Dental pathogens play a crucial role in oral health issues, including tooth decay, gum disease, and oral infections, and recent research suggests a link between these...
BACKGROUND
Dental pathogens play a crucial role in oral health issues, including tooth decay, gum disease, and oral infections, and recent research suggests a link between these pathogens and oral cancer initiation and progression. Innovative therapeutic approaches are needed due to antibiotic resistance concerns and treatment limitations.
METHODS
We synthesized and analyzed piperine-coated zinc oxide nanoparticles (ZnO-PIP NPs) using UV spectroscopy, SEM, XRD, FTIR, and EDAX. Antioxidant and antimicrobial effectiveness were evaluated through DPPH, ABTS, and MIC assays, while the anticancer properties were assessed on KB oral squamous carcinoma cells.
RESULTS
ZnO-PIP NPs exhibited significant antioxidant activity and a MIC of 50 µg/mL against dental pathogens, indicating strong antimicrobial properties. Interaction analysis revealed high binding affinity with dental pathogens. ZnO-PIP NPs showed dose-dependent anticancer activity on KB cells, upregulating apoptotic genes BCL2, BAX, and P53.
CONCLUSIONS
This approach offers a multifaceted solution to combatting both oral infections and cancer, showcasing their potential for significant advancement in oral healthcare. It is essential to acknowledge potential limitations and challenges associated with the use of ZnO NPs in clinical applications. These may include concerns regarding nanoparticle toxicity, biocompatibility, and long-term safety. Further research and rigorous testing are warranted to address these issues and ensure the safe and effective translation of ZnO-PIP NPs into clinical practice.
Topics: Zinc Oxide; Humans; Piperidines; Apoptosis; Alkaloids; Benzodioxoles; Mouth Neoplasms; bcl-2-Associated X Protein; Proto-Oncogene Proteins c-bcl-2; Tumor Suppressor Protein p53; Biofilms; Polyunsaturated Alkamides; Nanoparticles; Antioxidants; Microbial Sensitivity Tests; Metal Nanoparticles; Antineoplastic Agents; Microscopy, Electron, Scanning; X-Ray Diffraction; Cell Line, Tumor; KB Cells
PubMed: 38907185
DOI: 10.1186/s12903-024-04399-z -
The Tokai Journal of Experimental and... Jul 2024Panniculitis is an inflammation that occurs in subcutaneous adipose tissue. Panniculitis includes physical panniculitis (e.g., traumatic) and infectious panniculitis...
Panniculitis is an inflammation that occurs in subcutaneous adipose tissue. Panniculitis includes physical panniculitis (e.g., traumatic) and infectious panniculitis (e.g., bacterial, fungal, subcutaneous panniculitis-like T cell lymphoma [SPCTL], etc.). Accurate diagnosis is crucial due to similar clinical presentation of all types of panniculitis. Here, we report a case of SPCTL which was initially diagnosed with traumatic panniculitis. A 15-year-old male patient was admitted to a previous hospital due to a progressively enlarged right flank and inguinal mass after an abdominal bruise. He was initially diagnosed with traumatic panniculitis, but the mass expanded throughout the chest and abdomen accompanied by a fever of over 11 months. Computed tomography (CT) revealed a subcutaneous mass in the anterior chest and abdominal wall. Fludeoxyglucose F18 (FDG) uptake was observed at those lesions using FDG-positron emission tomography (PET). A biopsy of the mass lesion was performed, during which SPCTL was diagnosed based on pathological examination. He was initially treated with prednisolone and cyclosporine A for two weeks. His fever went down, but subcutaneous mass in the chest and abdominal wall persisted. Therefore, he received a cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) regimen. After 6 courses of CHOP, CT revealed no disease evidence. He remained in complete remission at 30 months of therapy.
Topics: Humans; Male; Panniculitis; Adolescent; Lymphoma, T-Cell; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Doxorubicin; Vincristine; Disease Progression; Prednisone; Tomography, X-Ray Computed; Positron-Emission Tomography; Fluorodeoxyglucose F18; Treatment Outcome; Biopsy; Diagnosis, Differential
PubMed: 38904233
DOI: No ID Found -
Journal of Nanobiotechnology Jun 2024Chemoresistance remains a significant challenge for effective breast cancer treatment which leads to cancer recurrence. CRISPR-directed gene editing becomes a powerful...
Chemoresistance remains a significant challenge for effective breast cancer treatment which leads to cancer recurrence. CRISPR-directed gene editing becomes a powerful tool to reduce chemoresistance by reprogramming the tumor microenvironment. Previous research has revealed that Chinese herbal extracts have significant potential to overcome tumor chemoresistance. However, the therapeutic efficacy is often limited due to their poor tumor targeting and in vivo durability. Here we have developed a tumor microenvironment responsive nanoplatform (H-MnO(ISL + DOX)-PTPN2@HA, M(I + D)PH) for nano-herb and CRISPR codelivery to reduce chemoresistance. Synergistic tumor inhibitory effects were achieved by the treatment of isoliquiritigenin (ISL) with doxorubicin (DOX), which were enhanced by CRISPR-based gene editing to target protein tyrosine phosphatase non-receptor type 2 (PTPN2) to initiate long-term immunotherapy. Efficient PTPN2 depletion was observed after treatment with M(I + D)PH nanoparticles, which resulted in the recruitment of intratumoral infiltrating lymphocytes and an increase of proinflammatory cytokines in the tumor tissue. Overall, our nanoparticle platform provides a diverse technique for accomplishing synergistic chemotherapy and immunotherapy, which offers an effective treatment alternative for malignant neoplasms.
Topics: Tumor Microenvironment; Animals; Immunotherapy; Doxorubicin; Humans; Mice; Cell Line, Tumor; Female; Mice, Inbred BALB C; Nanoparticles; Breast Neoplasms; Gene Editing; CRISPR-Cas Systems; Manganese Compounds; Drug Resistance, Neoplasm; Drug Delivery Systems; Clustered Regularly Interspaced Short Palindromic Repeats; Antineoplastic Agents; Oxides
PubMed: 38898493
DOI: 10.1186/s12951-024-02571-9 -
Science Advances Jun 2024Precision management of fibrotic lung diseases is challenging due to their diverse clinical trajectories and lack of reliable biomarkers for risk stratification and...
Precision management of fibrotic lung diseases is challenging due to their diverse clinical trajectories and lack of reliable biomarkers for risk stratification and therapeutic monitoring. Here, we validated the accuracy of CMKLR1 as an imaging biomarker of the lung inflammation-fibrosis axis. By analyzing single-cell RNA sequencing datasets, we demonstrated expression as a transient signature of monocyte-derived macrophages (MDMφ) enriched in patients with idiopathic pulmonary fibrosis (IPF). Consistently, we identified MDMφ as the major driver of the uptake of CMKLR1-targeting peptides in a murine model of bleomycin-induced lung fibrosis. Furthermore, CMKLR1-targeted positron emission tomography in the murine model enabled quantification and spatial mapping of inflamed lung regions infiltrated by CMKLR1-expressing macrophages and emerged as a robust predictor of subsequent lung fibrosis. Last, high expression by bronchoalveolar lavage cells identified an inflammatory endotype of IPF with poor survival. Our investigation supports the potential of CMKLR1 as an imaging biomarker for endotyping and risk stratification of fibrotic lung diseases.
Topics: Animals; Humans; Mice; Idiopathic Pulmonary Fibrosis; Pneumonia; Macrophages; Biomarkers; Disease Models, Animal; Positron-Emission Tomography; Pulmonary Fibrosis; Bleomycin; Lung; Male; Female; Mice, Inbred C57BL
PubMed: 38896611
DOI: 10.1126/sciadv.adm9817 -
Molecules (Basel, Switzerland) Jun 2024Apigenin, a naturally derived flavonoid, is increasingly being acknowledged for its potential therapeutic applications, especially in oncology. This research explores...
Apigenin, a naturally derived flavonoid, is increasingly being acknowledged for its potential therapeutic applications, especially in oncology. This research explores apigenin's capacity to modulate cancer cell viability, emphasizing its roles beyond its minimal antioxidant activity attributed to its basic molecular structure devoid of hydroxyl groups. We investigated apigenin's effects on two breast cancer cell lines, estrogen-dependent MCF-7 and non-estrogen-dependent MDA-MB-231 cells. Our findings reveal that apigenin exerts a dose-dependent cytotoxic and anti-migratory impact on these cells. Interestingly, both apigenin and doxorubicin-a standard chemotherapeutic agent-induced lipid droplet accumulation in a dose-dependent manner in MDA-MB-231 cells. This phenomenon was absent in MCF-7 cells and not evident when doxorubicin and apigenin were used concurrently, suggesting distinct cellular responses to these treatments that imply that their synergistic effects might be mediated through mechanisms unrelated to lipid metabolism. A further chemoinformatics analysis indicated that apigenin and doxorubicin might interact primarily at the level of ATP-binding cassette (ABC) transporter proteins, with potential indirect influences from the AKT and MYC signaling pathways. These results highlight the importance of understanding the nuanced interactions between apigenin and conventional chemotherapeutic drugs, as they could lead to more effective strategies for cancer treatment. This study underscores apigenin's potential as a modulator of cancer cell dynamics through mechanisms independent of its direct antioxidant effects, thereby contributing to the development of flavonoid-based adjunct therapies in cancer management.
Topics: Humans; Apigenin; Doxorubicin; Breast Neoplasms; Female; Cell Line, Tumor; Cell Survival; MCF-7 Cells; Cell Movement; Signal Transduction; Cell Proliferation; Drug Synergism
PubMed: 38893482
DOI: 10.3390/molecules29112603 -
Molecules (Basel, Switzerland) May 2024Doxorubicin (DOX) is a commonly used chemotherapeutic drug, from the anthracycline class, which is genotoxic to neoplastic cells via a DNA intercalation mechanism. It is...
Doxorubicin (DOX) is a commonly used chemotherapeutic drug, from the anthracycline class, which is genotoxic to neoplastic cells via a DNA intercalation mechanism. It is effective and universal; however, it also causes numerous side effects. The most serious of them are cardiotoxicity and a decrease in the number of myeloid cells. For this reason, targeted DOX delivery systems are desirable, since they would allow lowering the drug dose and therefore limiting systemic side effects. Recently, synthetic dyes, in particular Congo red (CR), have been proposed as possible DOX carriers. CR is a planar molecule, built of a central biphenyl moiety and two substituted naphthalene rings, connected with diazo bonds. In water, it forms elongated ribbon-shaped supramolecular structures, which are able to selectively interact with immune complexes. In our previous studies, we have shown that CR aggregates can intercalate DOX molecules. In this way, they preclude DOX precipitation in water solutions and increase its uptake by MCF7 breast cancer cells. In the present work, we further explore the interactions between DOX, CR, and their aggregates (CR/DOX) with phospholipid membranes. In addition to neutral molecules, the protonated doxorubicin form, DXP, is also studied. Molecular dynamics simulations are employed to study the transfer of CR, DOX, DXP, and their aggregates through POPC bilayers. Interactions of CR, DOX, and CR/DOX with model monolayers are studied with Langmuir trough measurements. This study shows that CR may support the transfer of doxorubicin molecules into the bilayer. Both electrostatic and van der Waals interactions with lipids are important in this respect. The former promote the initial stages of the insertion process, the latter keep guest molecules inside the bilayer.
Topics: Doxorubicin; Phospholipids; Molecular Dynamics Simulation; Congo Red; Humans; Lipid Bilayers; Drug Carriers; MCF-7 Cells
PubMed: 38893446
DOI: 10.3390/molecules29112567 -
Molecules (Basel, Switzerland) May 2024Breast cancer is a major health concern and the leading cause of death among women worldwide. Standard treatment often involves surgery, radiotherapy, and chemotherapy,...
Breast cancer is a major health concern and the leading cause of death among women worldwide. Standard treatment often involves surgery, radiotherapy, and chemotherapy, but these come with side effects and limitations. Researchers are exploring natural compounds like baicalin and baicalein, derived from the plant, as potential complementary therapies. This study investigated the effects of baicalin and baicalein on the cytotoxic, proapoptotic, and genotoxic activity of doxorubicin and docetaxel, commonly used chemotherapeutic drugs for breast cancer. The analysis included breast cancer cells (MCF-7) and human endothelial cells (HUVEC-ST), to assess potential effects on healthy tissues. We have found that baicalin and baicalein demonstrated cytotoxicity towards both cell lines, with more potent effects observed in baicalein. Both flavonoids, baicalin (167 µmol/L) and baicalein (95 µmol/L), synergistically enhanced the cytotoxic, proapoptotic, and genotoxic activity of doxorubicin and docetaxel in breast cancer cells. In comparison, their effects on endothelial cells were mixed and depended on concentration and time. The results suggest that baicalin and baicalein might be promising complementary agents to improve the efficacy of doxorubicin and docetaxel anticancer activity. However, further research is needed to validate their safety and efficacy in clinical trials.
Topics: Humans; Flavonoids; Flavanones; Docetaxel; Doxorubicin; MCF-7 Cells; Apoptosis; Breast Neoplasms; Female; DNA Damage; Drug Synergism; Antineoplastic Agents; Cell Survival; Human Umbilical Vein Endothelial Cells
PubMed: 38893380
DOI: 10.3390/molecules29112503 -
Molecules (Basel, Switzerland) May 2024Among brain tumors, glioblastoma (GBM) is very challenging to treat as chemotherapeutic drugs can only penetrate the brain to a limited extent due to the blood-brain...
The Application of Ultrasmall Gold Nanoparticles (2 nm) Functionalized with Doxorubicin in Three-Dimensional Normal and Glioblastoma Organoid Models of the Blood-Brain Barrier.
Among brain tumors, glioblastoma (GBM) is very challenging to treat as chemotherapeutic drugs can only penetrate the brain to a limited extent due to the blood-brain barrier (BBB). Nanoparticles can be an attractive solution for the treatment of GBM as they can transport drugs across the BBB into the tumor. In this study, normal and GBM organoids comprising six brain cell types were developed and applied to study the uptake, BBB penetration, distribution, and efficacy of fluorescent, ultrasmall gold nanoparticles (AuTio-Dox-AF647s) conjugated with doxorubicin (Dox) and AlexaFluor-647-cadaverine (AF647) by confocal laser scanning microscopy (CLSM), using a mixture of dissolved doxorubicin and fluorescent AF647 molecules as a control. It was shown that the nanoparticles could easily penetrate the BBB and were found in normal and GBM organoids, while the dissolved Dox and AF647 molecules alone were unable to penetrate the BBB. Flow cytometry showed a reduction in glioblastoma cells after treatment with AuTio-Dox nanoparticles, as well as a higher uptake of these nanoparticles by GBM cells in the GBM model compared to astrocytes in the normal cell organoids. In summary, our results show that ultrasmall gold nanoparticles can serve as suitable carriers for the delivery of drugs into organoids to study BBB function.
Topics: Doxorubicin; Glioblastoma; Metal Nanoparticles; Gold; Humans; Blood-Brain Barrier; Organoids; Brain Neoplasms; Cell Line, Tumor
PubMed: 38893345
DOI: 10.3390/molecules29112469 -
Nutrients May 2024Probiotics have garnered increasing attention as a potential therapeutic approach for type 2 diabetes mellitus (T2DM). Previous studies have confirmed that subsp....
Probiotics have garnered increasing attention as a potential therapeutic approach for type 2 diabetes mellitus (T2DM). Previous studies have confirmed that subsp. MN-Gup (MN-Gup) could stimulate the secretion of glucagon-like peptide-1 (GLP-1) in NCI-H716 cells, but whether MN-Gup has a hypoglycemic effect on T2DM in vivo remains unclear. In this study, a T2DM mouse model was constructed, with a high-fat diet and streptozotocin in mice, to investigate the effect of MN-Gup on diabetes. Then, different doses of MN-Gup (2 × 10 CFU/kg, 1 × 10 CFU/kg) were gavaged for 6 weeks to investigate the effect of MN-Gup on glucose metabolism and its potential mechanisms. The results showed that a high-dose of MN-Gup significantly reduced the fasting blood glucose (FBG) levels and homeostasis model assessment-insulin resistance (HOMA-IR) of T2DM mice compared to the other groups. In addition, there were significant increases in the short-chain fatty acids (SCFAs), especially acetate, and GLP-1 levels in the MN-Gup group. MN-Gup increased the relative abundance of and decreased the number of and . Moreover, the correlation analysis revealed that demonstrated a significant positive correlation with GLP-1 and a negative correlation with the incremental AUC. In summary, this study demonstrates that subsp. MN-Gup has significant hypoglycemic effects in T2DM mice and can modulate the gut microbiota, promoting the secretion of SCFAs and GLP-1.
Topics: Animals; Gastrointestinal Microbiome; Diabetes Mellitus, Type 2; Probiotics; Bifidobacterium animalis; Blood Glucose; Mice; Diabetes Mellitus, Experimental; Male; Glucagon-Like Peptide 1; Fatty Acids, Volatile; Insulin Resistance; Diet, High-Fat; Mice, Inbred C57BL; Streptozocin; Bifidobacterium
PubMed: 38892624
DOI: 10.3390/nu16111691