Search Results (181)

Nitrogen (N) is essential for crop growth, yet excessive fertilization causes environmental issues, highlighting the need to sustain yield and grain N concentration under reduced N input. miR396s are known to regulate plant development and stress responses. Here, we examined whether and how miR396 affects wheat yield and N status under high and low N conditions. TaMIM396 (transforming with the target mimicry construct of miR396) overexpression significantly increased plant height, spike length, grain yield, and grain N concentration under both N treatments. Physiological data showed TaMIM396 enhanced dry matter (DM) and N accumulation at anthesis and maturity, as well as improved post-anthesis remobilization of DM and N to grains. RNA-seq analysis revealed that, under low N, TaMIM396 specifically upregulated key photosynthetic antenna genes, including Lhca3 and Lhcb1/2/3/5, which are critical for light harvesting, suggesting improved photosynthetic efficiency that promotes DM accumulation under N limitation. Collectively, our results demonstrate that TaMIM396 acts as a broad-spectrum N-efficiency gene, coordinating carbon and N remobilization while boosting photosynthetic capacity, thereby supporting stable yield and grain N concentration across N supply levels. Therefore, TaMIM396 is a promising candidate for breeding N-efficient wheat cultivars compatible with sustainable high-yield agriculture. Full article

Nanomedicine has yielded clinically useful platforms, including liposomes, albumin-bound nanoparticles, and lipid nanoparticles; yet, many systems translate poorly because of nonspecific biodistribution, limited target-site accumulation, inefficient cellular uptake and intracellular delivery, immune clearance, and off-target toxicity. These bottlenecks are often shaped at cell membrane interfaces, where therapeutic materials are recognized, retained, internalized, or cleared and may elicit unsafe responses. Here, we frame cell membrane biophysics as a therapeutic interface for nanomedicine. We examine how lipid organization and fluidity, mechanics, electrochemical state, glycocalyx architecture, and membrane protein identity shape recognition, adhesion, endocytosis, fusion, trafficking, immune responses, and drug release. We assess how disease-associated membrane remodeling can create candidate therapeutic entry points and delivery barriers across cancer, neurodegeneration, inflammation, infection, and vascular disease. We then analyze receptor-mediated targeting, lipid-domain-associated uptake, membrane-coated nanocarriers, engineered extracellular vesicles, and hybrid platforms, with explicit context-of-use definitions and design boundaries. Finally, we propose translational qualification through function-linked critical quality attributes, mechanism-relevant potency assays, context-matched models, in vivo pharmacology and immune safety, scalable manufacturing, and regulatory evaluation. Progress will depend less on descriptive membrane mimicry than on measurable, reproducible, and qualified membrane-dependent functions. Full article

Adenosine deaminase acting on RNA 1 (ADAR1) is a critical regulator of innate immune signaling and a pan-cancer therapeutic target. Through catalyzing adenosine-to-inosine (A-to-I) editing and editing-independent mechanisms, ADAR1 suppresses activation of dsRNA sensing pathways, including protein kinase R (PKR), melanoma differentiation-associated protein 5 (MDA5), and oligodenylate-synthetase (OAS) signaling, that are critical for maintaining cellular tolerance to endogenous RNAs. In a subset of tumors characterized by elevated interferon-stimulated gene (ISG) expression and dsRNA stress, this function creates a dependency on ADAR1 for survival, establishing a therapeutic vulnerability that can be exploited to induce viral mimicry in cancer cells and enhance anti-tumor immune responses. Here, we review the emerging landscape of ADAR1 modulators, organizing reported compounds into mechanistic classes including nucleoside analogs, catalytic inhibitors, Zα domain modulators, RNA substrate engagement inhibitors, indirect pathway regulators, and PROTACs. We evaluate molecules within these classes with a focus on their mechanisms of action and experimental validation. We further discuss the challenges associated with distinguishing direct inhibition of ADAR1 activity from broader effects on RNA metabolism and innate immune activation. Finally, we highlight the therapeutic potential of ADAR1 targeting defined cancer subsets and examine combination strategies that leverage ADAR1 inhibition for improved sensitivity to current cancer therapeutics. Overall, this review outlines key considerations for the development of selective therapies targeting ADAR1. Full article

Myocarditis is a clinically challenging form of inflammatory heart disease with heterogeneous etiologies, limited diagnostic tools, no targeted therapies, and a substantial risk of progression to heart failure or sudden cardiac death, particularly in young adults. Emerging evidence has increasingly associated myocarditis with gut microbiota dysbiosis. This review explores the gut–myocarditis axis, highlighting key mechanisms and therapeutic strategies. Significant alterations in gut microbial composition are observed in myocarditis patients and animal models. Gut microbiota influences disease development through multiple pathways: compromised intestinal barrier integrity leading to bacterial translocation and systemic inflammation via MAMP/PRR signaling (e.g., TLRs, NLRs); production of metabolites—including pro-inflammatory trimethylamine N-oxide (TMAO), anti-inflammatory short-chain fatty acids (SCFAs), and immunomodulatory bile acids—that regulate host inflammatory responses, immune cell differentiation, oxidative stress, and fibrotic remodeling; and molecular mimicry, where microbial peptides (e.g., from Bacteroides thetaiotaomicron) trigger cross-reactive autoimmune responses against cardiac proteins. Regarding therapeutic strategies, this review discusses fecal microbiota transplantation (FMT), probiotics, prebiotics, dietary modulation, and emerging approaches including engineered bacteria and oral nanomedicines. Although these strategies hold promise, their efficacy and safety remain to be validated in large-scale clinical trials, and further investigation is warranted. Full article

Vasculogenic mimicry (VM) is a non-endothelial mode of tumor vascularization in which aggressive cancer cells form vessel-like networks that support microcirculation, metastasis, and resistance to anti-angiogenic therapies. VM is particularly prominent in triple-negative breast cancer (TNBC), but its molecular regulators remain incompletely understood. Focal adhesion kinase (FAK) and its paralog, proline-rich tyrosine kinase 2 (Pyk2), are closely related non-receptor tyrosine kinases implicated in epithelial-to-mesenchymal transition (EMT), invasion, and metastasis in TNBC. However, their roles in VM have not been defined. Here we perform transcriptomic analysis of FAK and Pyk2 clinical expression patterns using TNMplot V2, DepMap, and patient cohort datasets to systematically dissect the distinct contributions of FAK and Pyk2 to VM in TNBC. Our in vitro tube formation assay shows that in TNBC cells, knockdown of FAK, but not Pyk2, results in failure to form robust 3D vessel-like networks in Matrigel. Similarly, overexpression of Pyk2, but not FAK, in TNBC cells results in poor vessel-like network formation. Consistent with these findings, analysis of two independent patient cohorts (TCGA-BRCA and METABRIC) revealed selective upregulation of FAK in TNBC, while Pyk2 was inversely associated with vasculogenic-mimicry-associated gene expression, supporting the opposing roles of the two kinases in patient tumors. Taken together, these findings establish that FAK and Pyk2 govern VM through non-redundant, kinase-specific, and functionally opposed mechanisms: FAK acting as a positive regulator of VM, and Pyk2 as a context dependent suppressor of VM at elevated levels. These results nominate FAK as a candidate target for suppressing VM-driven tumor perfusion in TNBC and suggest that dual FAK/Pyk2 inhibition warrants caution hypotheses that remain to be tested pharmacologically. Full article

Autoimmune and immune-mediated inflammatory diseases (IMIDs) develop when genetically and environmentally susceptible hosts lose stable immune tolerance. The gut ecosystem is increasingly recognized as a biologically active interface in this process. Its bacterial, fungal, and viral components may shape mucosal and systemic immunity through antigenic stimulation, barrier regulation, and metabolite-dependent signaling, although the strength of evidence is uneven: bacteriome data are currently the most mature, whereas mycobiome, virome, and phageome findings remain more disease-specific and emerging. Dysbiosis may influence autoimmunity through overlapping routes, including epithelial barrier failure, altered short-chain fatty acid, bile acid, and tryptophan metabolism, molecular mimicry, and cross-kingdom microbial interactions. Nutrition is central to this network because dietary substrates determine microbial growth, metabolic output, epithelial integrity, and immune-cell differentiation. In this narrative review, we integrate evidence on disease-associated bacteriome, mycobiome, and virome patterns in systemic autoimmune diseases, with emphasis on rheumatoid arthritis, systemic lupus erythematosus, Sjögren’s syndrome, systemic sclerosis, spondyloarthritis, vasculitides, and idiopathic inflammatory myopathies. COVID-19 is considered not as a proven causal driver of autoimmunity, but as an example of an environmental and infectious insult capable of perturbing microbiome–barrier–immune communication. Finally, we discuss diet-based and microbiome-targeted approaches, including probiotics, prebiotics, synbiotics, and postbiotics, as adjunctive strategies that may help restore microbial resilience and immune balance. A better understanding of the diet–microbiome–host immunity axis may support more personalized preventive and therapeutic concepts in autoimmune disease. Full article

Mucormycosis is a devastating invasive fungal infection primarily caused by Mucor and Rhizopus species, presenting significant clinical challenges due to limited therapeutic options and emerging drug resistance in opportunistic yeasts such as Candida albicans. This study explores foliar endophytic fungi from Thai medicinal plants as potential reservoirs for novel bioactive metabolites targeting both fungal growth and virulence factors. We report the first isolation of Fusarium proliferatum as an endophyte from Lantana camara L. foliage (voucher number 01562), with its identity confirmed through morphological characterization and sequencing of the fungal ITS4/ITS5 regions. Antifungal susceptibility testing showed potent activity against a panel of environmental Mucorales, with minimum inhibitory concentrations (MICs) ranging from 0.3 to 1 mg/L. In dual-culture assays, F. proliferatum demonstrated significant mycelial inhibition rates of 93.30% to 93.67% against Mucor spp. and 88.67% to 93.67% against Rhizopus spp. Furthermore, the crude extract exhibited a potent anti-virulence effect by suppressing the C. albicans yeast-to-hyphal transition, achieving up to 68% germination inhibition in resistant strains. Liquid chromatography–mass spectrometry (LC-MS) analysis identified 51 secondary metabolites, including the cyclic peptide beauvericin and various polyketides and indole derivatives. These findings suggest that F. proliferatum utilizes metabolic mimicry and adaptive synergy with its host plant to produce a diverse chemical arsenal. This study positions foliar endophytes of L. camara as promising candidates for the development of dual-action therapeutics to combat invasive and resistant mycoses. Full article

Background: Differentiation therapy is a cornerstone in treating hematologic malignancies, particularly acute myeloid leukemia (AML). Differentiation agents target molecular defects blocking myeloid differentiation. However, rapid differentiation can precipitate a life-threatening complication, differentiation syndrome (DS). DS manifests with fever, pulmonary infiltrates, pleural or pericardial effusions, hypotension, and organ dysfunction, often mimicking sepsis or infection. Early recognition in the emergency department (ED) is critical to mitigate morbidity and mortality. This review aims to provide emergency clinicians with practical strategies for the timely identification and management of DS in patients undergoing differentiation therapy. Discussion: Suspicion for DS should be heightened in patients with acute promyelocytic leukemia (M3 AML) who recently started induction chemotherapy, including all-trans retinoic acid or arsenic trioxide, and in those with non-M3 AML receiving differentiation agents (i.e., isocitrate dehydrogenase inhibitors, menin inhibitors, FMS-like tyrosine kinase 3 inhibitors). Imaging can identify pulmonary infiltrates, effusions, and other cardiopulmonary manifestations. Laboratory workups should include complete blood counts with differentials, serum chemistries, cardiac biomarkers, and sepsis panels to exclude infection. Electrocardiography is advised for patients on QT-prolonging agents. Management emphasizes prompt initiation of high-dose corticosteroids and supportive measures such as blood pressure support, intravascular volume optimization, and oxygen therapy or ventilatory support. Multidisciplinary coordination with oncology, hematology, and critical care teams is important to tailor plans and monitor complications. Conclusions: DS represents a diagnostic challenge in the ED due to its nonspecific presentation and mimicry of infection. A high index of suspicion, combined with targeted imaging, laboratory evaluation, and early corticosteroid therapy, can improve outcomes. Full article

Background: Vasculogenic mimicry (VM) is a tumor-driven vascularization strategy in which aggressive cancer cells form perfusable, endothelium-independent channels that support tumor growth, metastasis, and therapy resistance. VM is prevalent in triple-negative breast cancer (TNBC), but within this group of tumors, VM heterogeneity is underexplored. Likewise, VM competence and its relationship to classical endothelial angiogenesis (EA) remain incompletely understood. Methods: Here, as a proof of concept, we combine functional analysis of three molecularly distinct TNBC cell lines with a panel-wide DepMap transcriptomic survey to characterize VM heterogeneity. Results: Using an in vitro tube formation assay, we show that the VM-competent TNBC cell lines MDA-MB-231 and MDA-MB-231-4175 form robust 3D vessel-like networks in a matrigel matrix, whereas the VM-incompetent line MDA-MB-468 does not. As a control, we use an immortalized endothelial cell line, 3B-11, that forms classical EA vessel-like networks. Moreover, we visualize VM (Laminin-5⁺) and EA (CD31⁺) markers in vessel-like networks of VM-competent TNBC xenografts using immunohistochemical staining and show that while they are distinctly labeled, they can also coexist to form mosaic-like vessels. Then, we use DepMap-based transcription profiles and reveal that VM competence is associated with a distinct signature. Interestingly, VM and EA transcription profiles partially overlap, yet they also remain transcriptionally distinct, with inferred mechanistic divergence, with VM being more associated with cancer cell stemness (CSC), epithelial-to-mesenchymal transition (EMT), and extracellular matrix (ECM) remodeling programs and EA being more associated with vessel strength. In addition, VM-competent TNBC cells display migration patterns and transcriptomic features consistent with endothelial-like mechanosensitivity. Conclusions: Together, these findings indicate that VM is a distinct, heterogeneous, and therapy-relevant state in TNBC that complements classical angiogenesis. Finally, the mechanistic distinction between VM and EA programs made here will motivate future studies on dual-targeting strategies that inhibit both vascularization processes while also motivating future studies on VM for precision treatment in TNBC. Full article

Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TILs) has achieved clinically and biologically relevant responses in patients with solid cancer. Clinical efficacy has been increasingly linked to a specific T-cell phenotype, particularly CD8⁺ TILs exhibiting a progenitor stem-cell-like profile (CD39⁻ CD69⁻). This review explores the critical role of the sphingosine-1-phosphate (S1P) axis in orchestrating these responses. We detail the biological antagonism between the activation marker CD69 and S1P receptor 1 (S1PR1), where mutual exclusivity dictates thymic selection, if T-cells are retained in tissues or allowed to recirculate and maintain long-term immune surveillance. The S1PR1:S1P axis is further recognized as a critical regulator of mitochondrial fitness, sustaining the high energetic demands of precursor T-cells. We examine the “double-edged sword” nature of S1P in the tumor microenvironment (TME), where it can drive pro-tumorigenic processes like angiogenesis and vascular mimicry (VM), be hijacked by cancer cells to create immune-excluded environments, or S1P can increase T-cell fitness. We summarize the current landscape of clinical trials (as of January 2026) that target S1P production or signaling to modulate anti-tumor responses or use S1P as a biologically relevant marker of treatment outcome. Full article

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system with onset typically in early adulthood and the potential for long-term disability. Current therapies are initiated after symptom onset and do not address early disease triggers, highlighting the need for preventive strategies. Epstein–Barr virus (EBV) infection has emerged as the strongest candidate upstream factor in MS development. This narrative review provides a focused and critical synthesis of current evidence, with particular emphasis on the prevention perspective and the conceptual framing of MS as a potentially infection-driven disease. We integrate epidemiological, immunological, and mechanistic data while explicitly addressing key uncertainties and limitations in causal interpretation. Longitudinal studies indicate that EBV infection precedes MS onset in most cases and is associated with a markedly increased risk following seroconversion. However, EBV infection alone is not sufficient to cause MS. Proposed mechanisms include immune dysregulation and molecular mimicry, though key uncertainties remain. Based on current evidence, EBV represents a promising but unproven target for MS prevention. Future strategies may include prevention of EBV infection or infectious mononucleosis, alongside improved risk stratification and long-term studies to assess the impact of EBV-targeted interventions on MS incidence. Full article

One of the most critical aspects of post-acute COVID-19 syndrome (PACS) and post-acute COVID-19 vaccination syndrome (PACVS) is the presence of autoantibodies. These autoantibodies are directed against various receptors in the autonomic and cardiovascular systems, including those targeting proteins of the renin–angiotensin system (RAS). The RAS plays a central role in regulating vascular homeostasis, inflammation, and endothelial function. During SARS-CoV-2 infection, the interaction of the spike (S) protein with angiotensin-converting enzyme 2 (ACE2) can alter the balance of the RAS, favoring an imbalance towards the ACE/Angiotensin II/AT1R axis, known for its pro-inflammatory, pro-thrombotic, and vasoconstrictive properties. Similar pathological mechanisms also come into play in response to vaccinations that use the S protein as an antigen. Studies conducted by other groups and us on patients with PACS and PACVS have revealed the presence of autoantibodies directed against these RAS components and the mechanisms by which these antibodies can worsen the clinical situation. In particular, anti-ACE2, presumably formed by the anti-idiotype network or molecular mimicry, is correlated with PACVS symptoms in many patients. Furthermore, the presence of anti-MAS1 antibodies can reduce the efficiency of the ACE2/Angiotensin-(1–7)/MAS1 axis, which normally acts as a counter-regulator. Considering this evidence, an analysis of RAS molecules and the autoantibodies implicated in reactions to them may be useful for evaluating a state of persistent dysregulation associated with post-vaccination symptoms such as asthenia, headache, skin edema and bruising, cardiovascular alterations, and neurovegetative manifestations. Finally, we offer insights into diagnosing these multifaceted syndromes and working hypotheses to guide research into possible therapeutic approaches. Full article

The polyamine metabolic pathway, an evolutionarily conserved nexus integrating nutrient sensing, translation control, and cellular proliferation, is fundamentally rewired in cancer. Melanoma, a malignancy of melanocytes notorious for its metastatic propensity and therapy resistance, exhibits a profound dependency on this pathway, extending beyond mere polyamine abundance to the specialized function of their derivative, hypusine. This review synthesizes cutting-edge insights into the deoxyhypusine synthase (DHPS)/eukaryotic initiation factor 5A (eIF5A) hypusination circuit as a critical amplifier of oncogenic signaling in melanoma. We dissect its role as a translational rheostat for pro-tumorigenic proteomes, a driver of phenotypic plasticity underpinning invasion and vasculogenic mimicry, and a modulator of the immunosuppressive tumor microenvironment. Moving beyond the classical inhibitor GC7, we explore the emergence of novel allosteric DHPS inhibitors with compelling preclinical efficacy. Finally, we propose a paradigm shift: targeting the DHPS/eIF5A axis represents a strategy to disrupt the “non-oncogene addiction” of melanoma—its reliance on hyperactive translation and adaptive survival mechanisms—offering a promising avenue alongside targeted therapies and immunotherapies. Full article

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer defined by the absence of estrogen and progesterone receptors, as well as the lack of human epidermal growth factor 2 receptor overexpression. TNBC is associated with early onset, high metastatic potential, therapeutic resistance, and poor clinical outcomes exacerbated by the limited availability of effective targeted therapies. Advances in multi-omics profiling have further stratified TNBC into distinct molecular subtypes, each exhibiting unique genomic, epigenomic, and immune-related features that influence therapeutic responsiveness. This review explores the interplay between TNBC molecular heterogeneity, immune evasion mechanisms, and epigenetic regulation. TNBC demonstrates variable immunogenicity, with tumor-infiltrating lymphocytes serving as important prognostic and predictive biomarkers. However, immune escape commonly occurs through tumor microenvironment remodeling, T-cell exhaustion, cancer stem cell enrichment, and immune checkpoint pathways activation. Although immune checkpoint inhibitors have improved outcomes in selected patients, particularly in combination with chemotherapy, primary and acquired therapeutic resistance remain a significant challenge. Emerging evidence highlights the central role of epigenetic mechanisms in regulating immune-related gene expression and shaping the tumor immune microenvironment. Epigenetic silencing of antigen presentation machinery, interferon signaling pathways, and chemokine expression contributes to immune evasion and immunotherapy resistance. Importantly, pharmacological modulation of epigenetic regulators can restore immune recognition and induce “viral mimicry” through reactivation of endogenous retroelements, thereby enhancing antitumor immunity. Collectively, this review underscores the therapeutic potential of integrating epigenetic therapies with immunotherapy and chemotherapy to overcome immune resistance in TNBC. A deeper understanding of epigenetic-immune interactions may facilitate the development of more precise and effective treatment strategies tailored to TNBC molecular subtypes. Full article

The purpose of this study was to compare the retinal gene expression profiles in canines with Sudden Acquired Retinal Degeneration Syndrome (SARDS) and Cancer-Associated Retinopathy (CAR) and identify shared and distinct molecular pathways. Previously published SARDS and CAR canine retinal microarray data were used for the purposes of retinal transcriptomic pathway analysis, followed by KEGG and GO pathway enrichment analysis using DAVID and MetaCore tools. Gene expression patterns were analyzed to detect the most important signaling pathways. ProteinBERT deep-learning language model, and large language models (LLM-Grok 4, ChatGPT4o) were used for analytical prediction of possible drug targets. Both diseases showed significant upregulation in T-cell co-stimulation and complement activation pathways, including CD86, DLA-79, and C5AR1. Downregulated genes were enriched in pathways associated with visual perception and cardiomyocyte signaling. CAR exhibited upregulation of tumor-related chemokine signaling (e.g., CCR5, CXCR4), while SARDS showed pronounced enrichment in vascular inflammation pathways. Analysis of drug targets identified different classes of drugs, which could be potentially utilized for SARDS and CAR treatment. SARDS and CAR share immune-related molecular signatures but potentially differ in secondary mechanisms—vascular inflammation and endothelial activation in SARDS versus paraneoplastic mimicry in CAR. These data provide potential insight into the pathogenesis of SARDS as well as CAR, and identify potential diagnostic and therapeutic targets. Full article