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1.
Int J Womens Health ; 16: 1541-1549, 2024.
Article in English | MEDLINE | ID: mdl-39319183

ABSTRACT

Background: Gynecological disorders are a wide range of health problems affecting the female reproductive system, which poses substantial health challenges worldwide. Increasing number of observational studies have associated mood instability to common female diseases, but the underlying causal relationship remains unclear. In this work, Mendelian randomization (MR) analysis was applied to explore the genetically predicted causal relationship of mood swings and several prevalent gynecological disorders. Methods: Instrumental variables (IVs) of mood swings were selected from UK Biobank (UKB), with 204,412 cases and 247,207 controls being incorporated. The genetic variants for female disorders were obtained from genome-wide association studies (GWASs) and FinnGen consortium. To avoid biases caused by racial difference, only European population was included here. Five strong analytical methodologies were used to increase the validity of the results, the most substantial of which was the inverse variance weighting (IVW) method. Pleiotropy, sensitivity, and heterogeneity were assessed to strengthen the findings. Results: We found mood swings was significantly positively associated with risk of endometrial cancer (OR= 2.60 [95% CI= 1.36, 4.95], P= 0.0037), cervical cancer (OR= 1.01[95% CI= 1.00,1.02], P= 0.0213) and endometriosis (OR= 2.58 [95% CI= 1.18, 5.60], P= 0.0170) by IVW method. However, there was no causal relationship between mood swing and ovarian cancer. No pleiotropy and heterogeneity existed and sensitivity tests were passed. Conclusion: This study reveals that mood swing may serve as a genetically predicted causal risk factor for endometrial cancer, cervical cancer, and endometriosis in the European population, while no such association was observed for ovarian cancer. These findings make up for observational research's inherent limitations and may improve patient outcomes in the field of gynecological health. However, the study's focus on European populations may limit the applicability of these results globally.

2.
Environ Sci Pollut Res Int ; 30(16): 45607-45642, 2023 Apr.
Article in English | MEDLINE | ID: mdl-36820972

ABSTRACT

As countries around the world pay more attention to environmental protection, the corresponding emission regulations have become more stringent. Exhaust pollutants cause great harm to the environment and people, and diesel engines are one of the most important sources of pollution. Diesel particulate filter (DPF) technology has proven to be the most effective way to control and treat soot. In this paper, we review the latest research progress on DPF regeneration and ash. Passive regeneration, active regeneration, non-thermal plasma-assisted DPF regeneration and regeneration mechanism, DPF regeneration control assisted by engine management, and uncontrolled DPF regeneration and its control strategy are mainly introduced. In addition, the source, composition, and deposition of ash are described in detail, as well as the effect of ash on the DPF pressure drop and catalytic performance. Finally, the issues that need to be further addressed in DPF regeneration research are presented, along with challenges and future work in ash research. Over all, composite regeneration is still the mainstream regeneration method. The formation of ash is complex and there are still many unanswered questions that require further in-depth research.


Subject(s)
Air Pollutants , Air Pollution , Humans , Particulate Matter/analysis , Dust , Air Pollutants/analysis , Vehicle Emissions/analysis , Air Pollution/analysis
3.
Circulation ; 139(7): 901-914, 2019 02 12.
Article in English | MEDLINE | ID: mdl-30586741

ABSTRACT

BACKGROUND: Mitsugumin 53 (MG53 or TRIM72), a striated muscle-specific E3 ligase, promotes ubiquitin-dependent degradation of the insulin receptor and insulin receptor substrate-1 and subsequently induces insulin resistance, resulting in metabolic syndrome and type 2 diabetes mellitus (T2DM). However, it is unknown how MG53 from muscle regulates systemic insulin response and energy metabolism. Increasing evidence demonstrates that muscle secretes proteins as myokines or cardiokines that regulate systemic metabolic processes. We hypothesize that MG53 may act as a myokine/cardiokine, contributing to interorgan regulation of insulin sensitivity and metabolic homeostasis. METHODS: Using perfused rodent hearts or skeletal muscle, we investigated whether high glucose, high insulin, or their combination (conditions mimicking metabolic syndrome or T2DM) alters MG53 protein concentration in the perfusate. We also measured serum MG53 levels in rodents and humans in the presence or absence of metabolic diseases, particularly T2DM. The effects of circulating MG53 on multiorgan insulin response were evaluated by systemic delivery of recombinant MG53 protein to mice. Furthermore, the potential involvement of circulating MG53 in the pathogenesis of T2DM was assessed by neutralizing blood MG53 with monoclonal antibodies in diabetic db/db mice. Finally, to delineate the mechanism underlying the action of extracellular MG53 on insulin signaling, we analyzed the potential interaction of MG53 with extracellular domain of insulin receptor using coimmunoprecipitation and surface plasmon resonance assays. RESULTS: Here, we demonstrate that MG53 is a glucose-sensitive myokine/cardiokine that governs the interorgan regulation of insulin sensitivity. First, high glucose or high insulin induces MG53 secretion from isolated rodent hearts and skeletal muscle. Second, hyperglycemia is accompanied by increased circulating MG53 in humans and rodents with diabetes mellitus. Third, systemic delivery of recombinant MG53 or cardiac-specific overexpression of MG53 causes systemic insulin resistance and metabolic syndrome in mice, whereas neutralizing circulating MG53 with monoclonal antibodies has therapeutic effects in T2DM db/db mice. Mechanistically, MG53 binds to the extracellular domain of the insulin receptor and acts as an allosteric blocker. CONCLUSIONS: Thus, MG53 has dual actions as a myokine/cardiokine and an E3 ligase, synergistically inhibiting the insulin signaling pathway. Targeting circulating MG53 opens a new therapeutic avenue for T2DM and its complications.


Subject(s)
Blood Glucose/metabolism , Diabetes Mellitus/blood , Energy Metabolism , Insulin Resistance , Membrane Proteins/metabolism , Adult , Animals , Antibodies, Monoclonal/pharmacology , Antigens, CD/metabolism , Biomarkers/blood , Blood Glucose/drug effects , Case-Control Studies , Diabetes Mellitus/drug therapy , Diabetes Mellitus/enzymology , Diabetes Mellitus/immunology , Disease Models, Animal , Energy Metabolism/drug effects , Female , HEK293 Cells , Homeostasis , Humans , Hypoglycemic Agents/pharmacology , Male , Membrane Proteins/antagonists & inhibitors , Membrane Proteins/genetics , Membrane Proteins/immunology , Mice , Mice, Inbred C57BL , Mice, Knockout , Muscle Proteins/metabolism , Muscle, Skeletal/enzymology , Myocardium/enzymology , Rats, Sprague-Dawley , Rats, Zucker , Receptor, Insulin/metabolism , Signal Transduction , Tripartite Motif Proteins/metabolism , Vesicular Transport Proteins/metabolism
4.
PLoS One ; 9(2): e87495, 2014.
Article in English | MEDLINE | ID: mdl-24498331

ABSTRACT

Spontaneous calcium waves in cardiac myocytes are caused by diastolic sarcoplasmic reticulum release (SR Ca(2+) leak) through ryanodine receptors. Beta-adrenergic (ß-AR) tone is known to increase this leak through the activation of Ca-calmodulin-dependent protein kinase (CaMKII) and the subsequent phosphorylation of the ryanodine receptor. When ß-AR drive is chronic, as observed in heart failure, this CaMKII-dependent effect is exaggerated and becomes potentially arrhythmogenic. Recent evidence has indicated that CaMKII activation can be regulated by cellular oxidizing agents, such as reactive oxygen species. Here, we investigate how the cellular second messenger, nitric oxide, mediates CaMKII activity downstream of the adrenergic signaling cascade and promotes the generation of arrhythmogenic spontaneous Ca(2+) waves in intact cardiomyocytes. Both SCaWs and SR Ca(2+) leak were measured in intact rabbit and mouse ventricular myocytes loaded with the Ca-dependent fluorescent dye, fluo-4. CaMKII activity in vitro and immunoblotting for phosphorylated residues on CaMKII, nitric oxide synthase, and Akt were measured to confirm activity of these enzymes as part of the adrenergic cascade. We demonstrate that stimulation of the ß-AR pathway by isoproterenol increased the CaMKII-dependent SR Ca(2+) leak. This increased leak was prevented by inhibition of nitric oxide synthase 1 but not nitric oxide synthase 3. In ventricular myocytes isolated from wild-type mice, isoproterenol stimulation also increased the CaMKII-dependent leak. Critically, in myocytes isolated from nitric oxide synthase 1 knock-out mice this effect is ablated. We show that isoproterenol stimulation leads to an increase in nitric oxide production, and nitric oxide alone is sufficient to activate CaMKII and increase SR Ca(2+) leak. Mechanistically, our data links Akt to nitric oxide synthase 1 activation downstream of ß-AR stimulation. Collectively, this evidence supports the hypothesis that CaMKII is regulated by nitric oxide as part of the adrenergic cascade leading to arrhythmogenesis.


Subject(s)
Adrenergic Agents/pharmacology , Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism , Calcium/metabolism , Myocytes, Cardiac/drug effects , Nitric Oxide/metabolism , Sarcoplasmic Reticulum/metabolism , Animals , Blotting, Western , Cells, Cultured , Enzyme Activation/drug effects , Enzyme Inhibitors/pharmacology , Isoproterenol/pharmacology , Mice , Mice, Inbred C57BL , Mice, Knockout , Myocytes, Cardiac/cytology , Myocytes, Cardiac/metabolism , NG-Nitroarginine Methyl Ester/pharmacology , Nitric Oxide Synthase Type I/antagonists & inhibitors , Nitric Oxide Synthase Type I/deficiency , Nitric Oxide Synthase Type I/genetics , Phosphorylation/drug effects , Proto-Oncogene Proteins c-akt/metabolism , Rabbits , Ryanodine Receptor Calcium Release Channel/metabolism
5.
Pharmacol Ther ; 142(3): 306-15, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24380841

ABSTRACT

Nitric oxide is a key signaling molecule in the heart and is produced endogenously by three isoforms of nitric oxide synthase, neuronal NOS (NOS1), endothelial NOS (NOS3), and inducible NOS (NOS2). Nitric oxide signals via cGMP-dependent or independent pathways to modulate downstream proteins via specific post translational modifications (i.e. cGMP-dependent protein kinase phosphorylation, S-nitrosylation, etc.). Dysfunction of NOS (i.e. altered expression, location, coupling, activity, etc.) exists in various cardiac disease conditions, such as heart failure, contributing to the contractile dysfunction, adverse remodeling, and hypertrophy. This review will focus on the signaling pathways of each NOS isoform during health and disease, and discuss current and potential therapeutic approaches targeting nitric oxide signaling to treat heart disease.


Subject(s)
Heart Failure/drug therapy , Nitric Oxide Synthase/physiology , Animals , Heart Failure/enzymology , Humans , Nitric Oxide/physiology , Nitric Oxide Synthase/antagonists & inhibitors , Nitric Oxide Synthase Type I/antagonists & inhibitors , Nitric Oxide Synthase Type I/physiology , Nitric Oxide Synthase Type II/antagonists & inhibitors , Nitric Oxide Synthase Type II/physiology , Nitric Oxide Synthase Type III/antagonists & inhibitors , Nitric Oxide Synthase Type III/physiology , Signal Transduction
6.
Basic Res Cardiol ; 108(2): 332, 2013 Mar.
Article in English | MEDLINE | ID: mdl-23377961

ABSTRACT

Exercise results in beneficial adaptations of the heart that can be directly observed at the ventricular myocyte level. However, the molecular mechanism(s) responsible for these adaptations are not well understood. Interestingly, signaling via neuronal nitric oxide synthase (NOS1) within myocytes results in similar effects as exercise. Thus, the objective was to define the role NOS1 plays in the exercise-induced beneficial contractile effects in myocytes. After an 8-week aerobic interval training program, exercise-trained (Ex) mice had higher VO(2max) and cardiac hypertrophy compared to sedentary (Sed) mice. Ventricular myocytes from Ex mice had increased NOS1 expression and nitric oxide production compared to myocytes from Sed mice. Remarkably, acute NOS1 inhibition normalized the enhanced contraction (shortening and Ca(2+) transients) in Ex myocytes to Sed levels. The NOS1 effect on contraction was mediated via greater Ca(2+) cycling that resulted from increased phospholamban phosphorylation. Intriguingly, a similar aerobic interval training program on NOS1 knockout mice failed to produce any beneficial cardiac adaptations (VO(2max), hypertrophy, and contraction). These data demonstrate that the beneficial cardiac adaptations observed after exercise training were mediated via enhanced NOS1 signaling. Therefore, it is likely that beneficial effects of exercise may be mimicked by the interventions that increase NOS1 signaling. This pathway may provide a potential novel therapeutic target in cardiac patients who are unable or unwilling to exercise.


Subject(s)
Adaptation, Physiological , Myocytes, Cardiac/enzymology , Nitric Oxide Synthase Type I/physiology , Physical Conditioning, Animal/physiology , Animals , Calcium/metabolism , Cardiac Output , Cardiomegaly, Exercise-Induced , Dogs , Mice , Mice, Inbred C57BL , Mice, Knockout , Myocardial Contraction , Nitric Oxide/metabolism , Sedentary Behavior , Signal Transduction/physiology
7.
PLoS One ; 7(12): e52005, 2012.
Article in English | MEDLINE | ID: mdl-23300588

ABSTRACT

Nitric oxide (NO) and superoxide (O(2) (-)) are important cardiac signaling molecules that regulate myocyte contraction. For appropriate regulation, NO and O(2) (.-) must exist at defined levels. Unfortunately, the NO and O(2) (.-) levels are altered in many cardiomyopathies (heart failure, ischemia, hypertrophy, etc.) leading to contractile dysfunction and adverse remodeling. Hence, rescuing the nitroso-redox levels is a potential therapeutic strategy. Nitrone spin traps have been shown to scavenge O(2) (.-) while releasing NO as a reaction byproduct; and we synthesized a novel, cell permeable nitrone, 2-2-3,4-dihydro-2H-pyrrole 1-oxide (EMEPO). We hypothesized that EMEPO would improve contractile function in myocytes with altered nitroso-redox levels. Ventricular myocytes were isolated from wildtype (C57Bl/6) and NOS1 knockout (NOS1(-/-)) mice, a known model of NO/O(2) (.-) imbalance, and incubated with EMEPO. EMEPO significantly reduced O(2) (.-) (lucigenin-enhanced chemiluminescence) and elevated NO (DAF-FM diacetate) levels in NOS1(-/-) myocytes. Furthermore, EMEPO increased NOS1(-/-) myocyte basal contraction (Ca(2+) transients, Fluo-4AM; shortening, video-edge detection), the force-frequency response and the contractile response to ß-adrenergic stimulation. EMEPO had no effect in wildtype myocytes. EMEPO also increased ryanodine receptor activity (sarcoplasmic reticulum Ca(2+) leak/load relationship) and phospholamban Serine16 phosphorylation (Western blot). We also repeated our functional experiments in a canine post-myocardial infarction model and observed similar results to those seen in NOS1(-/-) myocytes. In conclusion, EMEPO improved contractile function in myocytes experiencing an imbalance of their nitroso-redox levels. The concurrent restoration of NO and O(2) (.-) levels may have therapeutic potential in the treatment of various cardiomyopathies.


Subject(s)
Calcium/metabolism , Myocardial Contraction/drug effects , Myocytes, Cardiac/metabolism , Nitric Oxide Synthase Type I/physiology , Nitric Oxide/metabolism , Nitrogen Oxides/pharmacology , Sarcoplasmic Reticulum/metabolism , Animals , Esterification , Mice , Mice, Inbred C57BL , Mice, Knockout , Myocardial Infarction/drug therapy , Myocardial Infarction/metabolism , Myocardial Infarction/pathology , Myocytes, Cardiac/cytology , Myocytes, Cardiac/drug effects , Oxidation-Reduction , Sarcoplasmic Reticulum/drug effects , Spin Labels , Superoxides/metabolism
8.
J Fluoresc ; 18(2): 433-42, 2008 Mar.
Article in English | MEDLINE | ID: mdl-18058205

ABSTRACT

Puerarin is a widely used compound in Chinese traditional medicine and exhibits many pharmacological activities. Binding of puerarin to human serum albumin (HSA) was investigated by ultraviolet absorbance, fluorescence, circular dichroism and molecular docking. Puerarin caused a static quenching of intrinsic fluorescence of HSA, the quenching data was analyzed by Stern-Volmer equation. There was one primary puerarin binding site on HSA with a binding constant of 4.12 x 10(4) M(-1) at 298 K. Thermodynamic analysis by Van Hoff equation found enthalpy change (DeltaH(0)) and entropy change (DeltaS(0)) were -28.01 kJ/mol and -5.63 J/mol K respectively, which indicated the hydrogen bond and Van der Waas interaction were the predominant forces in the binding process. Competitive experiments showed a displacement of warfarin by puerarin, which revealed that the binding site was located at the drug site I. Puerarin was about 2.22 nm far from the tryptophan according to the observed fluorescence resonance energy transfer between HSA and puerarin. Molecular docking suggested the hydrophobic residues such as tyrosine (Tyr) 150, Tyr 148, Tyr 149 and polar residues such as lysine (Lys) 199, Lys 195, arginine 257 and histidine 242 played an important role in the binding reaction.


Subject(s)
Isoflavones/metabolism , Serum Albumin/metabolism , Binding, Competitive , Circular Dichroism , Humans , Hydrogen Bonding , Isoflavones/chemistry , Molecular Structure , Protein Binding , Protein Conformation , Serum Albumin/chemistry , Spectrometry, Fluorescence , Spectrophotometry, Ultraviolet , Thermodynamics , Warfarin/metabolism
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