Search Results (132)

Background and Objectives: The integration of chemotherapy (ChT) and immune checkpoint inhibitors (ICIs) has become a standard approach in oncology. Although the addition of ICIs to double-agent ChT regimens has demonstrated clinical benefit in multiple studies, other trials have reported no significant improvement. ChT is hypothesized to potentiate the effects of ICIs through multiple mechanisms, including tumor antigen release and modulation of the tumor microenvironment. This study aimed to evaluate whether nivolumab enhances the cytotoxic effects of cisplatin or paclitaxel in lung adenocarcinoma (A549) cell lines under immune-independent conditions. Materials and Methods: A549 lung alveolar carcinoma cell lines were treated with varying concentrations of nivolumab, cisplatin, and paclitaxel, individually and in combinations. Cytotoxicity and apoptosis were assessed using mitochondrial membrane potential analysis, cell viability assays, and morphological evaluation of cellular and nuclear alterations characteristic of apoptotic cell death. Results: Nivolumab alone exhibited no cytotoxic activity. The combination of cisplatin at its IC₅₀ (half-maximal inhibitory concentration) (3 µg/mL) with 13 µg/mL nivolumab yielded the most pronounced cytotoxicity (89%) compared to cisplatin alone (49%, p < 0.001). Paclitaxel combined with nivolumab increased cytotoxicity to 69% versus 51% for paclitaxel alone (p < 0.05). The enhancement effect was greater with cisplatin than with paclitaxel. Notably, adding nivolumab to the cisplatin–paclitaxel combination reduced cytotoxicity from 73% to 64%. Mechanistic analysis revealed a significant reduction in Rhodamine 123 fluorescence intensity in drug-treated groups versus controls (p < 0.001), indicating loss of mitochondrial membrane potential, a hallmark of intrinsic apoptotic activation, suggesting apoptotic priming. Conclusions: Nivolumab potentiates the cytotoxic effects of cisplatin and paclitaxel in A549 lung adenocarcinoma cells, with a more pronounced effect observed in combination with cisplatin. This enhancement is associated with mitochondrial membrane potential loss, supporting mitochondrial apoptotic priming as a potential underlying mechanism of drug synergy. Full article

C. burnetii (Cb) is an obligate intracellular bacterial pathogen that replicates within alveolar macrophages following aerosol infection. Unlike most intracellular bacteria, Cb establishes a lysosome-derived replicative niche (Coxiella-containing vacuole or CCV) through the action of its Type IVB secretion system (T4BSS). This system translocates a large repertoire of effector proteins into the host cytoplasm after phagosome acidification. These effectors interfere with diverse signaling pathways to co-opt host processes, such as vesicle trafficking, ubiquitylation, gene expression and lipid metabolism, promoting pathogen survival without triggering robust proinflammatory signaling or host cell death pathways. This effector-triggered immune silencing is particularly unique given the central role of macrophages as innate immune sentinels. In this review, we examine Cb T4BSS effectors that have been characterized as central determinants of innate immunity modulation. We discuss innate immune sensing pathways potentially engaged during infection, including Toll-like receptors, NOD-like receptors, RIG-I-like receptors, inflammasomes, and interferon signaling pathways, and highlight evidence indicating that these pathways are actively suppressed. Emphasis is placed on effector-mediated regulation of NF-κB signaling, type I interferon responses, and inflammasome activation. Finally, we address unresolved questions related to effector-triggered immunity, redundancy in immune suppression, and discrepancies between in vitro and in vivo infection models. Full article

Background: Severe lung compromise from COVID-19, ARDS, and recently AH3N2 can progress to life-threatening hypoxia. Past experience led to standardized protocols that assumed similarity to SARS-CoV. Methods: COVID-19 pathophysiology and histopathological lung biopsy photomicrographs are analyzed. Results: Pneumolysis is defined as progressive alveolar–capillary destruction resulting from SARS-CoV-2 attack on pneumocytes. In the final stages preceding pneumolysis, molecular mechanisms in the lungs include apoptosis in alveolar epithelial type I and II cells, compromising alveolar regeneration, and necrosis, resulting in leakage of intracellular contents and amplifying inflammation. Pyroptosis, driven by inflammasome activity, further disrupts alveolar integrity in ARDS. Histopathological findings include Masson bodies, alveolar-coating cells with nuclear atypia, reactive pneumocytes and reparative fibrosis, intra-alveolar hemorrhage, moderate inflammatory infiltrates and abscesses, microthrombi, hyaline membrane remnants, and emphysema. The three theoretical pathophysiological stages of progressive hypoxemia (silent hypoxemia, gasping, and death zone) are shown. Conclusions: Silent hypoxemia rapidly progresses to critical hypoxemia. This progression results from progressive pneumolysis, inflammation, immune overexpression, autoimmunity, and HAPE-type edema, leading to acute pulmonary insufficiency. Long-lasting COVID-19 can result in fibrosis and, as a compensatory mechanism, polierythrocythemia. The proposed treatment (based on tolerance to hypoxia and the hemoglobin factor) includes prompt oxygen administration, control of inflammatory and immune responses, antibiotics, rehydration, erythropoietin and platelet aggregation inhibitors. Full article

Background and Objectives: Pulmonary fibrosis (PF) is an interstitial lung disease that leads to death and is characterized by excessive collagen deposition and tissue scarring. Bleomycin (BLM) is widely used to induce PF in rodent models, closely resembling human idiopathic pulmonary fibrosis. Ivermectin, a broad-spectrum antiparasitic agent, has recently attracted interest due to its reported anti-inflammatory and antifibrotic effects. The beneficial effects of ivermectin to treat PF may be attributed to suppressing the NLRP3 inflammasome. Ivermectin can cause acute toxicity, including convulsions, when overdosed in animals. In humans, it may induce neurological disorders, particularly in individuals with mutations in the ABCB1 gene. This study aimed to investigate the potential protective role of ivermectin against BLM-induced PF in rats. Materials and Methods: Forty adult male albino rats were randomly allocated into four groups (n = 10 each): control, ivermectin-treated (0.6 mg/kg, orally on days 0, 1, 7, and 8), BLM-treated (single intratracheal dose of 5 mg/kg), and BLM- and ivermectin-treated. Lung tissues were collected for histopathological analysis and Mallory trichrome staining to assess collagen deposition. Mast cell (MC) infiltration was assessed using toluidine blue. Immunohistochemistry for α-SMA and Ki-67 was used to evaluate myofibroblast and cell proliferation. Oxidative stress parameters, including serum total antioxidant capacity, lung glutathione and lung nitric oxide were measured. Results: Ivermectin treatment markedly attenuated BLM-induced lung fibrosis, showing reduced collagen accumulation, restoration of alveolar architecture, and decreased inflammatory cell infiltration. Immunohistochemical evaluation revealed decreased expression of α-SMA and Ki-67, while biochemical analyses demonstrated improved oxidative stress markers. Conclusions: Ivermectin significantly mitigates BLM-induced pulmonary fibrosis in rats through modulation of inflammation, suppression of myofibroblast proliferation, and reduction in oxidative stress and collagen deposition. These findings highlight ivermectin as a potential candidate for the management of fibrotic lung diseases, warranting further mechanistic and clinical investigations. Full article

Background: Periodontitis is a disease characterized by the destruction of periodontal tissue and tooth loss. The molecular mechanisms behind this disease, however, are not clearly understood. Ferroptosis is an iron-dependent, lipid peroxidation-driven form of regulated cell death that seems to play a role in periodontal pathogenesis by increasing oxidative stress and reducing tissue regeneration. Objective: The current narrative review aims to summarize current knowledge of the involvement of ferroptosis in periodontal tissue destruction and potentially to identify new targets of therapy. Methods: A comprehensive search of PubMed, Embase, and Web of Science databases was conducted. Original human, animal, and in vitro studies published in English were selected. Data on experimental models, molecular markers, and key outcomes were extracted and synthesized in the review. Results: After screening, four studies were identified and selected. Ferroptosis activation in periodontal ligament fibroblasts, stem cells, and gingival tissues was associated with increased ACSL4 and decreased GPX4 expression, iron accumulation, and oxidative stress. The administration of Ferrostatin-1 or antioxidants like curcumin seemed to reduce inflammation and alveolar bone loss in vivo. Transcriptomic analyses further revealed immune-related ferroptosis gene signatures in human periodontitis tissues. Conclusions: Ferroptosis represents a crucial mechanism in periodontal tissue destruction through not yet completely understood. Understanding these molecular pathways could be the key to developing new therapeutic strategies for periodontal treatment. Full article

Orthodontic tooth movement (OTM), a complex biological process driven by orchestrated bone remodeling, involves osteoclastic bone resorption and osteoblastic bone formation in response to mechanical force. Traditionally, OTM-related cell death has been discussed in terms of apoptosis and necrosis. However, recent advances in cell death research have revealed various forms of regulated cell death (RCD) beyond these conventional categories. This review summarizes the current understanding of the diverse RCD pathways and their roles in various cell populations during OTM. It delineates the involvement of distinct RCD mechanisms, including apoptosis, autophagy, pyroptosis, ferroptosis, and necroptosis. On the compression side, these RCD pathways in periodontal ligament (PDL) cells, cementoblasts, cementocytes, and bone-related cells actively drive inflammatory responses, promote bone resorption, and contribute to root resorption. Conversely, on the tension side, specific RCD pathways, notably autophagy in the PDL and osteocytes, play crucial roles in promoting osteogenesis and tissue repair. Collectively, cell death is not merely a passive elimination of cells but actively functions as a critical switch for alveolar bone remodeling during OTM. Understanding these multifaceted RCD mechanisms provides novel insights into the biological regulation of tooth movement and identifies potential therapeutic targets for enhancing tooth movement efficiency and mitigating adverse effects. Full article

Background/Objectives: Cigarette smoke (CS) drives pathogenesis across the spectrum of chronic respiratory disorders, exerting its detrimental effects primarily through oxidative stress and programmed cell death. Scutellarein (Scu), a botanical-origin flavonoid enriched in respiratory therapeutics-oriented Chinese medicinal herbs, demonstrates established anti-inflammatory applications. This study systematically evaluated the protective roles of Scu against CS-induced lung injury and explored the underlying mechanisms. Methods: Subacute CS-exposed mice were used to evaluate the therapeutic effects of Scu on lung injury. Immunofluorescence and quantitative PCR were used to examine the expression levels of junctional proteins and proinflammatory mediators. Apoptotic cell death was quantified using Annexin V-FITC/7-AAD staining. Transepithelial electrical resistance and dextran permeability assay were used to access the barrier integrity in alveolar epithelial MLE-12 cells. Western blotting was used to detect the changes in the signal pathway. Results: In CS-exposed mice, Scu administration dose-dependently reduced histopathological scores, pulmonary edema, changes in the alveolar structure, and inflammatory cell infiltration. In MLE-12 cells, Scu significantly suppressed cigarette smoke condensate (CSC)-induced inflammatory mediators, oxidative stress, caspase-3 activation, and apoptosis and preserved CSC-suppressed tight junction protein expression and barrier disruption. Scu also rescued CSC-altered expression levels of Hrk, Ecscr, and Myo5b and mitigated the CSC-suppressed PI3K/AKT/mTOR pathway. Conclusions: Scu alleviates CS-induced subacute lung injury through its antioxidant, anti-apoptotic effects to maintain epithelial barrier integrity likely via the mitigation of the CSC-suppressed PI3K/AKT/mTOR pathway. Full article

Periodontitis is a chronic non-communicable inflammatory disease in which oxidative stress plays an important role in tissue destruction and alveolar bone loss. Excessive production of reactive oxygen species disrupts redox homeostasis, activates inflammatory signaling pathways, and promotes regulated cell death processes such as pyroptosis and ferroptosis. The Nrf2/Keap1 pathway is a key regulator of antioxidant defense and cellular adaptation to redox imbalance. Impaired Nrf2 signaling has been associated with enhanced oxidative injury, NF-κB and NLRP3 inflammasome activation, osteoclast-driven bone resorption, and reduced regenerative capacity in periodontal tissues. Experimental studies suggest that Nrf2 activation can restore the redox balance and attenuate inflammation and bone destructive responses in a periodontal model. Moreover, therapeutic approaches involving phytochemicals, microbial-derived metabolites, and redox-responsive biomaterials have been reported to influence Nrf2-related signaling in experimental settings. However, the majority of the available evidence is derived from in vitro or animal studies, and the relevance of these findings to clinical periodontitis remains to be established. This review summarizes the current advances linking oxidative stress, redox signaling, cell death pathways, and bone remodeling with Nrf2 dysfunction in periodontitis and outlines the key mechanistic insights while highlighting the existing knowledge gaps. Full article

There have been few reports of neoplasia in hyenas to date. In this report, we describe a captive adult female spotted hyena (Crocuta crocuta) that developed inappetence, lethargy and marked abdominal distension over a 3-day period. The hyena was chemically immobilised to allow clinical investigation of the severe symptoms; however, she died before any internal examination occurred. At necropsy, severe serosanguinous hydropericardium was evident, as well as pulmonary congestion and oedema, ascites and chronic passive congestion of the liver with mild fibrosis. Histopathological examination of the pericardial surface revealed fibrous proliferations lined by mostly a single layer of large proliferating neoplastic mesothelial cells forming papillary projections into the lumen of the pericardial sac as well as infiltration into the pericardial connective tissue, with innumerable haemosiderin-laden macrophages in places, suggestive of chronic haemorrhage. The liver revealed severe congestion and interstitial fibrosis, and the lung revealed congestion and oedema, with moderate numbers of alveolar macrophages and marked anthracosis. The diagnosis was pericardial well-differentiated papillary mesothelioma, with death under anaesthesia caused by cardiogenic shock due to pericardial mesothelioma-associated cardiac tamponade. As primary pericardial mesothelioma (PPM) is a rare tumour type for both animals and humans, and this is the first report of a PPM in a hyena, we compare the clinical findings with those seen in other species. Full article

Feline calicivirus (FCV) is widespread in multi-cat environments and typically causes acute upper respiratory tract disease (URTD). FCV also causes outbreaks of virulent systemic disease (VSD), mainly in adults, with multiple organ involvement. In this study, an FCV-VSD infection was described in a less-one-month-old Maine Coon kitten originating from a cattery where an outbreak of FCV-URTD had previously been reported. After spontaneous death, post-mortem examination as well as histopathological, immunohistochemical, bacteriological and virological investigations were carried out. Pathological findings were consistent with severe pneumonia and cutaneous oedema of the footpads. No concomitant bacterial infection was detected. FCV RNA was detected in several organs and the highest amount of viral RNA was observed in the lung sample, in which the presence of the FCV antigen was confirmed by immunohistochemistry. With the same immunohistochemical technique, the IBA-1 antibody detected sparse alveolar macrophages, the main viral target cell and pulmonary replication site. The nucleotide sequences of the viral ORF2 gene amplified from all positive tissues were identical with each other and phylogeny confirms that highly virulent FCV strains are not distinguishable from FCV-URTD phenotypes. Our findings reinforce the hypothesis that VSD outbreaks can occur even in small populations, due to the high genetic variability of FCV. Full article

Protein misfolding diseases are characterized by structurally abnormal proteins that lose their functionality, resulting in cellular and tissue dysfunction. Neurodegenerative diseases, including Parkinson’s disease, Alzheimer’s disease and Huntington’s disease, share a common etiopathogenesis characterize by the accumulation of misfolded proteins. These proteins autonomously aggregate within neuronal cells, triggering inflammation and cell death. The accumulation of misfolded proteins triggers endoplasmic reticulum (ER) stress, leading to alter Ca²⁺ homeostasis. This prolonged stress condition induces the cleavage of procaspase 4 which is resident in ER and activates NF-kB pathway activation, leading to inflammatory responses and cell death. In this study, the efficacy of the drug Vx-445 (Elexacaftor), used in the pharmacological treatment of cystic fibrosis, was assessed in human adenocarcinomic basal alveolar epithelial (A549) and neuronal (SH-SY5Y) cell lines, where ER stress was induced by Thapsigargin. The aim was to assess whether the corrector was able to reduce ER stress by restoring cellular homeostasis and, probably, the proper folding of misfolded proteins and reducing the inflammatory response triggered by these events. Therefore, protein levels of IkBα, p-STAT 3 and COXII were analyzed by flow cytofluorimetry, while Ca²⁺ content was measured by spectrofluorimetry. The results obtained suggest a significant effect of Vx-445 in restoring cellular homeostasis, leading to reduced expression of inflammation-related proteins, such as IL-6, tested by ELISA. Although preliminary, these results encourage further studies to explore the potential repurpose of Vx-445 as a therapeutic candidate for conditions involving ER stress and chronic inflammatory diseases associated with protein misfolding, beyond its current use in cystic fibrosis. Full article

Lung ischemia–reperfusion injury (LIRI) remains a major contributor to perioperative morbidity and mortality in thoracic surgery, especially for lung transplantations, where it is one of the principal drivers of primary graft dysfunction (PGD). Although substantial advances have been made in surgical technique, donor management, and perioperative care, LIRI continues to pose a significant clinical challenge. Mechanistically, LIRI reflects a combined pathology of oxidative stress, endothelial and glycocalyx disruption, innate immune activation, mitochondrial dysfunction, and regulated cell death, resulting in loss of alveolar–capillary barrier integrity and gas exchange failure. Current management is phase-specific and multimodal, spanning donor care and preservation, controlled reperfusion and lung-protective ventilation, and pharmacological treatments. Treatment candidates that target oxidative stress and inflammatory cascades (e.g., antioxidants, complement and adenosine pathways, mesenchymal stromal cell products, and dipeptidyl-peptidase-4 inhibition) show promise, yet translation into a clinical scenario remains difficult. Increasing evidence supports endothelial-preserving and mitochondria-sparing strategies, rigorous perioperative bundles, and biomarker-guided trials to move from pathophysiology to practice. Ultimately, addressing LIRI requires an integrated, multidisciplinary approach that spans surgical, anesthetic, and pharmacologic domains, with the goal of improving both early outcomes and long-term graft survival in lung transplant patients. Full article

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) primarily causes mild to moderate respiratory illness in humans, but infection can also lead to long-term complications, including chronic fatigue, respiratory and cardiac issues, or even death. In November 2021, the emergence of the highly transmissible Omicron variant marked a significant shift in the pandemic, with its subvariants rapidly spreading and continuing to evolve worldwide. The continuing introduction of Omicron subvariants underscores the need for the development of up-to-date vaccines, as well as for appropriate animal models in which they can be evaluated. Among these subvariants, XBB.1.5 stands out for its ability to evade the immune response from previous infection or vaccination. The objective of this study was to determine the disease course in African green monkeys (AGMs) following intranasal exposure to the XBB.1.5 subvariant. In four intranasally exposed AGMs, histopathological findings in the lungs consistent with SARS-CoV-2 infection included lymphohistiocytic and neutrophilic bronchiolitis with variable numbers of syncytial cells, to terminal bronchiole-centric, bronchointerstitial pneumonia with alveolar type II (AT2) pneumocyte hyperplasia, with evidence of acute alveolar injury, including alveolar septal necrosis and hyaline membrane formation. The two males showed more severe pneumonia compared to the two females. SARS-CoV-2 RNA was detected in the lungs or tracheobronchial lymph nodes in the males but not in the females, which correlated with higher cumulative lung pathology scores in the males. In the females, SARS-CoV-2 RNA was limited to the colon and nasal turbinates. Our results indicate that AGMs exhibit a disease course similar to most humans when exposed intranasally, making them a suitable model for studying mild to moderate SARS-CoV-2 infection. Therefore, further work is warranted to determine if this model could have utility for the evaluation of vaccine and therapeutic candidates against contemporary SARS-CoV-2 variants. Full article

Background: Acute lung injury (ALI) is a life-threatening respiratory condition and one of the leading causes of mortality worldwide, accounting for approximately 20% of global annual deaths. Despite its high prevalence and severity, effective therapeutic options remain limited. Eupatorium lindleyanum DC., a traditional medicinal herb, has demonstrated therapeutic potential against pulmonary diseases, particularly ALI, in both clinical and experimental settings. However, the protective effects and underlying mechanisms of its characteristic sesquiterpene lactone components against ALI remain unclear. Objective: This study aimed to evaluate the protective effects of sesquiterpene lactones from Eupatorium lindleyanum DC. (SLEL) against lipopolysaccharide (LPS)-induced ALI both in vivo and in vitro. Furthermore, it sought to elucidate the underlying mechanisms by integrating network pharmacology, multi-omics approaches (transcriptomics, metabolomics, and 16S rRNA sequencing), and various molecular biology techniques. Results: SLEL significantly attenuated inflammatory injury in alveolar epithelial cells and alleviated pulmonary edema, hemorrhage, and inflammatory infiltration in rats, accompanied by reduced TNF-α, IL-6, and IL-1β levels and improved lung injury indices. Mechanistically, SLEL exerted dual suppression of the PI3K-Akt and MAPK-NF-κB pathways. Network pharmacology, molecular docking, and UPLC-MS analyses identified Eupalinolide A and Eupalinolide K as potential bioactive constituents, which were further validated to inhibit phosphorylation of key signaling proteins, thereby partially accounting for SLEL’s pharmacological effects. Multi-omics integration further revealed that SLEL restored bile acid metabolism, reshaped gut microbial diversity, and reconstructed the microbiota–metabolite–inflammatory cytokine network, thereby maintaining gut–lung axis homeostasis and enhancing anti-inflammatory effects. Conclusions: SLEL alleviates ALI through multi-component synergistic actions that suppress pro-inflammatory signaling and modulate the gut–lung axis. These findings highlight the potential of SLEL as a promising therapeutic candidate for the treatment of ALI. Full article

Acute respiratory distress syndrome (ARDS) is a life-threatening condition with high mortality. A central driver in its pathogenesis is alveolar epithelial cell (AEC) dysfunction, which leads to disruption of the epithelial barrier, impaired fluid clearance, and dysregulated inflammatory responses. This review summarizes the key mechanisms underlying AEC injury, including programmed cell death (apoptosis, pyroptosis, necroptosis, ferroptosis), oxidative stress, mitochondrial dysfunction, epigenetic reprogramming (DNA methylation, histone modifications), metabolic rewiring (succinate accumulation), and spatiotemporal heterogeneity revealed by single-cell sequencing and spatial transcriptomics. Multicellular crosstalk involving epithelial–immune–endothelial networks and the gut-lung axis further shapes disease progression. Building on these mechanistic foundations, we evaluate emerging AEC-targeted interventions such as pharmacologic agents (antioxidants, anti-inflammatories), biologics (mesenchymal stem cells and engineered exosomes), and gene-based approaches (adeno-associated virus and CRISPR-Cas9 systems delivered via smart nanocarriers). Complementary strategies include microbiome modulation through probiotics, short-chain fatty acids, or fecal microbiota transplantation, and biomarker-guided precision medicine (e.g., sRAGE, exosomal miRNAs) to enable promise individualized regimens. We also discuss translational hurdles, including nanotoxicity, mesenchymal stem cell (MSC) heterogeneity, and gene-editing safety, and highlight future opportunities involving AI-driven multi-omics, lung-on-chip platforms, and epithelium-centered regenerative therapies. By integrating mechanistic insights with innovative therapeutic strategies, this review aims to outline a roadmap toward epithelium-targeted, precision-guided therapies for ARDS. Full article