Combination of ligand­based and structure­based virtual screening for the discovery of novel Janus kinase 2 inhibitors against philadelphia-negative myeloproliferative neoplasms.

The activating V617F mutation in Janus kinase 2 (JAK2) has been shown to be the major cause for classic Philadelphia-negative myeloproliferative neoplasms (MPNs). Thus, the development of pharmacologic JAK2 inhibitors is an essential move in combating MPNs. In this study, screening methods examining both ligands and their structures were developed to discover novel JAK2 inhibitors from the ChemDiv database with virtual screening identifying 886 candidate inhibitors. Next, these compounds were further filtered using ADMET, drug likeliness, and PAINS filtering, which reduced the compound number even further. This consolidated list of candidate compounds (n = 49) was then evaluated biologically at molecular level and the highest performing inhibitor with a novel scaffold was selected for further examination. This candidate inhibitor, CD4, was then subjected to molecular dynamics studies, with complex stability, root-mean-square deviation, radius of gyration, binding free energy, and binding properties all examined. The result suggested that CD4 interacts with JAK2 and that the CD4-JAK2 complex is stable. This study was able to identify a candidate inhibitor that warrants further examination and optimization and may potentially serve as a future MPN treatment.

A novel marine-derived anti-acute kidney injury agent targeting peroxiredoxin 1 and its nanodelivery strategy based on ADME optimization.

Insufficient therapeutic strategies for acute kidney injury (AKI) necessitate precision therapy targeting its pathogenesis. This study reveals the new mechanism of the marine-derived anti-AKI agent, piericidin glycoside S14, targeting peroxiredoxin 1 (PRDX1). By binding to Cys83 of PRDX1 and augmenting its peroxidase activity, S14 alleviates kidney injury efficiently in Prdx1-overexpression (Prdx1-OE) mice. Besides, S14 also increases PRDX1 nuclear translocation and directly activates the Nrf2/HO-1/NQO1 pathway to inhibit ROS production. Due to the limited druggability of S14 with low bioavailability (2.6%) and poor renal distribution, a pH-sensitive kidney-targeting dodecanamine-chitosan nanoparticle system is constructed to load S14 for precise treatment of AKI. l-Serine conjugation to chitosan imparts specificity to kidney injury molecule-1 (Kim-1)-overexpressed cells. The developed S14-nanodrug exhibits higher therapeutic efficiency by improving the in vivo behavior of S14 significantly. By encapsulation with micelles, the AUC0‒t , half-life time, and renal distribution of S14 increase 2.5-, 1.8-, and 3.1-fold, respectively. The main factors contributing to the improved druggability of S14 nanodrugs include the lower metabolic elimination rate and UDP-glycosyltransferase (UGT)-mediated biotransformation. In summary, this study identifies a new therapeutic target for the marine-derived anti-AKI agent while enhancing its ADME properties and druggability through nanotechnology, thereby driving advancements in marine drug development for AKI.

A quadrivalent recombinant influenza Hemagglutinin vaccine induced strong protective immune responses in animal models.

Globally, influenza poses a substantial threat to public health, serving as a major contributor to both morbidity and mortality. The current vaccines for seasonal influenza are not optimal. A novel recombinant hemagglutinin (rHA) protein-based quadrivalent seasonal influenza vaccine, SCVC101, has been developed. SCVC101-S contains standard dose protein (15µg of rHA per virus strain) and an oil-in-water adjuvant, CD-A, which enhances the immunogenicity and cross-protection of the vaccine. Preclinical studies in mice, rats, and rhesus macaques demonstrate that SCVC101-S induces robust humoral and cellular immune responses, surpassing those induced by commercially available vaccines. Notably, a single injection with SCVC101-S can induce a strong immune response in macaques, suggesting the potential for a standard-dose vaccination with a recombinant protein influenza vaccine. Furthermore, SCVC101-S induces cross-protection immune responses against heterologous viral strains, indicating broader protection than current vaccines. In conclusion, SCVC101-S has demonstrated safety and efficacy in preclinical settings and warrants further investigation in human clinical trials. Its potential as a valuable addition to the vaccines against seasonal influenza, particularly for the elderly population, is promising.

Soluble Programmed Cell Death 1 Protein Is a Promising Biomarker to Predict Severe Liver Inflammation in Chronic Hepatitis B Patients.

Background and Aims: Liver inflammation is important in guiding the initiation of antiviral treatment and affects the progression of chronic hepatitis B(CHB). The soluble programmed cell death 1 protein (sPD-1) was upregulated in inflammatory and infectious diseases and correlated with disease severity. We aimed to investigate the correlation between serum sPD-1 levels and liver inflammation in CHB patients and their role in indicating liver inflammation. Methods: 241 CHB patients who underwent liver biopsy were enrolled. The correlation between sPD-1 levels and the degree of liver inflammation was analyzed. Univariate and multivariate logistic regression analyses were performed to analyze independent variables of severe liver inflammation. Binary logistic regression analysis was conducted to construct a predictive model for severe liver inflammation, and the receiver operating characteristic curve (ROC) was used to evaluate the diagnostic accuracy of the predictive model. Results: sPD-1 was highest in CHB patients with severe liver inflammation, which was higher than that in CHB patients with mild or moderate liver inflammation (P < 0.001). Besides, sPD-1 was weakly correlated with AST (r = 0.278, P < 0.001). Multivariable analysis showed that sPD-1 was an independent predictor of severe liver inflammation. The predictive model containing sPD-1 had areas under the ROC (AUROCs) of 0.917 and 0.921 in predicting severe liver inflammation in CHB patients and CHB patients with ALT ≤ 1× upper limit of normal (ULN), respectively. Conclusions: Serum sPD-1 level is associated with liver inflammation in CHB patients, and high levels of sPD-1 reflect severe liver inflammation. Serum sPD-1 is an independent predictor of severe liver inflammation and shows improved diagnostic accuracy when combined with other clinical indicators.

Efficacy of the induced pluripotent stem cell derived and engineered CD276-targeted CAR-NK cells against human esophageal squamous cell carcinoma.

Introduction: Chimeric antigen receptor natural killer (CAR-NK) cells have been found to be successful in treating hematologic malignancies and present potential for usage in solid tumors. Methods: In this study, we created CD276-targeted CAR-expressing NK cells from pluripotent stem cells (iPSC CD276-targeted CAR-NK cells) and evaluated their cytotoxicity against esophageal squamous cell carcinoma (ESCC) using patient-specific organoid (PSO) models comprising of both CD276-positive and CD276-negative adjacent epithelium PSO models (normal control PSO, NC PSO) as well as primary culture of ESCC cell models. In addition, in vitro and in vivo models such as KYSE-150 were also examined. iPSC NK cells and NK-free media were used as the CAR-free and NK-free controls, respectively. Results: The positive CD276 staining was specifically detected on the ESCC membrane in 51.43% (54/105) of the patients of all stages, and in 51.35% (38/74) of stages III and IV. The iPS CD276-targeted CAR-NK cells, comparing with the iPS NK cells and the NK-free medium, exhibited specific and significant cytotoxic activity against CD276-positive ESCC PSO rather than CD276-negative NC PSO, and exhibited significant cytotoxicity against CD276-expressing cultured ESCC cells, as well as against CD276-expressing KYSE-150 in vitro and in BNDG mouse xenograft. Discussion: The efficacy of the iPSC CD276-targeted CAR-NK cells demonstrated by their successful treatment of CD276-expressing ESCC in a multitude of pre-clinical models implied that they hold tremendous therapeutic potential for treating patients with CD276-expressing ESCC.

Mechanical strain regulates osteogenesis via Antxr1/LncRNA H19/Wnt/ß-catenin axis.

Alleviating bone loss is an essential way to prevent osteoporotic fractures. Proper exercise improves bone density without the side effects of long-term medications, but the mechanism is unclear. Our study explored the role of Antxr1/LncRNA H19/Wnt/ß-catenin axis in the process of exercise-mediated alleviation of bone loss. Here we discovered that moderate-intensity treadmill exercise alleviates bone loss caused by ovariectomy and ameliorates bone strength accompanied by an increased lncRNA H19 expression. Concomitantly, Antxr1, a mechanosensitive protein was found downregulated by exercise but upregulated by ovariectomy. Interestingly, knockdown expression of Antxr1 increased lncRNA H19 expression and Wnt/ß-catenin signaling pathway in bone marrow mesenchymal stem cells, whereas overexpression of Antxr1 decreased lncRNA H19 expression and Wnt/ß-catenin signaling pathway. Hence, our study demonstrates the regulation of Antxr1/LncRNA H19/Wnt/ß-catenin axis in the process of mechanical strain-induced osteogenic differentiation, which provides further mechanistic insight into the role of mechanical regulation in bone metabolism.

m6A demethylase FTO and osteoporosis: potential therapeutic interventions.

Osteoporosis is a common bone disease, characterized by a descent in bone mass due to the dysregulation of bone homeostasis. Although different studies have identified an association between osteoporosis and epigenetic alterations in osteogenic genes, the mechanisms of osteoporosis remain unclear. N6-methyladenosine (m6A) modification is a methylated adenosine nucleotide, which regulates the translocation, exporting, translation, and decay of RNA. FTO is the first identified m6A demethylase, which eliminates m6A modifications from RNAs. Variation in FTO disturbs m6A methylation in RNAs to regulate cell proliferation, differentiation, and apoptosis. Besides, FTO as an obesity-associated gene, also affects osteogenesis by regulating adipogenesis. Pharmacological inhibition of FTO markedly altered bone mass, bone mineral density and the distribution of adipose tissue. Small molecules which modulate FTO function are potentially novel remedies to the treatment of osteoporosis by adjusting the m6A levels. This article reviews the roles of m6A demethylase FTO in regulating bone metabolism and osteoporosis.

Advances in the study of traditional Chinese medicine affecting bone metabolism through modulation of oxidative stress.

Bone metabolic homeostasis is dependent on coupled bone formation dominated by osteoblasts and bone resorption dominated by osteoclasts, which is a process of dynamic balance between bone formation and bone resorption. Notably, the formation of bone relies on the development of bone vasculature. Previous studies have shown that oxidative stress caused by disturbances in the antioxidant system of the whole organism is an important factor affecting bone metabolism. The increase in intracellular reactive oxygen species can lead to disturbances in bone metabolism, which can initiate multiple bone diseases, such as osteoporosis and osteoarthritis. Traditional Chinese medicine is considered to be an effective antioxidant. Cumulative evidence shows that the traditional Chinese medicine can alleviate oxidative stress-mediated bone metabolic disorders by modulating multiple signaling pathways, such as Nrf2/HO-1 signaling, PI3K/Akt signaling, Wnt/ß-catenin signaling, NF-κB signaling, and MAPK signaling. In this paper, the potential mechanisms of traditional Chinese medicine to regulate bone me-tabolism through oxidative stress is summarized to provide direction and theoretical basis for future research related to the treatment of bone diseases with traditional Chinese medicine.

Prediction of the effects of small molecules on the gut microbiome using machine learning method integrating with optimal molecular features.

BACKGROUND: The human gut microbiome (HGM), consisting of trillions of microorganisms, is crucial to human health. Adverse drug use is one of the most important causes of HGM disorder. Thus, it is necessary to identify drugs or compounds with anti-commensal effects on HGM in the early drug discovery stage. This study proposes a novel anti-commensal effects classification using a machine learning method and optimal molecular features. To improve the prediction performance, we explored combinations of six fingerprints and three descriptors to filter the best characterization as molecular features. RESULTS: The final consensus model based on optimal features yielded the F1-score of 0.725 ± 0.014, ACC of 82.9 ± 0.7%, and AUC of 0.791 ± 0.009 for five-fold cross-validation. In addition, this novel model outperformed the prior studies by using the same algorithm. Furthermore, the important chemical descriptors and misclassified anti-commensal compounds are analyzed to better understand and interpret the model. Finally, seven structural alerts responsible for the chemical anti-commensal effect are identified, implying valuable information for drug design. CONCLUSION: Our study would be a promising tool for screening anti-commensal compounds in the early stage of drug discovery and assessing the potential risks of these drugs in vivo.

Pharmacokinetics of Sirolimus Eye Drops Following Topical Ocular Administration in Rabbits.

Purpose: To evaluate the pharmacokinetics of sirolimus eye drops following topical instillation in rabbits. Methods: The study included 2 experiments. In single-dose pharmacokinetic study, rabbits received a single bilateral instillation of 0.05% sirolimus eye drops (0.5 mg/mL, 50 µL/eye). In repeat-dose pharmacokinetic study, 0.05% sirolimus eye drops (0.5 mg/mL, 50 µL/eye/time) were instilled into both eyes of rabbits four times a day for 6 consecutive days and one time on day 7. Whole blood, tears, aqueous humor, cornea, and conjunctiva samples were collected. Sirolimus concentration was determined by a validated liquid chromatography-tandem mass spectrometry. Results: Sirolimus was hardly detected in plasma or aqueous humor after either single or repeated dosing. The Cmax of sirolimus in tears, cornea, and conjunctiva after a single instillation was 163.34 ± 69.30 µg/g, 150.56 ± 84.98 ng/g, and 113.22 ± 49.82 ng/g, respectively. As the number of instillation elevated, the Cmax of sirolimus was increased to 486.18 ± 297.93 µg/g, 418.63 ± 41.07 ng/g, and 314.25 ± 63.74 ng/g, respectively. In repeat-dose administration, the steady state of sirolimus concentration was achieved on the third day. Ocular exposure to sirolimus after single and repeated dosing, based on AUC0-t, was highest in tears, followed by cornea and conjunctiva. Compared with single administration, a significant increase in sirolimus exposure as measured by AUC0-t was observed in tears, cornea, and conjunctiva following repeated administration. Conclusions: Topical administration of sirolimus eye drops results in extensive distribution of sirolimus in tears, cornea, and conjunctiva, while aqueous humor and systemic exposure were negligible. Repeat-dose administration increases sirolimus exposure in tears, cornea, and conjunctiva.

SARS-CoV-2 bivalent mRNA vaccine with broad protection against variants of concern.

Introduction: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant has rapidly spread around the globe. With a substantial number of mutations in its Spike protein, the SARS-CoV-2 Omicron variant is prone to immune evasion and led to the reduced efficacy of approved vaccines. Thus, emerging variants have brought new challenges to the prevention of COVID-19 and updated vaccines are urgently needed to provide better protection against the Omicron variant or other highly mutated variants. Materials and methods: Here, we developed a novel bivalent mRNA vaccine, RBMRNA-405, comprising a 1:1 mix of mRNAs encoding both Delta-derived and Omicron-derived Spike proteins. We evaluated the immunogenicity of RBMRNA-405 in BALB/c mice and compared the antibody response and prophylactic efficacy induced by monovalent Delta or Omicron-specific vaccine with the bivalent RBMRNA-405 vaccine in the SARSCoV-2 variant challenge. Results: Results showed that the RBMRNA-405 vaccine could generate broader neutralizing antibody responses against both Wuhan-Hu-1 and other SARS-CoV-2 variants, including Delta, Omicron, Alpha, Beta, and Gamma. RBMRNA-405 efficiently blocked infectious viral replication and lung injury in both Omicron- and Delta-challenged K18-ACE2 mice. Conclusion: Our data suggest that RBMRNA-405 is a promising bivalent SARS-CoV-2 vaccine with broad-spectrum efficacy for further clinical development.

Network Optimization of CNT Yarn Sensor Based on NNIA Algorithm in Damage Monitoring of 3D Braided Composites.

In order to solve the optimization problem of carbon nanotube (CNT) yarn sensor network embedded in three-dimensional (3D) braided composite materials and realize the structural health monitoring of internal damage of aerospace parts, the multi-objective optimization of the number and location of sensors was studied using non-dominated neighborhood immune algorithm (NNIA). Through the research of 3D six-direction braiding process, stress sensitivity of single CNT yarn sensor, and damage location of 3D braided composites, the number, position, and coverage constraint functions based on NNIA algorithm are constructed. In addition, the number and position of three-dimensional braided composite embedded CNT yarn sensors with different sizes are solved. Through the stress experiment and data analysis of damaged parts, it is proved that the optimized configuration result of CNT yarn sensor obtained by NNIA algorithm is suitable for the damage monitoring of 3D braided composites. The damage location error is less than 1 mm. This study lays a foundation for the establishment of damage source localization model of 3D braided composites.

Application and Molecular Mechanisms of Extracellular Vesicles Derived from Mesenchymal Stem Cells in Osteoporosis.

Osteoporosis (OP) is a chronic bone disease characterized by decreased bone mass, destroyed bone microstructure, and increased bone fragility. Accumulative evidence shows that extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) (MSC-EVs), especially exosomes (Exos), exhibit great potential in the treatment of OP. However, the research on MSC-EVs in the treatment of OP is still in the initial stage. The potential mechanism has not been fully clarified. Therefore, by reviewing the relevant literature of MSC-EVs and OP in recent years, we summarized the latest application of bone targeted MSC-EVs in the treatment of OP and further elaborated the potential mechanism of MSC-EVs in regulating bone formation, bone resorption, bone angiogenesis, and immune regulation through internal bioactive molecules to alleviate OP, providing a theoretical basis for the related research of MSC-EVs in the treatment of OP.

Immunization with a Prefusion SARS-CoV-2 Spike Protein Vaccine (RBMRNA-176) Protects against Viral Challenge in Mice and Nonhuman Primates.

There is an urgent need for a broad-spectrum and protective vaccine due to the emergence and rapid spreading of more contagious SARS-CoV-2 strains. We report the development of RBMRNA-176, a pseudouridine (Ψ) nucleoside-modified mRNA-LNP vaccine encoding pre-fusion stabilized trimeric SARS-CoV-2 spike protein ectodomain, and evaluate its immunogenicity and protection against virus challenge in mice and nonhuman primates. A prime-boost immunization with RBMRNA-176 at intervals of 21 days resulted in high IgG titers (over 1:819,000 endpoint dilution) and a CD4+ Th1-biased immune response in mice. RBMRNA-176 vaccination induced pseudovirus-neutralizing antibodies with IC50 ranging from 1:1020 to 1:2894 against SARS-CoV-2 spike pseudotyped wild-type and variant viruses, including Alpha, Beta, Gamma, and Kappa. Moreover, significant control of viral replication and histopathology in lungs was observed in vaccinated mice. In nonhuman primates, a boost given by RBMRNA-176 on day 21 after the prime induced a persistent and sustained IgG response. RBMRNA-176 vaccination also protected macaques against upper and lower respiratory tract infection, as well as lung injury. Altogether, these findings support RBMRNA-176 as a vaccine candidate for prevention of COVID-19.

Mitophagy-A New Target of Bone Disease.

Bone diseases are usually caused by abnormal metabolism and death of cells in bones, including osteoblasts, osteoclasts, osteocytes, chondrocytes, and bone marrow mesenchymal stem cells. Mitochondrial dysfunction, as an important cause of abnormal cell metabolism, is widely involved in the occurrence and progression of multiple bone diseases, including osteoarthritis, intervertebral disc degeneration, osteoporosis, and osteosarcoma. As selective mitochondrial autophagy for damaged or dysfunctional mitochondria, mitophagy is closely related to mitochondrial quality control and homeostasis. Accumulating evidence suggests that mitophagy plays an important regulatory role in bone disease, indicating that regulating the level of mitophagy may be a new strategy for bone-related diseases. Therefore, by reviewing the relevant literature in recent years, this paper reviews the potential mechanism of mitophagy in bone-related diseases, including osteoarthritis, intervertebral disc degeneration, osteoporosis, and osteosarcoma, to provide a theoretical basis for the related research of mitophagy in bone diseases.

Drug-Induced Immune Thrombocytopenia Toxicity Prediction Based on Machine Learning.

Drug-induced immune thrombocytopenia (DITP) often occurs in patients receiving many drug treatments simultaneously. However, clinicians usually fail to accurately distinguish which drugs can be plausible culprits. Despite significant advances in laboratory-based DITP testing, in vitro experimental assays have been expensive and, in certain cases, cannot provide a timely diagnosis to patients. To address these shortcomings, this paper proposes an efficient machine learning-based method for DITP toxicity prediction. A small dataset consisting of 225 molecules was constructed. The molecules were represented by six fingerprints, three descriptors, and their combinations. Seven classical machine learning-based models were examined to determine an optimal model. The results show that the RDMD + PubChem-k-NN model provides the best prediction performance among all the models, achieving an area under the curve of 76.9% and overall accuracy of 75.6% on the external validation set. The application domain (AD) analysis demonstrates the prediction reliability of the RDMD + PubChem-k-NN model. Five structural fragments related to the DITP toxicity are identified through information gain (IG) method along with fragment frequency analysis. Overall, as far as known, it is the first machine learning-based classification model for recognizing chemicals with DITP toxicity and can be used as an efficient tool in drug design and clinical therapy.

An automated, rapid fluorescent immunoassay to quantify serum soluble programmed death-1 (PD-1) protein using testing-on-a-probe biosensors.

OBJECTIVES: Soluble programmed death-1 (sPD-1) plays an essential role in the pathogenesis and progression of various diseases, including chronic hepatitis B (CHB) and hepatocellular carcinoma (HCC). Currently, there is no Food and Drug Administration-approved sPD-1 immunoassay available for routine clinical testing. Most sPD-1 detections employed enzyme-linked immunosorbent assay (ELISA) method for research purpose, which is complicated by intensive manual operation and cannot achieve automatic detection. Therefore, we aimed to develop an automated, rapid immunoassay for sPD-1 measurement based on testing-on-a-probe (TOP) biosensors and evaluate its performance in patients with hepatic diseases. METHODS: We developed an automatic fluorescent immunoassay using TOP biosensors using a pair of mouse anti-PD-1 monoclonal antibodies (mAbs), which were evaluated by biolayer interferometry. The sensitivity, linearity, and repeatability of the novel immunoassay were analyzed, and its compatibility with an established ELISA kit was evaluated. Further, we quantified sPD-1 level in healthy individuals as well as patients with CHB, hepatic cirrhosis, and HCC. RESULTS: The TOP assay to quantify sPD-1 was developed and performed on an automatic fluorescent analyzer within 20 min, which showed good precision with coefficients of variation less than 10% and good linearity ranging from 2 to 3,000 pg/mL. The results tested by our TOP assay correlated well with the established ELISA assay (r=0.92, p<0.0001). Using our TOP assay, sPD-1 was significantly elevated in patients with chronic hepatitis, hepatic cirrhosis and hepatocarcinoma if compared to healthy control, respectively (p<0.0001). CONCLUSIONS: An automated, rapid fluorescent immunoassay to quantify serological sPD-1 protein using TOP biosensors was developed and showed acceptable analytical performance including precision, linearity, and good correlation with the established ELISA assay, with the great potential in clinical practice.

Repetitive Blood Sampling from the Subclavian Vein of Conscious Rat.

Rats are widely used in pharmacokinetics (PK) and toxicokinetic (TK) studies that need to collect a certain amount of blood at specific time points to detect drug exposure. The rat blood sampling method determines the quality of the plasma and further affects the precision of the test results. The subclavian vein blood collection method described in this protocol collects blood samples repeatedly in the conscious state of animals to meet the needs of PK and TK tests. The skills of restraint handling and appropriate procedure of needle incision ensure the success rate of blood collection. It is easy to operate while ensuring the quality of plasma and at the same time catering to animal welfare. However, this method requires skilled operation, and an improper one may cause animal weakness, pain, lameness, and even mortality. The current method has been used in the testing facility for a 4-week oral toxicity study in Sprague Dawley (SD) rats with TK. The maximum amount of blood collected within 24 h did not exceed 20% of the animal's total blood. The animals' body weight was more than 200 g for males and females. The data showed that the animals' bodyweight increased steadily every week, and the clinical observation was normal after repetitive sample collection.

Effects of exercise on the expression of long non-coding RNAs in the bone of mice with osteoporosis.

Physical activity or exercise are known to promote bone formation and decrease bone resorption to maintain skeletal and bone health both in animal models and in humans with osteoporosis. Previous studies have indicated that long non-coding RNAs (lncRNAs) are able to regulate bone metabolism. Therefore, the present study aimed to evaluate whether lncRNAs responded to exercise by regulating the balance of bone metabolism in order to prevent osteoporosis. To meet this end, ovariectomized mice were used in the present study to establish an osteoporosis model. The exercise treatment groups were subjected to 9 weeks of treadmill running exercise in 4 weeks of the operation was performed Femurs were collected to measure bone mineral density, bone mass, bone formation and resorption. The expression levels of lncRNAs were subsequently measured using microarray and gene function analyses. The pairwise comparison results [ovariectomy (OVX) vs. OVX + exercise (EX); OVX vs. SHAM; SHAM vs. SHAM + EX; OVX + EX vs. SHAM + EX] of the gene microarray analysis revealed that the expression of 2,424 lncRNAs (1718 upregulated and 706 downregulated) were significantly altered in the mouse femurs following treadmill running. Gene Ontology (GO) analysis, incorporating the GO annotations 'biological processes', 'molecular function' and 'cellular components', of osteoporosis revealed that the VEGF, mTOR and NF-κB signaling pathways were potential targets of the lncRNAs. Moreover, it was possible to predict the target microRNAs (miRNAs) of six lncRNAs (LOC105246953, LOC102637959, NONMMUT014677, NONMMUT027251, ri|D130079K21|PX00187K16|1491 and NONMMUT006626), which suggested that the underlying mechanism by which lncRNAs respond to exercise involved bone regulation via lncRNA-miRNA sponge adsorption. Overall, these results suggested that the treadmill running exercise did regulate lncRNA expression in the bone, and that this was involved in the prevention of osteoporosis.

The Role of Long Non-coding RNA, Nuclear Enriched Abundant Transcript 1 (NEAT1) in Cancer and Other Pathologies.

Nuclear enriched abundant transcript 1 (NEAT1), consisting of two kinds of lncRNAs of 3.7 kB NEAT1-1 and 23 kB NEAT1-2, can be highly expressed in organs and tissues such as the ovary, prostate, colon, and pancreas, and is involved in paraspeckle formation and mRNA editing and gene expression. Therefore, NEAT1 is a potential biomarker for the treatment of a variety of diseases, which may be caused by two factors (isoforms of NEAT1 and NEAT1 sponging miRNA as ceRNA). However, there is still much confusion about the mechanism and downstream effector between the abnormal expression of NEAT1 and various diseases. This review summarizes recent research progress on NEAT1 in cancer and other pathologies and provides a more reliable theoretical basis for the treatment of related diseases.