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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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

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., (© 2024. The Author(s).)

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 (PrL Glu ) was significantly reduced during ORM retrieval. Chemogenetic activation of PrL Glu or glutamatergic projections from ventral CA1 to PrL (vCA1 Glu -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 PrL Glu 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 PrL Glu activity, possibly due to excessive DA activity on D2R. Selective activation of PrL Glu or vCA1 Glu -PrL may serve as a potential therapeutic strategy for METH-induced cognitive dysfunction., (© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Hou, Cong, Cai, Ba, Chen, Yang and Luo.)

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., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

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., (© 2024. The Author(s).)

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., (© 2023 Wiley-VCH GmbH.)

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., Competing Interests: The authors declare there are no competing interests., (©2023 Yang and Sun.)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yang, Liu, Lv, Guo, He, Zhang, Wang, Cui, Yan, Du, Wang, Ding, Liu, Xu and Jian.)

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., Competing Interests: Conflict of interest The authors declare no conflict of interest., (Copyright © 2022 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

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 IC 50 values ranging from 12.5 to 42.3  μ M.

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., (Copyright © 2022. Published by Elsevier Inc.)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wang, He, Yang, Liu, Guo, Liang, Wang, Xu and Jian.)

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)→Guanyuan (CV 4)" (support 46.7%) and the acupoint combination with the highest confidence was "Sanyinjiao (SP 6), Qihai (CV 6)→Guanyuan (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.

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.

We previously reported that pseudoginsenoside-F11 (PF11), an ocotillol-type saponin, significantly ameliorated Alzheimer's disease (AD)-associated cognitive defects in APP/PS1 and SAMP8 mice by inhibiting Aβ aggregation and tau hyperphosphorylation, suggesting a potential therapeutic effect of PF11 in the treatment of AD. In the present study we further evaluated the therapeutic effects of PF11 on relieving cognitive impairment in a rat model of sporadic AD (SAD). SAD was induced in rats by bilateral icv infusion of streptozotocin (STZ, 3 mg/kg). The rats were treated with PF11 (2, 4, 8 mg·kg -1 ·d -1 , ig) or a positive control drug donepezil (5 mg·kg -1 ·d -1 , ig) for 4 weeks. Their cognitive function was assessed in the nest building, Y-maze, and Morris water maze tests. We showed that STZ icv infusion significantly affected the cognitive function, tau phosphorylation, and insulin signaling pathway in the hippocampus. Furthermore, STZ icv infusion resulted in significant upregulation of the calpain I/cyclin-dependent protein kinase 5 (CDK5) signaling pathway in the hippocampus. Oral administration of PF11 dose-dependently ameliorated STZ-induced learning and memory defects. In addition, PF11 treatment markedly reduced the neuronal loss, protected the synapse structure, and modulated STZ-induced expression of tau phosphorylation by regulating the insulin signaling pathway and calpain I/CDK5 signaling pathway in the hippocampus. Donepezil treatment exerted similar beneficial effects in STZ-infused rats as the high dose of PF11 did. This study highlights the excellent therapeutic potential of PF11 in managing AD., (© 2020. CPS and SIMM.)

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 GSK3β 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., (Copyright © 2021 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.)

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., (© 2021 Wiley-VHCA AG, Zurich, Switzerland.)

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.

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.

Background: As a substrate of apoER2, Reelin has been verified to exert neuroprotection by preventing memory impairment. Pinocembrin is the most abundant natural flavonoid found in propolis, and it has been used to exert neuroprotection, blood-brain barrier protection, anti-oxidation, and inflammation diminishing, both in vitro and in vivo. However, the roles and molecular mechanisms of pinocembrin in neurobehavioral outcomes and neuronal repair after vascular dementia are still under investigation., Purpose: To explore the role of pinocembrin in the involvement of the Reelin-dab1 signaling pathway in improving memory impairment, both in cell culture and animals experiments., Material and Methods: Behavioral tests were conducted on day 48 to confirm the protection of pinocembrin against cognitive impairment. Cell and molecular biology experiments demonstrated that the Reelin-dab1 pathway mediates the underlying mechanism of cognitive improvement by pinocembrin., Results: It was showed that pinocembrin alleviated learning and memory deficits induced by vascular dementia, by inducing the expression of Reelin, apoER2, and p-dab1 in the hippocampus. The expression of Reelin and p-dab1 was both inhibited following Reelin RNA interference in SH-SY5Y prior to oxygen glucose deprivation (OGD) injury, suggesting that Reelin played a core role in pinocembrin's effect on OGD in vitro., Conclusion: Pinocembrin improves the cognition via the Reelin-dab1 signaling pathway., Competing Interests: The authors report no conflicts of interest in this work., (© 2020 Kang et al.)

The network pharmacology was used to investigate the material basis and molecular mechanism of Dachengqi Decoction(DCQD) in the treatment of acute pancreatitis(AP). Potential targets of components from DCQD and relevant pathogenic genes of AP were identified through database retrieval. Then, crucial targets were verified with relevant active chemical components via molecular docking. DAVID database was used to explore the functions and pathways involved in the treatment of AP. A total of 108 components were correlated with 28 targets. Molecular docking showed a strong binding ability of key targets and their corresponding compounds. DAVID enrichment analysis showed 438 biological process, 31 molecular functions, 17 cellular components and 96 KEGG pathways. DCQD may achieve its pharmacological effects through anti-inflammatory and anti-oxidative effects, negative regulation of apoptosis and regulation of pancreatic secretion, involving multiple signals, such as IL-17, TNF and NF-κB signaling pathway. In this study, it is the first time to use the method of network pharmacology to reveal the molecular mechanism of DCQD in the treatment of AP by multiple components and multi-signaling pathways, which provides a basis for further biological experiments of AP.

Objective: Clostridium difficile-associated diarrhea (CDAD) accounts for up to 25% of patients with antibiotic-associated diarrhea (AAD). We aimed to determine which probiotic is most effective in preventing CDAD using a network meta-analysis., Methods: Studies were identified by searching PubMed, EMBASE and the Cochrane Library databases for randomized controlled trials (RCTs) that evaluated the efficacy of probiotic interventions for CDAD. Primary outcomes were the incidence rates of AAD and CDAD, and secondary outcomes were the duration of diarrhea and the time until onset of diarrhea. The PROSPERO registered number of this study is CRD42018106115., Results: Ten RCTs including 11 analyses and including 4 692 patients were identified. Compared with the control group, probiotic intervention reduced the incidence rates of CDAD (odds ratio [OR] 0.33, 95% confidence interval [CI] 0.17-0.61) and AAD (OR 0.39, 95% CI 0.23-0.66). Similar results were observed regarding the duration of diarrhea and the time until onset of diarrhea. Meta-regression analysis showed a correlation between the type of probiotic used and the incidence of CDAD and AAD. All nine kinds of probiotic interventions were statistically more effective than the placebo, with Lactobacillus casei ranking as the best intervention (OR 0.19, 95% credible interval [CrI] 0.06-0.63) for decreasing the incidence rate of CDAD. L. casei also ranked the highest in reducing the incidence rate of AAD (OR 0.32, 95% CrI 0.14-0.74)., Conclusion: Lactobacilli strains, especially L. casei, have a good effect on the prevention of CDAD and AAD., (© 2019 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Methamphetamine (METH) causes memory changes, but the underlying mechanisms are poorly understood. Epigenetic mechanisms, including DNA methylation, can potentially cause synaptic changes in the brain. Oxytocin (OT) plays a central role in learning and memory, but little is known of the impact of OT on METH-associated memory changes. Here, we explored the role of OT in METH-induced epigenetic alterations that underlie spatial and cognitive memory changes. METH (2.0 mg/kg, i.p.) was administered to male C57BL/6 mice once every other day for 8 days. OT (2.5 μg, i.c.v.) or aCSF was given prior to METH. Spatial and cognitive memory were assessed. In Hip and PFC, synaptic structures and proteins were examined, levels of DNA methyltransferases (DNMTs) and methyl CpG binding protein 2 (MECP2) were determined, and the DNA methylation status at the Synaptophysin (Syn) promoter was assessed. METH enhanced spatial memory, decreased synapse length, downregulated DNMT1, DNMT3A, DNMT3B, and MECP2, and induced DNA hypomethylation at the Syn promoter in Hip. In contrast, METH reduced cognitive memory, increased synapse thickness, upregulated DNMT1, DNMT3A, and MECP2, and induced DNA hypermethylation at the Syn promoter in PFC. OT pretreatment specifically ameliorated METH-induced learning and memory alterations, normalized synapse structures, and regulated DNMTs and MECP2 to reverse the DNA methylation status changes at the Syn promoter in Hip and PFC. DNA methylation is an important gene regulatory mechanism underlying METH-induced learning and memory alterations. OT can potentially be used to specifically manipulate METH-related memory changes., (© 2018 Society for the Study of Addiction.)

Intracerebroventricular (icv) streptozotocin (STZ) injection decreases cerebral insulin signal pathway function and produces multiple effects that resemble the molecular, pathological, and behavioural features of Sporadic Alzheimer's disease (SAD). We previously reported that yonkenafil (yonk), the analogue of sildenafil and a novel PDE5 inhibitor exerts an anti-amyloidogenesis effect by regulating the Aβ level and inhibiting the expression of β-amyloid precursor protein in the APP/PS1 transgenic mice model. In this study, the effects of yonk on cognitive behaviors as well as the pathological features in streptozotocin-induced SAD rat model were investigated. The results demonstrated that administration of yonk at doses of 3 and 10 mg/kg for three weeks significantly improved cognitive deficits, attenuated STZ-induced neuronal death, inhibited the over-activation of microglia and astrocytes and the levels of pro-inflammatory markers, as well as decreased PDE5 protein expression in the hippocampus. Furthermore, yonk (3 mg/kg) notably prevented changes in tau hyperphosphorylation, decreased IRS-1and JNK phosphorylation and increased the GSK3β (ser9) phosphorylation induced by STZ. In summary, these data suggested that yonk significantly reversed STZ-induced memory deficits by inhibiting the over-activation of microglia and astrocytes, as well as ameliorated the levels of pro-inflammatory makers and tau hyperphosphorylation through regulating GSK3β signalling pathway., (Copyright © 2019. Published by Elsevier B.V.)

Two novel epimer pairs of acetaminophen derivatives penicilquei A-D (1-4) were isolated from Penicillium herquei JX4. Their structures were elucidated using comprehensive spectroscopic methods. The absolute configurations of penicilquei A-D (1-4) were determined by modifified Mosher's method, and comparing their experimental and calculated electronic circular dichroism (ECD) spectra. Penicilquei A-D (1-4) are the first example of acetaminophen derivatives featuring an unprecedented carbon skeleton. The inhibitory activities of all compounds against nine phytopathogenic fungi and α-glucosidase were evaluated. Penicilquei A-D (1-4) showed strong inhibitory activities against at least eight phytopathogenic fungus., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Antiplatelet therapies for secondary prevention of ischemic stroke or transient ischemic attack (TIA) is a highly active research topic with five critical drugs obtained by visual analysis. We aimed to compare and rank multiple antiplatelet therapies using a network meta-analysis., Methods: Relevant medical databases were searched. Eligible randomized controlled trials (RCTs) which examined any comparisons involving mono- or dual antiplatelet therapies, based on aspirin, clopidogrel, dipyridamole, ticlopidine, cilostazol and placebo for patients with noncardioembolic ischemic stroke or TIA, were included. 14 outcomes were assessed. Primary outcomes were stroke recurrence, composite events (stroke recurrence, myocardial infarction and vascular death), and intracranial hemorrhage. PROSPERO registered number CRD42017069728., Results: 45 RCTs with 173,131 patients were included in network meta-analysis, involving eight antiplatelet therapies. Cilostazol and clopidogrel were statistically more efficacious than aspirin (odds ratio (OR) = 0.64, 95% confidence interval (CI) = 0.47-0.88; OR = 0.77, 95%CI = 0.62-0.95) and dipyridamole (OR = 0.64, 95%CI = 0.44-0.93; OR = 0.76, 95%CI = 0.58-0.99) in reducing stroke recurrence, and showed significant benefits in reducing composite events compared with aspirin (OR = 0.63, 95%CI = 0.45-0.89; OR = 0.90, 95%CI = 0.83-0.97). No significant difference was found between cilostazol and clopidogrel in intracranial hemorrhage. Weighted regression suggested cilostazol was hierarchically the optimum treatment in consideration of both efficacy and safety, followed by clopidogrel., Conclusion: Cilostazol and clopidogrel are probably promising options for secondary prevention of ischemic stroke or TIA. Both of them reduce stroke recurrence similarly compared with aspirin or dipyridamole, and reduce composite events compared with aspirin. Further studies are needed to confirm this finding., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Foreground and background cues can assist humans in quickly understanding visual scenes. In computer vision, however, it is difficult to detect salient objects when they touch the image boundary. Hence, detecting salient objects robustly under such circumstances without sacrificing precision and recall can be challenging. In this paper, we propose a novel model for salient region detection, namely, the foreground-center-background (FCB) saliency model. Its main highlights as follows. First, we use regional color volume as the foreground, together with perceptually uniform color differences within regions to detect salient regions. This can highlight salient objects robustly, even when they touched the image boundary, without greatly sacrificing precision and recall. Second, we employ center saliency to detect salient regions together with foreground and background cues, which improves saliency detection performance. Finally, we propose a novel and simple yet efficient method that combines foreground, center, and background saliency. Experimental validation with three well-known benchmark data sets indicates that the FCB model outperforms several state-of-the-art methods in terms of precision, recall, F-measure, and particularly, the mean absolute error. Salient regions are brighter than those of some existing state-of-the-art methods.

Biliary epithelial cells (BEC) are closely related to some immune regulatory bile duct diseases. However, the complexity and polymorphism of the morphology and function of bile duct cells have hindered further investigation. Therefore, the aim of this study is to investigate how interleukin-6 (IL-6) affects the migration, cellular senescence, and apoptosis of human intrahepatic biliary epithelial cells (HIBECs). The HIBECs were stimulated by different concentrations of IL-6 (0, 5, 10, 15, and 20 ng/mL, respectively). Transwell assay was performed in order to measure the migration abilities, positive β-Galactosidase staining for the cellular senescence of HIBECs, MTT assay for changes of proliferation after IL-6 treatment and flow cytometry for cell cycle and apoptosis. The reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blotting were conducted in order to detect the mRNA and protein expressions of epithelial-mesenchymal transition (EMT) markers in HIBECs. In comparison to the 0 ng/mL group, in the 5, 10, 15, and 20 ng/mL groups, a significant increase in the number of migratory HIBECs, proliferation, along with mRNA and protein expressions of EMT markers was observed. While the mRNA and protein expressions of epithelial markers, the number of β-galactosidase positive staining cells, as well as apoptosis rate of HIBECs dramatic decreased. Further, the aforementioned changes were significantly more evident in the 15 and 20 ng/mL groups in comparison to the 5 and 10 ng/mL groups. IL-6 may stimulate EMT, enhance the migration and proliferation, and inhibit apoptosis of HIBECs, thus delaying cellular senescence., (© 2017 Wiley Periodicals, Inc.)

Disulfiram (DSF) in combination with copper (Cu) has been reported to override drug resistance in cancer cells, and DSF combined with chemotherapy based on the microtubule inhibitor vinorelbine appears to prolong survival in non-small cell lung cancer patients. Here, we investigated the mechanisms underlying these findings. DSF/Cu reversed the microtubule inhibitor resistance in A549/Taxol and KB/VCR cells in vitro, and had anti-tumor effects in A549/Taxol and KB/VCR xenograft mice. DSF/Cu and DSF reduced the cancer stem cell (CSC) characteristics of drug-resistant A549/Taxol and KB/VCR cells, including sphere formation, colony generation and migration, and DSF/Cu was more effective than DSF alone. DSF/Cu also decreased the aldehyde dehydrogenase (ALDH) activity and the expression of P-gp and stem cell transcription factors in A549/Taxol and KB/VCR cells. Knockdown of ALDH2 attenuated the CSC characteristics of resistant cancer cells and enhanced their sensitivity to Taxol or VCR. Importantly, DSF/Cu treatment inhibited the expression of ALDH2 in vitro and in vivo. Our findings suggest that DSF/Cu reverses microtubule inhibitor resistance in cancer cells by suppressing ALDH2 expression, and Cu improves the activity of DSF., (Copyright © 2017. Published by Elsevier Inc.)

Late-stage hepatocellular carcinoma (HCC) usually has a low survival rate because of the high risk of metastases and the lack of an effective cure. Disulfiram (DSF) has copper (Cu)-dependent anticancer properties in vitro and in vivo. The present work aims to explore the anti-metastasis effects and molecular mechanisms of DSF/Cu on HCC cells both in vitro and in vivo. The results showed that DSF inhibited the proliferation, migration and invasion of HCC cells. Cu improved the anti-metastatic activity of DSF, while Cu alone had no effect. Furthermore, DSF/Cu inhibited both NF-κB and TGF-β signalling, including the nuclear translocation of NF-κB subunits and the expression of Smad4, leading to down-regulation of Snail and Slug, which contributed to phenotype epithelial-mesenchymal transition (EMT). Finally, DSF/Cu inhibited the lung metastasis of Hep3B cells not only in a subcutaneous tumour model but also in an orthotopic liver metastasis assay. These results indicated that DSF/Cu suppressed the metastasis and EMT of hepatic carcinoma through NF-κB and TGF-β signalling. Our study indicates the potential of DSF/Cu for therapeutic use., (© 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Hypoxia-inducible factor-1 (HIF-1) is over-expressed in gliomas and has become one of the most compelling tumor targets. In this study, we found that oligomer procyanidins (F2) can suppress the expressions of HIF-1α and its target genes in U87 cells, and also down-regulate the EGFR/PI3K/AKT/mTOR and MAPK/ERK1/2 pathways in vitro and in vivo . Furthermore, hypoxia-induced formation of tubular structures by human umbilical vascular endothelial cells and the migration and invasion of U87 cells could be inhibited by F2 in a HIF-1 dependent manner. Moreover, in a U87 xenograft tumor model, F2 significantly reduced intra-tumor vessel density and cell proliferation and finally retarded tumor growth, indicating that F2 may be a potential HIF-1 inhibitor and serve as one of candidates for glioma therapy., Competing Interests: CONFLICTS OF INTEREST The authors have no conflicts of interest.

Aims: Pseudoginsenoside-F11 (PF11), an ocotillol-type ginsenoside, has been reported to exert wide-ranging neuroprotective properties. The aim of this study was to investigate the effect and potential mechanisms of PF11 on the autophagic/lysosomal pathway following ischemic stroke., Methods: Male Sprague-Dawley rats underwent permanent middle cerebral artery occlusion (pMCAO). Cerebral ischemia outcome, TUNEL staining, Fluoro-Jade B staining were carried out 24 hours poststroke. The autophagic/lysosomal-related proteins were measured., Results: A single administration of PF11 significantly decreased the infarct area, reduced the brain water content, and improved neurological functions, even 4 hours after the onset of pMCAO. Meanwhile, PF11 lessened the ischemic insult-mediated loss of neurons and activation of astrocytes and microglia. Furthermore, PF11 attenuated pMCAO-induced accumulations of autophagosomes and apoptosis. We further observed a remarkable effect of PF11 in reversing the ischemic insult-induced accumulation of autophagosomes (LC3-II) and abnormal aggregation of autophagic proteins (SQSTM1 and ubiquitin). Furthermore, PF11 was capable of improving lysosomal function and lysosome/autophagosome fusion following pMCAO, and this change was reversed by the lysosomal inhibitor chloroquine. Also, the improvement of ischemic outcome and the antiapoptotic effect induced by PF11 was reversed by CQ., Conclusion: These findings indicate that the autophagic flux is impaired in a rat model of pMCAO, and that PF11 exerts an excellent protective effect against ischemic stroke by alleviating autophagic/lysosomal defects., (© 2017 John Wiley & Sons Ltd.)

Background: Atrial AutoCapture™ (ACap™) was a new technological development that confirmed atrial capture by analyzing evoked response (ER) with a new method - paced depolarization integral ER detection - and optimized energy output to changes in the stimulation threshold. The purpose of this study was to evaluate the clinical performance of ACap™ function., Methods: This was a prospective, observational, nonrandomized two-center study. Between November 2008 and August 2014, 102 patients were enrolled from two different institutions. Data were collected by case report forms at enrollment, hospital discharge, and in-office follow-ups scheduled at 1, 2, 3, 6, and 12 months postimplantation., Results: Ambulatory ACap™ function started to become available for 20.6% of patients at 1 day, then progressed to 30.4% at 7 days, 38.6% at 1 month, 41.6% at 2 months, 47.5% at 3 months, 53.5% at 6 months, and 63.4% at 1 year. The cause of the unsuccessful attempts to perform ACap™ threshold was ER/polarization <2:1. Availability for SD, BND, and HOCM indications had shown better results than AVB indication. For SD indication cases, feasibility was significantly better for SD with paroxysmal atrial fibrillation (pAF) than SD without pAF (78.4% vs. 35.0% at 1 year, n = 71, P< 0.001). At each stage of the clinical follow-ups, there had been a strict correlation between ACap™ measurements and those conducted manually with P 0.001 (n = 299)., Conclusions: It has been concluded that ACap™ function was safe and effective to confirm atrial threshold and reduce energy output automatically. ACap™ function is unavailable for some patients at early stages of the implantation; however, availability has been progressively increasing during follow-up.

In the search for biologically active compounds from the roots of Bupleurum chinense D C., phytochemical investigation of its ethanol extract led to the isolation and identification of a new 8-O-4' neolignan glucoside, saikolignanoside A (1), along with eight known lignans (2-9). Their structures were determined on the basis of IR, UV, HRESIMS, and NMR spectroscopic analyses. The antioxidant and cytotoxic effects of isolated compounds were evaluated in vitro. The isolated compounds (IC 50  > 200 μM) did not display 2, 2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity. Whereas compounds 1-2, 5, 7, and 9 exhibited potent 2, 2'-azinobis(3-ethyl-benzothiazoline-6-sulfonic acid) (ABTS) free radical scavenging properties with IC 50 values ranging from 8.34 to 15.24 μM, while compounds 3-4, 6, 8 showed moderate properties. In addition, all compounds were evaluated for cytotoxicities against A549, HepG2, U251, Bcap-37, and MCF-7 cell lines. Compounds 5 and 9 (IC 50  < 51.62 μM) possessed stronger cytotoxic activities against all the tested tumor cell lines, compared with the positive control 5-Fluorouracil.

Person re-identification has been widely studied due to its importance in surveillance and forensics applications. In practice, gallery images are high resolution (HR), while probe images are usually low resolution (LR) in the identification scenarios with large variation of illumination, weather, or quality of cameras. Person re-identification in this kind of scenarios, which we call super-resolution (SR) person re-identification, has not been well studied. In this paper, we propose a semi-coupled low-rank discriminant dictionary learning (SLD 2 L) approach for SR person re-identification task. With the HR and LR dictionary pair and mapping matrices learned from the features of HR and LR training images, SLD 2 L can convert the features of the LR probe images into HR features. To ensure that the converted features have favorable discriminative capability and the learned dictionaries can well characterize intrinsic feature spaces of the HR and LR images, we design a discriminant term and a low-rank regularization term for SLD 2 L. Moreover, considering that low resolution results in different degrees of loss for different types of visual appearance features, we propose a multi-view SLD 2 L (MVSLD 2 L) approach, which can learn the type-specific dictionary pair and mappings for each type of feature. Experimental results on multiple publicly available data sets demonstrate the effectiveness of our proposed approaches for the SR person re-identification task.

Hypoxia-inducible factor-1 (HIF-1) plays an essential role in carcinogenesis. The overexpression of HIF-1 induced by hypoxia is closely associated with metastasis, poor prognosis and high mortality. In this study, a novel HIF-1 inhibitor SYP-5 was first observed by the luciferase reporter assay. Western blots results showed SYP-5 inhibited hypoxia-induced upregulation of HIF-1. Moreover, the proteins of vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMP)-2 that are targets of HIF-1, were down-regulated by SYP-5. Furthermore, in the tube formation assay, SYP-5 suppressed angiogenesis induced by hypoxia and VEGF in vitro. Additionally, using Transwell and RTCA assays, we found that SYP-5 also retarded the Hep3B and Bcap37 cells migration and invasion induced by hypoxia and FBS. Last, we also detected the upstream pathways related to HIF-1 and found both PI3K/AKT and MAPK/ERK were involved in the SYP-5 mediated invasive inhibition of Bcap37 cells. These results indicates that SYP-5 inhibits tumor cell migration and invasion, as well as tumor angiogenesis, which are mediated by suppressing PI3K/AKT- and MAPK/ERK-dependent HIF-1 pathway. It suggests that SYP-5 might be a potential HIF-1 inhibitor as an anticancer agent., (Copyright © 2016 Elsevier B.V. All rights reserved.)

SL4, a chalcone-based compound, has been shown to retard tumor invasion and angiogenesis by suppressing HIF1 activity and to induce apoptosis by promoting ROS release. Here, we report that SL4 is able to inhibit the proliferation of different types of breast cancer cell in vitro and in vivo by inducing G 2 /M cell cycle arrest. Our results showed that SL4 exhibited strong anti-proliferative activity in several human breast cancer cell lines, with IC 50 values lower than 1.3 μM. Further studies indicated that SL4 induced G 2 /M arrest in these cell lines. Mechanistically, SL4 reduces the expression of cyclin A2 and cdc25C and decreases the activity of the cdc2/cyclin B1 complex. Notably, SL4 treatment resulted in an obvious increase in p21 mRNA and protein levels through activation of MAPK signaling pathways, but not the TGF-β pathway. SP600125 and PD98059, specific inhibitors of JNK kinase and ERK kinase, significantly blocked the SL4-induced G 2 /M phase arrest and upregulation of p21. Furthermore, SL4 suppressed the growth of established breast tumors in nude mice through upregulation of p21 and downregulation of cdc25C, and displayed a good safety profile. Taken together, these findings demonstrate the potential value of SL4 as a novel multi-target anti-tumor drug candidate.

The accurate prediction of whether a protein will crystallize plays a crucial role in improving the success rate of protein crystallization projects. A common critical problem in the development of machine-learning-based protein crystallization predictors is how to effectively utilize protein features extracted from different views. In this study, we aimed to improve the efficiency of fusing multi-view protein features by proposing a new two-layered SVM (2L-SVM) which switches the feature-level fusion problem to a decision-level fusion problem: the SVMs in the 1st layer of the 2L-SVM are trained on each of the multi-view feature sets; then, the outputs of the 1st layer SVMs, which are the "intermediate" decisions made based on the respective feature sets, are further ensembled by a 2nd layer SVM. Based on the proposed 2L-SVM, we implemented a sequence-based protein crystallization predictor called TargetCrys. Experimental results on several benchmark datasets demonstrated the efficacy of the proposed 2L-SVM for fusing multi-view features. We also compared TargetCrys with existing sequence-based protein crystallization predictors and demonstrated that the proposed TargetCrys outperformed most of the existing predictors and is competitive with the state-of-the-art predictors. The TargetCrys webserver and datasets used in this study are freely available for academic use at: http://csbio.njust.edu.cn/bioinf/TargetCrys .

Objectives: Xiaochaihutang (XCHT) has antidepressant effects in multiple animal models of depression in our previous studies. But the antidepressant effects and exact mechanisms of XCHT in a rat model of chronic social isolation stress (CSIS) have never been studied. We therefore aimed to investigate the effects of XCHT on depressive/anxiety-related behaviours of CSIS-exposed rats and understand the neurological mechanism involving neurogenesis., Methods: We established the CSIS model and then investigated the effects of XCHT on behavioural change. HPLC-MS/MS was adopted to quantify neurotransmitter levels in the cerebrospinal fluid (CSF). Immunofluorescence technology was used to study the effects of XCHT on neurogenesis; while expressions of 5-HT1A receptor signalling pathway in the hippocampus were measured using Western blotting., Key Findings: Xiaochaihutang significantly alleviated depressive/anxiety-like behaviours of CSIS-exposed rats. XCHT significantly regulated levels of monoamine neurotransmitters in the CSF without affecting Glu, GABA and ACh. XCHT also significantly increased neurogenesis in CSIS-exposed rats. Additionally, XCHT reversed CSIS-induced decrease of 5-HT1A receptor expression and promoted the expression of BDNF in the hippocampus., Conclusion: Our results suggest that XCHT could significantly regulate the depressive/anxiety-like behaviours induced by CSIS, which are likely attributed to the promotion of hippocampal neurogenesis and neurotrophin expressions through the activation of serotonergic system., (© 2016 Royal Pharmaceutical Society.)

Unlabelled: The amygdala serves as emotional center to mediate innate fear behaviors that are reflected through neuronal responses to environmental aversive cues. However, the molecular mechanism underlying the initial neuron responses is poorly understood. In this study, we monitored the innate defensive responses to aversive stimuli of either elevated plus maze or predator odor in juvenile mice and found that glutamatergic neurons were activated in amygdala. Loss of EphB2, a receptor tyrosine kinase expressed in amygdala neurons, suppressed the reactions and led to defects in spine morphogenesis and fear behaviors. We further found a coupling of spinogenesis with these threat cues induced neuron activation in developing amygdala that was controlled by EphB2. A constitutively active form of EphB2 was sufficient to rescue the behavioral and morphological defects caused by ablation of ephrin-B3, a brain-enriched ligand to EphB2. These data suggest that kinase-dependent EphB2 intracellular signaling plays a major role for innate fear responses during the critical developing period, in which spinogenesis in amygdala glutamatergic neurons was involved., Significance Statement: Generation of innate fear responses to threat as an evolutionally conserved brain feature relies on development of functional neural circuit in amygdala, but the molecular mechanism remains largely unknown. We here identify that EphB2 receptor tyrosine kinase, which is specifically expressed in glutamatergic neurons, is required for the innate fear responses in the neonatal brain. We further reveal that EphB2 mediates coordination of spinogenesis and neuron activation in amygdala during the critical period for the innate fear. EphB2 catalytic activity plays a major role for the behavior upon EphB-ephrin-B3 binding and transnucleus neuronal connections. Our work thus indicates an essential synaptic molecular signaling within amygdala that controls synapse development and helps bring about innate fear emotions in the postnatal developing brain., (Copyright © 2016 the authors 0270-6474/16/3610151-12$15.00/0.)

Methamphetamine (METH) abuse is a serious social and health problem worldwide. At present, there are no effective medications to treat METH addiction. Here, we report that aggregated single-walled carbon nanotubes (aSWNTs) significantly inhibited METH self-administration, METH-induced conditioned place preference and METH- or cue-induced relapse to drug-seeking behaviour in mice. The use of aSWNTs alone did not significantly alter the mesolimbic dopamine system, whereas pretreatment with aSWNTs attenuated METH-induced increases in extracellular dopamine in the ventral striatum. Electrochemical assays suggest that aSWNTs facilitated dopamine oxidation. In addition, aSWNTs attenuated METH-induced increases in tyrosine hydroxylase or synaptic protein expression. These findings suggest that aSWNTs may have therapeutic effects for treatment of METH addiction by oxidation of METH-enhanced extracellular dopamine in the striatum.

Innate emotion response to environmental stimuli is a fundamental brain function that is controlled by specific neural circuits. Dysfunction of early emotional circuits may lead to neurodevelopmental disorders such as autism and schizophrenia. However, how the functional circuits are formed to prime initial emotional behaviours remain elusive. We reveal here using gene-targeted mutations an essential role for ephrin-B3 ligand-like activity in the development of innate fear in the neonatal brain. We further demonstrate that ephrin-B3 controls axon targeting and coordinates spinogenesis and neuronal activity within the amygdala. The morphological and behavioural abnormalities in ephrin-B3 mutant mice are rescued by conditional knock-in of wild-type ephrin-B3 during the critical period when axon targeting and fear responses are initiated. Our results thus define a key axonal molecule that participates in the wiring of amygdala circuits and helps bring about fear emotion during the important adolescence period.

The discovery of new natural compounds with pharmacological properties is an increasingly important field, and a continuous phytochemical investigation of the roots of Bupleurum chinense D.C. has led to the isolation of 17 triterpenoids, including three new oleanane triterpenes (1-3) together with 14 known ones. Their structures were determined on the basis of 1D and 2D NMR spectra as well as HR-ESI-MS data. The cytotoxicities of all compounds against five selected human cancer cell lines were assayed. Only compounds 9 and 14 exhibited moderate activities. Recently, a number of investigations have focused on the neuroprotective properties of triterpenoids in B. chinense. In order to expand our knowledge about this herb, the neuroprotective effects of compounds 1-17 against hydrogen peroxide (H2O2)-induced neuronal cell damage in human neuroblastoma SH-SY5Y cells were evaluated. Compounds 1-3, 6-7 showed significant neuroprotective effects against H2O2-induced SH-SY5Y cell death. Preliminary structure-activity relationships (SARs) between neuroprotective effects and the isolates were also discussed., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

G-protein-coupled receptors (GPCRs) are important targets of modern medicinal drugs. The accurate identification of interactions between GPCRs and drugs is of significant importance for both protein function annotations and drug discovery. In this paper, a new sequence-based predictor called TargetGDrug is designed and implemented for predicting GPCR-drug interactions. In TargetGDrug, the evolutionary feature of GPCR sequence and the wavelet-based molecular fingerprint feature of drug are integrated to form the combined feature of a GPCR-drug pair; then, the combined feature is fed to a trained random forest (RF) classifier to perform initial prediction; finally, a novel drug-association-matrix-based post-processing procedure is applied to reduce potential false positive or false negative of the initial prediction. Experimental results on benchmark datasets demonstrate the efficacy of the proposed method, and an improvement of 15% in the Matthews correlation coefficient (MCC) was observed over independent validation tests when compared with the most recently released sequence-based GPCR-drug interactions predictor. The implemented webserver, together with the datasets used in this study, is freely available for academic use at http://csbio.njust.edu.cn/bioinf/TargetGDrug., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Recently, the incidence and mortality of cancer has raised. More and more cytotoxic drugs and molecular targeted medicines have been used in clinic. However, most drugs just display a short-term anti- tumor effect. If patients received treatment for a long time, it would arise resistance to chemotherapy frequently. One of its important reasons is the accumulation of drug induced cancer cells. Thus, this paper emphasizes on biological character of drug induced cells, including cell biological phenotype, the change of gene and protein, variation of metabolism, dynamic change of signal transduction pathway and so on. Meanwhile, according to the characteristics of drug induced cells, we propose some strategies to inhibit drug induced cells, which would provide the foundation of clinical therapy and novel anti-tumor drug research and development.

Ethnopharmacological Relevance: Xiaochaihutang (XCHT), a famous Chinese herbal formula which consists of seven Chinese herbs, has been used clinically in depressive disorders in China. Our previous studies have demonstrated that XCHT improved depressive-like behavior in several animal models of depression. However, therapeutic basis of XCHT on depression are challenging, due to the complex active constituents of XCHT and the unclear pharmacological mechanism of action., Materials and Methods: To provide further insights into therapeutic basis of XCHT, the core in compatibility of XCHT on antidepressant therapy was assessed by the method of orthogonal array design. The comparative evaluations on antidepressant effects of XCHT and its core in compatibility were executed by tail suspension test (TST), forced swim test (FST), novelty suppressed feeding test (NSFT), reserpine-induced hypothermia and palpebral ptosis. Moreover, the potential mechanism was explored by investigating levels of monoamine neurotransmitters in hypothalamus and striatum and neurogenesis in hippocampus. Chemical profile of active constituents in plasma after oral administration of the core in compatibility of XCHT was revealed by ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS)., Results: The results of orthogonal array design experiment showed that Huangqin (Radix scutellariae), Renshen (Ginseng) and Gancao (Radix glycyrrhizae), defined as HRG, might be the core in compatibility of XCHT on antidepressant therapy. In accordance with XCHT, oral administration of HRG for 15 days significantly reduced immobility duration in TST and FST without affecting locomotor activity. Both HRG and XCHT increased immobility latency in FST, decreased the latency in NSFT, reversed reserpine-induced hypothermia and palpebral ptosis. Moreover, both HRG and XCHT significantly increased levels of 5-HT and DA in hypothalamus. In addition, HRG could remarkably increase Ki-67 and doublecortin (DCX) positive cells in hippocampus. A total 25 active constituents in plasma, including 14 prototype components and 11 metabolites, were identified by UPLC-MS/MS after oral administration of HRG., Conclusion: The present results reveal that HRG is supposed to be the core in compatibility of XCHT on antidepressant therapy. In accordance with XCHT, HRG exerts significant antidepressant-like effects, which are likely attributed to regulating serotonergic and dopaminergic systems and increasing hippocampal neurogenesis. The constituents identified in plasma after oral administration of HRG may be the potential active ingredients for the treatment of depression., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)