Aging

Oleksandr Demidenko1, * , Diogo Barardo2, * , Valery Budovskii1 , Robb Finnemore3 , Francis R. Palmer III3 , Brian K. Kennedy2,3,4,5 , Yelena V. Budovskaya1

doi : 10.18632/aging.203736

Volume 13, Issue 22, pp 24485—24499

The search continues for possible interventions that delay and/or reverse biological aging, resulting in extended healthspan and lifespan. Interventions delaying aging in animal models are well established; however, most lack validation in humans. The length of human lifespan makes it impractical to perform survival analysis. Instead, aging biomarkers, such as DNA methylation (DNAm) clocks, have been developed to monitor biological age. Herein we report a retrospective analysis of DNA methylation age in 42 individuals taking Rejuvant®, an alpha-ketoglutarate based formulation, for an average period of 7 months. DNAm testing was performed at baseline and by the end of treatment with Rejuvant® supplementation. Remarkably, individuals showed an average decrease in biological aging of 8 years (p-value=6.538x10-12). Furthermore, the supplementation with Rejuvant® is robust to individual differences, as indicated by the fact that a large majority of participants decreased their biological age. Moreover, we found that Rejuvant® is of additional benefit to chronologically and biologically older individuals. While continued testing, particularly in a placebo-controlled design, is required, the nearly 8-year reversal in the biological age of individuals taking Rejuvant® for 4 to 10 months is noteworthy, making the natural product cocktail an intriguing candidate to affect human aging.

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The effect of hyperbaric oxygen therapy on the pathophysiology of skin aging: a prospective clinical trial

Yafit Hachmo1, * , Amir Hadanny2,3,4, * , Sonia Mendelovic5 , Pnina Hillman5 , Eyal Shapira6 , Geva Landau6 , Hadar Gattegno1 , Avi Zrachya1 , Malka Daniel-Kotovsky2 , Merav Catalogna2 , Gregory Fishlev2 , Erez Lang2 , Nir Polak2 , Keren Doenyas2 , Mony Friedman2 , Yonatan Zemel2 , Yair Bechor2 , Shai Efrati1,2,3,7

doi : 10.18632/aging.203701

Volume 13, Issue 22, pp 24500—24510

Skin biopsies can be used to evaluate physiological effects of aging targeted intervention at the tissue/cellular levels. Recent clinical trials have shown that hyperbaric oxygen therapy (HBOT) can target aging hallmarks, including telomere shortening, senescent cells clearance and angiogenesis. The aim of this study was to evaluate the effects of HBOT on the skin of a normal, non-pathological, aging population.

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Hyperbaric oxygen therapy induces transcriptome changes in elderly: a prospective trial

Amir Hadanny1,2,3,4 , Relly Forer5 , Dina Volodarsky5 , Malka Daniel-Kotovsky1 , Merav Catalogna1 , Yonatan Zemel1,4 , Yair Bechor1,4 , Shai Efrati1,2,4,6

doi : 10.18632/aging.203709

Volume 13, Issue 22, pp 24511—24523

Aging is characterized by the progressive loss of physiological capacity. Changes in gene expression can alter activity in defined age-related molecular pathways leading to cellular aging and increased aging disease susceptibility. The aim of the current study was to evaluate whether hyperbaric oxygen therapy (HBOT) affects gene expression in normal, non-pathological, aging adults.

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Progressive reorganization of mitochondrial apparatus in aging skeletal muscle of naked mole rats (Heterocephalus glaber) as revealed by electron microscopy: potential role in continual maintenance of muscle activity

Valeriya Vays1 , Irina Vangely1 , Chupalav Eldarov1 , Susanne Holtze2 , Thomas Hildebrandt2 , Lora Bakeeva1 , Vladimir Skulachev1

doi : 10.18632/aging.203720

Volume 13, Issue 22, pp 24524—24541

The authors examined the ultrastructure of mitochondrial apparatus of skeletal muscles of naked mole rats (Heterocephalus glaber) from the age of 6 months to 11 years. The obtained results have demonstrated that the mitochondria in skeletal muscles of naked mole rats aged below 5 years is not well-developed and represented by few separate small mitochondria. Mitochondrial reticulum is absent. Starting from the age of 5 years, a powerful mitochondrial structure is developed. By the age of 11 years, it become obvious that the mitochondrial apparatus formed differs from that in the skeletal muscle of adult rats and mice, but resembles that of cardiomyocytes of rats or naked mole rats cardiomyocytes. From the age of 6 months to 11 years, percentage area of mitochondria in the skeletal muscle of naked mole rat is increasing by five times. The growth of mitochondria is mainly driven by increased number of organelles. Such significant growth of mitochondria is not associated with any abnormal changes in mitochondrial ultrastructure.

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Increased proliferation and differentiation capacity of placenta-derived mesenchymal stem cells from women of median maternal age correlates with telomere shortening

Erika N. Guerrero1,3, * , Shantal Vega1,2, * , Cindy Fu1,3 , Ruth De León1 , Davis Beltran4 , Mairim Alexandra Solis1,2,5

doi : 10.18632/aging.203724

Volume 13, Issue 22, pp 24542—24559

Mesenchymal stem cells (MSCs) experience functional decline with systemic aging, resulting in reduced proliferation, increased senescence, and lower differentiation potential. The placenta represents a valuable source of MSCs, but the possible effect of donor age on the properties of placenta-derived mesenchymal stem cells (PDMSCs) has not been thoroughly studied. Thus, the aim of this study was to underscore the effect of maternal age on the biological characteristics and stemness properties of PDMSCs. PDMSCs were isolated from 5 donor age groups (A: 18-21, B: 22-25, C: 26-30, D:31-35 and E: ?36 years) for comparison of morphological, proliferative and differentiation properties. The pluripotency markers NANOG, OCT4, and SSEA4, as well as multipotency and differentiation markers, showed higher expression in PDMSCs from mothers aged 22-35 years, with up to a 7-fold increase in adipogenesis. Cumulative population doubling, cell growth curves, and colony-forming unit-fibroblast assays revealed higher self-renewal ability in donors 26-30 years old. An increase in the proliferative characteristics of PDMSCs correlated with increased telomere shortening, suggesting that shorter telomere lengths could be related to cellular division rather than aging. A clear understanding of the effect of maternal age on MSC regenerative potential will assist in increasing the effectiveness of future cell therapies.

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Circular RNA CELF1 drives immunosuppression and anti-PD1 therapy resistance in non-small cell lung cancer via the miR-491-5p/EGFR axis

Wen Ge1, * , Hao Chi1, * , Hua Tang2 , Jianjun Xu1 , Jing Wang1 , Wan Cai1 , Haitao Ma3

doi : 10.18632/aging.203576

Volume 13, Issue 22, pp 24560—24579

To explore the immunoregulatory effects of circ_CELF1 in non-small cell lung cancer (NSCLC).

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BMPR2 promoter methylation and its expression in valvular heart disease complicated with pulmonary artery hypertension

Ni Li1,2, * , Linwen Zhu1, * , Caimin Zhu1 , Hua Zhou1 , Dawei Zheng1 , Guodong Xu1 , Huoshun Shi1 , Jianqing Gao2 , Albert Jiarui Li3 , Zhaoyang Wang1 , Lebo Sun1 , Xiajun Li4 , Guofeng Shao1

doi : 10.18632/aging.203690

Volume 13, Issue 22, pp 24580—24604

Valvular heart disease (VHD) is a common heart disease that affects blood flow. It usually requires heart surgery. Valvular heart disease complicated with pulmonary artery hypertension (VHD-PAH) may be lethal due to heart failure that results from increased heart burden. It is important for these patients to seek early treatment in order to minimize the heart damage. However, there is no reliable diagnosis method in VHD. In this study, we found DNA methylation was increased at the promoter of BMPR2 gene in the VHD patients compared with the healthy controls. This finding was confirmed by an independent cohort study of VHD patients and healthy controls. In addition, BMPR2 mRNA levels were reduced in the plasma of the VHD patients. There is strong correlation between BMPR2 promoter DNA methylation and the severity of VHD. Indeed, we found that both BMPR2 promoter DNA methylation and BMPR2 mRNA levels in the plasma are good biomarkers of VHD by themselves, with the respective AUC value of 0.879 and 0.725, respectively. When they were used in combination, the diagnostic value was even better, with the AUC value of 0.93. Consistent with the results in the VHD patients, we observed decreased BMPR2 and increased fibrosis in the lung of a PAH model mouse. BMPR2 was also decreased in the hearts of the PAH mice, whereas BMP4 was increased. Furthermore, BMPR2 was reduced in the heart valve tissue samples of human VHD patients after valve replacement with moderate/severe PAH compared with those with mild PAH. There was also increased apoptosis in the hearts of the PAH mice. BMPR2 promoter DNA methylation and its expression appear to be good biomarkers for VHD. Our results also suggest that DNA methylation may cause PAH through deregulation of BMP signaling and increased apoptosis.

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Knockdown of transient receptor potential melastatin 2 reduces renal fibrosis and inflammation by blocking transforming growth factor-?1-activated JNK1 activation in diabetic mice

Feng Hu1 , Yun Yu1 , Feng Lu2 , Xiaoshu Cheng1, &

doi : 10.18632/aging.203694

Volume 13, Issue 22, pp 24605—24620

Diabetic nephropathy is a major complication of diabetes. We explore the protective effect of TRPM2 knockdown on the progression of diabetic nephropathy.

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Construction of a genome instability-derived lncRNA-based risk scoring system for the prognosis of hepatocellular carcinoma

Dan-Ping Huang1, * , Mian-Mian Liao1,2, * , Jing-Jing Tong3, * , Wei-Qu Yuan4 , De-Ti Peng1 , Jian-Ping Lai1 , Yi-Hao Zeng2 , Yi-Jun Qiu5, & , Guang-Dong Tong1

doi : 10.18632/aging.203698

Volume 13, Issue 22, pp 24621—24639

Emerging evidence revealed the critical roles of long non-coding RNAs (lncRNAs) in maintaining genomic instability. However, genome instability-associated lncRNAs (GILncRNAs) and their performance in clinical prognostic significance in hepatocellular carcinoma (HCC) are rarely reported. Our study constructed a computational framework integrating somatic mutation information and lncRNA expression profiles of HCC genome and we identified 88 GILncRNAs of HCC. Function enrichment analysis revealed that GILncRNAs were involved in various metabolism processes and genome instability of cancer. A genome instability-derived lncRNA-based gene signature (GILncSig) was constructed using training set data. The performance of GILncSig for outcome prediction was validated in testing set and The Cancer Genome Atlas (TCGA) set. The multivariate cox regression analysis and stratification analysis demonstrated GILncSig could serve as an independent prognostic factor for the overall survival of HCC patients. The time-dependent Receiver Operating Characteristic (ROC) curve illustrated GILncSig outperformed two recently published lncRNA signatures for overall survival prediction. The combination of GILncSig and tumor protein p53 (TP53) mutation status exhibited better prognostic performance in survival evaluation compared to TP53 mutation status alone. AC145343.1 was further validated to be a risk factor for HCC in vitro among GILncSig. Overall, our study provided a novel approach for identification of genome instability-associated lncRNAs and established an independent risk score system for outcome prediction of HCC patients, which provided a new insight for exploring in-depth mechanism and potential therapy strategy.

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PPAR? agonist relieves spinal cord injury in rats by activating Nrf2/HO-1 via the Raf-1/MEK/ERK pathway

Haocong Zhang1, * , Dulei Xiang1,2, * , Xinwei Liu1 , Liangbi Xiang1

doi : 10.18632/aging.203699

Volume 13, Issue 22, pp 24640—24654

To observe the inhibitory effects of the peroxisome proliferator-activated receptor alpha (PPAR?) agonist palmitoylethanolamide (PEA) on inflammatory responses and oxidative stress injury in rats with spinal cord injury (SCI).

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Identification and replication of novel genetic variants of ABO gene to reduce the incidence of diseases and promote longevity by modulating lipid homeostasis

Xiaolin Ni1,2 , Chen Bai3,4 , Chao Nie5 , Liping Qi6 , Yifang Liu7 , Huiping Yuan1 , Xiaoquan Zhu1 , Liang Sun1 , Qi Zhou1 , Yan Li5 , Hefu Zhen5 , Huabing Su8 , Rongqiao Li8 , Rushu Lan8 , Guofang Pang8 , Yuan Lv8 , Wei Zhang8 , Fan Yang1,2 , Yao Yao3,4 , Chen Chen1 , Zhaoping Wang1 , Danni Gao9 , Nan Zhang1 , Shenqi Zhang1,2 , Li Zhang1,2 , Zhu Wu1 , Caiyou Hu8, & , Yi Zeng3,4 , Ze Yang1,2, &

doi : 10.18632/aging.203700

Volume 13, Issue 22, pp 24655—24674

Genes related to human longevity have not been studied so far, and need to be investigated thoroughly. This study aims to explore the relationship among ABO gene variants, lipid levels, and longevity phenotype in individuals (?90yrs old) without adverse outcomes.

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BMAL1 may be involved in angiogenesis and peritumoral cerebral edema of human glioma by regulating VEGF and ANG2

Fan Wang1, * , CaiYan Li2, * , Fei Han3 , LvAn Chen1 , Ling Zhu1

doi : 10.18632/aging.203708

Volume 13, Issue 22, pp 24675—24685

The rhythm gene BMAL1 (Brain and Muscle ARNT-Like 1) may play an important role in glioma tolerance for anti-angiogenesis therapy. In humans with glioma of different pathological grades, BMAL1 expression was significantly different, and the expression of ANG2 (Angiopoietin 2) and VEGF (Vascular endothelial growth factor) was positively correlated with the expression of BMAL1. Additionally, BMAL1 expression is positively correlated with the microvascular density and peritumoral edema of glioma. According to in vitro experiments, silencing the expression of BMAL1 in primary glioma cells results in a decrease in the expression of VEGF. In contrast, overexpression of BMAL1 promotes the expression of ANG2 and VEGF via HIF-1a pathway. Therefore, BMAL1 likely participates in the angiogenesis of glioma by modulating ANG2 and VEGF expression, alters the therapeutic effect of anti-angiogenic treatments, and promotes peritumoral brain edema of glioma.

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Genomic mutation features identify distinct BRCA-associated mutation characteristics in endometrioid carcinoma and endometrioid ovarian carcinoma

Canhui Cao1,2, * , Ruidi Yu1,2, * , Wenjian Gong1,2, * , Dan Liu1,2 , Xiaoxue Zhang1,2 , Yong Fang1,2 , Yu Xia1,2 , Wei Zhang1,2, & , Qinglei Gao1,2

doi : 10.18632/aging.203710

Volume 13, Issue 22, pp 24686—24709

Although endometrioid carcinoma (EC) and endometrioid ovarian carcinoma (EnOC) display similar pathological features, their molecular characteristics remain to be determined. Somatic mutation data from 2777 EC, 423 EnOC, and 57 endometriosis patients from the Catalogue of Somatic Mutations in Cancer (COSMIC) dataset were analyzed and showed similar profiles with different mutation frequencies among them. By using 275 overlapping mutated genes, EC was clustered into two groups with different disease outcomes and different clinical characteristics. Although BRCA-associated mutation characteristics were identified in both EC and EnOC, the mutation frequencies of BRCA1 (P=0.0146), BRCA2 (P=0.0321), ATR (P=3.25E-11), RAD51 (P=3.95E-08), RAD1 (P=0.0003), TP53 (P=6.11E-33), and BRIP1 (P=2.90E-09) were higher in EnOC. Further analysis showed that EnOC cell lines with BRCA-associated mutation characteristics were more sensitive to poly ADP-ribose polymerase (PARP) inhibitors than EC cell lines, including olaparib, talazoparib, rucaparib, and veliparib. Moreover, based on BRCA-associated mutational and transcriptomic profiles, EC with BRCA-associated mutational burdens shows lower levels of immune cell infiltration, higher expression of immunosuppressive checkpoint molecules and worse prognosis than EC without BRCA mutation. Our study comprehensively analyzed the genome mutation features of EC and EnOC and provide insights into the molecular characteristics of EC and EnOC.

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Detection of genomic structure variants associated with wrinkled skin in Xiang pig by next generation sequencing

Liu Xiaoli1 , Hu Fengbin1 , Huang Shihui1 , Niu Xi1 , Li Sheng1 , Wang Zhou1 , Ran Xueqin1 , Wang Jiafu1

doi : 10.18632/aging.203711

Volume 13, Issue 22, pp 24710—24739

Wrinkling is prominent manifestation of aging skin. A mutant phenotype characterized by systemic wrinkles and thickened skin was discovered in Xiang pig populations with incidence about 1-3%. The feature in histological structure was epidermal hyperplasia and thickening, collagen fibers disorder. To uncover genetic mechanisms for the mutant phenotype of Xiang pigs with systemic wrinkle (WXP), a genome-wide of structural variations (SVs) in WXP was described by next generation resequencing, taking Xiang pigs (XP) and European pigs (EUP) as compares. Total of 32,308 SVs were detected from three pig groups and 965 SVs were identified specifically from WXP, involving 481 protein-coding genes. These genes were mainly enriched in nuclear structure, ECM components and immunomodulatory pathways. According to gene function and enrichment analysis, we found that 65 candidate SVs in 59 protein genes were probably related with the systemic wrinkle of WXP. Of these, several genes are reported to be associate with aging, such as EIF4G2, NOLC1, XYLT1, FUT8, MDM2 and so on. The insertion/deletion and duplication variations of SVs in these genes resulted in the loss of stop-codon or frameshift mutation, and aberrant alternative splicing of transcripts. These genes are involved in cell lamin filament, intermediate filament cytoskeleton, supramolecular complex, cell differentiation and regulation of macromolecule metabolic process etc. Our study suggested that the loss of function or aberrant expression of these genes lead to structural disorder of nuclear and the extracellular matrix (ECM) in skin cells, which probably was the genetic mechanisms for the mutant phenotype of systemic skin wrinkle of Xiang pig.

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Inhibition of Fam114A1 protects melanocytes from apoptosis through higher RACK1 expression

Miaoni Zhou1 , Fuquan Lin1 , Xingang Wu1 , Zhuyi Ping1 , Wen Xu1 , Rong Jin1 , Aie Xu1

doi : 10.18632/aging.203712

Volume 13, Issue 22, pp 24740—24752

Fam114A1 is a gene closely related to the development of nerve cells, melanocytes, and nerve cells that originate from the neural crest of the embryonic ectoderm. Recent studies showed that Fam114A1 has a role in the occurrence of ankylosing myelitis spondylitis and autoimmune enteritis; still, its cellular function remains poorly understood. In this study, we investigated the effect of Fam114A1 on the biological activity of melanocytes. We found that the expression of Fam114A1 in vitiligo melanocytes (MCV-L, MCV-N, PI3V) was higher than that in normal melanocytes, and the biological function of melanocytes was significantly affected when the Fam114A1 gene was silenced. Inhibition of Fam114A1 increased proliferation, migration, and melanin synthesis proteins, decreased apoptosis, while its overexpression reversed this process. Mechanistically, we discovered that RACK1 is a target protein of Fam114A1 and that RACK1 can be negatively regulated by Fam114A1. Further study showed that Fam114A1 inhibition could not protect melanocytes from apoptosis once the expression of RACK1 protein was silenced. In summary, Fam114A1 is an effective regulatory protein for regulating the function of melanocytes. Inhibition Fam114A1 protects melanocytes from apoptosis through increasing RACK1.

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Fisetin inhibits the proliferation, migration and invasion of pancreatic cancer by targeting PI3K/AKT/mTOR signaling

Yanyi Xiao1, * , Yilong Liu2, * , Zhiwei Gao3, * , Xian Li2 , Min Weng1 , Chenghao Shi1 , Cheng Wang1 , Linxiao Sun1

doi : 10.18632/aging.203713

Volume 13, Issue 22, pp 24753—24767

Pancreatic cancer is an extremely malignant digestive tract tumor. With the increase of chemotherapeutic resistance of pancreatic cancer, clinical treatment is in a dilemma. Hence, it is pivotal to design an effective drug for treating individuals with pancreatic cancer. Fisetin extracted from vegetables, as well as fruits was explored to possess antioxidant, anti-cancer, anti-inflammatory along with anti-microbial properties. Nonetheless, there is limited research focusing on the utility of fisetin as an inhibitor of pancreatic cancer. Similarly, the mechanism through which Fisetin dampens pancreatic cancer remains unknown. This research work systematically evaluated the possible anti-cancer influences of fisetin in pancreatic cancer, as well as explored its responsible molecular mechanism. Our data revealed that fisetin obviously dampens pancreatic cancer progress in vitro along with in vivo dose-dependently. Furthermore, we established that fisetin repressed pancreatic cancer via explicitly targeting PI3K/AKT/mTOR signaling cascade and not the JAK2 cascade. Our data clarified that fisetin is a prospective anti-cancer drug for pancreatic cancer, as well as indicated the distinct molecular target of fisetin.

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Tumor purity as a prognosis and immunotherapy relevant feature in cervical cancer

Yali Deng1 , Zewen Song2 , Li Huang3 , Zhenni Guo3 , Binghua Tong3 , Meiqing Sun3 , Jin Zhao3 , Huina Zhang3 , Zhen Zhang2, & , Guoyin Li3,4

doi : 10.18632/aging.203714

Volume 13, Issue 22, pp 24768—24785

Tumor purity plays a vital role in the biological process of solid tumors, but its function in gynecologic cancers remains unclear. This study explored the correlation between tumor purity and immune function of gynecological cancers and its reliability as a prognostic indicator of immunotherapy.

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Excluding embryos with two novel mutations in FREM2 gene by the next-generation sequencing-based single nucleotide polymorphism haplotyping

Yao Zhou1,2,3, * , Xiaohui Yang1,2,3, * , Zheng Liu4, * , Yu Zhang1,2,3 , Huaye Chen1,2,3 , Yongfang Zhang1,2,3 , Yuxin Hu5 , Yanlin Ma1,2,3 , Qi Li1,2,3

doi : 10.18632/aging.203715

Volume 13, Issue 22, pp 24786—24794

Fraser syndrome is a rare autosomal recessive malformation disorder. It is characterized by cryptophthalmos, syndactyly, urinary tract abnormalities and ambiguous genitalia. This condition is due to homozygous or heterozygous mutations in the FRAS1, FREM1, FREM2, and GRIP1 genes. In the present study, we recruited a Chinese family with Fraser syndrome. Two novel mutations c.7542_7543insG and c.2689C>T in the FREM2 gene were detected in this Fraser syndrome family by PCR-based sequencing. The next-generation sequencing-based single nucleotide polymorphism haplotyping method was applied to exclude these two mutations in 9 blastocysts obtained from the patient. After obtaining consent and informing the risk, the patient received in vitro fertilization and embryo transfer treatment with an embryo carrying a heterozygous mutation. Finally, she delivered a healthy baby without any complications on March 17, 2019. In conclusion, we first reported two novel mutations in the FREM2 gene associated with the risk of Fraser syndrome. Moreover, we described a next-generation sequencing-based single nucleotide polymorphism haplotyping method to select the ‘right’ embryos from patients with Fraser syndrome for in vitro fertilization and embryo transfer treatment.

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Identification of pyroptosis-related signature for cervical cancer predicting prognosis

Cankun Zhou1 , Chaomei Li2 , Yuhua Zheng1 , Xiaochun Liu1, &

doi : 10.18632/aging.203716

Volume 13, Issue 22, pp 24795—24814

Cervical cancer (CC) is one of the most common malignancies encountered in gynecology practice. However, there is a paucity of information about specific biomarkers that assist in the diagnosis and prognosis of CC. Pyroptosis is a form of programmed cell death whose different elements are related to the occurrence, invasion, and metastasis of tumors. However, the role of pyroptosis phenomena in the progression of CC has not yet been elucidated. This study focuses on the development of a pyroptosis-associated prognostic signature for CC using integrated bioinformatics to delineate the relationships among the signature, tumor microenvironment, and immune response of the patients. In this respect, we identified a prognostic signature that depends on eight pyroptosis-related genes (PRGs) that designate with better prognostic survival in the low-risk group (P<0.05) and where AUC values were greater than 0.7. A multi-factor Cox regression analysis indicated that such a signature could be used as an independent prognostic factor, and both the DCA and the Nomogram suggested that the proposed prognostic signature had good predictive capabilities. Interestingly, this prognostic signature can be applied to multiple tumors and thus, is versatile from a clinical point of view. In addition, there were significant differences in the tumor microenvironment and immune infiltration status between the high- and low-risk groups (P<0. 05). The core gene granzyme B (GZMB) was screened and the CC-associated regulatory axis, GZMB/ miR-378a/TRIM52-AS1, was constructed, which may promote CC progression, and further experimentation is needed to validate these results.

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Atorvastatin combined with dexamethasone promote hematoma absorption in an optimized rat model of chronic subdural hematoma

Dong Wang1,2, * , Yueshan Fan1,2,3, * , Jun Ma1,2, * , Chuang Gao1,2 , Xuanhui Liu1,2,3 , Zilong Zhao1,2 , Huijie Wei1,2 , Guili Yang1,2 , Jinhao Huang1,2 , Rongcai Jiang1,2 , Jianning Zhang1,2

doi : 10.18632/aging.203717

Volume 13, Issue 22, pp 24815—24828

Previous studies found that atorvastatin and dexamethasone were effective in promoting the absorption of chronic subdural hematoma. In this study, we aimed to investigate the effect of pharmacotherapy in an optimized rat model of chronic subdural hematoma.

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Bone morphogenetic protein 9 enhances osteogenic and angiogenic responses of human amniotic mesenchymal stem cells cocultured with umbilical vein endothelial cells through the PI3K/AKT/m-TOR signaling pathway

Ziming Liu1,2, *,# , Yuwan Li1,2, *,# , Jianye Yang3 , Jiaxing Huang3 , Changqi Luo4 , Jun Zhang2 , Wenqiang Yan1 , Yingfang Ao1

doi : 10.18632/aging.203718

Volume 13, Issue 22, pp 24829—24849

Neovascularization plays an essential part in bone fracture and defect healing, constructing tissue engineered bone that targets bone regeneration. Bone morphogenetic protein 9 (BMP9) is a regular indicator that potentiates osteogenic and angiogenic differentiation of MSCs.

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Long noncoding RNA NEAT1 inhibits the acetylation of PTEN through the miR-524-5p /HDAC1 axis to promote the proliferation and invasion of laryngeal cancer cells

Jiajia Zhang1 , Ping Wang2 , Yanli Cui1

doi : 10.18632/aging.203719

Volume 13, Issue 22, pp 24850—24865

Long noncoding RNA nuclear paraspeckle assembly transcript 1 (lncRNA NEAT1) is abnormally expressed in numerous tumors and functions as an oncogene, but the role of NEAT1 in laryngocarcinoma is largely unknown. Our study validated that NEAT1 expression was markedly upregulated in laryngocarcinoma tissues and cells. Downregulation of NEAT1 dramatically suppressed cell proliferation and invasion through inhibiting miR-524-5p expression. Additionally, NEAT1 overexpression promoted cell growth and metastasis, while overexpression of miR-524-5p could reverse the effect. NEAT1 increased the expression of histone deacetylase 1 gene (HDAC1) via sponging miR-524-5p. Mechanistically, overexpression of HDAC1 recovered the cancer-inhibiting effects of miR-524-5p mimic or NEAT1 silence by deacetylation of tensin homolog deleted on chromosome ten (PTEN) and inhibiting AKT signal pathway. Moreover, in vivo experiments indicated that silence of NEAT1 signally suppressed tumor growth. Taken together, knockdown of NEAT1 suppressed laryngocarcinoma cell growth and metastasis by miR-524-5p/HDAC1/PTEN/AKT signal pathway, which provided a potential therapeutic target for laryngocarcinoma.

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A scoring model based on ferroptosis genes for prognosis and immunotherapy response prediction and tumor microenvironment evaluation in liver hepatocellular carcinoma

Lei Gao1 , Juan Xue2 , Xiaomin Liu1 , Lei Cao1 , Ruifang Wang1 , Liangliang Lei3

doi : 10.18632/aging.203721

Volume 13, Issue 22, pp 24866—24881

Ferroptosis is a type of iron-dependent programmed cell death. Ferroptosis inducers have been shown to have a great potential for cancer therapy. We aimed to generate a risk scoring model based on ferroptosis-related genes (FRGs) and validate its predictive performances in overall survival (OS) prediction and immunotherapy efficacy evaluation in liver hepatocellular carcinoma (LIHC). Differential and Univariate Cox regression analyses were applied to analyze RNA-seq data of LIHC samples from TCGA and GEO databases to identify prognosis-related ferroptosis genes. Patients were assigned to three clusters (Ferrclusters A, B, and C) based on the cluster analysis of prognostic ferroptosis genes. The principal component analysis (PCA) was performed to build a risk scoring model based on differentially expressed FRGs. Survival analysis revealed that Ferrcluster B LIHC patients had a lower OS rate alongside more severe immune cell infiltration versus Ferrcluster A and C patients; moreover, the LIHC patients in high-ferrscore group had significantly lower survival than the low-ferrscore group. Compared to low-ferrscore patients, Programmed cell death 1 (PD-1) mRNA expression significantly increased, and either PD-1 or PD-1 plus CTLA4 (cytotoxic T-lymphocyte associated protein 4) inhibitors showed unsatisfactory efficacy in high-ferrscore patients. Our study demonstrates the implication of FRGs in prognosis prediction and evaluation of immunotherapy efficacy in LIHC patients.

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Prognostic and immune infiltration signatures of proteasome 26S subunit, non-ATPase (PSMD) family genes in breast cancer patients

Do Thi Minh Xuan1, * , Chung-Che Wu2,3, * , Tzu-Jen Kao4 , Hoang Dang Khoa Ta1,5 , Gangga Anuraga1,5,6 , Vivin Andriani7 , Muhammad Athoillah6 , Chung-Chieh Chiao1,5 , Yung-Fu Wu8 , Kuen-Haur Lee1,5,9,10 , Chih-Yang Wang1,5 , Jian-Ying Chuang4,11,12

doi : 10.18632/aging.203722

Volume 13, Issue 22, pp 24882—24913

The complexity of breast cancer includes many interacting biological processes that make it difficult to find appropriate therapeutic treatments. Therefore, identifying potential diagnostic and prognostic biomarkers is urgently needed. Previous studies demonstrated that 26S proteasome delta subunit, non-ATPase (PSMD) family members significantly contribute to the degradation of damaged, misfolded, abnormal, and foreign proteins. However, transcriptional expressions of PSMD family genes in breast cancer still remain largely unexplored. Consequently, we used a holistic bioinformatics approach to explore PSMD genes involved in breast cancer patients by integrating several high-throughput databases, including The Cancer Genome Atlas (TCGA), cBioPortal, Oncomine, and Kaplan-Meier plotter. These data demonstrated that PSMD1, PSMD2, PSMD3, PSMD7, PSMD10, PSMD12, and PSMD14 were expressed at significantly higher levels in breast cancer tissue compared to normal tissues. Notably, the increased expressions of PSMD family genes were correlated with poor prognoses of breast cancer patients, which suggests their roles in tumorigenesis. Meanwhile, network and pathway analyses also indicated that PSMD family genes were positively correlated with ubiquinone metabolism, immune system, and cell-cycle regulatory pathways. Collectively, this study revealed that PSMD family members are potential prognostic biomarkers for breast cancer progression and possible promising clinical therapeutic targets.

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Correction for: Overexpressed ITGA2 contributes to paclitaxel resistance by ovarian cancer cells through the activation of the AKT/FoxO1 pathway

Linlin Ma1, * , Yan Sun2,3, * , Dan Li5 , Hansong Li1 , Xin Jin3,4 , Dianyun Ren2,3

doi : 10.18632/aging.203703

Volume 13, Issue 22, pp 24914

خرید پکیج و مشاهده آنلاین مقاله

Correction for: MicroRNA-126 engineered muscle-derived stem cells attenuates cavernosa injury-induced erectile dysfunction in rats

Zihao Zou1, * , Muyuan Chai2, * , Feixiang Guo1 , Xin Fu1 , Yu Lan1 , Shuqi Cao1 , Jianan Liu1 , Long Tian3 , Geng An1

doi : 10.18632/aging.203704

Volume 13, Issue 22, pp 24915—24916

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