Publications

Kavain for health promotion and disease mitigation: Pharmacological promise and therapeutic perspectives

Publications /

Abstract

Background

Chronic diseases remain a predominant cause of mortality worldwide despite existing therapies, which often have side effects and high costs. Natural compounds, such as kavain from Piper methysticum, have attracted attention for their therapeutic potential and safety, showing diverse biological activities useful in treating various health conditions.

Purpose

This study aimed to assess the potential role of kavain in the prevention and treatment of chronic diseases, with a particular focus on its anti-inflammatory, anxiolytic, antithrombotic, neuroprotective, and anticancer properties.

Method

A comprehensive literature search on kavain was conducted using PubMed, Scopus, Science direct and Web of Science databases, considering both preclinical and clinical studies. The term “kavain” was used, and all titles, abstracts, and keywords were screened for relevant information.

Results

Findings from various experimental models suggest that kavain exhibits significant biological and pharmacological activities across various pathological conditions, including inflammation, anxiety, neurological disorders, cardiovascular diseases, and cancer. Pharmacokinetic studies reveal its rapid absorption, moderate oral bioavailability, and efficient systemic clearance. Mechanistically, kavain regulates various molecular pathways including nuclear factor-κB and mitogen-activated protein kinase signaling, modulation of γ-aminobutyric acid type A receptor activity, and inhibition of osteoclastogenesis. Toxicity studies indicate that kavain is well-tolerated at physiologically relevant concentrations. Clinical reports show its anxiolytic potential with favorable safety profile.

Conclusion

Kavain has demonstrated considerable therapeutic potential in the prevention and management of various chronic diseases, with relatively few adverse effects. Consequently, further clinical investigations will be beneficial to validate its efficacy and safety in human populations.
Full Article: https://www.sciencedirect.com/science/article/abs/pii/S0944711326002540?via%3Dihub

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Preparing for CHANGE: How systems thinking supports an effective transition from animal studies to NAMs

Publications /

Overview of principal CHANGE publications.

CHANGE publications Summary
Time for CHANGE: system-level interventions for bringing forward the date of effective use of NAMs in regulatory toxicology (Mathisen et al., 2024) Commentary introducing the CHANGE project, its rationale, objectives, and three-phase “explore, reflect, design” methodological approach.
Exploring experiences of the regulatory toxicology system: system-level promoters and inhibitors of new approach methodologies (Bearth et al., 2025) Research article describing the “explore” phase of CHANGE, eliciting from people working in or around the regulatory toxicology system their experience of barriers and enablers of use of NAM data.
Improving how we use workshops when solving complex research problems: reflections from the CHANGE project (Jones et al., 2025) Methods article presenting recommendations for conduct of participatory research workshops, emphasising project team structures, effective social interaction, and facilitation strategies.
How to organise a successful toxicology workshop? A participant perspective on the Collaboration to Harmonise the Assessment of Next Generation Evidence (CHANGE) workshop in Oslo, 18–20 June 2024 (Diemar et al., 2025) Commentary and companion piece to Jones et al. (2025), presenting participant perspectives on the first in-person CHANGE workshop, reflecting on the strengths and challenges of the approaches used.
Modelling the Regulatory Toxicology System to Promote the Effective Use of New Approach Methodologies: A System Thinking Approach (Bearth et al., submitted) Research article describing the “reflect” phase of CHANGE, presenting the CHANGE system model and the methods used to derive the model from participants’ experience of working in or around the regulatory toxicology system.
Report of Collaboration to Harmonise the Assessment of Next Generation Evidence (CHANGE) 2nd workshop in Oslo, June 24 – 26, 2025 – participants perspectives on the CHANGE working methodology (Diemar et al., submitted) Provides participants’ reflections on the second (“reflect”) in-person workshop, including the collaborative approach used to refine system understanding, and the value of the workshop for identifying ways to support the uptake of NAMs.
A protocol for organising co-design research workshops (title to be decided, in preparation) A repeatable, step-by-step procedure to support the planning, design and delivery of successful co-creation or co-design workshops.
CHANGE white paper (title to be decided, in preparation) The main intended deliverable of CHANGE, a policy white paper for decision-makers working in or around regulatory toxicology, presenting a series of system-level interventions that can be expected to improve the effectiveness of use of NAMs in regulatory toxicology.
Designing system-level interventions for improving the effectiveness of use of NAMs in regulatory toxicology (title to be decided, forthcoming) Final research article describing the methods and results of the “design” phase of CHANGE, as the detailed work underpinning the White Paper.

Full Article: https://www.sciencedirect.com/science/article/pii/S3050620426000436?via%3Dihub#tbl0001

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Harnessing nanomedicine to target NF-κB signalling in cancer: at the intersection of inflammatory signalling, metabolic reprogramming, and therapeutic innovation

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Abstract

The nuclear factor kappa B (NF-κB) signalling pathway is a pivotal orchestrator of inflammation, tumour progression, immune modulation, and metabolic reprogramming within the dynamic landscape of the tumour microenvironment (TME). Aberrant and sustained activation of NF-κB is frequently associated with tumour proliferation, resistance to therapy, and poor clinical outcomes. However, conventional NF-κB inhibitors face significant limitations, including systemic toxicity, poor bioavailability, and lack of tumour specificity. Nanomedicine offers a transformative approach to overcome these barriers by enabling the targeted delivery of NF-κB modulators, such as small molecules, RNA interference agents, and gene-editing systems, directly to tumour sites. Recent advances in nanocarriers, including liposomes, polymeric nanoparticles, exosomes, and dendrimers, have demonstrated improved therapeutic indices, enhanced stability, and reduced off-target effects. This review highlights the convergence of nanotechnology, inflammatory signalling, and cancer metabolism, with a focus on how nanomedicine can precisely modulate NF-κB signalling to reprogramme tumour-associated macrophages and remodel the TME. It also discusses preclinical evidence supporting NF-κB-targeted nanomedicine, innovative delivery strategies, and the translational challenges that impede clinical adoption. Collectively, these insights highlight the potential of nanomedicine in advancing NF-κB-targeted cancer therapy by enhancing drug specificity, safety, and therapeutic responsiveness. Future developments integrating artificial intelligence, theranostic design, and personalised nanomedicine are expected to accelerate clinical translation and establish NF-κB-targeted nanotherapeutics as a cornerstone of next-generation precision oncology.

Full Article: https://link.springer.com/article/10.1186/s12964-025-02554-9

Harnessing nanomedicine to target NF-κB signalling in cancer: at the intersection of inflammatory signalling, metabolic reprogramming, and therapeutic innovation Read More »

Spatiotemporally controlled peroxynitrite nanogenerator disarms tumor physical barriers to potentiate immune activation

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Abstract

Therapeutic efficacy against solid tumors is limited by physical barriers and immunosuppressive tumor microenvironments (TME). Herein, we propose a peroxynitrite (ONOO−) overproduction-based strategy to simultaneously disrupt tumor barriers and activate antitumor immunity. A spatiotemporally controllable ONOO− nanogenerator (PNO-Y@M) was constructed by co-encapsulating hypericin within nitric oxide (NO)-donor polymeric nanoparticles coated with homologous tumor cell membranes. Upon laser irradiation, PNO-Y@M enables in-situ ONOO− generation via the coupling of photodynamically generated superoxide anions and photothermally triggered NO release. The resulting ONOO− effectively degrades extracellular matrix components and normalizes tumor vasculature, thereby enhancing nanoparticle penetration. Meanwhile, it induces immunogenic cell death, promoting dendritic cell maturation and M1 macrophage polarization, and ultimately activating robust adaptive immunity. This strategy significantly increased cytotoxic and helper T cell infiltration and induced strong immune memory in-vivo, leading to effective tumor suppression and metastasis inhibition. Overall, this work provides a promising strategy for overcoming the dual barriers of solid tumors through coordinated physical disruption and immune activation.

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The interplay between autophagy and immunogenic cell death: nanomaterial-based strategies for cancer immunotherapy

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Abstract

Cancer immunotherapy has significantly advanced the field of oncology. However, effectiveness of immunotherapy remains limited by tumor heterogeneity, immune evasion, and immunosuppressive tumor microenvironments. Immunogenic cell death (ICD) and autophagy are two interconnected biological mechanisms that play crucial roles in modulating tumor-immune interactions. ICD enhances antitumor immunity through the release of damage-associated molecular patterns (DAMPs), while autophagy affects the immunogenicity and viability of tumor cells in a context-dependent manner. Their complex interaction offers a distinctive platform to enhance immune responses and overcome resistance to immunotherapy. This review emphasizes recent advancements in using nanomaterials to regulate autophagy and ICD in cancer therapy. Various nanoplatforms, including metallic, polymeric, lipid-based, and carbon-based nanoparticles, have been engineered to deliver ICD inducers and autophagy modulators in a targeted TME-responsive manner. We discuss the underlying mechanisms, therapeutic synergies, and translational advantages of these dual-functioning systems. Furthermore, we address critical challenges such as biosafety, tumor specificity, and regulatory hurdles, and we explore strategies including PEGylation, biomimetic coating, and biodegradable carriers to improve clinical applications.

Full Article: https://link.springer.com/article/10.1186/s12951-026-04286-5

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The Treg-cell death axis in lung cancer: implications for immune evasion and novel therapeutic strategies

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Abstract

Regulatory T cells (Tregs) are central mediators of immune tolerance and key drivers of tumor immune evasion in non-small cell lung cancer (NSCLC). Within the tumor microenvironment (TME), Tregs accumulate and suppress antitumor responses, thereby limiting the durability of immune checkpoint inhibitor (ICI) responses. Emerging evidence indicates that Treg influence on immunotherapy outcomes extends beyond numerical abundance to involve a dynamic Treg-cell death axis, in which enhanced Treg survival and resistance to regulated cell death are coupled with dysfunction, exhaustion, or attrition of effector T cells. Tumor-derived chemokines, cytokines, and metabolic cues promote recruitment, stabilization, and metabolic fitness of Tregs, enabling their persistence within hypoxic and nutrient-deprived niches. Concurrently, Tregs suppress antigen-presenting cell activation, amplify checkpoint signaling, and exploit metabolic and redox adaptations including ferroptosis resistance to maintain immunosuppressive dominance under therapeutic pressure. Together, these mechanisms establish a survival-advantaged regulatory compartment that drives immune cell-fate asymmetry within the TME and limits the durability of immune checkpoint blockade. We propose the Treg-cell death axis as a unifying framework linking immune tolerance, regulated cell death, and immunotherapy resistance in lung cancer. Targeting this axis through mechanism-matched strategies that destabilize tumor-resident Tregs while preserving systemic immune homeostasis may provide new opportunities to overcome therapeutic resistance and improve clinical outcomes.

Full Article: https://link.springer.com/article/10.1186/s12943-026-02688-5

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TDCPP induces ferroptosis in THP-1 macrophages through mitochondrial regulation of Fe2 + homeostasis

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Abstract

Widespread environmental exposure to tris (1,3-dichloro-2-propyl) phosphate (TDCPP), a commonly used organophosphate esters, has raised significant concerns due to its structural similarity to organophosphate pesticides with known immunotoxicity. However, the immunotoxic and underlying mechanisms remain insufficiently understood. In this study, we used mRNA sequencing (mRNA-seq) to investigate the mechanisms underlying TDCPP-induced immunotoxicity following long-term low-dose exposure in THP-1 macrophages. Our findings revealed that TDCPP induces ROS generation, antioxidant depletion, iron accumulation, and lipid peroxidation lead to ferroptosis, as evidenced by lipid peroxidation and mitochondrial morphological changes observed via electron microscopy. Furthermore, TDCPP exposure led to a collapse of the cellular antioxidant defense system. The accumulation of Fe²⁺ and H₂O₂ triggered the Fenton reaction, resulting in oxidative stress and immune disorder. At the individual level, intravenous administration of TDCPP in BALB/C mice increased serum MDA levels and decreased GSH content, significantly affecting Fe²⁺ homeostasis in lymphocytes, confirming the systemic effects of TDCPP exposure. This study is the first to demonstrate TDCPP activates ferroptosis in macrophages through mitochondrial iron imbalance and oxidative stress, resulting in lipid peroxidation in mouse blood and iron imbalance in lymphocytes, providing a theoretical basis for potential health risks in humans. There is an urgent need for further regulatory action and the development of safer alternatives.

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Clinical meaningfulness of anti-amyloid therapies in early Alzheimer’s disease: Perspectives from the East and Southeast Asia region

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Abstract

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive accumulation of toxic amyloid species. The rising prevalence of AD in Asia has made it an increasing public health concern, placing a substantial burden on the economy and healthcare systems. Anti-amyloid therapies (AATs) have demonstrated statistically significant slowing of disease progression at the group level in pivotal trials in early symptomatic AD. We explore the clinical meaningfulness of AATs and considerations impacting on its meaning in East and Southeast Asia. We acknowledge that there is a lack of data on Asian populations, particularly from the perspectives of patients and caregivers, highlighting the need for such evidence to facilitate the successful adoption of AATs in the region. We also propose the conceptual Connect, Align, Reframe, Explain (CARE) communication framework and practical tools to support effective communication with patients and caregivers regarding the benefits of AATs. HIGHLIGHTS: Anti-amyloid therapies (AATs) have demonstrated statistically significant group-level effects in slowing of disease progression in early symptomatic Alzheimer’s disease. Translating clinical trial outcomes into measures of benefit that are truly meaningful to patients and caregivers is critical for the adoption of AATs. Asia, with its rapidly aging societies, diverse cultural norms and heterogeneous healthcare and reimbursement systems, presents a unique perspective on the clinical meaningfulness of AATs. The proposed Connect, Align, Reframe, Explain (CARE) communication framework concept and practical support tools, such as goal-setting checklist, visual aids and motivational messages, can facilitate effective communication with patients and caregivers regarding the benefit of AATs. Optimizing the full potential of AATs in Asia requires focused efforts on understanding patients’ and caregivers’ perspectives on treatment benefits, building regional registries to collect real-world data, and aligning care frameworks.

Full Article: https://pubmed.ncbi.nlm.nih.gov/41724687/

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Microvesicle release drives cycles of mitophagy flux disruption and inflammatory amplification in sepsis-induced myocardial dysfunction

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Abstract

Sepsis-induced myocardial dysfunction strongly contributes to high mortality in patients with sepsis by exacerbating systemic organ failure; however, the onset and molecular mechanisms driving this vicious cycle remain unclear. Here, we revealed that DRP1-mediated mitochondrial fission and excessive reactive oxygen species (ROS) accumulation are central to the disruption of mitophagy flux and triggering of inflammatory cascades. Using cecal ligation and puncture mice and lipopolysaccharide-treated HL-1 cell models, combined with advanced imaging and molecular analyses, we demonstrated that elevated ROS activates the RIP1/RIP3 pathway, impairing mitophagy flux and promoting the release of microvesicles containing mitochondrial inner membrane components and mitochondrial DNA. These microvesicles amplify inflammatory responses through the cGAS–STING and RIP1/RIP3 pathways, driving the production of damage- and pathogen-associated molecular patterns. This study highlights two interlinked vicious cycles, mitophagy flux disruption and damage- and pathogen-associated molecular pattern amplification, as critical drivers of sepsis-induced myocardial injury, providing therapeutic targets for mitigating inflammatory damage and improving clinical outcomes in patients with sepsis.

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Autophagy in thyroid cancer: Immune suppression and drug resistance

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Abstract

Thyroid cancer exhibits a broad spectrum of clinical behaviors, ranging from indolent differentiated tumors to highly aggressive, dedifferentiated malignancies that are refractory to radioactive iodine (RAI), targeted therapy, and immunotherapy. Autophagy, a highly conserved lysosome-mediated degradation pathway, has been identified as a crucial homeostatic mechanism with either tumor-suppressive or tumor-promoting effects depending on the regulatory context. Increasing evidence suggests that while basal autophagy may help attenuate genomic instability during early tumorigenic stages, advanced-stage tumors are more likely to utilize autophagic flux as a survival mechanism to maintain metabolic fitness, mitochondrial integrity, and resistance to therapeutic stress. This review integrates existing knowledge on the role of autophagy as a central hub amenable to drug targeting. It links MAPK-stimulated dedifferentiation and resistance to RAI with immune evasion and resistance to tyrosine kinase inhibitors and immune checkpoint blockade. Furthermore, we address the limitations of redifferentiation strategies and targeted therapies due to therapy-induced autophagy. We also discuss how autophagy modulates antitumor immunity within the tumor microenvironment, including its effects on antigen presentation, immune-cell polarization, and cytokine signaling. Emerging concepts, such as mitophagy sodium/iodide symporter (NIS) coupling, autophagy–exosome crosstalk, and compartment-specific autophagy requirements, are highlighted as understudied but therapeutically relevant areas. Additionally, we discuss the translational potential of next-generation lysosome-targeted agents, transcriptional regulators of the autophagy-lysosomal pathway, and selective autophagy-based degraders. Collectively, current evidence supports a genotype-, flux-, and timing-guided framework for modulating autophagy to overcome resistance and improve long-term disease control in advanced thyroid cancer.

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