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Frontiers in Pharmacology 2024Heart failure is the most costly cardiovascular disorder. New treatments are urgently needed. This study aims to evaluate the safety, pharmacokinetics, and...
Safety, tolerability, pharmacokinetics, and pharmacodynamics of a soluble guanylate cyclase stimulator, HEC95468, in healthy volunteers: a randomized, double-blinded, placebo-controlled phase 1 trial.
Heart failure is the most costly cardiovascular disorder. New treatments are urgently needed. This study aims to evaluate the safety, pharmacokinetics, and pharmacodynamic profile of HEC95468, a soluble guanylate cyclase (sGC) stimulator, in healthy volunteers. Sixty-two, eighteen, and forty-eight participants were enrolled in the single ascending dose (SAD) study, the food effect (FE) study, and the multiple ascending dose (MAD) study, respectively. The study conforms to good clinical practice and the Declaration of Helsinki. Overall, HEC95468 was safe and tolerable; a higher proportion of HEC95468-treated participants reported mild headaches, dizziness, decreased blood pressure, increased heart rate, and gastrointestinal-related treatment-emergent adverse events (TEAEs), similar to the sGC stimulators riociguat and vericiguat. In terms of pharmacokinetic parameters, the maximum observed plasma concentration (C) and the area under the concentration-time curve (AUC) were dose-proportional over the dose range. Moderate accumulation was observed after multiple administrations of HEC95468. Systolic blood pressure (SBP) and diastolic blood pressure decreased, while 3',5'-cyclic guanosine monophosphate (cGMP) concentration in plasma increased and heart rate was induced. Vasoactive hormones (renin, angiotensin II, and norepinephrine) in plasma were compensatorily elevated after oral administration. These data supported further clinical trials of HEC95468 in the treatment of heart failure and pulmonary arterial hypertension. http://www.chinadrugtrials.org.cn, identifier CTR20210064.
PubMed: 38933676
DOI: 10.3389/fphar.2024.1359939 -
Cureus May 2024The novel SARS-CoV-2 introduced several new inflammatory conditions including SARS-CoV-2-associated rhabdomyolysis and viral myositis. We present a 22-year-old man who...
The novel SARS-CoV-2 introduced several new inflammatory conditions including SARS-CoV-2-associated rhabdomyolysis and viral myositis. We present a 22-year-old man who noted a week of cough followed by myalgias, dark-colored urine, and decreased oral intake. He was found to have acute nontraumatic rhabdomyolysis after an acutely positive SARS-CoV-2 test. Initial creatine kinase (CK) level was above the reference range as were liver enzymes reflective of muscle breakdown. Treatment involved fluid resuscitation and pain control, with close monitoring of kidney, liver, and skeletal markers over five days of hospitalization till there was clinical and symptomatic improvement.
PubMed: 38933630
DOI: 10.7759/cureus.61172 -
Frontiers in Molecular Biosciences 2024Since the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) outbreak, several solutions have been proposed to manage the disease. The most viable option for...
Since the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) outbreak, several solutions have been proposed to manage the disease. The most viable option for controlling this virus is to produce effective vaccines. Most of the current SARS-CoV-2 vaccines have focused on the infusion spike protein. Spike exists as a trimer and plays a vital role in infecting host cells by binding to the Angiotensin-Converting Enzyme 2 (ACE2) receptor through its Receptor Binding Domain (RBD). Ferritin protein, a naturally occurring iron-storage protein, has gained attention for vaccine production due to its self-assembling property, non-toxic nature, and biocompatibility. Ferritin nanocages have recently been employed in the development of a SARS-CoV-2 vaccination eliciting not only long-term protective memory cells but also a sustained antibody response. In this study, a combination of investigations including molecular docking, molecular dynamics simulations, and immune simulations were carried out to computationally model the monomeric spike protein on the ferritin nanocage as well as to evaluate its stability and interactions for the first time. The structural dynamics of the modeled complex demonstrated noticeable stability. In particular, the Receptor Binding Domain (RBD) and ferritin within the monomeric spike-ferritin complex illustrated significant stability. The lack of alterations in the secondary structure further supported the overall steadiness of the complex. The decline in the distance between ferritin and spike suggests a strong interaction over time. The cross-correlation matrices revealed that the monomeric spike and ferritin move towards each other supporting the stable interaction between spike and ferritin. Further, the orientation of monomeric spike protein within the ferritin unit facilitated the exposure of critical epitopes, specifically upward active Receptor Binding Domain (RBD), enabling effective interactions with the ACE2 receptor. The immune simulations of the model indicated high-level stimulations of both cellular and humoral immunity in the human body. It was also found that the employed model is effective regardless of the mutated spikes in different variants. These findings shed light on the current status of the SARS-CoV-2-ferritin nanoparticle vaccines and could be used as a framework for other similar vaccine designs.
PubMed: 38933369
DOI: 10.3389/fmolb.2024.1403635 -
Acta Endocrinologica (Bucharest,... 2023The COVID-19 pandemic hit the world in late 2019, and by 2020, everyone was affected. Severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) belongs to the...
BACKGROUND
The COVID-19 pandemic hit the world in late 2019, and by 2020, everyone was affected. Severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) belongs to the beta-coronavirus genre and uses the angiotensin-converting enzyme 2 (ACE2) receptor to penetrate cells. Thyroid cells are rich in such receptors. Therefore, this gland is frequently involved alongside other organs in the COVID-19 disease.
AIM
To describe COVID-19 inflammation and, eventually, dysregulations of normal thyroid function in a case series of patients diagnosed in a tertiary endocrinology care centre.
PATIENTS AND METHODS
We described subacute thyroiditis cases related to COVID-19 infection or vaccination against SARS-CoV2 infection (clinical manifestations and evolution). We also reviewed the literature data regarding COVID-19 infection or vaccination implications in thyroid pathology.
RESULTS
The literature describes two types of thyroid involvement in SARS-CoV2 infection or vaccination: subacute thyroiditis (SAT) and non-thyroidal illness syndrome (NTIS). In our case series, 5 patients (3 males), aged 41-54 years, developed the classical clinical manifestation of SAT related to COVID-19 infection (3 patients, concomitantly to upper respiratory infection or a few weeks apart) or anti-SARS-CoV2 ARNm vaccination (1-2 weeks after the vaccine administration). Clinical, laboratory and imaging findings and the evolution (steroid anti-inflammatory treatment used in 4/5 cases) were unremarkable compared to other SAT etiologies.
CONCLUSION
We found no differences between the "typical" viral and post-COVID-19 SAT regarding clinical presentation, severity, response to treatment, and thyroid function alteration. The only remarkable difference is the association of SAT with anti-SARS-CoV2 ARNm vaccination.
PubMed: 38933252
DOI: 10.4183/aeb.2023.471 -
Viruses Jun 2024The Omicron variant and its sub-lineages are the only current circulating SARS-CoV-2 viruses worldwide. In this study, the conformational stability of the isolated...
The Omicron variant and its sub-lineages are the only current circulating SARS-CoV-2 viruses worldwide. In this study, the conformational stability of the isolated Receptor Binding Domain (RBD) of Omicron's spike protein is examined in detail. The parent Omicron lineage has over ten mutations in the ACE2 binding region of the RBD that are specifically associated with its β hairpin loop domain. It is demonstrated through biophysical molecular computations that the mutations in the β hairpin loop domain significantly increase the intra-protein interaction energies of intra-loop and loop-RBD interactions. The interaction energy increases include the formation of new hydrogen bonds in the β hairpin loop domain that help stabilize this critical ACE2 binding region. Our results also agree with recent experiments on the stability of Omicron's core β barrel domain, outside of its loop domain, and help demonstrate the overall conformational stability of the Omicron RBD. It is further shown here through dynamic simulations that the unbound state of the Omicron RBD remains closely aligned with the bound state configuration, which was not observed for the wild-type RBD. Overall, these studies demonstrate the significantly increased conformational stability of Omicron over its wild-type configuration and raise a number of questions on whether conformational stability could be a positive selection feature of SARS-CoV-2 viral mutational changes.
Topics: Spike Glycoprotein, Coronavirus; SARS-CoV-2; Mutation; Protein Binding; Humans; Molecular Dynamics Simulation; Angiotensin-Converting Enzyme 2; Protein Conformation; Protein Domains; Protein Stability; COVID-19; Binding Sites
PubMed: 38932204
DOI: 10.3390/v16060912 -
Viruses May 2024COVID-19 is a spectrum of clinical symptoms in humans caused by infection with SARS-CoV-2. The coalescence of SARS-CoV-2 with seasonal respiratory viruses, particularly...
Sequential Infection with Influenza A Virus Followed by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Leads to More Severe Disease and Encephalitis in a Mouse Model of COVID-19.
COVID-19 is a spectrum of clinical symptoms in humans caused by infection with SARS-CoV-2. The coalescence of SARS-CoV-2 with seasonal respiratory viruses, particularly influenza viruses, is a global health concern. To understand this, transgenic mice expressing the human ACE2 receptor (K18-hACE2) were infected with influenza A virus (IAV) followed by SARS-CoV-2 and the host response and effect on virus biology was compared to K18-hACE2 mice infected with IAV or SARS-CoV-2 alone. The sequentially infected mice showed reduced SARS-CoV-2 RNA synthesis, yet exhibited more rapid weight loss, more severe lung damage and a prolongation of the innate response compared to the singly infected or control mice. Sequential infection also exacerbated the extrapulmonary encephalitic manifestations associated with SARS-CoV-2 infection. Conversely, prior infection with a commercially available, multivalent live-attenuated influenza vaccine (Fluenz Tetra) elicited the same reduction in SARS-CoV-2 RNA synthesis, albeit without the associated increase in disease severity. This suggests that the innate immune response stimulated by IAV inhibits SARS-CoV-2. Interestingly, infection with an attenuated, apathogenic influenza vaccine does not result in an aberrant immune response and enhanced disease severity. Taken together, the data suggest coinfection ('twinfection') is deleterious and mitigation steps should be instituted as part of the comprehensive public health and management strategy of COVID-19.
Topics: Animals; COVID-19; Mice; Disease Models, Animal; SARS-CoV-2; Influenza A virus; Orthomyxoviridae Infections; Mice, Transgenic; Angiotensin-Converting Enzyme 2; Humans; Coinfection; Lung; Encephalitis, Viral; Influenza Vaccines; Female; Immunity, Innate
PubMed: 38932155
DOI: 10.3390/v16060863 -
Viruses May 2024The COVID-19 pandemic has been one of the most impactful events in our lifetime, caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Multiple... (Review)
Review
The COVID-19 pandemic has been one of the most impactful events in our lifetime, caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Multiple SARS-CoV-2 variants were reported globally, and a wide range of symptoms existed. Individuals who contract COVID-19 continue to suffer for a long time, known as long COVID or post-acute sequelae of COVID-19 (PASC). While COVID-19 vaccines were widely deployed, both unvaccinated and vaccinated individuals experienced long-term complications. To date, there are no treatments to eradicate long COVID. We recently conceived a new approach to treat COVID in which a 15-amino-acid synthetic peptide (SPIKENET, SPK) is targeted to the ACE2 receptor binding domain of SARS-CoV-2, which prevents the virus from attaching to the host. We also found that SPK precludes the binding of spike glycoproteins with the receptor carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) of a coronavirus, murine hepatitis virus-1 (MHV-1), and with all SARS-CoV-2 variants. Further, SPK reversed the development of severe inflammation, oxidative stress, tissue edema, and animal death post-MHV-1 infection in mice. SPK also protects against multiple organ damage in acute and long-term post-MHV-1 infection. Our findings collectively suggest a potential therapeutic benefit of SPK for treating COVID-19.
Topics: SARS-CoV-2; Humans; COVID-19; Animals; Spike Glycoprotein, Coronavirus; Mice; Post-Acute COVID-19 Syndrome; Angiotensin-Converting Enzyme 2; Peptides; Antiviral Agents; COVID-19 Drug Treatment
PubMed: 38932130
DOI: 10.3390/v16060838 -
Pharmaceuticals (Basel, Switzerland) May 2024: Acute heart failure (AHF) is associated with high morbidity and mortality, and the prognosis is particularly poor in older patients. Although the application of...
: Acute heart failure (AHF) is associated with high morbidity and mortality, and the prognosis is particularly poor in older patients. Although the application of guideline-directed medical therapy (GDMT) has shown a positive impact on prognosis, the effects are less clear in older age groups. The aim of this study was to analyze real-world data regarding GDMT and outcomes in older HF patients. : This is a prospective cohort study from a secondary care hospital in central Switzerland. A total of 97 consecutive patients aged ≥60 years were enrolled between January 2019 and 2022. The main outcome parameters were prescribed GDMT at discharge, and in case of rehospitalization, GDMT at readmission, and survival in terms of all-cause mortality and HF-related hospitalizations during a 3-year follow-up period. : Follow-up data were available for 93/97 patients. The mean age was 77.8 ± 9.8 years, 46% being female. The mean left ventricular ejection fraction (LVEF) was 35.3 ± 13.9%, with a mean BNP level of 2204.3 ± 239 ng/L. Upon discharge, 86% received beta-blockers and 76.3% received renin-angiotensin system (RAS) inhibitors. At rehospitalization for AHF, beta-blockers use was significantly lower and decreased to 52.8% ( = 0.003), whereas RAS inhibitor use increased slightly to 88.9% ( = 0.07), and SGLT-2 inhibitors showed a significant increase from 5.4% vs. 47.2% ( = 0.04). GDMT prescription was not dependent on LVEF. Overall, 73.1% of patients received two-stage or three-stage GDMT at discharge, whereas this percentage decreased to 61% at rehospitalization ( = 0.01). Kaplan-Meier analysis for the combined outcome rehospitalization and death stratified by LV function showed significant differences between LVEF groups (aHR: 0.6 [95% CI: 0.44 to 0.8]; = 0.0023). : Our results indicate that first, the majority of older AHF patients from a secondary care hospital in Switzerland were not on optimal GDMT at discharge and even fewer at readmission, and second, that prognosis of the population is still poor, with almost half of the patients having been rehospitalized or died during a 3-year follow-up period under real-world conditions, without significant difference between women and men. Our findings underline the need for further improvements in the medical treatment of AHF, in particular in older patients, to improve prognosis and to reduce the burden of disease.
PubMed: 38931378
DOI: 10.3390/ph17060711 -
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