Function (Oxford, England)最新文献

Inflammation is a critical immune response to tissue injury or infection, involving a cascade of molecular and cellular events. This review examines acute inflammation, focusing on the key receptors, signaling pathways, mediators, and cellular players involved in the response throughout the body. The latter part of the review narrows its focus to kidney inflammation, a vital organ often affected by both sterile and nonsterile insults. By exploring the roles of immune and nonimmune cells, this review highlights general inflammatory mechanisms and their impact on kidney-specific pathophysiology.

Circadian rhythms influence the pathophysiological effects of alcohol. This review examines how alcohol disrupts circadian regulation in peripheral organs, particularly the liver, intestine, cardiovascular system, and skeletal muscle, and how circadian disruption exacerbates metabolic dysfunction and organ injury. Evidence from preclinical and human studies indicates that both genetic and environmental circadian disruption increase alcohol-induced gut permeability, systemic inflammation, and liver disease. This review also presents how other lifestyle and environmental factors such as diet, smoking, and shift work worsen circadian disruption and alcohol-related toxicity. Emerging circadian-based therapeutic strategies and key research priorities are discussed. Advancing understanding of alcohol-circadian interactions is essential for developing more effective, personalized treatments for alcohol-associated diseases.

Alcohol use for pain relief dates back centuries. This profound analgesic efficacy also represents a strong motivational force that drives excessive drinking, fostering the development and severity of alcohol use disorder (AUD) in vulnerable individuals. Paradoxically, excessive alcohol drinking contributes to a multifactorial neuropathy, increasing nociceptive sensitivity (termed hyperalgesia) and pain-related negative affect, which may promote further alcohol use to manage either pre-existing or newly emerging pain symptoms via stress-related neural damage and potentiation of negative reinforcement behavioral systems. These close relationships reflect the urgent need for better research conceptualizations and translational successes for the treatment of both chronic pain and addiction-related disorders. Mitochondrial health is particularly important across critical networks of neurons and nociceptive fibers, where continuous bioenergetic supply is required for axonal transport, repair, and synaptic transmission. Specific bioenergetic mechanisms underlying peripheral nerve damage and subsequent central nervous system adaptations in functional association with pain and excessive alcohol drinking are starting to be discovered. This focused review proposes that mitochondrial damage may unify several convergent pathophysiological mechanisms known to manifest in the context of both chronic pain and AUD, and to be particularly relevant for vulnerable patient populations such as persons living with human immunodeficiency virus (HIV). Future research directions aimed at developing and testing novel therapeutic avenues to support mitochondrial health may provide safer and more effective medications for the management of both chronic pain states and AUD.

Bronchopulmonary dysplasia (BPD) is a serious and often lethal complication of pre-term birth that typically manifests about one month after pre-term delivery. The lungs of premature infants are underdeveloped and vulnerable to mechanical damage, inflammation, and oxidative stress. Collectively, these stressors impair the normal alveolarization of the premature lungs after birth. The multifactorial pathophysiology of BPD necessitates the identification of the molecular factors that mediate cell-to-cell communication that discriminate normal lung development from progression to BPD. Extracellular vesicles (EV) mediate intercellular crosstalk by transporting functional molecules, including proteins and nucleic acids, to recipient cells through biological fluids. This feasibility study determined the utility of profiling the discarded plasma-derived EV proteome to predict BPD susceptibility risk in extremely preterm infants. Discarded plasma was obtained from routine laboratory draws from infants born at less than 32 weeks of gestation and weighing less than 1500 grams. Plasma EVs were captured using a magnetic bead-based immunoaffinity method. Subsequently, mass spectrometry and differential protein content analysis workflow identified a novel nine-EV-protein signature (APOD, HNRNPM, HMGN2, ITLN1, PRTN3, RBM4, RBMX, TAF15, TCERG1) that distinguished preterm infants who developed BPD from those who did not. Application of machine learning statistical modeling using Promor tool trained on the nine-protein signature template identified a high specificity and selectivity prognostic threshold for the development of BPD. HNRNPM emerged as the most consistent biological response component predicting development of BPD in our patient cohort. Our study suggests that circulating EVs derived from discarded plasma are a suitable "liquid biopsy" to help stratify the vulnerability risk for BPD in preterm infants.

Background: Beyond the pineal gland, melatonin is produced locally in many extrapineal organs where it mediates local tissue homeostasis. However, little attention is paid to the physiological role of autocrine melatonin signaling across body organs. This study synthesizes original data to address this gap, as gaining insight into this topic could lead to new therapeutic approaches for diseases associated with melatonin. Methods: This systematic review employed a narrative synthesis, following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2020 guideline standards to synthesize original articles published between January 2000 and July 2025, using the Wiley Online Library and PubMed databases. Results: From the 41 studies reviewed, various targets for the physiological relevance of autocrine melatonin signaling in pineal and extra-pineal sites were noted. In descending order, the targets were immunoregulatory switch (8 studies), ovary and reproductive system (7 studies), pineal gland (6 studies), gut (5 studies), skin and hair follicles (3 studies), retina (3 studies), testes (3 studies), liver and metabolic tissues (2 studies), bone (2 studies), cardiovascular/endothelial compartment (1 study) and mitochondria (1 study). Conclusions: A layer of melatoninergic biology that is different from the traditional pineal endocrine signal and has biological and clinical significance is autocrine melatonin signaling in the pineal and numerous extra-pineal locations. While there is a translational potential, thorough mechanistic human research and better assays are required due to model heterogeneity and scarcity of human data.

Inflammation, which is commonly associated with lung and neurological disorders, undermines a form of spinal serotonin-dependent respiratory motor plasticity elicited by moderate acute intermittent hypoxia (mAIH), known as phrenic long-term facilitation (pLTF). In adult rats, pLTF suppression has been studied 24 hours following exposure to low-dose lipopolysaccharide (LPS) or 8 hours of intermittent hypoxia simulating sleep apnea. In this timeframe, pLTF is suppressed by an adenosine 2A (A^2A) receptor and p38 MAP kinase-dependent mechanism. However, the duration of plasticity suppression following acute inflammation is unknown. We hypothesized that pLTF recovers when neuroinflammatory molecules return to normal. Thus, in Sprague Dawley rats, we assessed pLTF, ventral spinal (C3-C6) adenosine, and pro-inflammatory molecules post-LPS (100 μg/kg i.p.). LPS increased spinal adenosine and microglial inflammatory genes at 24 hours, but not 1-week post-LPS. Regardless, mAIH-induced pLTF remained suppressed for 3 weeks, and then slowly recovered between 3 to 5 weeks post-LPS. Thus, pLTF suppression outlasts active inflammation. Contrary to 24 hours, at 1-week post-LPS, spinal A2A receptor inhibition (MSX-3) failed to restore pLTF, while spinal p38 MAPK inhibition (SB202190) rescued pLTF at both 24 hours and 1-week post-LPS. These findings suggest that distinct mechanisms underlie pLTF suppression at 24 hrs vs 1-week post-LPS, although both mechanisms share downstream p38 MAPK signaling. Since mAIH is emerging as a therapeutic modality to improve respiratory and non-respiratory motor function in people with neurological disorders, targeting p38 MAPK may prevent persistent plasticity suppression in individuals with a history of inflammation.

Kidneys are central in maintaining acid-base homeostasis by recovering filtered bicarbonate (HCO3-) in the proximal tubule and by secreting H+ in the collecting duct. Here, we demonstrate a critical role of the exchange protein directly activated by cAMP (Epac) signaling, and particularly the Epac2, in governing renal adaptation to dietary acid load. RNAseq analysis of the renal cortical area revealed that Epac1&2 deficiency was associated with changes in gene profile seen in acidosis. Renal expression of Epac2 but not Epac1 was enhanced by acid load. Epac2-/- mice developed a pronounced metabolic acidosis due to the inability to acidify urine in response to dietary acid load. Deletion of Epac2 and Epac1 exerted additive inhibitory actions on expression of the Na+/H+ exchanger (NHE-3, Slc9a3) in the proximal tubule. Using super-resolution STED microscopy, we detected NHE-3 redistribution to the base of the brush border, which led to the impaired recovery after acidification in freshly isolated split-opened proximal tubules from Epac1&2-/- mice. Deletion of Epac2 but not Epac1 diminished H+ secretion in freshly isolated split-opened collecting ducts, compromised apical translocation of V-ATPase, and reduced anion exchanger 1 (AE1, Slc4a1) expression in the A-type intercalated cells, and caused lower levels of titratable acids in urine, whereas ammoniagenesis was not compromised. Overall, we demonstrate a previously unrecognized role of Epac signaling in renal adaptation to dietary acidification. While both Epac1 and Epac2 isoforms control NHE-3-dependent H+ secretion in the proximal tubule, only Epac2 is essential to augment H+ transport in the collecting duct to acidify urine.

Our bone health as an adult is defined by patterns of development in early life, with perturbed growth during fetal and neonatal periods predisposing individuals to poor bone health in adulthood. Studies have identified poor maternal diet during pregnancy as a critical factor in shaping offspring bone development, with significant impacts on adult bone structure and health. However, the association between a father's diet and the bone health of his offspring remains poorly defined. To address this knowledge gap, we fed male C57BL/6 mice either a control normal protein diet (NPD; 18% protein) or an isocaloric low-protein diet (LPD; 9% protein) for a minimum of 8 wk. Using these males, we generated offspring through artificial insemination, in combination with vasectomized male mating. Using this approach, we derived offspring from either NPD or LPD sperm but in the presence of NPD or LPD seminal plasma. Using micro-computed tomography and synchrotron X-ray diffraction, we observed significant changes in offspring femur morphology and hydroxyapatite crystallographic parameters from just 3 wk of age in offspring derived from LPD sperm or seminal plasma. We also observed that differential femur morphology and hydroxyapatite crystallographic parameters were maintained into adulthood and into a second generation. Analysis of paternal sperm identified a down regulation of 26 osteogenic genes associated with extracellular matrix levels and maintenance, transcription and growth factors, and bone ossification. These observations indicate that poor paternal diet at the time of conception affects offspring bone development and morphology in an age and generation specific manner.

The extent of walking impairment varies among individuals with peripheral artery disease (PAD), which may reflect differences in the adaptability of lower extremity muscles to ischemia-reperfusion injury characteristic of the disease. Analyses of gastrocnemius muscle biopsies from 113 individuals with PAD [mean ankle-brachial index (ABI) = 0.65 ± 0.13, 38 (33.6%) women, 76 (67.2%) Black] showed a wide range of myofiber type distributions (9.6%-82.6% type 1 myofibers). The abundance of oxidative type 1 myofibers negatively correlated with ABI (r = -0.22, P = 0.02), a measure of PAD severity. The abundance of type 1 myofibers also negatively correlated to 2a/x myofiber abundance (r = -0.76, P < 0.001). Eighty % of participants had NCAM+ myofibers, a potential indicator of myofiber denervation. Overall, 3.2% of total myofibers were NCAM+. Of 113 muscle biopsies, 86 (76.1%) contained type 1 myofibers with regions lacking intermyofibrillar mitochondria (IMFM-), which may represent formation of target myofibers. In type 1 myofiber IMFM- areas, 77.8% contained 2x myosin heavy chain and/or the autophagy marker LC3. Electron microscopy within one muscle with IMFM- myofibers confirmed sarcomere disruption in IMFM- regions. These analyses support the possibility of type 2 myofibers transitioning to type 1 in PAD and suggest IMFM- target fibers may represent visualization of this process for the first time. Because type 1 myofibers are more resistant to oxidative damage, results suggest the possibility that a higher proportion of type 1 myofibers in PAD with increasing disease severity may be a compensatory mechanism to maintain muscle.