Nexus of Pathophysiology and Therapeutics (NPT)

Abstract Modern biomedical science has achieved unprecedented resolution in mapping disease at molecular, cellular, and systemic levels. Yet, a fundamental tension persists: mechanistic breakthroughs do not consistently translate into improved clinical interventions. This asymmetry—the persistent gap between biological explanation and therapeutic practice—is one of the defining challenges of contemporary medicine. It reflects a deeper structural issue in how knowledge is generated, interpreted, and integrated across disciplines. Nexus of Pathophysiology and Therapeutics (NPT) is founded to directly address this translational challenge. Rather than treating mechanistic depth and therapeutic relevance as isolated domains, NPT establishes them as intellectually continuous tasks. The journal seeks to bridge the distance between explanation and intervention by prioritizing research that leverages robust mechanistic insight to refine therapeutic reasoning, stratification, and clinical interpretation. Our scope is defined not by rigid disciplinary boundaries or organ systems, but by a shared scientific orientation. We invite experimental, computational, and clinical studies that interrogate conserved biological programs—such as chronic inflammation, dysregulated repair, and immunometabolic imbalance—that recur across diverse conditions. By emphasizing conceptual clarity and causal rigor, NPT provides a dedicated forum for work that moves beyond descriptive characterization toward actionable insight. We maintain a firm commitment to translational relevance without endorsing overstatement. In an era of rapid data expansion, we prioritize studies that distinguish signal from noise and assertion from evidence. NPT is positioned at the critical interface where biological explanation informs the future of therapeutic science. We invite contributions that bring structure to complexity, define the operative biology of disease, and offer a coherent framework for therapeutic intervention. By supporting an integrated approach to pathophysiology and therapeutics, NPT aims to define the next generation of biomedical inquiry.

Abstract Hantaviruses, members of the Hantaviridae family, are zoonotic pathogens characterized by distinct clinical syndromes, primarily manifested as hemorrhagic fever with renal syndrome (HFRS) or hantavirus cardiopulmonary syndrome (HCPS). While the clinical presentation varies geographically and by viral strain, a unifying theme in hantavirus pathogenesis is that disease severity is driven less by direct viral cytotoxicity and more by profound dysregulation of host immune and vascular responses. This review explores the complex interplay between viral tropism, endothelial dysfunction, and excessive host immune activation. Hantaviruses exhibit strong tropism for endothelial cells, macrophages, and epithelial cells. Crucially, infection induces functional barrier disruption rather than overt structural destruction. This endothelial hyper-responsiveness is mediated by an interconnected network of pro-inflammatory cytokines—including TNF-α, IL-6, and IFN-γ—alongside VEGF-dependent signaling and the activation of bradykinin and complement cascades. These pathways collectively destabilize endothelial junctions, promote vascular permeability, and exacerbate tissue edema and hypotension, which are hallmarks of severe disease. The observation that hantavirus-induced vascular leakage is primarily an immune-mediated phenomenon underscores the critical need for moving beyond traditional antiviral strategies. By characterizing the mechanistic bridge between innate immune activation and endothelial integrity, this paper highlights promising avenues for host-directed therapeutic interventions. Targeted modulation of cytokine signaling, vascular-protective agents, and pathways governing endothelial permeability offer potential strategies to mitigate severe outcomes. As the burden of hantavirus infection evolves due to ecological and environmental shifts, integrating molecular virology, vascular biology, and clinical immunopathology becomes essential. Such a multi-dimensional approach is necessary to refine our understanding of disease progression and to develop more effective, translational therapeutics that preserve vascular homeostasis and limit the morbidity associated with these persistent zoonotic threats.

Abstract Background: Preeclampsia is a pregnancy-specific disorder characterized by multisystem involvement and significant maternal–fetal morbidity. Emerging evidence suggests that hematological indices may reflect underlying pathophysiological mechanisms, including inflammation, oxidative stress, and impaired erythropoiesis.
Methods: This case–control study was conducted on 130 pregnant women (65 cases and 65 controls) referred to Shahid Rahimi Hospital between 2023 and 2024. Participants were matched based on maternal age and gestational age. Demographic characteristics and hematological parameters, including hemoglobin (Hb), hematocrit (HCT), red blood cell (RBC) count, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), and red cell distribution width (RDW), were extracted from medical records. Independent t-tests and analysis of covariance (ANCOVA) were used, adjusting for age, body mass index (BMI), education level, and parity.
Results: Significant differences were observed in MCV, MCHC, and RDW between groups. MCV and MCHC were significantly lower in the preeclampsia group, whereas RDW was significantly higher (P < 0.001 for all). These associations remained significant after adjustment for confounders. No significant differences were observed in Hb, HCT, RBC count, or MCH.
Conclusion: Alterations in red blood cell indices, particularly RDW, MCV, and MCHC, are associated with preeclampsia and may reflect underlying pathophysiological processes including inflammation, oxidative stress, and impaired erythropoiesis. These routinely available parameters may have potential value as adjunct biomarkers for clinical assessment and risk stratification in preeclampsia, although further prospective and mechanistic studies are required to confirm their clinical utility.
Mechanistic and Translational Relevance: These hematological indices may reflect underlying processes including inflammation, oxidative stress, and impaired erythropoiesis in preeclampsia. Given their routine availability and low cost, they may serve as accessible biomarkers of systemic involvement and could support adjunctive clinical assessment and risk stratification, particularly in resource-limited settings.

Abstract Hantavirus infections are primarily acquired through inhalation of aerosolized particles originating from rodent excreta and lead to severe pulmonary and renal syndromes. Although clinical features are well characterized, tissue-level mechanisms remain unclear. Histopathology consistently shows endothelial swelling, edema, and immune cell infiltration, indicating combined viral and host immune contributions to disease pathogenesis. The lungs and kidneys are the principal target organs, where microvascular dysfunction drives the most severe clinical manifestations. Hantaviruses preferentially infect endothelial cells of the microvasculature in these organs through integrin-mediated entry. Following infection, viral replication proceeds without marked cytopathic effects; instead, disruption of endothelial junctional proteins and cytoskeletal remodeling leads to progressive loss of barrier integrity. This results in increased vascular permeability, plasma leakage, and tissue edema. Activation of signaling pathways such as VEGF and RhoA/ROCK further amplifies endothelial dysfunction, contributing to pulmonary edema and renal impairment. In parallel, immune-mediated mechanisms play a central role in tissue injury. Recruitment of macrophages and cytotoxic T cells, together with elevated levels of proinflammatory cytokines including TNF-α and IL-6, intensifies vascular leakage and exacerbates organ damage. Disease severity appears to correlate more strongly with the magnitude of the host immune response than with direct viral cytotoxicity, emphasizing the importance of immunopathology in disease progression. From a mechanistic and translational perspective, hantavirus disease represents a paradigm of combined endothelial and immune-driven injury. The disruption of vascular integrity identifies potential therapeutic targets aimed at stabilizing endothelial junctions and modulating permeability-related signaling pathways such as VEGF and RhoA/ROCK. In addition, strategies that selectively attenuate excessive cytokine responses without inducing broad immunosuppression may reduce tissue damage and improve clinical outcomes. Histopathological features including endothelial swelling, tubular necrosis, and interstitial hemorrhage further provide measurable biomarkers for evaluating disease severity and therapeutic efficacy, bridging mechanistic insights with clinical application and supporting the development of targeted interventions.

Abstract improving diagnostic accuracy, and optimizing healthcare delivery systems. This perspective explores the expanding role of AI across clinical decision support systems, predictive analytics, and personalized medicine, highlighting its potential to support clinicians in managing complex and data-intensive healthcare environments. Evidence from recent studies suggests that AI algorithms can achieve high performance in specific diagnostic tasks, particularly in radiology, dermatology, and pathology; however, their real-world clinical effectiveness remains dependent on robust validation, workflow integration, and generalizability across diverse populations. Despite these promising developments, the integration of AI into clinical practice raises important ethical, practical, and regulatory challenges. Key concerns include limited explainability of complex models, data privacy and security risks, and the potential for algorithmic bias that may exacerbate existing healthcare disparities. In addition, gaps between retrospective model performance and prospective clinical impact continue to limit the translation of AI tools into routine care. These challenges underscore the need for a more holistic evaluation framework that extends beyond technical performance metrics to include clinical usability, transparency, and ethical robustness. A critical appraisal of current AI applications suggests that successful implementation in healthcare depends not only on algorithmic accuracy but also on trust, interpretability, and seamless integration into clinical workflows. Furthermore, clinicians must remain central to decision-making processes, ensuring that AI functions as an assistive technology rather than a replacement for human judgment. Overall, while AI holds substantial promise for improving patient outcomes and healthcare efficiency, its safe and effective adoption requires careful attention to ethical principles, regulatory oversight, and real-world clinical validation.

Abstract Biomedical research is increasingly shifting from empirical observation toward a mechanistic understanding of disease biology and therapeutic response. In this context, clinical pharmacology has evolved into an integrative discipline that links drug action to disease mechanisms across molecular, cellular, and systems levels. Central to this transformation are pharmacokinetic–pharmacodynamic (PK–PD) modeling, biomarker-based assessment, and systems pharmacology approaches, which together provide a quantitative framework for interpreting drug exposure, target engagement, and downstream biological effects. These approaches support a mechanistic understanding of dose–response relationships and facilitate more rational dose selection beyond traditional empirical strategies. The integration of dynamic biomarkers has further advanced the field by enabling real-time assessment of pathway activity and disease progression, particularly in heterogeneous disorders such as diabetes and immune-mediated metabolic diseases. For example, the clinical development of SGLT2 inhibitors such as empagliflozin illustrates how mechanistic PK–PD modeling and biomarker integration can reveal therapeutic effects extending beyond glycaemic control, including cardiovascular and renal benefits that were not predicted by glucose lowering alone. Early-phase clinical studies supported by model-informed drug development frameworks also allow earlier evaluation of mechanistic hypotheses in humans and improve the prediction of interindividual variability in therapeutic response and toxicity. In parallel, the bidirectional exchange of information between preclinical and clinical research through forward and reverse translation contributes to model refinement and strengthens predictive accuracy in drug development. Collectively, these advances position clinical pharmacology as a mechanistic framework within translational medicine, bridging experimental biology and clinical therapeutics. This evolving paradigm supports the transition toward precision and mechanism-guided drug development, where therapeutic strategies are increasingly informed by causal biological pathways rather than empirical associations.

Abstract Neurodegenerative disorders, including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis, are increasingly recognized as complex neuroimmune conditions rather than purely neuron-centric diseases. Although classical frameworks have emphasized protein aggregation, synaptic dysfunction, and progressive neuronal loss, these mechanisms alone do not fully explain disease heterogeneity or the limited efficacy of current disease-modifying therapies. Emerging evidence suggests that chronic neuroinflammation represents a central and sustained driver of neurodegeneration, acting through tightly interconnected neuronal, glial, and vascular pathways. At the mechanistic level, persistent activation of innate immune signaling—particularly microglial priming and NLRP3 inflammasome activation with downstream IL-1β and IL-18 signaling—establishes a chronic pro-inflammatory milieu within the central nervous system. Misfolded protein species, including amyloid-β and tau, further amplify immune activation by functioning as damage-associated molecular patterns, thereby linking proteinopathy with innate immune responses. Concurrently, progressive disruption of the blood–brain barrier facilitates bidirectional communication between the central and peripheral immune systems, enabling systemic inflammation to exacerbate ongoing neurodegenerative processes. Together, these mechanisms form a self-reinforcing neuroimmune loop that may contribute to disease initiation and progression. From a translational perspective, this integrated framework highlights the limitations of therapeutic strategies that primarily target neurotransmitter imbalance or protein aggregation. Instead, disease modification may require interventions that directly modulate neuroimmune pathways, including regulation of microglial activation states, inhibition of inflammasome signaling, and restoration of blood–brain barrier integrity. Importantly, such approaches necessitate a shift toward mechanism-guided clinical development supported by biomarkers reflecting immune activation, glial reactivity, and neurovascular dysfunction. This may enable improved patient stratification and identification of biologically distinct disease subtypes with differential therapeutic responsiveness. Overall, reframing neurodegeneration as a dynamic and interconnected neuroimmune process provides a more comprehensive understanding of disease pathogenesis and offers a rational foundation for developing mechanism-based therapeutic strategies aimed at modifying disease progression rather than merely alleviating symptoms

Abstract Background: Gestational diabetes mellitus (GDM) is a major pregnancy complication linked to subclinical inflammation. However, the predictive value of first-trimester upstream cytokines like interleukin-6 (IL-6) versus downstream acute-phase proteins like C-reactive protein (CRP) remains poorly defined. This prospective study evaluated the association of first-trimester maternal serum IL-6 and CRP levels with subsequent GDM risk.
Methods: A total of 300 pregnant women (<14 weeks of gestation) were enrolled in Khorramabad, Iran. Baseline serum IL-6 and CRP concentrations were quantified using automated assays. Participants were prospectively followed until 24 to 28 weeks, when GDM was diagnosed via a standard 75-g oral glucose tolerance test. Multivariable logistic regression adjusted for clinical confounding covariates.
Results: Of the 300 participants, 129 women (43.0%) developed GDM. These women exhibited significantly higher first-trimester median levels of both CRP (10.5 mg/L vs. 6.1 mg/L, p = 0.004) and IL-6 (3.8 pg/mL vs. 2.9 pg/mL, p = 0.010) compared to controls. In multivariable logistic regression, IL-6 was the sole independent predictor of GDM (Odds Ratio = 1.10, p < 0.001). Conversely, CRP (p = 0.767), maternal age (p = 0.114), and body mass index (p = 0.761) lost statistical significance. Additionally, a positive family history of diabetes demonstrated a profound univariate risk profile (79.4% GDM incidence vs. 25.6% without, p < 0.001).
Conclusion: First-trimester maternal serum IL-6 is a powerful, independent predictor of GDM that statistically outperforms downstream hepatic markers like CRP.
Mechanistic and Translational Relevance: Early IL-6 elevation reflects an upstream molecular insult driving insulin resistance, likely by impairing insulin receptor substrate phosphorylation before overt hyperglycemia develops. Identifying this inflammatory nexus during the first trimester shifts the paradigm from late-gestation reaction to early-pregnancy prevention, offering a proactive window for targeted preventive therapeutics to preserve beta-cell kinetics and improve perinatal metabolic outcomes.

Abstract Nitric oxide (NO) is a multifunctional gaseous signaling molecule that plays a central role in maintaining physiological homeostasis while also contributing to diverse pathological processes. Its biological effects are highly context dependent and are shaped by the interplay between nitric oxide synthase (NOS) isoforms, local redox balance, temporal dynamics, cellular environment, and concentration gradients. Under physiological conditions, NO support's vascular function, neuronal communication, and immune regulation through well-coordinated signaling pathways, including cyclic GMP production and post-translational protein modifications. However, under conditions of oxidative stress or sustained inflammatory activation, NO signaling can shift toward the generation of reactive nitrogen species, leading to cellular dysfunction, oxidative injury, and tissue damage. This review highlights the non-redundant roles of NOS isoforms—endothelial (eNOS), neuronal (nNOS), and inducible (iNOS)—as context-specific regulators of NO production, each contributing distinctly to physiological and pathological outcomes. eNOS primarily maintains vascular integrity, nNOS regulates neural signaling, and iNOS drives inflammatory responses, with their dysregulation playing a key role in cardiovascular, neuroinflammatory, oncologic, and renal diseases. Across these systems, the balance between protective and deleterious NO signaling is determined by isoform activity, redox environment, exposure time, and local concentration. Finally, we discuss emerging therapeutic strategies that aim to modulate NO signaling in a more precise and context-aware manner, including isoform-selective targeting, redox modulation, controlled NO delivery systems, and computationally guided drug design. Together, these approaches underscore the importance of integrating mechanistic insight with translational applications to better harness the therapeutic potential of NO while minimizing its cytotoxic effects.

Abstract Puumala orthohantavirus (PUUV) is the principal cause of hemorrhagic fever with renal syndrome in Europe, where it manifests as nephropathia epidemica. Although clinical features of PUUV infection are well described, disease severity is increasingly recognized to result from dysregulated host immune responses rather than direct viral cytopathicity. This review synthesizes current evidence on the immunopathogenic roles of interleukins in PUUV infection, with a particular focus on cytokine-mediated endothelial dysfunction and its translational implications. Acute PUUV infection is characterized by a pronounced systemic inflammatory response, often described as a cytokine storm, involving elevated levels of both pro-inflammatory cytokines (IL-6, TNF-α, IL-1β, IL-2, IL-8) and regulatory mediators (IL-10, TGF-β1). Among these, IL-6 and TNF-α are consistently associated with disease severity, renal impairment, and thrombocytopenia, and contribute to endothelial activation and increased vascular permeability. IL-6 trans-signaling has emerged as a key mechanism in endothelial barrier disruption, while TNF-α promotes vascular leakage and immune cell recruitment. In contrast, IL-10 and TGF-β1 appear to function as compensatory anti-inflammatory mediators whose delayed or insufficient responses may contribute to uncontrolled inflammation and tissue injury. Additional interleukins, including IL-2, IL-8, and IL-18, further contribute to T-cell activation, neutrophil recruitment, and inflammasome-associated inflammation, highlighting the complexity of cytokine networks in PUUV pathogenesis. Collectively, these pathways converge on endothelial dysfunction, which represents the central event driving vascular leakage and organ damage. Understanding interleukin dynamics in PUUV infection provides important mechanistic insight and identifies potential biomarkers for disease severity. Moreover, selective targeting of cytokine pathways, particularly IL-6 trans-signaling and TNF-α activity, offers promising therapeutic opportunities. However, given the dual protective and pathogenic roles of cytokines, precise immunomodulation rather than broad suppression is required. Overall, PUUV infection serves as a model of immune-mediated vascular disease, where cytokine-driven endothelial dysfunction determines clinical outcome and therapeutic strategies.