Temozolomide (TMZ) is a first-line alkylating agent for glioblastoma multiforme (GBM). Clarifying the mechanisms inducing TMZ insensitivity may be helpful in improving its therapeutic effectiveness ...against GBM. Insulin-like growth factor (IGF)-1 signaling and micro (mi)RNAs are relevant in mediating GBM progression. However, their roles in desensitizing GBM cells to TMZ are still unclear. We aimed to identify IGF-1-mediated miRNA regulatory networks that elicit TMZ insensitivity for GBM. IGF-1 treatment attenuated TMZ cytotoxicity via WNT/β-catenin signaling, but did not influence glioma cell growth. By miRNA array analyses, 93 upregulated and 148 downregulated miRNAs were identified in IGF-1-treated glioma cells. miR-513a-5p from the miR-513a-2 gene locus was upregulated by IGF-1-mediated phosphoinositide 3-kinase (PI3K) signaling. Its elevated levels were also observed in gliomas versus normal cells, in array data of The Cancer Genome Atlas (TCGA), and the GSE61710, GSE37366, and GSE41032 datasets. In addition, lower levels of neural precursor cell-expressed developmentally downregulated 4-like (NEDD4L), an E3 ubiquitin protein ligase that inhibits WNT signaling, were found in gliomas by analyzing cells, arrays, and RNA sequencing data of TCGA glioma patients. Furthermore, a negative correlation was identified between miR-513a-5p and NEDD4L in glioma. NEDD4L was also validated as a direct target gene of miR-513a-5p, and it was reduced by IGF-1 treatment. Overexpression of NEDD4L inhibited glioma cell viability and reversed IGF-1-repressed TMZ cytotoxicity. In contrast, miR-513a-5p significantly affected NEDD4L-inhibited WNT signaling and reduced TMZ cytotoxicity. These findings demonstrate a distinct role of IGF-1 signaling through miR-513a-5p-inhibited NEDD4L networks in influencing GBM's drug sensitivity to TMZ.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Temozolomide (TMZ), an alkylating agent of the imidazotetrazine series, is a first-line chemotherapeutic drug used in the clinical therapy of glioblastoma multiforme, the most common and high-grade ...primary glioma in adults. Micro (mi)RNAs, which are small noncoding RNAs, post-transcriptionally regulate gene expressions and are involved in gliomagenesis. However, no studies have reported relationships between TMZ and miRNA gene regulation. We investigated TMZ-mediated miRNA profiles and its molecular mechanisms underlying the induction of glioma cell death. By performing miRNA microarray and bioinformatics analyses, we observed that expression of 248 miRNAs was altered, including five significantly upregulated and 17 significantly downregulated miRNAs, in TMZ-treated U87MG cells. miR-128 expression levels were lower in different glioma cells and strongly associated with poor survival. TMZ treatment significantly upregulated miR-128 expression. TMZ significantly enhanced miR-128-1 promoter activity and transcriptionally regulated miR-128 levels through c-Jun N-terminal kinase 2/c-Jun pathways. The overexpression and knockdown of miR-128 expression significantly affected TMZ-mediated cell viability and apoptosis-related protein expression. Furthermore, the overexpression of miR-128 alone enhanced apoptotic death of glioma cells through caspase-3/9 activation, poly(ADP ribose) polymerase degradation, reactive oxygen species generation, mitochondrial membrane potential loss, and non-protective autophagy formation. Finally, we identified that key members in mammalian target of rapamycin (mTOR) signaling including mTOR, rapamycin-insensitive companion of mTOR, insulin-like growth factor 1, and PIK3R1, but not PDK1, were direct target genes of miR-128. TMZ inhibited mTOR signaling through miR-128 regulation. These results indicate that miR-128-inhibited mTOR signaling is involved in TMZ-mediated cytotoxicity. Our findings may provide a better understanding of cytotoxic mechanisms of TMZ involved in glioblastoma development.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Existing evidence indicates the importance of observing correct, normal actions on the motor cortical activities. However, the exact neurophysiological mechanisms, particularly in the somatosensory ...system, remain unclear. This study aimed to elucidate the effects of observing normal and abnormal hand movements on the contralateral primary somatosensory (cSI), contralateral (cSII) and ipsilateral (iSII) secondary somatosensory activities. Experiment I was designed to investigate the effects of motor outputs on the somatosensory processing, in which subjects were instructed to relax or manipulate a small cube. Experiment II was tailored to examine the somatosensory responses to the observation of normal (Normal) and abnormal (Abnormal) hand movements. The subjects received electrical stimulation to right median nerve and magnetoencephalography (MEG) recordings during the whole experimental period. Regional cortical activation and functional connectivity were analyzed. Compared to the resting condition, a reduction in cSI and an enhancement of SII activation was found when subjects manipulated a cube, suggesting the motor outputs have an influence on the somatosensory responses. Further investigation of the effects of observing different hand movements showed that cSII activity was significantly stronger in the Normal than Abnormal condition. Moreover, compared with Abnormal condition, a higher cortical coherence of cSI‐iSII at theta bands and cSII‐iSII at beta bands was found in Normal condition. Conclusively, the present results suggest stronger activation and enhanced functional connectivity within the somatosensory system during the observation of normal than abnormal hand movements. These findings also highlight the importance of viewing normal, correct hands movements in the stroke rehabilitation.
Evidence indicates the importance of observing normal hand actions on the motor cortical activities; however, the exact neurophysiological mechanisms in the somatosensory system remain unclear. By using MEG recordings, we found higher activation of SII regions and increased functional connectivity within the cortical somatosensory system in observing normal than abnormal hand movements. Our data provided a neural insight into the mirror therapy and action observation therapy for stroke patients.
In this study, a marine brown alga
-derived fungal strain,
SC29, was isolated and identified. Column chromatography of the extracts from liquid fermented products of the fungal strain was carried out ...and led to the isolation of six compounds. Their structures were elucidated by spectroscopic analysis and supported by single-crystal X-ray diffraction as four previously undescribed (
)-3-hydroxybutyric acid and glycolic acid derivatives, namely penisterines A (
) and C-E (
-
) and penisterine A methyl ether (
), isolated for the first time from natural resources, along with (
)-3-hydroxybutyric acid (
). Of these compounds identified, penisterine E (
) was a unique 6/6/6-tricyclic ether with an acetal and two hemiketal functionalities. All the isolates were subjected to in vitro anti-angiogenic assays using a human endothelial progenitor cell (EPCs) platform. Among these, penisterine D (
) inhibited EPC growth, migration, and tube formation without any cytotoxic effect. Further, in in vivo bioassays, the percentages of angiogenesis of compound
on
(
:EGFP) transgenic zebrafish were 54% and 37% as the treated concentration increased from 10.2 to 20.4 µg/mL, respectively, and the percentages of angiogenesis of compound
were 52% and 41% as the treated concentration increased from 8.6 to 17.2 µg/mL, respectively. The anti-angiogenic activity of penisterine D (
) makes it an attractive candidate for further preclinical investigation.
While the automatic inhibitory function of the human cerebral cortex has been extensively investigated by means of electrophysiological recordings, the corresponding modulating neurochemical ...mechanisms remain unclear. We aimed to examine whether the primary somatosensory (SI) and primary motor cortical (MI) inhibitory function is associated with endogenous GABA levels. Eighteen young participants received paired-pulse and single-pulse electrical stimulation to the median nerve during magnetoencephalographic recordings. The SI sensory gating (SG), considered as an automatic inhibitory ability, was measured as the amplitude ratio of Stimulus 2 over Stimulus 1, in the paired-pulse paradigm. In addition, stimulus-induced beta activity, considered to originate from MI and also to be related to inhibitory function, was estimated using the single-pulse paradigm. The GABA+ concentration of the sensorimotor cortex was acquired from each subject by using magnetic resonance spectroscopy (MRS). A lower SG ratio in SI was significantly associated with an increased beta power in MI. More importantly, the beta rebound power, but not SI SG ratio, was positively correlated with GABA+ concentration. Our findings show a tight functional relationship between SI and MI during processing of automatic inhibition. GABA+ levels appear to be more closely related to the automatic inhibitory function of MI than SI.
Purple sweet potato (PSP) is a root crop containing higher levels of certain nutrients including anthocyanins. PSP anthocyanins are known to have antioxidant activity and many health benefits. In ...this study, PSP anthocyanins were identified and quantitated by HPLC-DAD-ESI/MS and UPLC-Q-TOF-MS analysis. The color change at different pH values was measured through the CIELab scale. Gellan gum was combined with PSP to obtain stable gellan gum/PSP composite films. The composite films exhibited reduced hydrophilicity, swelling property and water vapor transmission rates (WVTR) as compared to the films prepared from gellan gum alone. PSP also increased the mechanical property and antioxidant activity of the composite films. The active packaging films were able to control the PSP anthocyanins release in simulated gastrointestinal fluids at pH 2.0, 6.0 and 7.4. Application of the intelligent films was performed by colorimetric detection of the pH changes caused by growing Escherichia coli on nutrient agar plates. When attaching the films on the cover of petri dishes, the films changed their color from purple (initial) to blue (6 h) and to yellow-green (24 h) with the growth of bacteria and digestion of proteins to produce volatile amines. The gellan gum/PSP composite film may have potential as an active and intelligent packaging material showing enhanced antioxidant, water-resistant and mechanical properties, and may be served as an easy-to-use indicator system to detect the spoilage of protein-rich foods caused by the growth of bacteria.
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•Gellan gum was blended with PSP to obtain gellan gum/PSP composite films.•PSP reduced hydrophilicity and swelling of gellan gum films.•PSP improved mechanical strength and antioxidant activity of gellan gum films.•the composite films can be used to monitor pH variations.
Fucoidan is a fucose-rich polysaccharide that has gained attention for its various anticancer properties. However, the effect and underlying mechanism of fucoidan on triple-negative breast cancer ...(TNBC) are still unknown. Herein, we investigated the anticancer potential of fucoidan from Laminaria japonica. We found that fucoidan showed modest antiproliferative activity against TNBC cells, while it effectively reduced migratory and invasive capacities. Mechanistically, fucoidan suppressed activation of MAPK and PI3K followed by inhibition of AP-1 and NF-κB signaling in TNBC. Additionally, fucoidan downregulated expressions of proangiogenic factors in TNBC cells, and fucoidan blocked tumor-elicited tube formation by human umbilical vascular endothelial cells (HUVECs). We also observed that fucoidan blocked tumor adhesion and invasion towards HUVECs. Surprisingly, fucoidan robustly suppressed tube formation on HUVECs. Moreover, fucoidan inhibited in vivo angiogenesis and micrometastasis in a transgenic zebrafish model. Together, L. japonica fucoidan exhibits potent antitumor effects by its attenuation of invasiveness and proangiogenesis in TNBC.
•Fucoidan from Laminaria japonica exerts antitumor effects.•Fucoidan suppresses proangiogenesis and micrometastasis in TNBC.•Fucoidan blocks MAPK and PI3K signaling in TNBC.
Gut dysbiosis has been proposed as one of pathologies in patients with Alzheimer's disease (AD) spectrum. Despite such enthusiasm, the relevant results remain substantially controversial.
A ...systematic review and meta-analysis were performed to investigate the differences of gut microbiota (GM) between patients with AD spectrum (including mild cognitive impairment MCI and AD) and healthy controls (HC).
PubMed, MEDLINE, Scopus, and Cochrane Library from January 2000 to August 2021. Eligibility criteria for study selection: Observational trials and pre-intervention data of intervention trials that investigated the abundance of GM in patients with AD spectrum and HC.
Two reviewers independently identified articles, extracted data, and evaluated the risk of bias. The effect sizes were performed by a random-effect, inverse-variance weighted model. The effects of different countries and of clinical stages on GM abundance were also examined.
11 studies consisting of 378 HC and 427 patients with AD spectrum were included in the meta-analysis. Patients with AD, but not MCI, showed significantly reduced GM diversity as compared to HC. We also found more abundance of
,
and
, but less abundance of
,
,
and
in patients with AD spectrum as compared with HC. The profiles of abundance of
and
in HC and AD spectrum were differentially affected by countries. Finally, when considering clinical stage as a moderator, the comparisons of abundance in
and
showed large effect sizes, with gradient changes from MCI to AD stage.
The inclusion of studies originating only from China and the U.S. was a possible limitation.
Patients with AD spectrum demonstrated altered GM abundance, which was differentially mediated by countries and clinical stages.
: Cancer cells reprogram cellular metabolism to fulfill their needs for rapid growth and metastasis. However, the mechanism controlling this reprogramming is poorly understood. We searched for ...upregulated signaling in metastatic colorectal cancer and investigated the mechanism by which Glut3 promotes tumor metastasis.
: We compared RNA levels and glycolytic capacity in primary and metastatic colon cancer. The expression and association of Glut3 with clinical prognosis in colon cancer tissues was determined by immunohistochemistry. Glut3 gain-of-function and loss-of-function were established using colon cancer HCT116, HT29, and metastatic 116-LM cells, and tumor invasiveness and stemness properties were evaluated. Metabolomic profiles were analyzed by GC/MS and CE-TOF/MS. The metastatic burden in mice fed a high-fat sucrose diet was assessed by intravenous inoculation with Glut3 knockdown 116-LM cells.
: Upregulation of glycolytic genes and glycolytic capacity was detected in metastatic colorectal cancer cells. Specifically, Glut3 overexpression was associated with metastasis and poor survival in colorectal cancer patients. Mechanistically, Glut3 promoted invasiveness and stemness in a Yes-associated protein (YAP)-dependent manner. Activation of YAP in turn transactivated Glut3 and regulated a group of glycolytic genes. Interestingly, the expression and phosphorylation of PKM2 were concomitantly upregulated in metastatic colorectal cancer, and it was found to interact with YAP and enhance the expression of Glut3. Importantly, a high-fat high-sucrose diet promoted tumor metastasis, whereas the inhibition of either Glut3 or YAP effectively reduced the metastatic burden.
: Activation of the Glut3-YAP signaling pathway acts as a master activator to reprogram cancer metabolism and thereby promotes metastasis. Our findings reveal the importance of metabolic reprogramming in supporting cancer metastasis as well as possible therapeutic targets.
Xanthohumol (XN), a prenylated chalcone extracted from hop plant Humulus lupulus L. (Cannabaceae), has potential for cancer therapy, including gliomas. Micro (mi)RNAs are small noncoding RNAs that ...control gene expression. Several miRNAs have been identified to participate in regulating glioma development. However, no studies have demonstrated whether miRNA is involved in XN cytotoxicity resulting in glioma cell death. This study investigated the effects of XN-mediated miRNA expression in activating apoptotic pathways in glioblastoma U87 MG cells. First, we found that XN significantly reduced cell viability and induced apoptosis via pro-caspase-3/8 cleavage and poly(ADP ribose) polymerase (PARP) degradation. We also identified that pro-caspase-9 cleavage, Bcl2 family expression changes, mitochondrial dysfunction, and intracellular ROS generation also participated in XN-induced glioma cell death. With a microarray analysis, miR-204-3p was identified as the most upregulated miRNA induced by XN cytotoxicity. The extracellular signal-regulated kinase (ERK)/c-Fos pathway was validated to participate in XN-upregulated miR-204-3p expression. With a promoter assay and ChIP analysis, we found that c-Fos dose-dependently bound to the miR-204-3p gene promoter region. Furthermore, miR-204-3p levels decreased in several glioma cell lines compared to astrocytes. Overexpression of miR-204-3p enhanced glioma cell apoptosis. IGFBP2, an upregulated regulator of glioma proliferation, was validated by a TCGA analysis as a direct target gene of miR-204-3p. XN's inhibition of the IGFBP2/AKT/Bcl2 pathway via miR-204-3p targeting played a critical role in mediating glioma cell death. These results emphasized that the XN-mediated miR-204-3p network may provide novel therapeutic strategies for future glioblastoma therapy and drug development.
•Xanthohumol enhanced 28 microRNA expressions and downregulated 3 microRNA levels in inducing glioblastoma apoptotic death.•The miR-204-3p levels is the most significantly upregulated microRNA in xanthohumol-treated glioma cells.•Xanthohumol upregulated miR-204-3p levels via ERK/c-Fos pathway.•IGFBP2 was validated as a direct target gene of miR-204-3p.•The miR-204-3p-targeted IGFBP2/AKT/Bcl2 pathway is involved in xanthohumol cytotoxicity.
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