Adenosine (adenosine, Sanofi / Adenoscan inj / Adenosine, Pfizer)

Author Correction: Remote control of AMPK via extracellular adenosine controls tissue growth.

Zhang Yao Y, Strassburger Katrin K, Teleman Aurelio A AA

Caffeine and Exercise in Obesity-Associated Brain Aging and Neurodegeneration: Mechanistic Insights into AMPK/SIRT1/PGC-1α, BDNF/TrkB, and NLRP3 Inflammasome Signaling.

Yan Xiao X, Li Jianying J, Wang Ting T

Brain aging and neurodegenerative disorders are increasingly associated with metabolic dysfunction, chronic low-grade inflammation, and physical inactivity. Obesity may accelerate adverse brain aging through neuroinflammation, insulin resistance, mitochondrial dysfunction, altered metabolic flexibility, and impaired neuroplasticity. Physical exercise remains a cornerstone strategy for metabolic and brain health, although individual responses vary. Caffeine has emerged as a potential adjunct to exercise because of its ergogenic effects and its ability to modulate adenosine signaling, energy metabolism, inflammation, and neuroplasticity. This narrative review critically synthesizes human and preclinical evidence on caffeine, exercise, and their combination in relation to exercise performance, metabolic health, cognitive function, brain aging, and neurodegeneration, with particular emphasis on obesity. Acute caffeine ingestion may improve selected aspects of exercise performance, perceived exertion, alertness, and cognition, whereas chronic caffeine use combined with exercise may favor body composition, cardiometabolic health, and neuronal resilience. Responses depend on caffeine dose and timing, habitual intake, exercise modality and intensity, and individual characteristics. Mechanistic evidence indicates convergence on adenosine A1/A2A receptors, AMPK/SIRT1/PGC-1α, BDNF/TrkB, mitochondrial quality control, and NLRP3-related inflammatory signaling, providing a plausible basis for complementary effects on metabolic adaptation, neuroinflammation, mitochondrial homeostasis, and synaptic plasticity. However, direct evidence demonstrating true caffeine-exercise synergy, particularly for human brain aging or neurodegenerative outcomes, remains limited, with substantial reliance on indirect and preclinical findings. Caffeine should therefore be considered a context-dependent adjunct rather than a disease-modifying intervention. Future adequately powered, long-term randomized trials integrating cognitive outcomes, neuroimaging, and mechanistic biomarkers are needed to establish whether combined interventions exert additive, synergistic, or independent effects and to develop safe, personalized protocols.

Indole-3-Propionic Acid Disrupts Glycolytic Adaptation and Promotes Oxidative Stress-Associated Injury in Oral Squamous Cell Carcinoma.

Taghavi Pourianazar Negar N

Oral squamous cell carcinoma (OSCC) shows aggressive invasion, frequent recurrence, and marked metabolic adaptability. Microbial tryptophan metabolites are increasingly recognized as potential modulators of cancer-related signaling; however, the direct role of indole-3-propionic acid (IPA) in OSCC remains poorly defined. This study examined whether IPA suppresses malignant fitness in HSC-3 and SCC-25 cells while using OKF6/TERT-1, an immortalized human oral keratinocyte cell line, as a non-malignant comparator where biologically appropriate. HSC-3 and SCC-25 cells were treated with vehicle or IPA. Based on the calculated IC50 values from 72 h viability assays, fixed concentrations of 300 µM IPA for HSC-3 cells and 400 µM IPA for SCC-25 cells were selected for subsequent functional experiments. OKF6/TERT-1 cells were used as a non-malignant comparator for baseline transcriptional analyses. Metabolic activity was assessed by the MTS assay. Cytotoxicity and cell death-related stress were additionally examined using lactate dehydrogenase release and colorimetric caspase-3 activity assays. Migration was determined by a wound-healing assay. Metabolic adaptation was evaluated by glucose consumption, lactate secretion, conditioned-medium pH, intracellular adenosine triphosphate, spectrophotometric intracellular reactive oxygen species measurement, and quantitative real-time polymerase chain reaction. Baseline profiling showed that glycolysis-associated transcripts were consistently higher in HSC-3 and SCC-25 cells than in OKF6/TERT-1 cells, with the strongest malignant shift observed in HSC-3. IPA (300 µM for HSC-3, 400 µM for SCC-25) reduced 72 h viability to 55.3% in HSC-3 and 64.8% in SCC-25 cells. IPA increased intracellular reactive oxygen species by 1.86-fold in HSC-3 and 1.49-fold in SCC-25 cells, increased caspase-3 activity, and elevated lactate dehydrogenase release. In parallel, glucose consumption, lactate secretion, adenosine triphosphate content, and migration decreased, whereas conditioned-medium pH and CDH1 expression increased. IPA may directly suppress OSCC cell survival, motility, and glycolytic adaptation while promoting oxidative stress-associated injury and modulating epithelial-mesenchymal transition markers. This metabolic framework may provide a novel experimental direction for OSCC research.

Polydeoxyribonucleotide Promotes Longitudinal Bone Growth Through the Hepatic JAK2-STAT5/IGF-1 Axis Involving A2A Receptor Signaling.

Jeong Kyung-Min KM, Choi Yu-Jin YJ, Yang Seong-Been SB, Kweon Minson M et al.

Longitudinal bone growth is primarily regulated by the growth hormone (GH)-insulin-like growth factor-1 (IGF-1) axis. However, non-hormonal and orally administered strategies for promoting longitudinal growth remain limited. Here, we investigated the effects and mechanisms of polydeoxyribonucleotide (PDRN) on longitudinal bone growth in vitro and in vivo. In HepG2 cells, PDRN significantly increased IGF-1 mRNA expression and JAK2 and STAT5 phosphorylation without affecting cell viability. Pretreatment with ZM241385, a selective adenosine A2A receptor (A2AR) antagonist, significantly attenuated these responses, supporting the involvement of A2AR signaling. In mice, oral PDRN for 5 weeks significantly increased body length gain, growth plate thickness, and hepatic JAK2/STAT5 activation, elevating serum IGF-1 levels without altering GH levels or systemic toxicity markers. Quantitative micro-computed tomography analysis demonstrated improved trabecular and cortical bone microarchitecture with reduced porosity. Furthermore, PDRN modulated bone remodeling-related responses by suppressing lipopolysaccharide-induced osteoclastogenic marker expression in RAW 264.7 cells and enhancing osteogenic marker expression while downregulating RANKL in MC3T3-E1 cells. Overall, oral PDRN promotes longitudinal bone growth and improves microarchitecture via increased hepatic IGF-1 signaling and altered bone remodeling-related gene expression, supporting its potential as an oral candidate for skeletal growth.