Extrachromosomal circular MiR-17-92 amplicon promotes HCC.

BACKGROUND AND AIMS: Extrachromosomal circular DNAs (eccDNAs) are prevalent in cancer genomes and emerge as a class of crucial yet less characterized oncogenic drivers. However, the structure, composition, genome-wide frequency, and contribution of eccDNAs in HCC, one of the most fatal and prevalent cancers, remain unexplored. In this study, we provide a comprehensive characterization of eccDNAs in human HCC and demonstrate an oncogenic role of microRNA (miRNA)-17-92-containing eccDNAs in tumor progression. APPROACH AND RESULTS: Using the circle-sequencing method, we identify and characterize more than 230,000 eccDNAs from 4 paired samples of HCC tumor and adjacent nontumor liver tissues. EccDNAs are highly enriched in HCC tumors, preferentially originate from certain chromosomal hotspots, and are correlated with differential gene expression. Particularly, a series of eccDNAs carrying the miRNA-17-92 cluster are validated by outward PCR and Sanger sequencing. Quantitative PCR analyses reveal that miRNA-17-92-containing eccDNAs, along with the expression of their corresponding miRNAs, are elevated in HCC tumors and associated with poor outcomes and the age of HCC patients. More intriguingly, exogenous expression of artificial DNA circles harboring the miR-17-92 cluster, which is synthesized by the ligase-assisted minicircle accumulation method, can significantly accelerate HCC cell proliferation and migration. CONCLUSIONS: These findings delineate the genome-wide eccDNAs profiling of HCC and highlight the functional significance of miRNA-containing eccDNAs in tumorigenesis, providing insight into HCC pathogenesis and cancer therapy, as well as eccDNA and miRNA biology.

Essential trace elements in patients with dyslipidemia: A meta-analysis.

BACKGROUND: Lipid metabolism is a complex process that includes lipid uptake, transport, synthesis, and degradation. Trace elements are vital in maintaining normal lipid metabolism in the human body. This study explores the relationship between serum trace elements and lipid metabolism Methods: In this study, we reviewed articles on the relationship between alterations in somatic levels of zinc, iron, calcium, copper, chrome, manganese, selenium, and lipid metabolism. In this systematic review and mate-analysis, databases such as PubMed, Web of Science, and China National Knowledge Infrastructure (CNKI), Wanfang was searched for articles on the relationship published between January 1, 1900, and July 12, 2022. The meta-analysis was performed using Review Manager5.3 (Cochrane Collaboration). RESULTS: No significant association was found between serum zinc and dyslipidemia, while other serum trace elements (Iron, selenium, copper, chromium, and manganese) were associated with hyperlipidemia. CONCLUSION: The present study suggested that the human body's zinc, copper, and calcium content may be related to lipid metabolism. However, findings on lipid metabolism and Iron, Manganese have not been conclusive. In addition, the relationship between lipid metabolism disorders and selenium levels still needs to be further studied. Further research is needed on treating lipid metabolism diseases by changing trace elements.

UBE2O promotes lipid metabolic reprogramming and liver cancer progression by mediating HADHA ubiquitination.

Cancer cells rely on heightened protein quality control mechanisms, including the ubiquitin-proteosome system that is predominantly driven by ubiquitination comprising E1, E2, and E3 trienzyme cascades. Although E3s have been extensively studied, the implication of E2s in tumorigenesis is poorly defined. Here we reveal a critical E2 in the pathogenesis of hepatocellular carcinoma (HCC). Among all of E2s, UBE2O shows the strongest association with HCC survival prognosis, and its expression is increased in HCC tumors. Accordingly, UBE2O deficiency inhibits HCC growth and metastasis both in vitro and in vivo, while its overexpression has opposite effects. Depending on both E2 and E3 enzymatic activities, UBE2O can interact with and mediate the ubiquitination and degradation of HADHA, a mitochondrial ß-oxidation enzyme, thereby modulating lipid metabolic reprogramming. HADHA is reduced in HCC tumors and inversely correlated with UBE2O levels. Importantly, HADHA acts as a tumor suppressor and primarily mediates UBE2O's function on HCC. Moreover, liver-specific deletion of Ube2o in mice are resistant to DEN-induced hepatocarcinogenesis, along with HADHA upregulation and reduced hepatic lipid accumulation. These data reveal UBE2O as a novel oncogenic driver for metabolic reprogramming and HCC development, highlighting the potential of targeting UBE2O/HADHA axis for HCC therapy.

Electroconvulsive therapy plays an irreplaceable role in treatment of major depressive disorder.

Major depressive disorder is a serious and common neuropsychiatric disorder that affects more than 350 million people worldwide. Electroconvulsive therapy is the oldest and most effective treatment available for the treatment of severe major depressive disorder. Electroconvulsive therapy modifies structural network changes in patients with major depressive disorder and schizophrenia. And it can also affect neuroinflammatory responses and may have neuroprotective effects. Electroconvulsive therapy plays an irreplaceable role in the treatment of major depressive disorder.

Inhibition of glutathione metabolism can limit the development of pancreatic cancer.

Pharmacological inhibitors of glutathione synthesis and circulation, such as buthionine-sulfoximine, inhibit glutathione metabolism. These drugs decrease the aggressiveness of pancreatic cancer, inhibit tumor stem cell survival, and reduce chemotherapy resistance. Nevertheless, buthionine-sulfoximine also decreases the content of glutathione in normal cells, disrupts the balance between reactive oxygen species and glutathione, and eventually induces cell apoptosis. Pancreatic cancer is usually diagnosed at an advanced stage and has a poor prognosis. Consequently, the use of biomarkers to screen high-risk patients can be an effective method.

Comment "Asymptomatic small intestinal ulcerative lesions: Obesity and Helicobacter pylori are likely to be risk factors".

There are many causes of anemia. It is unreasonable to simply associate anemia with asymptomatic ulcers in the small intestine.

Evaluation of a new frequency-volume chart for children with primary monosymptomatic nocturnal enuresis: a prospective, comparative study.

INTRODUCTION: To improve compliance with voiding diaries in children with primary monosymptomatic nocturnal enuresis (PMNE), a new modified 3-day weekend frequency-volume chart (FVC) was designed, and the compliance and validity of this modified FVC was evaluated by comparing with the International Children's Continence Society (ICCS) recommended voiding diary. METHODS: A total of 1200 patients with PMNE were enrolled in the study from 13 centers in China and were randomly assigned to record this modified FVC or the ICCS-recommended voiding diary. The primary outcome measure was the compliance, assessed by comparing the completing index and the quality score of diaries between two groups. The secondary outcome measure was the validity, evaluated by comparing the constituent of subtypes, micturition parameters and response rate to desmopressin. RESULTS: Among the 1200 participants enrolled in the study, 447 patients completed the ICCS-recommended voiding diary and 469 completed the modified diary. The diurnal completing index and the quality score of the modified FVC group were better than those of the ICCS group. In addition, there was no significant difference between these two groups in the subtype classification, or in the response rate to desmopressin. CONCLUSIONS: The modified FVC could be applied to obtain the voiding characteristics of children with PMNE as the ICCS-recommended voiding diary does and offers a reasonable and better choice for children with PMNE from the unselected population in the future.

Lentinan-Based Oral Nanoparticle Loaded Budesonide With Macrophage-Targeting Ability for Treatment of Ulcerative Colitis.

Ulcerative colitis (UC) is a global, chronic, and refractory disease. Corticosteroids are first-line drugs for the treatment of UC but also cause adverse side effects. Budesonide (BUD), a corticosteroid with relatively low side effects, has been approved by the Food and Drug Administration for use as enteric capsules (Entocort EC) for the treatment of inflammatory bowel disease (IBD). However, this formulation lacks specific targeting ability to UC lesions. Herein, we describe the development of an advanced macrophage-targeted oral lentinan (LNT)-based nanoparticles (NPs) loaded BUD for treatment of UC. Briefly, LNT was used as a food source and natural carrier to load BUD by a simple solvent evaporation method to form LNT/BUD-NPs. LNT showed good loading capacity with high encapsulation and loading efficiencies to BUD of approximately 92.19 and 9.58%, respectively. Evaluation of the gastric stability of LNT/BUD-NPs indicated that LNT could effectively protect BUD from gastric acid and digestive enzymes. The release behavior and transmission electron microscopy image of LNT/BUD-NPs in the intestinal content of mice confirmed that intestinal flora can promote BUD release from LNT. Moreover, evaluation of cellular uptake showed that LNT/BUD-NPs could specifically target macrophages and enhance their uptake rate via the Dectin-1 receptor. In biodistribution studies, LNT/BUD-NPs were able to efficiently accumulate in the inflamed colon of mice. As expected, LNT/BUD-NPs could significantly alleviate inflammation by inhibiting the TLR4/MyD88/NF-κB signaling pathway. Therefore, LNT/BUD-NPs have the advantages of good gastric stability, release mediated by mouse intestinal content, macrophage-targeting, and anti-UC effects. These advantages indicate LNT-based NPs are a promising oral drug delivery system for UC therapy.

RNA G-quadruplex regulates microRNA-26a biogenesis and function.

BACKGROUND & AIMS: RNA G-quadruplexes (RG4s) appear to be important in post-transcriptional gene regulation, but their pathophysiological functions remain unknown. MicroRNA-26a (miR-26a) is emerging as a therapeutic target for various human diseases, however the mechanisms underlying endogenous miR-26a regulation are poorly understood. Herein, we study the role of RG4 in miR-26a expression and function in vitro and in vivo. METHODS: Putative RG4s within liver-enriched miRNAs were predicted by bioinformatic analysis, and the presence of an RG4 structure in the miR-26a-1 precursor (pre-miR-26a-1) was further analyzed by biophysical and biochemical methods. RG4 stabilizers, pre-miR-26a-1 overexpression plasmids, and luciferase reporter assays were used to assess the effect of RG4 on pre-miR-26a-1 maturation. Both miR-26a knock-in and knockout mouse models were employed to investigate the influence of this RG4 on miR-26a expression and function. Moreover, the interaction between RG4 in pre-miR-26a-1 and DEAH-box helicase 36 (DHX36) was determined by biophysical and molecular methods. Finally, miR-26a processing and DHX36 expression were quantified in the livers of obese mice. RESULTS: We identify a guanine-rich sequence in pre-miR-26a-1 that can fold into an RG4 structure. This RG4 impairs pre-miR-26a-1 maturation, resulting in a decrease in miR-26a expression and subsequently an increase in miR-26a cognate targets. In line with known miR-26a functions, this RG4 can regulate hepatic insulin sensitivity and lipid metabolism in vitro and in vivo. Furthermore, we reveal that DHX36 can bind and unwind this RG4 structure, thereby enhancing miR-26a maturation. Intriguingly, there is a concordant decrease of miR-26a maturation and DHX36 expression in obese mouse livers. CONCLUSIONS: Our findings define a dynamic DHX36/RG4/miR-26a regulatory axis during obesity, highlighting an important role of RG4 in physiology and pathology. LAY SUMMARY: Specific RNA sequences called G-quadruplexes (or RG4) appear to be important in post-transcriptional gene regulation. Obesity leads to the formation of these RG4 structures in pre-miR-26a-1 molecules, impairing the maturation and function of miR-26a, which has emerged as a therapeutic target in several diseases. This contributes to hepatic insulin resistance and the dysregulation of liver metabolism.

Pancreatic ß cell microRNA-26a alleviates type 2 diabetes by improving peripheral insulin sensitivity and preserving ß cell function.

Type 2 diabetes (T2D) is characterized by insulin resistance along with pancreatic ß cell failure. ß cell factors are traditionally thought to control glucose homeostasis by modulating insulin levels, not insulin sensitivity. Exosomes are emerging as new regulators of intercellular communication. However, the role of ß-cell-derived exosomes in metabolic homeostasis is poorly understood. Here, we report that microRNA-26a (miR-26a) in ß cells not only modulates insulin secretion and ß cell replication in an autocrine manner but also regulates peripheral insulin sensitivity in a paracrine manner through circulating exosomes. MiR-26a is reduced in serum exosomes of overweight humans and is inversely correlated with clinical features of T2D. Moreover, miR-26a is down-regulated in serum exosomes and islets of obese mice. Using miR-26a knockin and knockout mouse models, we showed that miR-26a in ß cells alleviates obesity-induced insulin resistance and hyperinsulinemia. Mechanistically, miR-26a in ß cells enhances peripheral insulin sensitivity via exosomes. Meanwhile, miR-26a prevents hyperinsulinemia through targeting several critical regulators of insulin secretion and ß cell proliferation. These findings provide a new paradigm for the far-reaching systemic functions of ß cells and offer opportunities for the treatment of T2D.

Metabolism-induced tumor activator 1 (MITA1), an Energy Stress-Inducible Long Noncoding RNA, Promotes Hepatocellular Carcinoma Metastasis.

Metastasis is the main cause of cancer-related death, yet the underlying mechanisms are still poorly understood. Long noncoding RNAs (lncRNAs) are emerging as crucial regulators of malignancies; however, their functions in tumor metastasis remain largely unexplored. In this study, we identify a lncRNA, termed metabolism-induced tumor activator 1 (MITA1), which is up-regulated in hepatocellular carcinoma (HCC) and contributes to metastasis. MITA1, a chromatin-enriched lncRNA discovered by our nuclear RNA sequencing, is significantly induced by energy stress. This induction of MITA1 is governed by the liver kinase B1-adenosine monophosphate-activated protein kinase (LKB1-AMPK) pathway and DNA methylation. Knockdown of MITA1 dramatically inhibits the migration and invasion of liver cancer cells in vitro and HCC metastasis in vivo. Mechanistically, MITA1 promotes the epithelial-mesenchymal transition, an early and central step of metastasis, which may partly attribute to an increase in Slug (snail family zinc finger 2) transcription. MITA1 deficiency reduces the expression of the mesenchymal cell markers, especially Slug, whereas Slug overexpression greatly impairs the effects of MITA1 deficiency on HCC migration and invasion. Correspondingly, there is a positive correlation between the levels of MITA1 and Slug precursors in HCC tissues. Conclusion: Our data reveal MITA1 as a crucial driver of HCC metastasis, and highlight the identified AMPK-MITA1-Slug axis as a potential therapeutic strategy for HCC.

Broadband achromatic metalens in terahertz regime.

Achromatic focusing is essential for broadband operation, which has recently been realised from visible to infrared wavelengths using a metasurface. Similarly, multi-terahertz functional devices can be encoded in a desired metasurface phase profile. However, metalenses suffer from larger chromatic aberrations because of the intrinsic dispersion of each unit element. Here, we propose an achromatic metalens with C-shaped unit elements working from 0.3 to 0.8 THz with a bandwidth of approximately 91% over the centre frequency. The designed metalens possesses a high working efficiency of more than 68% at the peak and a relatively high numerical aperture of 0.385. We further demonstrate the robustness of our C-shaped metalens, considering lateral shape deformations and deviations in the etching depth. Our metalens design opens an avenue for future applications of terahertz meta-devices in spectroscopy, time-of-flight tomography and hyperspectral imaging systems.

MicroRNA-664-5p promotes myoblast proliferation and inhibits myoblast differentiation by targeting serum response factor and Wnt1.

MicroRNAs (miRNAs) are noncoding RNAs that regulate gene expression at the post-transcriptional level and are involved in the regulation of the formation, maintenance, and function of skeletal muscle. Using miRNA sequencing and bioinformatics analysis, we previously found that the miRNA miR-664-5p is significantly differentially expressed in longissimus dorsi muscles of Rongchang pigs. However, the molecular mechanism by which miR-664-5p regulates myogenesis remains unclear. In this study, using flow cytometry, 5-ethynyl-2'-deoxyuridine staining, and cell count and immunofluorescent assays, we found that cell-transfected miR-664-5p mimics greatly promoted proliferation of C2C12 mouse myoblasts by increasing the proportion of cells in the S- and G2-phases and up-regulating the expression of cell cycle genes. Moreover, miR-664-5p inhibited myoblast differentiation by down-regulating myogenic gene expression. In contrast, miR-664-5p inhibitor repressed myoblast proliferation and promoted myoblast differentiation. Mechanistically, using dual-luciferase reporter gene experiments, we demonstrated that miR-664-5p directly targets the 3'-UTR of serum response factor (SRF) and Wnt1 mRNAs. We also observed that miR-664-5p inhibits both mRNA and protein levels of SRF and Wnt1 during myoblast proliferation and myogenic differentiation, respectively. Furthermore, the activating effect of miR-664-5p on myoblast proliferation was attenuated by SRF overexpression, and miR-664-5p repressed myogenic differentiation by diminishing the accumulation of nuclear ß-catenin. Of note, miR-664-5p's inhibitory effect on myogenic differentiation was abrogated by treatment with Wnt1 protein, the key activator of the Wnt/ß-catenin signaling pathway. Collectively, our findings suggest that miR-664-5p controls SRF and canonical Wnt/ß-catenin signaling pathways in myogenesis.

MicroRNA-432 targeting E2F3 and P55PIK inhibits myogenesis through PI3K/AKT/mTOR signaling pathway.

Skeletal muscle is the dominant executant in locomotion and regulator in energy metabolism. Embryonic myogenesis and postnatal muscle growth are controlled by a cascade of transcription factors and epigenetic regulatory mechanisms. MicroRNAs (miRNAs), a family of non-coding RNA of 22 nucleotides in length, post-transcriptionally regulates expression of mRNA by pairing the seed sequence to 3' UTR of target mRNA. Increasing evidence has demonstrated that miRNAs are important regulators in diverse myogenic processes. The profiling of miRNA expression revealed that miR-432 is more enriched in the longissimus dorsi of 35-day-old piglets than that of adult pigs. Our gain of function study showed that miR-432 can negatively regulate both myoblast proliferation and differentiation. Mechanically, we found that miR-432 is able to down-regulate E2F transcription factor 3 (E2F3) to inactivate the expression of cell cycle and myogenic genes. We also identified that phosphatidylinositol 3-kinase regulatory subunit (P55PIK) is another target gene of miR-432 in muscle cells. downregulation of P55PIK by miR-432 leads to inhibition of P55PIK-mediated PI3K/AKT/mTOR signaling pathway during differentiation. The blocking effect of miR-432 on this pathway can be rescued by insulin treatment. Taken together, our findings identified microRNA-432 as a potent inhibitor of myogenesis which functions by targeting E2F3 and P55PIK in muscle cells.