Search Results (44)

White-nose syndrome (WNS), caused by the psychrophilic fungus Pseudogymnoascus destructans, poses a severe threat to wild bat populations. Caves serve as unique microecosystems. Exploring antagonistic microorganisms and their volatile antifungal compounds within these native environments has emerged as a promising ecological control strategy. In this study, we isolated four antagonistic bacterial strains from bat cave soil that completely inhibit P. destructans. Additionally, we identified benzaldehyde (BzH) and 2,5-dimethylpyrazine (2,5-DMP) as their primary antifungal volatile organic compounds (VOCs). Combined physiological, biochemical, and multi-omics analyses revealed that these two VOCs disrupt the structural integrity of the fungal cell wall and membrane. This disruption triggers abnormal energy metabolism and compensatory ATP accumulation, leading to a significant intracellular burst of reactive oxygen species and the impairment of primary antioxidant defenses. This sustained oxidative stress causes irreversible DNA damage, endoplasmic reticulum stress, and basal metabolic dysfunction. Consequently, this cascade induces apoptosis and significantly downregulates the expression of essential virulence genes. In conclusion, this study systematically elucidates the molecular network through which VOCs released by cave soil microorganisms antagonize P. destructans. These findings provide a theoretical foundation and candidate intervention molecules for the contactless biocontrol of WNS. Full article

Introduction: Teprotumumab (Tepezza^®), an insulin-like growth factor-1 receptor (IGF-1R) antagonist, is the first FDA-approved targeted therapy for thyroid eye disease (TED). While effective for reducing proptosis and inflammation, increasing post-marketing evidence has linked teprotumumab to auditory adverse events. IGF-1 signaling is essential for cochlear maintenance and neuroprotection; therefore, systemic IGF-1R inhibition presents a biologically plausible mechanism for ototoxicity. Despite growing recognition of these effects, no standardized approach exists for audiologic assessment or monitoring of patients receiving teprotumumab. This review aimed to (1) summarize proposed mechanisms and the reported spectrum of teprotumumab-related auditory effects, (2) evaluate current methods used to assess and monitor these patients, and (3) identify areas of consensus and ongoing uncertainty. Methods: An updated narrative review of the literature was conducting using PubMed, CINAHL, and Google Scholar using Boolean strings targeting teprotumumab exposure and hearing-related outcomes. Studies from 2022 onward were identified using Boolean search strings targeting teprotumumab exposure and hearing-related outcomes. Peer-reviewed English language studies reporting audiometric findings were eligible for inclusion. Results: Ten studies met inclusion criteria. Reported effects most commonly included bilateral high-frequency SNHL, tinnitus, and aural fullness, typically emerging after three to six infusions. Many cases demonstrated persistent deficits despite drug discontinuation. Baseline audiometric assessment was not uniformly reported across studies, and monitoring protocols varied considerably, with inconsistent incorporation of speech testing and immittance measures. Conclusions: Teprotumumab-associated ototoxicity is increasingly recognized and potentially irreversible. Current evidence is insufficient to guide standardized monitoring. Prospective studies are urgently needed to establish evidence-based audiologic surveillance protocols. Full article

In emphysema, the alveolar septal structure is progressively destroyed, which is believed to be irreversible. However, as it has recently been linked to vascular endothelial growth factor (VEGF) deficiency, we hypothesized that VEGF stimulation can promote lung cell proliferation/migration to reverse emphysema. Our sulfated caffeic acid dehydropolymer, CDSO3, was thus examined in vitro and in vivo, given its VEGF-stimulating activity via ferrous ion (Fe²⁺) chelation-mediated stabilization of hypoxia-inducible factor-1α (HIF-1α). In lung epithelial/endothelial cells, CDSO3 promoted proliferation and wound closure by 1.6–3.0-fold at 10 μM; however, these effects were negated by excess FeSO₄ or an HIF-1α inhibitor, indicating an Fe²⁺- and HIF-1α-dependent mechanism. In rat models of established emphysema induced by cigarette smoke extract or the VEGF receptor antagonist SU5416, two-week lung administration of CDSO3 at 60 μg/kg from day 21 enabled: 68–79% recovery of exercise endurance and airspace enlargement/destruction; a 1.8-fold increase in proliferating cell nuclear antigen above healthy levels; normalization of cleaved caspase-3; restoration of HIF-1α; and a 1.3-fold increase in VEGF above healthy levels. In contrast, CDSO3 pre-chelated with Fe²⁺ was ineffective. In conclusion, Fe²⁺ chelation-mediated HIF-1α stabilization and VEGF stimulation via local lung delivery of CDSO3 can reverse established emphysema by promoting cell growth and survival. Full article

Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss worldwide and is driven by complex pathophysiological processes, including oxidative stress, chronic inflammation, complement dysregulation, and vascular endothelial growth factor (VEGF)-mediated neovascularization. Nutritional interventions—particularly supplementation with carotenoids, omega-3 fatty acids, polyphenols, and essential micronutrients—have demonstrated clinical benefits in slowing disease progression, as evidenced by landmark trials such as AREDS and AREDS2. However, many AMD-relevant bioactives exhibit poor aqueous solubility, low chemical stability, and limited gastrointestinal bioavailability, which significantly constrain their therapeutic efficacy. Food-grade microgels have emerged as versatile colloidal delivery platforms capable of addressing these limitations through rational structural and physicochemical design. This review provides a systematic roadmap for developing food-grade microgels, organized into: (1) the molecular design of protein- and polysaccharide-based networks; (2) advanced fabrication strategies such as microfluidics and atomization; (3) spatiotemporal release programming within the gastrointestinal tract; and (4) multi-nutrient synergy for retinal protection. This approach highlights how controlled crosslinking, interfacial assembly, and tunable network architectures enhance nutrient stabilization. Particular emphasis is placed on spatiotemporal release programming within the gastrointestinal tract, including diffusion-limited gastric retention, pH- and bile-responsive swelling in the small intestine, and microbiota-triggered degradation in the colon. These mechanisms collectively enable region-specific release, improved micellar incorporation, enhanced systemic absorption, and more consistent retinal delivery. Furthermore, we discuss co-encapsulation strategies that accommodate both hydrophilic and lipophilic bioactives, thereby minimizing antagonistic interactions and enabling synergistic nutritional modulation of oxidative and inflammatory pathways implicated in AMD. A central novelty of this review is the integration of the gut–eye axis, framing microgel-based oral delivery as a systemic pathway to modulate retinal health via the intestinal environment. By bridging retinal disease biology with food colloid science, this review proposes food-grade microgels as a translational platform for next-generation nutraceutical interventions. The integration of programmable release behavior with clinically validated nutrient regimens offers a promising pathway toward more effective and mechanistically informed dietary management of AMD. Full article

Stone fruits, mainly represented by Prunus species, are economically important crops whose yield potential and final quality are largely determined during early fruit development. This early phase, encompassing pollination, fertilization, fruit set, cell division, and pit hardening, involves irreversible developmental decisions that govern fruit survival, size, and productivity. In this review, recent advances in endogenous hormonal regulation during early stone fruit development are synthesized, with emphasis on auxin, gibberellin (GA), cytokinin (CTK), and abscisic acid (ABA). Auxin and GA act as core growth-promoting signals that synergistically initiate fruit set, stimulate cell division and expansion, and support parthenocarpy development, while CTK reinforces early cell proliferation and contributes to final fruit size. In contrast, ABA primarily functions as a growth-inhibitory regulator, integrating developmental and environmental cues to promote fruit growth arrest and abscission under unfavorable conditions. These hormones interact through dynamic synergistic and antagonistic networks that are continuously reprogrammed across developmental stages and tissues. This review provides a regulatory framework for understanding hormone-mediated early fruit development in stone fruits and offers guidance for orchard management and future molecular breeding to stabilize fruit set and improve yield and quality. Full article

Excessive oxidative stress can cause irreversible cytotoxic damage to both healthy and cancer cells through the induction of reactive oxygen species (ROS) mediated lipid peroxidation. Ferroptosis has recently been shown to promote lipid peroxidation due to the over-accumulation of iron. Although cancer cells possess elevated antioxidant capacity to neutralize chemotherapy-induced oxidative stress, the co-delivery of polyphenol compounds such as curcumin (CUR) can overwhelm these defenses by elevating intracellular ROS levels to a toxic threshold, thereby increasing anticancer efficacy. In this study, we evaluated the potential of CUR to chemosensitize doxorubicin (DOX) towards the DOX-resistant lung cell line (H69AR). Our results demonstrated that the combination of DOX and CUR resulted in a concentration-dependent behavior, where low-dose concentrations exhibited antagonistic effects, while high-dose IC₅₀-equivalent concentrations shifted towards synergism. The combination induced significantly greater mitochondrial dysfunction, ATP depletion, cytochrome C release, and caspase-3 activation. This also resulted in excessive ROS generation, intracellular iron overload, and lipid peroxidation, accompanied by a reduction in antioxidant enzymatic activities. Pretreatment with N-acetyl-L-cysteine (ROS inhibitor) and ferrostatin-1 (ferroptosis inhibitor) further supported the involvement of oxidative stress and ferroptosis in modulating apoptosis and DNA fragmentation. Molecular docking analyses supported the binding of CUR and DOX to key ferroptosis regulators. This study shows the potential of CUR to sensitize DOX-resistant cancer cells through ferroptosis-linked-oxidative stress targeting. Full article

Alzheimer’s disease (AD) is an irreversible neurodegenerative disease of the central nervous system, responsible for 60–80% of dementia. Its pathogenesis is mainly based on the accumulation of beta-amyloid and tau proteins. Current pharmacological treatment includes acetylcholinesterase inhibitors, NMDA receptor antagonists, and monoclonal antibodies. However, their effect is limited by the blood–brain barrier (BBB). A new and promising way for different drugs to cross the BBB is the use of nanoparticles such as liposomes, micelles, solid lipid nanocarriers, polymeric nanoparticles, dendrimers, nanoemulsions, and inorganic nanoparticles as their carriers. Additionally, some nanoparticles present anti-inflammatory or neuroprotective effects. Some of them can also be used to treat cerebral amyloid angiopathy (CAA) by aiming at amyloid deposits in brain arterioles. All the properties of nanoparticles listed and discussed in the article allow us to hope that there will be more effective treatment in the future, which is extremely important as the number of patients with AD is still growing. Full article

Cancer therapy-related cardiac dysfunction (CTRCD) has emerged as a significant concern with the rise of effective cancer treatments like anthracyclines and targeted therapies such as trastuzumab. While these therapies have improved cancer survival rates, their unintended cardiovascular side effects can lead to heart failure, cardiomyopathy, and arrhythmias. The pathophysiology of CTRCD involves oxidative stress, mitochondrial dysfunction, and calcium dysregulation, resulting in irreversible damage to cardiomyocytes. Inflammatory cytokines, disrupted growth factor signaling, and coronary atherosclerosis further contribute to this dysfunction. Advances in cardio-oncology have led to the early detection of CTRCD using cardiac biomarkers like troponins and imaging techniques such as echocardiography and cardiac magnetic resonance (CMR). These tools help identify asymptomatic patients at risk of cardiac events before the onset of clinical symptoms. Preventive strategies, including the use of cardioprotective agents like beta-blockers, angiotensin-converting enzyme inhibitors, mineralocorticoid receptor antagonists, and sodium-glucose cotransporter-2 inhibitors have shown promise in reducing the incidence of CTRCD. This review summarizes the mechanisms, detection methods, and emerging treatments for CTRCD, emphasizing the importance of interdisciplinary collaboration between oncologists and cardiologists to optimize care and improve both cancer and cardiovascular outcomes. Full article

Alzheimer’s Disease (AD) is an irreversible, progressive syndrome characterized by neurocognitive impairment. Two neuropathological features seen in AD are extracellular amyloid plaques consisting of amyloid beta1-40 and 1-42, and intracellular neurofibrillary tangles (NFTs). For decades, neuroscience research has heavily focused on seeking to understand the primary mechanism of AD and searching for pharmacological approaches for the treatment of dementia. Three monoclonal antibodies that act against amyloid beta—aducanumab, lecanemab, and donanemab—have been approved by the Food and Drug Administration (FDA) for the treatment of mild cognitive impairment and mild AD, in addition to medications for cognitive symptom management such as acetylcholinesterase inhibitors and the N-methyl-D-aspartate (NMDA) antagonist. Further trials should focus on the combination of therapies targeting amyloid plaques and tau pathology. Full article

Fibrosis is a major medical challenge, as it leads to irreversible tissue remodeling and organ dysfunction. Its progression contributes significantly to morbidity and mortality worldwide, with limited therapeutic options available. Extensive research on the molecular mechanisms of fibrosis has revealed numerous factors and signaling pathways involved. However, the interactions between these pathways remain unclear. A comprehensive understanding of the entire signaling network that drives fibrosis is still missing. The TGF-β and Notch signaling pathways play a key role in fibrogenesis, and this review focuses on their functional interplay and molecular mechanisms. Studies have shown synergy between TGF-β and Notch cascades in fibrosis, but antagonistic interactions can also occur, especially in cardiac fibrosis. The molecular mechanisms of these interactions vary depending on the cell context. Understanding these complex and context-dependent interactions is crucial for developing effective strategies for treating fibrosis. Full article

Fibrosing interstitial lung diseases (ILDs) are characterized by the gradual and irreversible accumulation of scar tissue in the lung parenchyma. The role of the immune response in the pathogenesis of pulmonary fibrosis remains unclear. In recent years, substantial advancements have been made in our comprehension of the pathobiology driving fibrosing ILDs, particularly concerning various age-related cellular disturbances and immune mechanisms believed to contribute to an inadequate response to stress and increased susceptibility to lung fibrosis. Emerging studies emphasize cellular senescence as a key mechanism implicated in the pathobiology of age-related diseases, including pulmonary fibrosis. Cellular senescence, marked by antagonistic pleiotropy, and the complex interplay with immunity, are pivotal in comprehending many aspects of lung fibrosis. Here, we review progress in novel concepts in cellular senescence, its association with the dysregulation of the immune response, and the evidence underlining its detrimental role in fibrosing ILDs. Full article

Chronic kidney disease (CKD) is a slowly progressive condition characterized by decreased kidney function, tubular injury, oxidative stress, and inflammation. CKD is a leading global health burden that is asymptomatic in early stages but can ultimately cause kidney failure. Its etiology is complex and involves dysregulated signaling pathways that lead to fibrosis. Transforming growth factor (TGF)-β is a central mediator in promoting transdifferentiation of polarized renal tubular epithelial cells into mesenchymal cells, resulting in irreversible kidney injury. While current therapies are limited, the search for more effective diagnostic and treatment modalities is intensive. Although biopsy with histology is the most accurate method of diagnosis and staging, imaging techniques such as diffusion-weighted magnetic resonance imaging and shear wave elastography ultrasound are less invasive ways to stage fibrosis. Current therapies such as renin-angiotensin blockers, mineralocorticoid receptor antagonists, and sodium/glucose cotransporter 2 inhibitors aim to delay progression. Newer antifibrotic agents that suppress the downstream inflammatory mediators involved in the fibrotic process are in clinical trials, and potential therapeutic targets that interfere with TGF-β signaling are being explored. Small interfering RNAs and stem cell-based therapeutics are also being evaluated. Further research and clinical studies are necessary in order to avoid dialysis and kidney transplantation. Full article

Dacomitinib is an irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor indicated for the treatment of patients with advanced non-small-cell lung cancer (NSCLC) and EGFR-activating mutations. Proton-pump inhibitors decreased dacomitinib exposure. This analysis summarizes the effect of Histamine-2 receptor antagonists (H2RAs) on dacomitinib exposure. A within-patient comparison of the steady-state trough concentrations (C_trough,ss) of dacomitinib and its active metabolite and active moiety with and without concomitant use of H2RAs was conducted using a linear mixed effects model with pooled data from 11 clinical studies in patients with NSCLC. An oral absorption physiologically based pharmacokinetic (PBPK) model was constructed and verified using clinical pharmacokinetic (PK) data after a single dose of dacomitinib in healthy volunteers to estimate the effect of gastric pH altered by an H2RA on dacomitinib’s PKs. The adjusted geometric mean of the dacomitinib C_trough,ss of the dacomitinib parent, metabolite and active moiety following co-administration with an H2RA was approximately 86%, 104% and 100% relative to that following dacomitinib 45 mg administration without an H2RA (p > 0.05). The PBPK modeling showed negligible change in dacomitinib maximum concentration (C_max) and area under the drug concentration–time curve (AUC) over 0–24 h after H2RA administration when compared with those administered dacomitinib alone. Co-administration of an H2RA with dacomitinib is not expected to have any clinically relevant effect on dacomitinib exposure. Full article

Proton-pump inhibitors, PPIs, are widely prescribed and are available over the counter for prolonged reduction of stomach acid production and related disorders. PPIs irreversibly inhibit the hydrogen/potassium ATPase in gastric parietal cells. Recent retrospective studies have described an association between PPI use and depression. However, there is conflicting evidence that PPI therapy improves depressive symptoms. Considering the widespread use and over-the-counter availability of these drugs, further investigation into depression adverse event was warranted with a larger-scale postmarketing set of reports. Here we analyzed over 125,923 reports from the FDA Adverse Event Reporting System consisting of PPI and histamine-2 receptor antagonist monotherapy records and found a statistically significant association between use of PPIs and depression. Additionally, we analyzed each of the six currently marketed PPIs individually and observed the association with the depression adverse reaction for all of them. Full article

Background: Chronic kidney disease (CKD) is a multifactorial, world public health problem that often develops as a consequence of acute kidney injury (AKI) and inflammation. Strategies are constantly sought to avoid and mitigate the irreversibility of this disease. One of these strategies is to decrease the inflammation features of AKI and, consequently, the transition to CKD. Methods: C57Bl6J mice were anesthetized, and surgery was performed to induce unilateral ischemia/reperfusion as a model of AKI to CKD transition. For acute studies, the animals received the Kinin B1 receptor (B1R) antagonist before the surgery, and for the chronic model, the animals received one additional dose after the surgery. In addition, B1R genetically deficient mice were also challenged with ischemia/reperfusion. Results: The absence and antagonism of B1R improved the kidney function following AKI and prevented CKD transition, as evidenced by the preserved renal function and prevention of fibrosis. The protective effect of B1R antagonism or deficiency was associated with increased levels of macrophage type 2 markers in the kidney. Conclusions: The B1R is pivotal to the evolution of AKI to CKD, and its antagonism shows potential as a therapeutic tool in the prevention of CKD following AKI. Full article