Long Noncoding RNA PSMB8-AS1 Mediates the Tobacco-Carcinogen-Induced Transformation of a Human Bronchial Epithelial Cell Line by Regulating Cell Cycle.

Lung cancer is the main cause of cancer deaths around the world. Nitrosamine 4-(methyl nitrosamine)-1-(3-pyridyl)-1-butanone (NNK) is a tobacco-specific carcinogen of lung cancer. Abundant evidence implicates long noncoding RNAs (lncRNAs) in tumorigenesis. Yet, the effects and mechanisms of lncRNAs in NNK-induced carcinogenesis are still unclear. In this study, we discovered that NNK-induced transformed Beas-2B cells (Beas-2B-NNK) showed increased cell migration and proliferation while decreasing rates of apoptosis. RNA sequencing and differentially expressed lncRNAs analyses showed that lncRNA PSMB8-AS1 was obviously upregulated. Interestingly, silencing the lncRNA PSMB8-AS1 in Beas-2B-NNK cells reduced cell proliferation and migration and produced cell cycle arrest in the G2/M phase along with a decrease in CDK1 expression. Conclusively, our results demonstrate that lncRNA PSMB8-AS1 could promote the malignant characteristics of Beas-2B-NNK cells by regulating CDK1 and affecting the cell cycle, suggesting that it may supply a new prospective epigenetic mechanism for lung cancer.

Elevated Ozone Reduces the Quality of Tea Leaves but May Improve the Resistance of Tea Plants.

Tropospheric ozone (O3) pollution can affect plant nutritional quality and secondary metabolites by altering plant biochemistry and physiology, which may lead to unpredictable effects on crop quality and resistance to pests and diseases. Here, we investigated the effects of O3 (ambient air, Am; ambient air +80 ppb of O3, EO3) on the quality compounds and chemical defenses of a widely cultivated tea variety in China (Camellia sinensis cv. 'Baiye 1 Hao') using open-top chamber (OTC). We found that elevated O3 increased the ratio of total polyphenols to free amino acids while decreasing the value of the catechin quality index, indicating a reduction in leaf quality for green tea. Specifically, elevated O3 reduced concentrations of amino acids and caffeine but shows no impact on the concentrations of total polyphenols in tea leaves. Within individual catechins, elevated O3 increased the concentrations of ester catechins but not non-ester catechins, resulting in a slight increase in total catechins. Moreover, elevated O3 increased the emission of biogenic volatile organic compounds involved in plant defense against herbivores and parasites, including green leaf volatiles, aromatics, and terpenes. Additionally, concentrations of main chemical defenses, represented as condensed tannins and lignin, in tea leaves also increased in response to elevated O3. In conclusion, our results suggest that elevated ground-level O3 may reduce the quality of tea leaves but could potentially enhance the resistance of tea plants to biotic stresses.

Biosynthetic potential of uncultured anammox community bacteria revealed through multi-omics analysis.

Microbial secondary metabolites (SMs) and their derivatives have been widely used in medicine, agriculture, and energy. Growing needs for renewable energy and the challenges posed by antibiotic resistance, cancer, and pesticides emphasize the crucial hunt for new SMs. Anaerobic ammonium-oxidation (anammox) systems harbor many uncultured or underexplored bacteria, representing potential resources for discovering novel SMs. Leveraging HiFi long-read metagenomic sequencing, 1,040 biosynthetic gene clusters (BGCs) were unearthed from the anammox microbiome with 58% being complete and showcasing rich diversity. Most of them showed distant relations to known BGCs, implying novelty. Members of the underexplored lineages (Chloroflexota and Planctomycetota) and Proteobacteria contained lots of BGCs, showcasing substantial biosynthetic potential. Metaproteomic results indicated that Planctomycetota members harbored the most active BGCs, particularly those involved in producing potential biofuel-ladderane. Overall, these findings underscore that anammox microbiomes could serve as valuable resources for mining novel BGCs and discovering new SMs for practical application.

Proposals for the delineation of neck clinical target volume for definitive Radiation therapy in patients with oral/ oropharyngeal squamous cell cancer based on lymph node distribution.

PURPOSE/OBJECTIVE(S): To establish the distribution pattern of cervical lymph node metastasis (LNM) and propose optimized clinical target volume (CTV) boundaries specific to oral/ oropharyngeal squamous cell cancer (OSCC/OPSCC). MATERIALS/METHODS: 531 patients with pathologically confirmed OSCC/OPSCC were enrolled from January 2013 to June 2022. Patients were stratified into two groups based on the minimal distance from the lesion's edge to the body's midline: ≤1 cm or > 1 cm. The geometric center of cervical metastatic LN was marked on a template CT. LN distribution probability maps were established. The relationships between the LN distribution and consensus guidelines were analyzed to propose modifications for CTV boundaries specific to OSCC/OPSCC. RESULTS: A total of 1962 positive LNs were enrolled. Compared with the > 1 cm group, the ≤ 1 cm group has following feature tendencies: male smokers, younger, median organs, large gross lesion, infiltrative growth pattern, contralateral LNM. The most frequently involved level of LNM was ipsilateral II, but ipsilateral Ib had the highest involvement rate in the > 1 cm OSCC group. In addition, tongue cancer had a higher incidence of LN extranodal extension (ENE), which mainly distributes in ipsilateral level II. The skip metastasis was prone to from level III to Vb (3.5 %) in LN(+)/ENE (-), and level Ib to VIa (3.7 %) in LN(+)/ENE (+). Accordingly, we proposed the following modifications: 1. only including lateral and posterior margin of submandibular gland within 5 mm; 2. retracting posterior boundary of level II to front edge of levator scapula muscle, and descending the upper boundary to transverse process of C2 vertebra only for OSCC; 3. including posterior third of thyroglossal muscle or anterior edge of sternocleidomastoid muscle; 4. sparing level Va in case of only level II involvement; 5. including upper area of the thyroid cartilage plate in case of level Ib LN(+)/ENE (+); 6. sparing level VIIa is considered. CONCLUSION: This is the first description of LN topographic spread patterns for OSCC/OPSCC. Modified CTV for prophylactic irradiation was proposed to spare the organs at risk and minimize adverse effects.

Hyperforin ameliorates neuroinflammation and white matter lesions by regulating microglial VEGFR2 /SRC pathway in vascular cognitive impairment mice.

AIM: To explore the neuroprotective potential of hyperforin and elucidate its underlying molecular mechanisms involved in its therapeutic effects against vascular cognitive impairment (VCI). METHODS: The active compounds and possible targets of Hypericum perforatum L. that may be effective against VCI were found by network pharmacology in this research. We utilized bilateral common carotid artery occlusion (BCCAO) surgery to induce a VCI mouse model. Morris water maze (MWM) and Y-maze tests were used to assess VCI mice's cognitive abilities following treatment with hyperforin. To evaluate white matter lesions (WMLs), we utilized Luxol fast blue (LFB) stain and immunofluorescence (IF). Neuroinflammation was assessed using IF, western blot (WB), and enzyme-linked immunosorbent assay (ELISA). The effects of hyperforin on microglia were investigated by subjecting the BV2 microglial cell line to oxygen-glucose deprivation/reperfusion (OGD/R) stimulation. The expressions of VEGFR2 , p-SRC, SRC, VEGFA, and inflammatory markers including IL-10, IL-1ß, TNF-α, and IL-6 were subsequently assessed. RESULTS: The VEGFR2 /SRC signaling pathway is essential for mediating the protective properties of hyperforin against VCI according to network pharmacology analysis. In vivo findings demonstrated that hyperforin effectively improved BCCAO-induced cognitive impairment. Furthermore, staining results showed that hyperforin attenuated WMLs and reduced microglial activation in VCI mice. The hyperforin treatment group's ELISA results revealed a substantial decrease in IL-1ß, IL-6, and TNF-α levels. According to the results of in vitro experiments, hyperforin decreased the release of pro-inflammatory mediators (TNF-α, IL-6, and IL-1ß) and blocked microglial M1-polarization by modulating the VEGFR2 /SRC signaling pathway. CONCLUSION: Hyperforin effectively modulated microglial M1 polarization and neuroinflammation by inhibiting the VEGFR2 /SRC signaling pathways, thereby ameliorating WMLs and cognitive impairment in VCI mice.

Melt-blown fiber felt for efficient all-weather recovery of viscous oil spills by Joule heating and photothermal effect.

Adsorbents play a vital role in responding to marine oil spills, yet effectively cleaning up viscous oil spills remains a technical challenge. Herein, we present a superhydrophobic oil-adsorbing felt prepared using melt-blown technology and functionally enhanced with a photoelectric composite CNT/PANI coating for effectively cleaning up high-viscosity oil spills. By virtue of its superior solar/Joule heating ability and thermally conductive fiber network, p-CNT/PANI@PP notably reduced crude oil viscosity and enhanced the oil diffusion coefficient within pores. Leveraging primarily solar heating and supplemented by Joule heating, p-CNT/PANI@PP demonstrates an impressive in-situ adsorption rate of up to 560 g/h for ultra-high-viscosity crude oil (c.a. 138000 mPa·s), alongside an adsorption capacity of 15.57 g/g. This measure enables efficient viscosity reduction and continuous day-and-night recovery of viscous crude oil, addressing the challenges posed by seasonal fluctuations in seawater temperature and adverse weather conditions. Moreover, a conveyorized collector integrated with an oil-adsorbing felt realizes continuous recovery of viscous oil spills with speed control to tackle varying thicknesses of oil film. Given the top-down material design, superior functionality, and applicability to applications, this work provides a comprehensive and feasible solution to catastrophic large-area viscous oil spills.

Eosinophil dynamics during chemo-radiotherapy correlate to clinical outcome in stage â ¡-â £a nasopharyngeal carcinoma patients: Results from a large cohort study.

BACKGROUND AND PURPOSE: We investigated the dynamics of eosinophil depletion during definitive concurrent chemo-radiotherapy (CCRT) and their association with the prognosis of stage Ⅱ-Ⅳa nasopharyngeal carcinoma (NPC) patients. MATERIALS AND METHODS: Fuzzy C-means algorithm (FCMA) assessed longitudinal trends in circulating eosinophil counts (CECs) of 1225 patients throughout the period of radical radiotherapy. The prognostic impact on patients' survival was evaluated with Kaplan-Meier analysis and Cox proportional risk model was used to determine the hazard ratio for adverse prognostic effects in grades of eosinophil depletion. The interactive effect of pre-treatment CECs and CCRT on outcomes was evaluated using HRs within the framework of Cox regression models. RESULTS: Three grades of eosinophil depletion, as defined by the interaction between dynamic types of CECs in the period of treatment and the value of CECs at the termination of treatment, significantly stratified the poor prognosis in terms of progression-free survival (PFS), overall survival (OS), and distant metastasis-free survival (DMFS) [1.57-fold (P = 0.001), 1.69-fold (P = 0.007), and 1.51-fold (P = 0.019) for G1, 2.4-fold (P < 0.001), 2.76-fold (P < 0.001), and 2.31-fold (P < 0.001) for G2, as compared with G0]. Furthermore, high levels of pre-treatment CECs acted as the strongest protective factor against severe depletion grade (G0 vs. G2, HR = 0.20, P = 0.005; G1 vs. G2, HR = 0.14, P < 0.001). However, compared with radiotherapy alone, the benefit from CCRT was attenuated in patients with high pre-treatment CECs. CONCLUSIONS: CECs reduction after treatment in patients with NPC may be helpful in the clinical setting to aid in assessing the prognosis for standard treatment of NPC.

RNA aptamers with specific binding affinity to CD40 (CD40Apt) represents a promising antagonist of the CD40-CD40L signaling for thyroid-associated ophthalmopathy (TAO) treatment in mouse.

Thyroid-associated ophthalmopathy (TAO) is the most common autoimmune inflammatory diseases of the orbit. The CD40-CD40L pathway has been regarded as a potential molecular mechanism contributing to the development and progression of TAO, and RNA aptamers with specific binding affinity to CD40 (CD40Apt) represents a promising inhibitor of the CD40-CD40L signaling in TAO treatment. In this study, CD40Apt was confirmed to specifically recognize mouse CD40-positive ortibtal fibroblast. Mouse orbital fibroblasts were isolated from TAO mice model orbital tissues and validated. In TGF-ß-induced orbital fibroblast activation model in vitro, CD40Apt administration inhibited TGF-ß-induced cell viability, decreased TGF-ß-induced α-SMA, Collagen I, Timp-1, and vimentin levels, and suppressed TGF-ß-induced phosphorylation of Erk, p38, JNK, and NF-κB. In TAO mice model in vivo, CD40Apt caused no significant differences to the body weight of mice; furthermore, CD40Apt improved the eyelid broadening, ameliorated inflammatory infiltration and the hyperplasia in orbital muscle and adipose tissues in model mice. Concerning orbital fibroblast activation, CD40Apt reduced the levels of CD40, collagen I, TGF-ß, and α-SMA in orbital muscle and adipose tissues of model mice. Finally, CD40Apt administration significantly suppressed Erk, p38, JNK, and NF-κB phosphorylation. In conclusion, CD40Apt, specifically binds to CD40 proteins in their natural state on the cell surface with high affinity, could suppress mouse orbital fibroblast activation, therefore improving TAO in mice model through the CD40 and downstream signaling pathways. CD40Apt represents a promising antagonist of the CD40-CD40L signaling for TAO treatment.

Radiation-induced eosinophil increase ratio predicts patient outcomes in non-small celllung cancer.

Background and purpose: Radiotherapy (RT) is a double-edged sword in regulating immune responses. This study aimed to investigate the impact of thoracic RT on circulating eosinophils and its association with patient outcomes in non-small cell lung cancer (NSCLC). Materials and methods: This retrospective study included 240 patients with advanced NSCLC treated with definitive thoracic RT from January 2012 to January 2020. Statistics included Kaplan-Meier analysis of overall survival (OS) and progression-free survival (PFS), multivariate Cox analyses to identify significant variables, and Spearman's correlation to qualify the relationship between dose-volume histogram (DVH) parameters and EIR. Results: Absolute eosinophil counts (AECs) showed an increasing trend during RT and an obvious peak in the 1st month after RT. Thresholds of eosinophil increase ratio (EIR) at the 1st month after RT for both OS and PFS were 1.43. Patients with high EIR above 1.43 experienced particularly favorable clinical outcomes (five-year OS: 21% versus 10%, P<0.0001; five-year PFS: 10% versus 8%, P=0.014), but may not derive PFS benefit from the addition of chemotherapy to RT. The higher a patient's EIR, the larger the potential benefit in the absence of chemotherapy. DVH parameters including heart mean dose and heart V10 were negatively associated with EIR. None of these DVH parameters was correlated with the clinical outcomes. Conclusion: EIR may serve as a potential biomarker to predict OS and PFS in NSCLC patients treated with RT. These findings require prospective studies to evaluate the role of such prognostic marker to identify patients at risk to tailor interventions.

Novel microtubule inhibitor SQ overcomes multidrug resistance in MCF-7/ADR cells by inhibiting BCRP function and mediating apoptosis.

The occurrence of multidrug resistance (MDR) is one of the impediments in the clinical treatment of breast cancer, and MDR breast cancer has abnormally high breast cancer resistance protein (BCRP/ABCG2) expression. However, there are currently no clinical drugs that inhibit this target. Our previous study found that 2-Methoxy-5((3,4,5-trimethosyphenyl)seleninyl) phenol (SQ0814061/SQ), a small molecule drug with low toxicity to normal tissues, could target microtubules, inhibit the proliferation of breast cancer, and reduce its migration and invasion abilities. However, the effect and the underlying mechanism of SQ on MDR breast cancers are still unknown. Therefore, in this study, we investigated the effect of SQ on adriamycin-resistant MCF-7 (MCF-7/ADR) cells and explored the underlying mechanism. The MTT assay showed that SQ had potent cytotoxicity to MCF-7/ADR cells. In particular, the results of western blot and flow cytometry proved that SQ could effectively inhibit the expression of BCRP in MCF-7/ADR cells to decrease its drug delivery activity. In addition, SQ could block the cell cycle at G2/M phase in parental and MCF-7/ADR cells, thereby mediating cell apoptosis, which was related with the inhibition of PI3K-Akt-MDM2 pathway. Taken together, our findings indicate that SQ overcomes multidrug resistance in MCF-7/ADR cells by inhibiting BCRP function and mediating apoptosis through PI3K-Akt-MDM2 pathway inhibition.

Protein Phosphatase 2A-Dependent Mitotic hnRNPA1 Dephosphorylation and TERRA Formation Facilitate Telomere Capping.

The heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1), telomeric repeat-containing RNA (TERRA), and protection of telomeres 1 (POT1) have been reported to orchestrate to displace replication protein A (RPA) from telomeric overhangs, ensuring orderly telomere replication and capping. Our previous studies further demonstrated that DNA-dependent protein kinase catalytic subunit (DNA-PKcs)-dependent hnRNPA1 phosphorylation plays a crucial role in the promotion of hnRNPA1 binding to telomeric overhangs and RPA displacement during G2-M phases. However, it is unclear that how the subsequent exchange between hnRNPA1 and POT1 is orchestrated. Here we report that the protein phosphatase 2A (PP2A) depends on its scaffold subunit, which is called PPP2R1A, to interact with and dephosphorylate hnRNPA1 in the late M phase. Furthermore, PP2A-mediated hnRNPA1 dephosphorylation and TERRA accumulation act in concert to promote the hnRNPA1-to-POT1 switch on telomeric single-stranded DNA. Consequently, defective PPP2R1A results in ataxia telangiectasia and Rad3-related (ATR)-mediated DNA damage response at telomeres as well as induction of fragile telomeres. Combined inhibition of ATR and PP2A induces entry into a catastrophic mitosis and leads to synthetic lethality of tumor cells. In addition, PPP2R1A levels correlate with clinical stages and prognosis of multiple types of cancers. Taken together, our results indicate that PP2A is critical for telomere maintenance. IMPLICATIONS: This study demonstrates that the PP2A-dependent hnRNPA1 dephosphorylation and TERRA accumulation facilitates the formation of the protective capping structure of newly replicated telomeres, thus exerting essential oncogenic role in tumorigenesis.

Radiation-induced PD-L1 expression in tumor and its microenvironment facilitates cancer-immune escape: a narrative review.

Background and Objective: Radiotherapy (RT) is one of the fundamental anti-cancer regimens by means of inducing in situ tumor vaccination and driving a systemic anti-tumor immune response. It can affect the tumor microenvironment (TME) components consisting of blood vessels, immunocytes, fibroblasts, and extracellular matrix (ECM), and might subsequently suppress anti-tumor immunity through expression of molecules such as programmed death ligand-1 (PD-L1). Immune checkpoint inhibitors (ICIs), especially anti-programmed cell death 1 (PD-1)/PD-L1 therapies, have been regarded as effective in the reinvigoration of the immune system and another major cancer treatment. Experimentally, combination of RT and ICIs therapy shows a greater synergistic effect than either therapy alone. Methods: We performed a narrative review of the literature in the PubMed database. The research string comprised various combinations of "radiotherapy", "programmed death-ligand 1", "microenvironment", "exosome", "myeloid cell", "tumor cell", "tumor immunity". The database was searched independently by two authors. A third reviewer mediated any discordance of the results of the two screeners. Key Content and Findings: RT upregulates PD-L1 expression in tumor cells, tumor-derived exosomes (TEXs), myeloid-derived suppressor cells (MDSCs), and macrophages. The signaling pathways correlated to PD-L1 expression in tumor cells include the DNA damage signaling pathway, epidermal growth factor receptor (EGFR) pathway, interferon gamma (IFN-γ) pathway, cGAS-STING pathway, and JAK/STATs pathway. Conclusions: PD-L1 upregulation post-RT is found not only in tumor cells but also in the TME and is one of the mechanisms of tumor evasion. Therefore, further studies are necessary to fully comprehend this biological process. Meanwhile, combination of therapies has been shown to be effective, and novel approaches are to be developed as adjuvant to RT and ICIs therapy.

Reduced-dose radiation in human papillomavirus-associated oropharyngeal carcinoma can improve outcome: a systematic review and meta-analysis.

Background: Despite its effectiveness, the standard course of chemoradiation for the treatment of human papillomavirus (HPV)-related oropharyngeal carcinoma (OPC) results in considerable treatment-related adverse effects. Studies proved that HPV-positive OPC is very sensitive to radiotherapy. Using de-escalation therapy as a new strategy is critical to maintaining positive outcomes while alleviating side effects. However, some studies hold that reduced dose causes insufficient effect on tumor killing. We conducted this systematic review and meta-analysis of survival and adverse reactions in patients with HPV-related OPC by retrospective analysis and evaluated the therapeutic effect of reducing the radiation dose. Methods: Data were double-selected and extracted by searching seven electronic databases, Original studies in all language treated HPV-associated OPC with reduced-dose and standard-dose therapies were included. Overall survival (OS), progression-free survival (PFS), and incidence rates of adverse events were obtained by pooling analyses. Statistical analyses were performed using RStudio Version 1.1.383 (RStudio, Boston, MA, USA) via the Meta-Analysis R Package (metafor). Heterogeneity was evaluated using the I2 statistic and the Cochran Q test. We used Stata (version 15.0) for forest graph. Results: Thirteen studies were included in this meta-analysis, involving a dose range of 66-70 Gy for the standard treatment regimen and <66 Gy for the reduced-dose group. There was no significant difference in the age of the patients in the standard and the reduced treatment groups (60.9±5.9 vs. 58.6±2.4 years). Nine studies were included as standard cohort and thirteen studies were enrolled as reduced-dose cohort. The 2- and 3-year overall survival rates in the reduced-dose group (95.66% and 91.51%, respectively) were superior to those in the standard-dose group (88.36% and 87.46%, respectively). There was no significant difference in PFS between the two groups. A systematic review of articles on dose reduction and the standard dose was also conducted. The most common complication in reduced-dose radiation was oral mucositis (36.4%), followed by decreased white blood cell (WBC) count (30.5%) and dry mouth (29.1%). Conclusions: Reducing the radiation dose in patients with HPV-related OPC substantially alleviates the treatment toxicities and optimizes the quality of life of patients while at the same time maintaining favorable oncologic outcomes.

LncRNA LPAL2/miR-1287-5p/EGFR Axis Modulates TED-Derived Orbital Fibroblast Activation Through Cell Adhesion Factors.

CONTEXT: The activation of orbital fibroblasts, the prime targets in thyroid eye disease (TED), is central to its underlying pathogenesis. OBJECTIVE: We aimed to investigate the mechanism of TED orbital fibroblast activation from the perspective of noncoding RNA regulation. METHODS: Immunofluorescence (IF) staining was applied to evaluate the fibrotic changes in target cells. Cell proliferation was evaluated by 5-ethoxy 2-deoxyuridine and colony-formation assays. Collagen I concentration was determined by enzyme-linked immunosorbent assay. Human microarray analysis was performed on 3 TED and 3 healthy control orbital tissue samples. RESULTS: Bioinformatics analysis showed that cell adhesion signaling factors were differentially expressed in TED tissues, including intercellular adhesion molecule (ICAM)-1, ICAM-4, vascular cell adhesion molecule, and CD44, which were all upregulated in diseased orbital tissues. Long noncoding RNA LPAL2 level was also upregulated in orbital tissues and positively correlated with ICAM-1 and ICAM-4 expression. Stimulation of the TED orbital fibroblasts by transforming growth factor-ß1 (TGF-ß1) significantly increased the expression of ICAM-1, ICAM-4, and LPAL2. Knockdown of LPAL2 in orbital fibroblasts inhibited TGF-ß1-induced increases in cell adhesion factor levels and orbital fibroblast activation. Microarray profiling was performed on TED and normal orbital tissues to identify differentially expressed microRNAs, and miR-1287-5p was remarkably reduced within diseased orbital samples. miR-1287-5p was directly bound to the epidermal growth factor receptor (EGFR) 3' untranslated region and LPAL2, and LPAL2 modulated EGFR/protein kinase B (AKT) signaling through targeting miR-1287-5p. CONCLUSION: The LPAL2/miR-1287-5p axis modulated TGF-ß1-induced increases in cell adhesion factor levels and TED orbital fibroblast activation through EGFR/AKT signaling.

MNDR v3.0: mammal ncRNA-disease repository with increased coverage and annotation.

Many studies have indicated that non-coding RNA (ncRNA) dysfunction is closely related to numerous diseases. Recently, accumulated ncRNA-disease associations have made related databases insufficient to meet the demands of biomedical research. The constant updating of ncRNA-disease resources has become essential. Here, we have updated the mammal ncRNA-disease repository (MNDR, http://www.rna-society.org/mndr/) to version 3.0, containing more than one million entries, four-fold increment in data compared to the previous version. Experimental and predicted circRNA-disease associations have been integrated, increasing the number of categories of ncRNAs to five, and the number of mammalian species to 11. Moreover, ncRNA-disease related drug annotations and associations, as well as ncRNA subcellular localizations and interactions, were added. In addition, three ncRNA-disease (miRNA/lncRNA/circRNA) prediction tools were provided, and the website was also optimized, making it more practical and user-friendly. In summary, MNDR v3.0 will be a valuable resource for the investigation of disease mechanisms and clinical treatment strategies.

Role of Nrf2 in cell senescence regulation.

Nuclear factor-E2-related factor 2 (Nrf2) is a key transcription factor known to be involved in maintaining cell redox balance and signal transduction and plays central role in reducing intracellular oxidative stress damage, delaying cell senescence and preventing age-related diseases. However, it has been shown that the level of Nrf2 decreases with age and that the silencing of the Nrf2 gene is associated with the induction of premature senescence. Therefore, a plethora of researchers have focused on elucidating the regulatory mechanism of Nrf2 in the prevention of cell senescence. This complex regulatory mechanism of Nrf2 in the cell senescence process involves coordinated regulation of multiple signaling molecules. After summarizing the function of Nrf2 and its relationship with cell senescence pathway, this review focuses on the recent advances and progress made in elucidating the regulatory mechanism of Nrf2 in the cell senescence process. Additionally, the information collected here may provide insights for further research on Nrf2, in particular, on its regulatory mechanism in the cell senescence process.

Effects of fasting on the expression pattern of FGFs in different skeletal muscle fibre types and sexes in mice.

Fibroblast growth factors (FGFs) belong to a large family comprising 22 FGF polypeptides that are widely expressed in tissues. Most of the FGFs can be secreted and involved in the regulation of skeletal muscle function and structure. However, the role of fasting on FGF expression pattern in skeletal muscles remains unknown. In this study, we combined bioinformatics analysis and in vivo studies to explore the effect of 24-h fasting on the expression of Fgfs in slow-twitch soleus and fast-twitch tibialis anterior (TA) muscle from male and female C57BL/6 mice. We found that fasting significantly affected the expression of many Fgfs in mouse skeletal muscle. Furthermore, skeletal muscle fibre type and sex also influenced Fgf expression and response to fasting. We observed that in both male and female mice fasting reduced Fgf6 and Fgf11 in the TA muscle rather than the soleus. Moreover, fasting reduced Fgf8 expression in the soleus and TA muscles in female mice rather than in male mice. Fasting also increased Fgf21 expression in female soleus muscle and female and male plasma. Fasting reduced Fgf2 and Fgf18 expression levels without fibre-type and sex-dependent effects in mice. We further found that fasting decreased the expression of an FGF activation marker gene-Flrt2 in the TA muscle but not in the soleus muscle in both male and female mice. This study revealed the expression profile of Fgfs in different skeletal muscle fibre types and different sexes and provides clues to the interaction between the skeletal muscle and other organs, which deserves future investigations.

Cocktail of Hyaluronic Acid and Human Amniotic Mesenchymal Cells Effectively Repairs Cartilage Injuries in Sodium Iodoacetate-Induced Osteoarthritis Rats.

Osteoarthritis (OA) is one of the most common refractory degenerative articular cartilage diseases. Human amniotic mesenchymal cells (hAMSCs) have emerged as a promising stem cell source for cartilage repair, and hyaluronic acid (HA) has proven to be a versatile regulator for stem cell transplantation. Herein, an effective and straightforward intra-articular injection therapy using a cocktail of hAMSCs and HA was developed to treat knee OA in a rat model. The injured cartilage was remarkably regenerated, yielding results comparable to normal cartilage levels after 56 days of treatment. Both hAMSCs and HA were indispensable organic components in this therapy, in which HA could synergistically enhance the effects of hAMSCs on cartilage repair. The regenerative mechanism was attributed to the fact that the addition of HA comprehensively enhances the activities of hAMSCs, including chondrogenic differentiation, proliferation, colonization, and regenerative modulation. This cocktail paves a new avenue for injection therapy to treat OA, holding the potential to realize rapid clinical translation.

Ganoderal A effectively induces osteogenic differentiation of human amniotic mesenchymal stem cells via cross-talk between Wnt/ß-catenin and BMP/SMAD signaling pathways.

Osteogenic inducers play central roles in effective stem cell-based treatment of bone defects/losses. However, the current routine osteogenic inducer is a cocktail comprising three components that must be improved due to low induction efficiency and side effects. Therefore, there is an urgent need to develop safer and more effective osteoinducers. Herein, we demonstrated the osteogenic effect of Ganoderal A (GD-A), a tetracyclic triterpenoid compound from Ganoderma lucidum. GD-A showed no cytotoxicity toward human amniotic mesenchymal stem cells (hAMSCs) at doses of 0.001-10 µM; furthermore, 0.01 µM GD-A significantly induced the generation of osteoblast-specific markers, such as alkaline phosphatase, and calcium deposition in hAMSCs. At molecular levels, GD-A promoted the expression of multiple osteoblast differentiation markers, such as RUNX2, OSX, OPN, ALP, OCN, and COL1α1. Both Wnt/ß-catenin and BMP/SMAD signaling were shown as active during hAMSC osteodifferentiation. Furthermore, specific blocking of both signals by KYA1797K and SB431542 significantly inhibited alkaline phosphatase secretion and RUNX2 and ALP expression when used alone or in combination. Meanwhile, both signals were also blocked. These findings suggest that GD-A induces hAMSC differentiation into osteoblasts through signaling cross-talk between Wnt/ß-catenin and BMP/SMAD. Taken together, GD-A is a safe, effective, and novel osteoinducer and might be used for stem cell-based therapy for bone defects/losses.

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The combination of field trial and indoor incubation experiment were conducted to examine the long-term effects of one-time application of bio-organic fertilizer on soil organic carbon (C) components, organic C mineralization, and enzyme activity in cucumber continuous cropping. Compared with CK, bio-organic fertilizer application significantly increased the content of soil organic C, activated C pool, slow-release C pool and inert C pool during four continuous cucumber planting seasons. With the increases of the number of consecutive crops, the proportion of soil inert carbon gradually increased. After four continuous seasons of cucumber planting, the cumulative and daily mineralization rate of soil organic C in the bio-organic fertilizer treatment increased by 17.3%-31.0% and 7.8%-43.0%, respectively. In the stage of cucumber ripening, bio-organic fertilizer application increased the activities of continuous soil urease, catalase, sucrose and neutral phosphatase by 10.5%-62.1%, 4.8%-25.5%, 3.9%-21.4% and 4.6%-66.4%. The activities of those four enzymes increased with the increases of the application amount of organic fertilizer. Results from the correlation and path analysis showed that the activity of the four enzymes were significantly correlated with the dynamics of organic carbon components in soil cucumber continuous cropping process. Soil urease and invertase activities significantly affected organic carbon mineralization during the continuous cropping process of cucumber. Application of bio-organic fertilizer could increase soil organic carbon content and enzyme activity, improve inert carbon ratio of soil organic carbon pools, cumulative and mineralization rate of organic carbon in continuous cropping process, thereby enhance soil carbon sequestration capacity.