Ischemic stroke remains a leading cause of death and long-term disability, driven by oxidative stress, inflammation, and cellular energy failure. Among the adaptive mechanisms activated during ischemia, autophagy a lysosomal degradation process plays a paradoxical role in determining neuronal fate. This review provides a comprehensive analysis of autophagy’s temporal and context-dependent functions in ischemic stroke. Autophagy is initially activated as a neuroprotective response to clear damaged organelles and misfolded proteins, thereby maintaining mitochondrial integrity and reducing oxidative stress through the regulation of AMPK, mTOR, and SIRT1 signaling pathways. However, when excessively sustained, autophagy becomes maladaptive, promoting neuronal apoptosis, blood–brain barrier disruption, and neuroinflammation. Selective autophagy forms including mitophagy, lipophagy, ribophagy, pexophagy, and aggrephagy further modulate ischemic outcomes by targeting specific subcellular components for degradation. Experimental evidence demonstrates that controlled activation of autophagy alleviates ischemic injury, while overactivation leads to cellular demise. Pharmacologic modulators such as rapamycin, resveratrol, metformin, and propofol have shown potential in restoring autophagic balance and reducing infarct size in preclinical models. Collectively, autophagy functions as a double-edged sword in ischemic stroke, where its beneficial or detrimental effects depend on timing, duration, and intensity of activation. Understanding the molecular switches governing this balance could enable the design of targeted autophagy modulators to optimize neuroprotection and recovery in ischemic stroke.

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.

Alzheimer's disease (AD) and atherosclerosis (AS) are traditionally viewed as distinct neurodegenerative and vascular disorder respectively. However, emerging evidence reveals a profound molecular cross-talk and pathophysiological interplay between these two conditions. This review explores the molecular crossroads where AD and AS converge, identifying shared signaling pathways that offer novel therapeutic opportunities. At the center of this connection is amyloid-beta (Aβ), which serves as a systemic molecular nexus. While central Aβ accumulation is a hallmark of AD, peripheral Aβ, produced in tissues such as skeletal muscle and pancreas, can cross the blood-brain barrier (BBB) to induce endothelial dysfunction and neurovascular inflammation. This review highlights how common molecular hubs, including the PI3K/AKT/GSK3β, mTOR, PP2A, and PTEN signaling pathways, drive the pathogenesis of both diseases by regulating oxidative stress, inflammation, and autophagy. By addressing these shared mechanisms, the review proposes a paradigm shift toward dual-purpose therapies. Modulating Aβ clearance, inhibiting the over-activated GSK3β, or utilizing mTOR inhibitors and PP2A activators could concurrently mitigate neurodegeneration and stabilize atherosclerotic plaques. Ultimately, recognizing AD and AS as interconnected systemic disorders provides a compelling rationale for multidisciplinary clinical strategies and integrated pharmacological interventions to improve outcomes in an aging population.

Preeclampsia (PE), a major hypertensive disorder of pregnancy, is increasingly recognized as a significant risk factor for cognitive decline and Alzheimer's disease (AD). Placental ischemia in PE leads to an anti-angiogenic state, characterized by elevated soluble FMS-like tyrosine kinase-1 (sFlt-1) and reduced placental growth factor (PlGF) and vascular endothelial growth factor (VEGF), causing systemic endothelial dysfunction. These alterations may persist during the postpartum period, promoting cerebrovascular impairment, blood-brain barrier (BBB) disruption, and neuroinflammation. Furthermore, PE is associated with the release of AD-related proteins, including amyloid-beta (Aβ) and hyperphosphorylated tau protein. However, the potential link between AD and PE regarding the angiogenic and anti-angiogenic factors is not fully elucidated. This review aims to explore the shared pathophysiological pathways, focusing on the angiogenic and anti-angiogenic factors. The manuscript also evaluates the potential for repurposing pharmacological agents to mitigate the long-term risk of AD in women with a history of PE.

Hyperemesis gravidarum (HG) is a severe and potentially life-threatening form of nausea and vomiting in pregnancy, characterized by intractable vomiting, dehydration, electrolyte imbalance, nutritional deficiencies, and significant weight loss. Despite being a leading cause of early pregnancy hospitalization, its management remains inconsistent and often empirical. Emerging evidence suggests a paradigm shift in the understanding of HG pathophysiology, moving beyond traditional hormonal theories toward an integrated model involving genetic susceptibility and metabolic signaling pathways, particularly Growth Differentiation Factor 15 (GDF15) and RYR2-related mechanisms. This narrative review critically synthesizes current evidence regarding the evolving biological basis of HG and evaluates established and emerging therapeutic strategies. A multimodal, stepwise approach remains the cornerstone of management. First-line pharmacotherapy includes doxylamine–pyridoxine, followed by dopamine antagonists or 5-HT3 receptor antagonists such as metoclopramide and ondansetron, which demonstrate reassuring safety profiles in large cohort studies. Corticosteroids may be considered in refractory cases. Early correction of dehydration, electrolyte disturbances, and thiamine deficiency is essential to prevent complications such as Wernicke’s encephalopathy. Nutritional support, preferably through enteral tube feeding rather than parenteral nutrition, should be prioritized when oral intake is inadequate. Integrating biological insights with standardized, compassionate, and multidisciplinary care may improve clinical outcomes and reduce the substantial physical and psychological burden associated with HG.

Choriocarcinoma is a rare but highly aggressive gestational trophoblastic tumor, characterized by early vascular invasion and distant metastasis. While cure rates exceed 90

Obesity is a complex metabolic disorder driven by factors such as chronic inflammation, insulin resistance, and significant alterations in the gut microbiota. Dipeptidyl peptidase-4 (DPP-4), an enzyme primarily known for inactivating incretin hormones like glucagon-like peptide-1 (GLP-1), is now recognized as a critical link between metabolic dysfunction and gut microbiome dysbiosis. This review aims to examine the mechanistic role of DPP-4 and its inhibitors in obesity, specifically focusing on how they modulate the gut microbiome to influence host energy balance and metabolic health. Recent experimental and clinical evidence indicates that DPP-4 activity contributes to obesity by influencing microbial composition, diversity, and function. Studies demonstrate that DPP-4 inhibitors can reshape the gut microbiota by reducing dysbiosis, decreasing the Firmicutes-to-Bacteroidetes ratio, and enhancing the production of short-chain fatty acids (SCFAs). Furthermore, these inhibitors improve gut barrier integrity and regulate bile acid metabolism, which helps attenuate systemic inflammation and restore insulin sensitivity. While DPP-4 inhibitors are often weight-neutral in clinical settings, they appear to assist in maintaining metabolic stability by enhancing central satiety signaling and reducing neuroinflammation. The gut microbiome acts as a key intermediary in the metabolic regulation managed by DPP-4. By restoring microbial balance and promoting beneficial metabolites, DPP-4 inhibitors offer therapeutic advantages that extend beyond traditional glycemic control to include improved energy equilibrium and reduced adiposity. Targeting the interactions between DPP-4 and the microbiota represents a promising future therapeutic strategy for managing obesity and its associated metabolic complications.

Gestational trophoblastic neoplasia (GTN) includes a unique group of human neoplastic diseases that derive from fetal trophoblastic tissues. Choriocarcinoma is the most aggressive type of GTN, and patients tend to develop early systemic metastases. It can be either gestational or non-gestational in origin. Although most patients with gestational trophoblastic neoplasia are cured by chemotherapy and tumor resection, some patients suffer from metastatic diseases that are refractory to conventional chemotherapy. Therefore, new therapeutic regimens are needed to reduce the toxic effects associated with current chemotherapy and to salvage the occasional non-operable patients with recurrent and chemo-resistant disease. Until the fundamental biology of gestational trophoblastic neoplasia becomes more clearly understood, development of a new treatment will remain empirical. It has been shown that the antidiabetic metformin, by its antiproliferative effect, can reduce the proliferation and metastasis of choriocarcinoma. However, the fundamental cellular and molecular mechanisms of metformin in treating gestational choriocarcinoma are not fully elucidated. Therefore, this review will briefly summarize the recent advances in understanding the molecular mechanisms of metformin in gestational choriocarcinoma.

Biological aging is the risk factor underlying most of the chronic diseases of late life, such as cardiovascular disease, cancer, and neurodegeneration. Despite more than fifteen years of intensive research and the evaluation of hundreds of candidate compounds, no pharmacological therapy has yet been approved to target aging itself, leaving clinical medicine without an intervention that addresses the fundamental driver of multi-morbidity in older populations. It has been shown that the anti-diabetic metformin reduces mortality and the incidence of several age-related diseases in both diabetic and non-diabetic populations, independent of glycemic control. At standard therapeutic plasma concentrations achieved in aged human tissues, metformin engages multiple interconnected hallmarks of aging, such as activation of AMP-activated protein kinase (AMPK), inhibition of mechanistic target of rapamycin (mTOR) signaling, restoration of autophagy, modulation of other signaling pathways, improvement of mitochondrial function, and attenuation of senescence-associated inflammatory signaling. Large observational cohorts and meta-analyses further demonstrate that metformin use is associated with mechanistic plausibility, epidemiological consistency, and an unparalleled long-term safety record. Conversely, metformin may adversely affect the aging process when administered in aged animals, suggesting a controversial role of metformin effect on aging process. Nevertheless, the exact cellular and molecular mechanisms of the anti-aging role of metformin are not fully elucidated. Thus, this review integrates preclinical, epidemiological, and randomized clinical evidence supporting the role of metformin in aging to discuss and explain the possible anti-aging role of metformin.

Alzheimer's disease (AD) represents the most common cause of dementia in the elderly population worldwide. However, most of the anti-AD medications did not resolve the underlying neuropathology. Consequently, targeting other signaling pathways may be helpful in the management of AD. Particularly, preprotein convertase subtilisin/kexin type 9 (PCSK9), which is a regulator protein of low-density lipoprotein (LDL), is intricate in the pathogenesis of AD. Normally expressed PCSK9 in the brain plays a critical role in the regulation of neuronal differentiation and apoptosis, and degradation of LDL receptors (LDLRs). However, exaggerated brain PCSK9 via induction of inflammation and oxidative stress and related neurodegeneration may induce AD development. Therefore, neuronal PCSK9 has dual role in the CNS. Nevertheless, the exact role of PCSK9 in AD neuropathology is still elusive. Therefore, in the review, we try to revise and discuss the potential role of PCSK9 in the pathogenesis of AD, and how targeting of this protein may be helpful in the management of AD.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the accumulation of α-synuclein, mitochondrial dysfunction, and chronic neuroinflammation. In this complex pathology, pituitary adenylate cyclase-activating polypeptide (PACAP) has become a crucial neuroprotective regulator; however, its signaling pathways are markedly impaired in Parkinson's disease (PD). This review consolidates the increasing evidence that PACAP counteracts the pathogenesis of PD through multiple mechanisms: restoring autophagic flux, diminishing oxidative stress, altering the balance from pro-apoptotic to anti-apoptotic pathways, and alleviating microglial-mediated neuroinflammation. Recognizing the difficulties associated with peptide-based therapies, we explore novel strategies to utilize PACAP's protective properties, including the repurposing of FDA-approved medications like linagliptin and metformin, which engage PACAP-dependent pathways. Despite preclinical models consistently demonstrating significant neuroprotective effects, there is a marked absence of clinical validation. This review integrates mechanistic insights, evidence from particular models, and potential biomarkers to establish PACAP as a promising therapeutic target and delineates a strategy for accelerating its transition from laboratory research to clinical application in PD.

Temporal lobe epilepsy (TLE) is the most common type of focal epilepsy in adults that resists the conventional anti-seizure medications (ASMs). The spontaneous epileptic seizures in TLE are initiated within one or both temporal lobes, resulting in memory impairment, mood disorders, and learning defects, and may induce the development of secondary generalized epilepsy. Furthermore, a brain water channel, aquaporin 4 (AQP4), is highly dysregulated in epilepsy. AQP4 is intricate in the regulation of neuronal excitability and the development of epileptogenesis and epilepsy. It has been shown that upregulation and mislocalization of AQP4 in the hippocampus and frontal cortex are associated with the development of post-traumatic epilepsy. Additionally, overexpression of AQP4 in certain brain regions is linked with the development of epilepsy. Contrariwise, AQP4 expression in the hippocampus and piriform cortex is deregulated following status epilepticus (SE). Likewise, a reduction of AQP4 expression is associated with the frequency and the severity of epileptic seizures in animal models. These findings highlighted that AQP4 has a dual role, either protective or detrimental, in the pathogenesis of TLE. Therefore, this review aims to discuss the beneficial and detrimental role of AQP4 in TLE.

Alzheimer's disease (AD), the leading cause of dementia, is intrinsically linked to the aging process. A central mechanism driving this association is inflammaging, a state of chronic, low-grade inflammation resulting from innate immune dysregulation. Emerging evidence suggests that inflammaging is not merely a background feature of aging but an active pathogenic driver of AD, accelerating amyloid-β accumulation, tau hyperphosphorylation, and synaptic failure. This review synthesizes the molecular circuitry connecting inflammaging to AD, detailing the synergistic roles of the NLRP3 inflammasome, impaired autophagy, TREM2 signaling, and the cGAS-STING pathway. Furthermore, we critically evaluate pharmacological strategies designed to disrupt these cascades, including specific NLRP3 inhibitors, senolytic agents, and autophagy enhancers. We propose that these therapies offer a vital complementary approach to amyloid-targeting treatments, potentially modifying disease progression by extinguishing the persistent inflammatory milieu of the aging brain.

Portulaca oleracea L., commonly known as purslane, is an herbaceous plant from the Portulacaceae family, notable for its nutritional and medicinal properties. Widely distributed in subtropical and tropical regions, it is utilized in various cuisines and traditional medicines. This report provides a comprehensive review of the bioactive components, nutritional composition, ethnomedicinal uses, pharmacological activities, clinical studies, and potential toxicities of Portulaca oleracea. Relevant materials were gathered from Google Scholar, PubMed, Scopus, and Web of Science and reviewed for important properties and updates about the plant. P. oleracea is rich in omega-3 fatty acids, antioxidants, vitamins (A, C, E), and minerals such as phosphorus, potassium, and iron. Its chemical composition includes flavonoids, alkaloids, terpenoids, organic acids, and polysaccharides, which contribute to its nutritional and pharmacological activities. The plant demonstrates diverse pharmacological effects, including anti-inflammatory, neuroprotective, antimicrobial, anticonvulsant, hepatoprotective, antidiabetic, and antitumor activities. Toxicity studies indicate dose-dependent adverse effects on vital organs such as the lungs, kidneys, and liver, highlighting the need for safe dosage standardization. Moreover, emerging evidence from preclinical and early clinical studies underscores its potential therapeutic applications but also calls for rigorous, well-designed human trials. This review also provides critical insights into how new pharmacological findings may impact future research, including the potential derivatization of plant-derived compounds with enhanced pharmacological activity. In conclusion, P. oleracea represents a nutritionally dense and pharmacologically versatile plant with significant potential for integration into therapeutic and preventive healthcare. However, further mechanistic studies, clinical trials, and safety evaluations remain essential to validate its efficacy and ensure responsible medicinal use.

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.

INTRODUCTION:Parasitic infections remain a major global health challenge involving complex interactions between pathogens and host immunity. Emerging evidence indicates that epigenetic mechanisms, including DNA methylation, histone modifications, chromatin remodeling, and non-coding RNAs, critically regulate immune responses and influence host susceptibility, resistance, and disease progression. METHODS:This review synthesizes current evidence on epigenetic regulation of host immunity during parasitic infections, focusing on mechanisms underlying immune activation, immune evasion, host susceptibility, and parasite persistence. Emerging epigenetic biomarkers and therapeutic strategies targeting epigenetic pathways are also considered. RESULTS:Parasites can manipulate host epigenetic machinery to evade immune surveillance, suppress protective responses, and establish persistent infections. Conversely, epigenetic regulation in immune cells modulates cytokine production, macrophage polarization, T-cell differentiation, and immune memory, thereby influencing infection outcomes. Parasite-derived epigenetic factors and non-coding RNAs may additionally contribute to immune modulation and immunopathology. Epigenetic signatures associated with disease severity and treatment response show potential as biomarkers, while targeting epigenetic pathways may enhance antiparasitic immunity. DISCUSSION:Epigenetic regulation represents a central mechanism governing host-parasite interactions. Integrating advanced approaches, including single-cell epigenomics and spatial transcriptomics, may clarify cell-specific mechanisms and identify novel biomarkers and therapeutic targets. These advances could support personalized strategies to improve antiparasitic treatment and disease outcomes.

OBJECTIVES:To explore and discuss the possible neuroprotective effect of metformin in multiple sclerosis (MS), with emphasis on its metabolic mechanisms, particularly AMP-activated protein kinase (AMPK) activation and growth differentiation factor 15 (GDF15) induction. METHODS:A narrative review of recent preclinical and clinical studies examining the cellular and molecular effects of metformin relevant to neurodegeneration and MS was conducted. Literature addressing mitochondrial function, inflammatory signaling, oxidative stress, and metabolic pathways modulated by metformin were analyzed to elucidate its potential mechanisms in MS. RESULTS:Findings across multiple studies indicate that metformin exerts neuroprotective effects by modulating mitochondrial homeostasis, reducing oxidative stress, and attenuating pro-inflammatory pathways. Metformin has been shown to influence immune-inflammatory responses, improve metabolic balance in neural and immune cells, and potentially ameliorate pathological processes associated with disease progression in both human MS and animal models. DISCUSSION:Metformin demonstrates promising potential as an adjunct therapeutic agent in MS due to its capacity to modulate key metabolic and inflammatory pathways involved in neurodegeneration and neuroinflammation. Although current evidence supports its beneficial effects, the precise mechanisms by which metformin influences MS pathophysiology remain partially elucidated. Further targeted studies are required to clarify these mechanisms and to determine its clinical relevance in neuroimmune modulation and MS management.