mTOR Signaling Research Articles

Effect of spermidine intake on skeletal muscle regeneration after chemical injury in male mice.

Skeletal muscle has a high regenerative ability and maintains homeostasis by rapidly regenerating from frequent damage caused by intense exercise or trauma. In sports, skeletal muscle damage occurs frequently due to intense exercise, so practical methods to promote skeletal muscle regeneration are required. Recent studies have shown that it may be possible to promote skeletal muscle regeneration through new pathways, such as promoting autophagy and improving mitochondrial function. Spermidine is a type of polyamine, and oral intake of spermidine promotes autophagy and improves mitochondrial function without inhibiting mTOR. Therefore, we evaluate the effects of spermidine intake on skeletal muscle regeneration after injury using a mouse model of cardiotoxin-induced muscle injury. Our results showed no significant change in skeletal muscle wet weight with spermidine intake at all time points. In addition, although spermidine intake significantly increased the mean fiber cross-sectional area 14 days after injury, these effects were not observed at other time points. In addition, we analyzed stem cells, autophagy, mTOR signaling, inflammation, and mitochondria, but no significant effects of spermidine intake were observed at almost all time points and protein expression levels. Therefore, spermidine intake does not affect skeletal muscle regeneration after chemical injury, and if there is any, it is very limited.

Propofol Ameliorates Sepsis-Induced Myocardial Dysfunction via Anti-Apoptotic, Anti-Oxidative Properties, and mTOR Signaling.

Sepsis often leads to cardiomyopathy, contributing to increased mortality rates. 2,6-Diisopropylphenol (propofol), an anesthetic, has demonstrated efficacy in protecting cardiomyocytes from cell death caused by hypoxia and reoxygenation. This study examined the effects of propofol on sepsis-associated myocardial dysfunction and explored the underlying mechanism of action. Mice and rat cardiomyocytes (H9C2 cell line) were used to establish a sepsis-induced myocardial dysfunction model. Lipopolysaccharides (LPS)-treated mice and H9C2 cells were treated with propofol, with rapamycin used for mechanistic studies in H9C2 cells. Cardiac function was evaluated by echocardiographic measurements. Heart tissues were stained with hematoxylin and eosin, and heart weight/body weight ratio along with the levels of cardiac biomarkers were measured using Enzyme Linked Immunosorbent Assay (ELISA). Activation of the mammalian target of rapamycin (mTOR) pathway was assessed by western blotting. Apoptosis in heart tissues and H9C2 cells was evaluated using Terminal deoxynucleotidyl transferase (TdT) dUTP nick end labeling (TUNEL) assay, and cell viability was quantified using Cell Counting Kit (CCK)-8 assay. Oxidative stress in H9C2 cells was assessed by measuring reactive oxygen species (ROS) levels through immunofluorescence staining and malondialdehyde (MDA) and superoxide dismutase (SOD) levels using ELISA. Propofol reversed LPS-induced myocardial changes and cardiac dysfunction (p < 0.05). In mouse tissues and H9C2 cells, propofol reversed LPS-induced mTOR pathway inhibition and apoptosis (p < 0.001). Moreover, propofol alleviated oxidative stress in LPS-treated cells. The activation of the mTOR pathway by propofol, along with its inhibitory effects on oxidative stress and apoptosis in cardiomyocytes, was negated by rapamycin (p < 0.001). Propofol ameliorates sepsis-induced myocardial dysfunction triggered by LPS through the mTOR pathway, thereby promoting antioxidative stress and reducing cell apoptosis.

Aurantio‑obtusin regulates lipogenesis and ferroptosis of liver cancer cells through inhibiting SCD1 and sensitizing RSL3.

Ferroptosis, characterized by iron‑mediated non‑apoptotic cell death and alterations in lipid redox metabolism, has emerged as a critical process implicated in various cellular functions, including cancer. Aurantio‑obtusin (AO), a bioactive compound derived from Cassiae semen (the dried mature seeds of Cassie obtusifolia L. or Cassia toral L.), has anti‑hyperlipidemic and antioxidant properties; however, to the best of our knowledge, the effect of AO on liver cancer cells remains unclear. The Cell Counting Kit‑8, EdU staining and migration assays were employed to assess the anti‑liver cancer activity of AO. Intracellular levels of glutathione peroxidase 4 protein and lipid peroxidation were measured as indicators of ferroptotic status. Immunohistochemical analyses, bioinformatics analyses and western blotting were conducted to evaluate the potential of stearoyl‑CoA desaturase 1 (SCD1) in combination with ferroptosis inducers for the personalized treatment of liver cancer. The present study revealed that AO significantly inhibited the proliferation of liver cancer cells in vitro and in vivo. Mechanistically, AO inhibited AKT/mammalian target of rapamycin (mTOR) signaling, suppressed sterol regulatory element‑binding protein 1 (SREBP1) expression, and downregulated fatty acid synthase expression, thereby inhibiting de novo fatty acid synthesis. Further investigations demonstrated that AO suppressed glutathione peroxidase 4 protein expression through the nuclear factor erythroid 2‑related factor 2/heme oxygenase‑1 pathway, induced ferroptosis in liver cancer cells, and simultaneously inhibited lipogenesis by suppressing SCD1 expression through the AKT/mTOR/SREBP1 pathway. Consequently, this increased the sensitivity of liver cancer cells to the ferroptosis inducer RSL3. Additionally, the enhanced effects of AO and RSL3, which resulted in significant tumor suppression, were confirmed in a xenograft mouse model. In conclusion, the present study demonstrated that AO induced ferroptosis, downregulated the expression of SCD1 and enhanced the sensitivity of liver cancer cells to the ferroptosis inducer RSL3. The synergistic use of AO and a ferroptosis inducer may have promising therapeutic effects in liver cancer cells.

Shisandra Decoction Alleviates Parkinson's Disease Symptoms in a Mouse Model Through PI3K/AKT/mTOR Signalling Pathway.

The present study aimed to characterize neuroprotective effects of Schisandra Decoction (Sch D) treatment in a mouse model of Parkinson's disease (PD), and to explore underlying mechanisms focused on the mammalian target of rapamycin (mTOR) signaling pathway. 50 male C57 BL/6 mice were randomly assigned to either control (n = 10) or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model (n = 40) groups. PD mice were further divided into four groups of ten mice each: MPTP group, LY294002 group, Sch D group, and LY2940002 + Sch D group. Mice from each group were assessed in pole climbing, rotary rod and open field tests. Brain Tyrosine hydroxylase (TH) protein was observed using immunohistochemistry. mRNA levels of PTEN, PI3K and LC3 in brain tissue were measured using RT-PCR. Protein levels of PTEN, PI3K, Akt, p-Akt, mTOR, p-mTOR, p70s6K, p62, LC3II / I, α-synuclein (α-syn), TH in brain tissue were assessed by Western blotting (WB). In behavioral tests, PD mice treated with Sch D showed reduced pole climbing time, longer rotarod duration, and greater distance traveled. In terms of neuroprotection, PD mice in the Sch D group exhibited higher levels of TH protein and enhanced α-syn clearance. Regarding autophagy, compared to the control group, mice in the MPTP group had elevated PTEN protein expression, which inhibited PI3K, p-AKT/AKT, and p-mTOR/mTOR protein levels, decreased LC3II/I protein expression, and increased P62 protein expression. Treatment with Sch D reversed these effects. Sch D reduces α-syn aggregation in the brains of MPTP-induced PD model mice, exerts neuroprotective effects, and improves motor function. Additionally, Sch D inhibits autophagy through the PI3K/AKT/mTOR pathway. The neuroprotective effect of Sch D may involve the suppression of abnormal autophagy and its antioxidant properties, which indirectly reduces α-syn accumulation. Future studies should assess the impact of Sch D on oxidative stress markers to evaluate its antioxidant effects.

Electroacupuncture inhibits hippocampal oxidative stress and autophagy in sleep-deprived rats through the protein kinase B and mechanistic target of rapamycin signaling pathway.

To investigate the effects of acupuncture on learning and memory impairment, oxidative stress and autophagy induced by sleep depriv ation in rats, and to analyze the related mechanism. Thirty Wistar rats were randomly divided into a normal group, sleep deprivation group and acupuncture group. The rat model of sleep deprivation was established by a modified multiplatform sleep deprivation method. The Baihui (GV20), Shenmen (HT7) and Sanyinjiao (SP6) acupoints of rats were located to give electroacupuncture (density wave, frequency 20 Hz, intensity 1 mA) to maintain the needle feeling, and to keep the needle for 15 min and continuous acupuncture for 7 d. The spatial learning and memory abilities of the rats were detected by the water maze test. The content of malondialdehyde (MDA) and the activities of superoxide dismutase (SOD) and glutathione peroxidase (GPX) in the brain were detected by an assay kit, and the autophagy related proteins light chain 3 alpha (LC3A), light chain 3 beta (LC3B) and Beclin 1 and the activation of the protein kinase B (PKB/AKT) and mechanistic target of rapamycin (mTOR) signaling pathway in the rat's brain were detected by Western blotting. Compared with the normal group, the time spent in the target quadrant (P < 0.05) and the number of times entering the target quadrant (P < 0.05) in the rats of sleep deprivation group were significantly reduced, and the content of MDA was significantly increased (P < 0.01), while the activities of SOD and GPX (P < 0.01) in the brain were significantly decreased, and LC3A Ⅱ/Ⅰ, LC3B Ⅱ/Ⅰ and Beclin 1 increased significantly (P < 0.01), while p-AKT (ser473)/AKT, p-mTOR (ser2448)/mTOR and p-p70s6K (thr389)/p70S6 decreased significantly (P < 0.01). Compared with the sleep deprivation group, the time spent in the target quadrant and the times of entering the target quadrant (P < 0.05) in the rats of acupuncture group after 7 d of treatment were significantly increased, Additionally, the content of MDA was significantly decreased (P < 0.05), while the activities of SOD and GPX (P < 0.05) in the brain were significantly increased. Moreover, the levels of LC3A Ⅱ/Ⅰ, LC3BⅡ/Ⅰ and Beclin 1 decreased significantly (P < 0.05), and that of p-AKT (ser473)/AKT, p-mTOR (ser2448)/mTOR and p-p70s6K (thr389)/p70s6k increased significantly (P < 0.05). Acupuncture can significantly improve the learning and memory damage caused by sleep deprivation and inhibit oxidative stress and autophagy, and its effect is related to the activation of AKT/mTOR signaling.

Role and Mechanism of mTOR Signaling Activation in Nephronophthisis Type I

Role and Mechanism of mTOR Signaling Activation in Nephronophthisis Type I

Nonylphenol displays immunotoxicity by triggering hemocyte extracellular traps in Manila clam via ROS burst, ERK pathway and glycolysis

Nonylphenol (NP), an endocrine disruptor, has been demonstrated to be a harmful environmental contaminant and toxic to organisms. In this study, to address concerns regarding the immunotoxicity of NP, we treated clam Ruditapes philippinarum hemocytes with NP in vitro and explored the underlying mechanisms of NP-induced extracellular traps (ETs). NP could induce the formation of hemocytes ETs in a dose-dependent manner. Transcriptomics analysis revealed changes of signaling pathway involved in immunity and energy metabolism in hemocytes after NP stimulation. In this process, both reactive oxygen species (ROS) and myeloperoxidase (MPO) were up-regulated. Moreover, mitogen-activated protein kinase (MAPK) signaling pathway was proved to be activated in the formation of NP-induced ETs, manifested as enhanced phosphorylation of extracellular signal-regulated kinase (ERK) but not p38 or c-Jun N-terminal kinase (JNK). In the presence of U0126, an ERK phosphorylation inhibitor, the NP-induced expression of NADPH oxidase enzyme (NOX) was significantly decreased, which further alleviated the ROS production and ultimately limited the release of ETs. NP exposure increased glucose uptake, along with enhanced activities of glycolysis-related enzymes such as hexokinase (HK) and pyruvate kinase (PK). After inhibiting glycolysis by the inhibitor 2-DG, the formation of NP-induced ETs was significantly suppressed. ERK could regulate mTOR signaling and the PI3K/AKT pathway, potentially directing ETs formation by orchestrating the glycolysis through the activation of key transcription factors c-Myc and HIF-1α. Collectively, the results preliminary confirm that the ERK-NOX-ROS axis and glycolysis are involved in NP-induced ETs formation, contributing to the cellular immunotoxicity in clam.

AKT/mTOR-mediated autophagic signaling is associated with TCDD-induced cleft palate

In utero exposure to the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) can contribute to high rates of cleft palate (CP) formation, but the mechanistic basis for these effects remains uncertain. Here, multi-omics-based metabolomic and transcriptomic analyses were employed to characterize the etiological basis for TCDD-induced CP on gestational day 14.5 (GD14.5). These analyses revealed that TCDD-induced CP formation is associated with calcium, MAPK, PI3K-Akt, and mTOR pathway signaling. PI3K-Akt and mTOR signaling activity is closely linked with the maintenance of cellular proliferation and survival. Moreover, mTOR-mediated regulation of autophagic activity is essential for ensuring an appropriate balance between metabolic activity and growth. Murine embryonic palatal mesenchymal (MEPM) cell proliferation was thus characterized, autophagic activity in these cells was evaluated through electron microscopy and western immunoblotting was used to compare the levels of autophagy- and AKT/mTOR-related protein between the control and TCDD groups on GD14.5. These analyses indicated that MEPM cell proliferative and autophagic activity was inhibited in response to TCDD exposure with the concomitant activation of AKT/mTOR signaling, in line with the multi-omics data. Together, these findings suggested that following TCDD exposure, the activation of AKT/mTOR-related autophagic signaling may play a role in the loss of appropriate palatal cell homeostasis, culminating in the incidence of CP.

Adipocyte-derived glutathione promotes obesity-related breast cancer by regulating the SCARB2-ARF1-mTORC1 complex.

Obesity is a major risk factor for poor breast cancer outcomes, but the impact of obesity-induced tumor microenvironment (TME) metabolites on breast cancer growth and metastasis remains unclear. Here, we performed TME metabolomic analysis in high-fat diet (HFD) mouse models and found that glutathione (GSH) levels were elevated in the TME of obesity-accelerated breast cancer. The deletion of glutamate-cysteine ligase catalytic subunit (GCLC), the rate-limiting enzyme in GSH biosynthesis, in adipocytes but not tumor cells reduced obesity-related tumor progression. Mechanistically, we identified that GSH entered tumor cells and directly bound to lysosomal integral membrane protein-2 (scavenger receptor class B, member 2 [SCARB2]), interfering with the interaction between its N and C termini. This, in turn, recruited mTORC1 to lysosomes through ARF1, leading to the activation of mTOR signaling. Overall, we demonstrated that GSH links obesity and breast cancer progression by acting as an activator of mTOR signaling. Targeting the GSH/SCARB2/mTOR axis could benefit breast cancer patients with obesity.

Ribosome Quality Control mitigates the cytotoxicity of ribosome collisions induced by 5-Fluorouracil.

Ribosome quality control (RQC) resolves collided ribosomes, thus preventing their cytotoxic effects. The chemotherapeutic agent 5-Fluorouracil (5FU) is best known for its misincorporation into DNA and inhibition of thymidylate synthase. However, while a major determinant of 5FU's anticancer activity is its misincorporation into RNAs, the mechanisms by which cancer cells overcome the RNA-dependent 5FU toxicity remain ill-defined. Here, we report a role for RQC in mitigating the cytotoxic effects of 5FU. We show that 5FU treatment results in rapid induction of the mTOR signalling pathway, enhanced rate of mRNA translation initiation, and increased ribosome collisions. Consistently, a defective RQC exacerbates the 5FU-induced cell death, which is mitigated by blocking mTOR pathway or mRNA translation initiation. Furthermore, 5FU treatment enhances the expression of the key RQC factors ZNF598 and GIGYF2 via an mTOR-dependent post-translational mechanism. This adaptation likely mitigates the cytotoxic consequences of increased ribosome collisions upon 5FU treatment.

Whole-Transcriptome Analysis Reveals Potential CeRNA Regulatory Mechanism in Takifugu rubripes against Cryptocaryon irritans Infection.

Cryptocaryon irritans (C. irritans) is a proto-ciliate parasite that infects marine fishes, including the cultured species Takifugu rubripes (T. rubripes), causing disease and potential mortality. In host organisms, infection by parasites triggers an immune response that is modulated by regulatory elements including proteins and non-coding RNAs. In this study, the whole transcriptome RNA sequencing of T. rubripes gill tissue before and after infection with C. irritans was performed to reveal the competitive endogenous RNA (ceRNA) regulatory network. Histomorphology revealed gill segment swelling and parasitic invasion in the infected group. The analysis identified 18 differentially expressed miRNAs (DEMs), 214 lncRNAs (DELs), 2501 genes (DEGs), and 7 circRNAs (DECs) in the infected group. Gene Ontology (GO) enrichment analysis revealed that these genes were notably enriched in the Wnt signaling pathway and mTOR signaling pathway. The co-expression networks (lncRNA/circRNA-miRNA-mRNA) were constructed based on correlation analysis of the differentially expressed RNAs. Further analysis suggested that the LOC105418663-circ_0000361-fru-miR-204a-fzd3a ceRNA axis was potentially involved in the regulation of immune responses against C. irritans infection. Finally, the expression levels of DEG, DEL, and DEM were validated. This study reveals the regulatory mechanism of a candidate ceRNA network, providing insights into the potential mechanism of T. rubripes' infection with C. irritans.

Effect and Mechanism of Uric Acid in Regulating Larval Growth and Development of Drosophila Melanogaster

Objective To explore the effect and mechanism of uric acid (UA) in regulating the larval growth and development of Drosophila melanogaster. Methods A total of 1350 newly hatched first-instar larvae of wild-type Drosophila melanogaster (W1118) were collected,and the Drosophila melanogaster model of hyperuricemia was constructed with a high purine diet.The larvae were assigned into three groups (n=150):control (standard corn meal medium),low-dose adenine (corn meal medium containing 0.05% adenine),and high-dose adenine (corn meal medium containing 0.10% adenine),and two parallel groups were set up.The growth and development of larvae in each group was observed,and the UA and hormone levels were measured.In addition,the expression levels of genes involved in growth and development were determined. Results Compared with the control group,the low- and high-dose adenine groups showed elevated UA levels (both P<0.001) and prolonged developmental period (P=0.024,P<0.001).The high-dose adenine group showed decreased survival rate,pupation rate,and eclosion rate and elevated levels of juvenile hormone (JH) and 20-hydroxyecdysone (20E) (all P<0.001).The PCR results showed that compared with the control group,high-dose adenine upregulated the mRNA levels of reactive oxygen species (ROS),forkhead box O (FOXO),and mammalian target of rapamycin (mTOR) while downregulating the mRNA levels of Sestrin,mTOR complex 1(mTORC1),and AMP-activated protein kinase (all P<0.001). Conclusion High concentrations of UA may promote the expression of ROS/FOXO/mTORC1/mTOR signaling pathway by regulating the levels of JH and 20E,thereby inhibiting the larval growth and development of Drosophila melanogaster.

Integrated metagenomics and metabolomics analyses revealed biomarkers in β-casein A2A2-type cows.

In Holstein cows, β-casein, one of the most critical proteins in milk, exists in two main genotypes, A1 and A2. Herein, 45 Holstein cows [categorized into three groups based on β-casein A1A1, A1A2, and A2A2 genotypes (N = 15)] with the same feeding management and litter size were enrolled to explore differences in rumen microflora and metabolites across various β-casein genotypes. Rumen fluids were collected for metagenomics and metabolomics analyses. Metabolomics and weighted gene co-expression network analysis (WGCNA) revealed that arachidonic acid (AA), adrenic acid (AdA), glycocholic acid (GCA), and taurocholic acid (TCA) were significantly and positively correlated with milk fat % in dairy cows (p < 0.05). Furthermore, macro-genomics and Spearman's correlation analysis revealed significant positive correlations (p < 0.05) between the characteristic flora (g_Acetobacter, g_Pseudoxanthomonas, g_Streptococcus, and g_Pediococcus) and the five characteristic metabolites in the rumen of A2A2 dairy cows. Moreover, functional enrichment analysis revealed more genes enriched to the TRP channel's inflammatory mediator-regulated pathway and the mTOR signaling pathway in A2A2 genotyped cows. Additionally, the regulatory effects of AA on bovine mammary epithelial cells (BMECs) were examined using CCK-8, EdU, and qRT-PCR assays, revealing that AA promoted triglyceride (TG) synthesis and upregulated the milk fat marker genes including SREBF1, ACSS2, AGPAT6, and FASN. Overall, we identified characteristic microorganisms and metabolites in A2A2 Holstein cows and established that AA could be a biomarker for higher milk fat %.

Effects of dietary Bacillus pumilus on the growth, intestinal health, lipid metabolism, and mTOR signaling pathway of juvenile coho salmon (Oncorhynchus kisutch)

Effects of dietary Bacillus pumilus on the growth, intestinal health, lipid metabolism, and mTOR signaling pathway of juvenile coho salmon (Oncorhynchus kisutch)

388 (PB376): KO-2806, a next-generation farnesyl transferase inhibitor, re-sensitizes KRAS G12C NSCLC tumors to KRAS G12C mutant-specific inhibitors through mTOR signaling inhibition

388 (PB376): KO-2806, a next-generation farnesyl transferase inhibitor, re-sensitizes KRAS G12C NSCLC tumors to KRAS G12C mutant-specific inhibitors through mTOR signaling inhibition

Unraveling Neurodevelopmental Disorders: Signalling Pathways as Potential Targets for Therapeutic Intervention in Autism Spectrum Disorder

Introduction: Autism Spectrum Disorder (ASD) presents a multifaceted challenge with limited therapeutic options and a need for early biomarkers. Understanding disrupted signalling pathways offers promise for intervention and assessment. Methods: Literature review spanning genetic, pre-clinical, and patient studies elucidating pathways implicated in ASD pathogenesis, including melatonin, mTOR, Retinoic acid, Hedgehog, Notch and Wnt signalling. Results: Core components of key signalling pathways, such as melatonin, mTOR, Retinoic acid, Hedgehog, Notch and Wnt, are dysregulated in ASD. These pathways regulate crucial aspects of the nervous system, including immune function, neuronal growth, neurotransmission, and metabolism. Discussion: Manipulating these pathways could potentially modify ASD traits by influencing brain development and immune homeostasis. Targeting specific nodes within these pathways may offer novel therapeutic approaches for ASD management. Additionally, identifying biomarkers associated with pathway dysregulation could enable earlier diagnosis and monitoring of disease progression. Conclusion: Understanding the intricate interplay of signalling pathways in ASD pathogenesis provides insights into potential therapeutic targets and biomarkers. Further research into the manipulation of these pathways and their impact on ASD traits is warranted to advance personalized treatment strategies and improve outcomes for individuals with ASD.

LncRNA TUG1 regulates mir-34a-5p / SIRT6 to participate in benzene-induced hematotoxicity through PI3K / AKT /mTOR signaling pathway

LncRNA TUG1 plays pivotal roles in various diseases. However, its exact roles in benzene - induced hematotoxicity remain unclear. Herein, we aimed to investigate the role and mechanism of TUG1 in hematoxic injuries caused by benzene. In the current study, TUG1 was found dramatically decreased in WBCs of benzene exposure workers and negatively correlated with benzene exposure duration and urine SPMA. In vitro assays demonstrated that TUG1 overexpression attenuated 1,4-BQ-caused suppression of cell viability and proliferation, and promotion of ROS generation and apoptosis via PI3K/AKT/mTOR pathway. Bioinformatic prediction and molecular assay validated miR-34a-5p was negatively regulated by TUG1. The miR-34a-5p was upregulated in 1,4-BQ treated cells and downregulated in TUG1 overexpression cells. Moreover, miR-34a-5p upregulation partially reversed the protective effects of TUG1 overexpression on 1,4-BQ - caused cytotoxicity. Furthermore, SIRT6 was a downstream target gene of miR-34a-5p, whose expression was reduced in miR-34a-5p upregulation cells and elevated in TUG1 overexpression cells. Upregulated SIRT6 could counteract accelerated cytotoxicity mediated by miR-34a-5p upregulation after 1,4-BQ treatment. Taken together, our study revealed that the critical role of the TUG1/miR-34a-5p/SIRT6 axis in benzene-caused hematotoxicity, and provided scientific basis for further understanding the epigenetic regulatory mechanisms underlying benzene hematotoxicity.

Genomic and Transcriptomic Profile of HNF1A-Mutated Liver Adenomas Highlights Molecular Signature and Potential Therapeutic Implications.

Hepatocellular adenomas (HAs) are tumors that can develop under different conditions, including in patients harboring a germline mutation in HNF1A. However, little is known about the pathogenesis of such disease. This work aims to better define what mechanisms lie under the development of this condition. Six HAs were sampled from the liver of a 17-year-old male affected by diabetes and multiple hepatic adenomatosis harboring the heterozygous pathogenic germline variant c.815G>A, p.(Arg272His) in HNF1A, which has a dominant negative effect. All HAs were molecularly characterized. Four of them were shown to harbor a second somatic HNF1A variant and one had a mutation in the ARID1A gene, while no additional somatic changes were found in the remaining HA and normal parenchyma. A transcriptomic profile of the same HA samples was also performed. HNF1A biallelic mutations were associated with the up-regulation of several pathways including the tricarboxylic acid cycle, the metabolism of fatty acids, and mTOR signaling while angiogenesis, endothelial and vascular proliferation, cell migration/adhesion, and immune response were down-regulated. Contrariwise, in the tumor harboring the ARID1A variant, angiogenesis was up-modulated while fatty acid metabolism was down-modulated. Histological analyses confirmed the molecular data. Independently of the second mutation, energetic processes and cholesterol metabolism were up-modulated, while the immune response was down-modulated. This work provides a complete molecular signature of HNF1A-associated HAs, analyzing the association between specific HNF1A variants and the development of HA while identifying potential new therapeutic targets for non-surgical treatment.

Molecular docking and dynamics simulation of farnesol as a potential anticancer agent targeting mTOR pathway.

Farnesol is a natural acyclic sesquiterpene alcohol, found in various essential oils such as, lemon grass, citronella, tuberose, neroli, and musk. It has a molecular mass of 222.372g/mol and chemical formula of C₁₅H₂₆O. The main objective of this study was to assess the effect of farnesol on mTOR and its two downstream effectors, p70S6K and eIF4E, which are implicated in the development of cancer, via molecular dynamic simulation, and docking analysis in an in silico study. A multilayer, primarily computer-based analysis was conducted to assess farnesol's anticancer potential, with a focus on primary cancer targets. From the calculations performed, farnesol showed a binding affinity of - 9.66kcal/mol, followed by binding affinity of - 7.4kcal/mol and - 7.8kcal/mol for mTOR, p70S6K and eIF4E respectively. Rapamycin showed the binding affinity of - 10.45kcal/mol for mTOR, for p70S6K and eIF4E the calculated binding affinity was - 10.65kcal/mol and 8.16kcal/mol respectively. The binding affinity of farnesol was comparable to the standard drug rapamycin indicating its potential as an mTOR inhibitor. Molecular dynamics simulations suggest that the ligands (farnesol and rapamycin) were well trapped within the active site of the protein over a time gap of 50 ns. It is clear that farnesol showed relatively stable MD simulation results, with minor fluctuations and maintains a consistent binding orientation, suggesting a strong and stable interaction with the target proteins when compared to simulation data of standard drug. This study explores the potential of farnesol as an anticancer agent through an in-silico approach, focusing on its interaction with mTOR and its downstream effectors. Inhibition of mTOR signaling pathway may be responsible for the anticancer effect of farnesol. As this pathway plays a crucial role in cell proliferation and survival, making it a significant target in cancer research.

Targeting NCAPD2 as a Therapeutic Strategy for Crohn's Disease: Implications for Autophagy and Inflammation.

Our earlier studies identified that non-SMC condensin I complex subunit D2 (NCAPD2) induces inflammation through the IKK/NF-κB pathway in ulcerative colitis. However, its role in the development of Crohn's disease (CD) and the specific molecular mechanism still need to be further studied. NCAPD2 expression in clinical ileal CD mucosa vs normal mucosa was examined, alongside its correlation with CD patients' clinical characteristics via their medical records. The biological function and molecular mechanism of NCAPD2 in CD were explored using a 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced CD mouse model, along with immunofluorescence, western blot, quantitative real-time PCR, immunohistochemistry, hematoxylin and eosin staining, and cell functional analysis. NCAPD2 was overexpressed in CD tissues and significantly correlated with disease activity in CD patients (P = .016). In a TNBS-induced CD mouse model, NCAPD2 knockdown inhibited the development of TNBS-induced intestinal inflammation in mice. In addition, we found that NCAPD2 inhibited autophagy. Mechanistically, NCAPD2 promoted the phosphorylation of mammalian target of the rapamycin (mTOR) and its direct effector S6K and downregulated the expression of autophagy-related proteins Beclin1, LC3II, and Atg5. In addition, NCAPD2 activates the NF-κB signaling pathway, and the downstream inflammatory factors are continuously released, leading to the persistence of inflammation. Our results show that NCAPD2 suppresses autophagy and worsens intestinal inflammation by modulating mTOR signaling and impacting the NF-κB pathway, suggesting a critical role in CD progression. Targeting NCAPD2 could be a promising therapeutic approach to stop CD advancement.