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ETHNOPHARMACOLOGICAL RELEVANCE: Phellodendron chinense C.K.Schneid(P. chinense Schneid) is known in TCM as Huang Bo, is traditionally used to support gastrointestinal function and alleviate stomach-related ailments, including gastric ulcer bleeding and symptoms of gastroesophageal reflux disease. Helicobacter pylori (H. pylori) is classified by the WHO as a Group 1 carcinogen. However, the specific activity and mechanism of action of P. chinense Schneid against H. pylori infection remain unclear. It has been noted that Huangjiu processing may alter the bitter and cold properties of P. chinense Schneid, but its effect on antimicrobial activity requires further investigation. Additionally, it remains uncertain whether berberine is the sole antimicrobial active component of P. chinense Schneid. AIM OF STUDY: This study aims to elucidate the anti-H. pylori infection activity of P. chinense Schneid, along with its mechanism of action and key antimicrobial active components. MATERIALS AND METHODS: Phytochemical analysis was carried out by UPLC-MS/MS. HPLC was employed to quantify the berberine content of the extracts. Antimicrobial activity was assessed using the micro broth dilution method. Morphology was observed using SEM. The impact on urease activity was analyzed through in vitro urease enzyme kinetics. RT-qPCR was employed to detect the expression of virulence genes, including adhesin, flagellum, urease, and cytotoxin-related genes. The adhesion effect was evaluated by immunofluorescence staining and agar culture. RESULTS: P. chinense Schneid exhibited strong antimicrobial activity against both antibiotic-sensitive and resistant H. pylori strains, with MIC ranging from 40 to 160 µg/mL. Combination with amoxicillin, metronidazole, levofloxacin, and clarithromycin did not result in antagonistic effects. P. chinense Schneid induced alterations in bacterial morphology and structure, downregulated the expression of various virulence genes, and inhibited urease enzyme activity. In co-infection systems, P. chinense Schneid significantly attenuated H. pylori adhesion and urease relative content, thereby mitigating cellular damage caused by infection. Huangjiu processing enhanced the anti-H. pylori activity of P. chinense Schneid. Besides berberine, P. chinense Schneid contained seven other components with anti-H. pylori activity, with palmatine exhibiting the strongest activity, followed by jatrorrhizine. CONCLUSIONS: This study sheds light on the potential therapeutic mechanisms of P. chinense Schneid against H. pylori infection, demonstrating its capacity to disrupt bacterial structure, inhibit urease activity, suppress virulence gene transcription, inhibit adhesion, and protect host cells. The anti-H. pylori activity of P. chinense Schneid was potentiated by Huangjiu processing, and additional components beyond berberine were identified as possessing strong anti-H. pylori activity. Notably, jatrorrhizine, a core component of P. chinense Schneid, exhibited significant anti-H. pylori activity, marking a groundbreaking discovery.
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Antibacterianos , Berberina , Helicobacter pylori , Phellodendron , Extratos Vegetais , Helicobacter pylori/efeitos dos fármacos , Phellodendron/química , Antibacterianos/farmacologia , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Berberina/farmacologia , Testes de Sensibilidade Microbiana , Urease/metabolismo , Humanos , Infecções por Helicobacter/tratamento farmacológico , Infecções por Helicobacter/microbiologiaRESUMO
BACKGROUND: The aqueous extract of the dried buds of Syzygium aromaticum (SAAE) have the potential to alleviate Helicobacter pylori infection, but the specific molecular mechanism has not been fully elucidated. PURPOSE: This study aimed to investigate the underlying mechanisms of SAAE on H. pylori pathogenicity. METHODS: The inhibitory kinetics and anti-H. pylori adhesive capacity assays were conducted to examine the effects of SAAE on the growth and adhesive capability of H. pylori. The H. pylori outer membrane vesicles (OMVs) were purified from the culture supernatant through high-speed centrifugation, filtration, and two rounds of ultracentrifugation. Their characteristics and protein composition were then identified using transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and qualitative proteomics study. Subsequently, the effect of SAAE on the pathogenicity of H. pylori OMVs was investigated using the Griess reagent assay, enzyme-linked immunosorbent assay (ELISA), quantitative proteomics study, TEM, and western blotting assay. RESULTS: SAAE exhibited inhibitory effects on H. pylori growth and adhesion. The isolated H. pylori OMVs showed particle size of 27-242 nm and Zeta potential of -9.67 ± 0.53 mV. A total of 599 proteins were identified in the OMVs. Proteomics study indicated that the differential expressed proteins induced by OMVs with or without SAAE commonly enriched in P53 and autophagy pathways. Besides, SAAE counteracted the increased production of pro-inflammatory cytokines and attenuated the induction of cell autophagy caused by H. pylori OMVs. Furthermore, SAAE normalized the abnormal regulation of downstream targets (AIFM2 and IGFBP3) in the P53 signaling pathway caused by H. pylori OMVs. CONCLUSION: SAAE can inhibit the growth and adhesion of H. pylori, reduce the inflammation and autophagy induced by H. pylori OMVs, and combated the abnormal regulation of P53 signaling pathway caused by H. pylori OMVs. These findings may help elucidate the mechanisms through which SAAE reduces the pathogenicity of H. pylori.
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Helicobacter pylori , Extratos Vegetais , Syzygium , Helicobacter pylori/efeitos dos fármacos , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Syzygium/química , Humanos , Aderência Bacteriana/efeitos dos fármacos , Infecções por Helicobacter/tratamento farmacológico , Infecções por Helicobacter/microbiologia , Proteômica , Proteína Supressora de Tumor p53/metabolismo , Antibacterianos/farmacologia , Autofagia/efeitos dos fármacosRESUMO
Background: Helicobacter pylori (H. pylori) is thought to primarily colonize the human stomach and lead to various gastrointestinal disorders, such as gastritis and gastric cancer. Currently, main eradication treatment is triple or quadruple therapy centered on antibiotics. Due to antibiotic resistance, the eradication rate of H. pylori is decreasing gradually. Therefore, searching for anti-H. pylori drugs from herbal sources has become a strategy for the treatment. Our team proposed a Hezi Qingyou Formula (HZQYF), composed of Chebulae Fructus, Ficus hirta Vahl and Cloves, and studied its anti-H. pylori activity and mechanism. Methods: Chemical components of HZQYF were studied using UHPLC-MS/MS and HPLC. Broth microdilution method and agar dilution method were used to evaluate HZQYF's antibacterial activity. The effects of HZQYF on expression of adhesion genes (alpA, alpB, babA), urease genes (ureE, ureF), and flagellar genes (flaA, flaB) were explored using Reverse Transcription-quantitative Polymerase Chain Reaction (RT-qPCR) technology. Effects on morphology and permeability of the extracellular membrane were studied using scanning electron microscopy (SEM) and N-phenylnaphthalen-1-amine (NPN) uptake. Effect on urease activity was studied using a urease kinetics analysis in vitro. Immunofluorescence staining method was used to examine the effect on adhesion. Western blot was used to examine the effect on cagA protein. Results: Minimum inhibitory concentration (MIC) values of the formula against H. pylori clinical strains and standard strains were 80-160 µg/mL, and minimum bactericidal concentration (MBC) values were 160-320 µg/mL. The formula could down-regulate the expression of adhesion genes (alpA, alpB, babA), urease genes (ureE, ureF) and flagellar genes (flaA, flaB), change the morphology of H. pylori, increase its extracellular membrane permeability, and decrease its urease activity. Conclusion: Present studies confirmed that HZQYF had promising in vitro anti-H. pylori activities and demonstrated its possible mechanism of action by down-regulating the bacterial adhesion, urease, and flagellar gene expression, which provided scientific bases for further clinical investigations.
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To address the need for high-resolution imaging in lung nodule detection and overcome the limitations of the shallow imaging depth associated with high-frequency ultrasound and the complex structure of lung tissue, we successfully integrated 50 MHz ultrasound transducers with 18-gauge biopsy needles. Featuring a miniaturized size of 0.6 × 0.5 × 0.5 mm3, the 50 MHz micromachined 1-3 composite transducer was tested to perform mechanical scanning of a nodule within a lung-tissue-mimicking phantom in vitro. The high-frequency transducer demonstrated the ability to achieve imaging with an axial resolution of 30 µm for measuring nodule edges. Moreover, the integrated biopsy needle prototype exhibited high accuracy (1.74% discrepancy) in estimating nodule area compared to actual dimensions in vitro. These results underscore the promising potential of biopsy-needle-integrated transducers in enhancing the accuracy of endoscopic ultrasound-guided fine needle aspiration biopsy (EUS-FNA) for clinical applications.
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Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico , Transdutores , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico/métodos , Imagens de FantasmasRESUMO
Macrophages, a heterogeneous population of innate immune cells, exhibit remarkable plasticity and play pivotal roles in coordinating immune responses and maintaining tissue homeostasis within the context of metabolic diseases. The activation of inflammatory macrophages in obese adipose tissue leads to detrimental effects, inducing insulin resistance through increased inflammation, impaired thermogenesis, and adipose tissue fibrosis. Meanwhile, adipose tissue macrophages also play a beneficial role in maintaining adipose tissue homeostasis by regulating angiogenesis, facilitating the clearance of dead adipocytes, and promoting mitochondrial transfer. Exploring the heterogeneity of macrophages in obese adipose tissue is crucial for unraveling the pathogenesis of obesity and holds significant potential for targeted therapeutic interventions. Recently, the dual effects and some potential regulatory mechanisms of macrophages in adipose tissue have been elucidated using single-cell technology. In this review, we present a comprehensive overview of the intricate activation mechanisms and diverse functions of macrophages in adipose tissue during obesity, as well as explore the potential of drug delivery systems targeting macrophages, aiming to enhance the understanding of current regulatory mechanisms that may be potentially targeted for treating obesity or metabolic diseases.
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Tecido Adiposo , Macrófagos , Obesidade , Humanos , Obesidade/imunologia , Macrófagos/imunologia , Macrófagos/fisiologia , Tecido Adiposo/imunologia , Inflamação/imunologia , Resistência à Insulina , Animais , Termogênese/fisiologia , AdipócitosRESUMO
Pathological myocardial remodelling is the initial factor of chronic heart failure (CHF) and is induced by multiple factors. We previously demonstrated that histone acetylation is involved in CHF in transverse aortic constriction (TAC) mice, a model for pressure overload-induced heart failure. In this study, we investigated whether the histone deacetylase Sirtuin 6 (SIRT6), which mediates deacetylation of histone 3 acetylated at lysine 9 (H3K9ac), is involved pathological myocardial remodelling by regulating myocardial energy metabolism and explored the underlying mechanisms. We generated a TAC mouse model by partial thoracic aortic banding. TAC mice were injected with the SIRT6 agonist MDL-800 at a dose of 65 mg/kg for 8 weeks. At 4, 8 and 12 weeks after TAC, the level of H3K9ac increased gradually, while the expression of SIRT6 and vascular endothelial growth factor A (VEGFA) decreased gradually. MDL-800 reversed the effects of SIRT6 on H3K9ac in TAC mice and promoted the expression of VEGFA in the hearts of TAC mice. MDL-800 also attenuated mitochondria damage and improved mitochondrial respiratory function through upregulating SIRT6 in the hearts of TAC mice. These results revealed a novel mechanism in which SIRT6-mediated H3K9ac level is involved pathological myocardial remodelling in TAC mice through regulating myocardial energy metabolism. These findings may assist in the development of novel methods for preventing and treating pathological myocardial remodelling.
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Estenose da Valva Aórtica , Insuficiência Cardíaca , Sirtuínas , Camundongos , Animais , Histonas/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Sirtuínas/genética , Sirtuínas/metabolismo , Metabolismo EnergéticoRESUMO
Metformin has been used for the treatment of type II diabetes mellitus for decades due to its safety, low cost, and outstanding hypoglycemic effect clinically. The mechanisms underlying these benefits are complex and still not fully understood. Inhibition of mitochondrial respiratory-chain complex I is the most described downstream mechanism of metformin, leading to reduced ATP production and activation of AMP-activated protein kinase (AMPK). Meanwhile, many novel targets of metformin have been gradually discovered. In recent years, multiple pre-clinical and clinical studies are committed to extend the indications of metformin in addition to diabetes. Herein, we summarized the benefits of metformin in four types of diseases, including metabolic associated diseases, cancer, aging and age-related diseases, neurological disorders. We comprehensively discussed the pharmacokinetic properties and the mechanisms of action, treatment strategies, the clinical application, the potential risk of metformin in various diseases. This review provides a brief summary of the benefits and concerns of metformin, aiming to interest scientists to consider and explore the common and specific mechanisms and guiding for the further research. Although there have been countless studies of metformin, longitudinal research in each field is still much warranted.
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Diabetes Mellitus Tipo 2 , Metformina , Humanos , Metformina/uso terapêutico , Metformina/farmacocinética , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Hipoglicemiantes/uso terapêutico , Hipoglicemiantes/farmacologia , Proteínas Quinases Ativadas por AMP/metabolismo , EnvelhecimentoRESUMO
AIMS: Although childhood maltreatment has been widely supported to be a robust predictor of suicide behaviours, the effects of different childhood maltreatment subtypes remain controversial and inconclusive. Moreover, whether the effects differ by sex in urban and rural adolescents is still unknown. This study aimed to quantify the associations between five subtypes of childhood maltreatment and different suicide behaviour involvement. METHODS: A multistage cluster sampling method was adopted from April to December 2021 for adolescents aged 12 to 18 across five representative provinces of China. The Childhood Trauma Questionnaire-Short Form was used to measure childhood maltreatment subtypes. Suicide behaviour involvement was classified as none group, suicide ideator, suicide planner and suicide attempter. Confounding variables include demographic characteristics, smoking, drinking alcohol, depression and anxiety. RESULTS: Among a total of 18,980 adolescents, 2021 (10.6%) were suicide ideator, 1595 (8.4%) were suicide planner and 1014 (5.3%) were suicide attempter. Rural females had the highest proportion of suicide ideator (13.8%) and suicide planner (11.5%). Multinomial logistic regression analysis indicated that five childhood maltreatment subtypes were independently associated with suicide behaviours, except for associations between sexual abuse and suicide ideator as well as suicide planner (p > 0.05). Moreover, these associations differ by sex and residence. After adjusted for interactions of different subtypes, structural equation model indicated that the direct effects of childhood maltreatment subtypes on suicide behaviours from high to low were emotional abuse (ß = 0.363, p < 0.001), physical abuse (ß = 0.100, p < 0.001) and sexual abuse (ß = 0.033, p = 0.003), while the effects of physical neglect and emotional neglect were not significant (p > 0.05). CONCLUSIONS: Five subtypes of childhood maltreatment have specific and non-equivalence associations with suicide behaviours. Emotional abuse may have the strongest effect, and sexual abuse have an acute effect on suicide behaviours. Suicide prevention programs for Chinese adolescents could focus on those who experienced emotional, physical and sexual abuse. Furthermore, strategies should be tailored by sex and residence, and rural females deserve more attention.
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Maus-Tratos Infantis , Suicídio , Adolescente , Criança , Feminino , Humanos , População do Leste Asiático , Emoções , Ideação Suicida , MasculinoRESUMO
Sanguisorba officinalis L., a traditional Chinese medicine (TCM) called DiYu (DY) in China, has a strong tradition of utilization as a scorching, blood-cooling, and hemostatic medication, and was used for cancer prevention and treatment due to its potential immune-enhancing and hematological toxicity-reducing effects. Previous studies have reported significant effects of DY on cancers including colorectal cancer (CRC), which is one of the most common malignancies worldwide. The first-line cure 5-fluorouracil (5-FU) plays decisive commerce in the sedative of CRC as a clinically available chemotherapeutic agent. One of the primary causes of cancer treatment failure is the acquisition of chemotherapy drug resistance. In order to successfully combat the emergence of chemoresistance, it is essential to identify herbs or traditional Chinese medicine that have adjuvant therapeutic effects on CRC. Therefore, this study aimed to determine whether DY could improve the sensitivity, conquer the chemoresistance of 5-FU-resistant CRC cells, and investigate its intrinsic mechanism. Materials and methods: MTT, Hoechst 33258 staining, and flow cytometry assays were used to determine the anticancer activity of DY alone or in combination with 5-FU against 5-FU-resistant CRC cells (RKO-R and HCT15-R) and wound healing assays were conducted to detect cell migration. Transcriptomic techniques were carried out to explore the effect and mechanism of DY on drug-resistant CRC cells. Western Blot and RT q-PCR assays were performed to validate the mechanism by which DY overcomes drug-resistant CRC cells. Results: These results indicated that DY alone or in combination with 5-FU significantly inhibited the proliferation and the migration of resistant CRC cells, and potentiated the susceptibility of 5-FU to drug-resistant CRC cells. GO and KEGG enrichment analysis showed that the mechanisms of drug resistance in CRC cells and DY against drug-resistant CRC cells highly overlapped, involved in the modulation of biological processes such as cell migration, positive regulation of protein binding and cytoskeleton, and MAPK (Ras-ERK-MEK), PI3K/Akt, and other signaling pathways. Moreover, DY can mediate the expression of p-R-Ras, p-ERK1/2, p-MEK1/2, p-PI3K, p-AKT, HIF-1A and VEGFA proteins. In addition, DY significantly suppressed the expression of AKT3, NEDD9, BMI-1, and CXCL1 genes in resistant CRC cells. Conclusion: In conclusion, DY could inhibit the proliferation and migration of 5-FU-resistant cells and strengthen the sensitivity of 5-FU to CRC-resistant cells. Furthermore, DY may prevail over chemoresistance through the Ras/MEK/ERK and PI3K/Akt pathways. These findings imply that DY may be a potential drug for clinical treatment or adjuvant treatment of drug-resistant CRC.
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Polypropylene-fiber-reinforced foamed concrete (PPFRFC) is often used to reduce building structure weight and develop engineering material arresting systems (EMASs). This paper investigates the dynamic mechanical properties of PPFRFC with densities of 0.27 g/cm3, 0.38 g/cm3, and 0.46 g/cm3 at high temperatures and proposes a prediction model to characterize its behavior. To conduct the tests on the specimens over a wide range of strain rates (500~1300 s-1) and temperatures (25~600 °C), the conventional split-Hopkinson pressure bar (SHPB) apparatus was modified. The test results show that the temperature has a substantial effect on the strain rate sensitivity and density dependency of the PPFRFC. Additionally, the analysis of failure models demonstrates that with the melting of polypropylene fibers, the level of damage in PPFRFC under dynamic loading increases, resulting in the generation of a greater number of fragments.
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Helicobacter pylori (H. pylori) has infected more than half of the world's population, and is the major cause of gastric cancer. The efficacy of standard antibiotic-based triple therapy is declining due to drug resistance development. Herein, a pH-responsive reactive oxygen species (ROS) nanogenerator (Fe-HMME@DHA@MPN) composed of acid-responsive metal polyphenol network (MPN) shell and mesoporous metal-organic nanostructure core [Fe-HMME (hematoporphyrin monomethyl ether, sonosensitizer)] loaded with dihydroartemisinin (DHA) is reported. These nanoparticles generate more ROS singlet oxygen than sonosensitizer HMME under ultrasonication, and this sonodynamic process is fueled by oxygen generated through Fenton/Fenton-like reactions of the degraded product in gastric acid Fe (II) and hydrogen peroxide (H2 O2 ) in the infection microenvironment. The encapsulated DHA, as a hydroperoxide source, is found to enhance the peroxidase-like activity of the Fe-HMME@DHA@MPN to generate ROS hydroxyl radical, beneficial for the microenvironment without sufficient H2 O2 . In vitro experiments demonstrate that the ROS nanogenerators are capable of killing multidrug-resistant H. pylori and removing biofilm, and ROS nanogenerators show high therapeutic efficacy in a H. pylori infection mouse model. Unlike the triple therapy, the nanogenerators display negligible side effects toward the normal gut microbiota. Taken together, these self-enhanced ROS nanogenerators have a great potential for treatment of H. pylori infection.
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Microbioma Gastrointestinal , Infecções por Helicobacter , Helicobacter pylori , Animais , Camundongos , Infecções por Helicobacter/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo , Helicobacter pylori/metabolismo , Ácido Gástrico/metabolismoRESUMO
Pleurospermum is a taxonomically challenging taxon of Apiaceae, as its circumscription and composition remain controversial for morphological similarities with several related genera, leading to a dispute between Pleurospermum in the broad sense and strict sense. While evidence from previous molecular studies recognized plural branching lineages within the Pleurospermum s. l., it did not support the latest delimitation of Pleurospermum s. str. by only two closely related northern species. So far, no proper delimitation for Pleurospermum has come up, and many of the plural taxa in Pleurospermum s. l. remain unresolved, which may be due to poor phylogenetic resolution yielded barely from ITS sequences. Herein, we newly assembled 40 complete plastomes from 36 species of Pleurospermum s. l. and related genera, 34 of which were first reported and generated a well-resolved backbone phylogeny in a framework of the subfamily Apioideae. From the phylogeny with greatly improved resolution, a total of six well-supported monophyletic lineages within Pleurospermum s. l. were recognized falling in different major clades of Apioideae. Combining morphological characteristics with phylogenetic inference, we suggested to re-delimit the Pleurospermum s. str. by introducing nine species mainly from the Himalayan regions and proposed its boundary features; the remaining species were suggested to be excluded from Pleurospermum to incorporate into their more related taxa being revealed. On this basis, the plastome comparison revealed not only the high conservatism but also the mild differences among lineages in plastome structure and gene evolution. Overall, our study provided a backbone phylogeny essential for further studies of the taxonomically difficult taxa within Pleurospermum s. l.
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PURPOSE: To explore the localization value of drug-resistant temporal lobe epilepsy (TLE) aura for preoperative evaluation, based on stereoelectroencephalography (SEEG), and its prognostic value on the surgical outcome. METHODS: The data of patients with drug-resistant TLE who had SEEG electrodes implanted during preoperative evaluation at the First Affiliated Hospital of the University of Science and Technology of China (Hefei, China) were retrospectively analyzed. The patients were divided into aura-positive and aura-negative groups according to the presence of aura in seizures. To explore the clinical features of aura, we evaluated the localizing and prognostic values of aura for the outcome of anterior temporal lobectomy based on SEEG. RESULTS: Among forty patients, twenty-seven patients were in the aura-positive group and ten (25.0%) patients had multiple auras. The most common TLE aura was abdominal aura [thirteen (34.2%) patients]. The postoperative seizure frequency was significantly reduced in the preoperative aura-positive patients compared to the preoperative aura-negative patients (P = 0.011). Patients with abdominal (P = 0.029) and single (P = 0.036) auras had better surgical prognoses than aura-negative patients. In the preoperative evaluation, aura-positive patients had a better surgical outcome if the laterality of positron emission tomography-computed tomography (PET-CT) hypometabolism was concordant with the epileptogenic focus identified with SEEG (P = 0.031). A good postoperative epileptic outcome in aura-positive patients was observed among those with hippocampal sclerotic medial temporal lobe epilepsy (P = 0.025). CONCLUSION: Epileptic aura is valuable for the localization of the epileptogenic focus. Abdominal aura and single aura were good predictors of better surgical outcomes. Among patients with a preoperative diagnosis of hippocampal sclerosis or with laterality of PET-CT hypometabolism concordant with the epileptogenic focus identified using SEEG, those with aura are likely to benefit from surgery.
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Epilepsia Resistente a Medicamentos , Epilepsias Parciais , Epilepsia do Lobo Temporal , Epilepsia , Humanos , Epilepsia do Lobo Temporal/diagnóstico por imagem , Epilepsia do Lobo Temporal/cirurgia , Estudos Retrospectivos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Epilepsia/cirurgia , Epilepsia Resistente a Medicamentos/diagnóstico por imagem , Epilepsia Resistente a Medicamentos/cirurgia , Convulsões , Eletroencefalografia , Resultado do Tratamento , Imageamento por Ressonância MagnéticaRESUMO
BACKGROUND: Low-intensity transcranial focused ultrasound (tFUS) has gained considerable attention as a promising noninvasive neuromodulatory technique for human brains. However, the complex morphology of the skull hinders scholars from precisely predicting the acoustic energy transmitted and the region of the brain impacted during the sonication. This is due to the fact that different ultrasound frequencies and skull morphology variations greatly affect wave propagation through the skull. PURPOSE: Although the acoustic properties of human skull have been studied for tFUS applications, such as tumor ablation using a multielement phased array, there is no consensus about how to choose a single-element focused ultrasound (FUS) transducer with a suitable frequency for neuromodulation. There are interests in exploring the magnitude and dimension of tFUS beam through human parietal bone for modulating specific brain lobes. Herein, we aim to investigate the wave propagation of tFUS on human skulls to understand and address the concerns above. METHODS: Both experimental measurements and numerical modeling were conducted to investigate the transmission efficiency and beam pattern of tFUS on five human skulls (C3 and C4 regions) using single-element FUS transducers with six different frequencies (150-1500 kHz). The degassed skull was placed in a water tank, and a calibrated hydrophone was utilized to measure acoustic pressure past it. The cranial computed tomography scan data of each skull were obtained to derive a high-resolution acoustic model (grid point spacing: 0.25 mm) in simulations. Meanwhile, we modified the power-law exponent of acoustic attenuation coefficient to validate numerical modeling and enabled it to be served as a prediction tool, based on the experimental measurements. RESULTS: The transmission efficiency and -6 dB beamwidth were evaluated and compared for various frequencies. An exponential decrease in transmission efficiency and a logarithmic decrease of -6 dB beamwidth with an increase in ultrasound frequency were observed. It is found that a >750 kHz ultrasound leads to a relatively lower tFUS transmission efficiency (<5%), whereas a <350 kHz ultrasound contributes to a relatively broader beamwidth (>5 mm). Based on these observations, we further analyzed the dependence of tFUS wave propagation on FUS transducer aperture size. CONCLUSIONS: We successfully studied tFUS wave propagation through human skulls at different frequencies experimentally and numerically. The findings have important implications to predict tFUS wave propagation for ultrasound neuromodulation in clinical applications, and guide researchers to develop advanced ultrasound transducers as neural interfaces.
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Encéfalo , Crânio , Humanos , Crânio/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Ultrassonografia/métodos , Cabeça , Transdutores , Ondas UltrassônicasRESUMO
Objective: The impact of the mindfulness-based stress reduction (MBSR) program on psychological outcomes and quality of life (QoL) in lung cancer patients remains unclear. This meta-analysis aimed to evaluate the effectiveness of the MBSR program on psychological states and QoL in lung cancer patients. Methods: Eligible studies published before November 2021 were systematically searched from PubMed, EMBASE, Cochrane Library, PsycINFO, China National Knowledge Infrastructure (CNKI), and Wanfang databases. The risk of bias in eligible studies was assessed using the Cochrane tool. Psychological variables and QoL were evaluated as outcomes. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to grade the levels of evidence. Statistical analysis was conducted using RevMan 5.4 and STATA 14.0. Results: A total of 17 studies involving 1,680 patients were included for meta-analysis eventually. MBSR program significantly relieved cancer-related fatigue (standard mean difference [SMD], -1.26; 95% confidence interval [CI], -1.69 to -0.82; moderate evidence) and negative psychological states (SMD, -1.35; 95% CI, -1.69 to -1.02; low evidence), enhanced positive psychological states (SMD, 0.91; 95% CI, 0.56-1.27; moderate evidence), and improved quality of sleep (MD, -2.79; 95% CI, -3.03 to -2.56; high evidence). Evidence on MBSR programs' overall treatment effect for QoL revealed a trend toward statistical significance (p = 0.06, low evidence). Conclusion: Based on our findings, the MBSR program shows positive effects on psychological states in lung cancer patients. This approach should be recommended as a part of the rehabilitation program for lung cancer patients. Systematic Review Registration: https://archive.org/details/osf-registrations-mwvbq-v1, identifier: 10.17605/OSF.IO/MWVBQ.
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Background: Colorectal cancer (CRC) is the most common malignant cancer worldwide. Sanguisorba officinalis has been shown to have anti-inflammatory, anti-bacterial, antioxidant, and anti-tumor effects, while its molecular mechanism against CRC remains unclear. The aim of this study is to explore the underlying mechanism of S. officinalis against CRC cell lines using network pharmacology and transcriptomic sequencing methods. Method: Firstly, the active ingredients and potential targets of S. officinalis against CRC were screened from databases. Secondly, the networks of ingredient-target, ingredient-target-CRC and protein-protein interaction were constructed. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses of network pharmacology and transcriptomic sequencing were performed. Finally, the effect of S. officinalis against CRC was verified by in vitro experiments. Results: In total, 14 active ingredients and 273 potential targets against CRC were identified in S. officinalis by network pharmacology. PI3K-Akt, HIF-1, and MAPK signaling pathways related to cell proliferation were regulated by S. officinalis in enrichment analyses and transcriptomic sequencing. In vitro, S. officinalis inhibited the proliferation and migration of CRC cells and arrested the cell cycle at the G0-G1 phase. The western blot showed that S. officinalis downregulated the expression of p-PI3K, p-Akt, HIF-1A, VEGFA, cyclin D1, c-Myc, and p-MAPK proteins in CRC cells. Conclusion: In conclusion, network pharmacology and transcriptomic sequencing analyses, in combination with in vitro studies, have been successfully applied to study the underlying mechanism of S. officinalis against CRC cells. Our results demonstrate that S. officinalis suppresses the proliferation, survival, and migration of CRC cells through regulating the PI3K-Akt, HIF-1, and MAPK signaling pathways.
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Oncoprotein SS18-SSX is a hallmark of synovial sarcomas. However, as a part of the SS18-SSX fusion protein, SS18's function remains unclear. Here, we depict the structures of both human SS18/BRG1 and yeast SNF11/SNF2 subcomplexes. Both subcomplexes assemble into heterodimers that share a similar conformation, suggesting that SNF11 might be a homologue of SS18 in chromatin remodeling complexes. Importantly, our study shows that the self-association of the intrinsically disordered region, QPGY domain, leads to liquid-liquid phase separation (LLPS) of SS18 or SS18-SSX and the subsequent recruitment of BRG1 into phase-separated condensates. Moreover, our results show that the tyrosine residues in the QPGY domain play a decisive role in the LLPS of SS18 or SS18-SSX. Perturbations of either SS18-SSX LLPS or SS18-SSX's binding to BRG1 impair NIH3T3 cell transformation by SS18-SSX. Our data demonstrate that both LLPS and assembling into chromatin remodelers contribute to the oncogenic activity of SS18-SSX in synovial sarcomas.
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Proteínas Proto-Oncogênicas , Proteínas Repressoras , Sarcoma Sinovial , Animais , Transformação Celular Neoplásica , Humanos , Camundongos , Células NIH 3T3 , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Sarcoma Sinovial/genética , Sarcoma Sinovial/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
Multiple biological barriers and tumor metastasis severely impede the tumor therapy. To address these adversities, an acid-activated poly (ethylene glycol)-poly-l-lysine-2,3-dimethylmaleic anhydride/poly (ε-caprolactone)-poly(l-arginine)/ß-lapachone nanoparticles (mPEG-PLL-DMA/PCL-P(L-arg)/ß-Lap, PLM/PPA/ß-Lap NPs) were constructed with charge-reversal and size-reduction for ß-Lap delivery with a cascade reaction of reactive oxygen species (ROS) and nitric oxide (NO) production. The nanosystem exhibited highly penetrable, superior cellular uptake and desirable endo-lysosomal escape thanks to size-reduction, charge-reversal and proton sponge, respectively. The vast bulk of ROS, which rapidly generated from ß-Lap under high concentration quinone oxidoreductase 1 (NQO1), catalyzed guanidine groups to produce NO and generated highly toxic peroxynitrite (ONOO-). ONOO- would activate pro-matrix metalloproteinases (pro-MMPs) to generate MMPs, degrade the dense extracellular matrix (ECM) to augment the penetration capability, and aggravate DNA damage. NO and ONOO- influenced mitochondrial function by decreasing mitochondrial membrane potential and prevented the production of adenosine triphosphate (ATP), which inhibited the ATP-dependent tumor-derived microvesicles (TMVs) and restrained tumor metastasis. NO was defined as an epithelial mesenchymal transition (EMT) inhibitor to restrain tumor metastasis. All consequences demonstrated that PLM/PPA/ß-lap NPs exhibited efficient penetration capability, outstanding anti-metastasis activity and favorable antitumor efficacy. Those novel acid-activated NPs are intended to provide further inspiration for multifunctional NO gas therapy.
Assuntos
Nanopartículas , Neoplasias , Linhagem Celular Tumoral , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Óxido Nítrico/metabolismo , Ácido Peroxinitroso , Espécies Reativas de OxigênioRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: The dried flower bud of Syzygium aromaticum (L.) Merr. & L.M Perry (S. aromaticum) (Myrtaceae), also known as clove, was used in Traditional Chinese Medicine (TCM) to aid gastrointestinal function and treat stomach disorders including vomiting, flatulence and nausea. And it is a food homology medicine which is a promising candidate for H. pylori treatment. H. pylori is a Gram-negative bacterium that infects approximately 50% of the human population worldwide, which is closely related to multiple gastric diseases, including gastric cancer. However, there are still no sufficient studies on the anti-H. pylori activity of S. aromaticum, especially for the mechanism of action. AIM OF STUDY: This study aimed to study the antibacterial activities of S. aromaticum extracts on both antibiotic-sensitive and -resistant H. pylori strains, and to explore the underlying mechanisms of action. MATERIALS AND METHODS: The S. aromaticum extracts were obtained by heat reflux extraction and lyophilized to powder form. The phytochemical analyses were performed by High-performance liquid chromatography (HPLC) and UPLC-electrospray ionization mass spectrometry (ESI-MS). In vitro anti-H. pylori activity was evaluated by broth microdilution method. Mechanism of action studies included morphological observation using electron microscopy, determination of expression of virulence genes by reverse transcription quantitative polymerase chain reaction (RT-qPCR), genes expression profile identification by transcriptomic analysis, and exploration of anti-H. pylori infection mechanisms by network pharmacology analysis and western blotting validation. RESULTS: The S. aromaticum extracts, aqueous extract (AE) and 75% hydroalcoholic extract (HE), exerted significant antibacterial activities against both antibiotic-sensitive and -resistant H. pylori strains with MICs of 160â¼320 µg/ml, without developing drug resistance. Among them, AE was bactericide to all the tested strains with MBCs of less than 4MIC, while HE was merely bacteriostatic to most of the tested strains with MBCs of 2MICâ¼16MIC. Besides, they showed no antagonistic effects in combination with clarithromycin, metronidazole, levofloxacin, and amoxicillin. Additionally, these extracts altered the morphology and ultrastructure and down-regulated the virulence genes expression of H. pylori. And transcriptomic analysis showed that they regulated genes expression of multiple H. pylori biological processes, including tricarboxylic acid cycle (TAC) and pyruvate metabolic pathways. Furthermore, these extracts combated the abnormal activation of PI3K-Akt and MAPK signaling pathways caused by H. pylori infection. CONCLUSIONS: Overall, the present study firstly analyzed the chemical compositions of S. aromaticum extracts, and then confirmed their activities on both antibiotic-sensitive and -resistant H. pylori strains. In addition, the mechanisms of action of S. aromaticum extracts against H. pylori were found to be destroying the bacterial structure, down-regulating the expression of virulence genes, and interfering TAC and pyruvate metabolic pathways. Finally, S. aromaticum extracts were found to combated the abnormal activation of PI3K-Akt and MAPK signaling pathways to treat H. pylori infection. This study should accelerate further research and application of S. aromaticum against H. pylori infection.