Search Results (394)

Beet (Beta vulgaris L.) is an important economic crop widely cultivated across various regions worldwide. Its agricultural significance lies not only in its high sugar yield but also in its positive impact on agro-ecosystems and the economic value of its by-products. However, beet production and quality are adversely affected by multiple abiotic and biotic stresses, including pathogen infection, drought, salinity, and extreme temperatures. In recent years, numerous key stress-responsive genes have been identified, including BvPAL, BvPR, and Rz1-4, which mediate responses to biotic stresses, and BvM14-SAMS2, BvINT1;1, BvHMA3, BvCOLD1, and BvALKBH10B, which enhance tolerance to abiotic stresses. Meanwhile, core transcription factors such as bHLH, HSP, WRKY, and SPL show differential expression under stresses, suggesting that they may regulate stress-related genes and constitute major transcriptional modules enabling beet to withstand adverse conditions. In this study, we summarize the changes in beet under different stress conditions, combining gene information to reveal key regulatory changes in stress responses and how these molecular processes contribute to stress adaptation. This not only provides a theoretical basis for the improvement of beet stress tolerance and yield, but also offers potential directions for future breeding strategies in practical applications. Full article

Marrubium vulgare L. is a medicinal plant widely used in traditional medicine, with emerging evidence of anticancer potential. This study investigated its bioactive compounds as inhibitors of Heat Shock Protein 90 alpha (Hsp90α), a molecular chaperone essential for oncogenic protein stability. Organic and aqueous extracts were profiled using high-performance liquid chromatography–mass spectrometry (HPLC–MS), revealing a diverse phytochemical composition. Identified compounds were screened against the full-length crystal structure of Hsp90α using a structure-based computational workflow that included extra-precision and domain-specific molecular docking, molecular dynamics (MD) simulations, and MM/GBSA binding free energy calculations. Pharmacokinetic and toxicity profiles were evaluated through ADMET predictions. This study elucidated the chemical composition of the plant and identified two hit compounds: Forsythoside B bound preferentially to the middle domain, potentially interfering with client protein interactions, and chlorogenic acid targeted the C-terminal domain, which regulates dimerization and allosteric activity. Both ligands displayed stable protein–ligand interactions during MD and favorable ADMET properties. These findings provide the first integrated chemical and computational prediction framework, suggesting that some M. vulgare metabolites may interact with Hsp90, highlighting its potential as a source of novel anticancer scaffolds and laying the groundwork for experimental validation and drug development. Full article

Vascular Smooth Muscle Cells (VSMC) dysfunction is a major contributor to Type 1 diabetes (T1D)-associated vascular complications. Ca²⁺ is a key messenger responsible for maintaining VSMC tone and function, and alterations in its cytosolic levels are central to diabetes-related vasculopathy. Heat Shock Protein 70 (HSP70), a multifaceted chaperone present intracellularly (iHSP70), regulates vascular reactivity by supporting Ca²⁺ handling, and extracellularly (eHSP70) activates immune signaling. Disruption of eHSP70/iHSP70 balance has been implicated in T1D-associated VSMC dysfunction. Curcumin, a phytochemical found in turmeric, is an emerging therapeutic adjuvant for treating a wide range of pathologies, including diabetes. However, whether curcumin modulates Ca²⁺ dynamics and HSP70 expression, thereby improving VSMC function, in diabetic aorta remains unclear. To investigate this, Streptozotocin-induced diabetic rats (i.p. 65 mg/kg) were treated with curcumin (300 mg/kg) for 28 days. Vascular function was evaluated using wire myography to assess changes in biphasic contraction curve and Ca²⁺ dynamics, while HSP70 was quantified using Western blotting and ELISA. Structural alterations were analyzed by assessing collagen and elastin using Picrosirius staining and fluorescence microscopy. Chronic curcumin treatment improved vascular function by normalizing Ca²⁺ mishandling, restoring the eHSP70/iHSP70 ratio, reducing hypercontractility, and mitigating arterial structural alterations. These findings indicate that curcumin could potentially ameliorate diabetes-related VSMC dysfunction by restoring Ca²⁺ homeostasis and modulating HSP70. Full article

Apiin, a natural flavonoid sourced from parsley, demonstrates antioxidant properties; however, its specific anti-aging effects have yet to be investigated in Caenorhabditis elegans (C. elegans). This research utilized C. elegans models to examine the anti-aging effects of apiin and the underlying mechanisms. The findings indicated that 100 μg/mL apiin extended the mean lifespan of C. elegans by 26.70%. Furthermore, apiin improved age-related characteristics in C. elegans, such as reducing intestine lipofuscin accumulation and increasing head thrashes and body bends. Additionally, apiin significantly improved stress resistance under thermal, ultraviolet, and oxidative stress conditions. Transcriptomic analysis revealed that apiin induced the differential expression of genes related to fatty acid metabolism, lipid catabolism, and oxidoreductase activity in C. elegans. Metabolomic data further corroborated the modulation of fatty acid metabolic processes by apiin. Biochemical assays, including lipid staining, triglyceride quantification, and measurements of antioxidant enzyme activity, demonstrated a decrease in lipid content and an enhancement in antioxidant capacity in C. elegans treated with apiin. Moreover, apiin promoted the nuclear translocation of DAF-16 and upregulated key longevity-associated genes, including sod-3, hsp-12.6, mtl-1, and ech-9. These results indicate that apiin mitigates aging in C. elegans through mechanisms involving the activation of DAF-16 and the regulation of lipid metabolism and oxidative stress responses. Our findings underscore the potential of apiin as a natural therapeutic agent for aging and associated metabolic disorders. Full article

Heat hardening induces complex biochemical reprogramming that enhances thermal resilience in marine bivalves. Despite this technique’s promising results in marine animals, the molecular basis of heat hardening is far from understood. This study elucidates the molecular mechanisms underlying the hardening process in Mytilus galloprovincialis exposed to a 4-day sublethal heat treatment. Induction of hsf-1, hsp70, and hsp90 genes revealed the activation of the heat shock response and proteostasis machinery, ensuring proper protein folding and preventing oxidative and proteotoxic stress. Simultaneous upregulation of mitochondrial (atpase6, cox1, nadh) and glycolytic (pk, cs) genes reflects enhanced oxidative phosphorylation and glycolytic flux, maintaining ATP supply and metabolic flexibility under elevated temperatures. Increased hif-1α expression suggests transient hypoxia signaling, coordinating oxygen utilization with redox control. Reinforcement of antioxidant defenses, together with elevated autophagy-related transcription, denotes a shift toward oxidative stress mitigation and damaged organelle clearance. Balanced expression of pro- (bax) and anti-apoptotic (bcl-2) factors, along with nf-κb modulation, supports tight regulation of cell survival and inflammatory responses. These findings underscore a highly integrated biochemical network linking proteostasis, intermediary metabolism, redox balance, and antioxidant defense with cellular quality control, which together underpin the physiological plasticity of heat-hardened M. galloprovincialis, enhancing survival under transient thermal stress. Full article

Heat stress caused by global climate change poses a significant threat to agricultural production. Phytohormones, as critical signaling molecules, play pivotal roles in modulating plant responses to heat stress. This review systematically summarizes the molecular mechanisms by which eight phytohormones (auxin, gibberellin, cytokinin, ethylene, abscisic acid, brassinosteroid, salicylic acid, and strigolactone) enhance plant thermotolerance through the regulation of heat shock protein (HSP) expression and function. Specifically, auxin enhances thermotolerance by inducing auxin signaling repressor (Aux/IAA) degradation to upregulate HSP transcription, facilitating the formation of the auxin receptor (TIR1)-HSP90 complex to stabilize TIR1, and forming the auxin exporter (PIN)-HSP22 complex to promote auxin transport. Cytokinin enhances thermotolerance by upregulating HSP transcription, with stronger effects in leaves than roots. Gibberellin, salicylic acid, and ethylene enhance thermotolerance primarily by activating heat shock factor (HSF) to induce HSP transcription. Abscisic acid and brassinosteroid improve thermotolerance by inducing HSP transcription and HSP phosphorylation, while strigolactone acts via D14-mediated upregulation of HSP transcription. These phytohormones collaboratively regulate HSPs, forming an intricate network to enhance plant thermotolerance. Deciphering these mechanisms provides a theoretical framework for developing heat-resistant crops and optimizing cultivation techniques. Full article

Heat shock proteins (HSPs) are produced in response to stressful conditions, such as temperature, inflammation, infection, or exposure to environmental factors. HSPs are overexpressed in some malignancies, where they modulate the tumor microenvironment and influence cancer cell behavior and survival. Clinical trials for breast, prostate, colon, and lung cancers exist, but not for head and neck squamous cell carcinomas (HNSCCs). Nonetheless, clinical studies on HSPs in HNSCC are still lacking. We review the role of HSPs with regard to physiology and as potential targets for molecular therapy in HNSCC. Full article

Candida and other pathogenic yeast species, able to transition from non-invasive commensal organisms to invasive pathogens, are characterized by a high ability to adapt to stress conditions encountered in the human host, such as pH and temperature shifts, CO₂ and oxygen level variations, and nutritional limitations. Although Candida albicans remains the main cause of Candida-related infections, non-albicans Candida (NAC) species, including C. tropicalis, C. parapsilosis, C. krusei, and non-Candida species such as Yarrowia lipolytica, Candidozyma auris, and Nakaseomyces glabratus, are gaining clinical importance. These species exhibit diverse mechanisms of pathogenicity, including morphological transition, modulation of gene expression pathways (cAMP-PKA/MAPK, Hsp, calcineurin, GlcNAc-mediated signaling), cell wall remodeling, post-translational reprogramming, biofilm formation, antifungal resistance, and enzyme secretion. C. albicans exhibits high morphological and metabolic plasticity for survival across body niches. N. glabratus and C. tropicalis show strong azole resistance and biofilm formation, while C. parapsilosis and C. krusei pose risks through surface adhesion and treatment resistance. C. auris stands out for heat tolerance, multidrug resistance, and outbreak potential. Y. lipolytica, though rare, forms persistent filamentous biofilms in critical care settings. Cryptococcus neoformans remains a life-threatening pathogen capable of immune evasion and crossing the blood–brain barrier. This review compares molecular mechanisms of pathogenicity across these fungi, emphasizing environmental adaptation, conserved and species-specific responses, and potentially highlighting targets for therapeutic management. Full article

Peptides are recognized as multifunctional bioactive ingredients in cosmetic science, as they offer diverse beneficial effects such as skin rejuvenation, anti-aging, and skin barrier enhancement. In this study, we applied a cheminformatics-assisted peptidomimetic design platform to design novel peptides targeting heat shock protein 47 (Hsp47), a collagen-specific molecular chaperone that is downregulated during skin aging. Using molecular fingerprint similarity-based peptide design and protein–peptide docking simulations, five candidate peptides were screened, among which ICP-1225 (TY) emerged as a potent stimulator of Hsp47 and collagen (COL1A1 and COL3A1) expression in dermal fibroblasts. To improve stability and skin penetration, fatty acid-conjugated derivatives of ICP-1225 were synthesized, and acetyl-TY (ICP-1236) demonstrated the most consistent upregulation of Hsp47 and collagen in vitro. Restoration of Hsp47 protein expression and dermal collagen levels in UVB-damaged ex vivo human skin explants was also observed. These findings highlight the potential of cheminformatics-assisted peptide design in the development of next-generation cosmetic actives. ICP-1236 represents a promising anti-wrinkle candidate through the modulation of Hsp47 and collagen pathways, warranting further clinical evaluation. Full article

The internal organs of sea cucumbers (SCV) are a byproduct of the seafood processing industry and hold untapped potential as a functional food. This study investigates the antioxidant capacity of SCV and its regulatory effects on the gut microbiota in a mouse model of oxidative stress induced by chronic cold exposure. The results indicate that SCV possesses a rich nutritional composition, containing various components such as calcium, phosphorus, and polysaccharides, and exhibit strong scavenging activity against three types of free radicals in vitro: DPPH, OH⁻, and O₂⁻. SCV significantly reduced MDA levels in both serum and liver, while activating the Keap1-Nrf2/HO-1 pathway, leading to a significant decrease in the expression of HSP70 and HSP90 genes and a marked increase in Nrf2 gene expression, thereby alleviating oxidative damage. Histological analysis revealed that SCV alleviated liver damage, reducing hepatocellular vacuolization and inflammatory cell infiltration. Additionally, SCV modulated the diversity of the gut microbiota, increasing the abundance of Allobaculum, Turicibacter, Bifidobacterium, and Akkermansia, while enriching the synthesis pathway of vitamin B12 (PWY-7377). This study is the first to repurpose sea cucumber viscera waste into a functional food, demonstrating its dual mechanism of alleviating oxidative stress by activating the Keap1-Nrf2/HO-1 antioxidant pathway and regulating the gut microbiota. These findings offer an innovative strategy for the high-value utilization of agricultural by-products and the development of multifunctional health-promoting products. Full article

Background: Neurological disorders are the leading cause of disability, affecting over three billion people worldwide. Amyotrophic lateral sclerosis (ALS) is among the most feared and uniformly fatal neurodegenerative diseases, with no therapy capable of restoring lost function. Methods: We report the first application of therapeutic fever to ALS using Computerized Brain-Guided Intelligent Thermofebrile Therapy (CBIT²). This fully noninvasive treatment, delivered through an FDA-approved computerized platform, digitally reengineers the 1927 Nobel Prize-recognized malarial fever therapy into a modern treatment guided by the Brain–Eyelid Thermoregulatory Tunnel. CBIT² induces therapeutic fever through synchronized hypothalamic feedback, activating heat shock proteins, which are known to restore proteostasis and neuronal function. Case presentation: A 56-year-old woman was diagnosed with progressive ALS at the Mayo Clinic, with electromyography (EMG) demonstrating fibrillation and fasciculation indicative of denervation corroborated by neurological and MRI findings; the patient was informed that she had an expected survival of three to five years. A neurologist from Northwestern University confirmed the diagnosis and thus maintained the patient on FDA-approved ALS drugs (riluzole and edaravone). Her condition rapidly worsened despite pharmacological treatment, and she underwent CBIT², resulting in (i) electrophysiological reversal with complete disappearance of denervation; (ii) biomarker correction, including reductions in neurofilament and homocysteine, IL-10 normalization (previously linked to mortality), and robust HSP70 induction; (iii) restoration of gait, swallowing, respiration, speech, and cognition; (iv) reconstitution of tongue structure; and (v) return to complex motor tasks, including golf, pickleball, and swimming. Discussion: This case provides the first documented evidence that ALS can be reversed through digitally reengineered fever therapy aligned with thermoregulation, which induces heat shock response and upregulates heat shock proteins, resulting in the patient no longer meeting diagnostic criteria for ALS and discontinuation of ALS-specific medications. Beyond ALS, shared protein-misfolding pathology suggests that CBIT² may extend to Alzheimer’s, Parkinson’s, and related disorders. By modernizing this Nobel Prize-recognized therapeutic principle with computerized precision, CBIT² establishes a framework for large-scale clinical trials. A century after fever therapy restored lost brain function and so decisively reversed dementia paralytica such that it earned the 1927 Nobel Prize in Medicine, CBIT² now safely harnesses the therapeutic power of fever through noninvasive, intelligent, brain-guided thermal modulation. Amid a global brain health crisis, fever-based therapies may offer a path to preserve thought, memory, movement, and independence for the more than one-third of humanity currently affected by neurological disorders. Full article

Age-related changes in facial ligaments contribute to altered facial shape and soft tissue descent. Radiofrequency (RF) has been utilized for skin rejuvenation by promoting collagen fiber contraction and synthesis through increased expression of heat shock proteins (HSPs). The primary component of ligamentous collagen fibers undergoes structural modifications with age, exhibiting increased fragmentation and a reduced collagen type I/III ratio. This study aimed to investigate whether RF irradiation alleviates senescence-related changes in facial ligaments through HSP70-mediated molecular remodeling using a UV-induced photoaging rat model. In senescent fibroblasts, RF enhanced the interaction between HSP70 and IκBα kinase (IKK)γ while reducing IκBα phosphorylation, which was associated with decreased nuclear factor-kappa B (NF-κB) activation. These RF-mediated changes were attenuated by an HSP70 inhibitor, suggesting that RF reduces NF-κB activity via HSP70 modulation. RF also suppressed expression levels of matrix metalloproteinases and SMAD7 in senescent fibroblasts. Consistent with in vitro findings, RF increased the interaction between HSP70 and IKKγ while decreasing IκBα phosphorylation and NF-κB activity in the UV-induced photoaging (senescent) facial ligaments of rat models. Furthermore, RF enhanced the collagen type I/III ratio and increased collagen fiber density within the ligaments. Scanning electron microscopy revealed that RF irradiation increased collagen fiber bundle diameter and enhanced the helical structure of those fibers. Overall, RF mitigates senescence-related changes in facial ligaments through HSP70 modulation. Considering that facial ligament laxity contributes to soft tissue descent, facial ligament-targeting approaches may promote a more youthful facial structure. RF demonstrates the possibility in reducing senescence-associated changes within facial ligaments. Full article

The colonic epithelium renews rapidly and must balance proliferation with apoptosis to preserve barrier integrity. We investigated whether grape antioxidant dietary fiber (GADF), a grape pomace-derived dietary fiber matrix naturally rich in high molecular weight non-extractable polyphenols, modulates barrier integrity, through proliferation/cell cycle and apoptosis. To gain mechanistic insight, we examined the role of heat-shock proteins (Hsps), and AMP-activated protein kinase (AMPK)–mTOR–lipid-metabolism signaling in healthy proximal colon. Male Wistar rats received either a cellulose-based control diet or an isoenergetic diet where cellulose was replaced with 5% GADF for four weeks. Morphometric analysis, immunohistochemistry, Western blotting, TUNEL, and caspase activity assays quantified cell cycle, apoptotic, Hsps, and metabolic pathways. GADF strengthened the epithelial barrier, increasing goblet cells, occludin, and ZO-1, while reducing crypt depth. Proliferation was suppressed, as indicated by reduced PCNA, cyclins E and D1, and higher p-p53^Ser392, p21^Cip1/Waf1, and p27^Kip1 levels, consistent with G1 arrest. Apoptosis was attenuated, with increased mitochondrial Bcl-2/Bax and Bcl-xL/Bax ratios, lower cytosolic cytochrome c and apoptosis-inducing factor (AIF), and reduced caspase-9 and caspase-3 activities. Hsp27, but not Hsp70, was selectively induced. GADF activated AMPK and p-Raptor, enhanced ACC1 phosphorylation and CPT1, and supported a shift toward fatty acid β-oxidation. Correlation analysis revealed a strong association between Hsp27 and p-p53^Ser392, suggesting potential links between barrier proteins and metabolic pathways. In conclusion, GADF preserves barrier integrity and redirects metabolism via AMPK–Hsp27 signaling, thereby promoting colonic homeostasis. These findings highlight grape pomace as a sustainable source of functional ingredients for nutritional strategies to reinforce epithelial defenses and reduce disease risk. Full article

As artificial intelligence continues to evolve, reinforcement learning (RL) has shown remarkable potential for solving complex sequential decision problems and is now applied in diverse areas, including robotics, autonomous vehicles, and financial analytics. Among the various RL paradigms, multi-agent reinforcement learning (MARL) stands out for its ability to manage cooperative and competitive interactions within multi-entity systems. However, mainstream MARL algorithms still face critical challenges in training stability and policy generalization due to factors such as environmental non-stationarity, policy coupling, and inefficient sample utilization. To mitigate these limitations, this study introduces an enhanced algorithm named MATD3_AHD, developed by extending the MATD3 framework, which integrates TD3 and MADDPG principles. The goal is to improve the learning efficiency and overall policy effectiveness of agents operating in complex environments. The proposed method incorporates three key mechanisms: (1) an Adaptive Exploration Policy (AEP), which dynamically adjusts the perturbation magnitude based on TD error to improve both exploration capability and training stability; (2) a Hierarchical Sampling Policy (HSP), which enhances experience utilization through sample clustering and prioritized replay; and (3) a Dynamic Delayed Update (DDU), which adaptively modulates the actor update frequency based on critic network errors, thereby accelerating convergence and improving policy stability. Experiments conducted on multiple benchmark tasks within the Multi-Agent Particle Environment (MPE) demonstrate the superior performance of MATD3_AHD compared to baseline methods such as MADDPG and MATD3. The proposed MATD3_AHD algorithm outperforms baseline methods—by an average of 5% over MATD3 and 20% over MADDPG—achieving faster convergence, higher rewards, and more stable policy learning, thereby confirming its robustness and generalization capability. Full article

Coumarin derivatives constitute a versatile small-molecule chemotype with broad anticancer potential. This narrative review synthesizes recent in vitro and in vivo evidence on coumarin-based scaffolds, emphasizing breast cancer and covering lung, prostate, and colorectal models. We summarize major mechanisms of action—including induction of apoptosis (caspase activation and BAX/BCL-2 balance), modulation of PI3K/Akt/mTOR signaling, inhibition of angiogenesis (VEGFR-2), interference with estrogen biosynthesis (aromatase/ER axis), chaperone targeting (Hsp90), and attenuation of multidrug resistance (efflux pumps/autophagy)—and highlight representative chemotypes (e.g., benzimidazole, triazole, furocoumarins, topoisomerase- and CDK-oriented hybrids). Where available, we contrast potency and selectivity across models (e.g., MCF-7 vs. MDA-MB-231; A549; PC-3; colon lines) and discuss structure–activity trends linking substituent patterns (heteroaryl linkers, judicious halogenation, polar handles) to pathway engagement. We also delineate translational gaps limiting clinical progress—selectivity versus non-malignant cells, incomplete pharmacokinetic and safety characterization, and limited validation beyond xenografts. Finally, we outline priorities for preclinical optimization: biology-aligned target selection with biomarkers, resistance-aware combinations (e.g., PI3K/mTOR ± autophagy modulation; MDR mitigation), and early integration of ADME/tox and PK/PD to confirm on-target exposure. Collectively, the evidence supports coumarins as adaptable, multi-target anticancer leads, particularly promising in hormone-dependent breast cancer while remaining relevant to other tumor types. Full article