GV16 acupoint stimulation with bee venom reduces peripheral hypersensitivity via activation of α2 adrenoceptors in a nitroglycerin-induced migraine mouse model.

Background: Peripheral hypersensitivities develop in the face and hindpaws of mice with nitroglycerin (NTG)-induced migraine. We evaluated whether diluted bee venom (DBV) injections at acupoints prevented these peripheral hypersensitivities and c-Fos expression in the trigeminal nucleus caudalis (TNC). Methods: NTG (10 mg/kg, intraperitoneal, i.p.) was administered every other day for nine days. DBV (0.1 mg/kg) was subcutaneously injected into the ST36 (Zusanli), LI4 (Hegu), or GV16 (Fengfu) acupoints 75 min after each NTG injection. Mice were pretreated with naloxone (5 mg/kg, i.p.) or yohimbine (5 mg/kg, i.p.) 30 min before the DBV injections. Results: NTG injection caused facial cold allodynia, hindpaw mechanical allodynia, and increased c-Fos-immunoreactive (ir) cells in the TNC. Repetitive DBV injections at GV16, but not the ST36, or LI4 acupoints, suppressed NTG-induced hindpaw mechanical allodynia and facial cold allodynia. The number of c-Fos-ir cells also decreased in response to DBV injections at the GV16 acupoint. Remarkably, pretreatment with yohimbine reversed the anti-allodynic effects of DBV injections and attenuated the decreased c-Fos expression in response to GV16 DBV treatment. Naloxone did not block the effects of GV16 DBV stimulation. Conclusion: These findings demonstrate that repetitive DBV treatment at the GV16 acupoint relieves NTG-induced facial and hindpaw hypersensitivities and decreases in c-Fos expression in the TNC via activation of the alpha-2 adrenoceptors, but not the opioid receptors.

Association between Problematic Smartphone Use and Physical Activity among Adolescents: A Path Analysis Based on the 2020 Korea Youth Risk Behavior Web-Based Survey.

BACKGROUND: Physical activity is known to prevent several diseases and positively affect mental health. Previous studies have shown that smartphone addiction negatively affects the physical activity of children and adolescents. This study aimed to investigate the relationship between problematic smartphone use and physical activity among adolescents and the related factors using path analysis. METHODS: Using data from the 16th Youth Risk Behavior Web-based Survey from 2020, scores on the Smartphone Addiction Scale-Short Version for Adolescents, physical activity, sex, socioeconomic status (SES), academic performance, depression, smoking, drinking, and sitting time were assessed. Complex sampling and path analyses were performed. RESULTS: Of the total 54,948 students, 25.5% were smartphone risk users, including potential and high-risk users. The direct path coefficients of each factor indicated that female sex (-0.14 for male), low SES (-0.062), high academic performance (0.056), low sitting time for studying purposes (-0.033), high sitting time for non-studying purposes (0.071), and depressive mood (0.130) were related to problematic smartphone use (all P<0.001). Each factor affected problematic smartphone use, and subsequently had a negative effect on the amount of physical activity, with a direct path coefficient of -0.115 (P<0.001). CONCLUSION: In this study, we confirmed that problematic smartphone use among adolescents was negatively associated with performing an adequate amount of physical activity and that various factors, such as sex, SES, academic performance, and sitting time, directly and indirectly affected this relationship.

Effects of Aging Methods and Periods on Quality Characteristics of Beef.

The objective of this study was to determine effects of aging methods (wet-aged, dry-aged, and packaged dry-aged) during 60 d on quality traits and microbial characteristics of beef. Wet-aged beef was packed by vacuum packaging and stored in a 4°C refrigerator. Dry-aged beef was used without packaging. Packaged dry-aged beef was packaged in commercial bags. Dry-aged and packaged dry-aged samples were stored in a meat ager at 2°C-4°C with 85%-90% relative humidity. Meat color, crust thickness, aging loss, cooking loss, Warner-Bratzler shear force (WBSF), texture profile analysis, Torrymeter, meat pH, water activity, volatile basic nitrogen (VBN), thiobarbituric acid reactant substances (TBARS), and microbial analysis were measured or performed every 15 d until 60 d of aging time. Meat color changed significantly with increasing aging time. Differences in meat color among aging methods were observed. Aging losses of dry-aged and packaged dry-aged samples were higher than those of wet-aged samples. Wet-aged beef showed higher cooking loss, but lower WBSF than dry-aged and packaged dry-aged beef. VBN and TBARS showed an increasing tendency with increasing aging time. Differences of VBN and TBARS among aging methods were found. Regarding microbial analysis, counts of yeasts and molds were different among aging methods at the initial aging time. Packaged dry-aged and dry-aged beef showed similar values or tendency. Significant changes occurred during aging in all aging methods. Packaged dry aging and dry aging could result in similar quality traits and microbial characteristics of beef.

Different Involvement of ASIC and TRPA1 in Facial and Hindpaw Allodynia in Nitroglycerin-Induced Peripheral Hypersensitivities in Mice.

The pathophysiological mechanism underlying migraine-associated peripheral hypersensitivity remains unclear. Acid-sensing ion channels (ASICs) and transient receptor potential ankyrin 1 (TRPA1) are known to be causative pathogenic factors of mechanical and cold allodynia, respectively. Here, we sought to investigate their involvement in cold and mechanical allodynia of the face and hindpaws, respectively, in a mouse model of repetitive nitroglycerin (NTG)-induced migraine. NTG (10 mg/kg) was administered to the mice every other day for 9 days, followed 90 min later by HC-030031 (a TRPA1 blocker) or amiloride (a non-selective ASIC blocker). Mechanical or cold sensitivity of the hindpaw and facial regions was quantified using von-Frey filaments or acetone solution, respectively. Immunohistochemistry revealed that c-Fos expression was significantly increased in the trigeminal nucleus caudalis region but not in the spinal cord. Amiloride treatment only reduced NTG-induced hindpaw mechanical allodynia, whereas HC-030031 treatment only improved facial cold allodynia. Interestingly, the number of c-Fos positive cells decreased to a similar level in each drug treatment group. These findings demonstrate that facial cold allodynia and hindpaw mechanical allodynia are differentially mediated by activation of TRPA1 and ASIC, respectively, in mice with repetitive NTG-induced hypersensitivity.

Rapamycin reduces orofacial nociceptive responses and microglial p38 mitogen-activated protein kinase phosphorylation in trigeminal nucleus caudalis in mouse orofacial formalin model.

The mammalian target of rapamycin (mTOR) plays a role in various cellular phenomena, including autophagy, cell proliferation, and differentiation. Although recent studies have reported its involvement in nociceptive responses in several pain models, whether mTOR is involved in orofacial pain processing is currently unexplored. This study determined whether rapamycin, an mTOR inhibitor, reduces nociceptive responses and the number of Fos-immunoreactive (Fos-ir) cells in the trigeminal nucleus caudalis (TNC) in a mouse orofacial formalin model. We also examined whether the glial cell expression and phosphorylated p38 (p-p38) mitogen-activated protein kinases (MAPKs) in the TNC are affected by rapamycin. Mice were intraperitoneally given rapamycin (0.1, 0.3, or 1.0 mg/kg); then, 30 min after, 5% formalin (10 µl) was subcutaneously injected into the right upper lip. The rubbing responses with the ipsilateral forepaw or hindpaw were counted for 45 min. High-dose rapamycin (1.0 mg/kg) produced significant antinociceptive effects in both the first and second phases of formalin test. The number of Fos-ir cells in the ipsilateral TNC was also reduced by high-dose rapamycin compared with vehicle-treated animals. Furthermore, the number of p-p38-ir cells the in ipsilateral TNC was significantly decreased in animals treated with high-dose rapamycin; p-p38 expression was co-localized in microglia, but not neurons and astrocytes. Therefore, the mTOR inhibitor, rapamycin, reduces orofacial nociception and Fos expression in the TNC, and its antinociceptive action on orofacial pain may be associated with the inhibition of p-p38 MAPK in the microglia.

Comparison of Heart Proportions Compressed by Chest Compressions Between Geriatric and Nongeriatric Patients Using Mathematical Methods and Chest Computed Tomography: A Retrospective Study.

BACKGROUND: Current guidelines recommended that chest compression depths during car-diopulmonary resuscitation (CPR) should be at least one-fifth of the external chest ante-riorposterior (AP) diameter. The chest AP diameter increases because of dorsal kyphosis, senile emphysema, and poor lung compliance associated with aging. This study aimed to compare the proportion of the heart compressed by chest compression (based on the ejection fraction [EF]) in geriatric and nongeriatric patients. METHODS: We performed a retrospective analysis of the chest computed tomography findings obtained between January 2010 and August 2016 and measured the chest anatomical parameters such as the perpendicular external and internal chest AP diameters with the heart AP diameter. Based on values of these parameters, EFs with 50- and 60-mm depths were obtained. In addition, we investigated and compared the proportion of 50- and 60-mm depths and heart AP to external chest AP diameter between the 2 groups. RESULTS: We randomly selected and analyzed 100 of 1,921 geriatric and 100 of 22,090 nongeriatric populations from a database. The means±standard deviations of EFs with 50- and 60-mm depths for geriatric and nongeriatric people were 37.1%±12.1% vs. 43.2%±13.8% and 47.5%±12.8% vs. 54.6%±14.8%, respectively (all p<0.001). The proportion of 50- and 60-mm depths and heart AP to external chest AP diameter were significantly different between the 2 groups (all p<0.05). CONCLUSION: Chest compression depths based on current guidelines are not sufficient for geriatric patients during CPR; hence, deeper chest compressions would be considered.

Differential Development of Facial and Hind Paw Allodynia in a Nitroglycerin-Induced Mouse Model of Chronic Migraine: Role of Capsaicin Sensitive Primary Afferents.

Despite the relatively high prevalence of migraine or headache, the pathophysiological mechanisms triggering headache-associated peripheral hypersensitivities, are unknown. Since nitric oxide (NO) is well known as a causative factor in the pathogenesis of migraine or migraine-associated hypersensitivities, a mouse model has been established using systemic administration of the NO donor, nitroglycerin (NTG). Here we tried to investigate the time course development of facial or hindpaw hypersensitivity after repetitive NTG injection. NTG (10 mg/kg) was administrated to mice every other day for nine days. Two hours post-injection, NTG produced acute mechanical and heat hypersensitivity in the hind paws. By contrast, cold allodynia, but not mechanical hypersensitivity, occurred in the facial region. Moreover, this hindpaws mechanical hypersensitivity and the facial cold allodynia was progressive and long-lasting. We subsequently examined whether the depletion of capsaicin-sensitive primary afferents (CSPAs) with resiniferatoxin (RTX, 0.02 mg/kg) altered these peripheral hypersensitivities in NTG-treated mice. RTX pretreatment did not affect the NTG-induced mechanical allodynia in the hind paws nor the cold allodynia in the facial region, but it did inhibit the development of hind paw heat hyperalgesia. Similarly, NTG injection produced significant hindpaw mechanical allodynia or facial cold allodynia, but not heat hyperalgesia in transient receptor potential type V1 (TRPV1) knockout mice. These findings demonstrate that different peripheral hypersensitivities develop in the face versus hindpaw regions in a mouse model of repetitive NTG-induced migraine, and that these hindpaw mechanical hypersensitivity and facial cold allodynia are not mediated by the activation of CSPAs.

Repetitive Acupuncture Point Treatment with Diluted Bee Venom Relieves Mechanical Allodynia and Restores Intraepidermal Nerve Fiber Loss in Oxaliplatin-Induced Neuropathic Mice.

UNLABELLED: The chemotherapeutic agent, oxaliplatin, produces a robust painful neuropathy that results in the loss of intraepidermal nerve fibers (IENFs). We have previously reported that an acupuncture point (acupoint) injection of diluted bee venom (DBV) produces a temporary antiallodynic effect in oxaliplatin-induced neuropathic mice. Herein we show a significant long-lasting antinociceptive effect of repetitive DBV acupoint treatment on oxaliplatin-induced mechanical allodynia and a significant reduction in the loss of IENFs. DBV (0.1 mg/kg, subcutaneous) was administered once a day for 18 days beginning on day 15 after oxaliplatin injection. Immunohistochemistry for IENF was performed on the glabrous skin of the hind paw footpad using the pan-neuronal marker, protein gene product 9.5. A temporary increase in mechanical threshold was observed 60 minutes after a single DBV injection into the Zusanli acupoint, and this effect was enhanced over time with repetitive DBV treatments. The basal mechanical threshold before daily DBV injection also increased from day 7 after DBV injections, and peaked at day 14 after DBV treatment. Moreover, the oxaliplatin-induced loss of IENFs was significantly reduced in mice treated repetitively with DBV. Repetitive pretreatment with the α-2 adrenoceptor antagonist, yohimbine, (5 mg/kg, subcutaneous) completely prevented the antiallodynic effects and the increase in IENFs observed in mice treated repetitively with DBV. PERSPECTIVE: We showed that repetitive acupoint stimulation with DBV gradually and significantly reduced oxaliplatin-induced mechanical allodynia and restored the loss of IENFs in neuropathic mice via an α-2 adrenoceptor mechanism. Collectively, results of this study suggest that repetitive acupoint treatment with DBV can be a potential strategy for the management of chemotherapy-induced neuropathy.

Clonidine, an alpha-2 adrenoceptor agonist relieves mechanical allodynia in oxaliplatin-induced neuropathic mice; potentiation by spinal p38 MAPK inhibition without motor dysfunction and hypotension.

Cancer chemotherapy with platinum-based antineoplastic agents including oxaliplatin frequently results in a debilitating and painful peripheral neuropathy. We evaluated the antinociceptive effects of the alpha-2 adrenoceptor agonist, clonidine on oxaliplatin-induced neuropathic pain. Specifically, we determined if (i) the intraperitoneal (i.p.) injection of clonidine reduces mechanical allodynia in mice with an oxaliplatin-induced neuropathy and (ii) concurrent inhibition of p38 mitogen-activated protein kinase (MAPK) activity by the p38 MAPK inhibitor SB203580 enhances clonidine's antiallodynic effect. Clonidine (0.01-0.1 mg kg(-1), i.p.), with or without SB203580(1-10 nmol, intrathecal) was administered two weeks after oxaliplatin injection(10 mg kg(-1), i.p.) to mice. Mechanical withdrawal threshold, motor coordination and blood pressure were measured. Postmortem expression of p38 MAPK and ERK as well as their phosphorylated forms(p-p38 and p-ERK) were quantified 30 min or 4 hr after drug injection in the spinal cord dorsal horn of treated and control mice. Clonidine dose-dependently reduced oxaliplatin-induced mechanical allodynia and spinal p-p38 MAPK expression, but not p-ERK. At 0.1 mg kg(-1), clonidine also impaired motor coordination and decreased blood pressure. A 10 nmol dose of SB203580 alone significantly reduced mechanical allodynia and p-p38 MAPK expression, while a subeffective dose(3 nmol) potentiated the antiallodynic effect of 0.03 mg kg(-1) clonidine and reduced the increased p-p38 MAPK. Coadministration of SB203580 and 0.03 mg kg(-1) clonidine decreased allodynia similar to that of 0.10 mg kg(-1) clonidine, but without significant motor or vascular effects. These findings demonstrate that clonidine treatment reduces oxaliplatin-induced mechanical allodynia. The concurrent administration of SB203580 reduces the dosage requirements for clonidine, thereby alleviating allodynia without producing undesirable motor or cardiovascular effects.

EW-7197, a novel ALK-5 kinase inhibitor, potently inhibits breast to lung metastasis.

Advanced tumors produce an excessive amount of transforming growth factor ß (TGFß), which promotes tumor progression at late stages of malignancy. The purpose of this study was to develop anti-TGFß therapeutics for cancer. We synthesized a novel small-molecule TGFß receptor I kinase (activin receptor-like kinase 5) inhibitor termed N-[[4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl]methyl]-2-fluoroaniline (EW-7197), and we investigated its potential antimetastatic efficacy in mouse mammary tumor virus (MMTV)/c-Neu mice and 4T1 orthotopic-grafted mice. EW-7197 inhibited Smad/TGFß signaling, cell migration, invasion, and lung metastasis in MMTV/c-Neu mice and 4T1 orthotopic-grafted mice. EW-7197 also inhibited the epithelial-to-mesenchymal transition (EMT) in both TGFß-treated breast cancer cells and 4T1 orthotopic-grafted mice. Furthermore, EW-7197 enhanced cytotoxic T lymphocyte activity in 4T1 orthotopic-grafted mice and increased the survival time of 4T1-Luc and 4T1 breast tumor-bearing mice. In summary, EW-7197 showed potent in vivo antimetastatic activity, indicating its potential for use as an anticancer therapy.

Surface enhanced Raman scattering on non-SERS active substrates and in situ electrochemical study based on a single gold microshell.

A single gold microshell, which was elaborately fabricated to carry numerous hot spots on its own surface, enabled the acquisition of the SERS spectra from the molecules on non-SERS active substrates such as Si/SiO2, ITO, and glass. A self-assembled monolayer of 11-mercaptoundecanols on the gold microshell offered an easy and reliable way to electrically insulate from the underlying flat Pt electrode and accomplish in situ monitoring the electrochemical reaction with minimal interference.