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1.
Cell ; 187(15): 4061-4077.e17, 2024 Jul 25.
Artículo en Inglés | MEDLINE | ID: mdl-38878777

RESUMEN

NLRs constitute a large, highly conserved family of cytosolic pattern recognition receptors that are central to health and disease, making them key therapeutic targets. NLRC5 is an enigmatic NLR with mutations associated with inflammatory and infectious diseases, but little is known about its function as an innate immune sensor and cell death regulator. Therefore, we screened for NLRC5's role in response to infections, PAMPs, DAMPs, and cytokines. We identified that NLRC5 acts as an innate immune sensor to drive inflammatory cell death, PANoptosis, in response to specific ligands, including PAMP/heme and heme/cytokine combinations. NLRC5 interacted with NLRP12 and PANoptosome components to form a cell death complex, suggesting an NLR network forms similar to those in plants. Mechanistically, TLR signaling and NAD+ levels regulated NLRC5 expression and ROS production to control cell death. Furthermore, NLRC5-deficient mice were protected in hemolytic and inflammatory models, suggesting that NLRC5 could be a potential therapeutic target.


Asunto(s)
Inflamación , Péptidos y Proteínas de Señalización Intracelular , NAD , Animales , Ratones , Inflamación/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , NAD/metabolismo , Humanos , Inmunidad Innata , Ratones Endogámicos C57BL , Especies Reactivas de Oxígeno/metabolismo , Ratones Noqueados , Transducción de Señal , Células HEK293 , Inflamasomas/metabolismo , Proteínas Reguladoras de la Apoptosis/metabolismo , Proteínas Reguladoras de la Apoptosis/genética , Receptores Toll-Like/metabolismo , Masculino , Citocinas/metabolismo , Proteínas de Unión al Calcio
2.
Cell ; 186(13): 2783-2801.e20, 2023 06 22.
Artículo en Inglés | MEDLINE | ID: mdl-37267949

RESUMEN

Cytosolic innate immune sensors are critical for host defense and form complexes, such as inflammasomes and PANoptosomes, that induce inflammatory cell death. The sensor NLRP12 is associated with infectious and inflammatory diseases, but its activating triggers and roles in cell death and inflammation remain unclear. Here, we discovered that NLRP12 drives inflammasome and PANoptosome activation, cell death, and inflammation in response to heme plus PAMPs or TNF. TLR2/4-mediated signaling through IRF1 induced Nlrp12 expression, which led to inflammasome formation to induce maturation of IL-1ß and IL-18. The inflammasome also served as an integral component of a larger NLRP12-PANoptosome that drove inflammatory cell death through caspase-8/RIPK3. Deletion of Nlrp12 protected mice from acute kidney injury and lethality in a hemolytic model. Overall, we identified NLRP12 as an essential cytosolic sensor for heme plus PAMPs-mediated PANoptosis, inflammation, and pathology, suggesting that NLRP12 and molecules in this pathway are potential drug targets for hemolytic and inflammatory diseases.


Asunto(s)
Inflamasomas , Moléculas de Patrón Molecular Asociado a Patógenos , Animales , Ratones , Inflamasomas/metabolismo , Hemo , Inflamación , Piroptosis , Péptidos y Proteínas de Señalización Intracelular
3.
Proc Natl Acad Sci U S A ; 119(3)2022 01 18.
Artículo en Inglés | MEDLINE | ID: mdl-35027452

RESUMEN

Alzheimer's disease (AD) is characterized by complex, multifactorial neuropathology, suggesting that small molecules targeting multiple neuropathological factors are likely required to successfully impact clinical progression. Acid sphingomyelinase (ASM) activation has been recognized as an important contributor to these neuropathological features in AD, leading to the concept of using ASM inhibitors for the treatment of this disorder. Here we report the identification of KARI 201, a direct ASM inhibitor evaluated for AD treatment. KARI 201 exhibits highly selective inhibition effects on ASM, with excellent pharmacokinetic properties, especially with regard to brain distribution. Unexpectedly, we found another role of KARI 201 as a ghrelin receptor agonist, which also has therapeutic potential for AD treatment. This dual role of KARI 201 in neurons efficiently rescued neuropathological features in AD mice, including amyloid beta deposition, autophagy dysfunction, neuroinflammation, synaptic loss, and decreased hippocampal neurogenesis and synaptic plasticity, leading to an improvement in memory function. Our data highlight the possibility of potential clinical application of KARI 201 as an innovative and multifaceted drug for AD treatment.


Asunto(s)
Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Neuropatología/métodos , Animales , Encéfalo/metabolismo , Modelos Animales de Enfermedad , Hipocampo/metabolismo , Hipocampo/patología , Memoria , Ratones , Plasticidad Neuronal , Neuronas/metabolismo , Receptores de Ghrelina/metabolismo , Esfingomielina Fosfodiesterasa/genética , Esfingomielina Fosfodiesterasa/metabolismo
4.
J Neuroinflammation ; 21(1): 47, 2024 Feb 13.
Artículo en Inglés | MEDLINE | ID: mdl-38347588

RESUMEN

BACKGROUND: Progranulin (PGRN) haploinsufficiency due to progranulin gene (GRN) variants can cause frontotemporal dementia (FTD) with aberrant TAR DNA-binding protein 43 (TDP-43) accumulation. Despite microglial burden with TDP-43-related pathophysiology, direct microglial TDP-43 pathology has not been clarified yet, only emphasized in neuronal pathology. Thus, the objective of this study was to investigate TDP-43 pathology in microglia of patients with PGRN haploinsufficiency. METHODS: To design a human microglial cell model with PGRN haploinsufficiency, monocyte-derived microglia (iMGs) were generated from FTD-GRN patients carrying pathogenic or likely pathogenic variants (p.M1? and p.W147*) and three healthy controls. RESULTS: iMGs from FTD-GRN patients with PGRN deficiency exhibited severe neuroinflammation phenotype and failure to maintain their homeostatic molecular signatures, along with impaired phagocytosis. In FTD-GRN patients-derived iMGs, significant cytoplasmic TDP-43 aggregation and accumulation of lipid droplets with profound lysosomal abnormalities were observed. These pathomechanisms were mediated by complement C1q activation and upregulation of pro-inflammatory cytokines. CONCLUSIONS: Our study provides considerable cellular and molecular evidence that loss-of-function variants of GRN in human microglia can cause microglial dysfunction with abnormal TDP-43 aggregation induced by inflammatory milieu as well as the impaired lysosome. Elucidating the role of microglial TDP-43 pathology in intensifying neuroinflammation in individuals with FTD due to PGRN deficiency and examining consequential effects on microglial dysfunction might yield novel insights into the mechanisms underlying FTD and neurodegenerative disorders.


Asunto(s)
Demencia Frontotemporal , Enfermedad de Pick , Humanos , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Demencia Frontotemporal/genética , Haploinsuficiencia , Lisosomas/metabolismo , Microglía/patología , Enfermedades Neuroinflamatorias , Enfermedad de Pick/metabolismo , Progranulinas/genética , Progranulinas/metabolismo
5.
Addict Biol ; 29(2): e13360, 2024 02.
Artículo en Inglés | MEDLINE | ID: mdl-38380695

RESUMEN

Tobacco smoking is a serious health problem in society. While smoking rates are declining, smoking remains a serious risk to national health. Currently, there are several medications available to aid in smoking cessation. However, these medications have the disadvantages of low success rates in smoking cessation and various side effects. Therefore, natural-based smoking cessation aids are being suggested as a good alternative due to their accessibility and minimal side effects. The roots and stems of Acanthopanax koreanum (AK) Nakai, a plant that is native to Jeju Island, South Korea, have traditionally been used as tonic and sedatives. Moreover, eleutheroside B and chlorogenic acid are the main components of AK stem extract. In the present study, we investigated the effect of 70% ethanol AK extract and its components on ameliorating nicotine dependence and withdrawal symptoms by using behavioural tests in mice. In addition, alterations in the dopaminergic and DRD1-EPAC-ERK-CREB pathways were observed using dopamine ELISA and western blotting using mouse brains. Our findings demonstrate that the AK extract and its components effectively mitigated the effects of nicotine treatment in behavioural tests. Furthermore, it normalized the dopamine concentration and the expression level of nicotine acetylcholine receptor α7. Additionally, it was observed that AK extract and its components led to the normalization of DRD1, ERK and CREB expression levels. These results indicate that AK extract exhibits effects in ameliorating nicotine dependence behaviour and alleviating withdrawal symptoms. Moreover, EB and CGA are considered potential marker components of AK extract.


Asunto(s)
Eleutherococcus , Síndrome de Abstinencia a Sustancias , Tabaquismo , Animales , Ratones , Tabaquismo/tratamiento farmacológico , Nicotina/efectos adversos , Dopamina , Síndrome de Abstinencia a Sustancias/tratamiento farmacológico , Etanol
6.
Planta Med ; 2024 Jul 24.
Artículo en Inglés | MEDLINE | ID: mdl-39047773

RESUMEN

The increasing prevalence of sleep dysregulation cases has prompted the search for effective and safe sleep-enhancing agents. Numerous medications used in the treatment of sleep disorders function by enhancing γ-aminobutyric acid neurotransmitter activity. Unfortunately, these substances may induce significant adverse effects in chronic users, such as dependence and motor behavior impairments. Consequently, there is a growing interest in exploring therapeutic sleep-enhancing agents derived from natural sources, with the anticipation of causing less severe side effects. Prunella vulgaris (PV), a perennial plant indigenous to South Korea, exhibits various pharmacological effects, likely attributed to its chemical composition. Rosmarinic acid, one of its components, has previously demonstrated sleep-potentiating properties, suggesting the potential for PV to exhibit similar pharmacological effects. This study aims to investigate the potential effects of repeated administration of PV extract on the sleep behavior, brainwave activity, sleep-wake cycle, and physiological behavior of mice. Findings indicate that PV extracts exhibit sleep-enhancing effects in mice, characterized by prolonged sleep duration and a reduced onset time of pentobarbital-induced sleep. However, PV extracts only reduced alpha wave powers, with minor alterations in wakefulness and rapid-eye-movement sleep duration. In contrast to diazepam, PV extracts lack adverse effects on locomotor activity, motor coordination, or anxiety in mice. Receptor-binding assay and caffeine treatment support the potential involvement of adenosine A2A receptors in the effects of PV, suggesting distinct mechanisms of action compared to diazepam, despite both exhibiting sleep-altering effects. Overall, our results suggest that PV holds promise as a potential source of sleep-aiding agents.

7.
Dermatol Surg ; 2024 May 07.
Artículo en Inglés | MEDLINE | ID: mdl-38712848

RESUMEN

BACKGROUND: Hypertrophied submandibular glands provide a bulky contour to the lower face. Botulinum neurotoxin injection methods are commonly used for facial contouring; however, no studies have suggested injection points because of the lack of delicate anatomical information on the submandibular gland. OBJECTIVE: The aim of this study was to determine the optimal injection site for botulinum neurotoxin injections in the submandibular gland. MATERIALS AND METHODS: Anatomical considerations when injecting botulinum neurotoxin into the submandibular gland were determined using ultrasonography. The thickness of the submandibular gland, its depth from the skin surface, and the location of the vascular bundle were observed bilaterally in 42 participants. Two cadavers were dissected to measure the location of the submandibular gland corresponding to the ultrasonographic observation. RESULTS: The thickest part of the submandibular gland measured 11.12 ± 2.46 in width with a depth of 4.63 ± 0.76. At the point where it crosses the line of the lateral canthus, it measured 5.53 ± 1.83 in width and 8.73 ± 1.64 in depth. CONCLUSION: The authors suggest optimal injection sites based on external anatomical landmarks. These guidelines aim to maximize the effects of botulinum neurotoxin therapy by minimizing its deleterious effects, which can be useful in clinical settings.

8.
Proc Natl Acad Sci U S A ; 118(47)2021 11 23.
Artículo en Inglés | MEDLINE | ID: mdl-34785595

RESUMEN

MicroRNAs (miRNAs) have recently emerged as important regulators of ion channel expression. We show here that select miR-106b family members repress the expression of the KCNQ2 K+ channel protein by binding to the 3'-untranslated region of KCNQ2 messenger RNA. During the first few weeks after birth, the expression of miR-106b family members rapidly decreases, whereas KCNQ2 protein level inversely increases. Overexpression of miR-106b mimics resulted in a reduction in KCNQ2 protein levels. Conversely, KCNQ2 levels were up-regulated in neurons transfected with antisense miRNA inhibitors. By constructing more specific and stable forms of miR-106b controlling systems, we further confirmed that overexpression of precursor-miR-106b-5p led to a decrease in KCNQ current density and an increase in firing frequency of hippocampal neurons, while tough decoy miR-106b-5p dramatically increased current density and decreased neuronal excitability. These results unmask a regulatory mechanism of KCNQ2 channel expression in early postnatal development and hint at a role for miR-106b up-regulation in the pathophysiology of epilepsy.


Asunto(s)
Regulación Neoplásica de la Expresión Génica , Canal de Potasio KCNQ2/genética , Canal de Potasio KCNQ2/metabolismo , MicroARNs/metabolismo , Animales , Línea Celular Tumoral , Células HEK293 , Humanos , Ratones , Ratones Endogámicos C57BL , MicroARNs/genética , Proteínas del Tejido Nervioso , Neuronas , ARN Mensajero , Ratas , Ratas Sprague-Dawley , Regulación hacia Arriba
9.
Sensors (Basel) ; 24(9)2024 Apr 30.
Artículo en Inglés | MEDLINE | ID: mdl-38732993

RESUMEN

Information on boll distribution within a cotton plant is critical to evaluate the adaptation and response of cotton plants to environmental and biotic stress in cotton production. Cotton researchers have applied available conventional fiber measurements, such as the high volume instrument (HVI) and advanced fiber information system (AFIS), to map the location and the timing of boll development and distribution within plants and further to determine within-plant variability of cotton fiber properties. Both HVI and AFIS require numerous cotton bolls combined for the measurement. As an alternative approach, attenuated total reflection Fourier transform infrared (ATR FT-IR) spectroscopy was proposed to measure fiber maturity (MIR) and crystallinity (CIIR) of a sample as little as 0.5 mg lint. Extending fiber maturity and crystallinity measurement into a single boll for node-by-node mapping, FT-IR method might be advantageous due to less sampling amount compared with HVI and AFIS methods. Results showed that FT-IR technique enabled the evaluation of fiber MIR and CIIR at a boll level, which resulted in average MIR and CIIR values highly correlated with HVI micronaire (MIC) and AFIS maturity ratio (M). Hence, FT-IR technique possesses a good potential for a rapid and non-destructive node-by-node mapping of cotton boll maturity and crystallinity distribution.


Asunto(s)
Algoritmos , Fibra de Algodón , Gossypium , Fibra de Algodón/análisis , Espectroscopía Infrarroja por Transformada de Fourier/métodos , Gossypium/química , Gossypium/crecimiento & desarrollo
10.
Clin Anat ; 37(6): 628-634, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38146193

RESUMEN

Temporal tendinitis is characterized by acute inflammation often resulting from mechanical stress, such as repetitive jaw movements associated with jaw opening and closing and teeth clenching. Treatment for temporal tendinitis typically involves the administration of local anesthetic or corticosteroid injections. However, the complex anatomical structure of the coronoid process, to which the temporalis tendon attaches, located deep within the zygomatic arch, poses challenges for accurate injections. In this study, we aimed to establish guidelines for the safe and effective treatment of temporal tendinitis by using intraoral ultrasonography (US) to identify the anatomical structures surrounding the temporalis tendon and coronoid process. US was performed using an intraoral transducer on 58 volunteers without temporomandibular joint disease. The procedure involved placing the transducer below the occlusal plane of the maxillary second molar. Measurements were taken for the horizontal distance from the anterior border of the coronoid process, observed at the midpoint (MP) of the US images, and the depth of the coronoid process and temporalis muscle from the oral mucosa. The anterior border of the coronoid process was visualized on all US images and classified into three observed patterns at the MP: type A (anterior to the MP, 56.2%), type B (at the MP, 16.1%), and type C (posterior to the MP, 27.7%). The temporalis muscle was located at a mean depth of 3.12 ± 0.68 mm from the oral mucosa. The maxillary second molar is an intraoral landmark for visualizing the anterior border of the coronoid process. The new location information obtained using intraoral US could help identify the safest and most effective injection sites for the treatment of temporal tendinitis.


Asunto(s)
Tendinopatía , Ultrasonografía Intervencional , Humanos , Tendinopatía/diagnóstico por imagen , Tendinopatía/tratamiento farmacológico , Masculino , Femenino , Adulto , Ultrasonografía Intervencional/métodos , Adulto Joven , Músculo Temporal/diagnóstico por imagen , Músculo Temporal/anatomía & histología
11.
Clin Anat ; 37(2): 169-177, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-37255275

RESUMEN

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.


Asunto(s)
Toxinas Botulínicas , Humanos , Coloración y Etiquetado , Colorantes , Músculo Esquelético/inervación , Inyecciones
12.
J Oral Rehabil ; 2024 Jul 18.
Artículo en Inglés | MEDLINE | ID: mdl-39030872

RESUMEN

OBJECTIVE: This study aims to evaluate the effects on bite force and muscle thickness of the botulinum toxin (BoNT) injection for patients with sleep bruxism (SB) by comparing injections into the masseter muscle only and both the masseter and the anterior belly of the digastric muscle (ABDM) in a clinical trial. METHODS: Twelve SB patients received BoNT-A injections using US-guided techniques into the masseter muscle only (Group A), while the remaining 12 SB patients received injections into both the masseter and ABDM (Group B). Bite force and muscle thickness were measured before injection, as well as 1 and 2 months after injection. RESULTS: The bite force and masseter muscle thickness decreased in both Group A and Group B before injection, and at 1 and 2 months after injection. However, there was no significant difference (p > .05, repeated measures analysis of variance) between the two groups, and there was also no significant difference in ABDM thickness (p > .05, repeated measures analysis of variance). CONCLUSION: This study is the first to assess the short-term effects of BoNT injected into ABDM for SB control. Results show no influence on SB reduction, suggesting the need for further research on BoNT's effectiveness in controlling intense ABDM contractions during sleep and assessing suprahyoid muscle potential impact on rhythmic masticatory muscle activity occurrence.

13.
Molecules ; 29(5)2024 Mar 06.
Artículo en Inglés | MEDLINE | ID: mdl-38474685

RESUMEN

Microplastics (MP) encompass not only plastic products but also paint particles. Marine microdebris, including MP, was retrieved from five sampling stations spanning Nagasaki-Goto island and was classified into six types, primarily consisting of MP (A), Si-based (B), and Cu-based (C) paint particles. Type-A particles, i.e., MP, were exceedingly small, with 74% of them having a long diameter of 25 µm or less. The vertical distribution of type C, containing cuprous oxide, exhibited no depth dependence, with its dominant size being less than 7 µm. It was considered that the presence of type C was associated with a natural phenomenon of MP loss. To clarify this, polypropylene (PP) samples containing cuprous oxide were prepared, and their accelerated degradation behavior was studied using a novel enhanced degradation method employing a sulfate ion radical as an initiator. Infrared spectroscopy revealed the formation of a copper soap compound in seawater. Scanning electron microscopy/energy-dispersive X-ray spectroscopy analysis indicated that the chemical reactions between Cl- and cuprous oxide produced Cu+ ions. The acceleration of degradation induced by the copper soap formed was studied through the changes in the number of PP chain scissions, revealing that the presence of type-C accelerated MP degradation.

14.
Surg Radiol Anat ; 46(9): 1543-1548, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39014212

RESUMEN

PURPOSE: The anterior belly of the digastric muscle (ABDM) is the target of botulinum toxin injection; however, anatomical considerations related to the injection point are absent. This study used Sihler's staining to analyze the intramuscular nerve distribution of ABDM to identify the most effective botulinum toxin injection points. METHODS: We used 12 specimens from 6 embalmed cadavers in this study. The specimens were manually dissected to preserve the mylohyoid nerve and subjected to Sihler's staining. From the gnathion to and hyoid bone, the ABDM was divided into three equal parts, distinguishing the anterior, middle, and posterior thirds. RESULTS: Only a branch of the mylohyoid nerve entered the ABDM, and its entry point was located in the middle-third region in all cases. The nerve endings were concentrated in the middle third (100%), followed by the anterior third (58.3%) and were not observed in the posterior third. CONCLUSION: The landmarks used in this study (gnathion and hyoid bone) are easily palpable on the skin surface, allowing clinicians to target the most effective injection site (middle third of ABDM). These results provide scientific and anatomic evidence for injection points, and will aid in the management of ABDM injection procedures in clinical practice.


Asunto(s)
Cadáver , Humanos , Masculino , Femenino , Inyecciones Intramusculares/métodos , Anciano , Músculos del Cuello/inervación , Músculos del Cuello/anatomía & histología , Músculos del Cuello/efectos de los fármacos , Coloración y Etiquetado/métodos , Anciano de 80 o más Años , Toxinas Botulínicas/administración & dosificación , Puntos Anatómicos de Referencia
15.
Surg Radiol Anat ; 46(1): 3-9, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38036923

RESUMEN

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.


Asunto(s)
Párpados , Músculos Faciales , Humanos , Mejilla , Rotura , Fibras Musculares Esqueléticas
16.
Aesthet Surg J ; 44(3): 319-326, 2024 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-37548270

RESUMEN

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.


Asunto(s)
Toxinas Botulínicas , Humanos , Hombro , Brazo , Músculo Esquelético , Inyecciones
17.
J Cell Physiol ; 238(9): 2063-2075, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37334825

RESUMEN

Cholesterol sulfate (CS) is an activator of retinoic acid-related orphan receptor α (RORα). CS treatment or RORα overexpression attenuates osteoclastogenesis in a collagen-induced arthritis mouse model. However, the mechanism by which CS and RORα regulate osteoclast differentiation remains largely unknown. Thus, we aimed to investigate the role of CS and RORα in osteoclastogenesis and their underlying mechanism. CS inhibited osteoclast differentiation, but RORα deficiency did not affect osteoclast differentiation and CS-mediated inhibition of osteoclastogenesis. CS enhanced adenosine monophosphate-activated protein kinase (AMPK) phosphorylation and sirtuin1 (Sirt1) activity, leading to nuclear factor-κB (NF-κB) inhibition by decreasing acetylation at Lys310 of p65. The NF-κB inhibition was restored by AMPK inhibitor, but the effects of CS on AMPK and NF-κB were not altered by RORα deficiency. CS also induced osteoclast apoptosis, which may be due to sustained AMPK activation and consequent NF-κB inhibition, and the effects of CS were significantly reversed by interleukin-1ß treatment. Collectively, these results indicate that CS inhibits osteoclast differentiation and survival by suppressing NF-κB via the AMPK-Sirt1 axis in a RORα-independent manner. Furthermore, CS protects against bone destruction in lipopolysaccharide- and ovariectomy-mediated bone loss mouse models, suggesting that CS is a useful therapeutic candidate for treating inflammation-induced bone diseases and postmenopausal osteoporosis.


Asunto(s)
Resorción Ósea , Ésteres del Colesterol , FN-kappa B , Animales , Femenino , Ratones , Proteínas Quinasas Activadas por AMP/genética , Proteínas Quinasas Activadas por AMP/metabolismo , Diferenciación Celular , FN-kappa B/metabolismo , Osteoclastos/metabolismo , Osteogénesis , Ligando RANK/farmacología , Sirtuina 1/genética , Sirtuina 1/metabolismo , Ésteres del Colesterol/farmacología , Ésteres del Colesterol/uso terapéutico
18.
J Anat ; 243(3): 467-474, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-36988105

RESUMEN

Myofascial pain syndrome caused by myofascial trigger points is a musculoskeletal disorder commonly encountered in clinical practice. The infraspinatus muscle is the region most frequently involved in the myofascial pain syndrome in the scapular region. The characteristics of the myofascial trigger points are that they can be found constantly in the motor endplate zone. However, localizing myofascial trigger points within the motor endplate zone and establishing an accurate injection site of the infraspinatus muscle has been challenging because the anatomical position of the motor endplate zone of the infraspinatus muscle is yet to be described. Therefore, this cadaveric study aimed to scrutinize the motor endplate zone of the infraspinatus muscle, propose potential myofascial trigger points within the muscle, and recommend therapeutic injection sites. Twenty specimens of the infraspinatus muscle for nerve staining and 10 fresh frozen cadavers for evaluation of the injection were used in this study. The number of nerve branches penetrating the infraspinatus muscle and their entry locations were analyzed and photographed. Modified Sihler's staining was performed to examine the motor endplate regions of the infraspinatus muscle. The nerve entry points were mostly observed in the center of the muscle belly. The motor endplate was distributed equally throughout the infraspinatus muscle, but the motor endplate zone was primarily identified in the B area, which is approximately 20-40% proximal to the infraspinatus muscle. The second-most common occurrence of the motor endplate zone was observed in the center of the muscle. These detailed anatomical data would be very helpful in predicting potential pain sites and establishing safe and effective injection treatment using botulinum neurotoxin, steroids, or lidocaine to alleviate the pain disorder of the infraspinatus muscle.


Asunto(s)
Síndromes del Dolor Miofascial , Manguito de los Rotadores , Humanos , Placa Motora , Relevancia Clínica , Músculo Esquelético/inervación , Síndromes del Dolor Miofascial/tratamiento farmacológico
19.
J Neurol Neurosurg Psychiatry ; 95(1): 44-51, 2023 Dec 14.
Artículo en Inglés | MEDLINE | ID: mdl-37558399

RESUMEN

OBJECTIVES: Alzheimer's disease (AD) is characterised by amyloid-beta accumulation (A), tau aggregation (T) and neurodegeneration (N). Vascular (V) burden has been found concomitantly with AD pathology and has synergistic effects on cognitive decline with AD biomarkers. We determined whether cognitive trajectories of AT(N) categories differed according to vascular (V) burden. METHODS: We prospectively recruited 205 participants and classified them into groups based on the AT(N) system using neuroimaging markers. Abnormal V markers were identified based on the presence of severe white matter hyperintensities. RESULTS: In A+ category, compared with the frequency of Alzheimer's pathological change category (A+T-), the frequency of AD category (A+T+) was significantly lower in V+ group (31.8%) than in V- group (64.4%) (p=0.004). Each AT(N) biomarker was predictive of cognitive decline in the V+ group as well as in the V- group (p<0.001). Additionally, the V+ group showed more severe cognitive trajectories than the V- group in the non-Alzheimer's pathological changes (A-T+, A-N+; p=0.002) and Alzheimer's pathological changes (p<0.001) categories. CONCLUSION: The distribution and longitudinal outcomes of AT(N) system differed according to vascular burdens, suggesting the importance of incorporating a V biomarker into the AT(N) system.


Asunto(s)
Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides , Neuroimagen/métodos , Disfunción Cognitiva/complicaciones , Biomarcadores , Proteínas tau
20.
J Public Health (Oxf) ; 45(3): e522-e531, 2023 08 28.
Artículo en Inglés | MEDLINE | ID: mdl-37147915

RESUMEN

BACKGROUND: Vaccine hesitancy can prevent full immunization against coronavirus infectious disease-19 (COVID-19). We hypothesized that multiple factors, including an individual's personality and psychological factors, are associated with vaccine hesitancy. METHODS: A total of 275 non-vaccinated individuals were recruited for this study. Participants completed a self-report questionnaire including sociodemographic factors, health status, COVID-19 literacy and psychological factors (depressive symptoms, generalized anxiety, somatization, illness anxiety, temperament and character). In a hierarchical logistic regression analysis, a discrete set of hierarchical variables with vaccine acceptance or hesitancy as the dependent variable was added to the demographic factors for Model 1; Model 1 + health status for Model 2; Model 2 + COVID-19 literacy for Model 3 and Model 3 + psychological factors for Model 4. RESULTS: Models 3 and 4 could predict vaccine hesitancy. High scores on the Generalized Anxiety Disorder-7 and the Illness Attitude Scale, low confidence, low collective responsibility and low reward dependence were risk factors for vaccine hesitancy. CONCLUSIONS: The present study demonstrates that psychological factors play critical roles in vaccine hesitancy. In addition to conventional policies that emphasize COVID-19 vaccines' safety and efficacy and the collective benefits of vaccination, a more individualized approach that considers an individual's emotions and personality is necessary.


Asunto(s)
COVID-19 , Enfermedades Transmisibles , Humanos , Vacunas contra la COVID-19/uso terapéutico , COVID-19/epidemiología , COVID-19/prevención & control , Ansiedad , Estado de Salud
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