Asthma is a heterogeneous chronic inflammatory airway disease characterized by persistent inflammation, dysregulated immune signaling, and progressive airway remodeling. It has been shown that asthma pathogenesis involves multiple signaling pathways. It has been illustrated that the mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2 (MAPK/ERK1/2) cascade, which emerges as a central regulator linking immune activation, epithelial dysfunction, and structural remodeling of the airway, is implicated in the pathogenesis of asthma. Sustained ERK1/2 activation is consistently demonstrated in human asthmatic airways and experimental models, correlating with disease severity, inflammatory cell infiltration, and corticosteroid resistance. This review provides a comprehensive and critical discussion of the ERK1/2 signaling in asthma, spanning immune cells, airway epithelium, and airway smooth muscle. We evaluate preclinical and translational evidence supporting ERK1/2 as a therapeutic target and examine emerging pharmacological strategies, including indirect pathway modulation via AMP-activated protein kinase (AMPK) activation and drug repositioning with the anti-diabetic metformin. By integrating mechanistic insights with therapeutic implications, this review positions ERK1/2 as a pivotal signaling node for precision targeting in severe, treatment-refractory asthma.

Preeclampsia is a hypertensive disorder of pregnancy that has emerged as a significant prenatal risk factor for autism spectrum disorder (ASD) in offspring. Accumulating epidemiological and experimental evidence suggests that placental dysfunction, systemic inflammation, oxidative stress, and impaired cellular autophagy in preeclampsia contribute to fetal neurodevelopmental disturbances. This review elucidates the shared molecular pathways between preeclampsia and ASD, including over-activation of inflammatory signaling, dysregulation of placental growth factor (PlGF), and disturbances in autophagy. Genetic overlaps between preeclampsia and ASD further strengthen the biological plausibility of this association. These findings support the hypothesis that early-onset preeclampsia induces a neuroinflammatory and hypoxic intrauterine environment that adversely programs the fetal brain, potentially leading to ASD. Understanding of these mechanisms may open new preventive strategies targeting placental health and maternal immune modulation during pregnancy to mitigate ASD risk.

OBJECTIVES:Atherosclerosis (AS) is a chronic inflammatory vascular disorder driven by endothelial dysfunction, oxidative stress, lipid dysregulation, mitochondrial injury, and maladaptive immune activation. Metformin, the first-line therapy for type 2 diabetes, has vasculoprotective effects beyond glycemic control. This review summarizes current evidence on metformin as a multi-target modulator of AS through regulation of nuclear erythroid 2-related factor 2 (Nrf2)/Krüppel-like factor 2 (KLF2) signaling, AMP-activated protein kinase (AMPK)/sirtuin-1 pathways, cyclic GMP-AMP synthase and stimulator of interferon genes (cGAS-STING) signaling, mitochondrial homeostasis, lipid metabolism, and inflammation. METHODS:Relevant studies were identified through PubMed, Web of Science, Google Scholar, and China National Knowledge Infrastructure databases, focusing on the effects of metformin on atherosclerosis and related pathways involving oxidative stress, mitochondrial function, ferroptosis, inflammation, and innate immunity. KEY FINDINGS:Metformin enhances antioxidant defenses by activating Nrf2 through Kelch-like ECH-associated protein 1 degradation and increasing cytoprotective mediators such as heme oxygenase-1 and NAD(P)H quinone oxidoreductase 1. It also modulates cGAS-STING signaling and promotes AMPK-mediated KLF2 activation, thereby improving endothelial quiescence, increasing endothelial nitric oxide synthase-derived nitric oxide, and suppressing inflammatory signaling and adhesion molecules. Furthermore, metformin protects against ferroptosis by stabilizing mitochondrial function, reducing lipid peroxidation, and limiting iron-dependent oxidative injury. It also exerts systemic anti-atherogenic effects by modulating gut microbiota, lowering trimethylamine-N-oxide, and increasing short-chain fatty acids and glucagon-like peptide-1. CONCLUSIONS:Metformin attenuates plaque formation, inflammation, expansion of the necrotic core, and instability.

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition marked by deficits in social interaction, communication and repetitive behaviours. Emerging evidence implicates dysfunction in γ-aminobutyric acid (GABA) signalling, the brain's primary inhibitory neurotransmitter system, in the pathogenesis of ASD. GABAergic neurotransmission plays a pivotal role in neurodevelopment, particularly in balancing excitatory and inhibitory signalling, synaptic plasticity and neural circuit maturation. Dysregulation in GABA synthesis, receptor expression and transport has been observed in both clinical and preclinical models of ASD, leading to disrupted neuronal connectivity and atypical behavioural phenotypes. This review critically explores the alterations in GABAergic signalling in ASD, highlighting the role of various GABA receptor subtypes (GABAAR, GABABR and GABACR) and associated transport and metabolic enzymes. The therapeutic implications of modulating GABAergic activity are also examined. Pharmacological agents, such as GABA receptor agonists, GABA reuptake inhibitors and GABA transaminase inhibitors, exhibit varied efficacy profiles. Among these, GABAB receptor agonists, including arbaclofen and baclofen, show the most promise in improving social behaviour and reducing core ASD symptoms. Conversely, some agents that elevate GABA levels, such as vigabatrin and valproic acid, may exacerbate ASD-like features under certain conditions. Collectively, the data suggest that targeted modulation of GABAergic pathways, particularly GABAB receptor signalling, offers a viable avenue for therapeutic intervention in ASD. However, further mechanistic studies and well-designed clinical trials are required to elucidate the optimal strategies for harnessing GABA modulation in ASD management.

Epilepsy is a neurological condition characterized by recurrent, spontaneous seizures stemming from sudden, abnormal synchronization of neuronal activity in specific brain regions, driven by structural or functional alterations. This disorder is preceded by epileptogenesis, a dynamic process marked by cellular and molecular changes that heighten brain excitability. Although anti-seizure medications (ASMs) remain the cornerstone of treatment, roughly 30

Heat shock protein 90 (HSP90) is a central regulator of cellular proteostasis, coordinating the folding, stabilization, and turnover of a wide range of client proteins in the cytosol, endoplasmic reticulum, and mitochondria. Accumulating evidence indicates that the four HSP90 paralogs HSP90α, HSP90β, GRP94, and TRAP1 have distinct pathological roles in neurodegenerative and metabolic diseases. In neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, aberrant HSP90 activity contributes to the persistence of toxic protein conformers, defective autophagy, mitochondrial dysfunction, and chronic neuroinflammation. In metabolic disorders such as obesity, type 2 diabetes, and metabolic dysfunction-associated steatotic liver disease, GRP94- and TRAP1-dependent signaling promotes endoplasmic reticulum stress, impaired mitochondrial metabolism, insulin resistance, and inflammatory remodeling. These mechanistic insights have accelerated the development of a new generation of HSP90 inhibitors with improved selectivity, tissue targeting, and brain penetration. Unlike earlier pan-HSP90 inhibitors, these compounds are designed to exploit paralog-specific vulnerabilities and may enable safer long-term modulation of disease-relevant chaperone networks. This review summarizes current advances in the biology and pharmacology of HSP90 paralogs and proposes isoform-selective HSP90 targeting as a promising therapeutic strategy at the intersection of neurodegeneration and metabolic dysfunction.

The brain undergoes profound molecular and structural changes during the aging process, resulting in the development of neurodegeneration, cognitive impairment, and increased vulnerability to chronic diseases. At the cellular level, brain aging is characterized by oxidative damage, genomic instability, and chronic low-grade inflammation known as inflammaging. Central to this process is Sirtuin 1 (SIRT1), a NAD+-dependent class III histone deacetylase, known for its regulatory role in chromatin remodeling, oxidative stress responses, mitochondrial biogenesis, and neuroplasticity. Recent research has identified SIRT1 as a molecular target capable of reversing or attenuating several hallmarks of aging, particularly within the central nervous system (CNS). This narrative review critically evaluates the emerging evidence surrounding the geroprotective effects of SIRT1 activators, which exert dual actions, senomorphic and senolytic, via modulation of signaling pathways, thereby reducing neuronal senescence, enhancing autophagy, and mitigating inflammatory responses. The discussion also addresses the region-specific role of SIRT1 across the brain, particularly in the hippocampus and hypothalamus, which are essential for memory, energy homeostasis, and resilience to stress. Additionally, this review explores how SIRT1 depletion during aging contributes to the development of synaptic dysfunction, impaired cognitive function, and susceptibility to neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). The therapeutic potential of SIRT1 activators is supported by preclinical and early clinical studies, suggesting their value in preventing or delaying brain aging. Thus, SIRT1 could be a promising pharmacological target for age-associated brain disorders, warranting more robust translational studies to validate these findings in humans.

Background: Parkinson's disease (PD) is a progressive neurodegenerative disorder marked by α-synuclein aggregation and dopaminergic neuron degeneration in the substantia nigra. Evidence suggests that the leukotriene (LT) pathway contributes to PD progression through oxidative stress and neuroinflammatory mechanisms. Purpose: To evaluate the efficacy and neuroprotective potential of the leukotriene receptor antagonist montelukast in the management of PD. Research Design: A narrative review synthesizing evidence from preclinical and clinical studies investigating the effects of montelukast on PD-related neuropathology. Study Sample: Studies indexed in Scopus, Cochrane, Embase, PubMed, and CENTRAL that examined the role of montelukast in PD models or populations. Data Collection and/or Analysis: Two independent reviewers conducted database searches, screened studies for relevance, and extracted data on montelukast’s effects on neuroinflammation, oxidative stress, mitochondrial function, and autophagy. Results: The reviewed evidence indicates that montelukast exhibits neuroprotective activities, including attenuation of neuroinflammation, reduction of oxidative stress, improvement of mitochondrial dysfunction, and enhancement of autophagic processes. These mechanisms collectively contribute to slowing the onset and progression of PD-related neuropathology. Conclusions: Montelukast may offer therapeutic benefits in PD by modulating key pathological processes such as inflammatory signaling, oxidative damage, mitochondrial impairment, and autophagy dysregulation. Further clinical studies are warranted to validate its potential as an adjunct or novel therapeutic option.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) deposition, tau pathology, synaptic dysfunction, neuroinflammation, and metabolic impairment. Increasing evidence suggests that bile acids, traditionally recognized for their roles in lipid digestion and hepatic metabolism, act as endocrine signaling molecules that influence central nervous system (CNS) homeostasis. Through enterohepatic circulation and microbiota-dependent biotransformation, bile acid composition is dynamically regulated and can modulate peripheral metabolic and immune pathways with downstream effects on the brain. Notably, bile acid signaling via key receptors such as the farnesoid X receptor (FXR) and the Takeda G protein-coupled receptor 5 and G-protein-coupled bile acid receptor 1 (TGR5/GPBAR1) has emerged as a mechanistic bridge linking liver–gut physiology to neuroinflammatory and neurodegenerative processes. Altered bile acid profiles have been reported in AD and mild cognitive impairment, with accumulating findings suggesting that hydrophobic secondary bile acids may contribute to blood–brain barrier (BBB) disruption and neurotoxicity. In contrast, hydrophilic bile acids may exert neuroprotective and anti-inflammatory effects. In addition, bile acids drive the release of gut hormones such as glucagon-like peptide 1 (GLP-1) and fibroblast growth factor 19 (FGF19), highlighting indirect neurometabolic pathways relevant to cognition and neurodegeneration. This narrative review synthesizes current biochemical, experimental, and clinical evidence supporting a role for bile acid signaling in AD pathogenesis and progression. We discuss receptor-mediated pathways, microbiota-bile acid interactions, neuroimmune modulation, and translational perspectives, proposing that bile acid–based biomarkers and therapeutic strategies targeting FXR/TGR5 signaling may represent promising avenues for future AD intervention.

Parkinson’s disease (PD) is a chronically progressive neurodegenerative disorder primarily characterized by the degeneration of dopaminergic neurons within the substantia nigra pars compacta (SNpc). Insulin-like growth factor 1 (IGF-1) which is a protein recognized for its neuroprotective properties is naturally declines with aging. This age-related reduction in IGF-1 and its associated signaling pathways has been hypothesized to contribute to PD pathogenesis. Intriguingly, the early stage of PD is often marked by elevated brain and peripheral IGF-1 levels, suggesting a compensatory response to counteract progressive PD neuropathology and slowing disease progression. Conversely, as neurodegeneration advances in later stages of PD, a notable reduction in both IGF-1 levels and its expression is observed. Despite these seemingly contradictory findings regarding IGF-1’s dynamic changes throughout the disease course, its precise role in the complex pathogenesis of PD remains largely undefined. This review aims to comprehensively explore and critically discuss the multifaceted involvement of IGF-1 signaling in PD, and to evaluate the potential therapeutic benefits of targeting this pathway for the effective management of the disease.

Parkinson's disease (PD) is a systemic neurodegenerative disease, and is mainly related to the progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Despite extensive research regarding PD neuropathology, there are no active drugs to avert this disease. It has been described that the adenosine pathway, which is expressed centrally and peripherally, is involved in the pathogenesis of PD and other neurodegenerative diseases. Adenosine acts on adenosine receptors (ARs), including A1R, A2AR, A2BR, and A3R. Both A1R and A3R are neuroprotective, while A2AR and A2BR are neurotoxic for the brain. A2AR, in the SNpc, mediates the neurotoxicity of adenosine in PD. In addition, data from epidemiological studies highlighted controversial findings in PD and other neurodegenerative diseases. Therefore, the present review aims to revise from published articles the potential role of the adenosine pathway in PD neuropathology, and how methylxanthines affect the dopaminergic neurotransmission in the SNpc. This review highlighted that selective A2AR antagonists could be more effective than non-selective AR antagonists in the management of motor and non-motor symptoms of PD.

Diabetes is the most serious consequence of Type 2 Diabetes Mellitus, which affects almost all vital organs in the human body. According to the World Health Organization, 537 million adults worldwide are affected by diabetes and its complications. By 2030, this figure is expected to reach 643 million, and by 2045, it will reach 783 million. Up to 25

Coronavirus disease 2019 (COVID-19) is a global pandemic disease caused by a new type of respiratory virus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The primary factors contributing to inflammatory and immunological diseases in patients with severe COVID-19 are primarily attributed to the excessive activation of T cells and macrophages, resulting in the massive release of pro-inflammatory cytokines, including interleukins and chemokines. Studies have indicated that the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) possesses anti-inflammatory properties in mitigating certain inflammatory disorders. It has been shown that inflammation and oxidative stress caused by COVID-19 infection may lead to a disruption of GABAergic neurotransmission in COVID-19 patients. GABA and GABA agonists could be potential successful treatments for the management of COVID-19 by inhibiting the release of pro-inflammatory cytokines and inflammatory pathways such as nuclear factor kappa B (NF-κB) and the nod-like receptor pyrin 3 (NLRP3) inflammasome. Therefore, the purpose of this review was to discuss the potential role of GABA and GABA agonists in the alleviation of inflammatory disorders caused by COVID-19.

Diabetes mellitus (DM) is a metabolic chronic disease distinguished by unexpectedly and inappropriately elevated levels of glucose in the blood of any individual. It has various categories depending on various causative agents or differences in the etiology of each class. Diabetes is regrettably one of the most prevalent diseases worldwide and continues to be the seventh leading cause of death in the USA. To overcome this chronic disease, significant work has been done through decades leading to various research, different management techniques and a majorly large amount of work has been done in the usage of nanotechnology. This initiative leads to the production of various formulations for the treatment of diabetes using nanotechnology. Examples of these products are insulin liposomes, insulin noisome, and gold or zinc oxide nanoparticles which show greater therapeutic efficacy and subsequently good control of DM, and these are also used for precise drug deliveries. This review covers the use of different types of nanoparticles for enhanced delivery of various hypoglycemic agents in comparison to traditional therapies. Many new research and studies about antidiabetic drugs and nanotechnology are still going on and would be so profitable in managing and treating DM.

Neurogenesis is a complex process by which the neurons and supporting cells of the central nervous system (CNS) are generated by neural stem cells. Adult hippocampal neurogenesis (AHN) in the human brain is an active process during life and plays a critical role in the regulation of memory, cognition, and mood. It has been shown that epilepsy is linked with dysregulation of AHN. Of note, AHN is very sensitive to the pathological electrical stimuli during epileptic seizures, which result in the induction of neurogenesis in acute epilepsy and inhibition of neurogenesis in chronic epilepsy. Epileptic seizure-induced neurodegeneration activates the mobilization of neural stem cells during neurogenesis to substitute for neural loss in temporal lobe epilepsy (TLE), which is the most refractory type of epilepsy. Moreover, recurrent epileptic seizures in TLE trigger neurogenesis in certain brain regions. However, AHN is a transient acute epileptic seizure that terminated with 1-4 weeks following status epilepticus (SE). Nevertheless, adult AHN is dramatically reduced in chronic epilepsy and associated with the development of cognitive impairment in TLE. These findings indicate that impairment of AHN is linked with the severity of epileptic seizures. Hence, neurogenesis activators may attenuate the pathogenesis of TLE. Therefore, this review aims to discuss and explain the beneficial role of AHN in TLE and how neurogenesis activators could be effective in the management of epilepsy.

BACKGROUND:Parkinson's disease (PD) is a neurodegenerative disease characterized by progressive neurodegeneration of dopaminergic neurons (DNs) in the substantia nigra (SN). PD neuropathology is mainly related to inflammation, mitochondrial dysfunction, oxidative stress, and endoplasmic reticulum (ER) stress. The underlying causes for the progression of PD are linked to the uncontrolled activation of different signaling pathways, such as the renin-angiotensin system (RAS), which is highly expressed in the nigrostriatal pathway. RAS has two main pathways: the classical pathway, which includes angiotensin I (AngI), AngII, angiotensin-converting enzyme (ACE), Ang type 1 receptor (AT1R), and Ang type 2 receptor (AT2R), that has a neuro-detrimental effect on PD neuropathology, and the nonclassical pathway, which includes angiotensin-converting enzyme 2 (ACE2)/Angiotensin 1-7 (Ang1-7), that has a neuroprotective effect against different neurological disorders, including PD. The nonclassical pathway is activated to overcome the harmful impact of the classical pathway on the brain, thereby converting AngII to angiotensin A (Ang-A) via mononuclear leukocyte-derived aspartate decarboxylase (MILDAD). Ang-A is further converted to the neuroprotective alamandine, which acts on the mass-related G-protein coupled receptor member D (MrgD). In PD, overactivation of the classical pathway is associated with neurodegeneration of the DNs in the SN. However, the nonclassical pathway, mainly Ang1-7/alamandine, is deregulated in PD. The objective of the review: This review aims to explore and discuss the potential role of the nonclassical RAS pathway in the pathogenesis and progression of PD and its implications for future therapeutic strategies.

Objectives: The diagnosis of Parkinson's disease (PD) is mainly based on the assessment of motor symptoms, although the influence of non-motor symptoms sometimes may be more significant on the patient's disability than the cardinal clinical signs of the disease. The predominant subtype of postural instability and gait disturbance is known to be associated with more severe non-motor symptoms of Parkinson's disease. Yet, the association between motor subtypes and specific mood symptoms remains understudied. The study aimed to analyze an association between sleep and chronotype signs, motor subtypes, with the severity of depressive symptoms in PD patients. Methods: We have included 64 patients in the clinical study. The studied population was divided into the following groups: PIGD group - patients with PD and dominance of postural instability and gait disorders; nonPIGD group - patients with PD and dominance of tremor or intermediate motor subtype. We used the Unified Parkinson's Disease Rating Scale, Beck Depression Inventory, Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale, and Munich Chronotype Questionnaire. Results: Patients with the PIGD subtype have higher levels of depressive symptoms and excessive daytime sleepiness, poorer sleep quality, later sleep onset and mid-sleep, longer sleep latency, and sleep inertia. PIGD motor subtype (p < 0.001), poor sleep quality (p < 0.001), mid-sleep (p = 0.016), and sleep latency (p = 0.025) had a significant impact on the level of depression in univariate regression analysis. Still, only mid-sleep (p = 0.019) and poor sleep quality (p = 0.003) increased the probability of higher severity of depression in the multivariate model. Conclusion: Poor sleep quality and later mid-sleep may be predictors of more severe depressive symptoms in PD.