Modulation of <scp>TNF</scp>‐α, interleukin‐6, and interleukin‐10 by nebivolol–valsartan and nebivolol–lisinopril polytherapy in <scp>SHR</scp> rats

Diego, Lezama‐Martinez; Jazmin, Flores‐Monroy; Diana, Ramirez‐Hernandez; German‐Isauro, Garrido‐Farina; Salvador, Fonseca‐Coronado; Maria‐Elena, Hernandez‐Campos

doi:10.1002/prp2.1189

Cited by 3 publications

References 66 publications

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β2-Adrenergic Biased Agonist Nebivolol Inhibits the Development of Th17 and the Response of Memory Th17 Cells in an NF-κB-Dependent Manner

Hajiaghayi,

Gholizadeh,

Han

et al. 2024

Preprint

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IntroductionAdrenergic receptors regulate metabolic, cardiovascular and immunological functions in response to the sympathetic nervous system. The effect of β2-adrenergic receptor (AR) as a high-expression receptor on different subpopulations of T cells is complex and varies depending on the type of ligand and context. While traditional β2-AR agonists generally suppress T cells, they potentially enhance IL-17A production by Th17 cells. The effects of pharmacological drugs that count as biased agonists of AR like nebivolol are not completely understood. We investigated the impact of nebivolol on human memory CD4+ T (Th1, Th2, Th17) cells and polarized naïve Th17 cells highlighting its potential for IL-17A suppression via a non-canonical β2AR cell-signaling pathway.MethodsThe effects of nebivolol were tested on healthy human peripheral blood mononuclear cells, purified memory Th cells, and polarized naïve Th17 cells activated with antiCD3/antiCD28/antiCD2 ImmunoCult reagent. IFN-γ, IL-4, and IL-17A which are primarily derived from Th1, Th2, and Th17 cells respectively, were quantified by ELISA and flow cytometry. IL-10 was measured by ELISA. Gene expression of RORC, ADRB1, ADRB2, and ADRB3 was evaluated by qPCR. The ADRB2 gene was knocked out in memory Th cells using CRISPR/Cas9. Protein expression of phosphorylated-serine133-CREB and phosphorylated-NF-κB p65 was assessed by Western blot. Proliferation was assessed by fluorescent dye loading and flow cytometry.ResultsNebivolol treatment decreased IL-17A and IFN-γ secretion by activated-memory Th cells and elevated IL-4 levels. Nebivolol reduced the proportion of IL-17A+ Th cells and downregulated RORC expression. Unlike the β2-AR agonist terbutaline, nebivolol inhibited the shift of naïve CD4+ T cells towards the Th17 phenotype. IL-10 and proliferation index remained unchanged. Nebivolol-treated β2-knockout memory Th cells showed significant inhibition of β2AR-mediated signaling, evidenced by the absence of IL-17A suppression compared to controls. Phosphorylation of the NF-κB p65 subunit was inhibited by nebivolol, but CREB phosphorylation was not changed, suggesting a selective transcriptional control.ConclusionsThe findings demonstrate that nebivolol acts through a β2-AR-mediated signaling pathway, as a distinctive anti-inflammatory agent capable of selectively shifting Th17 cells and suppressing phosphorylation of NF-κB. This highlights nebivolol’s potential for therapeutic interventions in chronic autoimmune conditions with elevated IL-17A levels.

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β2-Adrenergic Biased Agonist Nebivolol Inhibits the Development of Th17 and the Response of Memory Th17 Cells in an NF-κB-Dependent Manner

Hajiaghayi,

Gholizadeh,

Han

et al. 2024

Preprint

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Synbiotic supplementation ameliorates anxiety and myocardial ischaemia–reperfusion injury in hyperglycaemic rats by modulating gut microbiota

Bulut,

Erol Kutucu,

Üstünova

et al. 2024

Experimental Physiology

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Hyperglycaemia, hyperlipidaemia, hypertension and obesity are the main risk factors affecting the development and prognosis of ischaemic heart disease, which is still an important cause of death today. In our study, male Sprague–Dawley rats were fed either a standard diet (SD) or a high fat and high carbohydrate diet (HF‐HCD) for 8 weeks and streptozotocin (STZ) was injected at the seventh week of the feeding period. In one set of rats, a mixture of a prebiotic and probiotics (synbiotic, SYN) was administered by gavage starting from the beginning of the feeding period. Experimental myocardial ischaemia–reperfusion (30 min/60 min) was induced at the end of 8 weeks. Hyperglycaemia, hypertension and increased serum low‐density lipoprotein levels occurred in SD‐ and HF‐HCD‐fed and STZ‐treated rats followed for 8 weeks. Increased density of the Proteobacteria phylum was observed in rats with increased blood glucose levels, indicating intestinal dysbiosis. The severity of cardiac damage was highest in the dysbiotic HF‐HCD‐fed hyperglycaemic rats, which was evident with increased serum creatine kinase‐MB (CK‐MB), cardiac troponin I (cTnI), tumour necrosis factor‐α, and interleukin‐6 levels, along with a decrease in ST‐segment resolution index. SYN supplementation to either a normal or a high‐fat high‐carbohydrate diet improved gut dysbiosis, reduced anxiety, decreased CK‐MB and cTnI levels, and alleviated myocardial ischaemia–reperfusion injury in hyperglycaemic rats.

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The Repurposing of FDA-Approved Drugs as FtsZ Inhibitors against Mycobacterium tuberculosis: An In Silico and In Vitro Study

Tovar-Nieto,

Flores-Padilla,

Rivas-Santiago

et al. 2024

Microorganisms

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Mycobacterium tuberculosis (Mtb), the causative pathogen of tuberculosis, remains one of the leading causes of death from a single infectious agent. Furthermore, the growing evolution to multi-drug-resistant (MDR) strains requires de novo identification of drug targets for evaluating candidates or repurposing drugs. Hence, targeting FtsZ, an essential cell division protein, is a promising target. Methods: Using an in silico pharmacological repositioning strategy, four FDA-based drugs that bind to the catalytic site FtsZ were selected. The Alamar Blue colorimetric assay was used to assess antimicrobial activity and the effect of drugs on Mtb growth through growth curves. Bacterial load was determined with an in vitro infection model using colony-forming units (CFU)/mL, and cytotoxicity on human monocyte-derived macrophages (MDMhs) was assessed by flow cytometry. Results: Paroxetine and nebivolol exhibited antimycobacterial activity against both reference TB and MDR strains at a concentration of 25 µg/mL. Furthermore, both paroxetine and nebivolol demonstrated a significant reduction (p < 0.05) in viable bacteria compared to the untreated group in the in vitro infection model. Conclusions: Collectively, our findings demonstrate that the use of paroxetine and nebivolol is a promising strategy to help in the control of tuberculosis infection.

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Modulation of TNF‐α, interleukin‐6, and interleukin‐10 by nebivolol–valsartan and nebivolol–lisinopril polytherapy in SHR rats

Cited by 3 publications

References 66 publications

β2-Adrenergic Biased Agonist Nebivolol Inhibits the Development of Th17 and the Response of Memory Th17 Cells in an NF-κB-Dependent Manner

β2-Adrenergic Biased Agonist Nebivolol Inhibits the Development of Th17 and the Response of Memory Th17 Cells in an NF-κB-Dependent Manner

Synbiotic supplementation ameliorates anxiety and myocardial ischaemia–reperfusion injury in hyperglycaemic rats by modulating gut microbiota

The Repurposing of FDA-Approved Drugs as FtsZ Inhibitors against Mycobacterium tuberculosis: An In Silico and In Vitro Study

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