Urinary C4d and progression of kidney disease in IgA vasculitis.

BACKGROUND: IgA vasculitis nephritis is the most common secondary IgA nephropathy. Urinary C4d have been identified associated with the development and progression in primary IgA nephropathy. However, its role in kidney disease progression of IgA vasculitis nephritis is still unclear. METHODS: This study enrolled 139 patients with IgA vasculitis nephritis (IgAVN), 18 healthy subjects, 23 Focal segmental glomerulosclerosis patients and 38 IgA nephropathy (IgAN) patients. Urinary C4d levels at kidney biopsy were measured using enzyme-linked immunosorbent assay. The association between urinary C4d/creatinine and kidney disease progression event, defined as 40% eGFR decline or ESKD, was assessed using Cox proportional hazards models and restricted cubic splines. RESULTS: The levels of urinary C4d/creatinine in IgAVN and IgAN patients were higher than in healthy controls. Higher levels of urinary C4d/creatinine were associated with higher proteinuria and severe Oxford C lesions and glomerular C4d deposition. After a median follow-up of 52.79 months, 18 (12.95%) participants reached composite kidney disease progression event. The risk of kidney disease progression event was higher with higher levels of ln (urinary C4d/creatinine). After adjustment for clinical data, higher levels of urinary C4d/creatinine were associated with kidney disease progression in IgA vasculitis nephritis (per ln transformed urinary C4d/creatinine, hazard ratio (HR) =1.573, 95% confidence interval (CI) 1.101-2.245; P = 0.013). Compared to the lower C4d/creatinine group, hazard ratio was 5.539(95%CI, 1.135-27.035; P = 0.034) for the higher levels group. CONCLUSIONS: Higher levels of urinary C4d/creatinine were associated with kidney disease progression event in patients IgAVN.

Relationship between intrinsic capacity and health-related quality of life among community-dwelling older adults: the moderating role of social support.

PURPOSE: To examine how social support might moderate the relationship between intrinsic capacity and health-related quality of life (HRQoL) based on the buffering model of social support. METHODS: This was a cross-sectional study with a sample of 1181 Chinese community-dwelling older adults aged ≥ 60 years in 2016. Social support was assessed using the Social Support Rating Scale. Intrinsic capacity was assessed using the revised integrated care for older people screening tool. HRQoL was measured by the 12-item Short Form Health Survey. Hierarchical linear regression analysis was implemented to test the moderating effect of social support. RESULTS: Support utilization attenuated the relationship between lower intrinsic capacity and poor physical HRQoL while subjective support attenuated the relationship between lower intrinsic capacity and poor mental HRQoL. However, objective support had no significant moderating effect on the relationship between intrinsic capacity and specific domains of HRQoL. CONCLUSION: The moderating effects of social support on the association between intrinsic capacity and HRQoL vary by support types. Effective interventions should target the perception and utilization of available support among older adults with lower intrinsic capacity to maintain their physical and mental HRQoL.

Effectiveness of interventions for informal caregivers of community-dwelling frail older adults: A systematic review and meta-analysis.

AIM: Systematic reviews on interventions for informal caregivers of community-dwelling frail older adults were published over a decade ago and they mistook frailty for other severe age-related conditions like disability and dementia. Therefore, this study aimed to systematically synthesize these interventions supporting these caregivers identified by an acknowledged frailty assessment instrument and to examine their effectiveness on caregiver-related outcomes. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Fourteen electronic databases, grey literature and reference lists were systematically searched for randomized controlled trials (RCTs) and non-randomized controlled trials (NRCTs) from inception to November 3, 2023. METHODS: Methodology quality and risk of bias were assessed. Data were meta-analysed using the Comprehensive Meta-Analysis, version 3.0. Studies and outcomes unsuitable for meta-analysis were summarized by narrative syntheses. RESULTS: Four studies consisting of three RCTs and one NRCT were included involving 350 participants. Interventions for caregivers of frail older adults included multicomponent interventions (n = 3) and education intervention (n = 1). Interventions had a moderate effect on reducing depression and showed nonsignificant effects on caregiver burden, caregiving time or quality of life (QoL). The PEDro scores for RCTs ranged from 6 to 8, indicating good methodologic quality, but were all judged as high risk of bias. The NRCT reported all methodologic aspects and was at low risk of bias. CONCLUSIONS: Few studies focus on interventions targeting caregivers of frail older adults, and their effectiveness may vary by outcomes. This review suggested the potential benefits of these interventions in reducing caregivers' depression. IMPACT: The differential effectiveness by outcomes and high risk of bias of studies implicate that more rigorous studies are warranted.

Joint trajectories of loneliness, social isolation and sarcopenia and associations with adverse outcomes: A prospective cohort study.

This study aimed to examine joint trajectories of loneliness, social isolation and sarcopenia and their associations with adverse outcomes. A total of 4701 participants aged ≥60 years who had a baseline and at least one follow-up assessment of loneliness, social isolation and sarcopenia across 2011, 2013 and 2015 waves in China Health and Retirement Longitudinal Study. Adverse outcomes were obtained in 2018 wave. Joint trajectories were fit using the parallel process latent class growth analysis, and their associations with adverse outcomes were evaluated using modified Poisson regression. Joint trajectory patterns for social relationship and sarcopenia did not vary by the assessment for sarcopenia, but did vary by the assessment for social relationship. Older adults exhibit distinct joint trajectories and those with persistent combination of loneliness or social isolation and sarcopenia experience greatest risk of adverse outcomes. These findings implicate integration of health care and social care for community-dwelling older adults.

Executive function and attentional bias as serial mediators in the relationship between frailty and depressive symptoms among older inpatients: A cross-sectional study.

AIMS AND OBJECTIVES: To examine the serial mediating effect of executive function and attentional bias in the relationship between frailty and depressive symptoms. BACKGROUND: Although the role of frailty in predicting depression has been well documented, the underlying mechanisms remain unclear. DESIGN: A cross-sectional study was conducted with 667 older inpatients aged 60-90 years in the internal medicine wards of a hospital in China. METHODS: Attentional bias, frailty and depressive symptoms were assessed using the Attention to Positive and Negative Information Scale, the Physical Frailty Phenotype and the 5-item Geriatric Depression Scale. Executive function was measured using 3 tests, including digital backward, category Verbal Fluency Test and Trail Making Test. The study followed the STROBE guideline. RESULTS: The latent profile analysis (LPA) identified four patterns of attentional bias, namely "no positive bias & no negative bias" (class 1, 9.3%), "minor positive bias & no negative bias" (class 2, 48.0%), "major positive bias & minor negative bias" (class 3, 25.6%) and "major positive bias & no negative bias" (class 4, 17.1%). Regression analysis found that frailty was associated with depressive symptoms. Frailty was also negatively associated with executive function, which was a protective factor for attentional bias class 1, 2 and 3 with reference to class 4. Attentional bias class 1 and 2 but not class 3 was associated with depressive symptoms with reference to class 4. The joint significance test confirmed executive function and attentional bias as serial mediators linking frailty to depressive symptoms. DISCUSSION: Unlike robust older adults who have the age-related positivity effect, frail older adults have attentional bias deficits due to executive dysfunction, and consequently experience clinically relevant depressive symptoms. RELEVANCE TO CLINICAL PRACTICE: Healthcare providers should take executive function training and attentional bias regulation into consideration to reduce the detrimental effects of frailty on emotional well-being.

Association between self-efficacy and self-management behaviours among individuals at high risk for stroke: Social support acting as a mediator.

AIMS AND OBJECTIVES: To explore the association between self-efficacy and self-management by modelling three types of social support as mediators among stroke high-risk populations. BACKGROUND: Self-efficacy and social support (i.e. objective support, subjective support and support utilisation) are important for self-management among stroke high-risk populations. Self-efficacy activates three types of social support, and the effect of social support on self-management varies by types among chronic patients. Therefore, social support may act as a mediator between self-efficacy and self-management, and the mediating role may vary by types of social support. Disentangling the role of these different types of social support can guide tailored interventions. DESIGN: A cross-sectional study. METHODS: This study was conducted among 448 Chinese adults at high risk for stroke. Self-efficacy, self-management and social support were assessed using the Self-Efficacy Scale, the Stroke Self-management Scale and the Social Support Rating Scale respectively. The PROCESS SPSS Macro version 3.3, model 4 was used to explore the mediating role of different types of social support in the relationship between self-efficacy and self-management. This study followed STROBE checklist for cross-sectional studies (Appendix S1). RESULTS: Self-efficacy improved three types of social support, and subjective support and support utilisation promoted self-management, but objective support hindered self-management. The specific indirect effect of objective support and subjective support was significant but not that of support utilisation. Objective support, subjective support and support utilisation attenuated the total effect of self-efficacy on self-management by -23.8%, 23.8% and 7.7% respectively. CONCLUSIONS: Mediating effect of social support in the relationship between self-efficacy and self-management varies by type, and the positive effect of subjective support is offset by the detrimental effect of objective support. RELEVANCE TO CLINICAL PRACTICE: Among stroke high-risk populations, interventions should target objective support and subjective support as well as self-efficacy to efficiently improve their self-management.

Effects of reversible cognitive frailty on disability, quality of life, depression, and hospitalization: a prospective cohort study.

OBJECTIVES: Cognitive frailty, a potentially reversible condition describing the concurrence of physical frailty and mild cognitive impairment (MCI), has been recently proposed to incorporate subjective cognitive decline (SCD), a reversible pre-MCI state with more readily available cognitive reserve, as well as pre-physical frailty. Reversible cognitive frailty has been associated with dementia and mortality. We aimed to examine the association of reversible cognitive frailty with other adverse outcomes including disability, poor quality of life (QOL), depression, and hospitalization. METHODS: This was a cohort study with 1-year follow-up among 735 Chinese community-dwelling older adults with intact cognition. Reversible cognitive frailty was operationalized with the presence of pre-physical or physical frailty identified by the Frailty Phenotype and SCD identified by the simplified SCD questionnaire including four self-report cognitive domains of memory, naming, orientation, and mathematical reasoning. Adverse outcomes included incident Activities of Daily Living (ADL)-Instrumental ADL (IADL) disability, poor physical, mental and overall QOL, depression, and hospitalization over 1-year follow-up. RESULTS: The prevalence of reversible cognitive frailty was 27.8%. Participants with reversible cognitive frailty had higher risk of the incidence of ADL-IADL disability, poor physical QOL, poor mental QOL, poor overall QOL, and depression (Odds Ratios: 1.67-4.38, P < 0.05), but not higher risk of hospitalization over 1-year follow-up. CONCLUSION: Reversible cognitive frailty was not uncommon and associated with incident disability, poor QOL, and depression among community-dwelling older adults. Early identification of reversible cognitive frailty can facilitate targeted interventions and may promote independence in older adults.Supplemental data for this article is available online at http://dx.doi.org/10.1080/13607863.2021.2011835.

A theory-driven exercise intervention among community-dwelling (pre)frail older adults: Protocol for a stepped-wedge cluster-randomized trial.

AIM: This study is aimed to evaluate the effectiveness of a theory-driven exercise intervention for Chinese community-dwelling (pre)frail older adults, and to clarify the underlying mechanisms of the exercise intervention in this population. DESIGN: A stepped-wedge cluster-randomized trial. METHODS: A stepped-wedge cluster-randomized trial will be conducted among (pre)frail older adults at six communities in a county of central China. A 12-week multicomponent exercise intervention based on the integration of the Health Belief Model (HBM) and the Theory of Planned Behaviour (TPB) will be implemented to all participants during the study period. The primary outcomes are frailty, muscle mass, muscle strength and physical performance. Secondary outcomes include beliefs in exercise, exercise behaviours and other physical, mental and social functioning. Assessments will be conducted at baseline and at week 12, 24 and 36. A multilevel regression model will be used to evaluate the effectiveness of exercise interventions. A multilevel mediation model will be used to clarify the underlying mechanisms of this exercise intervention. DISCUSSION: This study is expected to provide an effective and practical mode for exercise interventions among Chinese community-dwelling (pre)frail older adults, and contribute to the existing evidence in this field. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2100041981.

Patterns of intrinsic capacity among community-dwelling older adults: Identification by latent class analysis and association with one-year adverse outcomes.

OBJECTIVE: To identify patterns of intrinsic capacity (IC) and determine the association between these patterns with incident one-year outcomes. METHODS: A total of 756 older adults aged ≥ 60 years were followed up after 1 year. IC was assessed using the revised integrated care for older people screening tool, and its patterns were examined by the latent class analysis. Logistic regression models were conducted to compare the risk of adverse outcomes. RESULTS: Three IC patterns were identified. Both "sharp declines in sensory domain" (Class 2) and "sharp declines in locomotion, psychological, cognition and vitality domains" (Class 3) were at greater risk of disabilities and poor physical quality of life than "relatively healthy" (Class 1). The Class 3 was twice as likely to be hospitalized as Class 1. DISCUSSION: Assessment of IC could provide valuable information on stratifying older adults into heterogeneous groups, promoting targeted interventions to delay the adverse outcomes.

Expressive suppression and rumination mediate the relationship between frailty and depression among older medical inpatients.

OBJECTIVE: Frailty is common among older medical inpatients and has been found to be an independent risk factor for depression. However, few studies have explored the underlying mechanisms of the frailty-depression relationship. The present study was aimed to examine emotional regulation strategies as mediators in the frailty-depression relationship based on the process model of emotional regulation. METHODS: Older medical inpatients (N=684) completed questionnaires and tests on frailty, emotional regulation strategies, and depressive symptoms. RESULTS: Structural equation models showed that expressive suppression and rumination, but not cognitive reappraisal, mediated the relationship between frailty and depressive symptoms (RMSEA = 0.059, CFI = 0.963, TLI = 0.957). CONCLUSIONS: Frail older medical inpatients habitually use expressive suppression and rumination in their daily lives, which may lead to more psychological disturbance. Interventions targeting expressive suppression and rumination might be effective in reducing the detrimental effect of frailty on psychological well-being among older medical inpatients.

Effects of social support on frailty trajectory classes among community-dwelling older adults: The mediating role of depressive symptoms and physical activity.

OBJECTIVES: To investigate whether and how social support influenced frailty progression through depressive symptoms and physical activity. METHODS: Of 1235 community-dwelling older adults enrolled at baseline, 778 (63.0%) undergoing at least one yearly follow-up were included in the final analysis. Data were collected on frailty, social support, depressive symptoms, physical activity and covariates. RESULTS: Two frailty trajectory classes were identified and labeled as alleviated frailty and deteriorated frailty. Subjective support prevented the deterioration of frailty through decreased depressive symptoms, while objective support and support utilization prevented the deterioration of frailty through increased physical activity. CONCLUSIONS: The pathways through which social support ameliorates frailty vary by support types. Subjective support interventions should be included in the multifactorial interdisciplinary management of frailty to address social and psychological vulnerabilities, along with objective support and support utilization interventions addressing physical inactivity.

Functional specificity, diversity, and redundancy of Arabidopsis JAZ family repressors in jasmonate and COI1-regulated growth, development, and defense.

In response to jasmonates (JAs), the JA receptor Coronatine Insensitive 1 (COI1) recruits JA-zinc-finger inflorescence meristem (ZIM)-domain (JAZ) family repressors for destruction to regulate plant growth, development, and defense. As Arabidopsis encodes 13 JAZ repressors, their functional specificity, diversity, and redundancy in JA/COI1-mediated responses remain unclear. We generated a broad range of jaz mutants based on their phylogenetic relationship to investigate their roles in JA responses. The group I JAZ6 may play an inhibitory role in resistance to Botrytis cinerea, group II (JAZ10)/III (JAZ11/12) in JA-regulated root growth inhibition and susceptibility to Pseudomonas syringae pv tomato DC3000, and group IV JAZ3/4/9 in flowering time delay and defense against insects. JAZs exhibit high redundancy in apical hook curvature. The undecuple jaz1/2/3/4/5/6/7/9/10/11/12 (jaz1-7,9-12) mutations enhance JA responses and suppress the phenotypes of coi1-1 in flowering time, rosette growth, and defense. The JA hypersensitivity of jaz1-7,9-12 in root growth, hook curvature, and leaf yellowing is blocked by coi1-1. jaz1-7,9-12 does not influence the stamen phenotypes of wild-type and coi1-1. jaz1-7,9-12 affects JA-regulated transcriptional profile and recovers a fraction of that in coi1-1. This study contributes to elucidating the specificity, diversity, and redundancy of JAZ members in JA/COI1-regulated growth, development, and defense responses.

Calcineurin inhibitors ameliorate PAN-induced podocyte injury through the NFAT-Angptl4 pathway.

Podocyte injury plays a vital role in proteinuria and nephrotic syndrome. Calcineurin (CaN) inhibitors are effective in reducing proteinuria. However, their molecular mechanism is still not fully understood. Angiopoietin-like-4 (ANGPTL4) is a secreted protein that mediates proteinuria in podocyte-related nephropathy. In this study, we established a puromycin aminonucleoside (PAN)-induced minimal-change disease (MCD) rat model and a cultured podocyte injury model. We found that CaN inhibitors protected against PAN-induced podocyte injury, accompanied by an inhibition of Nfatc1 and Angptl4 both in vivo and in vitro. Nfatc1 overexpression and knockdown experiments indicated that Angptl4 was regulated by Nfatc1 in podocytes. ChIP assays further demonstrated that Nfatc1 increased Angptl4 expression by binding to the Angptl4 promoter. In addition, overexpression and knockdown of Angptl4 revealed that Angptl4 directly induced rearrangement of the cytoskeleton of podocytes, reduced the expression of synaptopodin, and enhanced PAN-induced podocyte apoptosis. Furthermore, in a cohort of 83 MCD and 94 membranous nephropathy (MN) patients, we found increased expression of serum ANGPTL4 compared to 120 healthy controls, and there were close correlations between serum ANGPTL4 and Alb, urinary protein, urinary Alb, eGFR, Scr, and BUN in MCD patients. No obvious correlation was found in MN patients. Immunofluorescence studies indicated that increased ANGPTL4 in MCD and MN patients was located mostly in podocytes. In conclusion, our results demonstrate that CaN inhibitors ameliorate PAN-induced podocyte injury by targeting Angptl4 through the NFAT pathway, and Angptl4 plays a vital role in podocyte injury and is involved in human podocyte-related nephropathy. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

ADAM10 mediates ectopic proximal tubule development and renal fibrosis through Notch signalling.

Disturbed intrauterine development increases the risk of renal disease. Various studies have reported that Notch signalling plays a significant role in kidney development and kidney diseases. A disintegrin and metalloproteinase domain 10 (ADAM10), an upstream protease of the Notch pathway, is also reportedly involved in renal fibrosis. However, how ADAM10 interacts with the Notch pathway and causes renal fibrosis is not fully understood. In this study, using a prenatal chlorpyrifos (CPF) exposure mouse model, we investigated the role of the ADAM10/Notch axis in kidney development and fibrosis. We found that prenatal CPF-exposure mice presented overexpression of Adam10, Notch1 and Notch2, and led to premature depletion of Six2+ nephron progenitors and ectopic formation of proximal tubules (PTs) in the embryonic kidney. These abnormal phenotypic changes persisted in mature kidneys due to the continuous activation of ADAM10/Notch and showed aggravated renal fibrosis in adults. Finally, both ADAM10 and NOTCH2 expression were positively correlated with the degree of renal interstitial fibrosis in IgA nephropathy patients, and increased ADAM10 expression was negatively correlated with decreased kidney function evaluated by serum creatinine, cystatin C, and estimated glomerular filtration rate. Regression analysis also indicated that ADAM10 expression was an independent risk factor for fibrosis in IgAN. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

"Age-Related Positivity Effect" in the Relationship Between Pain and Depression Among Chinese Community-Dwelling Older Adults: Sex Differences.

PURPOSE: To examine the "age-related positivity effect" and its sex differences in the pain-depression relationship among Chinese community-dwelling older adults. DESIGN: Cross-sectional design. METHODS: The study was conducted with a sample of 1,913 older adults in Jinan, China. Data were collected on pain intensity, age, sex, depressive symptoms, and potential covariates. RESULTS: The hierarchical linear regression analyses revealed that pain intensity was significantly related to depressive symptoms, there was a significant two-way interaction between age and pain intensity, and there was a significant three-way interaction between sex, age, and pain intensity. The Johnson-Neyman plot revealed that the relationship between pain and depressive symptoms decreased with advancing age, indicating an "age-related positivity effect." And the age-related positivity effect in the pain-depression relationship was significant only in men, but not in women. CONCLUSIONS: The study suggests that all older women and "young-old" men (younger senior citizens aged 60-79) in China are more likely to experience depressive symptoms from pain. Interventions on cognitive psychology should particularly target all older women and young-old men to reduce the detrimental effect of pain on emotional well-being.

Functional disability mediates the relationship between pain and depression among community-dwelling older adults: Age and sex as moderators.

OBJECTIVE: To examine the moderating effects of age and sex in the role of functional disability as a mediator between pain and depression. METHODS: Participants were 1917 community-dwelling older adults from Jinan, China. Data were collected on pain intensity, functional disability in activities of daily living and instrumental activities of daily living, depressive symptoms and covariates. RESULTS: Functional disability partially mediated the relationship between pain intensity and depressive symptoms (estimate = 0.015, SE = 0.007, 95% CI [0.004, 0.030]). Age and sex moderated both the direct and indirect effect of the mediation model. The mediating effect of functional disability was significant in the old-old men, young-old men, and young-old women, but not in the old-old women. CONCLUSIONS: Interventions should target both pain and pain-related functional disability to improve their emotional well-being among community-dwelling older adults. Importantly, strategies should be tailored across different age and sex groups to improve their effectiveness.

Sleep quality, depression and frailty among Chinese community-dwelling older adults.

We aimed to explore the relationship between sleep quality and frailty, and depression as a mediator and its interaction with sleep quality on frailty. This was a cross-sectional study among 936 Chinese community-dwelling adults aged≥60 years. Sleep quality, frailty and depression were measured by the Pittsburgh Sleep Quality Index (PSQI), the Frailty Phenotype and the 5-item Geriatric Depression Scale (GDS-5), respectively. We found that depression mediated the association between poor sleep quality and physical frailty, attenuating the association between poor sleep and physical frailty by 51.9%. Older adults with both poor sleep quality and depression had higher risk of frailty than those with poor sleep quality or depression alone. These results implicate multidisciplinary care for frail older adults with poor sleep quality.

Comparison of 6 frailty screening tools in diagnostic properties among Chinese community-dwelling older people.

We aimed to compare the diagnostic test accuracy (DTA) of six frailty screening tools against comprehensive geriatric assessment (CGA) in the community. A total of 1177 community-dwelling older people were recruited. Frailty was assessed by purely physical tools including Physical Frailty Phenotype (PFP), FRAIL (fatigue, resistance, ambulation, illness and loss of weight), Study of Osteoporotic Fracture (SOF), and multidimensional tools including Tilburg Frailty Indicator (TFI), Groningen Frailty Indicator (GFI) and Comprehensive Frailty Assessment Instrument (CFAI). The receiver operating characteristic curve analyses were performed. The GFI, TFI and CFAI [areas under the curve (AUCs): 0.78-0.80] had better diagnostic accuracy than SOF, PFP and FRAIL (AUCs: 0.69-0.72) (χ2: 6.37-26.76, P<.05). The optimal cut-offs for the PFP, FRAIL and SOF were identical to their original prefrail cut-offs. These results implicate that the multidimensional tools are more effective to identify frailty in the whole community setting, while the self-report FRAIL may be used to identify the prefrail and facilitate early interventions particularly in the community setting with adequate healthcare resources.

Predictive value of intrinsic capacity on adverse outcomes among community-dwelling older adults.

OBJECTIVE: To examine the predictive value of intrinsic capacity on one-year incident adverse outcomes among community-dwelling older adults. METHODS: A total of 756 community-dwelling older adults aged ≥ 60 years were followed up after 1 year. Intrinsic capacity was assessed using the revised integrated care for older people screening tool. Adverse outcomes included incident disability, recurrent falls, hospitalization, emergency department visits, and poor quality of life. Multivariate logistic regression models were performed to evaluate the predictive value of intrinsic capacity domains on adverse outcomes. RESULTS: Cognitive decline, limited mobility, visual impairment and depressive symptoms predicted incident disability. Visual impairment predicted recurrent falls. Cognitive decline and limited mobility predicted emergency department visits. Limited mobility predicted poor quality of life. DISCUSSION: Intrinsic capacity could predict incident adverse outcomes among community-dwelling older adults. Assessing intrinsic capacity would facilitate early identification of older adults at high risk of adverse outcomes and prompt targeted interventions.

Ginsenoside Rg1 Inhibits Cell Proliferation and Induces Markers of Cell Senescence in CD34+CD38- Leukemia Stem Cells Derived from KG1α Acute Myeloid Leukemia Cells by Activating the Sirtuin 1 (SIRT1)/Tuberous Sclerosis Complex 2 (TSC2) Signaling Pathway.

BACKGROUND Clinical relapse in acute myeloid leukemia (AML) is associated with the reduced treatment response of leukemia stem cells (LSCs). This study aimed to investigate the effects of the ginseng derivative, ginsenoside Rg1 (Rg1), on CD34+CD38- LSCs derived from KG1a human acute myeloid leukemia cells. MATERIAL AND METHODS CD34+CD38- LSCs were isolated from KG1a human acute myeloid leukemia cells by cell sorting. CD34+CD38- KG1alpha LSCs were divided into the control group and the Rg1 group (treated with Rg1). The cell counting kit-8 (CCK-8) assay evaluated the proliferation of CD34+CD38- KG1alpha LSCs and flow cytometry studied the cell cycle. The mixed colony-forming unit (CFU-Mix) assay and staining for senescence-associated beta-galactosidase (SA-ß-Gal) evaluated cell senescence. Expression of sirtuin 1 (SIRT1) and tuberous sclerosis complex 2 (TSC2) were evaluated using Western blot and quantitative reverse transcription-polymerase chain reaction (qRT-PCR). RESULTS CD34+CD38- KG1alpha LSCs were isolated at 98.72%. Rg1 significantly reduced the proliferation of CD34+CD38- KG1alpha LSCs compared with the control group (p<0.05). Cells in the G0/G1 phase were significantly increased, and cells in the G2/M and S phase were significantly reduced compared with the control group (p<0.05). Rg1 significantly increased SA-ß-Gal and reduced CFU-Mix formation compared with the control group (p<0.05), significantly down-regulated SIRT1 expression in CD34+CD38- KG1alpha LSCs compared with the control group (p<0.05), and significantly reduced TSC2 expression in CD34+CD38- KG1alpha LSCs compared with the control group (p<0.05). CONCLUSIONS Rg1 inhibited cell proliferation and induced cell senescence markers in CD34+CD38- KG1alpha LSCs by activating the SIRT1/TSC2 signaling pathway.