Sodium-glucose cotransporter 2 (SGLT2) inhibitors protect kidney function in diabetic and non-diabetic chronic kidney disease. By reducing proximal sodium-glucose transport, they initiate nephron-wide adaptations in transport workload, solute delivery, oxygen demand, tubuloglomerular feedback, glomerular vascular tone, and metabolic and inflammatory signaling. These responses may reduce mitochondrial stress, ferroptosis, inflammation, maladaptive repair, and fibrosis, while natriuresis, altered substrate use, and cardiac unloading provide additional protection. Although large outcome trials establish clinical efficacy, the contributions of individual pathways remain uncertain and may vary with diabetes type, nephron number, disease stage, and background therapy. This review integrates experimental and clinical evidence into a multiscale physiological model, distinguishes established effects from mechanistic hypotheses, and identifies priorities for physiological phenotyping, spatial and single-cell profiling, biomarker-guided combination therapy, and causal systems-level studies.
Sodium–glucose cotransporter 2 (SGLT2) inhibitors confer robust kidney and cardiovascular protection that extends beyond glycemic control, yet the physiological mechanisms remain incompletely understood. This review highlights how mathematical modeling has advanced understanding of SGLT2 inhibitor actions across tubular transport, tubuloglomerular feedback, renal hemodynamics, and oxygen energetics. Models predict that SGLT2 inhibition redistributes nephron transport work, lowers intraglomerular pressure via enhanced macula densa signaling, and produces spatially heterogeneous effects on cortical and medullary oxygen demand. Modeling studies further clarify treatment responses in diabetes, reduced nephron number, and sex-specific transporter architectures, while emerging human-based frameworks link transporter-level inhibition to clinical endpoints. Together, integrative modeling provides a quantitative bridge between molecular targets and cardiorenal outcomes.
Atherosclerosis is closely associated with vascular aging, where cellular senescence actively drives lesion initiation and progression. Senescent endothelial cells, vascular smooth muscle cells, and immune cells accumulate within plaques and secrete senescence-associated secretory phenotype factors that sustain inflammation, extracellular matrix remodeling, and thrombosis. Key mechanisms include DNA damage, telomere attrition, mitochondrial dysfunction, oxidative stress, impaired autophagy, and epigenetic reprogramming. Major signaling pathways such as p53/p21, p16INK4a/Rb, Nuclear Factor Kappa B (NF-κB), NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome, and AMP-activated Protein Kinase - Sirtuin Axis (AMPK-SIRT) axes are involved in the vascular senescence process. Extrinsic factors such as hyperglycemia, dyslipidemia, disturbed flow, infection, smoking, and hormonal changes further accelerate vascular senescence. Critically, single-cell and spatial transcriptomics have uncovered heterogeneous senescent cell populations with distinct inflammatory, fibrotic, and metabolic signatures, challenging uniform therapeutic approaches. Emerging therapies, including senolytics, senomorphics, metabolic modulators, and targeted delivery systems, offer promising strategies for precision cardiovascular intervention, though translational barriers remain.
Cognitive impairment is a core feature of schizophrenia and is among its most treatment-resistant symptom domains. Included in this area of cognitive impairment are working memory deficits, attention problems, compromised executive control, and reduced cognitive flexibility. Research shows that these cognitive deficits are most likely due to the malfunctioning of specific corticolimbic circuits. This review synthesizes findings from clinical neuroimaging, electrophysiology, and preclinical mechanistic studies to examine circuit-specific contributions to cognitive dysfunction in schizophrenia. We focus on four principal networks: the dorsolateral prefrontal cortex (DLPFC)–hippocampal circuit, the ventromedial prefrontal cortex (vmPFC)–amygdala circuit, the thalamocortical system, and the salience–executive network interaction. Multiple clinical neuroimaging approaches, including functional magnetic resonance imaging (fMRI), positron emission tomography (PET), magnetic resonance spectroscopy (MRS), electroencephalography (EEG), and diffusion tensor imaging (DTI), along with preclinical models involving N-methyl-D-aspartate (NMDA) receptor hypofunction, interneuron disruption, and pharmacological circuit manipulation, identify associations between circuit-level abnormalities and cognitive, emotional, and sensory-gating deficits, as well as impaired network switching. Targeting these circuits to restore functional integration/operation includes NMDA modulators, GABAergic enhancers, anti-inflammatory agents, various forms of rTMS, tDCS/tACS, cognitive remediation, and neurofeedback. The vulnerability of circuits and the response to treatments may be influenced by multiple factors, including developmental trajectories, sex, and other specifics, underscoring the need for stratified evaluation. A circuit-specific mechanistic framework may inform targeted therapeutic strategies, but their cognitive and functional benefits require confirmation in adequately powered longitudinal trials.
Ischemia-reperfusion injury (IRI) is a major cause of organ dysfunction, with mitochondrial impairment playing a central role. Aging increases susceptibility to IRI through microvascular remodeling, destabilization of mitochondrial membrane potential (ΔΨm), impaired mitochondrial quality control (MQC), and inflammaging, thereby creating biological barriers that limit the efficacy of conventional mitoprotective strategies. Over the past few years, nanoplatforms have evolved from relatively simple targeting systems to multistep and pathology-responsive designs that enhance mitochondrial localization and therapeutic exposure in heart, kidney, brain, and liver IRI models. However, most current strategies have been validated primarily in young models and remain focused largely on oxidative stress modulation. Future studies should prioritize the evaluation of delivery efficiency and long-term functional outcomes in aged models. Integrating MQC-targeted approaches with regulation of the autophagy-lysosome axis may further help overcome age-related constraints and improve translational relevance.
Methamphetamine (METH) is a highly addictive psychostimulant that profoundly remodels brain circuits underlying compulsive drug seeking, cognitive impairment, and relapse. Although extensive pharmacological, circuit-based, and neuroimaging studies have identified widespread alterations in cortical and subcortical networks, these findings have not yet been integrated into a comprehensive circuit-level framework. In this review, we synthesize current evidence on how METH-induced remodeling of excitatory/inhibitory (E/I) balance reshapes neural circuitry to drive behavioral adaptations and addiction. We highlight how METH disrupts dopaminergic, glutamatergic, and GABAergic neurotransmission within corticostriatal and mesocorticolimbic pathways, while also altering noradrenergic and cholinergic signaling. Emerging circuit nodes, including the claustrum and cerebellum, are discussed as previously underappreciated contributors to METH-associated neuroadaptations. Furthermore, neuroimaging studies consistently demonstrate aberrant connectivity across large-scale brain networks, particularly the default mode, salience, and frontoparietal networks. Collectively, converging evidence identifies the medial prefrontal cortex (mPFC) as a central integrative hub that coordinates cortical and subcortical communication governing reward processing, executive control, and relapse vulnerability. Based on these findings, we propose a unified framework in which METH-induced remodeling of E/I balance within the mPFC disrupts cortical-subcortical network integration, thereby promoting maladaptive reward processing, cognitive dysfunction, and relapse. This circuit-based perspective provides a mechanistic framework for understanding METH addiction and identifies mPFC-centered network dysfunction as a promising target for future therapeutic interventions.
More than one billion individuals worldwide are at risk of contracting dengue. Dengue virus (DENV) is a ssRNA(+)-flavivirus transmitted by Aedes mosquitoes. While most infections are mild (uncomplicated dengue), severe/hemorrhagic dengue carries substantial mortality and lacks specific treatment. Severe dengue is characterized by endothelial dysfunction, which can arise during both primary and secondary infection. In the latter, antibody-dependent enhancement of infection is a well-recognized risk factor, although the mechanistic links between viral infection and endothelial barrier failure remain unclear in either setting. Beyond inflammatory injury to the endothelium, DENV and other flaviviruses can trigger endothelial trans-differentiation toward a mesenchymal, migratory phenotype, weakening cell–cell junctions and compromising vascular integrity. In this review, we discuss the mechanical component of flavivirus-induced endothelial trans-differentiation and its impact on endothelial dysfunction, highlighting prospective mechanobiological targets for therapeutic intervention.
The human brain regulates perception, movement, emotion, motivation, and autonomic function through interconnected neural circuits. Emotional adaptation depends on coordinated interactions among reward, limbic, and prefrontal networks that govern motivation, threat detection, and cognitive control. Disruption of these processes underlies major depressive disorder (MDD), now viewed as a disorder of dysfunctional circuitry rather than solely neurochemical imbalance. Neuroimaging consistently reveals altered connectivity within cortico-limbic, cortico-striatal, and default mode networks, correlating with symptoms such as anhedonia, rumination, and negative affect. While early models emphasized monoaminergic deficits, systems neuroscience highlights impaired communication among mood, reward, and control networks. This review synthesizes recent human and preclinical evidence to advance understanding of the multiscale neural mechanisms underlying MDD, including intrinsic brain activity, neural oscillations, and highlights emerging circuit-based therapeutic strategies.
Cerebral cavernous malformation (CCM) is a sporadic or familial vascular disorder characterized by disorganized vascular structures and abnormal angiogenesis. Germline loss-of-function mutations in one of the genes encoding the CCM complex proteins, CCM1 (KRIT1), CCM2, or CCM3 (PDCD10), lead to familial CCM, whereas somatic loss-of-function mutations in CCM genes and gain-of-function mutations in MAP3K3 (encoding MEKK3) and PIK3CA have been shown to be associated with sporadic CCM. Loss of CCM protein function results in aberrant activation of the MEKK3 signaling pathway, upregulation of the shear-responsive transcription factors Krüppel-like factor 2 (KLF2) and Krüppel-like factor 4 (KLF4), increased production of inflammatory cytokines, and enhanced activation of RhoA and its downstream effectors, the Rho-associated kinases. These signaling alterations promote actin stress fiber formation and destabilization of endothelial cell–cell junctions. Interacting proteins such as HEG1 and CDC42 also play important regulatory roles in CCM-associated signaling networks.
Mitochondrial involvement in cardiomyopathy presents with a complex genetic landscape, requiring precise variant classification and interpretation. Apart from limited reports, mitochondrial variants among Asian cardiomyopathy patients may benefit from reassessment via the latest guides and evidence. In this review, mitochondrial variants reported in 67 Asian cardiomyopathy studies (1990–2025) were systematically reviewed, aggregating 93 reported mitochondrial variants. These variants underwent rigorous reassessment using updated American College of Medical Genetics and Genomics/Association for Molecular Pathology mitochondrial-specific guidelines to ensure the latest variant interpretation. Following a comprehensive synthesis, 21 clinically significant variants were identified (17 confirmed pathogenic/likely pathogenic, 4 newly reclassified likely pathogenic). Conversely, 25 variants were reclassified as benign, while 47 remained as variants of uncertain significance. Mapping the clinically significant variants revealed a major mutational hotspot within the MT-TL1 gene. Ultimately, this study refines the mitochondrial mutational spectrum in Asian populations, providing vital insights to enhance future diagnostic accuracy and patient care.
Physiological health is governed by redox signaling networks, whose dysregulation is central to numerous pathological conditions. Exercise, as a powerful physiological stimulus, can finely regulate this network. Moderate activity boosts tissue resilience through adaptive oxidative signaling, while intense, prolonged exertion can cause multi-organ damage by overwhelming antioxidant defenses. Although the biphasic response to exercise is widely recognized, the precise threshold where benefits turn detrimental remains elusive due to individual variability. This review examines these dose-dependent effects on oxidative stress and their implications for skeletal muscle, cardiovascular and respiratory systems, gut barrier integrity, and neurological performance, providing a framework for personalized exercise and nutrition.
Episodic memory enables humans to reconstruct personal experiences and events in terms of their content, temporal, and spatial context (what, where, and when). These episodic memories can then be used as templates to anticipate or imagine future events, which is the basis for future-oriented planning and proactive action. Deficits in remembering past experiences can severely impair affected individuals in their private and professional lives. With the development of the episodic-like object memory task, it became possible to investigate the retrospective and reconstructive part of this future-oriented planning and action system in laboratory rats and mice. Using the episodic-like object memory paradigm, the neural circuit underlying this multimodal and integrative memory system has been investigated using lesion and disconnection studies, as well as electrophysiological methods. This article provides an overview of the progress made in deciphering the neuroanatomical basis of episodic-like object memory in rats and mice.
Pulmonary hypertension (PH) in elderly patients is increasingly prevalent and is associated with a high comorbidity burden and poor clinical outcomes. Unlike young-onset pulmonary arterial hypertension, elderly PH — mainly World Health Organization group 2 and group 3 PH — is closely linked to pulmonary vascular aging, mitochondrial dysfunction, chronic inflammation, and vascular stiffening, mechanisms insufficiently targeted by current therapies. Pigment epithelium-derived factor (PEDF) is a multifunctional secreted glycoprotein involved in endothelial stability, oxidative stress regulation, inflammatory signaling, and mitochondrial homeostasis. Emerging evidence suggests that PEDF signaling is dysregulated in PH and may influence pulmonary vascular remodeling through modulation of mitochondrial stress responses, endothelial dysfunction, and oxidative injury. However, its role in pulmonary vascular aging remains poorly characterized. This review summarizes the potential relevance of PEDF in the interaction between mitochondrial dysfunction and pulmonary vascular aging in elderly PH and highlights PEDF-dependent pathways as potential modulators and therapeutic targets in aging-associated pulmonary vascular disease.
Physiology, like most scientific disciplines, is the product of colonial epistemologies. The question is how to engage in meaningful efforts to deconstruct coloniality in physiological research, teaching, and learning — and if so, how to go about it. Any effort to address this issue must engage people and individuals historically marginalized or underrepresented in the discipline, since Physiology, and thus Physiology education, is at the foundation of medicine. This work would have broad implications for teaching, research, and healthcare practice. In this essay/review, I reflect on how colonial epistemologies underpin modern Physiology and higher education. I follow with a discussion of possible frameworks for decolonial work in Physiology and map recent contributions to the literature on inclusive teaching to these frameworks.
Extended reality (XR) is increasingly used in medical education to teach physiology. Physiology instruction has evolved from lectures and laboratories to simulation and computer-based models, yet traditional approaches do not fully represent the dynamic nature of physiological processes. XR offers a way to visualize these processes in motion and allows learners to interact with them. Some studies report improved engagement, conceptual understanding, and short-term skill retention, though results are inconsistent and long-term benefits remain unclear. Adoption is limited by cost, equipment access, faculty training, and a lack of standardized assessment tools. Questions about user comfort and cognitive load also require further study. Future research should include stronger study designs, clearer outcome measures, and guidance for integrating XR into curricula. Generative AI may support more adaptive learning experiences, but its educational value has not been established. At present, XR appears most useful as a supplement to traditional physiology teaching rather than a replacement.
The balance between the learning of fearful events against safety is critically important for adaptive behavioural responses in human and non-human animals. Safety learning can occur through the extinction of fear memory, a new, inhibitory memory that competes with the original fear memory. In this brief review, we provide an update on rodent-based mechanistic insights into the canonical fear extinction neurocircuitry (basolateral amygdala, medial prefrontal cortex and hippocampus), before considering the role of distributed extinction circuits. Next, we focus on emerging themes in specific circuitry and neural substrates, including i) dopaminergic-dependent prediction error coding, ii) glutamatergic signalling through N-methyl-D-aspartate receptors and iii) excitatory and inhibitory balance at local synaptic, inhibitory gating and engram levels. Last, we consider whether our increased understanding of fear extinction neurocircuitry has led to the development of novel therapeutic strategies, including L-DOPA and D-cycloserine compounds, aimed at augmenting impaired fear extinction in psychopathology.
Axon initial segments are the main site of action potential initiation. Since the seminal discoveries by Grubb & Burrone and Kuba et al., which showed that axon initial segment length and location can be dynamically changed, a large number of studies have investigated the role of structural axon initial segment plasticity, particularly in light of homeostatic maintenance of neuronal activity and disease states. Recent advances are now starting to shed light on the role of axon initial segments in neuronal circuit function, as well as learning and memory, opening new avenues to understand axon initial segment plasticity in adaptive neuronal dynamics and behavior in health and disease.
