In silico study of androgen receptor N-terminal domain and exploration of its modulators.

The androgen receptor (AR, Uniprot: P10275) signaling plays a key role in the progression of prostate cancer, various AR-related ligands have been reported to treat prostate cancer. However, some resistance mechanisms limited the treating effect of these ligands. Since DBD binding or the allosteric binding sites in LBD of AR may allow the circumvention of some drug resistance mechanisms, anti-resistance is expected especially through the NTD (N-terminal domain) targeting. What's more, studies have shown that compounds including EPI-001 and its derivatives which bind to the Tau-5 region on NTD could be promising molecules for AR-based therapeutics. Herein, we employed aMD (accelerated molecular dynamics) simulation to fold Tau-5 unit proteins into native structure correctly. Subsequently, based on the predicted structural features of Tau-5, the virtual screening was conducted to discover new compounds targeting AR-NTD. We picked up 8 compounds (according to their docking scores and partly similar structural consists as known AR ligands) and analyzed their interaction with Tau-5, compared with the positive control EPI-001, four of the pick-up compounds showed better glide scores. Interestingly, although compound 8 had a lower docking score, it consisted of a similar component as the ligand EIQPN and the amide derivatives, this predicts that compound 8 has also the potential to be modified into an excellent AR-NTD binding molecule. These 8 compounds were all commercially available and could be tested to check whether there was a hit compound to bind the AR-NTD and to regulate its bio-activities. Together, this study described an in silico VLS approach to discover AR-NTD ligands and provided more choices for developing AR-targeted therapies.Communicated by Ramaswamy H. Sarma.

Mechanical pretreatment of typical agricultural biomass on shape characterization and NO emissions during combustion.

The impact of mechanical pretreatment of corn straw (CS), pea straw (PS), and wheat straw (WS), on shape characterization and NO emissions during combustion were investigated in this research. Particle size ranges were obtained and characterized their shape factors using Image J correction. The thermal properties and NO emissions of the different-sized particles were investigated by TG-MS and fixed-bed reactor. Compared with CS and PS, WS is more likely to break into smaller particles due to its moderate strength. Amine-N completely disappeared after pyrolysis, whereas pyrrolic-N and pyridinic-N were the main N functionalities in char-N. During the volatile burning stage, the maximum peak of NO concentration was 270, 354 and 311 ppm for CS, PS and WS, respectively. NO was detected at a steady level during the semicoke combustion stage, and the duration increased with particle size. The NO concentration decreased sharply in a short duration during the fixed carbon combustion stage.

Artesunate treats obesity in male mice and non-human primates through GDF15/GFRAL signalling axis.

Obesity, a global health challenge, is a major risk factor for multiple life-threatening diseases, including diabetes, fatty liver, and cancer. There is an ongoing need to identify safe and tolerable therapeutics for obesity management. Herein, we show that treatment with artesunate, an artemisinin derivative approved by the FDA for the treatment of severe malaria, effectively reduces body weight and improves metabolic profiles in preclinical models of obesity, including male mice with overnutrition-induced obesity and male cynomolgus macaques with spontaneous obesity, without inducing nausea and malaise. Artesunate promotes weight loss and reduces food intake in obese mice and cynomolgus macaques by increasing circulating levels of Growth Differentiation Factor 15 (GDF15), an appetite-regulating hormone with a brainstem-restricted receptor, the GDNF family receptor α-like (GFRAL). Mechanistically, artesunate induces the expression of GDF15 in multiple organs, especially the liver, in mice through a C/EBP homologous protein (CHOP)-directed integrated stress response. Inhibition of GDF15/GFRAL signalling by genetic ablation of GFRAL or tissue-specific knockdown of GDF15 abrogates the anti-obesity effect of artesunate in mice with diet-induced obesity, suggesting that artesunate controls bodyweight and appetite in a GDF15/GFRAL signalling-dependent manner. These data highlight the therapeutic benefits of artesunate in the treatment of obesity and related comorbidities.

Validating the Communicating Care Needs Tool for HIV (CCNT-HIV).

Health literacy has been identified as an influential factor affecting the HIV care continuum and HIV epidemic, but recent systematic reviews found mixed relationships between health literacy and HIV medication adherence. This may be partially due to discrepancies between health literacy conceptualizations, health literacy measures, and the lifeworld, day-to-day challenges that persons with HIV (PWH) face as they seek and receive care. To address these challenges, a new health literacy tool, Communicating Care Needs Tool for HIV (CCNT-HIV), was developed. With survey responses from 118 PWH, the current study compares CCNT-HIV with the Brief Health Literacy Screening Tool (BRIEF) and the All Aspects of Health Literacy Scale (AAHLS) by conducting a principal component analysis. Six principal components were identified for CCNT-HIV; one principal component was identified for BRIEF; and three principal components were identified for AAHLS. With a correlation analysis, relevance among principal components across the three tools validated CCNT-HIV. This study extended the scope of health literacy measures by emphasizing the relational, multi-variable, collaborative impacts stakeholders make on patients' health management. Practical implications for how health literacy tools, like the CCNT-HIV, can be used to directly benefit patients and their health management are also discussed.

Coumarins from Jinhua Finger Citron: Separation by Liquid-Liquid Chromatography and Potential Antitumor Activity.

In this paper, liquid-liquid chromatography was introduced for the first time for the separation of fingered citron (Citrus medica L. var. sarcodactylis Swingle). The fingered citron cultivated in Jinhua is of significant industrial and medicinal value, with several major coumarin compounds detected in its extract. Therefore, further separation for higher purity was of necessity. A preparative liquid-liquid chromatographic method was developed by combining two elution modes (isocratic and step-gradient) with selection according to different polarities of the target sample. Five coumarin derivatives-5,7-dimethoxycoumarin (52.6 mg, 99.6%), phellopterin (4.9 mg, 97.1%), 5-prenyloxy-7-methoxycoumarin (6.7 mg, 98.7%), 6-hydroxy-7-methoxycoumarin (7.1 mg, 82.2%), and byakangelicol (10.5 mg, 90.1%)-with similar structures and properties were isolated on a large scale from 100 mg of petroleum ether (PE) extract and 100 mg of ethyl acetate (EA) extract in Jinhua fingered citron. The productivity was much improved. The anti-growth activity of the isolated coumarins was evaluated against three cancer cell lines (HeLa, A549, and MCF7) with an MTT assay. The coumarins demonstrated potential anti-tumor activity on the HeLa cell line, with 5,7-dimethoxycoumarin in particular exhibiting the best anti-growth activity (IC50 = 10.57 ± 0.24 µM) by inhibiting proliferation. It inhibited colony formation and reduced the size of the tumor sphere in a concentration-dependent manner. The main mechanism was confirmed as inducing apoptosis. This work was informative for further studies aimed at exploring new natural-product-based antitumor agents.

Challenging the Good Life: An Institutional Theoretic Investigation of Consumers' Transformational Process Toward Sustainable Living.

In pursuit of sustainable living, ethics researchers as well as consumers themselves have challenged the status quo of consumption as an institution. Fueled by global economic, environmental, and societal concerns, responsible consumption has become an integral part of the sustainability and consumption ethics literature. One movement toward sustainability consists of confining living space into a smaller ecological footprint. Although motivations for such a lifestyle have been examined, little research has investigated the process of how members of the tiny house movement reconfigure learned consumption practices. This study investigates tiny house dwellers' transformational experiences through the theoretical lens of contemporary institutional change. Qualitative analysis reveals that these challengers of the status quo face significant normative, regulatory, and cognitive hurdles. However, by engaging in sensemaking, validation, and change agency practices, tiny house dwellers have attempted to legitimize a new way of sustainable living that can be in conflict with existing institutions. Implications and future research are discussed in terms of how examining institutional change processes can be a vital part of ethics and sustainability research. Implications are also provided for how marketing organizations can consider modifying their market offerings to capitalize on this segment of society.

Control of SARS-CoV-2 infection by MT1-MMP-mediated shedding of ACE2.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic. Angiotensin-converting enzyme 2 (ACE2) is an entry receptor for SARS-CoV-2. The full-length membrane form of ACE2 (memACE2) undergoes ectodomain shedding to generate a shed soluble form (solACE2) that mediates SARS-CoV-2 entry via receptor-mediated endocytosis. Currently, it is not known how the physiological regulation of ACE2 shedding contributes to the etiology of COVID-19 in vivo. The present study identifies Membrane-type 1 Matrix Metalloproteinase (MT1-MMP) as a critical host protease for solACE2-mediated SARS-CoV-2 infection. SARS-CoV-2 infection leads to increased activation of MT1-MMP that is colocalized with ACE2 in human lung epithelium. Mechanistically, MT1-MMP directly cleaves memACE2 at M706-S to release solACE218-706 that binds to the SARS-CoV-2 spike proteins (S), thus facilitating cell entry of SARS-CoV-2. Human solACE218-706 enables SARS-CoV-2 infection in both non-permissive cells and naturally insusceptible C57BL/6 mice. Inhibition of MT1-MMP activities suppresses solACE2-directed entry of SARS-CoV-2 in human organoids and aged mice. Both solACE2 and circulating MT1-MMP are positively correlated in plasma of aged mice and humans. Our findings provide in vivo evidence demonstrating the contribution of ACE2 shedding to the etiology of COVID-19.

Synthesis and Biological Evaluation of 1-(2-(6-Methoxynaphthalen-2-yl)-6-methylnicotinoyl)-4-Substituted Semicarbazides/Thiosemicarbazides as Anti-Tumor Nur77 Modulators.

Nur77 is an orphan nuclear receptor that participates in the occurrence and development of a variety of tumors. Many agonists of Nur77 have been reported to have significant anticancer effects. Our previous studies have found that the introduction of bicyclic aromatic rings, such as naphthalyl and quinoline groups, into the N'-methylene position of indoles' Nur77 modulators can effectively improve the anti-tumor activity of the target compounds. Following our previous studies, a series of novel 1-(2-(6-methoxynaphthalen-2-yl)-6-methylnicotinoyl)-4-substituted semicarbazide/thiosemicarbazide derivatives 9a-9w were designed and synthesized in four steps from 6-methoxy-2-acetonaphthone and N-dimethylformamide dimethylacetal. All compounds were characterized by 1H-NMR, 13C-NMR and HRMS, and their anti-tumor activity on various cancer cell lines such as A549, HepG2, HGC-27, MCF-7 and HeLa are also evaluated. From the series of compounds, 9h exhibited the most potent anti-proliferative activity against several cancer cells. Colony formation and cell cycle experiments showed that compound 9h inhibited cell growth and arrested the cell cycle. Additionally, 9h leads to the cleavage of PARP. We initially explored the mechanism of 9h-induced apoptosis and found that compound 9h can upregulate Nur77 expression and triggered Nur77 nuclear export, indicating the occurrence of Nur77-mediated apoptosis. These results suggested that 9h may be a promising anti-tumor leading compound for the further research.

E2F4 may be a core transcription factor in the lncRNA-TF regulatory network in cervical cancer.

BACKGROUND: Cervical cancer is the most common gynecological cancer worldwide and is associated with high morbidity and mortality. Despite improvements in therapeutic strategies, the network regulation mechanism remains unclear and the treatment effect is not satisfactory. Therefore, there is a need to continue studying the mechanism of cervical cancer to explore effective gene targets and precise targeted therapy drugs. METHODS: First, three paired tissues (cancer tissues and noncancerous tissues) from patients with cervical squamous cell carcinoma were collected, grouped, and analyzed by microarray. Second, differentially expressed mRNAs (DEMs) and differentially expressed lncRNAs (DELs) (|fold change| ≥ 2 and p < 0.05) between the two groups were screened. For DEMs, functional annotation and pathway analysis were performed using DAVID. Functional prediction of DELs was then performed and their cis-regulatory and trans-regulatory networks were explored. RESULTS: Function prediction of DELs (both up-regulated and down-regulated) shows that the highest frequency Cellular Component (CC) item is cytosol, the highest frequency Molecular function (MF) item is mitotic cell cycle and the highest frequency Biological Process (BP) item is protein binding. Through cis-regulation analysis of DELs, the cis-regulatory relationship of 96 DELs was predicted. The lncRNA-trans-regulation network analysis suggested that E2F4 may be the core transcription factor in the lncRNA-TF regulatory network in cervical cancer. CONCLUSIONS: The lncRNA-TF regulatory network plays an important role in the occurrence and progression of cervical cancer, and E2F4 may be a critical transcription factor in the regulatory network.

Discovery of a Nur77-mediated cytoplasmic vacuolation and paraptosis inducer (4-PQBH) for the treatment of hepatocellular carcinoma.

Nur77, an orphan nuclear receptor, has antitumor activity in hepatocellular carcinoma (HCC). However, its antitumor mechanisms of action in HCC are complicated and rarely reported. Our recent work demonstrated that certain quinoline-Schiff-base derivatives were good Nur77 mediators that exerted excellent anti-HCC activities in vitro and in vivo. Interestingly, these compounds shared similar chemical structures, but they displayed different Nur77-targeted anticancer mechanisms of action. As a continuous work, we synthesized a series of 4-(quinoline-4-amino) benzoylhydrazide derivatives and evaluated their anti-HCC activity and binding affinity to Nur77 in vitro. Compound 4-PQBH emerged as the best Nur77 binder (KD = 1.17 µM) and has potentially selective cytotoxicity to HCC cells. Mechanistically, 4-PQBH extensively induced caspase-independent cytoplasmic vacuolization and paraptosis through Nur77-mediated ER stress and autophagy. Moreover, 4-PQBH exhibited an effective xenograft tumor inhibition by modulating Nur77-dependent cytoplasmic vacuolation and paraptosis. This paper is the first to disclose that chemotherapeutic agents targeting Nur77-mediated cytoplasmic vacuolization and paraptosis may provide a promising strategy to combat HCC that frequently evade the apoptosis program.

Synthesis, SAR study, and bioactivity evaluation of a series of Quinoline-Indole-Schiff base derivatives: Compound 10E as a new Nur77 exporter and autophagic death inducer.

We previously reported 5-((8-methoxy-2-methylquinolin-4-yl)amino)-1H-indole- 2-carbohydrazide derivatives as new Nur77 modulators. In this study, we explored whether the 8-methoxy-2-methylquinoline moiety and bicyclic aromatic rings at the N'-methylene position were critical for their antitumor activity against hepatocellular carcinoma (HCC). For this purpose, a small library of 5-substituted 1H-indole-2-carbohydrazide derivatives was designed and synthesized. We found that the 8-methoxy-2-methylquinoline moiety was a fundamental structure for its biological function, while the introduction of the bicyclic aromatic ring into the N'-methylene greatly improved its anti-tumor effect. We found that the representative compound 10E had a high affinity to Nur77. The KD values were in the low micromolar (2.25-4.10 µM), which were coincident with its IC50 values against the tumor cell lines (IC50 < 3.78 µM). Compound 10E could induce autophagic cell death of liver cancer cells by targeting Nur77 to mitochondria while knocking down Nur77 greatly impaired anti-tumor effect. These findings provide an insight into the structure-activity relation of Quinoline-Indole-Schiff base derivatives and further demonstrate that antitumor agents targeting Nur77 may be considered as a promising strategy for HCC therapy.

Design, synthesis, and biological evaluation of 5-((8-methoxy-2-methylquinolin-4-yl)amino)-1H-indole-2-carbohydrazide derivatives as novel Nur77 modulators.

Nur77 is a potential target for the treatment of cancer such as HCC. Herein, we detailed the discovery of a novel series of 5-((8-methoxy-2-methylquinolin-4-yl)amino)-1H-indole-2-carbohydrazide derivatives as potential Nur77 modulators. The studies of antiproliferative activity and Nur77-binding affinity of target compounds resulted in the discovery of a lead candidate (10g), which was a good Nur77 binder (KD = 3.58 ± 0.16 µM) with a broad-spectrum antiproliferative activity against all tested hepatoma cells (IC50 < 2.0 µM) and was low toxic to normal LO2 cells. 10g could up-regulate Nur77 expression and mediate sub-cellular localization of Nur77 to induce apoptosis in hepatocellular carcinoma cell lines, which relied on 10g inducing Nur77-dependent autophagy and endoplasmic reticulum stress as the upstream of apoptosis. Moreover, the in vivo assays verified that 10g significantly inhibited xenograft tumor growth. These results indicate that 10g has the potential to be developed as a novel Nur77-targeting anti-hepatoma drug.

Promoting Transformative Community Change for Equitable Health: Peer Education and Intervention for Pre-Exposure HIV Prophylaxis.

Many new HIV infections occur through individuals who are unaware of their HIV status. HIV disparities are more prevalent among underserved populations, and the number of new cases in the U.S. is highest in the Southern region. Using the Social Network Intervention, 63 undergraduate students delivered a face-to-face, communication-centered, peer education to 333 peers in the underserved communities; of those, 220 verified cases were analyzed. A baseline assessment was followed by the intervention and the second assessment, with the third assessment 2 weeks later. Assessments measured intervention impacts on health information sharing, knowledge about HIV/AIDS, and the dimensions of vested interest theory. The peer education was effective in making changes in participants' vestedness, knowledge regarding HIV/AIDS, and trust and expectation toward informational sources. Communication and tailored messages through established relationship channels were proven crucial for promoting positive behaviors about HIV sexual health, with strong evidence of change in stigma and the culture of silence.

Health Literacy and Health Communication Training for Underserved Patients and Informal Family Caregivers.

Communication training effectiveness for health care providers has been well documented, however patient and caregiver training may present a prime opportunity to mitigate communication challenges that provider-only training cannot. The aim of this study is to describe the multi-step process of adapting a national, provider, health communication training program (COMFORT) for use with underserved patients and caregivers who (1) are not regular consumers within health care systems and/or (2) do not have ready access to providers. We examine three iterations of training feedback for implementation in future training.

Targeting Non-Genomic Activity of Retinoic Acid Receptor-Gamma by Acacetin.

Retinoic acid receptors (RARs) are ligand-dependent transcription factors of nuclear hormone receptor superfamily (NR). They are important pharmacological targets and current drug development paradigms are largely based on their nuclear transcription mechanism (genomic action). However, the side effects and limited therapeutic efficacy of retinoid-like drugs with such strategy remain a problem in clinical practice. Increasing evidences have demonstrated that many NRs including RARs can act outside the nucleus in a transcription-independent manner (non-genomic action), which are often implicated in human pathological conditions, suggesting that targeting to the non-genomic signaling of NRs is an alternative method for drug discovery. We recently reported that acacetin could antagonize the non-genomic action of RARγ via tipping the balance of AKT-p53 driven by RARγ from tumor promoting to tumor suppressive effect. This chapter provides methodology for identification of acacetin as a ligand and regulator of non-genomic signaling of RARγ. These laboratory protocols should be helpful for those researchers and beginners who are passionate about identifying chemical leads to probe the non-genomic roles of RARs and other NRs for developing new therapeutic technologies.

Targeting to the non-genomic activity of retinoic acid receptor-gamma by acacetin in hepatocellular carcinoma.

We recently demonstrated that retinoic acid receptor-γ (RARγ) is overexpressed and acts as a tumor promoter in hepatocellular carcinoma (HCC). The oncogenic activity of RARγ is mainly attributed to its physiological interaction with p85α regulatory subunit of PI3K leading to constitutive activation of AKT. Here we report RARγ as a negative regulator of p53 signaling and thus extend the oncogenic potential of RARγ to a new role in controlling the balance between AKT and p53. A natural flavonoid acacetin is then identified to be capable of modulating RARγ-dependent AKT-p53 network. It specifically binds to RARγ and inhibits all-trans retinoic acid (atRA) stimulation of RARγ transactivation. However, the anticancer action of acacetin is independent on its modulation of RARγ-driven transcriptional activity. Acacetin induces cancer cell apoptosis through antagonizing the non-genomic effect of RARγ on AKT and p53. When bound to RARγ, acacetin prevents RARγ from its activation of AKT followed by recovery of the normal p53 signaling. Given the implication of AKT-p53 dysregulation in most HCC, targeting the non-genomic signaling of RARγ that switches AKT-p53 from a pro-survival to a pro-apoptotic program in cancer cells should be a promising strategy for developing novel anti-HCC drugs.

In vitro evaluation of antiviral activity of tea seed saponins against porcine reproductive and respiratory syndrome virus.

BACKGROUND: Porcine reproductive and respiratory syndrome virus (PRRSV) is one of the major swine pathogens. This virus causes immune suppression and other secondary infections, leading to significant economic losses in the swine industry. Tea seed saponins (TS) are a natural extract from tea seeds with anti-cancer, anti-inflammatory and antiviral activity. In this study, we demonstrated that TS possessed anti-PRRSV activity. METHODS: MTT assay and trypan blue staining were used to evaluate the cytotoxicity and antiviral ability of TS in cell culture. Apoptosis was measured to assess the safety of TS on Marc-145 cells. Time-of-addition assay, entry inhibition assay and virucidal assay were used to assess the antiviral action of TS. The effect of TS on host cellular gene expression was analysed by real-time PCR. Absolute quantification RT-PCR and western blot were used to study the inhibitory effect of TS on PRRSV N gene and protein expression. RESULTS: Our results showed that 50% cytotoxic concentrations (CC50) and 50% effective concentration (EC50) of TS were 59.86 ±0.3841 µg/ml and 24.29 ±1.194 µg/ml, respectively. The maximum non-cytotoxic concentration of TS on Marc-145 cells was 30 µg/ml. TS inhibited PRRSV-induced cell apoptosis and effectively inhibited PRRSV replication by reducing the expression of host cellular gene PABP, and significantly inhibited virus N gene/protein expression. CONCLUSIONS: TS possessed anti-PRRSV activity in vitro and could serve as a potential antiviral drug for PRRSV prevention and control.

[The relationship between association of microalbuminuria and retinal vessel diameter in population with essential hypertension].

OBJECTIVE: To investigate the association of urinary albumin-to-creatinine ratio (UACR) and the diameter of retinal vessel in population with essential hypertension in Fujian coastal area. METHODS: Central retinal artery and vein equivalents (CRAE and CRVE) were measured from the avoiding mydriatic digitized photographs and semi-automatic fundus analysis software, as well as albumin and urine creatinine. RESULTS: There were significant differences in CRAE levels among the normal control group, normoalbuminuria with essential hypertension group and microalbuminuria with essential hypertension group [(135.68 ± 10.10) µm, (129.79 ± 10.48) µm, (125.29 ± 11.17) µm, all P values < 0.01]. The CRAE levels were significantly negative correlated with UACR (r = -0.29, P < 0.01). Linear regression analysis showed CRAE was associated with UACR in the patients with hypertension(ß = -5.0, P < 0.01). Logistic regression analysis showed, systolic blood pressure (ß = 1.08, P = 0.02) was risk factor for CRAE abnormality. The CRAE abnormality was increased in turn in the normal control group, normoalbuminuria with the essential hypertension group and microalbuminuria with essential hypertension group (P < 0.01). CONCLUSION: The reduction of central retinal artery diameter are associated with the hypertensive renal damage. UACR and CRAE could be used to evaluate the microvascular lesions and be used as an indicator to assess the target organs damage in essential hypertension patients.