Transcriptional Autophagy-Lysosome Coupling
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From Analysis:
Autophagy-lysosome pathway convergence across neurodegenerative diseases
Multiple NDDs converge on autophagy-lysosome dysfunction. Are there universal therapeutic targets?
Hypotheses from Same Analysis (6)
These hypotheses emerged from the same multi-agent debate that produced this hypothesis.
Description
Transcriptional Autophagy-Lysosome Coupling via FOXO1-TFEB Coordination
Overview: The Autophagy-Lysosome Mismatch in Neurodegeneration
Autophagy (self-eating) and the lysosomal degradation pathway are interdependent cellular quality control systems. Autophagosomes engulf damaged organelles and protein aggregates, then fuse with lysosomes where acidic hydrolases degrade the cargo. This autophagy-lysosome system is critical for neuronal health due to post-mitotic neurons' inability to dilute toxic aggregates through division.
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✓ Supporting Evidence 39
BACKGROUND: Many pathological states characterized by muscle atrophy are associated with an increase in circulating glucocorticoids and poor patient prognosis, making it an important target for treatment. The development of treatments for glucocorticoid-induced and wasting disorder-related skeletal muscle atrophy should be designed based on how the particular transcriptional program is orchestrated and how the balance of muscle protein synthesis and degradation is deregulated. Here, we investigated whether the obestatin/GPR39 system, an autocrine/paracrine signaling system acting on myogenesis and with anabolic effects on the skeletal muscle, could protect against glucocorticoid-induced muscle cell atrophy. METHODS: In the present study, we have utilized mouse C2C12 myotube cultures to examine whether the obestatin/GPR39 signaling pathways can affect the atrophy induced by the synthetic glucocorticoid dexamethasone. We have extended these findings to in vitro effects on human atrophy u
Ferroptosis is a form of regulated cell death triggered by lipid peroxidation after inhibition of the cystine/glutamate antiporter system Xc-. However, key regulators of system Xc- activity in ferroptosis remain undefined. Here, we show that BECN1 plays a hitherto unsuspected role in promoting ferroptosis through directly blocking system Xc- activity via binding to its core component, SLC7A11 (solute carrier family 7 member 11). Knockdown of BECN1 by shRNA inhibits ferroptosis induced by system Xc- inhibitors (e.g., erastin, sulfasalazine, and sorafenib), but not other ferroptosis inducers including RSL3, FIN56, and buthionine sulfoximine. Mechanistically, AMP-activated protein kinase (AMPK)-mediated phosphorylation of BECN1 at Ser90/93/96 is required for BECN1-SLC7A11 complex formation and lipid peroxidation. Inhibition of PRKAA/AMPKα by siRNA or compound C diminishes erastin-induced BECN1 phosphorylation at S93/96, BECN1-SLC7A11 complex formation, and subsequent ferroptosis. Accordin
Impaired mitochondrial respiratory activity contributes to the development of insulin resistance in type 2 diabetes. Metformin, a first-line antidiabetic drug, functions mainly by improving patients' hyperglycemia and insulin resistance. However, its mechanism of action is still not well understood. We show here that pharmacological metformin concentration increases mitochondrial respiration, membrane potential, and ATP levels in hepatocytes and a clinically relevant metformin dose increases liver mitochondrial density and complex 1 activity along with improved hyperglycemia in high-fat- diet (HFD)-fed mice. Metformin, functioning through 5' AMP-activated protein kinase (AMPK), promotes mitochondrial fission to improve mitochondrial respiration and restore the mitochondrial life cycle. Furthermore, HFD-fed-mice with liver-specific knockout of AMPKα1/2 subunits exhibit higher blood glucose levels when treated with metformin. Our results demonstrate that activation of AMPK by metformin i
Predisposition to Alzheimer's disease (AD) may arise from lipid metabolism perturbation, however, the underlying mechanism remains elusive. Here, we identify ATPase family AAA-domain containing protein 3A (ATAD3A), a mitochondrial AAA-ATPase, as a molecular switch that links cholesterol metabolism impairment to AD phenotypes. In neuronal models of AD, the 5XFAD mouse model and post-mortem AD brains, ATAD3A is oligomerized and accumulated at the mitochondria-associated ER membranes (MAMs), where it induces cholesterol accumulation by inhibiting gene expression of CYP46A1, an enzyme governing brain cholesterol clearance. ATAD3A and CYP46A1 cooperate to promote APP processing and synaptic loss. Suppressing ATAD3A oligomerization by heterozygous ATAD3A knockout or pharmacological inhibition with DA1 restores neuronal CYP46A1 levels, normalizes brain cholesterol turnover and MAM integrity, suppresses APP processing and synaptic loss, and consequently reduces AD neuropathology and cognitive
Adenosine monophosphate-activated protein kinase (AMPK) activity is stimulated to promote metabolic adaptation upon energy stress. However, sustained metabolic stress may cause cell death. The mechanisms by which AMPK dictates cell death are not fully understood. We report that metabolic stress promoted receptor-interacting protein kinase 1 (RIPK1) activation mediated by TRAIL receptors, whereas AMPK inhibited RIPK1 by phosphorylation at Ser415 to suppress energy stress-induced cell death. Inhibiting pS415-RIPK1 by Ampk deficiency or RIPK1 S415A mutation promoted RIPK1 activation. Furthermore, genetic inactivation of RIPK1 protected against ischemic injury in myeloid Ampkα1-deficient mice. Our studies reveal that AMPK phosphorylation of RIPK1 represents a crucial metabolic checkpoint, which dictates cell fate response to metabolic stress, and highlight a previously unappreciated role for the AMPK-RIPK1 axis in integrating metabolism, cell death, and inflammation.
Parkinson's disease (PD) is a neurodegenerative disease characterized by the death of dopaminergic neurons in the substantia nigra and the formation of Lewy bodies that are composed of aggregated α-synuclein (α-Syn). However, the factors that regulate α-Syn pathology and nigrostriatal dopaminergic degeneration remain poorly understood. Previous studies demonstrate cholesterol 24-hydroxylase (CYP46A1) increases the risk for PD. Moreover, 24-hydroxycholesterol (24-OHC), a brain-specific oxysterol that is catalyzed by CYP46A1, is elevated in the cerebrospinal fluid of PD patients. Herein, we show that the levels of CYP46A1 and 24-OHC are elevated in PD patients and increase with age in a mouse model. Overexpression of CYP46A1 intensifies α-Syn pathology, whereas genetic removal of CYP46A1 attenuates α-Syn neurotoxicity and nigrostriatal dopaminergic degeneration in the brain. Moreover, supplementation with exogenous 24-OHC exacerbates the mitochondrial dysfunction induced by α-Syn fibrils
TFEB overexpression in neurons clears phospho-tau aggregates and restores synaptic density in P301S transgenic… HIGH▼
Coordinated TFEB-TFE3 activation achieves 3-fold greater autophagy flux enhancement than TFEB alone in human n… HIGH▼
Various developmental projects and economic actions such as mining, industries, urban expansion, and agricultural activities contribute toxic heavy metals into the soils and it adversely affects to human health and broadly the environment. For the scientific study (coal mining region of Eastern India) around 120 soil samples were collected from top (0 - 20 cm) and subsurface soil (20 - 50 cm) of coal mining, semi mining and non mining type of land use sites to assess ten heavy metals applying standard methods and indices for the assessment of pollution load and human health risk. Statistical analysis clearly indicated that Fe, Mn, Zr are the most dominantly distributed in the study region. Coefficient of variance (CV)showed that there was very less variation in the metal values among samples of any particular landuse site. Correlation coefficient (0.05% level of significance) depicts that metals were very strongly correlated with each other in every site of Neturia block. Igeo (Geo- ac
Small molecule TFEB activators (BC-1215 analogs) show oral bioavailability and BBB penetration in rodent pharm… MEDIUM▼
When patients are unable to undergo diagnostics or treatments for various reasons, sedation can be applied. A psychological approach and/or non-pharmacological sedation is preferred. When this is not possible, pharmacological sedation may be considered. In principle, the level of sedation applied, will be no deeper than is necessary for the patient to undergo the treatment and for the practitioner to be able to perform the treatment. Sedation is aimed at reducing agitation, anxiety, and/or lowering consciousness. However, it is not a pain treatment. Pain treatment will therefore always require adequate local anaesthesia. This article highlights the different levels of sedation, areas of indication, and sedatives used in dentistry. The application of pharmacological sedation will always have to be considered for each individual situation, within a total treatment plan that is aimed at lastingly increasing treatability. Wanneer patiënten om uiteenlopende redenen niet in staat zijn om dia
Lysosomal pH restoration via TFEB-mediated v-ATPase upregulation rescues proteostasis in patient iPSC-derived … HIGH▼
OBJECTIVE: We examined the associations among advance directives (ADs) completion, coping, uncertainty in illness, and optimism and pessimism in patients with end-stage liver disease (ESLD). BACKGROUND: Although associations among ADs, coping, and uncertainty have been studied in patients with other life-limiting illnesses, these concepts have not been studied together in patients with ESLD. PATIENTS AND METHODS: Patients were recruited at 2 health care institutions as part of a larger prospective study. They were enrolled if they had a diagnosis of nonhepatocellular carcinoma ESLD, Sodium Model for End-Stage Liver Disease ≥15, and no prior history of liver transplantation. Uncertainty, coping, optimism, and pessimism were assessed using the Uncertainty in Illness Scale for Adults, Revised Ways of Coping Checklist, and Life Orientation Test-revised. AD documentation at the time of study enrollment was retrospectively extracted from patient medical records. RESULTS: In the sample [N = 1
BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) is becoming a severe liver disorder worldwide. Autophagy plays a critical role in liver steatosis. However, the role of autophagy in NAFLD remains exclusive and under debate. In this study, we investigated the role of S100 calcium binding protein A11 (S100A11) in the pathogenesis of hepatic steatosis. METHODS: We performed liver proteomics in a well-established tree shrew model of NAFLD. The expression of S100A11 in different models of NAFLD was detected by Western blot and/or quantitative polymerase chain reaction. Liver S100A11 overexpression mice were generated by injecting a recombinant adenovirus gene transfer vector through the tail vein and then induced by a high-fat and high-cholesterol diet. Cell lines with S100a11 stable overexpression were established with a recombinant lentiviral vector. The lipid content was measured with either Bodipy staining, Oil Red O staining, gas chromatography, or a triglyceride kit. The au
Forkhead box O (FoxO) transcription factors are downstream targets of the serine/threonine protein kinase B (PKB)/Akt. The Akt kinase regulates processes of cellular proliferation and survival. Phosphorylation of FoxOs by Akt inhibits transcriptional functions of FoxOs and contributes to cell survival, growth and proliferation. Emerging evidence suggests involvement of FoxOs in diverse intracellular signaling pathways with critical roles in a number of physiological as well as pathological conditions including cancer. The FoxO signaling is regulated by their interactions with other intracellular proteins as well as their post-translational modifications such as phosphorylation. FoxOs promote cell growth inhibitory and/or apoptosis signaling by either inducing expression of multiple pro-apoptotic members of the Bcl2-family of mitochondria-targeting proteins, stimulating expression of death receptor ligands such as Fas ligand and tumor necrosis factor-related apoptosis-inducing ligand (T
RATIONALE: Diabetic cardiomyopathy (DbCM) is a major complication in type-1 diabetes, accompanied by altered cardiac energetics, impaired mitochondrial function, and oxidative stress. Previous studies indicate that type-1 diabetes is associated with increased cardiac expression of KLF5 (Krüppel-like factor-5) and PPARα (peroxisome proliferator-activated receptor) that regulate cardiac lipid metabolism. OBJECTIVE: In this study, we investigated the involvement of KLF5 in DbCM and its transcriptional regulation. METHODS AND RESULTS: KLF5 mRNA levels were assessed in isolated cardiomyocytes from cardiovascular patients with diabetes and were higher compared with nondiabetic individuals. Analyses in human cells and diabetic mice with cardiomyocyte-specific FOXO1 (Forkhead box protein O1) deletion showed that FOXO1 bound directly on the KLF5 promoter and increased KLF5 expression. Diabetic mice with cardiomyocyte-specific FOXO1 deletion had lower cardiac KLF5 expression and were protected f
SGLT2 inhibitor downregulates ANGPTL4 to mitigate pathological aging of cardiomyocytes induced by type 2 diabe… MEDIUM▼
BACKGROUND: Senescence is recognized as a principal risk factor for cardiovascular diseases, with a significant association between the senescence of cardiomyocytes and inferior cardiac function. Furthermore, type 2 diabetes exacerbates this aging process. Sodium-glucose co-transporter 2 inhibitor (SGLT2i) has well-established cardiovascular benefits and, in recent years, has been posited to possess anti-aging properties. However, there are no reported data on their improvement of cardiomyocytes function through the alleviation of aging. Consequently, our study aims to investigate the mechanism by which SGLT2i exerts anti-aging and protective effects at the cardiac level through its action on the FOXO1-ANGPTL4 pathway. METHODS: To elucidate the underlying functions and mechanisms, we established both in vivo and in vitro disease models, utilizing mice with diabetic cardiomyopathy (DCM) induced by type 2 diabetes mellitus (T2DM) through high-fat diet combined with streptozotocin (STZ) a
PAX3-FOXO1 coordinates enhancer architecture, eRNA transcription, and RNA polymerase pause release at select g… HIGH▼
Transcriptional control is a highly dynamic process that changes rapidly in response to various cellular and extracellular cues, making it difficult to define the mechanism of transcription factor function using slow genetic methods. We used a chemical-genetic approach to rapidly degrade a canonical transcriptional activator, PAX3-FOXO1, to define the mechanism by which it regulates gene expression programs. By coupling rapid protein degradation with the analysis of nascent transcription over short time courses and integrating CUT&RUN, ATAC-seq, and eRNA analysis with deep proteomic analysis, we defined PAX3-FOXO1 function at a small network of direct transcriptional targets. PAX3-FOXO1 degradation impaired RNA polymerase pause release and transcription elongation at most regulated gene targets. Moreover, the activity of PAX3-FOXO1 at enhancers controlling this core network was surprisingly selective, affecting single elements in super-enhancers. This combinatorial analysis indicated t
TAZ alleviates ischemic stroke injury by activating Foxo1: Usp1-mediated deubiquitination is the pivotal mecha… MEDIUM▼
BACKGROUND: The pathological progression of ischemic stroke (IS) is closely associated with oxidative stress and neuronal apoptosis, yet current therapeutic strategies remain substantially limited. The critical role of the transcriptional coactivator TAZ in this process, particularly in modulating oxidative damage, is not well defined. METHODS: By integrating a middle cerebral artery occlusion (MCAO) mouse model with an oxygen-glucose deprivation/reoxygenation (OGD/R) neuronal injury model, this study reveals the critical role of the transcriptional coactivator TAZ in modulating oxidative damage via Foxo1 and by coordinating with the deubiquitination activity of ubiquitin-specific protease 1 (Usp1). RESULTS: Single-cell RNA sequencing combined with transcriptomic datasets demonstrated spatiotemporal dynamics of TAZ expression in ischemic brain tissues, showing significant downregulation at 24 hours post-reperfusion. This decline inversely correlated with peaks of oxidative stress marke
Amyotrophic Lateral Sclerosis (ALS) is a multisystemic neurodegenerative disorder, with accumulating evidence indicating metabolic disruptions in the skeletal muscle preceding disease symptoms, rather than them manifesting as a secondary consequence of motor neuron (MN) degeneration. Hence, energy homeostasis is deeply implicated in the complex physiopathology of ALS and skeletal muscle has emerged as a key therapeutic target. Here, we describe intrinsic abnormalities in ALS skeletal muscle, both in patient-derived muscle cells and in muscle cell lines with genetic knockdown of genes related to familial ALS, such as TARDBP (TDP-43) and FUS. We found a functional impairment of myogenesis that parallels defects of glucose oxidation in ALS muscle cells. We identified FOXO1 transcription factor as a key mediator of these metabolic and functional features in ALS muscle, via gene expression profiling and biochemical surveys in TDP-43 and FUS-silenced muscle progenitors. Strikingly, inhibitio
Human adipose and synovial-derived MSCs synergistically attenuate osteoarthritis by promoting chondrocyte auto… MEDIUM▼
BACKGROUND: Human adipose-derived stem cells (ADSCs) exert a strong anti-inflammatory effect, and synovium-derived stem cells (SDSCs) have high chondrogenic potential. Thus, this study aims to investigate whether a combination of human ADSCs and SDSCs will have a synergistic effect that will increase the chondrogenic potential of osteoarthritis (OA) chondrocytes in vitro and attenuate the cartilage degeneration of early and advanced OA in vitro. METHODS: ADSCs, SDSCs, and chondrocytes were isolated from OA patients who underwent total knee arthroplasty. The ADSCs-SDSCs mixed cell ratios were 1:0 (ADSCs only), 8:2, 5:5 (5A5S), 2:8, and 0:1 (SDSCs only). The chondrogenic potential of the OA chondrocytes was evaluated in vitro with a transwell assay or pellet culture with various mixed cell groups. The mixed cell group with the highest chondrogenic potential was then selected and injected into the knee joints of nude rats of early and advanced OA stages in vivo. The animals were then eval
Dysregulated protein degradation via the ubiquitin-proteasomal pathway can induce numerous disease phenotypes, including cancer, neurodegeneration, and diabetes. While small molecule-based targeted protein degradation (TPD) and targeted protein stabilization (TPS) platforms can address this dysregulation, they rely on structured and stable binding pockets, which do not exist to classically "undruggable" targets. Here, we expand the TPS target space by engineering "deubiquibodies" (duAbs) via fusion of computationally-designed peptide binders to the catalytic domain of the potent OTUB1 deubiquitinase. In human cells, duAbs effectively stabilize exogenous and endogenous proteins in a DUB-dependent manner. Using protein language models to generate target-binding peptides, we engineer duAbs to conformationally diverse target proteins, including key tumor suppressor proteins p53 and WEE1, and heavily-disordered fusion oncoproteins, such as PAX3::FOXO1. We further encapsulate p53-targeting d
The GLP-1 agonist semaglutide ameliorates cognitive regression in P301S tauopathy mice model via autophagy/ACE… MEDIUM▼
Tau hyper-phosphorylation has been recognized as an essential contributor to neurodegeneration in Alzheimer's disease (AD) and related tauopathies. In the last decade, tau hyper-phosphorylation has gained considerable concern in AD therapeutic development. Tauopathies are manifested with a broad spectrum of symptoms, from dementia to cognitive decline and motor impairments. Tau undergoes conformational changes and abnormal phosphorylation that mediate its detaching from microtubules, forming neurofibrillary tangles (NFTs). In the current study, a widely used P301S transgenic mice model of tauopathy was employed to evaluate the possible neuroprotective effects of semaglutide as an autophagy regulator through modifications of the brain renin-angiotensin system (RAS). Mice were divided into two groups according to their genotypes (wild type (Wt) and P301S), which were further subdivided to receive either vehicle (saline) or semaglutide (25 nmol/kg, i. p.), once every 2 days for 28 days. C
Mitochondrial homeostasis is important for the health and well-being of organ systems and organisms. Mitochondrial dysfunction is known to be the cause and consequence of metabolic diseases, including obesity, diabetes, cancer, neurodegeneration, cerebrovascular, and cardiovascular disease. For cardiovascular tissue, which relies mostly on oxidative phosphorylation, the role of mitochondria is inevitable. Rather than being biomarkers of mitochondrial health, miRNAs are now known as bioregulators of this important feature. Recent studies have shown a close interaction between Forkhead box other 1 (FoxO1) transcription factors and miRNAs in the cardiovascular system. These interactions have also been shown to regulate mitochondrial homeostasis. In this review, I highlight how understanding FoxO1 and miRNA interacting networks could enable us to limit mitochondrial dysfunction and associated pathologies.
Developing human neurons express abundant tau yet show little toxicity, suggesting built-in mechanisms that restrain tau when protein clearance falters. We combined human tissue analyses with cell-based perturbation assays to define this response. In iPSC-derived forebrain neurons, brief proteasome blockade with epoxomicin (0.25 μM, 24 h; n=3/condition) triggered a coordinated transcriptomic program: hierarchical clustering of RNA-seq data resolved two opposing modules-an up-regulated proteostasis module (ubiquitin-proteasome, autophagy-lysosome, chaperone-mediated folding) and a down-regulated MAPT-linked neuronal/energetic module (microtubule/organization/transport, synaptic signaling, oxidative phosphorylation). MAPT transcripts decreased by both PCR and RNA sequencing in proteasome but not-autophagy impaired neurons even though tau protein levels decreased in both. Expressing tau from a constitutive promoter bypassed this transcriptional brake and increased tau during proteasome in
PTEN loss drives B7H3 upregulation via the mTORC2/FOXO/c-Myc axis to promote tumor immune escape in ovarian ca… MEDIUM▼
Immune checkpoint blockade (ICB) therapy has shown limited efficacy in ovarian cancer (OC). PTEN loss is a common driver in OC, yet its impact on ICB efficacy remains poorly understood. Utilizing the single-cell RNA sequencing data and performing multiplex immunohistochemical staining on treatment-naive OC clinical specimens, we showed that PTEN reduction resulted in an immunosuppressive tumor microenvironment associated with upregulated B7H3. Mechanistically, PTEN depletion activates mTORC2, which phosphorylates FOXO1/3, thereby inhibiting their transcriptional activity and reducing MXI1 expression. This, in turn, diminishes the inhibitory effect on c-Myc, leading to enhanced c-Myc transcriptional activity and subsequent upregulation of B7H3. Notably, in mouse models, anti-B7H3 therapy exhibits heightened effectiveness in OC with PTEN loss. This enhanced response can be abrogated by removing CD8+ T cells. Our findings elucidate an immune evasion mechanism in PTEN-loss OC and suggest B
Transcriptomic identification of CREB1 and FOXO1 activation in neuregulin-1-mediated neuroprotection after str… MEDIUM▼
INTRODUCTION: Neuregulin-1 (NRG-1) is a growth factor that has been investigated for its neuroprotective properties following ischemic stroke. While NRG-1 has shown considerable promise in reducing neuronal damage, the molecular mechanisms underlying its protective effects remain unclear. This study aimed to examine the impact of NRG-1 treatment on ischemia-induced gene expression following permanent middle cerebral artery occlusion (MCAO) in rats. METHODS: Rats were treated with either NRG-1 or vehicle then sacrificed 3 and 12 h after permanent MCAO. RNA isolated from the peri-infarct cortex (ischemic penumbra) was hybridized to an Affymetrix Rat Genome 2.0 ST Microarray Gene Chip. Gene expression was analyzed using the Affymetrix Transcriptome Analysis Console (TAC) 4.0 software and the STRING Protein-Protein Interaction Networks database. RESULTS: NRG-1 treatment upregulated transcriptional programs promoting cell survival and anti-inflammatory signaling. CREB1 and FOXO1 transcripti
Mitogen-activated protein kinase (MAPK) phosphatases [MKPs, also known as dual-specificity phosphatases (DUSPs)] regulate MAPKs -key mediators of cellular processes such as proliferation, differentiation, and survival- by dephosphorylating the threonine and tyrosine residues required for MAPK activation. MKP-3/DUSP6 is an ERK-selective phosphatase that has also been reported to regulate the transcription factor FOXO1. The full-length MKP-3 transcript has been shown to encode the MKP-3L protein, whereas alternative splicing gives rise to the shorter isoform MKP-3S. However, the available information regarding the functional differences between these variants is limited. By combining biochemical and bioinformatic approaches, we demonstrate that these isoforms differ significantly in subcellular localization and enzymatic activity. Structural analysis and molecular docking reveal that while MKP-3S retains functional binding domains and recognizes ERK2 similarly to the full-length isoform.
Effects of Vitamin A Restriction on Carcass Characteristics, Antioxidant Capacity, Meat Quality and Meat Stora… MEDIUM▼
OBJECTIVE: To determine how dietary vitamin A (VA) level and duration affect intramuscular fat (IMF), meat quality, storage stability, and antioxidant gene expression in Yanbian yellow cattle. METHODS: Twenty 15-month-old Yanbian yellow cattle (314.13 ± 13.30 kg) were assigned to five treatments: CON (supplemental VA 2200 IU/kg DM), NVA1 (0 IU/kg DM supplemental VA for 180 d), NVA2 (0 IU/kg DM supplemental VA for 240 d), LVA1 (supplemental VA 1100 IU/kg DM for 180 d) and LVA2 (supplemental VA 1100 IU/kg DM for 240 d). Growth performance, carcass traits, physicochemical characteristics, and storage stability were measured. Serum biochemical and muscle antioxidant indexes were analyzed, and the mRNA expression of antioxidant-related genes (FOXO1, GSTA1, SOD) was quantified by qPCR. Statistical significance was set at p < 0.05. RESULTS: All VA-restricted groups showed higher IMF, marbling score, and lower muscle fiber diameter, drip loss, and shear force than the CON group (p < 0.05). Ser
Demonstrates FOXO1 pathway activation by melatonin, suggesting potential mechanism for transcriptional regulat… MEDIUM▼
Melatonin, a signaling molecule secreted by the pineal gland, is closely associated with physiological activities, such as animal growth, development, and reproduction. Multiple studies have indicated that melatonin acts on the adenohypophysis to promote the synthesis and secretion of growth hormone (GH), but the specific mechanism of melatonin remains unclear. We have previously reported that melatonin levels in bovine serum are closely correlated with GH levels. In the present study, transcrip
Shows FoxO1 activation can enhance antitumor activity, supporting the hypothesis of FOXO1's role in cellular q… MEDIUM▼
Although phosphoinositide 3-kinase-δ (PI3Kδ) inhibition demonstrates efficacy in relapsed/refractory follicular lymphoma (FL), its clinical benefit is often limited by adaptive resistance, underscoring the need for rational combination strategies. Here, we show that combining the PI3Kδ inhibitor linperlisib with the pan-peroxisome proliferator-activated receptor (PPAR) agonist chiglitazar, an agent that reprograms tumor metabolism, delivers robust antitumor activity across FL models, including c
Highlights FOXO1 signaling in muscle atrophy, indicating its broader role in cellular stress response and prot… MEDIUM▼
Sarcopenia is highly prevalent in individuals with diabetes and is associated with impaired physical function and increased mortality. Diabetes-associated skeletal muscle atrophy is driven by chronic inflammation, dysregulated anabolic-catabolic signaling, and activation of ubiquitin-proteasome-mediated protein degradation. Emerging evidence suggests that histone deacetylases (HDACs) act as epigenetic regulators of metabolic and inflammatory pathways; however, their role in diabetic sarcopenia r
Demonstrates FOXO1 geroprotective pathway restoration in aging, directly supporting the hypothesis of FOXO1's … MEDIUM▼
Aging of the male reproductive system is characterized by declining fertility, with epididymal dysfunction being a critical yet poorly understood contributor. Through a multimodal analysis in non-human primates that integrated histology and transcriptomics, we delineated a coherent epididymal aging phenotype encompassing epithelial senescence, chronic inflammation, fibrosis, and functional decline. Single-nucleus transcriptomics revealed principal cells (PCs) as the predominant and most transcri
Combining network pharmacology and multi-omics reveals the role of Shengdihuang-Huangqi herb pair in alleviati…▼
Comparative transcriptomics of adherent and suspension chicken fibroblast cell lines for the optimization of c…▼
Clinical and immunological significance of FOXO1 as a biomarker of improved response to immune checkpoint plus…▼
Metformin attenuates TBHP-induced oxidative injury in human lens epithelial cells and is associated with SIRT1…▼
Loss of FoxO in skeletal muscle leads to disrupted muscle metabolism and exacerbates starvation-induced hepati…▼
✗ Opposing Evidence 11
Hepatocyte FoxO1 Deficiency Protects From Liver Fibrosis via Reducing Inflammation and TGF-β1-mediated HSC Act… HIGH▼
BACKGROUND & AIMS: The O-class of the forkhead transcription factor FoxO1 is a crucial factor mediating insulin→PI3K→Akt signaling and governs diverse cellular processes. However, the role of hepatocyte FoxO1 in liver fibrosis has not been well-established. In his study, we investigated the role of hepatocyte FoxO1 in liver fibrosis and uncovered the underlying mechanisms. METHODS: Liver fibrosis was established by carbon tetrachloride (CCL4) administration and compared between liver-specific deletion of FoxO1 deletion (F1KO) and control (CNTR) mice. Using genetic and bioinformatic strategies in vitro and in vivo, the role of hepatic FoxO1 in liver fibrosis and associated mechanisms was established. RESULTS: Increased FoxO1 expression and FoxO1 signaling activation were observed in CCL4-induced fibrosis. Hepatic FoxO1 deletion largely attenuated CCL4-induced liver injury and fibrosis compared with CNTR mice. F1KO mice showed ameliorated CCL4-induced hepatic inflammation and decreased T
Cinobufagin induces FOXO1-regulated apoptosis, proliferation, migration, and invasion by inhibiting G9a in non… MEDIUM▼
ETHNOPHARMACOLOGICAL RELEVANCE: Bufonis (VB), an animal drug called Chansu in China, is the product of the secretion of Bufo gargarizans Cantor or B. melanostictus Schneider. As a traditional Chinese medicine (TCM) for a long time, it has been widely used in the treatment of heart failure, ulcer, pain, and various cancers. Cinobufaginn (CNB), the cardiotonic steroid or bufalene lactone extracted from VB, has the effects of detoxification, detumescence, and analgesia. AIM OF THE STUDY: The present study aimed to define the effects of CNB on non-small-cell lung cancer (NSCLC) and identify the potential molecular mechanisms. MATERIALS AND METHODS: A549 cells were treated with cinobufagin and cell viability, apoptosis, migration, and invasion were then evaluated using Cell Counting Kit-8 (CCK8) assays, flow cytometry, and Transwell assays, respectively. Moreover, the levels of proliferating cell nuclear antigen (PCNA), cytokeratin8 (CK8), poly ADP-ribose polymerase (PARP), Caspase3, Caspas
Constitutive TFEB nuclear localization promotes cellular senescence via mTORC1 suppression in post-mitotic neu… MEDIUM▼
BACKGROUND: Patients receiving home parenteral nutrition (HPN) are at high-risk for central line-associated bloodstream infections (CLABSI). There are no published management guidelines, however, for the antibiotic treatment of suspected CLABSI in this population. Historical microbiology data may help inform empiric antimicrobial regimens in this population. OBJECTIVE: The aim of the study was to describe antimicrobial resistance patterns and determine the most appropriate empiric antibiotic therapy in HPN-dependent children experiencing a community-acquired CLABSI. METHODS: Single-center retrospective cohort study evaluating potential coverage of empiric antibiotic regimens in children on HPN who developed a community-acquired CLABSI. RESULTS: From October 1, 2011 to September 30, 2017, there were 309 CLABSI episodes among 90 HPN-dependent children with median age 3.8 years old.Fifty-nine percent of patients carried the diagnosis of surgical short bowel syndrome. Organisms isolated du
Autophagy upregulation without matching lysosomal capacity leads to autophagic vacuole accumulation and parado… HIGH▼
RATIONALE: Neurofibromatosis type 1 (NF1) is a hereditary disease characterized by café-au-lait spots, peripheral neurofibromas, Lisch nodules, optic nerve glioma, and sphenoid wing dysplasia. Pulsating proptosis is associated with a sphenoid bony defect. Heavy eye syndrome is characterized by acquired esohypotropia in patients with high myopia. This study aimed to describe the presentation of pulsating proptosis and heavy eye syndrome precipitated by NF1 and its management. PATIENT CONCERNS: A 41-year-old woman presented with progressive pulsating proptosis and hypodeviation of the right eye over the past 2 years. The axial length of the right eye was 36.81 mm. The right eye presented with esohypotropia and hypoglobus. The ocular motility examination showed limitations in all directions, especially in supraduction. Brain computed tomography revealed sphenoid wing dysplasia of the right orbit. The meningocele protruded through the orbital defect, lifting the globe. Brain magnetic reson
TFEB-driven lysosome biogenesis increases cathepsin release during membrane permeabilization events, exacerbat… MEDIUM▼
OBJECTIVES: To determine if a simulated medical information system can improve the level of understanding of healthcare information technology students. METHODS: The study involved 40 healthcare information technology students. All the students took the healthcare information technology course using the simulated medical information system. The primary outcome was a measure of their level of understanding assessed with a questionnaire using a five-point Likert-type scale. The questions were all included in the required knowledge for the Specific Behavioral Objectives for Healthcare Information Technologists (2016) and Senior Healthcare Information Technologists (ver. 1.1, 2017). To measure the level of understanding, median with 10th-90th percentile CI values for both sets of questionnaires were calculated for all the students. The Wilcoxon signed-rank test was used to compare level of understanding before and after the training. RESULTS: Some students were excluded because they failed
Autophagy-lysosome pathway components show cell-type-specific regulation; astrocytic TFEB activation may compe… MEDIUM▼
PURPOSE: Unlike children with ALL who receive cancer care primarily at specialized cancer centers (SCCs; National Cancer Institute and/or Children's Oncology Group centers), adolescents and young adults (AYAs; 15-39 years) receive care in a variety of settings. Using population-based data, we describe where AYAs with ALL receive treatment and determine associations with overall survival (OS). METHODS: Data from the 2004 to 2018 California (CA, n = 2,283), New York (NY, n = 795), and Texas (TX, n = 955) state cancer registries were used to identify treatment setting of AYAs with newly diagnosed ALL. Multivariable Cox proportional hazards regression models evaluated associations with OS. RESULTS: Seventy percent were older than 18 years, and 65% were male. A majority in CA (63%) and TX (64%) were Hispanic while most in NY were non-Hispanic White (50%). Treatment at an SCC occurred in 48.2% (CA), 44.4% (NY), and 19.5% (TX). Across states, AYAs who were older or uninsured were less likely
Phase I trial of hydroxamic acid TFEB activator halted due to hepatotoxicity at efficacious doses, highlightin… HIGH▼
The presence of levofloxacin (LEV) in aqueous solutions can pose health risks to humans, have adverse effects on aquatic organisms and ecosystems, and contribute to the development of antibiotic-resistant bacteria. This study aims to investigate the feasibility of using electrocoagulation residuals (ECRs) as a heterogeneous catalyst in the electro-Fenton process for degrading LEV. By combining electrocoagulation residuals with sodium alginate, ECRs-alginate beads were synthesized as a heterogeneous electro-Fenton composite. The response surface method was employed to investigate the optimization and influence of various operating parameters such as the initial concentration of LEV (10-50 mg/L), voltage (15-35 V), pH (3-9), and catalyst dose (1-9 g/L). The successful incorporation of iron and other metals into the ECRs-alginate beads was confirmed by characterization tests such as EDX and FTIR. By conducting a batch reaction under optimal conditions (initial LEV concentration = 20 mg/L,
During the past decade, an abundance of new evidence highlighted the importance of inflammation in the development of chronic pathologies such as neurodegeneration, cancer, diabetes, cardiovascular disease and inflammatory bowel disease. However, most of the current therapies do not address the underlying problem and better therapies are urgently needed. A growing number of researchers have discovered various signaling pathways that are associated with the initiation and progression of inflammation. Among different pathways, we will focus on three classical inflammatory pathways: p38 MAPK, IL-6/JAK/STAT3 and PI3K; and a non-classical inflammatory pathway, the Hippo. Recently, the Hippo pathway has been linked to various inflammatory modulators such as FoxO1/3, TNFα, IL-6, COX2, HIF-1α, AP-1, JAK and STAT. In this review, the molecular mechanisms, associated pathologies and selected drugs (both preclinical and clinical) of these signaling pathways will be summarized. Finally, limitation
The constant increase in the elderly population presents significant challenges in addressing new social, economic, and health problems concerning this population. With respect to health, aging is a primary risk factor for age-related diseases, which are driven by interconnected molecular hallmarks that influence the development of these diseases. One of the main mechanisms that has attracted more attention to aging is autophagy, a catabolic process that removes and recycles damaged or dysfunctional cell components to preserve cell viability. The autophagy process can be induced or deregulated in response to a wide range of internal or external stimuli, such as starvation, oxidative stress, hypoxia, damaged organelles, infectious pathogens, and aging. Natural compounds that promote the stimulation of autophagy regulatory pathways, such as mTOR, FoxO1/3, AMPK, and Sirt1, lead to increased levels of essential proteins such as Beclin-1 and LC3, as well as a decrease in p62. These changes
Lipophagy, the selective autophagic degradation of lipid droplets (LDs), is a key mechanism for lipid homeostasis and cellular adaptation to metabolic and stress conditions. In mammals, lipophagy is governed by signaling pathways, LD-associated receptors (e.g. SQSTM1/p62, NBR1, OPTN, SPART, OSBPL8, DDHD2, VPS4A, ATG14, and TP53INP2), and transcription factors (TFEB, TFE3, FOXO1, PPARA, PPARG, and SREBF1/SREBP1) that coordinate LD recognition, sequestration, and lysosomal degradation. Dysregulated lipophagy contributes to the pathogenesis of metabolic and age-related diseases, including metabolic dysfunction-associated steatotic liver disease/nonalcoholic fatty liver disease (MASLD/NAFLD), alcoholic liver disease, diabetes, atherosclerosis, neurodegeneration and cancer. Several recent reviews have discussed lipophagy from different angles, including its roles in metabolic disorders, central nervous system diseases, and fundamental mechanisms across species. In contrast, this review focu
This review explores the multifaceted impact of physical exercise on FoxO signaling pathways, which play a central role in cellular homeostasis, stress response, metabolism, and longevity. Exercise influences FoxO proteins-particularly FoxO1, FoxO3, FoxO4, and FoxO6-through diverse mechanisms, including phosphorylation, acetylation, and ubiquitination, determining their localization, transcriptional activity, and stability. Regular exercise modulates FoxO signaling by activating pathways like PI3K/AKT, AMPK, SIRT1, and IGF-1, promoting cellular resilience against oxidative stress, apoptosis, and metabolic dysfunction. The review highlights how exercise-induced modulation of FoxO pathways contributes to improved insulin sensitivity, muscle hypertrophy, cardiovascular health, neuroprotection, and reduced risks of chronic diseases, including metabolic syndrome, neurodegeneration, cardiovascular disease, and cancer. Additionally, it addresses the role of exercise in preventing muscle atrop
🧬 Theorist Proposes novel mechanisms and generates creative hypotheses ▼
Novel Therapeutic Hypotheses for Autophagy-Lysosome Dysfunction in Neurodegeneration
1. Lysosomal Calcium Channel Modulation Therapy
Description: TRPML1 (mucolipin-1) calcium channels regulate lysosomal biogenesis and autophagosome-lysosome fusion. Pharmacological enhancement of TRPML1 activity could restore lysosomal function across multiple NDDs by promoting calcium-dependent lysosomal exocytosis and reformation.Target: MCOLN1 (TRPML1 channel)
Supporting Evidence: TRPML1 mutations cause mucolipidosis IV with neurodegeneration (PMID: 12023275). TRPML1 activation rescues l
🔍 Skeptic Identifies weaknesses, alternative explanations, and methodological concerns ▼
I'll provide a rigorous critique of each hypothesis, identifying key weaknesses and alternative explanations.
1. Lysosomal Calcium Channel Modulation Therapy (TRPML1)
Specific Weaknesses:
- Selectivity issues: TRPML1 activation would affect all cell types, potentially causing off-target cardiac and smooth muscle effects given calcium's universal signaling role
- Dose-response complexity: The evidence shows TRPML1 mutations cause disease, but this doesn't validate that enhancement is therapeutic - calcium homeostasis has narrow optimal ranges
- Limited mechanistic depth
🎯 Domain Expert Assesses practical feasibility, druggability, and clinical translation ▼
Practical Feasibility Assessment
I'll evaluate each hypothesis through the lens of drug development reality, focusing on druggability, existing chemical matter, and commercial viability.
1. TRPML1 Channel Modulation - MODERATE FEASIBILITY
Druggability Assessment
Target Class: Ion channel - historically druggable but challenging for selectivity Chemical Matter:- ML-SA1 (synthetic agonist, Sigma-Aldrich): Proof-of-concept but poor selectivity, CNS penetration unknown
- SN-2 (natural product derivative): Better selectivity but limited availability
- **Curcumin analog
⚖ Synthesizer Integrates perspectives and produces final ranked assessments ▼
Price History
| Event | Price | Change | Source | Time | |
|---|---|---|---|---|---|
| ⚖ | Recalibrated | $0.660 | ▲ 0.5% | market_dynamics | 2026-04-13 03:33 |
| 📄 | New Evidence | $0.657 | ▲ 0.8% | evidence_batch_update | 2026-04-13 02:18 |
| 📄 | New Evidence | $0.652 | ▲ 0.9% | evidence_batch_update | 2026-04-13 02:18 |
| ⚖ | Recalibrated | $0.646 | ▲ 0.2% | 2026-04-12 18:34 | |
| ⚖ | Recalibrated | $0.644 | ▲ 0.3% | 2026-04-12 10:15 | |
| ⚖ | Recalibrated | $0.642 | ▲ 0.6% | 2026-04-12 07:19 | |
| ⚖ | Recalibrated | $0.639 | ▼ 2.9% | 2026-04-12 05:13 | |
| ⚖ | Recalibrated | $0.658 | ▼ 0.4% | 2026-04-10 15:58 | |
| ⚖ | Recalibrated | $0.661 | ▲ 0.5% | 2026-04-10 15:53 | |
| ⚖ | Recalibrated | $0.658 | ▲ 2.7% | 2026-04-08 22:18 | |
| ⚖ | Recalibrated | $0.640 | ▲ 0.5% | 2026-04-08 18:39 | |
| ⚖ | Recalibrated | $0.637 | ▲ 2.2% | 2026-04-06 04:04 | |
| ⚖ | Recalibrated | $0.623 | ▼ 0.5% | 2026-04-04 16:38 | |
| ⚖ | Recalibrated | $0.626 | ▼ 0.6% | 2026-04-04 16:02 | |
| 📄 | New Evidence | $0.630 | ▲ 0.9% | evidence_batch_update | 2026-04-04 09:08 |
Clinical Trials (3) Relevance: 4%
Active
Completed
Total Enrolled
📚 Cited Papers (96)
📓 Linked Notebooks (1)
Wiki Pages
KG Entities (49)
Dependency Graph (2 upstream, 4 downstream)
Linked Experiments (8)
Related Hypotheses
Estimated Development
🧪 Falsifiable Predictions (7)
Knowledge Subgraph (130 edges)
associated with (7)
co associated with (21)
component of (1)
dysfunction causes (1)
encodes (6)
implicated in (7)
interacts with (1)
mediates (4)
participates in (7)
promoted: Transcriptional Autophagy-Lysosome Coupling (1)
promotes nuclear translocation (1)
Mechanism Pathway for FOXO1
Molecular pathway showing key causal relationships underlying this hypothesis
graph TD
FOXO1["FOXO1"] -->|encodes| FOXO1_protein["FOXO1_protein"]
FOXO1_protein_1["FOXO1_protein"] -->|regulates| autophagy_pathway["autophagy_pathway"]
FOXO1_protein_2["FOXO1_protein"] -->|promotes nuclear t| TFEB["TFEB"]
FOXO1_3["FOXO1"] -->|associated with| neurodegeneration["neurodegeneration"]
FOXO1_4["FOXO1"] -->|promoted: Transcri| neurodegeneration_5["neurodegeneration"]
FOXO1_6["FOXO1"] -->|participates in| Autophagy_lysosome_pathwa["Autophagy-lysosome pathway"]
STX17["STX17"] -->|co discussed| FOXO1_7["FOXO1"]
CHMP2B["CHMP2B"] -->|co discussed| FOXO1_8["FOXO1"]
LAMP1["LAMP1"] -->|co discussed| FOXO1_9["FOXO1"]
MCOLN1["MCOLN1"] -->|co discussed| FOXO1_10["FOXO1"]
FOXO1_11["FOXO1"] -->|co discussed| IGF2R["IGF2R"]
FOXO1_12["FOXO1"] -->|co discussed| RAB7A["RAB7A"]
IGF2R_13["IGF2R"] -->|co discussed| FOXO1_14["FOXO1"]
FOXO1_15["FOXO1"] -->|co discussed| CHMP2B_16["CHMP2B"]
FOXO1_17["FOXO1"] -->|co discussed| LAMP1_18["LAMP1"]
style FOXO1 fill:#ce93d8,stroke:#333,color:#000
style FOXO1_protein fill:#4fc3f7,stroke:#333,color:#000
style FOXO1_protein_1 fill:#4fc3f7,stroke:#333,color:#000
style autophagy_pathway fill:#81c784,stroke:#333,color:#000
style FOXO1_protein_2 fill:#4fc3f7,stroke:#333,color:#000
style TFEB fill:#4fc3f7,stroke:#333,color:#000
style FOXO1_3 fill:#ce93d8,stroke:#333,color:#000
style neurodegeneration fill:#ef5350,stroke:#333,color:#000
style FOXO1_4 fill:#ce93d8,stroke:#333,color:#000
style neurodegeneration_5 fill:#ef5350,stroke:#333,color:#000
style FOXO1_6 fill:#ce93d8,stroke:#333,color:#000
style Autophagy_lysosome_pathwa fill:#81c784,stroke:#333,color:#000
style STX17 fill:#ce93d8,stroke:#333,color:#000
style FOXO1_7 fill:#ce93d8,stroke:#333,color:#000
style CHMP2B fill:#ce93d8,stroke:#333,color:#000
style FOXO1_8 fill:#ce93d8,stroke:#333,color:#000
style LAMP1 fill:#ce93d8,stroke:#333,color:#000
style FOXO1_9 fill:#ce93d8,stroke:#333,color:#000
style MCOLN1 fill:#ce93d8,stroke:#333,color:#000
style FOXO1_10 fill:#ce93d8,stroke:#333,color:#000
style FOXO1_11 fill:#ce93d8,stroke:#333,color:#000
style IGF2R fill:#ce93d8,stroke:#333,color:#000
style FOXO1_12 fill:#ce93d8,stroke:#333,color:#000
style RAB7A fill:#ce93d8,stroke:#333,color:#000
style IGF2R_13 fill:#ce93d8,stroke:#333,color:#000
style FOXO1_14 fill:#ce93d8,stroke:#333,color:#000
style FOXO1_15 fill:#ce93d8,stroke:#333,color:#000
style CHMP2B_16 fill:#ce93d8,stroke:#333,color:#000
style FOXO1_17 fill:#ce93d8,stroke:#333,color:#000
style LAMP1_18 fill:#ce93d8,stroke:#333,color:#000
3D Protein Structure
🧬 FOXO1 — PDB 3CO6 Click to expand 3D viewer
Source Analysis
Autophagy-lysosome pathway convergence across neurodegenerative diseases
neurodegeneration | 2026-04-01 | completed