CKB Promotes Mitochondrial ATP Production by Suppressing Permeability Transition Pore.

Creatine kinases are essential for maintaining cellular energy balance by facilitating the reversible transfer of a phosphoryl group from ATP to creatine, however, their role in mitochondrial ATP production remains unknown. This study shows creatine kinases, including CKMT1A, CKMT1B, and CKB, are highly expressed in cells relying on the mitochondrial F1F0 ATP synthase for survival. Interestingly, silencing CKB, but not CKMT1A or CKMT1B, leads to a loss of sensitivity to the inhibition of F1F0 ATP synthase in these cells. Mechanistically, CKB promotes mitochondrial ATP but reduces glycolytic ATP production by suppressing mitochondrial calcium (mCa2+) levels, thereby preventing the activation of mitochondrial permeability transition pore (mPTP) and ensuring efficient mitochondrial ATP generation. Further, CKB achieves this regulation by suppressing mCa2+ levels through the inhibition of AKT activity. Notably, the CKB-AKT signaling axis boosts mitochondrial ATP production in cancer cells growing in a mouse tumor model. Moreover, this study also uncovers a decline in CKB expression in peripheral blood mononuclear cells with aging, accompanied by an increase in AKT signaling in these cells. These findings thus shed light on a novel signaling pathway involving CKB that directly regulates mitochondrial ATP production, potentially playing a role in both pathological and physiological conditions.

Quercetin promotes the proportion and maturation of NK cells by binding to MYH9 and improves cognitive functions in aged mice.

BACKGROUND: Quercetin is a flavonol compound widely distributed in plants that possesses diverse biological properties, including antioxidative, anti-inflammatory, anticancer, neuroprotective and senescent cell-clearing activities. It has been shown to effectively alleviate neurodegenerative diseases and enhance cognitive functions in various models. The immune system has been implicated in the regulation of brain function and cognitive abilities. However, it remains unclear whether quercetin enhances cognitive functions by interacting with the immune system. RESULTS: In this study, middle-aged female mice were administered quercetin via tail vein injection. Quercetin increased the proportion of NK cells, without affecting T or B cells, and improved cognitive performance. Depletion of NK cells significantly reduces cognitive ability in mice. RNA-seq analysis revealed that quercetin modulated the RNA profile of hippocampal tissues in aging animals towards a more youthful state. In vitro, quercetin significantly inhibited the differentiation of Lin-CD117+ hematopoietic stem cells into NK cells. Furthermore, quercetin promoted the proportion and maturation of NK cells by binding to the MYH9 protein. CONCLUSIONS: In summary, our findings suggest that quercetin promotes the proportion and maturation of NK cells by binding to the MYH9 protein, thereby improving cognitive performance in middle-aged mice.

Safety and efficacy of umbilical cord tissue-derived mesenchymal stem cells in the treatment of patients with aging frailty: a phase I/II randomized, double-blind, placebo-controlled study.

BACKGROUND: Mesenchymal stem cells (MSCs) hold a great promise for cell-based therapy in the field of regenerative medicine. In this study, we aimed to evaluate the safety and efficacy of intravenous infusion of human umbilical cord-derived MSCs (HUC-MSCs) in patients with aging frailty. METHODS: In this randomized, double-blind, placebo-controlled trial, participants diagnosed with aging frailty were randomly assigned to receive intravenous administrations of HUC-MSCs or placebo. All of serious adverse events and AEs were monitored to evaluate the safety of treatment during the 6-month follow-up. The primary efficacy endpoint was alteration of physical component scores (PCS) of SF-36 qualities of life at 6 months. The secondary outcomes including physical performance tests and pro-inflammatory cytokines, were also observed and compared at each follow-up visits. All evaluations were performed at 1 week, 1, 2, 3 and 6 months following the first intravenous infusion of HUC-MSCs. RESULTS: In the MSCs group, significant improvements in PCS of SF-36 were observed from first post-treatment visit and sustained throughout the follow-up period, with greater changes compared to the placebo group (p = 0.042). EQ-VAS scores of MSCs group improved significantly at 2 month (p = 0.023) and continued until the end of the 6-month visit (p = 0.002) in comparison to the placebo group. The timed up and go (TUG) physical performance test revealed significant group difference and showed continual enhancements over 6 months (p < 0.05). MSC transplantation improved the function of 4-m walking test (4MWT) compared with the placebo group with a decrease of 2.05 s at 6 months of follow-up (p = 0.21). The measurement of grip strength revealed group difference with MSCs group demonstrating better performance, particularly at 6 months (p = 0.002). Inflammatory cytokines (TNF-α, IL-17) exhibited declines in MSCs group at 6 months compared to the placebo group (p = 0.034 and 0.033, respectively). There was no difference of incidence of AEs between the two groups. CONCLUSION: Intravenous transplantation of HUC-MSCs is a safe and effective therapeutic approach on aging frailty. The positive outcomes observed in improving quality of life, physical performance, and reducing chronic inflammation, suggest that HUC-MSC therapy may be a promising potential treatment option for aging frailty. TRIAL REGISTRATION: Clinicaltrial.gov; NCT04314011; https://clinicaltrials.gov/ct2/show/NCT04314011 .

Photobiomodulation with 630-nm LED Inhibits M1 Macrophage Polarization via STAT1 Pathway Against Sepsis-Induced Acute Lung Injury.

Background: Sepsis-induced acute lung injury (ALI) is a clinical syndrome characterized by excessive uncontrolled inflammation. Photobiomodulation such as light-emitting diode (LED) irradiation has been used to attenuate inflammatory disease. Objective: The protective effect of 630 nm LED irradiation on sepsis-induced ALI remains unknown. The purpose of this study was to investigate the role of 630 nm LED irradiation in sepsis-induced ALI and its underlying mechanism. Methods and results: C57BL/6 mice were performed cecal ligation and puncture (CLP) for 12 h to generate experimental sepsis models. Histopathology analysis showed that alveolar injury, inflammatory cells infiltration, and hemorrhage were suppressed in CLP mice after 630 nm LED irradiation. The ratio of wet/dry weigh of lung tissue was significantly inhibited by irradiation. The number of leukocytes was reduced in bronchoalveolar lavage fluid. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) results and enzyme-linked immunosorbent assay showed that 630 nm LED irradiation significantly inhibited the mRNA and protein levels of M1 macrophage-related genes in the lung of CLP-induced septic mice. Meanwhile, LED irradiation significantly inhibited signal transducer and activator of transcription 1 (STAT1) phosphorylation in the lung of septic mice. In vitro experiments showed that 630 nm LED irradiation significantly inhibited M1 genes mRNA and protein expression in THP-1-derived M1 macrophages without affecting the cell viability. LED irradiation also significantly inhibited the level of STAT1 phosphorylation in THP-1-derived M1 macrophages. Conclusions: We concluded that 630 nm LED is promising as a treatment against ALI through inhibiting M1 macrophage polarization, which is associated with the downregulation of STAT1 phosphorylation.

BMP4 up-regulated by 630 nm LED irradiation is associated with the amelioration of rheumatoid arthritis.

Rheumatoid arthritis (RA) is caused by inflammatory response of joints with cartilage and damage of synovium and bone erosion. In our previous studies, it has showed that irradiation of 630 nm LED reduce inflammation of synovial fibroblasts and cartilage and bone destruction in RA. However, the key genes and mechanism in ameliorating RA by irradiation of 630 nm LED remains unknown. In this study, human fibroblast-like synoviocytes (FLS) cell line MH7A and primary human RA-FLSs were treated with TNF-α and 630 nm LED irradiation with the different energy density. The mRNA sequencing was performed to screen the differentially expressed genes (DEGs). In all datasets, 10 DEGs were identified through screening. The protein interaction network analysis showed that 8 out of the 10 DEGs interacted with each other including IL-6, CXCL2, CXCL3, MAF, PGF, IL-1RL1, RRAD and BMP4. This study focused on BMP4, which is identified as important morphogens in regulating the development and homeostasis. CCK-8 assay results showed that 630 nm LED irradiation did not affect the cell viability. The qPCR and ELISA results showed that TNF-α stimulation inhibited BMP4 mRNA and protein level and irradiation of 630 nm LED increased the BMP4 mRNA and protein level in MH7A cells. In CIA and transgenic hTNF-α mice models, H&E staining showed that irradiation of 630 nm LED decreased the histological scores assessed from inflammation and bone erosion, while BMP4 expression level was up-regulated after 630 nm LED irradiation. Pearson correlation analysis shown that BMP4 protein expression was negatively correlated with the histological score of CIA mice and transgenic hTNF-α mice. These results indicated that BMP4 increased by irradiation of 630 nm LED was associated with the amelioration of RA, which suggested that BMP4 may be a potential targeting gene for photobiomodulation.

Mutual regulation between GDF11 and TET2 prevents senescence of mesenchymal stem cells.

Growth differentiation factor 11 (GDF11) is a putative systemic rejuvenation factor. In this study, we characterized the mechanism by which GDF11 reversed aging of mesenchymal stem cells (MSCs). In culture, aged MSCs proliferate slower and are positive for senescence markers senescence-associated ß-galactosidase and P16ink4a . They have shortened telomeres, decreased GDF11 expression, and reduced osteogenic potential. GDF11 can block MSC aging in vitro and reverse age-dependent bone loss in vivo. The antiaging effect of GDF11 is via activation of the Smad2/3-PI3K-AKT-mTOR pathway. Unexpectedly, GDF11 also upregulated a DNA demethylase Tet2, which served as a key mediator for GDF11 to autoregulate itself via demethylation of the GDF11 promoter. Mutation of Tet2 facilitates MSC aging by blocking GDF11 expression. Mutagenesis of Tet2-regulated CpG sites also blocks GDF11 expression, leading to MSC aging. Together, a novel mutual regulatory relationship between GDF11 and an epigenetic factor Tet2 unveiled their antiaging roles.

Astragaloside IV antagonizes the malignant progression of breast cancer induced by macrophage M2 polarization through the TGF-ß-regulated Akt/Foxo1 pathway.

BACKGROUND: Astragaloside IV (AS­IV) was used for breast cancer (BC) treatment in China from ancient times; however, the mechanism of the prevention effect of AS-IV on BC remains not entirely clear. METHODS: qRT-PCR, western blot and flow cytometry were employed to validate the expression of gene and protein expressions. CCK-8 assay, scratch assay, and transwell assay were used to assess the BC cell proliferation, migration, and invasion. Co-culture of conditional medium from macrophages and BC were performed. RESULTS: AS-IV suppressed macrophage polarized to M2 phenotype and thereby inhibited M2 macrophage-induced BC progression. The inhibitory effect of AS-IV on M2 macrophage polarization was exerted via the deactivation of the Akt/Foxo1 signaling pathway in macrophages by suppressing TGF-ß. The addition of TGF-ß or the treatment with Akt activator SC79 reversed the regulatory effect of AS-IV on M2 macrophage polarization, which increased M2 macrophage polarization-induced BC cell proliferation, migration and invasion. CONCLUSION: This present study revealed a new mechanism of AS-IV inhibited M2 macrophage polarization-induced BC progression and may provide a potential target for the treatment of BC.

LED irradiation at 630 nm alleviates collagen-induced arthritis in mice by inhibition of NF-κB-mediated MMPs production.

Matrix metallopreteinase (MMP), a family of matrix degrading enzyme, plays a significant role in persistent and irreversible joint damage in rheumatoid arthritis (RA). Photobiomodulatory therapy (PBMT) has become an emerging adjunct therapy for RA. However, the molecular mechanism of PBMT on RA remains unclear. The purpose of this study is to explore the effect of 630 nm light emitting diode (LED) irradiation on RA and its underly molecular mechanism. Arthritis clinic scores, histology analysis and micro-CT results show that 630 nm LED irradiation ameliorates collagen-induced arthritis (CIA) in mice with the reduction of the extents of paw swelling, inflammation and bone damage. 630 nm LED irradiation significantly reduces MMP-3 and MMP-9 levels and inhibits p65 phosphorylation level in the paws of CIA mice. Moreover, 630 nm LED irradiation significantly inhibits the mRNA and protein levels of MMP-3 and MMP-9 in TNF-α-treated MH7A cells, a human synovial cell line. Importantly, 630 nm LED irradiation reduces TNF-α-induced the phosphorylated level of p65 but not alters STAT1, STAT3, Erk1/2, JNK and p38 phosphorylation levels. Immunofluorescence result showed that 630 nm LED irradiation blocks p65 nuclear translocation in MH7A cells. In addition, other MMPs mRNA regulated by NF-κB were also significantly inhibited by LED irradiation in vivo and in vitro. These results indicates that 630 nm LED irradiation reduces the MMPs levels to ameliorate the development of RA by inhibiting the phosphorylation of p65 selectively, suggesting that 630 nm LED irradiation may be a beneficial adjunct therapy for RA.Graphical abstract.

The rules and regulatory mechanisms of FOXO3 on inflammation, metabolism, cell death and aging in hosts.

The FOX family of transcription factors was originally identified in 1989, comprising the FOXA to FOXS subfamilies. FOXO3, a well-known member of the FOXO subfamily, is widely expressed in various human organs and tissues, with higher expression levels in the ovary, skeletal muscle, heart, and spleen. The biological effects of FOXO3 are mostly determined by its phosphorylation, which occurs in the nucleus or cytoplasm. Phosphorylation of FOXO3 in the nucleus can promote its translocation into the cytoplasm and inhibit its transcriptional activity. In contrast, phosphorylation of FOXO3 in the cytoplasm leads to its translocation into the nucleus and exerts regulatory effects on biological processes, such as inflammation, aerobic glycolysis, autophagy, apoptosis, oxidative stress, cell cycle arrest and DNA damage repair. Additionally, FOXO3 isoform 2 acts as an important suppressor of osteoclast differentiation. FOXO3 can also interfere with the development of various diseases, including inhibiting the proliferation and invasion of tumor cells, blocking the production of inflammatory factors in autoimmune diseases, and inhibiting ß-amyloid deposition in Alzheimer's disease. Furthermore, FOXO3 slows down the aging process and exerts anti-aging effects by delaying telomere attrition, promoting cell self-renewal, and maintaining genomic stability. This review suggests that changes in the levels and post-translational modifications of FOXO3 protein can maintain organismal homeostasis and improve age-related diseases, thus counteracting aging. Moreover, this may indicate that alterations in FOXO3 protein levels are also crucial for longevity, offering new perspectives for therapeutic strategies targeting FOXO3.

Akkermansia muciniphila, which is enriched in the gut microbiota by metformin, improves cognitive function in aged mice by reducing the proinflammatory cytokine interleukin-6.

BACKGROUND: Metformin, a type 2 diabetes treatment, improves the cognitive function of aged mice; however, whether the protective effects of metformin on cognitive function in aged mice are associated with the gut microbiome is poorly understood. Although some studies suggest that the gut microbe composition influences cognitive function and that manipulating the gut microbiota might protect against age-related cognitive dysfunction, there is no direct evidence to validate that the gut microbiota mediates the effect of metformin on cognitive improvement. RESULTS: In this study, we show that the gut microbiota is altered by metformin, which is necessary for protection against ageing-associated cognitive function declines in aged mice. Mice treated with antibiotics did not exhibit metformin-mediated cognitive function protection. Moreover, treatment with Akkermansia muciniphila, which is enriched by metformin, improved cognitive function in aged mice. Mechanistically, A. muciniphila decreased pro-inflammatory-associated pathways, particularly that of the pro-inflammatory cytokine interleukin (IL)-6, in both the peripheral blood and hippocampal profiles, which was correlated with cognitive function improvement. An IL-6 antibody protected cognitive function, and an IL-6 recombinant protein abolished the protective effect of A. muciniphila on cognitive function in aged mice. CONCLUSION: This study reveals that A. muciniphila, which is mediated in the gut microbiota by metformin, modulates inflammation-related pathways in the host and improves cognitive function in aged mice by reducing the pro-inflammatory cytokine IL-6. Video Abstract.

Glycyrrhizic acid inhibits myeloid differentiation of hematopoietic stem cells by binding S100 calcium binding protein A8 to improve cognition in aged mice.

BACKGROUND: Glycyrrhizic acid (GA), a saponin compound often used as a flavoring agent, can elicit anti-inflammatory and anti-tumor effects, and alleviate aging. However, the specific mechanism by which GA alters immune cell populations to produce these beneficial effects is currently unclear. RESULTS: In this study, we systematically analyzed single-cell sequencing data of peripheral blood mononuclear cells from young mice, aged mice, and GA-treated aged mice. Our in vivo results show that GA reduced senescence-induced increases in macrophages and neutrophils, and increased numbers of lymphoid lineage subpopulations specifically reduced by senescence. In vitro, GA significantly promoted differentiation of Lin-CD117+ hematopoietic stem cells toward lymphoid lineages, especially CD8+ T cells. Moreover, GA inhibited differentiation of CD4+ T cells and myeloid (CD11b+) cells by binding to S100 calcium-binding protein 8 (S100A8) protein. Overexpression of S100A8 in Lin- CD117+ hematopoietic stem cells enhanced cognition in aged mice and the immune reconstitution of severely immunodeficient B-NDG (NOD.CB17-Prkdcscid/l2rgtm1/Bcgen) mice. CONCLUSIONS: Collectively, GA exerts anti-aging effects by binding to S100A8 to remodel the immune system of aged mice.

Virtual reality distraction, a novel tool for pain alleviation during dressing change following surgical drainage of perianal abscess at Day Treatment Centre.

Background: The pain induced by postoperative dressing changes adversely influence recovery and quality of life. In this study, we try to evaluate the pain alleviation effect of virtual reality (VR) distraction during postoperative dressing changes of patients who received surgical drainage of perianal abscess. Methods: This was a prospective, randomized clinical trial. A total of 172 patients with perianal abscess were randomly assigned into control (only analgesics) and VR groups (VR distraction + analgesics). The pain and physiological measurements of all patients were collected before, during, and after the first dressing change following surgery. The difference in pain intensity and physiological parameters measurement between control and VR group was analyzed. Results: The baseline characteristics of VR and control group were comparable (all P > 0.05). There was no significant difference in mean pain scores prior to and after dressing change between groups (both P > 0.05). Mean pain scores of 5, 10, 15, and 20 min measuring points during the first dressing change were significantly lower in the VR group compared with the control group (all P < 0.05). Pulse rates and oxygen saturation were not significantly different between groups. Conclusion: VR can be used as an effective adjuvant pain distraction approach for postoperative dressing change.

Heat Shock Protein Is Associated with Inhibition of Inflammatory Cytokine Production by 630 nm Light-Emitting Diode Irradiation in Fibroblast-Like Synoviocytes Based on RNA Sequencing Analysis.

Background: Inflammatory cytokine secretion from fibroblast-like synoviocytes (FLS) plays a vital role in the pathological process of rheumatoid arthritis (RA). Photobiomodulation (PBM) has been widely used in the treatment of RA. However, the mechanism of PBM in RA has not been clarified. Objective: In this study, we investigated the underlying mechanism of 630 nm light-emitting diode (LED) irradiation on anti-inflammation using mRNA sequencing analysis. Methods and results: Reverse transcription (RT)-quantitative polymerase chain reaction (RT-qPCR) results showed that 630 nm LED irradiation significantly inhibited interleukin (IL)-1ß, IL-6, and IL-8 mRNA expression in rheumatoid arthritis fibroblast synovial cells (RA-FLS) and MH7A cells. A total of 1730 differentially expressed genes (DEGs) were identified between tumor necrosis factor α (TNF-α)+LED and TNF-α-treated RA-FLS and 1219 DEGs in MH7A cells by mRNA sequencing analysis. A total of 646 intersecting DEGs from the 2 cell models were used for gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses. Protein-protein interaction (PPI) network of DEGs was used, and 502 nodes and 1452 edges were found. A total of 14 clusters were generated in MCODE, and the top 3 clusters were selected as hub modules. PPI network showed that most of the nodes were DEGs of the heat shock protein (HSP) family. RT-qPCR verified that 630 nm LED irradiation significantly increased HSP70 mRNA expression in FLS. Conclusions: Taken together, our results revealed the correlation between HSP70 and the inhibition of inflammation caused by 630 nm LED irradiation. These findings suggested that HSP may be a novel target of 630 nm LED irradiation to alleviate inflammation in the treatment of RA.

Prognostic association between NLRP3 inflammasome expression level and operable pancreatic adenocarcinoma.

BACKGROUND: The NLRP3 inflammasome is significantly associated with tumor development and metastasis in various malignancies. However, the significance of the NLRP3 inflammasome in pancreatic adenocarcinoma has not been fully determined. Therefore, we try to evaluate the expression of the NLRP3 inflammasome in pancreatic adenocarcinoma and analyzed its prognostic significance. METHODS: This cohort study enrolled 98 patients with primary pancreatic adenocarcinoma who received curative surgery. The NLRP3 inflammasome expression levels in cancer tissue were determined by immunohistochemistry, and compared with that of adjacent normal tissues. The association between NLRP3 inflammasome expression levels and baseline clinicopathological characteristics were also analyzed. Moreover, the correlation between NLRP3 inflammasome expression levels and survival was analyzed by log-rank test, and the survival curve was made by the Kaplan-Meier survival analysis. RESULTS: Expression of each NLRP3 inflammasome component in cancer tissue was higher than that in the adjacent normal tissues (all P < 0.05), including NLRP3, IL-1ß, ASC, and Caspase-1. All four components of the NLRP3 inflammasome were closely associated with clinical stage and lymph node status (all P < 0.05). The Kaplan-Meier log rank test showed that the high expression level of the NLRP3 inflammasome was significantly related to poor overall survival in pancreatic adenocarcinoma patients. CONCLUSIONS: NLRP3 inflammasome expression was upregulated in cancer tissue and closely associated with the prognosis of operable pancreatic adenocarcinoma.

Web Crawling and mRNA Sequencing Analyze Mechanisms of Photobiomodulation.

Background: Photobiomodulation (PBM) is praised as a promising physical therapy, which has many advantages, such as being noninvasive and painless. However, the mechanisms are not fully elucidated. Methods: Using web crawling, mRNA sequence, and bioinformatics analysis, we selected genes, functional annotation, and mechanisms. The expressions of inflammatory cytokines were measured using quantitative real-time PCR (RT-qPCR). Results: A total of 146 human genes and 57 pathways were identified about PBM. The 630 nm light-emitting diode (LED)-stimulated-MH7A cells were sequenced to further analyze the mechanism of PBM. Two thousand nine hundred fifty differentially expressed genes were identified, and the gene ontology term enrichment analysis and Kyoto encyclopedia of genes and genomes pathway analysis were performed to better understand functions and pathways. The 12 pathways were matched with the KEGG results of PBM and MH7A cells. A protein-protein interaction network was performed among genes in 12 pathways, and 10 outstanding proteins were identified. Importantly, the 9 genes were predicted with potential research value. And we also demonstrated that expression of inflammatory factors [interleukin (IL)-6, IL-1ß, IL-8, and matrix metalloproteinase-3 (MMP-3)] was reduced; meanwhile, the expression of anti-inflammatory factor IL-10 was promoted after 630 nm LED. Conclusions: Using web crawling, bioinformatics analysis, and mRNA sequence, we obtained 9 key genes and 12 important pathways about PBM. Importantly, we demonstrated the anti-inflammatory effect of 630 nm LED red light by RT-qPCR.

A novel epithelial-mesenchymal transition-related gene signature for prognosis prediction in patients with lung adenocarcinoma.

Traditional pathological diagnoses and clinical methods are insufficient to accurately predict the prognosis of lung adenocarcinoma (LUAD). Epithelial-mesenchymal transition (EMT) process is closely related to tumor cell migration. However, the prognostic value of EMT-related genes in LUAD is still unclear. In this study, we collected bulk RNA-sequencing (RNA-seq) and microarray data of LUAD patients from public databases and identified different expressed EMT-related genes in tumor and normal tissues. Then, we used the least absolute shrinkage and selection operator Cox regression model to develop a multigene signature in the cancer genome atlas (TCGA) cohort and validated the model in the OncoSG (Singapore Oncology Data Portal) cohort as well as other datasets. Finally, we constructed a 12-gene signature to divide LUAD patients into high-risk and low-risk groups of overall survival (OS), which has a better stability and accuracy in predicating the OS of patients compared with some other published signatures of LUAD. In addition, evaluation of the risk model using the time-related receiver operating characteristic (ROC) curve confirmed the predictive ability of the model. Functional analysis showed that these genes are related to immunity. CD8 T cell and CD4 T cell types were significantly negatively correlated with the risk score in the analysis of immune infiltration. In general, our model provides useful information that may help clinicians better predict the prognosis of LUAD patients and provides potential targets for immunotherapy of LUAD.

Licochalcone A activation of glycolysis pathway has an anti-aging effect on human adipose stem cells.

Licochalcone A (LA) is a chalcone flavonoid of Glycyrrhiza inflata, which has anti-cancer, antioxidant, anti-inflammatory, and neuroprotective effects. However, no anti-aging benefits of LA have been demonstrated in vitro or in vivo. In this study, we explored whether LA has an anti-aging effect in adipose-derived stem cells (ADSCs). We performed ß-galactosidase staining and measured reactive oxygen species, relative telomere lengths, and P16ink4a mRNA expression. Osteogenesis was assessed by Alizarin Red staining and adipogenesis by was assessed Oil Red O staining. Protein levels of related markers runt-related transcription factor 2 and lipoprotein lipase were also examined. RNA sequencing and measurement of glycolysis activities showed that LA significantly activated glycolysis in ADSCs. Together, our data strongly suggest that the LA have an anti-aging effect through activate the glycolysis pathway.

Application of mesenchymal stem cell therapy for aging frailty: from mechanisms to therapeutics.

Aging frailty is a complex geriatric syndrome that becomes more prevalent with advancing age. It constitutes a major health problem due to frequent adverse outcomes. Frailty is characterized by disruption of physiological homeostasis and progressive decline of health status. Multiple factors contribute to development of frailty with advancing age, including genome instability, DNA damage, epigenetic alternations, stem cell exhaustion, among others. These interrelated factors comprehensively result in loss of tissue homeostasis and diminished reserve capacity in frailty. Therefore, the aged organism gradually represents symptoms of frailty with decline in physiological functions of organs. Notably, the brain, cardiovascular system, skeletal muscle, and endocrine system are intrinsically interrelated to frailty. The patients with frailty may display the diminished reserves capacity of organ systems. Due to the complex pathophysiology, no specific treatments have been approved for prevention of this syndrome. At such, effective strategies for intervening in pathogenic process to improve health status of frail patients are highly needed. Recent progress in cell-based therapy has greatly contributed to the amelioration of degenerative diseases related to age. Mesenchymal stem cells (MSCs) can exert regenerative effects and possess anti-inflammatory properties. Transplantation of MSCs represents as a promising therapeutic strategy to address the pathophysiologic problems of frail syndrome. Currently, MSC therapy have undergone the phase I and II trials in human subjects that have endorsed the safety and efficacy of MSCs for aging frailty. However, despite these positive results, caution is still needed with regard to potential to form tumors, and further large-scale studies are warranted to confirm the therapeutic efficacy of MSC therapy.

Licochalcone A improves the cognitive ability of mice by regulating T- and B-cell proliferation.

Licochalcone A (LA), a flavonoid found in licorice, has anticancer, antioxidant, anti-inflammatory, and neuroprotective properties. Here, we explored the effect of injecting LA into the tail vein of middle-aged C57BL/6 mice on their cognitive ability as measured by the Morris water maze (MWM) test and cerebral blood flow (CBF). The related mechanisms were assessed via RNA-seq, and T (CD3e+) and B (CD45R/B220+) cells in the spleen and whole blood were quantified via flow cytometry. LA improved the cognitive ability, according to the MWM test results, and upregulated the CBF level of treated mice. The RNA-seq results indicate that LA affected the interleukin (IL)-17 signaling pathway, which is related to T- and B-cell proliferation, and the flow cytometry data suggest that LA promoted T- and B-cell proliferation in the spleen and whole blood. We also performed immune reconstruction via a tail vein injection of lymphocytes into B-NDG (NOD-PrkdcscidIl2rgtm1/Bcge) mice before treating them with LA. We tested cognitive ability by subjecting these animals to new object recognition tests and quantified the splenic and whole blood T and B cells. Cognitive ability improved after immune reconstruction and LA treatment, and LA promoted T- and B-cell proliferation in the spleen and whole blood. This study demonstrates that LA, by activating the IL-17 signaling pathway, promotes T- and B-cell proliferation in the spleen and whole blood of mice and improves cognitive ability. Thus, LA may have immune-modulating therapeutic potential for improving cognition.

Corrigendum: Immune Cells Combined With NLRP3 Inflammasome Inhibitor Exert Better Antitumor Effect on Pancreatic Ductal Adenocarcinoma.

[This corrects the article DOI: 10.3389/fonc.2020.01378.].