Front Cover: The cover image is based on the Research Article Oleanolic acid exerts inhibitory effects on the late stage of osteoclastogenesis and prevents bone loss in osteoprotegerin knockout mice by Dongfeng Zhao et al., https://doi.org/10.1002/jcb.28994.

Cover Credit: Cover image © Dongfeng Zhao Images

Back Cover: The cover image is based on the Research Article Hypoxia alters the release and size distribution of extracellular vesicles in pancreatic cancer cells to support their adaptive survival by Mary C. Patton et al., https://doi.org/10.1002/jcb.29328.

Cover Credit: Cover image © Haseeb Zubair Images

Exosomes play a critical role in several processes such as the development of cancers, intercellular signaling, drug resistance mechanisms, and cell-to-cell communication by fusion onto the cell membrane of recipient cells. These vesicles contain endogenous proteins and both noncoding and coding RNAs (microRNAs and messenger RNAs) that can be delivered to various types of cells. Furthermore, exosomes exist in body fluids such as plasma, cerebrospinal fluid, and urine. Therefore, they could be used as a novel carrier to deliver therapeutic nucleic-acid drugs for cancer therapy.

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  Depression is characterized by mitochondrial dysfunctions.

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  Dysbiosis could exacerbate depression symptoms through decreasing mitochondrial functions.

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  Probiotics may relieve depression through improving mitochondrial functions.

These findings indicated that angiotensin II type 1 receptor silencing plays an inhibitory role in sepsis-induced myocardial injury by inhibiting the mitogen-activated protein kinase signaling pathway.

Our study indicated that pretreatment with electroacupuncture (EA) may pose a protective effect on neurons through downregulating the expression of cofilin. These findings may provide a novel mechanism of EA pretreatment.

Our current study included the following highlights: (1) microRNA-9 (miR-9) specifically inhibits oxidized low-density lipoprotein (lectin-like) receptor 1 (OLR1). (2) Upregulated miR-9 reduces atherosclerosis. (3) Upregulated miR-9 promotes vascular remodeling. (4) miR-9 inhibits p38-mitogen-activated protein kinase (p38MAPK) pathway to alleviate atherosclerosis via knockdown of OLR1. (5) miR-9 targeting OLR1 might be a novel target for the treatment of acute coronary syndrome (ACS).

miR-302b-3p accelerates fibroblast senescence. miR-302b-3p accelerates senescence via direct targeting JNK2.

Peimine (PM) markedly induced prostate cancer cells apoptosis, and suppressed cells growth and motility in vitro and vivo. PM suppressed oncogenesis in prostate cancer cells via disruption of intracellular Ca²⁺ homeostasis through Ca²⁺/CaMKII/JNK pathway in vitro and vivo.

Our study provides evidence that miR-194 negatively modulates thrombospondin 1 (THBS1) and inhibits the activation of transforming growth factor β (TGF-β)/SMAD pathway, thereby alleviating the inflammatory response and human dermal microvascular endothelial cells (HDMECs) permeability of mast cells in chronic idiopathic urticaria (CIU).

Our study provides a broader insight into the metabolic adaptations of bacterial cells during gene manipulation experiments that can be prolonged to improve the yield of heterologous gene products and concomitant production of valuable biomolecules. In the bacterial metabolite pathway figure. X-axis represents the impact of the identified metabolites on the indicated pathway. Y-axis indicates the extent to which the designated pathway is enriched in the identified metabolites. All the values were ascertained from MetaboAnalyst. Circle colors (see color scale for reference) indicate pathway enrichment significance. Circle size indicates pathway impact.

MicroRNA-132 (miR-132) has been shown to participate in many diseases. The aim of this study was to understand the relationship between the level of miR-132 and the severity of dementia post-ischemic stroke. Accordingly, we found that acetylcholinesterase (ACHE) was a virtual target of miR-132 and a negative regulatory relationship is present between miR-132 and ACHE. Additionally, miR-132 and ACHE have been shown to affect the cell viability and apoptosis in the central nervous system.

The process by which specificity protein 1 (SP1) bound to the nearest promoter region was expedited in GC cells, by which DNA was hypomethylated and CDCA3 expression was promoted. The effect on cell proliferation and progression by CDCA3 was under the regulation of SP1 and also affected by hypomethylation of DNA.

This study evaluated the effect of oleanolic acid (OA) on the late stage of osteoclastogenesis in vitro using receptor activator of nuclear factor kappa-B ligand (RANKL)-pretreated bone marrow macrophages (BMMs) and in vivo using osteoprotegerin (OPG) knockout mice.

miR-4319 was found to be downregulated in thyroid cancer cells and its overexpression inhibited proliferation, migration, and epithelial-to-mesenchymal transition (EMT) in thyroid cancer. miR-4319 was found to target SMAD-specific E3 ubiquitin protein ligase 1 (SMURF1) in thyroid cancer cells. miR-4319 inhibited the stabilization of SMURF1 messenger RNA by competing with fused in sarcoma to target SMURF1. miR-4319 inhibited cell proliferation, migration, and EMT through SMURF1 in thyroid cancer.

This paper investigates phagocytosis when the two major opsonic receptors are engaged. Binding, signaling, and actin remodeling are examined to understand how macrophages internalize dual-opsonized targets, compared with when a single receptor is involved.

Our findings highlight the importance of Pitx3–glial cell-derived neurotrophic factor (GDNF) interplay in dopamine signaling and indicate that our strategy might be useful for restoration of dopaminergic (DAergic) fate of Ntera2 (NT2) cells to make them clinically applicable toward cell replacement therapy of Parkinson's disease (PD).

miR-623 is downregulated in hepatocellular carcinoma (HCC) and its expression is associated with poor clinical outcomes of patients with HCC. miR-623 suppresses the progression of HCC by regulating the phosphoinositide 3-kinase/protein kinase B, Wnt/β-catenin, and ERK/JNK pathways by targeting X-ray repair cross complementing 5 in HCC in vitro

SNP of VD receptor in Myeloma

The objective of this study was to identify the correlation between actin-related protein 2/3 complex subunit 4 (ARPC4) and lymph node metastasis, and to examine the role of ARPC4 in the invasive migration of T24 bladder cancer cells. Finally, we found that the expression of ARPC4, as a risk factor, was associated with lymphatic metastasis and was elevated in bladder cancer tissues when compared with normal bladder tissues. Besides, inhibition of ARPC4 expression significantly attenuated bladder cancer cell proliferation, migration, and invasion, possibly as a consequence of defects in pseudopodia formation.

Epigenetic modulation through targeted histone deacetylase (HDAC) inhibition has recently been identified as an effective method for regulating inflammatory and bone destructive profiles in osteolytic diseases. This study identified the importance of the individual HDAC 1 and HDAC 2 isoform during proinflammatory signaling in monocytes/macrophages and osteoclastic bone resorption, whereby inhibition of these individual HDACs significantly suppresses the inflammatory processes and bone destruction in vitro.

In conclusion, this study revealed the cardioprotective function of long noncoding RNA (lncRNA)-low expression in tumor (LET). lncRNA-LET conferred its cardioprotective effects possibly via upregulation of microRNA-138 and thus repressing the c-Jun N-terminal kinase and p38MAPK pathways.

The cell fate of mouse embryonic stem cells (mESCs) with Matrigel surface coating points new insights into the stemness and differentiation capacity. This study shows acellular environments (Matrigel) modulate the mESCs’ behavior and indicates promising approaches for cell fate determination.

We investigated the potential regulatory role of TRAPPC9 and LPL-mediated OC cytoskeleton reorganization and actin ring formation.

The study pointed out the pivotal role of miR-124a in BMSC therapy for DN rats through mitigating EMT and fibrosis. Our results provide a novel insight into how therapeutic effects of BMSCs can be improved at the posttranscriptional level.

For the first time, ZFPM2-AS1 is studied in lung adenocarcinoma. ZFPM2-AS1/miR-18b-5p/VMA21 axis is brand new. ZFPM2-AS1 might serve as a new target in lung adenocarcinoma treatment.

SKP2 promotes the proliferation of retinoblastoma (RB). MiR-422a targets S-phase kinase-associated protein 2 (SKP2) and inhibits RB proliferation. Circ_ODC1 promotes RB proliferation via sequestering miR-422a and therefore elevating SKP2

(a) Overexpressed activated by transforming growth factor-β (ATB), underexpressed miR-200c were proposed as independent predictors for shortened survival of the patients with CRC. (b) Transfection of pcDNA3.1-ATB and miR-200c inhibitor could boost viability and proliferation and suppress apoptosis. (c) ATB was discovered to downregulate miR-200c expression by targeting it, and CDK2 was subjected to dual regulation of both ATB and miR-200c.

In this paper Tumor Protein P73 Antisense RNA 1 (TP73-AS1) is being studied in cervical cancer for the first time. The TP73-AS1/miR-877-5p/ARF1 axis is brand new. TP73-AS1 might serve as a novel regulator in cervical cancer.

OIP5 antisense RNA 1 (OIP5-AS1) silencing impairs cell growth and induces promotion of cell apoptosis in gastric cancer (GC). Nuclear OIP5-AS1 interacts with enhancer of zeste homolog 2 (EZH2) and negatively mediates Nod-like receptor pyrin domain-containing protein 6 (NLRP6) expression in GC cells. OIP5-AS1 represses NLRP6 expression by recruiting EZH2, increasing the H3K27me3 enrichment of NLRP6 promoter.

This study aimed to explore the roles of endothelial nitric oxide synthase (eNOS) in the control of metastasis of infection with endothelial dysfunction, and how -786T>C polymorphism in gene promoter in the control of metastasis of endothelial function. Accordingly, these findings provide support that down-expression of -786T>C located on the promoter of eNOS is associated with an increased risk of endothelial dysfunction.

This study aimed to investigate the effect of miR-33b in regulating daunorubicin sensitivity in acute myelocytic leukemia (AML). The results provide new insight into the possibility of miR-33b as a promising therapeutic target for AML.

The potential roles of circular RNAs in pancreatic ductal adenocarcinoma were explored from the perspectives of competitive endogenous RNA-related networks. Two circular RNAs (hsa_circ_0007767 and hsa_circ_0092367) were proven to be key regulators in the pathogenesis of pancreatic ductal adenocarcinoma by functioning as competitive endogenous RNAs, and four genes (CDH1, SERPINE1, IRS1 and FYN) were identified as their critical downstream targets. Additionally, three compounds (celastrol, 5109870 and MG-132) were determined to be therapeutic options for pancreatic ductal adenocarcinoma.

We could demonstrate antitumor activity of the HSP70 inhibitor VER155008 in both AR-positive and -negative prostate cancer cell lines by inhibiting proliferation and inducing apoptosis in a low micromolar range. In addition, VER155008 induced a distinct diminishing of HSP27, HOP and HSP90α expression, whereas the expression of HSP40, HSP60, HSP90βta, and HSP70 itself was not altered. VER155008 treatment also led to suppression of the AR and might represent a promising therapeutic agent for prostate cancer.

Excessive intermittent cyclic mechanical tension can induce the degeneration of endplate chondrocytes. Tension-sensitive circRNA_0058097 can upregulate the expression of downstream target gene histone deacetylase 4 by sponge adsorption of miR-365a-5p, which promoted morphological changes of endplate chondrocytes, and increased extracellular matrix degradation and degeneration of endplate cartilage.

Nuclear factor erythroid 2-related factor 2 (Nrf2) can alleviate diffuse axonal injury (DAI)-induced apoptosis by regulating the expression of heme oxygenase-1 (HO-1), while sulforaphane (SFN) was shown to reduce oxidative stress by increasing the expression of Nrf2. Therefore, we aimed to investigate the therapeutic effect of SFN in the treatment of DAI and the ability of SFN to reduce oxidative stress. Accordingly, we came to the conclusion that by activating the Nrf2/HO-1 signaling pathway and reducing the activity of caspase-3, SFN reduces the apoptosis of neurons in brain trauma-induced DAI.

This manuscript aims to investigate the biological function and underlying mechanisms of long noncoding RNA HOXD cluster antisense RNA 1 (lncRNA HOXD-AS1) in hepatocellular carcinoma (HCC) cells. We demonstrated that knockdown of lncRNA HOXD-AS1 could inhibit the proliferation, cell cycle progression, migration, and invasion of HCC cells through the MEK/ERK pathway, suggesting that HOXD-AS1, as an oncogene, might play a critical role in HCC progression and serve as a potential diagnostic and prognostic biomarker as well as a therapeutic target for HCC.

The results showed that increasing at miR-330 expression level could repress tumor cell growth and migration of melanoma cancer cells.

Esophageal cancer is one of the most lethal malignancies in the world. But the altered long noncoding RNAs (lncRNAs) in esophageal squamous cell carcinoma (ESCC) tissues require a deeper excavation, and the regulatory mechanisms are barely discussed. In this study, we combined lncRNA microarray datasets from Gene Expression Omnibus (GEO) and performed bioinformatic analysis to identify differentially expressed lncRNAs and mRNAs in ESCC tissues to determine novel lncRNA-protein regulatory mechanisms. We would like to claim that these findings are novel and significant considering about the following issues: (a) first study confirmed the downregulation of lncRNA HCG22 in ESCC tumors, and identified lncRNA HCG22 as a novel prognostic predictor for patients with ESCC and (b) first study inferred SPINK7 and ADAMTS12 as the potential regulatory targets of lncRNA HCG22.

In summary, the current study demonstrates that miR-140 was downregulated in human prostate cancer (PCa) cell lines, and overexpression of miR-140 suppressed PCa cells proliferation, migration, and invasion capacities at least partially by targeting YES1.

This study showed that RASSF1 downregulation plays a critical role in reducing cardiomyocyte apoptosis, improves cardiac function after AMI, and is regulated by miR-125b, which is implied that RASSF1 is a potential therapeutic target for ischemic heart disease.

In this research, we studied the effect of amifostine (AMI) on osteoclasts under irradiation condition. The result showed that AMI inhibits the maturation and differentiation of osteoclasts under radiation condition by reducing DNA damage and reactive oxygen species induced by radiation, thereby reducing the effect of radiation on the skeletal system, indicating that AMI could be a potential therapeutic target for radiation-induced osteoporosis.

Palbociclib (PD-0332991) treatment was effective to reduce cell viability and proliferation in a dose-dependent manner in Panc-1 and MiaPaCa-2 pancreatic cancer cells. Panc-1 cells were more sensitive to PD-0332991 compared with MiaPaCa-2 cells. MiaPaCa-2 cells were resistant to PD-0332991 treatment due to its expression profile of Rb and cyclin E.

This study reveals, for the first time, that N6-methyladenosine mRNA methylase METTL14 promotes renal ischemic reperfusion injury via suppressing YAP1. Thus, the discovery of the pathway of METTL14-YAP1 provides significant new insights into the understanding of AKI and unveils new therapeutic strategies and targets.

This paper highlights the interplay of codon usage and the key hepatitis C virus clearance candidate genes in relation to its expression. A total of 112 genes are collected from GenBank and subjected to major codon indices, such as relative synonymous codon usage, an effective number of codon, frequency of optimal codon, codon adaptation index, codon bias index, and base compositions.

Cripto-1 has become a popular biomarker for cancer prognosis, however, many studies utilize poorly characterized antibodies. We provide evidence for differential binding patterns of these antibodies in fluorescence microscopy and suggest a potential pitfall in cripto-1 antibody-based studies.

lncRNA B3GALT5-AS1 could be served as a diagnostic marker for gastric cancer.

In this study, we have successfully collected and subcultured human-derived stem cells (hUSCs) from fresh human urine. HUSCs had various biological characteristics of adult mesenchymal stem cells and could be induced to differentiate into hepatocyte-like cells by coculturing with human hepatocyte L02 cells.

In summary, NAM sensitized K562 and K562R cells to DOX, which by facilitating the activation of caspase-3/PARP and SIRT1 inhibition might pave the way for the development of a potential adjunct in the treatment of blast crisis CML patients.

We established a two-miRNA signature(miR-143/−4636) that was strongly and independently associated with prognosis in cervical cancer, and may serve as a promising prognosis predictor.

Collectively, our results indicate that ssc-miR-204 is a negative regulator that targets transforming growth factor β receptor 1 (TGFBR1) and TGFBR2 in the TGF-β signaling pathway to promote preadipocyte differentiation and apoptosis. A better understanding of ssc-miR-204 in the context of preadipocytes will be beneficial for human medical research.

Large intergenic noncoding RNA regulator of reprogramming (Linc-RoR) promoted proliferation, migration, and invasion of pancreatic cancer cells by activating the Hippo/YAP pathway. YAP might be an underlying target of Linc-RoR and mediate EMT in pancreatic cancer (PC); thus, Linc-RoR might be a very meaningful biomarker for PC

The present study assessed the molecular mechanism of microRNA-125a (miR-125a) in the proliferation and apoptosis of multiple myeloma cells. The results confirmed that miR-125a inhibited the expression of ubiquitin-specific peptidase 5.

This study laid a theoretical foundation for further understanding of idiopathic pulmonary fibrosis and searching for new molecular therapeutic targets.

HAS2-AS1 is upregulated in glioma tissues and cells. HAS2-AS1 promotes proliferation and invasion of glioblastoma multiforme (GBM) in vitro and in vivo. STAT1/HAS2-AS1/miR-608/PRPS1 axis may be a potential therapeutic target for GBM.

In the current study, we provided a comprehensive portrait of global changes in alternative splicing (AS) signature in papillary renal cell carcinoma (pRCC) for the first time. Furthermore, we constructed an independent prognostic signature comprised of 21 AS events, which showed robust prognostic capacity in both short- and long-term prognosis prediction for clinical patients with pRCC. Moreover, functional enrichment analysis, gene set enrichment analysis and splicing correlation network with prognostic splicing factors were performed to decipher the underlying mechanisms of AS in pRCC.

Upregulated circ-CDC45 is related to poor prognosis in glioma (GM) patients. circ-CDC45 could sponge miR-516b and miR-527. The oncogenic functions of circ-CDC45 is dependent on its regulation of miR-516b and miR-527.

microRNA-496 (miR-496) exercises a defensive function in H9c2 ischemia-reperfusion–injury via direct hook microtubule tethering protein 3 (Hook3) downregulation that suppresses cell apoptosis. And miR-496 targets Hook3 to activate the phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway as well for antiapoptotic and proliferative effects.

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  The first study to detect the expression of circRNAs in the umbilical cord blood of small for gestational age (SGA).

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  Expression of different circular RNA (circRNA) in maternal and umbilical cord blood were consistent.

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  A new circRNA15994-13 → miR-3619-5p → β-catenin network in SGA was predicted by biochemical function analysis and literature search.

Treatment with Dex increased the viability of both cell lines; this effect continued for at least 24 hours after Dex was removed. DDP toxicity was attenuated by 10 nM Dex added either before or with DDP treatment. However, pretreatment with 50 nM Dex instead enhanced the toxicity of DDP.

We newly described the role of LINC00346 and elucidated a potential mechanism in which Janus kinase–signal transducer and activator of transcription 3 (JAK-STAT3) signaling was regulated by LINC00346. Knockdown of LINC00346 contributed to the inhibition of hepatocellular carcinoma (HCC) progression. We revealed that LINC00346 participated in HCC and that it might be a novel HCC biomarker via modulating JAK-STAT3.

SPOCK1 over expression in PDAC patients was associated with tumor size, lymph node metastasis and worse overall survival. SPOCK1 might serve as an oncogene in PDAC pathogenesis by inactivating the PI3K/Akt signaling pathway.

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  A global view of long noncoding RNA transcription factor (lncRNA-TF) crosstalks was constructed for glioblastoma (GBM) investigation.

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  Integration of competing endogenous RNA (ceRNA) crosstalks and TF-DNA binding, some core lncRNA-TF feedback loops with strong prognostic effect were identified.

Upregulation of Nav1.9, mediated by protein kinase Cα (PKCα) in nociceptive dorsal root ganglion (DRG) neurons may contribute to the neuronal hyperexcitability of nociceptive nerves, and the generation of chronic pain in the condition of arthritic knee inflammation.

We showed that miR-605-5p plays a tumor-suppressor role in non–small-cell lung cancer (NSCLC). It functions mainly by targeting tumor necrosis factor α-induced protein 3 (TNFAIP3) expression. These findings suggest a specific mechanism of NSCLC progression and suggest miR-605-5p as a potential therapeutic target for NSCLC.

Our data indicate that SET domain-containing protein 2 (SETD2) maintains genome stability perhaps via regulating trimethylation status of histone H3 at lysine 36, consequently controlling the embryo quality. These findings pave the avenue for understanding the cross-talk between epigenome and SETD2 during early embryo development.

N-end rule pathway inhibitor drug sensitizes cancer cells.

Metformin is an anti-hyperglycemic drug commonly prescribed for type II diabetes mellitus that functions by activating numerous molecular targets including 5′-AMP-activated protein kinase and peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α). Population data shows circulating branched-chain amino acids (BCAA) positively correlate with the severity of insulin resistance/type II diabetes. Because metformin activates PGC-1α (which governs BCAA catabolic enzyme expression), we measured the effects of metformin on indicators of BCAA metabolism in cultured myotubes. We found that metformin suppresses BCAA catabolic enzyme expression and activity in cultured myotubes.

Hypoxia-induced changes in the release of extracellular vesicles (EV) by pancreatic tumor cells is an adaptive response mechanism. One of the functional significance is to promote their adaptive survival under hypoxia. Mechanistically, hypoxia-inducible factor-1α (HIF-1α) plays an important role in altered release of EVs and their potency to promote cell survival.

Pancreatic stellate cells augment the glucose-stimulated insulin secretion from Min6 cells, with no possible involvement of IL6-induced PLC-IP₃ -dependent pathway.

A set of lncRNAs played a vital role in the progression of bladder carcinoma through certain signaling pathways. The current analysis indicated that the newly-constructed risk prediction model might benefit the early diagnosis and the underlying pathways might be a potential therapeutic target in the future. The pathways, containing PI3K-Akt, HIF-1, and Jak-STAT signaling pathways, ought to be applied to clinical usage and warranted by advanced cytobiology technologies.

LINC01116 was highly expressed in head and neck squamous cell carcinoma. LINC01116 silencing inhibited the migration and invasion capacities of the tumor cells. LINC01116 regulated the tumor function through epithelial-mesenchymal transition process (EMT).

We constructed lncRNA-miRNA-mRNA network in gastric cancer and identified the key nodes based on complex network theory. Functional enrichment analysis and survival analysis of key genes in network related to key nodes were performed. The key factors in gastric cancer regulatory network can provide new insights into understanding the pathogenesis of gastric cancer and the diagnosis and treatment of gastric cancer.