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1.
J Phys Chem B ; 128(37): 8927-8932, 2024 Sep 19.
Artículo en Inglés | MEDLINE | ID: mdl-39231438

RESUMEN

The heterodimeric sweet taste receptor, TAS1R2/1R3, is a class C G protein-coupled receptor (GPCR) that couples to gustducin (Gt), a G protein (GP) specifically involved in taste processing. This makes TAS1R2/1R3 a possible target for newly developing low caloric ligands that taste sweet to address obesity and diabetes. The activation of TAS1R2/1R3 involves the insertion of the GαP C-terminus of the GP into the GPCR in response to ligand binding. However, it is not known for sure whether the GP inserts into the TAS1R2 or TAS1R3 intracellular region of this GPCR dimer. Moreover, TAS1R2/1R3 can also connect to other GPs, such as Gs, Gi1, Gt3, Go, Gq, and G12. These GPs have different C-termini that may modify GPCR signaling. To understand the possible GP dependence of sweet perception, we use molecular dynamic (MD) simulations to examine the coupling of various GαP C20 termini to TAS1R2/1R3 for various steviol glycoside ligands and an artificial sweetener. Since the C20 could interact with the transmembrane domain (TMD) of either TAS1R2 (TMD2) or TAS1R3 (TMD3), we consider both cases. Without any sweetener, we find that the apo GPCR shows similar Go and Gt selectivities, while all steviol glycoside ligands increase the selectivity of Gt but decrease Go selectivity at TMD2. Interestingly, we find that high sweet rebaudioside M (RebM) and RebD ligands show better interactions of C20 at TMD3 for the Gt protein, but low sweet RebC and hydRebM ligands show better interaction of C20 at TMD2 for the Gt protein. Thus, our MD simulation suggests that TAS1R2/1R3 may couple the GP to either 1R2 or to 1R3 and that it can couple other GPs compared to Gt. This will likely lead to multimodal functions producing multiple patterns of intracellular signaling for sweet taste receptors, depending on the particular sweetener. Directing the GP to one of the other may have beneficial therapeutic outcomes.


Asunto(s)
Simulación de Dinámica Molecular , Receptores Acoplados a Proteínas G , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/química , Ligandos , Humanos , Gusto , Transducina/metabolismo , Transducina/química , Multimerización de Proteína , Edulcorantes/química , Edulcorantes/metabolismo
2.
J Am Chem Soc ; 146(38): 26251-26260, 2024 Sep 25.
Artículo en Inglés | MEDLINE | ID: mdl-39266057

RESUMEN

Recently, there has been a great deal of excitement about new glucagon-like peptide 1 receptor (GLP-1R) agonists (e.g., semaglutide and tirzepatide) that have received FDA approval for type 2 diabetes and obesity. Although effective, these drugs come with side effects that limit their use. While research efforts continue to focus intensively on long-lasting, orally administered GLP-1R medications with fewer side effects, a major impediment to developing improved GLP-1R medications is that the mechanism by which an agonist activates GLP-1R to imitate signaling is not known. Here we present and validate the G protein (GP)-first mechanism for the GLP-1R supported by extensive atomistic simulations. We propose that GLP-1R is preactivated through the formation of a GLP-1R-GP precoupled complex at the cell membrane prior to ligand binding. Despite a transmembrane helix 6 (TM6)-bentout conformation characteristic of activated GLP-1R, this precoupled complex remains unactivated until an agonist binds to elicit signaling. Notably, this new hypothesis offers a unified and predictive model for the activities of a series of full and partial agonists, including the peptides ExP5, GLP-1(7-36), and GLP-1(9-36). Most surprisingly, our simulations reveal an N-terminus domain (NTD)-swing/agonist-insertion mechanism wherein the long extracellular NTD of GLP-1R tightly holds the C-terminal half of the peptide agonist and progressively shifts the N-terminal head of the peptide to facilitate insertion into the orthosteric pocket. Our findings provide novel mechanistic insights into the activation and function of class B GPCRs and should provide a realistic basis for structure-based ligand design.


Asunto(s)
Receptor del Péptido 1 Similar al Glucagón , Receptor del Péptido 1 Similar al Glucagón/agonistas , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Receptor del Péptido 1 Similar al Glucagón/química , Humanos , Simulación de Dinámica Molecular , Conformación Proteica , Proteínas de Unión al GTP/metabolismo , Proteínas de Unión al GTP/química , Dominios Proteicos , Modelos Moleculares
4.
BMC Med ; 22(1): 251, 2024 Jun 18.
Artículo en Inglés | MEDLINE | ID: mdl-38886720

RESUMEN

BACKGROUND: We investigated the association between exercise habits before or after thyroidectomy and incident type 2 diabetes mellitus (T2DM) in patients with thyroid cancer. METHODS: An observational cohort study of 69,526 thyroid cancer patients who underwent thyroidectomy for the treatment of thyroid cancer between 2010 and 2016 was performed using the Korean National Health Information Database. Regular exercise was defined as mid-term or vigorous exercise at least 1 day in a week based on a self-reported questionnaire. Patients were divided into four groups according to exercise habits before and after thyroidectomy: persistent non-exercisers, new exercisers, exercise dropouts, and exercise maintainers. RESULTS: During a median follow-up of 4.5 years, 2,720 (3.91%) patients developed T2DM. The incidence of T2DM per 1,000 person years was lower in patients who performed regular exercise before or after thyroidectomy than in persistent non-exercisers (10.77 in persistent non-exerciser group, 8.28 in new exerciser group, 8.59 in exercise dropout group, and 7.61 in exercise maintainer group). Compared with the persistent non-exerciser group, the new exerciser group (hazard ratio [HR] 0.87, 95% confidence interval [CI] 0.78-0.97), the exercise dropout group (HR 0.81, 95% CI 0.72-0.91), and the exercise maintainer group (HR 0.84, 95% CI 0.76-0.93) had lower risks of incident T2DM. Exercising < 1,500 MET-minutes/week in the exercise maintainer group was associated with a lower risk of incident T2DM compared with persistent non-exercisers (< 500: HR 0.80, 95% CI 0.67-0.96, P = 0.002; 500 to < 1,000: HR 0.81, 95% CI 0.71-0.93, P < 0.001; 1,000 to < 1,500: HR 0.81, 95% CI 0.69-0.94, P < 0.001). CONCLUSIONS: Regular exercise before or after thyroidectomy was associated with a lower risk of incident T2DM in patients with thyroid cancer.


Asunto(s)
Diabetes Mellitus Tipo 2 , Ejercicio Físico , Neoplasias de la Tiroides , Tiroidectomía , Humanos , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/complicaciones , Masculino , Femenino , Persona de Mediana Edad , Ejercicio Físico/fisiología , Neoplasias de la Tiroides/epidemiología , Neoplasias de la Tiroides/cirugía , Incidencia , Adulto , República de Corea/epidemiología , Tiroidectomía/efectos adversos , Anciano , Estudios de Cohortes
5.
ACS Pharmacol Transl Sci ; 7(2): 348-362, 2024 Feb 09.
Artículo en Inglés | MEDLINE | ID: mdl-38357278

RESUMEN

As the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus mutates, finding effective drugs becomes more challenging. In this study, we use ultrasensitive frequency locked microtoroid optical resonators in combination with in silico screening to search for COVID-19 drugs that can stop the virus from attaching to the human angiotensin-converting enzyme 2 (hACE2) receptor in the lungs. We found 29 promising candidates that could block the binding site and selected four of them that were likely to bind very strongly. We tested three of these candidates using frequency locked optical whispering evanescent resonator (FLOWER), a label-free sensing method based on microtoroid resonators. FLOWER has previously been used for sensing single macromolecules. Here we show, for the first time, that FLOWER can provide accurate binding affinities and sense the inhibition effect of small molecule drug candidates without labels, which can be prohibitive in drug discovery. One of the candidates, methotrexate, showed binding to the spike protein 1.8 million times greater than that to the receptor binding domain (RBD) binding to hACE2, making it difficult for the virus to enter cells. We tested methotrexate against different variants of the SARS-CoV-2 virus and found that it is effective against all four of the tested variants. People taking methotrexate for other conditions have also shown protection against the original SARS-CoV-2 virus. Normally, it is assumed that methotrexate inhibits the replication and release of the virus. However, our findings suggest that it may also block the virus from entering cells. These studies additionally demonstrate the possibility of extracting candidate ligands from large databases, followed by direct receptor-ligand binding experiments on the best candidates using microtoroid resonators, thus creating a workflow that enables the rapid discovery of new drug candidates for a variety of applications.

7.
Biosens Bioelectron ; 250: 116061, 2024 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-38278123

RESUMEN

The outbreak of emerging infectious diseases gave rise to the demand for reliable point-of-care testing methods to diagnose and manage those diseases in early onset. However, the current on-site testing methods including lateral flow immunoassay (LFIA) suffer from the inaccurate diagnostic result due to the low sensitivity. Herein, we present the surface-enhanced Raman scattering-based lateral flow immunoassay (SERS-LFIA) by introducing phage-templated hierarchical plasmonic assembly (PHPA) nanoprobes to diagnose a contagious disease. The PHPA was fabricated using gold nanoparticles (AuNPs) assembled on bacteriophage MS2, where inter-particle gap sizes can be adjusted by pH-induced morphological alteration of MS2 coat proteins to provide the maximum SERS amplification efficiency via plasmon coupling. The plasmonic probes based on the PHPA produce strong and reproducible SERS signal that leads to sensitive and reliable diagnostic results in SERS-LFIA. The developed SERS-LFIA targeting severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) antibodies for a proof of concept had <100 pg/mL detection limits with high specificity in serum, proving it as an effective diagnostic device for the infectious diseases. Clinical validation using human serum samples further confirmed that the PHPA-based SERS-LFIA can distinguish the patients with COVID-19 from healthy controls with significant accuracy. These outcomes prove that the developed SERS-LFIA biosensor can be an alternative point-of-care testing (POCT) method against the emerging infectious diseases, in combination with the commercially available portable Raman devices.


Asunto(s)
Bacteriófagos , Técnicas Biosensibles , Enfermedades Transmisibles Emergentes , Enfermedades Transmisibles , Nanopartículas del Metal , Humanos , Oro , Sistemas de Atención de Punto , Espectrometría Raman/métodos , Límite de Detección , Técnicas Biosensibles/métodos , Inmunoensayo/métodos , SARS-CoV-2 , Concentración de Iones de Hidrógeno
8.
Skin Res Technol ; 30(1): e13545, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38174806

RESUMEN

BACKGROUND: Acne scars present a complex challenge in dermatology and cosmetics, despite advancements in technological interventions such as fractional lasers, microneedling, and surgical procedures. Effective treatment remains elusive for many individuals. OBJECTIVE: This study aims to evaluate the efficacy of rotational fractional resection using 1 mm diameter rotating scalpels as a primary treatment for icepick and boxcar scars on the cheeks and glabella region. METHODS: Three patients with acne scars underwent a single treatment session of rotational fractional resection. Evaluation occurred at the 2-month post-treatment mark to assess improvements in scar appearance and potential skin-related side effects. RESULTS: Following the treatment, significant improvements were observed in the targeted acne scars. Notable enhancements were noted without major skin-related adverse effects, except for minor suture marks. CONCLUSION: The outcomes of this study underscore the potential of rotational fractional resection as an innovative and effective approach in treating acne scars. This single-session cosmetic procedure shows promise in yielding lasting and quantifiable results, offering a hopeful solution for individuals seeking comprehensive acne scar treatment.


Asunto(s)
Acné Vulgar , Cicatriz , Humanos , Cicatriz/etiología , Cicatriz/cirugía , Acné Vulgar/complicaciones , Acné Vulgar/terapia , Piel/patología , Resultado del Tratamiento
9.
Diabetes Metab J ; 48(2): 279-289, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38273793

RESUMEN

BACKGRUOUND: Recent diabetes management guidelines recommend that sodium-glucose cotransporter 2 inhibitors (SGLT2is) or glucagon-like peptide 1 receptor agonists (GLP-1RAs) with proven cardiovascular benefits should be prioritized for combination therapy in patients with type 2 diabetes mellitus (T2DM) and established cardiovascular disease (CVD). This study was aimed at evaluating SGLT2i or GLP-1RA usage rates and various related factors in patients with T2DM and established CVD. METHODS: We enrolled adults with T2DM aged ≥30 years who were hospitalized due to established CVD from January 2019 to May 2020 at 13 secondary and tertiary hospitals in Korea in this retrospective observational study. RESULTS: Overall, 2,050 patients were eligible for analysis among 2,107 enrolled patients. The mean patient age, diabetes duration, and glycosylated hemoglobin level were 70.0 years, 12.0 years, and 7.5%, respectively. During the mean follow-up duration of 9.7 months, 25.7% of the patients were prescribed SGLT2is after CVD events. However, only 1.8% were prescribed GLP-1RAs. Compared with SGLT2i non-users, SGLT2i users were more frequently male and obese. Furthermore, they had a shorter diabetes duration but showed worse glycemic control and better renal function at the time of the event. GLP-1RA users had a longer duration of diabetes and worse glycemic control at the time of the event than GLP-1RA non-users. CONCLUSION: The SGLT2i or GLP-1RA prescription rates were suboptimal in patients with T2DM and established CVD. Sex, body mass index, diabetes duration, glycemic control, and renal function were associated with the use of these agents.


Asunto(s)
Enfermedades Cardiovasculares , Diabetes Mellitus Tipo 2 , Adulto , Humanos , Masculino , Anciano , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/epidemiología , Hipoglucemiantes/farmacología , Estudios Retrospectivos , Enfermedades Cardiovasculares/complicaciones , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/inducido químicamente , República de Corea/epidemiología
10.
Proc Natl Acad Sci U S A ; 120(49): e2300919120, 2023 Dec 05.
Artículo en Inglés | MEDLINE | ID: mdl-38015850

RESUMEN

Smoothened (SMO) is an oncoprotein and signal transducer in the Hedgehog signaling pathway that regulates cellular differentiation and embryogenesis. As a member of the Frizzled (Class F) family of G protein-coupled receptors (GPCRs), SMO biochemically and functionally interacts with Gi family proteins. However, key molecular features of fully activated, G protein-coupled SMO remain elusive. We present the atomistic structure of activated human SMO complexed with the heterotrimeric Gi protein and two sterol ligands, equilibrated at 310 K in a full lipid bilayer at physiological salt concentration and pH. In contrast to previous experimental structures, our equilibrated SMO complex exhibits complete breaking of the pi-cation interaction between R4516.32 and W5357.55, a hallmark of Class F receptor activation. The Gi protein couples to SMO at seven strong anchor points similar to those in Class A GPCRs: intracellular loop 1, intracellular loop 2, transmembrane helix 6, and helix 8. On the path to full activation, we find that the extracellular cysteine-rich domain (CRD) undergoes a dramatic tilt, following a trajectory suggested by positions of the CRD in active and inactive experimental SMO structures. Strikingly, a sterol ligand bound to a shallow transmembrane domain (TMD) site in the initial structure migrates to a deep TMD pocket found exclusively in activator-bound SMO complexes. Thus, our results indicate that SMO interacts with Gi prior to full activation to break the molecular lock, form anchors with Gi subunits, tilt the CRD, and facilitate migration of a sterol ligand in the TMD to an activated position.


Asunto(s)
Proteínas Hedgehog , Esteroles , Humanos , Esteroles/metabolismo , Ligandos , Modelos Moleculares , Proteínas Hedgehog/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptor Smoothened/metabolismo
11.
Diabetes Metab J ; 47(5): 575-594, 2023 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-37793979

RESUMEN

In May 2023, the Committee of Clinical Practice Guidelines of the Korean Diabetes Association published the revised clinical practice guidelines for Korean adults with diabetes and prediabetes. We incorporated the latest clinical research findings through a comprehensive systematic literature review and applied them in a manner suitable for the Korean population. These guidelines are designed for all healthcare providers nationwide, including physicians, diabetes experts, and certified diabetes educators who manage patients with diabetes or individuals at risk of developing diabetes. Based on recent changes in international guidelines and the results of a Korean epidemiological study, the recommended age for diabetes screening has been lowered. In collaboration with the relevant Korean medical societies, recently revised guidelines for managing hypertension and dyslipidemia in patients with diabetes have been incorporated into this guideline. An abridgment containing practical information on patient education and systematic management in the clinic was published separately.


Asunto(s)
Dislipidemias , Estado Prediabético , Adulto , Humanos , Pueblo Asiatico , República de Corea/epidemiología , Sociedades Médicas , Diabetes Mellitus
12.
J Med Chem ; 66(21): 14564-14582, 2023 11 09.
Artículo en Inglés | MEDLINE | ID: mdl-37883692

RESUMEN

Chemokine-like receptor 1 (CMKLR1)─a G protein-coupled receptor─has functional roles in the immune system and related diseases, including psoriasis and metabolic diseases. Psoriasis is a chronic inflammatory disease characterized by skin redness, scaliness, and itching. In this study, we sought to develop novel CMKLR1 antagonists by screening our in-house GPCR-targeting compound library. Moreover, we optimized a phenylindazole-based hit compound with antagonistic activities and evaluated its oral pharmacokinetic properties in a murine model. A structure-based design on the human CMKLR1 homology model identified S-26d as an optimized compound that serves as a potent and orally available antagonist with a pIC50 value of 7.44 in hCMKLR1-transfected CHO cells. Furthermore, in the imiquimod-induced psoriasis-like mouse model, oral administration of S-26d for 1 week significantly alleviated modified psoriasis area and severity index scores (severity of erythema, scaliness, skin thickness) compared with the control group.


Asunto(s)
Psoriasis , Humanos , Animales , Ratones , Cricetinae , Cricetulus , Psoriasis/inducido químicamente , Psoriasis/tratamiento farmacológico , Piel/metabolismo , Imiquimod/efectos adversos , Imiquimod/metabolismo , Quimiocinas/metabolismo , Modelos Animales de Enfermedad , Ratones Endogámicos BALB C
13.
J Am Chem Soc ; 145(37): 20422-20431, 2023 09 20.
Artículo en Inglés | MEDLINE | ID: mdl-37672637

RESUMEN

The glucagon-like peptide-1 receptor (GLP-1R) is a key regulator of blood glucose and a prime target for the treatment of type II diabetes and obesity with multiple public drugs. Here we present a comprehensive computational analysis of the interactions of the activated GLP-1R-Gs signaling complex with a G protein biased agonist, Exendin P5 (ExP5), which possesses a unique N-terminal sequence responsible for the signal bias. Using a refined all-atom model of the ExP5-GLP-1R-Gs complex in molecular dynamics (MD) simulations, we propose a novel mechanism of conformation transduction in which the unique interaction network of ExP5 N-terminus propagates the binding signal across an array of conserved residues at the transmembrane domain to enhance Gs protein coupling at the cytoplasmic end of the receptor. Our simulations reveal previously unobserved interactions important for activation by ExP5 toward GDP-GTP signaling, providing new insights into the mechanism of class B G protein-coupled receptor (GPCR) signaling. These findings offer a framework for the structure-based design of more effective therapeutics.


Asunto(s)
Diabetes Mellitus Tipo 2 , Receptor del Péptido 1 Similar al Glucagón , Humanos , Transducción de Señal , Glucemia , Citoplasma
14.
J Clin Microbiol ; 61(10): e0041523, 2023 10 24.
Artículo en Inglés | MEDLINE | ID: mdl-37728341

RESUMEN

Monitoring of cytomegalovirus (CMV) viral load is critical for informing treatment decisions in order to prevent the severe health consequences of CMV infection or reactivation of latent CMV in immunocompromised individuals. This first field evaluation examined the analytical and clinical performance of the Alinity m CMV assay. Analytical performance was assessed with a commercially available six-member panel, while the clinical performance evaluation compared the Alinity m CMV assay to the RealTime CMV assay and a laboratory-developed test (LDT) as the test of record at three large hospital-based clinical laboratories. Precision of the Alinity m CMV assay was demonstrated with total standard deviation (SD) between 0.08 and 0.28 Log IU/mL. A total of 457 plasma specimens were tested on the Alinity m CMV assay and compared to the test of record at each site (n = 304 with RealTime CMV and n = 153 with LDT CMV). The Alinity m CMV assay had excellent correlation (correlation coefficient r ≥0.942) in comparison to the RealTime CMV or LDT CMV assays. The mean observed bias ranged from -0.03 to 0.34 Log IU/mL. Median onboard turnaround time of Alinity m CMV was less than 3 h. When the CMV assay is run on the Alinity m system, it has the capacity to shorten time to result and, therefore, to therapy.


Asunto(s)
Infecciones por Citomegalovirus , Citomegalovirus , Humanos , Citomegalovirus/genética , Carga Viral , Infecciones por Citomegalovirus/diagnóstico , ADN , Huésped Inmunocomprometido , ADN Viral/genética , Sensibilidad y Especificidad
15.
RSC Adv ; 13(39): 27225-27232, 2023 Sep 08.
Artículo en Inglés | MEDLINE | ID: mdl-37701275

RESUMEN

Serological detection of antibodies for diagnosing infectious diseases has advantages in facile diagnostic procedures, thereby contributing to controlling the spread of the pathogen, such as in the recent SARS-CoV-2 pandemic. Lateral flow immunoassay (LFIA) is a representative serological antibody detection method suitable for on-site applications but suffers from low clinical accuracy. To achieve a simple and rapid serological screening as well as the sensitive quantification of antibodies against SARS-CoV-2, a colorimetric and fluorescent dual-mode serological LFIA sensor incorporating metal-enhanced fluorescence (MEF) was developed. For the strong fluorescence signal amplification, fluorophore Cy3 was immobilized onto gold nanoparticles (AuNPs) with size-controllable spacer polyethyleneglycol (PEG) to maintain an optimal distance to induce MEF. The sensor detects the target IgG with a concentration as low as 1 ng mL-1 within 8 minutes. The employment of the MEF into the dual-mode serological LFIA sensor shows a 1000-fold sensitivity improvement compared with that of colorimetric LFIAs. The proposed serological LFIA sensor was tested with 73 clinical samples, showing sensitivity, specificity, and accuracy of 95%, 100%, and 97%, respectively. In conclusion, the dual-mode serological LFIA has great potential for application in diagnosis and an epidemiological survey of vaccine efficacy and immunity status of individuals.

16.
Endocrinol Metab (Seoul) ; 38(4): 445-454, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37461149

RESUMEN

BACKGRUOUND: Papillary thyroid carcinoma (PTC) can be classified into two distinct molecular subtypes, BRAF-like (BL) and RASlike (RL). However, the molecular characteristics of each subtype according to clinicopathological factors have not yet been determined. We aimed to investigate the gene signatures and tumor microenvironment according to clinicopathological factors, and to identify the mechanism of progression in BL-PTCs and RL-PTCs. METHODS: We analyzed RNA sequencing data and corresponding clinicopathological information of 503 patients with PTC from The Cancer Genome Atlas database. We performed differentially expressed gene (DEG), Gene Ontology, and molecular pathway enrichment analyses according to clinicopathological factors in each molecular subtype. EcoTyper and CIBERSORTx were used to deconvolve the tumor cell types and their surrounding microenvironment. RESULTS: Even for the same clinicopathological factors, overlapping DEGs between the two molecular subtypes were uncommon, indicating that BL-PTCs and RL-PTCs have different progression mechanisms. Genes related to the extracellular matrix were commonly upregulated in BL-PTCs with aggressive clinicopathological factors, such as old age (≥55 years), presence of extrathyroidal extension, lymph node metastasis, advanced tumor-node-metastasis (TNM) stage, and high metastasis-age-completeness of resection- invasion-size (MACIS) scores (≥6). Furthermore, in the deconvolution analysis of tumor microenvironment, cancer-associated fibroblasts were significantly enriched. In contrast, in RL-PTCs, downregulation of immune response and immunoglobulin-related genes was significantly associated with aggressive characteristics, even after adjusting for thyroiditis status. CONCLUSION: The molecular phenotypes of cancer progression differed between BL-PTC and RL-PTC. In particular, extracellular matrix and cancer-associated fibroblasts, which constitute the tumor microenvironment, would play an important role in the progression of BL-PTC that accounts for the majority of advanced PTCs.


Asunto(s)
Carcinoma Papilar , Neoplasias de la Tiroides , Humanos , Cáncer Papilar Tiroideo/genética , Cáncer Papilar Tiroideo/patología , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/patología , Proteínas Proto-Oncogénicas B-raf/genética , Carcinoma Papilar/genética , Carcinoma Papilar/patología , Mutación , Fenotipo , Microambiente Tumoral/genética
17.
Nat Chem ; 15(8): 1127-1137, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37349378

RESUMEN

There is considerable uncertainty about the mechanism by which the ß2-adrenergic receptor (ß2AR) is activated. Here we use molecular metadynamics computations to predict the mechanism by which an agonist induces the activation of the ß2AR and its cognate Gs protein. We found that binding agonist alone to the inactive ß2AR does not break the ionic lock and hence does not drive the ß2AR towards the activated conformation. However, we found that attaching the inactive Gs protein to the agonist-bound inactive ß2AR (containing the ionic lock) leads to partial insertion of Gαs-α5 into the core of ß2AR, which breaks the ionic lock, leading to activation of the Gs protein coupled to ß2AR. Upon activation, the Gαs protein undergoes a remarkable opening of the GDP binding pocket, making the GDP available for exchange or release. Concomitantly, Gαs-α5 undergoes a remarkable expansion in the ß2AR cytoplasmic region after the ionic lock is broken, inducing TM6 to displace outward by ~5 Å from TM3.


Asunto(s)
Subunidades alfa de la Proteína de Unión al GTP Gs , Transducción de Señal , Subunidades alfa de la Proteína de Unión al GTP Gs/química , Subunidades alfa de la Proteína de Unión al GTP Gs/metabolismo , Unión Proteica
18.
Clin Chim Acta ; 548: 117462, 2023 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-37390943

RESUMEN

BACKGROUND: Clinical laboratory tests are inevitably affected by various factors. Therefore, when comparing consecutive test results, it is crucial to consider the inherent uncertainty of the test. Clinical laboratories use reference change value (RCV) to determine a significant change between 2 results. Whereas the criteria for the interpretation of consecutive results by clinicians are not well known. We investigated the clinician's interpretation of a clinically significant change in consecutive laboratory test results and compared them to RCV. METHODS: We performed a questionnaire survey on clinicians, which comprised 2 scenarios with 22 laboratory test items suggesting initial test results. Clinicians were asked to choose a result showing clinically significant change. RCV of the analytes from EFLM database were collected. RESULTS: We received 290 valid questionnaire responses. Clinicians' opinions on clinically significant change was inconsistent between clinicians and scenarios, and was generally larger than RCV. Clinicians commented that they were not familiar with the variability of the laboratory tests. CONCLUSIONS: Clinicians' opinions on clinically significant changes were more prominent than RCV. Meanwhile, they tended to neglect the analytical and biological variation. Laboratories should properly guide clinicians on the RCV of tests for better decision-making on patients' clinical states.


Asunto(s)
Servicios de Laboratorio Clínico , Laboratorios , Humanos , Técnicas de Laboratorio Clínico , Incertidumbre , Valores de Referencia
19.
Commun Chem ; 6(1): 95, 2023 May 18.
Artículo en Inglés | MEDLINE | ID: mdl-37202473

RESUMEN

Macrocycle peptides are promising constructs for imaging and inhibiting extracellular, and cell membrane proteins, but their use for targeting intracellular proteins is typically limited by poor cell penetration. We report the development of a cell-penetrant high-affinity peptide ligand targeted to the phosphorylated Ser474 epitope of the (active) Akt2 kinase. This peptide can function as an allosteric inhibitor, an immunoprecipitation reagent, and a live cell immunohistochemical staining reagent. Two cell penetrant stereoisomers were prepared and shown to exhibit similar target binding affinities and hydrophobic character but 2-3-fold different rates of cell penetration. Experimental and computational studies resolved that the ligands' difference in cell penetration could be assigned to their differential interactions with cholesterol in the membrane. These results expand the tool kit for designing new chiral-based cell-penetrant ligands.

20.
iScience ; 26(4): 106422, 2023 Apr 21.
Artículo en Inglés | MEDLINE | ID: mdl-37096045

RESUMEN

The 25 human bitter taste receptors (TAS2Rs) are expressed on taste and extra-oral cells representing an integrated chemosensory system. The archetypal TAS2R14 is activated by > 150 topographically diverse agonists, raising the question of how this uncharacteristic accommodation is achieved for these GPCRs. We report the computationally derived structure of TAS2R14 with binding sites and energies for five highly diverse agonists. Remarkably, the binding pocket is the same for all five agonists. The energies derived from molecular dynamics are consistent with experiments determining signal transduction coefficients in live cells. TAS2R14 accommodates agonists through the breaking of a TMD3 H-bond instead of the prototypic strong salt bridge, a TMD1,2,7 interaction different from Class A GPCRs, and agonist-promoted TMD3 salt bridges for high affinity (which we confirmed by receptor mutagenesis). Thus, the broadly tuned TAS2Rs accommodate diverse agonists via a single (vs multiple) binding pocket through unique TM interactions for sensing disparate micro-environments.

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