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Two series of novel NLRP3 inflammasome inhibitors are designed, synthesized, and evaluated in an effort to develop diversified analogs based on the N-(phenylcarbamoyl)benzenesulfonamide scaffold. SAR studies reveal that the sulfonylurea linker can tolerate chemical modifications with either simply changing over the position of carbonyl and sulfonyl group or structurally flexibly inserting a cyclopropyl group, leading to identification of several more potent and diversified NLRP3 antagonists (e.g., 9) with low nanomolar inhibitory activities. Further studies indicate that these two series of compounds with low cytotoxicity exhibited weak effects on the generation of NO and TNF-a. The findings may serve as good starting points for the development of more potent NLRP3 inflammasome inhibitors as valuable pharmacological probes or potential drug candidates.

It has been well documented that rumination has a negative effect on sleep quality. However, the mechanism underlying this effect remains unclear. This study investigated the negative effect of rumination on sleep quality mediated by negative affect and bedtime procrastination. In the current study, Pittsburgh Sleep Quality Index, Ruminative Responses Scale, Negative Experience Scale, and Bedtime Procrastination Scale were administered to a sample of 1103 college students recruited from an online survey platform, among whom 63% were female. Their age ranged from 17 to 31 with a mean of 20.17 (SD = 1.43). The results indicated that rumination had a significant positive effect on poor sleep quality mediated by negative affect (Effect = 0.10; 95% CI = 0.06, 0.14) and bedtime procrastination (Effect = 0.05; 95% CI = 0.03, 0.07) separately. Meanwhile, this effect could be serially mediated by the two mediators (Effect = 0.04, 95% CI: 0.02, 0.06). These findings suggest that, to improve the sleep quality of college students with high levels of rumination, interventions could be targeted at developing their adaptive emotion regulation strategies and behavioral self-regulation skills.

s Parkinson’s disease (PD) is the second most common progressive neurodegenerative disease worldwide. However, there is no available therapy reversing the neurodegenerative process of PD. Based on the loss of dopamine or dopaminergic dysfunction in PD patients, most of the current therapies focus on symptomatic relief to improve patient quality of life. As dopamine replacement treatment remains the most effective symptomatic pharmacotherapy for PD, herein we provide an overview of the current pharmacotherapies, summarize the clinical development status of novel dopaminergic agents, and highlight the challenge and opportunity of emerging preclinical dopaminergic approaches aimed at managing the features and progression of PD.

Objective The purpose of this review was to evaluate the effectiveness of Qigong in improving the quality of life and relieving fatigue, sleep disturbance, and cancer-related emotional disturbances (distress, depression, and anxiety) in women with breast cancer. Methods The PubMed, Cochrane Central Register of Controlled Trials, Web of Science, Sinomed, Wanfang, VIP, and China National Knowledge Infrastructure databases were searched from their inceptions to March 2020 for controlled clinical trials. Two reviewers selected relevant trials that assessed the benefit of Qigong for breast cancer patients independently. A methodological quality assessment was conducted according to the criteria of the 12 Cochrane Back Review Group for risk of bias independently. A meta-analysis was performed by Review Manager 5.3. Results This review consisted of 17 trials, in which 1236 cases were enrolled. The quality of the included trials was generally low, as only five of them were rated high quality. The results showed significant effectiveness of Qigong on quality of life (n = 950, standardized mean difference (SMD), 0.65, 95 % confidence interval (CI) 0.23–1.08, P = 0.002). Depression (n = 540, SMD = −0.32, 95 % CI −0.59 to −0.04, P = 0.02) and anxiety (n = 439, SMD = −0.71, 95 % CI −1.32 to −0.10, P = 0.02) were also significantly relieved in the Qigong group. There was no significant benefit on fatigue (n = 401, SMD = −0.32, 95 % CI 0.71 to 0.07, P = 0.11) or sleep disturbance relief compared to that observed in the control group (n = 298, SMD = −0.11, 95 % CI 0.74 to 0.52, P = 0.73). Conclusion This review shows that Qigong is beneficial for improving quality of lifeand relieving depression and anxiety; thus, Qigong should be encouraged in women with breast cancer.

The 5-HT2C receptor has emerged as a promising target in the treatment of a variety of central nervous system disorders. We have first identified aporphines as a new class of 5-HT2C receptor agonists. Structure-activity relationship results indicate that the aporphine core may be required for 5-HT2C receptor activity, and substitutions at its C1 position are important for 5-HT2C receptor activity. Our efforts to optimize our hit 15781 lead to the identification of the highly potent and selective 5-HT2C agonist 18b (MQ02-439) with an EC50 value of 104 nM and weak antagonism at the 5-HT2A and 5-HT2B receptors. The findings may serve as good starting points for the development of more potent and selective 5-HT2C agonists as valuable pharmacological tools or potential drug candidates.

Subtype selectivity and functional bias are vital in current drug discovery for G protein-coupled receptors (GPCRs) as selective and biased ligands are expected to yield drug leads with optimal on-target benefits and minimal side-effects. However, structure-based design and medicinal chemistry exploration remain challenging in part because of highly conserved binding pockets within subfamilies. Herein, we present an affinity mass spectrometry approach for screening herbal extracts to identify active ligands of a GPCR, the 5-HT2C receptor. Using this method, we discovered a naturally occurring aporphine 1857 that displayed strong selectivity for activating 5-HT2C without activating the 5-HT2A or 5-HT2B receptors. Remarkably, this novel ligand exhibited exclusive bias toward G protein signaling for which key residues were identified, and it showed comparable in vivo efficacy for food intake suppression and weight loss as the antiobesity drug, lorcaserin. Our study establishes an efficient approach to discovering novel GPCR ligands by exploring the largely untapped chemical space of natural products.

Background: Chemoresistance blunts the therapeutic effect of cisplatin (DDP) on Triple-Negative Breast Cancer (TNBC). Researchers have not determined to date whether exosomes confer DDP resistance to other breast cancer cells or whether exosomal transfer of miRNAs derived from DDP-resistant TNBC cells confer DDP resistance. Objective: The aim of this study was to investigate the role of exosomes in chemoresistance in breast cancer. Methods: MDA-MB-231 cells resistant to DDP (231/DDP) were established. Exosomes were isolated from 231/DDP cells (DDP/EXO) and characterized by measuring the levels of protein markers, nanoparticle tracking analysis and transmission electron microscopy. MDA-MB-231, MCF-7 and SKBR-3 cell lines were treated with the isolated DDP/EXOs and cell proliferation and cytotoxicity to DDP were evaluated using MTT assays and apoptosis analyses. Western blotting was used to examine P-glycoprotein (P-gp) expression. Additionally, a microarray was used to analyse microRNA (miRNA) expression profiles in MDA-MB-231 and 231/DDP exosomes. The effects on miRNAs were determined using RT-PCR. Exosomal miR-423-5p was extracted, and differential expression was verified. The MTT cell viability assay, flow cytometry, and Transwell and immunofluorescence assays were performed to determine if differential expression of miR-423-5p sensitized cells to DDP in vitro. Results: Under a transmission electron microscope, the isolated exosomes exhibited a round or oval shape with a diameter ranging between 40 and 100 nm. DDP/EXOs labelled with PKH67 were taken up by MDA-MB-231 cells. After an incubation with DDP/EXOs, the cell lines exhibited a higher IC50 value for cisplatin, P-gp expression, migration and invasion capabilities and a lower apoptosis rate. Furthermore, 60 miRNAs from exosomes derived from 231/DDP cells were significantly up-regulated compared to exosomes from MDA-MB-231 cells. Notably, compared to the corresponding sensitive exosomes, miR-370-3p, miR-423-5p and miR-373 were the most differentially expressed miRNAs in DDP-resistant exosomes. We chose miR-423-5p, and up-regulation and down-regulation of exosomal miR-423-5p expression significantly affected DDP resistance. Conclusions: Exosomes from DDP-resistant TNBC cells (231/DDP) altered the sensitivity of other breast cancer cells to DDP in an exosomal miR-423-5p dependent manner. Our research helps to elucidate the mechanism of DDP resistance in breast cancer.

A series of substituted 4,6-dihydrospiro[[1,2,3]triazolo[4,5-b]pyridine-7,3'-indoline]-2',5(3H)-dione analogues were synthesized and evaluated as potent dengue virus inhibitors. Throughout a structure-activity relationship exploration on the amide of the indolone moiety, a wide range of substitutions were found to be well tolerated for chemical optimization at this position. Among these compounds, 15 (JMX0254) displayed the most potent and broad inhibitory activities, effective against DENV-1 to -3 with EC50 values of 0.78, 0.16, and 0.035 μM, respectively, while compounds 16, 21, 27-29, 47, and 70 exhibited relatively moderate to high activities with low micromolar to nanomolar potency against all four serotypes. The biotinylated compound 73 enriched NS4B protein from cell lysates in pull-down studies, and the findings together with the mutation investigations further validated dengue NS4B protein as the target of this class of compounds. More importantly, compound 15 exhibited good in vivo pharmacokinetic properties and efficacy in the A129 mouse model, indicating its therapeutic potential against the dengue virus infection as a drug candidate for further preclinical development.

Peripheral inflammation produces a long-lasting latent sensitization of spinal nociceptive neurons, that is, masked by tonic inhibitory controls. We explored mechanisms of latent sensitization with an established four-step approach: (1) induction of inflammation; (2) allow pain hypersensitivity to resolve; (3) interrogate latent sensitization with a channel blocker, mutant mouse, or receptor antagonist; and (4) disrupt compensatory inhibition with a receptor antagonist so as to reinstate pain hypersensitivity. We found that the neuropeptide Y Y1 receptor antagonist BIBO3304 reinstated pain hypersensitivity, indicative of an unmasking of latent sensitization. BIBO3304-evoked reinstatement was not observed in AC1 knockout mice and was prevented with intrathecal co-administration of a pharmacological blocker to the N-methyl-D-aspartate receptor (NMDAR), adenylyl cyclase type 1 (AC1), protein kinase A (PKA), transient receptor potential cation channel A1 (TRPA1), channel V1 (TRPV1), or exchange protein activated by cAMP (Epac1 or Epac2). A PKA activator evoked both pain reinstatement and touch-evoked pERK expression in dorsal horn; the former was prevented with intrathecal co-administration of a TRPA1 or TRPV1 blocker. An Epac activator also evoked pain reinstatement and pERK expression. We conclude that PKA and Epac are sufficient to maintain long-lasting latent sensitization of dorsal horn neurons that is kept in remission by the NPY-Y1 receptor system. Furthermore, we have identified and characterized 2 novel molecular signaling pathways in the dorsal horn that drive latent sensitization in the setting of chronic inflammatory pain: NMDAR→AC1→PKA→TRPA1/V1 and NMDAR→AC1→Epac1/2. New treatments for chronic inflammatory pain might either increase endogenous NPY analgesia or inhibit AC1, PKA, or Epac.

Background Professor Xinfang Wang first introduced the clinical application of trans nose pharynx esophagus echocardiography (TNPEE) in 2014. Subsequently, we developed the technology. In the present study we assess the feasibility of TNPEE in the ultrasonic diagnosis. Methods Select patients suitable for TNPEE examination. After obtaining written consent of patients or their families, oral dacronin hydrochloride gel local anesthesia was given 10–15 min before examination. The nostrils were disinfected and then smeared with tetracaine hydrochloride gel, which acted as local anesthesia and lubrication. The probe was inserted gently through the nostrils and entered the esophagus through the nasal cavity and pharynx. TNPEE is similar to transoral esophagus echocardiography (TOEE) after the probe reaches the esophagus. Results TNPEE was performed in 103 patients. Forty-five patients (43.7%) underwent the examination successfully, 46 patients (44.7%) failed because of objective reasons, 12 patients midway refused to accept the examination and cancelled the examination, accounting for 11.6%, 11 patients (12.1%) suffered from epistaxis. Of all the patients with epistaxis, 9 had taken anticoagulant drugs, accounting for 82% of the patients with epistaxis. The vital signs of all patients were stable and no serious complications occurred. Conclusion Compared with TOEE, TNPEE can cause less nausea and vomiting reaction, and patients take longer time to undergo examination, which is conducive to more detailed examination. However, TNPEE has a high requirement for the probe, and its success rate is relatively low. It is easy to cause nasal bleeding in patients, so its wide clinical application is limited.

KRAS plays an essential role in regulating cell proliferation, differentiation, migration and survival. Mutated KRAS is a major driver of malignant transformation in multiple human cancers. We showed previously that fendiline (6) is an effective inhibitor of KRAS plasma membrane (PM) localization and function. In this study, we designed, synthesized and evaluated a series of new fendiline analogs to optimize its drug properties. Systemic structure-activity relationship studies by scaffold repurposing led to the discovery of several more active KRAS PM localization inhibitors such as compounds 12f (NY0244), 12h (NY0331) and 22 (NY0335) which exhibit nanomolar potencies. These compounds inhibited oncogenic KRAS-driven cancer cell proliferation at single-digit micromolar concentrations in vitro. In vivo studies in a xenograft model of pancreatic cancer revealed that 12h and 22 suppressed oncogenic KRAS-expressing MiaPaCa-2 tumor growth at a low dose range of 1–5 mg/kg with no vasodilatory effects, indicating their potential as chemical probes and anticancer therapeutics.

This investigation attempted to discern whether formononetin restrained progression of triple-negative breast cancer (TNBC) by blocking lncRNA AFAP1-AS1-miR-195/miR-545 axis. We prepared TNBC cell lines (i.e. MDA-MB-231 and BT-549) and normal human mammary epithelial cell line (i.e. MCF-10A) in advance, and the TNBC cell lines were, respectively, transfected by pcDNA3.1-lncRNA AFAP1-AS1, si-lncRNA AFAP1-AS1, pcDNA6.2/GW/EmGFP-miR-545 or pcDNA6.2/GW/EmGFP-miR-195. Resistance of TNBC cells in response to 5-Fu, adriamycin, paclitaxel and cisplatin was evaluated through MTT assay, while potentials of TNBC cells in proliferation, migration and invasion were assessed via CCK8 assay and Transwell assay. Consequently, silencing of lncRNA AFAP1-AS1 impaired chemo-resistance, proliferation, migration and invasion of TNBC cells (P

The sigma-1 (σ1) receptor, an enigmatic protein originally classified as an opioid receptor subtype, is now understood to possess unique structural and functional features of its own and play critical roles to widely impact signaling transduction by interacting with receptors, ion channels, lipids, and kinases. The σ1 receptor is implicated in modulating learning, memory, emotion, sensory systems, neuronal development, and cognition and accordingly is now an actively pursued drug target for various neurological and neuropsychiatric disorders. Evaluation of the five selective σ1 receptor drug candidates (pridopidine, ANAVEX2-73, SA4503, S1RA, and T-817MA) that have entered clinical trials has shown that reaching clinical approval remains an evasive and important goal. This review provides up-to-date information on the selective targeting of σ1 receptors, including their history, function, reported crystal structures, and roles in neurological diseases, as well as a useful collation of new chemical entities as σ1 selective orthosteric ligands or allosteric modulators.

Background: Non-linguistic cognitive training has been suggested to improve the communication skills of patients with post-stroke aphasia (PSA). However, the association between language and non-linguistic cognitive functions is not fully understood. In this study, we used the Loewenstein Occupational Therapy Cognitive Assessment (LOTCA) to evaluate the characteristics of non-linguistic cognitive impairments in Chinese PSA patients.Methods: A total of 86 stroke patients were recruited in this study. Language and non-linguistic cognitive impairments were evaluated by the Western Aphasia Battery (WAB) and LOTCA, respectively. The patients were divided into two groups (PSA and non-PSA), and the Chinese norm (the data came from 44 Chinese individuals without neurological disorders in a previous study) was used as the control group. The LOTCA scores were compared among the three groups. Patients in the PSA group were subdivided into the fluent aphasia group (FAG) and the non-FAG according to the Chinese aphasia fluency characteristic scale. The LOTCA scores were also compared between the PSA subdivisions. Potential confounders were adjusted in the analysis of covariance. Partial correlation analysis between the subscores of WAB and LOTCA was also performed.Results: The total LOTCA scores in the PSA group (75.11 ± 17.08) were significantly lower compared with scores in the non-PSA (96.80 ± 7.75, P < 0.001) and the control group (97.65 ± 16.24, P < 0.001). The PSA group also had lower orientation, visual perception (VP), spatial perception (SP), visuomotor organization, thinking operation, and attention scores. The total LOTCA, orientation, VP, SP, and MP scores were lower in the non-FAG (69.24 ± 18.06, 8.62 ± 5.09, 12.76 ± 2.47, 7.48 ± 3.01, and 9.62 ± 2.25, respectively) compared with the FAG (80.36 ± 14.07, 12.14 ± 3.99, 14.09 ± 1.93, 9.68 ± 3.01, 10.55 ± 1.63, respectively, P's < 0.05). The aphasia quotient was positively correlated with the total score of LOTCA and scores of orientation, VP, SP, and MP (r = 0.710, 0.744, 0.565, 0.597, and 0.616; P < 0.001).Conclusion: Compared with stroke patients without aphasia, patients with PSA often have more extensive and serious non-linguistic cognitive impairments. Patients with non-fluent aphasia often present with serious cognitive impairments than those with fluent aphasia, especially the impairments of orientation and SP. Non-linguistic cognitive impairments correlate with language impairments in aphasia.

Background and aimsNumerous studies have shown that people who have Internet addiction (IA) are more likely to experience poor sleep quality than people who do not. However, few studies have explored mechanisms underlying the relation between IA and poor sleep quality. As a first attempt to address this knowledge gap, a cross-sectional design was applied, and structural equation modeling was used to explore the direct relationship between IA and poor sleep quality, as well as the potential mediating roles of rumination and bedtime procrastination.MethodsA convenience sample, consisting of 1,104 Chinese University students (696 females or 63%), completed an online survey that included the following measures: Young’s 8-item Internet Addiction Diagnosis Questionnaire, the Pittsburgh Sleep Quality Index, the Ruminative Responses Scale, and the Bedtime Procrastination Scale.ResultsWhile the direct path between IA and poor sleep quality was not found to be significant, rumination and bedtime procrastination were each shown to separately mediate the predictive effect of IA on poor sleep quality. However, the greatest level of support was found for the sequential mediating effects of rumination and bedtime procrastination between IA and poor sleep quality.ConclusionWhile rumination and bedtime procrastination were both shown to be important independent mediators for the relation between IA and poor sleep quality, their combined effect was as great as either alone.

The study investigated the level of contamination by total aerobic bacteria, coliform bacteria and food poisoning bacteria in commercial spices for the evaluation of microbiological safety. A total of 119 commercial spices was used for this study. The total aerobic bacterial count was 6.2 log CFU/g in HACCP certificated spices and 5.4 log CFU/g in HACCP non-certificated spices. Coliform bacteria were detected in 13 (35.1%) out of 37 HACCP certificated spices and 27 (32.9%) out of 82 HACCP non-certificated spices. Bacillus cereus was detected in 7 (18.9%) out of 37 HACCP certificated spices and 10 (11.8%) out of 82 non-certificated spices. All the B. cereus detected in this study possessed at least one toxin gene, and hemolysin BL enterotoxin was detected in 9 (52.9%) out of 17 B. cereus isolates. Overall, these results indicated that contamination with total aerobic bacteria was higher in HACCP certified spices, with more coliform bacteria and B. cereus detected, than in non-certificated spices. Hence, it is necessary to refine the HACCP system and introduce good agricultural practices for the improvement of microbiological safety of spices.

Background Platinum-based drugs are used extensively in neoadjuvant chemotherapy for triple-negative breast cancer (TNBC), but their use can be limited by resistance. In this study, we established cisplatin (DDP) resistant TNBC cells to investigate the potential relationship among ETS1, IKKα/NF-κB and resistance. Methods The sensitivity was evaluated by MTT, apoptosis analysis. The intracellular DDP concentration difference was tested by inductively coupled plasma mass spectrometry (ICP-MS) method. Molecular pathological mechanism of DDP resistance was explored by microarray analysis and PPI network analysis. The ETS1, NF-κB signaling change were assessed by western blot and q-PCR in vitro and vivo. The existing binds between ETS1 and the core IKKα promoter were found by luciferase assay and chromatin immunoprecipitation technique (ChIP). Results MDA-MB-231/DDP (231/DDP) cell had a higher IC50 value of cisplatin, lower intracellular DDP concentration, and lower apoptosis ratio than MDA-MB-231 (231/wt) cell line treated with DDP. Increased ABC transporters were induced by the activation of NF-κB pathway in 231/DDP cells. ETS1, RPL6, RBBP8, BIRC2, PIK3A and RARS were six important genes for DDP-resistance based on PPI network and expression validation. Protein expression of ETS1 and IKKα were significantly up-regulated in 231/DDP cells. However, inhibition of ETS1 expression enhances chemo-sensitivity to DDP and reversed the activation of NF-κB pathway in 231/DDP cells and subcutaneous transplantation tumor in vivo. Moreover, there is existing binds between ETS1 and the core IKKα promoter though luciferase assay and ChIP. Conclusion This study enables us to understand the functions of ETS1 in TNBC chemotherapy and suggests that ETS1 could be used as a novel marker of poor response to DDP and a potential therapeutic target for TNBC chemotherapy.

Lack of targeted strategies for preventing and treating estrogen receptor (ER)-negative breast cancer (ENBC) is an unmet clinical challenge. ENBCs including triple-negative BCs (TNBC) constitute 30-40% of BC cases and are prone to develop remote metastasis and local recurrence, resulting in the majority of deaths in BC patients. Dysregulated glucose and energy metabolism is critically involved in the development and progression of various cancers via promoting aberrant cell growth, malignant transformation and metastasis. Nevertheless, the potential role of glucose/energy metabolism in ENBC carcinogenesis has sparsely been explored, thus representing a key knowledge gap and a potential avenue for effective targeted therapies. Despite a substantial amount of effort has been made towards anticancer metabolic and biogenetic medications, none has progressed into clinical use, due to their limited potency, specificity or drug properties such as toxicity and poor bioavailability. We recently developed HJC0152, a novel small molecule anticancer agent, using structure- and fragment-based drug design strategies and molecular modeling techniques in our initial attempt to develop non-peptide STAT3 inhibitors for anticancer use. HJC0152 significantly inhibits proliferation of BC cells, induces apoptosis, reduces ER-negative mammary tumor development, suppresses ENBC xenograft tumor growth, and blocks lung metastasis in vivo. Intriguingly, HJC0152 differentially modulates expression of glycolytic enzymes including HK1, PFK-L, PFKFB2, ENO2, PDH, PDK1, PGAM1 and ALDOA in a time-dependent manner. HJC0152 also regulates the transcription of genes involved in glucose and mitochondrial energy metabolism, including the subunits of mitochondrial respiratory chain complexes. Functional assessments further demonstrate that HJC0152 significantly modulates respiratory chain complex function. Via in silico and Unique Polymer Technology (UPT) strategy, we identified a number of putative HJC0152-interacting targets for validation studies. Our findings suggest that HJC0152 is capable of reprogramming/restoring the dysregulated glucose metabolism by inducing specific glycolytic enzyme expression and mitochondrial respiratory chain function, likely via targeting upstream key signal molecule(s) that regulates glucose and energy metabolism, thereby suppressing breast cancer development and progression to metastasis. This work was supported by Grants P50 CA097007, and P30DA028821 (JZ) from the NIH, CPRIT (JZ), John Sealy Memorial Endowment Fund (JZ), DFI Grants from MD Anderson Cancer Center (QS), Holden Family Research Grant in BC Prevention (QS), and NCI PREVENT Program HHSN26100002 (QS). Citation Format: Dong J, Kim H, Xu J, Li D, Zhang Z, Zheng Z, Ye N, Chen H, Zhou J, Shen Q. Suppression of breast carcinogenesis and metastasis by targeting glucose metabolism with HJC0152 [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-21-19.

In this study, twenty novel cinnamic acid magnolol derivatives were synthesized, and screened for their anti-hyperglycemic potential. All synthesized compounds exhibited good to moderate α-glucosidase and α-amylase inhibitory activities with IC50 values: 5.11 ± 1.46–90.26 ± 1.85 µM and 4.27 ± 1.51–49.28 ± 2.54 µM as compared to the standard acarbose (IC50: 255.44 ± 1.89 μM and 80.33 ± 2.95 μM, respectively). Compound 6j showed the strongest inhibitory activity against α-glucosidase (IC50 = 5.11 ± 1.46 µM) and α-amylase (IC50 = 4.27 ± 1.51 µM). Kinetic study indicated that compound 6j was reversible and a mixed type inhibitor against α-glucosidase and α-amylase. In silico studies revealed the binding interaction between 6j and two enzymes, respectively. Finally, cells cytotoxicity assay revealed that compound 6j showed low toxicity against 3 T3-L1 cells and HepG2 cells.

An effective therapy for human adenovirus (HAdV) infections in immunocompromised patients and healthy individuals with community-acquired pneumonia remains an unmet medical need. We herein reported a series of novel substituted N-(4-amino-2-chlorophenyl)-5-chloro-2-hydroxybenzamide analogues as potent HAdV inhibitors. Compounds 6, 15, 29, 40, 43, 46, 47, and 54 exhibited increased selectivity indexes (SI > 100) compared to the lead compound niclosamide, while maintaining sub-micromolar to low micromolar potency against HAdV. The preliminary mechanistic studies indicated that compounds 6 and 43 possibly target the HAdV DNA replication process, while compounds 46 and 47 suppress later steps of HAdV life cycle. Notably, among these derivatives, compound 15 showed improved anti-HAdV activity (IC50 = 0.27 μM), significantly decreased cytotoxicity (CC50 = 156.8 μM), and low in vivo toxicity (maximum tolerated dose = 150 mg/kg in hamster) as compared with niclosamide, supporting its further in vivo efficacy studies for the treatment of HAdV infections., This work was supported by UTMB Technology Commercialization Program, John Sealy Memorial Endowment Fund, and Institute for Translational Sciences (ITS) at UTMB, Plan Nacional de I + D + i 2013–2016 and Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Economía, Industria y Competitividad, Spanish Network for Research in Infectious Diseases (REIPI RD16/0016/0009), co-financed by European Development Regional Fund “A way to achieve Europe”, Operative program Intelligent Growth 20142020, the Instituto de Salud Carlos III, Proyectos de Investigación en Salud (PI17/01055; PI18/01191) and Proyectos de Desarrollo Tecnológico en Salud (DTS17/00130), the Spanish Adenovirus Network (AdenoNet, BIO2015/68990-REDT), and the program “Nicolás Monardes” (C-0059-2018), Servicio Andaluz de Salud, Junta de Andalucía. J.Z. is also partially supported by John D. Stobo, M.D., Distinguished Chair Endowment Fund at UTMB. M.E.P.I. is a postdoctoral researcher belonging to the program “Nicolás Monardes” (C1-0038-2019), Servicio Andaluz de Salud, Junta de Andalucía, Spain.

Subtype selectivity and functional bias are vital in current drug discovery for G protein-coupled receptors (GPCRs) as selective and biased ligands are expected to yield drug leads with optimal on-target benefits and minimal side-effects. However, structure-based design and medicinal chemistry exploration remain challenging in part because of highly conserved binding pockets within subfamilies. Herein, we present an affinity mass spectrometry approach for screening herbal extracts to identify active ligands of a GPCR, the 5-HT2C receptor. Using this method, we discovered a naturally occurring aporphine 1857 that displayed strong selectivity for activating 5-HT2C without activating the 5-HT2A or 5-HT2B receptors. Remarkably, this novel ligand exhibited exclusive bias towards G protein signaling for which key residues were identified, and it showed comparable in vivo efficacy for food intake suppression and weight loss as the anti-obesity drug, lorcaserin. Our study establishes an efficient approach to discovering novel GPCR ligands by exploring the largely untapped chemical space of natural products.

Background Abnormally expressed long non-coding RNA (lncRNA) is associated with the development of breast cancer and multidrug resistance. However, the molecular mechanism by which lncRNA regulates cisplatin (DDP) in triple-negative breast cancer (TNBC) remains unclear. Methods DDP resistant cell line MDA-MB-231/DDP was established by gradually increasing doses of DDP. Abnormal expression of lncRNA between MDA-MB-231 and MDA-MB-231/DDP was evaluated with microarray. In addition, cell proliferation was evaluated by CCK-8 and Ki67 assays. Furthermore, cell apoptosis was evaluated by cell apoptosis and TUNEL assays. Western blotting assay was used to detect the protein expression. In vivo animal study was performed finally. Results HCP5 were significantly decreased in MDA-MB-231/DDP cells compared with MDA-MB-231 cells. Downregulation of HCP5 promoted DDP resistance in MDA-MB-231 cells by inhibiting PTEN expression. In contrast, overexpression of HCP5 reversed DDP resistance in MDA-MB-231/DDP cells by upregulating PTEN. In vivo experiments confirmed that overexpression of HCP5 inhibited DDP resistance in TNBC xenograft. Conclusion We found that downregulation of HCP5 contributed to DDP resistance in TNBC, while overexpression of HCP5 reversed the resistance via upregulating PTEN level. Therefore, DDP combined with overexpression of HCP5 might be considered as a therapeutic approach for the treatment of DDP-resistant TNBC.

Introduction The traditional treatment of myocardial infarction with ventricular septal rupture is surgical treatment. For the elderly patients with cardiac insufficiency, surgical treatment is very risky. The successful treatment of this case by interventional occlusion is a new method. No relevant literature reports have been found. Case A 77-year-old man with a past medical history of old myocardial infarction presented to the physician with sudden onset of palpitation and shortness of breath. Echocardiography showed thinning of the interventricular septum near the apex and bulging toward the right ventricular side with “paradoxical motion”, on which a rupture of about 8 mm in diameter was seen. CDFI: left ventricular blood shunted to the right ventricle through the rupture.Echocardiographic diagnosis: old left ventricular anteroseptal myocardial infarction with ventricular septal rupture. Due to the older age of the patient and reduced left ventricular function, surgical repair of the ventricular septal rupture site was more difficult. After multidisciplinary discussion, it was agreed that the patient could not afford thoracotomy and was not suitable for thoracotomy, and echocardiography guided interventional occlusion of the ruptured interventricular septum could be performed. Conclusion Transesophageal echocardiography-guided interventional occlusion of myocardial infarction with ventricular septal rupture in elderly patients with cardiac insufficiency is a new attempt, the successful treatment of this case shows that this method is feasible, for some patients is an appropriate treatment.

Stroke is a life-threatening disease that results in significant disability in the human population. Despite the advances in current stroke therapies, a host of patients do not benefit from the conventional treatments. Thus, more effective therapies are required. It has been previously reported that leucine-rich-α2-glycoprotein 1 (LRG1) is crucial during the formation of new blood vessels in retinal diseases. However, the function of LRG1 in the brain during the neovessel growth process following ischemic stroke has not been fully elucidated and the mechanism underlying its effect on angiogenesis remains unclear. The purpose of the current study was to demonstrate whether LRG1 may promote angiogenesis through the transforming growth factor (TGF)-β1 signaling pathway in ischemic rat brain following middle cerebral artery occlusion (MCAO). In the present study, the spatial and temporal expression of LRG1, TGF-β1, vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang-2) were detected in ischemic rat brain following MCAO using reverse transcription-quantitative polymerase chain reaction (RT-qPCR), western blot analysis and immunohistochemistry. CD34 immunohistochemistry staining was used as an indicator of microvessel density (MVD). The RT-qPCR and western blotting results revealed that the levels of LRG1 and TGF-β1 mRNA and protein expression were significantly increased as early as 6 and 12 h after MCAO (P

Objective Azathioprine (AZA) is widely used in Crohn's disease (CD) patients with a recommended dose, 2-2.5 mg/kg/d, for Westerners. Asian patients are suggested with a lower dose. However, many clinicians reported a poor efficacy with a reduced dose. Our prospective study aims to find a safe dose providing the best efficacy for Chinese CD patients. Methods Fifty active Chinese CD patients were enrolled in our test and randomly split into 2 groups, 25 each. All other treatments were the same except that group A took 1 mg/kg/d and group B took 2 mg/kg/d of AZA. We analysed the complete remission (CR) rate and the response rate on week 12, 24, 48 and with the method of intent-to-treat (ITT) and Per-Protocol (PP) analysis to evaluate the efficacy. Meantime, we evaluated the adverse events and the recurrence rate in both groups. Results On week 48, the CR rate and response rate in group B (ITT: 50.0% and 59.1%; PP: 57.9% and 68.4%) were significantly higher than those in group A (ITT: 13.0% and 17.4%; PP: 16.7% and 22.2%) (P

Overexpression of B cell lymphoma 2 (Bcl-2) proteins is associated with therapy resistance in various human cancers. Traditional approaches target the Bcl-2 homology (BH)3 domain of Bcl-2; however, the BH4 domain represents a superior therapeutic target in light of its unique structure and crucial involvement in many cellular functions. In this critical review, we focus on the structural and functional basis of targeting the BH4 domain of Bcl-2, and highlight the recent advances in drug discovery efforts toward small-molecule BH4 domain inhibitors (e.g. BDA-366). The proof-of-concept studies support the hypothesis that targeting the BH4 domain of Bcl-2 holds promise to offer a novel anticancer therapy through the induction of apoptosis and an increased potential to overcome therapeutic resistance.

The effective treatment for dengue virus infection continues to be a challenge. We herein reported our continued SAR exploration on the spiropyrazolopyridone scaffold. Introducing different substituents at the 3´- or 5´-site of the pyrazolopyridone core or moving the benzyl chain to the adjacent nitrogen led to a significant loss of potency on DENV-2. While a narrow range of substitutions were tolerated at the para-position of the phenyl ring, di-substitution on the phenyl ring is beneficial for DENV-2 potency and has variable influences on DENV-3 potency depending on the exact compound. Among these molecules, compounds 22 (JMX0376) with 4-chloro-3-fluorobenzyl and 24 (JMX0395) with 2,4-bis(trifluoromethyl)benzyl showed the most potent and broadest inhibitory activities against DENV-1 to -3 with nanomolar to low micromolar EC(50) values.

Obesity is a growing public health concern, with 37.5% of the adult population in need of therapeutics that are more efficacious with a better side effect profile. An innovative target in this regard is neuromedin U, a neuropeptide shown to suppress food intake and attenuate weight gain in animal models. These effects of neuromedin U on feeding behavior are thought to be related to agonism at the centrally expressed neuromedin U receptor 2 (NMUR2). As peptides present unique challenges that limit their therapeutic potential, the discovery of small‐molecule NMUR2 agonists is needed to validate the targets therapeutic value, but to date, none have been evaluated in any animal model of disease. We therefore assessed two small‐molecule NMUR2 agonists for their in vitro signaling and their in vivo efficacy. The NMUR2 agonists were synthesized and both NMUR2 agonists, NY0116 and NY0128, decreased cAMP while stimulating calcium signaling in stably expressing NMUR2 HEK293 cells. When small‐molecule NMUR2 agonists were tested in vivo, acute administration significantly decreased high‐fat diet consumption. Repeated administration of the compounds decreased body weight and more specifically, decreased the percentage of visceral adipose tissue (VAT) in obese mice. These results have confirmed small‐molecule NMUR2 agonists are efficacious in animal models to decrease fat content, food intake, and body weight, suggesting NMUR2 is a promising therapeutic target for metabolic disorders.

Bax, a central cell death regulator, is an indispensable gateway to mitochondrial dysfunction and a major proapoptotic member of the B-cell lymphoma 2 (Bcl-2) family proteins that control apoptosis in normal and cancer cells. Dysfunction of apoptosis renders the cancer cell resistant to treatment as well as promotes tumorigenesis. Bax activation induces mitochondrial membrane permeabilization, thereby leading to the release of apoptotic factor cytochrome c and consequently cancer cell death. A number of drugs in clinical use are known to indirectly activate Bax. Intriguingly, recent efforts demonstrate that Bax can serve as a promising direct target for small-molecule drug discovery. Several direct Bax activators have been identified to hold promise for cancer therapy with the advantages of specificity and the potential of overcoming chemo- and radioresistance. Further investigation of this new class of drug candidates will be needed to advance them into the clinic as a novel means to treat cancer.

Honokiol, as a pharmacological active small-molecule, has received significant attention for its strong pharmacological effects without remarkable toxicity. However, the metabolites of honokiol in the small intestine, one of the most important extrahepatic sites of drug biotransformation, are unknown. In this article, a method of 13C stable isotope labeling followed by ultra-high performance liquid chromatography/quadrupole time-of-flight tandem mass spectrometry (UHPLC/Q-TOF-MS) was applied to identify the metabolites of honokiol in rat small intestines. According to the unique isotopic patterns of two peaks with similar intensities and a ratio of nearly 1 : 1, and molecular weight difference of 6 Da between honokiol and 13C-labeled honokiol, a total of 20 metabolites were observed and tentatively characterized in the small intestine. Eight of these were reported for the first time. All of them were phase II metabolites and divided into sulfates, amino acid conjugates and glucuronide metabolites. This study, combined with a previously reported paper about honokiol metabolites in rat feces, plasma and urine, will benefit further studies of the metabolism and mechanism of action of honokiol in vivo.

Exchange proteins directly activated by cAMP (EPACs) are critical cAMP-dependent signaling pathway mediators that play important roles in cancer, diabetes, heart failure, inflammations, infections, neurological disorders and other human diseases. EPAC specific modulators are urgently needed to explore EPAC's physiological function, mechanism of action and therapeutic applications. On the basis of a previously identified EPAC specific inhibitor hit ESI-09, herein we have designed and synthesized a novel series of 2-substituted phenyl-N-phenyl-2-oxoacetohydrazonoyl cyanides as potent EPAC inhibitors. Compound 31 (ZL0524) has been discovered as the most potent EPAC inhibitor with IC50 values of 3.6 µM and 1.2 µM against EPAC1 and EPAC2, respectively. Molecular docking of 31 onto an active EPAC2 structure predicts that 31 occupies the hydrophobic pocket in cAMP binding domain (CBD) and also opens up new space leading to the solvent region. These findings provide inspirations for discovering next generation of EPAC inhibitors.

Background/Aims: Cell surface morphology plays pivotal roles in malignant progression and epithelial-mesenchymal transition (EMT). Previous research demonstrated that microvilli play a key role in cell migration of non-small cell lung cancer (NSCLC). In this study, we report that Forkhead box class O1 (FOXO1) is downregulated in human NSCLC and that silencing of FOXO1 is associated with the invasive stage of tumor progression. Methods: The cell proliferation, migration, and invasion were characterized in vitro, and we tested the expression of the Epithelial-mesenchymal transition (EMT) marker by immunofluorescence staining and also identified the effect of FOXO1 on the microvilli by scanning electron microscopy (SEM). Results: Functional analyses revealed that silencing of FOXO1 resulted in an increase in NSCLC cell proliferation, migration, and invasion; whereas overexpression of FOXO1 significantly inhibited the migration and invasive capability of NSCLC cells in vitro. Furthermore, cell morphology imaging showed that FOXO1 maintained the characteristics of epithelial cells. Immunofluorescence staining and western blotting showed that the E-cadherin level was elevated and Vimentin was reduced by FOXO1 overexpression. Conversely, the E-cadherin level was reduced and Vimentin was elevated in cells silenced for FOXO1. Furthermore, scanning electron microscopy (SEM) showed that FOXO1 overexpression increased the length of the microvilli on the cell surface, whereas FOXO1 silencing significantly reduced their length. Conclusions: FOXO1 is involved in human lung carcinogenesis and may serve as a potential therapeutic target in the migration of human lung cancer.

Parkinson's disease (PD) drug therapy remains a challenge. Dual modulation of dopamine and 5-HT receptors has emerged as a promising approach in anti-PD drug development. Taking advantage of the newly discovered aporphine analogue(s), (6aR)-11-amino-N-propyl-noraporphine (SOMCL-171), which exhibited dual D2/5-HT1A receptor agonistic activity, we studied the effects of the compound on levodopa-induced dyskinesia (LID) in a PD animal model. The results demonstrated that SOMCL-171 elicited a potent anti-PD effect in a 6-OHDA-lesioned rat model. Chronic use of SOMCL-171 reduced LID without compromising the antiparkinsonian efficacy. Furthermore, we found that the antidyskinesia effect of SOMCL-171 is associated with its 5-HT1A agonistic activity and the up-regulation of the striatal 5-HT1A receptor. The present data indicated that chronic SOMCL-171 alone produced potent antiparkinsonian effects with weak dyskinesia, compared with that of levodopa. In addition, chronic SOMCL-171 application attenuated the development of levodopa-induced LID at no expense to the antiparkinsonian efficacy. Taken together, our data suggested that dual modulation of D2/5-HT1A receptors may provide a novel approach for drug development in PD and LID.

Activator protein 1 (AP-1) is a pivotal transcription factor that regulates a wide range of cellular processes including proliferation, apoptosis, differentiation, survival, cell migration, and transformation. Accumulating evidence supports that AP-1 plays an important role in several severe disorders including cancer, fibrosis, and organ injury, as well as inflammatory disorders such as asthma, psoriasis, and rheumatoid arthritis. AP-1 has emerged as an actively pursued drug discovery target over the past decade. Excitingly, a selective AP-1 inhibitor T-5224 (51) has been investigated in phase II human clinical trials. Nevertheless, no effective AP-1 inhibitors have yet been approved for clinical use. Despite significant advances achieved in understanding AP-1 biology and function, as well as the identification of small molecules modulating AP-1 associated signaling pathways, medicinal chemistry efforts remain an urgent need to yield selective and efficacious AP-1 inhibitors as a viable therapeutic strategy for human diseases.

Most mammalian cells use glucose as a main fuel source. Glucose is metabolized via glycolysis to pyruvate, which enters the mitochondria and then generates ATP through Krebs cycle in normal condition. However, metabolism is characteristically reprogrammed and cancer cells or highly proliferative cells preferably generate ATP through lactate production by lactate dehydrogenase (LDH/LDHA), referred to as the Warburg effect or metabolic reprogramming toward aerobic glycolysis. Efficient control of energy metabolism is the key to maintaining metabolic homeostasis, and disturbance in energy balance provokes diseases such as obesity, diabetes and cancer. However, the mechanisms underlying efficient energy metabolic homeostasis and breast cancer development are poorly understood. HJC0152, a novel small molecule glucose metabolism modulator, was developed using structure- and fragment-based drug design strategies and molecular modeling techniques. Aggressively growing and metastatic breast cancer cells of triple-negative subtype (MDA-MB-231) treated with HJC0152 showed decreased activity and protein level of LDHA, which resulted in a decrease lactate production. In addition, these cells also exhibited decreased glucose uptake and HK2 protein level. Furthermore, the amount of intracellular ATP in MDA-MB-231 cells was significantly reduced. Our findings suggest that HJC0152 is capable of reprogramming caner metabolism by modulating glucose metabolism and ATP production. These results may provide a rationale to develop HJC0152 as an effective therapeutic for cancer and other metabolic diseases with aberrant glucose metabolism. In addition, HJC0152 can serve as a molecular probing tool for elucidating the key factors responsible for developing breast cancer and other metabolic diseases.This work was supported by Grants P50 CA097007, and P30DA028821 (JZ) from the NIH, CPRIT (JZ), John Sealy Memorial Endowment Fund (JZ), DFI Grants from MD Anderson Cancer Center (QS), Holden Family Research Grant in BC Prevention (QS), and NCI PREVENT Program HHSN26100002 (QS). Citation Format: Kim H, Dong J, Xu J, Li D, Zheng Z, Ye N, Zhang Z, Chen H, Zhou J, Shen Q. Reprogramming glucose metabolism and energy production in breast cancer cells [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-02-08.

Psychiatric disorders like schizophrenia and neurodegenerative diseases like Parkinson's disease are associated with poly-factorial pathogenic mechanisms, with several neurotransmitter systems closely involved. In addition to the cerebral dopaminergic (DA) system, the serotoninergic (5-HT) system also plays a crucial role in regulating psychoemotional, cognitive and motor functions in the central nervous system (CNS). Among the large 5-HT receptor family, accumulating data have revealed new insights into the therapeutic benefit of the 5-HT1A receptor in treating various CNS disorders, especially schizophrenia and Parkinson's disease. The present review discusses the advance of dual agents with mixed actions at the dopamine D2 and serotonin 5-HT1A receptors in the treatment of these diseases. Aripiprazole was the only marketed drug with dual D2 and 5-HT1A profile. It is a partial D2 and 5-HT1A receptor agonist and has been prescribed as an atypical antipsychotical drug. Two other drugs Cariprazine and Pardoprunox are being investigated in clinic. Most of the other candidate compounds, including Bifeprunox, Sarizotan, Mazapertine succinate, PF-217830, and Adoprazine were discontinued due to either non-optimal pharmacokinetic properties or insufficient therapeutical efficacy. Although much effort has been done to highlight the advantages of the 5-HT1A and D2 dual approach, it has to be pointed out that many of these drugs showed poly-pharmacological profile by targeting many other receptors and/or transporters besides the D2 and 5-HT1A receptors. In this regard, 'pure' compounds exclusively acting on the D2 and 5-HT1A receptors are highly needed to further validate this approach. Meanwhile, safety concerns and in vivo pharmacokinetic alerts should also be implanted to the drug design art early.

Oridonin (1) has attracted considerable attention in recent years because of its unique and safe anticancer pharmacological profile. Nevertheless, it exhibits moderate to poor effects against highly aggressive cancers including triple-negative and drug-resistant breast cancer cells. Herein, we report the rational design and synthesis of novel dienone derivatives with an additional α,β-unsaturated ketone system diversely installed in the A-ring based on this class of natural scaffold that features dense functionalities and stereochemistry-rich frameworks. Efficient and regioselective enone construction strategies have been established. Meanwhile, a unique 3,7-rearrangement reaction was identified to furnish an unprecedented dienone scaffold. Intriguingly, these new analogues have been demonstrated to significantly induce apoptosis and inhibit colony formation with superior antitumor effects against aggressive and drug-resistant breast cancer cells in vitro and in vivo while also exhibiting comparable or lower toxicity to normal human mammary epithelial cells in comparison with 1.

To observe the clinical therapeutic effects of acupuncture at single point Shiqizhui (EX-B8) and multi-points in time-varying treatment for primary dysmenorrhea.600 patients with primary dysmenorrhea were randomly assigned to the single point group (n=200) including group A (treating before the menstruation, n=100) and group B (immediately treating as soon as pain occurrence, n=100), the multi-points group (n=200) including group C (treating before the menstruation, n=100) and group D (immediately treating as soon as pain occurrence, n=100), or the control group, group E (n=200, no treatment). The therapeutic effects were analyzed after treatment for three menstrual cycles and interviewed for three follow-up periods.Acupuncture could effectively relieve menstrual pain for primary dysmenorrhea compared with the control group (P0.05, P0.01). Immediate pain relief occurred following acupuncture within 5 min in group B (P0.01) and group D (P0.01), and the two groups obviously relieved menstrual pain for VAS scores. Both group A and group C obviously relieved menstrual pain (P0.01), and group C was better than group A (P0.05). Compared with group D, Group C was much better for CMSS scores in cycle 1.Treating before the menstruation is better than immediately treating as soon as pain occurrence at the improvement in symptoms of dysmenorrheal at multi-points. And single point is better than multi-points when immediately treating as soon as pain occurrence. The present trial suggest Shiqizhui (EX-B8) should be chosen as a convenient point.

Signal transducer and activator of transcription 3 (STAT3) is involved in the tumor growth and metastasis of human head and neck squamous cell carcinoma (HNSCC) and is therefore a target with therapeutic potential. In this study, we show that HJC0152, a recently developed anticancer agent and a STAT3 signaling inhibitor, exhibits promising antitumor effects against HNSCC both in vitro and in vivo via inactivating STAT3 and downstream miR-21/β-catenin axis. HJC0152 treatment efficiently suppressed HNSCC cell proliferation, arrested the cell cycle at the G0–G1 phase, induced apoptosis, and reduced cell invasion in both SCC25 and CAL27 cell lines. Moreover, HJC0152 inhibited nuclear translocation of phosphorylated STAT3 at Tyr705 and decreased VHL/β-catenin signaling activity via regulation of miR-21. Loss of function of VHL remarkably compromised the antitumor effect of HJC0152 in both cell lines. In our SCC25-derived orthotopic mouse models, HJC0152 treatment significantly abrogated STAT3/β-catenin expression in vivo, leading to a global decrease of tumor growth and invasion. With its favorable aqueous solubility and oral bioavailability, HJC0152 holds the potential to be translated into the clinic as a promising therapeutic strategy for patients with HNSCC. Mol Cancer Ther; 16(4); 578–90. ©2017 AACR.

Reinforced concrete segment is the main body of structure in shield tunnel, and its durability has an important effect on shield tunnel. The durability of High Durability Reinforced Concrete Segment (abbr. HDRC Segment) was investigated by impermeability of single segment and chloride diffusion coefficient of core-drilling. HDRC Segment had high compact cover, concrete cover and high strength structural-layer. Permeable height of HDRC Segment was approximately 0.5 mm when Keeping 4 hours in the constant water pressure of 0.8 MPa, and chloride diffusion coefficient of HDRC Segment was only 4.9×10－13m2/s by NEL method. As for Water impermeability and chloride ion penetration resistance, HDRC Segment is far superior to those of conventional Reinforced Concrete Segment (abbr. conventional RC Segment). It is advantageous to increase durability of HDRC Segment and service life of tunnel engineering.

Most mammalian cells use glucose as the primary fuel source. Glucose is metabolized via glycolysis to pyruvate, which is further transferred into mitochondria for generation of ATP through the Krebs cycle in normal condition. However, metabolism is characteristically reprogrammed and cancer cells or highly proliferative cells preferably generate ATP through lactate production by lactate dehydrogenase (LDH/LDHA), referred to as the Warburg effect or metabolic reprogramming toward anaerobic glycolysis. Efficient control of energy metabolism is the key to maintaining metabolic homeostasis, and disturbance in energy balance provokes diseases such as obesity, diabetes and cancer. However, the mechanisms underlying efficient energy metabolic homeostasis and breast cancer development are poorly understood. HJC0152, a novel small-molecule glucose metabolism modulator, was developed using structure-/fragment-based drug design strategies and molecular modeling techniques. Aggressively growing and metastatic breast cancer cells of triple-negative subtype (MDA-MB-231) treated with HJC0152 showed inhibited cell growth. Intriguingly, HJC0152 decreased activity and protein level of LDHA, which resulted in a decrease of lactate production in breast cancer cells. In addition, these cells also exhibited a decrease of glucose uptake by reducing Glut1 and HK2 protein level and modulation of the expression of glycolytic enzymes. Furthermore, HJC0152 treatment causes decreased mitochondrial membrane energy potential, resulting in significantly reduced level of intracellular ATP in MDA-MB-231 cells. Our findings suggest that HJC0152 is capable of reprogramming caner metabolism by modulating glucose metabolism and ATP production. These results may provide a rationale to develop HJC0152 as an effective therapeutics for cancer and other metabolic diseases with aberrant glucose metabolism. In addition, HJC0152 can serve as a molecular probing tool for elucidating the key factors responsible for developing breast cancer and other metabolic diseases. Citation Format: Hyejin Kim, Jiabin Dong, Jimin Xu, Dengfeng Li, Zhi Zheng, Na Ye, Ziwei Zhang, Haiying Chen, Jia Zhou, Qiang Shen. Suppression of breast cancer by reprogramming glucose metabolism and energy production with HJC0152 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4883.