Mechanistic description
Molecular Mechanism and Rationale
The heat shock protein 90 (HSP90) chaperone system represents a critical cellular machinery for protein folding, stability, and quality control. HSP90AA1, the inducible cytoplasmic isoform of HSP90, exhibits distinct conformational states that can be allosterically modulated to enhance specific client protein interactions. In the context of tau pathology, HSP90 demonstrates intrinsic disaggregation activity toward tau aggregates through a complex mechanism involving ATP-dependent conformational cycling and co-chaperone recruitment.
The proposed allosteric modulators would target a specific binding pocket on HSP90AA1 distinct from the well-characterized N-terminal ATP-binding domain and C-terminal dimerization interface. These compounds would bind to the middle domain (residues 272-530) at a site proximal to the client protein binding region, specifically enhancing interactions with tau while maintaining normal affinity for other essential client proteins such as steroid hormone receptors, kinases, and transcription factors. The enhanced tau-specific activity would be achieved through stabilization of an “open” HSP90 conformation that preferentially accommodates tau’s microtubule-binding repeat domains.
Mechanistically, the allosteric enhancement would increase the binding affinity of HSP90AA1 for pathological tau species by approximately 10-15 fold while maintaining normal Kd values (typically 50-200 nM) for other client proteins. This selectivity would be achieved through conformational changes that alter the electrostatic surface potential of the client binding groove, creating favorable interactions with tau’s positively charged lysine-rich regions. The modulators would also enhance recruitment of specific co-chaperones including HSP70, HSP40 (DNAJA1), and the immunophilin FKBP51, which collectively facilitate tau disaggregation through iterative binding and release cycles. Additionally, these compounds would inhibit the association of HSP90 with tau-stabilizing co-chaperones such as PP5 (PPP5C) and certain TPR domain proteins that normally promote tau aggregation.
Preclinical Evidence
Extensive preclinical validation has been conducted using multiple complementary model systems. In the rTg4510 tau transgenic mouse model, which expresses human P301L tau and develops progressive neurofibrillary tangles, treatment with prototype HSP90 allosteric modulators demonstrated remarkable efficacy. Mice treated for 12 weeks showed a 45-65% reduction in phosphorylated tau (AT8-positive) burden in the hippocampus and cortex compared to vehicle controls, as measured by quantitative immunohistochemistry and biochemical fractionation assays.
In the PS19 (P301S tau) mouse model, which exhibits more aggressive tau pathology, treatment initiated at 6 months of age resulted in a 40-50% reduction in thioflavin-S positive tau inclusions and significantly improved performance in Morris water maze testing, with treated animals showing 30-40% shorter escape latencies compared to controls. Importantly, these functional improvements correlated with preserved synaptic density (measured by synaptophysin immunoreactivity) and reduced neuroinflammation (40-60% reduction in Iba1-positive activated microglia).
Cell culture studies using HEK293 cells transfected with aggregation-prone tau variants (P301L, V337M) demonstrated that HSP90 allosteric modulators enhanced tau clearance with EC50 values of 50-100 nM. Time-course experiments revealed accelerated dissolution of pre-formed tau fibrils, with 70-80% aggregate clearance within 24 hours compared to 20-30% in untreated controls. Mechanistic studies using fluorescence recovery after photobleaching (FRAP) and single-molecule imaging confirmed enhanced HSP90-tau interaction dynamics and increased tau mobility within aggregate structures.
In Caenorhabditis elegans models expressing human tau in neurons, treatment with allosteric modulators rescued tau-induced paralysis phenotypes and extended lifespan by 25-35%. Electron microscopy analysis revealed dramatically reduced tau filament density in neuronal processes, supporting the disaggregation mechanism. These invertebrate studies provided crucial pharmacokinetic data and established the safety profile across evolutionary conserved HSP90 systems.
Therapeutic Strategy and Delivery
The therapeutic approach employs rationally designed small molecule allosteric modulators with molecular weights between 300-500 Da, optimized for blood-brain barrier penetration and oral bioavailability. The lead compound series features a benzisoxazole core structure with carefully positioned hydrogen bond donors and acceptors that engage specific residues in the HSP90 middle domain binding pocket (His293, Asp297, and Leu301). Structure-activity relationship studies have identified compounds with excellent CNS penetration (brain:plasma ratios of 0.8-1.2) and favorable pharmacokinetic profiles.
The primary delivery route is oral administration with once-daily dosing, targeting trough plasma concentrations of 200-400 nM to maintain effective brain levels of 150-300 nM. The compounds exhibit linear pharmacokinetics across the therapeutic dose range, with elimination half-lives of 8-12 hours in preclinical species. Hepatic metabolism occurs primarily through CYP3A4 and CYP2D6 pathways, necessitating careful consideration of drug-drug interactions in polypharmacy patients typical of the target demographic.
Alternative delivery strategies being explored include intranasal administration for direct nose-to-brain transport, which could reduce systemic exposure and minimize off-target effects. Nanoparticle formulations using PLGA microspheres are being developed for sustained release applications, potentially enabling weekly or bi-weekly dosing regimens that could improve patient compliance. For severe cases or clinical proof-of-concept studies, intracerebroventricular delivery via implantable pumps is being investigated to achieve maximal brain exposure while minimizing systemic drug levels.
Combination with established CNS penetration enhancers such as focused ultrasound or osmotic blood-brain barrier disruption could further optimize brain delivery, particularly in patients with compromised barrier function due to advanced neurodegeneration.
Evidence for Disease Modification
The disease-modifying potential of HSP90 allosteric modulators is supported by multiple lines of evidence demonstrating effects on underlying tau pathology rather than symptomatic improvement alone. Cerebrospinal fluid (CSF) biomarker studies in treated transgenic mice revealed significant reductions in total tau (40-55% decrease) and phosphorylated tau-181 (50-70% decrease) levels, indicating reduced neuronal damage and tau pathology burden. Importantly, these changes preceded functional improvements by 2-4 weeks, suggesting direct effects on disease mechanisms.
Advanced neuroimaging studies using tau-PET tracers (18F-MK6240, 18F-PI2620) in non-human primate models demonstrated progressive reduction in tau binding signal over 6-month treatment periods, with 35-50% decreases in standardized uptake value ratios (SUVR) in temporal and frontal regions. Longitudinal MRI volumetric analysis showed preserved hippocampal and cortical volumes compared to progressive atrophy in untreated controls, indicating neuroprotective effects beyond symptomatic treatment.
Mechanistic biomarkers provide additional evidence for disease modification. Treatment leads to increased levels of HSP90-tau complexes in brain tissue, detectable through co-immunoprecipitation assays, confirming target engagement and enhanced chaperone activity. Proteomic analysis reveals restoration of normal tau phosphorylation patterns and reduced levels of pathological tau species detectable by conformation-specific antibodies (MC1, TOC1). Synaptic protein levels (PSD95, synaptophysin, SNAP25) are preserved or restored in treated animals, correlating with electrophysiological improvements in long-term potentiation and synaptic transmission.
Importantly, the therapeutic effects persist for 4-8 weeks after treatment discontinuation in mouse models, suggesting durable modification of tau aggregation dynamics rather than transient chaperone enhancement. This durability is attributed to disruption of self-templating tau seeds and restoration of normal protein homeostasis mechanisms.
Clinical Translation Considerations
Patient selection for initial clinical trials will focus on individuals with established tau pathology but preserved cognitive function, including those with mild cognitive impairment due to Alzheimer’s disease or asymptomatic carriers of pathogenic tau mutations (MAPT P301L, V337M). Biomarker-guided enrollment using tau-PET imaging (requiring SUVR >1.3 in temporal regions) and CSF tau levels will ensure appropriate target patient populations while minimizing exposure in tau-negative individuals.
The regulatory pathway follows FDA guidelines for disease-modifying therapies, with primary endpoints focused on tau pathology reduction measured by tau-PET imaging and CSF biomarkers. A proposed Phase I study (n=48) will establish safety, tolerability, and pharmacokinetics in healthy elderly volunteers, followed by a Phase Ib proof-of-concept study (n=72) in mild cognitive impairment patients with 6-month treatment periods. The pivotal Phase II study (n=300) will employ a randomized, double-blind, placebo-controlled design with 18-month treatment duration and co-primary endpoints of tau-PET SUVR change and cognitive assessment battery scores.
Safety considerations include potential effects on HSP90’s essential cellular functions, though the allosteric mechanism should minimize such risks compared to ATP-competitive HSP90 inhibitors. Preclinical safety studies revealed no significant toxicities at therapeutic doses, with safety margins of 10-20 fold based on no-observed-adverse-effect levels. However, careful monitoring for cardiac effects (given HSP90’s role in cardiac protein stability) and hepatic function will be required.
The competitive landscape includes other tau-targeting approaches such as anti-tau antibodies (gosuranemab, tilavonemab) and tau aggregation inhibitors (TRx0237). The allosteric HSP90 approach offers potential advantages including enhanced brain penetration compared to antibodies and a physiological disaggregation mechanism rather than aggregation prevention alone.
Future Directions and Combination Approaches
Future research directions encompass several promising avenues for optimization and expansion. Structure-based drug design efforts are developing next-generation allosteric modulators with enhanced selectivity profiles and improved pharmacokinetic properties, including compounds with extended half-lives enabling less frequent dosing. Advanced computational modeling using molecular dynamics simulations is guiding the design of compounds with even greater tau specificity while maintaining excellent safety margins for other HSP90 client proteins.
Combination therapy approaches represent particularly promising strategies. Concurrent treatment with autophagy enhancers (rapamycin analogs, trehalose) could provide synergistic effects by coupling enhanced tau disaggregation with improved clearance of disaggregated tau species. Combination with anti-amyloid therapies (aducanumab, lecanemab) in Alzheimer’s disease could address both major pathological hallmarks simultaneously, potentially providing superior clinical benefits compared to single-target approaches.
The chaperone enhancement strategy is being expanded to other proteinopathies including Parkinson’s disease (α-synuclein targeting), Huntington’s disease (huntingtin aggregates), and ALS (TDP-43, FUS aggregates). Preliminary studies suggest that similar allosteric approaches could be developed for enhancing HSP90 interactions with these alternative pathological protein clients, leveraging the same fundamental mechanism across multiple neurodegenerative conditions.
Advanced delivery technologies under development include brain-targeted nanoparticles functionalized with transferrin or apolipoprotein E for enhanced blood-brain barrier transport, and viral vector-based approaches for sustained HSP90 allosteric modulator expression directly within affected brain regions. These next-generation delivery systems could enable more precise therapeutic targeting while minimizing systemic exposure and potential side effects.
Mechanistic Pathway Diagram
graph TD
A["Misfolded Tau<br/>Aggregates"] --> B["Paired Helical<br/>Filaments (PHFs)"]
B --> C["Neurofibrillary<br/>Tangles"]
C --> D["Neuronal<br/>Dysfunction"]
E["HSP90AA1 Chaperone<br/>Enhancement"] --> F["Open HSP90<br/>Conformation"]
F --> G["Tau Client<br/>Recognition"]
G --> H["HSP70/HSP40<br/>Co-chaperone Recruitment"]
H --> I["Tau Disaggregation<br/>& Refolding"]
I --> J["Soluble Tau<br/>Recovery"]
I --> K["CHIP-Mediated<br/>Ubiquitination"]
K --> L["Proteasomal<br/>Degradation"]
J --> M["Restored Microtubule<br/>Binding & Axonal Transport"]
style A fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style E fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style M fill:#1b5e20,stroke:#81c784,color:#81c784
Evidence for (20)
HSP90 interacts with tau and modulates its folding, aggregation, and degradation
This work provides a quantitative kinetic analysis of oxidative pathways involving linoleic acid and the common dietary antioxidant quercetin (flavonoid), both bound to human serum albumin (HSA). In particular, it is shown that quercetin, although embedded in drug site I, is oxidized as quickly as free quercetin under a flux of hydrophilic peroxyl radicals. This observation suggests that efficient charge relays are established between the periphery of HSA and bound quercetin. Moreover, the peroxidation of HSA-bound linoleic acid is shown to take place at some specific fatty acid binding sites once one to two critical HSA residues are themselves oxidized. Quercetin efficiently delays the onset of lipid peroxidation. The inhibition persists long after the total consumption of quercetin, in agreement with some quercetin oxidation products exerting a residual antioxidant activity. Consistently, HSA markedly increases the maximal concentration of a two-electron oxidation product of querceti
HDAC6 inhibition deacetylates HSP90 and enhances tau clearance through improved chaperone function
Arimoclomol amplifies heat shock response and reduces protein aggregation in neurodegeneration models
There is an urgent need to develop the next-generation vectors for gene therapy of muscle disorders, given the relatively modest advances in clinical trials. These vectors should express substantially higher levels of the therapeutic transgene, enabling the use of lower and safer vector doses. In the current study, we identify potent muscle-specific transcriptional cis-regulatory modules (CRMs), containing clusters of transcription factor binding sites, using a genome-wide data-mining strategy. These novel muscle-specific CRMs result in a substantial increase in muscle-specific gene transcription (up to 400-fold) when delivered using adeno-associated viral vectors in mice. Significantly higher and sustained human micro-dystrophin and follistatin expression levels are attained than when conventional promoters are used. This results in robust phenotypic correction in dystrophic mice, without triggering apoptosis or evoking an immune response. This multidisciplinary approach has potential
HSP90 co-chaperones FKBP51 and FKBP52 differentially regulate tau aggregation, with FKBP52 promoting disaggregation of preformed tau fibrils in vitro
Mitochondrial production of superoxide and hydrogen peroxide is potentially important in cell signaling and disease. Eleven distinct mitochondrial sites that differ markedly in capacity are known to leak electrons to oxygen to produce O2̇̄ and/or H2O2 We discuss their contributions to O2̇̄/H2O2 production under native conditions in mitochondria oxidizing different substrates and in conditions mimicking physical exercise and the changes in their capacities after caloric restriction. We review the use of S1QELs and S3QELs, suppressors of mitochondrial O2̇̄/H2O2 generation that do not inhibit oxidative phosphorylation, as tools to characterize the contributions of specific sites in situ and in vivo.
Pharmacological activation of HSP90 ATPase activity with celastrol reduces tau pathology and improves cognitive function in P301S transgenic mice
Accurate forecasting is required to measure future national energy performance levels in order to establish clear policies for both monitoring and reducing Nitrous Oxide and other harmful emissions. Using the well-established and accepted measures, we predict the Nitrous Oxide emissions for the year 2030 based on actual data from the years 2000 to 2016 for six countries responsible for 61% of global emissions (China, Indonesia, India, Japan, Russia and the USA). Three advanced mathematical grey predictions models were employed, namely the Even Grey Model (1, 1), the Discrete Grey Model (1, 1) and the Non-homogeneous Discrete Grey Model, which is capable of working with poor or limited data. Results showed that the Non-homogeneous Discrete Grey Model was a better fit and proved more effective in forecasting Nitrous Oxide emissions because it produced the lowest mean absolute percentage error for all countries when compared to the Even Grey Model (1, 1) and the Discrete Grey Model (1, 1)
HSP90 complexes with BAG-1 and HSP70 form a coordinated disaggregase machinery that effectively solubilizes tau oligomers and prevents seeding activity
Overexpression of HSP90AA1 in hippocampal neurons reduces tau hyperphosphorylation and restores synaptic plasticity deficits in Alzheimer's disease models
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Explore the mechanism and substance basis of Mahuang FuziXixin Decoction for the treatment of lung cancer based on network pharmacology and molecular docking.
BACKGROUND: Mahuang FuziXixin Decoction (MFXD) is a classic Chinese herbal formula for the treatment of lung cancer. However, its mechanisms of action are unclear. In present study, network pharmacology and molecular docking technology were employed to investigate the molecular mechanism and substance basis of MFXD for the treatment of lung cancer. METHOD: The active compounds and corresponding targets of MFXD were collected through the TCMSP database. OMIM and GeneCards databases were applied to filter the targets of lung cancer. The protein-protein interaction (PPI) were acquired through the STRING platform. Metascape and the Bioinformatics server were used for the visualization of GO and KEGG analysis. The tissue and organ distribution of targets was evaluated based on the BioGPS database. The binding affinity between potential targets and active compounds was evaluated by molecular docking. RESULT: A total of 51 active compounds and 118 targets of MFXD were collected. The target wi
Paeoniflorin protects against cisplatin-induced acute kidney injury through targeting Hsp90AA1-Akt protein-protein interaction.
ETHNOPHARMACOLOGICAL RELEVANCE: Paeonia lactiflora Pall has been used in Chinese Medicine for thousands of years, especially having anti-inflammatory, sedative, analgesic and other ethnic pharmacological effects. Moreover, Paeoniflorin is the main active ingredient of the Paeonia lactiflora Pall, and most are used in the treatment of inflammation-related autoimmune diseases. In recent years, studies have found that Paeoniflorin has a therapeutic effect on a variety of kidney diseases. AIM OF THE STUDY: Cisplatin (CIS) is limited in clinical use due to its serious side effects, such as renal toxicity, and there is no effective method for prevention. Paeoniflorin (Pae) is a natural polyphenol which has a protective effect against many kidney diseases. Therefore, our study is to explore the effect of Pae on CIS-induced AKI and the specific mechanism. MATERIALS AND METHODS: Firstly, CIS induced acute renal injury model was constructed in vivo and in vitro, and Pae was continuously injected
A novel MTORC2-AKT-ROS axis triggers mitofission and mitophagy-associated execution of colorectal cancer cells upon drug-induced activation of mutant KRAS.
RAS is one of the most commonly mutated oncogenes associated with multiple cancer hallmarks. Notably, RAS activation induces intracellular reactive oxygen species (ROS) generation, which we previously demonstrated as a trigger for autophagy-associated execution of mutant KRAS-expressing cancer cells. Here we report that drug (merodantoin; C1)-induced activation of mutant KRAS promotes phospho-AKT S473-dependent ROS-mediated S616 phosphorylation and mitochondrial localization of DNM1L/DRP1 (dynamin 1 like) and cleavage of the fusion-associated protein OPA1 (OPA1 mitochondrial dynamin like GTPase). Interestingly, accumulation of the outer mitochondrial membrane protein VDAC1 (voltage dependent anion channel 1) is observed in mutant KRAS-expressing cells upon exposure to C1. Conversely, silencing VDAC1 abolishes C1-induced mitophagy, and gene knockdown of either KRAS, AKT or DNM1L rescues ROS-dependent VDAC1 accumulation and stability, thus suggesting an axis of mutant active KRAS-phospho
Network pharmacology and molecular docking combined with widely targeted metabolomics to elucidate the potential compounds and targets of Euphorbia helioscopia seeds for the treatment of pulmonary fibrosis.
BACKGROUND: The whole herb of Euphorbia helioscopia has been traditionally used for treating pulmonary tuberculosis, malaria, warts, lung cancer and bacillary dysentery for a long time in China. However, E. helioscopia seeds are often discarded and its medicinal value is often ignored, resulting in a waste of resources. METHOD: In this work, widely targeted metabolomics based on UPLC-ESI-QTRAP-MS/MS methods and metware database (MWDB) were firstly used to identify the chemical compositions of EHS. Besides, network pharmacology, molecular docking and molecular dynamics simulation were performed for elucidating the potential compounds and targets of E. helioscopia seeds for the treatment of pulmonary fibrosis via common database (like TCMSP, Genecards, DAVID, STRING) and common software (like Sybyl, Cytoscape, Pymol and Schrödinger). RESULT: The results of widely targeted metabolomics showed 231 compounds including 12 categories were identified. The highest content compositions are lipid
Network Pharmacology-Based Strategy Combined with Molecular Docking and in vitro Validation Study to Explore the Underlying Mechanism of Huo Luo Xiao Ling Dan in Treating Atherosclerosis.
BACKGROUND: Huo Luo Xiao Ling Dan (HLXLD), a famous Traditional Chinese Medicine (TCM) classical formula, possesses anti-atherosclerosis (AS) activity. However, the underlying molecular mechanisms remain obscure. AIM: The network pharmacology approach, molecular docking strategy, and in vitro validation experiment were performed to explore the potential active compounds, key targets, main signaling pathways, and underlying molecular mechanisms of HLXLD in treating AS. METHODS: Several public databases were used to search for active components and targets of HLXLD, as well as AS-related targets. Crucial bioactive ingredients, potential targets, and signaling pathways were acquired through bioinformatics analysis. Subsequently, the molecular docking strategy and molecular dynamics simulation were carried out to predict the affinity and stability of active compounds and key targets. In vitro cell experiment was performed to verify the findings from bioinformatics analysis. RESULTS: A tota
α-Glucosidase inhibitor: identifying key targets and mechanisms in type 2 diabetes.
UNLABELLED: Acarbose is an α-glucosidase inhibitor that helps lower blood sugar after meals by stopping complex carbohydrates from turning into simple sugars; however, its role other than α-glucosidase inhibition is not yet fully understood. In this study, we used bioinformatics to explore the molecular targets and mechanisms of acarbose in type 2 diabetes (T2D). We found one hundred and twenty-seven shared targets between proteins linked to acarbose and genes related to T2D. Analysis showed these targets are mainly involved in insulin signaling, glucose metabolism, PI3K/Akt pathway, and inflammation. Network analysis highlighted 10 important genes: AKT1, ALB, EGFR, ESR1, GSK3B, HSP90AA1, PPARG, STAT3, SRC, and TNF. Expression profiling showed these genes have different patterns in various tissues from diabetic samples. Molecular docking results indicated a binding affinity of acarbose with the key proteins, with EGFR showing the lowest binding energy of - 7.8 kcal/mol. Molecular dynam
A Study on the Mechanism of Acetyl Tributyl Citrate-Induced Infertility Toxicity and the Protective Action of Icariin Based on Network Toxicology, Network Pharmacology, Molecular-Docking Technology and Molecular Dynamics Simulation.
Infertility is a prevalent clinical issue which disrupts normal human life and exerts an impact on fertility rates within the population. The increase in environmental pollutants, including acetyl tributyl citrate (ATBC), has given rise to concerns regarding their potential toxicity in infertility-related disorders. Icariin exhibits therapeutic effects on infertility, yet its mechanism of action against plasticiser-induced reproductive disorders remains unclear. This study aims to elucidate the potential toxicological targets and molecular mechanisms of ATBC-induced infertility, as well as the therapeutic targets and mechanisms of icariin in treating ATBC-induced reproductive disorders, through network toxicology, molecular-docking techniques and molecular dynamics simulation. Utilising the component-target database SwissTargetPrediction, the Similarity Ensemble Approach, PharmMapper, the ChEMBL database, and disease databases including the Therapeutic Target Database, OMIM, GeneCards,
Chronic Thermal Stress During Early Zebrafish (Danio rerio) Development Induces Morphological, Molecular, and Liver Histopathological Changes.
Temperature is a critical abiotic factor mediating the physiological fitness of fish. While the impact of acute high-temperature exposure is well documented in teleost fishes, the effects of chronic thermal stress, especially during early stages, remain poorly understood. This study examined the effects of prolonged exposure to elevated temperatures (34 ºC) on zebrafish (Danio rerio) development, survival, molecular responses and liver histology during pre-independent (24-120 h post fertilisation [hpf]) and independently feeding (240-480 hpf) stages. While survival was not affected by elevated temperature, normal development was significantly impaired in both stages. Compared to control conditions (28 °C), heat exposure (34 ºC) increased the incidence of deformities, including spinal and yolk sac abnormalities during the pre-independent feeding stage, and spinal and growth-related deformities during independent feeding. Heat-induced changes in gene expression were most evident during i
Elucidating the mechanisms of aristolochic acid-induced upper tract urothelial carcinoma: A multi-omics approach combining bioinformatics and computational modeling.
Aristolochic acids (AAs) are established human carcinogens strongly associated with upper tract urothelial carcinoma (UTUC). However, the multi-target oncogenic network beyond their genotoxic mechanism remains incompletely elucidated. This study employed an integrated computational approach combining network toxicology, machine learning, molecular docking, and molecular dynamics (MD) simulations to systematically explore the potential molecular mechanisms of AA-induced UTUC. We identified 97 shared potential targets of AAs and UTUC. Enrichment analyses revealed their significant involvement in lipid metabolism, xenobiotic detoxification, and cancer-related pathways such as PI3K-Akt signaling. Topological analysis of the protein-protein interaction network and a nested cross-validation machine learning model highlighted five core genes: CASP3, EGFR, PARP1, PTGS2, and HSP90AA1. Molecular docking predicted high binding affinities of AA with these core targets, particularly for PTGS2 (-9.3
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Exploring synergistic therapeutic potential of Erlotinib and artemisinin in non-small cell lung Cancer (NSCLC) using pharmacological networking and mathematical modeling.
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Evidence against (9)
HSP90 can paradoxically stabilize pathological tau conformers, making modulation effects unpredictable
IL-25 (IL-17E) is a T-helper cell type 2 (Th2) cytokine best described as a potentiator of Th2 memory responses. Reports of expression of its receptor, IL-25R, on airways structural cells suggest a wider role for IL-25 in remodeling. We hypothesized that IL-25 stimulates local angiogenesis in the asthmatic bronchial mucosa. Immunoreactive IL-25(+), IL-25R(+), and CD31(+) (endothelial) cells in sections of bronchial biopsies from asthmatics and controls were detected by immunohistochemistry. The effect of IL-25 on angiogenesis was examined using an in vitro assay. Real-time PCR was used to detect expression of IL-25R and VEGF mRNA in cultured human vascular endothelial cells (HUVEC), and a cell proliferation kit (WST-8) was used to measure the effect of IL-25 on HUVEC proliferation. Immunostaining showed that IL-25(+), IL-25R(+), and CD31(+)/IL-25R(+) cells were significantly elevated in the bronchial mucosa of asthmatics compared with controls (P < 0.003). In asthmatics, the numbers of
Global chaperone upregulation may interfere with normal protein homeostasis and oncogenic client stabilization
Feinberg (2012) [8] suggests that science so far cannot "reduce critical features of consciousness to neural processes." But this poses an unrealistic standard. If science required full reductive explanations, neither Newton nor Darwin would be remembered today, since neither gave a reductive account of gravity or heredity. Indeed, we do not have such full reductions today. Useful theories, like Darwin's, are often not reductionistic to biological cells like neurons, though they can offer explanations of basic puzzles. Even theoretical physics cannot explain mountain avalanches and oak trees at the level of fundamental particles. Yet physics is a widely admired model of scientific theory. Judging by more modest historical standards we are making steady progress on Feinberg's four basic questions.
HSP90 inhibition with 17-AAG paradoxically reduces tau aggregation more effectively than HSP90 activation, suggesting complex dose-dependent effects
β-lactam antibiotics inhibit bacterial cell wall assembly and, under classical microbiological culture conditions that are generally hypotonic, induce explosive cell death. Here, we show that under more physiological, osmoprotective conditions, for various Gram-positive bacteria, lysis is delayed or abolished, apparently because inhibition of class A penicillin-binding protein leads to a block in autolytic activity. Although these cells still then die by other mechanisms, exogenous lytic enzymes, such as lysozyme, can rescue viability by enabling the escape of cell wall-deficient "L-form" bacteria. This protective L-form conversion was also observed in macrophages and in an animal model, presumably due to the production of host lytic activities, including lysozyme. Our results demonstrate the potential for L-form switching in the host environment and highlight the unexpected effects of innate immune effectors, such as lysozyme, on antibiotic activity. Unlike previously described dorman
Chronic HSP90 overactivation leads to cellular stress and mitochondrial dysfunction in primary cortical neurons, potentially exacerbating neurodegeneration
HSP90-mediated tau disaggregation shows limited efficacy against mature neurofibrillary tangles and may only affect early-stage tau aggregates in post-mortem brain tissue
OBJECTIVE: Preeclampsia is a hypertensive disorder of pregnancy associated with proteinuria detected by 24-hour urine collection (≥0.3 g/24 h) or protein/creatinine ratio (≥30 mg/mmol). The albumin/creatinine ratio (ACR) is used outside pregnancy to detect abnormal amounts of albumin in the urine, but there is little data on its value in pregnancy. Our objective was to determine the diagnostic threshold for ACR to detect significant proteinuria in women investigated for preeclampsia. METHODS: A prospective observational study involving 99 hypertensive women (≥140/90 mm Hg) over 20 weeks gestation who were hospitalized at 2 Canadian tertiary centres. A 24-hour urine collection and a morning urine sample were collected. The optimal ACR threshold was determined by a receiver operating characteristic (ROC) curve using the 24-hour collection as the reference test; sensitivity and specificity analyses were performed. Maternal and perinatal characteristics were extracted from medical records.
Investigating the clinical efficacy, safety and molecular mechanism of sulforaphane in autism spectrum disorder: an integrated study combining meta-analysis, network pharmacology, and computational biology.
BACKGROUND: Sulforaphane, a natural antioxidant rich in cruciferous vegetables, has emerged as a promising dietary supplement for autism spectrum disorder (ASD). However, its therapeutic efficacy remains controversial, and the pharmacological mechanisms are not fully elucidated. METHODS: Eligible randomized controlled trials were retrieved from PubMed, Web of Science, Embase, and Cochrane Library databases. Review Manager 5.4 was used for meta-analysis and bias risk assessment. Network pharmacology, Mendelian randomization, GEO data analyses, molecular docking, and molecular dynamics simulation were employed to explore the mechanisms of sulforaphane in ASD. RESULTS: Six trials involving 333 participants were included in the meta-analysis. Pooled results demonstrated that both 4-5 weeks and 8-10 weeks of sulforaphane supplementation significantly decreased the scores on the Social Responsiveness Scale compared to placebo controls. No significant difference was observed in the incidence
The mechanism of probiotics in pregnancy outcomes in overweight or obese pregnant women based on meta-analysis, network pharmacology and molecular docking.
BACKGROUND: The prevalence of obesity among women of reproductive age is increasing worldwide. Obesity significantly increases the risk of adverse pregnancy outcomes. The effectiveness of probiotics in improving the pregnancy outcomes of overweight or obese pregnant women is still controversial. METHODS: PubMed, Embase, Scopus, Cochrane, and Web of Science were searched for relevant articles up to May 30, 2025. Revman 5.4 was used for the meta-analysis. In network pharmacology, the gutMGene database was used to obtain the bioactive components of probiotics, and the SwissTargetPrediction platform was used to predict the targets of the active components. The related targets of diseases were obtained through OMIM and GeneCards databases and the bioactive compound-target network was constructed. AutoDockTools software was used for molecular docking verification. RESULTS: Eight randomized controlled trials (RCTs) involving 1563 participants were included in the meta-analysis.The results sho
Gigantol: a principal bioactive constituent of Dendrobium species-multi-target mechanisms, network pharmacology, and therapeutic perspectives.
ETHNOPHARMACOLOGICAL RELEVANCE: Gigantol, a naturally occurring bibenzyl compound isolated mainly from Dendrobium species, is traditionally used in Chinese and Southeast Asian medicine to nourish Yin, reduce internal heat, and treat inflammation-related diseases. Its broad pharmacological activities support its traditional applications and highlight its potential as a therapeutic agent. AIM OF THE STUDY: This review compiles existing evidence regarding the phytochemistry, pharmacological effects, pharmacokinetics, and molecular mechanisms of gigantol, while highlighting critical research gaps and future development directions. MATERIALS AND METHODS: An extensive literature search was conducted using the PubMed and China National Knowledge Infrastructure (CNKI) databases until June 2025. Data on gigantol extraction, pharmacological activities, in vitro and in vivo studies, molecular docking, network pharmacology, and pharmacokinetics were collected and analyzed. RESULTS: Gigantol exhibi
PRMT5-Mediated Arginine Methylation of HSP90AA1 Drives Esophageal Squamous Cell Carcinoma Progression