MicroRNA dysregulation and esophageal cancer development depend on the extent of zinc dietary deficiency

open9siopenFong, Louise Y.; Taccioli, Cristian; Jing, Ruiyan; Smalley, Karl J.; Alder, Hansjuerg; Jiang, Yubao; Fadda, Paolo; Farber, John L.; Croce, Carlo M.Fong, Louise Y.; Taccioli, Cristian; Jing, Ruiyan; Smalley, Karl J.; Alder, Hansjuerg; Jiang, Yubao; Fadda, Paolo; Farber, John L.; Croce, Carlo M

Integration of metabolomics, transcriptomics, and microRNA expression profiling reveals a miR-143-HK2-glucose network underlying zinc-deficiency-associated esophageal neoplasia

Esophageal squamous cell carcinoma (ESCC) in humans is a deadly disease associated with dietary zinc (Zn)-deficiency. In the rat esophagus, Zn-deficiency induces cell proliferation, alters mRNA and microRNA gene expression, and promotes ESCC. We investigated whether Zn-deficiency alters cell metabolism by evaluating metabolomic profiles of esophageal epithelia from Zn-deficient and replenished rats vs sufficient rats, using untargeted gas chromatography time-of-flight mass spectrometry (n = 8/group). The Zn-deficient proliferative esophagus exhibits a distinct metabolic profile with glucose down 153-fold and lactic acid up 1.7-fold (P \u3c 0.0001), indicating aerobic glycolysis (the Warburg effect ), a hallmark of cancer cells. Zn-replenishment rapidly increases glucose content, restores deregulated metabolites to control levels, and reverses the hyperplastic phenotype. Integration of metabolomics and our reported transcriptomic data for this tissue unveils a link between glucose down-regulation and overexpression of HK2, an enzyme that catalyzes the first step of glycolysis and is overexpressed in cancer cells. Searching our published microRNA profile, we find that the tumor-suppressor miR-143, a negative regulator of HK2, is down-regulated in Zn-deficient esophagus. Using in situ hybridization and immunohistochemical analysis, the inverse correlation between miR-143 down-regulation and HK2 overexpression is documented in hyperplastic Zndeficient esophagus, archived ESCC-bearing Zn-deficient esophagus, and human ESCC tissues. Thus, to sustain uncontrolled cell proliferation, Zn-deficiency reprograms glucose metabolism by modulating expression of miR-143 and its target HK2. Our work provides new insight into critical roles of Zn in ESCC development and prevention. © Fong et al

Human-like hyperplastic prostate with low ZIP1 induced solely by Zn deficiency in rats

Prostate cancer is a leading cause of cancer death in men over 50 years of age, and there is a characteristic marked decrease in Zn content in the malignant prostate cells. The cause and consequences of this loss have thus far been unknown. We found that in middle-aged rats a Zn-deficient diet reduces prostatic Zn levels (P = 0.025), increases cellular proliferation, and induces an inflammatory phenotype with COX-2 overexpression. This hyperplastic/inflammatory prostate has a human prostate cancer-like microRNA profile, with up-regulation of the Zn-homeostasis-regulating miR-183-96-182 cluster (fold change = 1.41-2.38; P = 0.029-0.0003) and down-regulation of the Zn importer ZIP1 (target of miR-182), leading to a reduction of prostatic Zn. This inverse relationship between miR-182 and ZIP1 also occurs in human prostate cancer tissue, which is known for Zn loss. The discovery that the Zn-depleted middle-aged rat prostate has a metabolic phenotype resembling that of human prostate cancer, with a 10-fold down-regulation of citric acid (P = 0.0003), links citrate reduction directly to prostatic Zn loss, providing the underlying mechanism linking dietary Zn deficiency with miR-183-96-182 overexpression, ZIP1 down-regulation, prostatic Zn loss, and the resultant citrate down-regulation, changes mimicking features of human prostate cancer. Thus, dietary Zn deficiency during rat middle age produces changes that mimic those of human prostate carcinoma and may increase the risk for prostate cancer, supporting the need for assessment of Zn supplementation in its prevention

Zinc Treatment Reverses and anti-Zn-Regulated miRs Suppress Esophageal Carcinomas In Vivo

Esophageal squamous cell carcinoma (ESCC) is a deadly disease with few prevention or treatment options. ESCC development in humans and rodents is associated with Zn deficiency (ZD), inflammation, and overexpression of oncogenic microRNAs: miR-31 and miR-21. In a ZD-promoted ESCC rat model with upregulation of these miRs, systemic antimiR-31 suppresses the miR-31-EGLN3/STK40-NF-κB-controlled inflammatory pathway and ESCC. In this model, systemic delivery of Zn-regulated antimiR-31, followed by antimiR-21, restored expression of tumor-suppressor proteins targeted by these specific miRs: STK40/EGLN3 (miR-31), PDCD4 (miR-21), suppressing inflammation, promoting apoptosis, and inhibiting ESCC development. Moreover, ESCC-bearing Zn-deficient (ZD) rats receiving Zn medication showed a 47% decrease in ESCC incidence vs. Zn-untreated controls. Zn treatment eliminated ESCCs by affecting a spectrum of biological processes that included downregulation of expression of the two miRs and miR-31-controlled inflammatory pathway, stimulation of miR-21-PDCD4 axis apoptosis, and reversal of the ESCC metabolome: with decrease in putrescine, increase in glucose, accompanied by downregulation of metabolite enzymes ODC and HK2. Thus, Zn treatment or miR-31/21 silencing are effective therapeutic strategies for ESCC in this rodent model and should be examined in the human counterpart exhibiting the same biological processes

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Intestinal Microbiota-Derived Short Chain Fatty Acids in Host Health and Disease

Intestinal microbiota has its role as an important component of human physiology. It produces metabolites that module key functions to establish a symbiotic crosstalk with their host. Among them, short chain fatty acids (SCFAs), produced by intestinal bacteria during the fermentation of partially and non-digestible polysaccharides, play key roles in regulating colon physiology and changing intestinal environment. Recent research has found that SCFAs not only influence the signal transduction pathway in the gut, but they also reach tissues and organs outside of the gut, through their circulation in the blood. Growing evidence highlights the importance of SCFAs level in influencing health maintenance and disease development. SCFAs are probably involved in the management of host health in a complicated (positive or negative) way. Here, we review the current understanding of SCFAs effects on host physiology and discuss the potential prevention and therapeutics of SCFAs in a variety of disorders. It provides a systematic theoretical basis for the study of mechanisms and precise intake level of SCFAs to promote human health

Difference in the recruitment of intrinsic foot muscles in the elderly under static and dynamic postural conditions

Background The effect of foot, especially intrinsic muscles, on postural control and its related mechanisms remain unclear due to the complex structure. Therefore, this study aims to investigate the activation of intrinsic foot muscles in the elderly under static and dynamic postural tasks. Methods Twenty-one elderly participants were included to perform different postural tests (sensory organization test (SOT), motor control test (MCT), limit of stability test (LOS), and unilateral stance test) by a NeuroCom Balance Manager System. The participants were instructed to maintain postural stability under conditions with combined different sensory inputs (vision, vestibular, and proprioception) in SOT as well as conditions with translation disturbance in MCT, and to perform an active weight-shifting tasks in LOS. During these tasks, muscle activation were simultaneously acquired from intrinsic foot muscles (abductor halluces (AbH) and flexor digitorum brevis (FDB)) and ankle muscles (anterior tibialis, medial head of gastrocnemius, lateral head of gastrocnemius, and peroneus longus). The root-mean-square amplitude of these muscles in postural tasks was calculated and normalized with the EMG activity in unilateral stance task. Results The activation of intrinsic foot muscles significantly differed among different SOT tasks (p < 0.001). Post-hoc tests showed that compared with that under normal condition 1 without sensory interference, EMGs increased significantly under sensory disturbance (conditions 2–6). By contrast, compared with that under the single-sensory disturbed conditions (conditions 2–4; 2 for disturbed vision, 3 for disturbed vestibular sensation, 4 for disturbed proprioception), activation was significantly greater under the dual-sensory disturbed postural tasks (conditions 5 and 6; 5 for disturbed vision and proprioception, 6 for disturbed vestibular sensation and proprioception). In MCT, EMGs of foot muscles increased significantly under different translation speeds (p < 0.001). In LOS, moderate and significant correlations were found between muscle activations and postural stability parameters (AbH, r = 0. 355–0.636, p < 0.05; FDB, r = 0.336–0.622, p < 0.05). Conclusion Intrinsic foot muscles play a complementary role to regulate postural stability when disturbances occur. In addition, the recruitment magnitude of intrinsic foot muscles is positively correlated with the limit of stability, indicating their contribution to increasing the limits of stability in the elderly

Toughness enhancement of polyamide 1012 with intermolecular hydrogen bonding with 3-pentadecylphenol

In order to improve the impact toughness of polyamide 1012 (PA1012) by reducing the amount of hydrogen bonding resulting from PA1012 itself, 3-pentadecylphenol (PDP) was considered to be added into PA1012 using melting extrusion. The hydrogen bonding interaction between PA1012 and PDP was characterized by Fourier transform infrared spectroscopy (FTIR) and nuclear magnetic resonance (NMR). The effects of PDP on the crystallization, melting process, and mechanical behavior of PA1012 were tested in detail. The results show that the PDP can reduce the temperature of PA1012 crystallization and melting but it can significantly improve elongation at break and impact toughness. The notched impact strength of the PA1012/PDP composites containing 20 wt% PDP reached to 70.6 kJ·m–2, which is about seven times that of the neat PA1012. The effects of PDP on PA1012 properties is ascribed to hydrogen bonding interaction between hydrogen bonding between phenol hydroxyl groups and amino groups on PA1012 chains. The deduction was also verified by adding acetylated 3-pentadecylphenol (APDP) to modify PA1012. It is believed the research will open up new prospects for the wide application of PA1012 toughening

The effects of low-dose Nepsilon-(carboxymethyl)lysine (CML) and Nepsilon-(carboxyethyl)lysine (CEL), two main glycation free adducts considered as potential uremic toxins, on endothelial progenitor cell function

<p>Abstract</p> <p>Background</p> <p>Patients with chronic kidney disease (CKD) are at high risk of cardiovascular disease (CVD). Endothelial progenitor cell (EPCs) dysfunction plays a key role in this pathogenesis. Uremic retention toxins have been reported to be in associated with EPC dysfunction. Advanced glycation end-products (AGEs) free adducts, including Nepsilon-(carboxymethyl)lysine (CML) and Nepsilon-(carboxyethyl)lysine (CEL), are formed by physiological proteolysis of AGEs and released into plasma for urinary excretion. They are retained in CKD patients and are considered to be potential uremic toxins. Though AGEs have been demonstrated to impair EPC function in various ways, the effect of AGE free adducts on EPC function has not been studied. Thus, we examined the role of CML and CEL in the regulation of growth-factor-dependent function in cultured human EPCs and the mechanisms by which they may affect EPC function.</p> <p>Methods</p> <p>Late outgrowth EPCs were incubated with different concentrations of CML or CEL for up to 72 hours. Cell proliferation was determined using WST-1 and BrdU assays. Cell apoptosis was tested with annexin V staining. Migration and tube formation assays were used to evaluate EPC function.</p> <p>Results</p> <p>Though CML and CEL were determined to have anti-proliferative effects on EPCs, cells treated with concentrations of CML and CEL in the range found in CKD patients had no observable impairment on migration or tube formation. CML and CEL did not induce EPC apoptosis. The reduced growth response was accompanied by significantly less phosphorylation of mitogen-activated protein kinases (MAPKs).</p> <p>Conclusions</p> <p>Our study revealed that CML and CEL at uremic concentrations have low biological toxicity when separately tested. The biologic effects of AGE free adducts on the cardiovascular system merit further study.</p

Zinc treatment reverses and anti-Zn-regulated miRs suppress esophageal carcinomas in&nbsp;vivo.

Esophageal squamous cell carcinoma (ESCC) is a deadly disease with few prevention or treatment options. ESCC development in humans and rodents is associated with Zn deficiency (ZD), inflammation, and overexpression of oncogenic microRNAs: miR-31 and miR-21. In a ZD-promoted ESCC rat model with upregulation of these miRs, systemic antimiR-31 suppresses the miR-31-EGLN3/STK40-NF-κB-controlled inflammatory pathway and ESCC. In this model, systemic delivery of Zn-regulated antimiR-31, followed by antimiR-21, restored expression of tumor-suppressor proteins targeted by these specific miRs: STK40/EGLN3 (miR-31), PDCD4 (miR-21), suppressing inflammation, promoting apoptosis, and inhibiting ESCC development. Moreover, ESCC-bearing Zn-deficient (ZD) rats receiving Zn medication showed a 47% decrease in ESCC incidence vs. Zn-untreated controls. Zn treatment eliminated ESCCs by affecting a spectrum of biological processes that included downregulation of expression of the two miRs and miR-31-controlled inflammatory pathway, stimulation of miR-21-PDCD4 axis apoptosis, and reversal of the ESCC metabolome: with decrease in putrescine, increase in glucose, accompanied by downregulation of metabolite enzymes ODC and HK2. Thus, Zn treatment or miR-31/21 silencing are effective therapeutic strategies for ESCC in this rodent model and should be examined in the human counterpart exhibiting the same biological processes