Critical roles of FTO-mediated mRNA m6A demethylation in regulating adipogenesis and lipid metabolism: Implications in lipid metabolic disorders.

The goal this review is to clarify the effects of the fat mass and obesity-associated protein (FTO) in lipid metabolism regulation and related underlying mechanisms through the FTO-mediated demethylation of m6A modification. FTO catalyzes the demethylation of m6A to alter the processing, maturation and translation of the mRNAs of lipid-related genes. FTO overexpression in the liver promotes lipogenesis and lipid droplet (LD) enlargement and suppresses CPT-1-mediated fatty acid oxidation via the SREBP1c pathway, promoting excessive lipid storage and nonalcoholic fatty liver diseases (NAFLD). FTO enhances preadipocyte differentiation through the C/EBPß pathway, and facilitates adipogenesis and fat deposition by altering the alternative splicing of RUNX1T1, the expression of PPARγ and ANGPTL4, and the phosphorylation of PLIN1, whereas it inhibits lipolysis by inhibiting IRX3 expression and the leptin pathway, causing the occurrence and development of obesity. Suppression of the PPARß/δ and AMPK pathways by FTO-mediated m6A demethylation damages lipid utilization in skeletal muscles, leading to the occurrence of diabetic hyperlipidemia. m6A demethylation by FTO inhibits macrophage lipid influx by downregulating PPARγ protein expression and accelerates cholesterol efflux by phosphorylating AMPK, thereby impeding foam cell formation and atherosclerosis development. In summary, FTO-mediated m6A demethylation modulates the expression of lipid-related genes to regulate lipid metabolism and lipid disorder diseases.

Long-term adenosine A1 receptor activation-induced sortilin expression promotes α-synuclein upregulation in dopaminergic neurons.

Prolonged activation of adenosine A1 receptor likely leads to damage of dopaminergic neurons and subsequent development of neurodegenerative diseases. However, the pathogenesis underlying long-term adenosine A1 receptor activation-induced neurodegeneration remains unclear. In this study, rats were intraperitoneally injected with 5 mg/kg of the adenosine A1 receptor agonist N6-cyclopentyladenosine (CPA) for five weeks. The mobility of rats was evaluated by forced swimming test, while their cognitive capabilities were evaluated by Y-maze test. Expression of sortilin, α-synuclein, p-JUN, and c-JUN proteins in the substantia nigra were detected by western blot analysis. In addition, immunofluorescence staining of sortilin and α-synuclein was performed to detect expression in the substantia nigra. The results showed that, compared with adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (5 mg/kg) + CPA co-treated rats, motor and memory abilities were reduced, surface expression of sortin and α-synuclein in dopaminergic neurons was reduced, and total sortilin and total α-synuclein were increased in CPA-treated rats. MN9D cells were incubated with 500 nM CPA alone or in combination with 10 µM SP600125 (JNK inhibitor) for 48 hours. Quantitative real-time polymerase chain reaction analysis of sortilin and α-synuclein mRNA levels in MN9D cells revealed upregulated sortilin expression in MN9D cells cultured with CPA alone, but the combination of CPA and SP600125 could inhibit this expression. Predictions made using Jasper, PROMO, and Alibaba online databases identified a highly conserved sequence in the sortilin promoter that was predicted to bind JUN in both humans and rodents. A luciferase reporter assay of sortilin promoter plasmid-transfected HEK293T cells confirmed this prediction. After sortilin expression was inhibited by sh-SORT1, expression of p-JUN and c-JUN was detected by western blot analysis. Long-term adenosine A1 receptor activation levels upregulated α-synuclein expression at the post-transcriptional level by affecting sortilin expression. The online tool Raptor-X-Binding and Discovery Studio 4.5 prediction software predicted that sortilin can bind to α-synuclein. Co-immunoprecipitation revealed an interaction between sortilin and α-synuclein in MN9D cells. Our findings indicate that suppression of prolonged adenosine A1 receptor activation potently inhibited sortilin expression and α-synuclein accumulation, and dramatically improved host cognition and kineticism. This study was approved by the University Committee of Animal Care and Supply at the University of Saskatchewan (approval No. AUP#20070090) in March 2007 and the Animals Ethics Committee of University of South China (approval No. LL0387-USC) in June 2017.

The zonal pattern of arterial supply to the brachial plexus and its clinical significance.

PURPOSE: To provide the anatomical basis of blood supply of brachial plexus for the clinical microsurgical treatment of brachial plexus injury. METHODS: Thirteen adult anticorrosive cadaveric specimens (8 males, 5 females) were dissected in this study. 3 fresh cases (2 males, 1 female) were used to observe the zonal pattern of arteries supplying brachial plexus, and 10 cases (6 males, 4 females) were used to observe the source and distribution of the brachial plexus arteries under microscope. RESULTS: The brachial plexus is supplied by branches of the subclavian-axillary axis (SAA), and these branches anastomose each other. According to distribution feature, blood supply of the brachial plexus could be divided into three zones. The first zone was from the nerve roots of intervertebral foramina to its proximal trunks, which was supplied by the vertebral artery and the deep cervical artery. The second zone was from the distal nerve trunks of the brachial plexus, encompassing the divisions to its proximal cords, which was supplied by direct branches of the subclavian artery or by branches originating from the dorsal scapular artery. The third zone was from the distal portion of the cords to terminal branches of the brachial plexus, which was supplied by direct branches of the axillary artery. CONCLUSIONS: The zonal pattern of arterial supply to the brachial plexus is a systematic and comprehensive modality to improve anatomical basis for the clinical microsurgical treatment for brachial plexus injury.

Microanatomy of the brachial plexus roots and its clinical significance.

PURPOSE: To provide the anatomical basis of brachial plexus roots for the diagnosis and treatment of brachial plexus root avulsion injury. METHODS: The morphological features of brachial plexus roots were observed and measured on 15 cervicothoracic spine of adult cadavers. The relationship of brachial plexus nerve roots and the surrounding tissues also were observed, as well as the blood supply of anterior and posterior roots of the brachial plexus. RESULTS: Origination of the nerve roots in the dorsal-ventral direction from the midline was fine-tuned at each level along the spinal cord. The minimum distance of the origin of the nerve root to midline was 2.2 mm at C 5, while the maximum was 3.1 mm at T 1. Inversely, the distance between the origin of the posterior root and the midline of the spinal cord gradually decreased, the maximum being 4.2 mm at C 5 and minimum 2.7 mm at T 1. Meanwhile, there was complicated fibrous connection among posterior roots of the brachial plexus. The C 5-6 nerve roots interlaced with tendons of the scalenus anterior and scalenus medius and fused with the transverse-radicular ligaments in the intervertebral foramina. However, these ligaments were not seen in C 7-8, and T 1. The blood supply of the anterior and posterior roots of the brachial plexus was from the segmental branches of the vertebral artery, deep cervical artery and ascending cervical artery, with a mean outer diameter of 0.61 mm. CONCLUSIONS: The systematic and comprehensive anatomic data of the brachial plexus roots provides the anatomical basis to diagnose and treat the brachial plexus root avulsion injury.

Sortilin: A novel regulator in lipid metabolism and atherogenesis.

Several lines of evidence have shown that SORT1 gene within 1p13.3 locus is an important modulator of the low-density lipoprotein-cholesterol (LDL-C) level and atherosclerosis risk. Here, we summarize the effects of SORT1, which codes for sortilin, on lipid metabolism and development of atherosclerosis and explore the mechanisms underlying sortilin effects on lipid metabolism especially in hepatocytes and macrophages. Recent epidemiological evidence demonstrated that sortilin has been implicated as the causative factor and regulates lipid metabolism in vivo. Hepatic sortilin overexpression leads to both increased and decreased LDL-C levels by several different mechanisms, suggesting the complex roles of sortilin in hepatic lipid metabolism. Macrophage sortilin causes internalization of LDL and probably a reduction in cholesterol efflux, resulting in the intracellular accumulation of excessive lipids. In addition, sortilin deficiency in an atherosclerotic mouse model results in decreased aortic atherosclerotic lesion. Sortilin involves in lipid metabolism, promotes the development of atherosclerosis, and possibly becomes a potential therapeutic target for atherosclerosis treatment.

Applied anatomical study of the vascularized ulnar nerve and its blood supply for cubital tunnel syndrome at the elbow region.

Cubital tunnel syndrome is often accompanied by paresthesia in ulnar nerve sites and hand muscle atrophy. When muscle weakness occurs, or after failure of more conservative treatments, anterior transposition is used. In the present study, the ulnar nerve and its blood vessels were examined in the elbows of 18 adult cadavers, and the external diameter of the nutrient vessels of the ulnar nerve at the point of origin, the distances between the origin of the vessels and the medial epicondyle of the humerus, and the length of the vessels accompanying the ulnar nerve in the superior ulnar collateral artery, the inferior ulnar collateral artery, and the posterior ulnar recurrent artery were measured. Anterior transposition of the vascularized ulnar nerve was performed to treat cubital tunnel syndrome. The most appropriate distance that the vascularized ulnar nerve can be moved to the subcutaneous tissue under tension-free conditions was 1.8 ± 0.6 cm (1.1-2.5 cm), which can be used as a reference value during the treatment of cubital tunnel syndrome with anterior transposition of the vascularized ulnar nerve.

Three-dimensional visualization of the cutaneous angiosome using angiography.

The purpose of this study was to establish the three-dimensional (3D) architecture of the cutaneous angiosome for assessment and design of the perforator flaps. Two fresh cadavers were injected with carboxymethyl cellulose (CMC)/lead oxide and computed tomography (CT) scanned before and after the injection. The various parts of the cutaneous and subcutaneous tissue derived from one of the injected cadavers were also CT scanned. Three-dimensional reconstruction of the cutaneous angiosome and the two flap designs were performed using Materialise's Interactive Medical Image Control System (MIMICS). Both the reconstructed cutaneous angiosomes and the digital flaps can be displayed independently or in conjunction with bones, source arteries, and skin. The 3D architecture of the cutaneous angiosome ensures clear display of the spatial location, distribution range, and anastomoses relationship of the cutaneous perforators. In addition, the caliber, length, and position of a particular source artery are illustrated in the exact spatial location. As a result, the technique provides visualization of the general area and the expandable direction of a respective flap. This technique has the potential to play an important role in assessing perforator blood supply territory and in the design of new flaps.

Anatomical study to the vessels of the lower limb by using CT scan and 3D reconstructions of the injected material.

PURPOSE: To find out the advantages and insufficiency of the 3D reconstruction and traditional anatomy by comparing them with each other. METHODS: 1. Infused with the radio-opaque material from the arteries and veins, respectively, fresh lower extremity specimens were subjected to spiral CT scanning and then 3D reconstruction was conducted to obtain 3D vessels. 2. Anatomizing the specimens to show the vessel system. 3. Comparing the images of 3D reconstruction and photos of the dissected specimens. RESULTS: 3D software could dissect and reconstruct the bones, vessels, skin and muscles, and the reconstructed photos could be shown, respectively or combinedly. On the other hand, the course, distribution, and anastomoses of the vessels could be viewed from different aspects and different layers, but the results were not completely correct, so they were not suitable for data acquisition. While the vessel systems could be observed clearly on the dissected specimens, so could the origin, course, distribution and the anastomoses of any vessel. The data acquisition could be conducted. CONCLUSIONS: The method of angiography with 3D reconstruction is very good and has considerable advantages for observing the 3D state of human blood vessels, and their distribution at different angles and different levels, but it cannot totally represent or replace the traditional dissected specimens.

Measurement and analysis of the perforator arteries in upper extremity for the flap design.

The aim of this study was to provide the anatomical basis for the skin flap pedicled with the nutrient vessels of the cutaneous nerves and cutaneous veins of the upper extremity. Radio-opaque material was injected into the common carotid arteries of five fresh cadavers. The skin and the fascia were meticulously dissected, removed, and radiographed. The Photoshop CS and Scion image 4.02 were used to analyze the cutaneous arteries, the density of vessels, and the vascular territories of the perforator arteries. The results showed that the cutaneous arteries of the upper extremity came from 16 original arteries, and accordingly, the superficial tissue of the upper extremity could be divided into 16 vascular territories. The external diameter and the area of blood supply of each perforator were growing downwards from the proximum to the distal end. But the points at which the perforator arteries came out from the deep tissue were concentrated near the cutaneous nerves and cutaneous veins, and the arteries formed vascular chains. The density of the arteries near the cutaneous nerves and cutaneous veins was much higher than that of other areas. This article discussed the regularity of the nutrient vessels of the cutaneous nerves and veins on the basis of the experimental results.

Demonstration of three injection methods for the analysis of extrinsic and intrinsic blood supply of the peripheral nerve.

BACKGROUND: The use of free vascularized nerve grafts requires an intimate and accurate knowledge of the blood supply of peripheral nerve. This study was designed to compare the advantages and disadvantages of three methods employed to reveal the blood supply of the peripheral nerve, and to provide morphological basis for vascularized nerve grafts. METHODS: The blood supply of brachial plexus and its main branches (ulnar, median, radial, musculocutaneous and axillary nerve) were observed using three vascular injection techniques: three specimens were injected with red latex through the thoracic aorta; two side specimens were injected with a Chinese ink solution, through the subclavian artery, for diaphanization and histology; one fresh cadaver was injected with the gelatin-lead oxide mixture through the femoral artery for radiography. RESULTS: The blood supply of the brachial plexus and its main branches was well examined using the three different vascular injection techniques. Perfusion with red latex exposed the extrinsic blood supply. Diaphanization and histology showed the intrinsic blood supply, while gelatin-lead oxide injection technique interactively displayed both the intrinsic and extrinsic blood supply to the peripheral nerve. CONCLUSION: The standard method for the study of the extrinsic blood supply to the peripheral nerve is the red latex perfusion; diaphanization and histology are very suitable to study the intrinsic blood supply of the peripheral nerve; while gelatin-lead oxide technique is the standard for visualization of the integral topography of the blood supply of the peripheral nerve.

[Anatomic study of the hypoglossal nerve in hypoglossal-facial nerve anastomosis].

OBJECTIVE: To determine the optimal position of hypoglossal nerve in hypoglossal-facial nerve anastomosis and the eligibility of hypoglossal-facial nerve anastomosis with the cervical loop. METHODS: The cervical course and adjacent structures of the hypoglossal nerve were observed on 21 adult cadavers. The hypoglossal nerve and facial nerve were taken from 3 fresh specimens, and the number of the fasciculus and the cross-sectional area of the nerve were measured. RESULTS: The facial nerve trunk were monofascicular with a cross-sectional area of 5.1-/+0.2 (range 4.6-5.7) mm(2). The number of the fasciculus and the cross-sectional areas of the nerve trunk and the fasciculus were 1.6-/+0.8 (range 1-4) mm(2) , 7.5-/+0.7 mm(2) (range 6.8-8.0) mm(2), and 4.7-/+0.6 (4.1-5.5) mm(2), respectively, at the proximal segment of the hypoglossal nerve, 3.6-/+0.5 (1-5) mm(2) , 5.6-/+0.5 (4.9-6.1) mm(2) , and 1.6-/+0.4 (0.9-2.2) mm(2) at the distal segment, and 2.4-/+0.8 (1-3) mm(2), 1.1-/+0.7 (0.6-2.2) mm(2), and 0.5-/+0.3 (0.3-1.2) mm(2) at the cervical loop. CONCLUSION: The cervical loop is inadequate for facial nerve anastomosis and the proximal segment is large enough to allow partial harvesting of the hypoglossal nerve for neurotisation of the facial nerve.