Metalated covalent organic frameworks as efficient catalysts for multicomponent tandem reactions.

Multicomponent tandem reactions have become indispensable synthetic methods due to their economic advantages and efficient usage in natural products and drug synthesis. The emergence of metalated covalent organic frameworks (MCOFs) has opened up new opportunities for the advancement of multicomponent tandem reactions. In contrast to commonly used homogeneous transition metal catalysts, MCOFs possess regular porosity, high crystallinity, and rich metal chelation sites that facilitate the uniform distribution and anchoring of metals within their cavities. Thus, they show extremely high activity and have recently been widely employed as catalysts for multicomponent tandem reactions. It is timely to conduct a review of MCOFs in multicomponent tandem reactions, in order to offer guidance and assistance for the synthesis of MCOF catalysts and their application in multicomponent tandem reactions. This review provides a comprehensive overview of the design and synthesis of MCOFs, their application and progress in multicomponent tandem reactions, and the primary challenges encountered during their current development with the aim of contributing to the promotion of the field.

Nanomedicines Promote Cartilage Regeneration in Osteoarthritis by Synergistically Enhancing Chondrogenesis of Mesenchymal Stem Cells and Regulating Inflammatory Environment.

Osteoarthritis (OA) is a degenerative joint disease characterized by progressive erosion of the articular cartilage and inflammation. Mesenchymal stem cells' (MSCs) transplantation in OA treatment is emerging, but its clinical application is still limited by the low efficiency in oriented differentiation. In our study, to improve the therapeutic efficiencies of MSCs in OA treatment by carbonic anhydrase IX (CA9) siRNA (siCA9)-based inflammation regulation and Kartogenin (KGN)-based chondrogenic differentiation, the combination strategy of MSCs and the nanomedicine codelivering KGN and siCA9 (AHK-CaP/siCA9 NPs) was used. In vitro results demonstrated that these NPs could improve the inflammatory microenvironment through repolarization of M1 macrophages to the M2 phenotype by downregulating the expression levels of CA9 mRNA. Meanwhile, these NPs could also enhance the chondrogenesis of bone marrow-derived mesenchymal stem cells (BMSCs) by upregulating the pro-chondrogenic TGF-ß1, ACAN, and Col2α1 mRNA levels. Moreover, in an advanced OA mouse model, compared with BMSCs alone group, the lower synovitis score and OARSI score were found in the group of BMSCs plus AHK-CaP/siCA9 NPs, suggesting that this combination approach could effectively inhibit synovitis and promote cartilage regeneration in OA progression. Therefore, the synchronization of regulating the inflammatory microenvironment through macrophage reprogramming (CA9 gene silencing) and promoting MSCs oriented differentiation through a chondrogenic agent (KGN) may be a potential strategy to maximize the therapeutic efficiency of MSCs for OA treatment.

Phenanthroline-Decorated Covalent Organic Framework for Catalytic Synthesis of 2-Aminobenzothiazoles in Water.

2-Aminobenzothiazoles are widely used in the fields of pharmaceuticals and pesticides. Herein, we report a metal-free protocol for the preparation of 2-aminobenzothiazoles by a covalent organic framework (COF) catalyzed tandem reaction. In the presence of catalytic amount of phenanthroline-decorated COF (Phen-COF), a variety of 2-aminobenzothiazoles are obtained in excellent yields by the cross-coupling of 2-iodoanilines with isothiocyanates at room temperature in water. In addition, the COF-catalyst is very stable and can be reused at least seven times without loss of its catalytic activity.

Construction of Multifunctional Covalent Organic Frameworks for Photocatalysis.

Covalent organic frameworks (COFs) have recently drawn intense attention due to their potential applications in photocatalysis. Herein, we report a multifunctional COF which consists of triphenylamine (TPA) and 2,2'-bipyridine (2, 2'-bipy) entities. The obtained TAPA-BPy-COF is a heterogeneous photocatalyst and can efficiently catalyze the oxidative coupling of thiols to disulfides. In addition, TAPA-BPy-COF can be further metalated by Pd(II) via 2,2'-bipy-metal coordination. The generated Pd@TAPA-BPy-COF can highly promote photocatalytic synthesis of 3-cyanopyridines via cascade addition/cyclization of arylboronic acids with γ-ketodinitriles in heterogeneous way. This work has demonstrated the way for the rational design and preparation of more efficient photoactive COFs for photocatalysis.

Mixed-Linkage Donor-Acceptor Covalent Organic Framework as a Turn-On Fluorescent Sensor for Aliphatic Amines.

Amine determination is crucial to our daily life, including the prevention of pollution, the treatment of certain disorders, and the evaluation of food quality. Herein, a mixed-linkage donor-acceptor covalent organic framework (named DSE-COF) was first constructed by the polymerization between 2,4-dihydroxybenzene-1,3,5-tricarbaldehyde (DTA) and 4,4'-(benzo[c][1,2,5]selenadiazole-4,7-diyl)dianiline (SEZ). DSE-COF displayed superior turn-on fluorescent responses to primary, secondary, and tertiary aliphatic amines, such as cadaverine, isopropylamine, sec-butylamine, cyclohexylamine, hexamethylenediamine, di-n-butylamine, and triethylamine in absolute acetonitrile than other organic species. Further experiments and theoretical calculations demonstrated that the combination of intramolecular charge transfer (ICT) and photoinduced electron transfer (PET) effects between the DSE-COF and aliphatic amines resulted in enhanced fluorescence. Credibly, DSE-COF can quantitatively detect cadaverine content in actual pork samples with satisfactory results. In addition, DSE-COF-based test papers could rapidly monitor cadaverine from real pork samples, manifesting the potential application of COFs in food quality inspection.

CAR-macrophage versus CAR-T for solid tumors: The race between a rising star and a superstar.

Adoptive cell therapy (ACT) has been demonstrated to be one of the most promising cancer immunotherapy strategies due to its active antitumor capabilities in vivo. Engineering T cells to overexpress chimeric antigen receptors (CARs), for example, has shown potent efficacy in the therapy of some hematologic malignancies. However, the efficacy of chimeric antigen receptor T cell (CAR-T) therapy against solid tumors is still limited due to the immunosuppressive tumor microenvironment (TME) of solid tumors, difficulty in infiltrating tumor sites, lack of tumor-specific antigens, antigen escape, and severe side effects. In contrast, macrophages expressing CARs (CAR-macrophages) have emerged as another promising candidate in immunotherapy, particularly for solid tumors. Now at its nascent stage (with only one clinical trial progressing), CAR-macrophage still shows inspiring potential advantages over CAR-T in treating solid tumors, including more abundant antitumor mechanisms and better infiltration into tumors. In this review, we discuss the relationships and differences between CAR-T and CAR-macrophage therapies in terms of their CAR structures, antitumor mechanisms, challenges faced in treating solid tumors, and insights gleaned from clinical trials and practice for solid tumors. We especially highlight the potential advantages of CAR-macrophage therapy over CAR-T for solid tumors. Understanding these relationships and differences provides new insight into possible optimization strategies of both these two therapies in solid tumor treatment.

Ferritin-based nanomedicine for disease treatment.

Ferritin is an endogenous protein which is self-assembled by 24 subunits into a highly uniform nanocage structure. Due to the drug-encapsulating ability in the hollow inner cavity and abundant modification sites on the outer surface, ferritin nanocage has been demonstrated great potential to become a multi-functional nanomedicine platform. Its good biocompatibility, low toxicity and immunogenicity, intrinsic tumor-targeting ability, high stability, low cost and massive production, together make ferritin nanocage stand out from other nanocarriers. In this review, we summarized ferritin-based nanomedicine in field of disease diagnosis, treatment and prevention. The different types of drugs to be loaded in ferritin, as well as drug-loading methods were classified. The strategies for site-specific and non-specific functional modification of ferritin were investigated, then the application of ferritin for disease imaging, drug delivery and vaccine development were discussed. Finally, the challenges restricting the clinical translation of ferritin-based nanomedicines were analyzed.

Anti-inflammatory therapeutic biomarkers identified of human bone marrow mesenchymal stem cell therapy on aging mice by serum proteomics and peptidomics study.

Aging is accompanied by deterioration in physical condition, and creates high risks of diseases. Stem cell therapy exhibited promising potential in delaying aging. However, the unelucidated therapeutic mechanism limits future clinical application. Herein, to systematically understand the response to stem cell transfusion at the molecular level, we performed quantitative serum proteomic and peptidomics analyses in the 24-month-old aging mice model with or without mesenchymal stem cell (MSC) treatment. As a result, a total of 560 proteins and 2131 endogenous peptides were identified, among which, 6 proteins and 9 endogenous peptides derived from 6 precursor proteins were finally identified as therapeutic biomarkers after MSC transfusion on aging mice both by untargeted label-free quantification and targeted parallel reaction monitoring (PRM) quantification. Amazingly, the biological function of these differential proteins was mainly related to inflammation, which is not only the important hallmark of aging, but also the main cause of inducing aging. The reduction of these inflammatory protein content after MSC treatment further suggests the anti-inflammatory effect of MSC therapy reported elsewhere. Therefore, our study provides new evidence for the anti-inflammatory effect of MSC therapy for anti-aging and offers abundant data to support deeper investigations of the therapeutic mechanism of MSC in delaying aging.

Nanomedicines Reprogram Synovial Macrophages by Scavenging Nitric Oxide and Silencing CA9 in Progressive Osteoarthritis.

Osteoarthritis (OA) is a progressive joint disease characterized by inflammation and cartilage destruction, and its progression is closely related to imbalances in the M1/M2 synovial macrophages. A two-pronged strategy for the regulation of intracellular/extracellular nitric oxide (NO) and hydrogen protons for reprogramming M1/M2 synovial macrophages is proposed. The combination of carbonic anhydrase IX (CA9) siRNA and NO scavenger in "two-in-one" nanocarriers (NAHA-CaP/siRNA nanoparticles) is developed for progressive OA therapy by scavenging NO and inhibiting CA9 expression in synovial macrophages. In vitro experiments demonstrate that these NPs can significantly scavenge intracellular NO similar to the levels as those in the normal group and downregulate the expression levels of CA9 mRNA (≈90%), thereby repolarizing the M1 macrophages into the M2 phenotype and increasing the expression levels of pro-chondrogenic TGF-ß1 mRNA (≈1.3-fold), and inhibiting chondrocyte apoptosis. Furthermore, in vivo experiments show that the NPs have great anti-inflammation, cartilage protection and repair effects, thereby effectively alleviating OA progression in both monoiodoacetic acid-induced early and late OA mouse models and a surgical destabilization of medial meniscus-induced OA rat model. Therefore, the siCA9 and NO scavenger "two-in-one" delivery system is a potential and efficient strategy for progressive OA treatment.

Resveratrol improves diabetes-induced cognitive dysfunction in part through the miR-146a-5p/TXNIP axis.

Resveratrol (RSV) has been shown to have a neuroprotective effect in various central nervous system disorders, although the role of RSV in diabetes-induced cognitive dysfunction is still not fully elucidated. Here, we investigated whether RSV improved diabetes-related cognitive dysfunction in vivo and in vitro. We induced a rat diabetic model with a high-fat and high-sucrose diet followed by intraperitoneal injection of streptozotocin and a diabetic neuron cell model by stimulation with high levels of glucose. We observed that RSV improved impairment in spatial learning and memory in the Morris water maze test (MWM) and novel object recognition test (ORT) in diabetic rats. RSV reversed the reduced miR-146a-5p and upregulated thioredoxin-interacting protein (TXNIP) and inhibited the diabetes-induced increase in interleukin (IL)-1ß and tumor necrosis factor (TNF)-α levels in vivo and in vitro. RSV also inhibited diabetes-induced endoplasmic reticulum stress (ESR) by reducing ESR-related protein expression in vivo and in vitro. Moreover, inhibition of miR-146a-5p partially abolished the protective effects of RSV in HG-treated primary neurons. Additionally, we used starBase to predict that miR-146a-5p interacts with TXNIP, which we then verified using a luciferase reporter gene assay. We further observed that miR-146a-5p regulates the mRNA and protein expression of TXNIP in vitro, indicating that the miR-146a-5p/TXNIP axis is involved in the regulation of cognitive dysfunction in a rat diabetic model. Collectively, these results demonstrate that RSV plays a neuroprotective role in diabetes-associated cognitive dysfunction at least in part through regulation of the miR-146a-5p/TXNIP axis.

Regeneration mechanism of a novel high-performance biochar mercury adsorbent directionally modified by multimetal multilayer loading.

Biochar that is directly obtained by pyrolysis exhibits a low adsorption efficiency; furthermore, the process of recycling adsorbents is ineffective. To solve these problems, conventional chemical coprecipitation, sol-gel, multimetal multilayer loading and biomass pyrolysis coking processes have been integrated. After selecting specific components for structural design, a novel high-performance biochar adsorbent was obtained. The effects of the O2 concentration and temperature on the regeneration characteristics were explored. An isothermal regeneration method to repair the deactivated adsorbent in a specific atmosphere was proposed, and the optimal regeneration mode and conditions were determined. The microscopic characteristics of the regenerated samples were revealed along with the mechanism of Hg0 removal and regeneration by using temperature-programmed desorption technology and adsorption kinetics. The results show that doping multiple metals can reduce the pyrolysis reaction barrier of the modified biomass. On the modified surface of the sample, the doped metals formed aggregated oxides, and the resulting synergistic effect enhanced the oxidative activity of the biochar carriers and the threshold effect of Ce oxide. The optimal regeneration conditions (5% O2 and 600 °C) effectively coordinated the competitive relationship between the deep carbonization process and the adsorption/oxidation site repair process; in addition, these conditions provided outstanding structure-effect connections between the physico-chemical properties and Hg0 removal efficiency of the regenerated samples. Hg0 adsorption by the regenerated samples is a multilayer mass transfer process that involves the coupling of physical and chemical effects, and the surface adsorption sites play a leading role.

ITGA5 Promotes Tumor Progression through the Activation of the FAK/AKT Signaling Pathway in Human Gastric Cancer.

Background: ITGA5 is an adhesion molecule that integrates the intracellular structures with the extracellular matrix to perform biological functions. However, ITGA5 is highly expressed in a variety of tumors and is involved in tumor progression by promoting cell proliferation and metastasis. Nevertheless, little research has been performed on its function in gastric cancer. Therefore, the aim of this study was to investigate the role of ITGA5 in gastric cancer, focusing on the mechanism regulating the proliferation, invasion and migration. Methods: The expression of ITGA5 in gastric cancer tissues was assessed by the use of molecular bioinformatics databases and high-throughput sequencing of gastric cancer tissues from patients. Western blot, qPCR, and immunohistochemistry were performed to detect the expression of ITGA5 in samples from gastric cancer patients and gastric cancer cell lines. Furthermore, the ITGA5 gene was silenced and overexpressed in gastric cancer cells, and the effect on proliferation, invasion, migration, and tumorigenic ability was assessed. Results: ITGA5 mRNA and protein expression were upregulated in gastric cancer cell lines and tissues from patients, and its expression was closely associated with tumor size, lymph node metastasis, and TNM stage. In vitro and in vivo experiments showed that ITGA5 silencing resulted in the inhibition of proliferation, invasion, migration, and graft growth of gastric cancer cells; conversely, the overexpression resulted in the promotion of these cell functions. Our results finally showed that the effect of ITGA5 on proliferation, invasion, and migration of gastric cancer cells was performed through the activation of the FAK/AKT pathway. Conclusions: ITGA5 promotes proliferation, invasion, and migration of gastric cancer cells through the activation of FAK/AKT signaling pathway, suggesting that ITGA5 may be potentially considered as a new target in gastric cancer therapy.

Brain structural and functional connectivity alterations are associated with fatigue in neuromyelitis optica spectrum disorder.

BACKGROUND: Many patients with neurological disorders experience chronic fatigue, but the neural mechanisms involved are unclear. OBJECTIVE: Here we investigated whether the brain structural and functional connectivity alterations were involved in fatigue related to neuromyelitis optica spectrum disorder (NMOSD). METHODS: This prospective pilot study used structural and resting-state functional brain magnetic resonance imaging to compare total cortical thickness, cortical surface area, deep gray matter volume and functional connectivity (FC) between 33 patients with NMOSD and 20 healthy controls (HCs). Patients were subgrouped as low fatigue (LF) and high fatigue (HF). RESULTS: HF patients scored higher on the Hamilton Anxiety Rating Scale and Hamilton Rating Scale for Depression than LF patients and HCs. The two patient subgroups and HC group did not differ significantly in cortical thickness, cortical surface area and volumes of the bilateral caudate nucleus, bilateral putamen, bilateral amygdala, bilateral hippocampus, bilateral thalamus proper or right nucleus accumbens (p > 0.05). However, after correcting for age, sex, years of education, anxiety and depression, HF patients showed larger left pallidum than HCs (0.1573 ± 0.0214 vs 0.1372 ± 0.0145, p = 0.009). Meanwhile, both LF patients (0.0377 ± 0.0052 vs 0.0417 ± 0.0052, p = 0.009) and HF patients (0.0361 ± 0.0071 vs 0.0417 ± 0.0052, p = 0.013) showed smaller left nucleus accumbens than HCs.. Compared with LF patients, HF patients showed significantly decreased FC between the left pallidum and bilateral cerebellar posterior lobes. CONCLUSIONS: This was the first evidence linking structural and functional alterations in the brain to fatigue in NMOSD, and in the future, long term follow-up was necessary.

Synthesis of Metal-Free Chiral Covalent Organic Framework for Visible-Light-Mediated Enantioselective Photooxidation in Water.

Although chiral covalent organic frameworks (CCOFs) presence grows in thermal asymmetric catalysis, their application in equally important asymmetric photocatalysis has yet to begin. Herein, we first report a propargylamine-linked and quaternary ammonium bromide decorated porphyrin-CCOF which can highly promote visible-light-driven enantioselective photooxidation of sulfides to sulfoxides in water and in air. This methodology has also been applied to the synthesis of (R)-modafinil, a wakefulness-promoting medication used for the treatment of excessive sleepiness. This research might open a new way for the application of CCOFs in asymmetric photocatalysis.

Non-viral vectors for RNA delivery.

RNA-based therapy is a promising and potential strategy for disease treatment by introducing exogenous nucleic acids such as messenger RNA (mRNA), small interfering RNA (siRNA), microRNA (miRNA) or antisense oligonucleotides (ASO) to modulate gene expression in specific cells. It is exciting that mRNA encoding the spike protein of COVID-19 (coronavirus disease 2019) delivered by lipid nanoparticles (LNPs) exhibits the efficient protection of lungs infection against the virus. In this review, we introduce the biological barriers to RNA delivery in vivo and discuss recent advances in non-viral delivery systems, such as lipid-based nanoparticles, polymeric nanoparticles, N-acetylgalactosamine (GalNAc)-siRNA conjugate, and biomimetic nanovectors, which can protect RNAs against degradation by ribonucleases, accumulate in specific tissue, facilitate cell internalization, and allow for the controlled release of the encapsulated therapeutics.

Non-Conventional Fluorescence and Cytotoxicity of Two Aliphatic Hyperbranched Polymer Dots Having Poly(amic acid) Structures: Implications for Labeling Nanodrug Carriers.

In this study, we used one-pot A2 + B3 polymerizations to synthesize two aliphatic + alicyclic polymer dots (PDs) having non-conjugated hyperbranched structures, employing two types of dianhydrides as the A2 components, possessing bridged bicyclic alkene (PD-BT) and non-alkene (PD-ET) units, and Jeffamine T403 polyetheramine (T403) as the B3 components. We prepared PD-ET from commercially available ethylenediaminetetraacetic dianhydride (EDTAD, A2) and T403 (B3) and PD-BT from bicyclo[2.2.2]oct-7-ene-2,3,5,6-tetracarboxylic dianhydride (BCDA, A2) and T403 (B3). These two types of PDs possessed non-conjugated hyperbranched poly(amic acid) structures with terminal amino functional groups. PD-BT and PD-ET exhibited non-conventional fluorescence with emissions at 435 and 438 nm, respectively, and quantum yields of 12.8 and 14.0%, respectively. The fluorescence intensity of PD-ET was influenced by the pH, but PD-BT was less affected because of its rigid aliphatic bridged bicyclic structure. In aqueous solutions, the sizes of the PD-BT and PD-ET nanoparticles were 3-5 nm, and their net charges can be adjusted by varying the pH. These PDs were non-cytotoxic toward human MCF-7 breast cancer cells and human keratinocyte HaCaT cells at concentrations of 50 µg mL-1 for PD-BT and 500 µg mL-1 for PD-ET. Confocal microscopic bioimaging revealed that the PDs were located within the cells after treatment for 6 h. These PDs were easy to prepare, highly water-soluble, and possessed a large number of peripheral functional groups for further modification. Combined with their non-conventional fluorescence, they appear to have potential uses in bioimaging and as drug-labeling carriers.

Enhanced cancer therapeutic efficiency of NO combined with siRNA by caspase-3 responsive polymers.

The combination of nitric oxide (NO) and siRNA is highly desirable for cancer therapy. Here, the furoxans-grafted PEI polymer (FDP) with caspase-3 responsive cleavable DEVD linker was synthesized, and used to bind siRNAs via electrostatic interaction and self-assembled into FDP/siRNA nanoplexes by hydrophobic force. After cellular uptake and lysosomal escape, the FDP/siRNA nanoplexes could achieve GSH-triggered NO release, and then increase the activity of caspase-3. The activated caspase-3 could specifically cleave the DEVD peptide sequence and enhance cell apoptosis. With the cleavage of DEVD peptide sequence, the disassembly of FDP/siRNA nanoplexes was further promoted, thereby resulting in increased siRNAs of ~40% were released at 48 h compared with the caspase-3 non-responsive FDnP/siRNA nanoplexes. By this way, cell apoptosis promotion and cell proliferation inhibition was achieved by siRNA-based downregulation of EGFR protein and the upregulated activity of caspase-3, followed by the enhanced cascade release of NO from FDP/siRNA nanoplexes. Furthermore, in vivo results demonstrated the improved anti-cancer efficiency of FDP/siEGFR nanoplexes without any detectable side effects. Therefore, it is believed that the caspase-3 responsive cleavable furoxans-grafted PEI polymers could provide a potential and efficient enhancement for cancer therapeutic efficiency by the co-delivery of nitric oxide and siRNA.

Engineering a "three-in-one" hirudin prodrug to reduce bleeding risk: A proof-of-concept study.

An ideal anticoagulant should have at least three properties including targeted delivery to the thrombosis site, local activation or releasing to centralize the anti-thrombosis effects and thus reduce the bleeding risks, and long persistence in circulation to avoid repeated administration. In the present study, we sought to test a "three-in-one" strategy to design new protein anticoagulants. Based on these criteria, we constructed two hirudin prodrugs, R824-HV-ABD and ABD-HV-R824. The R824 peptide can bind phosphatidylserine on the surface of the procoagulant platelets and thus guide the prodrug to the thrombosis sites; albumin-binding domain (ABDs) can bind the prodrug to albumin, and thereby increase its persistence in circulation; the hirudin (HV) core in the prodrug is flanked by factor Xa recognition sites, thus factor Xa at the thrombosis site can cleave the fusion proteins and release the activated hirudin locally. Hirudin prodrugs were able to bind with procoagulant platelets and human serum albumin in vitro with high affinity, targeted concentrated and prevented the formation of occlusive thrombi in rat carotid artery injury model. Their effective time was significantly extended compared to native hirudin, and R824-HV-ABD showed a significantly improved half-life of about 24 h in rats. The bleeding time of prodrug-treated mice was much shorter than that of hirudin-treated mice. The results from the proof-of-concept studies, for the first time, demonstrate that "three-in-one" prodrug strategy may be a good solution for protein or peptide anticoagulants to reduce their bleeding risks.

SIMPLE Is an Endosomal Regulator That Protects Against NAFLD by Targeting the Lysosomal Degradation of EGFR.

BACKGROUND AND AIMS: NAFLD has become a tremendous burden for public health; however, there is no drug for NAFLD therapy at present. Impaired endo-lysosome-mediated protein degradation is observed in a variety of metabolic disorders, such as atherosclerosis, type 2 diabetes mellitus, and NAFLD. Small integral membrane protein of lysosome/late endosome (SIMPLE) is a regulator of endosome-to-lysosome trafficking and cell signaling, but the role that SIMPLE plays in NAFLD progression remains unknown. Here we investigated SIMPLE function in NAFLD development and sophisticated mechanism therein. APPROACH AND RESULTS: This study found that in vitro knockdown of SIMPLE significantly aggravated lipid accumulation and inflammation in hepatocytes treated with metabolic stimulation. Consistently, in vivo experiments showed that liver-specific Simple-knockout (Simple-HKO) mice exhibited more severe high-fat diet (HFD)-induced, high-fat-high-cholesterol diet (HFHC)-induced, and methionine-choline-deficient diet (MCD)-induced steatosis, glucose intolerance, inflammation, and fibrosis than those fed with normal chow (NC) diet. Meanwhile, RNA-sequencing demonstrated the up-regulated signaling pathways and signature genes involved in lipid metabolism, inflammation, and fibrosis in Simple-HKO mice compared with control mice under metabolic stress. Mechanically, we found SIMPLE directly interact with epidermal growth factor receptor (EGFR). SIMPLE deficiency results in dysregulated degradation of EGFR, subsequently hyperactivated EGFR phosphorylation, thus exaggerating NAFLD development. Moreover, we demonstrated that using EGFR inhibitor or silencing EGFR expression could ameliorate lipid accumulation induced by the knockdown of SIMPLE. CONCLUSIONS: SIMPLE ameliorated NASH by prompting EGFR degradation and can be a potential therapeutic candidate for NASH.

Retrotransverse Foramen and Retrotransverse Groove Anatomic Variations of the Atlas Vertebra in the Chinese Population.

OBJECTIVE: To analyze the prevalence of retrotransverse foramen (RTF) or retrotransverse groove (RTG) anatomic variations in Chinese atlas vertebra (C1). METHODS: Three-dimensional volume-rendered computed tomography angiography images of 427 subjects (264 males, 163 females; 17-87 years old) were reviewed and evaluated using dedicated software. The prevalence of RTF and RTG anatomic variation of C1 was analyzed. RESULTS: RTF anatomic variants were present in 50 (11.7%) atlases. Bilateral RTF, unilateral left RTF, and unilateral right RTF were present in 16 (3.8%), 20 (4.9%), and 14 (3.3%) vertebrae. Comparison between males and females revealed differences in bilateral RTF (P = 0.010) and unilateral left RTF (P = 0.008). RTG anatomic variants were present in 113 (26.5%) atlases. Bilateral RTG, unilateral left RTG, and unilateral right RTG were present in 39 (9.1%), 30 (7.0%), and 44 (10.3%) vertebrae. Comparison between males and females revealed differences in RTG (P = 0.000), bilateral RTG (P = 0.006), and unilateral left RTG (P = 0.034). RTF was detected in 36 cases on the left and 30 cases on the right. RTG was detected in 69 cases on the left and 79 cases on the right. There were no side differences in the prevalence of RTF and RTG. CONCLUSIONS: The incidence of RTG is higher than the incidence of RTF. Incidence of bilateral RTF, bilateral RTG, unilateral left RTF, unilateral left RTG, and RTG differed between males and females. Preoperative understanding of these variations using three-dimensional computed tomography angiography is helpful for safe execution of upper cervical posterior approach surgery.