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Open Access

Review

24 June 2025

Obesity-Associated Chronic Inflammation: A Protective Mechanism against Type 2 Diabetes

Chronic inflammation is widely considered a risk factor for T2DM by inducing insulin resistance, but all attempts to translate the concept into clinical therapies have failed in the past 30 years. Anti-inflammatory medicines, including anti-TNF-α antibody (Etanercept), anti-IL1 antibody (Anakinra), anti-IL6 (Ziltivekimab), and NLRP3 inflammasome inhibitor (Colchicine) have excellent activities in the control of inflammation in arthritis. They reduced inflammation in T2DM patients in the clinical trials, but none improved insulin sensitivity. Some of them exhibited a mild and transient activity in the control of blood glucose, but the activities were related to the improvement of insulin secretion by β-cells. The failure may be related to followings: over-interpretation of TNF-α activity; ignoring the role of anti-inflammatory cytokines; differences between mice and humans. However, the species difference cannot fully explain the failure as these therapies did not work in the animal models as well. Moreover, genome-wide association studies (GWAS) show that T2DM is not associated with proinflammatory cytokine genes, including TNF-α, IL-1β, IL-6, and CCL2(MCP1). More studies suggest that inflammation has beneficial activities in the mobilization of energy stores and promotion of energy expenditure to prevent energy surplus, a risk factor of obesity-associated T2DM. Inflammatory cytokines induce lipolysis, thermogenesis, and satiety. In this regard, the inflammatory response is a compensatory event to obesity-associated stress with beneficial effects on energy metabolism. It is time to reconsider inflammation activity in obesity for protective activities.

Keywords: Obesity; Chronic inflammation; Insulin resistance; Type 2 diabetes; Clinical trial
Immune Discov.
2025,
1
(2), 10007; 
Open Access

Review

20 March 2025

The Fate and Dynamics of Neural Stem Cells (NSCs) and Their Neurogenic Decline in Alzheimer’s Disease

Neural stem cells (NSCs) are crucial for neurogenesis in the mammalian brain, supporting the generation of neurons and glial cells during both development and adulthood. However, aging—driven by factors such as reduced growth factors, heightened inflammation, oxidative stress, and epigenetic modifications—leads to a decline in NSC activity, which is closely associated with cognitive decline. This article explores the significant reduction in neurogenesis observed in Alzheimer’s disease (AD), where amyloid-beta (Aβ) accumulation, tau pathology, mitochondrial dysfunction, and chronic neuroinflammation disrupt NSC function in the hippocampus and subventricular zone (SVZ). These disruptions impair NSC proliferation, differentiation, and migration, contributing to the progression of cognitive deficits. Additionally, this article examines experimental studies suggesting that deficits in neurogenesis often precede amyloid plaque formation in animal models, positioning impaired neurogenesis as a potential early biomarker for AD. Therapeutic strategies targeting neurogenesis, epigenetics, and inflammation—such as anti-inflammatory treatments, environmental enrichment, and modulation of systemic factors—hold promise for reversing neurogenic deficits and enhancing cognitive function. Furthermore, this article discusses both pharmacological agents and non-pharmacological strategies that show potential in promoting neurogenesis, though further research is needed to evaluate their safety and efficacy. The decline of NSC is driven by many interconnected factors, making it challenging to understand and address fully. This highlights the need for ongoing research.

Keywords: Alzheimer’s disease; Neural stem cells; Adult hippocampal neurogenesis; Subventricular zone (SVZ) neurogenesis; Amyloid-beta; Tau pathology; Neuroinflammation; Therapeutic strategies
Lifespan Dev. Ment. Health
2025,
1
(2), 10005; 
Open Access

Review

02 December 2024

The Interplay of Heart Failure and Lung Disease: Clinical Correlations, Mechanisms, and Therapeutic Implications

Heart failure (HF) is a common clinical syndrome marked by reduced cardiac output, elevated intracardiac pressures, and heart dysfunction. Chronic HF (CHF) is a syndrome characterized by a lack of blood flow and impaired pumping ability to the heart over time, while acute HF (AHF) arises suddenly due to incidents like myocardial infarction or cardiac arrest. HF has a significant impact on pulmonary health and function, leading to conditions such as pulmonary edema and restrictive lung patterns. Clinical evidence highlights the bidirectional relationship between HF and lung dysfunction. Declining lung function serves as a predictor for HF progression and severity, while HF contributes to worsening lung health. Animal models that induce HF through surgical methods further demonstrate the connection between heart and lung pathology. The main mechanisms linking HF and lung dysfunction are pressure overload and chronic systemic inflammation, with changes in the extracellular matrix (ECM) also playing a role. Additionally, environmental factors like air pollution exacerbate lung inflammation, increasing the risk of both HF and chronic obstructive pulmonary disease (COPD) incidence. Combined treatment approaches involving pharmaceutical drugs such as statins, Angiotensin-converting enzyme (ACE) inhibitors, and Angiotensin receptor blockers (ARBs) may benefit by reducing inflammation. This review will explore the complex interplay between HF and lung function, emphasizing their interconnected pathophysiology and potential integrated treatment strategies.

Keywords: Chronic heart failure (CHF); Acute heart failure (AHF); Lung dysfunction; Chronic systemic inflammation; Pressure overload
J. Respir. Biol. Transl. Med.
2024,
1
(4), 10020; 
Open Access

Review

15 November 2024

Ion Channels in the Immune Response of Asthma

Asthma is a common respiratory disorder characterized by chronic inflammation of the lower airways, contributing to significant morbidity, mortality, and a substantial global economic burden. It is now understood as a heterogeneous condition, with ongoing research shedding light on its complex immunological underpinnings. Ion channels, which are specialized transmembrane proteins that facilitate ion movement based on electrochemical gradients, play a crucial role in the pathophysiology of asthma. Ion channels regulate essential processes like maintaining epithelial hydroelectrolyte balance and also play a role in modulating immune responses involved in asthma. We discuss the connection between ion channel activity and immune regulation in asthma, focusing on ion channel regulation of immune cell behavior, airway hyperresponsiveness, and inflammation in asthma. Understanding ion channels in asthma could lead to the development of targeted therapies modulating their activity, thereby enhancing disease management and patient outcomes.

Keywords: Asthma; Lung disease; Ion channel; Immune cells; Inflammation
J. Respir. Biol. Transl. Med.
2024,
1
(4), 10019; 
Open Access

Article

31 March 2024

The Asthma Risk Gene, GSDMB, Promotes Mitochondrial DNA-induced ISGs Expression

Released mitochondrial DNA (mtDNA) in cells activates cGAS-STING pathway, which induces expression of interferon-stimulated genes (ISGs) and thereby promotes inflammation, as frequently seen in asthmatic airways. However, whether the genetic determinant, Gasdermin B (GSDMB), the most replicated asthma risk gene, regulates this pathway remains unknown. We set out to determine whether and how GSDMB regulates mtDNA-activated cGAS-STING pathway and subsequent ISGs induction in human airway epithelial cells. Using qPCR, ELISA, native polyacrylamide gel electrophoresis, co-immunoprecipitation and immunofluorescence assays, we evaluated the regulation of GSDMB on cGAS-STING pathway in both BEAS-2B cells and primary normal human bronchial epithelial cells (nHBEs). mtDNA was extracted in plasma samples from human asthmatics and the correlation between mtDNA levels and eosinophil counts was analyzed. GSDMB is significantly associated with RANTES expression in asthmatic nasal epithelial brushing samples from the Genes-environments and Admixture in Latino Americans (GALA) II study. Over-expression of GSDMB promotes DNA-induced IFN and ISGs expression in bronchial epithelial BEAS-2B cells and nHBEs. Conversely, knockout of GSDMB led to weakened induction of interferon (IFNs) and ISGs in BEAS-2B cells. Mechanistically, GSDMB interacts with the C-terminus of STING, promoting the translocalization of STING to Golgi, leading to the phosphorylation of IRF3 and induction of IFNs and ISGs. mtDNA copy number in serum from asthmatics was significantly correlated with blood eosinophil counts especially in male subjects. GSDMB promotes the activation of mtDNA and poly (dA:dT)-induced activation of cGAS-STING pathway in airway epithelial cells, leading to enhanced induction of ISGs.

Keywords: cGAS-STING pathway, GSDMB, ISGs, Asthma, Airway inflammation
Open Access

Meeting Report

20 February 2024

The Cellular and Metabolic Bases of Organ Fibrosis: UNIA Workshop 2023 in Baeza, Spain

Fibrosis is defined by scarring and tissue hardening caused by excess deposition of extracellular matrix components, mainly collagens. A fibrotic response can occur in any tissue of the body and is the final outcome of an unbalanced reaction to inflammation and wound healing induced by a variety of insults, including persistent infections, autoimmune reactions, allergic responses, chemical exposure, radiation, and tissue injury. The accumulation of extracellular matrix proteins replaces the living tissue and disrupts the architecture leading to organ malfunction. Fibrosis remains a major clinical and therapeutic challenge and has been estimated to account for 45% of deaths in the developed world. While major advances regarding mechanistic knowledge on the underlying cell biology alterations in fibrosis have helped to characterize the main phases and mediators involved, this knowledge has not yielded significant progress in treatment. Only recently, the metabolic features associated to fibrosis have begun to emerge. This information, likely representing only the tip of the iceberg, suggests that metabolic derangement is a key culprit in the pathophysiology of fibrogenesis. The Workshop on The Cellular and Metabolic Bases of Organ Fibrosis, International University of Andalusia, Baeza, Spain, October 8–11, 2023 aimed to discuss the current knowledge and novel perspectives on the mechanisms contributing to the development of fibrosis in different organs and tissues, with particular focus on new methodological developments in metabolomics and therapeutic strategies.

Keywords: Fibrosis; Fibroblast; Inflammation; Metabolism; Tissue repair
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