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Molecular Aspects of Medicine Dec 2023In the last years, neuroprotective therapies have attracted the researcher interests as modern and challenging approach for the treatment of neurodegenerative diseases,... (Review)
Review
In the last years, neuroprotective therapies have attracted the researcher interests as modern and challenging approach for the treatment of neurodegenerative diseases, aimed at protecting the nervous system from injuries. Glaucoma is a neurodegenerative disease characterized by progressive excavation of the optic nerve head, retinal axonal injury and corresponding vision loss that affects millions of people on a global scale. The molecular basis of the pathology is largely uncharacterized yet, and the therapeutic approaches available do not change the natural course of the disease. Therefore, in accordance with the therapeutic regimens proposed for other neurodegenerative diseases, a modern strategy to treat glaucoma includes prescription of drugs with neuroprotective activities. With respect to this, several preclinical and clinical investigations on a plethora of different drugs are currently ongoing. In this review, first, the conceptualization of the rationale for the adoption of neuroprotective strategies for retina is summarized. Second, the molecular aspects highlighting glaucoma as a neurodegenerative disease are reported. In conclusion, the molecular and pharmacological properties of most promising direct neuroprotective drugs used to delay glaucoma progression are examined, including: neurotrophic factors, NMDA receptor antagonists, the α2-adrenergic agonist, brimonidine, calcium channel blockers, antioxidant agents, nicotinamide and statins.
Topics: Humans; Neurodegenerative Diseases; Retinal Ganglion Cells; Glaucoma; Brimonidine Tartrate; Retina; Retinal Diseases
PubMed: 38000334
DOI: 10.1016/j.mam.2023.101225 -
Journal of Biomedical Science Jul 2023Sustained, chronic activation of β-adrenergic receptor (β-AR) signaling leads to cardiac arrhythmias, with exchange proteins directly activated by cAMP (Epac1 and...
BACKGROUND
Sustained, chronic activation of β-adrenergic receptor (β-AR) signaling leads to cardiac arrhythmias, with exchange proteins directly activated by cAMP (Epac1 and Epac2) as key mediators. This study aimed to evaluate whether CD44, a transmembrane receptor mediating various cellular responses, participates in Epac-dependent arrhythmias.
METHODS
The heart tissue from CD44 knockout (CD44) mice, cultured HL-1 myocytes and the tissue of human ventricle were used for western blot, co-immunoprecipitaiton and confocal studies. Line-scanning confocal imaging was used for the study of cellular Ca sparks on myocytes. Optical mapping and intra-cardiac pacing were applied for arrhythmia studies on mice's hearts.
RESULTS
In mice, isoproterenol, a β-AR agonist, upregulated CD44 and Epac1 and increased the association between CD44 and Epac1. Isoproterenol upregulated the expression of phospho-CaMKII (p-CaMKII), phospho-ryanodine receptor (p-RyR), and phospho-phospholamban (p-PLN) in mice and cultured myocytes; these effects were attenuated in CD44 mice compared with wild-type controls. In vitro, isoproterenol, 8-CPT-cAMP (an Epac agonist), and osteopontin (a ligand of CD44) significantly upregulated the expression of p-CaMKII, p-RyR, and p-PLN; this effect was attenuated by CD44 small interfering RNA (siRNA). In myocytes, resting Ca sparks were induced by isoproterenol and overexpressed CD44, which were prevented by inhibiting CD44. Ex vivo optical mapping and in vivo intra-cardiac pacing studies showed isoproterenol-induced triggered events and arrhythmias in ventricles were prevented in CD44 mice. The inducibility of ventricular arrhythmias (VAs) was attenuated in CD44 HF mice compared with wild-type HF controls. In patients, CD44 were upregulated, and the association between CD44 and Epac1 were increased in ventricles with reduced contractility.
CONCLUSION
CD44 regulates β-AR- and Epac1-mediated Ca-handling abnormalities and VAs. Inhibition of CD44 is effective in reducing VAs in HF, which is potentially a novel therapeutic target for preventing the arrhythmias and sudden cardiac death in patients with diseased hearts.
Topics: Humans; Mice; Animals; Receptors, Adrenergic, beta; Isoproterenol; Guanine Nucleotide Exchange Factors; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Myocytes, Cardiac; Calcium; Arrhythmias, Cardiac; Calcium Signaling; Adrenergic Agents; Hyaluronan Receptors
PubMed: 37452346
DOI: 10.1186/s12929-023-00944-0 -
Circulation Research Dec 2023Nitric oxide (NO) has been identified as a signaling molecule generated during β-adrenergic receptor stimulation in the heart. Furthermore, a role for NO in triggering...
BACKGROUND
Nitric oxide (NO) has been identified as a signaling molecule generated during β-adrenergic receptor stimulation in the heart. Furthermore, a role for NO in triggering spontaneous Ca release via -nitrosylation of CaMKIIδ (Ca/calmodulin kinase II delta) is emerging. NO donors are routinely used clinically for their cardioprotective effects on the heart, but it is unknown how NO donors modulate the proarrhythmic CaMKII to alter cardiac arrhythmia incidence. We test the role of -nitrosylation of CaMKIIδ at the Cysteine-273 inhibitory site and cysteine-290 activating site in cardiac Ca handling and arrhythmogenesis before and during β-adrenergic receptor stimulation.
METHODS
We measured Ca-handling in isolated cardiomyocytes from C57BL/6J wild-type (WT) mice and mice lacking CaMKIIδ expression (CaMKIIδ-KO) or with deletion of the -nitrosylation site on CaMKIIδ at cysteine-273 or cysteine-290 (CaMKIIδ-C273S and -C290A knock-in mice). Cardiomyocytes were exposed to NO donors, -nitrosoglutathione (GSNO; 150 μM), sodium nitroprusside (200 μM), and β-adrenergic agonist isoproterenol (100 nmol/L).
RESULTS
Both WT and CaMKIIδ-KO cardiomyocytes responded to isoproterenol with a full inotropic and lusitropic Ca transient response as well as increased Ca spark frequency. However, the increase in Ca spark frequency was significantly attenuated in CaMKIIδ-KO cardiomyocytes. The protection from isoproterenol-induced Ca sparks and waves was mimicked by GSNO pretreatment in WT cardiomyocytes but lost in CaMKIIδ-C273S cardiomyocytes. When GSNO was applied after isoproterenol, this protection was not observed in WT or CaMKIIδ-C273S but was apparent in CaMKIIδ-C290A. In Langendorff-perfused isolated hearts, GSNO pretreatment limited isoproterenol-induced arrhythmias in WT but not CaMKIIδ-C273S hearts, while GSNO exposure after isoproterenol sustained or exacerbated arrhythmic events.
CONCLUSIONS
We conclude that prior -nitrosylation of CaMKIIδ at cysteine-273 can limit subsequent β-adrenergic receptor-induced arrhythmias, but that -nitrosylation at cysteine-290 might worsen or sustain β-adrenergic receptor-induced arrhythmias. This has important implications for the administration of NO donors in the clinical setting.
Topics: Mice; Animals; Isoproterenol; Nitric Oxide; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Cysteine; Mice, Inbred C57BL; Arrhythmias, Cardiac; Myocytes, Cardiac; Phosphorylation; Receptors, Adrenergic, beta; Calcium; Sarcoplasmic Reticulum
PubMed: 37961889
DOI: 10.1161/CIRCRESAHA.123.323571 -
Frontiers in Toxicology 2023Ocular surface disease (OSD), a disorder affecting the lacrimal and meibomian glands and the corneal and conjunctival epithelium, is a well-known complication of topical... (Review)
Review
Ocular surface disease (OSD), a disorder affecting the lacrimal and meibomian glands and the corneal and conjunctival epithelium, is a well-known complication of topical glaucoma therapy. OSD can present as a new or pre-existing condition that virtually any anti-glaucoma formulation can exacerbate. As such, both glaucoma and OSD frequently coexist. Typical OSD symptoms include ocular discomfort, redness, burning, and dryness, whereas signs include periorbital and eyelid skin pigmentation, conjunctival scarring, and superficial punctate keratitis. Pressure-lowering eyedrops can cause toxic, allergic, and inflammatory reactions on the ocular surface. The latter can result from either preservatives or direct toxicity from the active molecule. Although usually mild, OSD can cause significant symptoms that lead to poor quality of life, decreased compliance to therapy, glaucoma progression, and worse visual outcomes. Given the chronic nature of glaucoma, lack of curative therapy, and subsequent lifelong treatment, addressing OSD is necessary. This manuscript aims to provide an up-to-date overview of OSD's signs, symptoms, and pathogenic mechanisms from glaucoma therapy toxicity.
PubMed: 37547228
DOI: 10.3389/ftox.2023.1067942 -
Georgian Medical News Sep 2023The aim of this study was to evaluate current approaches to the pharmacotherapy of posttraumatic stress disorder. An information search was carried out in the databases...
The aim of this study was to evaluate current approaches to the pharmacotherapy of posttraumatic stress disorder. An information search was carried out in the databases PubMed, Ovid, EMBASE by keywords: "posttraumatic stress disorder", "treatment", and "medications". Search depth 2012-2022 years. From the general data (4877 articles) there were selected 14 articles with the highest degree of relevance. A content analysis of selected articles was carried out with the formation of recommendations for the use of pharmacotherapy in posttraumatic stress disorder. Currently, there are no unified approaches to the pharmacotherapy of posttraumatic stress disorder. Antidepressants (SSRI SNRIs) are primarily considered as first-line drugs, but only sertraline, paroxetine, and fluoxetine are approved by the FDA. But these drugs have a fairly wide range of side effects, including suicidal thoughts. The use of benzodiazepines should be limited as they increase the risk of developing posttraumatic stress disorder. Vortioxetine becomes a very promising option. The most significant benefits of vortioxetine are the significant positive effects of vortioxetine on attention, memory, and executive function. There is some evidence for the use of alpha-1 adrenoceptor antagonists and alpha-2 adrenoceptor agonists in therapy. In insomnia the use of prazosin and trazodone is recommended. Pharmacotherapy of posttraumatic stress disorder requires administration of medications with multimodal action. Currently, there are no unified approaches to the pharmacotherapy of posttraumatic stress disorder. Further randomized clinical trials are necessary for developing effective treatment of posttraumatic stress disorder.
Topics: Humans; Antidepressive Agents; Receptors, Adrenergic; Stress Disorders, Post-Traumatic; Vortioxetine
PubMed: 37991966
DOI: No ID Found -
European Journal of Anaesthesiology Oct 2023Pain after craniotomy can be intense and its management is often suboptimal.
BACKGROUND
Pain after craniotomy can be intense and its management is often suboptimal.
OBJECTIVES
We aimed to evaluate the available literature and develop recommendations for optimal pain management after craniotomy.
DESIGN
A systematic review using procedure-specific postoperative pain management (PROSPECT) methodology was undertaken.
DATA SOURCES
Randomised controlled trials and systematic reviews published in English from 1 January 2010 to 30 June 2021 assessing pain after craniotomy using analgesic, anaesthetic or surgical interventions were identified from MEDLINE, Embase and Cochrane Databases.
ELIGIBILITY CRITERIA
Each randomised controlled trial (RCT) and systematic review was critically evaluated and included only if met the PROSPECT requirements. Included studies were evaluated for clinically relevant differences in pain scores, use of nonopioid analgesics, such as paracetamol and NSAIDs, and current clinical relevance.
RESULTS
Out of 126 eligible studies identified, 53 RCTs and seven systematic review or meta-analyses met the inclusion criteria. Pre-operative and intra-operative interventions that improved postoperative pain were paracetamol, NSAIDs, intravenous dexmedetomidine infusion, regional analgesia techniques, including incision-site infiltration, scalp nerve block and acupuncture. Limited evidence was found for flupirtine, intra-operative magnesium sulphate infusion, intra-operative lidocaine infusion, infiltration adjuvants (hyaluronidase, dexamethasone and α-adrenergic agonist added to local anaesthetic solution). No evidence was found for metamizole, postoperative subcutaneous sumatriptan, pre-operative oral vitamin D, bilateral maxillary block or superficial cervical plexus block.
CONCLUSIONS
The analgesic regimen for craniotomy should include paracetamol, NSAIDs, intravenous dexmedetomidine infusion and a regional analgesic technique (either incision-site infiltration or scalp nerve block), with opioids as rescue analgesics. Further RCTs are required to confirm the influence of the recommended analgesic regimen on postoperative pain relief.
Topics: Humans; Pain Management; Dexmedetomidine; Acetaminophen; Analgesics; Pain, Postoperative; Craniotomy; Anti-Inflammatory Agents, Non-Steroidal
PubMed: 37417808
DOI: 10.1097/EJA.0000000000001877 -
Best Practice & Research. Clinical... Sep 2023Balanced anesthesia relies on the simultaneous administration of different drugs to attain an anesthetic state. The classic triad of anesthesia is a combination of a... (Review)
Review
Balanced anesthesia relies on the simultaneous administration of different drugs to attain an anesthetic state. The classic triad of anesthesia is a combination of a hypnotic, an analgesic, and a neuromuscular blocker. It is predominantly the analgesic pillar of this triad that became more and more supported by adjuvant therapy. The aim of this approach is to evolve into an opioid-sparing technique to cope with undesirable side effects of the opioids and is fueled by the opioid epidemic. The optimal strategy for balanced general anesthesia in ambulatory surgery must aim for a transition to a multimodal analgesic regimen dealing with acute postoperative pain and ideally reduce the most common adverse effects patients are faced with at home; sore throat, delayed awakening, memory disturbances, headache, nausea and vomiting, and negative behavioral changes. Over the years, this continuum of "multimodal general anesthesia" adopted many drugs with different modes of action. This review focuses on the most recent evidence on the different adjuvants that entered clinical practice and gives an overview of the different mechanisms of action, the potential as opioid-sparing or hypnotic-sparing drugs, and the applicability specifically in ambulatory surgery.
Topics: Humans; Balanced Anesthesia; Ambulatory Surgical Procedures; Analgesics, Opioid; Anesthesia, General; Drug-Related Side Effects and Adverse Reactions; Hypnotics and Sedatives
PubMed: 37938086
DOI: 10.1016/j.bpa.2022.12.003 -
Cancer Chemotherapy and Pharmacology Dec 2023Globally breast cancer accounts for 24.5% in incidence and 15.5% in cancer deaths in women. The triple-negative subtype lacks any specific therapy and is treated with...
PURPOSE
Globally breast cancer accounts for 24.5% in incidence and 15.5% in cancer deaths in women. The triple-negative subtype lacks any specific therapy and is treated with chemotherapy, resulting in significant side-effects. We aimed to investigate if the dose of chemotherapeutic drugs could be diminished by co-administering it with the β2-agonist salbutamol.
METHODS
Cell proliferation was measured by thymidine incorporation; gene expression, by real-time PCR and protein phosphorylation by WB. Apoptosis was assessed by acridine orange / ethidium bromide and TUNEL tests. Public patient databases were consulted. Cells were inoculated to nude mice and their growth assessed.
RESULTS
The β-agonist salbutamol synergizes in MDA-MB-231 cells in vitro with paclitaxel and doxorubicin on cell proliferation through ADRB2 receptors, while the β-blocker propranolol does not. The expression of this receptor was assessed in patient databases and other cell lines. Triple negative samples had the lowest expression. Salbutamol and paclitaxel decreased MDA-MB-231 cell proliferation while their combination further inhibited it. The pathways involved were analyzed. When these cells were inoculated to nude mice, paclitaxel and salbutamol inhibited tumor growth. The combined effect was significantly greater. Paclitaxel increased the expression of MDR1 while salbutamol partially reversed this increase.
CONCLUSION
While the effect of salbutamol was mainly on cell proliferation, suboptimal concentrations of paclitaxel provoked a very important enhancement of apoptosis. The latter enhanced transporter proteins as MDR1, whose expression were diminished by salbutamol. The expression of ADRB2 should be assessed in the biopsy or tumor to eventually select patients that could benefit from salbutamol repurposing.
Topics: Animals; Mice; Humans; Female; Paclitaxel; Breast Neoplasms; Triple Negative Breast Neoplasms; Mice, Nude; Albuterol; Cell Line, Tumor; Cell Proliferation; Propranolol; Adrenergic Agonists; Apoptosis
PubMed: 37725114
DOI: 10.1007/s00280-023-04586-9 -
The Journal of Clinical Investigation Sep 2023Asthma is a chronic inflammatory disease associated with episodic airway narrowing. Inhaled β2-adrenergic receptor (β2AR) agonists (β2-agonists) promote - with...
Asthma is a chronic inflammatory disease associated with episodic airway narrowing. Inhaled β2-adrenergic receptor (β2AR) agonists (β2-agonists) promote - with limited efficacy - bronchodilation in asthma. All β2-agonists are canonical orthosteric ligands that bind the same site as endogenous epinephrine. We recently isolated a β2AR-selective positive allosteric modulator (PAM), compound-6 (Cmpd-6), which binds outside of the orthosteric site and modulates orthosteric ligand functions. With the emerging therapeutic potential of G-protein coupled receptor allosteric ligands, we investigated the impact of Cmpd-6 on β2AR-mediated bronchoprotection. Consistent with our findings using human β2ARs, Cmpd-6 allosterically potentiated β2-agonist binding to guinea pig β2ARs and downstream signaling of β2ARs. In contrast, Cmpd-6 had no such effect on murine β2ARs, which lack a crucial amino acid in the Cmpd-6 allosteric binding site. Importantly, Cmpd-6 enhanced β2 agonist-mediated bronchoprotection against methacholine-induced bronchoconstriction in guinea pig lung slices, but - in line with the binding studies - not in mice. Moreover, Cmpd-6 robustly potentiated β2 agonist-mediated bronchoprotection against allergen-induced airway constriction in lung slices obtained from a guinea pig model of allergic asthma. Cmpd-6 similarly enhanced β2 agonist-mediated bronchoprotection against methacholine-induced bronchoconstriction in human lung slices. Our results highlight the potential of β2AR-selective PAMs in the treatment of airway narrowing in asthma and other obstructive respiratory diseases.
Topics: Humans; Mice; Animals; Guinea Pigs; Methacholine Chloride; Ligands; Asthma; Lung; Binding Sites; Receptors, Adrenergic, beta-2
PubMed: 37432742
DOI: 10.1172/JCI167337 -
Journal of Endocrinological... Nov 2023Adaptive thermogenesis represents the main mechanism through which the body generates heat in response to external stimuli, a phenomenon that includes shivering and... (Review)
Review
BACKGROUND
Adaptive thermogenesis represents the main mechanism through which the body generates heat in response to external stimuli, a phenomenon that includes shivering and non-shivering thermogenesis. The non-shivering thermogenesis is mainly exploited by adipose tissue characterized by a brown aspect, which specializes in energy dissipation. A decreased amount of brown adipose tissue has been observed in ageing and chronic illnesses such as obesity, a worldwide health problem characterized by dysfunctional adipose tissue expansion and associated cardiometabolic complications. In the last decades, the discovery of a trans-differentiation mechanism ("browning") within white adipose tissue depots, leading to the generation of brown-like cells, allowed to explore new natural and synthetic compounds able to favour this process and thus enhance thermogenesis with the aim of counteracting obesity. Based on recent findings, brown adipose tissue-activating agents could represent another option in addition to appetite inhibitors and inhibitors of nutrient absorption for obesity treatment.
PURPOSE
This review investigates the main molecules involved in the physiological (e.g. incretin hormones) and pharmacological (e.g. β3-adrenergic receptors agonists, thyroid receptor agonists, farnesoid X receptor agonists, glucagon-like peptide-1, and glucagon receptor agonists) modulation of adaptive thermogenesis and the signalling mechanisms involved.
PubMed: 37378828
DOI: 10.1007/s40618-023-02125-0