Identification of Novel, Selective Ataxia-Telangiectasia Mutated Kinase Inhibitors with the Ability to Penetrate the Blood-Brain Barrier: The Discovery of AZD1390.

The inhibition of ataxia-telangiectasia mutated (ATM) has been shown to chemo- and radio-sensitize human glioma cells in vitro and therefore might provide an exciting new paradigm in the treatment of glioblastoma multiforme (GBM). The effective treatment of GBM will likely require a compound with the potential to efficiently cross the blood-brain barrier (BBB). Starting from clinical candidate AZD0156, 4, we investigated the imidazoquinolin-2-one scaffold with the goal of improving likely CNS exposure in humans. Strategies aimed at reducing hydrogen bonding, basicity, and flexibility of the molecule were explored alongside modulating lipophilicity. These studies identified compound 24 (AZD1390) as an exceptionally potent and selective inhibitor of ATM with a good preclinical pharmacokinetic profile. 24 showed an absence of human transporter efflux in MDCKII-MDR1-BCRP studies (efflux ratio <2), significant BBB penetrance in nonhuman primate PET studies (Kp,uu 0.33) and was deemed suitable for development as a clinical candidate to explore the radiosensitizing effects of ATM in intracranial malignancies.

STING Agonist-Loaded Nanoparticles Promotes Positive Regulation of Type I Interferon-Dependent Radioimmunotherapy in Rectal Cancer.

Hypoxia-associated radioresistance in rectal cancer (RC) has severely hampered the response to radioimmunotherapy (iRT), necessitating innovative strategies to enhance RC radiosensitivity and improve iRT efficacy. Here, a catalytic radiosensitizer, DMPtNPS, and a STING agonist, cGAMP, are integrated to overcome RC radioresistance and enhance iRT. DMPtNPS promotes efficient X-ray energy transfer to generate reactive oxygen species, while alleviating hypoxia within tumors, thereby increasing radiosensitivity. Mechanistically, the transcriptomic and immunoassay analysis reveal that the combination of DMPtNPS and RT provokes bidirectional regulatory effects on the immune response, which may potentially reduce the antitumor efficacy. To mitigate this, cGAMP is loaded into DMPtNPS to reverse the negative impact of DMPtNPS and RT on the tumor immune microenvironment (TiME) through the type I interferon-dependent pathway, which promotes cancer immunotherapy. In a bilateral tumor model, the combination treatment of RT, DMPtNPS@cGAMP, and αPD-1 demonstrates a durable complete response at the primary site and enhanced abscopal effect at the distant site. This study highlights the critical role of incorporating catalytic radiosensitizers and STING agonists into the iRT approach for RC.

Methylglyoxal from gut microbes boosts radiosensitivity and radioimmunotherapy in rectal cancer by triggering endoplasmic reticulum stress and cGAS-STING activation.

BACKGROUND: Preoperative radiation therapy (preRT) is a fundamental aspect of neoadjuvant treatment for rectal cancer (RC), but the response to this treatment remains unsatisfactory. The combination of radiation therapy (RT) and immunotherapy (iRT) presents a promising approach to cancer treatment, though the underlying mechanisms are not yet fully understood. The gut microbiota may influence the response to RT and immunotherapy. Therefore, we aimed to identify the metabolism of gut microbiota to reverse radioresistance and enhance the efficacy of iRT. METHODS: Fecal and serum samples were prospectively collected from patients with locally advanced rectal cancer (LARC) who had undergone pre-RT treatment. Candidate gut microbiome-derived metabolites linked with radiosensitization were screened using 16s rRNA gene sequencing and ultrahigh-performance liquid chromatography-mass coupled with mass spectrometry. In vitro and in vivo studies were conducted to assess the radiosensitizing effects of the metabolites including the syngeneic CT26 tumor model and HCT116 xenograft tumor model, transcriptomics and immunofluorescence. The CT26 abscopal effect modeling was employed to evaluate the combined effects of metabolites on iRT. RESULTS: We initially discovered the gut microbiota-associated metabolite, methylglyoxal (MG), which accurately predicts the response to preRT (Area Under Curve (AUC) value of 0.856) among patients with LARC. Subsequently, we observed that MG amplifies the RT response in RC by stimulating intracellular reactive oxygen species (ROS) and reducing hypoxia in the tumor in vitro and in vivo. Additionally, our study demonstrated that MG amplifies the RT-induced activation of the cyclic guanosine monophosphate AMP synthase-stimulator of interferon genes pathway by elevating DNA double-strand breaks. Moreover, it facilitates immunogenic cell death generated by ROS-mediated endoplasmic reticulum stress, consequently leading to an increase in CD8+ T and natural killer cells infiltrated in the tumor immune microenvironment. Lastly, we discovered that the combination of anti-programmed cell death protein 1 (anti-PD1) therapy produced long-lasting complete responses in all irradiated tumor sites and half of the non-irradiated ones. CONCLUSIONS: Our research indicates that MG shows promise as a radiosensitizer and immunomodulator for RC. Furthermore, we propose that combining MG with iRT has great potential for clinical practice.

Discovery of AZD4747, a Potent and Selective Inhibitor of Mutant GTPase KRASG12C with Demonstrable CNS Penetration.

The glycine to cysteine mutation at codon 12 of Kirsten rat sarcoma (KRAS) represents an Achilles heel that has now rendered this important GTPase druggable. Herein, we report our structure-based drug design approach that led to the identification of 14, AZD4747, a clinical development candidate for the treatment of KRASG12C-positive tumors, including the treatment of central nervous system (CNS) metastases. Building on our earlier discovery of C5-tethered quinazoline AZD4625, excision of a usually critical pyrimidine ring yielded a weak but brain-penetrant start point which was optimized for potency and DMPK. Key design principles and measured parameters that give high confidence in CNS exposure are discussed. During optimization, divergence between rodent and non-rodent species was observed in CNS exposure, with primate PET studies ultimately giving high confidence in the expected translation to patients. AZD4747 is a highly potent and selective inhibitor of KRASG12C with an anticipated low clearance and high oral bioavailability profile in humans.

A novel anoikis-related gene prognostic signature and its correlation with the immune microenvironment in colorectal cancer.

Background: Anoikis is a type of apoptosis associated with cell detachment. Resistance to anoikis is a focal point of tumor metastasis. This study aimed to explore the relationship among anoikis-related genes (ARGs), immune infiltration, and prognosis in colorectal cancer (CRC). Methods: The transcriptome profile and clinical data on patients with CRC were retrieved from The Cancer Genome Atlas and Gene Expression Omnibus databases. Patients were divided into two clusters based on the expression of ARGs. Differences between the two ARG molecular subtypes were analyzed in terms of prognosis, functional enrichment, gene mutation frequency, and immune cell infiltration. An ARG-related prognostic signature for predicting overall survival in patients with CRC was developed and validated using absolute value convergence and selection operator (LASSO) regression analysis. The correlation between the signature risk score and clinicopathological features, immune cell infiltration, immune typing, and immunotherapy response was analyzed. The risk score combined with clinicopathological characteristics was used to construct a nomogram to assess CRC patients' prognosis. Results: Overall, 151 ARGs were differentially expressed in CRC. Two ARG subtypes, namely, ARG-high and ARG-low groups, were identified and correlated with CRC prognosis. The gene mutation frequency and immune, stromal, and ESTIMATE scores of the ARG-high group were higher than those of the ARG-low group. Moreover, CD8, natural killer cells, M1 macrophages, human leukocyte antigen (HLA), and immune checkpoint-related genes were significantly increased in the ARG-high group. An optimized 25-gene CRC prognostic signature was successfully constructed, and its prognostic predictive ability was validated. The high-risk score was correlated with T, N, M, and TNM stages. Risk scores were negatively correlated with dendritic cells, eosinophils, and CD4 cells, and significantly positively correlated with regulatory T cells. Patients in the high-risk group were more likely to exhibit immune unresponsiveness. Finally, the nomogram model was constructed and showed good prognostic predictive power. Conclusion: ARGs are associated with clinicopathological features and the prognosis of CRC, and play important roles in the immune microenvironment. Herein, we underpinned the usefulness of ARGs in CRC to develop more effective immunotherapy techniques.

Mitophagy disorder mediates cardiac deterioration induced by severe hypoglycemia in diabetic mice.

Severe hypoglycemia is closely related to adverse cardiovascular outcomes in patients with diabetes; however, the specific mechanism remains unclear. We previously found that severe hypoglycemia aggravated myocardial injury and cardiac dysfunction in diabetic mice, and that the mechanism of damage was related to mitochondrial oxidative stress and dysfunction. Based on the key regulatory role of mitophagy in mitochondrial quality control, this study aimed to further explore whether the myocardial damage caused by severe hypoglycemia is related to insufficient mitophagy and to clarify their underlying regulatory relationship. After severe hypoglycemia, mitochondrial reactive oxygen species increased, mitochondrial membrane potential and ATP content decreased, and pathological mitochondrial damage was aggravated in the myocardium of diabetic mice. This was accompanied by decreased mitochondrial biosynthesis, increased fusion, and downregulated PTEN-induced kinase 1 (PINK1)/Parkin-dependent mitophagy. Treating diabetic mice with the mitophagy activator and polyphenol metabolite urolithin A activated PINK1/Parkin-dependent mitophagy, reduced myocardial oxidative stress and mitochondrial damage associated with severe hypoglycemia, improved mitochondrial function, alleviated myocardial damage, and ultimately improved cardiac function. Thus, we provide insight into the prevention and treatment of diabetic myocardial injury caused by hypoglycemia to reduce adverse cardiovascular outcomes in patients with diabetes.

Smoking is a Factor in Discordance Between QuantiFERONTB Gold Assay and Tuberculosis Etiology: Especially in Older Patients.

Purpose: Exploring whether smoking is an influencing factor for the inconsistency between QuantiFERONTB Gold assay (QFT-GIT) and tuberculosis etiology. Patients and Methods: The clinical data of patients who were confirmed positive for Mycobacterium tuberculosis (MTB) after undergoing QFT-GIT testing from September 2017 to August 2021 were retrospectively analyzed. Chi-square and rank-sum tests were used to compare the differences in characteristics between smokers and non-smokers. Logistic regression was used to adjust for confounding factors affecting smoking. Propensity score matching (PSM) was used to verify the above conclusions again. Results: Positive results of tuberculosis etiology were adopted as the standard, the incidence of inconsistent results between QFT-GIT and tuberculosis etiology was 8.90% (108/1213), of which the false negative rate was 6.27% (76/1213) and the indeterminate rate was 2.64% (32/1213). In the overall population, the smokers had a lower level of basal IFN-γ (Z=-2.079, P=0.038). Among 382 elderly (≥65 years old) patients, the smokers had lower levels of antigen-stimulated IFN-γ (Z=-2.838, P=0.005). After performing BOX-COX transformation on all non-normally distributed data, logistic stepwise regression was used to adjust confounding factors. The results showed that smoking was an influencing factor for the inconsistency between QFT-GIT and tuberculosis etiology results (OR=1.69, P=0.020). Using PSM for 1:2 matching, the results showed that smoking was still an independent risk factor for the inconsistent results of QFT-GIT and tuberculosis etiology (OR= 1.95, P=0.019). Age-stratified analysis showed that smoking was an independent risk factor in discordance between QFT-GIT and tuberculosis etiology in patients aged ≥65 years (OR=2.40, P=0.005), but not in patients aged <65 years (P > 0.05). Conclusion: Smoking can reduce the body's IFN-γ release ability, and smoking (especially the elderly) is an influencing factor for the inconsistency between QFT-GIT and tuberculosis etiological results.

Clinical and genetic features of cystic fibrosis in Japan.

Cystic fibrosis (CF) is an autosomal recessive disease caused by pathogenic variants in CF transmembrane conductance regulator (CFTR). While CF is the most common hereditary disease in Caucasians, it is rare in East Asia. In the present study, we have examined clinical features and the spectrum of CFTR variants of CF patients in Japan. Clinical data of 132 CF patients were obtained from the national epidemiological survey since 1994 and CF registry. From 2007 to 2022, 46 patients with definite CF were analyzed for CFTR variants. All exons, their boundaries, and part of promoter region of CFTR were sequenced and the presence of large deletion and duplications were examined by multiplex ligation-dependent probe amplification. CF patients in Japan were found to have chronic sinopulmonary disease (85.6%), exocrine pancreatic insufficiency (66.7%), meconium ileus (35.6%), electrolyte imbalance (21.2%), CF-associated liver disease (14.4%), and CF-related diabetes (6.1%). The median survival age was 25.0 years. The mean BMI percentile was 30.3%ile in definite CF patients aged < 18 years whose CFTR genotypes were known. In 70 CF alleles of East Asia/Japan origin, CFTR-dele16-17a-17b was detected in 24 alleles, the other variants were novel or very rare, and no pathogenic variants were detected in 8 alleles. In 22 CF alleles of Europe origin, F508del was detected in 11 alleles. In summary, clinical phenotype of Japanese CF patients is similar to European patients, but the prognosis is worse. The spectrum of CFTR variants in Japanese CF alleles is entirely different from that in European CF alleles.

Mito-TEMPO, a Mitochondria-Targeted Antioxidant, Improves Cognitive Dysfunction due to Hypoglycemia: an Association with Reduced Pericyte Loss and Blood-Brain Barrier Leakage.

Hypoglycemia is associated with cognitive dysfunction, but the exact mechanisms have not been elucidated. Our previous study found that severe hypoglycemia could lead to cognitive dysfunction in a type 1 diabetes (T1D) mouse model. Thus, the aim of this study was to further investigate whether the mechanism of severe hypoglycemia leading to cognitive dysfunction is related to oxidative stress-mediated pericyte loss and blood-brain barrier (BBB) leakage. A streptozotocin T1D model (150 mg/kg, one-time intraperitoneal injection), using male C57BL/6J mice, was used to induce hypoglycemia. Brain tissue was extracted to examine for neuronal damage, permeability of BBB was investigated through Evans blue staining and electron microscopy, reactive oxygen species and adenosine triphosphate in brain tissue were assayed, and the functional changes of pericytes were determined. Cognitive function was tested using Morris water maze. Also, an in vitro glucose deprivation model was constructed. The results showed that BBB leakage after hypoglycemia is associated with excessive activation of oxidative stress and mitochondrial dysfunction due to glucose deprivation/reperfusion. Interventions using the mitochondria-targeted antioxidant Mito-TEMPO in both in vivo and in vitro models reduced mitochondrial oxidative stress, decreased pericyte loss and apoptosis, and attenuated BBB leakage and neuronal damage, ultimately leading to improved cognitive function.

Liraglutide reduces oxidative stress and improves energy metabolism in methylglyoxal-induced SH-SY5Y cells.

Diabetes mellitus can result in severe complications, such as neurodegenerative diseases including cognitive impairment and dementia. The glucagon-like peptide-1 (GLP-1) receptor agonist, liraglutide, is a novel antidiabetic drug with neuroprotective effects against neurodegenerative diseases. In this study, we explored the protective effect of liraglutide on SH-SY5Y cells exposed to methylglyoxal (MG), a byproduct of glucose metabolism that plays a key role in the development of diabetic encephalopathy. We found that liraglutide reduced the MG-induced oxidative stress, increased the activity of superoxide dismutase (SOD) and expression levels of P22phox, Gp91phox, and Xdh genes, and reduced reactive oxygen species (ROS) content. Metabolomics analysis based on 1H nuclear magnetic resonance showed that liraglutide induced alterations in metabolites involved in energy metabolism，including promotion of gluconeogenesis. Moreover, we found that liraglutide promoted oxidative phosphorylation and inhibited glycolysis in SH-SY5Y cells. This study revealed that liraglutide improved diabetes-related neuropathy damage by reducing the level of oxidative stress and maintaining the balance of energy metabolism, thus offering new insights into the potential mechanism of liraglutide in neuronal protection.

Anti-tumor Necrosis Factor-Alpha Therapy and Hypoglycemia: A Real-World Pharmacovigilance Analysis.

INTRODUCTION: An association between tumor necrosis factor (TNF)-α inhibitors and hypoglycemia has been detected in a few case reports and small case series; however, no relevant pharmacovigilance data have been published yet. OBJECTIVE: The objective of this study was to detect and characterize relevant safety signals between hypoglycemia and TNF-α inhibitor use. METHODS: Indication-focused disproportionality analysis was conducted to detect increased reporting of TNF-α-associated hypoglycemia compared with all other reports with the same indication during the same time period. Reporting odds ratios (RORs) with 95% confidence intervals (CIs) were calculated to determine disproportionality. To reduce potential confounding factors, adjusted RORs were further calculated by logistic regression to control for age, sex, diabetes status, and concomitant drugs that potentially affect blood glucose levels. RESULTS: In all, 1086 adverse drug reactions related to TNF-α inhibitors were reported as 'hypoglycemia'. There were no disproportionality signals of hypoglycemia in TNF-α inhibitor users with indication of inflammatory bowel disease. When TNF-α inhibitors were considered as a class, disproportion for hypoglycemia only emerged in indication of psoriasis (n = 267, ROR 1.20, 95% CI 1.02-1.41). In further analyses of specific TNF-α inhibitor type, significant RORs for hypoglycemia were found in indication of rheumatic disease, including adalimumab in ankylosing spondylitis (n = 37, ROR 1.97, 95% CI 1.28-3.04), psoriasis (n = 160, ROR 1.64, 95% CI 1.37-1.97), and rheumatoid arthritis (n = 230, ROR 1.35, 95% CI 1.16-1.56) and infliximab in psoriasis (n = 18, ROR 2.14, 95% CI 1.33-3.42). After adjusting for confounding factors, only the signals of adalimumab were stable. CONCLUSIONS: Our study identified some potential pharmacovigilance signals between hypoglycemia and TNF-α inhibitors, which warrants further validation.

Integration of Metabolomics and Transcriptomics for Investigating the Tolerance of Foxtail Millet (Setaria italica) to Atrazine Stress.

Foxtail millet (Setaria italica) is a monotypic species widely planted in China. However, residual atrazine, a commonly used maize herbicide, in soil, is a major abiotic stress to millet. Here, we investigated atrazine tolerance in millet based on the field experiments, then obtained an atrazine-resistant variety (Gongai2, GA2) and an atrazine-sensitive variety (Longgu31, LG31). To examine the effects of atrazine on genes and metabolites in millet plants, we compared the transcriptomic and metabolomic profiles between GA2 and LG31 seedling leaves. The results showed that 2,208 differentially expressed genes (DEGs; 501 upregulated, 1,707 downregulated) and 192 differentially expressed metabolites (DEMs; 82 upregulated, 110 downregulate) were identified in atrazine-treated GA2, while in atrazine-treated LG31, 1,773 DEGs (761 upregulated, 1,012 downregulated) and 215 DEMs (95 upregulated, 120 downregulated) were identified. The bioinformatics analysis of DEGs and DEMs showed that many biosynthetic metabolism pathways were significantly enriched in GA2 and LG31, such as glutathione metabolism (oxiglutatione, γ-glutamylcysteine; GSTU6, GSTU1, GSTF1), amino acid biosynthesis (L-cysteine, N-acetyl-L-glutamic acid; ArgB, GS, hisC, POX1), and phenylpropanoid biosynthesis [trans-5-o-(4-coumaroyl)shikimate; HST, C3'H]. Meanwhile, the co-expression analysis indicated that GA2 plants had enhanced atrazine tolerance owing to improved glutathione metabolism and proline biosynthesis, and the enrichment of scopoletin may help LG31 plants resist atrazine stress. Herein, we screened an atrazine-resistant millet variety and generated valuable information that may deepen our understanding of the complex molecular mechanism underlying the response to atrazine stress in millet.

Discovery of AZD4625, a Covalent Allosteric Inhibitor of the Mutant GTPase KRASG12C.

KRAS is an archetypal high-value intractable oncology drug target. The glycine to cysteine mutation at codon 12 represents an Achilles heel that has now rendered this important GTPase druggable. Herein, we report our structure-based drug design approach that led to the identification of 21, AZD4625, a clinical development candidate for the treatment of KRASG12C positive tumors. Highlights include a quinazoline tethering strategy to lock out a bio-relevant binding conformation and an optimization strategy focused on the reduction of extrahepatic clearance mechanisms seen in preclinical species. Crystallographic analysis was also key in helping to rationalize unusual structure-activity relationship in terms of ring size and enantio-preference. AZD4625 is a highly potent and selective inhibitor of KRASG12C with an anticipated low clearance and high oral bioavailability profile in humans.

Bicarbonate transport of airway surface epithelia in luminally perfused mice bronchioles.

HCO3- secretion in distal airways is critical for airway mucosal defense. HCO3-/H+ transport across the apical membrane of airway surface epithelial cells was studied by measuring intracellular pH in luminally microperfused freshly dissected mice bronchioles. Functional studies demonstrated that CFTR, ENaC, Cl--HCO3- exchange, Na+-H+ exchange, and Na+-HCO3- cotransport are involved in apical HCO3-/H+ transport. RT-PCR of isolated bronchioles detected fragments from Cftr, α, ß, γ subunits of ENaC, Ae2, Ae3, NBCe1, NBCe2, NBCn1, NDCBE, NBCn2, Nhe1, Nhe2, Nhe4, Nhe5, Slc26a4, Slc26a6, and Slc26a9. We assume that continuous decline of intracellular pH following alkaline load demonstrates time course of HCO3- secretion into the lumen which is perfused with a HCO3--free solution. Forskolin-stimulated HCO3- secretion was substantially inhibited by luminal application of CFTRinh-172 (5 µM), H2DIDS (200 µM), and amiloride (1 µM). In bronchioles from a cystic fibrosis mouse model, basal and acetylcholine-stimulated HCO3- secretion was substantially impaired, but forskolin transiently accelerated HCO3- secretion of which the magnitude was comparable to wild-type bronchioles. In conclusion, we have characterized apical HCO3-/H+ transport in native bronchioles. We have demonstrated that cAMP-mediated and Ca2+-mediated pathways are involved in HCO3- secretion and that apical HCO3- secretion is largely mediated by CFTR and H2DIDS-sensitive Cl--HCO3- exchanger, most likely Slc26a9. The impairment of HCO3- secretion in bronchioles from a cystic fibrosis mouse model may be related to the pathogenesis of early lung disease in cystic fibrosis.

Serum Fractalkine Levels Were Positively Associated with Disease Severity of Liver Cirrhosis.

OBJECTIVE: The chemokine receptor CX3CR1 and its specific ligand fractalkine (CX3CL1, FKN) has been implicated in modulating inflammatory and fibroproliferative diseases. The current study was performed to investigate the correlation of serum fractalkine levels with disease severity of liver fibrosis/cirrhosis (LC). METHODS: 162 LC patients and 140 healthy controls well enrolled in our study. Serum fractalkine levels were detected using commercial ELISA kit. Liver biopsy specimens were obtained using 16 G disposable needle in LC patients. The Child-Pugh grade was recorded to assess liver function. ROC curve analysis was performed to assess the potential diagnostic power of serum fractalkine with regard to the disease severity of Child-Pugh grade system. Pathological assessment of cirrhotic severity was performed by Laennec staging system. The L3 skeletal muscle index (L3SMI) was applicated to assess the nutrition status. RESULTS: Serum fractalkine levels were significantly higher in LC patients compared with healthy controls. The case group included 50 Child-Pugh A patients, 59 Child-Pugh B patients, and 53 Child-Pugh C patients. Cirrhosis patients with Child-Pugh C had drastically higher serum fractalkine levels compared with those with Child-Pugh B and A. Child-Pugh B patients showed significantly higher serum PACAP concentrations compared with those with Child-Pugh A. ROC curve analysis demonstrated that serum fractalkine may act as a potential indicator for disease progression of LC determined by Child-Pugh classification. Besides, serum fractalkine levels were positively related to ALT and AST concentrations and negatively related to L3SMI. CONCLUSION: Serum fractalkine levels were positively associated with disease severity of LC.

The Characteristics of Iodine Nutrition Status in China After 20 Years of Universal Salt Iodization: An Epidemiology Study Covering 31 Provinces.

Background: Despite the implementation of the universal salt iodization (USI) program for correction of iodine deficiency in China for ∼20 years, the actual iodine nutrition status of Chinese residents and the prevalence of iodine deficiency and iodine excess are issues that need to be addressed. This nationally representative cross-sectional study was conducted across all 31 provinces of mainland China to gather extensive data on iodine nutrition status and the influential factors. Methods: This study included 78,470 participants, aged 18 years or older, who were interviewed and asked to answer a questionnaire. Urine iodine concentration (UIC) was measured by the inductively coupled plasma mass spectrometry method, and goiter was examined by thyroid ultrasonography. In addition, sixty 9-11 years old school children in each province were randomly selected to evaluate the UIC and thyroid ultrasonography. The iodine nutrition status was determined according to the World Health Organization guidelines. Results: The iodized salt coverage was 95.37%. The median urine iodine (MUI) was 177.89 µg/L (interquartile range [IQR], 117.89-263.90 µg/L) and goiter prevalence was 1.17% (confidence interval [95% CI 0.95-1.43]) in the adult population. The MUI was 199.75 µg/L (IQR, 128.41-303.37 µg/L) in school-age children, and goiter prevalence was 3.50% [95% CI, 2.93-4.13]. The percentage of individuals with UIC <50 µg/L was 3.43%, <20%. Analysis indicated that sex, age, geographic factors, body mass index, and smoking habits influence the iodine nutrition level. Conclusion: The mandatory USI program has successfully eliminated iodine deficiency disorders, and the findings indicate that the iodine nutrition level in the general population is within the safe range.

CircCCT3 Acts as a Sponge of miR-613 to Promote Tumor Growth of Pancreatic Cancer Through Regulating VEGFA/VEGFR2 Signaling.

BACKGROUND: Circular RNAs (CircRNAs) have been recently implicated in the progression of pancreatic cancer (PC). AIMS: To investigate the involvement of CircCCT3 in PC and studying its interactions and functioning during the progression of PC in vitro and in vivo, using methods of molecular biology and bioinformatics. STUDY DESIGN: Experimental study. METHODS: The expressions of CircCCT3 and miR-613 in pancreatic carcinoma tissues and cell lines were evaluated by quantitative real-time polymerase chain reaction (PCR). The relationship between clinical pathologic features as well as the survival rate and CircCCT3 expression was analyzed with chi-square test and the Kaplan-Meier method. CCK-8, wound healing, transwell assays, and the fluorescein isothiocyanate- AnnexinV/propidium iodide (FITC-AnnexinV/PI) assay were used to assess cell proliferation, migration, invasion, and apoptosis after CircCCT3 overexpression or downregulation. The Dual- Luciferase reporter assay, RNA immunoprecipitation (RIP), RNA pull-down and fluorescence in situ hybridization (FISH) assays were performed to validate the potential interaction of CircCCT3, miR-613, and vascular endothelial growth factor (VEGFA). The nude mouse xenograft tumor assay was used to detect CircCCT3 effects on pancreatic tumorigenesis in vivo. Western blotting analysis was performed to examine the VEGFA and the vascular endothelial growth factor receptor 2 (VEGFR2) protein expressions following. RESULTS: CircCCT3 expression was significantly increased in PC tissues (3.41 ± 0.57 vs. 1.00 ± 0.10, P < .01) and cell lines (Patu8988 2.57 ± 0.20; SW1990 2.88 ± 0.10; BxPC-3 2.45 ± 0.20; Panc02 2.99 ± 0.10 vs. H6c7 1.00 ± 0.10; all P < .001). CircCCT3 expression was negatively correlated with miR-613 expression. PC patients with high CircCCT3 expression exhibited significantly poorer overall survival rate than those patients with low CircCCT3 expression (P = .013). Moreover, it was found that CircCCT3 promoted cell proliferation, migration, and invasion, and inhibited cell apoptosis in PC cells. The CircCCT3 acted as a sponge for the miR-613 to facilitate VEGFA and VEGFR2 expression. si-CirCCT3 also inhibited tumor growth of PC in nude mice. si-CircCCT3 reduced VEGFA and VEGFR2 expression, whereas overexpression of CircCCT3 increased VEGFA and VEGFR2 expression. CONCLUSION: Increased CircCCT3 suggests a poor prognosis for PC patients and promotes the migration and invasion through targeting VEGFA/VEGFR2 signaling. CircCCT3 may serve as a potential and promising therapeutic target for PC treatment.

Correlation between Thyroid Homeostasis and Obesity in Subclinical Hypothyroidism: Community-Based Cross-Sectional Research.

OBJECTIVE: It remains unknown whether obesity has an effect on the pituitary-thyroid feedback control axis in subclinical hypothyroidism (SCH). We aimed to investigate the association of thyroid homeostasis with obesity in a SCH population. METHODS: Our study consisted of a community-based and cross-sectional study from the Epidemiological Survey of Thyroid Diseases in Fujian Province, China. A total of 193 subjects with SCH (90 males and 103 females) without a history of treatment of thyroid disease, such as surgery, radiation, and thyroid hormone or antithyroid medication, were included in the present study. Indices of obesity, including body mass index (BMI), waist circumference (WC), and waist-height ratio (WHtR) were measured. RESULTS: Our results showed that the secretory capacity of the thyroid gland (SPINA-GT) and Jostel's thyrotropin index (TSHI) were negatively correlated with BMI, WC, and WHtR, whereas the reciprocal of the thyrotroph thyroid hormone resistance index (TTSI-1) was positively correlated with BMI (all p < 0.05). After adjustment for age, sex, smoking, iodine status, and glucolipid metabolism, the associations between TSHI, TTSI (reciprocal transformation), and BMI still persisted (all p < 0.05). CONCLUSIONS: These results suggest that low levels of thyroid homeostasis indexes may be associated with overall obesity in SCH, rather than central adiposity.

Lifestyle is associated with thyroid function in subclinical hypothyroidism: a cross-sectional study.

BACKGROUND: Few studies have focused on the association between lifestyle and subclinical hypothyroidism (SCH). The purpose of this study was to investigate the association between lifestyle and thyroid function in SCH. METHODS: This study was a part of a community-based and cross-sectional study, the Epidemiological Survey of Thyroid Diseases in Fujian Province, China. A total of 159 participants with SCH (81 males and 78 females) and 159 euthyroid (87 males and 72 females) participants without any missing data were included in the analysis. General information and lifestyle information including sleep, exercise, diet and smoking habits of the participants was collected by questionnaire and Pittsburgh sleep quality index scale (PSQI) was collected. Thyroid stimulating hormone (TSH), free thyroxine (FT4), thyroid peroxidase antibody (TPOAb), thyroid globulin antibody (TgAb) and urine iodine concentration (UIC) were tested. Thyroid homeostasis parameter thyroid' s secretory capacity (SPINA-GT), Jostel's TSH index (TSHI), thyrotroph T4 sensitivity index (TTSI) were calculated. Logistic regression and multiple linear regression were performed to assess associations. RESULTS: Compared with euthyroid subjects, patients with SCH were more likely to have poor overall sleep quality (15.1 vs.25.8 %, P = 0.018) and l less likely to stay up late on weekdays (54.7 vs. 23.9 % P < 0.001). In SCH group, exercise was the influencing factor of TSH (ß= -0.224, P = 0.004), thyroid secretory capacity (ß = 0.244, P = 0.006) and thyrotropin resistance (ß = 0.206, P = 0.009). Iodine excess was the influencing factor of thyroid secretory capacity (ß = 0.209, P = 0.001) and pituitary thyroid stimulating function (ß = 0.167, P = 0.034). Smoking was the influencing factor of pituitary thyroid stimulating function (ß = 0.161, P = 0.040). Staying up late on weekends was the influencing factor of thyroid secretory capacity (ß = 0.151, P = 0.047). After adjusting for possible confounders, logistic regression showed that those with poor overall sleep quality assessed by PSQI and iodine excess had an increased risk of SCH (OR 2.159, 95 %CI 1.186-3.928, P = 0.012 and OR 2.119, 95 %CI 1.008-4.456, P = 0.048, respectively). CONCLUSIONS: Lifestyle including sleep, smoking, diet and exercise was closely related to thyroid function especially thyroid homeostasis in SCH.

GLP-1 improves the neuronal supportive ability of astrocytes in Alzheimer's disease by regulating mitochondrial dysfunction via the cAMP/PKA pathway.

The glucagon-like peptide-1 (GLP-1) was shown to have neuroprotective effects in Alzheimer's disease (AD). However, the underlying mechanism remains elusive. Astrocytic mitochondrial abnormalities have been revealed to constitute important pathologies. In the present study, we investigated the role of astrocytic mitochondria in the neuroprotective effect of GLP-1 in AD. To this end, 6-month-old 5 × FAD mice were subcutaneously treated with liraglutide, a GLP-1 analogue (25 nmol/kg/qd) for 8 weeks. Liraglutide ameliorated mitochondrial dysfunction and prevented neuronal loss with activation of the cyclic adenosine 3',5'-monophosphate (cAMP)/phosphorylate protein kinase A (PKA) pathway in the brain of 5 × FAD mice. Next, we exposed astrocytes to ß-amyloid (Aß) in vitro and treated them with GLP-1. By activating the cAMP/PKA pathway, GLP-1 increased the phosphorylation of DRP-1 at the s637 site and mitigated mitochondrial fragmentation in Aß-treated astrocytes. GLP-1 further improved the Aß-induced energy failure, mitochondrial reactive oxygen species (ROS) overproduction, mitochondrial membrane potential (MMP) collapse, and cell toxicity in astrocytes. Moreover, GLP-1 also promoted the neuronal supportive ability of Aß-treated astrocytes via the cAMP/PKA pathway. This study revealed a new mechanism behind the neuroprotective effect of GLP-1 in AD.