Serum vitamin D is substantially reduced and predicts flares in diabetic retinopathy patients.

AIMS/INTRODUCTION: Research has suggested that vitamin D deficiency is associated with diabetic retinopathy (DR). Our study aimed to determine whether vitamin D deficiency is the cause of diabetic retinopathy or if diabetic retinopathy reduces vitamin D levels. MATERIALS AND METHODS: Participants with type-2 diabetes were recruited for this prospective observational clinical study and were divided into a diabetic group without retinopathy and a diabetic group with retinopathy, with additional healthy volunteers serving as a control group. The differences in clinical characteristics among the three groups were also compared. Patients without retinopathy were then followed for 1 year to monitor the incidence of diabetic retinopathy. After follow-up, participants were divided into subgroups based on whether diabetic retinopathy occurred. The baseline data of the subgroups were compared, and the independent risk factors were analyzed. RESULTS: Vitamin D levels were generally low. Participants with diabetic retinopathy had significantly lower vitamin D levels than did those without retinopathy (P < 0.01). A comparison of the two subgroups revealed lower baseline vitamin D concentrations in the new-DR subgroup than in the non-DR subgroup (P < 0.01). Vitamin D deficiency and elevated HbA1c levels were found to be independent risk factors for diabetic retinopathy (OR = 0.935, 95% CI: 0.867-0.981, P = 0.006; OR = 2.208, 95% CI: 1.764-2.764, P < 0.01). The limit of vitamin D intake according to the receiver-operating characteristic (ROC) curve was 26.01 ng/mL, and the area under the ROC curve was 0.603 (95% CI: 0.559-0.706, P = 0.002). CONCLUSIONS: Vitamin D levels were significantly lower in patients diagnosed with diabetic retinopathy. More importantly, vitamin D deficiency may accelerate the onset of diabetic retinopathy.

Elevated serum CA199 levels in patients suffering type 2 diabetes vs. various types of cancer.

AIMS: Carbohydrate antigen 199 (CA199) is a standard tumor marker, and recent studies have found elevated in CA199 levels in patients with diabetes. However, there is no systematic measurement and comparison of serum CA199 levels in patients with diabetes and cancer. Here, a detailed description of the changes in serum CA199 levels in patients with type 2 diabetes and various cancers was explored. METHODS: A total of 5,641 participants were screened for clinical laboratory test results of serum CA199 levels over the past three years (2020-2023). This study included 2,464 healthy controls, 688 patients with type 2 diabetes, and 2,489 patients with 16 different types of cancer. Each type of cancer had more than 30 independent serum CA199 level test results. The serum CA199 levels were compared between cancer groups, type 2 diabetes patients, and healthy controls. Additionally, the CA199 levels of cancer patients were compared with those of patients with type 2 diabetes. RESULTS: The serum CA199 levels of esophagus cancer, lung cancer, pancreatic cancer, ovarian cancer, breast cancer, rectum cancer, prostate cancer, bladder cancer, liver cancer, gastric cancer, cervical cancer, colon cancer, lymphoma, thyroid cancer, intracranial tumors, and nasopharyngeal laryngeal cancer were found to be elevated compared to healthy controls (P < 0.01). In addition, the serum CA199 levels of patients with type 2 diabetes were also significantly elevated compared to healthy controls (P < 0.01). Moreover, the degree of elevation in serum CA199 levels in patients with type 2 diabetes was not significantly different from that observed in some types of cancer, such as esophagus cancer (P = 0.163), breast cancer (P = 0.927), prostate cancer (P = 1.000), bladder cancer (P = 0.406), Lymphoma (P = 0.975), thyroid cancer (P = 1.000), intracranial tumors (P = 0.161), nasopharyngeal and laryngeal cancer (P = 1.000). CONCLUSIONS: Serum CA199 levels also increase in type 2 diabetes, and the magnitude of the increase is similar to that seen in some cancers.

Correlation between white matter hyperintensity and delusional symptoms in Alzheimer's disease.

BACKGROUND: Patients with Alzheimer's disease (AD) often exhibit neuropsychiatric symptoms (NPS), particularly delusions. Previous studies have shown an association between white matter hyperintensities (WMH) and specific NPS. This study aims to explore the relationship between WMH volume and delusions in AD patients by comparing the WMH volumes of delusional and non-delusional subgroups. METHODS: 80 AD patients were divided into a delusion group (n = 36) and a non-delusion group (n = 44) based on the Neuropsychiatric Inventory (NPI). The brain cortical volume and WMH volume were quantitatively calculated for all 80 patients, including total WMH volume, periventricular WMH (PVWMH) volume, deep WMH volume, as well as bilateral frontal lobe, temporal lobe, parietal lobe, and occipital lobe WMH volumes. Firstly, we compared the differences in WMH volumes between the delusion group and non-delusion group. Then, within the delusion group, we further categorized patients based on severity scores of their delusional symptoms into mild (1 point), moderate (2 points), or severe groups (3 points). We compared the WMH volumes among these three groups to investigate the role of WMH volume in delusional symptoms. RESULTS: There was a significant difference in left occipital lobe WMH volume between the delusion group and non-delusion group(P < 0.05). Within the delusion group itself, there were significant differences in overall WMH volume as well as PVWMH volume among patients with mild or severe levels of delusions(P < 0.05). CONCLUSION: Left occipital lobe WMH volume may be associated with the occurrence of delusional AD patients, and the total volume of whole-brain WMH and PVWMH volume may affect the degree of severity of delusional symptoms.

Association of altered fibrinogen indexes levels as a potential biomarker in determining the possible onset of diabetic retinopathy.

Research suggests that fibrinogen was related to diabetic retinopathy (DR). Then, the relationship between functional indices of fibrinogen and detailed staging of DR has not been explored. Type 2 diabetic and healthy control subjects (n = 960) were recruited in a cross-sectional study. Participants with type 2 diabetes mellitus were categorized into five stages according to their fundus lesions, and fibrinogen (Fib) and its functional indices (angle α and k value) were measured. The angle α levels increased in diabetic subjects with retinopathy compared with those without, and it was significantly elevated early in retinopathy. In contrast, the k value levels slightly decreased. Despite observing an increase in angle α levels and a decrease in k value levels during the later stages of retinopathy compared to the earlier stages, there was no statistically significant difference in the later stages. The association of the angle α and k value with DR was independent of the hyperglycaemic state and other potential confounders (OR = 1.672, 95% CI 1.489-1.876, P < 0.01; OR = 0.013, 95% CI 0.004-0.041, P < 0.01). The angle α levels and k value levels were closely correlated with retinopathy (r = 0.593, P < 0.00; r = - 0.646, P < 0.01). The ROC curve indicated that the diagnostic value of angle α and k value were (AUC = 0.897, P < 0.001; AUC = 0.859, P < 0.001). Fibrinogen function indexes, such as angle α and k value, may be valuable for the early diagnosis of DR but do not directly assess the severity of DR.

Multi-modal cross-attention network for Alzheimer's disease diagnosis with multi-modality data.

Alzheimer's disease (AD) is a neurodegenerative disorder, the most common cause of dementia, so the accurate diagnosis of AD and its prodromal stage mild cognitive impairment (MCI) is significant. Recent studies have demonstrated that multiple neuroimaging and biological measures contain complementary information for diagnosis. Many existing multi-modal models based on deep learning simply concatenate each modality's features despite substantial differences in representation spaces. In this paper, we propose a novel multi-modal cross-attention AD diagnosis (MCAD) framework to learn the interaction between modalities for better playing their complementary roles for AD diagnosis with multi-modal data including structural magnetic resonance imaging (sMRI), fluorodeoxyglucose-positron emission tomography (FDG-PET) and cerebrospinal fluid (CSF) biomarkers. Specifically, the imaging and non-imaging representations are learned by the image encoder based on cascaded dilated convolutions and CSF encoder, respectively. Then, a multi-modal interaction module is introduced, which takes advantage of cross-modal attention to integrate imaging and non-imaging information and reinforce relationships between these modalities. Moreover, an extensive objective function is designed to reduce the discrepancy between modalities for effectively fusing the features of multi-modal data, which could further improve the diagnosis performance. We evaluate the effectiveness of our proposed method on the ADNI dataset, and the extensive experiments demonstrate that our MCAD achieves superior performance for multiple AD-related classification tasks, compared to several competing methods. Also, we investigate the importance of cross-attention and the contribution of each modality to the diagnostics performance. The experimental results demonstrate that combining multi-modality data via cross-attention is helpful for accurate AD diagnosis.

Trait- and State-Dependent Changes in Cortical-Subcortical Functional Networks Across the Adult Lifespan.

BACKGROUND: How the functional interactions of the basal ganglia/thalamus with the cerebral cortex and the cerebellum change over the adult lifespan in movie-watching and resting-state is less clear. PURPOSE: To investigate the functional changes in the organization of the human cortical-subcortical functional networks over the adult lifespan using movie-watching and resting-state fMRI data. STUDY TYPE: Cohort. SUBJECTS: Healthy 467 adults (cross-sectional individuals aged 18-88 years) from the Cambridge Centre for Ageing and Neuroscience (www.cam-can.com). FIELD STRENGTH/SEQUENCE: fMRI using a gradient-echo echo-planar imaging (EPI) sequence at 3 T. ASSESSMENT: Functional connectivities (FCs) of the subcortical subregions (i.e. the basal ganglia and thalamus) with both the cerebral cortex and cerebellum were examined in fMRI data acquired during resting state and movie-watching. And, fluid intelligence scores were also assessed. STATISTICAL TESTS: Student's t-tests, false discovery rate (FDR) corrected. RESULTS: As age increased, FCs that mainly within the basal ganglia and thalamus, and between the basal ganglia/thalamus and cortical networks (including the dorsal attention, ventral attention, and limbic networks) were both increased/decreased during movie-watching and resting states. However, FCs showed a state-dependent component with advancing age. During the movie-watching state, the FCs between the basal ganglia/thalamus and cerebellum/frontoparietal control networks were mainly increased with age, and the FCs in the somatomotor network were decreased with age. During the resting state, the FCs between the basal ganglia/thalamus and default mode/visual networks were mainly increased with age, and the FCs in the cerebellum were mainly decreased with age. Moreover, inverse relationships between FCs and fluid intelligence were mainly found in these network regions. DATA CONCLUSION: Our study may suggest that changes in cortical-subcortical functional networks across the adult lifespan were both state-dependent and stable traits, and that aging fMRI studies should consider the effects of both physiological characteristics and individual situations. EVIDENCE LEVEL: 2. TECHNICAL EFFICACY: Stage 3.

Serum uric acid and diabetic peripheral neuropathy: a double-edged sword.

BACKGROUND AND OBJECTIVES: Research suggests that diabetic peripheral neuropathy (DPN) is related to high serum uric acid (SUA) level, although its correlation with low SUA level has not been reported. Here, diabetic patients with hyperuricemia were excluded, and the correlation between low SUA level and DPN was explored. SUBJECTS AND METHODS: This prospective observational clinical study enrolled 525 type 2 diabetes mellitus (T2DM) patients without hyperuricemia, who were divided into the diabetes with symptomatic neuropathy (150 cases), diabetes with asymptomatic neuropathy (125 cases) and diabetes with no neuropathy (250 cases) groups. RESULTS: The SUA slightly decreased in subjects with asymptomatic DPN compared with those with no neuropathy and greatly decreased in subjects with symptomatic DPN compared with those without (P < 0.001). The association of the SUA with diabetic neuropathy was independent of the hyperglycemic state and other potential confounders (odds ratio 0.985 [0.981-0.988], P < 0.001). The SUA was closely correlated with the means of motor/sensory nerve amplitude and CV (all P < 0.001). The optimal cut-off point for SUA to distinguish patients with diabetic neuropathy from those without was 324 umol/L, with a sensitivity of 76.0% and a specificity of 79.2% (AUC = 0.806). CONCLUSIONS: The low SUA level is closely associated with DPN. Future studies are warranted to clarify the relationship.

The predictive value of fibrinogen in the occurrence of mild cognitive impairment events in patients with diabetic peripheral neuropathy.

BACKGROUND: Research suggests that fibrinogen (Fib) is related to mild cognitive impairment (MCI) and diabetic peripheral neuropathy (DPN) and the risk of MCI in patients with DPN is greatly increased, although no studies have evaluated the predictive value of Fib for the risk of MCI in patients with DPN. METHODS: This prospective observational clinical study enrolled 207 type 2 diabetes mellitus (T2DM) patients, who were divided into diabetes with no neuropathy (102 cases) and diabetes with neuropathy (105 cases) groups. Meanwhile, 90 healthy unrelated subjects were recruited as controls. The incidence of MCI in the DPN patients was followed up for 2 years. Divide patients in the DPN group into subgroups according to whether MCI occur, use multivariate logistic regression to analyze independent factors of MCIs in DPN patients within 2 years, and use ROC curve to analyze the predictive value of Fib for MCI in DPN patients. RESULTS: Fib levels were significantly higher in diabetic subjects with neuropathy compared with those without (P < 0.001). In further subgroup analysis of DPN patients who were divided according to the occurrence of MCI, baseline data of the MCI subgroup showed Fib levels were higher than that in the non-MCI group while education levels declined (P < 0.001). The education level and increased Fib levels were independent factors for the occurrence of MCI within 2 years after the onset of DPN (OR = 0.769, 95% CI: 0.605 ~ 0.968, P = 0.037; OR = 2.674, 95% CI: 1.094 ~ 3.168, P = 0.002). The ROC curve indicated that the predictive value of Fib was (AUC = 0.764, 95% CI: 0.671 ~ 0.842, P < 0.001). CONCLUSIONS: Fib may function as a predictor for assessing the risk of MCI in DPN patients.

Microarray profiling and functional analysis reveal the regulatory role of differentially expressed plasma circular RNAs in Hashimoto's thyroiditis.

Circular RNAs (circRNAs) have been revealed as being abundantly expressed in a variety of tissues and have been found to contribute to the regulation of many autoimmune diseases. Although previous studies demonstrated that the pathogenesis of Hashimoto's thyroiditis (HT) is related with epigenetic dysregulation, the exact mechanism remains unclear. The important role of thyroid-specific circRNAs in HT attracted much attention but without any report revealed their expression profile and function in plasma of HT. In this study, the circRNA expression profile in plasma of HT was explored for the first time by using Arraystar CircRNA Microarray technology. We obtained 22 differentially expressed circRNAs (fold change ≥ 2.0 or ≤ - 2.0, p < 0.05) in plasma of HT, including 7 upregulated circRNAs and 15 downregulated circRNAs. By constructing circRNA-miRNA-mRNA competing endogenous RNA (ceRNA) network, we found that upregulated circRNAs may function as ceRNAs and affect the occurrence or development of HT through chemokine signaling pathway (p < 0.0001), HIF-1 signaling pathway (p = 0.02), and FoxO signaling pathway (p = 0.04). Notably, hsa_circ_0008193 verified by RT-qPCR were the major upregulation circRNAs involved in the chemokine signaling pathway. These results provide a comprehensive circRNA resource for further in-depth study of the regulatory mechanisms of circRNA in HT and may provide new insight into HT.

Effects of Morning Blue-Green 500 nm Light Therapy on Cognition and Biomarkers in Middle-Aged and Older Adults with Subjective Cognitive Decline and Mild Cognitive Impairment: Study Protocol for a Randomized Controlled Trial.

BACKGROUND: Given that there is no specific drug to treat Alzheimer's disease, non-pharmacologic interventions in people with subjective cognitive decline (SCD) and amnestic mild cognitive impairment (aMCI) are one of the most important treatment strategies. OBJECTIVE: To clarify the efficacy of blue-green (500 nm) light therapy on sleep, mood, and physiological parameters in patients with SCD and aMCI is an interesting avenue to explore. METHODS: This is a monocentric, randomized, and controlled trial that will last for 4 weeks. We will recruit 150 individuals aged 45 years or older from memory clinics and divide them into 5 groups: SCD treatment (n = 30), SCD control (n = 30), aMCI treatment (n = 30), aMCI control (n = 30), and a group of healthy adult subjects (n = 30) as a normal control (NC). RESULTS: The primary outcome is the change in subjective and objective cognitive performance between baseline and postintervention visits (4 weeks after baseline). Secondary outcomes include changes in performance assessing from baseline, postintervention to follow-up (3 months after the intervention), as well as sleep, mood, and physiological parameters (including blood, urine, electrophysiology, and neuroimaging biomarkers). CONCLUSION: This study aims to provide evidence of the impact of light therapy on subjective and objective cognitive performance in middle-aged and older adults with SCD or aMCI. In addition, we will identify possible neurophysiological mechanisms of action underlying light therapy. Overall, this trial will contribute to the establishment of light therapy in the prevention of Alzheimer's disease.

Circular RNA HIPK3 contributes to hyperglycemia and insulin homeostasis by sponging miR-192-5p and upregulating transcription factor forkhead box O1.

It has been shown that circular RNAs, a class of non-coding RNA molecules, play an important role in the regulation of glucose and lipid homeostasis. In the present study, we sought to investigate the function of circular RNA HIPK3 (circHIPK3) in diabetes-associated metabolic disorders, including hyperglycemia and insulin resistance. Results show that oleate stimulated circHIPK3 increase, and that circHIPK3 enhanced the stimulatory effect of oleate on adipose deposition, triglyceride (TG) content, and cellular glucose content in HepG2 cells. MiR-192-5p was the potential target of circHIPK3, since circHIPK3 significantly decreased miR-192-5p mRNA level, whereas anti-circHIPK3 significantly increased miR-192-5p mRNA level. Further study shows that transcription factor forkhead box O1 (FOXO1) was a downstream regulator of miR-192-5p, since miR-192-5p significantly decreased FOXO1 expression, whereas circHIPK3 significantly increased FOXO1 expression. Notably, the inhibitory effect of miR-192-5p was significantly reversed by circHIPK3. In vivo study shows that anti-miR-192-5p significantly increased blood glucose content, which was significantly inhibited by FOXO1 shRNA. MiR-192-5p significantly decreased adipose deposition and TG content in HepG2 cells, which was significantly reversed by the co-treatment with circHIPK3. Forskolin/dexamethasone (FSK/DEX) significantly increased cellular glucose, mRNA level of phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G6Pase), and this stimulatory effect of FSK/DEX was significantly inhibited by miR-192-5p. In the presence of circHIPK3, however, the inhibitory effect of miR-192-5p was totally lost. In summary, the present study demonstrated that circHIPK3 contributes to hyperglycemia and insulin resistance by sponging miR-192-5p and up-regulating FOXO1.

Berberine, a Traditional Chinese Medicine, Reduces Inflammation in Adipose Tissue, Polarizes M2 Macrophages, and Increases Energy Expenditure in Mice Fed a High-Fat Diet.

BACKGROUND The uncoupling protein 1 (UCP1) gene has a role in mitochondrial energy expenditure in brown adipose tissue. This study aimed to investigate the effects of berberine, a benzylisoquinoline alkaloid used in traditional Chinese medicine, on energy expenditure, expression of the UCP1 gene, the cell stress protein inositol-requiring enzyme 1α (IRE1α), apoptosis genes, and macrophage phenotype (M1 and M2) in white and brown adipose tissue in an obese mouse model fed a high-fat diet. MATERIAL AND METHODS Four-week-old C57BL/6J male mice (n=20) were divided into a high-fat diet group, a normal diet group, a group treated with berberine at 100 mg/kg/d in 0.9% normal saline, and a non-treated group. Whole-body fat mass, blood glucose, insulin resistance, and oxygen expenditure during physical activity were measured. After 16 weeks, the mice were euthanized for examination of liver and adipose tissue. The expression of pro-inflammatory cytokines, apoptosis genes, thermogenic genes (including UCP1), and IRE1α, were investigated using immunohistochemistry, Western blot, and quantitative reverse transcription polymerase chain reaction (qRT-PCR), in white and brown adipose tissue. Magnetic cell sorting harvested M1 and M2 macrophages in adipose tissue. Clodronate liposomes were used to inhibit macrophage recruitment. RESULTS Berberine treatment in mice fed a high-fat diet increased energy metabolism, glucose tolerance, and expression of UCP1, and reduced expression of pro-inflammatory cytokines, macrophage recruitment, and resulted in M2 macrophage polarization in white adipose tissue. Polarized M2 macrophages showed reduced expression of apoptotic genes and IRE1α. CONCLUSIONS Berberine improved metabolic function in a mouse model fed a high-fat diet.

Optimal iodine supplementation during antithyroid drug therapy for Graves' disease is associated with lower recurrence rates than iodine restriction.

OBJECTIVE: A relationship between iodine intake and the effectiveness of antithyroid drug (ATD) therapy for Graves' disease (GD) has been suggested, and strict restriction of iodine intake has been tried in the treatment of GD in some studies. However, it is unclear whether dietary iodine supplementation improves the prognosis of ATD therapy for GD. This study aimed to clarify whether optimal iodine supplementation during antithyroid drug therapy for GD is associated with lower recurrence rates than iodine restriction. METHODS: This was a prospective randomized trial of newly diagnosed patients with GD. Patients with newly diagnosed GD were recruited. After ATD therapy and strict dietary iodine restriction for 1 month, patients (n = 459) were randomly assigned to iodine-supplemented and iodine-restricted groups. After exclusion, 405 patients finally completed the study. The iodine-supplemented group included 203 patients (61 males and 142 females) with an average age of 32.2 ± 10.5 years (17-65 years), and the iodine-restricted group included 202 patients (61 males and 141 females) with an average age of 31.9 ± 11.8 years (16-64 years). Patients in the iodine-supplemented group were given about 10 grams of iodized salt every day, while the iodine-restricted group received noniodized salt with low-iodine or noniodine diet. The dietary iodine intervention lasted for 24 months. Urinary iodine concentration (UIC), thyrotropin receptor antibody (TRAb), free T3 (FT3), free T4 (FT4) and thyrotropin (TSH) of 2 groups were measured every 3 months. The recurrence rates within 12 months after withdrawal of ATD were evaluated. RESULTS: UIC in the iodine-supplemented group was within the recommended range for optimal iodine intake (135-162 µg/L) and was significantly higher than that in iodine-restricted group (30-58 µg/L). Within 12 months of withdrawal of ATD, the total recurrence rate in the iodine-supplemented group was 35.5%, significantly lower than in the iodine-restricted group, which was 45.5%. CONCLUSION: Optimal dietary iodine supplementation during antithyroid drug therapy for GD is associated with lower recurrence rates than iodine restriction, and therefore, diet control with strict iodine restriction might be an adverse factor in the management of GD.

Iodinated TG in Thyroid Follicles Regulate TSH/TSHR Signaling for NIS Expression.

Our previous research has suggested that high degree of iodinated thyroglobulin (TG) may inhibit the expression and function of sodium iodide symporter (NIS), but the underlying mechanism remains unclear. In present study, we discuss a newly constructed follicle model in vitro, which was used to simulate the follicular structure of the thyroid and explore the regulatory roles of iodinated TG in the follicular lumen on NIS expression. The results showed that both NIS expression and PKA activity were increased in lowly iodinated TG group, while decreased NIS expression with increased PKC activity was found in highly iodinated TG group. Also, NIS expression was increased in PKA agonist-treated group, while decreased NIS was found in PKC agonist-treated group. Moreover, when the PLC-PKC pathway was blocked by PKC-specific inhibitor, highly iodinated TG significantly promoted the expression of NIS. However, when the cAMP-PKA pathway was blocked by a PKA-specific blocker, highly iodinated TG slightly suppressed NIS expression. TG with a low degree of iodination had the reverse effect on NIS. When the PLC-PKC pathway was blocked, TG with a low degree of iodination slightly promoted NIS expression. However, when the cAMP-PKA pathway was blocked, TG with a low degree of iodination greatly inhibited NIS expression. All these suggested that iodinated TG inhibited the expression of NIS by PLC-PKC pathway and promoted NIS expression via the cAMP-PKA pathway. When highly iodinated TG was present, the PLC-PKC pathway became dominant. In the presence of lowly iodinated TG, the cAMP-PKA became the major pathway.

Iodinated TG in Thyroid Follicular Lumen Regulates TTF-1 and PAX8 Expression via TSH/TSHR Signaling Pathway.

Our previous study showed that highly iodinated thyroglobulin (TG) inhibited thyroid transcription factor-1 (TTF-1) and paired box gene 8 (PAX8) expression, but the potential mechanism remains unclear. In this study, we constructed a thyroid follicle model in vitro to mimic its natural physiological structure and explored how iodinated TG in the follicular lumen tuned TTF-1 and PAX8 expression. Our data showed that lowly iodinated TG enhanced PKA activity while upregulation of both TTF-1 and PAX8 expression; and that highly iodinated TG triggered PKC activity while suppression of TTF-1 and PAX8 expression. Further, PKA agonist alone could increase TTF-1 and PAX8 expression while PKC agonist decreased TTF-1 and PAX8 level. If blocking PLC-PKC pathway using PKC-specific inhibitor, highly iodinated TG significantly promoted the expressions of TTF-1 and PAX8, and similarly PKA-specific blocker moderately inhibited TTF-1 and PAX8 expression. And opposite tendencies of TTF1 and PAX8 aberrant expression were observed in the condition of low iodinated TG when blocking PLC-PKC and cAMP-PKA signaling pathways. Our results indicated that iodinated TG manipulated TTF-1 and PAX8 expression through PLC-PKC and cAMP-PKA pathways, and highly iodinated TG played inhibitory role via PLC-PKC pathway from the TTF1 and PAX8 perspective while low level of iodinated TG was an activator through cAMP-PKA pathway. Our findings proved that iodinated TG in thyroid follicular lumen regulated TTF-1 and PAX8 expression through thyroid stimulating hormone/thyroid stimulating hormone receptor (TSH/TSHR) mediated cAMP-PKA and PLC-PKC signaling pathways. J. Cell. Biochem. 118: 3444-3451, 2017. © 2017 Wiley Periodicals, Inc.

Low Iodine in the Follicular Lumen Caused by Cytoplasm Mis-localization of Sodium Iodide Symporter may Induce Nodular Goiter.

Iodine is a key ingredient in the synthesis of thyroid hormones and also a major factor in the regulation of thyroid function. A local reduction of iodine content in follicular lumen leads to overexpression of local thyroid-stimulating hormone receptor (TSHr), which in turn excessively stimulates the regional thyroid tissue, and result in the formation of nodular goiter. In this study, we investigated the relationship between iodine content and sodium iodide symporter (NIS) expression by using the clinical specimens from patients with nodular goiter and explored the pathogenesis triggered by iodine deficiency in nodular goiter. In total, 28 patients were clinically histopathologically confirmed to have nodular goiter and the corresponding adjacent normal thyroid specimens were harvested simultaneously. Western blot and immunohistochemistry were performed to assay NIS expression and localization in thyrocytes of both nodular goiter and adjacent normal thyroid tissues. NIS expression mediated by iodine in follicular lumen was confirmed by follicular model in vitro. Meanwhile, radioscan with iodine-131were conducted on both nodular goiter and adjacent normal thyroid. Our data showed that NIS expression in nodular goiter was significantly higher than that in adjacent normal tissues, which was associated with low iodine in the follicular lumen. Abnormal localization of NIS and lower amount of radioactive iodine-131 were also found in nodular goiter. Our data implied that low iodine in the follicular lumen caused by cytoplasm mis-localization of NIS may induce nodular goiter.

Glycolysis-associated enzymes existing in the follicular lumen of the thyroid may interfere with energy metabolism.

Synthesis and storage of the thyroid hormone precursor, thyroglobulin (TG), occurs within the follicular lumen of the thyroid and the TG is then absorbed into cells for further processing before release into the blood. However, the mechanism of energy metabolism in the follicular lumen of the thyroid remains unknown. In the present study, the three dimensional structure of thyroid follicles was constructed using a primary culture of swine cells and the follicular protein was identified via matrix-assisted laser desorption/ionization-time of flight mass spectrometry. Three glycolysis-associated enzymes, enolase, pyruvate kinase and phosphoglyceraldehyde dehydrogenase were identified in addition to TG. These results support the hypothesis that anaerobic glycolysis of glucose exists in the follicle and supports energy consumption for hormone synthesis.

Upregulation of TSHR, TTF-1, and PAX8 in Nodular Goiter Is Associated with Iodine Deficiency in the Follicular Lumen.

Objective. It has been testified that iodine regulates thyroid function by controlling thyroid-restricted genes expression and is closely related to diffuse goiter and thyroid dysfunction. However, the effects of follicular lumen iodine, the main form of iodine reserve in the body, on thyroid-restricted genes in nodular goiter are poorly understood. In this study, correlations between follicular lumen iodine and the expressions of thyroid stimulating hormone receptor (TSHR), its transcription factors TTF-1, and PAX8 in nodular goiter were investigated. Patients. In this study, 30 resection specimens clinically histopathologically confirmed to have nodular goiter and 30 normal thyroid specimens from adjacent tissues of nodular goiter are used. Measurement. Western blot immunohistochemistry was performed to assay TSHR, TTF-1, and PAX8 in thyrocytes of nodular goiter as well as in extranodular normal thyroid tissues. Meanwhile, follicular lumen iodine of both nodular goiter and extranodular normal thyroid tissues was detected as well. Results. The TSHR, TTF-1, and PAX8 in nodular goiter were significantly higher than those in the controls. The iodine content in nodular goiter was significantly lower than those in control tissues. Conclusion. Upregulation of TSHR, TTF-1, and PAX8 is associated with low follicular lumen iodine content in nodular goiter.

Presence of free triiodothyronine and free thyroxine in thyroid follicles may be correlated with the quick secretion of thyroid hormones under certain physiological conditions.

Thyroid cells are polarized and the follicle structure, consisting of follicle epithelial cells, is a prerequisite for thyroid hormone synthesis. However, a reliable in vitro model simulating thyroid function is not currently available. To the best of our knowledge, the present study reports for the first time a simulated follicle by inoculation of human thyroid cells on the filter in a Transwell plate to maintain the polarity of thyroid cells. The iodine uptake was analyzed by arsenic and cerium catalysis spectrophotometry, as well as the secretion of free triiodothyronine (FT3) and free thyroxine (FT4) by direct chemiluminescence. The data showed that thyroid cells growing in the Transwell chamber synthesized and secreted FT3 and FT4, while the monolayer cells directly seeded in the 6-well-plate did not produce these two thyroid hormones. Regarding the iodine uptake, cells in the Transwell chamber demonstrated a markedly higher capability than the monolayer cells. The data proved that the polarity of thyroid cells could be restored using the Transwell plate, which was critical for iodine uptake and thyroid hormone synthesis. The presence of FT3 and FT4 in follicles may be correlated with the quick secretion of thyroid hormones under certain physiological conditions.