Publications

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.

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

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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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.

Metabolic and inflammatory roles of glial cells in neurodegenerative and cerebrovascular diseases Read More »

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.

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

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.

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

Characterizing TDP-43 involvement in vascular dementia

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Abstract

INTRODUCTION

Vascular dementia (VaD) is a major therapeutic challenge. Tar DNA-binding protein 43 (TDP-43), known for its role in neurodegeneration, may contribute to VaD pathogenesis under chronic cerebral hypoperfusion (CCH). This study investigates TDP-43 dysregulation in VaD.

METHODS

TDP-43 and phosphorylated TDP-43 (pTDP-43) expression and localization were assessed in a VaD animal model, neuronal cells exposed to oxygen–glucose deprivation (OGD), and post mortem human brain tissues.

RESULTS

Bilateral Common Carotid Artery Stenosis (BCAS)-induced CCH led to increased pTDP-43 and aberrant redistribution of both TDP-43 and pTDP-43. In vitro OGD triggered similar mislocalization. Post mortem VaD brains showed no TDP-43 abnormalities, while Alzheimer’s and mixed dementia cases exhibited marked pathology.

DISCUSSION

TDP-43 dysregulation appears early in VaD under hypoperfusive stress, distinguishing it from other dementia subtypes. These findings indicate that TDP‑43 may warrant further investigation as a potential early molecular feature of VaD.

Full Article: https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.71196

Characterizing TDP-43 involvement in vascular dementia Read More »

Ethnic-specific effects of the LILRB2–LILRB5 locus and newly identified risk loci for Alzheimer’s disease in the East Asian population

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Abstract

INTRODUCTION

Genome-wide association studies have identified numerous Alzheimer’s disease (AD) susceptibility loci in European populations. However, the genetic architecture of AD in non-European populations remains underinvestigated.

METHODS

We performed a genetic association study in East Asians (N = 8514) to validate known AD loci and identify new susceptibility loci.

RESULTS

We identified LILRB2–LILRB5 as an AD susceptibility locus with ethnic-specific effects between Europeans and East Asians. The lead variant, rs587709-T, was associated with decreased AD risk and increased LILRB5 expression in Europeans. Conversely, in East Asians, the same allele was associated with increased AD risk and increased LILRB2 expression. Furthermore, genome-wide analysis identified TTC3 and FAM135A as candidate susceptibility loci for AD or cognition.

DISCUSSION

The results establish LILRB2–LILRB5 as a cross-ancestry AD-associated locus with ethnic-specific genetic mechanisms and reveal new susceptibility loci, extending the understanding of the genetic etiology of AD.

Full Article: https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.71219

Ethnic-specific effects of the LILRB2–LILRB5 locus and newly identified risk loci for Alzheimer’s disease in the East Asian population Read More »

c-Myc: Central regulator of autophagy and senescence in cancer

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Abstract

Among the transcriptional regulators of cell fate, c-Myc is one of the most frequently deregulated oncogenes, exerting pleiotropic effects on cellular metabolism, survival, and stress adaptation. C-Myc occupies a pivotal position at the intersection of autophagy and senescence, two essential, yet paradoxical processes in cancer biology. Autophagy can both suppress tumor formation and support the survival of established tumors. In contrast, senescence acts as a barrier to malignant transformation but can also promote tumor progression through the senescence-associated secretory phenotype. C-Myc modulates both autophagy and senescence in a highly context-dependent manner. It acts as either an inducer or a suppressor depending on cellular state and microenvironmental conditions. This dual regulatory capacity underscores its role as a central hub in cell fate decisions. In this review, we first summarize how c-Myc, autophagy, and senescence contribute to tumor biology. We then highlight the molecular mechanisms through which c-Myc regulates autophagy and senescence. We examine how these interactions influence cancer progression. Finally, we discuss emerging therapeutic strategies and clinical trials targeting the c-Myc-mediated autophagy/senescence axis. We also address future challenges and opportunities for exploiting this network in precision oncology.

c-Myc: Central regulator of autophagy and senescence in cancer Read More »

Designing nucleic acid-based therapeutics for cancer treatment: Updates on the state of the art

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Abstract

As in art, the ability of nucleic acids to be designed and synthesized as a novel treatment modality is limited only by the imagination. Nucleic acids of virtually all sizes and forms can be synthesized on demand, from short antisense oligonucleotides to large mRNAs and to entire chromosomes. Given the genetic basis of cancer, nucleic acid-based therapy is a particularly promising avenue for anticancer therapeutic development. This has led to a profusion of studies exploring strategies to utilize nucleic acid-based drugs to treat cancer, with some approaches demonstrating great potential for clinical translation. In this review, we summarize the various nucleic acid-based strategies being developed for cancer therapy. We also provide a comprehensive overview of current efforts to enhance the potency and safety of nucleic acid-based drugs, exploring advances in nucleotide composition, design, and delivery strategies.

Designing nucleic acid-based therapeutics for cancer treatment: Updates on the state of the art Read More »

Effect of SSRIs on clinical progression in amnestic mild cognitive impairment stratified by Alzheimer’s disease pathology

Publications /

Abstract

Introduction: This study examined whether selective serotonin reuptake inhibitors (SSRIs) treatment influenced cognitive trajectory and progression to Alzheimer’s disease (AD) dementia in amnestic mild cognitive impairment (MCI) patients, stratified by AD pathology.

Methods: Four hundred fifty-seven amnestic MCI participants in the ADNI database were analyzed. AD pathology was determined by baseline amyloid beta (Aβ) and tau positron emission tomography. Kaplan-Meier survival analysis and Cox proportional hazards models evaluated MCI-to-AD progression. Linear mixed models analyzed longitudinal cognitive trajectories, amyloid accumulation, and cortical thickness.

Results: SSRI treatment showed no significant effect on AD dementia progression (hazard ratio = 1.64, 95% confidence interval: 0.61 to 4.38) or cognitive trajectories, regardless of AD pathology. No significant differences in Aβ accumulation or cortical thickness were observed between SSRI users and non-users. External validation confirmed no significant SSRI effect on AD progression or cognitive decline.

Discussion: SSRI treatment was not associated with long-term cognitive effects in amnestic MCI, irrespective of underlying AD pathology.

Highlights: SSRI treatment was not associated with long-term AD dementia risk in MCI. SSRI treatment had no impact on long-term cognitive performance changes in MCI. SSRI treatment did not affect Aβ accumulation or cortical thickness in MCI. SSRIs had no effect on MCI progression, regardless of underlying AD pathology.

Full Article: https://pubmed.ncbi.nlm.nih.gov/41292493/

Effect of SSRIs on clinical progression in amnestic mild cognitive impairment stratified by Alzheimer’s disease pathology Read More »

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