The role of the primary cilium in thyroid function and dysfunction with implications for thyroid disease Inés Martín-Lacave, Victoria Vázquez-Román, Beatriz Pérez-Fernández, José María Fernández-Santos Histochemistry and Cell Biology, 2025 The thyroid gland is a unique endocrine organ, composed of morpho-functional units called thyroid follicles, which are responsible for thyroid hormone (TH) biosynthesis, an iodination process demanding a highly oxidative yet protected environment. Despite primary cilium (PC) being observed in the thyroid gland more than a century ago, its precise role in thyroid activity remains rather unexplored. Given its strategic position at the apical surface of follicular epithelium, projecting into the lumen, PCs are crucial for the regulation of TH biosynthetic processes. Consequently, changes in thyroid function, either physiological or pathological, are reflected in PC characteristics. Similarly, defects in ciliogenesis are expected to lead to different pathological thyroid alterations. This review summarizes the current understanding of PC’s involvement in regulating normal thyroid activity and its modifications in functional and neoplastic thyroid diseases. Particular focus will be given to the notable loss of PCs in certain types of thyroid cancer and the promising potential of their restoration as a tumor suppressor strategy in thyroid tumorigenesis.
Anti-obesogenic effect of lupin-derived protein hydrolysate through modulation of adiposopathy, insulin resistance and gut dysbiosis in a diet-induced obese mouse Eduardo Ponce-España, Ivan Cruz-Chamorro, Guillermo Santos-Sánchez, Ana Isabel Álvarez-López, José María Fernández-Santos, Justo Pedroche, María Carmen Millán-Linares, Ignacio Bejarano, Patricia Judith Lardone, Antonio Carrillo-Vico Biomedicine and Pharmacotherapy, 2024 The prevalence of obesity is increasingly widespread, resembling a global epidemic. Lifestyle changes, such as consumption of high-energy-dense diets and physical inactivity, are major contributors to obesity. Common features of this metabolic pathology involve an imbalance in lipid and glucose homeostasis including dyslipidemia, insulin resistance and adipose tissue dysfunction. Moreover, the importance of the gut microbiota in the development and susceptibility to obesity has recently been highlighted. In recent years, new strategies based on the use of functional foods, in particular bioactive peptides, have been proposed to counteract obesity outcomes. In this context, the present study examines the effects of a lupin protein hydrolysate (LPH) on obesity, dyslipidemia and gut dysbiosis in mice fed a high-fat diet (HFD). After 12 weeks of LPH treatment, mice gained less weight and showed decreased adipose dysfunction compared to the HFD-fed group. HFD-induced dyslipidemia (increased triglycerides, cholesterol and LDL concentration) and insulin resistance were both counteracted by LPH consumption. Discriminant analysis differentially distributed LPH-treated mice compared to non-treated mice. HFD reduced gut ecological parameters, promoted the blooming of deleterious taxa and reduced the abundance of commensal members. Some of these changes were corrected in the LPH group. Finally, correlation analysis suggested that changes in this microbial population could be responsible for the improvement in obesity outcomes. In conclusion, this is the first study to show the effect of LPH on improving weight gain, adiposopathy and gut dysbiosis in the context of diet-induced obesity, pointing to the therapeutic potential of bioactive peptides in metabolic diseases.
Dietary oleacein, a secoiridoid from extra virgin olive oil, prevents collagen-induced arthritis in mice María Ángeles Rosillo, Isabel Villegas, Victoria Vázquez-Román, José María Fernández-Santos, Juan Ortega-Vidal, Sofía Salido, María Luisa González-Rodríguez, Catalina Alarcón-de-la-Lastra Food and Function, 2024 Nutritional therapy has been considered a promising approach in RA management. OLA might provide a new dietary strategy in immunoinflammatory-mediated diseases.
C-cell differentiation in the wall of an aberrant ultimobranchial sinus in the thyroid gland of an old rat Victoria Vázquez‐Román, José M. Fernández‐Santos, Inés Martín‐Lacave Veterinary Medicine and Science, 2023 Background In mammals, the thyroid gland possesses two types of endocrine cells, follicular cells and C cells, which have different functions but share a similar endodermal origin (although from different regions of the primitive pharynx). Specifically, follicular cells derive from the ventral pharyngeal floor, while C cells derive from the fourth pair of pharyngeal pouches through the ultimobranchial bodies (UBBs). Disruptions to human midline thyroid morphogenesis are relatively frequent and known as thyroid dysgenesis, which is the leading cause of congenital hypothyroidism. In contrast, fourth branchial apparatus anomalies are very rare clinical entities. Objectives The aim of this study was to analyze the morphological features and the immunohistochemical pattern of an aberrant ultimobranchial remnant, align with its persistent contribution to the formation of new C cells. Methods The thyroid gland of an old rat was serially sectioned and immunostained for the following markers: calcitonin, thyroglobulin, cytokeratins, PCNA, P63 , E‐cadherin, beta‐tubulin and CD3. Results We detected a spontaneous congenital defect in the organogenesis of the UBB in an old rat, giving rise to an ‘ultimobranchial sinus’, which was accompanied by thymic tissue and an abscess. The epithelium contained basal/stem cells and contributed to the formation of abundant C cells and scarce follicular cells. Conclusions The ultimobranchial sinus is an exceptional finding for representing the first spontaneous abnormality in the development of UBB reported in rats, and the opportunity to observe sustained C‐cell differentiation from stem cells in an old rat. These findings are consistent with a common origin of both C cells and follicular cells from UBB.
Histopathological Features of Pendred Syndrome Thyroids Align with Differences in the Expression of Thyroid-Specific Markers, Apical Iodide Transporters, and Ciliogenesis Process V. Vázquez-Román, J. M. Cameselle-Teijeiro, J. M. Fernández-Santos, M. J. Ríos-Moreno, L. Loidi, T. Ortiz, I. Martín-Lacave Endocrine Pathology, 2022 Pendred syndrome (PDS) is an autosomal recessive disorder caused by mutations in the gene that encodes pendrin. Pendred thyroid tissue is supposedly altered by the absence of functional pendrin, but it is still unknown whether other iodide exchangers could compensate for the loss of the protein. Moreover, we have recently described that primary cilium, a conserved structure present at the apical surface of normal follicular cells, suffers different alterations in functional thyroid diseases. We aimed (1) to better understand the histopathological changes experienced by PDS thyroids, (2) to analyze the expression of different thyroid-specific genes and alternative iodide transporters and, finally, (3) to determine whether those changes may alter the morphological pattern of primary cilia in follicular cells. Thyroid samples from a series of four PDS patients were analyzed by immunohistochemistry, double immunofluorescence, and morphometry to evaluate changes in primary cilia frequency and length. We found thyroid follicular nodular disease in all PDS thyroids, frequently in association with follicular adenomas. There were only slight changes in the expression of thyroid-specific markers. Although no positivity for pendrin was found, cytoplasmic immunostaining for ANO-1, CLC-5, and CFTR was stronger in diffuse hyperplastic areas when compared to areas with highly cellular follicular nodules (HCFNs). HCFNs and follicular adenomas always showed diminished ciliary frequency and length. Our results suggest a direct relationship between the absence of functional pendrin and the loss of the normal thyroid architecture in PDS patients, which was also accompanied by differences in the expression of specific immunohistochemical markers and altered ciliogenesis. The present data may help the pathologist in screening for PDS.
Lupinus angustifolius protein hydrolysates reduce abdominal adiposity and ameliorate metabolic associated fatty liver disease (Mafld) in western diet fed-apoe−/− mice Guillermo Santos-Sánchez, Ivan Cruz-Chamorro, Ana Isabel Álvarez-Ríos, José María Fernández-Santos, María Victoria Vázquez-Román, Beatriz Rodríguez-Ortiz, Nuria Álvarez-Sánchez, Ana Isabel Álvarez-López, María del Carmen Millán-Linares, Francisco Millán, Justo Pedroche, María Soledad Fernández-Pachón, Patricia Judith Lardone, Juan Miguel Guerrero, Ignacio Bejarano, Antonio Carrillo-Vico Antioxidants, 2021 Metabolic-associated fatty liver disease (MAFLD) is the most important cause of liver disease worldwide. It is characterized by the accumulation of fat in the liver and is closely associated with abdominal obesity. In addition, oxidative stress and inflammation are significant features involved in MAFLD. Recently, our group demonstrated that lupin protein hydrolysates (LPHs) had lipid lowering, antioxidant, and anti-inflammatory effects. Sixty male mice fed with a Western diet were intragastrically treated with LPHs (or vehicle) for 12 weeks. Liver and adipose tissue lipid accumulation and hepatic inflammatory and oxidant status were evaluated. A significant decrease in steatosis was observed in LPHs-treated mice, which presented a decreased gene expression of CD36 and LDL-R, crucial markers in MAFLD. In addition, LPHs increased the hepatic total antioxidant capacity and reduced the hepatic inflammatory status. Moreover, LPHs-treated mice showed a significant reduction in abdominal adiposity. This is the first study to show that the supplementation with LPHs markedly ameliorates the generation of the steatotic liver caused by the intake of a Western diet and reduces abdominal obesity in ApoE−/− mice. Future clinical trials should shed light on the effects of LPHs on MAFLD.
Primary Cilium in the Human Thyrocyte: Changes in Frequency and Length in Relation to the Functional Pathology of the Thyroid Gland José María Fernández-Santos, José Carmelo Utrilla, Victoria Vázquez-Román, José Luis Villar-Rodríguez, Lorenzo Gutiérrez-Avilés, Inés Martín-Lacave Thyroid, 2019 BACKGROUND: Primary cilia (PC) are conserved structures in the adult thyroid gland of different mammals. It was recently described that in humans, PC are usually present as a single copy per follicular cell emerging from the follicular cell apex into the follicular lumen. METHODS: To understand the role developed by PC in thyroid hormonogenesis better, their changes in different human functional thyroid diseases (diffuse toxic hyperplasia/Graves' disease [GD] and nodular hyperplasia [NH]/nodular goiter), in comparison to normal thyroid tissue, were investigated using immunofluorescence, morphometry, and electron microscopy analyses. RESULTS: Significantly decreased ciliary frequencies were found in both NH (51.16 ± 11.69%) and GD (44.43 ± 23.70%) compared to normal thyroid tissue (76.09 ± 7.31%). Similarly, PC lengths were also significantly decreased in both NH (2.02 ± 0.35 μm) and GD (2.4 ± 0.48 μm) compared to normal glands (3.93 ± 0.90 μm). Moreover, in GD patients, hyperactive-follicle foci always showed diminished ciliary frequency and length compared to any other thyroid follicle pattern, independent of their thyroid status. Finally, in GD, the percentage of thyrocytes exhibiting PC in the "normal-appearance areas" was significantly lower in correspondence with the subsistence of signs of thyroid biosynthetic hyperactivity after long-term antithyroid drug treatment. CONCLUSIONS: The results suggest a direct relationship between ciliogenesis and both follicle activity and tissue heterogeneity in the functional pathology of the thyroid gland.
Immunohistochemical profiling of the ultimobranchial remnants in the rat postnatal thyroid gland Victoria Vázquez‐Román, José C. Utrilla, José M. Fernández‐Santos, Inés Martín‐Lacave Journal of Morphology, 2017 Ultimobranchial (UB) remnants are a constant presence in the thyroid throughout rat postnatal life; however, the difficulty in identifying the most immature forms from the surrounding thyroid tissue prompted us to search for a specific marker. With that objective, we applied a panel of antibodies reported to be specific for their human counterpart, solid cell nests (SCNs), using double immunohistochemistry and immunofluorescence. Our results demonstrated that cytokeratin 34βE12 and p63 are highly sensitive markers for the immunohistologic screening of UB‐remnants, independently of their maturity or size. Furthermore, rat UB‐follicles (UBFs) coincided with human SCNs in the immunohistochemical pattern exhibited by both antigens. In contrast, the pattern displayed for calcitonin and thyroglobulin differs considerably but confirm the hypothesis that rat UB‐cells can differentiate into both types of thyroid endocrine cells. This hypothesis agrees with recent findings that thyroid C‐cells share an endodermic origin with follicular cells in rodents. We suggest that the persistence of p63‐positive undifferentiated cells in UB‐remnants may constitute a reservoir of basal/stem cells that persist beyond embryogenesis from which, in certain unknown conditions, differentiated thyroid cells or even unusual tumors may arise.
Melatonin in the thyroid gland: Regulation by thyroid-stimulating hormone and role in thyroglobulin gene expression Journal of Physiology and Pharmacology, 2015
Comparative study of the primary cilia in thyrocytes of adult mammals J. C. Utrilla, F. Gordillo‐Martínez, A. Gómez‐Pascual, J. M. Fernández‐Santos, C. Garnacho, V. Vázquez‐Román, J. Morillo‐Bernal, R. García‐Marín, A. Jiménez‐García, I. Martín‐Lacave Journal of Anatomy, 2015
Decrease in calcitonin and parathyroid hormone mRNA levels and hormone secretion under long-term hypervitaminosis D3 in rats Histology and Histopathology, 2001
CDNA sequence and genomic structure of the rat RET proto-oncogene Ivana Matera, Manuel De Miguel-rodríguez, José Maria Fernández-santos, Giuseppe Santamaria, Aldamaria Puliti, Roberto Ravazzolo, Giovanni Romeo, Hugo Galera-davidson, Isabella Ceccherini Mitochondrial DNA, 2000
Apoptosis in breast carcinoma Ricardo González-Cámpora, María Rosa Galera Ruiz, Francisco Vázquez Ramírez, Juan José Ríos Martín, José María Fernández Santos, María del Mar Ramos Martos, Amparo Gómez Pascual Pathology Research and Practice, 2000
