Metformin ameliorates mitochondrial damage induced by C9orf72 poly(GR) via upregulating AKT phosphorylation.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are devastating neurodegenerative diseases with no effective cure. GGGGCC repeat expansion in C9orf72 is the most common genetic cause of both ALS and FTD. A key pathological feature of C9orf72 related ALS/FTD is the presence of abnormal dipeptide repeat proteins translated from GGGGCC repeat expansion, including poly Glycine-Arginine (GR). In this study, we observed that (GR)50 conferred significant mitochondria damage and cytotoxicity. Metformin, the most widely used clinical drug, successfully relieved (GR)50 induced mitochondrial damage and inhibited (GR)50 related cytotoxicity. Further research revealed metformin effectively restored mitochondrial function by upregulating AKT phosphorylation in (GR)50 expressed cells. Taken together, our results indicated restoring mitochondrial function with metformin may be a rational therapeutic strategy to reduce poly(GR) toxicity in C9orf72 ALS/FTD patients.

Dinuclear Titanium(III)-Catalyzed Radical-Type Kinetic Resolution of Epoxides for the Enantioselective Synthesis of cis-Glycidic Esters.

Glycidic esters represent pivotal constituents in synthetic chemistry, offering enhanced versatility for tailoring toward a diverse array of molecular targets in comparison with simple epoxides. While considerable progress has been made in the asymmetric synthesis of trans- and trisubstituted glycidic esters, achieving enantioselective preparation of cis-glycidic esters has remained a long-standing challenge. Here, we demonstrate a selectivity-predictable modular platform for the asymmetric synthesis of cis-glycidic esters via a novel dinuclear (salen)titanium(III)-catalyzed radical-type kinetic resolution (KR) approach. This radical KR protocol operates under mild conditions and demonstrates a wide substrate scope, facilitating the synthesis of alkyl- and aryl-substituted cis-glycidic esters with high levels of regioselectivity and enantioselectivity, along with hydroxy ester byproducts representing synthetically valuable motifs as well. This study presents a unique exploration of radical-type KR applied to epoxides, effectively overcoming the steric challenges inherent in conventional nucleophilic-type methodologies typically employed in epoxide chemistry.

Quaternary Stereocenters via Catalytic Enantioconvergent Allylation of Epoxides.

The development of catalytic and enantioselective transformations for the synthesis of all-carbon quaternary stereocenters has long been recognized as a significant challenge in organic synthesis. While considerable progress has been made in asymmetric allylations, their potential to functionalize the commonly used synthon, epoxide, remains largely underexplored. Here we demonstrate the first highly regio- and enantioselective allylation of epoxides that delivers a range of quaternary stereocenters in the face of potentially problematic elimination and protonation reactions. The reaction proceeds via a radical approach under mild conditions and benefits from the use of earth-abundant titanium with a highly sophisticated salen ligand, which facilitates remarkable enantiocontrol and suppresses undesired side reactions. The resulting allylation products are multifunctional building blocks that can be elaborated chemo- and stereoselectively to a broad array of stereodefined structural motifs.

(Salen)Titanium-Catalyzed Asymmetric Hydrogen Atom Transfer for Epoxides Reduction.

Asymmetric hydrogen atom transfer (HAT) represents arguably one of the most straightforward access to the significant chiral tertiary carbon centers, however, remains a long-standing challenge. Herein, the first example of catalytic coordination-induced asymmetric HAT reaction has been developed relying on a sequential (salen)TiIII -initiated radical generation and (salen)TiIV -controlled enantioselective HAT process. The reaction transforms easily accessible glycidic esters, thioesters and amides to synthetically valuable formal formaldehyde aldol adducts in an enantioconvergent manner, along with broad scope and highly regio- and enantioselectivities.

The value of [18F]FDG PET/CT in avoiding overtreatment of 131l avidity pulmonary metastasis of differentiated thyroid cancer.

INTRODUCTION: We usually use 131I-whole body scan (131I-WBS) and serum thyroglobulin (Tg) values to determine whether differentiated thyroid cancer (DTC) patients need to receive 131I treatment, but not all ¹³¹I-avid (functioning) patients have a good response to ¹³¹I therapy. Our study aims to assess the data of [¹8F]fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography ([¹8F] FDG PET/CT) to research the status of 131I-avid pulmonary metastases (PMs) and the prognosis of the patients. MATERIAL AND METHODS: The 131I-avid PMs of DTC patients who underwent [18F]FDG PET/CT scans were included. The maximum standardized uptake value (SUVmax), metabolic tumour volume (MTV), and total lesion glycolysis (TLG) were used to estimate [¹8F]FDG uptake. The mean follow-up period was 34.14 ± 18.64 months. Progression-free survival (PFS) was estimated by the Kaplan-Meier method. The study was based on per-patient and per-lesion analyses. RESULTS: Among the 42 included patients, 34 (34/42, 81%) showed [¹8F]FDG uptake, which was defined as abnormal foci (SUVmax > 1.0) in the lungs. SUVmax, MTV, TLG, and tumour size were the factors that influenced the outcome of 131I treatment based on Tg levels (p = 0.000, 0.016, 0.000, 0.000) in per-lesion analysis. The only independent factor was the size of the lesion. There was a significant difference in response to ¹³¹I therapy between PMs with F-I+ and F+/I+ according to both Tg levels and Response Evaluation Criteria in Solid Tumours (RECIST) (version 1.1) (p = 0.044, 0.001), in the per-lesion analysis. When the changes in size or metabolism of some lesions are inconsistent the prognosis of these patients is poor (p = 0.003). CONCLUSIONS: We concluded that higher [18F]FDG uptake and larger tumour size predict poor therapeutic effects and a high risk of disease progression in ¹³¹I-avid PMs of DTC. For evaluating the efficiency of ¹³¹I treatment, per-lesion analyses and assessing the data of [¹8F] FDG PET/CT would be more reliable than per-patient evaluation only. And early focal treatment modalities may improve their life span.

Role of Lymphangiogenesis in Cardiac Repair and Regeneration.

This article highlights the importance of the structure and function of cardiac lymphatics in cardiovascular diseases and the therapeutic potential of cardiac lymphangiogenesis. Specifically, we explore the innate lymphangiogenic response to damaged cardiac tissue or cardiac injury, derive key findings from regenerative models demonstrating how robust lymphangiogenic responses can be supported to improve cardiac function, and introduce an approach to imaging the structure and function of cardiac lymphatics.

HHEX suppresses advanced thyroid cancer by interacting with TLE3.

Haematopoietically Expressed Homeobox (HHEX) gene is highly expressed in the thyroid gland and plays critical roles in the development and differentiation of the thyroid gland. While it has been indicated to be downregulated in thyroid cancer, its function and the underlying mechanism remain unclear. Herein, we observed low expression and aberrant cytoplasmic localization of HHEX in thyroid cancer cell lines. Knockdown of HHEX significantly enhanced cell proliferation, migration and invasion, while overexpression of HHEX showed the opposite effects in vitro and in vivo. These data provide evidence that HHEX is a tumor suppressor in thyroid cancer. Additionally, our results showed that HHEX overexpression upregulated the expression of sodium iodine symporter (NIS) mRNA and also enhanced NIS promoter activity, suggesting a favorable effect of HHEX in promoting thyroid cancer differentiation. Mechanistically, HHEX exerted a regulatory effect on the expression of transducin-like enhancer of split 3 (TLE3) protein, which inhibited the Wnt/ß-catenin signaling pathway. Nuclear localized HHEX bound to and upregulated TLE3 expression by preventing TLE3 protein from being distributed to the cytoplasm and being ubiquitinated. In conclusion, our study suggested that restoring HHEX expression has the potential to be a new strategy in the treatment of advanced thyroid cancer.

Three-dimensional graphene network deposited with mesoporous nitrogen-doped carbon from non-solvent induced phase inversion for high-performance supercapacitors.

Three-dimensional graphitic carbon materials with controllable composition and hierarchically porous structure are promising electrode materials for supercapacitors. In this work, a modified phase inversion method combined with a calcination process was developed to prepare three-dimensional graphene networks embedded with nitrogen-doped carbon nanoparticles. When used as electrode for supercapacitors, the as-prepared material delivered a high capacitance of 431.9 F g-1 at 0.1 A g-1 and 156.8 F g-1 at 20 A g-1, as well as a stable cyclic behavior with no capacitance decay after 5000 cycles. Such a remakable capacitive performance was attributed to its hierarchically porous structure and proper nitrogen doping content (9.68 ±â€¯0.24 at%), which facilitated the migration of electrolyte ions and provided abundant redox active sites for the faradic reactions. The synthetic strategy may be exploited for the rational design and synthesis of new carbon materials with controlled doping level and three-dimensional porous structure.