Search Results (1,122)

Mango fruits are popular for their flavor. Sugar, a key component of fruit nutrition and flavor, determines fruit quality via its composition and content. While many studies explore molecular regulatory pathways of sugar metabolism in various fruits, large-scale physiological screening of related enzymes via advanced mathematical methods is largely neglected, and the physiological mechanism of sugar accumulation in mango remains unclear. This study analyzed glucose, fructose, sucrose and starch contents, and the activities of 11 sugar metabolism-related enzymes (adenosine diphosphate glucose pyrophosphorylase (AGP); sucrose synthase (SS); sucrose phosphate synthase (SPS); protein kinase (PK); starch debranching enzyme (DBE); phosphoglucomutase (PGM); α-amylase; β-amylase; isoamylase (ISA); sucrose invertase (INV); acid invertase (AI)) from fruit growth to post-ripening stages of mango cultivar ‘Renong No.1’, determined the correlations among soluble sugar, starch and enzyme activities, and constructed mathematical models of inter-group relationships using R language. The results showed that glucose, fructose and starch accumulated during fruit growth, while sucrose accumulated during post-ripening. Fructose content was significantly positively correlated with AGP, α-amylase, AI, β-amylase and SPS activities; so was glucose content and AGP activity; sucrose content and AGP, AI, PK, α-amylase, ISA, INV and SPS activities; and sweetness value and AGP, α-amylase, AI, SPS, SS and β-amylase activities. AI, AGP and α-amylase were identified as the key enzymes influencing sweetness value. Ultimately, a new visualizing and digitizing statistical approach for roles of eleven key enzymes in sweet value and soluble sugar component content during mango development was shown. Full article

In contrast to foreign nucleic acids, some of our own endogenously synthesized nucleic acids may become immunologically active without being considered “foreign”. For example, abnormalities in chromatin organization, transcription termination, ribonucleic acid (RNA) splicing, and RNA editing, together with damage to mitochondrial integrity, may render normally functional deoxyribonucleic acid (DNA) and RNA persistently available and aberrantly structured ligands for innate immunity. Z-DNA-binding protein 1 (ZBP1), recently identified as an important component of this innate immune system, recognizes both left-handed DNA (Z-DNA) and left-handed RNA (Z-RNA) using its tandem Z-alpha (Zα) domains and couples recognition of these conformational states to receptor-interacting serine/threonine-protein kinase 1 (RIPK1)-, receptor-interacting serine/threonine-protein kinase 3 (RIPK3)-, and mixed-lineage kinase domain-like pseudokinase (MLKL)-dependent inflammatory and cell-death pathways. More recent studies have also shown that ZBP1 plays a role in recognizing damaged self-nucleic acids associated with tauopathies, Alzheimer’s disease (AD), traumatic brain injury (TBI), and amyloid-associated neuroinflammation. The nucleic-acid forms associated with these conditions include transposable-element activation, extended repeat-containing transcripts, RNA–RNA duplexes or RNA:DNA hybrids, oxidized mitochondrial DNA (mtDNA), and intercellularly transferred nucleic acids, all of which may exhibit substrate structures compatible with Z-form formation. Signaling by ZBP1 does not occur simply based upon nucleic-acid abundance; rather, signaling occurs after prolonged exposure to a nucleic acid when it persists in a structurally competent state, sufficient receptors are present to bind its exposed regions, the receptor proteoforms are competent to participate in signaling, receptor-interacting protein homotypic interaction motif (RHIM)-dependent assembly occurs, and the appropriate adaptor molecules are present. Furthermore, the identity of the cell type expressing ZBP1 determines whether the response produces RIPK3–MLKL-dependent neuronal injury, microglia-mediated inflammation, apoptosis, or mixed cell death. Finally, competition with adenosine deaminase acting on RNA 1 (ADAR1), melanoma differentiation-associated protein 5 (MDA5), double-stranded RNA-dependent protein kinase (PKR), the cyclic guanosine monophosphate–adenosine monophosphate synthase–stimulator of interferon genes (cGAS–STING) pathway, and other nucleic-acid-sensing proteins divides the available pool of endogenous nucleic acids among the outcomes of immune tolerance, type I interferon (IFN-I) signaling, translational inhibition, neuroinflammation, and necroptosis. Full article

Neurologic manifestations of long COVID, also called neurologic post-acute sequelae of SARS-CoV-2 infection (Neuro-PASC: NP) include persistent alteration of cognitive functions. We investigated whether these could be driven by immune perturbations. We combined flow cytometry (FC), sleep profiling, and single-cell RNA sequencing of peripheral blood immune cells from older adult (>55 years) individuals with and without NP to evaluate relationships with objective cognitive performance. NP participants showed reduced numbers of blood monocytes with increased mitochondrial superoxide, indicating an altered monocyte mitochondrial redox state. Higher peripheral capillary oxygen saturation (SpO₂) was associated with better processing speed in NP participants. Monocyte transcriptional analyses identified mitochondrial adenosine triphosphate (ATP) synthase/Complex V (Complex V) pathway associated with cognitive performance in people without NP; this coupling was abrogated in NP patients, in whom cognitive performance instead showed an opposite relationship with Complex V. Shared leading-edge genes defined a 13-gene monocyte anchor representing this cognition-associated NP phenotype. Higher anchor scores were associated with coordinated oxidative phosphorylation and cytotoxic programs across CD3⁺ T-cell subsets in individuals without NP, but not in NP participants. T-cell receptor stratified analyses showed that this altered relationship occurred in both expanded and unexpanded T-cell populations. FC correlations also supported reduced monocyte-to-lymphocyte mitochondrial coordination in NP. These exploratory findings identify a sleep and cognition-linked monocyte mitochondrial phenotype characterized by altered myeloid–lymphoid immune coordination in NP. Full article

Background: Cordyceps militaris (C. militaris) is a medicinal mushroom recognized for its diverse pharmacological activities, largely attributed to its principal bioactive nucleosides, cordycepin and adenosine. Although accumulating evidence supports their neuroprotective potential, the molecular mechanisms underlying their effects against Alzheimer’s disease (AD) remain incompletely understood. This study investigated the neuroprotective effects of cordycepin and adenosine against amyloid-β (Aβ₄₂)-induced neurotoxicity and explored their potential molecular mechanisms using integrated experimental and computational approaches. Methods: SH-SY5Y neuroblastoma cells were pretreated with cordycepin (COR), adenosine (ADE), or donepezil (DNPZ) prior to Aβ₄₂ exposure, and cell viability was assessed using the MTT assay. Drug-likeness and absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties were evaluated in silico, followed by network pharmacology to identify potential therapeutic targets and enriched biological pathways. Molecular docking and molecular dynamics simulations were performed to elucidate the interactions of the compounds with selected Alzheimer’s disease-related proteins. Results: COR and ADE significantly attenuated Aβ₄₂-induced cytotoxicity and improved SH-SY5Y cell viability. Network pharmacology identified 84 shared molecular targets, including 9 AD-associated genes. Protein–protein interaction analysis revealed hub genes involved in signal transduction, epigenetic regulation, and purine metabolism, while Gene Ontology and KEGG enrichment analyses highlighted pathways associated with neuroactive ligand–receptor interaction, calcium signaling, and inflammatory regulation. ADMET analysis predicted favorable pharmacokinetic properties for both compounds, although cordycepin was predicted to be AMES-positive. Molecular docking and molecular dynamics simulations demonstrated stable interactions of COR and ADE with liver X receptors (LXRα and LXRβ), whereas donepezil exhibited stronger binding affinity toward β-secretase (BACE1). Conclusions: COR and ADE exert neuroprotective effects through coordinated modulation of multiple AD-related signaling pathways rather than a single molecular target. These findings provide mechanistic insights into the neuroprotective activities of C. militaris-derived nucleosides and support further investigation of their potential as multi-target therapeutic candidates for AD and other neurodegenerative disorders. Full article

5′-Adenosine monophosphate-activated protein kinase (AMPK) is the principal cellular energy sensor that coordinates metabolic adaptation by balancing anabolic and catabolic pathways in response to energic stress. Beyond its canonical role in maintaining energy homeostasis, AMPK has emerged as a central regulator of host–pathogen interactions by integrating lipid metabolism, autophagy, mitochondrial dynamics, oxidative stress, and innate immune signaling. Flaviviruses, including dengue virus, Zika virus, West Nile virus, Japanese encephalitis virus, and yellow fever virus, extensively remodel host metabolism to establish productive infection. As a master regulator of cellular metabolism, AMPK can either restrict or facilitate flavivirus replication in a context-dependent manner by regulating lipid droplet biogenesis, fatty acid synthesis and beta-oxidation, autophagy, mitochondrial homeostasis, and interferon-mediated antiviral responses. Conversely, flaviviruses actively manipulate AMPK signaling and its downstream metabolic networks to promote endoplasmic reticulum remodeling, replication organelle biogenesis, energy production, and immune evasion. In this review, we summarize recent advances in understanding the multifaceted roles of AMPK during flavivirus infection, with an emphasis on its regulation of metabolic reprogramming, organelle remodeling, and antiviral immunity. We further discuss the therapeutic potential of pharmacologically targeting AMPK and its downstream pathways as a host-directed strategy for broad-spectrum antiviral intervention against flaviviruses. Full article

Bacterial infection triggered excessive inflammatory responses, yet the mechanisms linking inflammatory activation to immunometabolic adaptation remained incompletely understood. The mitochondrial translocator protein (TSPO) has been implicated in inflammatory activation and cellular metabolism. This study aimed to investigate the role of TSPO in inflammation mediated by Toll-like receptor 4 (TLR4). Herein, we integrated transcriptomic data from the human peripheral blood dataset GSE72829, and single-cell transcriptomic profiles from the CELLxGENE platform with cellular mechanistic experiments in BV2 microglia and RAW264.7 macrophages. Transcriptomic analyses revealed that TSPO expression was markedly upregulated in patients with bacterial infection (n = 52) and exhibited diagnostic potential to distinguish bacterial infection from healthy controls (HCs, n = 16) and viral infection (n = 92). TSPO-correlated genes were enriched in Toll-like receptor (TLR) signaling, inflammatory response, and immunometabolic pathways. Mechanistically, TSPO interacted with TLR4 and selectively modulated TLR4-driven inflammatory activation. TSPO deficiency augmented lipopolysaccharide (LPS) induced tumor necrosis factor‑α (TNF-α) and interleukin‑6 (IL-6) secretion, accompanied by disrupted Ca²⁺ homeostasis, impaired cholesterol balance, and compensatory metabolic remodeling characterized by elevated L-lactate and sustained Adenosine triphosphate (ATP) levels. Collectively, these findings identified TSPO as an immunometabolic regulator bridging TLR4 signaling and metabolic adaptation during inflammatory activation. Besides, TSPO represented a promising biomarker and therapeutic target to limit exaggerated inflammatory responses. Full article

Polydeoxyribonucleotide (PDRN) is a DNA-derived biological therapy gaining prominence in the treatment of musculoskeletal disorders. It functions as an adenosine A2A receptor (A2AR) agonist and serves as a substrate in the nucleotide salvage pathway. These mechanisms drive anti-inflammatory effects, stimulate angiogenesis via vascular endothelial growth factor, and promote collagen synthesis. In osteoarthritis, PDRN reduces cartilage degradation and promotes the chondrogenic differentiation of stem cells. PDRN has shown therapeutic potential in tendinopathies, including Achilles and rotator cuff injuries, by supporting tissue repair. Preliminary reports suggest it may offer a non-steroidal alternative for managing spinal radiculopathy when corticosteroids are contraindicated, though robust comparative trials are needed. Preclinical and clinical evidence indicate favorable preliminary safety profiles and potential pain reduction. Future large-scale trials are needed to standardize the dosing protocols for integrated orthopedic rehabilitation. Full article

The Asian citrus psyllid (Diaphorina citri, ACP) is the primary vector of citrus huanglongbing and exhibits positive phototactic behavior. Octopamine (OA) is a critical neuromodulator of diverse insect behaviors, yet its regulatory mechanism in ACP phototactic behavior remains largely uncharacterized. In this study, three core genes of the OA signaling pathway in ACP were identified and characterized: the biosynthetic enzyme DcTβH and two β-adrenergic-like OA receptors (DcOctβ1R, DcOctβ2R). All three genes exhibited a U-shaped developmental expression pattern and high transcript abundance in the head, suggesting potential involvement in the early nymphal and adult stages and essential roles in central nervous system. Pharmacology assays revealed that DcOctβ1R activation by OA and tyramine induced cyclic adenosine monophosphate (cAMP) accumulation, with agonists and antagonists exerting differential effects on its activity. In contrast, no cAMP response was observed in cells expressing DcOctβ2R regardless of ligand treatment. Combined RNA interference and behavioral assays demonstrated that silencing DcTβH or DcOctβ1R significantly impairs ACP phototactic behavior. These findings revealed that the OA signaling positively regulates phototactic behavior via DcOctβ1R in ACP. This study enhances the understanding of OA-mediated phototactic behavior in agricultural pests and lays a foundation for exploring the molecular mechanisms of insect behaviors. Full article

High-altitude hypoxic environments constrain yaks’ survival capacity and metabolic adaptability. Subcutaneous adipose tissue helps yaks withstand cold and resist hypoxic stress, and ADM participates in cellular stress and metabolic regulation. To explore the regulatory role of ADM in the hypoxia adaptation of yak subcutaneous preadipocytes in high-altitude environments, we established three cell culture groups (normoxia, physiological hypoxia, and hypoxia). We further systematically examined cell proliferation, apoptosis, adenosine triphosphate (ATP) production, and lipid metabolic markers, and we performed transcriptome sequencing to reveal their regulatory effects. ADM exhibited a bidirectional regulatory effect: Low doses alleviated hypoxia-induced cell damage and restored energy and lipid synthesis, whereas high doses, in conjunction with hypoxia, activated multiple metabolic pathways and altered cellular energy-supply patterns. Under physiological hypoxia, cells emphasized metabolic regulation, while under hypoxia, they prioritized stress defense. This study demonstrates that under hypoxic stress, ADM regulates the survival and physiological function of yak subcutaneous preadipocytes in a dose-dependent manner, with cells relying on staged stress-defense and metabolic-remodeling responses to achieve adaptation to hypoxia, providing important experimental and theoretical insights into the mechanisms of high-altitude hypoxia adaptation in yaks. Full article

Glioblastoma (GBM) is one of the most aggressive and treatment-resistant cancers, shaped by a tumor microenvironment (TME) that is both metabolically demanding and strongly immunosuppressive. GBM relies heavily on fatty acid (FA) metabolism to sustain growth of rapidly dividing tumor cells and survive metabolic stress. GBM cells enhance lipid uptake, activate sterol regulatory element-binding protein 1 (SREBP-1)-driven lipogenesis, store excess lipids in droplets to prevent toxicity, and depend on fatty acid oxidation (FAO) to generate adenosine triphosphate (ATP) and maintain redox balance, particularly under nutrient-limited conditions. GBM TME is also consistently enriched with regulatory T cells (Tregs), which maintain suppressive activity despite the nutrient restrictions that impair effector T cells (Teffs). In hypoxia and nutrient limitation within the TME, Tregs can adapt by using FAO, lactate oxidation, and OXPHOS, supported by forkhead box P3 (Foxp3)-dependent metabolic programming, cluster of differentiation 36 (CD36)-mediated FA uptake, and hypoxia-related signals. At the same time, programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) signaling reduces glycolytic activity in Teffs and contributes to metabolic dysfunction, while also supporting the stability of oxidative metabolism in Tregs. Evidence from pre-clinical and clinical studies suggests a possible association between Treg enrichment in GBM and reduced responsiveness to immune checkpoint inhibitors (ICIs), although this relationship is not yet fully defined. Overall, current findings point to FA metabolism as a shared metabolic axis that supports both tumor progression and Treg-mediated immune resistance. Targeting lipid-driven pathways may offer an opportunity to disrupt these advantages and improve the effectiveness of existing immunotherapies for GBM. Full article

This study investigated the effects of noni fruit flavonoids (NFF) on antioxidant status and anti-inflammatory responses in cashmere goats and explored the underlying mechanisms based on liver transcriptomics and metabolomics. Sixteen male Albas cashmere goats were randomly assigned to two groups: a control (CON) group and a group supplemented with 0.1% NFF. The adaptation and trial periods were 2 and 12 weeks, respectively. The results showed that NFF significantly enhanced antioxidant capacity, with mean increases of 32.9%, 20.7%, and 35.5% for total antioxidant capacity (T-AOC), glutathione peroxidase (GPx), and catalase (CAT) activities, respectively, across serum, liver, spleen, and thymus (p < 0.05). NFF also modulated the inflammatory profile, with a mean increase of 18.0% for interleukin (IL)-10 and mean reductions of 18.6%, 19.4%, and 16.7% for IL-1β, IL-2, and tumor necrosis factor (TNF)-α, respectively, across the serum, liver, and thymus (p < 0.05). Integrative transcriptomic and metabolomic analyses suggested that the AMPK signaling pathway, glutathione metabolism, and TGF-β signaling pathway may be critically involved in mediating these effects. GPX3, GPX8, GCLM, NFKB1, and IL1B were identified as key candidate genes, while adenosine-5′-monophosphate (AMP), cysteinylglycine, and pyroglutamic acid were key differential metabolites. Dietary supplementation with 0.1% NFF enhanced the antioxidant levels and anti-inflammatory response in cashmere goats. Full article

Baker’s yeast with high freeze tolerance is essential for frozen-dough technology. The CYR1 gene, which encodes adenylate cyclase, is a central element of the cyclic adenosine monophosphate (cAMP) signaling pathway that regulates cellular stress tolerance. In this study, we aimed to enhance the freeze tolerance by modulating the expression level of CYR1. A series of diploid strains (BY14-30, BY14-60, BY14-90, and BY14-120) were constructed via a two-step integration method, in which the CYR1 promoter was truncated by 30, 60, 90, and 120 base pairs, respectively. Compared with the parent strain, strains BY14-30 and BY14-60 exhibited 4.3- and 4.2-fold higher survival rates after freezing, 60.0% and 40.0% increases in post-thaw dough-leavening ability, 88.9% and 64.6% increases in trehalose content, and 60.0% and 82.5% increases in proline levels, respectively. Collectively, our results demonstrate a novel strategy for regulating freeze tolerance in baker’s yeast, leading to improved cell viability and fermentation activity after freezing. 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

Triple-negative breast cancer (TNBC) remains a highly aggressive malignancy with limited therapeutic options and frequent resistance to platinum-based chemotherapy. Rosmarinic acid (RA), a naturally occurring polyphenol, has attracted considerable interest as a potential chemosensitising agent. This study investigated the anticancer activity and the underlying mechanisms of RA combined with cisplatin (CDDP) in 4T1 breast cancer cells while assessing the cytotoxic responses of non-cancerous HaCaT keratinocytes as a preliminary indicator of differential treatment sensitivity. Cytotoxicity was assessed using the MTT assay, followed by calculation of the Combination Index (CI), Drug Reduction Index (DRI), and Selectivity Index (SI). The generation of intracellular reactive oxygen species (ROS) was evaluated by DCFH-DA fluorescence imaging, and the functional contribution of oxidative stress was examined using N-acetyl-L-cysteine (NAC) rescue experiments. Apoptosis was analysed by Annexin V/PI flow cytometry, NucBlue nuclear staining, and Calcein-AM/propidium iodide (PI) Live/Dead fluorescence imaging. Three-dimensional (3D) tumour spheroids were used to assess treatment-induced alterations in spheroid morphology, morphometric parameters, viability based on adenosine triphosphate (ATP), and Live/Dead staining. The expression of genes related to apoptosis was determined by RT-qPCR, and potential molecular mechanisms were explored using the construction of protein–protein interaction (PPI) networks together with Gene Ontology (GO) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway enrichment analyses. The combination of RA + CDDP exhibited strong synergistic cytotoxicity in 4T1 cells while demonstrating comparatively lower toxicity toward HaCaT keratinocytes. Combination treatment markedly increased intracellular ROS generation, whereas NAC significantly reduced ROS accumulation and partially restored cell viability, indicating that oxidative stress is a major but not exclusive mediator of cytotoxicity. Combined treatment significantly enhanced apoptotic cell death, increased chromatin condensation and membrane damage, upregulated the expression of Bax, Casp9, Cycs, and Trp53, and downregulated Bcl2, consistent with transcriptional regulation of intrinsic apoptotic signalling. In 3D tumour spheroids, the combination markedly reduced spheroid size, disrupted structural integrity, decreased ATP-based viability, and substantially increased tumour cell death compared to monotherapy. Bioinformatic analyses identified central genes related to apoptosis and cell survival and predicted significant enrichment of PI3K/Akt, p53, MAPK, and apoptosis signalling pathways. RA significantly potentiates the antitumor efficacy of CDDP through synergistic induction of ROS-associated apoptotic signalling while showing a more favourable cytotoxic response in 4T1 breast cancer cells than in non-cancerous HaCaT keratinocytes. The integrated findings from two-dimensional (2D) and 3D models, NAC rescue experiments, molecular analyses, and bioinformatics collectively support the potential of RA as a promising chemosensitising adjuvant for CDDP-based breast cancer therapy and warrant further validation in preclinical in vivo models. Full article

Background: Conventional tyrosinase (TYR) inhibitors irritate skin and trigger rebound pigmentation, necessitating safer and more effective depigmenting agents. Methods: Biocompatibility was assessed by cell viability. Melanin content and TYR activity were measured spectrophotometrically. Reactive oxygen species (ROS), adenosine triphosphate (ATP), and inflammatory cytokines were detected by fluorescence, luminescence, and ELISA. Western blot and RT-qPCR assessed oxidative stress, inflammatory, and melanogenic targets. Molecular docking simulated Ganoderic Acid A (GAA) interactions with key proteins. Results: GAA exhibits good biocompatibility, inhibits melanin synthesis and TYR activity in B16-F10 cells, and reverses ultraviolet B-induced pigmentation. Mechanistically, GAA restores mitochondrial homeostasis by scavenging ROS, replenishing ATP, activating the nuclear factor erythroid 2-related factor 2 (Nrf2) axis, and inhibiting nuclear factor kappa-B (NF-κB) and cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) to regulate the inflammatory microenvironment. This synergistic regulation inhibits the mitogen-activated protein kinase (MAPK) signaling pathway and down-regulates the microphthalmia-associated transcription factor (MITF) transcriptional network and the expression of TYR, tyrosinase-related protein 1 (TRP-1), and tyrosinase-related protein 2 (TRP-2). Conclusion: GAA eliminates ultraviolet B-induced hyperpigmentation through a multi-target mechanism of mitochondrial repair, inflammation inhibition, and direct binding to tyrosinase, and is a potential natural candidate drug for the treatment of skin diseases. Full article