The growing comorbidity between cardiovascular and neuropsychiatric disorders presents a major global health challenge. This reciprocal interaction worsens patient prognosis and hinders the diagnosis and treatment of these comorbid conditions. In recent years, the concept of the "gut-heart-brain axis" has highlighted the central pathogenic and therapeutic role of the gut microbiota in linking these distal systems. This review therefore aims to clarify this axis and to explore how specific gut microbiota metabolites modulate this bidirectional physiological interaction. We have integrated recent research to elucidate how gut microbiota dysbiosis regulates cardiovascular-neuropsychiatric comorbidities through the following convergent pathways: gut barrier disruption leading to metabolic endotoxemia; NLRP3 inflammasome activation; adaptive immunity shifting towards Th17 cell dominance and suppressing regulatory T cells; hypothalamic-pituitary-adrenal axis overactivation; and autonomic nervous system dysfunction. We critically reviewed microbiome-targeted interventions, noting that although the existing literature provides reliable epidemiological associations and proof of concept in animal models, definitive causal relationships in human populations remain insufficiently confirmed. Establishing such causal relationships between specific microbial metabolites and the outcomes of chronic cardiovascular or neuropsychiatric diseases will require rigorous longitudinal and interventional studies.
BACKGROUND:Ischemic stroke remains a major cause of disability and death worldwide, and effective neuroprotective treatments are urgently needed. This study investigated whether Terazosin (TZ), a clinically approved drug with neuroprotective potential, ameliorated Cerebral Ischemia-Reperfusion Injury (CIRI) and explored the underlying mechanisms. METHODS:This study integrated network pharmacology analysis with in vivo experimental validation to investigate the neuroprotective effects of TZ against CIRI. Neurological deficits, infarct volume, and brain edema were evaluated in mice. TTC, TUNEL, and Nissl staining, as well as Western blotting, immunofluorescence staining, and quantitative real-time PCR (qPCR), were used to evaluate cell apoptosis, inflammation, and the activity of the PI3K/AKT/mTOR signaling pathway. Potential targets associated with TZ and CIRI were obtained from public databases, followed by GO and KEGG enrichment analyses of the overlapping targets. Statistical analyses were performed using GraphPad Prism 10.1, and P < 0.05 was considered statistically significant. RESULTS:TZ treatment significantly reduced cerebral infarct volume and improved neurological function in a mouse MCAO/R model. It attenuated neuronal apoptosis, as evidenced by increased Bcl-2 expression and decreased Bax expression, and suppressed neuroinflammation, as indicated by reduced levels of pro-inflammatory cytokines IL-1β, IL-6, and TNF-α and decreased microglial activation. Bioinformatics analysis identified 140 overlapping targets between TZ and CIRI, with PIK3CA, MTOR, and several other genes emerging as key hub genes. KEGG enrichment analysis revealed significant enrichment of the PI3K/AKT signaling pathway. Further mechanistic investigations revealed that TZ activated the PI3K/AKT/mTOR signaling pathway. Importantly, the neuroprotective effects of TZ were abolished by the PI3K inhibitor LY294002, supporting an essential role of this pathway in mediating the protective effects of TZ against CIRI. DISCUSSION:These findings indicate that TZ may protect against CIRI by suppressing apoptosis and neuroinflammation through activation of the PI3K/AKT/mTOR signaling pathway, thereby providing preclinical evidence for its potential repurposing as a treatment for ischemic stroke. CONCLUSION:In summary, this study demonstrates that TZ exerts neuroprotective effects against CIRI by activating the PI3K/AKT/mTOR signaling pathway. These results provide a preclinical basis for repurposing TZ as a treatment for ischemic stroke and highlight the PI3K/AKT/mTOR axis as a potential neuroprotective target.
Introduction: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by a multifactorial etiology, including amyloid β1-42 (Aβ1-42) accumulation, oxidative stress, tau hyperphosphorylation, and neuroinflammation. Among these pathological processes, redox imbalance and inflammation are key drivers of neuronal injury and are closely linked to dysregulation of AMPK signaling. Artemisinin (ART), a clinically safe antimalarial sesquiterpene lactone, has emerged as a promising neuroprotective candidate due to its antioxidant and anti-inflammatory properties. However, its role in modulating AMP-activated protein kinase (AMPK)-dependent neuroprotection in AD remains to be fully elucidated. Given that AMPK is a master regulator of cellular energy homeostasis, oxidative stress mitigation, and neuronal survival, and that its progressive dysregulation heavily accelerates Alzheimer’s disease pathology, this study aimed to determine whether artemisinin (ART) counteracts Aβ1-42-induced neurotoxicity through the targeted activation of AMPK signaling. This work provides critical mechanistic insights supporting the therapeutic repurposing of ART for AD intervention. Methods: Therefore, Aβ1-42-insulted PC12 catecholaminergic, SH-SY5Y neuroblastoma, and primary neuronal cell cultures were used to assess the neuroprotective effects of ART. Compound C and shAMPK were used to confirm AMPK dependency. In vivo efficacy was assessed with 3xTg-AD mice. Results: ART restored viability, reduced reactive oxygen species, stabilized mitochondrial function, and prevented apoptosis. AMPK was activated by ART in a dose- and time-dependent manner and was reversed by Compound C and shAMPK. In 3xTg-AD mice, ART elevated brain P-AMPK expression. Together, these results show that ART activates AMPK in relation to neuroprotection against Aβ-induced toxicity. discussion: ART confers neuroprotection through AMPK mediated redox and inflammatory homeostasis. Repurposing ART represents a translatable strategy for AD. This is the first study linking ART induced AMPK activation to AD neuroprotection. Discussion: These findings collectively demonstrate that ART confers robust neuroprotection primarily via AMPK activation, thereby restoring redox homeostasis, preserving mitochondrial structural integrity, and suppressing caspase-dependent apoptosis. The high consistency of these therapeutic effects across complementary in vitro and in vivo models highlights the indispensable role of the AMPK cascade. Conclusion: Given its established clinical safety profile and high blood-brain barrier permeability, ART represents a compelling candidate for repurposing as a disease-modifying drug in AD.
Background: The blood-brain barrier (BBB) blocks over 98% of neuroactive drugs from reaching the brain, constituting a major obstacle to effective treatment for ischemic stroke. Nanotechnology offers innovative solutions for overcoming this barrier; however, the field currently lacks a unified framework to guide the rational design of nanocarriers. This study aims to systematically evaluate nanotechnology-based drug delivery systems for ischemic stroke according to their underlying BBB transport mechanisms-namely, adsorption-mediated transport (AMT), receptor-mediated transport (RMT), and cell-mediated transport (CMT)-and to validate the hypothesis that CMT strategies are superior for targeted delivery to the ischemic hemisphere. Methods: In a murine MCAO model, targeted nanoparticles were employed alongside a non-targeted control for original validation (n = 3/group; 60-minute occlusion; 5 mg/kg intravenous dose). Outcomes included NIR-II fluorescence imaging (1-24 hours), T2-weighted MRI (72 hours), histology, immunofluorescence, TUNEL apoptosis assays, and RNA-seq transcriptomics. Results: Compared to the AMT/RMT methods, CMT-based strategies-exemplified by neutrophil "hitchhiking" (and neutrophil elastase inhibition -demonstrated superior accumulation within the ischemic hemisphere. Targeted Nano treatment achieved: (i) significantly enhanced cerebral fluorescence at 8 hours compared to non-targeted Nano treatment (ii) a reduction in infarct volume from (iii) reduced neutrophil infiltration and decreased apoptosis (iv) preservation of blood-brain barrier integrity and reduced Evans blue extravasation; (v) absence of acute organ toxicity; and (vi) normalization of transcriptomic pathways associated with inflammation (TNF, NF-κB, IL-17) and oxidative stress. Conclusion: Endogenous cell-mediated transport(CMT) represents a superior strategy for traversing the blood-brain barrier in ischemic stroke, enabling the attainment of therapeutic drug concentrations at the lesion site while simultaneously mitigating systemic toxicity. Neutrophil-targeted nanotherapy-whether achieved through drug-loaded nanoparticle "hitchhiking" or the inhibition of neutrophil elastase-offers a paradigm-shifting approach to the treatment of acute ischemic stroke.
G Protein-Coupled Receptors (GPCRs) are the most widely used drug targets in neuropsychiatric disorders. GPR158, an orphan class C GPCR, is highly enriched in the central nervous system and has emerged as a critical regulator of stress-related depression. However, its precise mechanisms in depression remain incompletely understood. This review aims to establish a systematic framework spanning the molecular structure to physiological function, highlighting the role of GPR158 in the onset and progression of depression. We summarize the expression pattern, unique structural features, novel ligands, and downstream signaling pathways of GPR158, with a focused discussion on its multiple regulatory mechanisms in depression, including Cyclic Adeno-sine Monophosphate (cAMP) signaling, neuronal excitability, Brain-derived Neurotrophic Factor (BDNF) translation, glutamatergic transmission, and mitophagy. Abnormally upregulated GPR158 in the prefrontal cortex and hippocampus promotes depressive-like behaviours, whereas knockout or inhibition of GPR158 exerts antidepressant-like effects. These findings not only reveal the potential regulatory function of GPR158 in the pathological process of depression but also provide a solid theoretical basis for the development of antidepressant drugs targeting GPCRs, facilitating the subsequent development of more accurate and efficient antidepressant candidate drugs.
Background: Cocaine abuse is associated with an increased risk of stroke, yet the under-lying molecular mechanisms remain poorly understood. Methods: An integrated framework combining network toxicology, machine learning, Mendelian randomization (MR), single-cell RNA sequencing (scRNA-seq), virtual knockout, molecular dock-ing, and molecular dynamics (MD) simulations was applied to identify and validate key molecular links between cocaine exposure and stroke. Results: A total of 319 shared targets were identified, from which three core genes (TNF, INS, CDC42) were screened. MR analysis demonstrated a potential causal association between INS and stroke. scRNA-seq showed high expression of Ins2 (murine homolog of human INS) in epithelial cells, with extensive intercellular communication between epithelial and endothelial cells. Additionally, 196 genes exhibited significant changes following virtual knockout of Ins2, which were enriched in neurogenic and metabolic pathways. Molecular docking and MD simulations confirmed stable bind-ing between cocaine and INS. Discussion: Mechanistically, cocaine-induced stroke is mediated by a mutually reinforcing pathological network forming a "mitochondrial damage-oxidative stress-inflammation-coagulation" vicious cycle, wherein cocaine crosses the blood-brain barrier to disrupt cerebral vasculature func-tion, activate platelets, and trigger proinflammatory responses. INS, identified as a candidate gene via MR analysis (overcoming confounding biases of observational studies), is specifically highly expressed in choroid plexus epithelial cells (CPECs) and forms a choroid plexus-insulin signaling axis that regulates cerebral energy metabolism, oxidative stress, inflammation, and neurovascular homeostasis via cerebrospinal fluid. Virtual knockout of Ins2 perturbed pathways linked to energy metabolism disorder and neural repair, confirming its pivotal role in maintaining cerebral homeostasis, while stable cocaine-INS binding suggests cocaine may interfere with this protective axis. Conclusion: INS may serve as a potential key regulatory factor linking cocaine exposure with stroke risk. This study provides novel mechanistic insights and a systematic analytical framework for investigating drug-induced cerebrovascular diseases.
The dorsal raphe nucleus (DRN), the brain's primary source of serotonin, is a critical hub for regulating arousal, mood, pain, and sleep-wake cycles. Here we review what is currently known about how the DRN modulates general anesthesia. We focus on four neuronal groups, namely serotonergic, GABAergic, glutamatergic, and dopaminergic, and how they interact to shape induction and emergence. Serotonergic neurons, by promoting cortical arousal, are a key driver of anesthetic emergence; their activation accelerates recovery, while their inhibition deepens unconsciousness. GABAergic neurons provide potent local inhibition of the serotonergic system, a mechanism exploited by many anesthetic agents to induce and maintain hypnosis. Recent studies highlight functional heterogeneity within these populations, revealing that GABAergic neurons can either promote or constrain arousal depending on their projection targets, and serotonergic neurons produce opposing sleep-wake effects based on firing pattern. Glutamatergic neurons exhibit resistance to anesthetic suppression, while dopaminergic neurons encode salience and modulate pain perception. These parallel, non-serotonergic pathways expand the DRN's functional repertoire beyond its traditional serotonergic framework, and this mechanistic understanding has direct clinical implications. For patients with serotonergic disorders such as depression and anxiety, anesthetic responses often deviate from the usual pattern, so perioperative plans need to account for individual differences. Furthermore, the DRN presents a promising target for personalized anesthesia, where future strategies may leverage neuroimaging or genetic biomarkers to predict individual susceptibility and guide drug selection or novel neuromodulation therapies. Understanding the DRN at the circuit level could help translate basic neuroscience into clinical anesthetic practice and improve patient care.
BACKGROUND:Diabetic neuropathy is one of the most serious complications of diabetes mellitus, which is associated with pain, loss of sensation, and numbness in the extremities. Several cellular triggers, such as oxidative stress, inflammation, and glycation products, all cause nerve damage. These changes affect quality of life and may cause ulcers or amputations, so effective management is essential. OBJECTIVES:This review is conducted to identify and summarize the main pharmacological strategies that are used in the treatment of diabetic neuropathy, both the approved treatments and those that are currently under research. METHODS:This review was conducted by searching scientific databases and repositories, including Google Scholar, PubMed, and DOAJ, using keywords such as diabetic neuropathy, pharmacological treatment of pain, and antidepressant. After excluding articles, the final number of articles included in our study was approximately 107, comprising clinical studies and review articles. RESULTS:Tricyclic antidepressants as well as serotonin-norepinephrine reuptake inhibitors have been proven to help with neuropathic pain but can be associated with sedation or gastrointestinal side effects. The anticonvulsants, including pregabalin and gabapentin, decrease neuronal excitability and are reliable in reducing pain. Local therapies, such as capsaicin and lidocaine, are more local and less systemic. Opioids are also used in the treatment of recalcitrant cases due to risks of tolerance and dependence. Other recent alternatives, such as alpha-lipoic acid and erythropoietin, show promise for antioxidant and neuroprotective effects. DISCUSSION:In addition to traditionally approved medications, several drugs were tested as promising treatments. One of them is suzetrigine (VX548), which reduces pain and is recognized as a potential none opioid option. Engensis (VM202) also has clinical benefits. Acetyl-L-carnitine and Cibinetide (ara290) also show improvement in the Neuropathic score; other treatments, such as Nicotinamide riboside, after long-term use, were associated with symptomatic relief of pain. CONCLUSION:Managing diabetic neuropathy necessitates personalized treatment that equilibrates analgesia with tolerability. Current medications primarily alleviate symptoms; however, ongoing investigations into antioxidant and neuroprotective agents present the potential for therapies that may decelerate or reverse nerve damage.
Neuropsychiatric and neurodegenerative disorders show wide variability in treatment response, thus limiting the effectiveness of traditional symptom-based neuropharmacology. Precision medicine offers a more targeted approach by combining pharmacogenomics, multi-omics data, and artificial intelligence to guide individualized therapy. It's a rapidly evolving field with demonstrable promise, but its broader clinical integration still depends on stronger biomarker validation, reproducibility across populations, equitable implementation, regulatory maturity, and prospective clinical utility studies. Genetic markers could predict drug metabolism, while multi-omics profiling enables the identification of disease-specific molecular patterns; in parallel, AI tools improve treatment prediction, integrate complex datasets, and accelerate drug discovery. Although some of these approaches are already used in clinical practice, most remain under development. This review presents a multi-layered approach that includes neurotransmitter pathways, pharmacogenomics, multi-omics analysis, artificial intelligence, and translational science, providing a more holistic insight and bridging the gap between synaptic mechanisms and personalized treatments.
INTRODUCTION:Pregabalin is a structural analogue of γ-aminobutyric acid (GABA) that functions as a potent modulator of excitatory neurotransmission through high-affinity binding to the α2δ subunit of voltage-gated calcium channels. This review provides a comprehensive overview of its pharmacological properties, clinical efficacy, and therapeutic scope across neuropathic and non-neuropathic conditions. METHOD:This review is a narrative, descriptive, and integrative type of review conducted using current evidence regarding pharmacology, therapeutic applications, comparative efficacy, and pregabalin safety profile. RESULTS:Pregabalin exhibits rapid absorption, high bioavailability, linear pharmacokinetics, renal elimination, and minimal hepatic metabolism, supporting predictable dosing. Clinically, it demonstrates proven efficacy in neuropathic pain syndromes, including diabetic neuropathy, postherpetic neuralgia, fibromyalgia, and spinal cord injury-related pain, where it acts as a first-line or adjunctive agent. Beyond analgesia, pregabalin serves as an adjunct in partial seizures, a recognized treatment for generalized anxiety disorder, and an emerging option for sleep disturbances and comorbid psychiatric conditions. Comparative analyses indicate similar or superior efficacy to gabapentin and other first-line agents, with added benefit in improving sleep and global function. Adverse effects such as dizziness, somnolence, and peripheral edema are generally mild and dose-related. DISCUSSION:Future studies should clarify its role in treatment-resistant pain, psychiatric comorbidities, and sleep-related disorders to optimize its clinical use. CONCLUSION:Owing to its favorable safety profile, limited drug-drug interactions, and broad therapeutic potential, pregabalin remains an essential component of neuropathic pain.
Introduction: Plant-derived Exosome-like Nanovesicles (PELNs) have the potential to exhibit improved biological functions in multiple pathological disorders, particularly in neurodegenerative and age-related brain diseases. In this review, advanced isolation techniques, including Differential Ultracentrifugation (dUC), Size-Exclusion Chromatography (SEC), and Polyethylene Glycol (PEG) precipitation, were systematically evaluated to optimize the structural integrity, purity, and biological activity of PELNs. Methods: Novel studies on PELNs were the primary focus of this review. Evidence-based studies were compared and discussed in terms of chemical and functional characteristics, as well as optimized production strategies to enhance the therapeutic properties of PELNs. Results: According to the consensus of reviewed studies, PELNs demonstrate efficient cellular uptake due to their lipophilic chemical structures and modulate intracellular signaling pathways related to neurodegeneration. The main drawbacks of PELNs' utilization mostly depend on the extraction methods and limited delivery through the BBB. A combination of optimized methods, such as dUC and SEC, may exhibit maintained therapeutic strategies for neurological applications. Discussion: Due to the limited number of experimental studies in Parkinson’s Disease (PD) and Alzheimer’s Disease (AD), and brain aging, advances in PELNs extraction methods have been shown to enhance BBB delivery and therapeutic efficacy. Every study claims the superiority of its own method; however, none of these methods fully addresses the limitations inherent in producing optimal results. Conclusion: PELNs represent a promising platform for neurological dysfunction and brain aging-related disorders. However, isolation and characterization methods must be carefully optimized and validated to ensure the production of therapeutically active PELNs suitable for BBB delivery.
Introduction: Spinal cord injury (SCI) is a severe central nervous system injury. Mitochondrial dysfunction is a key driver of the secondary injury cascade, disrupting energy metabolism and calcium homeostasis and activating cell death pathways. Although bibliometric approaches have been widely used to map research trends, hotspots, and knowledge structures across biomedical fields, systematic analyses of research at the intersection of SCI and mitochondrial dysfunction remain limited. Methods: Relevant publications on mitochondrial dysfunction in SCI published between 2000 and 2025 were retrieved from the Web of Science Core Collection (WoSCC). After screening according to predefined eligibility criteria, 993 articles and reviews were included. Bibliometrix, VOSviewer, and CiteSpace were used for bibliometric analysis and visualization of publication output, countries and institutions, authors, journals, co-citation networks, and keywords. Results: Annual publication output increased exponentially (R² = 0.9453), with particularly rapid growth after 2017. China produced the most publications (n = 442), whereas the United States received the most total citations (25,855). The University of Kentucky ranked first in institutional publication output, while several Chinese institutions showed strong recent citation bursts. Patrick G. Sullivan was a prominent early contributor, whereas Xifan Mei exhibited the strongest recent author burst. Keyword analysis identified five major thematic clusters and indicated a temporal shift in research emphasis from apoptosis-related mechanisms toward inflammation, regeneration, and immunometabolism. Discussion: The number of publications in this field has grown rapidly since 2017, reflecting increasing research attention to mitochondrial dysfunction and mitochondria-targeted therapeutic strategies. Keywords indicate that the research topic has gradually expanded from mechanism research focused on apoptosis to inflammation, regeneration, and immunometabolism. Mitochondria may be an important regulator of the inflammation and regeneration microenvironment after SCI. Given the complexity of the secondary injury cascade, a single-target intervention strategy makes it difficult to achieve optimal recovery of neurological function. Conclusion: This first bibliometric study, focusing on spinal cord injury and mitochondria, demonstrates that the field is advancing rapidly and exhibits distinct translational research orientations. Immunemetabolism has emerged as a novel research frontier, yet relevant clinical trials in this area remain scarce, underscoring the need to accelerate the translation of basic research outcomes into clinical practice.
Background:: Spinal Cord Injury (SCI) is a highly disabling disease owing to unexpected mechanical damage, which may trigger serious complications. Tauroursodeoxycholic Acid (TUDCA) serves as a neuroprotective agent for SCI. Therefore, this study assessed the effect of TUDCA for intervening in SCI in existing preclinical tests, with a summary of its mechanism simultaneously. Methods: This systematic review was presented according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 statement. Literature retrieval, without language restriction, to identify in vivo studies on SCI treatment using TUDCA was performed by searching databases such as PubMed, Embase, Web of Science, China National Knowledge Infrastructure, and SinoMed from their inception to May 2025, coupled with the collection of grey literature. Literature retrieval and risk-of-bias assessment using SYRCLE’s RoB tool were independently conducted by two reviewers. A subsequent meta-analysis was conducted using the Review Manager 5.4 software. In addition, network pharmacology combined with molecular docking was utilized to explore the potential mechanism of TUDCA in treating SCI. Results: A total of 14 studies were finally enrolled, over half of which had at least 5 items rating low risk of bias. The results of the meta-analysis showed that motor function, as assessed by the BBB score, was significantly enhanced after TUDCA treatment (14th day; WMD = 3.11 [1.84 to 4.37], p < 0.0001). Meanwhile, the inclined plane test and TUNEL indicated that TUDCA contribut-ed to SCI recovery. Subgroup analysis suggested a more pronounced effect of TUDCA in females (WMD = 3.76 [2.51, 5.10], p < 0.0001) than in males. Moreover, TUDCA at 200 mg/kg improved motor function (WMD = 2.90 [2.03, 3.77]; p < 0.0001). Network pharmacology identified AKT1, EGFR, HSP90AA1, and SRC as key targets, with the identification of PI3K-Akt, Foxo, estrogen signaling pathway, and apoptosis, etc. Molecular docking suggested that PPARγ, PARP1, and GSK3β bound to TUDCA better. Additionally, this review revealed the unique advantages and potential mechanisms of TUDCA, supporting the potential of neuroprotective agents for SCI treatment. Discussion: The identified optimal dose and sex-dependent efficacy of TUDCA provide critical insights for its future development as a neuroprotective agent. Network pharmacology and molecular docking provide sufficient evidence for SCI treatment with TUDCA. Conclusion: TUDCA can enhance neuronal autophagy and inhibit inflammatory factor expression, reducing inflammatory response and suppressing neuronal apoptosis in SCI. Due to the limited number and uneven quality of included studies, further laboratory studies and validation in clinical trials are necessary to clarify the neuroprotective effect of TUDCA.
Introduction: This narrative review systematically examines the available empirical evidence for interactions between delta-9-tetrahydrocannabinol (Δ9-THC or THC) and C. sativa’s other phytochemical constituents hypothesized to underpin the popular yet controversial notion of ‘entourage effects’ experienced with botanical cannabis. Many relevant preclinical and clinical studies have been conducted in the last decade to elucidate the individual contributions of various phytocannabinoids and bioactive terpenes to the pharmacodynamic effects of C. sativa. However, their varied methods and results complicate their interpretation. Here, a particular emphasis is placed on synthesizing data from clinical studies of THC’s modulation by Cannabis sativa’s other phytochemical constituents. Methods: A systematic search of the scientific literature indexed in PubMed was conducted to identify controlled clinical and preclinical studies evaluating the modulation of THC’s effects by individual phytochemicals. Studies that evaluated the phytocannabinoids cannabidiol (CBD), cannabinol (CBN), tetrahydrocannabivarin (THCV), cannabigerol (CBG), cannabichromene (CBC), and cannabis terpenes α-pinene, d-limonene, β-myrcene, linalool, α-humulene, β-caryophyllene, bisabolol, terpinene, and terpineol were included in the literature search for discussion. Results: Cannabidiol and THC interactions have been extensively studied, with recent findings showing significant exacerbation of THC effects when orally coadministered, but not when inhaled. Clinical studies examining THC interactions with constituents beyond CBD remain comparatively limited. Recent clinical evidence suggests that THCV may reduce certain subjective and cognitive effects of THC. At the same time, some terpenes, such as limonene, can selectively modulate adverse effects associated with high THC doses in humans. Clinical studies have often failed to translate the interactive effects between THC and minor phytocannabinoids/terpenes observed in animal models. Discussion: Although interest in the clinical pharmacology of minor cannabinoids and terpenes has grown in recent years, the evidence supporting meaningful modulation of THC’s effects in humans remains exceptionally limited. The mixed results from preliminary studies underscore the complexity of phytochemical interactions and the inherent challenges of translating preclinical findings into measurable clinical outcomes. Conclusion: Well-designed, controlled clinical studies of individual phytochemical interactions on subjective, therapeutic, and adverse effects are still required to support entourage effects in humans. In particular, the effects of many bioactive terpenes and trace cannabinoids have not yet begun to be evaluated in humans, either as individual phytochemicals or when combined with THC.
Introduction: L-carnosine is a powerful natural antioxidant found in the brain, muscles, and digestive systems of all vertebrates, including humans, that helps fight Reactive Oxygen Species (ROS) and other harmful byproducts of oxidative stress. L-carnosine has antioxidant properties as well as the ability to bind with metal ions and prevent glycation, a process that can damage cells. This review article highlights the protective effects of L-carnosine against a variety of pathological conditions, such as Alzheimer's Disease (AD), Parkinson's Disease (PD), ischemia‒reperfusion injury, Huntington's disease, stroke, depression, traumatic brain injury, cancer, diabetes, ageing, etc. Among these conditions, mitochondrial dysfunction and increased oxidative stress are common. Moreover, methylglyoxal (MG), another metabolic product, and Advanced Glycation End products (AGEs) damage cells through interactions with proteins. Through receptor-mediated endocytosis, macrophages absorb them and release proinflammatory chemicals that induce severe inflammation and lead to cell death. Methods: Search engines, including PubMed, ScienceDirect, ProQuest, Scopus, ResearchGate, MDPI, journals, websites, and databases such as Google Scholar, were thoroughly searched and reviewed. The search strategy for articles published between 2000 and 2025 used various combinations of key Medical Subject Headings (MeSH) terms and phrases, including L-carnosine, alanine, histidine, Randomized Controlled Trial (RCT), aging, cancer, cardiovascular disease, diabetes, and neurodegenerative disorders, and various non-MeSH terms. Results: L-carnosine exhibits protective effects on models of neurological, ischemic, metabolic, and malignant diseases because of its antioxidant, anti-inflammatory, and neuroprotective properties. In Alzheimer's disease, carnosine specifically increases the production of heat shock proteins (Hsps). In Parkinson's disease, it increases dopamine levels and stops alpha-synuclein protein accumulation. In ischemia‒reperfusion injury, L-carnosine inhibits the release of inflammatory mediators such as cytokines and TNF-alpha. In cancer, it inhibits the Mitogen-Activated Protein Kinase (MAPK)/ Extracellular Signal-Related Kinase (ERK) signaling pathway. It mitigates aging-related damage to proteins. Additionally, L-carnosine inhibits the formation of MG and AGEs, suggesting its potential therapeutic efficacy in a range of diseases. Discussion: L-carnosine shows multitarget therapeutic potential through antioxidant, anti-inflammatory, and antiglycation actions, as well as mitochondrial protection. It influences key pathways involved in neurodegeneration, including protein aggregation and oxidative stress. Evidence from preclinical and early clinical studies suggests benefits in neurological and metabolic disorders. Despite promising outcomes, challenges such as rapid degradation and limited bioavailability affect clinical translation. Further studies are needed to define the optimal dosing and therapeutic use. Conclusion: L-carnosine acts as a cytoprotective molecule in multiple ways, including mitigating oxidative stress, protein glycation, mitochondrial dysfunction, and inflammation, thereby modulating pathways characteristic of chronic illnesses. By altering these interconnected pathways, L-carnosine has the potential for several therapeutic applications as an adjuvant for a range of neurological, metabolic, ischemic, cancer, and aging-related illnesses.
Introduction: Statins are well established for the primary prevention of cardiovascular disease (CVD) up to approximately 75 years of age; however, direct evidence in adults aged 80 years and older remains limited. Extrapolation from younger populations is uncertain because advanced age is associated with greater competing mortality, frailty, multimorbidity, polypharmacy, and a shorter remaining time in which benefit can accrue. Methods: We conducted a systematic review in accordance with PRISMA 2020. A prespecified protocol was developed before screening. PubMed/MEDLINE, Embase, and Cochrane CENTRAL were searched through October 12, 2025. Eligible evidence comprised randomized trials, age-stratified trial analyses, pooled or individual-participant meta-analyses, systematic reviews with age-stratified quantitative data, and adjusted observational cohorts of older adults without established atherosclerotic cardiovascular disease. Outcomes included major adverse cardiovascular events (MACE), myocardial infarction, stroke, all-cause and cardiovascular mortality, adverse events, cognition, disability, and functional outcomes. Risk of bias or methodological quality was assessed using RoB 2, the Newcastle-Ottawa Scale, or AMSTAR 2, as appropriate, and certainty of evidence was rated using GRADE. Results: Twelve studies or trial programs met the inclusion criteria. Randomized evidence directly applicable to adults aged 80 years and older was minimal. PROSPER enrolled participants up to 82 years of age but combined primary and secondary prevention; ALLHAT-LLT showed no benefit in adults aged 75 years and older; and JUPITER and HOPE-3 showed reductions in cardiovascular events among adults aged 70 years and older but included few octogenarians. Observational cohorts suggested lower mortality or cardiovascular event rates among statin users, although these estimates were limited by healthy-user bias, residual confounding, and heterogeneity in age strata and outcome definitions. A formal meta-analysis of the primary-prevention population aged 80 years and older was not feasible because no randomized trial provided a directly comparable, extractable estimate for this group and the observational estimates were clinically and methodologically heterogeneous. Discussion: Evidence supports statin benefit through approximately 75 years of age, but evidence beyond 80 years is indirect and of low to very low certainty. Benefit is most plausible in robust octogenarians at high cardiovascular risk who have sufficient life expectancy, whereas routine initiation is unlikely to offer meaningful benefit to frail adults with a limited prognosis. Conclusion: Current evidence is insufficient to support routine statin initiation for primary prevention in all adults aged 80 years and older. Decisions should be individualized through shared decision-making that considers baseline cardiovascular risk, frailty, life expectancy, time to benefit, treatment burden, potential drug interactions, and the patient’s goals while definitive evidence from ongoing late-life primary-prevention trials is awaited.
INTRODUCTION:Although HIV infection can now be kept under control in almost all people living with HIV (PLWH), these individuals are prone to developing several non-AIDS complications due to chronic immune impairments, such as HIV-associated neurocognitive disorders (HAND). Unfortunately, no marker has been identified to predict these conditions, but there is growing interest in neurotrophins, such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF). METHODS:In this pilot study, we evaluated the serum levels of these neurotrophins in 13 antiretroviral therapy (ART)-naive and 12 ART-treated PLWH, and in two matched groups of 13 and 12 HIVnegative volunteers, respectively. RESULTS:ART-naive PLWH showed higher levels of NGF (p = 0.0036) and lower levels of BDNF (p < 0.0001) in their serum compared to HIV-negative individuals. In contrast, the neurotrophin levels of ART-treated PLWH were similar to those of HIV-negative people. Furthermore, serum NGF showed a negative correlation with blood CD4+ T cell count and a positive correlation with peak (zenith) HIV-RNA. Conversely, serum BDNF had a positive correlation with blood CD4+ T cell count and CD4/CD8 ratio. DISCUSSION:The dysregulation in neurotrophin homeostasis due to HIV infection appears to be restricted to ART-naive individuals. However, NGF and BDNF levels remain influenced by both the viro-immunological status at diagnosis and the current immune status, even after effective ART. CONCLUSION:These findings suggest a distinct neurotrophin signature in untreated HIV infection, as well as a strong correlation between NGF and BDNF levels and current or historical immune status. This supports the need for further exploration of neurotrophins as potential biomarkers of HAND.
Neuropeptides (NPs) are central regulators of neuronal communication, homeostasis, and adaptive responses to stress. Beyond their well-established roles in modulating behaviour, metabolism, and circadian rhythms, NPs exert potent neuroprotective effects in acute neurological disorders, including ischemic stroke, traumatic brain injury, epilepsy, and neuroinflammatory insults. These protective actions encompass suppression of neuroinflammation, attenuation of excitotoxicity, preservation of mitochondrial integrity, and promotion of neuronal survival and plasticity. However, the efficacy and spatial precision of NP signalling critically depend on the biology of their precursors (NPPs), which are increasingly recognised as active regulators rather than inert biosynthetic intermediates. In this review, we synthesise emerging evidence that NPPs self-assemble and condense within dense-core secretory vesicles through tightly regulated, liquid-liquid phase separation (LLPS)-like mechanisms governed by pH, Ca2+, lipid composition, and intrinsic sequence features. This regulated condensation facilitates selective cargo sorting, efficient proteolytic processing, and controlled release of mature NPs. Importantly, we contrast this physiological, reversible self-assembly with the pathological protein aggregation characteristic of neurodegenerative disease, highlighting how dysregulation of NPP condensation and processing may contribute to impaired neuroprotective signalling in acute and chronic neurological disorders. We further review how key neuroprotective NPs, including α-melanocyte-stimulating hormone (α-MSH), galanin, orexins, neuropeptide Y (NPY), neuropeptide S (NPS), nesfatin-1, and adrenocorticotropic hormone (ACTH)-derived peptides, mitigate acute neuronal injury by modulating microglial activation, inflammatory cytokine production, excitatory-inhibitory balance, and apoptotic pathways. Finally, we discuss therapeutic strategies that leverage NPP and NP biology, including stabilisation of precursor processing, modulation of vesicular environments, and development of peptide analogues and peptidomimetics. By reframing NPPs as upstream determinants of neuroprotective peptide availability, this review highlights new conceptual and translational avenues for innovative neuroprotective therapies in acute neurological disorders.
