Search Results (2,980)

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

Background and Objectives: Diffuse large B-cell lymphomas (DLBCLs) are heterogeneous neoplasms. CD79B and MYD88 mutations are associated with the activated B-cell-like (ABC) subtype of DLBCL and often co-occur and lead to constitutive activation of the NF-κB pathway. Several different genetic classifications to date have recognized CD79B- and MYD88-mutated DLBCLs as a unique subtype with poor response to therapy and unfavorable survival. However, little is known about gene expression in DLBCLs with mutated CD79B (and MYD88) in comparison to their wild type counterparts. The objective of this study was to compare the gene expression in DLBCLs according to their CD79B mutational status. Methods: A total of 48 primary, treatment-naïve DLBCLs (CD79B-mutated: 35%/n = 17, CD79B-wild type: 65%/n = 31) were investigated using RNA expression profiling (770 genes), followed by immunohistochemical analysis of the up-regulated genes and survival analysis. Results: The gene expression analysis revealed that downstream of CD79B CARD11 and the NF-κB targets NFKBIZ, IL10, IL12A, PIM1 and BCL2A1 were up-regulated in CD79B-mutated DLBCLs. The strongest up-regulation was detected for ARNT2 and WNT11. Other up-regulated genes included the apoptosis-related BID and granzyme B, as well as genes of cell cycle regulation such as RUNX1, RUNX1T1 and RASGRF1. Up-regulation was also found for IL7, STAT3, MLLT4, CD14 and the HSP90B1 subunit. TP53 mutation showed an association with poorer overall survival in a secondary analysis, consistent with prior reports, while survival by CD79B/MYD88 mutation status and the differentially expressed genes showed no significant differences in this cohort. Conclusions: In conclusion, the current study identified novel up-regulated genes in CD79B-mutated DLBCLs beyond NF-κB pathway signaling, which may contribute to a better definition of potential therapeutic targets and further improves the characterization of this distinct and aggressive DLBCL subgroup. 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

Although aging is an irreversible process, the rate of aging can be delayed by a reasonable diet. As a nutrient-dense natural product, royal jelly (RJ) has an enormous potential for applications in medicine and health promotion. However, the exact physiological activity of RJ with varying freshness and concentration has not been fully clarified, and more investigation is needed to determine their precise contributions. Here, fresh RJ (just produced recently) and RJ stored for 2 weeks at −20 °C, 4 °C or 25 °C were tested at concentrations of 100, 50, 25 and 12.5 μg/mL on Caenorhabditis elegans. Fresh RJ, with concentrations of 100 μg/mL, 50 μg/mL and 25 μg/mL, could extend the lifespan of C. elegans by 16.37%, 9.53% and 4.32%, while RJs stored at 4 °C and 25 °C were ineffective. In terms of body length, treatment with fresh RJ significantly enlarged the body size by around 48%. Although RJ stored at 4 °C and 25 °C could also promote nematode growth, its activity diminishes as storage temperature increases. RJs stored at −20 °C and 4 °C with concentrations of 100 μg/mL significantly increased the pumping rate of nematodes by 58% and 50%. But non-fresh RJ or low-concentration RJ (≤25 μg/mL) had no effects on the motility of C. elegans. In addition, fresh RJ could improve the reproductive capacity of C. elegans, with the highest increase reaching approximately 25%. Even when stored at 25 °C, RJ also significantly enhanced the reproductive capacity of C. elegans, increasing it by approximately 14.8%. Moreover, qPCR showed that RJ could significantly affect the expression of multiple genes associated with aging and vitality. Fresh RJ significantly up-regulated bec1 and hsp16.2 3.19- and 2.80-fold, while RJ stored at 25 °C significantly up-regulated sod3 and gpd1 3.80- and 3.40-fold. Our results suggested that the activity of RJ on C. elegans is related to its freshness and concentration, while RJ also contains active components that are independent of freshness. Therefore, it is necessary to explore effective methods for accurately assessing the freshness of RJ. Full article

One of the current and serious environmental problems is the pollution due to microplastics. There is an urgent need for biodegradable and bio-based materials for numerous applications, including food packaging. In this work we examine the bio-based polyester cutin for its potential to be used as food packaging material, in terms of migration, based on the Hansen Solubility Parameters (HSP). Cutin is a cross-linked polymer that is swelled by various solvents. We use the degree of swelling of cutin in carefully selected solvents of various polarities in order to estimate the HSP of cutin. Some solvents can induce alteration of the chemical structure of cutin, as proven by Fourier Transform Infrared (FTIR) measurements. This interferes with the process of estimation of the HSP and is discussed in depth. The distance R_a and the Relative Energy Difference (RED) between the HSP of cutin and various food components are calculated and used to predict the existence of favorable interactions between cutin and the food components, which is translated to a high probability for the existence of migration and permeation. Experimental confirmation of one prediction based on HSP is provided by UV-VIS photometry. Similar calculations were performed for other polyesters (poly(lactic acid) and poly(hydroxy butyrate)). Cutin exhibits compatibility with substances of low polarity, such as fats and lipids and non-polar compounds found in essential oils. Thus, migration into fatty foods is expected as well as sorption and permeation of some (volatile) compounds into cutin. Nevertheless, we conclude that the overall migration risk for cutin is lower than the one of other bio-based polyesters. HSP can be used for initial screening of potential migration risks; however, further research is necessary in order to assess the occurrence, extent, and significance of the actual migration. Full article

Salinity is one of the key threats to food security and sustainability. To make saline soils productive again, we need to develop salt-tolerant crop varieties. Developing salt-tolerant wheat requires a detailed understanding of the molecular mechanisms underlying salt stress responses. In this study, we analyzed the Chinese Spring genome and identified 559 putative NAC transcription factors (TFs), which are recognized as key regulators of both abiotic and biotic stress. Protein family analysis revealed four distinct domain architectures, with more than 95% of the proteins containing a single NAC domain, consistent with their conserved regulatory role. Through in silico analyses, four salt stress-responsive TFs, NAC_1D, NAC_2D, NAC_4A, and NAC_5A, were highlighted, sharing nine of 13 DNA-binding residues. Promoter analysis of their putative target genes identified seven candidates, which, together with the NAC TFs, were subjected to RT-qPCR expression analysis in BARI Gom-25 plants exposed to 100 mM NaCl. The expression data revealed contrasting regulatory patterns between NAC TFs and their target genes. For example, Hsp70 was strongly upregulated in both shoots and roots, despite opposite patterns of NAC_1D expression between tissues. Similarly, bZIP expression mirrored the downregulation of NAC_2D, whereas HKT8 expression remained stable under salt stress. NAC_4A showed a root-specific pattern suggestive of positive regulation of a Non-specific serine/threonine protein kinase, while NAC_5A upregulation corresponded with downregulation of Plant cadmium resistance 2. Collectively, these results provide functional insights into four NAC TFs and identify potential molecular targets for improving wheat salt tolerance. By targeting key tolerance genes at the DNA level offers greater precision and can significantly reduce breeding time. Full article

This study elucidates the hepatoprotective mechanisms of heat-processed Gynostemma pentaphyllum (Thunb.) Makino saponins (HGyp) against APAP-induced liver injury using serum pharmacochemistry, metabolomics, and network pharmacology. HGyp significantly mitigated liver damage in mice, as confirmed by biochemical and histopathological analyses. UPLC-MS identified 38 bioactive compounds, including 16 prototype saponins and 11 metabolites. Network pharmacology and molecular docking revealed damulin A/B, gypenosides (L/LI/LVI/XLVI), and ginsenosides (Rg3/Rd) as key components targeting GRB2, FGF2, MMP2, STAT3, CASP3, and HSP90A. Western blotting confirmed the HGyp-mediated downregulation of hepatic HSP90A and STAT3. Metabolomics identified four critical pathways, PPAR, ferroptosis, and the inflammatory mediator regulation of TRP channels involved in hepatoprotection. HGyp exerts multi-target effects via anti-inflammatory activity, apoptosis, and metabolism, providing a framework for Chinese medicine and ethnomedicine research. Full article

Background/Objectives: Honokiol (HK), a bioactive phenolic compound, exhibits significant anti-cancer properties. This study aimed to investigate the anti-cancer effects of HK in colorectal cancer (CRC) cells by focusing on its direct interaction with heat shock protein 27 (Hsp27) as a molecular target, and to elucidate the underlying mechanisms involved. Methods: HK was isolated via silica/ODS chromatography. Anchorage-independent growth of CRC cells was quantified using a soft agar assay with increasing HK concentrations. Apoptosis and cell cycle were analyzed by flow cytometry, and cell viability by MTS assay. Hsp27 binding to HK was validated by pull-down assay with HK-conjugated Sepharose 4B beads. Hsp27 knockdown was performed using lentiviral shRNA in CRC cells. Molecular docking of HK-Hsp27 interaction employed Schrödinger Suite 2016. Protein expressions, including chaperone and apoptotic proteins, were evaluated by Western blotting. Results: HK dose-dependently suppressed anchorage-independent growth of CRC cells and induced G₀/G₁ arrest. It triggered apoptosis through cytochrome c release, PARP cleavage, and Bcl-2 downregulation. HK directly bound to the α-crystallin domain of Hsp27 at Asn102 and His103 residues, confirmed by computational molecular docking and site-directed mutagenesis. Hsp27 knockdown in CRC cells dramatically reduced anchorage-independent growth. HK markedly decreased Hsp27 protein levels while having less effect on other heat shock proteins in CRC cells. Conclusions: HK exerts anti-cancer effects in CRC cells, associated with Hsp27 inhibition, resulting in suppressed cell growth and increased apoptosis. This interaction between HK and Hsp27 may support a mechanistic foundation supporting the potential utility of HK as a natural therapeutic agent for CRC. Full article

Background: Heat shock protein 90 (HSP90) is a molecular chaperone that stabilizes numerous oncogenic proteins and supports tumor survival. Small molecules targeting HSP90 offer a novel approach to overcome drug resistance and immune suppression in breast cancer. Methods: A novel thiazolyl benzodiazepine (TB) containing a hydrazone moiety was evaluated in breast cancer cell lines (ER⁺ MCF-7, TNBC MDA-MB-231, and HER2⁺ SK-BR-3). Cytotoxicity was assessed using the CCK-8 assay, followed by PCR sequencing, flow cytometry, RT-qPCR, protein profiling, and HSP90 binding assays. Results: TB showed the strongest activity in MCF-7 cells (IC₅₀ = 7.21 µM) compared to MDA-MB-231 (IC₅₀ = 28.07 µM) and SK-BR-3 (IC₅₀ = 12.8 µM) cells. Mechanistic studies showed that TB binds to HSP90 (Kd = 3.10 µM), leading to disruption of the oncogenic signal. TB induced G2/M cell cycle arrest, promoted apoptosis via Bax and Caspase-3 activation, and suppressed cancer stem cell markers (NANOG, OCT4, SOX2). Additionally, TB activated immune-related pathways via ERK/MAPK signaling and upregulated genes such as SMAD2, SMAD3, and JUN.Conclusions: TB functions as an HSP90 inhibitor with dual anticancer and immunomodulatory properties in Estrogen Receptor-Positive (ER⁺) breast cancer cells. These findings suggest that TB represents a promising scaffold for the development of multi-targeted breast cancer therapies. Full article

Background: Physical plasma, the fourth state of matter formed through gas ionization, has shown promise in various clinical applications, including wound healing and antimicrobial therapy. Recently, Non-invasive physical plasma (NIPP) selectively disrupts tumor cell proliferation and metabolism without inducing cytoprotective stress responses, positioning it as a promising adjunct in oncological therapies, though its underlying mechanisms remain insufficiently understood. Methods: In this study, we investigated the effects of NIPP (Plasma Care device) on six tumor cell lines, ovarian (SKOV-3, OVCAR-3), prostate (LNCaP, PC-3), and breast (MCF-7, MDA-MB-231). Cell proliferation and migration were assessed using CASY analysis and scratch assays, while cytoskeletal integrity, heat shock protein (HSP) expression, and key metabolic indicators were evaluated through immunofluorescence, Western blotting, and biochemical assays. Results: NIPP treatment significantly inhibited tumor cell proliferation and migration, disrupted cytoskeletal organization, and altered metabolic activity in a time-dependent manner. These effects were associated with increased intracellular reactive oxygen species (ROS), decreased mitochondrial membrane potential (MMP), enhanced glycolysis, and elevated lactate production. Notably, despite cellular stress, neither HSP expression nor superoxide dismutase (SOD) activity showed significant changes, suggesting a lack of classical stress-response activation. Conclusions: Our findings indicate that NIPP selectively impairs tumor cell function by inducing oxidative stress and metabolic disruption, without triggering protective HSP-mediated resistance pathways commonly seen in radiotherapy and chemotherapy. These results highlight the therapeutic potential of NIPP, particularly via the Plasma Care device, as a novel anticancer strategy. Full article

Reinforced concrete walls (RC walls) are widely used in transportation, building structures, and civil air defence engineering. RC walls are vulnerable to low-velocity impact, such as the fall of components caused by earthquakes or explosions, for example, and the impact from road objects, such as vehicles, during their service life. When subjected to instantaneous high-energy impact, RC walls at key positions are prone to severe damage, which can further lead to structural collapse. Therefore, it is necessary to consider improving the impact resistance of key RC walls in a structure. Using a porous honeycomb structure with excellent energy absorption performance to provide impact protection for key RC walls is an effective way to reduce the damage of RC walls and thereby enhance the impact resistance of a structure. Therefore, based on the author’s previous series of experimental and numerical studies on the impact resistance of RC walls, as well as the high-mass pendulum impact experimental study on the honeycomb sandwich panel composite RC wall (HSP-RC wall), this paper adopts a multi-scale modelling method in micro-mechanics and macro-mechanics to establish a pendulum impact finite element model (FEM) for the HSP-RC wall. The representative volume element (RVE) and periodic boundary condition (PBC) are used to calculate the elastic property parameters of the honeycomb, which guide the establishment of the FEMs for the HSP-RC wall. The FEMs can avoid the computational difficulty caused by refined simulation, analyse the impact damage of the HSP-RC walls more accurately, quantify the impact protection effect of the honeycomb sandwich panel, and thus facilitate the parametric analysis of the impact resistance of HSP-RC walls with different honeycomb panel structural parameters in subsequent studies. 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

Bradysia odoriphaga Yang et Zhang damages roots of 30 plant species, resulting in >50% yield loss. Heat stress can not only affect the survival but also affect the expression of heat shock proteins of B. odoriphaga. In this study, two small heat shock protein genes, Hsp21.9 and Hsp22.3, were cloned from B. odoriphaga. The full-length cDNA sequences of BoHsp21.9 and BoHsp22.3 were 749 and 941 bp in length and contained a 588 and 594 bp open reading frame (ORF), encoding a protein of 196 and 198 amino acids with a calculated molecular weight of 21.9 and 22.3 kDa and an isoelectric point of 6.84 and 6.91. Phylogenetic tree analysis showed that BoHsp21.9 and BoHsp22.3 clustered into one branch with flies. qRT-PCR analyses indicated that BoHsp21.9 and BoHsp22.3 were expressed in all tested developmental stages and body segments, especially induced by heat stress. RNAi-mediated silencing of BoHsp21.9 and BoHsp22.3 significantly decreased the survival rate of fourth-instar larvae when exposed to 38 °C. This is the first study on small heat shock proteins in B. odoriphaga, and BoHsp21.9, and BoHsp22.3 play important roles in the molecular mechanism of B. odoriphaga to theromotolerance. Full article

Background/Objectives: Targeting Hsp90β with isoform-selective inhibitors offers a promising therapeutic strategy with reduced toxicity compared to pan-Hsp90 inhibition. However, mechanisms of resistance to Hsp90β-selective inhibition remain poorly defined. This study aimed to identify molecular determinants of Hsp90β dependency and pharmacologic resistance across cancer types. Methods: We integrated gene dependency, transcriptomic, proteomic, metabolomic, and drug sensitivity data from the Cancer Cell Line Encyclopedia with in vitro validation using the Hsp90β-selective inhibitor, NDNB-25. Comparative and correlation analyses were performed to identify resistance-associated pathways, followed by network and combination drug testing to validate functional interactions. Results: Resistant cell lines exhibited extensive rewiring of Rho GTPase signaling, cytoskeletal remodeling, and metabolic adaptation, including mitochondrial dysfunction and redox imbalance. Integrated analyses linked these phenotypes to aryl hydrocarbon receptor (AHR) activation and compensatory Hsp90α expression. Experimental validation confirmed increased kynurenine levels, a known endogenous AHR ligand, in NDNB-25–acquired resistant cells. Gene–drug network integration revealed collateral sensitivity to carboplatin, which synergized with Hsp90β inhibition in resistant models. Conclusions: This study defines the molecular features and adaptive programs underlying resistance to Hsp90β-selective inhibition and identifies therapeutic vulnerabilities that can be exploited to overcome it. The findings establish a systems-level framework for predicting Hsp90β inhibitor response and support rational combination strategies, including carboplatin co-treatment, for future preclinical development. Full article

Background: Permanent cancer resolution requires a complete immunological response with generation of memory against malignant cells. Immunogenic cell death (ICD) achieves this by coupling cell death with the emission of damage-associated molecular patterns (DAMPs). Current cancer treatments immunosuppress the host; thus, new alternatives are needed. Ganoderma species produce anticancer triterpenoids (GTs); however, their mechanism remains unclear. Objective: This systematic review aims to provide insights into GTs’ pharmacodynamics and assess hypothetical ICD potential. Methods: Web of Science and PubMed databases were consulted following PRISMA guidelines. Studies from inception until 2024, reporting molecular changes associated with GTs’ anticancer effects, were considered. Nonhuman models were excluded. GTs and GTs-ICD converging molecular targets were listed and submitted to Cytoscape’s stringApp to construct protein interaction networks. Topological and enrichment analysis were performed. Results: A total of 204 articles were found, and 69 remained after screening. Overall anticancer effects include loss of mitochondrial membrane potential, DNA and RNA damage, autophagy, cell cycle arrest, and leukocyte activation. 136 molecular targets of GTs were identified; upregulated proteins include CHOP, PERK, p-eIF2α, and HSP70, a key DAMP. GTs and ICD share 24 molecular targets. GO:BP and KEGG enrichment analysis suggest that GTs’ anticancer effects are related to stress response, cell death regulation, and PD-L1/PD-1 checkpoint inhibition. GT-ICD enrichment converges on endoplasmic reticulum stress, unfolded protein response, and organelle membrane perforation. Conclusions: GTs exhibit polypharmacological anticancer effects, including anti-immunosuppression, upregulation of ICD-adjacent machinery, and even an increase in HSP. However, further studies are required to confirm a proper causal link between GTs’ cancer cell treatment and DAMP emission. Full article