Publications Archives - Pharmacology

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

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.

Full Article: https://www.sciencedirect.com/science/article/pii/S014765132600761X?via%3Dihub

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

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.

Full Article: https://www.pnas.org/doi/10.1073/pnas.2510914123

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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.

Full Article: https://www.sciencedirect.com/science/article/abs/pii/S1368764626000889?via%3Dihub

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Metabolic and inflammatory roles of glial cells in neurodegenerative and cerebrovascular diseases

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Abstract

Chronic neuroinflammation is a hallmark of neurodegenerative and cerebrovascular diseases and is largely driven by dysfunctional activation of microglia and astrocytes. Recent advances in single-cell transcriptomics and metabolic profiling have revealed the remarkable heterogeneity and plasticity of these glial cells, highlighting their dual roles in neuroprotection and neurotoxicity. Upon activation, microglia adopt pro-inflammatory phenotypes and undergo metabolic reprogramming characterized by a shift from oxidative phosphorylation to glycolysis, resulting in the release of cytokines and reactive oxygen species (ROS). Concurrently, astrocytes display dysregulated lipid metabolism, leading to the accumulation of toxic lipid species and amplification of inflammatory responses through metabolic and cytokine-mediated crosstalk, including lactate-mediated interactions between glial cells. Key inflammatory pathways regulate these processes, such as nuclear factor kappa B (NF-κB) signaling, activation of the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome, and the complement component 3/complement component 3a receptor (C3/C3aR) signaling axis. These pathways coordinate glial activation and sustain deleterious feedback loops between microglia and astrocytes, ultimately promoting neuronal injury. These responses are often initiated by ROS and damage-associated molecular patterns (DAMPs) that trigger innate immune signaling. These pathological interactions are further amplified by impaired cholesterol transport, extracellular vesicle-mediated communication, and mitochondrial dysfunction. Collectively, these mechanisms exacerbate neuroinflammation and contribute to neurodegenerative progression and neurovascular impairment. Despite these advances, important gaps remain in understanding context-specific glial interactions and the limitations of current experimental models. This review summarizes current insights into glial-mediated neuroinflammation in ageing-related neurological disorders and discusses emerging therapeutic strategies targeting glial metabolism and immune signaling to mitigate disease progression.

Full Article: https://www.sciencedirect.com/science/article/abs/pii/S1568163726001121?via%3Dihub

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Evolution of cortical cerebral microinfarcts on 3T MRI: risk factors and clinical relevance

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Abstract

INTRODUCTION

Cortical cerebral microinfarcts (CMIs) are associated with cognitive dysfunction and dementia, while their evolution on sequential magnetic resonance imaging (MRI) remains unclear.

METHODS

The study enrolled 490 patients (72.5 ± 7.9 years) from a memory-clinic cohort, with 5-year follow-up. Cortical CMIs were graded at baseline and year 2 to identify incident lesions and other evolutionary patterns. Cognitive function was assessed annually. Clinical events, including dementia, stroke, and mortality, were recorded with time to event.

RESULTS

Forty-one (8.4%) patients showed incident cortical CMIs at year 2. Additionally, 12 had CMIs becoming invisible, and six showed CMIs incorporated into new large infarctions. Baseline cortical CMIs and large cortical infarcts showed the strongest association with incident CMIs. Incident cortical CMIs were associated with cognitive decline, white matter hyperintensity progression, and incident dementia, independent of prevalent lesions.

DISCUSSION

Cortical CMI evolution may reflect dynamic changes in brain vascular pathology and represent a potential target for interventions aimed at preserving cognitive function.

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Bioorthogonal catalytic centres engineered for gastrointestinal stabilization provide oral delivery for the treatment of gastric cancer

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Abstract

Background

Gastric cancer, the fifth most prevalent cancer globally, poses significant treatment challenges due to factors such as late diagnosis, early metastasis, limited surgical options, and the systemic toxicity of chemotherapy. Because luminal barriers are often compromised in gastric cancers , orally administered therapies that enable localized absorption and drug release represent a promising new direction for site-specific treatment with limited side effects.

Results

We introduce a disulfide-linked thermostable exoshell system that orally delivers protein-based bioorthogonal catalytic centres directly to cancer tissues. The highly engineered exoshells effectively encapsulated and stabilized labile catalytic centres, preventing degradation in the harsh gastric environment. In vivo gastric tumors were treated using the anti-cancer properties of active metabolites of the prodrug indole-3-acetic acid (IAA) converted in situ via bioorthogonal catalysis. In vitro cell studies revealed a dose- and time-dependent inhibition of gastric cancer cell growth, irrespective of their HER2 status. This inhibition was accompanied by upregulation of mitochondrial lipid peroxidation, reduced mitochondrial membrane potential, and activation of necroptotic pathway markers such as RIP1, RIP3, and MLKL at both mRNA and protein levels. In a mouse model of gastric cancer induced by N-Methyl-N-Nitrosourea, oral administration of catalytic exoshells for 6 weeks significantly inhibited gastric inflammation and tumour polyp growth. Additionally, LC/MS/MS-based metabolomic analysis of plasma obtained from treated mice showed significant upregulation of cytotoxic metabolites of IAA. Notably, metabolites relevant to redox regulation, including alpha-tocopherol (vitamin E), glutathione (GSH), homocysteine, methyl cysteine, and cysteine sulfinic acid, were identified as the top differentially expressed metabolites, indicating potent suppression of inflammation and tumour growth. Histological analysis of gastric tissue showed a reduced number of polyps and subsequent development of gastric tumours.

Conclusion

Our in vitro and in vivo results demonstrated that exoshells possessed significant potential as an orally administered, titratable therapeutic platform for the management of gastrointestinal cancers.

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Characterizing TDP-43 involvement in vascular dementia

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