In Silico Discovery of Stapled Peptide Inhibitor Targeting the Nur77-PPARγ Interaction and Its Anti-Breast-Cancer Efficacy.

The binding of peroxisome proliferator-activated receptor γ (PPARγ) to the orphan nuclear receptor Nur77 facilitates the ubiquitination and degradation of Nur77, and leads to aberrant fatty acid uptake for breast cancer progression. Because of its crucial role in clinical prognosis, the interaction between Nur77 and PPARγ is an attractive target for anti-breast-cancer therapy. However, developing an inhibitor of the Nur77-PPARγ interaction poses a technical challenge due to the absence of the crystal structure of PPARγ and its corresponding interactive model with Nur77. Here, ST-CY14, a stapled peptide, is identified as a potent modulator of Nur77 with a KD value of 3.247 × 10-8 M by in silico analysis, rational design, and structural modification. ST-CY14 effectively increases Nur77 protein levels by blocking the Nur77-PPARγ interaction, thereby inhibiting lipid metabolism in breast tumor cells. Notably, ST-CY14 significantly suppresses breast cancer growth and bone metastasis in mice. The findings demonstrate the feasibility of exploiting directly Nur77-PPARγ interaction in breast cancer, and generate what to the best knowledge is the first direct inhibitor of the Nur77-PPARγ interaction available for impeding fatty acid uptake and therapeutic development.

Progress in RAS-targeted therapeutic strategies: From small molecule inhibitors to proteolysis targeting chimeras.

As a widely considerable target in chemical biology and pharmacological research, rat sarcoma (RAS) gene mutations play a critical driving factor in several fatal cancers. Despite the great progress of RAS subtype-specific inhibitors, rapid acquired drug resistance could limit their further clinical applications. Proteolysis targeting chimera (PROTAC) has emerged as a powerful tool to handle "undruggable" targets and exhibited significant therapeutic benefit for the combat of drug resistance. Owing to unique molecular mechanism and binding kinetics, PROTAC is expected to become a feasible strategy to break the bottleneck of classical RAS inhibitors. This review aims to discuss the current advances of RAS inhibitors and especially focus on PROTAC strategy targeting RAS mutations and their downstream effectors for relevant cancer treatment.

Nanotechnology-based photo-immunotherapy: a new hope for inhibition of melanoma growth and metastasis.

Melanoma is the most aggressive form of skin cancer and there is a need for the development of effective anti-melanoma therapies as it shows high metastatic ability and low response rate. In addition, it has been identified that traditional phototherapy could trigger immunogenic cell death (ICD) to activate antitumor immune response, which could not only effectively arrest primary tumour growth, but also exhibit superior effects in terms of anti-metastasis, anti-recurrence for metastatic melanoma treatment. However, the limited tumour accumulation of photosensitizers/photothermal agents and immunosuppressive tumour microenvironment severely weaken the immune effects. The application of nanotechnology facilitates a higher accumulation of photosensitizers/photothermal agents at the tumour site, which can thus improve the antitumor effects of photo-immunotherapy (PIT). In this review, we summarise the basic principles of nanotechnology-based PIT and highlight novel nanotechnologies that are expected to enhance the antitumor immune response for improved therapeutic efficacy.

A novel aptamer beacon for rapid screening of recombinant cells and in vivo monitoring of recombinant proteins.

Recombinant protein drugs, which are typically produced by mammalian host cells, have been approved for the treatment of a range of diseases. Accordingly, systems for selecting recombinant cell lines with efficient protein expression and for testing the content of recombinant proteins in vivo are crucial to the large-scale production and application of protein-based therapeutic drugs. In this study, we designed three aptamer beacons to detect His-tag, a common label of recombinant proteins. We found that all three beacons could specifically and quantitatively measure the His-tagged recombinant proteins with a short reaction time. Among these three beacons, the 6H5-MU beacon had the highest sensitivity for His polypeptides with a detection limit of 250 ng/mL and the shortest detection time within 1 min. Furthermore, we established a rapid and highly effective recombinant cell line construction system, which could obtain monoclonal cell lines with high yields of target proteins within 21 days, by combining 6H5-MU with pSB, a novel plasmid composed of a Sleeping Beauty transposase and a transposon. Finally, 6H5-MU also discriminately tested the serum concentration of His-tagged recombinant proteins in vivo, with consistent results compared to enzyme-linked immunosorbent assay (ELISA). We thus established a rapid and high-throughput method for generating recombinant cell lines and in vivo monitoring of recombinant protein levels, thereby providing a new platform for the development and preparation of recombinant protein drugs. KEY POINTS: • The 6H5-MU aptamer beacon rapidly and accurately binds to His-tagged recombinant proteins. • A system for rapid and high-throughput generation of recombinant cell lines is established using 6H5-MU and pSB. • 6H5-MU allows in vivo monitoring of recombinant protein levels.

Chinese medicinal herbs as potential prodrugs for obesity.

Obesity is a leading worldwide health threat with ever-growing prevalence, it promotes the incidence of various diseases, particularly cardiovascular disease, metabolic syndrome, diabetes, hypertension, and certain cancers. Traditional Chinese Medicine (TCM) has been used to control body weight and treat obesity for thousands of years, Chinese medicinal herbs provide a rich natural source of effective agents against obesity. However, some problems such as complex active ingredients, poor quality control, and unclear therapeutic mechanisms still need to be investigated and resolved. Prodrugs provide a path forward to overcome TCM deficiencies such as absorption, distribution, metabolism, excretion (ADME) properties, and toxicity. This article aimed to review the possible prodrugs from various medicinal plants that demonstrate beneficial effects on obesity and seek to offer insights on prodrug design as well as a solution to the global obesity issues.

Passive smoking and urinary oxidative biomarkers: A pilot study of healthy travelers from Los Angeles to Beijing.

There is a great heterogeneity in smoking prevalence and tobacco control policy across different countries. However, it is unknown whether this heterogeneity could cause increased passive smoking and adverse health effects among international travelers. In this pilot study, we collected 190 urine samples from 26 Los Angeles residents before (LA-before), during (Beijing), and after (LA-after) a 10-week visit to Beijing to measure biomarkers of passive smoking (cotinine), exposure to polycyclic aromatic hydrocarbons (OH-PAHs), and oxidative stress (malondialdehyde, 8-isoprostane, and uric acid). The geometric mean concentrations of urinary cotinine were 0.14, 1.52, and 0.22 µg/g creatinine in LA-before, Beijing, and LA-after, respectively. Likewise, OH-PAH levels were significantly higher in Beijing as compared to LA-before or LA-after, in association with the urinary cotinine levels. One-fold increase in urinary cotinine levels was associated with 10.1% (95% CI: 5.53-14.8%), 8.75% (95% CI: 2.33-15.6%), and 25.4% (95%CI: 13.1-39.1%) increases in urinary levels of malondialdehyde, 8-isoprotane, and uric acid, respectively. OH-PAHs mediated 9.1-23.3% of the pro-oxidative effects associated with passive smoking. Taken together, our findings indicate that traveling to a city with higher smoking prevalence may increase passive smoking exposure, in association with pro-oxidative effects partially mediated by PAHs.

Arachidonic acid metabolism and inflammatory biomarkers associated with exposure to polycyclic aromatic hydrocarbons.

Exposure to polycyclic aromatic hydrocarbons (PAHs) has been associated with systemic inflammation, yet what mechanisms regulate PAHs' inflammatory effects are less understood. This study evaluated the change of arachidonic acid (ARA) metabolites and inflammatory biomarkers in response to increased exposure to PAHs among 26 non-smoking healthy travelers from Los Angeles to Beijing. Traveling from Los Angeles to Beijing significantly increased urinary metabolites of dibenzofuran (800%), fluorene (568%), phenanthrene (277%), and pyrene (176%), accompanied with increased C-reactive protein, fibrinogen, IL-8, and IL-10, and decreased MCP-1, sCD40L, and sCD62P levels in the blood. Meanwhile, the travel increased the levels of ARA lipoxygenase metabolites that were positively associated with a panel of pro-inflammatory biomarkers. Concentrations of cytochrome P450 metabolite were also increased in Beijing and were negatively associated with sCD62P levels. In contrast, concentrations of ARA cyclooxygenase metabolites were decreased in Beijing and were negatively associated with anti-inflammatory IL-10 levels. Changes in both inflammatory biomarkers and ARA metabolites were reversed 4-7 weeks after participants returned to Los Angeles and were associated with urinary PAH metabolites, but not with other exposures such as secondhand smoke, stress, or diet. These results suggested possible roles of ARA metabolic alteration in PAHs-associated inflammatory effects.

Selenium protects against the likelihood of fetal neural tube defects partly via the arginine metabolic pathway.

BACKGROUND AND AIMS: Neural tube defects (NTDs) are severe congenital malformations and have a complex etiology. This study aimed to explore the association between selected essential trace elements (ETEs) and metabolic pathway markers in the serum of women and the likelihood of NTDs. METHODS: The study included 99 mothers of offspring with and 114 mothers of offspring without NTDs. Five ETEs (iron, zinc, selenium [Se], cobalt, and molybdenum) and 106 metabolic pathway markers in maternal serum were quantified. The associations between ETEs and metabolic pathway markers and the chance of NTDs were examined. Mediating effects of the metabolic pathway markers on the association between Se and the likelihood of NTDs were evaluated. RESULTS: Compared to a Se concentration below the median, a concentration above the median was associated with a decreased chance of NTDs with an odds ratio of 0.29 (95% confidence interval: 0.11-0.66). The concentrations of 32 metabolic pathway markers differed between mothers of offspring with and without NTDs; five of these (asymmetric dimethylarginine, ornithine, glutamate, proline, and phenylalanine) were associated with increased chances of NTDs, with adjusted odds ratios of 3.01 (1.31-7.31), 2.79 (1.18-6.86), 2.38 (1.03-5.75), 2.41 (1.05-5.75), and 2.27 (1.09-5.40), respectively, for the higher interquartile of concentration compared to the lower one. Three arginine pathway metabolic markers (i.e., dimethylarginine, ornithine, and proline) mediated the association between Se and the occurrence of NTDs. CONCLUSION: This study suggests an association between Se and a reduced chance of NTDs. The arginine pathway may play a role in mediating this association.

Risk factors in air pollution exposome contributing to higher levels of TNFα in COPD patients.

BACKGROUND: Air pollutants are found associated with various health effects in chronic obstructive pulmonary patients. Given the complicate chemical components of air pollutants, it is not clear which components are the main risk factors for these health effects. OBJECTIVES: Based on the COPD in Beijing (COPDB) study and exposome concept, we examined comprehensively the air pollution components to screen out high-risk factors for systemic inflammation of COPD patients. METHODS: Concentrations of PM with aerodynamic diameter ≤ 2.5 µm (PM2.5), ultrafine and accumulated-mode particles (UFPs and Acc), PM2.5-contained carbonaceous components/elements/water soluble ions, gaseous pollutants, temperature, and relative humidity (RH) were continuously monitored around participants. Urinary polycyclic aromatic hydrocarbons (PAHs) and cotinine, and serum tumor necrosis factor α (TNFα) were measured from 53 COPD and 82 non-COPD participants. Lifestyle variables were recorded using follow-up questionnaire. Linear mixed effects (LME) models were used to assess the associations of TNFα differences with exposure to air pollutants, meteorological variations, and lifestyle. RESULTS: In COPD patients, the associations of TNFα differences with exposure to ozone, Cd, UFPs, Acc, 2-hydroxydibenzofuran, temperature and RH parameters, and several elements in PM2.5 were significant in certain time-windows. For example, per interquartile range (IQR) increase in average ozone concentration 14 d before visits was associated with 17.3% (95% confidence interval: 6.8%, 27.7%) TNFα difference. Associations between ozone, Cd, UFPs, Acc, the maximum value of RH, and 2-hydroxydibenzofuran exposure and TNFα differences remained robust in two-pollutant models, and contributed to 19.0%, 10.5%, 2.2%, 1.6%, 2.1%, and 1.5% TNFα differences, respectively. Among the high-risk factors for COPD patients, the responses to UFPs, Acc, and 2-hydroxydibenzofuran were not robust in non-COPD participants. DISCUSSION: Ozone, Cd, UFPs, Acc, PAHs exposure and RH variation were high-risk factors of systemic inflammation for COPD patients, and the profile of high-risk factors were different from those in general population.

Susceptibility of individuals with lung dysfunction to systemic inflammation associated with ambient fine particle exposure: A panel study in Beijing.

BACKGROUND: The underlying mechanism on the susceptibility of chronic obstructive pulmonary disease (COPD) patients to air pollution has yet to be clarified. OBJECTIVES: Based on the COPD in Beijing (COPDB) study, we examined whether lung dysfunction contributed to pollutant-associated systemic inflammation in COPD patients. METHODS: Proinflammatory biomarkers including interleukin-8 (IL-8) and tumor necrosis factor α (TNFα) were measured in serum samples collected from 53 COPD and 82 healthy participants. Concentrations of particulate matter with aerodynamic diameter ≤ 2.5 µm (PM2.5), carbonaceous components in PM2.5, and PM size distribution were continuously monitored. Linear mixed effects models were used to examine the associations of biomarker differences with particle exposure, between COPD and healthy participants, and across subgroups with different levels of lung dysfunction. RESULTS: COPD patients showed higher differences in IL-8 and TNFα levels associated with exposure to measured pollutants, comparing to healthy controls. In advanced analysis, particle-associated differences in IL-8 and TNFα levels were higher in participants with poorer lung ventilation and diffusion capacity, and higher ratio of residual volume. For example, an interquartile range increase in average PM2.5 concentration 2 weeks before visits was associated with a 15.7% difference in IL-8 level in participants with the lowest ratio of measured value to predicted value of forced expiratory volume in 1 s (FEV1%pred) (65.2%), and the association decreased monotonically with increasing FEV1%pred. Associations between differences in TNFα level and average ultrafine particle concentration 1 week before visits increased gradually with increasing ratio of measured value to predicted value of residual volume/total lung capacity. CONCLUSIONS: COPD patients, especially those with poorer lung function, are more susceptible to systemic inflammation associated with fine particle exposure.