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Respiratory syncytial virus (RSV) is a major cause of respiratory tract infection in children. Despite decades of efforts, no effective therapies are available. We recently reported that extracts of Ephedra Herb and Cinnamon Bark interacted with the G attachment protein of RSV to inhibit infectivity. The present in vitro study aimed to investigate the antiviral effect of ephedrine alkaloids-free Ephedra Herb extract (EFE), which is characterized by free of harmful effects of ephedrine alkaloids in Ephedra Herb, on experimental RSV infection. Infection of RSV into A549 cells simultaneously with EFE resulted the significant reduction of RSV RNA, viral protein, and viral titers after the incubation of the cells. We found that RSV attachment to the cell surface was inhibited both in the presence of EFE and when RSV particles were pre-treated with EFE. We also found that EFE specifically interacted with the central conserved domain of RSV G protein by surface plasmon resonance, demonstrating that specific binding of G protein to the cellular receptor was inhibited by EFE. Another mechanism was found in which a higher concentration of EFE inhibited the viral load immediately after the viral entry into host cells, suggesting the inhibition of viral RNA replication. These results demonstrate that EFE worked against RSV infection through multiple antiviral mechanisms, a unique feature of this crude drug extract.
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We previously reported that the combined application of Ephedra Herb extract (EHE) and epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), erlotinib, is effective in suppressing the growth of erlotinib-resistant non-small-cell lung cancer (NSCLC) cell line, H1993, xenograft tumor, and cell proliferation, and that EHE downregulates c-Met and wild-type EGFR in H1993 cells. However, it was unclear whether EHE could affect EGFR with active mutations. Clinically, advanced NSCLC patients who are eligible for EGFR-TKI treatment are those with detected EGFR with activating mutations. Therefore, it is important to clarify the effect of EHE on EGFR with activating mutations. H1975 cells express EGFR with activating mutations, L858R and T790M, and c-Met; this NSCLC cell line was used in the present study. EHE downregulated the expression of EGFR with activating mutations and c-Met, and inhibited autophosphorylation of c-Met. Proliferation of H1975 cells was suppressed by EHE in a concentration-dependent manner. These results suggest that EHE may be effective against NSCLC harboring EGFR with activating mutations. Considering the fact that advanced NSCLC patients, with an EGFR T790M mutation, are currently widely treated with the third-generation EGFR-TKI, osimertinib, we examined the combined effects of osimertinib and EHE on H1975 cells. The osimertinib and EHE combination downregulated the expression of these receptors and suppressed the proliferation of H1975 cells more effectively than did osimertinib alone, suggesting that this combination may be effective in treating patients with advanced NSCLC with the L858R + T790M EGFR mutation and c-Met. Graphical Abstract was created with BioRender.com.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Cloridrato de Erlotinib , Receptores ErbB/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Inibidores de Proteínas Quinases/farmacologia , Mutação , Linhagem Celular , Linhagem Celular TumoralRESUMO
We report for the first time that ephedrine alkaloids-free Ephedra Herb extract (EFE) directly inhibits the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro and that the addition of EFE to the culture medium before viral infection reduces virus titers in the culture supernatant of SARS-CoV-2, including those of variant strains, by more than 99%, 24 h after infection. The addition of Ephedra Herb macromolecule condensed-tannin, which is the main active ingredient responsible for the anticancer, pain suppression, and anti-influenza effects of EFE, similarly suppressed virus production in the culture supernatant by 99% before infection and by more than 90% after infection. Since EFE does not have the side effects caused by ephedrine alkaloids, such as hypertension, palpitations, and insomnia, our results showed the potential of EFE as a safe therapeutic agent against coronavirus disease 2019.
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ETHNOPHARMACOLOGICAL RELEVANCE: In our previous study, we reported that Ephedra Herb extract (EHE) increased the locomotor activity of mice in the open-field test and reduced the immobility time in the forced swim test. Ephedrine alkaloids (EAs) are thought to be responsible for the adverse effects of Ephedra Herb. However, there are no reports to verify that the adverse effects of Ephedra Herb are caused by the amount of EAs in the herb. Therefore, we investigated whether these adverse effects of EHE are caused by the amounts of ephedrine (Eph) and pseudoephedrine (Pse) in the herbal extract. In a preliminary study of the time course analysis of the open field test, we newly observed that EHE evoked switching from transient sedation to sustained excitement. AIM OF THE STUDY: We aimed to confirm whether EHE evokes switching from transient sedation to sustained excitement, investigate whether these actions of EHE are caused by the amount of ephedrine (Eph) and pseudoephedrine (Pse) in the herbal extract, and clarify the molecular mechanism of the transient sedative effect. MATERIALS AND METHODS: The locomotor activity of mice was tested using the open-field test. The immobility times were measured using a forced swim test, and the motor dysfunction in mice was tested using the rotarod test. RESULTS: EHE, Eph, and Pse induced transient motionlessness between 0 and 15 min after oral administration, however, they did not induce depression-like behavior and motor dysfunction in mice, suggesting that the motionlessness induced by EHE, Eph, or Pse resulted from sedation. The α2a adrenoceptor inhibitor, atipamezole, decreased their sedative effects. Thus, immediately after EHE administration, the transient sedative effect is mediated through the activation of the α2a adrenoreceptor by Eph and Pse. EHE and Eph increased total locomotor activity for 15-120 min after oral administration; however, Pse had no effect. Therefore, the slow-onset and sustained excitatory effects of EHE are mediated by Eph. CONCLUSIONS: We discovered for the first time that EHE evokes diphasic action by switching from transient sedation to sustained excitement. The transient sedation was evoked by the Eph and Pse in the herbal extract via activation of the α2a adrenoceptor and the sustained excitement was caused by the Eph in the herbal extract.
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Alcaloides , Ephedra , Camundongos , Animais , Ephedra/química , Efedrina/farmacologia , Pseudoefedrina , Alcaloides/química , Extratos Vegetais/química , Hipnóticos e Sedativos/farmacologia , Receptores AdrenérgicosRESUMO
Apricot and Peach Kernels are commercial crude drugs used in many formulas of traditional Japanese medicine, Kampo. Although their applications are quite different, it is difficult to distinguish them using conventional methods such as HPLC. The study aimed at near-infrared (NIR) metabolic profiling to discriminate Apricot and Peach Kernels (Armeniacae Semen and Persicae Semen) collected from Japanese markets. A fast, simple, non-destructive, and robust NIR measurement of kernel surface with no sample pre-treatment was achieved in situ. Principal component analysis and orthogonal partial least squares discriminant analysis (OPLS-DA) models showed discrimination between the two crude drugs with good fitting and prediction values. These results indicate that NIR metabolic profiling is useful for discriminating Apricot and Peach Kernels based on their chemical constituents using a simple and non-destructive procedure.
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Prunus armeniaca , Prunus persica , Metabolômica , Análise de Componente Principal , Cromatografia Líquida de Alta PressãoRESUMO
BACKGROUND/AIMS: Gastroprokinetic agents are used for patients with postoperative ileus (POI), and the Japanese traditional herbal medicine daikenchuto (DKT) is one such agent used in the clinical setting. POI is caused by inflammation. DKT and rikkunshito have anti-inflammatory abilities in addition to their gastroprokinetic effects. The efficacy of Kampo formulations, including hangekobokuto (HKT), in patients with POI has been reported recently. Several authors have described the efficacy of honokiol, the primary component of Magnoliae Cortex, in HKT in mouse models of POI. We therefore analyzed the effect of HKT on POI model mice to determine the similarities in the mechanism of action between HKT and DKT. METHODS: HKT was administered orally to each mouse before and after intestinal manipulation was performed on the distal ileum. The gastrointestinal transit in vivo, leukocyte infiltration, and levels of inflammatory mediators, such as cytokines and chemokines, were analyzed. RESULTS: HKT significantly inhibited the infiltration of neutrophils and macrophages and led to the recovery of delayed intestinal transit. In addition, it significantly decreased inducible nitric oxide synthase (iNOS) as well as honokiol levels, suggesting anti-inflammatory activity. However, it did not inhibit the increase in levels of interleukin (IL)-1beta and IL-6, which are related to iNOS induction. In contrast, HKT increased levels of nerve growth factor (NGF) and suppressed those of nuclear factor-κB (NFκB), which are related to iNOS induction, suggesting the possibility of a neuronal anti-inflammatory mechanism. CONCLUSIONS: HKT exerted a POI-relieving effect similar to DKT in a murine POI model, and findings suggest that it may exert its anti-inflammatory activity through NGF.
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Anti-Inflamatórios , Íleus , Preparações de Plantas , Plantas Medicinais , Compostos Alílicos , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Compostos de Bifenilo , Íleus/tratamento farmacológico , Mediadores da Inflamação , Interleucina-6/uso terapêutico , Japão , Camundongos , NF-kappa B/uso terapêutico , Fator de Crescimento Neural/uso terapêutico , Óxido Nítrico Sintase Tipo II/uso terapêutico , Fenóis , Preparações de Plantas/farmacologia , Preparações de Plantas/uso terapêutico , Complicações Pós-Operatórias/tratamento farmacológicoRESUMO
Intron retention (IR) is a regulatory mechanism that can retard protein production by acting at the level of mRNA processing. We recently demonstrated that IR occurs at the pre-symptomatic state during the aging process of a mouse model of aging, providing a promising biomarker for that state, and can be restored to the normal state by juzentaihoto (JTT), a Japanese herbal medicine (Kampo) (Okada et al. 2021). Here we characterized the genes that accumulate retained introns, examined the biological significance of increased IR in these genes for the host, and determined whether drugs other than JTT can have this effect. By analyzing RNA-sequencing data generated from the hippocampus of the 19-week-old SAMP8 mouse, a model for studying age-related depression and Alzheimer's disease, we showed that genes with increased IR are generally involved in multiple metabolic pathways and have pivotal roles in sensing homeostasis. We thus propose that IR is a stress response and works to fine-tune the expression of many downstream target genes, leading to lower levels of their translation under stress conditions. Interestingly, Kampo medicines, as well as other organic compounds, restored splicing of a specific set of retained introns in these sensor genes in accordance with the physiological recovery conditions of the host, which corresponds with the recovery of transcripts represented by differentially expressed genes. Thus, analysis of IR genes may have broad applicability in evaluating the pre-symptomatic state based on the extent of IR of selective sensor genes, opening a promising early diagnosis of any diseases and a strategy for evaluating efficacies of several drugs based on the extent of IR restoration of these sensor genes.
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Doença de Alzheimer , Plantas Medicinais , Doença de Alzheimer/genética , Animais , Íntrons/genética , Japão , Camundongos , Plantas Medicinais/genética , Splicing de RNA , Análise de Sequência de RNARESUMO
Aim: In Kampo medicine, there exists an important system of diagnosis called Fukushin, or abdominal diagnosis or palpation. By applying pressure to the abdomen of the patient, the physician can gain important information on the patient's physical state and use those indications to choose a suitable Kampo formulation. We have previously developed a Fukushin simulator, a teaching tool that reproduces the important abdominal patterns that doctors will encounter in clinical practice and that has received favourable feedback for students and practitioners. In order to make diagnosis and prescription easier, it is desirable to have matched formula-pattern pairings. The present study aims to develop such pairings. Methods: With the previously developed models as a foundation, in the present study the production team (two members) used materials such as urethane foam and silicone rubber to build an additional 13 standard abdominal pattern models matched to Kampo herbal formulas commonly used by practitioners in Japan. Subsequently, the evaluation team (the remaining 10 authors) investigated the viability of these models. Results: The evaluation team determined that abdominal pattern models matched to the following typical Kampo formulas were created successfully: Dai-saiko-To (), Dai-joki-To (), Shigyaku-San (), Saiko-ka-ryukotsu-borei-To (), Keishi-bukuryo-Gan (), Hachimi-jio-Gan (), Hange-shashin-To (), Sho-saiko-To (), Hochu-ekki-To (), Sho-kenchu-To (), Toki-shakuyaku-San (), Ninjin-To (), and Dai-kenchu-To (). Conclusion: We suggest that these new formula-pattern models can make an important contribution to the standardization of abdominal diagnosis and prescription and to Kampo education.
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Aging-induced neuroinflammation, also known as neuroinflammaging, plays a pivotal role in emotional disturbances, including depression and anxiety, in older individuals, thereby leading to cognitive dysfunction. Although numerous studies have focused on therapeutic strategies for cognitive impairment in older individuals, little research has been performed on treating its preceding emotional disturbances. Here, we examined whether Kampo formulas (kososan [KS], nobiletin-rich kososan [NKS], and hachimijiogan [HJG]) can ameliorate aging-induced emotional disturbances and neuroinflammation in mice. The depression-like behaviors observed in SAMP8 mice, relative to normally aging SAMR1 mice, were significantly prevented by treatment with Kampo formulas for 13 weeks. Western blot analysis revealed that hippocampal neuroinflammation was significantly abrogated by Kampo formulas. KS and NKS also significantly attenuated the hippocampal neuroinflammatory priming induced by lipopolysaccharide (LPS, 0.33 mg/kg, i.p.) challenge in SAMP8 mice. Hippocampal IL-1ß, IL-6, and MCP-1 levels were significantly decreased in NKS-treated SAMP8 mice. KS and NKS showed significantly reduced tau accumulation in the brains of SAMP8 mice. RNA-sequencing revealed that each Kampo formula led to unique dynamics of hippocampal gene expression and appeared to abrogate hippocampal inflammatory responses. HJG significantly blocked the LPS-induced increase in serum IL-6 and MCP-1. These results suggest that Kampo formulas would be useful for treating aging-induced depression, in part by regulating neuroinflammatory pathways. This finding may pave the way for the development of therapeutic strategies for aging-related emotional disturbances, which may contribute to the prevention of cognitive dysfunction in older individuals.
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Envelhecimento/patologia , Ansiedade/etiologia , Comportamento Animal/efeitos dos fármacos , Depressão/tratamento farmacológico , Medicina Kampo , Animais , Citocinas/genética , Citocinas/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Lipopolissacarídeos/toxicidade , Masculino , Camundongos , Camundongos EndogâmicosRESUMO
Depression is deemed a mood disorder characterized by a high rate of relapse. Therefore, overcoming of the recurrent depression is globally expecting. Kososan, a traditional Japanese herbal medicine, has been clinically used for mild depressive mood, and our previous studies have shown some evidence for its antidepressive-like efficacy in experimental animal models of depression. However, it remains unclear whether kososan has beneficial effects on recurrent depression. Here, we examined its effect using a mouse model of modified repeated social defeat stress (SDS) paradigm. Male BALB/c mice were exposed to a 5-min SDS from unfamiliar aggressive CD-1 mice for 5 days. Kososan extract (1.0 kg/kg/day) or an antidepressant milnacipran (60 mg/kg/day) was administered orally for 26 days (days 7-32) to depression-like mice with social avoidant behaviors on day 6. Single 5 min of SDS was subjected to mice recovered from the social avoidance on day 31, and then the recurrence of depression-like behaviors was evaluated on day 32. Hippocampal gene expression patterns were also assayed by DNA microarray analysis. Water- or milnacipran-administered mice resulted in a recurrence of depression-like behaviors by re-exposure of single SDS, whereas kososan-administered mice did not recur depression-like behaviors. Distinct gene expression patterns were also found for treating kososan and milnacipran. Collectively, this finding suggests that kososan exerts a preventive effect on recurrent depression-like behaviors in mice. Pretreatment of kososan is more useful for recurrent depression than that of milnacipran.
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Antidepressivos/farmacologia , Depressão/prevenção & controle , Medicamentos de Ervas Chinesas/farmacologia , Proteínas do Tecido Nervoso/genética , Derrota Social , Estresse Psicológico/tratamento farmacológico , Administração Oral , Animais , Depressão/genética , Depressão/fisiopatologia , Depressão/psicologia , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Ontologia Genética , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Japão , Masculino , Medicina Kampo/métodos , Camundongos , Camundongos Endogâmicos BALB C , Milnaciprano/farmacologia , Anotação de Sequência Molecular , Proteínas do Tecido Nervoso/classificação , Proteínas do Tecido Nervoso/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Recidiva , Estresse Psicológico/genética , Estresse Psicológico/fisiopatologiaRESUMO
Coronavirus disease 2019 (COVID-19) spread to Japan in 2020, where the number of infected patients exceeded 250,000 and COVID-related deaths exceeded 3,500 in one year. Basic guidelines for infection control were implemented in Japan, and research and development of effective drugs and vaccines were promoted. This included considering Kampo medicine, which has a long history of treating recurring emerging viral infections. Considering the characteristics of the disease (inflammation of the upper and lower respiratory tract as well as potential neural damage and vasculitis), Kampo medicine could be considered as a treatment strategy due to its antiviral and anti-inflammatory effects induced by multiple active substances that could aid in disease prevention and recovery. In this study, case reports on the management of COVID-19 with Kampo medicine, which were published until March 31, 2021, were reviewed. The search strategy involved the use of Medline and hand-searching. Twenty two patients were treated using Kampo medicines with or without Western medicine, based on individual conditions. On the other hand, the effects of Kampo medicines as a potential preventive treatment (pre-infection), active treatment (especially in the acute and subacute stage), or treatment of sequelae to aid recovery (after infection) in the different stages of COVID-19 are being studied as research projects in the Japan Society for Oriental Medicine (JSOM). JSOM has also organized a pioneering project of clinical trials for COVID-19, some of which are now in progress.
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OBJECTIVE: To examine how Kampo education in Japanese medical schools changed between 2011 and 2019. METHODS: We administered nationwide postal questionnaire surveys about current characteristics of Kampo medicine education in all 82 Japanese medical schools, directed to the persons responsible for Kampo education at each university. One survey was conducted in 2011 and one in 2019. Analysis used Welch's t-test and a chi-squared test. RESULTS: The average class meeting time was shorter in 2019 than in 2011. The proportion of class meetings that were about Kampo saw a statistically significant increase in the third year and a significant decrease in the fourth and sixth years of medical school. Curriculum standardisation, preparation of simple textbooks, and fostering Kampo medicine instructors were the primary problems in both years. The proportion of mainstream medical education contents focusing on traditional Japanese Kampo medicine did not change over time, nor did the percentage of those considering using standardised textbooks. Other changes were statistically nonsignificant. CONCLUSION: In Japanese medical schools, the number of class meetings teaching Kampo medicine has increased; however, this number is not statistically significant. Persistent problems in Kampo education, including curriculum standardisation, need to be addressed.
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Educação Médica , Medicina Kampo , Currículo , Humanos , Japão , Faculdades de MedicinaRESUMO
Shofuku-fujin is an abnormal physical finding in Kampo medical practice. It is assumed to be often found in the elderly and contributes to the selection of Kampo formulas used mainly in elderly patients. However, few objective reports about Shofuku-fujin have been published to date. The aim of this study was to clarify the clinical features of patients showing Shofuku-fujin by using bioelectrical impedance analysis (BIA) and to objectively assess the potential clinical implications of these findings. We conducted a cross-sectional study of 1330 patients who visited our institute to undergo a medical examination by using data collected from September 2010 to March 2016. We extracted data on patient sex and age, anthropometric data, and body composition data that could potentially affect the appearance of Shofuku-fujin. Logistic regression analyses were performed by sex to analyze the various factors related to the appearance of Shofuku-fujin. Of the 1330 patients, the data of 386 men and 942 women were used for analysis. Multivariate logistic regression analysis showed that Shofuku-fujin was associated with older age (odds ratio (OR), 1.07; 95% confidence interval (CI), 1.05-1.10; p < 0.001), lower skeletal muscle mass index (SMI) (OR, 0.60; 95% CI, 0.43-0.85; p = 0.004), and lower body fat percentage (OR, 0.89; 95% CI, 0.85-0.93; p < 0.001) in men and older age (OR, 1.06; 95% CI, 1.04-1.07, p < 0.001) and lower body fat percentage (OR, 0.94; 95% CI, 0.92-0.96; p < 0.001) in women. On the basis of these results, the factors causing the appearance of Shofuku-fujin were aging, decreased muscle mass, and decreased body fat in men and aging and decreased body fat in women. Our results demonstrated that it may be better to consider a loss of muscle mass when examining a male patient with Shofuku-fujin.
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Identifying different species of the genus Atractylodes which are commonly used in Chinese and Japanese traditional medicine, using chromatographic approaches can be difficult. 1H NMR metabolic profiling of DNA-authenticated, archived rhizomes of the genus Atractylodes was performed for genetic and chemical evaluation. The ITS region of the nuclear rDNA was sequenced for five species, A. japonica, A. macrocephala, A. lancea, A. chinensis, and A. koreana. Our samples had nucleotide sequences as previously reported, except that part of the A. lancea cultivated in Japan had a type 5, hybrid DNA sequence. Principal component analysis (PCA) using 1H NMR spectra of extracts with two solvent systems (CD3OD, CDCl3) was performed. When CDCl3 extracts were utilized, the chemometric analysis enabled the identification and classification of Atractylodes species according to their composition of major sesquiterpene compounds. The 1H NMR spectra using CD3OD contained confounding sugar peaks. PCA removal of these peaks gave the same result as that obtained using CDCl3 and allowed species distinction. Such chemometric methods with multivariate analysis of NMR spectra will be useful for the discrimination of plant species, without specifying the index components and quantitative analysis on multi-components.
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Atractylodes/química , Atractylodes/classificação , Metabolômica , Compostos Fitoquímicos/análise , Sequência de Bases , DNA de Plantas/genética , DNA Espaçador Ribossômico/genética , Japão , Espectroscopia de Ressonância Magnética , Filogenia , Análise de Componente Principal , Rizoma/química , Rizoma/genética , Sesquiterpenos/análiseRESUMO
Aging causes psychological dysfunction and neurodegeneration, and can lead to cognitive impairments. Although numerous studies have reported that neurodegeneration and subsequent cognitive impairments are involved in neuroinflammation, relationship between psychological disturbance and neuroinflammation with aging (neuroinflammaging) remains unclear. Here, to clarify the relationship, we examined whether neuroinflammaging affects emotional behaviors in senescence-accelerated mouse prone 8 (SAMP8) mice. Microglial inflammatory responses to a subsequent lipopolysaccharide (LPS) challenge were significantly enhanced in male SAMP8 mice relative to normal aging senescence-accelerated mouse resistant 1 (SAMR1) mice at 17â¯weeks, but not 8â¯weeks of age. LPS injection also significantly increased brain and systemic inflammation in SAMP8 mice at 17â¯weeks. In a battery of behavioral tests, SAMP8 mice at 17â¯weeks, but not 8â¯weeks, exhibited anxiety- and depression-like behaviors and circadian rhythm disruption. Taken together, SAMP8 mice at 17â¯weeks possess a brain microenvironment in which it is easier to trigger neuroinflammatory priming; this may lead to an emergence of anxiety- and depression-like behaviors and circadian rhythm disruption. These findings provide new insights into the temporal relationship between neuroinflammaging and emotion.
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Envelhecimento , Ritmo Circadiano , Animais , Ansiedade , Encéfalo , Emoções , Masculino , CamundongosRESUMO
Prolonged stress triggers neuroinflammation, which plays a significant role in the development of depression; however, stressed people do not always suffer from depression because of individual differences in stress vulnerability. Negative cognitive bias (NCB) toward pessimistic judgment often underlies depressive episodes. However, a relationship between stress vulnerability, neuroinflammation, and NCB remains elusive. In addition, an animal model with all the traits would be a powerful tool for studying the etiology of depression and its therapeutic approaches. Accordingly, this study evaluated the effect of stress vulnerability on neuroinflammation and depression-related behaviors, including NCB in males, using a modified version of repeated social defeat stress (mRSDS) paradigm, a validated animal model of psychosocial stress. Exposure to mRSDS, consisting of 5â¯min of social defeat by unfamiliar CD-1 aggressor mice for five consecutive days, caused NCB, which co-occurred with depressive- and anxiety-like behaviors, and neuroinflammation in male BALB/c mice. Treatment with minocycline, an antibiotic with anti-inflammatory property, blocked mRSDS-induced depressive-like behaviors and neuroinflammation, but not NCB, indicating the limited effect of an anti-inflammatory intervention. In addition, marked differences were found in neuroinflammatory profiles and hippocampal gene expression patterns between resilient and unstressed mice, as well as between susceptible and resilient mice. Therefore, mice resilient to mRSDS are indeed not intact. Our findings provide insights into the unique features of the mRSDS model in male BALB/c mice, which could be used to investigate the etiological mechanisms underlying depression as well as bridge the gap in the relationship between stress vulnerability, neuroinflammation, and NCB in males.
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Derrota Social , Estresse Psicológico , Animais , Ansiedade , Depressão/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BLRESUMO
Previously, we reported that the c-Met inhibitory effect of Ephedra Herb extract (EHE) is derived from ingredients besides ephedrine alkaloids. Moreover, analgesic and anti-influenza activities of EHE and ephedrine alkaloids-free Ephedra Herb extract (EFE) have been reported recently. In this study, we examined the fractions containing c-Met kinase inhibitory activity from EHE and the fractions with analgesic and anti-influenza activities from EFE, and elucidated the structural characteristics of the active fractions. Significant c-Met kinase activity was observed in 30, 40, and 50% methanol (MeOH) eluate fractions obtained from water extract of EHE using Diaion HP-20 column chromatography. Similarly, 20 and 40% MeOH, and MeOH eluate fractions obtained from water extract of EFE were found to display analgesic and anti-influenza activities. Reversed phase-HPLC analysis of the active fractions commonly showed broad peaks characteristic of high-molecular mass condensed tannin. The active fractions were analyzed using 13C-NMR and decomposition reactions; the deduced structures of active components were high-molecular mass condensed tannins, which were mainly procyanidin B-type and partly procyanidin A-type, including pyrogallol- and catechol-type flavan 3-ols as extension and terminal units. HPLC and gel permeation chromatography (GPC) analyses estimated that the ratio of pyrogallol- and catechol-type was approximately 9 : 2, and the weight-average molecular weight based on the polystyrene standard was >45000. Furthermore, GPC-based analysis was proposed as the quality evaluation method for high-molecular mass condensed tannin in EHE and EFE.
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Ephedra/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Alcaloides/química , Alcaloides/farmacologia , Analgésicos/química , Analgésicos/farmacologia , Animais , Antivirais/química , Antivirais/farmacologia , Biflavonoides/química , Biflavonoides/farmacologia , Catequina/química , Catequina/farmacologia , Linhagem Celular Tumoral , Cães , Efedrina/química , Efedrina/farmacologia , Humanos , Células Madin Darby de Rim Canino , Masculino , Camundongos , Proantocianidinas/química , Proantocianidinas/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidoresRESUMO
Ephedra Herb is defined in the 17th edition of the Japanese Pharmacopoeia (JP) as the terrestrial stem of Ephedra sinica Stapf., Ephedra intermedia Schrenk et C.A. Meyer, or Ephedra equisetina Bunge (Ephedraceae). The stems of Ephedra Herb contain greater than 0.7% ephedrine alkaloids (ephedrine and pseudoephedrine). Despite its high effectiveness, Ephedra Herb exert several adverse effects, including palpitation, excitation, insomnia, and dysuria. Both the primary and adverse effects of Ephedra Herb have been traditionally believed to be mediated by these ephedrine alkaloids. However, our study found that several pharmacological actions of Ephedra Herb were not associated with ephedrine alkaloids. We prepared an ephedrine alkaloid-free Ephedra Herb extract (EFE) by eliminating ephedrine alkaloids from Ephedra Herb extract (EHE) using ion-exchange column chromatography. EFE exerted analgesic, anti-influenza, and anticancer activities in the same manner as EHE. Moreover, EFE did not induce adverse effects due to ephedrine alkaloids, such as excitation, insomnia, and arrhythmias, and showed no toxicity. Furthermore, we evaluated the safety of EFE in healthy volunteers. The number of adverse event cases was higher in the EHE-treated group than in the EFE-treated group, although the difference was not significant. Our evidence suggested that EFE was safer than EHE.
Assuntos
Medicamentos de Ervas Chinesas/efeitos adversos , Medicamentos de Ervas Chinesas/química , Ephedra/química , Idoso , Analgésicos , Antineoplásicos Fitogênicos , Antivirais , Cromatografia por Troca Iônica , Medicamentos de Ervas Chinesas/farmacologia , Efedrina/efeitos adversos , Efedrina/isolamento & purificação , Feminino , Humanos , Masculino , Pseudoefedrina/efeitos adversos , Pseudoefedrina/isolamento & purificação , SegurançaRESUMO
The analgesic effect of Ephedra Herb (EH) is believed to be derived from the anti-inflammatory action of pseudoephedrine (Pse). We recently reported that ephedrine alkaloids-free EH extract (EFE) attenuates formalin-induced pain to the same level as that achieved by EH extract (EHE), which suggests that the analgesic effect of EH may not be due to ephedrine alkaloids (EAs). To examine the contribution of EAs to the analgesic effect of EH, mice were injected with formalin to induce a biphasic pain reaction (first phase, 0-5 min; second phase, 10-45 min) at various time points after oral administration of the following test drugs: ephedrine (Eph), Pse, "authentic" EHE from Tsumura & Co. (EHE-Ts), EFE, and EHE that was used as the source of EFE (EHE-To). Biphasic pain was suppressed at 30 min after administration of Eph, EHE-Ts, and EHE-To. At 6 h after administration of EFE, EHE-To, and Pse-and at 4 to 6 h after administration of EHE-Ts-only second-phase pain was suppressed; however, the effect of Pse at 6 h was not significant. These results suggested that EHE has a biphasic analgesic effect against biphasic formalin-induced pain: in the first phase of analgesia (30 min after administration), biphasic pain is suppressed by Eph; in the second phase of analgesia (4-6 h after administration), second-phase pain is alleviated by constituents other than EAs, although Pse may partially contribute to the relief of second-phase pain.