Targeting metabolism to influence cellular senescence a promising anti-cancer therapeutic strategy.

Metabolic disorders are considered the hallmarks of cancer and metabolic reprogramming is emerging as a new strategy for cancer treatment. Exogenous and endogenous stressors can induce cellular senescence; the interactions between cellular senescence and systemic metabolism are dynamic. Cellular senescence disrupts metabolic homeostasis in various tissues, which further promotes senescence, creating a vicious cycle facilitating tumor occurrence, recurrence, and altered outcomes of anticancer treatments. Therefore, the regulation of cellular senescence and related secretory phenotypes is considered a breakthrough in cancer therapy; moreover, proteins involved in the associated pathways are prospective therapeutic targets. Although studies on the association between cellular senescence and tumors have emerged in recent years, further elucidation of this complex correlation is required for comprehensive knowledge. In this paper, we review the research progress on the correlation between cell aging and metabolism, focusing on the strategies of targeting metabolism to modulate cellular senescence and the progress of relevant research in the context of anti-tumor therapy. Finally, we discuss the significance of improving the specificity and safety of anti-senescence drugs, which is a potential challenge in cancer therapy.

Surface plasmon field enhanced upconversion luminescence for the screening and detection of phenolic environmental estrogens.

The endocrine system's interference caused by environmental estrogens (EEs) residue in food is a topic of public concern. Here, we construct an aptasensor for the sensitive detection of EEs based on luminescence resonance energy transfer (LRET). With MoS2 nanosheets acting as the energy acceptor and upconversion luminescence nanoparticles@gold nanoparticles (UCNPs@Au) as the luminescence donor, autofluorescence from food is prevented from interfering. The in-situ deposition of AuNPs not only induces local field enhancement to significantly increase the luminescence intensity of UCNPs, but also conduces to the modification of aptamer through Au-S bond. This aptasensor can respond to multiple estrogens thanks to the choice of a universal aptamer that recognizes phenolic hydroxyl group, and it offers the probability to screen unidentified phenolic estrogens. This method has a high sensitivity and a low limit of detection (LOD), and the satisfactory recovery rates acquired from water and milk samples confirmed its considerable application value.

[Effects of short-segment pedicle screw internal fixation surgery combined with hyperbaric oxygen treatment for acute spinal injury on the morphology and function of the spine].

OBJECTIVE: To explore effect of short-segment pedicle screw internal fixation combined with hyperbaric oxygen in treating acute spinal fractures and its influence on recovery of spinal nerve function. METHODS: A total of 96 patients with acute spinal fracture admitted from February 2017 to March 2020 were divided into combined group and control group, with 48 cases in each group. Both groups were treated with short-segment pedicle screw internal fixation. The combined group was given hyperbaric oxygen after surgery. The operation time, surgical blood loss, incision length and other general operation conditions between two groups were recorded. The differences in spinal morphology and function, Ameraican Spinal Injury Assiciation(ASIA) neurological function grade, serum inflammatory factors and ability of daily living activities were observed before and after surgery. RESULTS: There was no significant difference in operation time, surgical blood loss, and incision length between combined group and control group(P>0.05). There were no significant differences in anterior height ratio and Cobb angle between two groups before surgery, 1 week and 6 months after surgery(P>0.05). The height ratio of anterior margin of the injured spine was significantly improved in both groups at 1 week and 6 months after surgery compared with preoperative period (P<0.05), and Cobb angle was significantly reduced in both groups compared with preoperative period (P<0.05). There was no statistically significant difference in serum interleukin-6(IL-6), interleukin-8(IL-8), and tumor necrosis factor-α(TNF-α) levels between two groups at 1 d after surgery(P>0.05);the serum IL-6, IL-8, and TNF-α levels of combined group were lower than those of control group at 1 week after surgery (P<0.05). At 6 months after surgery, ASIA neurological function grade of combined group was C grade in 2 cases, D grade in 23 cases, E grade in 22 cases. In control group, 7 cases was grade C, 26 cases was grade D, 13 cases was grade E, and the difference between two groups was statistically significant(P<0.05). The Barthel score of combined group was higher than that of control group at 1 month and 3 months after surgery, and the difference was statistically significant (P<0.05);at 6 months after surgery, there was no significant difference in Barthel score between two groups(P>0.05). CONCLUSION: Short-segment pedicle screw internal fixation combined with hyperbaric oxygen for the treatment of acute spinal fractures is beneficial to the recovery of spinal nerve function after surgery, and has a certain effect on the early improvement of the patients' activities of daily living.

Tackling cellular senescence by targeting miRNAs.

Cellular senescence, which is characterized by permanent proliferation arrest, has become an important target for the amelioration of various human diseases. The activity of senescent cells is mainly related to the senescence-associated secretory phenotype (SASP). The SASP can cause chronic inflammation in local tissues and organs through autocrine and paracrine mechanisms, and a series of factors secreted by senescent cells can deteriorate the cellular microenvironment, promoting tumor formation and exacerbating aging-related diseases. Therefore, avoiding the promotion of cancer is an urgent problem. In recent years, increased attention has been given to the mechanistic study of microRNAs in senescence. As important posttranscriptional regulators, microRNAs possess unique tissue-specific expression in senescence. MicroRNAs can regulate the SASP by regulating proteins in the senescence signaling pathway, the reverse transcriptase activity of telomerase, the generation of reactive oxygen species and oxidative damage to mitochondria. Numerous studies have confirmed that removing senescent cells does not cause significant side effects, which also opens the door to the development of treatment modalities against senescent cells. Herein, this review discusses the double-edged sword of cellular senescence in tumors and aging-related diseases and emphasizes the roles of microRNAs in regulating the SASP, especially the potential of microRNAs to be used as therapeutic targets to inhibit senescence, giving rise to novel therapeutic approaches for the treatment of aging-associated diseases.

Combination treatment with cisplatin, paclitaxel and olaparib has synergistic and dose reduction potential in ovarian cancer cells.

Ovarian cancer is the most lethal type of gynecological cancer. Due to its high heterogeneity and complicated pathological mechanisms, the 5-year survival rate of patients with ovarian cancer is <40%. Tumor cytoreductive surgery and systemic chemotherapy of platinum combined with paclitaxel are currently considered the gold standard for the treatment of ovarian cancer, and chemotherapy resistance has become a key constraint in improving the cure rate of ovarian cancer. Therefore, it is important to identify novel treatment methods and strategies for ovarian cancer. Targeted drugs can not only be used in combination with chemotherapy, but also act as maintenance therapy to promote patient survival time. PARP inhibitor is a novel type of ovarian cancer treatment targeted drug, which can induce an anticancer effect by inhibiting DNA damage and repair of ovarian cancer cells. The present study investigated the different effects of olaparib, cisplatin and paclitaxel in several dosages by single use and combinations on the proliferation of different human ovarian cancer cell lines, in order to verify the synergistic effects of the combinations of the three anticancer agents in pairs. The proliferation inhibitory rate of the cell lines was determined using a Cell Counting Kit-8 assay, while the combination index (CI) value of the combination of three agents in pairs was analyzed using Compusyn software. The proliferation was observed using a crystal violet assay, and the apoptosis ratio was measured via flow cytometry. The results of the present study revealed that the combination of cisplatin with olaparib group had a higher inhibition effect than each single group and had a higher dose-reduction index of >1 than the other two combinations at all concentrations in A2780 and OVCAR-3 cell lines. The difference in proliferation inhibition and induced apoptosis rate of A2780 cell lines was significant in the combination of cisplatin with olaparib group and the control group (P<0.01) at 0.25x IC50. For the OVCAR-3 cell line, the difference was also significant between two groups (P<0.05). The CI values in the A2780 cell line revealed significant differences between the low-dose group (0.0625x, 0.125x and 0.25x IC50) and the high-dose group (0.5x, 1.0x and 2.0x IC50) for the group that received the combination of cisplatin with olaparib (P<0.05). The present study highlighted that the group receiving a combination of cisplatin with olaparib exhibited the most significant synergistic effects among the three combinations, particularly at low doses.

Targeting senescent cells and tumor therapy (Review).

Cell senescence is caused by the activation of cell cycle inhibition pathways induced by an accumulation of cellular damage, where cells permanently leave the cell cycle. Senescent cells undergo changes in cell morphology, transcription, protein homeostasis, metabolism and other characteristic alterations. At the same time, senescent cells are able to resist apoptosis and accumulate in multiple organs and tissues in vivo. Senescent cells are capable of activating inflammatory factor secretion pathways, generating local, non­infectious inflammatory microenvironments within tissues, leading to organ degeneration and the development of aging­associated diseases. A large number of recently published studies have demonstrated that removing senescent cells from the body delays the occurrence of various aging­associated diseases. Therefore, the targeted killing of senescent cells potentially has important clinical applications in the treatment of various aging­associated diseases, aiming to improve the life span of patients. The present review summarizes recent progress that has been made in the field of senescent cell clearance and various anti­aging strategies. The history of cell senescence research is briefly reviewed, along with the association between cell senescence and tumor therapy. Furthermore, the potential of senescent cells to be used as therapeutic targets in various senescence­associated diseases is primarily discussed, and the limitations, as well as the future prospects of this line of research, are reviewed.

Rosiglitazone ameliorates senescence and promotes apoptosis in ovarian cancer induced by olaparib.

OBJECTIVE: Senescence mechanisms are vital to resistance to long-term olaparib maintenance treatment. Recently, peroxisome proliferator-activated receptor-γ agonists (e.g., rosiglitazone) have been reported to ameliorate the senescence-like phenotype by modulating inflammatory mediator production. This study examined synergistic effects on the anti-tumor activity of rosiglitazone combined with olaparib in ovarian cancer treatment. METHODS: A2780 and SKOV3 mouse subcutaneous xenograft models were established for observing anti-tumor effects in living organisms and were randomly split into combination (both olaparib and rosiglitazone), rosiglitazone (10 mg/kg), olaparib (10 mg/kg), control (solvent) groups that received treatment once every 2 or 3 days (n = 6 per group). Cell counting kit-8 (CCK-8) assays were used to test the influences of rosiglitazone and olaparib on cell proliferation. PI and Annexin-V-FITC staining was used with flow cytometry to assess the cell cycle distribution and cell apoptosis. Senescence-associated ß-galactosidase (SA-ß-Gal) staining was used to observe cellular senescence. We performed quantitative real-time polymerase chain reaction assays to study the senescence-related secretory phenotype (SASP). RESULTS: Olaparib and rosiglitazone were observed to synergistically retard subcutaneous ovarian cancer growth in vivo, and synergistically suppress ovarian cancer cell proliferation in vitro. Compared with olaparib alone, the percentage of positive cells expressed SA-ß-gal and SASP were significantly decreased in the treatment of combination of olaparib and rosiglitazone. Furthermore, olaparib plus rosiglitazone increased the percentage of apoptosis in ovarian cancer cell compared with olaparib alone. In A2780 cells, it showed lower expression of P53, phospho-p53 (Ser15), P21, and P18 protein in combination treatment compared with olaparib alone. While, in SKOV3 cells, it showed lower expression of phosphor-retinoblastoma protein (Rb) (Ser807/811), and higher expression of cyclin D1, P21, and P16 protein in combination treatment compared with olaparib alone. CONCLUSIONS: Rosiglitazone combined with olaparib can help manage ovarian cancer by ameliorating olaparib-induced senescence and improving anti-tumor effects.

RETRACTED: Knockdown PEG10 deteriorates H2O2-injury of PC-12 cells by targeting miR-34a-5p/TLX.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the Editor-in-Chief. As originally reported in https://pubpeer.com/publications/9D9EBE8EAD0041A196D37E10E1BF18, Fig. 6I shows evidence of data manipulation, visible as patterns of repeated background artifacts in independent western blots that are unlikely to be the result of serendipity. The authors were contacted to investigate further the validity of these allegations and to provide the raw data but the journal received no response and therefore the Editor-in-Chief decided to retract the article.

Olaparib induced senescence under P16 or P53 dependent manner in ovarian cancer.

OBJECTIVE: Poly (ADP-ribose) polymerase (PARP) is an important molecule in the early stress response of DNA damage, which is involved in DNA damage repair and cellular senescence. Olaparib, as PARP inhibitor, has an anti-tumor effect on high grade serous ovarian cancer, but its effects on cellular senescence have not been reported. This study intends to explore the role of olaparib in the regulation of senescence in ovarian cancer cells. METHODS: The effects of olaparib on the senescence of ovarian cancer cells were detected by using the senescence-associated ß-galactosidase (SA-ß-Gal) and senescence-associated heterochromatin aggregation (SAHF). Quantitative real-time polymerase chain reaction was used to analyze the senescence-associated secretory phenotype (SASP). Cell cycle and apoptosis were detected by flow cytometry. The effect of olaparib on tumor growth was analyzed in a nude mouse xenograft transplantation model. RESULTS: Long-term (6 days) treatment with olaparib (5 µ) significantly inhibited the growth of ovarian cancer cells, leading to arrest the cell cycle at G0/G1 phase, significant increase the number of positive SA-ß-Gal stained cells and positive SAHF cells. The expression of P16 and retinoblastoma protein (p-RB) were significantly enhanced in SKOV3 cells under olaparib treated, meanwhile, the expression of P53 and p-RB were upregulated in A2780 cells. In OVCAR-3 cells, the expression of P53 was downregulated and p-RB was upregulated. Mice with SKOV3 xenograft transplantation was given olaparib (10 mg/kg/day) via abdominal cavity administration, the tumor volume was reduced (p<0.01). CONCLUSION: Continuous low dosage administration of olaparib induced senescence under P16 or P53 dependent manner in ovarian cancer.

Silencing SUMO2 promotes protection against degradation and apoptosis of nucleus pulposus cells through p53 signaling pathway in intervertebral disc degeneration.

OBJECTIVE: Intervertebral disc degeneration (IDD), as a common cause of back pain, is related to the promotion of cellular senescence and reduction in proliferation. Based on recent studies, small ubiquitin-related modifier (SUMO) proteins have been implicated in various biological functions. Therefore, in the present study, we investigated the effects of SUMO2 on proliferation and senescence of nucleus pulposus cells (NPCs) via mediation of p53 signaling pathway in rat models of IDD. METHODS: After the establishment of rat models of IDD for the measurement of positive expression of SUMO2/3 protein, the mRNA and protein levels of SUMO2, molecular phenotype [matrix metalloproteinase-2 (MMP-2) and hypoxia-inducible factor-1α (HIF-1α)] and p53 signaling pathway-related genes [p21, murine double minute-2 (MDM2), growth arrest and DNA-damage-inducible protein 45 α (GADD45α), cyclin-dependent kinase 2/4 (CDK2/4), and CyclinB1] were determined, followed by the detection of cell proliferation, cell cycle, apoptosis, and cell senescence. RESULTS: The rat models of IDD were successfully constructed. The results obtained showed that there was a higher positive expression of SUMO2/3 protein in IDD rats. Moreover, the silencing of the SUMO2 gene decreases the levels of SUMO2, p53, p21, MDM2, GADD45α, MMP-2, and HIF-1α expressions and p53 phosphorylation level while it increases the levels of CDK2/4 and CyclinB1 expressions. In addition, SUMO2 gene silencing enhances proliferation and suppresses apoptosis and cell senescence of NPCs. CONCLUSION: In conclusion, SUMO2 gene silencing promotes proliferation, and inhibits the apoptosis and senescence of NPCs in rats with IDD through the down-regulation of the p53 signaling pathway. Thus, SUMO2 is a potential target in the treatment of IDD.

Screening of candidate key genes associated with human osteosarcoma using bioinformatics analysis.

The aim of the present study was to identify the key genes associated with osteosarcoma (OS) using a bioinformatics approach. Microarray data (GSE36004) was downloaded from the Gene Expression Omnibus database, including 19 OS cell lines and 6 normal controls. Differentially expressed genes (DEGs) in the OS cell lines were identified using the Limma package, and differentially methylated regions were screened with methyAnalysis in R. Copy number analysis was performed and genes with copy number gains/losses were further screened using DNAcopy and cghMCR packages. Functional enrichment analyses were performed using the Database for Annotation, Visualization and Integrated Discovery online tool, and protein-protein interactions were identified based on information obtained from the Search Tool for the Retrieval of Interacting Genes database. A total of 47 downregulated genes were screened in hyper-methylated regions, including the fragment crystallizable (Fc) region of immunoglobulin E, high affinity I, receptor for; γ polypeptide (FCER1G), leptin (LEP) and feline Gardner-Rasheed sarcoma viral oncogene homolog (FGR). In addition, a total of 17 upregulated genes, including the TPase family, AAA domain containing 2 (ATAD2) and cyclin-dependent kinase 4 (CDK4), exhibited copy number gains, while 5 downregulated genes, including Rho GTPase activating protein 9 (ARHGAP9) and major histocompatibility complex, class II, DO α (HLA-DOA), exhibited copy number losses. These results indicate that hyper-methylation of FCER1G, LEP, and FGR may serve a crucial function in the development of OS. In addition, copy number alterations of these DEGs, including ATAD2, CDK4, ARHGAP9 and HLA-DOA, may also contribute to OS progression. These DEGs may be candidate targets for the diagnosis and treatment of this disease.