Inhibitory protein-protein interactions of the SIRT1 deacetylase are choreographed by post-translational modification.

Regulation of SIRT1 activity is vital to energy homeostasis and plays important roles in many diseases. We previously showed that insulin triggers the epigenetic regulator DBC1 to prime SIRT1 for repression by the multifunctional trafficking protein PACS-2. Here, we show that liver DBC1/PACS-2 regulates the diurnal inhibition of SIRT1, which is critically important for insulin-dependent switch in fuel metabolism from fat to glucose oxidation. We present the x-ray structure of the DBC1 S1-like domain that binds SIRT1 and an NMR characterization of how the SIRT1 N-terminal region engages DBC1. This interaction is inhibited by acetylation of K112 of DBC1 and stimulated by the insulin-dependent phosphorylation of human SIRT1 at S162 and S172, catalyzed sequentially by CK2 and GSK3, resulting in the PACS-2-dependent inhibition of nuclear SIRT1 enzymatic activity and translocation of the deacetylase in the cytoplasm. Finally, we discuss how defects in the DBC1/PACS-2-controlled SIRT1 inhibitory pathway are associated with disease, including obesity and non-alcoholic fatty liver disease.

A novel histologic description of the fibrous networks in the lid-cheek junction and infraorbital region.

The aim of this study was to identify the anatomical feature of retaining ligament and fat compartment on the lower eyelid and infraorbital region using a histological method, and to investigate clear definitions for them which could be used generally in the clinical area. Eighteen specimens from eight fresh Korean cadavers were stained with Masson trichrome or hematoxylin and eosin. The ligamentous and fascial fibrous tissue were clearly identified. The ligamentous fibrous tissue which traversed in the superficial and deep fat layer was skin ligament and orbicularis retaining ligament (ORL). The fascial fibrous tissue enclosed the orbicularis oculi muscle (OOc) and circumferencial adipose tissue. Based on the ligamentous and fascial structure, three fat compartments, septal, suborbicularis oculi and infraorbital fat compartment, could be identified. The OOc attached to orbital rim and dermis by ORL and skin ligament, and the muscle fascicle and fat fascicle provided the connection point to the ORL and skin ligament as enclosing all muscle and fat tissue. The combination of the force made by the skin ligament in the lower eyelid and ORL may decide the level and form of the infraorbital grooves.

Anatomical Considerations for the Injection of Botulinum Neurotoxin in Shoulder and Arm Contouring.

The utilization of botulinum neurotoxin in the field of body contouring is on the rise. Body contouring procedures typically focus on specific muscle groups such as the superior trapezius, deltoid, and lateral head of the triceps brachii. The authors propose identifying optimal injection sites for botulinum neurotoxin to achieve desired aesthetic contouring of the shoulders and arms. The authors conducted a modified Sihler's staining method on specimens of the superior trapezius, deltoid, and lateral head of the triceps brachii muscles, totaling 16, 14, and 16 specimens, respectively. The neural distribution exhibited the most extensive branching patterns within the horizontal section (between 1/5 and 2/5) and the vertical section (between 2/4 and 4/4) of the superior trapezius muscle. In the deltoid muscle, the areas between the anterior and posterior deltoid bellies, specifically within the range of the horizontal 1/3 to 2/3 lines, showed significant intramuscular arborization. Furthermore, the middle deltoid muscle displayed arborization patterns between 2/3 and the axillary line. Regarding the triceps brachii muscle, the lateral heads demonstrated arborization between 4/10 and 7/10. The authors recommend targeting these regions, where maximum arborization occurs, as the optimal and safest points for injecting botulinum toxin.

Sihler's staining technique: How to and guidance for botulinum neurotoxin injection in human muscles.

The Sihler's stain is a whole-mount nerve staining technique that allows visualization of the nerve distribution and permits mapping of the entire nerve supply patterns of the organs, skeletal muscles, mucosa, skin, and other structures that contain myelinated nerve fibers. Unlike conventional approaches, this technique does not require extensive dissection or slide preparation. To date, the Sihler's stain is the best tool for demonstrating the precise intramuscular branching and distribution patterns of skeletal muscles. The intramuscular neural distribution is used as a guidance tool for the application of botulinum neurotoxin injections. In this review, we have identified and summarized the ideal botulinum neurotoxin injection points for several human tissues.

A novel description of the supporting system of the orbicularis oculi muscle in the infraorbital area: Tear trough muscle fiber.

BACKGROUND: The aim of this study was to elucidate the anatomical structures of supporting system of the infraorbital area. MATERIALS AND METHODS: Forty-four hemifaces from eleven Korean and eleven Thai cadavers were used to dissect the infraorbital area. Based on the dissection and previous histologic results, they were analyzed. RESULTS: The orbicularis oculi muscle (OOc) had two portions (palpebral and orbital portion) and four subparts (pretarsal, preseptal, prezygomatic, and premaxillary part). The elliptical muscle fiber of OOc was supported by circumferential connective tissue including skin ligament, orbicularis retaining ligament, zygomatic ligament, and zygomatic cutaneous ligament. The vertical muscle fiber, the tear trough muscle fiber, and medial muscular band directly attached to the skin. CONCLUSION: Full of subcutaneous tissue in the tear trough groove, strong attachment to the bone by tear trough ligament and to the skin by tear trough muscle fiber would multiply result in the tear trough on the face.

Mefenamic Acid-Upregulated Nrf2/SQSTM1 Protects Hepatocytes against Oxidative Stress-Induced Cell Damage.

Mefenamic acid (MFA) is a commonly prescribed non-steroidal anti-inflammatory drug (NSAID) with anti-inflammatory and analgesic properties. MFA is known to have potent antioxidant properties and a neuroprotective effect against oxidative stress. However, its impact on the liver is unclear. This study aimed to elucidate the antioxidative effects of MFA and their underlying mechanisms. We observed that MFA treatment upregulated the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. Treatment with various anthranilic acid derivative-class NSAIDs, including MFA, increased the expression of sequestosome 1 (SQSTM1) in HepG2 cells. MFA disrupted the interaction between Kelch-like ECH-associated protein 1 (Keap1) and Nrf2, activating the Nrf2 signaling pathway. SQTM1 knockdown experiments revealed that the effect of MFA on the Nrf2 pathway was masked in the absence of SQSTM1. To assess the cytoprotective effect of MFA, we employed tert-Butyl hydroperoxide (tBHP) as a ROS inducer. Notably, MFA exhibited a protective effect against tBHP-induced cytotoxicity in HepG2 cells. This cytoprotective effect was abolished when SQSTM1 was knocked down, suggesting the involvement of SQSTM1 in mediating the protective effect of MFA against tBHP-induced toxicity. In conclusion, this study demonstrated that MFA exhibits cytoprotective effects by upregulating SQSTM1 and activating the Nrf2 pathway. These findings improve our understanding of the pharmacological actions of MFA and highlight its potential as a therapeutic agent for oxidative stress-related conditions.

A standardized protocol for needle placement in the infraspinatus muscle: an anatomical perspective.

PURPOSE: This study aimed to evaluate the morphology of the three parts of the infraspinatus muscle based on surface landmarks for precise and effective access, and to propose the most effective fine-wire electrode insertion technique and sites. METHODS: Fifteen Asian fresh cadavers were used. We investigated the probability of the presence of the superior, middle, and inferior parts in each infraspinatus muscle based on surface landmarks. Based on the positional characteristics of the muscle, we determined the needle insertion method and confirmed its effectiveness by dissection. RESULTS: The superior part was mostly observed near the spine of the scapula. The middle part was broadly observed within the infraspinous fossa. The inferior part showed variable location within the infraspinous fossa. The injection accuracy of the superior, middle, and inferior parts in the infraspinatus muscle was 95.8%, 100%, and 91.7%, respectively. Targeting the superior and middle parts for injection of the infraspinatus muscle is relatively more straightforward than targeting the inferior part. Targeting the inferior part of the infraspinatus muscle in this study was more challenging than targeting the superior and middle parts. CONCLUSION: Needling for electromyography should be performed with special care to avoid unintended muscle parts, which could lead to inaccurate data acquisition and affect the conclusions about muscle function.

A three-dimensional analysis of the tibialis anterior tendon: emphasizing tendon insertion patterns for effective repair and understanding hallux valgus development.

PURPOSE: The present study aimed to evaluate the insertion site of the tibialis anterior tendon three-dimensionally. METHODS: Seventy lower limbs were dissected. The tibialis anterior tendon was dissected to verify the insertion site to the medial cuneiform and the base of the first metatarsal bone. The three-dimensional (3D) territory of the tibialis anterior tendon insertion on the medial cuneiform and the first metatarsal bones was measured on a reconstructed 3D model. RESULTS: The insertion pattern of the tibialis anterior tendon was classified into three types, the most common being Type I: a single tibialis anterior tendon dividing into two equal-sized bands to the medial cuneiform and base of the first metatarsal bone (57.1%, 40/70 of cases). The 3D territory of the tibialis anterior tendon was larger in the plantar aspect than in the medial side of both the medial cuneiform and the base of the first metatarsal bone. The width of the tendon inserted into the medial cuneiform was wider than that inserted into the first metatarsal bone. CONCLUSION: The tibialis anterior tendon was more commonly attached to the plantar part than the medial part in both the medial cuneiform and the base of the first metatarsal bone. This anatomical information will help surgeons perform anatomical reconstruction of the tibialis anterior tendon, reduce further tendon damage in the first metatarsocuneiform joint area and also provide valuable knowledge to improve understanding of hallux valgus pathogenesis.

Botulinum neurotoxin injection for treating plunged nose and post-rhinoplasty: anatomical perspectives of depressor septi nasi, nasalis, leveator labii superioris alaeque nasi muscle.

Botulinum neurotoxin (BoNT) injection for the treating plunged nose, post-rhinopasty and hyaluronic filler migration is common procedures in clinical settings. However, the lack of thorough anatomical understanding makes it difficult to locate the nose region muscles. The anatomical considerations concerned with BoNT injection into the nasalis, levator labii superioris alaeque, and depressor septi nasi muscles were reviewed in this study. The injection spots have been presented for the nasalis, levator labii superioris alaeque, and depressor septi nasi muscles, with the recommended injection technique for each muscle. We have suggested the ideal injection sites in association with outer anatomical landmarks of the nose region. Moreover, these proposals would support a more accurate procedure of BoNT injection in relieving plunged nose, preventing post-rhinoplasty deviation, and migration of the hyaluronic acid filler.

Chaperone-mediated autophagy dysregulation during aging impairs hepatic fatty acid oxidation via accumulation of NCoR1.

OBJECTIVE: Alterations in lipid metabolism are associated with aging and age-related diseases. Chaperone-mediated autophagy (CMA) is a lysosome-dependent process involved in specific protein degradation. Heat shock cognate 71 kDa protein (Hsc70) recognizes cytosolic proteins with KFERQ motif and allows them to enter the lysosome via lysosome-associated membrane glycoprotein 2 isoform A (LAMP2A). CMA deficiency is associated with dysregulated lipid metabolism in the liver. In this study, we examined the effect of CMA on lipid metabolism in the aged liver. METHODS: 12-week-old and 88-week-old mice were employed to assess the effect of aging on hepatic CMA activity. We generated CMA-deficient mouse primary hepatocytes using siRNA for Lamp2a and liver-specific LAMP2A knockdown mice via adeno-associated viruses expressing short hairpin RNAs to investigate the influence of CMA on lipid metabolism. RESULTS: We noted aging-induced progression toward fatty liver and a decrease in LAMP2A levels in total protein and lysosomes. The expression of genes associated with fatty acid oxidation was markedly downregulated in the aged liver, as verified in CMA-deficient mouse primary hepatocytes. In addition, the aged liver accumulated nuclear receptor corepressor 1 (NCoR1), a negative regulator of peroxisome proliferator-activated receptor α (PPARα). We found that Hsc70 binds to NCoR1 via the KFERQ motif. Lamp2a siRNA treatment accumulated NCoR1 and decreased the fatty acid oxidation rate. Pharmacological activation of CMA by AR7 treatment increased LAMP2A expression, leading to NCoR1 degradation. A liver-specific LAMP2A knockdown via adeno-associated viruses expressing short hairpin RNAs caused NCoR1 accumulation, inactivated PPARα, downregulated the expression of fatty acid oxidation-related genes and significantly increased liver triglyceride levels. CONCLUSIONS: Our results elucidated a novel PPARα regulatory mechanism involving CMA-mediated NCoR1 degradation during aging. These findings demonstrate that CMA dysregulation is crucial for the progression of aging-related fatty liver diseases.

Botulinum neurotoxin injection in the deltoid muscle: application to cosmetic shoulder contouring.

BACKGROUND AND OBJECTIVES: This study describes the intramuscular nerve branching of the deltoid muscle in relation to shoulder surface anatomy, with the aim of providing essential information regarding the most appropriate sites for botulinum neurotoxin injection during shoulder line contouring. METHODS: The modified Sihler's method was used to stain the deltoid muscles (16 specimens). The intramuscular arborization areas of the specimens were demarcated using the marginal line of the muscle origin and the line connecting the anterior and posterior upper edges of the axillary region. RESULTS: The intramuscular neural distribution of the deltoid muscle had the greatest arborization patterns in the area between the horizontal 1/3 and 2/3 lines of the anterior and posterior deltoid bellies, and 2/3 to axillary line in middle deltoid bellies. The greatest part of the posterior circumflex artery and axillary nerve ran below the areas with the highest aborizations. CONCLUSION: We propose that botulinum neurotoxin injections should be administered in the area between the 1/3 and 2/3 lines of the anterior and posterior deltoid bellies, and 2/3 to axillary line on middle deltoid bellies. Accordingly, clinicians will ensure minimal dose injections and fewer adverse effects of the botulinum neurotoxin injection. Deltoid intramuscular injections, such as vaccines and trigger point injections, should ideally be adapted according to our results.

Hyaluronic acid-coated gold nanoparticles as a controlled drug delivery system for poorly water-soluble drugs.

Hyaluronic acid (HA) is a natural linear polysaccharide which has been widely used in cosmetics and pharmaceuticals including drug delivery systems because of its excellent biocompatibility. In this study, we investigated the one-pot synthesis of HA-coated gold nanoparticles (AuNP-HA) as a drug delivery carrier. The HAs with different molecular weights were produced by e-beam irradiation and employed as coating materials for AuNPs. Sulfasalazine (SSZ), a poorly water-soluble drug, was used to demonstrate the efficiency of drug delivery and the controlled release behaviour of the AuNP-HA. As the molecular weight of the HA decreased, the drug encapsulation efficiency of the SSZ increased up to 94%, while drug loading capacity of the SSZ was maintained at the level of about 70%. The prepared AuNP-HA-SSZ exhibited slow release of the SSZ over a short time and excellent sensitivity to different pHs and physiological conditions. The SSZ release rate was the lowest in simulated gastric conditions and the highest in simulated intestinal conditions. In this case, the AuNP-HA protects the SSZ from release under the acidic pH conditions in the stomach; on the other hand, the drug release was facilitated in the basic environment of the small intestine and colon. The SSZ was released under simulated intestinal conditions through anomalous drug transport and followed the Korsmeyer-Peppas model. Therefore, this study suggests that AuNP-HA is a promising orally-administered and intestine-targeted drug delivery system with controlled release characteristics.

Novel anatomical proposal for botulinum neurotoxin injection targeting depressor anguli oris for treating drooping mouth corner.

The depressor anguli oris (DAO) muscle is a thin, superficial muscle located below the corner of the mouth. It is the target for botulinum neurotoxin (BoNT) injection therapy, aimed at treating drooping mouth corners. Hyperactivity of the DAO muscle can lead to a sad, tired, or angry appearance in some patients. However, it is difficult to inject BoNT into the DAO muscle because its medial border overlaps with the depressor labii inferioris and its lateral border is adjacent to the risorius, zygomaticus major, and platysma muscles. Moreover, a lack of knowledge of the anatomy of the DAO muscle and the properties of BoNT can lead to side effects, such as asymmetrical smiles. Anatomical-based injection sites were provided for the DAO muscle, and the proper injection technique was reviewed. We proposed optimal injection sites based on the external anatomical landmarks of the face. The aim of these guidelines is to standardize the procedure and maximize the effects of BoNT injections while minimizing adverse events, all by reducing the dose unit and injection points.

Distribution of the intramuscular innervation of the triceps brachii: Clinical importance in the treatment of spasticity with botulinum neurotoxin.

This study aimed to identify ideal sites for botulinum toxin injection by analyzing the intramuscular nerve patterns of the triceps brachii muscles. A modified Sihler's method was applied to the triceps brachii muscle (15 specimens), with long, medial, and lateral heads. The intramuscular arborization areas of the long, medial, and lateral heads of the triceps brachii muscle were measured as a percentage of the total distance from the midpoint of the olecranon (0%) to the anteroinferior point of the acromion (100%), by dividing the medial and lateral parts based on the line connecting the midpoint of the olecranon and the anteroinferior point of the acromion. Intramuscular arborization patterns were observed at the long head at two medial regions, proximally 30%-50% and distally 60%-70%; medial head of 30%-40%; and lateral head of 30%-60%. These results suggest that the treatment of spasticity of the triceps brachii muscles involves botulinum toxin injections in specific areas. The areas corresponding to the areas of maximum arborization are recommended as the most effective and safe points for botulinum toxin injection.

New anatomical insights of the superficial branch of the zygomaticotemporal nerve for treating temporal migraines: An anatomical study.

The zygomaticotemporal nerve is known to contribute to temporal migraines; however, its precise anatomy remains unknown. The potential accessory branches of the zygomaticotemporal nerve may be considered a cause of continued temporal migraines after surgical procedures. In this study, we defined the novel superficial branch of the zygomaticotemporal nerve (sZTN) and investigated its anatomical course, distribution, and clinical implications. Twenty-two hemifaces from 11 fixed Korean cadavers (six males, five females; mean age, 78.3 years) were used in this study. The piercing points of the sZTN through the deep and superficial layers of the deep temporal fascia, and the superficial temporal fascia were defined as P1, P2, and P3, respectively. The distance of each point from the zygomatic tubercle was measured using an image analysis software. The sZTN ascended between the bone and the temporalis after emerging from the zygomaticotemporal foramen. It then pierced the deep temporal fascia without penetrating the temporalis. After then, it pierced the superficial layer of the deep temporal fascia and turned superiorly toward the upper posterior temple. When the sZTN passed through the superficial temporal fascia, it intersected with the superficial temporal artery in every case. The novel findings of the sZTN may help in the treatment of intractable temporal migraines refractory to injection or surgical procedure. Based on our findings, targeting the sZTN may be applied as an alternative treatment strategy for patients who do not show significant improvement with treatment targeted to trigger sites.

Associations of Polyp Characteristics in Children and Adolescents Presenting with Less Than Five Colorectal Polyps: A Full Colonoscopy Is Still Required.

Background/Aims: A full colonoscopy is currently required in children and adolescents with colorectal polyps, because of their potential of neoplastic transformation and complications such as intussusception. We aimed to analyze the associations of polyp characteristics in children and adolescents with colorectal polyps. Based on these findings, we also aimed to reevaluate the necessity of conducting a full colonoscopy. Methods: Pediatric patients <18 years of age who had undergone a colonoscopic polypectomy and those with <5 colorectal polyps were included in this multicenter, retrospective study. Baseline clinicodemographics, colonoscopic and histologic findings were investigated. Results: A total of 91 patients were included. Multivariate logistic regression analysis showed that polyp size was the only factor associated with the presence of any polyps located proximal to the splenic flexure (odds ratio [OR], 2.25; 95% confidence interval [CI], 1.28 to 4.28; p=0.007). Furthermore, polyp location proximal to the splenic flexure and sessile morphology were associated with the presence of any adenomatous polyp (OR, 8.51; 95% CI, 1.43 to 68.65; p=0.023; OR, 18.41; 95% CI, 3.45 to 173.81; p=0.002, respectively). Conclusions: In children and adolescents presenting with <5 colorectal polyps, polyp size and the presence of any adenomatous polyp were positively associated with polyp location proximal to the splenic flexure. This finding supports the necessity of a full colonoscopic exam in pediatric patients with colorectal polyps for the detection of polyps before the occurrence of complications such as intussusception or neoplastic transformation.

Face painting as an anatomical learning tool based on individual ultrasonographic examination.

Considering the shift to online education during the COVID-19 pandemic, new and easily accessible educational videos and content on clinical anatomy are necessary. This study utilized numerous references and data on the anatomy of Asian facial muscles and blood vessels to accurately depict human anatomy through face painting. It aimed to provide clinicians accurate educational video content on anatomy to help prevent possible complications during noninvasive facial and surgical procedures. A 26-year-old Korean-Chinese male volunteer was used as a face painting model. The location of the blood vessels of the face was confirmed through ultrasonography images using a real-time two-dimensional B-mode. The model's face was painted by an artist majoring in anatomy. To reveal most anatomical structures on both sides of the face, the left side showed the structures observed when the skin and superficial fat layer are removed, and the right side revealed the deeper layer structures that can be seen when some muscles are cut. Fifteen superficial and deep muscles important in esthetic procedures were meticulously painted on the face. The face painting took a total of 6 h, and the video was edited to 5 min. This study merged the advantages of 2D and 3D by painting directly on the skin surface of a living model. Thus, it can provide more dynamic surface anatomy data. These contents inform clinicians about 3D anatomic location, which can help avoid complications when performing clinical procedures on the face.

The Deep Temporal Arteries: Anatomical Study with Application to Augmentations Procedures of the Temple.

The aim of this study was to determine the anatomical features of the deep temporal arteries (DTAs) and thereby provide clinical information for the temple augmentation procedure. Forty-two adult hemifaces from 15 Korean and 6 Thai cadavers (12 males, 9 females; mean age at death, 79.6 years) with no history of trauma or surgical procedure on the temple area were used for anatomical study. A detailed dissection was performed to identify the locations of the anterior and posterior deep temporal arteries (ADTA and PDTA) with reference to the vertical plane passing through the zygomatic tubercle. Fifty-eight healthy Korean participants (31 males and 27 females; mean age, 24.7 years) were included in the ultrasonographic study. The distance from the bone to the DTAs was measured at the level of the zygomatic tubercle (HZt ) and the eyebrow (HEb ). The DTAs were not found within 7.2-12.6 mm posterior to the zygomatic tubercle; instead, the locations varied widely at the HEb . The distances between the bone and the ADTA were 1.7 ± 1.2 mm (mean ± SD) and 1.3 ± 0.8 mm, and those between the bone and the PDTA were 2.1 ± 1.2 mm and 2.0 ± 1.4 mm at HZt and HEb , respectively. Our findings indicate that at HZt , the area 1 cm posterior to the zygomatic tubercle may be a safe area for deep temple augmentation procedures. However, because the distribution patterns of the DTAs at HEb and depth of the DTAs are variable, additional care is required to minimize the risks of the procedure.

Mitochondrial H2O2 Is a Central Mediator of Diclofenac-Induced Hepatocellular Injury.

Nonsteroidal anti-inflammatory drug (NSAID) use is associated with adverse consequences, including hepatic injury. The detrimental hepatotoxicity of diclofenac, a widely used NSAID, is primarily connected to oxidative damage in mitochondria, which are the primary source of reactive oxygen species (ROS). The primary ROS responsible for inducing diclofenac-related hepatocellular toxicity and the principal antioxidant that mitigates these ROS remain unknown. Peroxiredoxin III (PrxIII) is the most abundant and potent H2O2-eliminating enzyme in the mitochondria of mammalian cells. Here, we investigated the role of mitochondrial H2O2 and the protective function of PrxIII in diclofenac-induced mitochondrial dysfunction and apoptosis in hepatocytes. Mitochondrial H2O2 levels were differentiated from other types of ROS using a fluorescent H2O2 indicator. Upon diclofenac treatment, PrxIII-knockdown HepG2 human hepatoma cells showed higher levels of mitochondrial H2O2 than PrxIII-expressing controls. PrxIII-depleted cells exhibited higher mitochondrial dysfunction as measured by a lower oxygen consumption rate, loss of mitochondrial membrane potential, cardiolipin oxidation, and caspase activation, and were more sensitive to apoptosis. Ectopic expression of mitochondrially targeted catalase in PrxIII-knockdown HepG2 cells or in primary hepatocytes derived from PrxIII-knockout mice suppressed the diclofenac-induced accumulation of mitochondrial H2O2 and decreased apoptosis. Thus, we demonstrated that mitochondrial H2O2 is a key mediator of diclofenac-induced hepatocellular damage driven by mitochondrial dysfunction and apoptosis. We showed that PrxIII loss results in the critical accumulation of mitochondrial H2O2 and increases the harmful effects of diclofenac. PrxIII or other antioxidants targeting mitochondrial H2O2 could be explored as potential therapeutic agents to protect against the hepatotoxicity associated with NSAID use.