Community-based exercises improve health status in pre-frail older adults: A systematic review with meta-analysis.

BACKGROUND: Pre-frailty is associated with increased healthcare utilization. Over the past decade, public health interventions such as community-based exercises to target pre-frailty have been increasingly studied. However, the effects of community-based exercises on clinical outcome measures amongst community-dwelling older adults with pre-frailty remain unclear. This review aims to better understand the effects of community-based exercise on physical function, cognition, quality of life and frailty status in community-dwelling pre-frail older adults. A secondary objective was to investigate the optimal exercise parameters on clinical outcomes. METHODS: Searches of MEDLINE, CINAHL, Google Scholar and Web of Science databases were conducted. Articles were included if they were randomized controlled trials (RCTs), and excluded if the participants consist of less than 50% pre-frail community-dwelling older adults. Meta-analyses (where possible) with either a fixed- or random- effect(s) model, standardized mean difference (SMD), odds ratio (OR) and tests of heterogeneity were performed. Multivariable meta-regression was performed to identify predictors of statistically significant outcome measures. The risk of bias was assessed using the modified Cochrane Risk-of-Bias tool. RESULTS: Twenty-two RCTs with 900 participants in the experimental group and 1015 participants in the control group were included. When compared to minimal intervention, community-based exercises significantly improved lower limb strength (10 RCTs, 384 participants in the experimental group and 482 participants in the control group) with SMD 0.67 (95% CI 0.29 to 1.04), and lower limb function (5 RCTs, 120 participants in the experimental group and 219 participants in the control group) with SMD 0.27 (95% CI 0.03 to 0.51). Those who have received community-based exercises were more likely to reverse from pre-frailty to healthy state (OR = 2.74, 95% CI 1.36 to 5.51) (6 RCTs, 263 participants in the experimental group and 281 participants in the control group). The frequency of exercise sessions was a significant predictor of the effect size for gait speed (P<0.05). CONCLUSIONS: Community-based exercise intervention is superior to minimal intervention for improving health status in pre-frail older adults. This has implications on the implementation of community-based exercise intervention by healthcare providers and policymakers. OTHER: Nil funding for this review. PROSPERO registration number CRD42022348556.

Parallel SCF adaptor capture proteomics reveals a role for SCFFBXL17 in NRF2 activation via BACH1 repressor turnover.

Modular cullin-RING E3 ubiquitin ligases (CRLs) use substrate binding adaptor proteins to specify target ubiquitylation. Many of the ~200 human CRL adaptor proteins remain poorly studied due to a shortage of efficient methods to identify biologically relevant substrates. Here, we report the development of parallel adaptor capture (PAC) proteomics and its use to systematically identify candidate targets for the leucine-rich repeat family of F-box proteins (FBXLs) that function with SKP1-CUL1-F-box protein (SCF) E3s. In validation experiments, we identify the unstudied F-box protein FBXL17 as a regulator of the NFR2 oxidative stress pathway. We demonstrate that FBXL17 controls the transcription of the NRF2 target HMOX1 via turnover of the transcriptional repressor BACH1 in the absence or presence of extrinsic oxidative stress. This work identifies a role for SCF(FBXL17) in controlling the threshold for NRF2-dependent gene activation and provides a framework for elucidating the functions of CRL adaptor proteins.

The G2/M regulator histone demethylase PHF8 is targeted for degradation by the anaphase-promoting complex containing CDC20.

Monomethylated histone H4 lysine 20 (H4K20me1) is tightly regulated during the cell cycle. The H4K20me1 demethylase PHF8 transcriptionally regulates many cell cycle genes and is therefore predicted to play key roles in the cell cycle. Here, we show that PHF8 protein levels are the highest during G2 phase and mitosis, and we found PHF8 protein stability to be regulated by the ubiquitin-proteasome system. Purification of the PHF8 complex led to the identification of many subunits of the anaphase-promoting complex (APC) associated with PHF8. We showed that PHF8 interacts with the CDC20-containing APC (APC(cdc20)) primarily during mitosis. In addition, we defined a novel, KEN- and D-box-independent, LXPKXLF motif on PHF8 that is required for binding to CDC20. Through various in vivo and in vitro assays, we demonstrate that mutations of the LXPKXLF motif abrogate polyubiquitylation of PHF8 by the APC. APC substrates are typically cell cycle regulators, and consistent with this, the loss of PHF8 leads to prolonged G2 phase and defective mitosis. Furthermore, we provide evidence that PHF8 plays an important role in transcriptional activation of key G2/M genes during G2 phase. Taken together, these findings suggest that PHF8 is regulated by APC(cdc20) and plays an important role in the G2/M transition.

SCF(FBXO22) regulates histone H3 lysine 9 and 36 methylation levels by targeting histone demethylase KDM4A for ubiquitin-mediated proteasomal degradation.

Reversible methylation of lysine residues has emerged as a central mechanism for epigenetic regulation and is a component of the "histone code," which engenders histones with gene regulatory information. KDM4A is a histone demethylase that targets tri- and dimethylation marks on histone H3 lysines 9 and 36. While the abundance of KDM4A oscillates in the cell cycle, little is known how this enzyme is regulated to achieve targeted effects on specific histone residues in chromatin. Here, we report that a previously unstudied SCF(FBXO22) ubiquitin ligase complex controls the activity of KDM4A by targeting it for proteasomal turnover. FBXO22 functions as a receptor for KDM4A by recognizing its catalytic JmjN/JmjC domains via its intracellular signal transduction (FIST) domain. Modulation of FBXO22 levels by RNA interference or overexpression leads to increased or decreased levels of KDM4A, respectively. Changes in KDM4A abundance correlate with alterations in histone H3 lysine 9 and 36 methylation levels, and transcription of a KDM4A target gene, ASCL2. Taken together, these results demonstrate that SCF(FBXO22) regulates changes in histone H3 marks and cognate transcriptional control pathways by controlling KDM4A levels, and they suggest a potential role for FBXO22 in development, differentiation, and disease through spatial and temporal control of KDM4A activity.

The ZIIR element of the Epstein-Barr virus BZLF1 promoter plays a central role in establishment and maintenance of viral latency.

The Epstein-Barr virus (EBV) BZLF1 gene encodes the immediate-early (IE) protein Zta, which plays a central role in regulating the switch between viral latency and lytic replication. A silencing element, ZIIR, is located between the ZID and ZII positive regulatory elements in the BZLF1 promoter Zp. We report here the phenotypes of variants of EBV strain B95.8 containing base substitution mutations in this ZIIR element. HEK293 cells infected with ZIIR mutant (ZIIRmt) virus produced at least 20-fold more viral IE Zta and Rta and early (E) EAD protein than did cells infected with the parental wild-type (WT) virus, leading to viral DNA replication and production of infectious virus. However, ZIIR mutant virus was 1/10 as efficient as WT virus in establishing proliferating B-cell clones following infection of human primary blood B cells. The ZIIRmt-infected lymphoblastoid cell lines (LCLs) that did grow out exhibited a phenotype similar to the one observed in 293 cells, including marked overproduction of IE and E gene products relative to WT-infected LCLs and lytic replication of the viral genome. Incubation of the ZIIRmt-infected LCLs with the chemical inducer 12-O-tetradecanoyl-phorbol-13-acetate (TPA) led to much greater activation of Zp than did the same treatment of WT- or ZVmt-infected LCLs. Furthermore, a protein kinase C (PKC) inhibitor, bis-indolylmaleimide, eliminated this activation by TPA. Thus, we conclude that ZIIR is a potent silencing element of Zp; it plays a key role in establishment and maintenance of EBV latency by inhibiting activation of Zp through the PKC signal transduction pathway.

Histone H4K20/H3K9 demethylase PHF8 regulates zebrafish brain and craniofacial development.

X-linked mental retardation (XLMR) is a complex human disease that causes intellectual disability. Causal mutations have been found in approximately 90 X-linked genes; however, molecular and biological functions of many of these genetically defined XLMR genes remain unknown. PHF8 (PHD (plant homeo domain) finger protein 8) is a JmjC domain-containing protein and its mutations have been found in patients with XLMR and craniofacial deformities. Here we provide multiple lines of evidence establishing PHF8 as the first mono-methyl histone H4 lysine 20 (H4K20me1) demethylase, with additional activities towards histone H3K9me1 and me2. PHF8 is located around the transcription start sites (TSS) of approximately 7,000 RefSeq genes and in gene bodies and intergenic regions (non-TSS). PHF8 depletion resulted in upregulation of H4K20me1 and H3K9me1 at the TSS and H3K9me2 in the non-TSS sites, respectively, demonstrating differential substrate specificities at different target locations. PHF8 positively regulates gene expression, which is dependent on its H3K4me3-binding PHD and catalytic domains. Importantly, patient mutations significantly compromised PHF8 catalytic function. PHF8 regulates cell survival in the zebrafish brain and jaw development, thus providing a potentially relevant biological context for understanding the clinical symptoms associated with PHF8 patients. Lastly, genetic and molecular evidence supports a model whereby PHF8 regulates zebrafish neuronal cell survival and jaw development in part by directly regulating the expression of the homeodomain transcription factor MSX1/MSXB, which functions downstream of multiple signalling and developmental pathways. Our findings indicate that an imbalance of histone methylation dynamics has a critical role in XLMR.