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Background and Purpose: Pneumoconiosis, especially silicosis, is a prevalent occupational disease with substantial global economic implications and lacks a definitive cure. Both pneumoconiosis and idiopathic pulmonary fibrosis (IPF) are interstitial lung diseases, which share many common physiological characteristics. Because pirfenidone and nintedanib are approved to treat IPF, their potential efficacy as antifibrotic agents in advanced silicosis deserves further exploration. Thus, we aimed to evaluate the individual and combined effects of pirfenidone and nintedanib in treating advanced silicosis mice and elucidate the underlying mechanisms of their therapeutic actions via multiomics., Experimental Approach: We administered monotherapy or combined therapy of pirfenidone and nintedanib, with low and high doses, in silicosis established after 6 weeks and evaluated lung function, inflammatory responses and fibrotic status. Additionally, we employed transcriptomic and metabolomic analyses to uncover the mechanisms underlying different therapeutic strategies., Key Results: Both pirfenidone and nintedanib were effective in treating advanced silicosis, with superior outcomes observed in combination therapy. Transcriptomic and metabolomic analyses revealed that pirfenidone and nintedanib primarily exerted their therapeutic effects by modulating immune responses, signalling cascades and metabolic processes involving lipids, nucleotides and carbohydrates. Furthermore, we experimentally validated both monotherapy and combined therapy yielded therapeutic benefits through two common signalling pathways: steroid biosynthesis and purine metabolism., Conclusion and Implications: In conclusion, pirfenidone and nintedanib, either individually or in combination, demonstrate substantial potential in advanced silicosis. Furthermore, combined therapy outperformed monotherapy, even at low doses. These therapeutic benefits are attributed to their influence on diverse signalling pathways and metabolic processes., (© 2024 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

The mesenchymal stem/stromal cells (MSCs) are multipotent cells that were initially discovered in the bone marrow in the late 1960s but have so far been discovered in almost all tissues of the body. The multipotent property of MSCs enables them to differentiate into various cell types and lineages, such as adipocytes, chondrocytes, and osteocytes. The immunomodulation capacity and tumor-targeting features of MSCs made their use crucial for cell-based therapies in cancer treatment, yet limited advancement could be observed in translational medicine prospects due to the need for more information regarding the controversial roles of MSCs in crosstalk tumors. In this review, we discuss the therapeutic potential of MSCs, the controversial roles played by MSCs in cancer progression, and the anticancer therapeutic strategies that are in association with MSCs. Finally, the clinical trials designed for the direct use of MSCs for cancer therapy or for their use in decreasing the side effects of other cancer therapies are also mentioned in this review to evaluate the current status of MSC-based cancer therapies., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Objectives: Alpha-1-antitrypsin deficiency is a genetic disorder caused by mutations in the SERPINA1 gene encoding alpha-1-antitrypsin (AAT), the major serine protease inhibitor in plasma. Reduced AAT levels are associated with elevated risk of developing emphysema mainly due to uncontrolled activity of neutrophil elastase in the lungs. The prevalent Z-AAT mutant and many rare pathogenic AAT variants also predispose to liver disease due to their accumulation as polymeric chains in hepatocytes. Part of these polymers are secreted into the bloodstream and could represent biomarkers of intra-hepatic accumulation. Moreover, being inactive, they further lower lung protection against proteases. Aim of our study is to accurately quantify the percentage of circulating polymers (CP) in a cohort of subjects with different SERPINA1 genotypes., Methods: CP concentration was measured in plasma or Dried Blood Spot (DBS) by a sensitive sandwich ELISA based on capture by the polymer-specific 2C1 monoclonal antibody., Results: CP were significantly elevated in patients with the prevalent PI*SZ and PI*ZZ genotypes, with considerable intra-genotype variability. Notably, higher percentage of polymers was observed in association with elevated C-reactive protein. CP levels were also increased in carriers of the M malton variant, and of M procida , I, P lowell and M herleen in heterozygosity with Z-AAT., Conclusions: These findings highlight the importance of implementing CP quantification in a clinical laboratory. Indeed, the variable amount of CP in patients with the same genotype may correlate with the variable severity of the associated lung and liver diseases. Moreover, CP can reveal the polymerogenic potential of newly discovered ultrarare AAT variants., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)

Dysregulation of the renin–angiotensin–aldosterone-system (RAAS) in sepsis is a complex and early phenomenon with a likely significant contribution to organ failure and patient outcomes. A better understanding of the pathophysiology and intricacies of the RAAS in septic shock has led to the use of exogenous angiotensin II as a new therapeutic agent. In this review, we report a multinational and multi-disciplinary expert panel discussion on the role and implications of RAAS modulation in sepsis and the use of exogenous angiotensin II. The panel proposed guidance regarding patient selection and treatment options with exogenous angiotensin II which should trigger further research. [ABSTRACT FROM AUTHOR]

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) have been the standard treatment for patients with sensitizing EGFR mutation. However, almost all patients eventually acquire resistance to EGFR-TKIs. Therefore, easily available parameters to estimate the outcome of lung adenocarcinoma patients treated with EGFR-TKIs are in urgent need. Lung adenocarcinoma patients harbored EGFR sensitive mutant and received EGFR-TKIs as first-line or second-line treatment were recruited in the study. X-tile software were utilized to determine the optimal cut-off value of Alkaline phosphatase (ALP), direct bilirubin (DB), total bile acid (TBA), and high-density lipoprotein-cholesterol (HDL-C). The prognostic value of ALP, DB, TBA, and HDL-C for Progression-free survival (PFS) in patients were evaluated by the Kaplan-Meier curve. We applied univariate and multivariate survival analysis to identify the independent predictor for PFS in patients with EGFR-mutant advanced lung adenocarcinoma and received EGFR-TKIs. A total of 131 lung adenocarcinoma patients with a median age of 58 years old were included in the final analysis. Patients with elevated level of DB and HDL-C showed a longer PFS, while high level of ALP and TBA indicated shorter PFS in response to EGFR-TKI treatment. The multivariate survival analyses revealed a significant association of prolonged PFS with increased DB, and decreased TBA. In conclusion, these findings suggest that DB and TBA were significant independent predictors of PFS in EGFR-TKI-treated patients with advanced lung adenocarcinoma. [ABSTRACT FROM AUTHOR]

Due to the vital importance of the lungs, lung-related diseases and their control are very important. Severe inflammatory responses mediated by immune cells were among the leading causes of lung tissue pathology and damage during the COVID-19 pandemic. In addition, uncontrolled immune cell responses can lead to lung tissue damage in other infectious and non-infectious diseases. It is essential to control immune responses in a way that leads to homeostasis. Immunosuppressive drugs only suppress inflammatory responses and do not affect the homeostasis of reactions. The therapeutic application of mesenchymal stem cells (MSCs), in addition to restoring immune homeostasis, can promote the regeneration of lung tissue through the production of growth factors and differentiation into lung-related cells. However, the communication between MSCs and immune cells after treatment of pulmonary diseases is essential, and investigating this can help develop a clinical perspective. Different studies in the clinical phase showed that MSCs can reverse fibrosis, increase regeneration, promote airway remodeling, and reduce damage to lung tissue. The proliferation and differentiation potential of MSCs is one of the mechanisms of their therapeutic effects. Furthermore, they can secrete exosomes that affect the function of lung cells and immune cells and change their function. Another important mechanism is that MSCs reduce harmful inflammatory responses through communication with innate and adaptive immune cells, which leads to a shift of the immune system toward regulatory and hemostatic responses. [ABSTRACT FROM AUTHOR]

Background: The Blood-Brain Barrier (BBB) is a complex and dynamic interface that regulates the exchange of molecules and cells between the blood and the central nervous system. It undergoes structural and functional throughout oxidative stress and inflammation, which may compromise its integrity and contribute to the pathogenesis of neurodegenerative diseases. Main body: Maintaining BBB integrity is of utmost importance in preventing a wide range of neurological disorders. NRF2 is the main transcription factor that regulates cellular redox balance and inflammation-related gene expression. It has also demonstrated a potential role in regulating tight junction integrity and contributing to the inhibition of ECM remodeling, by reducing the expression of several metalloprotease family members involved in maintaining BBB function. Overall, we review current insights on the role of NRF2 in addressing protection against the effects of BBB dysfunction, discuss its involvement in BBB maintenance in different neuropathological diseases, as well as, some of its potential activators that have been used in vitro and in vivo animal models for preventing barrier dysfunction. Conclusions: Thus, emerging evidence suggests that upregulation of NRF2 and its target genes could suppress oxidative stress, and neuroinflammation, restore BBB integrity, and increase its protection. [ABSTRACT FROM AUTHOR]

Cross‐presentation by MHCI is optimally efficient in type 1 dendritic cells (DC) due to their high capacity for antigen processing. However, through specific pathways, other DCs, such as type 2 DCs and inflammatory DCs (iDCs) can also cross‐present antigens. FcγR‐mediated uptake by type 2 DC and iDC subsets mediates antibody‐dependent cross‐presentation and activation of CD8+ T cell responses. Here, an important role for the p84 regulatory subunit of PI3Kγ in mediating efficient cross‐presentation of exogenous antigens in otherwise inefficient cross‐presenting cells, such as type 2 DCs and GM‐CSF‐derived iDCs is identified. FcγR‐mediated cross‐presentation is shown in type 2 and iDCs depend on the enzymatic activity of the p84/p110γ complex of PI3Kγ, which controls the activity of the NADPH oxidase NOX2 and ROS production in murine spleen type 2 DCs and GM‐CSF‐derived iDCs. In contrast, p84/p110γ is largely dispensable for cross‐presentation by type 1 DCs. These findings suggest that PI3Kγ‐targeted therapies, currently considered for oncological practice, may interfere with the ability of type 2 DCs and iDCs to cross‐present antigens contained in immune complexes. [ABSTRACT FROM AUTHOR]

Background: Repeated inhalation of granulocyte-macrophage colony-stimulating factor (GM-CSF) was recently approved in Japan as a treatment for autoimmune pulmonary alveolar proteinosis. However, the detailed physiological and pathological effects of repeated inhalation in the long term, especially at increasing doses, remain unclear. Methods: In this chronic safety study, we administered 24 cynomolgus monkeys (Macaca fascicularis) aged 2–3 years with aerosolized sargramostim (a yeast-derived recombinant human GM-CSF [rhGM-CSF]) biweekly for 26 weeks across four dosing groups (0, 5, 100, and 500 µg/kg/day). We measured the serum GM-CSF antibody (GM-Ab) concentration by an ELISA and assessed the neutralizing capacity of GM-Ab using the GM-CSF-dependent cell line TF-1. We subjected lung tissue samples taken from all monkeys at 27 weeks to histopathological assessment using a sargramostim-specific monoclonal antibody to detect localization of residual sargramostim. Results: All the animals maintained good body condition and showed steady weight gain throughout the study. The pathological analyses of the lung revealed the formation of induced bronchus-associated lymphoid tissue (iBALT) in the lower respiratory tract, even at the clinical dose of 5 µg/kg/day. There was a relationship between the number or size of BALT and sargramostim dose or the serum GM-Ab levels. Immunohistochemical analyses revealed GM-Ab–producing cells in the follicular region of iBALT, with residual sargramostim in the follicles. Leucocyte counts were inversely correlated with GM-Ab levels in the high-dose groups. Additionally, serum GM-Ab from the treated animals significantly suppressed the alveolar macrophage proliferation activity of both Cynomolgus recombinant and rhGM-CSF in vitro. Conclusion: Long-term repeated inhalation of sargramostim led to iBALT formation in the lower respiratory tract, even at the clinical dose of 5 µg/kg/day, with the extent of iBALT formation increasing in a dose-dependent manner. Inhaled sargramostim was localized to the follicular region of iBALT nodules, which may induce the production of GM-Ab. [ABSTRACT FROM AUTHOR]

While met with initial and ground-breaking success targeting blood borne cancers, cellular immunotherapy remains significantly hindered in the context of solid tumors by the tumor microenvironment. Focused ultrasound, in conjunction with microbubbles, has found tremendous potential as a targeted and local drug/gene delivery technique for cancer therapy. The specific immunomodulating effects of this technique on immune cells, including T-cells, remain unexplored. Here, with freshly isolated human immune cells, we examine how focused ultrasound can viably modulate immune cell membrane permeability and influence the secretion of over 90 cytokines, chemokines and other analytes relevant to a potent immune response against cancer. We determine that microbubble-mediated focused ultrasound modulates the immune cell secretome in a time-dependent manner – ranging in ~0.1-3.6-fold changes in the concentration of a given cytokine compared to sham controls over 48 hours post-treatment (e.g. IL-1β, TNF-α, CX3CL1, CCL21). Further, we determine the general trend of a negative correlation between secreted cytokine concentration and viable ultrasound-assisted membrane permeability with negligible loss of cell viability. Taken together, the data presented here highlights the potential of microbubble-mediated focused ultrasound to viably enhance T-cell permeability and modulate key pro-immune pathways, offering a novel approach to augment targeted cellular therapies for solid tumors. [ABSTRACT FROM AUTHOR]

Introduction: Multiple myeloma (MM) is an incurable hematological malignancy with high chromosome instability and heavy dependence on the immunosuppressive bone marrow microenvironment. P53 mutations are adverse prognostic factors in MM; however, clinically, some patients without P53 mutations also exhibit aggressive disease progression. DNp73, an inhibitor of TP53 tumor suppressor family members, drives drug resistance and cancer progression in several solid malignancies. Nevertheless, the biological functions of DNp73 and the molecular mechanisms in myelomagenesis remain unclear. Methods: The effects of DNp73 on proliferation and drug sensitivity were assessed using flow cytometry and xenograft models. To investigate the mechanisms of drug resistance, RNA-seq and ChIP-seq analyses were performed in MM cell lines, with validation by Western blot and RT-qPCR. Immunofluorescence and transwell assays were used to assess DNA damage and cell invasion in MM cells. Additionally, in vitro phagocytosis assays were conducted to confirm the role of DNp73 in immune evasion. Results: Our study found that activation of NF-kB-p65 in multiple myeloma cells with different p53 mutation statuses upregulates DNp73 expression at the transcriptional level. Forced expression of DNp73 promoted aggressive proliferation and multidrug resistance in MM cells. Bulk RNA-seq analysis was conducted to assess the levels of MYCN, MYC, and CDK7. A ChIP-qPCR assay was used to reveal that DNp73 acts as a transcription factor regulating MYCN gene expression. Bulk RNA-seq analysis demonstrated increased levels of MYCN, MYC, and CDK7 with forced DNp73 expression inMMcells. A ChIP-qPCR assay revealed that DNp73 upregulates MYCN gene expression as a transcription factor. Additionally, DNp73 promoted immune evasion of MM cells by upregulating MYC target genes CD47 and PD-L1. Blockade of the CD47/SIRPa and PD-1/PD-L1 signaling pathways by the SIRPa-Fc fusion protein IMM01 and monoclonal antibody atezolizumab significantly restored the anti-MM activity of macrophages and T cells in the microenvironment, respectively. Discussion: In summary, our study demonstrated for the first time that the p53 family member DNp73 remarkably induces proliferation, drug resistance, and immune escape of myeloma cells by directly targeting MYCN and regulating the MYC pathway. The oncogenic function of DNp73 is independent of p53 status in MMcells. These data contribute to a better understanding of the function of TP53 and its family members in tumorigenesis. Moreover, our study clarified that DNp73 overexpression not only promotes aggressive growth of tumor cells but, more importantly, promotes immune escape of MM cells through upregulation of immune checkpoints. DNp73 could serve as a biomarker for immunotherapy targeting PD-L1 and CD47 blockade in MM patients. [ABSTRACT FROM AUTHOR]

Background/Aim: Non-small-cell lung cancer (NSCLC) is the most frequently diagnosed malignancy and the first cause of cancer-related death. Thus, finding alternative therapeutic options is crucial. Drug repurposing offers therapeutic options in a simplified and affordable manner, especially to cancer patients in developing countries. Several drugs including antihistamines and beta-adrenergic receptor blockers (beta-blockers) display antiproliferative properties on cancer cells. Interestingly, NSCLC patients who had used either antihistamines or beta-blockers showed improved response to chemotherapy or reduced mortality in comparison to non-users of any of these drugs. However, combination therapy is gaining substantial interest in many cancers including non-EGFR mutated NSCLC. Here, we investigated the antineoplastic effect of the combination of the antihistamine loratadine, the beta-blocker nebivolol, and the tyrosine-kinase inhibitor gefitinib on NSCLC cell lines. Materials and Methods: A-549 and NCI-H1975 cell lines were used. The effect of nebivolol, gefitinib, and loratadine on the metabolic activity was studied using the MTT assay. The inhibitory concentrations (IC20 and IC50) were calculated and used in the drug-combination experiments. Apoptosis was investigated using flow cytometry; and cell survival using the colony formation assay. Results: The combination nebivolol-loratadine-gefitinib produced a significant synergistic effect on inhibiting the metabolic activity and colony formation, as well as on promoting apoptosis in both cell lines. Noteworthy, the effect on the cell line carrying the EGFR mutation (NCI-H1975) was very similar to the cell line that does not exhibit such mutation (A-549 cells). Conclusion: The nebivolol-gefitinib-loratadine combination may be a promising alternative for lung cancer treatment. [ABSTRACT FROM AUTHOR]

Aspiration pneumonia exacerbates swallowing and respiratory muscle atrophy. It induces respiratory muscle atrophy through three steps: proinflammatory cytokine production, caspase-3 and calpain, and then ubiquitin–proteasome activations. In addition, autophagy induces swallowing muscle atrophy. Nrf2 is the central detoxifying and antioxidant gene whose function in aspiration pneumonia is unclear. We explored the role of Nrf2 in aspiration pneumonia by examining swallowing and respiratory muscle mass and function using wild-type and Nrf2-knockout mice. Pepsin and lipopolysaccharide aspiration challenges caused aspiration pneumonia. The swallowing (digastric muscles) and respiratory (diaphragm) muscles were isolated. Quantitative RT-PCR and Western blotting were used to assess their proteolysis cascade. Pathological and videofluoroscopic examinations evaluated atrophy and swallowing function, respectively. Nrf2-knockouts showed exacerbated aspiration pneumonia compared with wild-types. Nrf2-knockouts exhibited more persistent and intense proinflammatory cytokine elevation than wild-types. In both mice, the challenge activated calpains and caspase-3 in the diaphragm but not in the digastric muscles. The digastric muscles showed extended autophagy activation in Nrf2-knockouts compared to wild-types. The diaphragms exhibited autophagy activation only in Nrf2-knockouts. Nrf2-knockouts showed worsened muscle atrophies and swallowing function compared with wild-types. Thus, activation of Nrf2 may alleviate inflammation, muscle atrophy, and function in aspiration pneumonia, a major health problem for the aging population, and may become a therapeutic target. [ABSTRACT FROM AUTHOR]

Brain cancer is regarded as one of the most life-threatening forms of cancer worldwide. Oxidative stress acts to derange normal brain homeostasis, thus is involved in carcinogenesis in brain. The Nrf2/Keap1/ARE pathway is an important signaling cascade responsible for the maintenance of redox homeostasis, and regulation of anti-inflammatory and anticancer activities by multiple downstream pathways. Interestingly, Nrf2 plays a somewhat, contradictory role in cancers, including brain cancer. Nrf2 has traditionally been regarded as a tumor suppressor since its cytoprotective functions are considered to be the principle cellular defense mechanism against exogenous and endogenous insults, such as xenobiotics and oxidative stress. However, hyperactivation of the Nrf2 pathway supports the survival of normal as well as malignant cells, protecting them against oxidative stress, and therapeutic agents. Plants possess a pool of secondary metabolites with potential chemotherapeutic/chemopreventive actions. Modulation of Nrf2/ARE and downstream activities in a Keap1-dependant manner, with the aid of plant-derived secondary metabolites exhibits promise in the management of brain tumors. Current article highlights the effects of Nrf2/Keap1/ARE cascade on brain tumors, and the potential role of secondary metabolites regarding the management of the same. [ABSTRACT FROM AUTHOR]

Diabetic retinopathy (DR) is the leading cause of visual impairment, particularly in the proliferative form (proliferative DR [PDR]). The impact of the PDR microenvironment on microglia, which are the resident immune cells in the central nervous system, and the specific pathological changes it may induce remain unclear. This study aimed to investigate the role of microglia in the progression of PDR under hypoxic and inflammatory conditions. We performed a comprehensive gene expression analysis using human-induced pluripotent stem cell-derived microglia under different stimuli (dimethyloxalylglycine (DMOG), lipopolysaccharide (LPS), and DMOG + LPS) to mimic the hypoxic inflammatory environment characteristic of PDR. Principal component analysis revealed distinct gene expression profiles, with 76 genes synergistically upregulated under combined stimulation. Notably, prostaglandin-endoperoxide synthase 2 (encoding cyclooxygenase (COX)-2) exhibited the most pronounced increase, leading to elevated prostaglandin E2 (PGE2) levels and driving pathological angiogenesis and inflammation via the COX-2/PGE2/PGE receptor 2 signaling axis. Additionally, the upregulation of the fibrogenic genes snail family transcriptional repressor 1 and collagen type I alpha 1 chain suggested a role for microglia in fibrosis. These findings underscore the critical involvement of microglia in PDR and suggest that targeting both the angiogenic and fibrotic pathways may present new therapeutic strategies for managing this condition. [ABSTRACT FROM AUTHOR]

This study aimed to evaluate the osteogenic potential of mesenchymal stromal cell (MSC) spheroids combined with the basic fibroblast growth factor (bFGF) in a mouse femur fracture model. To begin, MSC spheroids were generated, and the expression of key trophic factors (bFGF Bmp2, and Vegfa) was assessed using quantitative PCR (qPCR). A binding assay confirmed the interaction between the bFGF and the spheroids' extracellular matrix. The spheroid cultures significantly upregulated bFGF, Bmp2, and Vegfa expression compared to the monolayers (p < 0.001), and the binding assay demonstrated effective bFGF binding to the MSC spheroids. Following these in vitro assessments, the mice were divided into five groups for the in vivo study: (1) no treatment (control), (2) spheroids alone, (3) bFGF alone, (4) bFGF-loaded spheroids (bFGF-spheroids), and (5) non-viable (frozen) bFGF-loaded spheroids (bFGF-dSpheroids). Bone formation was analyzed by a micro-CT, measuring the bone volume (BV) and bone mineral content (BMC) of the mice four weeks post-fracture. A high dose of the bFGF (10 µg) significantly promoted bone formation regardless of the presence of spheroids, as evidenced by the increases in BV (bFGF, p = 0.010; bFGF-spheroids, p = 0.006; bFGF-dSpheroids, p = 0.032) and BMC (bFGF, p = 0.023; bFGF-spheroids, p = 0.004; bFGF-dSpheroids, p = 0.014), compared to the controls. In contrast, a low dose of the bFGF (1 µg) combined with the MSC spheroids significantly increased BV and BMC compared to the control (BV, p = 0.012; BMC, p = 0.015), bFGF alone (BV, p = 0.012; BMC, p = 0.008), and spheroid (BV, p < 0.001; BMC, p < 0.001) groups. A low dose of the bFGF alone did not significantly promote bone formation (p > 0.05). The non-viable (frozen) spheroids loaded with a low dose of the bFGF resulted in a higher BV and BMC compared to the spheroids alone (BV, p = 0.003; BMC, p = 0.017), though the effect was less pronounced than in the viable spheroids. These findings demonstrate the synergistic effect of the bFGF and MSC spheroids on bone regeneration. The increased expression of the BMP-2 and VEGF observed in the initial experiments, coupled with the enhanced bone formation in vivo, highlight the therapeutic potential of this combination. Future studies will aim to elucidate the underlying molecular mechanisms and assess the long-term outcomes for bone repair strategies. [ABSTRACT FROM AUTHOR]

Control of oxidation/antioxidation homeostasis is important for cellular protective functions, and disruption of the antioxidation balance by exogenous and endogenous ligands can lead to profound pathological consequences of cancerous commitment within cells. Although cancers are sensitive to antioxidation drugs, these drugs are sometimes associated with problems including tumor resistance or dose-limiting toxicity in host animals and patients. These problems are often caused by the imbalance between the levels of oxidative stress-induced reactive oxygen species (ROS) and the redox efficacy of antioxidants. Increased ROS levels, because of abnormal function, including metabolic abnormality and signaling aberrations, can promote tumorigenesis and the progression of malignancy, which are generated by genome mutations and activation of proto-oncogene signaling. This hypothesis is supported by various experiments showing that the balance of oxidative stress and redox control is important for cancer therapy. Although many antioxidant drugs exhibit therapeutic potential, there is a heterogeneity of antioxidation functions, including cell growth, cell survival, invasion abilities, and tumor formation, as well as the expression of marker genes including tumor suppressor proteins, cell cycle regulators, nuclear factor erythroid 2-related factor 2, and Jun dimerization protein 2; their effectiveness in cancer remains unproven. Here, we summarize the rationale for the use of antioxidative drugs in preclinical and clinical antioxidant therapy of cancer, and recent advances in this area using cancer cells and their organoids, including the targeting of ROS homeostasis. [ABSTRACT FROM AUTHOR]

Representing severe morbidity and mortality globally, respiratory infections associated with chronic respiratory diseases, including complicated pneumonia, asthma, interstitial lung disease, and chronic obstructive pulmonary disease, are a major public health concern. Lung health and the prevention of pulmonary disease rely on the mechanisms of airway surface fluid secretion, mucociliary clearance, and adequate immune response to eradicate inhaled pathogens and particulate matter from the environment. The antimicrobial proteins and peptides contribute to maintaining an antimicrobial milieu in human lungs to eliminate pathogens and prevent them from causing pulmonary diseases. The predominant antimicrobial molecules of the lung environment include human α- and β-defensins and cathelicidins, among numerous other host defense molecules with antimicrobial and antibiofilm activity such as PLUNC (palate, lung, and nasal epithelium clone) family proteins, elafin, collectins, lactoferrin, lysozymes, mucins, secretory leukocyte proteinase inhibitor, surfactant proteins SP-A and SP-D, and RNases. It has been demonstrated that changes in antimicrobial molecule expression levels are associated with regulating inflammation, potentiating exacerbations, pathological changes, and modifications in chronic lung disease severity. Antimicrobial molecules also display roles in both anticancer and tumorigenic effects. Lung antimicrobial proteins and peptides are promising alternative therapeutics for treating and preventing multidrug-resistant bacterial infections and anticancer therapies. [ABSTRACT FROM AUTHOR]

The aim of this study was to explore the post-earthquake experiences, difficulties, and coping strategies of older adults who experienced the Kahramanmaraş earthquakes that occurred in Türkiye in 2023. This research was designed as a qualitative descriptive study. The study was conducted with 21 (13 female and 8 male) older adults and the mean age of the participants was 70.2 (in the range of 65–85). In line with the data obtained from the participants, " Fulfilling Basic Needs of Older Adults, Emotional Turmoil in Later Life, Healthcare Disparities in Aging, Adaptive Response of Older Adults" themes and sub-themes related to the theme were formed. Both physical and socio-emotional challenges, as well as coping strategies and support systems that older adults face in the aftermath of earthquakes, demonstrate unique characteristics for this demographic group. Therefore, it is recommended to plan programs by considering these differences while planning intervention programs before, during, and after the disaster. [ABSTRACT FROM AUTHOR]

Idiopathic pulmonary fibrosis (IPF) is a devastating condition characterized by progressive lung scarring and uncontrolled fibroblast proliferation, inevitably leading to organ dysfunction and mortality. Although elevated iron levels have been observed in patients and animal models of lung fibrosis, the mechanisms linking iron dysregulation to lung fibrosis pathogenesis, particularly the role of macrophages in orchestrating this process, remain poorly elucidated. Here we evaluate iron metabolism in macrophages during pulmonary fibrosis using both in vivo and in vitro approaches. In murine bleomycin- and amiodarone-induced pulmonary fibrosis models, we observed significant iron deposition and lipid peroxidation in pulmonary macrophages. Intriguingly, the ferroptosis regulator glutathione peroxidase 4 (GPX4) was upregulated in pulmonary macrophages following bleomycin instillation, a finding corroborated by single- cell RNA sequencing analysis. Moreover, macrophages isolated from fibrotic mouse lungs exhibited increased transforming growth factor (TGF)-β1 expression that correlated with lipid peroxidation. In vitro, iron overload in bone marrow-derived macrophages triggered lipid peroxidation and TGF-β1 upregulation, which was effectively suppressed by ferroptosis inhibitors. When cocultured with iron-overloaded macrophages, lung fibroblasts exhibited heightened activation, evidenced by increased a-smooth muscle actin and fibronectin expression. Importantly, this profibrotic effect was attenuated by treating macrophages with a ferroptosis inhibitor or blocking TGF-β receptor signaling in fibroblasts. Collectively, our study elucidates a novel mechanistic paradigm in which the accumulation of iron within macrophages initiates lipid peroxidation, thereby amplifying TGF-β1 production, subsequently instigating fibroblast activation through paracrine signaling. Thus, inhibiting iron overload and lipid peroxidation warrants further exploration as a strategy to suppress fibrotic stimulation by disease-associated macrophages. [ABSTRACT FROM AUTHOR]

Human T cell leukaemia virus type-1 (HTLV-1) is an oncogenic retrovirus that causes lifelong infection in ~5–10 million individuals globally. It is endemic to certain First Nations populations of Northern and Central Australia, Japan, South and Central America, Africa, and the Caribbean region. HTLV-1 preferentially infects CD4+ T cells and remains in a state of reduced transcription, often being asymptomatic in the beginning of infection, with symptoms developing later in life. HTLV-1 infection is implicated in the development of adult T cell leukaemia/lymphoma (ATL) and HTLV-1-associated myelopathies (HAM), amongst other immune-related disorders. With no preventive or curative interventions, infected individuals have limited treatment options, most of which manage symptoms. The clinical burden and lack of treatment options directs the need for alternative treatment strategies for HTLV-1 infection. Recent advances have been made in the development of RNA-based antiviral therapeutics for Human Immunodeficiency Virus Type-1 (HIV-1), an analogous retrovirus that shares modes of transmission with HTLV-1. This review highlights past and ongoing efforts in the development of HTLV-1 therapeutics and vaccines, with a focus on the potential for gene therapy as a new treatment modality in light of its successes in HIV-1, as well as animal models that may help the advancement of novel antiviral and anticancer interventions. [ABSTRACT FROM AUTHOR]

Background: Idiopathic pulmonary fibrosis (IPF) is a serious, progressive lung disease for which treatments are scarce. Pirfenidone has been approved for the treatment of IPF in Taiwan since 2016. This study aimed to gain a better insight into pirfenidone's real-world safety and effectiveness in adult IPF patients in Taiwan. Methods: We conducted a prospective, multicenter, post-marketing surveillance study, and analyzed data from a small sample of 50 IPF patients treated with pirfenidone. Results: Most patients were men, with a mean age of 72.8 years (±10.3). They were in physiology stage I or II with a baseline mean forced vital capacity (FVC) of 2.236 L (73.8% of predicted value). After treatment with pirfenidone, the mean FVC decreased by 0.088 L at week 24 and 0.127 L at week 52. The mean 6 min walk test was 325.5 m at baseline, increased by 8.1 m at week 24, but then decreased by 23.0 m at week 52. These changes from baseline did not reach statistical significance. Pirfenidone prevented worsening of cough but did not stabilize dyspnea. During 52 weeks of treatment, the incidence of total adverse drug reactions was 62.0%, with decreased appetite (32.0%) and pruritis (10.0%) being the most common. The adverse events leading to treatment discontinuation were decreased appetite (8.0%), nausea (4.0%), and respiratory failure (4.0%). No safety concern was raised by the study. Treatment with pirfenidone stabilized both FVC and the subjective symptom of cough in most patients. Conclusions: This post-marketing surveillance study demonstrated that pirfenidone is an effective, safe, and well-tolerated treatment in patients with IPF in Taiwan. [ABSTRACT FROM AUTHOR]

It is known that there are abnormalities of tight junction functions, cell migration and mitochondrial metabolism in human endometriosis and endometrial carcinoma. In this study, we investigated the effects of growth factors and their inhibitors on the epithelial permeability barrier, cell migration and mitochondrial metabolism in 2D and 2.5D cultures of human endometrioid endometrial carcinoma Sawano cells. We also investigated the changes of bicellular and tricellular tight junction molecules and ciliogenesis induced by these inhibitors. The growth factors TGF-β and EGF affected the epithelial permeability barrier, cell migration and expression of bicellular and tricellular tight junction molecules in 2D and 2.5D cultures of Sawano cells. EW-7197 (a TGF-β receptor inhibitor), AG1478 (an EGFR inhibitor) and SP600125 (a JNK inhibitor) affected the epithelial permeability barrier, cell migration and mitochondrial metabolism and prevented the changes induced by TGF-β and EGF in 2D and 2.5D cultures. EW-7197 and AG1478 induced ciliogenesis in 2.5D cultures. In conclusion, TGF-β and EGF promoted the malignancy of endometrial cancer via interplay among the epithelial permeability barrier, cell migration and mitochondrial metabolism. EW-7197 and AG1478 may be useful as novel therapeutic treatments options for endometrial cancer. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is the predominant form of liver cancer and ranks as the third leading cause of cancer-related mortality globally. The liver performs a wide range of tasks and is the primary organ responsible for metabolizing harmful substances and foreign compounds. Oxidative stress has a crucial role in growth and improvement of hepatocellular carcinoma (HCC). Nuclear factor erythroid 2 (1)-related factor 2 (Nrf2) is an element that regulates transcription located in the cytoplasm. It controls the balance of redox reactions by stimulating the expression of many genes that depend on antioxidant response elements. Nrf2 has contrasting functions in the normal, healthy liver and HCC. In the normal liver, Nrf2 provides advantageous benefits, while in HCC it promotes harmful effects that support the growth and survival of HCC. Continuous activation of Nrf2 has been detected in HCC and promotes its advancement and aggressiveness. In addition, Activation of Nrf2 may lead to immune evasion, weakening the immune cells' ability to attack tumors and thereby promoting tumor development. Furthermore, chemoresistance in HCC, which is considered a form of stress response to chemotherapy medications, significantly impedes the effectiveness of HCC treatment. Stress management is typically accomplished by activating specific signal pathways and chemical variables. One important element in the creation of chemoresistance in HCC is nuclear factor-E2-related factor 2 (Nrf2). Nrf2 is a transcription factor that regulates the activation and production of a group of genes that encode proteins responsible for protecting cells from damage. This occurs through the Nrf2/ARE pathway, which is a crucial mechanism for combating oxidative stress within cells. [ABSTRACT FROM AUTHOR]

Pulmonary hypertension (PH) in interstitial lung disease (ILD) is relatively common, affecting up to 50% of patients with idiopathic pulmonary fibrosis (IPF). It occurs more frequently in advanced fibrotic ILD, although it may also complicate milder disease and carries significant clinical implications in terms of morbidity and mortality. Key pathological processes driving ILD-PH include hypoxic pulmonary vasoconstriction and pulmonary vascular remodelling. While current understanding of the complex cell signalling pathways and molecular mechanisms underlying ILD-PH remains incomplete, there is evidence for an interplay between the disease pathogenesis of fibrotic ILD and PH, with interest in the role of the pulmonary endothelium in driving pulmonary fibrogenesis more recently. This review examines key clinical trials in ILD-PH therapeutics, including recent research showing promise for the treatment of both ILD-PH and the underlying pulmonary fibrotic process, further supporting the hypothesis of interrelated pathogenesis. Other important management considerations are discussed, including the value of accurate phenotyping in ILD-PH and the success of the "pulmonary vascular" phenotype. This article highlights the close and interconnected nature of fibrotic ILD and PH disease pathogenesis, a perspective likely to improve our understanding and therapeutic approach to this complex condition in the future. [ABSTRACT FROM AUTHOR]

Glioblastoma represents the predominant and a highly aggressive primary neoplasm of the central nervous system that has an abnormal metabolism. Our previous study showed that chrysomycin A (Chr-A) curbed glioblastoma progression in vitro and in vivo. However, whether Chr-A could inhibit orthotopic glioblastoma and how it reshapes metabolism are still unclear. In this study, Chr-A markedly suppressed the development of intracranial U87 gliomas. The results from airflow-assisted desorption electrospray ionization mass spectrometry imaging (AFADESI-MSI) indicated that Chr-A improved the abnormal metabolism of mice with glioblastoma. Key enzymes including glutaminase (GLS), glutamate dehydrogenases 1 (GDH1), hexokinase 2 (HK2) and glucose-6-phosphate dehydrogenase (G6PD) were regulated by Chr-A. Chr-A further altered the level of nicotinamide adenine dinucleotide phosphate (NADPH), thus causing oxidative stress with the downregulation of Nrf-2 to inhibit glioblastoma. Our study offers a novel perspective for comprehending the anti-glioma mechanism of Chr-A, highlighting its potential as a promising chemotherapeutic agent for glioblastoma. [ABSTRACT FROM AUTHOR]

Sarcoidosis is an inflammatory condition that can affect multiple organ systems and is characterized by the formation of non-caseating granulomas in various organs, including the heart. Due to suboptimal diagnostic rates, the true prevalence and incidence of cardiac sarcoidosis (CS) remain to be determined. In patients with suspected CS, an initial examination should include 12-lead ECG or ambulatory ECG monitoring, and echocardiography with the estimation of LV, RV function, and strain rate. In patients with confirmed extracardiac sarcoidosis and with high clinical suspicion for CS, sophisticated imaging modalities, including cardiac MRI and PET, are indicated. Typical inflammation patterns and myocardial scarring should pose a high suspicion for CS. In patients without diagnosed extracardiac sarcoidosis and high clinical suspicion, although with low diagnostic probability, an endomyocardial biopsy should be considered to establish the diagnosis of definite isolated cardiac sarcoidosis. Timely diagnosis enables the initiation of therapy and close monitoring of adverse cardiac events that can be life-threatening, including sudden cardiac death, ventricular tachycardia, high-degree AV block, and heart failure. Implementing biomarkers in correlation to cardiac imaging can determine the disease's severity and progression but can also be helpful in following the treatment response. The formation of larger global registries can be helpful in the identification of independent predictors of adverse clinical events and the development of specific diagnostic algorithms to reduce the overall risk of this serious condition. [ABSTRACT FROM AUTHOR]

The NR2F family, including NR2F1, NR2F2, and NR2F6, belongs to the nuclear receptor superfamily. NR2F family members function as transcription factors and play essential roles in the development of multiple organs or tissues in mammals, including the central nervous system, veins and arteries, kidneys, uterus, and vasculature. In the central nervous system, NR2F1/2 coordinate with each other to regulate the development of specific brain subregions or cell types. In addition, NR2F family members are associated with various cancers, such as prostate cancer, breast cancer, and esophageal cancer. Nonetheless, the roles of the NR2F family in the development and diseases of the lung have not been systematically summarized. In this review, we mainly focus on the lung, including recent findings regarding the roles of the NR2F family in development, physiological function, and cancer. [ABSTRACT FROM AUTHOR]

The role of mitochondria in neurodegenerative diseases is crucial, and recent developments have highlighted its significance in cell therapy. Mitochondrial dysfunction has been implicated in various neurodegenerative disorders, including Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, and Huntington's diseases. Understanding the impact of mitochondrial biology on these conditions can provide valuable insights for developing targeted cell therapies. This mini-review refocuses on mitochondria and emphasizes the potential of therapies leveraging mesenchymal stem cells, embryonic stem cells, induced pluripotent stem cells, stem cell–derived secretions, and extracellular vesicles. Mesenchymal stem cell–mediated mitochondria transfer is highlighted for restoring mitochondrial health in cells with dysfunctional mitochondria. Additionally, attention is paid to gene-editing techniques such as mito-CRISPR, mitoTALENs, mito-ZNFs, and DdCBEs to ensure the safety and efficacy of stem cell treatments. Challenges and future directions are also discussed, including the possible tumorigenic effects of stem cells, off-target effects, disease targeting, immune rejection, and ethical issues. [ABSTRACT FROM AUTHOR]

Introduction: Idiopathic pulmonary fibrosis (IPF) is a progressive-fibrosing lung disease with a median survival of less than 5 years. Currently, two agents, pirfenidone and nintedanib are approved for this disease, and both have been shown to reduce the rate of decline in lung function in patients with IPF. However, both have significant adverse effects and neither completely arrest the decline in lung function. Areas covered: Thirty experimental agents with unique mechanisms of action that are being evaluated for the treatment of IPF are discussed. These agents work through various mechanisms of action, these include inhibition of transcription nuclear factor k-B on fibroblasts, reduced expression of metalloproteinase 7, the generation of more lysophosphatidic acids, blocking the effects of transforming growth factor ß, and reducing reactive oxygen species as examples of some unique mechanisms of action of these agents. Expert opinion: New drug development has the potential to expand the treatment options available in the treatment of IPF patients. It is expected that the adverse drug effect profiles will be more favorable than current agents. It is further anticipated that these new agents or combinations of agents will arrest the fibrosis, not just slow the fibrotic process. [ABSTRACT FROM AUTHOR]

Background: Pulmonary sarcomatoid carcinoma is a rare tumor that is resistant to cytotoxic agents. This observational study aimed to evaluate the detection rate of driver gene alteration and the efficacy of targeted therapy for pulmonary sarcomatoid carcinoma. Methods: We established a database of patients with pulmonary sarcomatoid carcinoma and their clinical information, including EGFR mutation, ALK fusion gene, ROS1 fusion gene, BRAF mutation, and MET exon 14 skipping mutation. The present study retrieved and analyzed the data of patients with pulmonary sarcomatoid carcinoma in whom driver gene alterations were evaluated, and the survival duration after the initiation of treatment with targeted therapy was examined. Results: A total of 44 patients were included in the present study. The EGFR mutation, ALK fusion gene, and MET exon 14 skipping mutation were detected in 2/43 patients (4.7%), 2/34 patients (5.9%), and 2/16 patients (12.5%), respectively. The ROS1 fusion gene (0/18 patients) and BRAF mutation (0/15 patients) were not detected. Female patients (P = 0.063, Fisher's exact test) and patients without smoking history (P = 0.025, Fisher's exact test) were the dominant groups in which any driver mutation was detected. Five patients with driver gene alterations were treated with targeted therapy. Progression-free survival (PFS) was 1.3 months and 1.6 months in 2 of the patients treated with gefitinib. Two patients with the ALK fusion gene showed 2.1 and 14.0 months of PFS from the initiation of treatment with crizotinib, and a patient with the MET exon 14 skipping mutation showed 9.7 months of PFS from the initiation of treatment with tepotinib. Conclusion: The EGFR mutation, ALK fusion gene, and MET exon 14 skipping mutation were detected in patients with pulmonary sarcomatoid carcinoma in clinical practice, and some patients achieved long survival times after receiving targeted therapy. Further investigation is necessary to evaluate the efficacy of targeted therapy for pulmonary sarcomatoid carcinoma. [ABSTRACT FROM AUTHOR]

Background: Community-acquired pneumonia remains a major health concern, characterized by significant morbidity and mortality. The underlying pathophysiology of community-acquired pneumonia involves substantial oxidative stress and inflammation, which contribute to lung tissue damage and impaired immune function. Main body: Variations in oxidative metabolism contribute to the inflammatory cascade which triggers pneumonia to commence and evolve, whereas oxidative stress as well as inflammatory processes is strongly related. Understanding the underlying immunological dysregulation and unbalanced redox that heighten vulnerability to a variety of illnesses has improved over the past several decades attributable to research. One of the key strategies for addressing oxidative stress is to lower the reactive oxygen species creation in the mitochondrion which is one of the main sites of their generation by using antioxidants, where they prevent oxidants from transferring electrons to other molecules. Consequently, antioxidants either directly or indirectly reduce the risk of damage and preserve the redox equilibrium. Therefore, antioxidants, due to their ability to neutralize reactive oxygen species and modulate inflammatory processes, have been explored as potential adjuvant therapies to enhance the treatment outcomes of community-acquired pneumonia. Where recent research has explored the potential of antioxidants as adjuvant therapy in the treatment of community-acquired pneumonia, aiming to mitigate these detrimental effects. Antioxidants such as N-acetylcystein, vitamin C, vitamin E, astaxanthin, and zinc have shown promising results in both preclinical and clinical studies. Conclusion: Outcomes of several in vitro as well as in vivo antioxidant studies have demonstrated the antioxidants' promising potential as an adjunct pneumonia therapy. For an assessment of its effectiveness in this therapeutic context, more research involving humans will be required. [ABSTRACT FROM AUTHOR]

Background: The metabolic reprogramming of amino acids is critical for cancer cell growth and survival. Notably, intracellular accumulation of cysteine is often observed in various cancers, suggesting its potential role in alleviating the oxidative stress associated with rapid proliferation. The liver is the primary organ for cysteine biosynthesis, but much remains unknown about the metabolic alterations of cysteine and their mechanisms in hepatocellular carcinoma cells. Methods: RNA-seq data from patients with hepatocarcinoma were analyzed using the TNMplot database. The underlying mechanism of the oncogenic alteration of cysteine metabolism was studied in mice implanted with BNL 1ME A.7 R.1 hepatocarcinoma. Results: Database analysis of patients with hepatocellular carcinoma revealed that the expression of enzymes involved in de novo cysteine synthesis was down-regulated accompanying with increased expression of the cystine uptake transporter xCT. Similar alterations in gene expression have also been observed in a syngeneic mouse model of hepatocarcinoma. The enhanced expression of DNA methyltransferase in murine hepatocarcinoma cells caused methylation of the upstream regions of cysteine synthesis genes, thereby repressing their expression. Conversely, suppression of de novo cysteine synthesis in healthy liver cells induced xCT expression by up-regulating the oxidative-stress response factor NRF2, indicating that reduced de novo cysteine synthesis repulsively increases cystine uptake via enhanced xCT expression, leading to intracellular cysteine accumulation. Furthermore, the pharmacological inhibition of xCT activity decreased intracellular cysteine levels and suppressed hepatocarcinoma tumor growth in mice. Conclusions: Our findings indicate an underlying mechanism of the oncogenic alteration of cysteine metabolism in hepatocarcinoma and highlight the efficacy of alteration of cysteine metabolism as a viable therapeutic target in cancer. [ABSTRACT FROM AUTHOR]

Head and neck cancer (HNC) entails a heterogenous neoplastic disease that arises from the mucosal epithelium of the upper respiratory system and the gastrointestinal tract. It is characterized by high morbidity and mortality, being the eighth most common cancer worldwide. It is believed that the mesenchymal/stem stromal cells (MSCs) present in the tumour milieu play a key role in the modulation of tumour initiation, development and patient outcomes; they also influence the resistance to cisplatin-based chemotherapy, the gold standard for advanced HNC. MSCs are multipotent, heterogeneous and mobile cells. Although no MSC-specific markers exist, they can be recognized based on several others, such as CD73, CD90 and CD105, while lacking the presence of CD45, CD34, CD14 or CD11b, CD79α, or CD19 and HLA-DR antigens; they share phenotypic similarity with stromal cells and their capacity to differentiate into other cell types. In the tumour niche, MSC populations are characterized by cell quiescence, self-renewal capacity, low reactive oxygen species production and the acquisition of epithelial-to-mesenchymal transition properties. They may play a key role in the process of acquiring drug resistance and thus in treatment failure. The present narrative review examines the links between MSCs and HNC, as well as the different mechanisms involved in the development of resistance to current chemo-radiotherapies in HNC. It also examines the possibilities of pharmacological targeting of stemness-related chemoresistance in HNSCC. It describes promising new strategies to optimize chemoradiotherapy, with the potential to personalize patient treatment approaches, and highlights future therapeutic perspectives in HNC. [ABSTRACT FROM AUTHOR]

Background: Combining pemetrexed with bevacizumab may have some potential in improving the efficacy in patients with non-small-cell lung cancer (NSCLC), and this meta-analysis aims to explore the impact of pemetrexed addition to bevacizumab on treatment efficacy for NSCLC. Methods: PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases were systematically searched, and we included randomized controlled trials (RCTs) assessing the effect of pemetrexed addition to bevacizumab on treatment efficacy in patients with NSCLC. Overall survival and progression-free survival were included in this meta-analysis. Results: Four RCTs were finally included in the meta-analysis. Overall, compared with bevacizumab for NSCLC, pemetrexed addition showed significantly improved overall survival (hazard ratio [HR] = 0.87; 95% confidence interval [CI] = 0.76 to 0.99; P = 0.03), survival rate (odd ratio [OR] = 1.41; 95% CI = 1.06 to 1.86; P = 0.02), progression-free survival (HR = 0.63; 95% CI = 0.55 to 0.72; P < 0.00001) and progression-free survival rate (OR = 1.92; 95% CI = 1.38 to 2.67; P < 0.00001), but led to the increase in grade ≥ 3 adverse events (OR = 2.15; 95% CI = 1.62 to 2.84; P < 0.00001). Conclusions: Pemetrexed addition may be effective to improve treatment efficacy for NSCLC compared to bevacizumab treatment. [ABSTRACT FROM AUTHOR]

To explore serum KL-6 level and investigate its diagnostic value in interstitial lung diseases (ILDs). Methods: Serum KL-6 level was measured using the chemiluminescent enzyme immunoassay. Statistical analysis was performed for determining the KL-6 concentration of each group. Results: KL-6 level (U/mL) in the ILD group was 1388.321 ± 1943.116, which was higher than that in the control group, showing a significant statistical difference. ROC curve analysis based on the receiver operating characteristic curve showed the optimal cut-off value of 402.5U/mL, sensitivity of 77.4%, specificity of 93.4%, and accuracy of 89.4%; through Chi-square test with the two groups, the positive rate of KL-6 in patients with ILD was proved to be significantly higher than that in the control group. KL-6 level was 1063.00± 504.757 in the idiopathic pulmonary fibrosis (IPF) group, 1346.892 ± 1827.252 in the connective tissue disease-associated interstitial lung disease (CTD-ILD) group, 467.889± 288.859 in the organizing pneumonia (OP) group, 8252.333± 6050.625 in the pulmonary alveolar proteinosis (PAP) group, and 359.200± 392.707 in the sarcoidosis group. The rank sum test showed that the differences were statistically significant. KL-6 level was the lowest in the sarcoidosis group, followed by that in the OP group. Conclusion: Serum KL-6 level was confirmed to be highly sensitive, specific, and accurate in the diagnosis of ILD. Subgroup analysis showed that the KL-6 level was the lowest in the sarcoidosis group, followed by that in the OP group. [ABSTRACT FROM AUTHOR]

Para-hydroxycinnamic acid (pHCA) is one of the most abundant naturally occurring hydroxycinnamic acids, a class of chemistries known for their antioxidant properties. In this study, we evaluated the impact of pHCA on different parameters of skin aging in in vitro skin models after H2O2 and UV exposure. These parameters include keratinocyte senescence and differentiation, inflammation, and energy metabolism, as well as the underlying molecular mechanisms. Here we demonstrate that pHCA prevents oxidative stress-induced premature senescence of human primary keratinocytes in both 2D and 3D skin models, while improving clonogenicity in 2D. As aging is linked to inflammation, referred to as inflammaging, we analyzed the release of IL-6, IL-8, and PGE2, known to be associated with senescence. All of them were downregulated by pHCA in both normal and oxidative stress conditions. Mechanistically, DNA damage induced by oxidative stress is prevented by pHCA, while pHCA also exerts a positive effect on the mitochondrial and glycolytic functions under stress. Altogether, these results highlight the protective effects of pHCA against inflammaging, and importantly, help to elucidate its potential mechanisms of action. [ABSTRACT FROM AUTHOR]

CX3CL1 is one of the 50 up-to-date identified and characterized chemokines. While other chemokines are produced as small, secreted proteins, CX3CL1 (fractalkine) is synthetized as a transmembrane protein which also leads to a soluble form produced as a result of proteolytic cleavage. The membrane-bound protein and the soluble forms exhibit different biological functions. While the role of the fractalkine/CX3CR1 signaling axis was described in the nervous system and was also related to the migration of leukocytes to sites of inflammation, its actions are controversial in cancer progression and anti-tumor immunity. In the present review, we first describe the known biology of fractalkine concerning its action through its cognate receptor, but also its role in the activation of different integrins. The second part of this review is dedicated to its role in cancer where we discuss its role in anti-cancer or procarcinogenic activities. [ABSTRACT FROM AUTHOR]

Background and objective: Pooled analyses of previous randomized controlled trials reported that antifibrotics improved survival in patients with idiopathic pulmonary fibrosis (IPF), but the results were only based on short-term outcome data from selected patients who met strict criteria. Observational studies/meta-analyses also suggested that antifibrotics improve survival, but these studies failed to control for immortal time bias that considerably exaggerates drug effects. Therefore, whether antifibrotics truly improve long-term survival in patients with IPF in the real world remains undetermined and requires external validity. Methods: We used data from the Japanese National Claims Database to estimate the intention-to-treat effect of antifibrotics on mortality. To address immortal time bias, we employed models treating antifibrotic initiation as a time-dependent covariate and target trial emulation (TTE), both incorporating new-user designs for antifibrotics and treating lung transplantation as a competing event. Results: Of 30,154 patients with IPF, 14,525 received antifibrotics. Multivariate Fine–Gray models with antifibrotic initiation as a time-dependent covariate revealed that compared with no treatment, nintedanib (adjusted hazard ratio [aHR], 0.85; 95% confidence interval [CI], 0.81–0.89) and pirfenidone (aHR, 0.89; 95% CI, 0.86–0.93) were associated with reduced mortality. The TTE model also replicated the associations of nintedanib (aHR, 0.69; 95% CI, 0.65–0.74) and pirfenidone (aHR, 0.81; 95% CI, 0.78–0.85) with reduced mortality. Subgroup analyses confirmed this association regardless of age, sex, and comorbidities, excluding certain subpopulations. Conclusions: The results of this large-scale real-world analysis support the generalizability of the association between antifibrotics and improved survival in various IPF populations. [ABSTRACT FROM AUTHOR]

Inflammatory bowel disease (IBD) is a chronic immune-mediated condition that affects the digestive systemand includes Crohn's disease (CD) and ulcerative colitis (UC). Although the exact etiology of IBD remains uncertain, dysfunctional immunoregulation of the gut is believed to be the main culprit. Amongst the immunoregulatory factors, reactive oxygen species (ROS) and reactive nitrogen species (RNS), components of the oxidative stress event, are produced at abnormally high levels in IBD. Their destructive effects may contribute to the disease's initiation and propagation, as they damage the gut lining and activate inflammatory signaling pathways, further exacerbating the inflammation. Oxidative stressmarkers, such as malondialdehyde (MDA), 8-hydroxy-2'-deoxyguanosine (8- OHdG), and serum-free thiols (R-SH), can be measured in the blood and stool of patients with IBD. These markers are elevated in patients with IBD, and their levels correlatewith the severity of the disease. Thus, oxidative stressmarkers can be used not only in IBD diagnosis but also in monitoring the response to treatment. It can also be targeted in IBD treatment through the use of antioxidants, including vitamin C, vitamin E, glutathione, and N-acetylcysteine. In this review, we summarize the role of oxidative stress in the pathophysiology of IBD, its diagnostic targets, and the potential application of antioxidant therapies to manage and treat IBD. [ABSTRACT FROM AUTHOR]

Introduction: Immunogenic cell death (ICD) has emerged as a novel option for cancer immunotherapy. The key determinants of ICD encompass antigenicity (the presence of antigens) and adjuvanticity, which involves the release of damageassociated molecular patterns (DAMPs) and various cytokines and chemokines. CX3CL1, also known as neurotactin or fractalkine, is a chemokine involved in cellular signalling and immune cell interactions. CX3CL1 has been denoted as a "find me" signal that stimulates chemotaxis of immune cells towards dying cells, facilitating efferocytosis and antigen presentation. However, in the context of ICD, it is uncertain whether CX3CL1 is an important mediator of the effects of ICD. Methods: In this study, we investigated the intricate role of CX3CL1 in immunogenic apoptosis induced by mitoxantrone (MTX) in cancer cells. The Luminex xMAP technology was used to quantify murine cytokines, chemokines and growth factors to identify pivotal regulatory cytokines released by murine fibrosarcoma MCA205 and melanoma B16-F10 cells undergoing ICD. Moreover, a murine tumour prophylactic vaccination model was employed to analyse the effect of CX3CL1 on the activation of an adaptive immune response against MCA205 cells undergoing ICD. Furthermore, thorough analysis of the TCGASKCM public dataset from 98 melanoma patients revealed the role of CX3CL1 and its receptor CX3CR1 in melanoma patients. Results: Our findings demonstrate enhanced CX3CL1 release from apoptotic MCA205 and B16-F10 cells (regardless of the cell type) but not if they are undergoing ferroptosis or accidental necrosis. Moreover, the addition of recombinant CX3CL1 to non-immunogenic doses of MTX-treated, apoptotically dying cancer cells in the murine prophylactic tumour vaccination model induced a robust immunogenic response, effectively increasing the survival of the mice. Furthermore, analysis of melanoma patient data revealed enhanced survival rates in individuals exhibiting elevated levels of CD8+ T cells expressing CX3CR1. Conclusion: These data collectively underscore the importance of the release of CX3CL1 in eliciting an immunogenic response against dying cancer cells and suggest that CX3CL1 may serve as a key switch in conferring immunogenicity to apoptosis. [ABSTRACT FROM AUTHOR]

Combined gene and cell therapy are promising strategies for cancer treatment. Given the complexity of cancer, several approaches are actively studied to fight this disease. Using mesenchymal stem cells (MSCs) has demonstrated dual antitumor and protumor effects as they exert massive immune/regulatory effects on the tissue microenvironment. MSCs have been widely investigated to exploit their antitumor target delivery system. They can be genetically modified to overexpress genes and selectively or more efficiently eliminate tumor cells. Current approaches tend to produce more effective and safer therapies using MSCs or derivatives; however, the effect achieved by engineered MSCs in solid tumors is still limited and depends on several factors such as the cell source, transgene, and tumor target. This review describes the progress of gene and cell therapy focused on MSCs as a cornerstone against solid tumors, addressing the different MSC-engineering methods that have been approached over decades of research. Furthermore, we summarize the main objectives of engineered MSCs against the most common cancers and discuss the challenges, limitations, risks, and advantages of targeted treatments combined with conventional ones. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE, lupus) is a debilitating, multisystem autoimmune disease that can affect any organ in the body. The disease is characterized by circulating autoantibodies that accumulate in organs and tissues, which triggers an inflammatory response that can cause permanent damage leading to significant morbidity and mortality. Lyn, a member of the Src family of non-receptor protein tyrosine kinases, is highly implicated in SLE as remarkably both mice lacking Lyn or expressing a gain-of-function mutation in Lyn develop spontaneous lupus-like disease due to altered signaling in B lymphocytes and myeloid cells, suggesting its expression or activation state plays a critical role in maintaining tolerance. The past 30 years of research has begun to elucidate the role of Lyn in a duplicitous signaling network of activating and inhibitory immunoreceptors and related targets, including interactions with the interferon regulatory factor family in the toll-like receptor pathway. Gain-offunction mutations in Lyn have now been identified in human cases and like mouse models, cause severe systemic autoinflammation. Studies of Lyn in SLE patients have presented mixed findings, which may reflect the heterogeneity of disease processes in SLE, with impairment or enhancement in Lyn function affecting subsets of SLE patients that may be a means of stratification. In this review, we present an overview of the phosphorylation and protein-binding targets of Lyn in B lymphocytes and myeloid cells, highlighting the structural domains of the protein that are involved in its function, and provide an update on studies of Lyn in SLE patients. [ABSTRACT FROM AUTHOR]

NRF2 is an important transcription factor that regulates redox homeostasis in vivo and exerts its anti-oxidative stress and anti-inflammatory response by binding to the ARE to activate and regulate the transcription of downstream protective protein genes, reducing the release of reactive oxygen species. Ferroptosis is a novel iron-dependent, lipid peroxidation-driven cell death mode, and recent studies have shown that ferroptosis is closely associated with acute lung injury/acute respiratory distress syndrome (ALI/ARDS). NRF2 is able to regulate ferroptosis through the regulation of the transcription of its target genes to ameliorate ALI/ARDS. Therefore, This article focuses on how NRF2 plays a role in ALI/ARDS by regulating ferroptosis. We further reviewed the literature and deeply analyzed the signaling pathways related to ferroptosis which were regulated by NRF2. Additionally, we sorted out the chemical molecules targeting NRF2 that are effective for ALI/ARDS. This review provides a relevant theoretical basis for further research on this theory and the prevention and treatment of ALI/ARDS. The intended audience is clinicians and researchers in the field of respiratory disease. [ABSTRACT FROM AUTHOR]