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Toward establishing a worldwide net of canine biobanks
Sára Sándor, Silvan Urfer, Enikő Kubinyi
doi : 10.18632/aging.203961
pp 2436—2437
Targeting anxiety and senescence with senolytics
Marco Raffaele, Manlio Vinciguerra
doi : 10.18632/aging.203985
pp 2438—2439
Regulation of mTOR complexes in long-lived growth hormone receptor knockout and Snell dwarf mice
Xiaofang Shi1 , S. Joseph Endicott1 , Richard A. Miller1,2,3
doi : 10.18632/aging.203959
Volume 14, Issue 6 pp 2442—2461
Downregulation of mTOR (mechanistic target of rapamycin) can extend lifespan in multiple species, including mice. Growth hormone receptor knockout mice (GHRKO) and Snell dwarf mice have 40% or greater lifespan increase, and have lower mTORC1 function, which might reflect alteration in mTORC1 components or alteration of upstream proteins that modulate mTOR activity. Here we report reduction of mTORC components DEPTOR and PRAS40 in liver of these long-lived mice; these changes are opposite in direction to those that would be expected to lead to lower mTORC1 function. In contrast, levels of the upstream regulators TSC1 and TSC2 are elevated in GHRKO and Snell liver, kidney and skeletal muscle, and the ratio of phosphorylated TSC2 to total TSC2 is lower in the tissues of the long-lived mutant mice. In addition, knocking down TSC2 in GHRKO fibroblasts reversed the effects of the GHRKO mutation on mTORC1 function. Thus increased amounts of unphosphorylated, active, inhibitory TSC may contribute to lower mTORC1 function in these mice.
Association between social isolation and reduced mental well-being in Swedish older adults during the first wave of the COVID-19 pandemic: the role of cardiometabolic diseases
Abigail Dove1, * , Jie Guo1, * , Amaia Calderón-Larrañaga1 , Davide Liborio Vetrano1 , Laura Fratiglioni1,2 , Weili Xu1
doi : 10.18632/aging.203956
Volume 14, Issue 6 pp 2462—2474
Social isolation has been recommended as a strategy for reducing COVID-19 risk, but it may have unintended consequences for mental well-being. We explored the relationship between social isolation and symptoms of depression and anxiety in older adults during the first wave of the COVID-19 pandemic and assessed the role of cardiometabolic diseases (CMDs) in this association. Between May and September 2020, 1,190 older adults from the Swedish National Study on Aging and Care in Kungsholmen were surveyed about their behaviors and health consequences during the first wave of the COVID-19 pandemic. In total, 913 (76.7%) participants reported socially isolating at home to avoid infection during this period. Social isolation was associated with a greater likelihood of reduced mental well-being (i.e., feelings of depression or anxiety) (OR: 1.74, 95% CI: 1.15-2.65). In joint exposure analysis, there was a significant likelihood of reduced mental well-being only among people who were socially isolating and had CMDs (OR: 2.13, 95% CI: 1.22-3.71) (reference: not isolating, CMD-free). In conclusion, social isolation as a COVID-19 prevention strategy was related to reduced mental well-being in an urban sample of Swedish older adults, especially among individuals with CMDs.
Hallmarks of aging-based dual-purpose disease and age-associated targets predicted using PandaOmics AI-powered discovery engine
Frank W. Pun1, * , Geoffrey Ho Duen Leung1, * , Hoi Wing Leung1, * , Bonnie Hei Man Liu1 , Xi Long1 , Ivan V. Ozerov1 , Ju Wang1 , Feng Ren1 , Alexander Aliper1 , Evgeny Izumchenko2 , Alexey Moskalev3 , João Pedro de Magalhães4 , Alex Zhavoronkov1,5
doi : 10.18632/aging.203960
Volume 14, Issue 6 pp 2475—2506
Aging biology is a promising and burgeoning research area that can yield dual-purpose pathways and protein targets that may impact multiple diseases, while retarding or possibly even reversing age-associated processes. One widely used approach to classify a multiplicity of mechanisms driving the aging process is the hallmarks of aging. In addition to the classic nine hallmarks of aging, processes such as extracellular matrix stiffness, chronic inflammation and activation of retrotransposons are also often considered, given their strong association with aging. In this study, we used a variety of target identification and prioritization techniques offered by the AI-powered PandaOmics platform, to propose a list of promising novel aging-associated targets that may be used for drug discovery. We also propose a list of more classical targets that may be used for drug repurposing within each hallmark of aging. Most of the top targets generated by this comprehensive analysis play a role in inflammation and extracellular matrix stiffness, highlighting the relevance of these processes as therapeutic targets in aging and age-related diseases. Overall, our study reveals both high confidence and novel targets associated with multiple hallmarks of aging and demonstrates application of the PandaOmics platform to target discovery across multiple disease areas.
Evaluation of the effect of age of the younger mice on the rejuvenation of the older mice by heterochronic parabiosis
Yushi Suzuki1 , Kento Takaya1 , Shiho Watanabe1 , Marika Otaki1 , Hikaru Kono1 , Kazuo Kishi1
doi : 10.18632/aging.203966
Volume 14, Issue 6 pp 2507—2512
Heterochronic parabiosis is used to study the systemic effects of aging and involves surgically connecting two animals of different ages such that they have common blood circulation. Although this technique has been prevalent for a long time, there is no scientific consensus on the age of the animals that should be used. We hypothesized that the younger the animal, the greater would be its rejuvenating effect. Hence, to test this hypothesis, we created parabiosis of 67-week-old mice with younger mice of different ages (4-week-old and 8-week-old). We evaluated the changes in appearance and the expression IL-1A, IL-6, and Cdkn2a (p16) in the liver, kidney, brain, and skin. These cytokines belong to the senescence-associated secretory phenotype (SASP) factors, and are indicators of aging. Although we did not find any significant changes in the appearance of the mice, we found statistically significant differences in some SASP factors between the liver of the 4-week-old and 8-week-old pairs. However, overall, compared to the 8-week-old mice, the 4-week-old does not exert a significantly higher rejuvenation effect on the older mice. Hence, we concluded that the rejuvenation of older mice during heterochronic parabiosis might not be affected by the exact age of the younger mice.
Ovarian reserve parameters and IVF outcomes in 510 women with poor ovarian response (POR) treated with intraovarian injection of autologous platelet rich plasma (PRP)
Yigit Cakiroglu1,2 , Aysen Yuceturk1 , Ozge Karaosmanoglu1 , Sule Yildirim Kopuk1 , Zeynep Ece Utkan Korun1 , Nola Herlihy3,4 , Richard T. Scott3,4 , Bulent Tiras1,2 , Emre Seli3,5
doi : 10.18632/aging.203972
Volume 14, Issue 6 pp 2513—2523
The aim of the current study was to characterize ovarian reserve parameters and IVF outcomes in women with a history of poor ovarian response (POR) treated with intraovarian injection of autologous platelet rich plasma (PRP). Reproductive age women (N=510; age range 30-45yo) diagnosed with POR based on Poseidon criteria were included in the study. PRP treatment resulted in higher AFC, higher serum AMH, lower serum FSH, and a higher number of mature oocytes and cleavage and blastocyst stage embryos. After PRP injection, 22 women (4.3%) conceived spontaneously, 14 (2.7%) were lost to follow up, and 474 (92.9%) attempted IVF. Among women who attempted IVF, 312 (65.8%) generated embryos and underwent embryo transfer, 83 (17.5%) achieved a pregnancy, and 54 (11.4%) achieved sustained implantation/live birth (SI/LB). In total, of the 510 women with POR and mean age of 40.3, PRP resulted in improvement of ovarian reserve parameters, a pregnancy rate of 20.5% and SI/LB rate of 12.9%. Our findings suggest that PRP treatment may be considered in women with POR. For wider clinical application, its clinical efficacy will need to be demonstrated in prospective randomized clinical trials.
VEGF-A-related genetic variants protect against Alzheimer’s disease
Alexandros M. Petrelis1 , Maria G. Stathopoulou2 , Maria Kafyra1,3 , Helena Murray4 , Christine Masson1 , John Lamont4 , Peter Fitzgerald4 , George Dedoussis1,3 , Frances T. Yen5 , Sophie Visvikis-Siest1
doi : 10.18632/aging.203984
Volume 14, Issue 6 pp 2524—2536
The Apolipoprotein E (APOE) genotype has been shown to be the strongest genetic risk factor for Alzheimer’s disease (AD). Moreover, both the lipolysis-stimulated lipoprotein receptor (LSR) and the vascular endothelial growth factor A (VEGF-A) are involved in the development of AD. The aim of the study was to develop a prediction model for AD including single nucleotide polymorphisms (SNP) of APOE, LSR and VEGF-A-related variants.
Association between serum uric acid and α-klotho protein levels in the middle-aged population
Hyo-Jung Lee1 , Ju-Young Choi1 , Jaeho Lee1,4 , Donghoon Kim1,4 , Jin-Young Min2 , Kyoung-Bok Min1,3,4
doi : 10.18632/aging.203987
Volume 14, Issue 6 pp 2537—2547
This study investigated the association between hyperuricemia and serum klotho protein levels in a representative sample of adults in the United States. We included 11,734 adults aged 40–80 years with available data of serum klotho, uric acid, covariates related to demographics, health behavior-related variables, and medical histories. Hyperuricemia was defined as a serum uric acid level of ≥7.0 mg/dL in men and ≥6.0 mg/dL in women. The geometric mean of serum klotho was 806.5 pg/mL (95% confidence interval: 801.7–811.4). The log-klotho level was negatively correlated with the uric acid level (r = −0.154; p < 0.0001). After adjustment for potential covariates, each one-unit increase in uric acid was significantly associated with a decrease in the log-klotho level (adjusted beta = −0.028; p < 0.0001). Compared with subjects without hyperuricemia, those with hyperuricemia had significantly lower serum klotho levels (adjusted beta = −0.062; p < 0.0001). We found a significant inverse association between serum uric acid and serum klotho levels in the general population, that is, an increase in serum uric acid levels was associated with a decrease in klotho levels. This finding suggests that loss of klotho may be due to the progression of hyperuricemia or, subsequently, gout.
Maslinic acid protects against pressure-overload-induced cardiac hypertrophy by blocking METTL3-mediated m6A methylation
Ming Fang1 , Jun Deng1 , Qiangping Zhou1 , Zhengbang Hu1 , Lixia Yang2
doi : 10.18632/aging.203860
Volume 14, Issue 6 pp 2548—2557
Coordinated response of the heart to physiological stressors (including stress overload, ischemia, hypothyroidism, and metabolic signals) is a hallmark of heart disease. However, effective treatment and its molecular targets are unknown. Although Maslinic Acid (MA) has been shown to inhibit inflammatory responses with strong anti-tumor, anti-bacterial, and antioxidant effects, information on its role and underlying mechanism in cardiac hypertrophy are scanty. The present study revealed that 10-103 μg/ml MA treatment significantly inhibited Ang-II induced hypertrophy in NMCMs and the dosage did not influence the cell viability of H9C2 and NCMCs. Moreover, the anti-hypertrophy effect of MA (30 mg/kg·day) was verified in the TAC-induced hypertrophy mouse model in vivo. Further analysis showed that MA administration decreased the total RNA m6A methylation and METTL3 levels in Ang-II treated NMCMs and TAC stressed hearts. Rescue experiments under adenovirus-mediated myocardial METTL3 overexpression confirmed that METTL3-mediated m6A methylation is essential in M-driven inhibition of myocardial hypertrophy. Collectively, MA exerts a significant anti-hypertrophy effect by regulating the modification of METTL3-mediated m6A methylation in vitro and in vivo. These findings may provide a platform for establishing a new target and strategy for cardiac hypertrophy treatment.
Pan-cancer analysis revealed the significance of the GTPBP family in cancer
Yiming Hu1, * , Liang Chen2, * , Qikai Tang3, * , Wei Wei2, * , Yuan Cao4 , Jiaheng Xie5 , Jing Ji1
doi : 10.18632/aging.203952
Volume 14, Issue 6 pp 2558—2573
Background: At present, cancer is still one of the principal diseases to represent a serious danger to human health. Although research on the pathogenesis and treatment of cancer is progressing rapidly, the current knowledge on this topic is far from sufficient. Some tumors with poor prognoses lack effective prognostic biomarkers.
Progesterone attenuates neurological deficits and exerts a protective effect on damaged axons via the PI3K/AKT/mTOR-dependent pathway in a mouse model of intracerebral hemorrhage
Chang Liu1, * , Weina Gao2, * , Long Zhao3 , Yi Cao4, &
doi : 10.18632/aging.203954
Volume 14, Issue 6 pp 2574—2589
Intracerebral hemorrhage (ICH) is a devastating event with high disability and fatality rates. However, there is a lack of effective treatments for this condition. We aimed to investigate the neuroprotective and axonal regenerative effects of progesterone after ICH. For this purpose, an ICH model was established in adult mice by injecting type VII collagenase into the striatum; the mice were then treated with progesterone (8 mg/kg). Hematoma absorption, neurological scores, and brain water content were evaluated on days one, three, and seven after the ICH. The effect of progesterone on inflammation and axonal regeneration was examined on day three after the ICH using western blotting, immunohistochemistry, immunofluorescence, as well as hematoxylin-eosin, Nissl, and Luxol fast blue staining. In addition, we combined progesterone with the phosphoinositide 3-kinase/serine/threonine-specific protein kinase (PI3K/AKT) inhibitor, LY294002, to explore its potential neuroprotective mechanisms. Administration of progesterone attenuated the neurological deficits and expression of inflammatory cytokines and promoted axonal regeneration after ICH, this effect was blocked by LY294002. Collectively, these results suggest that progesterone could reduce axonal damage and produced partial neuroprotective effects after ICH through the PI3K/AKT/mTOR pathway, providing a new therapeutic target and basis for the treatment of ICH.
The TLR4/NF-κB/MAGI-2 signaling pathway mediates postoperative delirium
Wei Zhang1 , Ruohan Wang2 , Jingli Yuan2 , Bing Li1 , Luyao Zhang1 , Yangyang Wang1 , Ruilou Zhu1 , Jiaqiang Zhang1, * , Ting Huyan3, *
doi : 10.18632/aging.203955
Volume 14, Issue 6 pp 2590—2606
Purpose: To evaluate the TLR4/NF-κB/MAGI-2 signaling pathway in postoperative delirium.Methods: Elderly patients aged 65-80 years who received unilateral hip arthroplasty under subarachnoid anesthesia were included. Pre-anesthesia cerebrospinal fluid and perioperative blood samples were collected. After follow-up, patients were divided into two groups according to the occurrence of postoperative delirium (POD) after surgery. The potential differentially expressed proteins in the two groups were determined by proteomics assay and subsequent western blot validation. A POD model of aged mice was established, and the TLR4/NF-κB/MAGI-2 signaling pathway was determined.
2, 3, 5, 4’-tetrahydroxystilbene-2-O-beta-D-glucoside protects against neuronal cell death and traumatic brain injury-induced pathophysiology
Yu-Hsin Chen1,2 , Yen-Chou Chen1 , Yu-Tang Chin3 , Ching-Chiung Wang4 , Ling-Ling Hwang1,2 , Liang-Yo Yang5,6 , Dah-Yuu Lu7,8
doi : 10.18632/aging.203958
Volume 14, Issue 6 pp 2607—2627
Traumatic brain injury (TBI) is a global health issue that affects at least 10 million people per year. Neuronal cell death and brain injury after TBI, including apoptosis, inflammation, and excitotoxicity, have led to detrimental effects in TBI. 2, 3, 5, 4’-tetrahydroxystilbene-2-O-beta-D-glucoside (THSG), a water-soluble compound extracted from the Chinese herb Polygonum multiflorum, has been shown to exert various biological functions. However, the effects of THSG on TBI is still poorly understood. THSG reduced L-glutamate-induced DNA fragmentation and protected glial and neuronal cell death after L-glutamate stimulation. Our results also showed that TBI caused significant behavioral deficits in the performance of beam walking, mNSS, and Morris water maze tasks in a mouse model. Importantly, daily administration of THSG (60 mg/kg/day) after TBI for 21 days attenuated the injury severity score, promoted motor coordination, and improved cognitive performance post-TBI. Moreover, administration of THSG also dramatically decreased the brain lesion volume. THSG reduced TBI-induced neuronal apoptosis in the brain cortex 24 h after TBI. Furthermore, THSG increased the number of immature neurons in the subgranular zone (SGZ) of the dentate gyrus (DG) of the hippocampus. Our results demonstrate that THSG exerts neuroprotective effects on glutamate-induced excitotoxicity and glial and neuronal cell death. The present study also demonstrated that THSG effectively protects against TBI-associated motor and cognitive impairment, at least in part, by inhibiting TBI-induced apoptosis and promoting neurogenesis.
Five-gene signature predicts acute kidney injury in early kidney transplant patients
Xia Zhai1 , Hongqiang Lou1 , Jing Hu1
doi : 10.18632/aging.203962
Volume 14, Issue 6 pp 2628—2644
Patients with acute kidney injury (AKI) show high morbidity and mortality, and a lack of effective biomarkers increases difficulty in its early detection. Weighted gene co-expression network analysis (WGCNA) detected a total of 22 gene modules and 6 miRNA modules, of which 4 gene modules and 3 miRNA modules were phenotypically co-related. Functional analysis revealed that these modules were related to different molecular pathways, which mainly involved PI3K-Akt signaling pathway and ECM-receptor interaction. The brown modules related to transplantation mainly involved immune-related pathways. Finally, five genes with the highest AUC were used to establish a diagnosis and prediction model of AKI. The model showed a high area under curve (AUC) in the training set and validation set, and their prediction accuracy for AKI was as high as 100%. Similarly, the prediction accuracy of AKI after 24 h in the 0 h transplant sample was 100%. This study may provide new features for the diagnosis and prediction of AKI after kidney transplantation, and facilitate the diagnosis and drug development of AKI in kidney transplant patients.
Clinical utility of serum fucosylated fraction of alpha-fetoprotein in the diagnostic of hepatocellular carcinoma: a comprehensive analysis with large sample size
Aibin Liu1 , Yanyan Li2 , Lin Shen3 , Liangfang Shen3 , Zhanzhan Li3,4
doi : 10.18632/aging.203963
Volume 14, Issue 6 pp 2645—2664
We conducted a comprehensive meta-analysis of the utility of AFP-L3 for the diagnosis of hepatocellular carcinoma, to provide a more accurate estimation for the clinical utility of AFP-L3. We performed online searches in five databases (PubMed, China National Knowledge Infrastructure, Wanfang, Web of Science, and Embase), from inception to December 31, 2021. Pooled sensitivity, specificity, and area under the curve (AUC) with the matching 95% confidence intervals (95% CIs) were calculated to estimate the diagnostic value of AFP-L3. Thirty-four studies were included in the meta-analysis. The pooled sensitivity was 0.70 [95% confidence interval (CI): 0.63–0.77], and the specificity was 0.91 (95% CI: 0.88–0.94). The estimated area under the curve (AUC) was 0.90 (95% CI: 0.87–0.92). The positive likelihood ratio and negative likelihood ratio were 7.78 (95% CI: 5.7–10.7) and 0.33 (95% CI: 0.26–0.41), respectively. The diagnostic odds ratio was 24 (95% CI: 16–37). The subgroup analysis indicated moderate sensitivity (0.79) and high specificity (0.89) for the Asian population (AUC = 0.89), and similar specificity (0.95) but lower sensitivity (0.35) for Caucasians (AUC = 0.80). Deeks’ funnel plot asymmetry test detected no publication bias (P = 0.460). The sensitivity analysis showed that the pooled results were stable. Taken together, our results indicated that AFP-L3 demonstrates high diagnostic ability for HCC, especially among Asian populations. AFP-L3 is a useful means for high-volume screening, which can help doctors optimize diagnosis workflow, reduce workload, and improve detection sensitivity. The combination of multiple biomarkers may provide more accurate diagnostic tools for HCC in the future.
Adipose-derived mesenchymal stem cells may reduce intestinal epithelial damage in ulcerative colitis by communicating with macrophages and blocking inflammatory pathways: an analysis in silico
Nan Zhang1, * , Yixuan Chen1, * , Chengyu Huang1, * , Mengxin Wei1, * , Ting Li1 , Yufeng Lv2 , Qiong Song1,3 , Shaowen Mo1,3
doi : 10.18632/aging.203964
Volume 14, Issue 6 pp 2665—2677
Ulcerative colitis is a chronic, non-specific inflammatory disease that affects mainly the colonic mucosa and submucosa. The pathogenesis of ulcerative colitis is unclear, which limits the development of effective treatments. In this study, single-cell sequencing data from 18 ulcerative colitis samples and 12 healthy controls were downloaded from the Single Cell Portal database, cell types were defined through cluster analysis, and genes in each cluster that were differentially expressed in ulcerative colitis were identified. These genes were enriched in functional pathways related to apoptosis, immunity and inflammation. Analysis using iTALK software suggested extensive communication among immune cells. Single-cell sequencing data from adipose-derived mesenchymal stem cells from three healthy female donors were obtained from the Sequence Read Archive database. The SingleR package was used to identify different cell types, for each of which a stemness score was calculated. Pseudotime analysis was performed to infer the trajectory of cells. SCENIC software was used to identify the gene regulatory network in adipose-derived mesenchymal stem cells, and iTALK software was performed to explore the relationship among macrophages, adipose-derived mesenchymal stem cells and enterocytes. Molecular docking confirmed the possibility of cell-cell interactions via binding between surface receptors and their ligands. The bulk data were downloaded and analyzed to validate the expression of genes. Our bioinformatics analyses suggest that ulcerative colitis involves communication between macrophages and enterocytes via ligand-receptor pairs. Our results further suggest that adipose-derived mesenchymal stem cells may alleviate ulcerative colitis by communicating with macrophages to block inflammation.
piRNA-6426 increases DNMT3B-mediated SOAT1 methylation and improves heart failure
Nier Zhong1, * , Xiting Nong2, * , Jiayu Diao1 , Guang Yang1
doi : 10.18632/aging.203965
Volume 14, Issue 6 pp 2678—2694
Purpose: Previous studies found that piRNAs could participate in disease progression by regulating DNA methylation, but there are few reports on their roles in heart failure (HF).
Effects of caloric overload before caloric restriction in the murine heart
Martin Maldonado1 , Jianying Chen1 , Huiqin Duan1 , Shuling Zhou1 , Lujun Yang2 , Mazhar Ali Raja1 , Tianhua Huang1 , Gu Jiang1 , Ying Zhong1
doi : 10.18632/aging.203967
Volume 14, Issue 6 pp 2695—2719
The beneficial effects of caloric restriction (CR) against cardiac aging and for prevention of cardiovascular diseases are numerous. However, to our knowledge, there is no scientific evidence about how a high-calorie diet (HCD) background influences the mechanisms underlying CR in whole heart tissue (WHT) in experimental murine models.
Tumor-associated macrophages related signature in glioma
Lin-Jian Wang1,2,3, * , Yimeng Xue2, * , Yongli Lou3
doi : 10.18632/aging.203968
Volume 14, Issue 6 pp 2720—2735
Background: Glioma is the most common malignant primary tumor with a poor prognosis. Infiltration of tumor-associated macrophages (TAMs) is a hallmark of glioma. However, the regulatory mechanism of TAMs and the prognostic value of related signature in glioma remain unclear.
The association between rs1260326 with the risk of NAFLD and the mediation effect of triglyceride on NAFLD in the elderly Chinese Han population
Fan Yuan1, * , Zhan Gu2, * , Yan Bi1 , Ruixue Yuan1 , Weibo Niu1 , Decheng Ren1 , Lei Zhang2 , Guang He1 , Bao-Cheng Liu2
doi : 10.18632/aging.203970
Volume 14, Issue 6 pp 2736—2747
Background: Accumulated studies have pointed out the striking association between variants in or near APOC3, GCKR, PNPLA3, and nonalcoholic fatty liver disease (NAFLD) at various ages from multiple ethnic groups. This association remained unclear in the Chinese Han elderly population, and whether this relationship correlated to any clinical parameters was also unclear.
Ischemic postconditioning protects nonculprit coronary arteries against ischemia-reperfusion injury via downregulating miR-92a, miR-328 and miR-494
Jian Wang1 , Wu Wang2 , Chengying Yan2 , Tianzhen Wang3
doi : 10.18632/aging.203971
Volume 14, Issue 6 pp 2748—2757
Background: Nonculprit lesions are closely related to the prognosis of patients with ST-segment elevation myocardial infarction (STEMI). Our previous research found that ischemic postconditioning (IP) could inhibit the progression of nonculprit lesions. However, the mechanism by which IP regulates the occurrence and development of nonculprit lesions remains unclear.
GSDMs are potential therapeutic targets and prognostic biomarkers in clear cell renal cell carcinoma
Lei Yao1, * , Juanni Li2, * , Zhijie Xu2 , Yuanliang Yan3,4 , Kuan Hu1
doi : 10.18632/aging.203973
Volume 14, Issue 6 pp 2758—2774
GSDM family is a group of critical proteins that mediate pyroptosis and plays an important role in cell death and inflammation. However, their specific function in clear cell renal cell carcinoma (ccRCC, KIRC) have not been clarified comprehensively. In this study, we assessed the roles of the GSDM family in expression, prognostic value, functional enrichment analysis, genetic alterations, immune infiltration and DNA methylation in ccRCC patients by using different bioinformatics databases. We found that the expression levels of GADMA-E were significantly higher in ccRCC tissues compared with normal tissues, while the expression level of PJVK was decreased. Moreover, survival analysis indicated that upregulation of GSDME was related to poor overall survival (OS) and recurrence-free survival (RFS) of ccRCC patients. The main function of differentially expressed GSDM homologs was related to ion transport. We also found that the expression profiles of the GSDM family were highly correlated with infiltrating immune cells (i.e., CD8+ T cells, CD4+ T cells, B cells, macrophages, neutrophils and dendritic cells), and there were significant differences in the expression of GSDM family in different ccRCC immune subtypes. Furthermore, DNA methylation analysis indicated that the DNA methylation levels of GSDMA/B/D/E were decreased, while the DNA methylation level of PJVK was increased. In conclusion, this study provides integrated information about abnormal GSDM family members as potential biomarkers for the diagnosis and prognosis of ccRCC. Especially, GSDME was a potential clinical target and prognostic biomarkers for patients with ccRCC.
Construction and evaluation of a nomogram for predicting survival in patients with lung cancer
Jin Ouyang1,2,3 , Zhijian Hu4 , Jianlin Tong4 , Yong Yang3 , Juan Wang3 , Xi Chen3 , Ting Luo1 , Shiqun Yu1 , Xin Wang1 , Shaoxin Huang1,3,5
doi : 10.18632/aging.203974
Volume 14, Issue 6 pp 2775—2792
Background: Lung cancer is a heterogeneous disease with a severe disease burden. Because the prognosis of patients with lung cancer varies, it is critical to identify effective biomarkers for prognosis prediction.
Local anesthetic levobupivacaine inhibits stemness of osteosarcoma cells by epigenetically repressing MAFB though reducing KAT5 expression
Zhan Wang1,2 , Yuxin Song1,2 , Hui Zhang2 , Yang Yang2 , Suifeng Zhang2 , Wenji Wang1
doi : 10.18632/aging.203975
Volume 14, Issue 6 pp 2793—2804
Osteosarcoma is the most prevalent bone cancer and accounts for over half of sarcomas. In this study, we identified that the treatment of levobupivacaine suppressed proliferation of osteosarcoma cells in vitro. The tumor xenograft analysis showed that levobupivacaine significantly repressed the osteosarcoma cell growth in the nude mice. The treatment of levobupivacaine improved the apoptosis rate and attenuated invasion and migration abilities of osteosarcoma cells. The sphere formation capabilities of osteosarcoma cells were repressed by levobupivacaine. The protein levels of Sox-2, Oct3/4, and Nanog were inhibited by the treatment of levobupivacaine in osteosarcoma cells. Regarding mechanism, we identified that levobupivacaine inhibited MAFB and KAT5 expression in osteosarcoma cells. We observed that lysine acetyltransferase 5 could enriched in the promoter region of MAF BZIP transcription factor B, while levobupivacaine treatment could repressed the enrichment. The suppression of KAT5 by siRNA repressed the enrichment of histone H3 acetylation at lysine 27 and RNA polymerase II on promoter of MAFB. The expression of MAFB was decreased by KAT5 knockdown in osteosarcoma cells. The expression of MAFB was repressed by levobupivacaine, while the overexpression of KAT5 could reverse the repression of MAFB. KAT5 contributes to the cell proliferation and stemness of osteosarcoma cells. The overexpression of KAT5 or MAFB could reverse levobupivacaine-attenuated cell proliferation and stemness of osteosarcoma cells. Therefore, we concluded that local anesthetic levobupivacaine inhibited stemness of osteosarcoma cells by epigenetically repressing MAFB though reducing KAT5 expression. Levobupivacaine may act as a potential therapeutic candidate for osteosarcoma by targeting cancer stem cells.
Altered regional brain white matter in dry eye patients: a brain imaging study
Yun-Qing Luo1, * , Rong-Bin Liang2, * , San-Hua Xu2, * , Yi-Cong Pan2 , Qiu-Yu Li2 , Hui-Ye Shu2 , Min Kang2 , Pin Yin2 , Li-Juan Zhang2 , Yi Shao2
doi : 10.18632/aging.203976
Volume 14, Issue 6 pp 2805—2818
This study aimed to investigate the regional changes of brain white matter (WM) in DE patients using diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI). A total of 25 dry eye patients (PAT) and 25 healthy controls (HC) were recruited. All subjects underwent DTI and NODDI, fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), isotropic volume fraction (FISO), intra-cellular volume fraction (FICVF), and orientation dispersion index (ODI) were obtained respectively. Then complete Hospital Anxiety and Depression Scale (HADS), anxiety score (AS) or depression scores (DS) were obtained. Receiver operating characteristic (ROC) curve analysis was used to evaluate the reliability of DTI and NODDI in distinguishing the two groups. DTI revealed that PAT had lower FA in both the left superior longitudinal fasciculus (LSLF) and the corpus callosum (CC), and higher MD in the LSLF, the right posterior limb of the internal capsule and the right posterior thalamic radiation. PAT had significant AD changes in regions including the genu of the CC, the right posterior limb of internal capsule, and the right splenium of the CC. From NODDI, PAT showed increased ODI in the LSLF and increased FISO in the right splenium of the CC. FICVF showed a significant decrease in the LSLF while increased in the left anterior corona radiata and the CC. Furthermore, the average values of MD and FICVF were significantly correlated with DS and AS. Hence the results of this study suggest that there are regional changes in WM in DE patients which may contribute to further understanding of the pathological mechanism of DE.
Next-generation sequencing identifies HOXA6 as a novel oncogenic gene in low grade glioma
Jiang Xiulin1,4, * , Chunyan Wang1, * , Jishu Guo5, * , Chenyang Wang1 , Chenglong Pan1 , Zhi Nie2,3,4
doi : 10.18632/aging.203977
Volume 14, Issue 6 pp 2819—2854
Background: Low grade glioma is one of the most common lethal cancers in the human nervous system. Emerging evidence has demonstrated that homeobox A cluster (HOXA) gene family plays a critical role in the transcriptional regulation as well as cancer initiation and progression. However, the expression, biological functions and upstream regulatory mechanism of 11 HOXAs in low grade glioma are not yet clear.
Cyclin B2 overexpression promotes tumour growth by regulating jagged 1 in hepatocellular carcinoma
Yening Xiao1 , Jiamei Ma1 , Chunliu Guo1 , Danni Liu1 , Jing Pan1 , Xiaoxi Huang1
doi : 10.18632/aging.203979
Volume 14, Issue 6 pp 2855—2867
Background: Our previous study showed that Cyclin B2 (CCNB2) is closely related to the occurrence and progression of hepatocellular carcinoma (HCC).
TP53/BRAF mutation as an aid in predicting response to immune-checkpoint inhibitor across multiple cancer types
Jia-Zheng Cao1, * , Gao-Sheng Yao2, * , Fei Liu3, * , Yi-Ming Tang2 , Peng-Ju Li2 , Zi-Hao Feng2 , Jun-Hang Luo2 , Jin-Huan Wei2
doi : 10.18632/aging.203980
Volume 14, Issue 6 pp 2868—2879
Immunotherapy with checkpoint inhibitors, such as PD-1/PD-L1 blockage, is becoming standard of practice for an increasing number of cancer types. However, the response rate is only 10%-40%. Thus, identifying biomarkers that could accurately predict the ICI-therapy response is critically important. We downloaded somatic mutation data for 46,697 patients and tumor-infiltrating immune cells levels data for 11070 patients, then combined TP53 and BRAF mutation status into a biomarker model and found that the predict ability of TP53/BRAF mutation model is more powerful than some past models. Commonly, patients with high-TMB status have better response to ICI therapy than patients with low-TMB status. However, the genotype of TP53MUTBRAFWT in high-TMB status cohort have poorer response to ICI therapy than the genotype of BRAFMUTTP53WT in low-TMB status (Median, 18 months vs 47 month). Thus, TP53/BRAF mutation model can add predictive value to TMB in identifying patients who benefited from ICI treatment, which can enable more informed treatment decisions.
A systematic pan-cancer study demonstrates the oncogenic function of heterogeneous nuclear ribonucleoprotein C
Chenxi Pan1,2 , Qian Wu1 , Nianjie Feng1
doi : 10.18632/aging.203981
Volume 14, Issue 6 pp 2880—2901
Although complex links between heterogeneous nuclear ribonucleoprotein C (HNRNPC) and numerous types of cancer have been shown in both cell and animal models, a comprehensive pan-cancer investigation on the features and activities of HNRNPC is still lacking. Based on the Cancer Genome Atlas and Gene Expression Omnibus datasets, we investigated the possible oncogenic effects of HNRNPC in thirty-three cancers. HNRNPC expression was detected in the majority of cancers, and its expression level was shown to be significantly linked with cancer patient prognosis. HNRNPC increased the phosphorylation of S220, which was detected in various cancers, including ovarian cancer and colon cancer. HNRNPC expression was also shown to be related to cancer-associated cell infiltration, most notably in uveal melanoma, testicular germ cell tumors, and thymoma. Additionally, the signaling pathway for vascular endothelial growth factors and RNA transport were implicated in HNRNPC's functioning processes. In short, HNRNPC may further influence cancer progression through gene mutation, protein phosphorylation, cancer associated fibroblasts infiltration and related molecular pathways. This work was intended to provide a relatively thorough knowledge of the oncogenic activities of HNRNPC across a variety of tumor types by performing a systematic pan-cancer investigation.
Mitophagy and mitochondrial dynamics in type 2 diabetes mellitus treatment
Zhao Shan1 , Wei Hong Fa1 , Chen Run Tian1 , Chen Shi Yuan1 , Ning Jie1
doi : 10.18632/aging.203969
Volume 14, Issue 6 pp 2902—2919
The prevalence of type 2 diabetes is associated with inflammatory bowels diseases, nonalcoholic steatohepatitis and even a spectrum of cancer such as colon cancer and liver cancer, resulting in a substantial healthcare burden on our society. Autophagy is a key regulator in metabolic homeostasis such as lipid metabolism, energy management and the balance of cellular mineral substances. Mitophagy is selective autophagy for clearing the damaged mitochondria and dysfunctional mitochondria. A myriad of evidence has demonstrated a major role of mitophagy in the regulation of type 2 diabetes and metabolic homeostasis. It is well established that defective mitophagy has been linked to the development of insulin resistance. Moreover, insulin resistance is further progressed to various diseases such as nephropathy, retinopathy and cardiovascular diseases. Concordantly, restoration of mitophagy will be a reliable and therapeutic target for type 2 diabetes. Recently, various phytochemicals have been proved to prevent dysfunctions of β-cells by mitophagy inductions during diabetes developments. In agreement with the above phenomenon, mitophagy inducers should be warranted as potential and novel therapeutic agents for treating diabetes. This review focuses on the role of mitophagy in type 2 diabetes relevant diseases and the pharmacological basis and therapeutic potential of autophagy regulators in type 2 diabetes.
Correction for: Long non-coding RNA PVT1 encapsulated in bone marrow mesenchymal stem cell-derived exosomes promotes osteosarcoma growth and metastasis by stabilizing ERG and sponging miR-183-5p
Wei Zhao1 , Pan Qin1 , Da Zhang1 , Xichun Cui1 , Jing Gao1 , Zhenzhu Yu1 , Yuting Chai1 , Jiaxiang Wang1 , Juan Li2
doi : 10.18632/aging.203990
Volume 14, Issue 6 pp 2920—2922
Correction for: The effects of psyllium husk on gut microbiota composition and function in chronically constipated women of reproductive age using 16S rRNA gene sequencing analysis
Chuanli Yang1, * , Shuai Liu2, * , Hongxia Li3 , Xinshu Bai2 , Shuhua Shan4 , Peng Gao5 , Xiushan Dong1
doi : 10.18632/aging.203991
Volume 14, Issue 6 pp 2923
