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American Journal of Physiology. Lung... Mar 2024Respiratory-related diseases are a leading cause of death in rheumatoid arthritis (RA) and are disproportionately higher in men, which may be attributable to...
Respiratory-related diseases are a leading cause of death in rheumatoid arthritis (RA) and are disproportionately higher in men, which may be attributable to environmental risk factors. Animal studies have demonstrated potentiated autoimmunity, arthritis, and profibrotic/inflammatory lung disease with a combination of airborne exposures and collagen-induced arthritis (CIA). This study aimed to determine whether hormone-dependent differences explained these observations. Arthritis-prone male intact and castrated DBA/1J mice received intranasal inhalation of lipopolysaccharide (LPS) daily for 5 wk and CIA induction. Arthritis scores and serum pentraxin-2 levels were increased in castrated versus intact mice. In contrast, airway cell influx, lung tissue infiltrates, and lung levels of proinflammatory and profibrotic markers (C5a, IL-33, and matrix metalloproteinases) were reduced in castrated versus intact mice. CIA + LPS-induced lung histopathology changes and the expression of lung autoantigens including malondialdehyde acetaldehyde (MAA)- and citrulline (CIT)-modified proteins and vimentin were reduced in castrated animals. There were no differences in serum anti-MAA or anti-CIT protein antibody (ACPA) levels or serum pentraxin levels between groups. Testosterone replacement led to a reversal of several lung inflammatory/profibrotic endpoints noted earlier in castrated male CIA + LPS-treated mice with testosterone supplementation promoting neutrophil influx, MAA expression, and TNF-α, IL-6, and MMP-9. These findings imply that testosterone contributes to lung and arthritis inflammatory responses following CIA + LPS coexposure, but not to systemic autoantibody responses. The CIA + LPS model provides a paradigm for investigations focused on the mechanistic underpinnings for epidemiologic and phenotypic sex differences in RA-related lung disease. Our study shows that testosterone acts as a key immunomodulatory hormone contributing to critical features of rheumatoid arthritis (RA)-associated lung disease in the setting of airborne endotoxin (lipopolysaccharide; LPS) exposures and concomitant arthritis induction in mice. The exaggerated airway inflammation observed following combined exposures in male mice was accompanied by increases in profibrotic mediators, netosis, and increased expression of lung autoantigens, all relevant to the pathogenesis of lung disease in arthritis.
Topics: Humans; Male; Female; Animals; Mice; Arthritis, Experimental; Lipopolysaccharides; Endotoxins; Testosterone; Mice, Inbred DBA; Arthritis, Rheumatoid; Lung Diseases; Autoantigens
PubMed: 38086040
DOI: 10.1152/ajplung.00221.2023 -
Aging Dec 2023Recently, there has been a great deal interest in cuproptosis, a form of programmed cell death that is mediated by copper. The specific mechanism through which...
Integrative analysis of single-cell and bulk RNA seq to reveal the prognostic model and tumor microenvironment remodeling mechanisms of cuproptosis-related genes in colorectal cancer.
BACKGROUND
Recently, there has been a great deal interest in cuproptosis, a form of programmed cell death that is mediated by copper. The specific mechanism through which cuproptosis-related genes impact the development of colorectal cancer (CRC) remains unknown.
METHODS
Here, we combined bulk RNA-seq with scRNA-seq to investigate the CRGs functions within CRC. A number of 61 cuproptosis-related genes were chosen for further investigation. Nine prognostic CRGs were identified by Lasso-Cox. The RiskScore was created and the patients have been separated into two different groups, low- and high-RiskScore group. The CIBERSORT, ESTIMATE, MCP-counter, TIDE, and IPS have been employed to score the TME, and GSVA and GSEA were utilized to evaluate the pathway within the both groups. Further, we used cell communication analysis to explore the tumor microenvironment remodeling mechanisms of the COX17 and DLAT based on scRNA-seq. Finally, we used IHC and qPCR to validate the expression of COX17 and DLAT.
RESULTS
AOC3, CCS, CDKN2A, COX11, COX17, COX19, DLD, DLAT, and PDHB have been recognized as prognostic CRGs in CRC. The high-risk group exhibited the worst prognosis, an immune-deficient phenotype, and were more resistant to ICB treatment. Further, scRNA-seq analysis revealed that elevated expression of COX17 in CD4-CXCL13Tfh could contribute to the immune evasion while DLAT had the opposite effect, reversing T cell exhaustion and inducing pyroptosis to boost CD8-GZMKT infiltration.
CONCLUSIONS
The current investigation has developed a prognostic framework utilizing cuproptosis-related genes that is highly effective in predicting prognosis, TME type, and response to immunotherapy in CRC patients. Furthermore, our study reveals a novel finding that elevated levels of COX17 expression within CD4-CXCL13 T cells in CRC mediates T cell exhaustion and Treg infiltration, while DLAT has been found to facilitate the anti-tumor immunity activation through the T cell exhaustion reversal and the induction of pyroptosis.
Topics: Humans; RNA-Seq; Prognosis; Tumor Microenvironment; Genes, p16; Apoptosis; Copper; Colorectal Neoplasms
PubMed: 38078879
DOI: 10.18632/aging.205324 -
Biological Research Dec 2023Atherosclerosis (AS), a significant contributor to cardiovascular disease (CVD), is steadily rising with the aging of the global population. Pyroptosis and apoptosis,...
BACKGROUND
Atherosclerosis (AS), a significant contributor to cardiovascular disease (CVD), is steadily rising with the aging of the global population. Pyroptosis and apoptosis, both caspase-mediated cell death mechanisms, play an essential role in the occurrence and progression of AS. The human pineal gland primarily produces melatonin (MT), an indoleamine hormone with powerful anti-oxidative, anti-pyroptotic, and anti-apoptotic properties. This study examined MT's anti-oxidative stress and anti-pyroptotic effects on human THP-1 macrophages treated with nicotine.
METHODS
In vitro, THP-1 macrophages were induced by 1 µM nicotine to form a pyroptosis model and performed 30 mM MT for treatment. In vivo, ApoE mice were administered 0.1 mg/mL nicotine solution as drinking water, and 1 mg/mL MT solution was intragastric administrated at 10 mg/kg/day. The changes in pyroptosis, apoptosis, and oxidative stress were detected.
RESULTS
MT downregulated pyroptosis, whose changes were paralleled by a reduction in reactive oxygen species (ROS) production, reversal of sirtuin3 (SIRT3), and Forkhead box O3 (FOXO3α) upregulation. MT also inhibited apoptosis, mainly caused by the interaction of caspase-1 and caspase-3 proteins. Vivo studies confirmed that nicotine could accelerate plaque formation. Moreover, mice treated with MT showed a reduction in AS lesion area.
CONCLUSIONS
MT alleviates pyroptosis by regulating the SIRT3/FOXO3α/ROS axis and interacting with apoptosis. Importantly, our understanding of the inhibitory pathways for macrophage pyroptosis will allow us to identify other novel therapeutic targets that will help treat, prevent, and reduce AS-associated mortality.
Topics: Mice; Humans; Animals; Melatonin; Pyroptosis; Reactive Oxygen Species; Sirtuin 3; Nicotine; Apoptosis; Atherosclerosis; Caspases
PubMed: 38041171
DOI: 10.1186/s40659-023-00479-6 -
Frontiers in Pharmacology 2023Unmanaged Diabetes Mellitus (DM) usually results to tissue wastage because of mitochondrial dysfunction. Adverse effects of some drugs used in the management of DM...
Unmanaged Diabetes Mellitus (DM) usually results to tissue wastage because of mitochondrial dysfunction. Adverse effects of some drugs used in the management of DM necessitates the search for alternative therapy from plant origin with less or no side effects. (L.) (OG) has been folklorically used in the management of DM. However, the mechanism used by this plant is not fully understood. This study was designed to investigate the effects of chloroform fraction of OG leaf (CFOG) in the reversal of tissue wastage in DM via inhibition of mitochondrial-mediated cell death in streptozotocin (STZ)-induced diabetic male Wistar rats. Air-dried OG leaves were extracted with methanol and partitioned successively between -hexane, chloroform, ethylacetate and methanol to obtain their fractions while CFOG was further used because of its activity. Diabetes was induced in fifteen male Wistar rats, previously fed with high fat diet (28 days), via a single intraperitoneal administration of STZ (35 mg/kg). Diabetes was confirmed after 72 h. Another five fed rats were used as the normal control, treated with corn oil (group 1). The diabetic animals were grouped (n = 5) and treated for 28 days as follows: group 2 (diabetic control: DC) received corn oil (10 mL/kg), groups 3 and 4 were administered 400 mg/kg CFOG and 5 mg/kg glibenclamide, respectively. Body weight and Fasting Blood Glucose (FBG) were determined while Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) and beta cell (HOMA-β), and pancreatic tissue regenerating potential by CFOG were assessed. Activity-guided purification and characterization of the most active principle in CFOG was done using chromatographic and NMR techniques. The animals were sacrificed after 28 days, blood samples were collected and serum was obtained. Liver mitochondria were isolated and mitochondrial permeability transition (mPT) was investigated by spectrophotometry. CFOG reversed diabetic-induced mPT pore opening, inhibited ATPase activity and lipid peroxidation. CFOG reduced HOMA-IR but enhanced HOMA-β and caused regeneration of pancreatic cells relative to DC. Lupanol was a major metabolite of CFOG. Normoglycemic effect of CFOG, coupled with reversal of mPT, reduced HOMA-IR and improved HOMA-β showed the probable antidiabetic mechanism and tissue regenerating potentials of OG.
PubMed: 38035005
DOI: 10.3389/fphar.2023.1231826 -
ACS Omega Nov 2023Osteosarcoma, a highly metastasizing bone neoplasm, is a leading cause of death and disability in children and adolescents worldwide. Osteosarcoma is only suboptimally...
Osteosarcoma, a highly metastasizing bone neoplasm, is a leading cause of death and disability in children and adolescents worldwide. Osteosarcoma is only suboptimally responsive to surgery and radio- and chemotherapy, that too with adverse side effects. Hence, there is a necessary need for safer alternative therapeutic approaches. This study evaluated the anticancer effects of the semi-synthetic compound, pterostilbene-isothiocyanate (PTER-ITC), on human osteosarcoma MG-63 cells through cytotoxicity, wound-healing, and transwell-migration assays. Results showed that PTER-ITC specifically inhibited the survival, proliferation, and migration of osteosarcoma cells. PTER-ITC induced apoptosis in MG-63 cells by disrupting mitochondrial membrane potential, as evident from the outcomes of different cytological staining. The antimetastatic potential of PTER-ITC was evaluated through immunostaining, RT-qPCR, and immunoblotting. (molecular docking and dynamic simulation) and, subsequently, biochemical [co-immunoprecipitation (Co-IP) and luciferase reporter] assays deciphered the underlying mode-of-action of this compound. PTER-ITC increased E-cadherin and reduced N-cadherin levels, thereby facilitating the reversal of epithelial-mesenchymal transition (EMT). It also modulated the expressions of proliferative cell nuclear antigen (PCNA), caspase-3, poly [ADP-ribose] polymerase (PARP-1) and matrix metalloproteinase-2/9 (MMPs-2/9) at transcriptional and translational levels. PTER-ITC interfered with the β-catenin/transcription factor-4 (TCF-4) interaction by occupying the β-catenin binding site on TCF-4, confirmed by their reduced physical interactions (Co-IP assay). This inhibited transcriptional activation of TCF-4 by β-catenin (as shown by luciferase reporter assay). In conclusion, PTER-ITC exhibited potent anticancer effects against human osteosarcoma cells by abrogating the β-catenin/TCF-4 interaction. Altogether, this study suggests that PTER-ITC may be regarded as a new approach for osteosarcoma treatment.
PubMed: 38027335
DOI: 10.1021/acsomega.3c02732 -
Frontiers in Pharmacology 2023Cancer is one of the leading causes of death worldwide, and the development of resistance to chemotherapy drugs is a major challenge in treating malignancies. In recent...
Cancer is one of the leading causes of death worldwide, and the development of resistance to chemotherapy drugs is a major challenge in treating malignancies. In recent years, researchers have focused on understanding the mechanisms of multidrug resistance (MDR) in cancer cells and have identified the overexpression of ATP-binding cassette (ABC) transporters, including ABCC1/MRP1 and ABCC10/MRP7, as a key factor in the development of MDR. In this study, we aimed to investigate whether three drugs (sertraline, fluoxetine, and citalopram) from the selective serotonin reuptake inhibitor (SSRI) family, commonly used as antidepressants, could be repurposed as inhibitors of MRP1 and MRP7 transporters and reverse MDR in cancer cells. Using a combination of predictions and validations, we analyzed the interaction of MRP1 and MRP7 with the drugs and evaluated their ability to hinder cell resistance. We used computational tools to identify and analyze the binding site of these three molecules and determine their binding energy. Subsequently, we conducted experimental assays to assess cell viability when treated with various standard chemotherapies, both with and without the presence of SSRI inhibitors. Our results show that all three SSRI drugs exhibited inhibitory/reversal effects in the presence of chemotherapies on both MRP1-overexpressed cells and MRP7-overexpressed cells, suggesting that these medications have the potential to be repurposed to target MDR in cancer cells. These findings may open the door to using FDA-approved medications in combination therapy protocols to treat highly resistant malignancies and improve the efficacy of chemotherapy treatment. Our research highlights the importance of investigating and repurposing existing drugs to overcome MDR in cancer treatment.
PubMed: 38026953
DOI: 10.3389/fphar.2023.1290255 -
Journal of Functional Biomaterials Nov 2023Multidrug resistance (MDR) is a key factor in chemotherapy failure and tumor recurrence. The inhibition of drug efflux and autophagy play important roles in MDR therapy....
Multidrug resistance (MDR) is a key factor in chemotherapy failure and tumor recurrence. The inhibition of drug efflux and autophagy play important roles in MDR therapy. Herein, a multifunctional delivery system (HA-MIL-125@DVMA) was prepared for synergistically reverse tumor MDR. Tumor-targeted hollow MIL-125-Ti nanoparticles were used to load the doxorubicin-vitamin E succinate (DV) prodrug and 3-methyladenine (3-MA) to enhance reverse MDR effects. The pH-sensitive DV can kill tumor cells and inhibit P-gp-mediated drug efflux, and 3-MA can inhibit autophagy. HA-MIL-125@DVMA had uniformly distributed particle size and high drug-load content. The nanoparticles could effectively release the drugs into tumor microenvironment due to the rapid hydrazone bond-breaking under low pH conditions, resulting in a high cumulative release rate. In in vitro cellular experiments, the accumulation of HA-MIL-125@DVMA and HA-MIL-125@DV in MCF-7/ADR cells was significantly higher than that in the control groups. Moreover, the nanoparticles significantly inhibited drug efflux in the cells, ensuring the accumulation of the drugs in cell cytoplasm and causing drug-resistant cells' death. Importantly, HA-MIL-125@DVMA effectively inhibited tumor growth without changes in body weight in tumor-bearing mice. In summary, the combination of the acid-sensitive prodrug DV and autophagy inhibitor 3-MA in a HA-MIL-125 nanocarrier can enhance the antitumor effect and reverse tumor MDR.
PubMed: 37998115
DOI: 10.3390/jfb14110546 -
Cell Death & Disease Nov 2023The transcription factor MYB plays a pivotal role in haematopoietic homoeostasis and its aberrant expression is involved in the genesis and maintenance of acute myeloid...
The transcription factor MYB plays a pivotal role in haematopoietic homoeostasis and its aberrant expression is involved in the genesis and maintenance of acute myeloid leukaemia (AML). We have previously demonstrated that not all AML subtypes display the same dependency on MYB expression and that such variability is dictated by the nature of the driver mutation. However, whether this difference in MYB dependency is a general trend in AML remains to be further elucidated. Here, we investigate the role of MYB in human leukaemia by performing siRNA-mediated knock-down in cell line models of AML with different driver lesions. We show that the characteristic reduction in proliferation and the concomitant induction of myeloid differentiation that is observed in MLL-rearranged and t(8;21) leukaemias upon MYB suppression is not seen in AML cells with a complex karyotype. Transcriptome analyses revealed that MYB ablation produces consensual increase of MAFB expression in MYB-dependent cells and, interestingly, the ectopic expression of MAFB could phenocopy the effect of MYB suppression. Accordingly, in silico stratification analyses of molecular data from AML patients revealed a reciprocal relationship between MYB and MAFB expression, highlighting a novel biological interconnection between these two factors in AML and supporting new rationales of MAFB targeting in MLL-rearranged leukaemias.
Topics: Humans; Cell Line; Leukemia, Myeloid, Acute; MafB Transcription Factor; Myeloid-Lymphoid Leukemia Protein; Phenotype; RNA, Small Interfering
PubMed: 37996430
DOI: 10.1038/s41419-023-06276-z -
Cancer Biology & Therapy Dec 2023With the success of immune checkpoint inhibitors (ICI), such as anti- programmed death-1 (PD-1) antibody for solid tumors and lymphoma immunotherapy, a number of...
With the success of immune checkpoint inhibitors (ICI), such as anti- programmed death-1 (PD-1) antibody for solid tumors and lymphoma immunotherapy, a number of clinical trials with ICIs have been attempted for acute myeloid leukemia (AML) immunotherapy; however, limited clinical efficacy has been reported. This may be due to the heterogeneity of immune microenvironments and various degrees of T cell exhaustion in patients and may be involved in the IFN-γ pathway. In this study, we first characterized the percentage of PD-1+ and T cell immunoglobulin mucin-domain-containing-3 (Tim-3) +IFN-γ+ T cells in peripheral blood (PB) in AML compared with healthy individuals (HIs) by flow cytometry and further discussed the possibility of the reversal of T cell exhaustion to restore the secretion capacity of cytokines in T cells in AML based on blockade of PD-1 or Tim-3 (anti-PD-1 and anti-Tim-3 antibody) in vitro using a cytokine protein chip. A significantly increased percentage of PD-1+, Tim-3+, and PD-1+Tim-3+ IFN-γ+ T cells was observed in PB from patients with AML in comparison with HIs. Moreover, higher PD-1+IFN-γ+CD3+/CD8+ T cell levels were associated with poor overall survival in AML patients. Regarding leukemia cells, the percentage of Tim-3 in CD117+CD34+ AML cells was positively correlated with PD-1 in IFN-γ+CD4+ T cells. Furthermore, blocking PD-1 and Tim-3 may involve multiple cytokines and helper T cell subsets, mainly Th1 and Treg cells. Blockade of PD-1 or Tim-3 tends to restore cytokine secretion to a certain extent, a synergistic effect shown by the co-blockade of PD-1 and Tim-3. However, we also demonstrated the heterogeneity of secretory cytokines in ICI-treated T cells in AML patients.
Topics: Humans; Cytokines; Hepatitis A Virus Cellular Receptor 2; Interferon-gamma; Leukemia, Myeloid, Acute; Prognosis; Programmed Cell Death 1 Receptor; Tumor Microenvironment
PubMed: 37962843
DOI: 10.1080/15384047.2023.2278229 -
Frontiers in Immunology 2023Schistosomiasis-associated Pulmonary Arterial Hypertension (Sch-PAH) is a life-threatening complication of chronic infection that can lead to heart failure and death....
Schistosomiasis-associated Pulmonary Arterial Hypertension (Sch-PAH) is a life-threatening complication of chronic infection that can lead to heart failure and death. During PAH, the expansion of apoptosis-resistant endothelial cells (ECs) has been extensively reported; however, therapeutic approaches to prevent the progression or reversal of this pathological phenotype remain clinically challenging. Previously, we showed that depletion of the anti-apoptotic protein Caveolin-1 (Cav-1) by shedding extracellular vesicles contributes to shifting endoprotective bone morphogenetic protein receptor 2 (BMPR2) towards transforming growth factor beta (TGF-β)-mediated survival of an abnormal EC phenotype. However, the mechanism underlying the reduced endoprotection in PAH remains unclear. Interestingly, recent findings indicate that, similar to the gut, healthy human lungs are populated by diverse microbiota, and their composition depends significantly on intrinsic and extrinsic host factors, including infection. Despite the current knowledge that the disruption of the gut microbiome contributes to the development of PAH, the role of the lung microbiome remains unclear. Thus, using a preclinical animal model of Sch-PAH, we tested whether infection alters the gut-lung microbiome composition and causes EC injury, initiating the expansion of an abnormal EC phenotype observed in PAH. Indeed, stimulation with eggs significantly altered the gut-lung microbiome profile, in addition to promoting injury to the lung vasculature, characterized by increased apoptotic markers and loss of endoprotective expression of lung Cav-1 and BMPR2. Moreover, egg stimulus induced severe pulmonary vascular remodeling, leading to elevated right ventricular systolic pressure and hypertrophy, characteristic of PAH. , exposure to the immunodominant egg antigen p40 activated TLR4/CD14-mediated transient phosphorylation of Cav-1 at Tyr14 in human lung microvascular EC (HMVEC-L), culminating in a mild reduction of Cav-1 expression, but failed to promote death and shedding of extracellular vesicles observed . Altogether, these data suggest that disruption of the host-associated gut-lung microbiota may be essential for the emergence and expansion of the abnormal lung endothelial phenotype observed in PAH, in addition to eggs and antigens.
Topics: Animals; Mice; Bone Morphogenetic Protein Receptors, Type II; Caveolin 1; Endothelial Cells; Gastrointestinal Microbiome; Hypertension, Pulmonary; Lung; Pulmonary Arterial Hypertension; Pulmonary Artery; Schistosomiasis
PubMed: 37908354
DOI: 10.3389/fimmu.2023.1254762