Manish Kumar Singh

Background: Cholesteatomatous otitis media (CholeOM) is a non-cancerous growth characterized by severe clinical manifestations, a high risk of complications, and a high rate of recurrence after surgery, but understanding of its pathogenesis is incomplete. This study investigated the relationships of the expression levels of IL-1β (a pro-inflammatory cytokine), NOX4 (an NADPH oxidase), and three antioxidant genes (CAT, HO-1, and SOD2) with the pathogenesis and clinical features of CholeOM. Methods: Clinical and audiological characteristics were evaluated in 60 patients undergoing surgery for CholeOM. The mRNA expression levels of five target genes (IL-1β, NOX4, CAT, HO-1, and SOD2) were determined by quantitative real-time PCR in successfully extracted unpaired surgical cholesteatoma (n = 23) and postauricular skin (n = 32) tissue specimens. Results: Otorrhea was present in 58.3% of patients, bacterial cultures were positive in 16.7% of patients, and conductive hearing loss (63.3%) was more common than sensorineural hearing loss (35.0%) and normal hearing (1.7%). Comparison of gene expression in cholesteatoma and postauricular skin indicated the cholesteatoma had significantly greater expression of IL-1β (p = 0.024) and significantly less expression of SOD2 (p < 0.001), but there were no differences in the expression of NOX4, CAT, and HO-1 (all p > 0.05). The expression of these five genes in cholesteatoma was unrelated to sex, history of revision surgery, presence of otorrhea, or type of hearing loss (all p > 0.05). Conclusions: Comparison of gene expression indicated cholesteatoma had significantly increased expression of IL-1β and decreased expression of SOD2 compared to postauricular skin. These changes highlight distinct inflammatory and oxidative stress profiles in cholesteatoma tissue, though causal links to the initial pathogenesis of CholeOM require further investigation using normal middle-ear mucosa controls.

Cancer remains one of the leading causes of mortality worldwide, accounting for approximately 20% of all deaths and posing a major threat to global health. Mechanistically, tumorigenesis is driven by complex molecular and cellular mechanisms that enable malignant cells to evade current therapeutic interventions, thereby limiting treatment efficacy and contributing to disease progression. Despite extensive efforts to identify and target key molecular regulators and signaling pathways involved in cancer development, effective and durable treatments remain limited for many cancers, underscoring the need for novel treatment strategies. Consequently, diverse therapeutic strategies are being developed to overcome barriers to treatment response, improve clinical outcomes, and extend patient survival. Among emerging therapeutic targets, HSPs have attracted considerable attention because of their critical roles in maintaining proteostasis, promoting tumor cell survival, and facilitating resistance to therapy. In addition to stress adaptation, oxidative stress and hypoxia are key components of the tumor microenvironment that promote malignant progression through extensive crosstalk with oncogenic signaling pathways. Growing evidence indicates that these pathways are highly interconnected and collectively contribute to cancer metastasis and poor clinical outcomes. In this review, we explore the mechanistic interplay among HSPs, reactive oxygen species (ROS), and hypoxia across various cancers, highlight their potential as integrated therapeutic targets, and explore future strategies to develop more effective anticancer interventions.

Oral Squamous Cell Carcinoma (OSCC) is often diagnosed at advanced stages despite the oral cavity’s anatomical accessibility, highlighting the need for molecular adjuncts that can identify disease-associated changes before overt morphological progression. This review evaluates the biological roles and salivary diagnostic potential of microRNA-21 (miR-21) and miR-31, two miRNAs repeatedly associated with OSCC pathogenesis and progression. We examine current clinical evidence supporting their use as salivary biomarkers and discuss major sources of methodological variability, including differences in saliva collection, RNA recovery, normalization, and diagnostic thresholds. We pay particular attention to the transition from laboratory-based RT-qPCR to Recombinase Polymerase Amplification (RPA) for decentralized detection. Although RPA offers rapid, low-temperature amplification with reduced hardware requirements, mature miRNAs present a key technical challenge because their short length requires prior target extension or conversion. Successful chairside translation will depend on standardized sample processing, robust target-specific amplification, contamination control, and validation in clinically relevant early-stage and comparator populations.

Studies of allergic rhinitis (AR) have increasingly recognized that reactive oxygen species (ROS) are not simply byproducts of oxidative metabolism but function as modulators of the type 2 inflammatory network during the pathogenesis of this disease. This narrative review summarizes the role of ROS in the pathophysiology of AR by analyzing studies that examined markers of systemic oxidative stress, dysfunction of the epithelial barrier, ROS derived from immune cells, mitochondrial redox signaling, and inflammasome-related pathways. Our structured search of the literature reviewed five major databases (PubMed, Scopus, EMBASE, Cochrane Library, and Google Scholar) and identified 17 eligible studies published between 2000 and 2026. Clinical studies suggest that patients with AR exhibit altered systemic redox homeostasis, including thiol–disulfide imbalance and increased lipid peroxidation. However, these findings are primarily from measurements of markers in peripheral blood, not nasal mucosa. Experimental studies consistently demonstrated that allergen exposure increased the levels of ROS in nasal epithelial and immune cells, disrupted the epithelial barrier, downregulated tight junction proteins, and activated inflammatory signaling pathways. Although direct nasal tissue data remain limited, evidence extrapolated from peripheral blood and bronchial challenge models suggests that eosinophils and neutrophils contribute to the generation of ROS during the late phase of the allergic response, thereby potentially amplifying and sustaining airway inflammation. There is also evidence that mitochondrial ROS and DUOX-dependent signaling contribute to epithelial dysfunction, including the release of damage-associated molecular patterns and activation of inflammasome pathways. In parallel, antioxidant defense mechanisms, such as the KEAP1/NRF2 axis and mitophagy-related pathways, appear to modulate disease severity by maintaining redox homeostasis. Experimental strategies such as ROS scavengers and oxidative stress-responsive drug delivery systems have shown early proof-of-concept potential in preclinical and pilot studies, but rigorous and large-scale clinical support is strictly required before any clinical application can be considered. Overall, current evidence indicates that ROS function in AR as context-dependent redox mediators rather than as primary causes. The biological effects of ROS appear to depend on site of synthesis, subcellular localization, and the balance between oxidant generation and antioxidant defenses. Further studies that directly assess the dynamics of nasal mucosal ROS and well-designed clinical trials are needed to clarify the translational relevance of these studies and the therapeutic potential of different treatments for AR.

For over three decades, Proton Pump Inhibitors (PPIs) have served as the established primary therapy for acid-suppressive therapy; however, their clinical utility is frequently compromised by their slow onset of action, meal-time dependency, and metabolic variability driven by CYP2C19 polymorphisms. Potassium-competitive acid blockers (P-CABs) represent a definitive pharmacological shift, offering rapid, reversible, and genotype-independent inhibition of the H⁺/K⁺-ATPase. This review outlines the emergence of South Korea as a global epicenter for P-CAB innovation, predicated upon a strategic partnership between a high domestic burden of Helicobacter pylori infection and a rising incidence of refractory gastroesophageal reflux disease (GERD). We analyze the clinical and structural developments of indigenous Korean agents, specifically tegoprazan and fexuprazan, the latter of which features an optimized 9-h elimination half-life engineered to mitigate nocturnal acid breakthrough. A critical evaluation of recent clinical evidence is provided, including the most recent 2024 prospective Phase III data, which demonstrate that 14-day P-CAB-based triple therapy achieves significantly improved eradication rates in high-clarithromycin-resistance environments. Furthermore, we explore the emerging 2025 trend toward personalized, on-demand maintenance therapy and address critical long-term safety considerations, including the duration-dependent risk of metachronous gastric cancer identified in recent multicenter longitudinal studies. Ultimately, the South Korean clinical framework is providing the foundational evidence for a global transition toward P-CAB-centered treatment algorithms, redefining the standards of care in modern gastroenterology.

Excessive adipose tissue expansion contributes to metabolic dysfunction, highlighting the need to identify compounds that restrain adipocyte differentiation without causing nonspecific cytotoxicity. This study investigated whether 2-O-methylhonokiol suppresses adipogenesis in 3T3-L1 preadipocytes and examined its effects on adipogenic transcription, metabolic signaling, ER stress-related responses, kinase activity, and early cell cycle progression. 3T3-L1 cells were induced to differentiate with an MDI cocktail and treated with 25 or 50 µM 2-O-methylhonokiol during differentiation. Lipid accumulation was evaluated by Oil Red O staining, protein expression and phosphorylation were analyzed by immunoblotting, cell cycle distribution was assessed 24 h after MDI induction, and basal viability was measured using the CCK-8 assay. 2-O-methylhonokiol markedly reduced neutral lipid accumulation and suppressed key adipogenic regulators and maturation markers, including C/EBPβ, PPARγ, C/EBPα, FABP4, and FASN. At the signaling level, 2-O-methylhonokiol increased AMPKα phosphorylation without altering total AMPKα and reduced FASN expression, whereas mTOR phosphorylation was reduced at 50 µM. These findings suggest that 2-O-methylhonokiol is associated with metabolic and lipogenic signaling remodeling during adipocyte differentiation. 2-O-methylhonokiol also modified kinase-associated responses, increasing AKT and JNK phosphorylation while reducing the detectable phosphorylated ERK signal, with total AKT, ERK, and JNK remaining largely unchanged. ER stress-related signaling displayed a selective profile, characterized by increased IRE1α expression, XBP1s induction, elevated p-eIF2α, unchanged total eIF2α, and no compensatory increase in GRP78. During early adipogenesis, 2-O-methylhonokiol attenuated MDI-induced cell cycle redistribution by preserving a larger G0/G1 population and limiting progression toward later cell cycle phases, consistent with impaired mitotic clonal expansion. These effects occurred at concentrations that did not significantly reduce basal cell viability. Overall, 2-O-methylhonokiol suppresses 3T3-L1 adipogenesis by reducing adipogenic and lipogenic execution, accompanied by AMPK-associated metabolic remodeling, kinase signaling changes, selective ER stress-related responses, and restriction of early cell cycle progression. Further pathway-specific studies are required to define the causal contribution of each signaling axis.

Chronic rhinosinusitis (CRS) is an inflammatory disease of the sinonasal mucosa whose pathogenesis is characterized by complex interactions of immunological and environmental factors. The maintenance of normal sinonasal function requires a balance of sinus ostial patency, mucociliary clearance, and mucus secretion, and disruption of this balance can lead to CRS. Although many studies have examined the pathophysiology of CRS, the role of reactive oxygen species (ROS) remains incompletely understood. In this review, we analyzed 22 studies of CRS that examined the effects of ROS on epithelial barrier function, local immune responses, and tissue remodeling. The results from in vitro studies, animal models, and human tissue analyses suggest that ROS are not merely by-products of inflammation, but appear to function as key mediators in the pathophysiology of CRS, particularly in the formation and persistence of the CRS phenotype with nasal polyps (CRSwNP). In particular, CRSwNP is characterized by increased activity of enzymes in the dual oxidase (DUOX) and NADPH oxidase (NOX) families, mitochondrial dysfunction, and decreased activity of superoxide dismutase (SOD) and peroxiredoxin 2 (PRDX2). At the molecular level, these alterations increase the generation of ROS and impair antioxidant defense. At the cellular level, these alterations disrupt the epithelial barrier, activate inflammasomes, increase pyroptosis, and induce the formation of neutrophilic and eosinophilic extracellular traps. These changes culminate in the epithelial–mesenchymal transition (EMT), with the formation of nasal polyps and tissue remodeling. Increased oxidative stress can also occur in CRS without nasal polyps (CRSsNP), but this phenotype appears to have relatively preserved antioxidant defense systems, which may partly explain the more limited structural remodeling. External stimuli, such as fungal proteases, bacterial toxins, and certain antibiotics, can also increase the production of ROS and may contribute to disease chronicity. Taken together, the level and pathophysiological roles of ROS differ in the two primary phenotypes of CRS. Further mechanistic studies are needed to clarify the specific alterations of redox pathways in these two phenotypes and to develop novel therapeutic strategies that target ROS.

Hypertension remains the primary modifiable driver of global cardiovascular morbidity, yet the long-standing paradigm of universal sodium restriction is increasingly challenged by the intricate biological heterogeneity of salt sensitivity. This review elucidates the evolving pathophysiological landscape of sodium-induced hypertension, transcending the classical Guytonian pressure-natriuresis model to incorporate emerging evidence of endothelial glycocalyx degradation, non-osmotic interstitial sodium sequestration, and gut–immune axis dysregulation. Furthermore, we critically interrogate the epidemiological “salt controversy,” examining how methodological artifacts—specifically the systematic biases inherent in spot urine sampling—may contribute to the observed J-shaped associations between sodium intake and clinical outcomes. By integrating the modulatory role of the dietary sodium-to-potassium ratio and the genetic/epigenetic determinants of individual salt-sensitive phenotypes, we propose a paradigmatic shift toward a precision nutrition approach.

Skeletal muscle plasticity is modulated by a delicate equilibrium between reactive oxygen species (ROS)-mediated signaling and oxidative distress. Although excessive oxidant accumulation impairs excitation–contraction coupling, accelerates fatigue, and contributes to muscle dysfunction, transient and compartmentalized ROS signals are now recognized as important modulators of mitochondrial biogenesis, metabolic remodeling, proteostasis, and tissue repair processes after contractile stress. This review synthesizes the biphasic nature of redox biology in exercise physiology, interpreting this duality through the paradigm of hormesis. We discuss modality-specific redox responses associated with endurance, resistance and high-intensity interval training, emphasizing that adaptive outcomes depend not on global redox shifts, but on spatiotemporally confined signaling cascades within specific nanodomains. Furthermore, we evaluate the controversial role of antioxidant supplementation, highlighting evidence that high-dose or poorly timed antioxidant intake attenuates specific exercise-induced adaptive responses. We further discuss how aging and chronic disease narrow the adaptive redox window by impairing mitochondrial quality control, inflammatory resolution, and recovery capacity. This paradigm supports a precision exercise strategy in which training modality, intensity, recovery, and nutritional interventions are aligned to preserve adaptive redox signaling while avoiding cumulative oxidative injury.

Background/Objectives: Acute otitis media (AOM) remains a leading cause of pediatric morbidity and a primary indication for antibiotic prescription worldwide. Given the potential for serious complications and the evolving landscape of antimicrobial resistance, up-to-date epidemiological data on causative bacteria are essential. This study aimed to assess the global prevalence of major bacterial pathogens in pediatric AOM and evaluate variations across geographic regions and temporal periods (pre-2000 vs. post-2000). Methods: A systematic search of PubMed, Embase, and Web of Science (1980–2025) was conducted to identify studies reporting middle ear fluid culture results in children (0–18 years) with AOM. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, 45 studies encompassing 16,305 AOM episodes were included. Data were synthesized from North America, Europe, the Middle East, Asia, Oceania, and Africa. Pooled prevalence estimates and 95% confidence intervals (CIs) were calculated using a random-effects model, and heterogeneity was assessed via the I² statistic. Results: The overall pooled culture-positive rate was 66.6% (95% CI, 62.2–70.8%). Regional pooled estimates ranged from 56.1% in the Middle East (95% CI, 40.3–70.6%; underlying counts, 3776/10,652) to 77.5% in North America (95% CI, 68.2–84.7%; underlying counts, 1567/2125). Streptococcus pneumoniae was the most prevalent pathogen, with a pooled proportion of 29.0% (95% CI, 26.3–31.8%), followed by Haemophilus influenzae (22.3%; 95% CI, 19.3–25.6%) and Moraxella catarrhalis (4.6%; 95% CI, 3.4–6.1%). While S. pneumoniae remained the leading pathogen in most regions, H. influenzae showed marked geographic variability, peaking in the Middle East at 27.5% (95% CI, 17.0–41.2%; underlying counts, 2280/10,652) and reaching its lowest level in Asia at 13.5% (95% CI, 7.8–22.4%; underlying counts, 336/1854). The pooled culture-positive rate declined from 72.5% before 2000 (95% CI, 67.6–76.9%; underlying counts, 5769/8199) to 59.4% in 2000 and later (95% CI, 52.1–66.3%; underlying counts, 6661/15,707), although S. pneumoniae remained the predominant isolate in both periods. Conclusions: S. pneumoniae remains the primary bacterial driver of pediatric AOM globally. However, the observed geographic disparities and the temporal shift in pathogen prevalence following pneumococcal conjugate vaccine (PCV) introduction underscore the necessity for region-specific empirical antibiotic selection. These findings highlight the critical need for sustained microbiological surveillance to inform future vaccination and treatment strategies.