The tumour suppressor Fat1 is dispensable for normal murine hematopoiesis.

Loss and overexpression of FAT1 occurs among different cancers with these divergent states equated with tumor suppressor and oncogene activity, respectively. Regarding the latter, FAT1 is highly expressed in a high proportion of human acute leukemias relative to normal blood cells, with evidence pointing to an oncogenic role. We hypothesized that this occurrence represents legacy expression of FAT1 in undefined hematopoietic precursor subsets that is sustained following transformation, predicating a role for FAT1 during normal hematopoiesis. We explored this concept by using the Vav-iCre strain to construct conditional knockout (cKO) mice where Fat1 expression was deleted at the hematopoietic stem cell stage. Extensive analysis of precursor and mature blood populations using multi-panel flow cytometry revealed no ostensible differences between Fat1 cKO mice and normal littermates. Further functional comparisons involving colony forming unit and competitive bone marrow transplantation assays support the conclusion that Fat1 is dispensable for normal murine hematopoiesis.

Efficacy and optimal combination timing of chemotherapy combined with PD-1 inhibitor in advanced cervical cancer: a multicenter retrospective cohort study.

Background: This study aimed to investigate the efficacy and safety of chemotherapy combined with programmed cell death protein 1 (PD-1) inhibitors in the treatment of advanced cervical cancer and the effect of optimal combination timing on prognosis. Methods: From March 2020 to December 2021, the clinical data of 116 patients with advanced cervical cancer who received PD-1 inhibitors combined with chemotherapy were collected. The clinical characteristics and adverse events of the patients were recorded until the cut-off date of follow-up. The primary endpoints were progression-free survival (PFS), the objective response rate (ORR), and safety; the secondary endpoints were the disease-control rate (DCR) and overall survival (OS). Multivariate Cox proportional hazards regression was used to analyze the prognostic factors affecting the PFS of patients and to assess the effect of the timing of combination therapies on PFS. Results: In total, 85 patients from 4 study centers were included in this study. The median PFS was 10.3 months [95% confidence interval (CI): 9.47-11.13 months], the ORR was 44.7%, the DCR was 75.3%, and the median OS was not reached. The multivariate Cox proportional hazards regression analysis showed that the early combination of chemotherapy with a PD-1 inhibitor provided better PFS than the late combination [hazard ratio (HR) 0.40, 95% CI: 0.24-0.67, P=0.001]. Lymph node metastasis (HR 2.04, 95% CI: 1.24-3.38, P=0.005), and previous treatment (HR 1.79, 95% CI: 1.09-3.00, P=0.023) were also independent risk factors for PFS. During the treatment and follow-up periods, the overall incidence of adverse events in this study was 56.5%, and that of grade ≥3 adverse events was 12.9%. Thrombocytopenia, neutropenia, anemia, and hypothyroidism were the main treatment-related adverse events, all of which were tolerated, and no serious adverse events leading to death were observed. There were no treatment-related deaths. Conclusions: PD-1 inhibitors combined with chemotherapy have good efficacy and controllable safety in patients with advanced cervical cancer. The early combination of PD-1 inhibitors and chemotherapy may provide better survival benefits than the late combination for patients.

The VvWRKY37 Regulates Bud Break in Grape Vine Through ABA-Mediated Signaling Pathways.

Dormancy is a common survival strategy in plants to temporarily suspend visible growth under unsuitable conditions. The elaborate mechanism underlying bud break in perennial woody plants is gradually illustrated. Here, we identified a grape vine WRKY transcription factor, VvWRKY37, which was highly expressed in dormant buds. It was particularly induced by the application of exogenous abscisic acid, and depressed on exposure to gibberellin and low temperature (4°C) stress at the transcript level. The yeast one-hybrid assay confirmed that VvWRKY37 had a transcriptional activity. Ectopic over-expression of VvWRKY37 significantly delayed bud break of transgenic poplar plants. As an ABA-inducible gene, VvWRKY37 also depressed the expression of ABA catabolic gene CYP707As and enhanced the accumulation of endogenous ABA in transgenic poplar plants. The molecular pieces of evidence showed that VvWRKY37 preferentially recognized and bound W-box 5'-G/CATTGACT/C/G-3' cis-element in vitro. Additionally, VvABI5 and VvABF2 acted as the upstream transcriptional activators of VvWRKY37 via protein-DNA interactions. Taken together, our findings provided valuable insights into a new regulatory mechanism of WRKY TF by which it modulates bud break through ABA-mediated signaling pathways.

AlepPBP2, but not AlepPBP3, may involve in the recognition of sex pheromones and maize volatiles in Athetis lepigone.

Athetis lepigone Möschler (Lepidoptera, Noctuidae) is a common maize pest in Europe and Asia. However, there is no long-term effective management strategy is available yet to suppress its population. Adults rely heavily on olfactory cues to locate their optimal host plants and oviposition sites. Pheromone-binding proteins (PBPs) are believed to be responsible for recognizing and transporting different odorant molecules to interact with receptor membrane proteins. In this study, the ligand-binding specificities of two AlepPBPs (AlepPBP2 and AlepPBP3) for sex pheromone components and host plant (maize) volatiles were measured by fluorescence ligand-binding assay. The results demonstrated that AlepPBP2 had a high affinity with two pheromones [(Z)-7-dodecenyl acetate, Ki = 1.11 ± 0.1 µM, (Z)-9-tetradecenyl acetate, Ki = 1.32 ± 0.15 µM] and ten plant volatiles, including (-)-limonene, α-pinene, myrcene, linalool, benzaldehyde, nonanal, 2-hexanone, 3-hexanone, 2-heptanone and 6-methyl-5-hepten-2-one. In contrast, we found that none of these chemicals could bind to AlepPBP3. Our results clearly show no significant differences in the functional characterization of the binding properties between AlepPBP2 and AlepPBP3 to sex pheromones and host plant volatiles. Furthermore, molecular docking was employed for further detail on some crucial amino acid residues involved in the ligand-binding of AlepPBP2. These findings will provide valuable information about the potential protein binding sites necessary for protein-ligand interactions which appear as attractive targets for the development of novel technologies and management strategies for insect pests.

Intelligently Thermoresponsive Ionic Liquid toward Molecular Firefighting and Thermal Energy Management.

Hydrocarbon-based phase change materials (PCMs) are accompanied by an inherent fire risk, which is hindering their further application especially in construction. Molecular-firefighting PCMs can be ideal and promising candidates to simultaneously ensure the highly efficient energy management and fire safety of PCMs. In this work, two novel phosphorus/nitrogen-containing ionic liquids ([DP][MI] and [DP][TEA]), composed of imidazole (MI) or triethylamine (TEA) cations and dicetyl phosphate (DP) anion, were synthesized for fire-proofing thermal energy management. The fire risk assessment confirmed that the extinguishing time of prepared [DP][MI] and [DP][TEA] was greatly shortened to 20 s and 3.5 min from 45 min for controlled sample, respectively. Moreover, the thermal enthalpy of [DP][MI] reached about 99.0 J g-1. In addition, [DP][MI] and [DP][TEA] achieved low supercooling extents of 2.2 and 4.4 °C, separately. Both molecular firefighting and efficient energy management were achieved for [DP][MI] and [DP][TEA]. As applied in wood-plastic composite which is ubiquitous in construction, [DP][TEA] endowed the composite with temperature-regulating capability of about 10 °C in hut test and remarkably suppressed fire hazard of the composite, displaying a potential application value.

Nanoflake-Constructed Supramolecular Hierarchical Porous Microspheres for Fire-Safety and Highly Efficient Thermal Energy Storage.

The leakage and fire hazard of organic solid-liquid phase change material (PCM) tremendously limit its long-term and safe application in thermal energy storage and regulation. In this work, novel nanoflake-fabricated organic-inorganic supramolecular hierarchical microspheres denoted as BPL were synthesized through the electrostatically driven assembly of poly(ethylene ammonium phenylphosphamide) (BP) decorated layered double hydroxides using sodium dodecyl sulfate as a template. Then the BPL was simultaneously utilized as a porous supporting material and flame retardant for polyethylene glycol to fabricate shape-stabilized PCM (BS-PCM). Benefiting from the structural uniqueness of the BPL microsphere, the BS-PCM possessed a high latent heat capacity of 116.7 J g-1 and excellent thermoregulatory capability. Moreover, the BS-PCM had no apparent leakage after a 200-cycle heating/cooling process and showed excellent thermal reversibility, superior to similar solid-liquid PCMs reported in recent literature. More interestingly, unlike flammable PEG, BS-PCM showed excellent fire resistance when exposed to a fire source. The unique BPL porous microsphere provided not only a microcontainer with high storage capacity for solid-liquid PCM, but also a fire resistant barrier to PEG, supplying a promising solution for highly efficient and fire-safe thermal energy storage.

Ultrasound-guided continuous thoracic paravertebral block alleviates postoperative delirium in elderly patients undergoing esophagectomy: A randomized controlled trial.

BACKGROUND: Delirium is a common postoperative complication in older patients undergoing thoracic surgery and presages poor outcomes. Postoperative pain is an important factor in the progression of delirium. The purpose of this study was to test whether continuous thoracic paravertebral block (PVB), a more effective approach for analgesia, could decrease the incidence of delirium in elderly patients undergoing esophagectomy. METHODS: A total of 180 geriatric patients undergoing esophagectomy were randomly divided into 2 groups and treated with PVB or patient-controlled analgesia (PCA). Perioperative plasma CRP, IL-1ß, IL-6, and TNF-α levels were detected in all patients. Pain intensity was measured by a numerical rating scale. Delirium was assessed using the confusion assessment method. RESULTS: The incidence of postoperative delirium was significantly lower in the PVB group than in the PCA group. Patients in the PVB group had lower plasma CRP, IL-1ß, IL-6, and TNF-α levels and less pain when coughing after surgery. CONCLUSIONS: Ultrasound-guided continuous thoracic paravertebral block improved analgesia, reduced the inflammatory reaction and decreased the occurrence of delirium after surgery.

Functional characterization of WRKY46 in grape and its putative role in the interaction between grape and phylloxera (Daktulosphaira vitifoliae).

WRKY transcription factors are involved in defense responses caused by biotic stresses. Phylloxera (Daktulosphaira vitifoliae Fitch), a pest widespread in viticulture, elicits transcriptional reprogramming of plant defense-associated components, such as regulons related to WRKYs and salicylic acid (SA) signaling. In this study, we characterized WRKY46, a WRKY transcription factor responsible for phylloxera attack, and revealed the molecular mechanism for WRKY-mediated defense responses to phylloxera. qRT-PCR and GUS staining analyses revealed that WRKY46 is induced in response to phylloxera damage and mechanical wounding. VvWRKY46 is a nuclear-localized transcription factor that activates its downstream target VvCHIB by direct protein-DNA interaction. Regulons involved in the SA-mediated defense response were regulated during incompatible interactions between "1103 Paulsen" rootstock and phylloxera. In addition, WRKY46 exhibited a higher transcript abundance in "1103 Paulsen" than in "Crimson Seedless", regardless of whether the plants were infected with phylloxera. Furthermore, the enhanced expression of VvWRKY46 significantly attenuated phylloxera attack and delayed nymph development of composite grape plants. In summary, we demonstrated that WRKY46 plays a role in the SA-mediated defense-regulatory network by directly binding to the downstream structural gene VvCHIB. The phylloxera-responsive gene WRKY46 was identified, which could improve the understanding of the basic mechanism of grapevine in response to phylloxera.

[Characteristics of soil phosphorus fractions of different vegetation types in subtropical forests and their driving factors.] / äºšçƒ­å¸¦ä¸åŒæ¤è¢«ç±»åž‹åœŸå£¤ç£·ç»„åˆ†ç‰¹å¾åŠå ¶å½±å“å› ç´ .

Soil P fraction, microbial biomass P (MBP), and activities of acid phosphomonoesterase (ACP) and phosphodiesterase (PD) were analyzed under evergreen broad-leaved forest, mixed forest and coniferous forest in Daiyun Mountains. The results showed that labile-P comprised only 1.0%-4.5% of soil total phosphorus (TP). The ratio of soil carbon to organic phosphorus (C:Po) was >200, indicating phosphorus limitation across the three vegetation types. Organic phosphorus (Po) was a significant fraction of soil P, which accounted for 44.8%-47.1% and 28.6%-30.6% of TP in A and B horizons, respectively. Results from the redundancy analysis showed that the changes in P fractions were mainly driven by PD in the A horizon and by ACP in the B horizon. Moreover, the activities of PD and ACP had a significant negative correlation with Po. The results suggested that phosphorus deficiency occurred in the three vegetation types, and that PD and ACP could play major roles in the depletion of soil Po in response to phosphorus limitation in subtropical forests.

Increased intracranial pressure in Guillain-Barré syndrome: A case report.

RATIONALE: Guillain-Barré syndrome (GBS) is an inflammatory autoimmune demyelinating polyneuropathy that affects most of the peripheral nervous system. Papilledema and raised intracranial pressure (ICP) are seen in some patients, and are thought to be associated with elevated cerebrospinal fluid (CSF) protein-though CSF protein levels are normal in some patients, thus the specific mechanisms remain unclear. Interleukin (IL)-17 levels are elevated in the CSF and plasma in GBS patients, and elevated IL-17 in the CSF of patients with idiopathic intracranial hypertension has been reported. Intravenous immunoglobulin (IVIG) exerts therapeutic effects by downregulating IL-17 in GBS patients. PATIENT CONCERNS: Herein we describe a case of a 14-year-old girl who initially presented with relapsing limb weakness. DIAGNOSES: Magnetic resonance imaging revealed an enlarged ventricle, electromyography, and nerve conduction studies were suggestive of polyradiculopathy, and lumbar puncture revealed elevated ICP with normal cells and elevated protein values. INTERVENTIONS: She was treated with IVIG 0.4 g/kg per day for 5 days. OUTCOMES: At a 6-month follow-up there had been no recurrence. LESSONS SUBSECTIONS: In GBS patients who have a relapsing course and develop papilledema with possible immunological disturbance, an accurate early diagnosis in conjunction with the prompt initiation of immunotherapy may improve clinical symptoms and the prognosis.

Urotensin II inhibitor eases neuropathic pain by suppressing the JNK/NF-κB pathway.

Urotensin II (U-II), a cyclic peptide originally isolated from the caudal neurosecretory system of fishes, can produce proinflammatory effects through its specific G protein-coupled receptor, GPR14. Neuropathic pain, a devastating disease, is related to excessive inflammation in the spinal dorsal horn. However, the relationship between U-II and neuropathic pain has not been reported. This study was designed to investigate the effect of U-II antagonist on neuropathic pain and to understand the associated mechanisms. We reported that U-II and its receptor GPR14 were persistently upregulated and activated in the dorsal horn of L4-6 spinal cord segments after chronic constriction injury (CCI) in rats. Intrathecal injection of SB657510, a specific antagonist against U-II, reversed CCI-induced thermal hyperalgesia and mechanical allodynia. Furthermore, we found that SB657510 reduced the expression of phosphorylated c-Jun N-terminal kinase (p-JNK) and nuclear factor-κB (NF-κB) p65 as well as subsequent secretion of interleukin-1ß (IL-1ß), IL-6 and tumor necrosis factor-α (TNF-α). It was also showed that both the JNK inhibitor SP600125 and the NF-κB inhibitor PDTC significantly attenuated thermal hyperalgesia and mechanical allodynia in CCI rats. Our present research showed that U-II receptor antagonist alleviated neuropathic pain possibly through the suppression of the JNK/NF-κB pathway in CCI rats, which will contribute to the better understanding of function of U-II and pathogenesis of neuropathic pain.

Propofol Inhibits Lipopolysaccharide-Induced Inflammatory Responses in Spinal Astrocytes via the Toll-Like Receptor 4/MyD88-Dependent Nuclear Factor-κB, Extracellular Signal-Regulated Protein Kinases1/2, and p38 Mitogen-Activated Protein Kinase Pathways.

BACKGROUND: In this study, we investigated the effect of propofol, a commonly used IV anesthetic, on lipopolysaccharide (LPS)-induced inflammatory responses in astrocytes and explored the molecular mechanisms by which it occurs. METHODS: Astrocytes were stimulated with LPS (1.0 µg/mL) in the absence and presence of different concentrations of propofol. The expression of astrocyte marker glial fibrillary acidic protein (GFAP) in astrocytes was detected using immunofluorescence staining and Western blot analysis. The levels of interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α were measured using an enzyme-linked immunosorbent assay. The mRNA level of Toll-like receptor 4 (TLR4) was determined by semiquantitative reverse transcriptase-polymerase chain reaction. The protein expressions of TLR4, myeloid differentiation factor 88 (MyD88), p- extracellular signal-regulated protein kinases (ERK)1/2, p-c-Jun N-terminal kinase, p-p38 mitogen-activated protein kinase (MAPK), p-I-κBα, I-κBα, and p-nuclear factor-κB (NF-κB)p65 were detected by Western blot. RESULTS: Our results show that after stimulation with LPS, the levels of IL-1ß, IL-6, and tumor necrosis factor-α and the expression of GFAP in astrocytes were up-regulated significantly. In addition, the expression of TLR4, MyD88, p-ERK1/2, p-c-Jun N-terminal kinase, p-p38 MAPK, and p-NF-κBp65 increased, whereas the expression of total I-κBα decreased upon stimulation with LPS. Propofol (10 µM) reduced the secretion of proinflammatory cytokines, inhibited the expressions of GFAP, TLR4, MyD88, p-ERK1/2, p-p38 MAPK, and p-NF-κBp65 in astrocytes challenged with LPS. CONCLUSIONS: In the present study, propofol 10 µM but not lower clinically relevant or higher supra-clinical concentrations attenuated LPS-induced astrocyte activation and subsequent inflammatory responses by inhibiting the TLR4/MyD88-dependent NF-κB, ERK1/2, and p38 MAPK pathways.

Ketamine interferes with the proliferation and differentiation of neural stem cells in the subventricular zone of neonatal rats.

BACKGROUND: Previous studies have shown ketamine can alter the proliferation and differentiation of neural stem cells (NSCs) in vitro. However, these effects have not been entirely clarified in vivo in the subventricular zone (SVZ) of neonatal rats. The present study was designed to investigate the effects of ketamine on the proliferation and differentiation of NSCs in the SVZ of neonatal rats in vivo. METHODS: Postnatal day 7 (PND-7) male Sprague-Dawley rats were administered four injections of 40 mg/kg ketamine at 1-h intervals, and then 5-bromodeoxyuridine (BrdU) was injected intraperitoneally at PND-7, 9 and 13. NSC proliferation was assessed with Nestin/BrdU double-labeling immunostaining. Neuronal and astrocytic differentiation was evaluated with ß-tubulin III/BrdU and GFAP/BrdU double-labeling immunostaining, respectively. The expressions of nestin, ß-tubulin III and GFAP were measured using Western blot analysis. The apoptosis of NSCs and astrocytes in the SVZ of neonatal rats was evaluated using nestin/caspase-3 and GFAP/caspase-3 double-labeling immunostaining. RESULTS: Neonatal ketamine exposure significantly reduced the number of nestin/BrdU and GFAP/BrdU double-positive cells in the SVZ. Meanwhile, the expressions of nestin and GFAP in the SVZ from the ketamine group were significantly decreased compared those in the control group. Still, no double-positive cells for nestin/caspase-3 and GFAP/caspase-3 were found after ketamine exposure. In addition, the neuronal differentiation of NSCs in the SVZ was markedly promoted by ketamine with an increased number of ß-tubulin III/BrdU double-positive cells and enhanced expression of ß-tubulin III. These effects of ketamine on the NSCs in the SVZ often lasted at least 1 week after ketamine anesthesia. CONCLUSION: In the present study, it was demonstrated that ketamine could alter neurogenesis by inhibiting the proliferation of NSCs, suppressing their differentiation into astrocytes and promoting the neuronal differentiation of the NSCs in the SVZ of neonatal rats during a critical period of their neurodevelopment.

Ketamine inhibits proliferation of neural stem cell from neonatal rat hippocampus in vitro.

BACKGROUND/AIMS: Ketamine is a widely used anesthetic in obstetric and pediatric anesthesia. In the developing brain, the widespread neuron apoptosis triggered by ketamine has been demonstrated. However, little is known about its effect on neural stem cells (NSCs) function. This study aimed to investigate the effect of ketamine on proliferation of NSCs from neonatal rat hippocampus. METHODS: Neural stem cells were isolated from the hippocampus of Sprague-Dawley rats on postnatal day 3. In dose-response experiments, cultured neural stem cells (NSCs) were exposed to different concentrations of ketamine (0-1000 µM) for 24 hrs. The proliferative activity of NSCs was evaluated by 5-Bromo-2'-deoxyuridine (BrdU) incorporation assay. Apoptosis of neural stem cells were assessed using caspase-3 by western blot. The intracellular Ca(2+) concentration ([Ca(2+)]i) in NSCs was analyzed by flow cytometry. The activation of protein kinase C-α (PKCα) and the phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2) were measured by western blot analysis. RESULTS: Clinical relevant concentration of ketamine (10, 20 and 50 µM) did not markedly alter the proliferation of NSCs from neonatal rat hippocampus in vitro. However, ketamine (200, 500, 800 and 1000µM) significantly inhibited the proliferation of NSCs and did not affect the expression of caspase-3. Meanwhile, ketamine (200, 500, 800 and 1000µM) also markedly decreased [Ca(2+)]i as well as suppressed PKCα activation and ERK1/2 phosphorylation in NSCs. A combination of subthreshold concentrations of ketamine (100 µM) and Ca(2+) channel blocker verapamil (2.5 µM), PKCα inhibitor chelerythrine (2.5 µM) or ERK1/2 kinase inhibitor PD98059 (5 µM) significantly produced suprathreshold effects on PKCα activation, ERK1/2 phosphorylation and NSC proliferation. CONCLUSION: Ketamine inhibited proliferation of NSCs from neonatal rat hippocampus in vitro. Suppressing Ca(2+)-PKCα-ERK1/2 signaling pathway may be involved in this inhibitory effect of ketamine on NSCs proliferation.

Catalyst-free reductive amination of aromatic aldehydes with ammonium formate and Hantzsch ester.

The protocol of the reductive amination of aromatic aldehydes using ammonium formate and Hantzsch ester is described. It is a mild, convenient, acid- and catalyst-free system applied for the synthesis of both symmetric and asymmetric aromatic secondary amines.

Translational repression of cyclin D3 by a stable G-quadruplex in its 5' UTR: implications for cell cycle regulation.

cyclin D3 (CCND3) is one of the three D-type cyclins that regulate the G1/S phase transition of the cell cycle. Expression of CCND3 is observed in nearly all proliferating cells; however, the presence of high levels of CCND3 has been linked to a poor prognosis for several types of cancer. Therefore, further mechanistic studies on the regulation of CCND3 expression are urgently needed to provide therapeutic implications. In this study, we report that a conserved RNA G-quadruplex-forming sequence (hereafter CRQ), located in the 5' UTR of mammalian CCND3 mRNA, is able to fold into an extremely stable, intramolecular, parallel G-quadruplex in vitro. The CRQ G-quadruplex dramatically reduces the activity of a reporter gene in human cell lines, but it has little impact on its mRNA level, indicating a translational repression. Moreover, the CRQ sequence in its natural context inhibits translation of CCND3. Disruption of the G-quadruplex structure by G/U-mutation or deletion results in an elevated expression of CCND3 and an increased phosphorylation of Rb, a downstream target of CCND3, which promotes progression of cells through the G1 phase. Our results add to the growing understanding of the regulation of CCND3 expression and provide a potential therapeutic target for cancer treatment.

Triggering Fbw7-mediated proteasomal degradation of c-Myc by oridonin induces cell growth inhibition and apoptosis.

The transcription factor c-Myc is important in cell fate decisions and is frequently overexpressed in cancer cells, making it an attractive therapeutic target. Natural compounds are among the current strategies aimed at targeting c-Myc, but their modes of action still need to be characterized. To explore the mechanisms underlying the anticancer activity of a natural diterpenoid, oridonin, we conducted miRNA expression profiling and statistical analyses that strongly suggested that c-Myc was a potential molecular target of oridonin. Furthermore, experimental data showed that oridonin significantly reduced c-Myc protein levels in vitro and in vivo and that this reduction was mediated by the ubiquitin-proteasome system. Fbw7, a component of the ubiquitin-proteasome system and an E3 ubiquitin ligase of c-Myc, was upregulated rapidly in K562 cells and other leukemia and lymphoma cells, resulting in the rapid turnover of c-Myc. In cell lines harboring mutations in the WD domain of Fbw7, the degradation of c-Myc induced by oridonin was attenuated during short-term treatment. GSK-3, an Fbw7 priming kinase, was also activated by oridonin, along with an increase in T58-phosphorylated c-Myc. Furthermore, the knockdown of Fbw7 or the forced expression of stable c-Myc resulted in reduced sensitization to oridonin-induced apoptosis. Our observations help to clarify the anticancer mechanisms of oridonin and shed light on the application of this natural compound as an Fbw7-c-Myc pathway targeting agent in cancer treatment.