Arginine-methylated c-Myc affects mitochondrial mitophagy in mouse acute kidney injury via Slc25a24.

The transcription factor methylated c-Myc heterodimerizes with MAX to modulate gene expression, and plays an important role in energy metabolism in kidney injury but the exact mechanism remains unclear. Mitochondrial solute transporter Slc25a24 imports ATP into mitochondria and is central to energy metabolism. Gene Expression Omnibus data analysis reveals Slc25a24 and c-Myc are consistently upregulated in all the acute kidney injury (AKI) cells. Pearson correlation analysis also shows that Slc25a24 and c-Myc are strongly correlated (⍴ > 0.9). Mutant arginine methylated c-Myc (R299A and R346A) reduced its combination with MAX when compared with the wild type of c-Myc. On the other hand, the Slc25a24 levels were also correspondingly reduced, which induced the downregulation of ATP production. The results promoted reactive oxygen species (ROS) production and mitophagy generation. The study revealed that the c-Myc overexpression manifested the most pronounced mitochondrial DNA depletion. Additionally, the varied levels of mitochondrial proteins like TIM23, TOM20, and PINK1 in each group, particularly the elevated levels of PINK1 in AKI model groups and lower levels of TIM23 and TOM20 in the c-Myc overexpression group, suggest potential disruptions in mitochondrial dynamics and homeostasis, indicating enhanced mitophagy or mitochondrial loss. Therefore, arginine-methylated c-Myc affects mouse kidney injury by regulating mitochondrial ATP and ROS, and mitophagy via Slc25a24.

Effectiveness of virtual reality in preventing falls in non-disabled older adults: A meta-analysis and systematic review.

OBJECTIVE: This study was conducted to evaluate the effectiveness of virtual reality interventions in preventing falls among non-disabled older adults. METHODS: We conducted a librarian-designed database search. Two researchers independently screened eligible studies. The Cochrane Handbook for Systematic Reviews of Interventions was used to assess the risk of bias in the included studies. RESULTS: Virtual reality interventions can effectively improve gait and dynamic and static balance function, enhance lower limb muscle strength, and reduce the risk of falls in the non-disabled elderly. However, the effect of virtual reality on reducing the fear of falling remains controversial. CONCLUSION: Virtual reality interventions can effectively prevent falls in nondisabled elderly individuals. Higher quality, larger sample size, and long-term follow-up studies are needed to further verify the long-term effectiveness of virtual reality training in preventing falls in non-disabled elderly individuals.

Clinical perspectives and outcomes of the giant breast phyllodes tumor and sarcoma: a real-world retrospective study.

BACKGROUND: Giant breast malignant phyllodes tumor or sarcoma (GBPS) are rare entities with diameter larger than 10 cm and variously histological pleomorphisms. This disease poses a significant threat to the quality of life of individuals, and its prognosis remains unclear. This study aimed to explore the differential diagnosis, treatment, and prognosis of GBPS in a real-world retrospective cohort. METHODS: We collected GBPS (diameter > 10 cm, n = 10) and BPS (diameter ≤ 10 cm, n = 126) from patients diagnosed with sarcoma or malignant phyllodes tumor between 2008 and 2022. We analyzed clinical characteristics, histological status, treatment, and local recurrence using the Fisher's exact test between GBPS (diameter > 10 cm) and BPS (diameter ≤ 10 cm) cohort. We described overall survival (OS) and disease-free survival (DFS) using Kaplan-Meier curves and identified risk factors for local recurrence using logistic regression. The tumor size, age at diagnosis, and differential immunohistochemistry markers of breast sarcoma or phyllodes tumor to determine the prognosis of GBPS. RESULTS: In our retrospective analysis of breast malignancies, we identified 10 cases of GBPS and 126 cases of BPS, corresponding to a GBPS prevalence of 0.17% (10/6000). The median age was 38.5 years (inter-quartile range, IQR: 28.25-48.5 years). During the follow-up of period (median: 80.5 months, IQR: 36.75-122 months), the local recurrence (LR) rate was 40% and 20.6%, respectively. Clinical characteristics of young age (HR:2.799, 95%CI -00.09276-0.017, p < 0.05) and cytological characteristics of marked stromal atypia (HR:0.88, 95% CI 0.39-1.40, p < 0.05) were risk factors for the poor prognosis of GBPS by COX regression model analysis. The Kaplan-Meier curves of GBPS 5-year disease-free survival (DFS) and overall survival (OS) were 31.5 months and 40 months, respectively, and were not associated with adjuvant radiation or chemotherapy. CONCLUSION: We recommend mastectomy with a clear surgical margin as the preferred treatment for GBPS. Age and stromal atypia are significantly associated with recurrence. Adjuvant radiation therapy is advised; however, there was no improvement in overall survival. There is no consensus on the effectiveness of adjuvant chemotherapy and genetic methods, highlighting the need for further research into this aggressive tumor. We recommend a multidisciplinary approach involving a dedicated team for the management of GBPS.

GBP5 Inhibition Ameliorates the Progression of Lupus Nephritis by Suppressing NLRP3 Inflammasome Activation.

BACKGROUND: The inflammatory response and NLRP3 inflammasome activation are typical characteristics of lupus nephritis (LN). Guanylate-binding protein 5 (GBP5) has effects on the release of proinflammatory cytokines and the activation of NLRP3 inflammasome. However, it is largely unknown whether and how GBP5 contributes to the progression of LN. METHODS: To detect the role of GBP5 in LN, MRL/lpr mice were administrated with the lentiviral vectors that knockdown GBP5 via tail vein. Proximal tubular epithelial HK-2 cells were treated with LPS and ATP to mimic the inflammatory response of LN in vitro. RESULTS: GBP5 expression was increased in the renal cortical tissues of LN mice. The in vivo results showed that GBP5 inhibition prevented the progression of LN, as evidenced by the decreased levels of 24-hour proteinuria, blood urea nitrogen and creatinine, accompanied by the ameliorated renal pathological damages. The increased mRNA and protein levels of proinflammatory factors (IL-6, TNF-α, iNOS and COX-2) in the renal cortex of LN mice were suppressed by GBP5 knockdown. In vitro, we demonstrated that the treatment of LPS combined with ATP induced an increase in GBP5 mRNA and protein expression in HK-2 cells. Mechanically, knockdown of GBP5 inhibited the activation of NLRP3 inflammasome and the secretion of IL-1ß and IL-18 both in vivo and in vitro. CONCLUSION: Our findings reveal that GBP5 inhibition prevents the progression of LN, most likely by suppressing NLRP3 inflammasome activation. It provides a novel insight into the therapeutic interventions for LN.

Effectiveness of virtual reality in reducing preoperative anxiety in adults: A systematic review and meta-analysis.

AIM: To evaluate the impact of a virtual reality (VR) intervention on adult patients' preoperative anxiety, heart rate, respiration rate and blood pressure. DESIGN: A systematic review and meta-analysis of randomized controlled trials (RCTs). DATA SOURCES: A librarian-designed search of the Cochrane Library, PubMed, Web of Science, EMBASE, CINAHL, CBM, CNKI and Wanfang databases was conducted to identify research studies in English or Chinese on RCTs from their inception to 31 May 2022. Detailed search strategies and the checklist are provieded in Supplementary files S1 and S2. REVIEW METHODS: Two researchers independently screened eligible studies. The Cochrane Handbook for Systematic Reviews of Interventions was used to assess the risk of bias in the included studies. A fixed- or random-effects meta-analysis model was used to determine the pooled mean difference based on the results of the heterogeneity test. RESULTS: This study included 11 articles with a total of 892 participants. VR distraction comprised five studies, and VR exposure consisted of six studies. The results indicated that VR could reduce preoperative anxiety in adult patients and VR exposure seems to be more effective. The results also indicated that VR intervention can effectively reduce patients' heart rate and blood pressure compared to traditional intervention methods, but had no significant effect on respiration rate. CONCLUSION: VR technology could relieve preoperative anxiety in adult patients through distraction or exposure. More well-designed RCTs containing a wider range of surgical types are needed to verify our findings before we can make strong recommendations. IMPACT: Our systematic review and meta-analysis show a positive effect of VR distraction and exposure interventions in reducing preoperative anxiety in adult patients. We suggest incorporating VR into preoperative procedures as an auxiliary way to reduce negative emotions in eligible patients. NO PATIENT OR PUBLIC CONTRIBUTION: Our paper is a systematic review and meta-analysis and such details do not apply to our work.

Effectiveness of virtual reality intervention on reducing the pain, anxiety and fear of needle-related procedures in paediatric patients: A systematic review and meta-analysis.

AIMS: To evaluate the effectiveness of virtual reality (VR) intervention in the management of pain, anxiety and fear in paediatric patients undergoing needle-related procedures. DESIGN: A systematic review and meta-analysis of randomized controlled trials (RCTs). DATA SOURCES: A librarian-designed search of the Cochrane Library, PubMed, Web of Science, EMBASE, CINAHL, CBM, CNKI, and Wanfang databases was conducted to identify research articles in English or Chinese on RCTs up to February 28, 2022. REVIEW METHODS: Two researchers independently screened eligible articles. The Cochrane Handbook for Systematic Reviews was used to assess the risk of bias in the included studies. A fixed- or random-effects meta-analysis model was used to determine the pooled mean difference based on the results of the heterogeneity test. RESULTS: A total of 2269 articles were initially screened. The meta-analysis included data from 27 studies representing 2224 participants. Compared with the non-VR group, the VR intervention group significantly reduced pain, anxiety, and fear in paediatric patients who underwent puncture-related procedures. Subgroup analysis showed that VR has advantages over conventional and other distraction methods. CONCLUSION: Paediatric patients undergoing needle-related procedures would benefit from VR interventions for pain, anxiety and fear management. IMPACT: VR intervention has the potential to reduce pain, anxiety and fear in paediatric patients undergoing puncture-related procedures. Future clinical interventions could incorporate VR into puncture procedures as an effective method to reduce negative emotions in children eligible for VR distractions. PATIENT OR PUBLIC CONTRIBUTION: Our paper is a systematic review and meta-analysis and such details don't apply to our work.

Effectiveness of home-based cardiac telerehabilitation in patients with heart failure: A systematic review and meta-analysis of randomised controlled trials.

AIMS AND OBJECTIVES: To evaluate the effectiveness of home-based cardiac telerehabilitation in patients with heart failure. DESIGN: This systematic review and meta-analysis of randomised controlled trials were designed and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. METHODS: Two researchers independently screened eligible studies. The Cochrane Handbook for Systematic Reviews of Interventions was used to assess the risk of bias within the included studies. A fixed- or random-effects meta-analysis model was used to determine the mean difference, based on the results of the heterogeneity test. DATA SOURCES: A librarian-designed search of the Cochrane Library, PubMed, Web of Science, EMBASE, CINAHL, CBM, CNKI and Wanfang databases was conducted to identify studies in English or Chinese on randomised controlled trials up to 15 August 2022. RESULTS: A total of 2291 studies were screened. The meta-analysis included data from 16 studies representing 4557 participants. The results indicated that home-based cardiac telerehabilitation could improve heart rate, VO2 peak, 6-minute walk distance, quality of life and reduce readmission rates. No significant differences were observed in the left ventricular ejection fraction percentages between the home-based cardiac telerehabilitation and usual care groups. Compared with centre-based cardiac rehabilitation, home-based cardiac telerehabilitation showed no significant improvement in outcome indicators. CONCLUSION: Patients with heart failure benefit from home-based cardiac telerehabilitation intervention. With the rapid development of information and communication technology, home-based cardiac telerehabilitation has great potential and may be used as an adjunct or substitute for centre-based cardiac rehabilitation. IMPACT: This systematic review and meta-analysis found that patients with heart failure would benefit from home-based cardiac telerehabilitation intervention in terms of cardiac function, functional capacity, quality-of-life management and readmission rate. Future clinical interventions should consider home-based cardiac telerehabilitation as an alternative to conventional cardiac rehabilitation in patients with heart failure to improve their quality of life. NO PATIENT OR PUBLIC CONTRIBUTION: Our paper is a systematic review and meta-analysis, and such details do not apply to our work.

Gut microbial metabolite TMAO contributes to renal dysfunction in a mouse model of diet-induced obesity.

Emerging evidence shows that obesity induces renal injury and is an independent risk factor for the development of chronic kidney disease (CKD), even without diabetes or hyperglycemia. Although multiple metabolic factors have been suggested to account for obesity-associated renal injury, the precious underlying mechanisms are not completely understood. Recent study shows that increased trimethylamine N-Oxide (TMAO), a gut microbiota-generated metabolite, directly contributes to renal interstitial fibrosis and dysfunction. Circulating TMAO is elevated in high-fat diets (HFD)-induced obese animals. Here we tested the hypothesis that elevated TMAO might play a contributory role in the development of renal dysfunction in a mouse model of HFD-induced obesity that mimics human obesity syndrome. Male C57BL/6 mice received either a low-fat diet (LFD) or a HFD, without or with 3,3-Dimethyl-1-butanol (DMB, a trimethylamine formation inhibitor) for 16 weeks. Compared with mice fed a LFD, mice fed a HFD developed obesity and metabolic disorders, and exhibited significantly elevated plasma TMAO levels at the end of the experiment. Molecular and morphological studies revealed that renal interstitial fibrosis, phosphorylation of SMAD3 (a key regulator of renal fibrosis), expression of kidney injury molecule-1 and plasma cystatin C were significantly increased in mice fed a HFD, compared with mice fed a LFD. Additionally, expression of NADPH oxidase-4 and pro-inflammatory cytokines tumor necrosis factor-α and interleukin-1 ß was also augmented in mice fed a HFD as compared to mice fed a LFD. These molecular and morphological alterations observed in mice fed a HFD were prevented by concomitant treatment with DMB, which reduced plasma TMAO levels. Furthermore, elevated circulating TMAO levels were positively correlated with increased renal interstitial fibrosis and expression of kidney injury molecule-1. Notable, there was no difference in blood pressure among groups, and DMB treatment had no effects on body weight and metabolic parameters. These data suggest that HFD-induced obesity leads to elevations in gut microbiota-generated metabolite TMAO in the circulation, which contributes to renal interstitial fibrosis and dysfunction by promoting renal oxidative stress and inflammation. These findings may provide new insights into the mechanisms underlying obesity-associated CKD. Targeting TMAO may be a novel strategy for prevention and treatment of CKD in patients with obesity.

Silencing of adipocyte enhancer-binding protein 1 (AEBP1) alleviates renal fibrosis in vivo and in vitro via inhibition of the ß-catenin signaling pathway.

Renal fibrosis is the common final pathway in many renal diseases regardless of the underlying etiology. Adipocyte enhancer-binding protein 1 (AEBP1) was reported to play a vital role in the development of organ fibrosis, but its role in renal fibrosis has not been reported. Thus, the aim of this study was to investigate the possible function of AEBP1 in renal fibrosis and the mechanism associated with the ß-catenin signaling pathway. A total of 83 genes upregulated after unilateral ureteral obstruction (UUO) were screened from two Gene Expression Omnibus (GEO) datasets and subjected to Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Among them, AEBP1 was enriched in collagen binding and the regulation of collagen fibril organization and was confirmed to be upregulated in UUO kidneys and TGF-ß1-induced cells. Knockdown of AEBP1 ameliorated renal fibrosis via reducing collagen accumulation, inhibiting epithelial-mesenchymal transition and fibroblast transformation, as evidenced by decreases in the expression of collagen I and III, Col1a1, Col3a1, fibronectin, Snail, α-SMA, as well as collagen-specific staining of kidney tissues, whereas the E-cadherin was increased. Besides, AEBP1 silencing inhibited the expression of ß-catenin in nucleus and ß-catenin downstream proteins (Axin2, Myc, and Ccnd1). Continuously active ß-catenin-S33Y further restored the inhibitory effect of AEBP1 silencing on renal fibrosis. These findings indicate that knockdown of AEBP1 could potentially slow down renal fibrosis by blocking the ß-catenin signaling pathway, highlighting the potential of AEBP1 as a therapeutic target for renal fibrosis.

Effects of Nonimmersive Virtual Reality Intervention on Children With Spastic Cerebral Palsy: A Meta-analysis and Systematic Review.

ABSTRACT: This review aimed to assess the effectiveness of nonimmersive virtual reality intervention compared with traditional rehabilitation in improving the functions of the upper and lower limbs, balance, and social participation among children with spastic cerebral palsy. We used librarian-designed searches of 10 databases to identify research articles on randomized controlled trials that assessed the effectiveness of nonimmersive virtual reality in intervening spastic cerebral palsy patients up to April 15, 2023. Independent evaluation was conducted by two trained investigators using the evaluation criteria of randomized controlled trial quality indicated in the Cochrane Manual of Assessment "risk-of-bias tool." The Physical Therapy Evidence Database scale was used to evaluate the method and quality of the literature. Twenty-one research articles involving 779 patients with spastic cerebral palsy were included. Significant differences between the nonimmersive virtual reality rehabilitation and traditional rehabilitation groups were observed in all indicators, except for the Jebsen-Taylor Hand Function Test. Nonimmersive virtual reality intervention is effective in improving the function of the lower extremity, balance, and social participation in children with spastic cerebral palsy, but its effect on upper limb function is still controversial.

FOSL2 participates in renal fibrosis via SGK1-mediated epithelial-mesenchymal transition of proximal tubular epithelial cells.

Background: Fos-related antigen 2 (FOSL2) plays a facilitative role in fibrotic disease; however, its role in renal fibrosis remains unclear. This study aimed to clarify the role and underlying mechanisms of FOSL2 in renal fibrosis. Methods: Upregulated genes in unilateral ureteral obstruction (UUO)-injured kidneys were screened in Gene Expression Omnibus (GEO) databases, and overlapping genes were identified using Venn diagram software. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed for these genes. The UUO-induced mouse model and transforming growth factor-ß1 (TGF-ß1)-induced cell model were used for the in vivo and in vitro studies. Results: A total of 43 commonly upregulated genes were identified. GO and KEGG pathway analyses indicated that FOSL2 may be involved in fibrosis. Furthermore, FOSL2 was confirmed to be upregulated in UUO-injured kidneys and TGF-ß1-induced cells. Knockdown of FOSL2 ameliorated interstitial fibrosis, extracellular matrix deposition, and epithelial-mesenchymal transition via the downregulation of fibronectin, α-smooth muscle actin (α-SMA), collagen type I (Col1a1 and Col1a2), and Col5a1 and upregulation of E-cadherin. Bioinformatics analysis revealed that serum/glucocorticoid regulated kinase 1 (SGK1) may be regulated by FOSL2 and involved in renal fibrosis. Further experiments confirmed that TGF-ß1 enhanced SGK1 expression and transcription, which were reversed by FOSL2 silencing. Moreover, FOSL2 was bound to the SGK1 promoter, and SGK1 overexpression reversed the effects of FOSL2 silencing in TGF-ß1-induced cells. Conclusion: FOSL2 plays an essential role in promoting renal fibrosis in an SGK1-dependent manner, and targeting the FOSL2/SGK1 signaling axis may offer a potential strategy for the treatment of renal fibrosis.

Hepatocyte nuclear factor 4 a (HNF4α): A perspective in cancer.

HNF4α, a transcription factor, plays a vital role in regulating functional genes and biological processes. Its alternative splicing leads to various transcript variants encoding different isoforms. The spotlight has shifted towards the extensive discussion on tumors interplayed withHNF4α abnormalities. Aberrant HNF4α expression has emerged as sentinel markers of epigenetic shifts, casting reverberations upon downstream target genes and intricate signaling pathways, most notably with cancer. This review provides a comprehensive overview of HNF4α's involvement in tumor progression and metastasis, elucidating its role and underlying mechanisms.

c-MYC-induced long noncoding RNA MEG3 aggravates kidney ischemia-reperfusion injury through activating mitophagy by upregulation of RTKN to trigger the Wnt/ß-catenin pathway.

Ischemia-reperfusion injury (IRI)-induced acute kidney injury (AKI) is a life-threatening disease. The activation of mitophagy was previously identified to play an important role in IRI. Maternally expressed 3 (MEG3) can promote cerebral IRI and hepatic IRI. The present study was designed to study the role of MEG3 in renal IRI. Renal IRI mice models were established, and HK-2 cells were used to construct the in vitro models of IRI. Hematoxylin-eosin staining assay was applied to reveal IRI-triggered tubular injury. MitoTracker Green FM staining and an ALP kit were employed for detection of mitophagy. TdT-mediated dUTP-biotin nick-end labeling assay was used to reveal cell apoptosis. The results showed that renal cortex of IRI mice contained higher expression of MEG3 than that of sham mice. MEG3 expression was also elevated in HK-2 cells following IRI, suggesting that MEG3 might participate in the development of IRI. Moreover, downregulation of MEG3 inhibited the apoptosis of HK-2 cells after IRI. Mitophagy was activated by IRI, and the inhibition of MEG3 can restore mitophagy activity in IRI-treated HK-2 cells. Mechanistically, we found that MEG3 can bind with miR-145-5p in IRI-treated cells. In addition, rhotekin (RTKN) was verified to serve as a target of miR-145-5p. MEG3 upregulated RTKN expression by binding with miR-145-5p. Further, MEG3 activated the Wnt/ß-catenin pathway by upregulation of RTKN. The downstream effector of Wnt/ß-catenin pathway, c-MYC, served as the transcription factor to activate MEG3. In conclusion, the positive feedback loop of MEG3/miR-145-5p/RTKN/Wnt/ß-catenin/c-MYC promotes renal IRI by activating mitophagy and inducing apoptosis, which might offer a new insight into the therapeutic methods for renal IRI in the future.