Search Results (127)

Objectives: An ideal cardiotoxicity inhibitor targeting the angiotensin (Ang) II type 1 (AT₁) receptor would be a β-arrestin-biased orthostatic ligand, which inhibits the G protein pathway and activates the β-arrestin pathway. Therefore, this study examined seven Ang II mimetic peptides (MP1–7), Ang A and TRV027 as potential β-arrestin-biased AT₁ receptor ligands to prevent doxorubicin (Dox)-induced cardiotoxicity. Methods: Competition binding study, inositol phosphate (IP) production assay and extracellular signal-regulated kinase (ERK) 1/2 activation were performed using COS7 cells. Changes in phosphorylated Akt (Ser473), c-Jun N-terminal kinase (JNK) (Thr183/Tyr185), Bad (Ser112), Bcl-2 (Ser70), p53 (Ser46), active caspase-8 (Asp384) and active caspase-9 (Asp315) in cell lysates were measured using AT₁ receptor-transfected H9C2 cells. Results: Binding assays showed Ang II and Ang A had the highest affinity, with MP2 and MP7 similar to TRV027. IP production was strong for Ang II and Ang A, minimal for MP1 and MP7, and no stimulation for MP2 and TRV027. Ang II and Ang A significantly activated ERK1/2 in this cell system. MP2 and MP7 in addition to TRV027 also significantly activated ERK1/2, whereas MP1 did not activate it. Dox-activated JNK and Bad, while Ang A, TRV027, MP2, and MP7 inhibited JNK activation without affecting Bad or Akt. Conclusions: MP2, which is a candidate biased ligand for the AT₁ receptor and has similar amino acid sequence to TRV027, along with TRV027, attenuated Dox-induced JNK activation while avoiding excessive G protein-mediated activation. Interestingly, MP7, which showed minimal G protein-mediated activation with β-arrestin-mediated ERK activation, also attenuated Dox-induced JNK activation, a marker of pro-apoptotic stress signaling. Full article

The dopamine D₃ receptor (D₃R) has long been considered a secondary target in the treatment of Parkinson’s disease (PD), with therapeutic strategies primarily focused on D₂ receptor–mediated motor control. However, accumulating evidence now supports D₃R as a functionally distinct dopaminergic receptor subtype with specific relevance to non-motor symptom domains and dopaminergic signaling under hypodopaminergic conditions. Recent advances in high-resolution structural biology have elucidated the molecular basis of D₃R/D₂R discrimination, revealing how subtle residue-level and microstructural differences within a conserved G protein–coupled receptor framework shape ligand recognition and receptor activation. In parallel, the emergence of ligand-dependent biased signaling has refined current understanding of D₃R pharmacology. Selected ligands can preferentially engage Gα_i/o-mediated pathways while limiting β-arrestin recruitment and associated regulatory processes, providing a mechanistic rationale for more stable modulation of mesolimbic dopaminergic circuits involved in affective and motivational regulation. Beyond symptomatic modulation, preclinical studies suggest that D₃R signaling may influence neuronal resilience, synaptic plasticity, and adaptive responses to dopaminergic injury; however, such effects remain experimental and have not been demonstrated in clinical PD. This review integrates recent structural, signaling, and functional insights into D₃R biology, with particular emphasis on biased agonism and emerging therapeutic concepts. Although D₃R-targeted strategies do not currently represent disease-modifying interventions, they offer a rational framework for the development of next-generation dopaminergic therapies aimed at improving precision, tolerability, and long-term signaling stability in Parkinson’s disease. Full article

Background/Objectives: Selective inhibition of JAK1 remains a major challenge in cytokine-signaling therapeutics due to the high structural similarity of the JAK family. Here, we present an integrated computational framework that combines large-scale binding-site conformational analysis, ensemble docking, and protein–ligand interaction fingerprinting (PLIF) to elucidate the structural determinants of JAK1 selectivity and prioritize JAK1-biased scaffolds. Methods: A curated set of JAK1 and JAK2 catalytic-domain structures was clustered to capture binding-site diversity, and representative conformers were evaluated using >2300 annotated ligands. Docking performance was assessed via AUC, early enrichment metrics, and structural pose validation against experimentally resolved complexes. The workflow was subsequently applied to a library of ~6000 drug-like compounds to prioritize candidates with predicted JAK1 preference. Results: Across the ensemble, the most predictive features reliably separated active from inactive ligands (AUC = 0.78–0.82) and captured subtle, systematic rank shifts supporting the reported JAK1 bias. Interaction fingerprint analysis revealed a conserved hinge-binding motif required for potency, alongside a JAK1-enriched hotspot adjacent to Glu aD.55 that contributes to isoform discrimination. Applied to a library of ~6000 drug-like molecules, the workflow yielded 174 candidates predicted to exhibit preferential JAK1 recognition and reduced JAK2 engagement. Conclusions: These findings define the structural and physicochemical features underlying JAK1 selectivity and illustrate how ensemble-based modeling can guide the discovery of next-generation selective kinase inhibitors. Full article

Background: Epimedium is a natural herb with immunomodulatory potential, but its vaccine adjuvant properties remain poorly understood. Objective: The aim of this study was to elucidate the adjuvant effects of Epimedium and the underlying molecular mechanisms. Methods: Network pharmacology was used to identify bioactive compounds and targets of Epimedium from the TCMSP database, and immunomodulation-related targets from GeneCards and OMIM. PPI networks, KEGG/GO enrichment, molecular docking, and molecular dynamics (MD) simulations were performed. In vivo, female BALB/c mice were immunized with the Staphylococcus aureus (S. aureus) vaccine subunit HI antigen, either alone or with low- or high-dose icariin (ICA). Serum antibody responses (IgG, IgG1, IgG2a, IgG2b) were measured by ELISA. Survival against lethal S. aureus USA300 challenge was monitored. Results: Network pharmacology predicted 488 targets and 13 pathways. Core targets included IL6, TP53, EGFR, CTNNB1, HIF1A, HSP90AA1, JUN, MTOR, SRC, and AKT1. KEGG/GO analysis indicated involvement of T cell receptor and NOD-like receptor signaling pathways in inflammatory responses. Molecular docking and MD simulations confirmed stable ligand-target binding. Experimental validation showed that ICA significantly enhanced HI-specific antibody responses and induced a Th2-biased humoral immune response (IgG1/IgG2a ratio > 1), which is particularly relevant for vaccines targeting extracellular pathogens such as S. aureus. ICA also improved survival after lethal bacterial challenge. Conclusions: This study identifies potential bioactive compounds, core targets, and key pathways of Epimedium as a vaccine adjuvant. Experimentally, ICA, as a representative component, enhanced HI-specific antibody responses and conferred protection against lethal S. aureus challenge. Together, these findings offer a computational–experimental basis that may guide further mechanistic investigation. Full article

Myocardial fibrosis is a key pathological process driving the progression of cardiovascular diseases toward heart failure, closely linked to persistent inflammation and immune dysregulation. Among CC chemokines, CCL17 has emerged as an important mediator connecting immune cell dynamics with fibrotic remodeling. This review outlines current understanding of the cellular sources, regulatory mechanisms, and functional roles of CCL17, with particular attention to its impact on regulatory T cell (Treg) recruitment through ligand-biased signaling. Beyond this mechanism, CCL17 likely operates within a broader inflammatory network, with potential interactions involving CCR2⁺ macrophages and IL-17-related pathways. Experimental studies show that disruption of CCL17 signaling attenuates fibrosis and improves cardiac function, while clinical data link elevated circulating CCL17 to cardiac dysfunction and adverse outcomes. However, the absence of clinical trials and the redundancy of chemokine networks remain key challenges for translation. Overall, CCL17 may serve as a biomarker and therapeutic target, although its clinical application will require a more integrated, network-based understanding. Full article

Lung cancer remains the leading cause of cancer-related mortality worldwide, with non-small cell lung cancer accounting for the majority of cases and exhibiting persistent challenges related to therapy resistance and metastatic progression. Increasing evidence indicates that dysregulated G protein-coupled receptor signaling and ion channel activity function cooperatively as master regulators of tumor cell proliferation, migration, survival, and therapeutic response. Cannabinoids, including phytocannabinoids such as delta-9-tetrahydrocannabinol and cannabidiol, as well as endogenous endocannabinoids, are uniquely positioned to modulate both G protein-coupled receptors and ion channels, thereby influencing key oncogenic signaling networks. This review synthesizes current knowledge on the role of major ion channel families, including transient receptor potential channels, potassium channels, and sodium channels, and principal G protein-coupled receptor pathways involved in lung cancer progression. We further discuss how cannabinoids reprogram these interconnected signaling systems through canonical cannabinoid receptors, non-classical targets such as G protein-coupled receptor 55 and adenosine receptors, and direct modulation of ion channel activity. Special attention is given to G protein-coupled receptor–ion channel coupling within membrane microdomains and to the capacity of cannabinoids to act as biased ligands, redirecting downstream pathways, such as the phosphoinositide 3-kinase–protein kinase B–mechanistic target of rapamycin and epidermal growth factor receptor signaling, toward apoptosis and reduced metastatic potential. Emerging strategies, including cannabinoid-based combination therapies, selective receptor biasing, and targeted delivery systems, are also highlighted. Altogether, cannabinoid-driven rewiring of G protein-coupled receptor and ion channel signaling represents a promising mechanistic framework for developing innovative therapeutic approaches against lung cancer. Full article

Chronic non-healing wounds, prevalent in diabetic and vascular diseases, arise from dysregulated chemokine signaling that disrupts angiogenesis, immune coordination, and tissue remodeling. This review synthesizes current knowledge on chemokine biology in wound repair, with a focus on their spatiotemporal regulation across the hemostasis, inflammation, proliferation, and remodeling phases. We detail chemokine classification (CC, CXC, CX3C, and C families), receptor interactions, and downstream pathways, including G protein-dependent and β-arrestin-biased mechanisms. Furthermore, we evaluate emerging therapeutic strategies, including neutralizing antibodies, receptor antagonists, engineered chemokines, and biomaterial-based delivery systems designed to restore chemokine gradient integrity and promote healing. Recent advances in structural biology and protein engineering are highlighted as enabling the design of biased ligands and multi-target inhibitors to overcome chemokine redundancy. The review concludes that precision modulation of chemokine networks offers a promising translational framework to redirect chronic inflammation toward regenerative healing, thereby addressing a significant unmet clinical need in chronic wound management. Full article

The female immune system operates within an evolutionary stability-plasticity trade-off, where the physiological demands of pregnancy necessitate a considerable degree of regulatory T cell (Treg) plasticity. This essential flexibility, however, inherently lowers the threshold for autoimmune dysregulation. Recent mechanistic evidence has identified Xist ribonucleoprotein complexes as female-specific autoantigens that constitutively sensitize innate sensors, thereby establishing an intrinsic state of autoimmune priming. This review introduces the Metabolic Calibration Hypothesis, proposing that commensal microbiota-derived metabolites function as essential extrinsic stabilizers specifically required to maintain female immune homeostasis. Beyond canonical short-chain fatty acid signaling, we synthesize emerging evidence regarding host-microbiota metabolic integration, emphasizing the roles of histone lactylation in the reproductive tract and the ligand-specific activation of nuclear receptors by secondary bile acids in orchestrating Treg fate. We posit that female immune pathologies, ranging from systemic autoimmunity to gynecologic malignancies, represent a context-dependent dysregulation or co-option of this metabolic calibration. Ultimately, we discuss the clinical necessity of transitioning from generic biotic interventions toward Sexual Dimorphic Metabotyping, providing a precision framework to restore physiological tolerance and manage sex-biased immune pathologies. Full article

Invariant natural killer T (iNKT) cells are a unique lymphocyte subset that bridge innate and adaptive immunity through recognition of glycolipid antigens presented by CD1d. Upon activation by ligands such as α-galactosylceramide (α-GalCer), iNKT cells rapidly secrete cytokines, including IFN-γ and TNF-α, thereby activating dendritic cells, natural killer (NK) cells, and cytotoxic T lymphocytes (CTLs) to promote antitumor immunity. Despite their therapeutic promise, clinical translation has been limited by rapid α-GalCer clearance, induction of iNKT cell anergy following repeated stimulation, and the immunosuppressive tumor microenvironment (TME). Recent advances in lipid-engineered nanoparticle systems offer solutions to these challenges by improving ligand stability, enhancing antigen-presenting cell targeting, and enabling controlled release that sustains Th1-biased activation while reducing anergy. Liposomal and polymer-based nano-formulations enhance bioavailability and promote more durable IFN-γ-mediated responses. In parallel, chimeric antigen receptor (CAR)-engineered iNKT cells provide antigen-specific tumor targeting while preserving intrinsic CD1d-restricted immunomodulatory functions, demonstrating encouraging safety and efficacy in early-phase studies. Combination strategies further strengthen iNKT-based immunotherapy. Integration with chemotherapy, immune checkpoint inhibitors such as anti-PD-1 and anti-CTLA-4, and cytokine support enhances effector activation, counteracts TME-induced suppression, and improves therapeutic outcomes. However, challenges remain, including optimization of dosing, control of off-target immune activation, scalable manufacturing, and long-term safety evaluation. Collectively, the convergence of nanotechnology, CAR engineering, and rational combination approaches establishes iNKT cell-based therapy as a promising next-generation immunotherapeutic strategy. Continued refinement of delivery systems, genetic engineering platforms, and translational protocols may enable durable immune reprogramming and improved clinical outcomes in resistant and immunosuppressive cancers. Full article

Vitamin D signaling via the vitamin D receptor (VDR) regulates calcium–phosphate homeostasis and extensive gene programs controlling cell proliferation, differentiation, immune tone, and metabolism. However, systemic use of the natural agonist 1α,25-dihydroxyvitamin D₃ (calcitriol) for extraskeletal indications is limited by dose-limiting hypercalcemia. This review summarizes VDR biology and the structural basis of ligand action, emphasizing how ligand-induced repositioning of helix 12 and altered coregulator recruitment can be exploited to engineer selective VDR modulators. We highlight medicinal chemistry strategies spanning secosteroidal analogs with side-chain or ring modifications and emerging non-seco scaffolds and discuss clinically established agents (e.g., calcipotriol and paricalcitol) alongside experimental “super-agonists”, partial agonists, and antagonists designed to widen the therapeutic window. Finally, we discuss current evidence for VDR targeting across cancer, metabolic disease, fibrosis, and immune-inflammatory disorders, including mechanisms of resistance such as dysregulated vitamin D metabolism and epigenetic repression. Structural and epigenomic insights are positioning next-generation VDR ligands as tissue- and pathway-biased therapeutics that may enable safer, mechanism-guided translation beyond bone and mineral indications. Full article

The neuropharmacology of psychedelics has traditionally focused on serotonergic mechanisms, particularly 5-HT2A receptor activation. However, this paradigm incompletely explains the diversity of neurobiological and therapeutic effects observed across psychedelic compounds. Non-classical psychedelics such as salvinorin A, the primary active constituent of Salvia divinorum, challenge this framework through direct kappa opioid receptor (KOR) agonism, representing a serotonin-independent pathway to altered consciousness. This review systematically examines the role of the endogenous opioid system in mediating psychedelic effects, with emphasis on salvinorin A’s unique KOR-dependent mechanisms. We synthesized preclinical and clinical evidence from in vitro studies, genetically modified animal models, optogenetic circuit dissection, and human neuroimaging trials. Salvinorin A’s selective KOR activation is characterized by pronounced β-arrestin-biased signaling, distinguishing it from endogenous dynorphins and classical KOR agonists. This produces rapid receptor desensitization, transient functional plasticity, and profound dissociative effects mediated through thalamocortical disruption, mesolimbic dopaminergic suppression, and fragmentation of large-scale brain networks. Classical serotonergic psychedelics indirectly engage opioid systems through downstream 5-HT2A signaling, contributing to analgesic and mood-regulatory effects via secondary MOR/DOR modulation. Despite being a potent opioid agonist, salvinorin A exhibits low abuse potential due to aversive phenomenology, dopaminergic suppression, and absence of positive reinforcement in animal models. Incorporating opioid receptor pharmacology into psychedelic neuroscience expands mechanistic understanding beyond serotonin-centric models, revealing multiple neurochemical pathways capable of inducing therapeutically relevant altered states. This framework enables rational development of biased KOR ligands and establishes salvinorin A as a paradigmatic model for non-serotonergic psychedelia with applications in treatment-resistant depression, addiction, and chronic pain. Full article

The cannabinoid receptor type 2 (CB₂) is increasingly recognized as a crucial regulator of neuroimmune balance in the brain. In addition to its well-established role in immunity, the CB₂ receptor has been identified in specific populations of neurons and glial cells throughout various brain regions, and its expression is dynamically increased during inflammatory and neuropathological conditions, positioning it as a potential non-psychoactive target for modifying neurological diseases. The expression of the CB₂ gene (CNR2) is finely tuned by epigenetic processes, including promoter CpG methylation, histone modifications, and non-coding RNAs, which regulate receptor availability and signaling preferences in response to stress, inflammation, and environmental factors. CB₂ signaling interacts with TRP channels (such as TRPV1), nuclear receptors (PPARγ), and orphan G Protein-Coupled Receptors (GPCRs, including GPR55 and GPR18) within the endocannabinoidome (eCBome), influencing microglial characteristics, cytokine production, and synaptic activity. We review how these interconnected mechanisms affect neurodegenerative and neuropsychiatric disorders, underscore the species- and cell-type-specificities that pose challenges for translation, and explore emerging strategies, including selective agonists, positive allosteric modulators, and biased ligands, that leverage the signaling adaptability of the CB₂ receptor while reducing central effects mediated by the CB₁ receptor. This focus on the neuro-centric perspective repositions the CB₂ receptor as an epigenetically informed, context-dependent hub within the eCBome, making it a promising candidate for precision therapies in conditions featuring neuroinflammation. Full article

G protein-coupled receptors (GPCRs) are the largest family of diverse receptors in eukaryotic organisms, playing a critical role in modulating human physiology. It therefore comes as no surprise that about 36% of all currently available drugs target this superfamily. When an agonist binds to a GPCR, it induces conformational changes in the receptor that allow it to interact with intracellular proteins. This interaction triggers downstream signaling cascades that alter the cell’s activity. GPCR signaling is complex, as GPCRs transmit signals through coupling with G proteins, arrestins, and numerous other intracellular effectors. Different ligands, receptor subtypes, and cellular environments can result in the activation of distinct signaling pathways. Biased signaling through GPCRs has emerged as a frontier area in pharmacological research efforts towards designing targeted therapeutic interventions and enhancing drug efficacy and safety. This review presents the types of bias associated with GPCRs and the mechanisms underlying biased signaling. Examples of biased ligands and their therapeutic implications will be discussed. In addition, the inherent challenges in measuring signaling bias, and especially the translational gap between in vitro and in vivo assays and clinical outcomes, will be outlined. Full article

Inhibition of agonist-induced M₂ muscarinic receptor (M₂R) activation by functional anti-M₂R autoantibodies has been associated with cardiac parasympathetic dysfunction in patients with chronic Chagas disease (CD). This study explored the allosteric nature of that inhibitory effect by assessing the ability of serum IgG from patients with CD and dysautonomia (DCD IgG) to modulate the interaction between M₂R and β-arrestins in HEK 293T cells using bioluminescence resonance energy transfer. DCD IgG alone did not stimulate arrestin-2 or arrestin-3 recruitment. When cells were preincubated with DCD IgG and then treated with carbachol, arrestin-2 translocation decreased in a concentration-dependent manner, while arrestin-3 recruitment remained unaffected. Inhibition curve analysis showed a submaximal inhibitory effect (68.1 ± 2.4%) and a Hill slope less than −1 (−4.03 ± 0.39). Carbachol concentration–response assays after preincubation with DCD IgG revealed a noncompetitive inhibition of arrestin-2 recruitment, with no change in arrestin-3 translocation. Unlikely, simultaneous exposure to DCD IgG and carbachol potentiated agonist-induced Arr-2 recruitment. We conclude that anti-M₂R autoantibodies selectively inhibit agonist-induced arrestin-2 recruitment, acting as negative allosteric modulators of agonist efficacy. The direction of autoantibody-induced allosteric modulation depends on the timing of IgG application relative to the agonist and the duration of receptor exposure to autoantibodies. Full article

Our understanding of Ghrelin, an endogenous ligand of the growth hormone secretagogue receptor 1a (GHSR1a), has expanded from considering it to be a “hunger hormone” to a pleiotropic regulator of whole-body physiology. This review synthesizes the current advances spanning ghrelin biogenesis, signaling, and systems biology. Physiologically, preproghrelin processing and O-acylation by ghrelin O-acyltransferase (GOAT) generate acyl-ghrelin, a high-potency GHSR1a agonist; des-acyl ghrelin predominates in circulation and exerts context-dependent, GHSR1a-independent, or low-potency effects, while truncated “mini-ghrelins” can act as competitive antagonists. The emergence of synthetic ligands, agonists, antagonists, and reverse-agonists has provided the necessary tools to decipher GHSR1a activity. Recent cryo-EM structures of GHSR1a with peptide and small-molecule ligands reveal a bipartite binding pocket and provide a framework for biased signaling, constitutive activity, and receptor partner selectivity. Beyond the regulation of feeding and growth-hormone release, ghrelin modulates glucose homeostasis, gastric secretion and motility, cardiovascular tone, bone remodeling, renal hemodynamics, and innate immunity. Ghrelin broadly dampens pro-inflammatory responses and promotes reparative macrophage phenotypes. In the emerging scholarship on ghrelin’s activity in the central nervous system, ghrelin has been found to influence neuroprotection, stress reactivity, and sleep architecture, and has also been implicated in depression, Alzheimer’s disease, and substance-abuse disorders. Practical and transitional aspects are also highlighted in the literature: approaches for ghrelin stabilization; recent GHSR1a agonists/antagonists and inverse agonists findings; LEAP-2-based strategies; and emerging GOAT inhibitors. Together, structural insights and pathway selectivity position the ghrelin system as a druggable axis for the management of inflammatory diseases, neuropsychiatric and addiction conditions, and for obesity treatment in the post-GLP-1 receptor agonist era. Full article