Current chemotherapy regimens on acute myeloid leukemia (AML) still have some drawbacks, such as intolerance and drug resistance, which calls need for the development of targeted therapy. Signal ...transducer and activator of transcription 5 (STAT5) is often overexpressed or abnormally activated in leukemia and involved in cell self‐renewal, proliferation, and stress adaptation. Overexpressed Aurora A (AURKA) is associated with poor prognosis in tumors, and inhibitors against AURKA are already in clinical trials. However, it has rarely been reported whether AURKA inhibitors restrain STAT5‐activated leukemia cells. In this study, we constructed STAT5 constitutively activated (cS5) cells and found that STAT5 promoted cell proliferation and colony formation. Moreover, cS5 cells showed elevated reactive oxygen species (ROS) and adenosine triphosphate (ATP) levels, which indicated higher mitochondrial metabolism in cS5 cells. A novel AURKA inhibitor AKI604 was synthesized and showed significant inhibitory effects to the proliferation and colony formation in both STAT5 constitutively activated and nonactivated AML cells. AKI604 induced mitochondrial impairment, leading to the disruption of mitochondrial membrane potential and the elevation of ROS as well as cellular calcium (Ca2+) levels. AKI604 could also decline basal oxygen consumption rate and ATP biosynthesis, indicating the damage of oxidative phosphorylation. Furthermore, AKI604 exhibited significant antitumor effect in the HL‐60 cS5 xenograft model of the BALB/c nude mice without an obvious influence on mice body weight and other healthy indicators. This study suggested that AKI604 was a potential strategy to overcome STAT5‐induced leukemic proliferation in AML treatment by inducing mitochondrial impairment.
AKI604 exhibited significant antitumor effect both in vitro and in vivo by inducing mitochondrial impairment.
Background
Degenerative joint disease (DJD) can be associated with disc displacement (DD) in temporomandibular disorder (TMD) patients. However, the relationship between different types of DDs and ...DJD remains unclear.
Objectives
To investigate the odds ratios of different types of sagittal and coronal DDs confirmed by magnetic resonance imaging (MRI) and DJD confirmed by cone‐beam computed tomography (CBCT) in TMD patients.
Methods
Radiographic data from 69 males and 232 females were collected for analysis. CBCT was used to diagnose DJD, with criteria including erosion, osteophytes, generalised sclerosis and cysts in the joint. Eight types of DDs were evaluated by sagittal and coronal MRIs: NA, no abnormality; SW, sideways; ADDR, anterior with reduction; ADDR+SW; ADDNR, anterior without reduction; ADDNR + SW; single SW; PDD, posterior; PDD + SW. The odds ratios of DJD in joints with different types of DDs were determined after joint correlation, age and gender adjustment.
Results
Compared with NA, the odds ratio of DJD in ADDR was 2.397 (95% CI confidence interval: 1.070–5.368), ADDR + SW was 4.808 (95% CI: 1.709–3.528), ADDNR was 29.982 (95% CI: 15.512–57.950) and ADDNR + SW was 25.974 (95% CI: 12.743–52.945). Erosion was significantly increased in ADDR, ADDR + SW, ADDNR and ADDNR + SW; osteophytes were significantly increased in ADDR + SW, ADDNR and ADDNR + SW; and generalised sclerosis and cysts were significantly increased in ADDNR and ADDNR + SW. There were no significant associations between single SW, PDD, PDD + SW and the DJD.
Conclusions
ADDR, ADDR+SW, ADDNR and ADDNR+SW were associated with DJD. ADDNR had a significantly higher prevalence of DJD than ADDR. There were no significant relationships between single SW, PDD, PDD + SW and the DJD.
•POCOP pincer Pt thiolate and hydride complexes are good catalysts for hydrosilylation of aldimines.•The thiolate complexes are more active than the hydride complexes.•The reactions feature with good ...functional group compatibility and wide substrate scope.•The expected amine products can be isolated in good to excellent yields.
In order to get information about the catalytic activities of bis(phosphinite) (POCOP) pincer ligated group 10 metal thiolate and hydride complexes against the hydrosilylation of unsaturated carbon-heteroatom bonds, platinum(II) complexes 2,6-(tBu2PO)2C6H3PtX (X = SH, 1a; SPh, 1b; H, 1c) and 2,6-(iPr2PO)2C6H3PtH (2) were applied to the catalytic hydrosilylation of aldimines. It was found that both auxiliary ligand and donor substituent play very important roles in affecting the catalytic activity of the platinum center. The hydride complex 1c is almost inactive in catalyzing the reactions; however, the hydride complex 2, which processes less bulky donor substituents (iPr vs tBu), is an active catalyst. Meanwhile, the thiolate complexes 1a and 1b, which have the same donor substituents as 1c, are active catalysts and 1a is among most effective catalysts for this type of reaction. The catalytic reactions are featured with a wide substrate scope with relatively high turnover frequencies. Both aromatic and aliphatic aldimines were successfully hydrosilylated and the expected amines were isolated in good to excellent yields after basic hydrolysis of the hydrosilylation products. Functional groups such as OMe, halogens and internal C=C double bond were unaffected during the reactions. Although the hydride complex 2 is an active catalyst, it is less effective than the thiolate complex 1a despite the fact that the metal center in 2 is less sterically hindered by the donor substituents. As a result, the thiolate complexes are more active than the hydride complexes in catalyzing the reactions. The possible reasons for the different catalytic activities of these complexes are discussed.
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In a variety of cancers, long non-coding RNAs (lncRNAs) were believed to play important roles. Nevertheless,
possible molecular mechanism related to miR-20b-5p has not yet been explored in ...endometrial cancer. Differential lncRNAs in endometrial cancer were identified based on microarray analysis (GSE23339). In this research, in the first place,
expression was detected to be increased but miR-20b-5p to be decreased in endometrial cancer tissues and cells. Besides,
expression displayed a negative relationship to miR-20b-5p expression in endometrial cancer tissues. According to gain- and loss-of-function experiments of
, like a ceRNA,
elevated
level and
expression so as to stimulate the migration, proliferation and EMT process of endometrial cancer. Additionally, the knockdown of
slowed down tumor growth, promoted apoptosis and upregulated miR-20b-5p expression but lowered the expressions of
, PCNA and
. Furthermore,
was also verified to stimulate the activity of endometrial cancer with
inhibitor BGB324
and
. To sum up,
accelerates the tumor formation of endometrial cancer through the miR-20b-5p/
/
signaling pathway, thereby providing a novel target for diagnosing and treating endometrial cancer.
Drought is the most important factor that limits rice production in drought-prone environments. Plant microRNAs (miRNAs) are involved in biotic and abiotic stress responses. Common wild rice (Oryza ...rufipogon Griff.) contains abundant drought-resistant genes, which provide an opportunity to explore these excellent resources as contributors to improve rice resistance, productivity, and quality.
In this study, we constructed four small RNA libraries, called CL and CR from PEG6000-free samples and DL and DR from PEG6000-treated samples, where 'R' indicates the root tissue and 'L' indicates the shoot tissue. A total of 200 miRNAs were identified to be differentially expressed under the drought-treated conditions (16% PEG6000 for 24 h), and the changes in the miRNA expression profile of the shoot were distinct from those of the root. At the miRNA level, 77 known miRNAs, which belong to 23 families, including 40 up-regulated and 37 down-regulated in the shoot, and 85 known miRNAs in 46 families, including 65 up-regulated and 20 down-regulated in the root, were identified as differentially expressed. In addition, we predicted 26 new miRNA candidates from the shoot and 43 from the root that were differentially expressed during the drought stress. The quantitative real-time PCR analysis results were consistent with high-throughput sequencing data. Moreover, 88 miRNAs that were differentially-expressed were predicted to match with 197 targets for drought-stress.
Our results suggest that the miRNAs of O. rufipogon are responsive to drought stress. The differentially expressed miRNAs that are tissue-specific under drought conditions could play different roles in the regulation of the auxin pathway, the flowering pathway, the drought pathway, and lateral root formation. Thus, the present study provides an account of tissue-specific miRNAs that are involved in the drought adaption of O. rufipogon.
Objectives
Mutant C/EBPα p30 (mp30), the product of C/EBPα double mutations (DM), lacks transactivation domain 1 and has C‐terminal loss‐of‐function mutation. Acute myeloid leukaemia (AML) patients ...harbouring C/EBPα DM could be classified as a distinct subgroup with favourable prognosis. However, the underlying mechanism remains elusive.
Materials and Methods
Autophagy regulated by mp30 was detected by western blot and immunofluorescence. Immune infiltration analysis and GSEA were performed to investigate autophagic and inflammatory status of AML patients from the GSE14468 cohort. Flow cytometry was applied to analyse T cell activation.
Results
Mp30 inhibited autophagy by suppressing nucleus translocation of NF‐κB. Autophagy‐associated secretion of IL‐1β was decreased in mp30‐overexpressed AML cells. Bioinformatic analysis revealed that inflammatory status was attenuated, while CD8+ T cell infiltration was upregulated in C/EBPα DM AML patients. Consistently, the proportion of CD8+CD69+ T cells in peripheral blood mononuclear cells (PBMCs) was upregulated after co‐culture with mp30 AML cell conditional culture medium. Knock‐out of IL‐1β in AML cells also enhanced CD8+ T cell activation. Accordingly, IL‐1β expression was significantly reduced in the bone marrow (BM) cells of C/EBPα DM AML patients compared to the wildtype, while the CD8+CD69+ T cell proportion was specifically elevated.
Conclusions
C/EBPα DM alleviates immunosuppression of CD8+ T cells by inhibiting the autophagy‐associated secretion of IL‐1β, which elucidated that repression of autophagy‐related inflammatory response in AML patients might achieve a favourable clinical benefit.
Mp30 suppresses autophagy‐associated IL‐β secretion, which ultimately alleviates the immunosuppression of CD8+ T cells in the microenvironment, contributing to favourable prognosis of AML patients.
Abstract
The biogeography research of orchids through species distribution models (SDMs), a vital tool in the biogeography field, is critical to understanding the fundamental geographic distribution ...patterns and identifying conservation priorities. The correspondence between species occurrence and environmental information is crucial to the model's performance. However, ecological preferences unique to different orchid species, such as their life forms, are often overlooked during the modeling process. This oversight can introduce bias and increase model uncertainty. Additionally, human activities, as an important potential predictor, have not been quantified in any orchid SDMs. Taking the Hengduan Mountains as an example, we preprocessed all orchid species' occurrences based on physiological characteristics. Choosing five spatial factors related to human activities to quantify the interference and enter into models as HI factor. Using different modeling methods (GLM, MaxEnt, and RF) and evaluation indices (AUC, TSS, and Kappa), diverse modeling strategies have been constructed in the study. A double‐ranking method has been adopted to select the critical orchid distribution regions. The results showed that classification models based on physiological characteristics significantly improved the model's accuracy while adding the HI factor had the same effect but the absence of enough significance. Suitability maps indicated that highly heterogeneous mountainous areas were vital for the distribution of orchids in the Hengduan Mountains. Different distribution patterns and critical regions existed between various orchid life forms geographically – terrestrial orchids were dominant in the mountain, and mycoherterophical orchids were primarily located in the north, more influenced by vegetation and temperature. Critical regions of epiphytic orchids were in the south due to a greater dependence on precipitation and temperature. These studies are informative for understanding the orchids' geographic distribution patterns in the Hengduan Mountains, promoting conservation and providing references for similar research beyond orchids.
To investigate the roles of plasma
in the pathogenic process of Type 2 diabetes (T2D) with diabetic retinopathy (DR). T2D patients included patients without DR (NDR) group, patients with ...non-proliferative/background DR (BDR) group and patients with proliferative DR (PDR) group. Healthy individuals served as control group. Fasting plasma glucose (FPG), glycosylated haemoglobin (HbA1c), triacylglycerol (TG), total cholesterol (TC), urine creatinine (Cr), fasting blood glucose (FBG), blood urea nitrogen (BUN), low-density lipoprotein cholesterol (LDL-C), fasting insulin (FINS) and plasma
expression were measured. Quantitative real-time PCR (qRT-PCR) was applied to detect
expression. Pearson analysis was used to conduct correlation analysis and receiver operating characteristic (ROC) curve was used to analyse the diagnostic value of
in T2D with DR. Compared with the control group, FBG and HbA1c increased in the NDR group; compared with the control and NDR groups, disease course, HbA1c, FPG levels and homoeostasis model assessment of insulin resistance (HOMA-IR) were increased in the BDR and PDR groups; and compared with the BDR group, disease course, HbA1c and FPG levels were higher in the PDR group.
expression was higher in the BDR group than the control group, and higher in the PDR group than the BDR group.
expression was positively related with disease course, HbA1C, FPG and HOMA-IR, and had diagnostic value for T2D with DR and PDR. The plasma
expression was increased in the development of T2D with DR and can be used as an indicator for the severity of T2D with DR.
The ecological suitability prediction and analysis of specific taxonomic groups at finer geographic scales provide vital references for identifying and prioritizing biodiversity hotspots, especially ...for uneven species richness. Yet, in predicting suitability for multi-species or groups by species distribution models (SDMs) under highly heterogeneous environments, species bias may occur cause of the unequal protection status and the spatial autocorrelation processing of occurrences. For this, diversity, and protection hotspots were mapped in the south of the Hengduan Mountains, a significant site for global biodiversity. Specifically, it involved creating a network of 1 km
2
grid cells spanning the region, counting the orchid species, quantifying the protection value, and classifying attributes by the Jenks Natural Breaks Classification in ArcGIS. Each grid has a 5 and 10 km buffer zone that contains attributes composing the diversity and protection hotspot layers, which were compared to the orchid suitability map modeled by SDMs. Results showed that even though there were extensively suitable habitats for orchids, the model results cannot completely cover the whole diversity and protection hotspots at any scale. Based on the map attributes, multi-scenario conservation planning was proposed, respectively the strict conservation scenario (SS), the economical conservation scenario (ES), and the positive conservation scenario (PS), representing different conservation objectives and efforts. This study identifies the critical areas of ecological suitability, diversity, and protection of orchids that facilitate to display of the fundamental biogeographical patterns in this region, which provides meaningful references for regional or global biodiversity conservation and transferable methods for similar studies.
Oxytocin is a well-known neurohypophysial hormone that plays an important role in behavioral anxiety and nociception. Two major forms of long-term potentiation, presynaptic LTP (pre-LTP) and ...postsynaptic LTP (post-LTP), have been characterized in the anterior cingulate cortex (ACC). Both pre-LTP and post-LTP contribute to chronic-pain-related anxiety and behavioral sensitization. The roles of oxytocin in the ACC have not been studied. Here, we find that microinjections of oxytocin into the ACC attenuate nociceptive responses and anxiety-like behavioral responses in animals with neuropathic pain. Application of oxytocin selectively blocks the maintenance of pre-LTP but not post-LTP. In addition, oxytocin enhances inhibitory transmission and excites ACC interneurons. Similar results are obtained by using selective optical stimulation of oxytocin-containing projecting terminals in the ACC in animals with neuropathic pain. Our results demonstrate that oxytocin acts on central synapses and reduces chronic-pain-induced anxiety by reducing pre-LTP.
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•Oxytocin microinjected into ACC attenuates injury-related pain and anxiety responses•Oxytocin blocks the maintenance of pre-LTP, but not post-LTP•Oxytocin depolarizes the interneurons and decreases the ratio of E/I transmission•Activation of PVN-ACC pathway blocks pre-LTP and has analgesic and anxiolytic effects
Li et al. report that microinjection of oxytocin into the ACC attenuates nerve-injury-induced nociceptive and anxiety behavioral responses. They show that oxytocin blocks the maintenance of pre-LTP and potentiates inhibitory transmission. Optical activation of endogenous oxytocin release in the ACC blocks pre-LTP and produces analgesic and anxiolytic effects.
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