Posttranscriptional regulation of de novo lipogenesis by glucose-induced O-GlcNAcylation.

O-linked ß-N-acetyl glucosamine (O-GlcNAc) is attached to proteins under glucose-replete conditions; this posttranslational modification results in molecular and physiological changes that affect cell fate. Here we show that posttranslational modification of serine/arginine-rich protein kinase 2 (SRPK2) by O-GlcNAc regulates de novo lipogenesis by regulating pre-mRNA splicing. We found that O-GlcNAc transferase O-GlcNAcylated SRPK2 at a nuclear localization signal (NLS), which triggers binding of SRPK2 to importin α. Consequently, O-GlcNAcylated SRPK2 was imported into the nucleus, where it phosphorylated serine/arginine-rich proteins and promoted splicing of lipogenic pre-mRNAs. We determined that protein nuclear import by O-GlcNAcylation-dependent binding of cargo protein to importin α might be a general mechanism in cells. This work reveals a role of O-GlcNAc in posttranscriptional regulation of de novo lipogenesis, and our findings indicate that importin α is a "reader" of an O-GlcNAcylated NLS.

Regulation of the Hippo-YAP Pathway by Glucose Sensor O-GlcNAcylation.

The Hippo pathway is crucial in organ size control and tissue homeostasis, with deregulation leading to cancer. An extracellular nutrition signal, such as glucose, regulates the Hippo pathway activation. However, the mechanisms are still not clear. Here, we found that the Hippo pathway is directly regulated by the hexosamine biosynthesis pathway (HBP) in response to metabolic nutrients. Mechanistically, the core component of Hippo pathway (YAP) is O-GlcNAcylated by O-GlcNAc transferase (OGT) at serine 109. YAP O-GlcNAcylation disrupts its interaction with upstream kinase LATS1, prevents its phosphorylation, and activates its transcriptional activity. And this activation is not dependent on AMPK. We also identified OGT as a YAP-regulated gene that forms a feedback loop. Finally, we confirmed that glucose-induced YAP O-GlcNAcylation and activation promoted tumorigenesis. Together, our data establish a molecular mechanism and functional significance of the HBP in directly linking extracellular glucose signal to the Hippo-YAP pathway and tumorigenesis.

BGL3 lncRNA mediates retention of the BRCA1/BARD1 complex at DNA damage sites.

Long non-coding RNAs (lncRNAs) are emerging regulators of genomic stability and human disease. However, the molecular mechanisms by which nuclear lncRNAs directly contribute to DNA damage responses remain largely unknown. Using RNA antisense purification coupled with quantitative mass spectrometry (RAP-qMS), we found that the lncRNA BGL3 binds to PARP1 and BARD1, exhibiting unexpected roles in homologous recombination. Mechanistically, BGL3 is recruited to DNA double-strand breaks (DSBs) by PARP1 at an early time point, which requires its interaction with the DNA-binding domain of PARP1. BGL3 also binds the C-terminal BRCT domain and an internal region (amino acids 127-424) of BARD1, which mediates interaction of the BRCA1/BARD1 complex with its binding partners such as HP1γ and RAD51, resulting in BRCA1/BARD1 retention at DSBs. Cells depleted for BGL3 displayed genomic instability and were sensitive to DNA-damaging reagents. Overall, our findings underscore the biochemical versatility of RNA as a mediator molecule in the DNA damage response pathway, which affects the accumulation of BRCA1/BARD1 at DSBs.

Effects of vaginal microbiota on human papillomavirus infection and its related diseases.

With the knowledge of female reproductive tract microbiota gradually increasing, the connection between vaginal microbiota (VMB) and its related diseases is increasingly highlighted. Manifestation of VMB keeps changing with various dominated bacteria, which can affect the immune response of mucosal barrier and the entrance of pathogens. Human papillomavirus (HPV), as an oncogenic virus, is closely related to viral-associated cancer, such as cervical cancer. According to HPV infection status, VMB can transform into different types, and result in accelerating or restraining the progression of diseases, which have exposed the inner link between VMB and HPV. Therefore, probiotics therapy promises to be a new complementary therapy to rebuild a healthy VMB for patients, but there's still a long way to go before its ready for the clinic. This review focuses on composition, immune response, and application of VMB in HPV and its associated diseases and aims to provide the new ideas and directions for the research on VMB.

Social Contact, Social Participation, and Emotional Well-Being Among Older Adults During the COVID-19 Pandemic: The Roles of Giving and Receiving Social Support.

This study examined whether social contact, social participation, and social support during the COVID-19 pandemic were associated with depression and anxiety. Data were taken from the 2020 COVID-19 Supplement of the National Health and Aging Trends Study (N = 2,778). Depression and anxiety were regressed on social contact frequency, social participation, and social support. Path analyses were also performed. The results showed that in-person contact was related to lower levels of depression, while in-person contact and attending religious services were related to lower levels of anxiety. Giving and receiving support were associated with higher levels of depression and anxiety. Giving support mediated the link between virtual contact, volunteering, and depression, while receiving support mediated the link between virtual contact and depression. Receiving and giving support mediated the association between virtual social contact, volunteering, and anxiety. During the pandemic, being socially connected provided some benefits in terms of emotional well-being, but in some cases being socially connected did not provide salubrious effects.

Age and Cohort Trends in Formal Volunteering and Informal Helping in Later Life: Evidence From the Health and Retirement Study.

Formal volunteering holds great importance for the recipients of volunteer services, individuals who volunteer, and the wider society. However, how much recent birth cohorts volunteer in middle and late adulthood compared with earlier birth cohorts is not well understood. Even less well-known are the age and cohort trends in informal helping provided to friends and neighbors in later adulthood. Using longitudinal data from the Health and Retirement Study, we estimated age and cohort trends in formal volunteering and informal helping from 1998 to 2018 for a wide range of birth cohorts born between 1909 and 1958. We used multivariate, multilevel models based on Bayesian generalized modeling methods to estimate the probabilities of volunteering and informal helping simultaneously in a single model. Despite having advantages in human and health capital, recent birth cohorts showed volunteering levels in late adulthood that are similar to those of their predecessors. Moreover, more recent birth cohorts were consistently less engaged in informal helping than earlier birth cohorts throughout the observation period. More research is needed to illuminate the sociocultural drivers of changes in helping behaviors and overall prosocial and civic engagement.

Frailty, cognitive impairment, and depressive symptoms in Chinese older adults: an eight-year multi-trajectory analysis.

BACKGROUND: Frailty, cognitive impairment, and depressive symptoms are closely interrelated conditions in the aging population. However, limited research has longitudinally analyzed the concurrent trajectories of these three prominent conditions in older adults in China. This study aimed to explore the eight-year trajectories of frailty, cognitive impairment, and depressive symptoms, and to identify individual-level and structural-level factors associated with the trajectories. METHODS: Four waves of data from the China Health and Retirement Longitudinal Study (2011-2018) were used to identify 6,106 eligible older adults. The main measures included frailty by the frailty index constructed using 30 indicators, cognitive impairment by the summary score of immediate and delayed word recall, figure drawing, serial subtraction, and orientation, and depressive symptoms by the Center for Epidemiologic Studies Depression Scale. Multi-trajectory models identified the trajectories of frailty, cognitive impairment, and depressive symptoms over time. Multinomial logistic regression was employed to estimate the associations between individual-level capital factors and one structural factor (hukou and geographic residency) with the identified trajectories, adjusting for demographic characteristics. RESULTS: Four trajectories emerged: (1) worsening frailty, worsening cognitive impairment, depression (14.0%); (2) declining pre-frailty, declining cognition, borderline depression (20.0%); (3) pre-frailty, worsening cognitive impairment, no depression (29.3%); and (4) physically robust, declining cognition, no depression (36.7%). Using the "physically robust, declining cognition, no depression" as the reference, not working, no social activity participant, worse childhood family financial situation, and poorer adult health were most strongly associated with the "worsening frailty, worsening cognitive impairment, depression" trajectory; worse health during childhood had the highest association with the "declining pre-frailty, declining cognition, borderline depression" trajectory; less education, lower household consumption, and rural hukou had the greatest association with the increased likelihood of the "pre-frailty, worsening cognitive impairment, no depression" trajectory. CONCLUSIONS: Findings could inform the understanding of the interrelationship of frailty, cognitive impairment, and depressive symptoms in older adults in China and may help practitioners detect adults at risk for adverse trajectories to implement strategies for proper care.

Cognitive function and cognitive decline among older rural Chinese adults: the roles of social support, pension benefits, and medical insurance.

OBJECTIVES: This study investigated whether social support, pension benefits, and medical insurance coverage are related to cognitive function and decline among older rural Chinese adults and whether depressive symptoms represented a pathway linking these factors with cognitive function. METHODS: Data are taken from three waves of the China Health and Retirement Longitudinal Study (N = 5,135). Cognitive function is assessed with episodic memory and depressive symptoms are assessed with the 10-item CESD Scale. Social support (intergenerational financial transfers, weekly contact with children, perceived availability of future support, and living arrangements), pension benefits, and medical insurance coverage are self-reported measures. Multilevel linear regression models are employed. RESULTS: Intergenerational financial transfers, perceived availability of future support, and pension income are associated with higher levels of cognitive function. Living with others, perceived availability of future support, medical insurance coverage, and pension income are associated with a slower risk of cognitive decline. Depressive symptoms mediated the association between perceived availability of future support, living with others, pension income and level of cognitive function and the link between perceived availability of future support, pension income, and cognitive decline. CONCLUSION: The findings suggested these modifiable factors should be taken into account when screening older adults for possible cognitive impairment and decline. Early interventions may also be helpful by expanding social resources and reducing psychological distress.

Social capital, perceived neighborhood environment, and depressive symptoms among older adults in rural China: the role of self-rated health.

OBJECTIVES: This study examined the relationships between social capital, perceived neighborhood environment, and depressive symptoms among older adults living in rural China, and the moderating effect of self-rated health (SRH) in these relationships. PARTICIPANTS: A quota sampling method was applied to recruit 447 participants aged 60 years and older in rural communities in Jilin province, China in 2019. MEASUREMENTS: Depressive symptoms were measured by the Center for Epidemiologic Studies Depression Scale. Structural equation modeling was used to build latent constructs of social capital and test the proposed model. Multiple group analysis was used to test the moderation effects. RESULTS: Cognitive social capital and structural social capital were both associated with depressive symptoms controlling for participants' demographics, socioeconomic status, and health status. After adding perceived environment variables in the model, the relationship between cognitive social capital and depressive symptoms became nonsignificant, while structural social capital remained became a significant factor (ß = -.168, p < .01). Satisfaction with health care was significantly associated with depressive symptoms among those with poor SRH (ß = -.272, p < .01), whereas satisfaction with security and transportation were strongly associated with depressive symptoms among those with good SRH (security: ß = -.148, p < .01; transportation: ß = -.174, p < .01). CONCLUSIONS: Study findings highlighted the importance of social capital and neighborhood environment as potential protective factors of depressive symptoms in later life. Policy and intervention implications were also discussed.

Home and Community-Based Service Utilization among Older Adults in Urban China: The Role of Social Capital.

Home and community-based service (HCBS) utilization is considered important for older adults who want to maintain their independence and remain in their communities. This study examined the relationship between structural (e.g., citizenship activities, volunteering) and cognitive (e.g., social trust, a sense of belonging) social capital and HCBS utilization among older Chinese adults. We analyzed survey data from 441 community-dwelling older adults in the Gusu district of the city of Suzhou, China in 2015. Quota sampling was used to select respondents. Negative binomial regression was used within the structural equation modeling framework to test the proposed model for HCBS utilization. Structural social capital had a direct association with HCBS utilization, controlling for predisposing, enabling, and need factors in the model. Further, cognitive social capital showed an indirect association with HCBS utilization via structural social capital. The results suggested the importance of establishing intervention programs that foster structural social capital to promote HCBS utilization.

And-1 coordinates with CtIP for efficient homologous recombination and DNA damage checkpoint maintenance.

To prevent genomic instability, cells respond to DNA lesions by blocking cell cycle progression and initiating DNA repair. Homologous recombination repair of DNA breaks requires CtIP-dependent resection of the DNA ends, which is thought to play a key role in activation of CHK1 kinase to induce the cell cycle checkpoint. But the mechanism is still not fully understood. Here, we establish that And-1, a replisome component, promotes DNA-end resection and DNA repair by homologous recombination. Mechanistically, And-1 interacts with CtIP and regulates CtIP recruitment to DNA damage sites. And-1 localizes to sites of DNA damage dependent on MDC1-RNF8 pathway, and is required for resistance to many DNA-damaging and replication stress-inducing agents. Furthermore, we show that And-1-CtIP axis is critically required for sustained ATR-CHK1 checkpoint signaling and for maintaining both the intra-S- and G2-phase checkpoints. Our findings thus identify And-1 as a novel DNA repair regulator and reveal how the replisome regulates the DNA damage induced checkpoint and genomic stability.

HDAC10 inhibition represses melanoma cell growth and BRAF inhibitor resistance via upregulating SPARC expression.

Secreted protein acidic and rich in cysteine (SPARC), a conserved secreted glycoprotein, plays crucial roles in regulating various biological processes. SPARC is highly expressed and has profound implications in several cancer types, including melanoma. Understanding the mechanisms that govern SPARC expression in cancers has the potential to lead to improved cancer diagnosis, prognosis, treatment strategies, and patient outcomes. Here, we demonstrate that histone deacetylase 10 (HDAC10) is a key regulator of SPARC expression in melanoma cells. Depletion or inhibition of HDAC10 upregulates SPARC expression, whereas overexpression of HDAC10 downregulates it. Mechanistically, HDAC10 coordinates with histone acetyltransferase p300 to modulate the state of acetylation of histone H3 at lysine 27 (H3K27ac) at SPARC regulatory elements and the recruitment of bromodomain-containing protein 4 (BRD4) to these regions, thereby fine-tuning SPARC transcription. HDAC10 depletion and resultant SPARC upregulation repress melanoma cell growth primarily by activating AMPK signaling and inducing autophagy. Moreover, SPARC upregulation due to HDAC10 depletion partly accounts for the resensitization of resistant cells to a BRAF inhibitor. Our work reveals the role of HDAC10 in gene regulation through indirect histone modification and suggests a potential therapeutic strategy for melanoma or other cancers by targeting HDAC10 and SPARC.

O-GlcNAcylation of MITF regulates its activity and CDK4/6 inhibitor resistance in breast cancer.

Cyclin-dependent kinases 4 and 6 (CDK4/6) play a pivotal role in cell cycle and cancer development. Targeting CDK4/6 has demonstrated promising effects against breast cancer. However, resistance to CDK4/6 inhibitors (CDK4/6i), such as palbociclib, remains a substantial challenge in clinical settings. Using high-throughput combinatorial drug screening and genomic sequencing, we find that the microphthalmia-associated transcription factor (MITF) is activated via O-GlcNAcylation by O-GlcNAc transferase (OGT) in palbociclib-resistant breast cancer cells and tumors. Mechanistically, O-GlcNAcylation of MITF at Serine 49 enhances its interaction with importin α/ß, thus promoting its translocation to nuclei, where it suppresses palbociclib-induced senescence. Inhibition of MITF or its O-GlcNAcylation re-sensitizes resistant cells to palbociclib. Moreover, clinical studies confirm the activation of MITF in tumors from patients who are palbociclib-resistant or undergoing palbociclib treatment. Collectively, our studies shed light on the mechanism regulating palbociclib resistance and present clinical evidence for developing therapeutic approaches to treat CDK4/6i-resistant breast cancer patients.

Friendship in Later Life: A Pathway Between Volunteering Hours and Depressive Symptoms.

OBJECTIVES: Friendships are essential in the face of social network changes in later life and friendships may be important for reducing depression risk. Social participation through volunteering is also associated with fewer depressive symptoms. What is less well-understood is whether friendships serve as a pathway in the link between volunteering and depression. METHODS: We used panel data from the Health and Retirement Study (2010, 2014, 2018). Negative binomial regression within the SEM modeling framework was employed to analyze the association between volunteering and friendship, focusing on the indirect effect of friendships for understanding the volunteering and depressive symptoms relationship. RESULTS: Volunteer hours were positively associated with friendship (1-99 hr: ß = 0.17, p < .001, 100-199 hr: ß = 0.15, p < .001, 200 hr and more: ß = 0.23, p < .001) and negatively associated with number of depressive symptoms (1-99 hr: ß = -0.07, p = .06, 100-199 hr: ß = -0.14, p < .001, 200 hr and more: ß = -0.17, p < .001). Friendship mediated the relationship between volunteer hours and depressive symptoms (indirect effects; 1-99 hr: ß = -0.01, 95% confidence interval [CI] = [-0.02, -0.00], p = .03), 100-199 hr: ß = -0.01, 95% CI = [-0.02, -0.00], p = .03), 200 hr and more: ß = -0.02, 95% CI = [-0.03, -0.00], p = .03). DISCUSSION: Our findings underscored the role of volunteering in generating and maintaining friendships, as well as for friendships as a pathway between volunteer hours and depressive symptoms. Providing opportunities to maintain and grow friendships in later life may be a possible intervention strategy for older adults at risk of depression.

Trapoxin A Analogue as a Selective Nanomolar Inhibitor of HDAC11.

Histone deacetylases (HDACs) are enzymes that regulate many important biological pathways. There is a need for the development of isoform-selective HDAC inhibitors for further biological applications. Here, we report the development of trapoxin A analogues as potent and selective inhibitors of HDAC11, an enzyme that can efficiently remove long-chain fatty acyl groups from proteins. In particular, we show that one of the trapoxin A analogues, TD034, has nanomolar potency in enzymatic assays. We show that in cells, TD034 is active at low micromolar concentrations and inhibits the defatty acylation of SHMT2, a known HDAC11 substrate. The high potency and selectivity of TD034 would permit further development of HDAC11 inhibitors for biological and therapeutic applications.

Hukou Status and Cognitive Function Among Older Chinese Adults: Does Support from Friends Matter?

OBJECTIVES: This study examined whether older Chinese adults with different types of hukou status (government household registration system) exhibited different cognitive outcomes and whether receiving support from friends, an under-appreciated resource, helped mitigate the negative impacts of agricultural hukou status on cognitive health disparities. METHODS: Using nationally representative data from the China Longitudinal Aging Social Survey, this study tested these relationships with well-validated measures. RESULTS: Our results showed that older Chinese adults with agricultural hukou were more likely to have worse cognitive function than those with non-agricultural hukou. Further, friend support characteristics moderated the association between hukou status and cognitive function, whereby having better friend support was related to a weaker negative effect of agricultural hukou status on cognitive function. DISCUSSION: The findings suggested that agricultural hukou status reflects the effects of accumulated disadvantage across the life course with negative consequences for late-life cognition. The cognitive health disparities between agricultural and non-agricultural residents may be reduced in the context of a higher level of friend support, supporting a stress buffering hypothesis.

HDAC10 blockade upregulates SPARC expression thereby repressing melanoma cell growth and BRAF inhibitor resistance.

Secreted Protein Acidic and Rich in Cysteine (SPARC), a highly conserved secreted glycoprotein, is crucial for various bioprocesses. Here we demonstrate that histone deacetylase 10 (HDAC10) is a key regulator of SPARC expression. HDAC10 depletion or inhibition upregulates, while overexpression of HDAC10 downregulates, SPARC expression. Mechanistically, HDAC10 coordinates with histone acetyltransferase p300 to modulate the acetylation state of histone H3 lysine 27 (H3K27ac) at SPARC regulatory elements and the recruitment of bromodomain-containing protein 4 (BRD4) to these regions, thereby tuning SPARC transcription. HDAC10 depletion and resultant SPARC upregulation repress melanoma cell growth, primarily by induction of autophagy via activation of AMPK signaling. Moreover, SPARC upregulation due to HDAC10 depletion partly accounts for the resensitivity of resistant cells to a BRAF inhibitor. Our work reveals the role of HDAC10 in gene regulation through epigenetic modification and suggests a potential therapeutic strategy for melanoma or other cancers by targeting HDAC10 and SPARC. Highlights: HDAC10 is the primary HDAC member that tightly controls SPARC expression. HDAC10 coordinates with p300 in modulating the H3K27ac state at SPARC regulatory elements and the recruitment of BRD4 to these regions. HDAC10 depletion and resultant SPARC upregulation inhibit melanoma cell growth by inducing autophagy via activation of AMPK signaling.SPARC upregulation as a result of HDAC10 depletion resensitizes resistant cells to BRAF inhibitors.

Tumor protein D52 (TPD52) affects cancer cell metabolism by negatively regulating AMPK.

BACKGROUND: The AMP-activated protein kinase (AMPK) is a central regulator of energy homeostasis, with deregulation leading to cancer and other diseases. However, how this pathway is dysregulated in cancer has not been well clarified. METHODS: Using a tandem affinity purification/mass-spec technique and biochemical analyses, we identified tumor protein D52 (TPD52) as an AMPKα-interacting molecule. To explore the biological effects of TPD52 in cancers, we conducted biochemical and metabolic assays in vitro and in vivo with cancer cells and TPD52 transgenic mice. Finally, we assessed the clinical significance of TPD52 expression in breast cancer patients using bioinformatics techniques. RESULTS: TPD52, initially identified to be overexpressed in many human cancers, was found to form a stable complex with AMPK in cancer cells. TPD52 directly interacts with AMPKα and inhibits AMPKα kinase activity in vitro and in vivo. In TPD52 transgenic mice, overexpression of TPD52 leads to AMPK inhibition and multiple metabolic defects. Clinically, high TPD52 expression predicts poor survival of breast cancer patients. CONCLUSION: The findings revealed that TPD52 is a novel regulator of energy stress-induced AMPK activation and cell metabolism. These results shed new light on AMPK regulation and understanding of the etiology of cancers with TPD52 overexpression.

O-GlcNAcylation of MITF regulates its activity and CDK4/6 inhibitor resistance in breast cancer.

Cyclin-dependent kinases 4 and 6 (CDK4/6) play a pivotal role in cell cycle and cancer development. Targeting CDK4/6 has demonstrated promising effects against breast cancer. However, resistance to CDK4/6 inhibitors (CDK4/6i), such as palbociclib, remains a substantial challenge in clinical settings. Using high-throughput combinatorial drug screening and genomic sequencing, we found that the microphthalmia-associated transcription factor (MITF) is activated via O-GlcNAcylation by O-GlcNAc transferase (OGT) in palbociclib-resistant breast cancer cells and tumors; O-GlcNAcylation of MITF at Serine 49 enhanced its interaction with importin α/ß, thus promoting its translocation to nuclei, where it suppressed palbociclib-induced senescence; inhibition of MITF or its O-GlcNAcylation re-sensitized resistant cells to palbociclib. Remarkably, clinical studies confirmed the activation of MITF in tumors from patients who are palbociclib-resistant or undergoing palbociclib treatment. Collectively, our studies shed light on a novel mechanism regulating palbociclib-resistance, and present clinical evidence for developing therapeutic approaches to treat CDK4/6i-resistant breast cancer patients.

Perceptions of Childhood Neighborhood Social Cohesion and Cognitive Function in Middle and Late Adulthood.

BACKGROUND AND OBJECTIVES: Framed within the life course perspective and the neighborhood stress model, this study investigated the association between perceptions of childhood neighborhood social cohesion and cognitive function among middle-aged and older Chinese adults. We also examined whether gender, childhood hukou status, the Chinese national administrative household registration system, and birth cohort moderated the association. RESEARCH DESIGN AND METHODS: This study used 3 waves of nationally representative data from the China Health and Retirement Longitudinal Study (2011-2015; N = 11,469). Cognitive function was measured with the Telephone Interview for Cognition Status instrument. Two-level multilevel modeling was employed to address the research questions. RESULTS: A higher overall level of childhood neighborhood social cohesion was associated with a higher baseline level of cognitive function (b = 0.26, p < .001) and a slower rate of cognitive decline (b = 0.10, p = .010). Birth cohort membership moderated the linkage between childhood neighborhood social cohesion and the level of cognitive function (b = 0.35, p < .001) and cognitive decline (b = 0.19, p = .014). Gender and childhood hukou status did not moderate these associations. DISCUSSION AND IMPLICATIONS: These findings underscored the long-term ramifications of childhood conditions for later-life cognitive function. Social cohesion at the neighborhood level during childhood may be a factor that promotes healthy cognitive aging.