Cerebrovascular disease is a potential risk factor for Alzheimer's disease (AD). Although acute cerebral hypoperfusion causes neuronal necrosis and infarction, chronic cerebral hypoperfusion induces apoptosis in neurons, but its effects on the cognitive impairment are not clear. The purpose of this study was to evaluate the effects of chronic cerebral hypoperfusion on AD pathology and cerebral glucose metabolism. A model of chronic cerebral hypoperfusion was established by ligating the common carotid arteries bilaterally in adult male rats (CAL group). Sham-operated rats underwent the same procedures without artery ligation (control group). At 12 weeks after ligation, expression levels of amyloid-β (Aβ) and hyperphosphorylated tau (p-tau), as well as the regional cerebral glucose metabolism, were evaluated using Western blots and positron emission tomography with fluorine-18 fluorodeoxyglucose, respectively. The expression levels of Aβ in the frontal cortex and hippocampus and of p-tau in the temporal cortex were significantly higher in the CAL group than those in the control group. The cerebral glucose metabolism of the amygdala, entorhinal cortex, and hippocampus was significantly decreased in the CAL group compared to that in the control. These results suggest that chronic cerebral hypoperfusion can induce AD pathology and may play a significant role in AD development.

Purpose: New strategies to restore sodium iodide symporter (NIS) expression and function in radioiodine therapy-refractive anaplastic thyroid cancers (ATCs) are urgently required. Recently, we reported the regulatory role of estrogen-related receptor gamma (ERRg) in ATC cell NIS function. Herein, we identified DN200434 as a highly potent (functional IC 50 ¼ 0.006 mmol/L), selective, and orally available ERRg inverse agonist for NIS enhancement in ATC. Experimental Design: We sought to identify better ERRgtargeting ligands and explored the crystal structure of ERRg in complex with DN200434. After treating ATC cells with DN200434, the change in iodide-handling gene expression, as well as radioiodine avidity was examined. ATC tumorbearing mice were orally administered with DN200434, followed by 124 I-positron emission tomography/CT (PET/CT). For radioiodine therapy, ATC tumor-bearing mice treated with DN200434 were administered 131 I (beta ray-emitting therapeutic radioiodine) and then bioluminescent imaging was performed to monitor the therapeutic effects. Histologic analysis was performed to evaluate ERRg expression status in normal tissue and ATC tissue, respectively. Results: DN200434-ERRg complex crystallographic studies revealed that DN200434 binds to key ERRg binding pocket residues through four-way interactions. DN200434 effectively upregulated iodide-handling genes and restored radioiodine avidity in ATC tumor lesions, as confirmed by 124 I-PET/CT. DN200434 enhanced ATC tumor radioiodine therapy susceptibility, markedly inhibiting tumor growth. Histologic findings of patients with ATC showed higher ERRg expression in tumors than in normal tissue, supporting ERRg as a therapeutic target for ATC. Conclusions: DN200434 shows potential clinical applicability for diagnosis and treatment of ATC or other poorly differentiated thyroid cancers.

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Ethnopharmacological Relevance. Morus alba L. leaves (MAE) have been used in fork medicine for the treatment of beriberi, edema, diabetes, hypertension, and atherosclerosis. However, underlying mechanism of MAE on cardiovascular protection remains to be elucidated. Therefore, we investigated whether MAE affect platelet aggregation and thrombosis. Materials and Methods. The anti-platelet activity of MAE was studied using rat platelets. The extent of anti-platelet activity of MAE was assayed in collagen-induced platelet aggregation. ATP and serotonin release was carried out. The activation of integrin α IIb β 3 and phosphorylation of signaling molecules, including MAPK and Akt, were investigated with cytofluorometer and immunoblotting, respectively. The thrombus formation in vivo was also evaluated in arteriovenous shunt model of rats. Results. HPLC chromatographic analysis revealed that MAE contained rutin and isoquercetin. MAE dose-dependently inhibited collagen-induced platelet aggregation. MAE also attenuated serotonin secretion and thromboxane A2 formation. In addition, the extract in vivo activity showed that MAE at 100, 200, and 400 mg/kg significantly and dose-dependently attenuated thrombus formation in rat arterio-venous shunt model by 52.3% (P < 0.001), 28.3% (P < 0.01), and 19.1% (P < 0.05), respectively. Conclusions. MAE inhibit platelet activation, TXB2 formation, serotonin secretion, aggregation, and thrombus formation. The plant extract could be considered as a candidate to anti-platelet and antithrombotic agent.

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An inverse agonist of estrogen-related receptorγ (ERRγ), an orphan nuclear receptor encoded by Esrrg, enhances sodium iodide symporter-mediated radioiodine uptake in anaplastic thyroid cancer (ATC) cells, thereby facilitating responsiveness to radioiodine therapy in vitro. We synthesized potent, selective, and orally bioavailable ERRγinverse agonists and evaluated their activity by analyzing in vitro pharmacology and absorption, distribution, metabolism, excretion, and toxicity profiles. X-ray crystallographic analysis of the ligand and ERRγ complex showed that 35 completely binds to the target protein (PDB 6A6K). Our results showed improved radioiodine avidity in ATC cells through compound 35mediated upregulation of iodide-handling genes, leading to enhanced responsiveness to radioiodine therapy in vitro. Importantly, in vivo 124 I-positron emission tomography/computed tomography imaging revealed that 35 increases radioiodine avidity in CAL62 tumors. Collectively, these results demonstrated that 35 can be developed as a promising treatment for ERRγrelated cancer in the future.

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