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Objectives: Postmenopausal women are at higher risk of metabolic syndrome and cardiovascular disease, which are aggravated by obesity. Although estrogen provides cardiometabolic protection, chronic high-dose treatment could be harmful. This study investigated the efficacy of combined N-acetylcysteine (NAC) and low-dose estrogen treatment against cardiometabolic dysfunction in female estrogen-deprived obese rats with cardiac ischemia-reperfusion (I/R) injury., Methods: Bilateral ovariectomized (O) female Wistar rats were fed a high-fat diet (H) for 12 weeks. Then, rats were treated for 4 weeks with one of the following: vehicle (OH; sesame oil), regular-dose estrogen (E; 50 μg/kg/d), low-dose estrogen (e; 25 μg/kg/d), NAC (N; 100 mg/kg/d), or combined low-dose estradiol with NAC (eN). All rats then underwent cardiac I/R injury, and the left ventricle (LV) function and mitochondrial function were investigated (n = 6/group). Statistical analysis was performed by one-way ANOVA followed by Fisher's least significant difference post hoc test., Results: Body weight, visceral fat, plasma glucose, and plasma cholesterol were significantly increased with impaired LV function and heart rate variability in OH rats. OH-E rats had decreased plasma insulin and Homeostatic Model Assessment for Insulin Resistance index. Both OH-E and OH-eN rats had similarly improved heart rate variability and LV function. During cardiac I/R, OH-E and OH-eN rats had preserved left ventricular ejection fraction, stroke volume, and attenuated arrhythmias. Impaired cardiac mitochondrial function and infarct size were similarly reduced in OH-E and OH-eN rats., Conclusions: Combined NAC and low-dose estrogen treatment shares similar efficacy as regular-dose estrogen in attenuating cardiac dysfunction, cardiac mitochondrial dysfunction, and protecting the heart against I/R injury in estrogen-deprived obese insulin-resistant rats., Competing Interests: Financial disclosure/conflicts of interest: None reported., (Copyright © 2024 by The Menopause Society.)

High-fat diet consumption for an extended period causes obesity, systemic metabolic disturbance, and brain insulin resistance, resulting in neuroinflammation. Although the beneficial effect of Cyclosorus terminans extract on obesity-related insulin resistance has been demonstrated, little is known about how it affects neuroinflammation and brain insulin resistance in obese rats. Male Wistar rats were given either a normal diet (ND, n = 6) or a high-fat diet (HFD, n = 24) for a total of 14 weeks. At the beginning of the week, 13 rats in the ND group were given vehicle orally for 2 weeks, while rats on HFD diets were randomized to one of four groups and given either vehicle, 100 mg/kg/day of Cyclosorus terminans extract, 200 mg/kg/day of Cyclosorus terminans extract, or 20 mg/kg/day of pioglitazone orally for 2 weeks. After the experimental period, blood and brain samples were taken to assess metabolic and brain parameters. HFD-fed rats had obesity, systemic and brain insulin resistance, brain inflammation, microglial and astrocyte hyperactivity, and brain necroptosis. Treatment with 200 mg/kg/day of Cyclosorus terminans extract and pioglitazone equally attenuated obesity, insulin resistance, brain insulin dysfunction, and neuroinflammation in insulin resistant rats. Our findings suggest that Cyclosorus terminans extract may hold promise as a therapeutic agent for insulin resistance and neuroinflammation in obese conditions., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Alzheimer's disease (AD), Parkinson's disease (PD), and age-related macular degeneration (AMD) are common among neurodegenerative diseases, but investigations into novel therapeutic approaches are currently limited. Humanin (HN) is a mitochondrial-derived peptide found in brain tissues of patients with familial AD and has been increasingly investigated in AD and other neurodegenerative diseases., Scope of Review: In this review, we summarize and discuss the effects of HN on the pathology of neurodegenerative diseases and cognition based on several studies from preclinical to clinical models. The association between cardiac ischemia-reperfusion (I/R) injury and brain are also included. Findings from in vitro studies and those involving mice provide the most fundamental information on the impact of HN and its potential association with clinical studies., Major Conclusions: HN plays a considerable role in countering the progression and neuropathology of AD. Inhibition and reduction of oxidative stress and neuroinflammation of the original amyloid hypothesis is the mainstay mechanism. Multiple intracellular mechanisms will be elucidated, including those involved in the anti-apoptotic signaling cascades, the insulin signaling pathway, and mitochondrial function, and especially autophagic activity. These beneficial roles are also found following cardiac I/R injury. Cognitive improvement was found to be related to maintenance of synaptic integrity and neurotransmitter modulation. Small humanin-like peptide 2 demonstrates the neuroprotective effects in PD and AMD via prevention of mitochondrial loss., General Significance: Comprehensive knowledge of HN effects on cognition and neurodegenerative diseases emphasizes its potential to treat a viable disease, as it ameliorates the pathogenesis of the disease., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The accumulation of lipid as a result of long-term consumption of a high-fat diet (HFD) may lead to metabolic and brain dysfunction. Atorvastatin, a recommended first-line lipid-lowering agent, has shown beneficial effects on metabolic and brain functions in several models. Recently, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor was approved as an effective therapeutic drug for dyslipidemia patients. However, few studies have reported on the effect of this PCSK9 inhibitor on brain function. In addition, the comparative efficacy on the improvement of metabolic and brain functions between PCSK9 inhibitor and atorvastatin in obese models have not been elucidated. We hypothesized that PCSK9 inhibitor improves metabolic and brain functions in an obese model to a greater extent than atorvastatin. Thirty-two female rats were fed with either a normal diet (ND) or HFD for 15 weeks. At week 13, ND rats were given normal saline and HFD rats were given either normal saline, atorvastatin (40 mg/kg/day) or PCSK9 inhibitor (4 mg/kg/day) for 3 weeks. Oxidative stress, blood brain barrier breakdown, microglial hyperactivity, synaptic dysplasticity, apoptosis, amyloid proteins production in the hippocampus and cognitive decline were found in HFD-fed rats. Atorvastatin and PCSK9 inhibitor therapies equally attenuated hippocampal apoptosis and amyloid protein production in HFD-fed rats. Interestingly, PCSK9 inhibitor had the greater efficacy than atorvastatin on the amelioration of hippocampal oxidative stress, blood brain barrier breakdown, microglial hyperactivity, synaptic dysplasticity in the hippocampus and cognitive decline. These findings suggest that PCSK9 inhibitor may be another drug of choice for improving brain function in the obese condition with discontinued statin therapy., Competing Interests: Declaration of competing interest None., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Myocardial damage and mitochondrial dysfunction caused by cardiac ischemia-reperfusion (I/R) injury are intensified by endogenous estrogen deprivation. Although N-acetylcysteine (NAC) exerted cardioprotective effects, its benefits when used in combination with hormone therapy are unknown. We tested the hypothesis that a combination of NAC with low-dose estrogen improves cardiometabolic function and protects cardiac mitochondria against I/R injury, to a similar extent to regular-dose estrogen treatment, in estrogen-deprived rats. Female Wistar rats had a bilateral ovariectomy (OVX) or sham operation. Twelve weeks after the operation, OVX rats were treated with regular-dose estrogen (E; 50 µg/kg/day), low-dose estrogen (e; 25 µg/kg/day), NAC (N; 100 mg/kg/day) or combined low-dose estradiol with NAC (eN) for 4 weeks (n = 6/group). Metabolic parameters, echocardiography, heart rate variability and then cardiac I/R protocol involving 30-min coronary artery ligation, followed by 120-min reperfusion, were performed. OVX rats had increased body weight, visceral fat, fasting plasma glucose, HOMA-IR index, triglycerides, cholesterol and LDL levels (P < 0.05 vs sham). Only OVX-E and OVX-eN had a similarly improved HOMA-IR index. LVEF was increased in all treatment groups, but HRV was restored only by OVX-E and OVX-eN. After I/R, myocardial infarct size was decreased in both OVX-E and OVX-eN groups. OVX-E and OVX-eN rats similarly had a reduced mitochondrial ROS level and increased mitochondrial membrane potential in the ischemic myocardium. In conclusion, combined NAC with low-dose estrogen and regular-dose estrogen therapy similarly improve cardiometabolic function, prevent cardiac mitochondrial dysfunction and reduces the infarct size in estrogen-deprived rats with cardiac I/R injury.

Although insulin and atorvastatin have been shown to exert glycemic control and could improve brain function, the effects of atorvastatin or insulin as well as the combination of atorvastatin plus insulin on brain pathology in diabetes mellitus type 1 (T1DM) are unclear. Therefore, this study investigated the effect of atorvastatin, insulin or combined drugs on brain pathology in streptozotocin-induced diabetic rats. Thirty-six male rats were divided into two groups, a control group (n = 12) and a diabetic or experimental group (n = 24). Diabetic rats were further divided into four groups (n = 6/group) and the groups received either a vehicle (normal saline), atorvastatin (10 mg/kg/day), insulin (4 U/day) or a combination of the drugs for 4 weeks. The control group rats were divided into two groups (n = 6/group) to receive either just the vehicle or atorvastatin for 4 weeks. We found that streptozotocin-induced diabetic rats developed hyperglycemia, showing evidence of increased brain oxidative stress, impaired brain mitochondrial function, increased brain apoptosis, increased tau protein expression, increased phosphorylation of tau protein expression and amyloid beta levels, and decreased dendritic spine density. Although atorvastatin and insulin therapies led to an equal reduction in plasma glucose level in these diabetic rats, the combined drug therapy showed the greatest efficacy in decreasing plasma glucose level. Interestingly, atorvastatin, insulin and the combined drugs equally mitigated brain pathology. Our findings indicate that the combined drug therapy showed the greatest efficacy in improving metabolic parameters. However, atorvastatin, insulin and the combined drug therapy shared a similar efficacy in preventing brain damage in T1DM rats., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Alzheimer's disease (AD) is a multifactorial neurodegenerative disease mainly caused by β-amyloid (Aβ) accumulation in the brain. Among the several factors that may concur to AD development, elevated cholesterol levels and brain cholesterol dyshomeostasis have been recognized to play a relevant role. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protein primarily known to regulate plasma low-density lipoproteins (LDLs) rich in cholesterol and to be one of the main causes of familial hypercholesterolemia. In addition to that, PCSK9 is also recognized to carry out diverse important activities in the brain, including control of neuronal differentiation, apoptosis, and, importantly, LDL receptors functionality. Moreover, PCSK9 appeared to be directly involved in some of the principal processes responsible for AD development, such as inflammation, oxidative stress, and Aβ deposition. On these bases, PCSK9 management might represent a promising approach for AD treatment. The purpose of this review is to elucidate the role of PCSK9, whether or not cholesterol-related, in AD pathogenesis and to give an updated overview of the most innovative therapeutic strategies developed so far to counteract the pleiotropic activities of both humoral and brain PCSK9, focusing in particular on their potentiality for AD management. [ABSTRACT FROM AUTHOR]

Background: The incidence of diabetes-associated cognitive dysfunction (DACD) is increasing; however, few clinical intervention measures are available for the prevention and treatment of this disease. Research has shown that proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, particularly SBC-115076, have a protective effect against various neurodegenerative diseases. However, their role in DACD remains unknown. In this study, we aimed to explore the impact of PCSK9 inhibitors on DACD. Methods: Male Sprague-Dawley (SD) rats were used to establish an animal model of type 2 diabetes mellitus (T2DM). The rats were randomly divided into three groups: the Control group (Control, healthy rats, n = 8), the Model group (Model, rats with T2DM, n = 8), and the PCSK9 inhibitor-treated group (Treat, T2DM rats treated with PCSK9 inhibitors, n = 8). To assess the spatial learning and memory of the rats in each group, the Morris water maze (MWM) test was conducted. Hematoxylin-eosin staining and Nissl staining procedures were performed to assess the structural characteristics and functional status of the neurons of rats from each group. Transmission electron microscopy was used to examine the morphology and structure of the hippocampal neurons. Determine serum PCSK9 and lipid metabolism indicators in each group of rats. Use qRT-PCR to detect the expression levels of interleukin (IL)-1β, IL-6, and tumor necrosis factor-alpha (TNF-α) in the hippocampal tissues of each group of rats. Western blot was used to detect the expression of PCSK9 and low-density lipoprotein receptor (LDLR) in the hippocampal tissues of rats. In addition, a 4D label-free quantitative proteomics approach was used to analyse protein expression in rat hippocampal tissues. The expression of selected proteins in hippocampal tissues was verified by parallel reaction monitoring (PRM) and immunohistochemistry (IHC). Results: The results showed that the PCSK9 inhibitor alleviated cognitive dysfunction in T2DM rats. PCSK9 inhibitors can reduce PCSK9, total cholesterol (TC), and low-density lipoprotein (LDL) levels in the serum of T2DM rats. Meanwhile, it was found that PCSK9 inhibitors can reduce the expression of PCSK9, IL-1β, IL-6, and TNF-α in the hippocampal tissues of T2DM rats, while increasing the expression of LDLR. Thirteen potential target proteins for the action of PCSK9 inhibitors on DACD rats were identified. PRM and IHC revealed that PCSK9 inhibitors effectively counteracted the downregulation of transthyretin in DACD rats. Conclusion: This study uncovered the target proteins and specific mechanisms of PCSK9 inhibitors in DACD, providing an experimental basis for the clinical application of PCSK9 inhibitors for the potential treatment of DACD. [ABSTRACT FROM AUTHOR]

Proprotein convertase substilin/kexin type 9 (PCSK9), a pivotal protein regulating lipid metabolism, has been implicated in promoting microthrombotic formation and inflammatory cascades, thereby contributing to cardiovascular ischemia/reperfusion (I/R) injury. However, its involvement in cerebral I/R injury and its potential role in microcirculation protection remain unexplored. In this investigation, we utilized a middle cerebral artery occlusion/reperfusion (MCAO/R) mouse model to simulate ischemic stroke. Different concentrations of evolocumab (1, 5, 10 mg/kg, i.v.), a PCSK9 inhibitor, were administered to assess its impact. Immunofluorescence staining was employed to analyze changes in the expression of occludin, claudin-5, thrombocyte, ICAM-1, VCAM-1, and CD45, providing insights into blood-brain barrier integrity, platelet adhesion, and immune cell infiltration. Moreover, the Morris water maze and elevated plus maze were utilized to evaluate neurological and behavioral functions in MCAO/R mice, shedding light on the effects of PCSK9 inhibition. Our findings revealed a surge in plasma PCSK9 levels post-MCAO/R, peaking at 24 h post-reperfusion. Evolocumab (10 mg/kg) treatment significantly mitigated brain infarction and neurological deficits, evidenced by enhanced locomotor function and reduced post-stroke anxiety. However, it did not ameliorate cognitive impairment following MCAO/R. Additionally, evolocumab administration led to diminished leakage of evans blue solution and upregulated expression of occludin and claudin-5. Thrombocyte, ICAM-1, VCAM-1, and CD45 levels were notably reduced in the penumbral area post-evolocumab treatment. These protective effects are speculated to be mediated through the inhibition of the ERK/NF-κB pathway. The PCSK9 inhibitor evolocumab holds promise as a therapeutic agent during the acute phase of stroke, exerting its beneficial effects by modulating the ERK/NF-κB signaling pathway., Competing Interests: Declarations Competing Interests The authors declare no competing interests. Ethics Approval This study was performed in accordance with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University (Date 2022-03-07/No. 2022DZGKJDWLS-0043). Consent to Participate Not applicable. Consent to Publish Not applicable., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Iron overload in many brain regions is a common feature of aging and most neurodegenerative diseases. In this review, the causes, mechanisms, mathematical models, and possible therapies are summarized. Indeed, physiological and pathological conditions can be investigated using compartmental models mimicking iron trafficking across the blood–brain barrier and the Cerebrospinal Fluid-Brain exchange membranes located in the choroid plexus. In silico models can investigate the alteration of iron homeostasis and simulate iron concentration in the brain environment, as well as the effects of intracerebral iron chelation, determining potential doses and timing to recover the physiological state. Novel formulations of non-toxic nanovectors with chelating capacity are already tested in organotypic brain models and could be available to move from in silico to in vivo experiments. [ABSTRACT FROM AUTHOR]

Simple Summary: Humanin was discovered in 2001 as a biological factor with neuroprotective activity. This review article presents research results that have supported the neuroprotective action of humanin as well as of specific humanin analogues (most of which are synthetic) in various cellular and animal models; it also presents possible mechanisms of neuroprotective action and briefly discusses the prospects for exploiting the therapeutic potential of humanin and humanin analogues in the fight against neurodegenerative disorders. Humanin is a 24-mer peptide first reported in the early 2000s as a new neuroprotective/cytoprotective factor rescuing neuronal cells from death induced by various Alzheimer's disease-associated insults. Nowadays it is known that humanin belongs to the novel class of the so-called mitochondrial-derived peptides (which are encoded by mitochondrial DNA) and has been shown to exert beneficial cytoprotective effects in a series of in vitro and/or in vivo experimental models of human diseases, including not only neurodegenerative disorders but other human diseases as well (e.g., age-related macular degeneration, cardiovascular diseases, or diabetes mellitus). This review article is focused on the presentation of recent in vitro and in vivo research results associated with the neuroprotective action of humanin as well as of various, mainly synthetic, analogues of the peptide; moreover, the main mode(s)/mechanism(s) through which humanin and humanin analogues may exert in vitro and in vivo regarding neuroprotection have been reported. The prospects of humanin and humanin analogues to be further investigated in the frame of future research endeavors against neurodegenerative/neural diseases have also been briefly discussed. [ABSTRACT FROM AUTHOR]

Post-traumatic stress disorder (PTSD) remains a highly prevalent, underdiagnosed, and under-treated psychiatric disorder that often deteriorates over time, and is highly comorbid with major depressive disorder, suicidality, and substance use disorder. Several biomarkers have been proposed but have yet to be implemented into clinical practice. Treatments, including selective serotonin reuptake inhibitors, are efficacious in only a small number of patients, which underscores the need to develop novel, efficient treatments. Mitochondrial dysfunction resulting from chronic oxidative stress has been linked with both altered neurotransmitter signaling and the inflammatory response. Hereinafter, we discuss mechanisms by which mitochondrial dysfunction may contribute to the development of PTSD symptoms, and how these may even increase PTSD susceptibility. We also highlight possible therapeutic targets to reduce oxidative stress to prevent or treat PTSD symptoms. [ABSTRACT FROM AUTHOR]

Background: Oligoasthenozoospermia is a common cause of male infertility, for which effective treatments are urgently needed. Humanin (HN) is a peptide associated with this condition., Objectives: To investigate the ameliorative effect of [Gly14]-Humanin (HNG) on oligoasthenozoospermia and the mechanisms., Materials and Methods: Mice were treated with cyclophosphamide (CP) to construct a mice model of oligoasthenozoospermia. The resulting model mice were treated with saline or HNG. Subsequently, the testis weights, organ indices, testicular structure, sperm counts and motilities, litter sizes, and serum testosterone concentrations of the mice were determined. Differential gene expression in testicular tissues was determined by RNA sequencing. TM3, TM4, GC1, and GC2 cells were exposed to erastin to induce ferroptosis, followed by treatment with HNG or HNG + ML385 (a nuclear factor erythroid 2-related factor 2 inhibitor). Levels of reactive oxygen species (ROS), malondialdehyde (MDA), glutathione (GSH), and ferrous ions (Fe 2+ ) were determined and their expression of ferroptosis-related proteins was determined by immunofluorescence and western blot., Results: The HNG treatment improved testis and sperm parameters and increased litter size and serum testosterone concentrations in model mice. Kyoto Encyclopaedia of Genes and Genomes pathway enrichment analysis revealed significant differential expression of ferroptosis-related genes. The expression of ferroptosis-related proteins increased in testicular tissues after the HNG treatment. The concentrations of ROS, MDA, and Fe 2+ decreased and the concentrations of GSH increased in testicular tissues and in TM3 and TM4 cells after HNG treatment. In vitro experiments confirmed that HNG activated the nuclear factor erythroid 2-related factor 2/glutathione peroxidase 4 (Nrf2/GPX4) pathway. However, these effects of HNG were blocked by ML385 treatment., Discussion and Conclusion: HNG demonstrated a therapeutic effect on oligoasthenozoospermia in a mouse model by reducing oxidative stress and ferroptosis. In TM3 and TM4 cells, HNG attenuated cellular oxidative stress and inhibited ferroptosis via the Nrf2/GPX4 pathway., (© 2024 American Society of Andrology and European Academy of Andrology.)

The myeloid differentiation factor 2 (MD-2)-toll-like receptor 4 (TLR4) signaling pathway has been linked to cognitive decline in obese rats. However, more research is required to fully understand the mechanistic role of MD-2-TLR4 signalling pathway in obese-related cognitive impairment. In this study, we used two novel MD-2 inhibitors-MAC28 (a mono-carbonyl analogue of curcumin 28) and 2i-10 (a cinnamamide-derivative compound)-to better comprehend the mechanistic role of the MD-2-TLR4 signalling pathway in obese-related cognitive impairment. A normal diet (ND) (n = 16) and a high-fat diet (HFD) (n = 64) were given to randomly divided groups of male Wistar rats for 16-weeks. At week 13, 2 types of vehicles were randomly administered to ND-fed and HFD-fed rats, whereas MAC28 (3-doses) and 2i-10 (3-doses) were randomly given to HFD-fed rats until week 16. HFD-fed rats developed obesity with metabolic disturbances, a variety of brain pathologies and cognitive decline. In obese rats, blocking the brain MD-2-TLR4 signalling pathway with MAC28 or 2i-10 improved cognition via reducing brain inflammation, neurodegeneration, microglial activation, dendritic spine loss, brain oxidative stress, as well as preserving adult hippocampal neurogenesis. Our findings highlight to better understand the role of MD-2-TLR4 signaling pathway in obese-related cognitive decline, and MD-2 could be a potential therapeutic target for brain pathologies and cognitive decline in obesity., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: The main pathophysiological mechanisms in restless legs syndrome (RLS) are known as genetic predisposition, brain iron deficiency, and dopaminergic dysfunction. While some genetic variants and polymorphisms were defined, the genetic basis and etiopathogenesis of RLS remain unclear. We aimed to identify new candidate genes and/or potential biomarkers associated with increased RLS risk., Methods: Twenty-three patients with RLS, 30 patients with Parkinson's disease (PD), and 27 healthy controls were enrolled. Agilent Human 8X60K Oligo Microarray was used for the identification of gene expression levels in peripheral blood cells. Gene ontology (GO) analysis was used for functional annotation of differentially expressed genes (DEGs). Serum levels of selected DEGs were measured by ELISA for validation., Results: Patients with RLS showed 30 downregulated DEGs compared to healthy controls. Two genes, MTRNR2L10 and MTRNR2L3, involved negative regulation of the execution phase of apoptosis were highlighted in GO analysis. These genes encode humanin-like 10 and 3, respectively, were encoded by these genes, and their levels, along with CSF-1, linked to neurodegeneration, were reduced in RLS patients. Humanin-like 10 and CSF-1 levels correlated with sleep efficiency and N2 sleep duration, while humanin-like 3 levels correlated with mean sleep oxygen saturation during sleep., Conclusion: Our study showed that several neuroprotective genes were downregulated in RLS, which may confer susceptibility to neuronal death associated with decreased sleep efficiency. Microarray results differed between RLS and PD patients, suggesting diverse pathogenetic mechanisms. CSF-1, which is involved in iron, dopamine metabolism, and blood oxygenation, appears to partake in RLS pathophysiology., Competing Interests: Declarations. Conflict of interest: The authors have no competing interests to declare that are relevant to the content of this article. Ethical approval: Approval was obtained from the Istanbul University Istanbul Medical Faculty Clinical Research Ethics Committee (date: 17/11/2023 number: 2023/2022). Written informed consent was obtained from all patients. The procedures used in this study adhere to the tenets of the Declaration of Helsinki., (© 2024. The Author(s) under exclusive licence to Belgian Neurological Society.)

Platelet activation and proprotein convertase subtilisin kexin 9 (PCSK9) play pivotal roles in the progression of atherosclerosis to cardiovascular events. It has been reported that hyperlipidemia, a well-documented risk factors for cardiovascular diseases, tends increase platelet activation and PCSK9 expression. However, little is known about this specific mechanism, particularly how nutrition affects platelet activation and PCSK9 levels in hyperlipidemia conditions. This study aimed to assess how a high-fat diet influences platelet activation, its association with PCSK9, and the effects on blood pressure in an animal model. Here, male Wistar rats were divided into four groups, subjected to different high-fat diets for ten weeks with varying nutrient components. The results showed that high-fat diet-induced hypercholesterolemia and hypertriglyceridemia significantly increased the plasma levels of β-thromboglobulin (β-TG), p-selectin, and platelet factor 4 (PF-4). The blood pressure readings were also elevated post high-fat diet induction. Interestingly, the group with the highest percentage of saturated fatty acid and trans-fat exhibited the highest PCSK9 levels, along with the highest increase in plasma cholesterol, triglycerides, and platelet activation parameters. These findings confirm that high-fat diet-induced hypercholesterolemia and hypertriglyceridemia stimulate platelet activity and PCSK9 levels. Moreover, our results suggest that PCSK9, implicated in hypercholesterolemia and hypertriglyceridemia, may synergistically mediate platelet hyperactivity, aligning with clinical studies. Notably, our results highlight the association between a high-fat diet and PCSK9, providing insights for drug discovery targeting platelet activation in atherosclerosis-induced cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Purpose: This study investigated the Humanin levels in the umbilical cord blood of fetuses with late fetal growth restriction (FGR) and -evaluated their association with perinatal outcomes. Materials and Methods: A total of 95 single pregnancies between 32–41 wk (45 with late FGR and 50 controls) were included. Doppler parameters, birth weight and the need for neonatal intensive care unit admission (NICU) were assessed. Correlations between Humanin levels and these parameters were analyzed. Results: Higher Humanin levels were found in fetuses with late FGR compared to the control group (p < 0.05). No significant correlation was observed between Humanin levels and Doppler parameters. Elevated Humanin levels were associated with an increased need for NICU (p < 0.05). Conclusions: The statistically higher levels of Humanin in fetuses with late FGR may suggest the potential of Humanin as an indicator of late FGR. Further research is needed to explore the clinical utility of Humanin. [ABSTRACT FROM AUTHOR]

Background: Bradykinesia, tremor, rigidity and postural instability are the hallmark of Parkinson's disease (PD). Non-motor symptoms including cognitive, behavioral, and neuropsychiatric changes, sensory and sleep disturbances that may precede the motor symptoms by years. The peculiar pathological features of PD are decreased dopaminergic neurons and dopamine levels in the substantia nigra pars compacta and pontine locus coeruleus. Humanin is produced by a small gene peptide, which is located in the mitochondria genome. Inflammation, oxidative stress, mitochondrial dysfunction and altered transcription have been recognized as causative factors of PD. This evidence has prompted many researchers to focus on studying the functions of DNA and mitochondria. The purpose of the present study was to evaluate Humanin mRNA levels in peripheral blood mononuclear cells (PBMCs) of PD subjects, compared with those in PBMCs of normal control (NC) subjects. Methods and results: A total of 220 participants, including 154 PD patients (57 females and 97 males; mean age 71.54 years, SD 7.8) and 66 CN (28 females and 38 males; mean age 70.54 years, SD 9.45) were enrolled for the qRT-PCR analysis. Increased Humanin mRNA levels were found in PD samples, compared to controls. Conclusion: In conclusion, the present data confirm the tendency of mitochondria to overexpress mRNA in PD, which could be a cellular attempt to reduce apoptotic damage in PD subjects. Humanin might be useful as a marker for a better diagnosis of PD, and we cannot exclude that in the future it might also play a role on prognosis and in the possible therapies for PD. [ABSTRACT FROM AUTHOR]

There is increasing evidence of a positive association of type 2 diabetes with Alzheimer's disease (AD), the most prevalent form of dementia. Suggested pathways include cerebral vascular dysfunction; central insulin resistance, or exaggerated brain abundance of potentially cytotoxic amyloid-b (Ab), a hallmark feature of AD. However, contemporary studies find that Ab is secreted in the periphery by lipogenic organs and secreted as nascent triglyceride-rich lipoproteins (TRL's). Pre-clinical models show that exaggerated abundance in blood of TRL-Ab compromises blood-brain barrier (BBB) integrity, resulting in extravasation of the TRL-Ab moiety to brain parenchyme, neurovascular inflammation and neuronal degeneration concomitant with cognitive decline. Inhibiting secretion of TRL-Ab by peripheral lipogenic organs attenuates the early-AD phenotype indicated in animal models, consistent with causality. Poorly controlled type 2 diabetes commonly features hypertriglyceridemia because of exaggerated TRL secretion and reduced rates of catabolism. Alzheimer's in diabetes may therefore be a consequence of heightened abundance in blood of lipoprotein-Ab and accelerated breakdown of the BBB. This review reconciles the prevailing dogma of amyloid associated cytotoxicity as a primary risk factor in lateonset AD, with substantial evidence of a microvascular axis for dementia-indiabetes. Consideration of potentially relevant pharmacotherapies to treat insulin resistance, dyslipidaemia and by extension plasma amyloidemia in type 2 diabetes are discussed. [ABSTRACT FROM AUTHOR]

The Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) involvement in Alzheimer's disease (AD) is poorly investigated. We evaluated the in vitro PCSK9 modulation of astrocyte cholesterol metabolism and neuronal cholesterol supplying, which is fundamental for neuronal functions. Moreover, we investigated PCSK9 neurotoxic effects. In human astrocytoma cells, PCSK9 reduced cholesterol content (−20%; p < 0.05), with a greater effect in presence of beta amyloid peptide (Aβ) (−37%; p < 0.01). PCSK9 increased cholesterol synthesis and reduced the uptake of apoE-HDL-derived cholesterol (−36%; p < 0.0001), as well as the LDL receptor (LDLR) and the apoE receptor 2 (ApoER2) expression (−66% and −31%, respectively; p < 0.01). PCSK9 did not modulate ABCA1- and ABCG1-cholesterol efflux, ABCA1 levels, or membrane cholesterol. Conversely, ABCA1 expression and activity, as well as membrane cholesterol, were reduced by Aβ (p < 0.05). In human neuronal cells, PCSK9 reduced apoE-HDL-derived cholesterol uptake (−41%; p < 0.001) and LDLR/apoER2 expression (p < 0.05). Reduced cholesterol internalization occurred also in PCSK9-overexpressing neurons exposed to an astrocyte-conditioned medium (−39%; p < 0.001). PCSK9 reduced neuronal cholesterol content overall (−29%; p < 0.05) and increased the Aβ-induced neurotoxicity (p < 0.0001). Our data revealed an interfering effect of PCSK9, in cooperation with Aβ, on brain cholesterol metabolism leading to neuronal cholesterol reduction, a potentially deleterious effect. PCSK9 also exerted a neurotoxic effect, and thus represents a potential pharmacological target in AD. [ABSTRACT FROM AUTHOR]

It has recently been accepted that long-term high-fat diet (HFD) intake is a significant possible cause for prediabetes and cognitive and brain dysfunction through the disruption of brain mitochondrial function and dynamic balance. Although modulation of mitochondrial dynamics by inhibiting fission and promoting fusion has been shown to reduce the morbidity and mortality associated with a variety of chronic diseases, the impact of either pharmacological inhibition of mitochondrial fission (Mdivi-1) or stimulation of fusion (M1) on brain function in HFD-induced prediabetic models has never been studied. Thirty-two male Wistar rats were separated into 2 groups and fed either a normal diet (ND, n = 8) or HFD (n = 24) for 14 weeks. At week 12, HFD-fed rats were divided into 3 subgroups (n = 8/subgroup) and given an intraperitoneal injection of either saline, Mdivi-1 (1.2 mg/kg/day), or M1 (2 mg/kg/day) for 2 weeks. Cognitive function and metabolic parameters were determined toward the end of the protocol. The rats then were euthanized, and the brain was immediately removed in order to evaluate brain mitochondrial function and mitochondrial dynamics. HFD-fed rats experienced prediabetes, evidenced by elevated plasma insulin and the HOMA index, impaired mitochondrial function in the brain, altered dynamic regulation, and cognitive impairment were also found. Mdivi-1 and M1 treatment exerted neuroprotection to a similar extent by improving metabolic parameters, balancing mitochondrial dynamics, and reducing mitochondrial dysfunction, resulting in a gradual increase in cognitive function. Therefore, pharmacological targeting of mitochondrial fission and fusion protected the brain against chronic HFD-induced prediabetes. [ABSTRACT FROM AUTHOR]

Background: The mortality of trauma combined with seawater immersion is higher than that of land injury, however, research on how to treat this critical case and which treatments to adopt is lacking. Methods: The effect of the thiol compound, N-acetyl-L-Cysteine (NAC), on survival, acidosis, coagulopathy, vital signs, oxidative stress, and mitochondrial and multi-organ function was assessed in a rat model of hemorrhagic shock combined with seawater immersion (Sea-Shock). Results: Hemorrhagic shock combined with seawater immersion caused a severe lethal triad: multi-organ impairment, oxidative stress, and mitochondrial dysfunction. NAC (30 mg/kg) with lactated Ringer's (LR) solution (2 × blood volume lost) significantly improved outcomes compared to LR or hetastarch (HES 130/0.4) alone. NAC significantly prolonged survival time to 52.48 ± 30.09 h and increased 72 h survival rate to 11/16 (68%). NAC relieved metabolic acidosis and recovered the pH back to 7.33. NAC also restored coagulation, with APTT, PT, and PT-INR decreased by 109.31, 78.09, and 73.74%, respectively, while fibrinogen level increased 246.23% compared with untreated Sea-Shock. Administration of NAC markedly improved cardiac and liver function, with some improvement of kidney function. Conclusion: The addition of NAC to crystalloid resuscitation fluid alleviated oxidative stress, restored redox homeostasis, and provided multi-organ protection in the rats after Sea-Shock. NAC may be an effective therapeutic measure for hemorrhagic shock combined with seawater immersion. [ABSTRACT FROM AUTHOR]

Background and Purpose. Mild cognitive impairment (MCI) is a common condition, which threatens the quality of life of older adults. Tai Chi (TC) is growing in popularity among patients with MCI. This study is aimed at evaluating the effectiveness and safety of TC in older adults with MCI. Design. Randomized controlled trials (RCTs) from multiple databases from inception to December 2020 published in English were searched. Two researchers independently performed eligible study screening and data extraction. The methodological quality was assessed with the Jadad score. Meta-analysis of RCTs on TC in the treatment of MCI was performed with RevMan Version 5.4.1. Results. Seven RCTs with 1265 participants were included. For most RCTs, the overall reporting of methodological quality was high. Results of the meta-analysis indicate that TC improved MCI patients' cognitive function significantly, including overall cognitive function (MD = − 2.24 , 95% CI -3.51 to -0.97, P = 0.0005), memory and learning (SMD = 0.83 , 95% CI 0.22 to 1.45, P = 0.008), visuospatial ability (MD = 3.15 , 95% CI 0.74 to 5.56, P = 0.01), executive functions (MD = 0.32 , 95% CI 0.03 to 0.61, P = 0.03), and physical activity (MD = 18.78 , 95% CI 10.80 to 26.76, P < 0.00001). However, no significant benefit was found for TC on psychological activity (MD = 0.17 , 95% CI -0.62 to 0.96, P = 0.36) and biomarker improvement. Conclusion. The meta-analysis confirmed the clinical therapeutic effect of TC for MCI. More rigorous and long-term follow-up RCTs should be conducted in the future. [ABSTRACT FROM AUTHOR]

Exogenous treatment of a neurotensin receptor 1 (NTR1) agonist exerted the neuroprotection in an obese and Alzheimer's model. However, the effects of NTR1 modulation on peripheral/hippocampal impairment and cognitive deficit following sustained HFD consumption are poorly understood. Forty rats received a normal diet (ND) or HFD for 16 weeks. At week 13, the ND group received a vehicle (n = 8). Thirtytwo HFD-fed group were randomized into four subgroups (n = 8/subgroup) with a vehicle, 1 mg/kg of NTR1 agonist, 1 mg/kg of NTR antagonist, and combined treatment (NTR1 agonist-NTR antagonist) for 2 weeks, s.c. injection. Then, the cognitive tests and peripheral/hippocampal parameters were determined. Our findings demonstrated that NTR1 activator reversed obesity and attenuated metabolic impairment in pre-diabetic rats. It also alleviated hippocampal pathologies and synaptic dysplasticity, leading to deceleration or prevention of cognitive impairment progression. Therefore, NTR1 activation would be a possible novel therapy to decelerate or prevent progression of neuropathology and cognitive impairment in the pre-diabetes. [ABSTRACT FROM AUTHOR]

Obesity causes cognitive weakening and increases the risk of neurodegenerative diseases. Myrtus communis extract (MC) has anti-inflammatory and antioxidant properties. In this study, it is aimed to investigate the effects of Myrtus communis on oxidative brain damage caused by a high-fat diet (HFD), using behavioral and biochemical parameters. Twenty-four Wistar albino rats (200-250 g) were divided into three groups. The control group (C) received a standard diet, while HFD groups were received HFD for 16 weeks. MC (100 mg/kg, oral) was given to the HFD + MC group for the last 4 weeks. At the end of the study, the novel object recognition test (NORT) was performed and the hippocampus and blood samples were collected. Acetylcholinesterase (AChE) and Na+/K+- ATPase activities, malondialdehyde (MDA), 8-hydroxy-2'-deoxyguanosine (8-OHdG) and reduced glutathione (GSH) levels were measured in the hippocampal samples and cholesterol levels were analyzed in sera. Findings have shown that NORT performance of the HFD group was reduced, while administration of MC prevents this reduction and in parallel, increased AChE and decreased Na+/K+ -ATPase activities were ameliorated by administration of MC. Increased MDA and 8-OHdG levels observed in the HFD group, were decreased in the MC treated HFD group. Our results point out that MC has ameliorative effects on hippocampal oxidative stress and cognitive impairment in high fat nutritioninduced obesity. [ABSTRACT FROM AUTHOR]

Diabetes mellitus (DM) is a gradually rising metabolic disease which is currently affecting millions of people worldwide. Diabetes is associated with various complications like nephropathy, neuropathy, retinopathy, diabetic foot, cognitive impairment, and many more. Evidence suggests that cognitive dysfunction is a rising complication of diabetes which adversely affects the brain of patients suffering from diabetes. Age‐related memory impairment is a complication having its major effect on people suffering from diabetes and Alzheimer's. Patients suffering from diabetes are at two times higher risk of developing cognitive dysfunction as compared with normal individuals. Multiple factors which are involved in diabetes related complications are found to play a role in the development of neurodegeneration in Alzheimer's. The problem of insulin deficiency and insulin resistance is well reported in diabetes but there are many studies which suggest dysregulation of insulin levels as a reason behind the development of Alzheimer's. As the link between diabetes and Alzheimer disease (AD) is deepening, there is a need to understand the plausible tie‐ins between the two. Emerging role of major factors like insulin imbalance, advanced glycation end products and micro‐RNA's involved in diabetes and Alzheimer's have been discussed here. This review helps in understanding the plausible mechanism underlying the pathophysiology of amyloid beta (Aβ) plaque formation and tau hyperphosphorylation as well provides information about studies carried out in this area of research. The final thought is to enhance the scientific knowledge on this correlation and develop future therapeutics to treat the same. [ABSTRACT FROM AUTHOR]

Purpose: Garlic has been shown to exhibit antioxidant effects and cardioprotective properties. However, the effects of garlic extract on the heart in insulin resistance induced by long-term high-fat-diet consumption are not well defined. Therefore, we sought to determine the effects of garlic extract in the obese insulin-resistant rats. Methods: Male Wistar rats (180-200 g) were divided into two groups: normal-diet or high-fat-diet ( n = 24/group) fed for 12 weeks. Rats in each groups were divided into three subgroups ( n = 8 each): vehicle or garlic extract (250 or 500 mg/kg/day, respectively) treated for 28 days. At the end of the treatment, the metabolic parameters, heart rate variability (HRV), cardiac function, and cardiac mitochondrial function were determined. Results: Rats that received a high-fat-diet for 12 weeks had increased body weight, visceral fat, plasma insulin levels, total cholesterol, oxidative stress levels, depressed HRV, and cardiac mitochondrial dysfunction. Garlic extract at both concentrations significantly decreased the plasma insulin, total cholesterol, homeostasis model assessment index, and oxidative stress levels. Furthermore, garlic extract at both doses restored the HRV, cardiac function, and cardiac mitochondrial function. Conclusion: We concluded that garlic extract at both concentrations exerted cardioprotective effects against cardiac dysfunction and mitochondrial dysfunction in obese insulin-resistant rats. [ABSTRACT FROM AUTHOR]

Insulin and liraglutide have been demonstrated to control blood glucose and exert neuroprotective effects. However, the impact of liraglutide or insulin alone or in combination on brain pathology in type 1 diabetes mellitus (T1DM) and their underlying mechanisms are unclear. In the present study, diabetes mellitus (DM) was induced via intraperitoneal injection of streptozotocin in mice and subsequently mice were treated with insulin, liraglutide, a combination of the two drugs or saline. Changes in body weight and blood glucose were assessed weekly. The pathological changes in the brain tissue and the apoptosis of neurons were assessed using H&E staining and TUNEL staining. The mRNA and protein expression levels of apoptosis-related proteins were detected using reverse transcription-quantitative PCR (RT-qPCR) and western blotting, respectively. Moreover, Ki67 protein expression was analyzed using immunohistochemistry and the mRNA and protein expression levels of Wnt/β-catenin signaling pathway-related proteins were examined using RT-qPCR and western blotting, respectively. The results of the present study suggested that DM mice developed hyperglycemia and weight loss and also exhibited significantly increased neural cell apoptosis and significantly reduced numbers of Ki67-positive cells. Liraglutide significantly decreased blood glucose levels in DM mice, whereas both insulin and the combination of the two drugs failed to control blood glucose well. Insulin, liraglutide and their combination also failed to control body weight well, but significantly attenuated brain pathological changes and activation of the pro-apoptotic proteins Caspase-3 and Bax, which may have resulted in the significant increase in the expression levels of Wnt/β-catenin signaling pathway-associated molecules such as Wnt3a and S9-pGSK-3β. Liraglutide also promoted the protein expression of the neurogenesis marker of Ki67 and the antiapoptotic factor Bcl-2. These results suggested that insulin and liraglutide may improve brain damage via upregulation of the Wnt/β-catenin signaling pathway and could be of therapeutic relevance for improvement of cognitive impairment in patients with DM. [ABSTRACT FROM AUTHOR]

Acute myocardial infarction (MI) is associated with an intense inflammatory response that is critical for cardiac repair but is also involved in the pathogenesis of adverse cardiac remodeling, i.e., the set of size, geometry, and structure changes that represent the structural substrate for the development of post-MI heart failure. Deciphering the pathophysiological mechanisms underlying cardiac repair after MI is, therefore, critical to favorably regulate cardiac wound repair and to prevent development of heart failure. Catecholamines and estrogen play an active role in regulating the inflammatory response in the infarcted area. For example, stress-induced catecholamines alter recruitment and trafficking of leukocytes to the heart. Additionally, estrogen affects rate of cardiac rupture during the acute phase of MI, as well as infarct size and survival in animal models of MI. In this review, we will summarize the role of β-adrenergic receptors and estrogen in cardiac repair after infarction in preclinical studies. [ABSTRACT FROM AUTHOR]

Several lines of epidemiological evidence link increased levels of high-density lipoprotein-cholesterol (HDL-C) with lower risk of Alzheimer's disease (AD). This observed relationship might reflect the beneficial effects of HDL on the cardiovascular system, likely due to the implication of vascular dysregulation in AD development. The atheroprotective properties of this lipoprotein are mostly due to its proteome. In particular, apolipoprotein (Apo) A-I, E, and J and the antioxidant accessory protein paraoxonase 1 (PON1), are the main determinants of the biological function of HDL. Intriguingly, these HDL constituent proteins are also present in the brain, either from in situ expression, or derived from the periphery. Growing preclinical evidence suggests that these HDL proteins may prevent the aberrant changes in the brain that characterize AD pathogenesis. In the present review, we summarize and critically examine the current state of knowledge on the role of these atheroprotective HDL-associated proteins in AD pathogenesis and physiopathology. [ABSTRACT FROM AUTHOR]