Emerging roles of SIRT1 activator, SRT2104, in disease treatment.

Silent information regulator 1 (SIRT1) is a NAD+-dependent class III deacetylase that plays important roles in the pathogenesis of numerous diseases, positioning it as a prime candidate for therapeutic intervention. Among its modulators, SRT2104 emerges as the most specific small molecule activator of SIRT1, currently advancing into the clinical translation phase. The primary objective of this review is to evaluate the emerging roles of SRT2104, and to explore its potential as a therapeutic agent in various diseases. In the present review, we systematically summarized the findings from an extensive array of literature sources including the progress of its application in disease treatment and its potential molecular mechanisms by reviewing the literature published in databases such as PubMed, Web of Science, and the World Health Organization International Clinical Trials Registry Platform. We focuses on the strides made in employing SRT2104 for disease treatment, elucidating its potential molecular underpinnings based on preclinical and clinical research data. The findings reveal that SRT2104, as a potent SIRT1 activator, holds considerable therapeutic potential, particularly in modulating metabolic and longevity-related pathways. This review establishes SRT2104 as a leading SIRT1 activator with significant therapeutic promise.

EIF4A3-negatively driven circular RNA ß-catenin (circß-catenin) promotes colorectal cancer progression via miR-197-3p/CTNND1 regulatory axis.

BACKGROUND: Circß-catenin, our first reported circRNA, has been reported to mediate tumorigenesis in various cancers. However, its biological functions and underlying mechanisms in colorectal cancer (CRC) remain unknown. METHODS: The qRT-PCR examination was used to detect the expression of circß-catenin, miR-197-3p, and CTNND1 in cells and human tissues. Western blot was conducted to detect the protein expression levels. The biological function of circß-catenin was verified by MTT, colony formation, wound healing, and transwell assays. The in vivo effects of circß-catenin were verified by nude mice xenograft and metastasis models. The regulatory network of circß-catenin/miR-197-3p/CTNND1 was confirmed via dual-luciferase reporter and RIP assays. RESULTS: In the present study, circß-catenin was found to promote CRC cell proliferation and metastasis in vitro and in vivo. Mechanistically, circß-catenin served as miRNA decoy to directly bind to miR-197-3p, then antagonized the repression of the target gene CTNND1, and eventually promoted the malignant phenotype of CRC. More interestingly, the inverted repeated Alu pairs termed AluJb1/2 and AluY facilitated the biogenesis of circß-catenin, which could be partially reversed by EIF4A3 binding to Alu element AluJb2. CONCLUSIONS: Our findings illustrated a novel mechanism of circß-catenin in modulating CRC tumorigenesis and metastasis, which provides a potential therapeutic target for CRC patients.

The network pharmacology study and molecular docking to investigate the potential mechanism of Acoritataninowii Rhizoma against Alzheimer's Disease.

Alzheimer's Disease is considered as an insidious neurodegenerative progressive disease but its pathogenesis has not been elucidated. Acoritataninowii Rhizoma exhibits anti-dementia effects as a traditional Chinese medicine (TCM), which is linked to its anti- Alzheimer's Disease mechanism. In this study, network pharmacology and molecular docking were used to examine the potential of Acoritataninowii Rhizoma for Alzheimer's Disease. In order to construct PPI networks and drug-component-target-disease networks, disease-related genes and proteins were gathered from the database. Gene ontology (GO), pathway enrichment (KEGG), and molecular docking were used to forecast the potential mechanism of Acoritataninowii Rhizoma on Alzheimer's disease. Therefore, 4 active ingredients and 81 target genes were screened from Acoritataninowii Rhizoma, 6765 specific target genes were screened from Alzheimer's Disease, and 61 drug-disease cross genes were validated. GO analysis showed that Acoritataninowii Rhizoma can regulate processes such as the protein serine/threonine kinase associated with MAPK. KeGG pathway analysis showed that the signaling pathways affected by Acoritataninowii Rhizoma were fluid shear stress and atherosclerosis, AGE-RAGE and other pathways. Molecular docking implied that the pharmacological influences of the bioactive constituents of Acoritataninowii Rhizoma (Cycloaartenol and kaempferol) on Alzheimer's Disease may related to ESR1 and AKT1, respectively. AKT1 and ESR1 may be the core target genes of the treatment for Alzheimer's disease. Kaempferol and Cycloartenol might be core bioactive constituents for treatment.

LncRNA-NEF suppressed oxaliplatin resistance and epithelial-mesenchymal transition in colorectal cancer through epigenetically inactivating MEK/ERK signaling.

A major cause of oxaliplatin chemoresistance in colorectal cancer (CRC) is acquired epithelial-mesenchymal transition (EMT) in cancer cells, making the cancer cells easy to metastasis and recurrence. LncRNA Neighboring Enhancer of FOXA2 (lncRNA-NEF) has been characterized as a tumor suppressor to mediate cancer metastasis in multiple cancer types. However, whether it mediated the drug resistance remains unknown. In the present study, an oxaliplatin-resistant CRC cell line (SW620R) was established and lncRNA-NEF was obviously down-regulated in this resistant cell line. The further loss and gain-of-function studies demonstrated that this lncRNA suppressed oxaliplatin resistance as well as EMT programme in vitro and inhibited metastasis in vivo. Mechanistically, lncRNA-NEF epigenetically promoted the expression of DOK1 (Downstream of Tyrosine kinase 1), a negative regulator of MEK/ERK signaling, by disrupting DNA methyltransferases (DNMTs)-mediated DNA methylation. DOK1, in turn, induced the inactivation of MEK/ERK signaling, forming the lncRNA-NEF/DOK1/MEK/ERK regulatory axis to mediate oxaliplatin resistance in CRC. Collectively, our work reveals the critical function of lncRNA-NEF in mediating the oxaliplatin chemotherapy resistance in CRC, and provides a promising therapeutic strategy for CRC patients with oxaliplatin resistance.

Linc-ROR drive adriamycin resistance by targeting AP-2α/Wnt/ß-catenin axis in hepatocellular carcinoma.

Adriamycin is widely used as a chemotherapeutic strategy for advanced hepatocellular carcinoma (HCC). However, the clinical response was disappointing because of the acquired drug resistance with long-term usage. Revealing the underlying mechanism could provide promising therapeutics for the drug-resistant patients. The recently identified linc-ROR (long intergenic non-protein-coding RNA, regulator of reprogramming) has been found to be an oncogene in various cancers, and it also demonstrated to mediate drug resistance and metastasis. We thereby wonder whether this lincRNA could mediate adriamycin chemoresistance in HCC. In this study, linc-ROR was found to be upregulated in adriamycin-resistant HCC cells. And its overexpression accelerated epithelial-mesenchymal transition (EMT) program and adriamycin resistance. Conversely, its silence suppressed EMT and made HCC cells sensitize to adriamycin in vitro and in vivo. Further investigation revealed that linc-ROR physically interacted with AP-2α, mediated its stability by a post-translational modification manner, and sequentially activated Wnt/ß-catenin pathway. Furthermore, linc-ROR expression was positively associated with ß-catenin expression in human clinical specimens. Taken together, linc-ROR promoted tumorigenesis and adriamycin resistance in HCC via a linc-ROR/AP-2α/Wnt/ß-catenin axis, which could be developed as a potential therapeutic target for the adriamycin-resistant patients.

Possible linkage between asymmetry of atmospheric meridional circulation and tropical cyclones in the Central Pacific during El Niño years.

The El Niño-Southern Oscillation is one of the most important drivers of climate change on Earth, and is characterised by warmer (El Niño) or colder (La Niña) ocean surface temperatures in the equatorial Pacific. Tropical cyclones (TCs) and meridional circulation are the most influential weather events and climate phenomena, respectively. However, the link between TCs and meridional circulation anomalies (MCA) during El Niño years is unclear. Therefore, we calculated the accumulated cyclone energy index of TCs and the mass stream function of MCA from 1980 to 2018. Our results showed that TCs were closely related to the asymmetry of the MCA in the Central Pacific during El Niño years. An updraft anomaly in the North Pacific was found, which affected the response of MCA to El Niño from May to October during El Niño years. Therefore, the MCA intensity difference between the North and South Pacific increased, and the asymmetry was strengthened. This phenomenon may be strengthened by the combined effects of the equatorial westerly wind, relative vorticity, and warm ocean surfaces, which are controlled by El Niño. The equatorial westerly wind produces positive shear north of the equator, which increases the relative vorticity. The increase in relative vorticity is accompanied by a monsoon trough, leading to increased precipitation and updrafts. The background of the relative vorticity, updraft, and monsoon trough may be conducive to the generation and development of TCs. Our results prove that the possible link between TCs and the asymmetry of the MCA during El Niño years is derived from the combined effect of the equatorial westerly wind, relative vorticity, and warm ocean surfaces, thus providing a partial explanation for the link between TCs and the MCA.

High expression of NEK2 promotes gastric cancer progression via activating AKT signaling.

Never in mitosis gene A-related kinase 2 (NEK2) has been recognized as an oncogene involved in the initiation and progression of various human cancers. However, our knowledge is still lacking in regard to the function of NEK2 in gastric cancer, the most common cancer in Eastern Asia associated with poor prognosis. Therefore, in the present study, we investigated the association of NEK2 with gastric cancer. We found that the development of gastric cancer is associated with NEK2 overexpression, particularly in patients with large tumor size and lymph node metastasis. We also provided evidence that NEK2 overexpression binds to and inhibits protein phosphatase 1 (PP1), which subsequently activates AKT and the downstream oncogenic pathways. As a result, via AKT/HIF1α axis, the glucose metabolism is reprogrammed towards aerobic glycolysis to provide rapid energy for the growth of gastric cancer cells. Moreover, the autophagic activity is suppressed via AKT/mTOR axis, leading to impaired response to cancer treatment and enhanced cell survival. In contrast, inactivating AKT by NEK2 silencing decreases aerobic glycolysis and promotes autophagic cell death, which eventually inhibits the growth of gastric cancer cell. All these results revealed that NEK2 promotes gastric cancer progression via activating AKT-mediated signaling pathways, which expanded our knowledge on gastric cancer pathogenesis and also provided novel target for clinical treatment.

Upregulation of c-mesenchymal epithelial transition expression and RAS mutations are associated with late lung metastasis and poor prognosis in colorectal carcinoma.

The present study aimed to investigate whether c-mesenchymal epithelial transition factor (C-MET) overexpression combined with RAS (including KRAS, NRAS and HRAS) or BRAF mutations were associated with late distant metastases and the prognosis of patients with colorectal cancer (CRC). A total of 374 patients with stage III CRC were classified into 4 groups based on RAS/BRAF and C-MET status for comprehensive analysis. Mutations in RAS/BRAF were determined using Sanger sequencing and C-MET expression was examined using immunohistochemistry. The associations between RAS/BRAF mutations in combination with C-MET overexpression and clinicopathological variables including survival were evaluated. In addition, their predictive value for late distant metastases were statistically analyzed via logistic regression and receiver operating characteristic analysis. Among 374 patients, mutations in KRAS, NRAS, HRAS, BRAF and C-MET overexpression were observed in 43.9, 2.4, 0.3, 5.9 and 71.9% of cases, respectively. Considering RAS/BRAF mutations and C-MET overexpression, vascular invasion (P=0.001), high carcino-embryonic antigen level (P=0.031) and late distant metastases (P<0.001) were more likely to occur in patients of group 4. Furthermore, survival analyses revealed RAS/BRAF mutations may have a more powerful impact on survival than C-MET overexpression, although they were both predictive factors for adverse prognosis. Further logistic regression suggested that RAS/BRAF mutations and C-MET overexpression may predict late distant metastases. In conclusion, RAS/BRAF mutations and C-MET overexpression may serve as predictive indicators for metastatic behavior and poor prognosis of CRC.

Predictive and Prognostic Implications of Mutation Profiling and Microsatellite Instability Status in Patients with Metastatic Colorectal Carcinoma.

To investigate whether mutation profiling and microsatellite instability (MSI) status were associated with clinicopathological features and the prognosis in metastatic colorectal cancer (mCRC), mutations in RAS (including KRAS, NRAS, and HRAS) and BRAF were determined by Sanger sequencing. Tumor mismatch repair proteins and MSI status were examined using immunohistochemistry and polymerase chain reaction, respectively. The clinical value of these abnormalities was statistically analyzed, and prognostic value of different treatment regimens was also evaluated. Among 461 mCRC patients, mutations in RAS, BRAF, and MSI-high (MSI-H) status were observed in 45.3% (209/461), 5.6% (26/461), and 6.5% (30/461) of cases, respectively. Brain metastasis and high carcinoembryonic antigen level were highly correlated with KRAS mutation (P = 0.011 and P < 0.001), and tumors from females or located in the right colon tended to harbor BRAF mutation (P = 0.039 and P = 0.001). RAS/BRAF mutations may predict brain and/or lung metastases. Although neither clinical nor prognostic importance of MSI status was identified in our study, KRAS and BRAF mutations were demonstrated to be independent prognostic factors for overall survival and progression-free survival. Besides, in wild-type group, patients treated with chemotherapy plus targeted therapy exhibited the most favorable prognosis. Therefore, RAS/BRAF mutations may serve as indicators for prognosis and treatment options in mCRC.

Evaluation of Burma Reed as Substrate for Production of Pleurotus eryngii.

Burma reed (Neyraudia reynaudiana), a giant C4 grass, was included in substrate at the rates of 0, 20, 40 and 66 % to partially or wholly substitute sawdust and cottonseed hulls to evaluate its suitability for Pleurotus eryngii cultivation. Inclusion of 20 and 40 % Burma reed did not significantly affect linear mycelial growth, dry matter loss, spawn run period and fructification, and achieved high fruiting body yields and biological efficiency of 336.67 g/bag, 67.33 % and 342.15 g/bag, 68.43 %, respectively, which were not significantly different from 350.08 g/bag to 70.02 % obtained from the control substrate. Enzyme assay revealed that on the mixed substrates laccase and manganese peroxidase activity were significantly enhanced, but cellulase was significantly reduced in the middle stage of incubation as compared with the control substrate. Even on Burma reed substrate without sawdust and cottonseed hulls, fruiting body yield (313.56 g/bag) and biological efficiency (62.71 %) were satisfactory, although significantly lower than that on the control substrate. Therefore, Burma reed was a promising potential substrate for P. eryngii production to largely substitute sawdust and cottonseed hulls.