ABSTRACT
Several studies have reported side effects of finasteride (FIN), such as anxiety/depression in young men. Obesity is also positively associated with anxiety/depression symptoms; however, the impacts of long-term FIN treatment and FIN withdrawal in young obese individuals are still elusive. The present study aimed to investigate the effect of long-term treatment and its withdrawal on anxiety/depression and brain pathologies in lean and obese adult male rats. Forty-eight male Wistar rats were equally divided into two groups and fed either a normal or high-fat diet. At age 13 weeks, rats in each dietary group were divided into three subgroups: 1) the control group receiving drinking water, 2) the long-term treatment group receiving FIN orally at 5â¯mg/kg/day for 6 weeks, and 3) the withdrawal group receiving FIN orally at 5â¯mg/kg/day for 2 weeks followed by a 4-week withdrawal period. Anxiety/depression-like behaviors, biochemical analysis, brain inflammation, oxidative stress, neuroactive steroids, brain metabolites, and microglial complexity were tested. The result showed that lean rats treated with long-term FIN and its withdrawal exhibited metabolic disturbances, depressive-like behavior, and both groups showed increased neurotoxic metabolites and reduced microglial complexity. Obesity itself led to metabolic disturbances and brain pathologies, including increased inflammation, oxidative stress, and quinolinic acid, as well as reduced microglial complexity, resulting in increased anxiety- and depression-like behaviors. Interestingly, the long-term FIN treatment group in obese rats showed attenuation of depressive-like behaviors, brain inflammation, and oxidative stress, along with increased brain antioxidants, suggesting the possible benefits of FIN in obese conditions.
Subject(s)
5-alpha Reductase Inhibitors , Anxiety , Depression , Diet, High-Fat , Finasteride , Obesity , Rats, Wistar , Animals , Male , Obesity/drug therapy , Depression/drug therapy , Depression/etiology , 5-alpha Reductase Inhibitors/pharmacology , Rats , Finasteride/pharmacology , Diet, High-Fat/adverse effects , Anxiety/drug therapy , Oxidative Stress/drug effects , Behavior, Animal/drug effects , Brain/drug effects , Brain/metabolism , Disease Models, AnimalABSTRACT
Calcineurin inhibitors (CNI), including cyclosporine A (CsA) and tacrolimus (TAC), are cornerstones of immunosuppressive therapy in solid organ transplant recipients. While extensively recognized for their capacity to induce nephrotoxicity, hypertension, and dyslipidemia, emerging reports suggest potential direct cardiovascular toxicities associated with CNI. Evidence from both in vitro and in vivo studies has demonstrated direct cardiotoxic impact of CNI, manifesting itself as induction of cardiomyocyte apoptosis, enhanced oxidative stress, inflammatory cell infiltration, and cardiac fibrosis. CNI enhances cellular apoptosis through CaSR via activation of the p38 MAPK pathway and deactivation of the ERK pathway, and enhancement of miR-377 axis. Although CNI could attenuate cardiac hypertrophy in certain animal models, CNI concurrently impaired systolic function, enhanced cardiac fibrosis, and increased the risk of heart failure. Evidence from in vivo studies demonstrated that CNI prolong the duration of action potentials through a decrease in potassium current. CNI also exerted direct effects on endothelial cell injury, inducing apoptosis and enhancing oxidative stress. CNI may induce vascular inflammation through TLR4 via MyD88 and TRIF pathways. In addition, CNI affects vascular function by impairing endothelial-dependent vasodilation and promoting vasoconstriction. Clinical studies in transplant patients also revealed an increased incidence of cardiac remodeling. However, the evidence is constrained by the limited number of participants and potential confounding factors. Several studies indicate differing cardiovascular toxicity profiles between CsA and TAC, and these could be potentially due to their different interactions with calcineurin subunits and calcineurin-independent effects. Further studies are needed to clarify these mechanisms to improve cardiovascular outcomes for transplant patients with CNI.
Subject(s)
Calcineurin Inhibitors , Cardiovascular Diseases , Humans , Calcineurin Inhibitors/adverse effects , Animals , Cardiovascular Diseases/chemically induced , Immunosuppressive Agents/adverse effectsABSTRACT
Post-traumatic osteoarthritis of the ankle (PTOA) is frequently observed following a debilitating consequence of intra-articular ankle fractures. Numerous risk factors contribute to the pathogenesis of PTOA, including articular incongruity, joint malalignment, and concomitant soft tissue damage. Despite attempts to restore joint anatomy and manage soft tissues to avoid long-term complications after intra-articular ankle fractures, the incidence of PTOA remains markedly elevated. Inflammatory processes triggered by intra-articular ankle fractures have emerged as potential instigators that expedite the progression of PTOA. Injury to the articular cartilage and subchondral bone may lead to the release of inflammatory mediators, which can contribute to cartilage degradation and bone resorption. This study provides a narrative review on the current knowledge concerning the association between inflammation and the development of PTOA following intra-articular ankle fractures. We also discuss novel therapeutic agents that target inflammatory pathways to impede the progression of post-traumatic osteoarthritis after intra-articular ankle fractures. These medication and interventions were summarized within this review article.
Subject(s)
Inflammation , Osteoarthritis , Humans , Osteoarthritis/etiology , Osteoarthritis/pathology , Osteoarthritis/metabolism , Inflammation/pathology , Animals , Cartilage, Articular/pathology , Cartilage, Articular/metabolism , Ankle Joint/pathology , Ankle Fractures/complications , Ankle Fractures/pathology , Ankle Fractures/metabolism , Ankle Injuries/complications , Ankle Injuries/pathologyABSTRACT
Pediatric sepsis is a serious issue globally and is a significant cause of illness and death among infants and children. Refractory septic shock and multiple organ dysfunction syndrome are the primary causes of mortality in children with sepsis. However, there is incomplete understanding of mechanistic insight of sepsis associated organ dysfunction. Biomarkers present during the body's response to infection-related inflammation can be used for screening, diagnosis, risk stratification/prognostication, and/or guidance in treatment decision-making. Research on biomarkers in children with sepsis can provide information about the risk of poor outcomes and sepsis-related organ dysfunction. This review focuses on clinically used biomarkers associated with immune dysregulation and organ dysfunction in pediatric sepsis, which could be useful for developing precision medicine strategies in pediatric sepsis management in the future. IMPACT: Sepsis is a complex syndrome with diverse clinical presentations, where organ dysfunction is a key factor in morbidity and mortality. Early detection of organ complications is vital in sepsis management, and potential biomarkers offer promise for precision medicine in pediatric cases. Well-designed studies are needed to identify phase-specific biomarkers and improve outcomes through more precise management.
ABSTRACT
Mitochondrial dysfunction and the activation of multiple programmed cell death (PCD) have been shown to aggravate the severity and mortality associated with the progression of myocardial infarction (MI). Although pharmacological modulation of mitochondrial dynamics, including treatment with the fusion promoter (M1) and the fission inhibitor (Mdivi-1), exerted cardioprotection against several cardiac complications, their roles in the post-MI model have never been investigated. Using a MI rat model instigated by permanent left-anterior descending (LAD) coronary artery occlusion, post-MI rats were randomly assigned to receive one of 4 treatments (n = 10/group): vehicle (DMSO 3%V/V), enalapril (10 mg/kg), Mdivi-1 (1.2 mg/kg) and M1 (2 mg/kg), while a control group of sham operated rats underwent surgery without LAD occlusion (n = 10). After 32-day treatment, cardiac and mitochondrial function, and histopathological morphology were investigated and molecular analysis was performed. Treatment with enalapril, Mdivi-1, and M1 significantly mitigated cardiac pathological remodeling, reduced myocardial injury, and improved left ventricular (LV) function in post-MI rats. Importantly, all interventions also attenuated mitochondrial dynamic imbalance and mitigated activation of apoptosis, necroptosis, and pyroptosis after MI. This investigation demonstrated for the first time that chronic mitochondrial dynamic-targeted therapy mitigated mitochondrial dysfunction and activation of PCD, leading to improved LV function in post-MI rats.
Subject(s)
Apoptosis , Enalapril , Mitochondrial Dynamics , Myocardial Infarction , Ventricular Dysfunction, Left , Animals , Myocardial Infarction/drug therapy , Myocardial Infarction/pathology , Myocardial Infarction/physiopathology , Mitochondrial Dynamics/drug effects , Male , Ventricular Dysfunction, Left/drug therapy , Ventricular Dysfunction, Left/physiopathology , Rats , Enalapril/pharmacology , Enalapril/therapeutic use , Apoptosis/drug effects , Rats, Sprague-Dawley , Quinazolinones/pharmacology , Quinazolinones/therapeutic use , Disease Models, Animal , Mitochondria, Heart/drug effects , Mitochondria, Heart/metabolism , Mitochondria, Heart/pathologyABSTRACT
An impact of donepezil against doxorubicin-induced gut barrier disruption and gut dysbiosis has never been investigated. Twenty-four male Wistar rats were divided into three groups. Each group was treated with either vehicle as a control, doxorubicin, or doxorubicin-cotreated with donepezil. Heart rate variability was assessed to reflect the impact of doxorubicin and donepezil. Then, animals were euthanized, and the ileum and its contents were collected in each case to investigate the gut barrier and gut microbiota, respectively. The microbiota-derived endotoxin, trimethylamine N-oxide (TMAO), and short-chain fatty acids (SCFAs) in the serum were determined. An increase in the sympathetic tone, endotoxins, and TMAO levels with disruption of the gut barrier and a decrease in SCFAs levels were observed in doxorubicin-treated rats. Gut microbiota of doxorubicin-treated rats was significantly different from that of the control group. Donepezil treatment significantly decreased the sympathetic tone, restored the gut barrier, and reduced endotoxin and TMAO levels in doxorubicin-treated rats. Nonetheless, donepezil administration did not alter the gut microbiota profile and levels of SCFAs in doxorubicin-treated rats. Doxorubicin impaired the autonomic balance and the gut barrier, and induced gut dysbiosis, resulting in gut toxicity. Donepezil partially improved the doxorubicin-induced gut toxicity through balancing the autonomic disturbance.
Subject(s)
Donepezil , Doxorubicin , Gastrointestinal Microbiome , Rats, Wistar , Animals , Donepezil/pharmacology , Doxorubicin/toxicity , Male , Gastrointestinal Microbiome/drug effects , Rats , Fatty Acids, Volatile/metabolism , Dysbiosis/chemically induced , Methylamines , Endotoxins/toxicityABSTRACT
Multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) are two of the most devastating immune-mediated central demyelinating disorders. NMOSD was once considered as a variant of MS until the discovery of an antibody specific to the condition. Despite both MS and NMOSD being considered central demyelinating disorders, their pathogenesis and clinical manifestations are distinct, however the exact mechanisms associated with each disease remain unclear. Extracellular vesicles (EVs) are nano-sized vesicles originating in various cells which serve as intercellular communicators. There is a large body of evidence to show the possible roles of EVs in the pathogenesis of several diseases, including the immune-mediated central demyelinating disorders. Various types of EVs are found across disease stages and could potentially be used as a surrogate marker, as well as acting by carrying a cargo of biochemical molecules. The possibility for EVs to be used as a next-generation targeted treatment for the immune-mediated central demyelinating disorders has been investigated. The aim of this review was to comprehensively identify, compile and discuss key findings from in vitro, in vivo and clinical studies. A summary of all findings shows that: 1) the EV profiles of MS and NMOSD differ from those of healthy individuals, 2) the use of EV markers as liquid biopsy diagnostic tools appears to be promising biomarkers for both MS and NMOSD, and 3) EVs are being studied as a potential targeted therapy for MS and NMOSD. Any controversial findings are also discussed in this review.
ABSTRACT
Chemotherapy causes undesirable long-term neurological sequelae, chemotherapy-induced cognitive impairment (CICI), or chemobrain in cancer survivors. Activation of programmed cell death (PCD) has been proposed to implicate in the development and progression of chemobrain. Neuronal apoptosis has been extensively recognized in experimental models of chemobrain, but little is known about alternative forms of PCD in response to chemotherapy. Activation of acetylcholine receptors (AChRs) is emerging as a promising target in attenuating a wide variety of the neuronal death associated with neurodegeneration. Thus, this study aimed to investigate the therapeutic capacity of AChR agonists on cognitive function and molecular hallmarks of multiple PCD against chemotherapy neurotoxicity. To establish the chemobrain model, male Wistar rats were assigned to receive six doses of doxorubicin (DOX: 3 mg/kg) via intraperitoneal injection. The DOX-treated rats received either an a7nAChR agonist (PNU-282987: 3 mg/kg/day), mAChR agonists (bethanechol: 12 mg/kg/day), or the two as a combined treatment. DOX administration led to impaired cognitive function via neuroinflammation, glial activation, reduced synaptic/blood-brain barrier integrity, defective mitochondrial ROS-detoxifying capacity, and dynamic imbalance. DOX insult also mediated hyperphosphorylation of Tau and simultaneously induced various PCD, including apoptosis, necroptosis, and pyroptosis in the hippocampus. Concomitant treatment with either PNU-282987, bethanechol, or a combination of the two potently attenuated neuroinflammation, mitochondrial dyshomeostasis, and Tau hyperphosphorylation, thereby suppressing excessive apoptosis, necroptosis, and pyroptosis and improving cognitive function in DOX-treated rats. Our findings suggest that activation of AChRs using their agonists effectively protected against DOX-induced neuronal death and chemobrain.
ABSTRACT
Kidney transplantation is a highly effective treatment for end-stage kidney disease. However, allograft rejection remains a significant clinical challenge in kidney transplant patients. Although kidney allograft biopsy is the gold-standard diagnostic method, it is an invasive procedure. Since the current monitoring methods, including screening of serum creatinine and urinary protein, are not of sufficient sensitivity, there is a need for effective post-transplant monitoring to detect allograft rejection at an early stage. Extracellular vesicles are vesicles with a lipid bilayer that originate from different cell types in pathological and physiological conditions. The content of extracellular vesicles reflects the status of cells at the time of their production. This review comprehensively summarizes clinical, in vivo, and in vitro reports that highlight the potential of extracellular vesicles as diagnostic biomarkers for kidney allograft rejection. Clarification would facilitate differentiation between rejection and non-rejection and identification of the mechanisms involved in the allograft rejection. Despite increasing evidence, further research is necessary to establish the clinical utility of extracellular vesicles in the diagnosis and monitoring of allograft rejection in kidney transplant recipients. Using extracellular vesicles as non-invasive biomarkers for diagnosis of kidney allograft rejection could have tremendous benefits in improving patient outcomes and reduce the need for invasive procedures.
Subject(s)
Extracellular Vesicles , Kidney , Humans , Kidney/pathology , Transplantation, Homologous , Biomarkers/urine , Allografts , Graft Rejection/diagnosis , Graft Rejection/etiologyABSTRACT
The cardio-ankle vascular index (CAVI) is a noninvasive parameter reflecting vascular stiffness. CAVI correlates with the burden of atherosclerosis and future cardiovascular events. Mitochondria of peripheral blood mononuclear cells (PBMCs) have been identified as a noninvasive source for assessing systemic mitochondrial bioenergetics. This study aimed to investigate the relationship between CAVI values and mitochondrial bioenergetics of PBMCs in the older adults.. This cross-sectional study enrolled participants from the Electricity Generating Authority of Thailand between 2017 and 2018. A total of 1 640 participants with an ankle-brachial index greater than 0.9 were included in this study. All participants were stratified into 3 groups based on their CAVI values as high (CAVIâ ≥â 9), moderate (9â >â CAVIâ ≥â 8), and low (CAVIâ <â 8), in which each group comprised 702, 507, and 431 participants, respectively. The extracellular flux analyzer was used to measure mitochondrial respiration of isolated PBMCs. The mean age of the participants was 67.9 years, and 69.6% of them were male. After adjusted with potential confounders including age, sex, smoking status, body mass index, diabetes, dyslipidemia, hypertension, and creatinine clearance, participants with high CAVI values were independently associated with impaired mitochondrial bioenergetics, including decreased basal respiration, maximal respiration, and spare respiratory capacity, as well as increased mitochondrial reactive oxygen species. This study demonstrated that CAVI measurement reflects the underlying impairment of cellular mitochondrial bioenergetics in PBMCs. Further longitudinal studies are necessary to establish both a causal relationship between CAVI measurement and underlying cellular dysfunction.
Subject(s)
Energy Metabolism , Leukocytes, Mononuclear , Mitochondria , Vascular Stiffness , Humans , Male , Female , Aged , Cross-Sectional Studies , Energy Metabolism/physiology , Leukocytes, Mononuclear/metabolism , Mitochondria/metabolism , Vascular Stiffness/physiology , Ankle Brachial Index , Thailand , Cardio Ankle Vascular Index , Middle AgedABSTRACT
BACKGROUND: We aimed to compare the changes in blood metabolomes and cardiac parameters following doxorubicin treatment in HER2-positive and HER2-negative breast cancer patients. Additionally, the potential roles of changes in blood metabolomes as severity and prognostic markers of doxorubicin-induced cardiotoxicity were determined. METHODS: HER2-positive (n = 37) and HER2-negative (n = 37) breast cancer patients were enrolled. Cardiac function assessment and blood collection were performed at baseline and 2 weeks after completion of doxorubicin treatment in all patients, as well as at three months after completion of doxorubicin treatment in HER2-negative breast cancer patients. Blood obtained at all three-time points was processed for measuring cardiac injury biomarkers. Blood obtained at baseline and 2 weeks after completion of doxorubicin treatment were also processed for measuring systemic oxidative stress and 85 metabolome levels. RESULTS: Cardiac injury and systolic dysfunction 2 weeks after completion of doxorubicin treatment were comparable between these two groups of patients. However, only HER2-negative breast cancer patients exhibited increased systemic oxidative stress and cardiac autonomic dysfunction at this time point. Moreover, 33 and 29 blood metabolomes were altered at 2 weeks after completion of doxorubicin treatment in HER2-positive and HER2-negative breast cancer patients, respectively. The changes in most of these metabolomes were correlated with the changes in cardiac parameters, both at 2 weeks and 3 months after completion of doxorubicin treatment. CONCLUSIONS: The changes in blood metabolomes following doxorubicin treatment were dependent on HER2 status, and these changes might serve as severity and prognostic markers of doxorubicin-induced cardiotoxicity. TRIAL REGISTRATION: The study was conducted under ethical approval from the Institutional Review Board of the Faculty of Medicine, Chiang Mai University (Registration number: MED-2563-07001; Date: April 28, 2020). The study also complied with the Declaration of Helsinki.
Subject(s)
Breast Neoplasms , Cardiotoxicity , Doxorubicin , Metabolome , Receptor, ErbB-2 , Humans , Breast Neoplasms/drug therapy , Breast Neoplasms/blood , Female , Doxorubicin/adverse effects , Receptor, ErbB-2/metabolism , Receptor, ErbB-2/blood , Middle Aged , Prognosis , Cardiotoxicity/blood , Oxidative Stress/drug effects , Biomarkers/blood , Biomarkers/metabolism , AdultABSTRACT
Mitochondrial dysfunction and inflammation contribute to the pathophysiology of metabolic dysfunction-associated steatohepatitis (MASH). This study aims to evaluate the potential association between mitochondrial dynamics and cell death markers from peripheral blood mononuclear cells (PBMCs) and the presence of MASH with significant liver fibrosis among metabolic dysfunction-associated steatotic liver disease (MASLD) patients. Consecutive patients undergoing bariatric surgery from January to December 2022 were included. Patients with histologic steatosis were classified into MASH with significant fibrosis (F2-4) group or MASLD/MASH without significant fibrosis group (F0-1). Mitochondrial dynamic proteins and cell death markers were extracted from PBMCs. A total of 23 MASLD/MASH patients were included (significant fibrosis group, n = 7; without significant fibrosis group, n = 16). Of the mitochondrial dynamics and cell death markers evaluated, OPA1 protein, a marker of mitochondrial fusion is higher in MASH patients with significant fibrosis compared to those without (0.861 ± 0.100 vs. 0.560 ± 0.260 proportional to total protein, p = 0.001). Mitochondrial fusion/fission (OPA1/DRP1) ratio is significantly higher in MASH patients with significant fibrosis (1.072 ± 0.307 vs. 0.634 ± 0.313, p = 0.009). OPA1 (per 0.01 proportional to total protein) was associated with the presence of significant liver fibrosis with an OR of 1.08 (95%CI, 1.01-1.15, p = 0.035), and adjusted OR of 1.10 (95%CI, 1.00-1.21, p = 0.042). OPA1 from PBMCs is associated with MASH and substantial fibrosis. Future studies should explore if OPA1 could serve as a novel non-invasive liver fibrosis marker.
ABSTRACT
Iron overload has detrimental effects on bone marrow mesenchymal stem cells (BMMSCs), cells crucial for bone marrow homeostasis and hematopoiesis support. Excessive iron accumulation leads to the production of reactive oxygen species (ROS), resulting in cell death, cell cycle arrest, and disruption of vital cellular pathways. Although apoptosis has been extensively studied, other programmed cell death mechanisms including autophagy, necroptosis, and ferroptosis also play significant roles in iron overload-induced bone marrow cell death. Studies have highlighted the involvement of ROS production, DNA damage, MAPK pathways, and mitochondrial dysfunction in apoptosis. In addition, autophagy and ferroptosis are activated, as shown by the degradation of cellular components and lipid peroxidation, respectively. However, several compounds and antioxidants show promise in mitigating iron overload-induced cell death by modulating ROS levels, MAPK pathways, and mitochondrial integrity. Despite early indications, more comprehensive research and clinical studies are needed to better understand the interplay between these programmed cell death mechanisms and enable development of effective therapeutic strategies. This review article emphasizes the importance of studying multiple cell death pathways simultaneously and investigating potential rescuers to combat iron overload-induced bone marrow cell death.
Subject(s)
Iron Overload , Iron , Humans , Iron/metabolism , Reactive Oxygen Species/metabolism , Bone Marrow/metabolism , Iron Overload/metabolism , Apoptosis , Bone Marrow Cells/metabolismABSTRACT
AIM: Prolonged high-fat diet (HFD) consumption has been shown to impair cognition and depression. The combined effects of HFD and lipopolysaccharide (LPS) administration on those outcomes have never been thoroughly investigated. This study investigated the effects of LPS, HFD consumption, and a combination of both conditions on microglial dysfunction, microglial morphological alterations, synaptic loss, cognitive dysfunction, and depressive-like behaviors. METHODS: Sixty-four male Wistar rats were fed either a normal diet (ND) or HFD for 12 weeks, followed by single dose-subcutaneous injection of either vehicle or LPS. Then, cognitive function and depressive-like behaviors were assessed. Then, rats were euthanized, and the whole brain, hippocampus, and spleen were collected for further investigation, including western blot analysis, qRT-PCR, immunofluorescence staining, and brain metabolome determination. RESULTS: HFD-fed rats developed obese characteristics. Both HFD-fed rats with vehicle and ND-fed rats with LPS increased cholesterol and serum LPS levels, which were exacerbated in HFD-fed rats with LPS. HFD consumption, but not LPS injection, caused oxidative stress, blood-brain barrier disruption, and decreased neurogenesis. Both HFD and LPS administration triggered an increase in inflammatory genes on microglia and astrocytes, increased c1q colocalization with microglia, and increased dendritic spine loss, which were exacerbated in the combined conditions. Both HFD and LPS altered neurotransmitters and disrupted brain metabolism. Interestingly, HFD consumption, but not LPS, induced cognitive decline, whereas both conditions individually induced depressive-like behaviors, which were exacerbated in the combined conditions. CONCLUSIONS: Our findings suggest that LPS aggravates metabolic disturbances, neuroinflammation, microglial synaptic engulfment, and depressive-like behaviors in obese rats.
ABSTRACT
Increasing global obesity rates and an aging population are independently linked to cardiac complications. Consequently, it is crucial to comprehensively understand the mechanisms behind these conditions to advance innovative therapies for age-related diseases. Mitochondrial dysfunction, specifically defects in mitochondrial fission/fusion processes, has emerged as a central regulator of cardiac complications in aging and age-related diseases (e.g., obesity). Since excessive fission and impaired fusion of cardiac mitochondria lead to disruptions in mitochondrial dynamics and cellular metabolism in aging and obesity, modulating mitochondrial dynamics with either fission inhibitors or fusion promoters has offered cardioprotection against these pathological conditions in preclinical models. This review explores the molecular mechanisms governing mitochondrial dynamics as well as the disturbances observed in aging and obesity. Additionally, pharmaceutical interventions that specifically target the processes of mitochondrial fission and fusion are presented and discussed. By establishing a connection between mitochondrial dynamism through fission and fusion and the advancement or mitigation of age-related diseases, particularly obesity, this review provides valuable insights into the progression and potential prevention strategies for such conditions.
Subject(s)
Heart Diseases , Mitochondrial Dynamics , Humans , Aged , Heart , Aging/metabolism , Heart Diseases/metabolism , ObesityABSTRACT
BACKGROUND: Postmenopausal women with obesity are markedly at risk of cognitive impairment and several health issues. Emerging evidence demonstrated that both diet and exercise, particularly physical-cognitive exercise are involved in cognitive and health benefits. However, the comparative effect of diet, exercise, and combined interventions in postmenopausal women with obesity on cognition and cardiometabolic health is still lacking. Identifying the effective health promotion program and understanding changes in cardiometabolic health linking these interventions to cognition would have important medical implications. This RCT aimed to examine the effect of single and combined interventions of diet and exercise on cognitive function and cardiometabolic health in postmenopausal women with obesity. METHODS: Ninety-two postmenopausal women with obesity were randomly assigned to diet group (intermittent fasting 2 days/week, 3 months), exercise group (physical-cognitive exercise 3 days/week, 3 months), combined group, or control group (n = 23/group). All cognitive outcomes and cardiometabolic outcomes were measured at baseline and post-3 months. Primary outcomes were executive functions, memory, and plasma BDNF levels. Secondary outcomes were global cognition, attention, language domain, plasma adiponectin levels, IL-6 levels, metabolic parameters, and physical function. RESULTS: At the end of the 3-month intervention, the exercise and combined group demonstrated significant memory improvement which was accompanied by significant improvements in plasma BDNF level, insulin levels, HOMA-IR, %body fat, and muscle strength when compared to controls (p < 0.05). Only the combined intervention group demonstrated a significant improvement in executive function and increased plasma adiponectin levels when compared to control (p < 0.05). Surprisingly, no cognitive improvement was observed in the diet group (p > 0.05). Significant reduction in cholesterol levels was shown in the diet and combined groups when compared to controls (p < 0.05). Among the three intervention groups, there were no significant differences in all cognitive outcomes and cardiometabolic outcomes (p > 0.05). However, all three intervention groups showed significant improvements in plasma BDNF levels, weight, BMI, WHR, fat mass, and predicted VO2 max, when compared to control (p < 0.05). CONCLUSION: These findings suggest that combined physical-cognitive exercise and dietary intervention are promising interventions to improve cognition and obesity-related complications of postmenopausal women with obesity. TRIAL REGISTRATION: NCT04768725 ( https://clinicaltrials.gov ) 24th February 2021.
Subject(s)
Adiponectin , Cardiovascular Diseases , Female , Humans , Brain-Derived Neurotrophic Factor , Postmenopause , Cognition , Obesity/complications , Obesity/therapy , Cardiovascular Diseases/prevention & controlABSTRACT
Background/purpose: The toll-like receptor 4 (TLR4)-myeloid differentiation factor 2 (MD-2) complex is known to have a role in inflammation. Blocking MD-2 can suppress inflammatory process. However, the actual action of MD-2 inhibitors, including MAC28, L6H21, and 2i-10, on the inflamed human dental pulp cells (HDPCs) has never been examined. This study aims to determine the pharmacological effects of these 3 compounds on cell viability, inflammation, and osteo/odontogenic differentiation of lipopolysaccharide (LPS)-treated HDPCs. Materials and methods: HDPCs were pretreated with 10 µM of MAC28, L6H21, or 2i-10 for 2 h followed by either 20 µg/mL LPS or vehicle for 24 h. Cell viability was assessed using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The mRNA and expression of the proteins TLR4, MD-2, tumor necrosis factor alpha (TNF-α), and interleukin 6 (IL-6) were determined using quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot analysis. Osteo/odontogenic differentiation was investigated using qRT-PCR and Alizarin Red staining. Results: LPS did not alter cell viability but significantly increased the expression levels of TLR4, MD-2, TNF-α, and IL-6 in HDPCs while the osteo/odontogenic differentiation ability decreased significantly when compared to the vehicle-treated group. MAC28, L6H21, and 2i-10-pretreatment in LPS-treated HDPCs reduced inflammation and restored osteo/odontogenic differentiation to similar levels as the vehicle-treated group. Conclusion: MAC28, L6H21, and 2i-10 exhibited equal efficacy in attenuating inflammation through downregulation of TLR4-MD-2 signaling and restored osteo/odontogenic differentiation in LPS-treated HDPCs. These MD-2 inhibitors could be considered as the potential therapeutic supplement for curing inflammation of dental pulp in future studies.
ABSTRACT
OBJECTIVE: Whether or not the effects of anemia in the early phase, while the fetuses attempts to increase cardiac output to meet oxygen requirement in peripheral organs, is detrimental to the fetal developing vital organs is little-known. The objective of this is to compare prenatal cardiovascular changes and post-abortal cellular damages in the myocardium as a pumping organ and the brain as a perfused organ between anemic fetuses (using fetal Hb Bart's disease as a study model) in pre-hydropic phase and non-anemic fetuses. METHODS: Fetuses affected by Hb Bart's disease and non-anemic fetuses at 16-22 weeks were recruited to undergo comprehensive fetal echocardiography. Cord blood analysis was used to confirm the definite diagnosis of fetal Hb Bart's disease and normal fetuses. Fetal cardiac and brain tissues were collected shortly after pregnancy termination for the determination of oxidative stress and mitochondrial function, including mitochondrial ROS production and mitochondrial membrane changes. RESULTS: A total of 18 fetuses affected by Hb Bart's disease and 13 non-anemic fetuses were recruited. The clinical characteristics of both groups were comparable. The affected fetuses showed a significant increase in cardiac dimensions, cardiac function, cardiac output and brain circulation without deteriorating cardiac contractility and preload. However, in the affected fetuses, mitochondrial dysfunction was clearly demonstrated in brain tissues and in the myocardium, as indicated by a significant increase in the membrane potential change (p-value < 0.001), and a significant increase in ROS production in brain tissues, with a trend to increase in myocardium. The findings indicated cellular damage in spite of good clinical compensation. CONCLUSION: The new insight is that, in response to fetal anemia, fetal heart increases in size (dilatation) and function to increase cardiac output and blood flow velocity to provide adequate tissue perfusion, especially brain circulation. However, the myocardium and brain showed a significant increase in mitochondrial dysfunction, suggesting cellular damage secondary to anemic hypoxia. The compensatory increase in circulation could not completely prevent subtle brain and heart damage.
Subject(s)
Anemia , Fetal Diseases , Hemoglobins, Abnormal , Mitochondrial Diseases , alpha-Thalassemia , Female , Pregnancy , Humans , Pregnancy Trimester, Second , Reactive Oxygen Species , Hemoglobins, Abnormal/analysis , Fetal Diseases/diagnosis , Fetal Heart/diagnostic imaging , Myocardium/chemistry , Edema , Cardiac OutputABSTRACT
Exposure to air pollutants, especially in the case of particulate matter (PM), poses significant health risks throughout the body. The ocular surface is directly exposed to atmospheric PM making it challenging to avoid. This constant exposure makes the ocular surface a valuable model for investigating the impact of air pollutants on the eyes. This comprehensive review assembles evidence from across the spectrum, from in vitro and in vivo investigations to clinical studies and epidemiological studies, offering a thorough understanding of how PM10 and PM2.5 affect the health of the ocular surface. PM has been primarily found to induce inflammatory responses, allergic reactions, oxidative stress, DNA damage, mitochondrial impairment, and inhibit the proliferation and migration of ocular surface cells. In toto these effects ultimately lead to impaired wound healing and ocular surface damage. In addition, PM can alter tear composition. These events contribute to ocular diseases such as dry eye disease, blepharitis, conjunctivitis, keratitis, limbal stem cell deficiency and pterygium. Importantly, preexisting ocular conditions such as dry eye, allergic conjunctivitis, and infectious keratitis can be worsened by PM exposure. Adaptive responses may partially alleviate the mentioned insults, resulting in morphological and physiological changes that could be different between periods of short-term and long-term exposure. Particle size is not the only determinant of the ocular effect of PM, the composition and solubility of PM also play critical roles. Increasing awareness of how PM affects the ocular surface is crucial in the field of public health, and mechanistic insights of these adverse effects may provide guidelines for preventive and therapeutic strategies in dealing with a polluted environment.