Search Results (121)

Background: Cervical cancer is primarily caused by the human papillomavirus (HPV), with persistent infections progressing to low- (LGSIL) and high-grade (HGSIL) lesions. Emerging evidence indicates that the cervicovaginal microbiota influences HPV persistence and disease progression, although the underlying metabolic mechanisms remain unclear. Therefore, we assessed the relationship between the cervicovaginal microbiota and the metabolic milieu in women with cervical dysplasia and HPV infections. Methods: We recruited 36 non-menopausal, non-pregnant women who were classified as negative, LGSIL, or HGSIL based on pathology and HPV results. Cervical swabs were collected for genomic DNA extraction to characterize bacterial communities using 16S rRNA sequencing and to perform HPV genotyping. Cervical lavages were collected for untargeted metabolomic profiling using Gas Chromatography-Mass Spectrometry. Integrative multiomic analysis was performed using the MIMOSA2 pipeline. Results: Although bacterial community structure was not different between groups, women with HGSIL had higher richness and exhibited a higher abundance of Prevotella bivia, Prevotella buccalis, and Lachnospiraceae G-9 oral taxon 924. Lesion-positive samples had shifts in tyramine and putrescine, biogenic amines linked to cancer development. Specifically, Pseudomonas was identified as a potential contributor to tyramine oxidation. Conclusions: Cervical lesions and HPV risk are associated with shifts in the cervicovaginal microbial metabolic milieu, highlighting the role of low-abundant anaerobic bacteria. Despite the small sample size, biogenic amines were associated with anaerobic taxa and microbial dysbiosis. These findings warrant further assessment of microbial-derived metabolites and their potential to promote tumor progression by driving a pro-inflammatory, metabolically altered microenvironment. Full article

This research analyzed metabolomic and proteomic differences between participants with gingivitis (>20 bleeding sites) and generally healthy participants (≤3 bleeding sites) at baseline and 4 weeks post stannous fluoride (SnF₂) dentifrice treatment. Sixty-two metabolites were different (p < 0.05) between groups at baseline. Forty cytokines were analyzed using immunoassays and a group of proinflammatory cytokines (IL-1α, IL-1β, TNF-α, SAA, ICAM-1, VCAM-1) was elevated in participants with gingivitis (p < 0.1) versus healthy gingiva at baseline, with C-reactive protein (p < 0.05) being significantly elevated. Proteomic analysis carried out in baseline oral lavage revealed four of the top hits (p < 0.0004) were central-metabolism-related: aldolase A, triosephosphate isomerase, lactate dehydrogenase, and malate dehydrogenase. Enzymatic assays confirmed the proteomic finding that malate dehydrogenase and triosephosphate isomerase activities were elevated in gingivitis samples; SnF₂ dentifrice treatment reduced their activity. Collectively, 20 proteins with the lowest p-values in oral lavage appeared to be indicative of periodontal health, potentially forming the basis to cluster samples into healthy and unhealthy groups. A TLR-ATP biosensor model was established and demonstrated that microbial virulence factors induced the observed changes in oral lavage. Combined findings suggest gingivitis involves upregulation of host cell bioenergetic processes involving enzymatic activity in the glycolysis and citric acid cycle pathways. Full article

Background: Cytokine storm-like inflammation includes an imbalanced immune response, where excessive interleukin-6 (IL-6) and inadequate IL-10 play a central role in increasing tissue injury. Melaleuca cajuputi leaves are known to contain anti-inflammatory bioactive compounds. However, the potential to modulate the dysregulated cytokine response remains underexplored. Objective: This study aimed to evaluate the immunomodulatory effects of Melaleuca cajuputi subsp. cajuputi Powell Ethanolic Leaf Extract (MC-ELE) on IL-6, IL-6R, and IL-10 levels in a BALB/c mouse model of lung inflammation induced by lipopolysaccharide (LPS). Methods: Phytochemical screening was performed to identify active constituents in MC-ELE. Male BALB/c mice were intratracheally challenged with LPS (mg·kg⁻¹ BW) to induce cytokine storm-like inflammation. After 24 h, mice received oral MC-ELE at doses of 750, 1500, 3000 mg·kg⁻¹ BW, or dexamethasone (10 mg·kg⁻¹ BW), for seven consecutive days. On day eight, serum and bronchoalveolar lavage fluid (BALF) were collected for IL-6, IL-6R, and IL-10 assessment using ELISA. Furthermore, body weight changes and clinical symptoms were monitored throughout the study. Results: MC-ELE was confirmed to contain anti-inflammatory compounds. Across all groups, IL-6 concentrations in BALF were consistently higher than in serum, with the LPS-only group showing the greatest elevation. Serum IL-6R levels exceeded BALF IL-6R levels in most groups, except at 1500 mg·kg⁻¹ BW MC-ELE dose. BALF IL-10 was higher compared with serum in all MC-ELE-treated groups. Therefore, MC-ELE might preferentially enhance anti-inflammatory responses within the pulmonary microenvironment. There was no observed toxicity or weight loss at doses up to 3000 mg·kg⁻¹ BW. Conclusions: MC-ELE reported promising immunomodulatory activity by lowering IL-6 and IL-6R levels while enhancing IL-10 responses in lung inflammation induced by LPS within lung tissue. These results suggested its potential as a natural therapeutic candidate for managing severe inflammatory conditions. Full article

Background: Proton pump inhibitors (PPIs) have been associated with lung dysbiosis and increased respiratory risk. Micro-aspiration is a proposed mechanism, but reliable biomarkers remain elusive. This study evaluates the potential of fluorescein as a biomarker of micro-aspiration and PPI-associated pulmonary risk. Methods: We conducted a retrospective analysis of 137 bronchial washing fluid samples from patients with pulmonary conditions to assess microbial colonization in relation to PPI use. Bacterial burden was determined by culture and PCR and categorized as 0, 1 or ≥2 pathogens. Micro-aspiration was evaluated by quantifying fluorescein-laden macrophages in bronchoalveolar lavage following oral fluorescein administration. Associations between PPI use, fluorescein levels and pathogen burden were analyzed using adjusted ordinal regression models. Results: PPI use was associated with higher odds of increased pathogen burden, though not statistically significant (OR = 1.40, 95% CI: 0.71–2.75, p = 0.33). Fluorescein-laden macrophages were higher in PPI users (41.5 versus 31.2 ng/mL), but showed no meaningful correlation with pathogen load (p = 0.09). Corticosteroid therapy was significantly associated with Gram stain results (OR = 2.37, 95% CI: 1.12–5.15, p = 0.03). Conclusions: These findings suggest a potential link between PPI use and airway colonization. Fluorescein shows promise as a biomarker for micro-aspiration, but its clinical utility requires further validation. Full article

Particulate matter (PM) is a complex mixture of airborne solid particles and liquid droplets originating from various environmental sources, and it has been implicated in the initiation, development, and progression of pulmonary inflammation and respiratory diseases. However, the underlying associated molecular mechanisms remain unclear. Adenophora divaricate Franch. & Sav. (AD) is a medicinal herb classified within the Campanulaceae family and genus Adenophora, with a broad geographic distribution across East Asia, including Korea, Asia, and Russia. In this study, we investigated the mechanisms underlying the effects of AD on PM-induced lung inflammation in both PM-stimulated RAW264.7 cells and PM-exposed mice. Considering that the reactive oxygen species (ROS)-mediated thioredoxin-interacting protein (TXNIP) and NOD-like receptor pyrin domain containing (NLRP3) inflammasome pathway plays a role in PM-induced inflammatory responses, we focused on determining whether AD exerts its anti-inflammatory effects through modulation of this signaling pathway. The anti-inflammatory properties of the methanolic extract of AD were evaluated using PM-stimulated RAW264.7 cells and PM-exposed mice. PM was administered intranasally to mice for 7 days, whereas AD or dexamethasone was orally administered for the same duration. AD treatment significantly attenuated pulmonary inflammation, as evidenced by reduced inflammatory cell counts and decreased cytokine levels in bronchoalveolar lavage fluid. In addition, AD decreased oxidative stress marker (ROS and thiobarbituric acid reactive substances) while increasing glutathione content, leading to suppression of TXNIP/NLRP3 inflammasome expression. Histopathological analysis revealed a marked alleviation of inflammatory responses in lung tissue, characterized by diminished inflammatory cell infiltration and reduced alveolar wall thickening. Collectively, these findings suggest ROS-mediated TXNIP serves as a key regulatory factor, and AD may serve as a potential therapeutic agent for pulmonary inflammation. Full article

Background and Clinical Significance: Polycythemia vera (PV) is a myeloproliferative neoplasm associated with a markedly increased risk of arterial and venous thrombosis. Superior mesenteric artery (SMA) thrombosis is an exceptionally rare but potentially fatal complication. Case Presentation: We report the case of a 25-year-old man with previously diagnosed, JAK2-negative PV who presented with acute abdominal pain, nausea, vomiting, abdominal distension, and absence of stool and flatus, consistent with clinical features of intestinal obstruction. Laboratory testing revealed marked leukocytosis, elevated inflammatory markers, and subtherapeutic anticoagulation (INR 1.2) despite ongoing oral therapy. Multislice computed tomography demonstrated occlusion of the SMA with developed collateral circulation and features of small-bowel ischemia. Due to progression to an acute abdomen, emergency laparotomy was performed, revealing jejunal perforation with preserved viability of the remaining bowel. Primary closure was carried out, followed by peritoneal lavage and drainage. The postoperative course was uneventful. After correction of anticoagulation and therapeutic INR monitoring, no recurrent thrombotic events were observed during follow-up. Conclusions: This case underscores the importance of strict anticoagulation control, early imaging, and prompt surgical intervention in patients with PV, even in young individuals and in atypical vascular territories. Full article

Objectives: The present study evaluated the efficacy of a preparation based on bacterial lysates of Streptococcus oralis, Aggregatibacter actinomycetemcomitans and Fusobacterium nucleatum in the treatment of experimental periodontitis in rats, compared to metronidazole. Methods: Twenty female Wistar rats were used, divided into three groups: control, bacterial lysates and metronidazole, administered for 10 days by oral lavage/gavage. Periodontitis was induced by ligatures contaminated with bacterial suspensions (10⁹ CFU/mL) for 4 weeks. Lysates were obtained by culturing bacterial strains, centrifugation, washing, heat inactivation, ultrasonication and filtration. The evaluations included biocompatibility on HGF-1 fibroblasts, microbiological stability, clinical parameters, hematological, biochemical and histopathological analyses. Results: The lysates demonstrated the absence of cytotoxicity (cell viability 90–100%) and significant antimicrobial effect at the optimal concentration (2 × 10⁹ CFU/mL equivalent). Both treatments significantly reduced periodontal inflammation, with no statistical differences between them. Systemic immunoinflammatory indices (SII, SIRI, AISI) increased comparably, demonstrating controlled immune mobilization, and ALT was maintained within physiological limits. Histopathological examination revealed a reduction in inflammatory infiltrate, connective tissue reorganization and bone regeneration in both treated groups. Conclusions: Bacterial lysates represent a viable therapeutic alternative with comparable efficacy to metronidazole, favorable safety profile and immunomodulatory potential in the treatment of periodontitis. Full article

Acute lung injury (ALI) is a severe inflammatory condition with high mortality rates, necessitating the development of effective therapeutic agents. Polydeoxyribonucleotide (PDRN), a DNA-derived compound known for its tissue repair and anti-inflammatory properties, has gained attention as a potential therapeutic agent. However, the efficacy of PDRN derived from marine sources, particularly Porphyra sp. (laver), remains unexplored in respiratory inflammation. In this study, we investigated the protective effects of Porphyra sp.-derived PDRN (Ps-PDRN) against LPS-induced ALI in mice through two administration routes: intranasal (IN) and oral (PO). Ps-PDRN treatment significantly attenuated fever, pulmonary edema, and histopathological changes in LPS-challenged mice. Both IN and PO administration of Ps-PDRN markedly reduced proinflammatory cytokines (TNF-α, IL-1β, and IL-6) and chemokines (MCP-1, RANTES, CXCL1, and MIP-2) in bronchoalveolar lavage fluid (BALF) and serum. Comparative analysis of the two administration routes revealed distinct efficacy profiles, with oral administration demonstrating superior chemokine inhibition, while intranasal delivery showed advantages in certain cytokine suppression. Histological examination revealed that Ps-PDRN preserved alveolar architecture and reduced inflammatory cell infiltration. Furthermore, in vitro studies using RAW 264.7 macrophages demonstrated that Ps-PDRN inhibited LPS-induced production of proinflammatory cytokines, such as TNF-α and IL-6, in a dose-dependent manner. These findings suggest that Ps-PDRN exerts potent anti-inflammatory effects against ALI through both local and systemic administration routes, highlighting its potential as a novel therapeutic agent for inflammatory lung diseases. Full article

Inflammation underpins pulmonary disease progression during tobacco smoke exposure, which may culminate in irreversible pulmonary disease. While primary smoke poses a notable risk, nearly half of the US population is also susceptible due to frequent exposure to secondhand smoke (SHS). In the present study, we assessed the potential role of VYN202, a novel small molecular bromodomain and extra-terminal inhibitor, as a possible means of attenuating SHS-mediated inflammation. We exposed wild-type mice to an acute time course of room air (RA), SHS via a nose-only delivery system (Scireq Scientific, Montreal, Canada), or to both SHS and 10 mg/kg VYN202 (efficacious dose from prior inflammatory models) via oral gavage three times a week. Specific smoke exposure delivery to mice involved SHS from two cigarettes over 10 min, equilibration in room air for 10 min, followed by exposure to SHS from one cigarette for an additional 10 min, for a total SHS exposure of 20 min per day, five days a week for 30 days. We evaluated leukocyte abundance and the secretion of inflammatory mediators in bronchoalveolar lavage fluid (BALF). We also assessed general morphology via histology staining and the activation of receptor tyrosine kinase (RTK) family members. While standard hematoxylin and eosin (H&E) staining resulted in unchanged morphology, SHS-mediated increases in BALF protein abundance, total cellularity, and percent PMNs were attenuated with concomitant administration of VYN202. We also discovered SHS-induced activation of RTKs that were pro-inflammatory (JAK1, JAK3, ABL1, and ACK1), as well as RTKs related to endothelial and vascular remodeling (VEGFR3, VEGFR2, EphB4, EphB6, and FAK). Furthermore, inflammatory cytokines including GCSF, IFN-γ, IL-12p70, IL-17A, LIX, and TNF-α were all augmented by SHS exposure. Despite SHS exposure, each of these RTKs and cytokines/chemokines was significantly attenuated by VYN202. In summary, inflammatory responses induced by SHS exposure were mitigated by VYN202. These data reveal fascinating potential for the utility of VYN202 in lessening smoke-induced pulmonary exacerbations. Full article

Current asthma therapies reduce inflammation and symptoms but there are concerns regarding adverse effects and the long-term treatment burden. The anti-asthmatic potential of Dictamnine (Dic) has not been investigated. The therapeutic effect of Dic on airway inflammation and remodeling was investigated by targeting the tumor growth factor (TGF)-β/Smad2/3 pathway. A murine model of ovalbumin (OVA)-induced asthma was used to evaluate the effects of orally-administered Dic on airway hyperresponsiveness, inflammatory cytokines in bronchoalveolar lavage fluid (BALF), OVA-specific IgE in the serum, and histopathological changes. The expression of TGF-β/Smad2/3 and epithelial markers was assessed. Human bronchial epithelial cells were used in vitro to examine the effects of Dic on TGF-β-induced Smad2/3 phosphorylation. Network pharmacology was conducted to predict Dic-associated targets and pathways. Dic substantially reduced the levels of Th2 cytokines, mucin 5AC in BALF, and OVA-specific IgE in the serum. Histology indicated reduced inflammatory cell infiltration, bronchial wall thickening, and peribronchial fibrosis in Dic-treated mice. Dic downregulated TGF-β and p-Smad2/3 expression and upregulated ZO-1 expression in the lung tissue. Dic downregulated TGF-β-induced Smad2/3 phosphorylation in bronchial epithelial cells. Network pharmacology indicated enrichment of Dic-related genes in the TGF-β pathway. Dic exhibited anti-asthmatic effects and is a potential therapeutic candidate. Full article

Airborne particulate matter (PM), particularly PM_2.5, contributes to pulmonary injury by inducing oxidative stress and inflammation. Thyme (Thymus vulgaris L.) contains bioactive compounds with anti-inflammatory, antioxidant, and expectorant properties. Here, we evaluated the dose-dependent protective effects of thyme extract (TV) against PM_2.5-induced pulmonary injury in mice, using dexamethasone (DEXA) as a reference anti-inflammatory drug. Subacute pulmonary injury was induced in male Balb/c mice via intranasal administration of PM_2.5 (1 mg/kg, twice at 48 h intervals). Mice received oral TV (50, 100, or 200 mg/kg) or DEXA (0.75 mg/kg) daily for 10 days. Assessments included lung weight, serum AST/ALT, bronchoalveolar lavage fluid (BALF) leukocyte counts, cytokines (TNF-α, IL-6), chemokines, oxidative stress markers (ROS, lipid peroxidation, antioxidant enzymes), histopathology, and mRNA expression of genes related to inflammation (PI3K/Akt, MAPK, and NF-κB), mucus production (MUC5AC, MUC5B), and apoptosis (Bcl-2, Bax). Exposure to PM_2.5 caused oxidative stress, pulmonary inflammation, mucus hypersecretion, and histopathological changes. TV treatment dose-dependently reduced leukocyte infiltration, cytokine/chemokine release, ROS generation, and mucus overproduction, while enhancing antioxidant defenses and improving tissue pathology. Effects were comparable but slightly less potent than DEXA. Notably, unlike DEXA, TV reduced mucus hyperplasia and enhanced expectorant activity. No hepatotoxicity was observed. These results indicate that thyme extract could serve as a promising natural candidate for alternative respiratory therapeutics or functional food development. Full article

Stress is a predisposing factor for pulmonary diseases; however, its effects on the lungs of healthy individuals have not been fully elucidated. Since bovine lactoferrin (bLf) is a powerful immunomodulator, this study aimed to evaluate whether lactoferrin can modulate the effects of chronic stress on humoral and cellular immunity in the lungs. We performed chronic restraint stress (RS) and oral administration of bLf in a BALB/c model, assessing serum corticosterone, body weight, and various lung immunity parameters, including immunoglobulin concentrations in serum and tracheobronchial lavages (TBLs), secretory IgA (S-IgA) levels in TBLs, IgA-secreting plasma cells, relative expression of pIgR, CD4⁺ lymphocyte Th1 and Th2 populations, and antigen-presenting cell (APC) populations in the lungs. Our results demonstrate that stress increases corticosterone and production of total IgA and IgG, while decreasing levels of IgM and S-IgA, promotes a Th1/Th2 profile imbalance, and decreases APC populations. Interestingly, bLf modulates serum corticosterone levels and stress-induced weight loss, and it also modulates humoral and cellular effects produced by chronic stress. These results demonstrate that bLf should be considered a new therapeutic target for further studies, focusing on prophylactic and co-therapeutic administration to treat and prevent respiratory diseases. Full article

Background: Scedosporium apiospermum is a filamentous fungus increasingly recognized as an opportunistic pathogen in immunocompromised hosts, though rare infections in immunocompetent individuals with structural lung disease have been reported. Its diagnosis and management remain challenging due to non-specific clinical presentation and intrinsic resistance to multiple antifungal agents. Case Presentation: We report the case of a 66-year-old immunocompetent woman with idiopathic bilateral non-cystic fibrosis bronchiectasis, who presented with subacute cough and increased sputum production. Chest high-resolution CT revealed new subsolid and ground-glass infiltrates superimposed on stable bronchiectatic changes. Bronchoalveolar lavage (BAL) cultures isolated S. apiospermum as the sole pathogen. The patient was treated with oral voriconazole (200 mg BID) for 4 weeks, followed by a 4-week course of aerosolized amphotericin B. Clinical and radiological improvement was observed, and no relapse occurred during follow-up. Discussion: This case highlights the potential for S. apiospermum to cause clinically relevant pulmonary infection in structurally abnormal but immunocompetent lungs. Non-CF bronchiectasis may facilitate fungal colonization due to impaired mucociliary clearance and chronic mucus retention. Combined antifungal therapy involving systemic voriconazole and inhaled amphotericin B (though not yet standardized) was employed based on clinical rationale and the available literature, resulting in favorable outcomes. Conclusions:S. apiospermum pulmonary infection, although rare in immunocompetent hosts with bronchiectasis, should be considered in cases of new or persistent infiltrates. Early recognition and individualized antifungal strategies, including the potential role of inhaled agents, may improve clinical outcomes. This case reinforces the importance of multidisciplinary collaboration in the management of complex fungal infections in chronic airway disease. Full article

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide, primarily driven by chronic airway inflammation due to cigarette smoke exposure. Despite its burden, however, current anti-inflammatory therapies offer limited efficacy in preventing disease progression. Plasminogen activator inhibitor-1 (PAI-1), as a key regulator of fibrinolysis, has recently been implicated in structural airway changes and persistent inflammation in patients with COPD. This study aimed to investigate the ability of the PAI-1 inhibitor TM5441 to attenuate airway inflammation and structural lung damage induced by a cigarette smoke extract (CSE) in a mouse model. Mice received intratracheal CSE or vehicle on days 1, 8, and 15, and were sacrificed on day 22. TM5441 (20 mg/kg) was administered orally from days 1 to 22. The CSE significantly increased the mean linear intercept, destructive index, airway resistance, and reductions in dynamic compliance. The CSE also increased the numbers of neutrophils and macrophages in the bronchoalveolar lavage fluid, systemic PAI-1 activity, and neutrophil elastase mRNA and protein expression in the lungs. TM5441 treatment significantly suppressed these changes without affecting coagulation time. These findings suggest that TM5441 may be a novel therapeutic agent for COPD by targeting PAI-1-mediated airway inflammation and emphysema. Full article

Background: The efficacy of EA575 in the treatment of respiratory diseases is described in various clinical studies, improving patients’ disease-related symptoms. However, mechanistic in vivo data proving its beneficial effects are limited. Methods: Focusing on the treatment of acute airway inflammation and accompanying cough, this study aimed to elucidate antitussive and mucoactive properties of EA575, applying two animal models. Animals were treated orally twice daily for 7 days, resulting in 43, 215.2, or 430.5 mg/kg bw/d of EA575. Antitussive effects were investigated within an acute lung inflammation model of bleomycin-treated guinea pigs after citric acid exposure. Hereby, the number of coughs, enhanced pause (penH), and bronchoalveolar lavage fluid (BALF) were investigated. Mucoactivity of EA575 was assessed within a murine model, determining phenol red concentration in BALF. Results: EA575 treatment within the acute lung inflammation model reduced cough events up to 56% while reducing inflammatory cell influx in BALF dose-dependently, e.g., reducing neutrophils in BALF up to 70.9%. This suggests a strong connection between anti-inflammatory and antitussive properties of EA575. Furthermore, penH decreased in a dose-dependent manner, suggesting an ease in respiration. Mucoactivity was shown by a dose-dependent increase in phenol red concentration in BALF up to 38.9%. Notably, EA575/salbutamol co-administration resulted in enhanced phenol red secretion compared to respective single administrations. Conclusions: These data highlight the benefits of EA575 in treating cough-related respiratory diseases, particularly when accompanied by sputum, as EA575 has been shown to obtain mucoactivity. Furthermore, the combinatory effect of EA575/salbutamol treatment provides a foundation for future research in the treatment of chronic respiratory diseases. Full article