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Esophageal squamous cell carcinoma (ESCC) possesses a poor prognosis and treatment outcome. Dysregulated metabolism contributes to unrestricted growth of multiple cancers. However, abnormal metabolism, such as highly activated pentose phosphate pathway (PPP) in the progression of ESCC remains largely unknown. Herein, we report that high-mobility group AT-hook 1 (HMGA1), a structural transcriptional factor involved in chromatin remodeling, promoted the development of ESCC by upregulating the PPP. We found that HMGA1 was highly expressed in ESCC. Elevated HMGA1 promoted the malignant phenotype of ESCC cells. Conditional knockout of HMGA1 markedly reduced 4-nitroquinoline-1-oxide (4NQO)-induced esophageal tumorigenesis in mice. Through the metabolomic analysis and the validation assay, we found that HMGA1 upregulated the non-oxidative PPP. With the transcriptome sequencing, we identified that HMGA1 upregulated the expression of transketolase (TKT), which catalyzes the reversible reaction in non-oxidative PPP to exchange metabolites with glycolytic pathway. HMGA1 knockdown suppressed the PPP by downregulating TKT, resulting in the reduction of nucleotides in ESCC cells. Overexpression of HMGA1 upregulated PPP and promoted the survival of ESCC cells by activating TKT. We further characterized that HMGA1 promoted the transcription of TKT by interacting with and enhancing the binding of transcription factor SP1 to the promoter of TKT. Therapeutics targeting TKT with an inhibitor, oxythiamine, reduced HMGA1-induced ESCC cell proliferation and tumor growth. Together, in this study, we identified a new role of HMGA1 in ESCCs by upregulating TKT-mediated activation of PPP. Our results provided a new insight into the role of HMGA1/TKT/PPP in ESCC tumorigenesis and targeted therapy.
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Progressão da Doença , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Proteína HMGA1a , Via de Pentose Fosfato , Transcetolase , Regulação para Cima , Humanos , Animais , Transcetolase/metabolismo , Transcetolase/genética , Carcinoma de Células Escamosas do Esôfago/patologia , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/metabolismo , Proteína HMGA1a/metabolismo , Proteína HMGA1a/genética , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Camundongos , Regulação para Cima/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Proliferação de Células , Camundongos Nus , Fator de Transcrição Sp1/metabolismo , Fator de Transcrição Sp1/genéticaRESUMO
Hypoxic pulmonary hypertension (HPH) is a serious and life-threatening chronic cardiopulmonary disease characterized by progressive elevation of pulmonary artery pressure and pulmonary vascular remodeling. Mesenchymal stem cell- derived exosomes (MSC-Exos) can relieve HPH by reversing pulmonary vascular remodeling. The HPH model was established in healthy male Sprague-Dawley (SD) rats aged 6 to 8 weeks. The rats were placed in a room with oxygen concentration of (10 ± 1) % for 8 hours a day over 28 days, were then injected intravenously with MSC-Exos (100 ug protein/kg) or equal-volume phosphate buffer saline (PBS) once a day over 1 week. Right ventricular systolic pressure (RVSP), right ventricular hypertrophy index (RVHI) and pulmonary vascular remodeling were observed after anesthesia. In addition, platelet-derived growth factor BB (PDGF-BB) was used to stimulate rat pulmonary artery smooth muscle cells (PASMCs) to construct HPH pathological cell models. The results showed that MSC-Exos could not only reduce the elevation of RVSP, right ventricular hypertrophy and the degree of pulmonary vascular remodeling in HPH rats, but also reduce the proliferation, migration and apoptosis resistance of PASMCs. Finally, GSE53408 and GSE113439 datasets were analyzed and showed that the expression of Hsp90aa1 and pERK/ERK were significantly increased in HPH, also could be inhibited by MSC-Exos. Meanwhile, inhibition of Hsp90aa1 also reduced PASMCs migration and pERK/ERK protein level. In conclusion, MSC-Exos alleviated HPH by suppressing PASMCs proliferation, migration and apoptosis resistance through inhibiting the Hsp90aa1/ERK/pERK pathway.
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Exossomos , Proteínas de Choque Térmico HSP90 , Hipertensão Pulmonar , Sistema de Sinalização das MAP Quinases , Células-Tronco Mesenquimais , Ratos Sprague-Dawley , Animais , Masculino , Ratos , Exossomos/metabolismo , Exossomos/transplante , Proteínas de Choque Térmico HSP90/metabolismo , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/terapia , Hipóxia/metabolismo , Hipóxia/terapia , Sistema de Sinalização das MAP Quinases/fisiologia , Células-Tronco Mesenquimais/metabolismo , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/fisiologiaRESUMO
Methamphetamine (METH), an abused psychostimulant, impairs cognition through prolonged or even single-dose exposure, but animal experiments have shown contradictory effects on memory deficits. In this study we investigated the effects and underlying mechanisms of single-dose METH administration on the retrieval of object recognition memory (ORM) in mice. We showed that single-dose METH administration (2 mg/kg, i.p.) significantly impaired ORM retrieval in mice. Fiber photometry recording in METH-treated mice revealed that the activity of prelimbic cortex glutamatergic neurons (PrLGlu) was significantly reduced during ORM retrieval. Chemogenetic activation of PrLGlu or glutamatergic projections from ventral CA1 to PrL (vCA1Glu-PrL) rescued ORM retrieval impairment. Fiber photometry recording revealed that dopamine (DA) levels in PrL of METH-treated mice were significantly increased, and micro-infusion of the D2 receptor (D2R) antagonist sulpiride (0.25 µg/side) into PrL rescued ORM retrieval impairment. Whole-cell recordings in brain slices containing the PrL revealed that PrLGlu intrinsic excitability and basal glutamatergic synaptic transmission were significantly reduced in METH-treated mice, and the decrease in intrinsic excitability was reversed by micro-infusion of Sulpiride into PrL in METH-treated mice. Thus, the impaired ORM retrieval caused by single-dose METH administration may be attributed to reduced PrLGlu activity, possibly due to excessive DA activity on D2R. Selective activation of PrLGlu or vCA1Glu-PrL may serve as a potential therapeutic strategy for METH-induced cognitive dysfunction.
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Esophageal carcinoma is amongst the prevalent malignancies worldwide, characterized by unclear molecular classifications and varying clinical outcomes. The PI3K/AKT/mTOR signaling, one of the frequently perturbed dysregulated pathways in human malignancies, has instigated the development of various inhibitory agents targeting this pathway, but many ESCC patients exhibit intrinsic or adaptive resistance to these inhibitors. Here, we aim to explore the reasons for the insensitivity of ESCC patients to mTOR inhibitors. We assessed the sensitivity to rapamycin in various ESCC cell lines by determining their respective IC50 values and found that cells with a low level of HMGA1 were more tolerant to rapamycin. Subsequent experiments have supported this finding. Through a transcriptome sequencing, we identified a crucial downstream effector of HMGA1, FKBP12, and found that FKBP12 was necessary for HMGA1-induced cell sensitivity to rapamycin. HMGA1 interacted with ETS1, and facilitated the transcription of FKBP12. Finally, we validated this regulatory axis in in vivo experiments, where HMGA1 deficiency in transplanted tumors rendered them resistance to rapamycin. Therefore, we speculate that mTOR inhibitor therapy for individuals exhibiting a reduced level of HMGA1 or FKBP12 may not work. Conversely, individuals exhibiting an elevated level of HMGA1 or FKBP12 are more suitable candidates for mTOR inhibitor treatment.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Proteína HMGA1a , Inibidores de MTOR , Proteína Proto-Oncogênica c-ets-1 , Proteína 1A de Ligação a Tacrolimo , Animais , Humanos , Camundongos , Linhagem Celular Tumoral , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas do Esôfago/metabolismo , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/patologia , Proteína HMGA1a/metabolismo , Proteína HMGA1a/genética , Camundongos Nus , Inibidores de MTOR/farmacologia , Inibidores de MTOR/uso terapêutico , Proteína Proto-Oncogênica c-ets-1/metabolismo , Proteína Proto-Oncogênica c-ets-1/genética , Transdução de Sinais/efeitos dos fármacos , Sirolimo/farmacologia , Sirolimo/uso terapêutico , Proteína 1A de Ligação a Tacrolimo/metabolismo , Proteína 1A de Ligação a Tacrolimo/genética , Serina-Treonina Quinases TOR/metabolismoRESUMO
Objectives: This study aimed to analyze the influencing factors of hospitalization cost of hypertensive patients in TCM (traditional Chinese medicine, TCM) hospitals, which can provide a scientific basis for hospitals to control the hospitalization cost of hypertension. Methods: In this study, 3,595 hospitalized patients with a primary diagnosis of tertiary hypertension in Tianshui City Hospital of TCM, Gansu Province, China, from January 2017 to June 2022, were used as research subjects. Using univariate analysis to identify the relevant variables of hospitalization cost, followed by incorporating the statistically significant variables of univariate analysis as independent variables in multiple linear regression analysis, and establishing the path model based on the results of the multiple linear regression finally, to explore the factors influencing hospitalization cost comprehensively. Results: The results showed that hospitalization cost of hypertension patients were mainly influenced by length of stay, age, admission pathways, payment methods of medical insurance, and visit times, with length of stay being the most critical factor. Conclusion: The Chinese government should actively exert the characteristics and advantages of TCM in the treatment of chronic diseases such as hypertension, consistently optimize the treatment plans of TCM, effectively reduce the length of stay and steadily improve the health literacy level of patients, to alleviate the illnesses pain and reduce the economic burden of patients.
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Hospitalização , Hipertensão , Medicina Tradicional Chinesa , Humanos , Feminino , Hipertensão/economia , Masculino , Pessoa de Meia-Idade , Medicina Tradicional Chinesa/economia , Medicina Tradicional Chinesa/estatística & dados numéricos , Hospitalização/economia , Hospitalização/estatística & dados numéricos , China , Idoso , Tempo de Internação/estatística & dados numéricos , Tempo de Internação/economia , Adulto , Custos Hospitalares/estatística & dados numéricosRESUMO
Chemotherapy is a primary treatment for esophageal squamous cell carcinoma (ESCC). Resistance to chemotherapeutic drugs is an important hurdle to effective treatment. Understanding the mechanisms underlying chemotherapy resistance in ESCC is an unmet medical need to improve the survival of ESCC. Herein, we demonstrate that ferroptosis triggered by inhibiting high mobility group AT-hook 1 (HMGA1) may provide a novel opportunity to gain an effective therapeutic strategy against chemoresistance in ESCC. HMGA1 is upregulated in ESCC and works as a key driver for cisplatin (DDP) resistance in ESCC by repressing ferroptosis. Inhibition of HMGA1 enhances the sensitivity of ESCC to ferroptosis. With a transcriptome analysis and following-up assays, we demonstrated that HMGA1 upregulates the expression of solute carrier family 7 member 11 (SLC7A11), a key transporter maintaining intracellular glutathione homeostasis and inhibiting the accumulation of malondialdehyde (MDA), thereby suppressing cell ferroptosis. HMGA1 acts as a chromatin remodeling factor promoting the binding of activating transcription factor 4 (ATF4) to the promoter of SLC7A11, and hence enhancing the transcription of SLC7A11 and maintaining the redox balance. We characterized that the enhanced chemosensitivity of ESCC is primarily attributed to the increased susceptibility of ferroptosis resulting from the depletion of HMGA1. Moreover, we utilized syngeneic allograft tumor models and genetically engineered mice of HMGA1 to induce ESCC and validated that depletion of HMGA1 promotes ferroptosis and restores the sensitivity of ESCC to DDP, and hence enhances the therapeutic efficacy. Our finding uncovers a critical role of HMGA1 in the repression of ferroptosis and thus in the establishment of DDP resistance in ESCC, highlighting HMGA1-based rewiring strategies as potential approaches to overcome ESCC chemotherapy resistance. Schematic depicting that HMGA1 maintains intracellular redox homeostasis against ferroptosis by assisting ATF4 to activate SLC7A11 transcription, resulting in ESCC resistance to chemotherapy.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Ferroptose , Animais , Camundongos , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/genética , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Proteína HMGA1a/genética , Resistencia a Medicamentos Antineoplásicos/genética , Ferroptose/genética , Proteína HMGA1b , Linhagem Celular TumoralRESUMO
Background: Artemia sinica is a brine shrimp species distributed in hypersaline salt lakes in northern China and Siberia and a successful invasive species in some coastal salterns. Although it is a commercially harvested and cultured species, knowledge of its reproductive characteristics is limited, and existing studies are often contradictory. The combined effects of temperature, salinity, and photoperiod on reproduction characteristics are experimentally studied to better understand its reproductive features. Methods: There were 36 combinations of three environmental factors (3 × 3 × 4), each with three or four levels, namely temperature (16, 25, 30 °C), photoperiod (6 L:18 D, 12 L:12D, 18 L:6D), and salinity (50, 100, 150, 200 PSU). In each treatment, 48 to 80 pairs of A. sinica from Yuncheng Salt Lake (Shanxi, China) were cultured. Females were observed daily for reproductive mode and the number of offspring produced. Results: Temperature, photoperiod, salinity, and their interactions significantly affected the lifespan and reproduction of A. sinica. The reproductive period was the longest and accounted for the largest proportion of life span at moderate temperature (25 °C). Total offspring, offspring per brood, and offspring per day increased as salinity decreased, and the number of broods per female was highest at 25 °C. Temperature, photoperiod, and salinity significantly influenced reproductive modes, and interactions among these factors were identified. Artemia sinica primarily reproduces oviparously under low temperature and short daylight conditions, and ovoviviparously under high temperature and long daylight conditions, with the maximum oviparity ratio recorded in treatments of 16 °C, 6L:18D, and 50 or 100 PSU. The maximum ovoviviparity ratio was recorded under 30 °C, 12L:12D, and 100 PSU. Unlike that documented for other Artemia species or populations, the brood size of A. sinica kept increasing throughout the reproductive period. It did not decline even in the last two broods. For the same brood number, the sizes of oviparous and ovoviviparous broods were similar. The length of the oviparous interval was often greater than that of the ovoviviparous interval, suggesting that oviparous offspring might require additional energy and time to construct the multi-layered eggshell. Compared to other species and populations, the A. sinica from Yuncheng Salt Lake has a relatively shorter pre-reproductive development time, a preference for ovoviviparity, and relatively higher fecundity and population growth capacity, making it a suitable culture species for obtaining fresh biomass.
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Anostraca , Artemia , Animais , Feminino , Temperatura , Fotoperíodo , Salinidade , ReproduçãoRESUMO
New acyclic cucurbit[n]urils (ACBs) with eight carboxylate groups were synthesized. These hosts are highly soluble in water, and can form stable inclusion complexes with cationic bitter compounds. ACBs are confirmed to be non-toxic and biocompatible. Two-bottle preference (TBP) tests on mice show that all ACBs are tasteless to mammals. ACBs are discovered to mask the bitterness of berberine and denatonium benzoate, but not quinine hydrochloride, due to different binding modes.
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Leite Humano , Sobrepeso , Gravidez , Feminino , Humanos , Sobrepeso/genética , Ácidos Graxos Insaturados , Ácidos Graxos , Adiponectina/genéticaRESUMO
Abdominal irradiation (IR) destroys the intestinal mucosal barrier, leading to severe intestinal infection. There is an urgent need to find safe and effective treatments to reduce IR-induced intestinal injury. In this study, we reported that metformin protected mice from abdominal IR-induced intestinal injury by improving the composition and diversity of intestinal flora. The elimination of intestinal microbiota (Abx) abrogated the protective effects of metformin on irradiated mice. We further characterized that treatment of metformin increased the murine intestinal abundance of Lactobacillus, which mediated the radioprotective effect. The administration of Lactobacillus or fecal microbiota transplantation (FMT) into Abx mice considerably lessened IR-induced intestinal damage and restored the radioprotective function of metformin in Abx mice. In addition, applying the murine intestinal organoid model, we demonstrated that IR inhibited the formation of intestinal organoids, and metformin alone bore no protective effect on organoids after IR. However, a combination of metformin and Lactobacillus or Lactobacillus alone displayed a strong radioprotection on the organoid formation. We demonstrated that metformin/Lactobacillus activated the farnesoid X receptor (FXR) signaling in intestinal epithelial cells and hence upregulated tight junction proteins and mucins in intestinal epithelia, increased the number of goblet cells, and augmented the mucus layer thickness to maintain the integrity of intestinal epithelial barrier, which eventually contributed to reduced radiation intestinal injury. In addition, we found that Lactobacillus abundance was significantly increased in the intestine of patients receiving metformin while undergoing abdominal radiotherapy and the abundance was negatively correlated with the diarrhea duration of patients. In conclusion, our results demonstrate that metformin possesses a protective effect on IR-induced intestinal injury by upregulating the abundance of Lactobacillus in the intestine.
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The mammalian gastrointestinal tract is colonized with a majority of gut microbes, affecting host metabolism and homeostasis. Gut microbiota plays a vital role in nutrient exchange, signaling transduction between intestinal epithelial cells, and resistance to pathogen invasion. Gut microbiota is divided into mucus layer bacteria and intestinal lumen bacteria based on the colonization distribution. Akkermansia muciniphila (A. muciniphila) prefers to colonize in the intestinal mucus layer, and specifically degrades mucins to produce short-chain fatty acids, providing energy for the host and promoting colonization of the bacterium itself. Degradation of mucins prompts the host to compensate for the production of more mucins, thereby maintaining the dynamics of these proteins. In the intestinal micro-ecosystem, A. muciniphila is non-pathogenic, and its colonization with suitable abundance contributes to the development of immune system, thus promoting intestinal health. The mechanisms by which A. muciniphila bears a protective role in the host intestine are currently unclear. In this review, we summarize the microenvironment for the colonization of A. muciniphila, physiological characteristics and pathophysiological impact of A. muciniphila on intestinal diseases, such as irritable bowel syndrome, inflammatory bowel diseases, and intestinal tumors. We also provided updates for current studies on signals that A. muciniphila enhances intestinal barrier integrity and regulates immune response. Together, we conclude that A. muciniphila is a promising probiotic, which could be a microbial target for the treatment of multiple intestinal diseases.
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Ecossistema , Doenças Inflamatórias Intestinais , Akkermansia , Animais , Ácidos Graxos Voláteis/metabolismo , Humanos , Mamíferos , Mucinas/metabolismo , Verrucomicrobia/metabolismoRESUMO
BACKGROUND: Age-related chronic inflammatory process is often referred to as "inflammaging", which had been described in several human disorders, including sarcopenia. Recently, mitochondrial DNA (MtDNA) has moved into the spotlight as a "damage-associated molecular pattern" (DAMP) agent that can potentially elicit inflammation. Yet, the roles of this mitochondrial DAMP have never been investigated in sarcopenia. DESIGN: Cross-sectional study. PARTICIPANTS: From January 2021 to June 2021, elderly outpatients ≥65 years and able to finish a comprehensive geriatric assessment were recruited in our study. METHODS: Participants were divided into sarcopenia group and non-sarcopenia group according to the DXA scans and grip strength. Genomic DNA was extracted from plasma and peripheral blood mononuclear cells (PBMCs), and changes in MtDNA copies were quantified using qPCR. Plasma levels of inflammatory cytokines were measured using ELISA kits. Loss of mitochondrial membrane potential (Δψm) in PBMCs was analyzed using the fluorescent probe JC-1. RESULTS: Participants with sarcopenia were significantly older, more likely to be physically inactive, and had higher levels of circulating cell-free MtDNA (ccf-MtDNA) (all p < 0.05). After adjusting for potential confounders, ccf-MtDNA was independently associated with increased odds of sarcopenia (adjusted odds ratio (AOR), 1.576; p = 0.009). Furthermore, ROC curve analysis showed that ccf-MtDNA had an area under the curve (AUC) of 0.726 (95% CI: 0.607-0.844; p < 0.05) for distinguishing elderly subjects from sarcopenia. Compared with non-sarcopenia subjects, plasma interleukin (IL)-6 and IL-8 were significantly higher in sarcopenia subjects (both p < 0.05). By performing a correlation test, it was found that the level of IL-6 was positively correlated with ccf-MtDNA (r = 0.301; p < 0.05). Then, PBMCs were used as surrogates for mitochondria-rich cells, and the results showed that the relative amplification of MtDNA in PBMCs was significantly reduced (p < 0.05), whereas the depolarization of Δψm was significantly increased in sarcopenia subjects (p < 0.05). CONCLUSIONS: Taken together, our data suggested that circulating MtDNA might be a novel and important source of inflammatory stimuli potentially relevant for sarcopenia in elderly people, and this would provide an attractive therapeutic target to improve this disease.
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Ácidos Nucleicos Livres , Sarcopenia , Idoso , Ácidos Nucleicos Livres/genética , Estudos Transversais , DNA Mitocondrial/genética , Humanos , Interleucina-6 , Leucócitos Mononucleares , Mitocôndrias/genéticaRESUMO
Deficiency in T cell-mediated adaptive immunity, such as low CD8+ T cell infiltration, inhibits the immune surveillance, promotes malignant transformation, and facilitates tumor growth. Microbiota dysbiosis diminishes the immune system and contributes to the occurrence of cancer. However, the impact of oral dysbiosis on the occurrence and molecular mechanisms of oropharyngeal cancer (OPC) remains largely unknown. In the current study, we used 4-nitroquinoline-1-oxide (4NQO) to mimic tobacco-related carcinogenesis to generate a murine OPC model and determine the role of microbiota changes in OPC tumorigenesis. Our results showed that the oral flora composition of mice was deregulated during the tumorigenesis of OPC. The abundance of Streptococcus, Veillonella, Muribacter, Rodentibacter, and Gemella was increased, whereas the dominant genus Lactobacillus was gradually decreased with disease progression. We further demonstrated that infiltration of CD8+ T lymphocytes was markedly reduced due to the reduction of Lactobacillus. Supplementation of Lactobacillus increased the infiltration of CD8+ T cells, promoted the expression of IFN-γ and granzyme B, and lessened the OPC progression. Analyzing the metabolites of the Lactobacillus, we demonstrated that Lactobacillus enhanced the anti-tumor immune response by producing acetate in OPC development. Administration of acetate to mice could increase the expression of IFN-γ and IFN-γ-inducible chemokines in tumor tissues by activating GPR43 to promote the infiltration of CD8+ T lymphocytes and substantially delay the development of OPC. Together, our data suggest that dysbiosis of oral microbiota promotes the tumorigenesis of OPC through downregulation of cytotoxic T lymphocytes. Lactobacillus and its metabolite acetate improve the tumor microenvironment, which could be applied in the treatment of OPC.
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Data mining technology was adopted to analyze the rules of acupoint selection in treatment of erectile dysfunction with acupuncture and moxibustion. All of the articles for acupuncture and moxibustion in treatment of erectile dysfunction were searched from the databases, i.e. Chinese national knowledge infrastructure (CNKI), Wanfang database, VIP, Chinese biomedical literature database (SinoMed) and PubMed, and the clinical trials on erectile dysfunction treated with acupuncture and moxibustion were screened. The database was set up by using Excel 2019 and input into R 4.0.3, and then, the therapeutic method, use frequency of acupoint, meridian tropism, collection visualization analysis, cluster analysis and association rule analysis were summarized. A total of 240 articles were included, with 516 prescriptions and 145 acupoints involved. The methods for treatment of erectile dysfunction included acupuncture and moxibustion therapy, acupuncture, acupoint injection, electroacupuncture, etc. The acupoints with high use frequency were Guanyuan (CV 4), Shenshu (BL 23), Sanyinjiao (SP 6), Mingmen (GV 4), Zusanli (ST 36), Zhongji (CV 3), Ciliao (BL 32), Qihai (CV 6), Taixi (KI 3) and Taichong (LR 3). The meridians involved with high frequency were the bladder meridian of foot-taiyang, the conception vessel, the spleen meridian of foot-taiyin, etc. The common acupoint combination was Shangliao (BL 31), Zhongliao (BL 33), Ciliao (BL 32), Xialiao (BL 34) and Sanyinjiao (SP 6), Shenshu (BL 23), Guanyuan (CV 4). In association rule analysis (confidence ≥ 90%, support ≥ 20%), there were 27 association rules in total. The acupoint combination with the highest support referred to "Shenshu (BL 23), Sanyinjiao (SP 6)âGuanyuan (CV 4)" (support 46.7%) and the acupoint combination with the highest confidence was "Sanyinjiao (SP 6), Qihai (CV 6)âGuanyuan (CV 4)" (confidence 98.0%). The acupoints could be divided into 5 effective clusters. Acupuncture and moxibustion therapy has a certain of rules of acupoint selection in treatment of erectile dysfunction, which provides the evidences for modern clinical trial and treatment.
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Terapia por Acupuntura , Disfunção Erétil , Meridianos , Moxibustão , Pontos de Acupuntura , Mineração de Dados , Disfunção Erétil/terapia , Humanos , Masculino , TecnologiaRESUMO
The limited accuracy of cerebral infarct detection on CT images caused by the low contrast of CT hinders the desirable application of CT as a first-line diagnostic modality for screening of cerebral infarct. This research was aimed at utilizing convolutional neural network to enhance the accuracy of automated cerebral infarct detection on CT images. The CT images underwent a series of preprocessing steps mainly to enhance the contrast inside the parenchyma, adjust the orientation, spatially normalize the images to the CT template, and create a t-score map for each patient. The input format of the convolutional neural network was the t-score matrix of a 16 × 16-pixel patch. Non-infarcted and infarcted patches were selected from the t-score maps, on which data augmentation was conducted to generate more patches for training and testing the proposed convolutional neural network. The convolutional neural network attained a 93.9% patch-wise detection accuracy in the test set. The proposed method offers prompt and accurate cerebral infarct detection on CT images. It renders a frontline detection modality of ischemic stroke on an emergent or regular basis.
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Two new flavanoids fissistiganoids A and B (1 and 2), together with two known pterocarpans derivatives (3 and 4), were isolated from the stems of Fissistigma tungfangense. The structures of these compounds were elucidated using comprehensive spectroscopic methods. The absolute configurations of fissistiganoids A and B (1 and 2) were determined by comparing their ECD spectra with quantum-mechanics ECD calculations. The inhibitory activities of all compounds against three cancer cell lines HeLa, MCF-7 and A549 were evaluated. Compounds 1-4 showed moderate inhibitory effects on HeLa, MCF-7 and A549 cells with IC50 values ranging from 12.5 to 42.3 µM.
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Annonaceae , Pterocarpanos , Células A549 , Flavonoides/química , Flavonoides/farmacologia , Humanos , Estrutura MolecularRESUMO
Brucea javanica oil emulsion (BJOE) has been used to treat tumor in China for more than 40 years. However, its components and effectiveness in the treatment of acute lymphocytic leukemia (ALL) and its mechanism of anti-cancer activity remain unknown. In the current study, high-performance liquid chromatography-evaporative light scattering detector (HPLC-ELSD) was used to analyze the components of BJOE. Then, the anti-leukemia effects of BJOE were examined both in vitro and in vivo using ALL Jurkat cells and the p388 mouse leukemia transplant model, respectively. The primary ALL leukemia cells were also used to confirm the anti-leukemia effects of BJOE. The apoptotic-related results indicated that BJOE induced apoptosis in Jurkat cells and were suggestive of intrinsic apoptotic induction. Moreover, BJOE inhibited Akt (protein kinase B) activation and upregulated its downstream targets p53 and FoxO1 (forkhead box gene, group O-1) to initiate apoptosis. The activation of GSK3ß was also involved. Our findings demonstrate that BJOE has anti-leukemia effects on ALL cells and can induce apoptosis in Jurkat cells through the phosphoinositide3-kinase (PI3K) /Akt signaling pathway.
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Apoptose , Brucea , Óleos de Plantas/farmacologia , Leucemia-Linfoma Linfoblástico de Células Precursoras , Animais , Brucea/química , Quinase 3 da Glicogênio Sintase , Humanos , Células Jurkat , Camundongos , Fosfatidilinositol 3-Quinases/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/genética , Sementes/química , Transdução de SinaisRESUMO
Nine secondary metabolites(S)-5-hydroxy-4-methylchroman-2-one(1), 4-methoxynaphthalene-1,5-diol(2), 8-methoxynaphthalene-1,7-diol(3), 1,8-dimethoxynaphthalene(4),(2R,4S)-2,3-dihydro-2-methyl-benzopyran-4,5-diol(5),(2R,4R)-3,4-dihydro-4-methoxy-2-methyl-2H-1-benzopyran-5-ol(6), 7-O-α-D-ribosyl-2,3-dihydro-5-hydroxy-2-methyl-chromen-4-one(7),(R)-3-methoxyl-1-(2,6-dihydroxyphenyl)-butan-1-one(8) and helicascolide A(9) were isolated from endophytic fungus Cladosporium sp. JJM22 by using column chromatographies of silica gel and ODS, and semi-preparative HPLC. Their structures were analyzed on the basis of spectroscopic and chemical data, especially NMR and MS. All isolated compounds were evaluated for their anti-inflammatory activities by examining the inhibitory activities on nitric oxide(NO) production induced by lipopolysaccharide in mouse macrophage RAW264.7 cells in vitro. Compounds 2-4 showed inhibitory activities.
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Rhizophoraceae , Animais , Benzopiranos , Cladosporium , Fungos , Camundongos , Estrutura MolecularRESUMO
Five undescribed triene derivatives, pinophols B-F (2-6), together with one known compound, pinophol A (1), were obtained from the mangrove endophytic fungus Penicillium herquei JX4. The structures of compounds 1-6 were elucidated using IR, HR-ESI-MS, and NMR methods. The absolute configurations of compounds 1-6 were confirmed by comparing their experimental or calculated ECD spectra. Pinophols C and D (3 and 4) showed inhibitory activities against LPS-induced NO production.
Assuntos
Óxido Nítrico/antagonistas & inibidores , Penicillium/química , Animais , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Estrutura Molecular , Óxido Nítrico/biossíntese , Células RAW 264.7 , EstereoisomerismoRESUMO
With the expansion of data, increasing imbalanced data has emerged. When the imbalance ratio (IR) of data is high, most existing imbalanced learning methods decline seriously in classification performance. In this paper, we systematically investigate the highly imbalanced data classification problem, and propose an uncorrelated cost-sensitive multiset learning (UCML) approach for it. Specifically, UCML first constructs multiple balanced subsets through random partition, and then employs the multiset feature learning (MFL) to learn discriminant features from the constructed multiset. To enhance the usability of each subset and deal with the non-linearity issue existed in each subset, we further propose a deep metric based UCML (DM-UCML) approach. DM-UCML introduces the generative adversarial network technique into the multiset constructing process, such that each subset can own similar distribution with the original dataset. To cope with the non-linearity issue, DM-UCML integrates deep metric learning with MFL, such that more favorable performance can be achieved. In addition, DM-UCML designs a new discriminant term to enhance the discriminability of learned metrics. Experiments on eight traditional highly class-imbalanced datasets and two large-scale datasets indicate that: the proposed approaches outperform state-of-the-art highly imbalanced learning methods and are more robust to high IR.