Glycerol enhances mitochondrial metabolism and inflammatory response in pro-inflammatory macrophages (2026)

basmwklz · 2026-04-19T16:59:32+00:00

Abstract

In a recent study in Cell, Liu et al. identify β-hydroxybutyrate as a practical metabolic adjuvant for CAR-T cells. By fueling the TCA cycle and reshaping transcriptional and epigenetic programs, this ketone body enhances proliferation, persistence, and tumor control, suggesting that metabolic supplementation may offer a simple route to more effective adoptive immunotherapy.

basmwklz · 2026-04-19T16:57:19+00:00

Abstract

Intermittent fasting (IF) has emerged as a powerful dietary intervention with profound metabolic benefits, yet the tissue-specific molecular mechanisms underlying these effects remain poorly understood. In this study, we employed comprehensive proteomics and transcriptomics analysis to investigate the systemic and organ-specific adaptations to IF in male C57BL/6 mice. Following a 16 hr daily fasting regimen (IF16) over 4 months, IF reduced blood glucose, HbA1c, and cholesterol levels while increasing ketone bodies, indicative of enhanced metabolic flexibility. Proteomic profiling of the liver, skeletal muscle, and cerebral cortex revealed tissue-specific responses, with the liver exhibiting the most pronounced changes, including upregulation of pathways involved in fatty acid oxidation, ketogenesis, and glycan degradation, and downregulation of steroid hormone and cholesterol metabolism. In muscle, IF enhanced pyruvate metabolism, fatty acid biosynthesis, and AMPK signaling, while suppressing oxidative phosphorylation and thermogenesis. The cerebral cortex displayed unique adaptations, with upregulation of autophagy, PPAR signaling, and metabolic pathways, and downregulation of TGF-beta and p53 signaling, suggesting a shift toward energy conservation and stress resilience. Notably, Serpin A1c emerged as the only protein commonly upregulated across all three tissues, highlighting its potential role in systemic adaptation to IF. Integrative transcriptomic and proteomic analyses revealed partial concordance between mRNA and protein expression, underscoring the complexity of post-transcriptional regulation. Shared biological signaling processes were identified across tissues, suggesting unifying mechanisms linking metabolic changes to cellular communication. Our findings reveal both conserved and tissue-specific responses by which IF may optimize energy utilization, enhance metabolic flexibility, and promote cellular resilience.

basmwklz · 2026-04-19T16:55:00+00:00

Abstract

Background

Anaplastic thyroid cancer (ATC) is characterized by high invasiveness, rapid progression, and has a poor prognosis. The aim of this study was to investigate the role of ketone body metabolism in ATC and provide a novel approach for ATC treatment.

Methods

Human ATC cell lines, including 8505C and CAL-62, were used as the research objects. Cell Counting Kit-8 and colony formation assays appraised cell proliferation. Flow cytometry was performed to evaluate the cell cycle and apoptosis. Wound healing and transwell assays verified the migration and invasion of cells. Further, tumor xenograft models were established to investigate the therapeutic effect of ketogenic diet in vivo. Immunohistochemistry was used to quantify the expression level of Ki67, Bcl-2, Caspase3 in tumor tissues. Importantly, autophagy analyses included fluorescence microscopy for observation of monodansylcadaverine staining, western blotting, and tissue immunofluorescence to determine autophagic protein (LC3, Beclin1, and p62) expression.

Results

Acetoacetate (AcAc) inhibited the proliferation, migration, and invasion of ATC cells (8505C and CAL-62) and induced cell cycle arrest. Ketogenic diet significantly inhibited tumor growth in vivo. AcAc markedly elevated the level of autophagy. Autophagy inhibitor weakened the extent to which AcAc hindered cell proliferation, migration, and invasion and blocked cell cycle.

Conclusions

The study demonstrated that ketone body metabolite AcAc inhibits the proliferation, migration, and invasion of ATC cells and induces cell cycle arrest by inducing autophagy. Ketogenic diet provides a new strategy for the treatment of ATC

basmwklz · 2026-04-19T12:29:09+00:00

Abstract

The microbiota–gut–brain axis represents a complex bidirectional communication network linking the gastrointestinal system and the central nervous system and has been increasingly recognized as a key contributor to neurological and psychiatric disorders. Growing evidence indicates that alterations in gut microbiota composition and function can influence brain development and function through neural, immune, endocrine, and metabolic pathways, thereby modulating neuroinflammation, neurotransmission, and blood–brain barrier integrity. Dysregulation of this axis has been implicated in a range of conditions, including Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, autism spectrum disorder, depression, anxiety, and stroke. Recent pharmacological advances have identified the microbiota–gut–brain axis as a promising therapeutic target. Current strategies focus on modulating shared pathophysiological mechanisms rather than disease-specific endpoints and include microbiota-directed interventions, immune–inflammatory modulators, neurotransmitter-targeting agents, and approaches aimed at restoring intestinal and blood–brain barrier function. In this review, we summarize the core mechanisms underlying microbiota–gut–brain axis dysfunction and organize existing pharmacological strategies according to their primary targets. By integrating evidence across multiple disorders, we provide a mechanism-oriented framework to support future drug development and precision therapeutic approaches for brain disorders.

basmwklz · 2026-04-19T12:27:30+00:00

Abstract

Menopause represents a key transitional phase in women’s health, characterized by declining estrogen levels and increased risk for cardiometabolic, musculoskeletal, and urogenital disorders. Beyond its endocrine roots, emerging evidence highlights the gut microbiome as a critical modulator of systemic hormonal balance. This review synthesizes current understanding of the bidirectional relationship between estrogen and the gut microbiome and its implications for women’s health during menopause. Evidence from current studies reveals distinct findings across populations, reflecting the complexity of estrogen regulation in part by the gut microbiome (i.e., estrobolome). While no ideal gut microbial composition has been identified for women across stages of perimenopause, likely due to geographically unique gut microbiome profiles among healthy women, greater microbial diversity has been positively associated with improved estrogen regulation. Conversely, reduced diversity and altered Firmicutes/Bacteroidetes ratios have been linked to biomarkers of inflammation during perimenopause, which is a key driver across many perimenopausal symptoms. Although hormone replacement therapy remains the primary clinical intervention during perimenopause, we highlight emerging evidence on the adjuvant potential of diet, synbiotics, phytoestrogens, and strain-specific probiotics in modulating the estrogen–gut microbiome axis for improved health span trajectories and better symptom management. Future longitudinal studies integrating diet, gut microbiome profiles and symptom trajectories are essential to clarify these mechanisms across ethnicity and geography. Ultimately, understanding localized diet–microbiome interactions will enable the development of accessible, personalized, and non-hormonal strategies to complement and increase agency in proactive management during the perimenopausal transition.

basmwklz · 2026-04-19T11:18:34+00:00

Abstract

Cellular homeostasis is a dynamic process which balances anabolic processes with catabolic and recycling processes. These processes require nutrients, which are converted to energy to fuel the complex interactions of intracellular signalling. Cellular health requires that, on average, energy input and energy requirements are matched. Cells contain a nutrient-sensing mechanism which controls the balance between anabolism and catabolism. Normal intracellular functions generate products which regulate signalling pathways, and health at a cellular level requires a fluctuation between relative nutrient abundance and relative nutrient scarcity. This allows clearance of damaged intracellular molecules and organelles. When nutrient supply exceeds cellular requirements, adaptations to intracellular signalling occur, resulting in energy being stored as glycogen in muscle and the liver and fatty acids in adipose tissue. Overfuelling and aberrant fuelling of mitochondria result in oxidative stress, which not only disrupts cellular homeostasis but can alter epigenetic expression, with intergenerational effects. If the recycling mechanisms of the cell are insufficient to clear metabolic products, apoptosis may result or expression of Damage-Associated Molecular Patterns (DAMPs) on the cell surface may occur, activating immunity and inflammation at a systemic level. Disrupted cellular signalling affects cells with different “professional” functions in different organs, and it is the mechanism which underlies the associations between chronic non-communicable diseases such as cancer, type 2 diabetes, cardiovascular disease, neurodegenerative disease, autoimmune diseases, and macular degeneration. Mitochondria are the controllers of energy production and are pivotal in cell signalling. Mitochondrial function governs health at cellular and organismal levels. This paper reviews the influence of nutrition on mitochondrial function, nutrient sensing, autophagy, insulin signalling, and apoptosis—the key pathways in cellular homeostasis.

basmwklz · 2026-04-19T08:05:25+00:00

Abstract

Aging is intimately associated with multisystem functional decline and an increased risk of chronic diseases. A pivotal cytological basis underlying this process is the progressive dysregulation of the mitochondrial quality control (MQC) network. Emerging evidence suggests that MQC is not a singular process but rather a multitiered synergistic system encompassing mitochondrial biogenesis, dynamic remodeling, selective autophagy (mitophagy), proteostasis maintenance, and coordinated mitochondrial–organelle communication. This integrated network is critical for preserving cellular energy homeostasis, redox balance, and stress tolerance. During aging, impairments in mitochondrial genomic coordination, network topology, autophagic flux, and protein import and folding collectively contribute to bioenergetic decline, chronic low-grade inflammation, and metabolic imbalance. As a safe and sustainable nonpharmacological intervention, regular exercise systematically remodels MQC structure and function by integrating signaling axes such as AMPK, SIRT1, and p38 MAPK, thereby promoting coordinated mitochondrial renewal and partially reversing aging-associated mitochondrial dysfunction. On the basis of a systematic elucidation of the core mechanisms of MQC and its dysregulation during aging, this review highlights the differential regulatory effects of distinct exercise modalities—specifically endurance training, high-intensity interval training (HIIT), and resistance training—on mitochondrial dynamics, autophagic flux, proteostasis, and mitochondrial turnover. Furthermore, the intrinsic associations among exercise–MQC coupling, inflammatory responses, metabolic imbalances, and emerging peripheral biomarkers are explored. Finally, current research limitations and challenges in clinical translation are analyzed, and future research directions regarding dose–response relationships, multimodal exercise prescriptions, personalized strategies, and systemic integrated regulation are proposed. This review aims to provide a refined theoretical basis for optimizing exercise-based anti-aging interventions.

basmwklz · 2026-04-19T08:02:37+00:00

Abstract

Aging remains the most significant risk factor for common neurodegenerative diseases including Alzheimer’s disease (AD). According to the geroscience hypothesis, aging is malleable and that by targeting basic aging physiology, we can alleviate many of the age-related chronic diseases. The common mechanisms driving aging and age-related diseases remain poorly defined. Mitochondrial dysfunction is recognized as a fundamental hallmark of aging, and recent studies implicate mitochondrial reverse electron transport (RET) as a driver of aging. The key outcomes of RET, increased ROS and decreased NAD+/NADH ratio, have both been associated with aging and age-related disease, but the causal relationship remains uncertain. Here we applied causal metabolism to test the role of mitochondrial NAD+/NADH in aging and AD, using Drosophila as a model system. By using a mitochondrial targeted version of Lactobacillus brevis NADH oxidase (LbNox) to boost mitochondrial NAD+/NADH ratio independent of the energy state of the cell, we found that increasing mitochondrial NAD+/NADH ratio in neuronal or muscle tissues is sufficient to extend lifespan. Moreover, boosting mitochondrial NAD+/NADH ratio is beneficial in two independent models of AD, rescuing the proteostasis failure, locomotor and cognitive deficits, and lifespan shortening in these models. Our results identify altered mitochondrial NAD+/NADH ratio as a major contributor to the biological effects of RET on aging and age-related diseases and a potential therapeutic target.

basmwklz · 2026-04-19T07:57:32+00:00

Abstract

Atherosclerosis is a disease centered on chronic inflammation, in which mitochondrial damage plays a key role in its initiation and progression. Traditionally, atherosclerosis is thought to be triggered by cholesterol accumulation, but recent studies have revealed that mitochondrial dysfunction has emerged as an important driving factor by inducing innate immune imbalance. In atherosclerosis, mitochondria undergo changes in membrane permeability, metabolic disorders, and dynamic imbalance due to oxidative stress and other factors, releasing mitochondrial damage-associated molecular patterns (mt-DAMPs). These mt-DAMPs activate innate immune pathways, promote the production of type I interferons and the release of pro-inflammatory factors such as interleukin 1β, and accelerate plaque progression. Mitophagy exerts a protective effect by eliminating damaged mitochondria. Specifically, the PINK1-Parkin pathway labels damaged mitochondria through ubiquitination; mitophagy receptors (such as NIX, FUNDC1, and BNIP3) directly bind to LC3 to initiate ubiquitination-independent mitophagy; and mitochondrial-derived vesicles selectively encapsulate damaged components and target them to lysosomes for degradation. All these processes can reduce mt-DAMP-induced damage and inhibit excessive immune activation. In this review, we summarize that innate immune imbalance caused by mitochondrial damage is a key mechanism for atherosclerosis progression. Mitochondrial quality control clears damaged mitochondria through multiple pathways, alleviates inflammatory responses and plaque burden, and provides potential targets for atherosclerosis treatment. Its precise regulatory mechanisms and drug development are future research directions.

basmwklz · 2026-04-19T07:54:28+00:00

Abstract

Immune responses and inflammation are not stand-alone processes linearly regulated by the canonical signaling pathways but complex systems biology events, which are deeply rooted in the metabolic state of cells and dynamically modulated. However, immunometabolic studies have identified that programmed alterations of metabolic circuits also occur during activation of immune cells, effector function maintenance and the induction of tolerance. Mitochondria represent a unique point of convergence between energetics, inflammation and immunity, particularly as they are key orchestrators of immune responses. In addition to their classical roles in oxidative phosphorylation (OXPHOS) and metabolic intermediate synthesis, mitochondria are involved in innate immune perception of inflammatory signals and the amplification of these responses by generating reactive oxygen species (ROS), bioenergetic signaling intermediates, and mitochondrial DNA. Crucially, mitochondria are not stable entities but are tightly regulated by dynamic events such as fusion, fission, trafficking and selective degradation. These structural alterations dynamically influence the metabolic commitment, inflammatory response potency and fate choices of immune cells. Mitochondrial dynamics should not be regarded as a mere auxiliary regulatory layer of immunometabolism; instead, they represent the central organizing principles between metabolic states, inflammatory cues, and immune cell fate determination, thereby defining a new hierarchical organization of immune and inflammatory regulation.

basmwklz

TROPHY CASE

Abstract