Publications by authors named "Jiankang Liu"

275 Publications

Exercise promotes angiogenesis by enhancing endothelial cell fatty acid use via liver-derived extracellular vesicle miR-122-5p.

J Sport Health Sci 2021 Oct 1. Epub 2021 Oct 1.

School of Aerospace Medicine, Fourth Military Medical University, Xi'an 710032, China.

Background: Angiogenesis constitutes a major mechanism responsible for exercise-induced beneficial effects. Our previous study identified a cluster of differentially expressed extracellular vesicle microRNAs (miRNAs) after exercise and found that some of them act as exerkines. However, whether these extracellular vesicle miRNAs mediate the exercise-induced angiogenesis remains unknown.

Methods: A 9-day treadmill training was used as an exercise model in C57BL/6 mice. Liver-specific adeno-associated virus 8 was used to knock down microRNA-122-5p (miR-122-5p). Human umbilical vein endothelial cells were used in vitro.

Results: Among these differentially expressed extracellular vesicle miRNAs, miR-122-5p was identified as a potent pro-angiogenic factor that activated vascular endothelial growth factor signaling and promoted angiogenesis both in vivo and in vitro. Exercise increased circulating levels of miR-122-5p, which was produced mainly by the liver and shuttled by extracellular vesicles in mice. Inhibition of circulating miR-122-5p or liver-specific knockdown of miR-122-5p significantly abolished the exercise-induced pro-angiogenic effect in skeletal muscles, and exercise-improved muscle performance in mice. Mechanistically, miR-122-5p promoted angiogenesis through shifting substrate preference to fatty acids in endothelial cells, and miR-122-5p upregulated endothelial cell fatty-acid use by targeting 1-acyl-sn-glycerol-3-phosphate acyltransferase (AGPAT1). In addition, miR-122-5p increased capillary density in perilesional skin tissues and accelerated wound healing in mice.

Conclusion: These findings demonstrated that exercise promotes angiogenesis through upregulation of liver-derived extracellular vesicle miR-122-5p, which enhances fatty acid use by targeting AGPAT1 in endothelial cells, highlighting the therapeutic potential of miR-122-5p in tissue repair.
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http://dx.doi.org/10.1016/j.jshs.2021.09.009DOI Listing
October 2021

Dynamic motions and architectural changes in DNA supramolecular aggregates visualized transmission electron microscopy without liquid cells.

Nanoscale 2021 Oct 1;13(37):15928-15936. Epub 2021 Oct 1.

The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, Shaanxi, China.

In the last decade, breakthroughs in liquid-phase transmission electron microscopy (TEM) have enabled visualization of the motion dynamics of nanostructures in liquid media with unprecedented detail. However, it remains a significant challenge to perform liquid-phase TEM due to the intricate preparation procedure of liquid cells to keep liquid from evaporating under ultrahigh vacuum conditions in TEM columns. In the present study, the nonvolatility and remarkable solvation property of ionic liquids (ILs) is exploited to image the dynamic processes of DNA supramolecular aggregates and Au nanoparticle (NP) aggregates encompassing Brownian motions, interactions among individual nanoobjects and changes in architecture at nanometer resolution. Significant differences in motion behaviors are observed between DNA supramolecular aggregates and Au NP aggregates. Moreover, the temperature and dose dependence of dynamic motions are also investigated. The findings provide insights into the dynamics of DNA supramolecular aggregates and Au NP aggregates in ILs and present an easily accessible approach for probing the dynamic processes of biomacromolecular and other soft matter aggregates with various kinds of ILs at the nanoscale level.
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http://dx.doi.org/10.1039/d1nr04133aDOI Listing
October 2021

Integrating High-Sensitivity Troponin T and Sacubitril/Valsartan Treatment in HFpEF: The PARAGON-HF Trial.

JACC Heart Fail 2021 Sep 7;9(9):627-635. Epub 2021 Jul 7.

Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts, USA. Electronic address:

Objectives: This study examined the relationship among high-sensitivity troponin-T (hs-TnT), outcomes, and treatment with sacubitril/valsartan in patients with heart failure (HF) and preserved ejection fraction (HFpEF).

Background: hs-TnT is a marker of myocardial injury in HF.

Methods: The PARAGON-HF trial randomized 4,796 patients with HFpEF to sacubitril/valsartan or valsartan. We compared the risk of the composite outcome of cardiovascular death (CVD) and total HF hospitalization (HHF) according to hs-TnT. We also assessed the effect of allocated treatment on hs-TnT.

Results: hs-TnT was available in 1,141 patients (24%) at run-in (median value: 17 ng/L) and 1,260 (26%) at randomization, with 58.3% having hs-TnT >14 ng/L (upper limit of normal). During a median follow-up of 34 months, there were 393 outcome events (82 CVD, 311 HHF). Adjusting for demographics, comorbidities, left ventricular ejection fraction (LVEF), and N-terminal pro B-type natriuretic peptide (NT-proBNP), log-hs-TnT at randomization was an independent predictor of the composite outcome (HR: 1.38; 95% CI: 1.19-1.59; P < 0.001). Compared with valsartan, sacubitril/valsartan significantly reduced hs-TnT by 9% at week 16 (P < 0.001). Patients whose hs-TnT decreased from randomization to 16 weeks to at or below the median value of 17 ng/L subsequently had a lower risk of CVD/HHF compared with those with persistently elevated hs-TnT (P = 0.046). Patients with higher baseline hs-TnT (>17 ng/L) appeared to have a greater benefit from sacubitril/valsartan treatment when accounting for other potential effect modifiers (P interaction = 0.07).

Conclusions: Higher baseline hs-TnT was associated with increased risk of CVD/HHF, whereas hs-TnT decrease at 16 weeks led to lower subsequent risk of CVD/HHF compared with those who had persistently elevated values. Sacubitril/valsartan significantly reduced hs-TnT compared with valsartan. hs-TnT may be helpful in identifying patients with HFpEF who are more likely to benefit from sacubitril/valsartan.
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http://dx.doi.org/10.1016/j.jchf.2021.04.009DOI Listing
September 2021

Regulation of IFN-Is by MEF2D Promotes Inflammatory Homeostasis in Microglia.

J Inflamm Res 2021 29;14:2851-2863. Epub 2021 Jun 29.

Department of Experimental Surgery, Tangdu Hospital, Airforce Medical University of PLA, Xi'an, Shaanxi, 710038, People's Republic of China.

Background: Microglia play an essential role in the central nervous system immune response. The transcription factor myocyte enhancer factor-2 D (MEF2D) is known to participate in stress regulation in various cell types and is easily activated in microglia. MEF2D has been shown to transcriptionally regulate several cytokine genes in immune cells and directly regulates the inflammatory response, suggesting that MEF2D may act as a key stimulus response regulator of microglia and is involved in the regulation of brain microhomeostasis. To uncover the molecular mechanism of MEF2D in the inflammatory system, in the present study, we investigated the global effect of MEF2D in activated microglia and explored its potential regulatory network.

Methods: Experiments with a recombinant lentiviral vector containing either shRNA or overexpressing MEF2D were performed in the murine microglial BV2 cell line. Transcriptome sequencing and global gene expression patterns were analysed in lipopolysaccharide-stimulated shMEF2D BV2 cells. Pro- and anti-inflammatory factors were assessed by Western blot, qPCR or ELISA, and microglial activity was assessed by phagocytosis and morphologic analysis. The direct binding of MEF2D to the promoter region of interferon regulatory factor 7 (IRF7) was tested by ChIP-qPCR. The interferon-stimulated genes (ISGs) were tested by qPCR.

Results: MEF2D actively participated in the inflammatory response of BV2 microglial cells. Stably expressed RNAi-induced silencing of MEF2D disrupted the microglial immune balance in two ways: (1) the expression of proinflammatory factors, such as NLRP3, IL-1β, and iNOS was promoted; and (2) the type-I interferon signalling pathway was markedly inhibited by directly modulating IRF7 transcription. In contrast, overexpression of MEF2D significantly reduced the expression of NLRP3 and iNOS under LPS stimulation and alleviated the level of immune stress in microglia.

Conclusion: These findings demonstrate that MEF2D plays an important role in regulating inflammatory homeostasis partly through transcriptional regulation of the type-I interferon signalling pathway.
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http://dx.doi.org/10.2147/JIR.S307624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8254549PMC
June 2021

The COVID-19 pandemic and physical activity.

Sports Med Health Sci 2020 Jun 30;2(2):55-64. Epub 2020 May 30.

The Laboratory of Physiological Hygiene and Exercise Science, School of Kinesiology, University of Minnesota Twin Cities, Minneapolis, USA.

The SARS-CoV-2-caused COVID-19 pandemic has resulted in a devastating threat to human society in terms of health, economy, and lifestyle. Although the virus usually first invades and infects the lung and respiratory track tissue, in extreme cases, almost all major organs in the body are now known to be negatively impacted often leading to severe systemic failure in some people. Unfortunately, there is currently no effective treatment for this disease. Pre-existing pathological conditions or comorbidities such as age are a major reason for premature death and increased morbidity and mortality. The immobilization due to hospitalization and bed rest and the physical inactivity due to sustained quarantine and social distancing can downregulate the ability of organs systems to resist to viral infection and increase the risk of damage to the immune, respiratory, cardiovascular, musculoskeletal systems and the brain. The cellular mechanisms and danger of this "second wave" effect of COVID-19 to the human body, along with the effects of aging, proper nutrition, and regular physical activity, are reviewed in this article.
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http://dx.doi.org/10.1016/j.smhs.2020.05.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261095PMC
June 2020

Hypermethylation of Hepatic Mitochondrial Provokes Systemic Insulin Resistance.

Adv Sci (Weinh) 2021 06 2;8(11):2004507. Epub 2021 May 2.

Center for Mitochondrial Biology and Medicine The Key Laboratory of Biomedical Information Engineering of Ministry of Education School of Life Science and Technology Xi'an Jiaotong University Xi'an Shaanxi 710049 China.

Mitochondrial epigenetics is rising as intriguing notion for its potential involvement in aging and diseases, while the details remain largely unexplored. Here it is shown that among the 13 mitochondrial DNA (mtDNA) encoded genes, NADH-dehydrogenase 6 () transcript is primarily decreased in obese and type 2 diabetes populations, which negatively correlates with its distinctive hypermethylation. Hepatic mtDNA sequencing in mice unveils that presents the highest methylation level, which dramatically increases under diabetic condition due to enhanced mitochondrial translocation of DNA methyltransferase 1 (DNMT1) promoted by free fatty acid through adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) activation. Hepatic knockdown of or overexpression of similarly impairs mitochondrial function and induces systemic insulin resistance both in vivo and in vitro. Genetic or chemical targeting hepatic DNMT1 shows significant benefits against insulin resistance associated metabolic disorders. These findings highlight the pivotal role of epigenetic network in regulating mitochondrial function and onset of insulin resistance, shedding light on potential preventive and therapeutic strategies of insulin resistance and related metabolic disorders from a perspective of mitochondrial epigenetics.
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http://dx.doi.org/10.1002/advs.202004507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8188198PMC
June 2021

Effect of sacubitril/valsartan vs. enalapril on changes in heart failure therapies over time: the PARADIGM-HF trial.

Eur J Heart Fail 2021 09 21;23(9):1518-1524. Epub 2021 Jun 21.

Division of Cardiology, Brigham and Women's Hospital, Boston, MA, USA.

Aims: Sacubitril/valsartan improves morbidity and mortality in patients with heart failure and reduced ejection fraction (HFrEF). Whether initiation of sacubitril/valsartan limits the use and dosing of other elements of guideline-directed medical therapy for HFrEF is unknown. We examined the effects of sacubitril/valsartan, compared with enalapril, on β-blocker and mineralocorticoid receptor antagonist (MRA) use and dosing in a large randomized clinical trial.

Methods And Results: Patients with full data on medication use were included. We examined β-blocker and MRA use in patients randomized to sacubitril/valsartan vs. enalapril through 12-month follow-up. New initiations and discontinuations of β-blocker and MRA were compared between treatment groups. Overall, 8398 (99.9%) had full medication and dose data at baseline. Baseline use of β-blocker and MRA at any dose was 87% and 56%, respectively. Mean doses of β-blocker and MRA were similar between treatment groups at baseline and at 6-month and 12-month follow-up. New initiations through 12-month follow-up were infrequent and similar in the sacubitril/valsartan and enalapril groups for β-blockers [37 (9.0%) vs. 42 (10.2%), P = 0.56] and MRA [127 (7.6%) vs. 143 (9.2%), P = 0.10]. Among patients on MRA therapy at baseline, there were fewer MRA discontinuations in patients on sacubitril/valsartan as compared with enalapril at 12 months [125 (6.2%) vs. 187 (9.0%), P = 0.001]. Discontinuations of β-blockers were not significantly different between groups in follow-up (2.2% vs. 2.6%, P = 0.26).

Conclusions: Initiation of sacubitril/valsartan, even when titrated to target dose, did not appear to lead to greater discontinuation or dose down-titration of other key guideline-directed medical therapies, and was associated with fewer discontinuations of MRA. Use of sacubitril/valsartan (when compared with enalapril) may promote sustained MRA use in follow-up.
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http://dx.doi.org/10.1002/ejhf.2259DOI Listing
September 2021

LncRNA SAMMSON Mediates Adaptive Resistance to RAF Inhibition in BRAF-Mutant Melanoma Cells.

Cancer Res 2021 06 18;81(11):2918-2929. Epub 2021 Mar 18.

Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi, China.

The long noncoding RNA (lncRNA) SAMMSON is required for human melanoma cell growth and survival. However, whether SAMMSON regulates the response of mutant BRAF melanoma cells to RAF inhibitors remains unknown. In this work, we showed that SAMMSON is rapidly induced upon inhibition of ERK signaling, and SAMMSON overexpression conferred resistance to vemurafenib-induced cytotoxicity in melanoma cells. SOX10 mediated transcriptional induction of SAMMSON by vemurafenib, and SOX10 sumoylation at K55 was essential for this function. In addition, depletion of SAMMSON activated p53 signaling, which is dependent on the SAMMSON-interacting protein CARF. Depletion of SAMMSON sensitized mutant BRAF melanoma cells to RAF inhibitors and , while CARF knockdown reversed the enhanced sensitivity. In summary, these findings suggest that SAMMSON may function as a new mediator of adaptive resistance to RAF inhibitors in melanoma by modulating CARF-p53 signaling. SIGNIFICANCE: This study highlights the role of a SAMMSON/CARF/p53 signaling axis in modulating the adaptive resistance of mutant BRAF melanoma to RAF inhibitors.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-3145DOI Listing
June 2021

Topological reorganizations of mitochondria isolated from rat brain after 72 hours of paradoxical sleep deprivation, revealed by electron cryo-tomography.

Am J Physiol Cell Physiol 2021 07 12;321(1):C17-C25. Epub 2021 May 12.

Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China.

Sleep deprivation has profound influence on several aspects of health and disease. Mitochondria dysfunction has been implicated to play an essential role in the neuronal cellular damage induced by sleep deprivation, but little is known about how neuronal mitochondrial ultrastructure is affected under sleep deprivation. In this report, we utilized electron cryo-tomography to reconstruct the three-dimensional (3-D) mitochondrial structure and extracted morphometric parameters to quantitatively characterize its reorganizations. Isolated mitochondria from the hippocampus and cerebral cortex of adult male Sprague-Dawley rats after 72 h of paradoxical sleep deprivation (PSD) were reconstructed and analyzed. Statistical analysis of six morphometric parameters specific to the mitochondrial inner membrane topology revealed identical pattern of changes in both the hippocampus and cerebral cortex but with higher significance levels in the hippocampus. The structural differences were indistinguishable by conventional phenotypic methods based on two-dimensional electron microscopy images or 3-D electron tomography reconstructions. Furthermore, to correlate structure alterations with mitochondrial functions, high-resolution respirometry was employed to investigate the effects of PSD on mitochondrial respiration, which showed that PSD significantly suppressed the mitochondrial respiratory capacity of the hippocampus, whereas the isolated mitochondria from the cerebral cortex were less affected. These results demonstrate the capability of the morphometric parameters for quantifying complex structural reorganizations and suggest a correlation between PSD and inner membrane architecture/respiratory functions of the brain mitochondria with variable effects in different brain regions.
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http://dx.doi.org/10.1152/ajpcell.00077.2021DOI Listing
July 2021

Global Differences in Heart Failure With Preserved Ejection Fraction: The PARAGON-HF Trial.

Circ Heart Fail 2021 04 19;14(4):e007901. Epub 2021 Apr 19.

National Heart Centre Singapore (J.T., C.S.P.L.).

Background: Heart failure with preserved ejection fraction (HFpEF) is a global public health problem with important regional differences. We investigated these differences in the PARAGON-HF trial (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in HFpEF), the largest and most inclusive global HFpEF trial.

Methods: We studied differences in clinical characteristics, outcomes, and treatment effects of sacubitril/valsartan in 4796 patients with HFpEF from the PARAGON-HF trial, grouped according to geographic region.

Results: Regional differences in patient characteristics and comorbidities were observed: patients from Western Europe were oldest (mean 75±7 years) with the highest prevalence of atrial fibrillation/flutter (36%); Central/Eastern European patients were youngest (mean 71±8 years) with the highest prevalence of coronary artery disease (50%); North American patients had the highest prevalence of obesity (65%) and diabetes (49%); Latin American patients were younger (73±9 years) and had a high prevalence of obesity (53%); and Asia-Pacific patients had a high prevalence of diabetes (44%), despite a low prevalence of obesity (26%). Rates of the primary composite end point of total hospitalizations for HF and death from cardiovascular causes were lower in patients from Central Europe (9 per 100 patient-years) and highest in patients from North America (28 per 100 patient-years), which was primarily driven by a greater number of total hospitalizations for HF. The effect of treatment with sacubitril-valsartan was not modified by region (interaction >0.05).

Conclusions: Among patients with HFpEF recruited worldwide in PARAGON-HF, there were important regional differences in clinical characteristics and outcomes, which may have implications for the design of future clinical trials. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01920711.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.120.007901DOI Listing
April 2021

Compartmentally scavenging hepatic oxidants through AMPK/SIRT3-PGC1α axis improves mitochondrial biogenesis and glucose catabolism.

Free Radic Biol Med 2021 05 29;168:117-128. Epub 2021 Mar 29.

Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, People's Republic of China. Electronic address:

Early treatment can prevent the occurrence of diabetes; however, there are few pharmacological treatment strategies to date. The liver is a major metabolic organ, and hepatic glucose homeostasis is dysregulated in type 1 and type 2 diabetes mellitus. However, the potential of specifically targeting the liver to prevent diabetes has not been fully exploited. In this study, we found that compartmentally inhibiting hepatic oxidants by nano-MitoPBN, a liver mitochondrial-targeting ROS scavenger, could effectively prevent diabetes. Our results demonstrated that nano-MitoPBN reversed the downregulation of PGC-1α and the enhanced gluconeogenesis in the livers of diabetic mice. PGC-1α, through an AMPK- and SIRT3-mediated mechanism, promoted mitochondrial biogenesis, increased the number of mitochondria, and enhanced the rate of aerobic oxidation, leading to decreased glucose levels in the blood by increasing glucose uptake and catabolism in the liver. Moreover, the increase in PGC-1α activity did not promote the activation of gluconeogenesis. Our study demonstrated that by regulating the redox balance of liver mitochondria in the early stage of diabetes, PGC-1α could selectively inhibit gluconeogenesis in the liver and promote hepatic mitochondrial function, which accelerated the catabolism of hepatic glucose and reduced blood glucose. Thus, glucose tolerance can be normalized through only three weeks of intervention. Our results showed that nano-MitoPBN could effectively prevent diabetes in a short period of time, highlighting the effectiveness and importance of early intervention for diabetes and suggesting the potential advantages of hepatic mitochondrial targeting oxidants nano-inhibitors in the prevention and early treatment of diabetes.
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http://dx.doi.org/10.1016/j.freeradbiomed.2021.03.029DOI Listing
May 2021

Htd2 deficiency-associated suppression of α-lipoic acid production provokes mitochondrial dysfunction and insulin resistance in adipocytes.

Redox Biol 2021 05 19;41:101948. Epub 2021 Mar 19.

Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi, 710049, China; National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shannxi, 710004, China; Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi, 710049, China. Electronic address:

Mitochondria harbor a unique fatty acid synthesis pathway (mtFAS) with mysterious functions gaining increasing interest, while its involvement in metabolic regulation is essentially unknown. Here we show that 3-Hydroxyacyl-ACP dehydratase (HTD2), a key enzyme in mtFAS pathway was primarily downregulated in adipocytes of mice under metabolic disorders, accompanied by decreased de novo production of lipoic acid, which is the byproduct of mtFAS pathway. Knockdown of Htd2 in 3T3-L1 preadipocytes or differentiated 3T3-L1 mature adipocytes impaired mitochondrial function via suppression of complex I activity, resulting in enhanced oxidative stress and impaired insulin sensitivity, which were all attenuated by supplement of lipoic acid. Moreover, lipidomic study revealed limited lipid alterations in mtFAS deficient cells which primarily presenting accumulation of triglycerides, attributed to mitochondrial dysfunction. Collectively, the present study highlighted the pivotal role of mtFAS pathway in regulating mitochondrial function and adipocytes insulin sensitivity, demonstrating supportive evidence for lipoic acid being potential effective nutrient for improving insulin resistance and related metabolic disorders.
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http://dx.doi.org/10.1016/j.redox.2021.101948DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8027779PMC
May 2021

Serum potassium and outcomes in heart failure with preserved ejection fraction: a post-hoc analysis of the PARAGON-HF trial.

Eur J Heart Fail 2021 05 8;23(5):776-784. Epub 2021 Mar 8.

British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, UK.

Aims: The relationship between serum potassium concentration and outcomes in patients with heart failure and preserved ejection fraction (HFpEF) is not well-established. The aim of this study was to explore the association between serum potassium and clinical outcomes in the PARAGON-HF trial in which 4822 patients with HFpEF were randomised to treatment with sacubitril/valsartan or valsartan.

Methods And Results: The relationship between serum potassium concentrations and the primary study composite outcome of total (first and recurrent) heart failure hospitalisations and cardiovascular death was analysed. Hypo-, normo-, and hyperkalaemia were defined as serum potassium <4 mmol/L, 4-5 mmol/L and >5 mmol/L, respectively. Both screening and time-updated potassium (categorical and continuous spline-transformed) were studied. Patient mean age was 73 years and 52% were women. Patients with higher baseline potassium more often had an ischaemic aetiology and diabetes and mineralocorticoid receptor antagonist treatment. Compared with normokalaemia, both time-updated (but not screening) hypo- and hyperkalaemia were associated with a higher risk of the primary outcome [adjusted hazard ratio (HR) for hypokalaemia 1.55, 95% confidence interval (CI) 1.30-1.85; P < 0.001, and for hyperkalaemia HR 1.21, 95% CI 1.02-1.44; P = 0.025]. Hypokalaemia had a stronger association with a higher risk of all-cause, cardiovascular and non-cardiovascular death than hyperkalaemia. The association of hypokalaemia with increased risk of all-cause and cardiovascular death was most marked in participants with impaired kidney function (interaction P < 0.05). Serum potassium did not significantly differ between sacubitril/valsartan and valsartan throughout the follow-up.

Conclusions: Both hypo- and hyperkalaemia were associated with heart failure hospitalisation but only hypokalaemia was associated with mortality, especially in the context of renal impairment. Hypokalaemia was as strongly associated with death from non-cardiovascular causes as with cardiovascular death. Collectively, these findings suggest that potassium disturbances are a more of a marker of HFpEF severity rather than a direct cause of death.
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http://dx.doi.org/10.1002/ejhf.2134DOI Listing
May 2021

Hydroxytyrosol Acetate Improves the Cognitive Function of APP/PS1 Transgenic Mice in ERβ-dependent Manner.

Mol Nutr Food Res 2021 02 28;65(3):e2000797. Epub 2020 Dec 28.

Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, China.

Scope: Alzheimer's disease (AD) is the most prevalent form of dementia in the aging population; however, no effective therapy has been established. It has been previously demonstrated that daily intake of hydroxytyrosol (HT), a polyphenol in olive oil, at a daily dietary level mildly improves cognition in AD mice. In the present study, HT acetate (HT-ac), which is a natural derivative of HT in olive oil that exhibits better bioactivity than HT improves cognition.

Methods And Results: HT-ac to APP/PS1 is orally administered to transgenic mice and used Aβ-treated neuronal cultures to explore the neuroprotective effects of HT-ac in preventing AD progression. It is found that HT-ac remarkably improved the escape latency, escape distance, and the number of platform crossings of AD mice in the water maze test by ameliorating neuronal apoptosis and decreasing inflammatory cytokine levels. It is further demonstrated that HT-ac stimulated the transcription of ERβ and enhanced neuronal viability and electrophysiological activity in primary neurons but that these beneficial effects of HT-ac are abolished upon ERβ deficiency.

Conclusions: This study suggests that as the bioactive component of olive oil, HT-ac is a promising neuroprotective nutrient that may be used to alleviate AD-related cognitive dysfunction.
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http://dx.doi.org/10.1002/mnfr.202000797DOI Listing
February 2021

SGLT-2 inhibitors may be targeting higher risk patients with diabetes possibly justifying higher cost: Single center repeated cross-sectional analysis.

J Diabetes Complications 2021 02 7;35(2):107761. Epub 2020 Oct 7.

Kidney and Hypertension Section, Joslin Diabetes Center, E. P Joslin Research Laboratory, USA; Department of Medicine, Beth Israel Deaconess Hospital, USA.

Introduction: We studied the use of all hypoglycemic agents in periods before and after introduction of SGLT-2 inhibitors in the USA by repeated cross sectional analysis to initially assess improvement in HbA1c control among patients with type 2 diabetes and hypertension. We sought to identify changes in glucose management related to the availability of the SGLT-2 inhibiting agents. We hypothesized that patients transitioned to SGLT-2 inhibitor-based therapy represented a higher risk group that derived benefits in terms of Hba1c control.

Methods: Deidentified records of patients seen at least twice during the relevant time periods at Joslin Clinic between January 1, 2010 and December 31, 2012 and/or between January 1, 2014 and December 31, 2016 were examined. Records required all of the following: demographic information of gender, age, height, weight, BMI, HbA1c, eGFR, blood pressure, smoking status and completed medication lists.

Results: 10,191 patients met criteria for analysis, 7769 seen in period 1 and 6576 in period 2. 4625 patients were seen in both periods. The group of patients defined by SGLT-2 use had significantly higher BMI and HbA1c. Notable shifts in medication use were observed as SGLT-2 use increased from none to 14%. Increased use (all p < 0.001) of GLP-1 agents (16.0 to 23.8%), insulin (56.1 to 60.5%) and statins (78.4 to 81.5%) and statistically significant decreases (all p < 0.001) in use of biguanides (69.5 to 66.3%) and sulfonylurea compounds (44.7 to 39.4%), thiazolidinediones (13.6 to 3.4%) and diuretics (32.4 to 28.9%) were observed. Statistically significant decreases (all p < 0.001) of HbA1c (7.9 to 7.8%), BMI (32.5 to 32.1), eGFR (80.6 to 77.5 ml/min) and increased systolic blood pressure (130 to 132 mm Hg) were documented.

Conclusions: In the absence of glycemia treatment resistance or clinical heart failure SGLT-2 inhibitor use may not be cost effective. Enthusiasm for use of SGLT-2 inhibition should be based upon long-term cardiorenal protection rather than short-term glycemia control given limited impact upon HbA1c levels in our tertiary care type 2 diabetes population.
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http://dx.doi.org/10.1016/j.jdiacomp.2020.107761DOI Listing
February 2021

A Noncoding Variant Near PPP1R3B Promotes Liver Glycogen Storage and MetS, but Protects Against Myocardial Infarction.

J Clin Endocrinol Metab 2021 01;106(2):372-387

Brigham and Women's Hospital, Havard University, Boston, MA, USA.

Context: Glycogen storage diseases are rare. Increased glycogen in the liver results in increased attenuation.

Objective: Investigate the association and function of a noncoding region associated with liver attenuation but not histologic nonalcoholic fatty liver disease.

Design: Genetics of Obesity-associated Liver Disease Consortium.

Setting: Population-based.

Main Outcome: Computed tomography measured liver attenuation.

Results: Carriers of rs4841132-A (frequency 2%-19%) do not show increased hepatic steatosis; they have increased liver attenuation indicative of increased glycogen deposition. rs4841132 falls in a noncoding RNA LOC157273 ~190 kb upstream of PPP1R3B. We demonstrate that rs4841132-A increases PPP1R3B through a cis genetic effect. Using CRISPR/Cas9 we engineered a 105-bp deletion including rs4841132-A in human hepatocarcinoma cells that increases PPP1R3B, decreases LOC157273, and increases glycogen perfectly mirroring the human disease. Overexpression of PPP1R3B or knockdown of LOC157273 increased glycogen but did not result in decreased LOC157273 or increased PPP1R3B, respectively, suggesting that the effects may not all occur via affecting RNA levels. Based on electronic health record (EHR) data, rs4841132-A associates with all components of the metabolic syndrome (MetS). However, rs4841132-A associated with decreased low-density lipoprotein (LDL) cholesterol and risk for myocardial infarction (MI). A metabolic signature for rs4841132-A includes increased glycine, lactate, triglycerides, and decreased acetoacetate and beta-hydroxybutyrate.

Conclusions: These results show that rs4841132-A promotes a hepatic glycogen storage disease by increasing PPP1R3B and decreasing LOC157273. rs4841132-A promotes glycogen accumulation and development of MetS but lowers LDL cholesterol and risk for MI. These results suggest that elevated hepatic glycogen is one cause of MetS that does not invariably promote MI.
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http://dx.doi.org/10.1210/clinem/dgaa855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823249PMC
January 2021

Cardiac Myosin Activator Omecamtiv Mecarbil Improves Left Ventricular Myocardial Deformation in Chronic Heart Failure: The COSMIC-HF Trial.

Circ Heart Fail 2020 12 12;13(12):e008007. Epub 2020 Nov 12.

Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (T.B.-S., M.M., B.C., J.L., S.D.S.).

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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.120.008007DOI Listing
December 2020

Hyperoside from Z. bungeanum leaves restores insulin secretion and mitochondrial function by regulating pancreatic cellular redox status in diabetic mice.

Free Radic Biol Med 2021 01 5;162:412-422. Epub 2020 Nov 5.

Center for Mitochondrial Biology & Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, PR China. Electronic address:

Type 2 diabetes mellitus (T2DM) is characterized by peripheral insulin resistance and insufficient insulin secretion caused by pancreatic β-cell dysfunction. Excessive production of reactive oxygen species (ROS) and activation of caspases in mitochondria inhibit insulin secretion and promote apoptosis of pancreatic β-cells. Studies have demonstrated that positive correlation between the consumption of flavonoid-rich diets and diabetes prevention. Zanthoxylum bungeanum leaves have been used as food for a long time and are rich in flavonoids with strong radical scavenging abilities. We and others have identified hyperoside as the major bioactive component of total flavonoids exacted from Zanthoxylum bungeanum leaves. We hypothesize that hyperoside from Z. bungeanum leaves (HZL) may prevent T2DM by inhibiting excessive ROS formation and reducing pancreatic β-cells apoptosis. In current study, HZL was administered to high fat diet and alloxan-induced diabetic mice, and appeared to significantly ameliorate the damage of glucose metabolism and insulin secretion as well as restore the structural integrity of pancreas, and inhibit β-cell apoptosis. Pancreatic antioxidant enzyme activities were also restored by HZL supplementation. In cultured MIN6 cells, which produce and secret insulin, HZL treatment restored insulin secretion through inhibiting the expression of TXNIP and lowering intracellular calcium concentration. These observations mechanistically linked the beneficial effects of HZL with the regulation on cellular redox status and mitochondrial function. Taken together, our findings suggest that HZL has protective effect on pancreatic β-cell function and may be a beneficial nutritional supplementation for prevention and adjuvant therapy of T2DM.
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http://dx.doi.org/10.1016/j.freeradbiomed.2020.10.320DOI Listing
January 2021

The functional analysis of Cullin 7 E3 ubiquitin ligases in cancer.

Oncogenesis 2020 Oct 31;9(10):98. Epub 2020 Oct 31.

Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, China.

Cullin (CUL) proteins have critical roles in development and cancer, however few studies on CUL7 have been reported due to its characteristic molecular structure. CUL7 forms a complex with the ROC1 ring finger protein, and only two F-box proteins Fbxw8 and Fbxw11 have been shown to bind to CUL7. Interestingly, CUL7 can interact with its substrates by forming a novel complex that is independent of these two F-box proteins. The biological implications of CUL-ring ligase 7 (CRL7) suggest that the CRL7 may not only perform a proteolytic function but may also play a non-proteolytic role. Among the existing studied CRL7-based E3 ligases, CUL7 exerts both tumor promotion and suppression in a context-dependent manner. Currently, the mechanism of CUL7 in cancer remains unclear, and no studies have addressed potential therapies targeting CUL7. Consistent with the roles of the various CRL7 adaptors exhibit, targeting CRL7 might be an effective strategy for cancer prevention and treatment. We systematically describe the recent major advances in understanding the role of the CUL7 E3 ligase in cancer and further summarize its potential use in clinical therapy.
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http://dx.doi.org/10.1038/s41389-020-00276-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7603503PMC
October 2020

Fine particulate matter inhibits phagocytosis of macrophages by disturbing autophagy.

FASEB J 2020 12 30;34(12):16716-16735. Epub 2020 Oct 30.

Center for Translational Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, China.

Mounting evidence from epidemiological and clinical studies has revealed marked correlations between the air pollutant fine particulate matter (FPM) and respiratory diseases. FPM reaches distal airways and deposits in alveolar regions where it can act directly on alveolar macrophages. However, the detailed effect of FPM on the physiological function of alveolar macrophages and the underlying mechanisms remain unclear. In this study, we showed that exposing THP-1-derived macrophages to FPM led to autophagy dysfunction. FPM activated the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway, which promoted the expression of autophagy-related 2A (ATG2A) and reactive oxygen species generation. The overexpression of ATG2A enhanced the synthesis of autophagic membranes, and the excessive production of reactive oxygen species caused autophagy flux inhibition through disrupting the lysosomal activity. More importantly, FPM impaired the phagocytic ability of macrophages on Escherichia coli and apoptotic neutrophils. Finally, we showed that restoring autophagy rescued the impairment of phagocytic ability induced by FPM. In summary, these results reveal the molecular mechanism of autophagy dysfunction caused by FPM and provide a novel approach to resolve the impaired function of macrophages in respiratory diseases induced by FPM.
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http://dx.doi.org/10.1096/fj.202000657RDOI Listing
December 2020

Neuroprotective and Preventative Effects of Molecular Hydrogen.

Curr Pharm Des 2021 ;27(5):585-591

Center for Mitochondrial Biology and Medicine and Center for Translational Medicine, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, China.

One of the beneficial effects of molecular hydrogen (H, hydrogen gas) is neuroprotection and prevention of neurological disorders. It is important and useful if taking H every day can prevent or ameliorate the progression of neurodegenerative disorders, such as Parkinson's disease or Alzheimer's disease, both lacking specific therapeutic drugs. There are several mechanisms of how H protects neuronal damage. Anti-oxidative, anti-inflammatory, and the regulation of the endocrine system via stomach-brain connection seem to play an important role. At the cellular and tissue level, H appears to prevent the production of reactive oxygen species (ROS), and not only hydroxy radical (•OH) but also superoxide. In Parkinson's disease model mice, chronic intake of H causes the release of ghrelin from the stomach. In Alzheimer's disease model mice, sex-different neuroprotection is observed by chronic intake of H. In female mice, declines of estrogen and estrogen receptor-β (ERβ) are prevented by H, upregulating brain-derived neurotrophic factor (BDNF) and its receptor, tyrosine kinase receptor B (TrkB). The question of how drinking H upregulates the release of ghrelin or attenuates the decline of estrogen remains to be investigated and the mechanism of how H modulates endocrine systems and the fundamental question of what or where is the target of H needs to be elucidated for a better understanding of the effects of H.
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http://dx.doi.org/10.2174/1381612826666201019103020DOI Listing
April 2021

Deubiquitinase OTUD6A promotes proliferation of cancer cells via regulating Drp1 stability and mitochondrial fission.

Mol Oncol 2020 12 6;14(12):3169-3183. Epub 2020 Nov 6.

Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and Technology, Xi'an Jiaotong University, China.

Dynamin-related protein 1 (Drp1) is a cytosolic protein responsible for mitochondrial fission and is essential in the initiation and development of several human diseases, including cancer. However, the regulation of Drp1, especially of its ubiquitination, remains unclear. In this study, we report that the ovarian tumor-associated protease deubiquitinase 6A (OTUD6A) deubiquitylates and stabilizes Drp1, thereby facilitating regulation of mitochondrial morphology and tumorigenesis. OTUD6A is upregulated in human patients with colorectal cancer. The depletion of OTUD6A leads to lower Drp1 levels and suppressed mitochondrial fission, and the affected cells are consequently less prone to tumorigenesis. Conversely, the overexpression of OTUD6A increases Drp1 levels and its protein half-life and enhances cancer cell growth. Therefore, our results reveal a novel upstream protein of Drp1, and its role in tumorigenesis that is played, in part, through the activation of mitochondrial fission mediated by Drp1.
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http://dx.doi.org/10.1002/1878-0261.12825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718948PMC
December 2020

Punicalagin improves hepatic lipid metabolism modulation of oxidative stress and mitochondrial biogenesis in hyperlipidemic mice.

Food Funct 2020 Nov;11(11):9624-9633

Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, Shaanxi, China.

Hyperlipidemia is closely associated with various liver diseases, and effective intervention for prevention and treatment is in great need. Here, we aim to explore the protective effects of punicalagin (PU), a major ellagitannin in pomegranate, on acute hyperlipidemia-induced hepatic lipid metabolic disorders. Male C57bl/6J mice were pretreated with 50 or 200 mg kg-1 day-1 PU for 9 days before the injection of poloxamer 407 to induce acute hyperlipidemia. PU significantly lowered lipids and liver damage markers in serum, reduced excessive lipid accumulation in the liver, attenuated hepatic oxidative stress by activating the NF-E2 related factor 2 (Nrf2)-mediated antioxidant pathway, and enhanced hepatic mitochondrial complex activities and mitochondrial DNA copy number by promoting the peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α)-mediated mitochondrial biogenesis pathway. Moreover, the decreased mitochondrial fusion-related proteins were also restored by PU treatment. In vitro, PU effectively decreased triglycerides and total cholesterol levels, up-regulated Nrf2 and mitochondrial biogenesis pathways and partially restored the mitochondrial morphology in palmitic acid-treated HepG2 cells. These results suggest that PU could improve acute hyperlipidemia-induced hepatic lipid metabolic abnormalities via decreasing oxidative stress and improving mitochondrial function both in vivo and in vitro, indicating that PU might be a potential intervention for hyperlipidemia-related liver diseases.
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http://dx.doi.org/10.1039/d0fo01545hDOI Listing
November 2020

Omega-3 polyunsaturated fatty acids prevent obesity by improving tricarboxylic acid cycle homeostasis.

J Nutr Biochem 2021 02 19;88:108503. Epub 2020 Sep 19.

Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, China. Electronic address:

The beneficial effects of omega-3 polyunsaturated fatty acids (n-3 PUFAs) on preventing obesity are well known; however, the underlying mechanism by which n-3 PUFAs influence tricarboxylic acid (TCA) cycle under obesity remains unclear. We randomly divided male C57BL/6 mice into 5 groups (n=10) and fed for 12 weeks as follows: mice fed a normal diet (Con, 10% kcal); mice fed a high-fat diet (HFD, lard, 60% kcal); and mice fed a high-fat diet (60% kcal) substituting half the lard with safflower oil (SO), safflower oil and fish oil (SF) and fish oil (FO), respectively. Then we treated HepG2 cells with palmitic acid and DHA for 24 h. We found that body weight in FO group was significantly lower than it in HFD and SO groups. N-3 PUFAs reduced the transcription and translation of TCA cycle enzymes, including IDH1, IDH2, SDHA, FH and MDH2, to enhance mitochondrial function in vivo and vitro. DHA significantly inhibited protein expression of the mTORC1 signaling pathway, increased p-AKT protein expression to alleviate insulin resistance and improved mitochondrial oxygen consumption rate and glycolysis ability in HepG2 cells. In addition, the expressions of IDH2 and SDHB were reduced by rapamycin. N-3 PUFAs could prevent obesity by improving TCA cycle homeostasis and mTORC1 signaling pathway may be upstream.
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http://dx.doi.org/10.1016/j.jnutbio.2020.108503DOI Listing
February 2021

Pinitol attenuates LPS-induced pneumonia in experimental animals: Possible role via inhibition of the TLR-4 and NF-κB/IκBα signaling cascade pathway.

J Biochem Mol Toxicol 2021 Jan 14;35(1):e22622. Epub 2020 Sep 14.

The Key Laboratory of Biomedical Information Engineering of Ministry of Education, Center for Mitochondrial Biology and Medicine, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi, China.

Pneumonia is a chronic disorder of the respiratory system associated with worsening quality of life and a significant economic burden. Pinitol, a plant cyclic polyol, has been documented for immune-inflammatory potential. The aim of present investigation was to evaluate the potential and possible mechanism of action of pinitol against lipopolysaccharide (LPS)-induced pneumonia in the experimental animal model. Pneumonia was induced in Sprague-Dawley rats by intratracheal administration of LPS (2 mg/kg). Animals were treated with either vehicle or dexamethasone or pinitol (5 or 10 or 20 mg/kg). Potential of pinitol against LPS-induced pulmonary insult was assessed based on behavioral, biochemical, molecular, and ultrastructural studies. Intratracheal instillation of LPS induced significant (P < .05) inflammatory infiltration in bronchoalveolar lavage fluid (BALF) and lung tissue reflected by elevated pleural effusion volume, lung edema, BALF polymorphonuclear leukocytes count and lung myeloperoxidase levels, which was attenuated by pinitol (10 and 20 mg/kg) administration. Pinitol also markedly (P < .05) inhibited LPS-induced alterations in electrocardiographic, hemodynamic changes, right ventricular, and lung function tests. The LPS-induced downregulated nuclear factor erythroid 2-related factor 2 (Nrf-2) and heme oxygenase-1 (HO-1), whereas upregulated transforming growth factor-β (TGF-β), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3), and inducible nitric oxide synthase (iNOs) lung messenger RNA expressions were significantly (P < .05) inhibited by pinitol. Western blot analysis suggested pinitol markedly (P < .05) decreased nuclear factor-κB (NF-κB), inhibitor of nuclear factor κB (IkBα), toll-like receptor 4 (TLR-4), and cyclooxygenase-II (COX-II) protein expressions in the lung. These findings were further supported by histological and ultrastructural analyses of lung tissue that show pinitol significantly (P < .05) ameliorates LPS-induced aberrations in lung tissue. In conclusion, pinitol attenuated LPS-induced pneumonia via inhibition of TLR-4 to downregulate the NF-κB/IκBα signaling cascade and thus ameliorated the production of proinflammatory cytokines (TNF-α, ILs, NLRP3, and TGF-β), inflammatory mediators (COX-II and iNOs) and elevated oxidative stress (Nrf-2 and HO-1).
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http://dx.doi.org/10.1002/jbt.22622DOI Listing
January 2021

Associations Between Depressive Symptoms and HFpEF-Related Outcomes.

JACC Heart Fail 2020 12 9;8(12):1009-1020. Epub 2020 Sep 9.

Division of Cardiovascular Medicine, Stanford University School of Medicine, Palo Alto, California, USA. Electronic address:

Objectives: This study analyzed changes in depressive symptoms in patients with heart failure and preserved ejection fraction (HFpEF) who were enrolled in the TOPCAT (Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function) trial.

Background: There are limited longitudinal data for depressive symptoms in patients with HFpEF.

Methods: In patients enrolled in the United States and Canada (n = 1,431), depressive symptoms were measured using Patient Health Questionnaire-9 (PHQ-9). Clinically meaningful changes in PHQ-9 scores were defined as worse (≥3-point increase) or better (≥3-point decrease). Multivariate models were used to identify predictors of change in depressive symptoms. Cox proportional hazard models were used to determine the impact of symptom changes from baseline on subsequent incident cardiovascular events.

Results: At 12 months, 19% of patients experienced clinically worsening depressive symptoms, 31% better, and 49% unchanged. Independent predictors of clinically meaningful improvement in depressive symptoms included higher baseline PHQ-9 scores, male sex, lack of chronic obstructive pulmonary disease, and randomization to spironolactone. After data were adjusted for cardiovascular comorbidities, higher baseline PHQ-9 was associated with all-cause mortality (hazard ratio [HR]: 1.09; 95% confidence interval [CI]: 1.02 to 1.16; p = 0.011), whereas worsening depressive symptoms at 12 months were associated with cardiovascular death (HR: 2.47; 95% CI: 1.32 to 4.63; p = 0.005) and all-cause mortality (HR: 1.82; 95% CI: 1.13 to 2.93; p = 0.014). Randomization to spironolactone was associated with modest but statistically significant reduction in depressive symptoms over the course of the trial (p = 0.014).

Conclusions: Higher baseline depressive symptoms and worsening depressive symptoms were associated with all-cause mortality. Randomization to spironolactone was associated with modest reduction in depressive symptoms. (Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function [TOPCAT]; NCT00094302).
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http://dx.doi.org/10.1016/j.jchf.2020.06.010DOI Listing
December 2020

Aster-B coordinates with Arf1 to regulate mitochondrial cholesterol transport.

Mol Metab 2020 12 29;42:101055. Epub 2020 Jul 29.

Sam and Ann Barshop Institute for Longevity and Aging Studies, Department of Pharmacology, University of Texas Health Science Center at San Antonio, Texas Research Park Campus - MC 7755, 15355 Lambda Drive, San Antonio, TX, 78245, USA; Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, PR China. Electronic address:

Objective: Cholesterol plays a pivotal role in mitochondrial steroidogenesis, membrane structure, and respiration. Mitochondrial membranes are intrinsically low in cholesterol content and therefore must be replenished with cholesterol from other subcellular membranes. However, the molecular mechanisms underlying mitochondrial cholesterol transport remains poorly understood. The Aster-B gene encodes a cholesterol binding protein recently implicated in cholesterol trafficking from the plasma membrane to the endoplasmic reticulum (ER). In this study, we investigated the function and underlying mechanism of Aster-B in mediating mitochondrial cholesterol transport.

Methods: CRISPR/Cas9 gene editing was carried out to generate cell lines deficient in Aster-B expression. The effect of Aster-B deficiency on mitochondrial cholesterol transport was examined by both confocal imaging analysis and biochemical assays. Deletion mutational analysis was also carried out to identify the function of a putative mitochondrial targeting sequence (MTS) at the N-terminus of Aster-B for its role in targeting Aster-B to mitochondria and in mediating mitochondrial cholesterol trafficking.

Results: Ablation of Aster-B impaired cholesterol transport from the ER to mitochondria, leading to a significant decrease in mitochondrial cholesterol content. Aster-B is also required for mitochondrial transport of fatty acids derived from hydrolysis of cholesterol esters. A putative MTS at the N-terminus of Aster-B mediates the mitochondrial cholesterol uptake. Deletion of the MTS or ablation of Arf1 GTPase which is required for mitochondrial translocation of ER proteins prevented mitochondrial cholesterol transport, leading to mitochondrial dysfunction.

Conclusions: We identified Aster-B as a key regulator of cholesterol transport from the ER to mitochondria. Aster-B also coordinates mitochondrial cholesterol trafficking with uptake of fatty acids derived from cholesterol esters, implicating the Aster-B protein as a novel regulator of steroidogenesis.
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http://dx.doi.org/10.1016/j.molmet.2020.101055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7476871PMC
December 2020
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