Integrated transcriptomic and proteomic analyses reveal the effects of chronic benzene exposure on the central nervous system in mice.

Benzene exposure is known to cause serious damage to the human hematopoietic system. However, recent studies have found that chronic benzene exposure may also cause neurological damage, but there were few studies in this issue. The aim of this study was to investigate the mechanism of damage to the central nervous system (CNS) by chronic benzene exposure with a multi-omics analysis. We established a chronic benzene exposure model in C57BL/6J mice by gavage of benzene-corn oil suspension, identified the differentially expressed proteins (DEPs) and differentially expressed genes (DEGs) in mice brain using 4D Label-free proteomic and RNA-seq transcriptomic. We observed that the benzene exposure mice had a significant loss of body weight, reduction in complete blood counts, abnormally high MRI signals in brain white matter, as well as extensive brain edema and neural demyelination. 162 DEPs were identified by the proteome, including 98 up-regulated and 64 down-regulated proteins. KEGG pathway analysis of DEPs showed that they were mainly involved in the neuro-related signaling pathways such as metabolic pathways, pathways of neurodegeneration, chemical carcinogenesis, Alzheimer disease, and autophagy. EPHX1, GSTM1, and LIMK1 were identified as important candidate DEGs/DEPs by integrated proteomic and transcriptomic analyses. We further performed multiple validation of the above DEGs/DEPs using fluorescence quantitative PCR (qPCR), parallel reaction monitoring (PRM), immunohistochemistry, and immunoblotting to confirm the reliability of the multi-omics study. The functions of these DEGs/DEPs were further explored and analyzed, providing a theoretical basis for the mechanism of nerve damage caused by benzene exposure.

Elucidation of the folding pathway of a circular permutant of topologically knotted YbeA by tryptophan substitutions.

CP74 is an engineered circular permutant of a deep trefoil knotted SpoU-TrmD (SPOUT) RNA methyl transferase protein YbeA from E. coli. We have previously established that the circular permutation unties the knotted topology of YbeA and CP74 forms a domain-swapped dimer with a large dimeric interface of ca. 4600 Å2. To understand the impact of domain-swapping and the newly formed hinge region joining the two folded domains on the folding and stability of CP74, the five equally spaced tryptophan residues were individually substituted into phenylalanine to monitor their conformational and stability changes by a battery of biophysical tools. Far-UV circular dichroism, intrinsic fluorescence, and small-angle X-ray scattering dictated minimal global conformational perturbations to the native structures in the tryptophan variants. The structures of the tryptophan variants also showed the conservation of the domain-swapped ternary structure with the exception that the W72F exhibited significant asymmetry in the α-helix 5. Comparative global thermal and chemical stability analyses indicated the pivotal role of W100 in the folding of CP74 followed by W19 and W72. Solution-state NMR spectroscopy and hydrogen-deuterium exchange mass spectrometry further revealed the accumulation of a native-like intermediate state in which the hinge region made important contributions to maintain the domain-swapped ternary structure of CP74.

Effects of school myopia management measures on myopia onset and progression among Chinese primary school students.

BACKGROUND: Schools play an organizational role in managing myopia-related behavioral habits among students. We evaluated the effects of school myopia management measures on myopia onset and progression in a school-based prospective 1-year observational study. METHODS: In total, 8319 children from 26 elementary schools were included. Online questionnaire completed by a parent, in which school myopia management experience including outdoor activities in recess or physical education class, teachers' supervision, and teaching facilities. Variables were defined as implemented well or poorly, according to the Comprehensive Plan to Prevent Myopia among Children and Teenagers. Children underwent ophthalmic examinations, and the incidence and progression of myopia from 2019 to 2020 were estimated. Multilevel logistic regression models were constructed to analyze the association between school management measures and myopia development in 8,9 years and 10,11 years students. RESULTS: From 2019 to 2020, the incidence of myopia among primary school students was 36.49%; the mean difference of spherical equivalent in myopic children was - 0.29 ± 1.22 diopters. The risk of incident myopia was reduced by 20% in 8,9 years participants with well-implemented class recess compared with those with poorly implemented class recess (adjusted odds ratio [aOR]: 0.80, p = 0.032). PE outdoor time was significantly associated with myopia incidence in 10,11 years students (aOR: 0.76, p = 0.043). Compared with poorly implemented reading and writing posture, desk and chair height, 10,11 participants with well-implemented desk and chair height were less likely to have rapid myopic progression (p = 0.029, p = 0.022). CONCLUSION: In Shanghai, children's myopia is associated with better implementation of school myopia management measures. The present findings suggest that outdoor activities during class recess or PE class, providing suitable desks and chairs, and adequate instruction in reading and writing postures might protect against pathological eye growth. An age-specific myopia prevention and control programs in school is of primary importance.

Purification performance from bypass ecological treatment systems treating WWTPs effluents and improvement of water quality in receiving rivers: A case study in southern China.

Effluents from wastewater treatment plants (WWTPs) is the main source of pollution in rivers in developing countries. In this case study, three bypass ecological treatment systems along urban rivers achieved high removal efficiencies for chemical oxygen demand (COD; 55.7-64.0%), ammonium N (NH4+-N; 63.1-89.4%) and total phosphorous (TP; 27.6-76.7%). 16 S rRNA gene sequencing analysis confirmed that Proteobacteria was the main bacterial phylum (44.4%) in the ecological treatment system, and members were enriched significantly in the non-aeration area (59.3%). The relative abundance of Nitrospirae was highest in the inflow area (25.0%), but restrained in the non-aeration area (5.7%). 18 S rRNA gene annotation results indicated that phylum Rotifer was gradually inhibited with the direction of water flow and diffusion, while phylum Rhodophyta displayed the opposite trend. After implementation of bypass ecological treatment systems, receiving rivers were improved significantly from Grade Ⅴ to Ⅳ, and the biodiversity of zooplankton, zoobenthos and fish communities was greatly improved.

Oxidative stress of Microcystis aeruginosa induced by algicidal bacterium Stenotrophomonas sp. KT48.

Cyanobacterial harmful algal blooms are a worldwide problem with substantial adverse effects on the aquatic environment as well as human health. Among the multiple physicochemical and biotic approaches, algicidal bacterium is one of the most promising and eco-friendly ways to control bloom expansion. In this study, Stenotrophomonas sp. KT48 isolated from the pond where cyanobacterial blooms occurred exhibited a strong inhibitory effect on Microcystis aeruginosa. However, the algicidal performance and mechanisms of Stenotrophomonas sp. remain under-documented. To explore the algicidal performance and physiological response againt M. aeruginosa, further works were implemented here. Our results indicated that the algicidal rate of strain KT48 cultured in 1/8 LB medium supplemented with 0.3% starch or glucose was about 30% higher than that in 1/8 LB medium. Strain KT48 culture, cell-free filtrate, and cells re-suspended were inoculated into the M. aeruginosa culture, and the Chl-a content was determined. Those results indicated that the algicidal activity of cells re-suspended was far higher than that of cell-free filtrate and culture. Thus, strain KT48 exhibited algicidal activity mainly through direct attacking M. aeruginosa rather than excretion of algicides. Furthermore, strain KT48 led to an increase in cellular reactive oxygen species (ROS) and caused lipid peroxidation as supported by the increase in malondialdehyde (MDA) levels. The ROS and MDA levels in algal cells treated with strain KT48 cells re-suspended were about 3.23-fold and 2.80-fold higher than those of untreated algal cells on day 11. And a further inhibition to the antioxidant system is suggested by a sharp decrease in the superoxide dismutase (SOD), catalase (CAT), and peroxidase (POD) activities. In addition, we also observed that the morphology of most algal cells changed from integrity to break. This study not only indicated strain KT48 with strong algicidal activity, but also explored the underlying algicidal mechanisms to provide a source of bacterial agent for the biocontrol of cyanobacterial blooms. KEY POINTS: • Strain KT48 exhibited strong algicidal activity mainly through direct attacking M. aeruginosa. • The addition of glucose could enhance the algicidal rate of strain KT48 by about 30%. • Strain KT48 led to an increase in cellular reactive oxygen species (ROS) level that causes membrane damage as supported by the increase in malondialdehyde (MDA) levels.

Neural Regeneration in Regenerative Endodontic Treatment: An Overview and Current Trends.

Pulpal and periapical diseases are the most common dental diseases. The traditional treatment is root canal therapy, which achieves satisfactory therapeutic outcomes-especially for mature permanent teeth. Apexification, pulpotomy, and pulp revascularization are common techniques used for immature permanent teeth to accelerate the development of the root. However, there are obstacles to achieving functional pulp regeneration. Recently, two methods have been proposed based on tissue engineering: stem cell transplantation, and cell homing. One of the goals of functional pulp regeneration is to achieve innervation. Nerves play a vital role in dentin formation, nutrition, sensation, and defense in the pulp. Successful neural regeneration faces tough challenges in both animal studies and clinical trials. Investigation of the regeneration and repair of the nerves in the pulp has become a serious undertaking. In this review, we summarize the current understanding of the key stem cells, signaling molecules, and biomaterials that could promote neural regeneration as part of pulp regeneration. We also discuss the challenges in preclinical or clinical neural regeneration applications to guide deep research in the future.

Changes in Laminin in Acute Heart Failure.

Laminin is a major component of the basement membrane of cardiomyocytes and has been found at a high level in patients with heart failure. However, detailed information on the relationship between disease management and progression in patients with acute heart failure (AHF) remains lacking. We focused on the levels of laminin (LN) before and after admission to the hospital in AHF patients. One hundred twelve AHF patients who were hospitalized in the Affiliated Hospital 2 of Nantong University from January 2020 to February 2021 were selected as the main subjects of the study. The control group consisted of 137 hospitalized patients in New York Heart Association (NYHA) classes I-II during the same time period. Serum laminin levels were measured at baseline in all patients. Besides, laminin levels of AHF patients were measured again 1 week after admission. The serum laminin levels at admission were significantly higher in AHF patients than those in the patients of NYHA classes I-II [73.79 (41.04, 129.75) ng/mL versus 27.98 (20.75, 37.49) ng/mL, respectively, P < 0.001]. After 1 week of treatment, laminin levels in AHF patients were 41.56 (27.92, 78.67) ng/mL, which was significantly lower than before treatment (Z = -6.357, P < 0.001). Bivariate linear correlation analysis showed that LN was associated with NT-proBNP both in the acute phase and after treatment. Laminin levels were significantly higher in AHF patients who had atrial fibrillation (AF) than in those without AF. As a result, we speculated that laminin reflected improved heart function and the occurrence of myocardial fibrosis.

Ergosta-7, 9 (11), 22-trien-3ß-ol Interferes with LPS Docking to LBP, CD14, and TLR4/MD-2 Co-Receptors to Attenuate the NF-κB Inflammatory Pathway In Vitro and Drosophila.

Ergosta-7, 9 (11), 22-trien-3ß-ol (EK100) was isolated from Cordyceps militaris, which has been used as a traditional anti-inflammatory medicine. EK100 has been reported to attenuate inflammatory diseases, but its anti-inflammatory mechanism is still unclear. We were the first to investigate the effect of EK100 on the Toll-like receptor 4 (TLR4)/nuclear factor of the κ light chain enhancer of B cells (NF-κB) signaling in the lipopolysaccharide (LPS)-stimulated RAW264.7 cells and the green fluorescent protein (GFP)-labeled NF-κB reporter gene of Drosophila. EK100 suppressed the release of the cytokine and attenuated the mRNA and protein expression of pro-inflammatory mediators. EK100 inhibited the inhibitor kappa B (IκB)/NF-κB signaling pathway. EK100 also inhibited phosphatidylinositol-3-kinase (PI3K)/Protein kinase B (Akt) signal transduction. Moreover, EK100 interfered with LPS docking to the LPS-binding protein (LBP), transferred to the cluster of differentiation 14 (CD14), and bonded to TLR4/myeloid differentiation-2 (MD-2) co-receptors. Compared with the TLR4 antagonist, resatorvid (CLI-095), and dexamethasone (Dexa), EK100 suppressed the TLR4/AKT signaling pathway. In addition, we also confirmed that EK100 attenuated the GFP-labeled NF-κB reporter gene expression in Drosophila. In summary, EK100 might alter LPS docking to LBP, CD14, and TLR4/MD-2 co-receptors, and then it suppresses the TLR4/NF-κB inflammatory pathway in LPS-stimulated RAW264.7 cells and Drosophila.

Structure-Based Functional Analysis of a Hormone Belonging to an Ecdysozoan Peptide Superfamily: Revelation of a Common Molecular Architecture and Residues Possibly for Receptor Interaction.

A neuropeptide (Sco-CHH-L), belonging to the crustacean hyperglycemic hormone (CHH) superfamily and preferentially expressed in the pericardial organs (POs) of the mud crab Scylla olivacea, was functionally and structurally studied. Its expression levels were significantly higher than the alternative splice form (Sco-CHH) in the POs, and increased significantly after the animals were subjected to a hypo-osmotic stress. Sco-CHH-L, but not Sco-CHH, significantly stimulated in vitro the Na+, K+-ATPase activity in the posterior (6th) gills. Furthermore, the solution structure of Sco-CHH-L was resolved using nuclear magnetic resonance spectroscopy, revealing that it has an N-terminal tail, three α-helices (α2, Gly9-Asn28; α3, His34-Gly38; and α5, Glu62-Arg72), and a π-helix (π4, Cys43-Tyr54), and is structurally constrained by a pattern of disulfide bonds (Cys7-Cys43, Cys23-Cys39, and Cys26-Cys52), which is characteristic of the CHH superfamily-peptides. Sco-CHH-L is topologically most similar to the molt-inhibiting hormone from the Kuruma prawn Marsupenaeus japonicus with a backbone root-mean-square-deviation of 3.12 Å. Ten residues of Sco-CHH-L were chosen for alanine-substitution, and the resulting mutants were functionally tested using the gill Na+, K+-ATPase activity assay, showing that the functionally important residues (I2, F3, E45, D69, I71, and G73) are located at either end of the sequence, which are sterically close to each other and presumably constitute the receptor binding sites. Sco-CHH-L was compared with other members of the superfamily, revealing a folding pattern, which is suggested to be common for the crustacean members of the superfamily, with the properties of the residues constituting the presumed receptor binding sites being the major factors dictating the ligand-receptor binding specificity.

Antimicrobial Peptide TP4 Targets Mitochondrial Adenine Nucleotide Translocator 2.

Tilapia piscidin (TP) 4 is an antimicrobial peptide derived from Nile tilapia (Oreochromis niloticus), which shows broad-spectrum antibacterial activity and excellent cancer-killing ability in vitro and in vivo. Like many other antimicrobial peptides, TP4 treatment causes mitochondrial toxicity in cancer cells. However, the molecular mechanisms underlying TP4 targeting of mitochondria remain unclear. In this study, we used a pull-down assay on A549 cell lysates combined with LC-MS/MS to discover that TP4 targets adenine nucleotide translocator (ANT) 2, a protein essential for adenine nucleotide exchange across the inner membrane. We further showed that TP4 accumulates in mitochondria and colocalizes with ANT2. Moreover, molecular docking studies showed that the interaction requires Phe1, Ile2, His3, His4, Ser11, Lys14, His17, Arg21, Arg24 and Arg25 residues in TP4 and key residues within the cavity of ANT2. These findings suggest a mechanism by which TP4 may induce mitochondrial dysfunction to disrupt cellular energy metabolism.

Structural Insights into the Active Site Formation of DUSP22 in N-loop-containing Protein Tyrosine Phosphatases.

Cysteine-based protein tyrosine phosphatases (Cys-based PTPs) perform dephosphorylation to regulate signaling pathways in cellular responses. The hydrogen bonding network in their active site plays an important conformational role and supports the phosphatase activity. Nearly half of dual-specificity phosphatases (DUSPs) use three conserved residues, including aspartate in the D-loop, serine in the P-loop, and asparagine in the N-loop, to form the hydrogen bonding network, the D-, P-, N-triloop interaction (DPN-triloop interaction). In this study, DUSP22 is used to investigate the importance of the DPN-triloop interaction in active site formation. Alanine mutations and somatic mutations of the conserved residues, D57, S93, and N128 substantially decrease catalytic efficiency (kcat/KM) by more than 102-fold. Structural studies by NMR and crystallography reveal that each residue can perturb the three loops and induce conformational changes, indicating that the hydrogen bonding network aligns the residues in the correct positions for substrate interaction and catalysis. Studying the DPN-triloop interaction reveals the mechanism maintaining phosphatase activity in N-loop-containing PTPs and provides a foundation for further investigation of active site formation in different members of this protein class.

Identification and expression profiling of selected MADS-box family genes in Dendrobium officinale.

Dendrobium officinale, a herb with highly medicinal and ornamental value, is widely distributed in China. MADS-box genes encode transcription factors that regulate various growth and developmental processes in plants, particular in flowering. However, the MADS-box genes in D. officinale are largely unknown. In our study, expression profiling analyses of selected MADS-box genes in D. officinale were performed. In total, 16 DnMADS-box genes with full-length ORF were identified and named according to their phylogenetic relationships with model plants. The transient expression of eight selected MADS-box genes in the epidermal cells of tobacco leaves showed that these DnMADS-box proteins localized to the nucleus. Tissue-specific expression analysis pointed out eight flower-specific expressed MADS-box genes in D. officinale. Furthermore, expression patterns of DnMADS-box genes were investigated during the floral transition process. DnMADS3, DnMADS8 and DnMADS22 were significantly up-regulated in the reproductive phase compared with the vegetative phase, suggesting putative roles of these DnMADS-box genes in flowering. Our data showed that the expressions of MADS-box genes in D. officinale were controlled by diverse exogenous phytohormones. Together, these findings will facilitate further studies of MADS-box genes in Orchids and broaden our understanding of the genetics of flowering.

Comparative transcriptomic analysis reveal the regulation mechanism underlying MeJA-induced accumulation of alkaloids in Dendrobium officinale.

Dendrobium officinale is a traditional medicinal herb with a variety of bioactive components. Alkaloid is one of the major active ingredients of Dendrobium plants, and its immune regulatory effects have been well-studied. Although a number of genes involved in the biosynthetic pathway of alkaloids have been elucidated, the regulation mechanism underlying the methyl-jasmonate (MeJA)-induced accumulation of alkaloids in D. officinale is largely unknown. In our study, a total of 4,857 DEGs, including 2,943 up- and 1,932 down-regulated genes, were identified between the control and MeJA-treated groups. Kyoto Encyclopedia of Genes and Genomes annotation showed that a number of DEGs were associated with the putative alkaloid biosynthetic pathway in D. officinale. The main group of Dendrobium alkaloids are sesquiterpene alkaloids, which are the downstream products of mevalonate (MVA) and methylerythritol 4-phosphate (MEP) pathway. Several MVA and MEP pathway genes were significantly up-regulated by the MeJA treatment, suggesting an active precursor supply for the alkaloid biosynthesis under MeJA treatment. A number of MeJA-induced P450 family genes, aminotransferase genes and methyltransferase genes were identified, providing several important candidates to further elucidate the sesquiterpene alkaloid biosynthetic pathway of D. officinale. Furthermore, a large number of MeJA-induced transcript factor encoding genes were identified, suggesting a complex genetic network affecting the sesquiterpene alkaloid metabolism in D. officinale. Our data aids to reveal the regulation mechanism underlying the MeJA-induced accumulation of sesquiterpene alkaloids in D. officinale.

Role of the RAD51-SWI5-SFR1 Ensemble in homologous recombination.

During DNA double-strand break and replication fork repair by homologous recombination, the RAD51 recombinase catalyzes the DNA strand exchange reaction via a helical polymer assembled on single-stranded DNA, termed the presynaptic filament. Our published work has demonstrated a dual function of the SWI5-SFR1 complex in RAD51-mediated DNA strand exchange, namely, by stabilizing the presynaptic filament and maintaining the catalytically active ATP-bound state of the filament via enhancement of ADP release. In this study, we have strived to determine the basis for physical and functional interactions between Mus musculus SWI5-SFR1 and RAD51. We found that SWI5-SFR1 preferentially associates with the oligomeric form of RAD51. Specifically, a C-terminal domain within SWI5 contributes to RAD51 interaction. With specific RAD51 interaction defective mutants of SWI5-SFR1 that we have isolated, we show that the physical interaction is indispensable for the stimulation of the recombinase activity of RAD51. Our results thus help establish the functional relevance of the trimeric RAD51-SWI5-SFR1 complex and provide insights into the mechanistic underpinnings of homology-directed DNA repair in mammalian cells.

Nile Tilapia Derived Antimicrobial Peptide TP4 Exerts Antineoplastic Activity Through Microtubule Disruption.

Some antimicrobial peptides (AMPs) exhibit anti-cancer activity, acting on cancer cells either by causing membrane lysis or via intracellular effects. While intracellular penetration of AMPs has been shown to cause cancer cell death, the mechanisms of toxicity remain largely unknown. Here we show that a tilapia-derived AMP, Tilapia piscidin (TP) 4, penetrates intracellularly and targets the microtubule network. A pull-down assay identified α-Tubulin as a major interaction partner for TP4, and molecular docking analysis suggested that Phe1, Ile16, and Arg23 on TP4 are required for the interaction. TP4 treatment in A549 cells was found to disrupt the microtubule network in cells, and mutation of the essential TP4 residues prevented microtubule depolymerization in vitro. Importantly, the TP4 mutants also showed decreased cytotoxicity in A549 cells, suggesting that microtubule disruption is a major mechanistic component of TP4-mediated death in lung carcinoma cells.

Biomarker discovery for neuroendocrine cervical cancer.

Neuroendocrine cervical cancer is an aggressive but rare form of cervical cancer. The majority of neuroendocrine cervical cancer patients present with advanced-stage diseases. However, the limited numbers of neuroendocrine tumor markers are insufficient for clinical purposes. Thus, we used a proteomic approach combining lysine labeling 2D-DIGE and MALDI-TOF MS to investigate the biomarkers for neuroendocrine cervical cancer. By analyzing the global proteome alteration between the neuroendocrine cervical cancer line (HM-1) and non-neuroendocrine cervical cancer lines (CaSki cells, ME-180 cells, and Hela cells), we identified 82 proteins exhibiting marked changes between HM-1 and CaSki cells, and between ME-180 and Hela cells. Several proteins involved in protein folding, cytoskeleton, transcription control, signal transduction, glycolysis, and redox regulation exhibited significant changes in abundance. Proteomic and immunoblot analyses indicated respective 49.88-fold and 25-fold increased levels of transgelin in HM-1 cells compared with that in other non-neuroendocrine cervical cancer cell lines, implying that transgelin is a biomarker for neuroendocrine cervical cancer. In summary, we used a comprehensive neuroendocrine/non-neuroendocrine cervical cancer model based proteomic approach for identifying neuroendocrine cervical cancer markers, which might contribute to the prognosis and diagnosis of neuroendocrine cervical cancer.

CPred: a web server for predicting viable circular permutations in proteins.

Circular permutation (CP) is a protein structural rearrangement phenomenon, through which nature allows structural homologs to have different locations of termini and thus varied activities, stabilities and functional properties. It can be applied in many fields of protein research and bioengineering. The limitation of applying CP lies in its technical complexity, high cost and uncertainty of the viability of the resulting protein variants. Not every position in a protein can be used to create a viable circular permutant, but there is still a lack of practical computational tools for evaluating the positional feasibility of CP before costly experiments are carried out. We have previously designed a comprehensive method for predicting viable CP cleavage sites in proteins. In this work, we implement that method into an efficient and user-friendly web server named CPred (CP site predictor), which is supposed to be helpful to promote fundamental researches and biotechnological applications of CP. The CPred is accessible at http://sarst.life.nthu.edu.tw/CPred.

The Potential Role and Therapeutic Relevance of Cellular Senescence in Skeletal Pathophysiology.

Biological aging profoundly impairs the homeostasis of the skeletal system. Cellular senescence, a hallmark of biological aging, plays an instrumental role in bone disease. The underlying mechanisms of cellular senescence, triggered by both intracellular and extracellular stimuli, are multifaceted and yet to be uncovered. Recent research indicates that acute cellular senescence often serves beneficial roles, such as contributing to growth, development, and tissue regeneration. By contrast, chronic cellular senescence, primarily driven by the accumulation of senescent cells (SnCs) and the release of senescence-associated secretory phenotypes (SASP), has detrimental effects on the skeletal system by irreversibly disrupting bone homeostasis and promoting age-related disorders. Furthermore, the bone marrow is rich in immune cells and their exposure to SASP often leads to immune dysfunction, resulting in unresolved chronic inflammation and compromised adaptive immunity. Until now, the impact of SnCs and SASP on the skeleton has remained elusive. Meanwhile, extensive efforts are being made to combat age-related diseases through various strategies. Among them, SnCs and SASP are the primary targets for antiaging therapeutic clearance, resulting in the development of "senolytics" and "senomorphics," respectively. In this review, we summarize and highlight the role of SnCs and SASP in skeletal pathophysiology, the mechanism of cellular senescence in affecting bone metabolism, and potential therapeutic approaches, particularly senolytics and senomorphics, in treating cellular senescence-related bone diseases.

The LEPIS-HuR-TMOD4 axis regulates hepatic cholesterol homeostasis and accelerates atherosclerosis.

BACKGROUND AND AIMS: Long noncoding RNAs (lncRNAs) play important roles in the progression of atherosclerosis. In this study, we identified an uncharacterized lncRNA, Liver Expressions by PSRC1 Induced Specifically (LEPIS). This study aimed to clarify the mechanism though which LEPIS affects atherosclerosis (AS). METHODS: The expression of LEPIS and its potential target, tropomodulin 4 (TMOD4), was increased in the livers of ApoE-/- mice fed a high-fat diet (HFD). An ApoE-/- mouse model in which LEPIS or TMOD4 was overexpressed in the liver was established. The plaque load in the aorta was assessed, plasma was collected to measure blood lipid levels, and the liver was collected to study cholesterol metabolism. RESULTS: We found that both LEPIS and TMOD4 increased the AS burden and reduced hepatic cholesterol levels. A further study revealed that LEPIS and TMOD4 affected the expression of genes related to hepatic cholesterol homeostasis, including proprotein convertase subtilisin/kexin type 9 (PCSK9) and low-density lipoprotein receptor (LDLR), which are closely related to hypercholesterolemia. Mechanistically, human antigen R (HuR), an RNA-binding protein (RBP), was shown to be critical for the regulation of TMOD4 by LEPIS. Furthermore, we found that verexpression of LEPIS promoted the shuttling of HuR from the nucleus to the cytoplasm, enhanced the stability of TMOD4 mRNA, and in turn promoted the expression of TMOD4. In addition, TMOD4 was found to affect intracellular cholesterol levels through PCSK9. CONCLUSIONS: These results suggest that the LEPIS-HuR-TMOD4 axis is a potential intervention target for dysregulated hepatic cholesterol homeostasis and AS and may provide the basis for further reductions in the circulating LDL-C concentration and arterial plaque burden.

Circulating long noncoding RNA, Zfpm2-As1, and XIST based on medical data analysis are potential plasma biomarkers for gastric cancer diagnosis.

BACKGROUND: Long noncoding RNAs (lncRNAs) participate in diseases, especially tumorigenesis, including gastric cancer (GC). Although lncRNAs in GC tissues have been extensively studied in previous research, the possible significance of circulating lncRNAs in diagnosing GC is still unknown. OBJECTIVE: The present work investigated lncRNAs ZFPM2-AS1 and XIST with high expression in GC tissues proved as potential plasma biomarkers from 20 early GC cases, 100 GC cases, and 90 normal subjects. METHODS: The possible correlation between ZFPM2-AS1 and XIST expression levels was analyzed with general characteristics and clinicopathological features. The performance in diagnosis was assessed according to receiver operating characteristic (ROC) analysis. RESULTS: According to the results, XIST and ZFPM2-AS1 expression remarkably increased within GC plasma relative to normal subjects (P< 0.01); besides, lncRNA XIST expression after surgery had a tendency of downregulation compared with preoperative levels (P< 0.05). Moreover, the area under ROC curve (AUC) values were 0.62 for ZFPM2-AS1 and 0.68 for XIST, while the pooled AUC value of CA-724 and two lncRNAs was 0.751. CONCLUSION: Circulating lncRNAs ZFPM2-AS1 and XIST can serve as the candidate plasma biomarkers used to diagnose GC.