Progress on the development of Class A GPCR-biased ligands.

Class A G protein-coupled receptors (GPCRs) continue to garner interest for their essential roles in cell signalling and their importance as drug targets. Although numerous drugs in the clinic target these receptors, over 60% GPCRs remain unexploited. Moreover, the adverse effects triggered by the available unbiased GPCR modulators, limit their use and therapeutic value. In this context, the elucidation of biased signalling has opened up new pharmacological avenues holding promise for safer therapeutics. Functionally selective ligands favour receptor conformations facilitating the recruitment of specific effectors and the modulation of the associated pathways. This review surveys the current drug discovery landscape of GPCR-biased modulators with a focus on recent advances. Understanding the biological effects of this preferential coupling is at different stages depending on the Class A GPCR family. Therefore, with a focus on individual GPCR families, we present a compilation of the functionally selective modulators reported over the past few years. In doing so, we dissect their therapeutic relevance, molecular determinants and potential clinical applications.

Homodimerization of CB2 cannabinoid receptor triggered by a bivalent ligand enhances cellular signaling.

G protein-coupled receptors (GPCRs) exist within a landscape of interconvertible conformational states and in dynamic equilibrium between monomers and higher-order oligomers, both influenced by ligand binding. Here, we show that a homobivalent ligand formed by equal chromenopyrazole moieties as pharmacophores, connected by 14 methylene units, can modulate the dynamics of the cannabinoid CB2 receptor (CB2R) homodimerization by simultaneously binding both protomers of the CB2R-CB2R homodimer. Computational and pharmacological experiments showed that one of the ligand pharmacophores binds to the orthosteric site of one protomer, and the other pharmacophore to a membrane-oriented pocket between transmembranes 1 and 7 of the partner protomer. This results in unique pharmacological properties, including increased potency in Gi-mediated signaling and enhanced recruitment of ß-arrestin. Thus, by modulating dimerization dynamics, it may be possible to fine-tune CB2R activity, potentially leading to improved therapeutic outcomes.

Post-translational modifications of vertebrate striated muscle myosin heavy chains.

Post-translational modifications (PTMs) play a crucial role in regulating the function of many sarcomeric proteins, including myosin. Myosins comprise a family of motor proteins that play fundamental roles in cell motility in general and muscle contraction in particular. A myosin molecule consists of two myosin heavy chains (MyHCs) and two pairs of myosin light chains (MLCs); two MLCs are associated with the neck region of each MyHC's N-terminal head domain, while the two MyHC C-terminal tails form a coiled-coil that polymerizes with other MyHCs to form the thick filament backbone. Myosin undergoes extensive PTMs, and dysregulation of these PTMs may lead to abnormal muscle function and contribute to the development of myopathies and cardiovascular disorders. Recent studies have uncovered the significance of PTMs in regulating MyHC function and showed how these PTMs may provide additional modulation of contractile processes. Here, we discuss MyHC PTMs that have been biochemically and/or functionally studied in mammals' and rodents' striated muscle. We have identified hotspots or specific regions in three isoforms of myosin (MYH2, MYH6, and MYH7) where the prevalence of PTMs is more frequent and could potentially play a significant role in fine-tuning the activity of these proteins.

The CB1 receptor interacts with cereblon and drives cereblon deficiency-associated memory shortfalls.

Cereblon/CRBN is a substrate-recognition component of the Cullin4A-DDB1-Roc1 E3 ubiquitin ligase complex. Destabilizing mutations in the human CRBN gene cause a form of autosomal recessive non-syndromic intellectual disability (ARNSID) that is modelled by knocking-out the mouse Crbn gene. A reduction in excitatory neurotransmission has been proposed as an underlying mechanism of the disease. However, the precise factors eliciting this impairment remain mostly unknown. Here we report that CRBN molecules selectively located on glutamatergic neurons are necessary for proper memory function. Combining various in vivo approaches, we show that the cannabinoid CB1 receptor (CB1R), a key suppressor of synaptic transmission, is overactivated in CRBN deficiency-linked ARNSID mouse models, and that the memory deficits observed in these animals can be rescued by acute CB1R-selective pharmacological antagonism. Molecular studies demonstrated that CRBN interacts physically with CB1R and impairs the CB1R-Gi/o-cAMP-PKA pathway in a ubiquitin ligase-independent manner. Taken together, these findings unveil that CB1R overactivation is a driving mechanism of CRBN deficiency-linked ARNSID and anticipate that the antagonism of CB1R could constitute a new therapy for this orphan disease.

Medición de la fuerza muscular en adultos como predictor de extubación en Unidades de Cuidados Intensivos. Revisión narrativa / Measurement of muscular strength in adults as a predicator of extubation in intensive care units. Narrative review

Resumen: Introducción: uno de los principales efectos de la ventilación mecánica invasiva es la lesión de los músculos respiratorios, específicamente, sobre el diafragma en el que pueden ocurrir alteraciones estructurales y funcionales que modifican parcial o totalmente su función. Durante la ventilación mecánica se produce un proceso de atrofia por desuso de dicho músculo. Por ello la utilidad clínica de la medición de la fuerza muscular diafragmática es importante para conocer si el paciente tiene la capacidad de activar los mecanismos protectores de la vía aérea para lograr la extubación exitosa y el retiro del ventilador mecánico en el menor tiempo posible. Objetivos: describir la medición de la fuerza muscular como predictor de la extubación en las unidades de cuidados intensivos. Material y métodos: se realizó una revisión de la literatura, entre 2011 y 2022. Resultados: los pacientes que son sometidos a ventilación mecánica invasiva prolongada generalmente desarrollan una afección muscular diafragmática, lo que se convierte en una problemática para el proceso de extubación temprana, por lo cual es vital conocer los métodos de medición de fuerza muscular como predictor de extubación.

Abstract: Introduction: one of the main effects of invasive mechanical ventilation is injury to the respiratory muscles, specifically the diaphragm. In which structural and functional alterations can occur that partially or totally modify its function. During mechanical ventilation, a process of disuse atrophy of said muscle occurs. Therefore, the clinical utility of measuring diaphragmatic muscle strength is important to know if the patient has the ability to activate the protective mechanisms of the airway to achieve successful extubation and removal of the mechanical ventilator in the shortest time possible. Objective: describe the measurement of muscle strength as a predictor of extubation in intensive care units. Material and methods: a literature review was carried out, carried out between 2011 and 2022. Results: patients who are subjected to prolonged mechanical ventilation generally develop a diaphragmatic muscle disorder, becoming a problem for the weaning, for it is important know the methods of measuring muscle strength.

Activation of CB2R by synthetic CB2R agonist, PM289, improves brain endothelial barrier properties, decreases inflammatory response and enhances endothelial repair.

The Cannabinoid 2 Receptor (CB2R) has been found to provide immunological modulation in different cell types. More recently, detection of CB2R in the cerebral endothelium suggests a possible role in the resolution of inflammation at the level of the blood-brain-barrier (BBB). Here, the notion that CB2R upregulation in brain endothelial cells could be exploited to promote vascular protection and BBB integrity was evaluated. Targeting and activation of CB2R was accomplished by a novel and highly specific chromenopyrazole based CB2R agonist, PM289. This study demonstrates that CB2R upregulation is induced as early as 8 h in the cortical vasculature in an experimental mouse model of TBI. Unlike CB2R, CB1R was marginally detected and not significantly induced. In the human brain endothelial cell line, hCMEC/D3 cells, similar induction of CB2R was observed upon stimulation with TNFα. Analysis of transendothelial electrical resistance shows that PM289 markedly prevented the barrier-leakiness induced by TNFα. The BBB is also responsible for maintaining an immunological barrier. The five-fold increase in ICAM1 expression in stimulated endothelial cells was significantly diminished due to CB2R activation. Utilizing wounding assays, results showed that wound repair could be accomplished in nearly half the time when the novel CB2R agonist is present compared to the untreated control. Lastly, mechanistically, the effects of CB2R may be explained by the observed inhibition of the p65 NFκB subunit. Overall, these studies support the notion that targeting and activating CB2R in the brain vasculature could aid in BBB and vascular protection in the context of neuroinflammation.

Localização topográfica da emergência do condóito nasolagrimal medido em tomografia como reparação anatômica para procedimentos de cirurgia maxilofacial / Topographic location of the nasolagrimal conduit emergence measured on ct scans as an anatomical repair for maxillofacial surgery procedures / Ubicación topográfica de la emergencia del conducto nasolagrimal medida en tomografías como reparo anatómico para procedimientos de cirugía maxilofacial

Contexto: Na cirurgia maxilofacial existem procedimentos que envolvem o ducto nasolacrimal, pelo que esta medida é um ponto de referência para evitar a sua lesão. Artigos anteriores tomam como referência o fenótipo anglo-saxão e não a população latino-americana, o que é uma grande limitação quando se extrapola para a cirurgia maxilofacial. Objetivo: Medir a distância do ducto nasolacrimal às estruturas anatômicas adjacentes em uma amostra de tomografias computadorizadas do Hospital Universitário San Ignacio em Bogotá, Colômbia, em 2021. Métodos: Foi realizado um estudo observacional retrospetivo com base em tomografias computadorizadas do HUSI. Foi utilizada uma amostragem não probabilística, na qual foram identificadas 150 tomografias computadorizadas. Informações sobre sexo, idade e distância do ducto nasolacrimal em milímetros foram coletadas em um banco de dados em planilha Excel, tendo como marcos anatômicos o entalhe piriforme, o forame infraorbitário e o assoalho da fossa nasal em cortes axiais, sagitais e coronais. Resultados: A análise das medidas mostrou que nenhuma das distribuições de medidas se comportou de forma diferente da distribuição normal. Em relação à comparação das medidas por sexo, a idade foi semelhante entre homens e mulheres, enquanto nas comparações por idade foram evidenciadas diferenças significativas. Conclusão: Os resultados são consistentes com os dados publicados em estudos anteriores. Em termos de distribuição por sexo, o comprimento do ducto nasolacrimal é maior nos homens do que nas mulheres, e a distribuição por idade indica que, à medida que a idade aumenta, a distância do ducto a estas estruturas diminui... (AU)

Background: In maxillofacial surgery there are procedures that involve the nasolacrimal duct, so this measure is a reference point to avoid its injury. Previous articles take as reference the Anglo-Saxon phenotype and not the Latin American population, which is a great limitation when extrapolating it to maxillofacial surgical procedures. Objective: To measure the distance of the nasolacrimal duct to adjacent anatomical structures in a sample of CT scans from the Hospital Universitario San Ignacio in Bogotá- Colombia in 2021. Methods: A retrospective observational study was performed based on CT scans from HUSI. A non-probabilistic sampling was used in which 150 CT scans were identified. Information on sex, age and distance of the nasolacrimal duct in millimeters was collected in an Excel spreadsheet database, taking as anatomical landmarks the piriform notch, the infraorbital foramen and the floor of the nasal fossa in axial, sagittal and coronal sections. Results: The analysis of the measurements showed that none of the measurement distributions had a behavior different from the normal distribution. In relation to the comparison of the measurements by sex, age was similar in men and women, while significant differences were evidenced in the comparisons by age. Conclusion: The results coincide with the data published in previous studies. Regarding the distribution by sex, the length of the nasolacrimal duct is greater in men than in women, and the distribution by age indicates that as age increases the distance of the duct to these structures decreases... (AU)

Antecedentes: En cirugía maxilofacial existen procedimientos que involucran el conducto nasolagrimal, por lo cual esta medida es un punto de referencia para evitar su lesión. Artículos previos toman como referencia el fenotipo anglosajón y no la población Latinoamericana, lo cual supone una gran limitante al extrapolarlo a intervenciones quirúrgicas maxilofaciales. Objetivo: Medir la distancia del conducto nasolagrimal a estructuras anatómicas adyacentes en una muestra de tomografías del Hospital Universitario San Ignacio en BogotáColombia en 2021. Métodos: Se realizó un estudio observacional retrospectivo basado en tomografías del HUSI. Se utilizó un muestreo no probabilístico en el que se identificaron 150 tomografías. En una base de datos en hoja de cálculo en Excel se recolectó información sobre sexo, edad y distancia del conducto nasolagrimal en milímetros, teniendo como reparo anatómico la escotadura piriforme, el agujero infraorbitario y el piso de la fosa nasal en los cortes axial, sagital y coronal. Resultados: El análisis de las mediciones realizadas mostró que ninguna de las distribuciones de medición tuvo un comportamiento distinto a la distribución normal. En relación con la comparación de las medidas por sexo la edad fue similar en los hombres y mujeres, mientras que se evidenciaron diferencias significativas en las comparaciones por edad. Conclusión: Los resultados coinciden con los datos publicados en estudios previos. En cuanto a la distribución por sexo, la longitud del conducto nasolagrimal es mayor en hombres que en mujeres, y la distribución por edad indica que conforme aumenta la edad la distancia del conducto a estas estructuras disminuye... (AU)

Drug-Induced Kounis Syndrome: Latest Novelties.

Kounis syndrome (KS) is defined by an acute coronary syndrome associated with hypersensitivity reactions, an under-diagnosed life-threatening medical emergency. Although multiple causes have been described, drugs constitute the most frequent cause. The purpose of this review is to update knowledge about drug-induced KS, to give guidelines on the correct diagnosis and treatment. This article reviews the literature on drug-induced KS from the last 5 years. Antibiotics and NSAIDs are the most frequently implicated drugs. In addition, data on pathophysiology, clinical presentation, diagnosis, and management are reviewed in detail. Highlight that there is a great deal of variability in the diagnosis and especially in the treatment of KS. This review provides a valuable selection of practical resources for all stakeholders to support effective care for KS, from a cardiologic and allergologic point of view. Future research should focus on developing validated, evidence-based, and patient-centered tools to improve the management of KS.

Viewpoint on the Second Transatlantic GPCR Symposium for Early Career Investigators.

The second Transatlantic Early Career Investigator (ECI) G Protein-Coupled Receptor (GPCR) Symposium was an online scientific meeting geared at young GPCR investigators, with the primary goal of expanding opportunities for sharing research and networking among trainees in North America and Europe. Here, we discuss the format of our meeting, its impact, and the challenges and opportunities facing meetings like it in the future.

Thienopyrimidine Derivatives as GPR55 Receptor Antagonists: Insight into Structure-Activity Relationship.

GPR55 is an orphan G-protein coupled receptor involved in various pathophysiological conditions. However, there are only a few noncannabinoid GPR55 ligands reported so far. The lack of potent and selective GPR55 ligands precludes a deep exploration of this receptor. The studies presented here focused on a thienopyrimidine scaffold based on the GPR55 antagonist ML192, previously discovered by high-throughput screening. The GPR55 activities of the new synthesized compounds were assessed using ß-arrestin recruitment assays in Chinese hamster ovary cells overexpressing human GPR55. Some derivatives were identified as GPR55 antagonists with functional efficacy and selectivity versus CB1 and CB2 cannabinoid receptors.

Use of Telehealth Among Cancer Survivors: A Scoping Review.

Background: Long-term cancer survivors have specific needs that are frequently neglected. Telehealth, as a new form of health care, can benefit this growing population. Objective: To identify, analyze, and synthesize the existing evidence on the use of telehealth in the care of cancer survivors after the end of treatment. Methods: A scoping review was conducted in the databases PubMed, CINAHL, COCHRANE, SCIELO, DIALNET, and LILACS and reference institutions in cancer. Results: The initial search yielded 406 publications with 59 articles meeting the eligibility criteria. There are different types of telehealth (video calls, phone calls, websites, mobile applications, and short message services) used for the care of cancer survivors. Most telehealth interventions focus on improving the physical and mental spheres of quality of life in the extended survival phase (from 1 to 3 years postdiagnosis), with only two articles (3%) on long-term cancer survivors (>5 years postdiagnosis). Survivors are satisfied with telehealth interventions, noting the importance of improving comprehensibility, personalization of the platforms, and the lack of excessive information included. Conclusions: Telehealth is a feasible modality for cancer survival care. The scarcity of interventions aimed at long-term survivors stands out, as does the general neglect of the social and spiritual spheres of quality of life. Implications for Practice: Telehealth platforms must adapt their content, format, and items to the preferences reported by the survivors.

Eficacia y tolerabilidad de Nitazoxanida para parasitismo intestinal en escolares atendidos en el Centro de Salud de la Universidad del Quindío / Efficacy and tolerability of Nitazoxanide for intestinal parasitism in schoolchildren treated at the Health Center of the University of Quindío

Resumen Objetivo: Describir la efectividad del tratamiento antiparasitario intestinal brindado a niños de cuatro a nueve años atendidos en el centro de Salud de la Universidad del Quindío entre Julio de 2017 a marzo de 2018. Materiales y métodos: Estudio observacional prospectivo. Se extrajeron datos de historias clínicas de pacientes con rango de edad de 4 a 9 años, quienes consultaron en el Centro de Salud de la Universidad del Quindío y se diagnosticaron mediante coprológico con blastocistosis o giardiasis. Se seleccionaron las historias cuyo tratamiento fuese Nitazoxanida y tuviesen un coprológico control postratamiento. Se presentan estadísticas descriptivas; porcentaje de eficacia y tolerabilidad. Resultados: De 15 niños tratados con Nitazoxanida, respondieron al tratamiento 10, en quienes no se hallaron parásitos en el coprológico control. Con una eficacia del 83,3% (IC95% 60 - 100) en blastocistosis, 57,1% (IC95% 32 - 82%) en giardiasis. Conclusión: Se evidenciaron resultados porcentuales similares a los reportados en la literatura, siendo más eficaz en blastocisotisis que en giardiasis.

Abstract Objective: To describe the effectiveness of the intestinal antiparasitic treatment given to children ranging between 4 and 9 years old that were attended in the Health Center of the University of Quindío in the period of July 2017 and March 2018. Materials and methods: Prospective observational study. Data were extracted from medical records of patients with an age range of 4 to 9 years, who consulted at the Health Center of the University of Quindío and were diagnosed through coprological tests with Blastocystis and Giardiasis. The clinical records were selected by whose treatment was done with Nitazoxanide or Albendazole with coprological results of post-treatment check-up. Descriptive statistics are presented along with percentage of efficacy and tolerability. Results: From 15 children treated with Nitazoxanide, 10 responded to the treatment, who presented no parasites in the coprological check-up. The remaining population presented some type of parasitic infection (n = 5). With an efficiency of 83,3% (IC95% 32 - 82%) in blastocystis, and 57,1% (IC95% 32 - 82%) in giardiasis. Conclusion: Percentage results similar to those reported in the literature were evidenced, being more effective in blastocystis than in giardiasis.

The oncogenic lysophosphatidylinositol (LPI)/GPR55 signaling.

GPR55 is a class A orphan G protein-coupled receptor that has drawn important therapeutic attention in the last decade because of its role in pathophysiological processes including vascular functions, metabolic dysfunction, neurodegenerative disorders, or bone turnover among others. Several cannabinoids of phytogenic, endogenous, and synthetic nature have shown to modulate this receptor leading to propose it as a member of the endocannabinoid system. The putative endogenous GPR55 ligand is L-α-lysophosphatidylinositol (LPI) and it has been associated with several processes that control cell survival and tumor progression. The relevance of GPR55 in cancer is currently being extensively studied in vitro and in vivo using diverse cancer models. The LPI/GPR55 axis has been reported to participate in pro-oncogenic processes including cellular proliferation, differentiation, migration, invasion, and metastasis being altered in several cancer cells via G12/13 and Gq signaling. Moreover, GRP55 and its bioactive lipid have been proposed as potential biomarkers for cancer diagnosis. Indeed, GPR55 overexpression or high expression has been shown to correlate with cancer aggressiveness in specific tumors including acute myeloid leukemia, uveal melanoma, low grade glioma and renal cancer. This review aims to analyze and summarize current evidence on the cancerogenic role of the LPI/GPR55 axis providing a critical view of the therapeutic prospects of this promising target.

Targeting CB2 and TRPV1: Computational Approaches for the Identification of Dual Modulators.

Both metabotropic (CBRs) and ionotropic cannabinoid receptors (ICRs) have implications in a range of neurological disorders. The metabotropic canonical CBRs CB1 and CB2 are highly implicated in these pathological events. However, selective targeting at CB2 versus CB1 offers optimized pharmacology due to the absence of psychoactive outcomes. The ICR transient receptor potential vanilloid type 1 (TRPV1) has also been reported to play a role in CNS disorders. Thus, activation of both targets, CB2 and TRPV1, offers a promising polypharmacological strategy for the treatment of neurological events including analgesia and neuroprotection. This brief research report aims to identify chemotypes with a potential dual CB2/TRPV1 profile. For this purpose, we have rationalized key structural features for activation and performed virtual screening at both targets using curated chemical libraries.

The Binding Mode to Orthosteric Sites and/or Exosites Underlies the Therapeutic Potential of Drugs Targeting Cannabinoid CB2 Receptors.

The classical terms agonists and antagonists for G protein coupled receptors (GPCRs) have often become misleading. Even the biased agonism concept does not describe all the possibilities already demonstrated for GPCRs. The cannabinoid CB2 receptor (CB2R) emerged as a promising target for a variety of diseases. Reasons for such huge potential are centered around the way drugs sit in the orthosteric and/or exosites of the receptor. On the one hand, a given drug in a specific CB2R conformation leads to a signaling cascade that differs qualitatively and/or quantitatively from that triggered by another drug. On the other hand, a given drug may lead to different signaling outputs in two different tissues (or cell contexts) in which the conformation of the receptor is affected by allosteric effects derived from interactions with other proteins or with membrane lipids. This highlights the pharmacological complexity of this receptor and the need to further unravel the binding mode of CB2R ligands in order to fine-tune signaling effects and therapeutic propositions.

Preclinical Investigation in Neuroprotective Effects of the GPR55 Ligand VCE-006.1 in Experimental Models of Parkinson's Disease and Amyotrophic Lateral Sclerosis.

Cannabinoids act as pleiotropic compounds exerting, among others, a broad-spectrum of neuroprotective effects. These effects have been investigated in the last years in different preclinical models of neurodegeneration, with the cannabinoid type-1 (CB1) and type-2 (CB2) receptors concentrating an important part of this research. However, the issue has also been extended to additional targets that are also active for cannabinoids, such as the orphan G-protein receptor 55 (GPR55). In the present study, we investigated the neuroprotective potential of VCE-006.1, a chromenopyrazole derivative with biased orthosteric and positive allosteric modulator activity at GPR55, in murine models of two neurodegenerative diseases. First, we proved that VCE-006.1 alone could induce ERK1/2 activation and calcium mobilization, as well as increase cAMP response but only in the presence of lysophosphatidyl inositol. Next, we investigated this compound administered chronically in two neurotoxin-based models of Parkinson's disease (PD), as well as in some cell-based models. VCE-006.1 was active in reversing the motor defects caused by 6-hydroxydopamine (6-OHDA) in the pole and the cylinder rearing tests, as well as the losses in tyrosine hydroxylase-containing neurons and the elevated glial reactivity detected in the substantia nigra. Similar cytoprotective effects were found in vitro in SH-SY5Y cells exposed to 6-OHDA. We also investigated VCE-006.1 in LPS-lesioned mice with similar beneficial effects, except against glial reactivity and associated inflammatory events, which remained unaltered, a fact confirmed in BV2 cells treated with LPS and VCE-006.1. We also analyzed GPR55 in these in vivo models with no changes in its gene expression, although GPR55 was down-regulated in BV2 cells treated with LPS, which may explain the lack of efficacy of VCE-006.1 in such an assay. Furthermore, we investigated VCE-006.1 in two genetic models of amyotrophic lateral sclerosis (ALS), mutant SOD1, or TDP-43 transgenic mice. Neither the neurological decline nor the deteriorated rotarod performance were prevented with this compound, and the same happened with the elevated microglial and astroglial reactivities, albeit modest spinal motor neuron preservation was achieved in both models. We also analyzed GPR55 in these in vivo models and found no changes in both TDP-43 transgenic and mSOD1 mice. Therefore, our findings support the view that targeting the GPR55 may afford neuroprotection in experimental PD, but not in ALS, thus stressing the specificities for the development of cannabinoid-based therapies in the different neurodegenerative disorders.