Alzheimer's disease (AD) is a prevalent, chronic, and progressive neurodegenerative disorder that predominantly affects the elderly population, and no effective pharmacological treatments are currently available. Histone deacetylase 6 (HDAC6) is overexpressed in the hippocampus of AD patients, and its inhibition has been shown to clear amyloid-β (Aβ) deposits, promote tau protein degradation, ameliorate mitochondrial transport deficits, and restore α-tubulin acetylation. Thus, selective HDAC6 inhibition represents a promising therapeutic strategy for AD, yet the underlying mechanisms by which HDAC6 inhibitors ameliorate cognitive impairment in AD remain elusive. In our previous study, a series of novel imidazo [1,2-a]pyridine-based HDAC6 inhibitors were developed, among which compound a17 exhibited potent HDAC6 inhibitory activity with an IC50 value of 7.51 nM, warranting further investigation into its anti-AD effects. Herein, we demonstrated that a17 exerted robust neuroprotective effects against L-Glutamate (L-Glu-)/Aβ25-35-induced HT22 cell injury. Additionally, a17 displayed favorable blood-brain barrier (BBB) permeability in vitro and drug-likeness properties. In vivo studies revealed that a17 significantly attenuated AD-like phenotypes in an Aluminium chloride (AlCl3)-induced zebrafish AD model, a mechanism potentially associated with the differential regulation of ODC1, Serpine1, and PAG-1. Furthermore, a17 markedly improved scopolamine-induced memory deficits in mice. Collectively, these findings indicate that an HDAC6 inhibitor, a17, was found to attenuate AD-associated pathological and behavioral markers by regulating the expression of ODC1, Serpine1, or PAG-1. Accordingly, a17 merit consideration for a pharmacological treatment of choice for AD.
Acute lung injury (ALI) remains a clinical challenge due to scarce therapeutic targets and insufficient drug specificity, with lipopolysaccharide (LPS) as a key inducer of infection-related ALI. The transient receptor potential melastatin 2 (TRPM2) channel mediates pulmonary inflammation, oxidative stress and apoptosis, but its role in LPS-induced ALI and the lack of selective inhibitors hinder clinical translation. This study evaluated three classes of self-developed TRPM2 inhibitors. In vitro screening identified N-(p-amylcinnamoyl) anthranilic acid (ACA) analogs (compounds 5, 8, 9) that exert significant protective effects against LPS-induced cell damage, along with prominent anti-apoptotic, anti-inflammatory and antioxidant activities, with no obvious cytotoxicity. In vivo, compounds 8 and 9 showed favorable safety profiles, significantly improved lung pathology and function, mitigated hepatorenal impairment and increased the 7-day survival rate of LPS-induced ALI mice. Mechanistically, they inhibited TRPM2 activation at both transcriptional and protein levels, blocking the NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome and cysteine aspartyl protease-3 (caspase-3) pathway. Collectively, selective TRPM2 inhibitors, especially compound 8, are promising candidates, providing experimental evidence for TRPM2-targeted ALI therapy.
Acute myocardial infarction (AMI) is a persistent ischaemic and anoxic necrosis of the myocardium that triggers oxidative stress and ultimately leads to remodelling and heart failure. Fraxin is a traditional Chinese medicine that is commonly used in clinical practice. In this study, Fraxin improved cardiac function, reduced the area of myocardial infarction, and reduced cardiac damage such as myocardial inflammation and fibrosis. Fraxin reduced myocardial oxidative stress injury, myocardial inflammation index and myocardial apoptosis level. Network pharmacology analysis identified hexokinase II (HXK2) as the key target protein and the phosphatidylinositol-3-kinase (PI3K)/AKT pathway as the key signalling pathway. Molecular docking revealed strong binding affinity between Fraxin and HXK2. Fraxin was found to reduce oxidative stress damage, inflammation and apoptosis by enhancing HXK2's mitochondrial localization and its interaction with voltage-dependent anion channels (VDAC) via HXK2 inhibitors and HXK2-VDAC binding domain peptides. Furthermore, inhibition of the PI3K/AKT signalling pathway abolished the regulatory effects of Fraxin on HXK2 during myocardial infarction. Taken together, Fraxin exerts a cardioprotective effect by regulating HXK2 through PI3K/AKT signaling pathway to reduce reactive oxygen species (ROS) levels, inflammation and myocardial apoptosis. This study provides a scientific basis for the therapeutic potential of the traditional Chinese medicine Fraxin in AMI.
Hepatic fibrosis (HF) is a crucial and reversible stage, yet there is a paucity of effective clinical antifibrotic drugs. Salvianic acid A (SAA) has shown antifibrotic potential in preliminary studies; however, its molecular mechanisms and potential targets remain incompletely understood. To evaluate the therapeutic efficacy and mechanisms of SAA in mitigating HF, we employed a carbon tetrachloride (CCl4)-induced HF mouse model. In parallel, we used transforming growth factor beta 1 (TGF-β1)-stimulated LX-2 cells and primary mouse hepatic stellate cells (HSCs) for in vitro studies. In CCl4-induced mice, SAA markedly improved liver function and suppressed HF, as evidenced by significant reduction in α-smooth muscle actin and collagen I expression and alleviation of inflammatory response. Similar antifibrotic and anti-inflammatory effects were observed in vitro. To investigate the targets and mechanism of SAA in HF, we employed network pharmacology, molecular docking, molecular dynamics simulations, and microscale thermophoresis. We found that SAA was predicted to interact with the allosteric pocket of RAC-alpha serine/threonine-protein kinase 1 (AKT1), accompanied by inhibition of AKT1 phosphorylation and the downstream nuclear factor-kappa B (NF-κB) signaling. To further explore the involvement of AKT1 in SAA's antifibrotic effects, we used the AKT activator SC79. In CCl4-induced mice, SC79 partly reversed the antifibrotic effects of SAA. Consistently, we observed that SC79 partially restored the inflammatory and fibrotic markers in TGF-β1-simulated HSCs, counteracting the inhibitory efficacy of SAA. Our findings suggest that SAA exerts antifibrotic effects in part through suppression of the AKT1/NF-κB axis and may represent a promising therapeutic candidate for HF.
Drug-induced liver injury (DILI) is a major cause of acute liver failure, with acetaminophen (APAP) overdose representing the leading cause of intrinsic hepatotoxicity worldwide. Although the mechanisms of APAP-induced liver injury have been extensively characterized, recent evidence highlights a critical role for extracellular vesicles (EVs) in mediating intercellular communication during hepatic stress and injury. EVs are lipid bilayer-enclosed vesicles released by hepatocytes and non-parenchymal liver cells under physiological and pathological conditions, carrying diverse bioactive cargo, including microRNAs, mRNAs, proteins, and mitochondrial components. Following APAP exposure, EV release is rapidly increased, often preceding overt hepatocellular necrosis and elevations in conventional biomarkers such as alanine aminotransferase (ALT). EVs actively contribute to the progression of liver injury by transferring stress signals that promote oxidative stress, activate c-Jun N-terminal kinase (JNK) signaling, and stimulate innate immune responses, including neutrophil recruitment and cGAS-STING-mediated inflammation. EV-associated cargo, particularly liver-specific microRNAs such as miR-122, demonstrates greater stability and diagnostic sensitivity than traditional compared serum biomarkers, supporting its utility as an early and reliable biomarker of hepatocellular injury. Beyond their diagnostic potential, EVs also exhibit therapeutic potential. Mesenchymal stromal cell-derived EVs have been shown to attenuate APAP-induced liver injury by delivering regulatory microRNAs, such as miR-186-5p, which suppresses chemokine signaling and reduces inflammatory cell infiltration. Collectively, EV function as dynamic mediators of liver injury, serving as biomarkers and intercellular communicators, while also showing potential as therapeutic agents. A better understanding of EV biology may facilitate the development of novel diagnostic and therapeutic strategies for APAP-induced liver injury.
AMP-activated protein kinase (AMPK) functions as a principal regulator of cellular energy homeostasis, acting as a metabolic stress sensor that coordinates essential signaling pathways, including mTOR inhibition, autophagy induction, gluconeogenesis, and lipid metabolism. Recent research underscores AMPK's pivotal role as a modulator in the initiation and progression of various diseases, particularly cancer and cardiovascular disorders. In the context of oncology, AMPK demonstrates context-dependent roles, serving as a tumor suppressor during the early stages of tumorigenesis while potentially facilitating tumor adaptation and survival in established cancers, contingent upon tissue type, disease stage, and microenvironmental factors. In the cardiovascular system, AMPK is instrumental in maintaining vascular integrity, optimizing myocardial energy dynamics, and providing substantial protection against ischemic injury. This review provides a comprehensive synthesis of the molecular functions of AMPK and highlights recent advancements that position it as a promising therapeutic target. We explore its critical roles in metabolic regulation and modulation of immune responses. By systematically summarizing these relationships, this work offers a novel perspective and emphasizes the significant potential for ongoing research into AMPK-mediated regulation of cell fate. Despite the encouraging clinical potential of AMPK-targeting pharmacotherapies, challenges such as drug specificity and efficacy remain, underscoring the necessity for innovative strategies in future therapeutic development.
BACKGROUND:Pulmonary arterial hypertension (PAH)-induced right ventricular (RV) failure increases reliance on ketones. The efficacy of SGLT2 inhibitors, known to modulate ketone metabolism, in this context remains unclear. METHODS:A PAH model was established in Sprague-Dawley rats via a single intraperitoneal injection of monocrotaline (MCT), followed by daily oral administration of dapagliflozin (DAPA). Pulmonary hemodynamics and RV function were evaluated using echocardiography and right heart catheterization. Myocardial injury, fibrosis, and mitochondrial ultrastructure were assessed via histological staining and transmission electron microscopy (TEM). Ketone body levels and metabolic enzyme expression were determined by ELISA and immunoblotting, with transcriptomic analysis identifying potential targets validated by rescue experiments. RESULTS:DAPA reduced pulmonary arterial pressure, improved RV systolic function, and attenuated RV hypertrophy and fibrosis. These benefits were associated with elevated β-hydroxybutyrate (β-OHB) and acetoacetate levels, alongside the upregulation of key ketone metabolic enzymes, including 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), β-hydroxybutyrate dehydrogenase 1 (BDH1), and succinyl-CoA:3-oxoacid CoA transferase (SCOT). Furthermore, DAPA restored mitochondrial homeostasis by increasing adenosine triphosphate (ATP) production, reducing oxidative stress, and shifting mitochondrial dynamics towards fusion-specifically by increasing mitofusin 1 (MFN1) and mitofusin 2 (MFN2), while decreasing dynamin-related protein 1 (DRP1) and fission 1 (FIS1). Transcriptomics revealed significant ADAMTS8 downregulation following DAPA treatment; crucially, adenovirus-mediated ADAMTS8 overexpression partially abrogated these cardioprotective effects. CONCLUSION:DAPA effectively alleviates PAH-induced right heart failure by suppressing ADAMTS8 expression, thereby enhancing myocardial ketone body metabolism and improving mitochondrial function. These findings identify ADAMTS8 as a key therapeutic target and provide novel evidence supporting the application of DAPA in PAH.
PURPOSE:We examined the therapeutic effects of the soluble guanylate cyclase stimulator, trans-3-methoxy-β-nitrostyrene (T3MN), on monocrotaline (MCT)-induced pulmonary hypertension (PH) in rats. EXPERIMENTAL APPROACH:Four weeks following subcutaneous MCT (60 mg/kg) injection, Male Wistar rats were orally treated for two weeks with sildenafil (10 mg/kg/day, MCT-SILD group), T3MN at 25, 50, and 75 mg/kg/day (MCT-T3MN75 group) or with its vehicle (MCT-V group). Control (CNT) rats received only MCT vehicle at Day 0 (D0). All experimental procedures were performed on D43, except for the echodopplercardiography analysis which was performed in D42 in rats from the CNT, MCT-V, MCT-T3MN75 and MCT-SILD groups. KEY RESULTS:Compared to CNT rats, MCT-V rats showed significant (1) increase in right ventricle (RV) free wall thickness and Fulton index, (2) decreases of RV stroke volume, pulmonary artery acceleration time (PAAT), PAAT/time of ejection ratio, tricuspid annular plane systolic excursion and velocity-time integral, (3) increase in RV systolic pressure, (4) increase in both pulmonary fibrosis and wall thickness of pulmonary arterioles, and (5) endothelial dysfunction. All these morphometric, invasive hemodynamic, vascular reactivity and pulmonary remodeling changes were significantly and dose-dependently reduced by T3MN. Indeed, changes in hemodynamic parameters recorded by echodopplercardiography were reversed in the MCT-T3MN75 group. CONCLUSION:T3MN treatment reversed dose-dependently the established PH in rats, as evidenced by its inhibitory effects on MCT-induced RV hypertrophy, lung congestion, RV systolic dysfunction, RV pressure overload, pulmonary artery stiffness, endothelial dysfunction, pulmonary artery remodeling and collagen deposition. Further mechanistic studies of these therapeutic effects of T3MN are warranted.
The NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome plays a crucial role in host defense; however, its aberrant activation leads to excessive release of pro-inflammatory cytokines, triggering inflammatory responses and tissue damage in human diseases. In this study, the inhibitory effect and anti-inflammatory potential of carabrone on the NLRP3 inflammasome were systematically evaluated. Carabrone suppressed lipopolysaccharide (LPS) + ATP/Nigericin-induced IL-1β secretion, Caspase-1 activation, and apoptosis-associated speck-like protein (ASC) speck formation. Mechanistic investigations revealed that carabrone inhibited the NLRP3-NEK7 interaction and bound to Gln 624 and Ser 658 within the NACHT domain of NLRP3, thereby stabilizing the local conformation and inhibiting inflammasome activation. In addition, carabrone showed protective effects in Alzheimer's disease (AD) models, which were associated with NLRP3 inflammasome inhibition. Similar effects were also observed in other NLRP3 inflammasome-related disease models, including sepsis, gouty arthritis, and acute peritonitis. Collectively, these results indicate that carabrone might act as a modulator of NLRP3 inflammasome activation across multiple inflammatory disease contexts.
Atherosclerosis continues to be a primary contributor to global cardiovascular mortality, influenced by intricate lipid and inflammatory mechanisms. Despite the efficacy of conventional pharmacotherapies, ongoing issues of patient non-adherence and residual risk have prompted the exploration of more enduring therapeutic alternatives. This review examines the significant transition in cardiovascular research from conventional, wide knockout models to the utilization of advanced precision genome editing methods, particularly emphasizing CRISPR-Cas9, base editing, and prime editing. These sophisticated molecular tools allow for the accurate insertion and rectification of single-nucleotide variants without causing double-strand breaks, marking a significant shift from rudimentary gene disruption to precise variant engineering. By specifically targeting essential lipid-regulating genes like proprotein convertase subtilisin/kexin type 9 (PCSK9) and angiopoietin-like 3 (ANGPTL3), precision editing presents an exceptional opportunity for lasting, one-shot lipid-lowering treatments. Additionally, we examine the advancement of preclinical modeling, emphasizing humanized models that precisely represent population genetics. This review highlights the essential obstacles to clinical translation, focusing on the optimization of delivery systems such as adeno-associated viruses (AAVs) and lipid nanoparticles (LNPs), as well as the thorough assessment of off-target effects and ethical implications.
Immune checkpoint blockade (ICB) therapies, particularly antibodies blocking, the programmed cell death protein 1 (PD-1)/programmed cell death-ligand 1 (PD-L1), have shown clinical success but remain limited by suboptimal response rates, often due to insufficient immune activation. T-cell immunoglobulin and mucin domain-containing protein-3 (TIM-3), a non-redundant immune checkpoint frequently co-expressed with PD-1, drives severe T-cell exhaustion in solid tumors and contributes to resistance against anti-PD-1/PD-L1 therapy. Thus, dual blockade of TIM-3 and PD-1 may restore more effective anti-tumor immunity. Compared to antibodies, low-molecular-weight peptides offer advantages in combination therapy, including better tissue penetration, lower immunogenicity, improved tolerability and low production costs. Cyclic peptides, in particular, provide enhanced biological activity and proteolytic stability. Here, we present TBP1, a cyclic peptide identified via a bacterial surface display library, which binds TIM-3 with high affinity and specificity. Competitive blocking assays and molecular docking confirmed that TBP1 effectively disrupts TIM-3 interactions with Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM-1) and Phosphatidylserine (PtdSer). In vitro, TBP1 restored exhausted T-cell function by disrupting the TIM-3/CEACAM-1 interaction. In CT26 tumor-bearing mice, TBP1 synergized with an anti-PD-1 antibody, enhancing anti-tumor immunity by promoting CD4+ T cell infiltration and IL-2 secretion. These findings identify TBP1 as a novel TIM-3-targeting cyclic peptide and support its potential application in combination immune checkpoint blockade.
Dimethylcurcumin (ASC-J9), a derivative of curcumin, has been reported to possess anticancer activity. However, its potential impact on oral squamous cell carcinoma (OSCC) has not been fully characterized. In this study, we aimed to determine whether ASC-J9 inhibits OSCC metastasis and to elucidate the molecular mechanisms involved. Our findings indicate that ASC-J9 treatment significantly reduced OSCC metastasis both in vitro and in vivo. Notably, ASC-J9 treatment led to a marked decrease in both mRNA and protein levels of integrin beta 8 (ITGB8) in OSCC cells. In addition, ASC-J9 suppresses epithelial-mesenchymal transition (EMT) through the upregulation of E-cadherin and the downregulation of vimentin, fibronectin, Snail, and Slug expression. Moreover, ASC-J9 treatment led to a reduction in phosphorylated STAT3 (p-STAT3) levels. Activation of STAT3 by the selective activator colivelin reversed the ASC-J9-induced suppression of ITGB8 expression and cell migration. These findings suggest that ASC-J9 inhibits ITGB8 in OSCC cells by blocking STAT3 activation, thereby reducing their invasive and migratory capabilities. Collectively, our results support ASC-J9 as a promising therapeutic candidate for the treatment of OSCC.
Cerebellar abnormalities have been associated with attention-deficit/hyperactivity disorder (ADHD) in human studies. Animal models also implicate cerebellar microcircuit dysfunction, particularly reduced inhibitory control of granule cells (GCs) in mice lacking Git1, an ADHD risk gene. Excitatory GCs are the most abundant neuronal population in the cerebellum and are enriched in α6 subunit-containing GABAA (α6GABAA) receptors. Thus, α6GABAA receptor-selective positive allosteric modulators (PAMs), such as pyrazoloquinolinones (PQs), may represent a novel therapeutic approach for ADHD. Here, we tested this hypothesis using PQ Compound 6 in juvenile (P28) ICR mice treated with dizocilpine (MK-801, 0.2 mg/kg, intraperitoneally, i.p.), an NMDA receptor antagonist. In both sexes, MK-801 induced behavioral abnormalities resembling the three core symptoms of ADHD- hyperlocomotion, impulsivity, and inattention-as assessed by locomotor activity, cliff avoidance reaction, and novel object recognition tests, respectively. Compound 6 (3 mg/kg, i.p.) normalized these ADHD-like behavioral impairments. Atomoxetine, an approved ADHD medication, also attenuated ADHD-like phenotypes, although with sedative effects. The therapeutic-like effects of Compound 6 were abolished by intracerebellar microinjection of furosemide, an α6GABAA receptor antagonist, and were absent in Gabra6 (α6-encoding gene)-knockout mice, indicating that positive modulation of cerebellar α6GABAA receptors underlies the observed behavioral improvements. Together, these findings provide proof-of-concept that enhancing cerebellar α6GABAA receptor-mediated inhibition can ameliorate ADHD-relevant behavioral impairments and highlight α6GABAA receptor-selective PAMs as a potential pharmacotherapeutic strategy for ADHD.
OBJECTIVE:This study aims to investigate the impact of psychotropic medication interactions on sleep architecture. With the growing use of psychotropics, including antidepressants, antipsychotics, and mood stabilizers, this research seeks to understand how these drugs and their cumulative burden may affect key sleep parameters. MATERIAL AND METHODS:This retrospective study analyzed 60 non-psychotropic medication users, as well as 61 psychotropic medication users who underwent hospital polysomnography and met all inclusion criteria. Sociodemographic and polysomnographic data were obtained from a sleep laboratory database, between January 2018 and December 2021. Statistical analysis included normality assessment and appropriate parametric or non-parametric tests for group comparisons. Multivariable general linear models adjusted for age, sex, and BMI with HC3 robust errors evaluated associations. Cumulative psychotropic burden was analyzed as a continuous predictor. RESULTS:Medicated individuals exhibited reduced sleep efficiency (p = .001), prolonged sleep onset and REM latency (p = .001), increased light sleep, and fewer sleep cycles. Multivariable analyses showed antidepressants markedly increased REM latency (p = .001) and periodic limb movements (p = .015), while anticonvulsants enhanced slow-wave sleep (p = .013) and antipsychotics reduced arousals (p = .004). A dose-response relationship was observed, with greater psychotropic burden independently associated with longer REM latency (p = .029) and reduced arousal index (p = .001). CONCLUSION:Psychotropic medications alter sleep architecture in recognizably class-specific ways, and these effects compound as the number of concurrent agents grows. Clinically, this argues for treating total psychotropic burden as a relevant variable in the interpretation of polysomnography, and underscores the need for prospective studies that account for dosage, serum levels, and cognitive outcomes.
BACKGROUND:SHR-2106 is a humanized IgG1 monoclonal antibody that blocks CD40-CD40L interactions and has demonstrated immunosuppressive activity and graft-prolonging effects in preclinical studies. This first-in-human Phase I study evaluated the safety, pharmacokinetics, pharmacodynamics, and immunogenicity of single intravenous or subcutaneous doses of SHR-2106 in healthy adults. METHODS:This randomized, double-blind, placebo-controlled Phase I study enrolled healthy participants. Fifty-one participants were enrolled in seven cohorts and received five intravenous doses (50-1200 mg) or two subcutaneous doses (300 and 600 mg). Safety, serum pharmacokinetics, CD40 occupancy on B cells, and anti-drug antibodies were assessed using standard clinical and bioanalytical methods. RESULTS:SHR-2106 demonstrated a favorable safety and tolerability profile, and most treatment-emergent adverse events were mild to moderate laboratory abnormalities with incidence rates comparable to placebo. SHR-2106 exhibited nonlinear pharmacokinetics consistent with target-mediated drug disposition, with a dose-dependent increase in geometric mean terminal half-life following intravenous administration (1.83-10.7 days). Absolute bioavailability after subcutaneous administration was approximately 60%. CD40 occupancy exceeded 80% within 24 h at all doses, with saturation duration increasing from 7 to 70 days across the intravenous dose range and remaining comparable between routes at matched doses. Anti-drug antibody incidence decreased with increasing intravenous dose and did not significantly affect pharmacokinetics or pharmacodynamics. CONCLUSION:SHR-2106 was well tolerated and achieved rapid and sustained CD40 engagement, supporting dose and route selection for Phase II studies.
Cancer remains a leading cause of global mortality, underscoring the need for therapeutic strategies that not only target tumor cells but also enhance antitumor immunity. Thymosin α-1 (Tα1), a naturally occurring thymic peptide, has emerged as a promising immunomodulatory agent with potential applications in cancer therapy. Tα1 regulates both adaptive and innate immune responses by promoting T-cell maturation and T helper cell type 1 (Th1) polarization, enhancing natural killer cell activity, modulating dendritic cell function, and influencing tumor-associated macrophages and myeloid-derived suppressor cells. Through these actions, Tα1 may contribute to immune surveillance and modulation of the tumor microenvironment. Preclinical and clinical studies suggested that Tα1 may possess antitumor activity and could enhance the efficacy of conventional and emerging cancer therapies, including chemotherapy, radiotherapy, and immune checkpoint inhibitors. Emerging evidence also indicates that Tα1 may improve immune infiltration in immunologically "cold" tumors and help mitigate certain immune-related adverse events associated with immunotherapy. Clinical investigations in malignancies, such as non-small cell lung cancer, hepatocellular carcinoma, and metastatic melanoma, have reported a favorable safety profile and potential therapeutic benefits, although the available evidence remains limited and heterogeneous. This review summarizes the biological functions, immunoregulatory mechanisms, and therapeutic potential of Tα1 in oncology. We discuss recent advances in Tα1-based combination strategies, clinical observations, translational opportunities, and current limitations of the evidence. Furthermore, key challenges and future research directions are highlighted to provide an updated perspective on the role of Tα1 as a potential adjunctive immunomodulatory agent in modern cancer immunotherapy.
BACKGROUND:Myocardial injury (MI), a subset of cardiovascular diseases, remains a leading cause of deaths globally, driven by pathological inflammation, oxidative stress, and apoptosis. Despite advances in interventional cardiology, high relapse rates and therapeutic limitations underscore the urgent need for novel pharmacological agents. Phytochemicals, with their multi-target approach and favorable safety profiles, offer promising alternatives for mitigating ischemic injury. METHODS:The cardioprotective effects of 1,8-cineole, a monoterpene derived from Eucalyptus species, was investigated in a rat model of isoproterenol-induced myocardial injury. Serum levels of cardiac enzymes (creatine kinase (CK), lactate dehydrogenase (LDH)) and pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) were quantified. Preliminary histopathological analysis was performed to assess the extent of myocardial damage. Key molecular mechanisms were evaluated via western blotting and immunohistochemistry, examining pathways related to inflammation (NF-κB), apoptosis (Bcl-2/Bax, caspase-3), endoplasmic reticulum (ER) stress (GRP78, CHOP, PERK-eIF2α), and antioxidant defense (GSH, SOD, CAT). RESULTS:Our results demonstrate that 1,8-cineole significantly reduced the levels of serum cardiac enzymes (CK-MB, LDH), and histopathological damage. Mechanistically, 1,8-cineole also suppressed pro-inflammatory cytokine release (TNF-α, IL-6, and IL-1β) via inhibition of the NF-κB pathway. Furthermore, it attenuated cardiomyocyte apoptosis by modulating Bcl-2/Bax expression and inhibiting caspase-3 activation. Additionally, 1,8-cineole alleviated ER stress by downregulating GRP78, CHOP, and PERK-eIF2α signaling. Importantly, we identified enhanced Nrf2 nuclear translocation and subsequent upregulation of antioxidant enzymes (GSH, SOD, CAT) as key contributors to its cytoprotective effects. CONCLUSIONS:1,8-Cineole exhibits potent cardio-protection in experimental myocardial injury by targetinginflammation, apoptosis, ER stress, and oxidative stress through modulation of p38 MAPK/JNK, suppression of inflammatory markers (TNF-α, IL-6, IL-1β) and apoptotic markers (Bax, p53). Its natural origin, bioavailability, and multi-mechanistic effectiveness make it a promising candidate for translational development as an adjunct therapy for myocardial injury.
Sepsis-induced cardiomyopathy (SICM) is a prevalent cardiac complication of sepsis that is characterized by inflammatory dysregulation, mitochondrial dysfunction, metabolic disturbance, and changes in the myocardial microenvironment. Mitochondrial open reading frame of the 12S rRNA type-c (MOTS-c) is a mitochondrial-derived microprotein with metabolic regulatory and stress-responsive properties. Existing studies have linked MOTS-c to AMP-activated protein kinase-related energy metabolism, antioxidant responses, inflammatory restraint, endothelial and microvascular protection, and mitochondrial quality control. These processes are relevant to SICM; however, there is limited direct SICM-specific evidence for MOTS-c, and several proposed mechanisms, such as stress-responsive nuclear signaling, have been established primarily in non-SICM settings. This review summarizes the biological characteristics and stress-responsive regulation of MOTS-c, evaluates its potential involvement in pathological processes related to SICM, and distinguishes direct SICM evidence from findings extrapolated from other cardiovascular, metabolic, and inflammatory disease models. We also discuss the exploratory value and current limitations of MOTS-c as a stress-related adjunctive biomarker and potential therapeutic candidate, with particular attention to biomarker specificity, post-treatment efficacy, target-cell mechanisms, and pharmacokinetic or biodistribution issues under septic conditions. Overall, MOTS-c represents a plausible but insufficiently validated molecule in SICM research, and its translational relevance will depend on disease-specific mechanistic and pharmacological validation.
