Glycolysis is critical for cancer stem cell reprogramming; however, the underlying regulatory mechanisms remain elusive. Here, we show that pyruvate dehydrogenase kinase 1 (PDK1) is enriched in ...breast cancer stem cells (BCSCs), whereas depletion of PDK1 remarkably diminishes ALDH
subpopulations, decreases stemness-related transcriptional factor expression, and inhibits sphere-formation ability and tumor growth. Conversely, high levels of PDK1 enhance BCSC properties and are correlated with poor overall survival. In mouse xenograft tumor, PDK1 is accumulated in hypoxic regions and activates glycolysis to promote stem-like traits. Moreover, through screening hypoxia-related long non-coding RNAs (lncRNAs) in PDK1-positive tissue, we find that lncRNA H19 is responsible for glycolysis and BCSC maintenance. Furthermore, H19 knockdown decreases PDK1 expression in hypoxia, and ablation of PDK1 counteracts H19-mediated glycolysis and self-renewal ability in vitro and in vivo. Accordingly, H19 and PDK1 expression exhibits strong correlations in primary breast carcinomas. H19 acting as a competitive endogenous RNA sequesters miRNA let-7 to release Hypoxia-inducible factor 1α, leading to an increase in PDK1 expression. Lastly, aspirin markedly attenuates glycolysis and cancer stem-like characteristics by suppressing both H19 and PDK1. Thus, these novel findings demonstrate that the glycolysis gatekeeper PDK1 has a critical role in BCSC reprogramming and provides a potential therapeutic strategy for breast malignancy.
Phosphate originated from industrial effluents is one of the key factors responsible for eutrophication of the receiving waterways especially in the developing countries such as China. In the current ...study we proposed a novel process to immobilize nanoparticulate hydrated ferric oxide (HFO) within a macroporous anion exchange resin D-201, and obtained a hybrid adsorbent (HFO-201) for enhanced phosphate removal from aqueous system. The resulting HFO-201 possesses two types of adsorption sites for phosphate removal, the ammonium groups bound to the D-201 matrix and the loaded HFO nanoparticles. The coexisting sulfate anion strongly competes for ammonium groups, which bind phosphate through electrostatic interaction. However, it does not pose any noticeable effect on phosphate adsorption by the loaded HFO nanoparticles, which is driven by the formation of the inner-sphere complexes. Batch adsorption experiments also indicated that HFO-201 exhibits a little higher capacity for phosphate than the commercially available phosphate-specific adsorbent ArsenX
np, which possesses similar structure of HFO-201 and is produced by another patented technique. Fixed-bed column tests indicate that phosphate retention by HFO-201 from the synthetic waters results in the significant decrease of P from 2
mg/L to less than 0.01
mg/L, with the treatment capacity of ∼700 bed volume (BV) per run, while that for D-201 was less than 200 BV under otherwise identical conditions. Such satisfactory performance of the hybrid adsorbent is mainly attributed to the specific affinity of HFO toward phosphate as well as the Donnan membrane effect exerted by the anion exchanger support D-201. Moreover, the exhausted HFO-201 was amenable to efficient in situ regeneration with a binary NaOH–NaCl solution for repeated use without any significant capacity loss. Similar satisfactory results were also observed by using a phosphate-containing industrial effluent as the feeding solution.
Tumor immune microenvironment (TIME) include tumor cells, immune cells, cytokines, etc. The interactions between these components, which are divided into anti-tumor and pro-tumor, determine the trend ...of anti-tumor immunity. Although the immune system can eliminate tumor through the cancer-immune cycle, tumors appear to eventually evade from immune surveillance by shaping an immunosuppressive microenvironment. Immunotherapy reshapes the TIME and restores the tumor killing ability of anti-tumor immune cells. Herein, we review the function of immune cells within the TIME and discuss the contribution of current mainstream immunotherapeutic approaches to remolding the TIME. Changes in the immune microenvironment in different forms under the intervention of immunotherapy can shed light on better combination treatment strategies.
Two doses of AZD1222 generated NAb activity against the Wildtype strain bearing a spike identical to that encoded by the vaccine in all participants (median NAbT IC50=419), with a 2·1–fold (95% CI ...2·0–2·2) reduction in median NAbT relative to two doses of BNT162b2 (appendix p 2). ...median NAbTs against all SARS-CoV-2 variants were further reduced relative to BNT162b2: 2·4-fold (95% CI 2·3–2·6) against D614G, 2·4-fold against B.1.1.7 (2·2–2·5), 2·5-fold (1·3–2·8) against B.1.351, and 2·5-fold (1·4–2·7) against B.1.617.2. After a single AZD1222 dose, participants with prior COVID-19 symptoms (16 32% of 50) had significantly higher NAbTs against all strains than those without prior COVID symptoms (5·1 × 10−5 ≤3·1 × 10−4). Since many responses fell outside of the quantitative limit of detection, stratification of NAbTs was again informative. Prevention of infection, however, appears to require substantially higher NAbTs than prevention of the most severe COVID-19 disease and death. ...although reduced in-vitro neutralisation of VOCs predicts reduced AZD1222 vaccine efficacy against symptomatic infection with the same VOCs, close monitoring of the unfolding pandemic will reveal the extent to which the link with severe or fatal COVID-19 has been broken by all current vaccines.
Elucidation of the molecular mechanisms governing the osteogenic differentiation of human mesenchymal stem cells (hMSCs) is of great importance for improving the treatment of bone-related diseases. ...MicroRNAs (miRNAs or miRs), a class of small non-coding RNAs, are critical in a number of biological processes, including the proliferation, differentiation and survival of cells and organisms. Emerging evidence indicates that miRNAs are essential in regulating osteoblastogenesis and bone formation. However, the role of miRNAs in osteoblast mechanotransduction remains to be defined. The present study aimed to examine the role of miR-153 in the osteogenesis of hMSCs and to investigate the impact of miR-153 on bone morphogenetic protein receptor type II (BMPR2) expression. The overexpression of miR-153 inhibited the osteogenic differentiation of hMSCs, whereas downregulation of miR-153 enhanced the process. Furthermore, bioinformatic analysis predicted that miR-153 is a potential regulator of BMPR2. The direct binding of miR-153 to the BMPR2 3'-untranslated region (3'-UTR) was demonstrated by a luciferase reporter assay using a construct containing the BMPR2 3'-UTR. In addition, knockdown of BMPR2 by RNA interference inhibited the osteogenic differentiation of hMSCs, with a similar effect to the upregulation of miR-153. In conclusion, the results suggest that miR-153 is a mechano-sensitive miRNA that regulates osteoblast differentiation by directly targeting BMPR2, and that therapeutic inhibition of miR-153 may be an efficient anabolic strategy for skeletal disorders caused by pathological mechanical loading.
Mincle (macrophage-inducible C-type lectin, Clec4e) is a transmembrane pattern recognition receptor involving the innate immunity, but its role in kidney disease is still unexplored. In the ...obstructed kidney of the unilateral ureteral obstruction model of renal injury, Mincle was specifically detected in the infiltrating M1 macrophages (CD68+iNOS+ cells) on day one but was rapidly reduced following reduction of M1 macrophages during the progression of kidney injury. Interestingly, Mincle-expressing macrophages were progressively increased in the cisplatin-induced acute kidney injury model, where iNOS expression was detected in the CD68+ cells following Mincle induction. Adaptive transfer of Mincle+ M1 macrophages largely promoted cisplatin-induced renal inflammation, which was prevented by the knockdown of Mincle in the transferred cells. Mincle was tightly regulated by TLR4/NF-κB signaling as evidenced by the binding of NF-κB/p65 to the promoter region of Mincle in LPS-primed macrophages. Blocking TLR4 or NF-κB suppressed LPS-induced Mincle expression on macrophages. Importantly, Mincle was found to be essential for maintaining the inflammatory phenotypes of M1 macrophages through the Syk signaling pathway since knockdown of Mincle or inhibition of Syk suppressed LPS-induced IL-1β, MCP-1, and iNOS expression. Thus, Mincle is induced specifically on M1 macrophages, where Mincle-Syk signaling promotes and maintains inflammatory phenotypes of M1 macrophages in acute renal inflammation. Hence, targeting Mincle may be a novel therapy for acute kidney injury associated with M1 macrophages.
The aim of the present study was to determine whether probiotics could help to improve the eradication rates and reduce the side effects associated with anti-Helicobacter pylori treatment, and to ...investigate the optimal time and duration of probiotic administration during the treatment, thus providing clinical practice guidelines for eradication success worldwide. By searching Pubmed, Embase, the Cochrane Central Register of Controlled Trials and the Science Citation Index, all the randomized controlled trials (RCTs) comparing probiotics as adjuvant agents of anti-H. pylori standard triple-therapy regimens with placebo or no treatment were selected. Statistical analysis was performed with the Comprehensive Meta Analysis Software. Subgroup, meta-regression and sensitivity analyses were also carried out. Twenty-one RCTs involving a total of 3,814 participants met the inclusion criteria. The pooled eradication rates of the probiotic group were 80.3% (1,709/2,128) by intention-to-treat (ITT) and 83.8% (1,709/2,039) by pro-protocol analyses; the pooled relative risk (RR) by ITT for probiotic supplementation versus treatment without probiotics was 1.12 95% confidence interval (CI), 1.06-1.19. A reduced risk of overall H. pylori therapy-related adverse effects was also found with probiotic supplementation (RR, 0.60; 95% CI, 0.40-0.91). The subgroup analyses showed that probiotic supplementation prior and subsequent to the treatment regimen both improved eradication rates for H. pylori infection. Furthermore, probiotic treatment lasting >2 weeks and including Lactobacillus or multiple probiotic strains significantly enhanced the efficacy. In conclusion, supplementation with probiotics for H. pylori eradication may be effective in increasing eradication rates and decreasing therapy-related side effects. Probiotic administration prior or subsequent to therapy and for a duration of >2 weeks may increase the eradication efficacy.
Mitochondrial oxidative damage is hypothesized to contribute to the pathogenesis of chronic cholestatic liver diseases. Melatonin, an indolamine synthesized in the pineal gland, shows a wide range of ...physiological functions, and is under clinical investigation for expanded applications. Melatonin has demonstrated efficient protective effects against various types of oxidative damage in the liver system. This study investigates the protective effects of melatonin pretreatment on glycochenodeoxycholic acid (GCDCA)-induced hepatotoxicity and elucidates the potential mechanism of melatonin-mediated protection. Melatonin markedly decreased mitochondrial ROS (mROS) production in L02 cells treated with 100 μM GCDCA, and inhibited GCDCA-stimulated cytotoxicity. Notably, melatonin exerted its hepatoprotective effects by upregulating sirtuin 3 (SIRT3) activity and its expression level, thus regulating superoxide dismutase 2 (SOD2) acetylation and inhibiting the production of mROS induced by GCDCA. Moreover, siRNA targeting SIRT3 blocked the melatonin-mediated elevation in mitochondrial function by inhibiting SIRT3/SOD2 signaling. Importantly, melatonin-activated SIRT3 activity was completely abolished by AMP-activated, alpha 1 catalytic subunit (AMPK) siRNA transfection. Similar results were obtained in rat with bile duct ligation or BDL. In summary, our findings indicate that melatonin is a novel hepatoprotective small molecule that functions by elevating SIRT3, stimulating SOD2 activity, and suppressing mitochondrial oxidative stress at least through AMPK, and that SIRT3 may be of therapeutic value in liver cell protection for GCDCA-induced hepatotoxicity.
Many schizophrenia susceptibility loci have been identified through genome-wide association studies (GWASs) in European populations. However, until recently, schizophrenia GWASs in non-European ...populations were limited to small sample sizes and have yielded few loci associated with schizophrenia. To identify genetic risk variations for schizophrenia in the Han Chinese population, we performed a two-stage GWAS of schizophrenia comprising 4384 cases and 5770 controls, followed by independent replications of 13 single-nucleotide polymorphisms in an additional 4339 schizophrenia cases and 7043 controls of Han Chinese ancestry. Furthermore, we conducted additional analyses based on the results in the discovery stage. The combined analysis confirmed evidence of genome-wide significant associations in the Han Chinese population for three loci, at 2p16.1 (rs1051061, in an exon of VRK2, P=1.14 × 10
, odds ratio (OR)=1.17), 6p22.1 (rs115070292 in an intron of GABBR1, P=4.96 × 10
, OR=0.77) and 10q24.32 (rs10883795 in an intron of AS3MT, P=7.94 × 10
, OR=0.87; rs10883765 at an intron of ARL3, P=3.06 × 10
, OR=0.87). The polygenic risk score based on Psychiatric Genomics Consortium schizophrenia GWAS data modestly predicted case-control status in the Chinese population (Nagelkerke R
: 1.7% ~5.7%). Our pathway analysis suggested that neurological biological pathways such as GABAergic signaling, dopaminergic signaling, cell adhesion molecules and myelination pathways are involved in schizophrenia. These findings provide new insights into the pathogenesis of schizophrenia in the Han Chinese population. Further studies are needed to establish the biological context and potential clinical utility of these findings.
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