AMPK is a metabolic sensor that helps maintain cellular energy homeostasis. Despite evidence linking AMPK with tumor suppressor functions, the role of AMPK in tumorigenesis and tumor metabolism ...is unknown. Here we show that AMPK negatively regulates aerobic glycolysis (the Warburg effect) in cancer cells and suppresses tumor growth in vivo. Genetic ablation of the α1 catalytic subunit of AMPK accelerates Myc-induced lymphomagenesis. Inactivation of AMPKα in both transformed and nontransformed cells promotes a metabolic shift to aerobic glycolysis, increased allocation of glucose carbon into lipids, and biomass accumulation. These metabolic effects require normoxic stabilization of the hypoxia-inducible factor-1α (HIF-1α), as silencing HIF-1α reverses the shift to aerobic glycolysis and the biosynthetic and proliferative advantages conferred by reduced AMPKα signaling. Together our findings suggest that AMPK activity opposes tumor development and that its loss fosters tumor progression in part by regulating cellular metabolic pathways that support cell growth and proliferation.
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► Loss of AMPKα1 cooperates with the Myc oncogene to accelerate lymphomagenesis ► AMPKα dysfunction enhances aerobic glycolysis (Warburg effect) ► Inhibiting HIF-1α reverses the metabolic effects of AMPKα loss ► HIF-1α mediates the growth advantage of tumors with reduced AMPK signaling
Stem cell-derived exosomes (SC-EXO) was an emerging therapeutic agent in regenerative medicine. Intratunical injection of SC-EXO is considered as a prospective approach for erectile dysfunction (ED) ...treatment. However, high vascularization of cavernous body makes effective retention a major challenge for SC-EXO intratunical injection. In this study, a Polydopamine nanoparticles (PDNPs) incorporated poly (ethylene glycol)-poly(ε-caprolactone-co-lactide) (PDNPs-PELA) thermosensitive hydrogels were fabricated by a facile in situ polymerization for intratunical administration of adipose stem cell-derived exosomes (EXO). The hydrogels exhibited sol-gel transition at body temperature. Moreover, the in-situ polymerization of PDNPs using poly (ethylene glycol)-poly(ε-caprolactone-co-lactide) (PELA) block copolymer as a template was found to be more stable dispersion in the gel system. After being encapsulated into the hydrogel, EXO shows sustained release behavior within two weeks. In vivo animal experiments revealed that exosomes released from hydrogel lead to the healing of endothelial cells and neurons, increase of the cavity's pressure, thereby restoring the erectile function. In particular, since the PDNPs in thermosensitive gels have excellent photoacoustic performance, the hydrogel can be accurately delivered into the tunica albuginea by the guidance of real-time photoacoustic imaging. These results suggest that the as-prepared PDNPs-PELA has a promising future as an injectable exosome carrier for ED treatment.
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•A temperature-sensitive hydrogel with photoacoustic activity was developed for intratunical injection by in-situ polymerization.•The exosomes encapsulated in the hydrogel can be slowly released and effectively restore damaged nerve and vascular endothelial cells.•The injection guided by photoacoustic images realizes accurate puncture and real-time filling detection of hydrogel in the corpus cavernosum.
The mine return air flow has the characteristics of basically constant temperature and humidity all year round and is a high-quality waste heat resource. Its direct discharge not only wastes energy ...but also causes environment pollution. It has important economic value and application prospect to solve the problem of shaft antifreeze using new technology to recover the waste heat of mine return air. Gravity heat pipe is widely used in the heat recovery of mine return air. Its heat transfer process is a complex process with multiple parameters. The current research focuses on the influence of a single factor on heat transfer, which has many limitations. To analyze the effects of different parameters on the heat recovery effect of gravity heat pipe in mine return air and to optimize heat pipe heat exchanger parameters in the heat exchange system, mathematical models of gas–water countercurrent heat and mass transfer, entransy dissipation and exergy efficiency were established in this paper, based on the entransy dissipation theory. Under the condition of the given initial parameters, the effects of different parameters on the dimensionless factor, β, of heat transfer, total heat transfer, and entransy dissipation thermal resistance were analyzed. The experimental and calculation results show the entransy dissipation theory can be used to evaluate the heat transfer performance of the gravity heat pipe. When the entransy dissipation thermal resistance was minimum, the heat transfer performance was optimal. During the heat transfer process between the mine return air and the gravity heat pipe with high humidity under a given working condition, increasing the Reynolds number was beneficial to increase the heat transfer dimensionless factor, β.
Gliomas are the most common primary brain tumors in children and adults. We recently identified frequent alterations in chromatin remodelling pathways including recurrent mutations in
H3F3A
and ...mutations in
ATRX
(α-thalassemia/mental-retardation-syndrome-X-linked) in pediatric and young adult glioblastoma (GBM, WHO grade IV astrocytoma).
H3F3A
mutations were specific to pediatric high-grade gliomas and identified in only 3.4 % of adult GBM. Using sequencing and/or immunohistochemical analyses, we investigated ATRX alterations (mutation/loss of expression) and their association with
TP53
and
IDH1
or
IDH2
mutations in 140 adult WHO grade II, III and IV gliomas, 17 pediatric WHO grade II and III astrocytomas and 34 pilocytic astrocytomas. In adults, ATRX aberrations were detected in 33 % of grade II and 46 % of grade III gliomas, as well as in 80 % of secondary and 7 % of primary GBMs. They were absent in the 17 grade II and III astrocytomas in children, and the 34 pilocytic astrocytomas. ATRX alterations closely overlapped with mutations in
IDH1
/
2
(
p
< 0.0001) and
TP53
(
p
< 0.0001) in samples across all WHO grades. They were prevalent in astrocytomas and oligoastrocytomas, but were absent in oligodendrogliomas (
p
< 0.0001). No significant association of ATRX mutation/loss of expression and alternative lengthening of telomeres was identified in our cohort. In summary, our data show that ATRX alterations are frequent in adult diffuse gliomas and are specific to astrocytic tumors carrying
IDH1
/
2
and
TP53
mutations. Combined alteration of these genes may contribute to drive the neoplastic growth in a major subset of diffuse astrocytomas in adults.
Glycoprotein non-metastatic melanoma protein B (GPNMB)/Osteoactivin (OA) is a transmembrane protein expressed in approximately 40-75% of breast cancers. GPNMB/OA promotes the migration, invasion and ...metastasis of breast cancer cells; it is commonly expressed in basal/triple-negative breast tumors and is associated with shorter recurrence-free and overall survival times in patients with breast cancer. Thus, GPNMB/OA represents an attractive target for therapeutic intervention in breast cancer; however, little is known about the functions of GPNMB/OA within the primary tumor microenvironment.
We have employed mouse and human breast cancer cells to investigate the effects of GPNMB/OA on tumor growth and angiogenesis. GPNMB/OA-expressing tumors display elevated endothelial recruitment and reduced apoptosis when compared to vector control-derived tumors. Primary human breast cancers characterized by high vascular density also display elevated levels of GPNMB/OA when compared to those with low vascular density. Using immunoblot and ELISA assays, we demonstrate the GPNMB/OA ectodomain is shed from the surface of breast cancer cells. Transient siRNA-mediated knockdown studies of known sheddases identified ADAM10 as the protease responsible for GPNMB/OA processing. Finally, we demonstrate that the shed extracellular domain (ECD) of GPNMB/OA can promote endothelial migration in vitro.
GPNMB/OA expression promotes tumor growth, which is associated with enhanced endothelial recruitment. We identify ADAM10 as a sheddase capable of releasing the GPNMB/OA ectodomain from the surface of breast cancer cells, which induces endothelial cell migration. Thus, ectodomain shedding may serve as a novel mechanism by which GPNMB/OA promotes angiogenesis in breast cancer.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background: LncRNA FGD5-AS1 regulates the pathogenesis of many human diseases. We aimed to elucidate the function of lncRNA FGD5-AS1 and the regulatory mechanism of lncRNA FGD5-AS1/miR-129-5p in ...myocardial ischemia-reperfusion (I/R) injury.
Methods: Myocardial I/R injury mice model and H/R treated H9c2 cells were established. RT-qPCR and Western blot analysis were used to detect the mRNA and protein expression. Cell viability was detected by MTT assay. Dual luciferase reporter assay was applied to confirm the relationship between lncRNA FGD5-AS1 and miR-129-5p.
Results: LncRNA FGD5-AS1 was upregulated in myocardial I/R injury mice models and H/R treated H9c2 cells. Functionally, knockdown of lncRNA FGD5-AS1 promoted cell viability and inhibited apoptosis in H/R treated H9c2 cells. In addition, lncRNA FGD5-AS1 directly targets miR-129-5p. Upregulation of lncRNA FGD5-AS1 weakened the protective effect of miR-129-5p on myocardial I/R injury.
Conclusion: LncRNA FGD5-AS1 aggravates myocardial I/R injury by downregulating miR-129-5p.
In order to solve the oversize problem of continuously variable transmission, a rod gear pulse continuously variable transmission is designed. The kinematic mathematical models of key components are ...established by the matrix method and are simulated by MATLAB in a single phase, based on the analysis of basic structure and working principle of transmission. Also, the length requirements of each rod are studied, and the effect of three adjustment manners on the output-speed is simulated in the single phase. Furthermore, the simulations of the movement law of annular gear are achieved on two conditions of both different phases and different eccentricities on 8-phase. The results show that the manner of adjusting the eccentricity of eccentric wheel is the preferential selection of out-speed regulating method, and 8-phase is an optimal phase of transmission; meanwhile, for the rod gear pulse continuously variable transmission, the variable range of transmission ratio is wider and the pulsation rate is far less than the other traditional continuously variable transmissions.
To investigate the correlation between prognosis and intracranial carotid artery calcification (ICAC) in patients with acute ischemic stroke (AIS) who receive intravenous thrombolysis (IVT).
A total ...of 156 AIS patients who received IVT from March 2019 to March 2020 were enrolled. The modified Woodcock visual score was used to evaluate ICAC in nonenhanced head CT scans. Patients were divided into high calcification burden (HCB; score ≥3) and low calcification burden (LCB; score <3) groups. Demographic, laboratory, imaging and clinical data were compared between the two groups, and whether HCB was a prognostic factor was evaluated.
Compared with the LCB group, the HCB group had a higher incidence of atrial fibrillation (49.2 vs.22.1%,
< 0.001) and coronary heart disease (24.6 vs. 10.0%,
= 0.019) and higher serum homocysteine 15.31 (12.15, 17.50) vs. 14.40 (11.20, 16.20),
= 0.036 and hemoglobin A1c (6.93 ± 1.77 vs. 6.37 ± 0.74,
= 0.023) levels. Binary logistic regression analysis showed that atrial fibrillation (OR = 3.031, 95% CI: 1.312-7.006,
= 0.009) and HbA1c (OR = 1.488, 95% CI: 1.050-2.109,
= 0.026) were independent risk factors for ICAC. After adjusting for other risk factors, symptomatic-side and bilateral ICACs were independent risk factors for poor prognosis (OR = 1.969, 95% CI: 1.220-3.178,
= 0.006), (OR = 1.354, 95% CI: 1.065-1.722,
= 0.013) and mortality (OR = 4.245, 95% CI: 1.114-16.171,
= 0.034), (OR = 2.414, 95% CI = 1.152-5.060,
= 0.020) in patients with AIS who received IVT.
ICAC is closely related to the prognosis of acute ischemic stroke after intravenous thrombolysis.
Although the murine orthologue of glycoprotein nonmetastatic B (GPNMB), Osteoactivin, promotes breast cancer metastasis in an in vivo mouse model, its importance in human breast cancer is unknown. We ...have examined the significance of GPNMB expression as a prognostic indicator of recurrence and assessed its potential as a novel therapeutic target in breast cancer.
The clinical significance of GPNMB expression in breast cancer was addressed by analyzing GPNMB levels in several published gene expression data sets and two independent tissue microarrays derived from human breast tumors. GPNMB-expressing human breast cancer cell lines were further used to validate a toxin-conjugated anti-GPNMB antibody as a novel therapeutic agent.
GPNMB expression correlates with shorter recurrence times and reduced overall survival of breast cancer patients. Epithelial-specific GPNMB staining is an independent prognostic indicator for breast cancer recurrence. GPNMB is highly expressed in basal and triple-negative breast cancers and is associated with increased risk of recurrence within this subtype. GPNMB expression confers a more migratory and invasive phenotype on breast cancer cells and sensitizes them to killing by CDX-011 (glembatumumab vedotin), a GPNMB-targeted antibody-drug conjugate.
GPNMB expression is associated with the basal/triple-negative subtype and is a prognostic marker of poor outcome in patients with breast cancer. CDX-011 (glembatumumab vedotin) is a promising new targeted therapy for patients with metastatic triple-negative breast cancers, a patient population that currently lacks targeted-therapy options.
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