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Nutrients Jun 2024Post-traumatic stress disorder (PTSD) is a persistent psychiatric condition that arises following exposure to traumatic events such as warfare, natural disasters, or...
Effects of Evodiamine on Behavior and Hippocampal Neurons through Inhibition of Angiotensin-Converting Enzyme and Modulation of the Renin Angiotensin Pathway in a Mouse Model of Post-Traumatic Stress Disorder.
Post-traumatic stress disorder (PTSD) is a persistent psychiatric condition that arises following exposure to traumatic events such as warfare, natural disasters, or other catastrophic incidents, typically characterized by heightened anxiety, depressive symptoms, and cognitive dysfunction. In this study, animals subjected to single prolonged stress (SPS) were administered evodiamine (EVO) and compared to a positive control group receiving sertraline. The animals were then assessed for alterations in anxiety, depression, and cognitive function. Histological analysis was conducted to examine neuronal changes in the hippocampus. In order to predict the core targets and related mechanisms of evodiamine intervention in PTSD, network pharmacology was used. The metabolic markers pre- and post-drug administration were identified using nontargeted serum metabolomics techniques, and the intersecting Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were screened. Finally, the core targets were validated through molecular docking, enzyme-linked immunosorbent assays, and immunofluorescence staining to confirm the anti-PTSD effects and mechanisms of these targets. As well as improving cognitive impairment, evodiamine reversed anxiety- and depression-like behaviors. It also inhibited the reduction in the number of hippocampal neuronal cells and Nissl bodies in SPS mice inhibited angiotensin converting enzyme (ACE) levels in the hippocampus of SPS mice, and modulated the renin angiotensin pathway and its associated serum metabolites in brain tissue. Evodiamine shows promise as a potential candidate for alleviating the symptoms of post-traumatic stress disorder.
Topics: Animals; Stress Disorders, Post-Traumatic; Hippocampus; Quinazolines; Mice; Neurons; Disease Models, Animal; Male; Renin-Angiotensin System; Behavior, Animal; Angiotensin-Converting Enzyme Inhibitors; Depression; Molecular Docking Simulation; Anxiety; Mice, Inbred C57BL; Network Pharmacology
PubMed: 38931311
DOI: 10.3390/nu16121957 -
Plants (Basel, Switzerland) Jun 2024Carotenoids constitute compounds of significant biological interest due to their multiple biological activities, such as antimicrobial, anticancer, antiadipogenic,... (Review)
Review
Carotenoids constitute compounds of significant biological interest due to their multiple biological activities, such as antimicrobial, anticancer, antiadipogenic, antidiabetic, and antioxidant properties. Metabolic syndrome (MetS) comprehends a series of metabolic abnormalities (e.g., hypertension, obesity, and atherogenic dyslipidemia) that can affect children, adolescents, and the elderly. The treatment of MetS involves numerous medications, which, despite their efficacy, pose challenges due to prolonged use, high costs, and various side effects. Carotenoids and their derivatives have been proposed as alternative treatments to MetS because they reduce serum triglyceride concentrations, promote insulin response, inhibit adipogenesis, and downregulate angiotensin-converting enzyme activity. However, carotenoids are notably sensitive to pH, light exposure, and temperature. This review addresses the activity of carotenoids such as lycopene, lutein, fucoxanthin, astaxanthin, crocin, and -carotene towards MetS. It includes a discussion of sources, extraction methods, and characterization techniques for analyzing carotenoids. Encapsulation approaches are critically reviewed as alternatives to prevent degradation and improve the biological performance of carotenoids. A brief overview of the physiopathology and epidemiology of the diseases, including MetS, is also provided.
PubMed: 38931016
DOI: 10.3390/plants13121584 -
Journal of Clinical Medicine Jun 2024: The aim of this study was to examine the association between in-hospital initiation of sodium glucose co-transporter 2 inhibitors (SGLT2is) and outcomes in...
: The aim of this study was to examine the association between in-hospital initiation of sodium glucose co-transporter 2 inhibitors (SGLT2is) and outcomes in hospitalized heart failure (HHF) patients utilizing data from a Greek center. : The present work was a single-center, retrospective, observational study of consecutive HF patients hospitalized in a tertiary center. The study endpoint was all-cause mortality or HF rehospitalization. Univariate and multivariate Cox proportional-hazard models were conducted to investigate the association between SGLT2i administration at discharge and the study endpoint. : Sample consisted of 171 patients, 55 of whom (32.2%) received SGLT2is at discharge. Overall, mean follow-up period was 6.1 months (SD = 4.8 months). Patients who received SGLT2is at discharge had a 43% lower probability of the study endpoint compared to those who did not receive SGLT2is at discharge (HR = 0.57; 95% CI: 0.36-0.91; = 0.018). After adjusting for age, gender, smoking, hemoglobin (Hgb), use of SGLT2is at admission, use of Angiotensin-Converting Enzyme Inhibitors (ACEI-Is)/Angiotensin Receptor Blockers (ARBs) at discharge and Sacubitril/Valsartan at discharge, the aforementioned result remained significant (HR = 0.38; 95% CI: 0.19-0.73; = 0.004). The 55 patients who received SGLT2is at discharge were propensity score matched with the 116 patients who did not receive SGLT2is at discharge. Receiving SGLT2is at discharge continued to be significantly associated with a lower probability of the study endpoint (HR= 0.43; 95% CI: 0.20-0.89; = 0.024). : Initiation of SGLT2is in HHF patients may be associated with better outcomes.
PubMed: 38930091
DOI: 10.3390/jcm13123562 -
Journal of Clinical Medicine Jun 2024: Dapagliflozin has shown efficacy in clinical trials in patients with heart failure and reduced ejection fraction (HFrEF). However, real-world data on its use and...
Safety and Efficacy of Dapagliflozin in Patients with Heart Failure with Reduced Ejection Fraction: Multicentre Retrospective Study on Echocardiographic Parameters and Biomarkers of Heart Congestion.
: Dapagliflozin has shown efficacy in clinical trials in patients with heart failure and reduced ejection fraction (HFrEF). However, real-world data on its use and outcomes in routine clinical practice are limited. We aimed to evaluate the utilisation and safety profile of dapagliflozin in a real-world population of HFrEF patients within the Marche region. : Nine cardiology departments within the Marche region retrospectively included HFrEF patients who were initiated on dapagliflozin therapy in an outpatient setting. Data on medical history, comorbidities, echocardiographic parameters, and laboratory tests were collected at baseline and after 6 months. Telephone follow-up interviews were conducted at 1 and 3 months to assess adverse events. We defined the composite endpoint score as meeting at least 50% of four objective measures of improvement among: weight loss, NYHA decrease, ≥50% Natriuretic peptides (NP) decrease, and guideline/directed medical therapy (GDMT) up titration. : We included 95 HFrEF patients aged 66 ± 12 years, 82% were men, 48% had ischemic heart disease, and 20% had diabetes. At six months, glomerular filtration rate declined ( = 0.03) and natriuretic peptides levels decreased, on average, by 23% ( < 0.001). Echocardiographic measurements revealed a decrease in pulmonary artery pressure ( < 0.001) and E/e' ( < 0.001). In terms of drug therapy, furosemide dosage decreased ( = 0.001), and the percentage of the target dose achieved for angiotensin receptor-neprilysin inhibitors increased ( = 0.003). By multivariable Cox regression, after adjustment for age, sex, the presence of diabetes/prediabetes, and HF duration, higher baseline Hb concentrations (HR 1.347, 95% CI 1.038-1.746, = 0.025), and eGFR levels (HR 1.016, 95% CI 1.000-1.033, = 0.46). : In a real-life HFrEF population, dapagliflozin therapy is safe and well-tolerated, improves echocardiographic parameters and biomarkers of congestion, and can also facilitate the titration of drugs with a prognostic impact.
PubMed: 38930049
DOI: 10.3390/jcm13123522 -
International Journal of Molecular... Jun 2024Graphene, when electrified, generates far-infrared radiation within the wavelength range of 4 μm to 14 μm. This range closely aligns with the far-infrared band (3 μm...
Graphene, when electrified, generates far-infrared radiation within the wavelength range of 4 μm to 14 μm. This range closely aligns with the far-infrared band (3 μm to 15 μm), which produces unique physiological effects. Contraction and relaxation of vascular smooth muscle play a significant role in primary hypertension, involving the nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate pathway and the renin-angiotensin-aldosterone system. This study utilized spontaneously hypertensive rats (SHRs) as an untr-HT to investigate the impact of far-infrared radiation at specific wavelengths generated by electrified graphene on vascular smooth muscle and blood pressure. After 7 weeks, the blood pressure of the untr-HT group rats decreased significantly with a notable reduction in the number of vascular wall cells and the thickness of the vascular wall, as well as a decreased ratio of vessel wall thickness to lumen diameter. Additionally, blood flow perfusion significantly increased, and the expression of F-actin in vascular smooth muscle myosin decreased significantly. Serum levels of angiotensin II (Ang-II) and endothelin 1 (ET-1) were significantly reduced, while nitric oxide synthase (eNOS) expression increased significantly. At the protein level, eNOS expression decreased significantly, while α-SMA expression increased significantly in aortic tissue. At the gene level, expressions of and in aortic tissue significantly increased. Furthermore, the content of nitric oxide (NO) in the SHR's aortic tissue increased significantly. These findings confirm that graphene far-infrared radiation enhances microcirculation, regulates cytokines affecting vascular smooth muscle contraction, and modifies vascular morphology and smooth muscle phenotype, offering relief for primary hypertension.
Topics: Animals; Rats; Blood Pressure; Rats, Inbred SHR; Male; Muscle, Smooth, Vascular; Graphite; Infrared Rays; Hypertension; Nitric Oxide Synthase Type III; Angiotensin II; Endothelin-1; Nitric Oxide
PubMed: 38928382
DOI: 10.3390/ijms25126675 -
International Journal of Molecular... Jun 2024Human infection with the coronavirus disease 2019 (COVID-19) is mediated by the binding of the spike protein of the severe acute respiratory syndrome coronavirus 2...
Human infection with the coronavirus disease 2019 (COVID-19) is mediated by the binding of the spike protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to the human angiotensin-converting enzyme 2 (ACE2). The frequent mutations in the receptor-binding domain (RBD) of the spike protein induced the emergence of variants with increased contagion and can hinder vaccine efficiency. Hence, it is crucial to better understand the binding mechanisms of variant RBDs to human ACE2 and develop efficient methods to characterize this interaction. In this work, we present an approach that uses machine learning to analyze the molecular dynamics simulations of RBD variant trajectories bound to ACE2. Along with the binding free energy calculation, this method was used to characterize the major differences in ACE2-binding capacity of three SARS-CoV-2 RBD variants-namely the original Wuhan strain, Omicron BA.1, and the more recent Omicron BA.5 sublineages. Our analyses assessed the differences in binding free energy and shed light on how it affects the infectious rates of different variants. Furthermore, this approach successfully characterized key binding interactions and could be deployed as an efficient tool to predict different binding inhibitors to pave the way for new preventive and therapeutic strategies.
Topics: Machine Learning; SARS-CoV-2; Angiotensin-Converting Enzyme 2; Humans; Spike Glycoprotein, Coronavirus; Protein Binding; Molecular Dynamics Simulation; COVID-19; Binding Sites; Mutation; Protein Interaction Domains and Motifs
PubMed: 38928241
DOI: 10.3390/ijms25126535 -
International Journal of Molecular... Jun 2024The pathogenic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a global health concern. Cell entry of SARS-CoV-2 depends on viral spike (S) proteins...
The pathogenic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a global health concern. Cell entry of SARS-CoV-2 depends on viral spike (S) proteins binding to cellular receptors (ACE2) and their subsequent priming by host cell proteases (TMPRSS2). Assessing effects of viral-induced host response factors and determining which cells are used by SARS-CoV-2 for entry might provide insights into viral transmission, add clarity to the virus' pathogenesis, and possibly reveal therapeutic targets. Mast cells (MCs) are ubiquitously expressed tissue cells that act as immune sentinels given their ability to react specifically to pathogens at environmental interfaces, such as in the lung. Several lines of evidence suggest a critical role for MCs in SARS-CoV-2 infections based on patients' mediator profiles, especially the "cytokine storm" responsible for most morbidity and mortality. In this pilot study, we demonstrated that human lung MCs ( = 3 donors) are a source of renin and that they upregulate the membrane receptor for SARS-CoV-2 (ACE2) as well as the protease required for cellular entry (TMPRSS2) under certain conditions. We hypothesized that infection of human MCs with SARS-CoV-2 may be a heretofore-unrecognized mechanism of viral pathogenesis, and further studies are required to assess this question.
Topics: Humans; Mast Cells; SARS-CoV-2; COVID-19; Angiotensin-Converting Enzyme 2; Lung; Serine Endopeptidases; Virus Internalization; Spike Glycoprotein, Coronavirus
PubMed: 38928216
DOI: 10.3390/ijms25126511 -
International Journal of Molecular... Jun 2024Opinions on the effects of osteoprotegerin (OPG) have evolved over the years from a protein protecting the vasculature from calcification to a cardiovascular risk factor...
Opinions on the effects of osteoprotegerin (OPG) have evolved over the years from a protein protecting the vasculature from calcification to a cardiovascular risk factor contributing to inflammation within the vascular wall. Nowadays, the link between OPG and angiotensin II (Ang II) appears to be particularly important. In this study, the endothelial function was investigated in OPG-knockout mice (B6.129.S4-OPG, OPG) and wild-type (C57BL/6J, OPG) mice under basic conditions and after Ang II exposure by assessing the endothelium-dependent diastolic response of aortic rings to acetylcholine in vitro. A further aim of the study was to compare the effect of Ang II on the expression of cytokines in the aortic wall of both groups of mice. Our study shows that rings from OPG mice had their normal endothelial function preserved after incubation with Ang II, whereas those from OPG mice showed significant endothelial dysfunction. We conclude that the absence of OPG, although associated with a pro-inflammatory cytokine profile in the vascular wall, simultaneously protects against Ang II-induced increases in pro-inflammatory cytokines in the murine vascular wall. Our study also demonstrates that the absence of OPG can result in a decrease in the concentration of pro-inflammatory cytokines in the vascular wall after Ang II exposure. The presence of OPG is therefore crucial for the development of Ang II-induced inflammation in the vascular wall and for the development of Ang II-induced endothelial dysfunction.
Topics: Animals; Angiotensin II; Osteoprotegerin; Mice; Endothelium, Vascular; Mice, Knockout; Mice, Inbred C57BL; Cytokines; Male; Aorta; Acetylcholine
PubMed: 38928140
DOI: 10.3390/ijms25126434 -
Biomedicines Jun 2024A complication of diabetes is neuropathic pain, which is difficult to control with medication. We have confirmed that neuropathic pain due to mechanical allodynia in...
A complication of diabetes is neuropathic pain, which is difficult to control with medication. We have confirmed that neuropathic pain due to mechanical allodynia in diabetic mice is mediated by a characteristic neuropeptide in the spinal cord. We evaluated the strength of mechanical allodynia in mice using von Frey filaments. When mice were intravenously injected with streptozotocin, mechanical allodynia appeared 3 days later. Antibodies of representative neuropeptides were intrathecally (i.t.) administered to allodynia-induced mice 7 days after the intravenous administration of streptozotocin, and allodynia was reduced by anti-cholecystokinin octapeptide antibodies, anti-nociceptin/orphanin FQ antibodies, and anti-hemokinin-1 antibodies. In contrast, i.t.-administered anti-substance P antibodies, anti-somatostatin antibodies, and anti-angiotensin II antibodies did not affect streptozotocin-induced diabetic allodynia mice. Mechanical allodynia was attenuated by the i.t. administration of CCK-B receptor antagonists and ORL-1 receptor antagonists. The mRNA level of CCK-B receptors in streptozotocin-induced diabetic allodynia mice increased in the spinal cord, but not in the dorsal root ganglion. These results indicate that diabetic allodynia is caused by cholecystokinin octapeptide, nociceptin/orphanin FQ, and hemokinin-1 released from primary afferent neurons in the spinal cord that transmit pain to the brain via the spinal dorsal horn.
PubMed: 38927539
DOI: 10.3390/biomedicines12061332 -
Biomedicines Jun 2024Abnormal skin healing resulting in chronic wounds or hypertrophic scarring remains a major healthcare burden. Here, the antifibrotic angiotensin II type 2 receptor...
Abnormal skin healing resulting in chronic wounds or hypertrophic scarring remains a major healthcare burden. Here, the antifibrotic angiotensin II type 2 receptor (AT2R) signaling pathway was modulated to determine its impact on cutaneous wound healing. Balb/c mice received two splinted full-thickness wounds. Topical treatments with the selective AT2R agonist compound 21 (C21) and/or selective antagonist PD123319 or saline vehicle were administered until sacrifice on post-wounding days 7 or 10. The rate of wound re-epithelialization was accelerated by PD123319 and combination treatments. In vitro, C21 significantly reduced human fibroblast migration. C21 increased both collagen and vascular densities at days 7 and 10 post-wounding and collagen I:III ratio at day 10, while PD123319 and combination treatments decreased them. Genes associated with regeneration and repair were upregulated by C21, while PD123319 treatment increased the expression of genes associated with inflammation and immune cell chemotaxis. C21 treatment reduced wound total leukocyte and neutrophil staining densities, while PD123319 increased these and macrophage densities. Overall, AT2R activation with C21 yields wounds that mature more quickly with structural, cellular, and gene expression profiles more closely approximating unwounded skin. These findings support AT2R signal modulation as a potential therapeutic target to improve skin quality during wound healing.
PubMed: 38927444
DOI: 10.3390/biomedicines12061238