Molecular Response Research Articles

Background: Heart failure (HF) involves complex interactions among cardiac cell types that drive disease progression. The neuregulin (NRG-1)/ErbB pathway is critical for cardiac repair, but clinical use of NRG-1 is limited by poor stability and receptor specificity. JK07, a fusion of an anti-ErbB3 antibody and the EGF-like domain, selectively activates ErbB4 while blocking ErbB3 activation to reduce side effects. While JK07 has demonstrated early promise in the treatment of HF clinically, its cellular mechanisms underpinning these effects remain unclear. This study explores how JK07 impact on gene expression across key cardiac cell populations. Hypothesis: We hypothesized that JK07 modulates gene expression in key cardiac cell types, inducing distinct molecular responses depending on treatment duration. Methods: BALB/c mice with MI-induced HF (EF<40%) received either a single or four weekly doses of JK07 (1 mg/kg) or vehicle. Hearts were collected 1 and 7 days after treatment for the single-dose experiments, or 7 and 28 days after the last dose for the four-dose experiments. Assessments included echocardiography, heart weight, histology, and single-nuclei RNA sequencing. Results: JK07 promoted cardiac recovery by reducing interstitial fibrosis and increasing capillary density in multi-dose groups. NT-proBNP levels decreased 7 days post-treatment in both protocols. Single-nuclei transcriptomics showed significant JK07-induced changes in cardiomyocytes, fibroblasts, macrophages, and endothelial cells, most prominently 1 and 7 days after a single dose. In cardiomyocytes, JK07 partially reversed HF-associated gene expression and enhanced mitochondrial and metabolic pathways, with confirmation in vitro via Seahorse mito stress test. In fibroblasts, JK07 altered key HF-related genes, including upregulation of Htra3 and downregulation of Igfbp7 , implicating the Htra3–TGFβ–Igfbp7 axis in antifibrotic effects. Further subclustering revealed an ErbB4-high fibroblast subtype with high expression of WNT pathway genes and potential roles in cell interactions. In endothelial cells, JK07 activated angiogenic, cytoskeletal, and repair pathways. Conclusion: JK07 promotes cardiac repair by driving cell-type-specific transcriptional programs that support metabolic adaptation in cardiomyocytes, modulate ErbB4-high fibroblast functions, and enhance endothelial regeneration. These findings highlight the therapeutic potential of JK07 as a disease-modifying agent in HF.

Background: Exercise improves cardiac health and lowers cardiovascular disease (CVD) risk, yet its protective molecular mechanisms remain incompletely understood. The Molecular Transducers of Physical Activity Consortium (MoTrPAC) provides a multi-omic atlas of endurance exercise responses in rat tissues. We performed a sex- and time-resolved integration of heart data to identify key adaptations and their relevance to CVD prevention. Methods: We applied MEFISTO, a time-aware extension of Multi-Omics Factor Analysis (MOFA2), to integrate longitudinal MoTrPAC multi-omics data—including transcriptomics, epigenomics, proteomics, post-translational modifications, and metabolomics—collected across 1 to 8 weeks of endurance training in male and female rats. Latent factors, which summarize multi-omics features covariation, were used to identify sex-specific molecular responses to endurance exercise. These factors were compared to public CVD datasets to assess shared and divergent molecular signatures. Results: We identified six latent factors spanning at least three omics layers, including four associated with endurance training. Factors 3, 4, and 5 reflected early, sex-specific adaptations involving energy and fatty acid metabolism. Particularly, Factor 1 captured a progressive, sex-shared signature, strongly correlated with VO2max (r > 0.8, p < 1e–6; Figure 1). This factor reflected a shift from acute metabolic responses to long-term remodeling, with upregulation of ATP metabolism, cardiac morphogenesis, and contractility pathways, supported by epigenetic and post-translational regulation (Figure 2). These findings suggest that endurance exercise enhances mitochondrial efficiency and promotes cardiac tissue maturation. Comparison with human CVD signatures revealed significant inverse enrichment in ischemic heart disease (p < 2e–10), heart failure (p < 2e–3), and cardiac hypertrophy (p < 6e–4). Genes associated with Factor 1 and inversely linked to CVD signatures were enriched for reduced T cell immunity and increased extracellular matrix organization, highlighting a coordinated immunomodulatory and structural adaptation. Conclusion: Endurance exercise drives sustained molecular remodeling, shifting from early metabolic activation to enhanced mitochondrial efficiency, epigenetic regulation, and cardiac development. Its inverse association with CVD signatures highlights exercise’s protective role through immune modulation and structural remodeling of the heart.

Clinical case reports in oncology are an untapped resource of patient data that include relationships between molecular alterations, tumor types, and response to targeted therapy. A current challenge to widespread utilization of case reports in clinical practice is the lack of systematic organization of clinical evidence across disease types, patient outcomes, therapies, and associated molecular features. To address this challenge, we sought to demonstrate the utility of Cancer Knowledgebase (CKB) (https://ckb.genomenon.com/) in interpreting oncology case report data for health care providers. We analyzed data from 5527 manually curated case reports in CKB to gain insights related to treatment options and patient response associated with specific molecular alterations. Each case report in CKB is represented as a unique efficacy evidence annotation and is associated with a specific molecular profile, therapy, indication, and response to therapy. Efficacy evidence from case reports spans over 500 genes, 2800 molecular profiles, and 300 tumor types, including several rare cancers and pediatric tumor types. CKB is a powerful resource for leveraging case reports to identify treatment options for patients with rare cancers and oncogenic variants, patients for whom multiple therapies exist, and patients experiencing resistance to first-line therapy.

This study evaluated the physiological, biochemical traits, molecular responses, and vase life of cut Alstroemeria hybrida ‘Amatista’ in response to preharvest applications of putrescine and melatonin. A factorial experiment was arranged in a completely randomized design with three replications. The treatments included foliar sprays of putrescine (0, 1.5, and 3 mM), melatonin (0, 50, and 100 µM), and four postharvest sampling times (0, 5, 10, and 15 days). Measured parameters included chlorophyll index, relative fresh weight, solution uptake, ion leakage, malondialdehyde (MDA), hydrogen peroxide (H2O2), polyphenol oxidase (PPO) activity, vase life, and the relative expression of chlorophyllase (CHL) and ACC oxidase (ACO) genes. Postharvest senescence was associated with a time-dependent decline in chlorophyll index, water content, and solution uptake, along with increased ion leakage, MDA, H₂O₂ levels, and PPO activity. However, preharvest application of putrescine and melatonin effectively delayed these detrimental changes. Notably, the combined application of 1.5 mM putrescine and 50 µM melatonin resulted in the greatest improvement in postharvest performance, extending vase life from 16.00 to 23.66 days and enhancing physiological and biochemical traits. Moreover, gene expression analysis indicated that these treatments suppressed the expression of CHL and ACO, suggesting a molecular mechanism involved in delayed senescence. Overall, the findings highlight the potential of putrescine and melatonin as eco-friendly preharvest treatments to improve the postharvest quality and longevity of cut Alstroemeria flowers by modulating key physiological, biochemical, and molecular processes.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12870-025-07530-6.

Traumatic brain injury (TBI) affects millions of people globally each year, yet effective treatments remain limited. A major challenge is the complexity of cellular and molecular responses to brain injury, many of which overlap with those seen in aging. A key hallmark of aging is nucleolar enlargement in brain and other tissues, reflecting increased ribosome biogenesis. Nucleolar size is regulated by the target of rapamycin (TOR) signaling pathway, which during aging is aberrantly activated. Inhibiting TOR reduces nucleolar size and extends lifespan in several model organisms. Using a Drosophila melanogaster model of closed-head TBI, we investigated whether injury influences nucleolar dynamics. Immunofluorescence microscopy of fibrillarin, a major nucleolar protein, revealed that brains of young, injured flies had substantially larger nucleoli than uninjured controls within one day of injury. Over the following weeks, the difference gradually diminished as nucleolar size increased in uninjured flies, eventually matching that of injured flies, which remained relatively stable. Additionally, heterogeneity in nucleolar size across cells became more pronounced with injury and aging. Finally, injury of older flies resulted in little or no nucleolar enlargement and even shrinkage within a few days of injury. These results suggest that TBI and aging converge on shared mechanisms that regulate nucleolar size, which may reach a maximal limit through either process. Consistent with this, mortality at 24 hours post-injury in young flies was significantly reduced by pharmacological inhibition of TOR with rapamycin or RapaLink-1, indicating that nucleolar enlargement contributes to TBI-induced damage. Overall, our results suggest that TBI accelerates the aging-associated increase in nucleolar size, implicating elevated ribosome biogenesis in TBI pathogenesis and highlighting TOR inhibition as a promising therapeutic approach.

BackgroundRapid and efficient epithelial regeneration is fundamental for tissue homeostasis and proper function. As the outermost ocular structure, the cornea is transparent, multilayered, and vital for clear vision. Due to its exposed position, the cornea frequently undergoes various forms of injury affecting either the epithelium itself or its surrounding microenvironment, including corneal innervation and the tear film. Corneal abrasion, occurring commonly through trauma or as part of refractive surgical procedures, is typically viewed as a minor event since it usually resolves rapidly. Consequently, the cornea serves as an excellent model for studying epithelial wound healing. However, complications such as persistent epithelial defects or corneal opacity can develop, underscoring critical gaps in understanding the underlying molecular mechanisms.MethodsUtilizing a unilateral corneal abrasion mouse model, we conducted a comprehensive multi-omics analysis, integrating transcriptomics, proteomics, and epitranscriptomics, to dissect the dynamic molecular responses post-injury in both wounded and contralateral tissues. To elucidate the role of the tear film, we performed additional studies involving lacrimal gland ablation combined with corneal injury. We applied RNA sequencing to profile transcriptomic changes in corneal and lacrimal gland tissues, and mass spectrometry to study tear proteomics and epitranscriptomic modifications.ResultsWe revealed a major modulation of the cornea transcriptome after abrasion, suggesting a regulation of pathways including JAK-STAT, Wnt and TGF-β, and a reduction of nucleoside modifications. The lacrimal gland transcriptome and tears proteome were also significantly affected. Plus, we highlighted a bilateralization, both in the cornea transcriptome and tears proteome. In the tear-deficient conditions, the wound closure rate and molecular responses were altered, and the bilateralization was impacted, with an increased matrix remodeling and a modulation of keratins expression.ConclusionsOur multi-omics analyses revealed extensive epithelial cellular plasticity as a key mechanism driving rapid wound closure, characterized by profound remodeling of transcriptional networks and RNA modifications. Importantly, we uncovered a previously underappreciated role of the lacrimal gland and tear film in mediating bilateral molecular responses following unilateral injury, emphasizing their pivotal roles in tissue regeneration. Additionally, we identified novel regulatory roles for RNA methylation events and critical signaling pathways implicated in epithelial healing.Graphical abstractSupplementary InformationThe online version contains supplementary material available at 10.1186/s11658-025-00804-9.

Endocrine-disrupting chemicals (EDCs) are widespread contaminants that interfere with hormonal signaling and compromise reproductive success in aquatic organisms. Vitellogenin (VTG) is one of the most widely established biomarkers of estrogenic exposure, especially in males and juveniles. However, evidence from multi-omics studies indicates that VTG induction occurs within broader transcriptional and regulatory networks, involving genes such as cyp19a1 (aromatase), cyp1a (cytochrome P4501A), and other stress-responsive genes, underscoring the complexity of endocrine disruption. This review focuses on nuclear receptor isoforms, including estrogen receptor alpha (ERα), estrogen receptor beta (ERβ), and androgen receptor (AR) variants. We examine the diversification of vtg gene repertoires across teleost genomes and epigenetic mechanisms, such as DNA methylation and microRNAs, that modulate sex-dependent sensitivity. In addition, we discuss integrative approaches that combine VTG with transcriptomic, epigenetic, and histological endpoints. Within the Adverse Outcome Pathway (AOP) and weight-of-evidence (WoE) frameworks, these strategies provide mechanistic links between receptor activation and reproductive impairment. Finally, we outline future directions, focusing on the development of sex-specific biomarker panels, the integration of omics-based data with machine learning, and advances in ecogenomics. Embedding molecular responses into ecological and regulatory contexts will help bridge mechanistic insights with environmental relevance and support sustainability goals such as SDG 14 (Life Below Water).

Traditional research in plant stress biology has predominantly focused on physiological and molecular response mechanisms under single stressors [...]

Immune checkpoint inhibitors (ICIs) have revolutionised the treatment of advanced non-small cell lung cancer (NSCLC). Quantitative monitoring of disease burden may prove predictive in these cases. We hypothesised that serial ctDNA molecular response assessment may be predictive of response to nivolumab. 44 NSCLC patients who received nivolumab were included. All the patients underwent response assessment by RECIST every four cycles. Peripheral blood samples were obtained at baseline and after four cycles of therapy, and the quantification of ctDNA was performed by qubit dsDNA HS assay. A variant allele fraction (VAF) of >0.3% was considered to be used for tracking. A cut-off change of 50% in VAF and ctDNA was considered for molecular response. Radiological evaluations were performed at baseline and every four cycles as per RECIST 1.1 criteria. The median ctDNA concentration was higher in patients with time to progression (TTP) of <4 months (P = 0.05). Detectable alterations with >0.3% VAF were detected in 31 patients, and a molecular response of >50% was observed in patients with PR, stable disease (SD) and two patients with PD. The patients with <50%molecular response had a median PFS of 3.9 months vs. those with >50% had a median of 5.8 months (P = 0.06). A cut of 0.3 ng/microlitre baseline ctDNA concentration was predictive of PFS. This is an initial experience from India using liquid biopsy next-generation sequencing (NGS) for dynamic monitoring in immunotherapy-treated patients. A 50% cut-off for response as well as a baseline ctDNA 0f 0.3 ng/microlitre showed a trend for better PFS in these patients. This study highlights the need for serial monitoring. To our knowledge, this is among the first real-world Indian studies validating serial NGS-based ctDNA monitoring in immunotherapy-treated NSCLC. It demonstrates feasibility, predictive value, and real-world applicability in a lower-middle-income context.

Substantiating chemical groups for read-across using molecular response profiles.

Mechanisms of cellular and molecular responses in Mytilus galloprovincialis exposed to human pharmaceuticals ibuprofen, paroxetine and their mixture.

Drought is a major abiotic constraint that limits plant growth and productivity worldwide. To cope with water scarcity, plants employ complex adaptive strategies, with stomatal regulation serving as a central mechanism for balancing water conservation and photosynthetic efficiency. Phytohormones are crucial signaling mediators in this process, coordinating the molecular, physiological, and biochemical responses that govern stomatal dynamics during drought. Abscisic acid (ABA) is the principal regulator of drought-induced stomatal closure; however, other hormones, including salicylic acid, methyl jasmonates, ethylene, gibberellins, cytokinins, and auxins, modulate stomatal function through synergistic or antagonistic interactions. Such hormonal crosstalk shapes guard cell sensitivity to ABA, regulates ion channel activity, influences transcriptional networks, and ultimately determines water-use efficiency. While earlier reviews have addressed the broader roles of phytohormones in drought adaptation, they often overlook the nuanced regulation of stomatal behavior. This review uniquely synthesizes recent advances in phytohormone signaling networks, with particular emphasis on their synergistic and antagonistic crosstalk and downstream signaling cascades that govern stomatal regulation under drought stress. It further integrates current insights into hormone-mediated adaptive responses coordinated with stomatal dynamics, establishing a mechanistic framework that links molecular signaling with physiological regulation and drought tolerance. We also highlight emerging strategies to harness hormonal regulation to enhance drought resilience and outline key research priorities for translating these insights into crop improvement.

The source of nitrogen conditions transcriptomic responses to water deficit in common bean roots.

Comparative transcriptomic and meat quality responses to electrical and controlled atmosphere stunning in broiler chickens.

Immune function and transcriptome of hemocytes in northern quahogs Mercenaria mercenaria in response to acute salinity challenges.

Transcriptome analysis of OsNCED3 transgenic rice reveals the response mechanism to alkaline stress.

Multi-omics insights into ROS-mediated molecular responses of extracellular polymeric substances in aerobic granular sludge under micro/nanoplastic stress

Identification and analysis of caspase genes in bivalves and their expression patterns in noble scallop Chlamys nobilis under low-temperature stress.

Common mycorrhizal network transfers virus infection signals between neighboring grapevines.

Comparative transcriptomics reveal universal and compound-specific mechanisms of insecticide response in the mulberry looper (Phthonandria atrilineata).