Programmable Chemical Evolution with Natural/non-natural Building Blocks.

Non-natural building blocks (BBs) present a vast reservoir of chemical diversity for molecular recognition and drug discovery. However, leveraging evolutionary principles to efficiently generate bioactive molecules with a larger number of diverse BBs poses challenges within current laboratory evolution systems. Here, we introduce programmable chemical evolution (PCEvo) by integrating chemoinformatic classification and high-throughput array synthesis/screening. PCEvo initiates evolution by constructing a diversely combinatorial library to create ancestral molecules, streamlines the molecular evolution process and identifies high-affinity binders within 2-4 cycles. By employing PCEvo with 108 BBs and exploring >10^17 chemical space, we identify bicyclic peptidomimetic binders against targets SAR-CoV-2 RBD and Claudin18.2, achieving nanomolar affinity. Remarkably, Claudin18.2 binders selectively stain gastric adenocarcinoma cell lines and patient samples. PCEvo achieves expedited evolution in a few rounds, marking a significant advance in utilizing non-natural building blocks for rapid chemical evolution applicable to targets with or without prior structural information and ligand preference.

Association between oxidative balance score and 10-year atherosclerotic cardiovascular disease risk: results from the NHANES database.

Introduction: The oxidative balance score (OBS) is a holistic measure that represents the overall equilibrium between prooxidants and antioxidants in one's diet and lifestyle. Little research has been conducted on the correlation between OBS and 10-year atherosclerotic cardiovascular disease risk (ASCVD). Therefore, the objective of this investigation was to examine the potential correlation between OBS and 10-year risk. Methods: A total of 11,936 participants from the NHANES conducted between 2001 and 2016 were chosen for the study and their dietary and lifestyle factors were used to assess the OBS score. Logistic regression and restricted cubic splines (RCS) were employed in the cross-sectional study to evaluate the correlation between OBS and the 10-year ASCVD risk. The cohort study utilized Cox proportional hazards models and RCS to assess the correlation between OBS and all-causes and cardiovascular disease (CVD) mortality in individuals with high ASCVD risk. Results: The cross-sectional study found that the OBS (OR = 0.94, 95% CI = 0.93-0.98), as well as the dietary OBS (OR = 0.96, 95% CI = 0.92-0.96) and lifestyle OBS (OR = 0.74, 95% CI = 0.69-0.79), were inversely associated with the 10-year ASCVD risk. A significant linear relationship was observed between OBS, dietary OBS, lifestyle OBS, and the 10-year ASCVD risk. The cohort study found that the OBS was inversely associated with all-cause (aHRs = 0.97, 95% CI = 0.96-0.99) and CVD (aHRs = 0.95, 95% CI = 0.93-0.98) mortality in individuals with high ASCVD risk. A significant linear correlation was observed between OBS, dietary OBS, lifestyle OBS, and all-cause and CVD mortality in participants with high ASCVD risk. Conclusion: The findings indicate that OBS, OBS related to diet, and OBS related to lifestyle were significantly inversely correlated with the 10-year ASCVD risk. Adopting a healthy eating plan and making positive lifestyle choices that result in increased OBS levels can help lower the likelihood of all-cause and CVD mortality in individuals with high ASCVD risk.

Solobacterium moorei promotes the progression of adenomatous polyps by causing inflammation and disrupting the intestinal barrier.

BACKGROUND: Adenomatous polyps (APs) with inflammation are risk factors for colorectal cancer. However, the role of inflammation-related gut microbiota in promoting the progression of APs is unknown. METHODS: Sequencing of the 16S rRNA gene was conducted to identify characteristic bacteria in AP tissues and normal mucosa. Then, the roles of inflammation-related bacteria were clarified by Spearman correlation analysis. Furthermore, colorectal HT-29 cells, normal colon NCM460 cells, and azoxymethane-treated mice were used to investigate the effects of the characteristic bacteria on progression of APs. RESULTS: The expression levels of inflammation-related markers (diamine oxidase, D-lactate, C-reactive protein, tumor necrosis factor-α, interleukin-6 and interleukin-1ß) were increased, whereas the expression levels of anti-inflammatory factors (interleukin-4 and interleukin-10) were significantly decreased in AP patients as compared to healthy controls. Solobacterium moorei (S. moorei) was enriched in AP tissues and fecal samples, and significantly positively correlated with serum inflammation-related markers. In vitro, S. moorei preferentially attached to HT-29 cells and stimulated cell proliferation and production of pro-inflammatory factors. In vivo, the incidence of intestinal dysplasia was significantly increased in the S. moorei group. Gavage of mice with S. moorei upregulated production of pro-inflammatory factors, suppressed proliferation of CD4+ and CD8+cells, and disrupted the integrity of the intestinal barrier, thereby accelerating progression of APs. CONCLUSIONS: S. moorei accelerated the progression of AP in mice via activation of the NF-κB signaling pathway, chronic low-grade inflammation, and intestinal barrier disruption. Targeted reduction of S. moorei presents a potential strategy to prevent the progression of APs.

Food groups and urologic cancers risk: a systematic review and meta-analysis of prospective studies.

Background: To assess the association between 12 food groups intake and the risk of urologic cancers. Methods: We scanned PubMed and Web of Science databases up to April 1st, 2023, and 73 publications met the inclusion criteria in the meta-analysis. We used a random effects model to estimate the summary risk ratios (RRs) and 95% confidence intervals (95% CI). Results: In the linear dose-response meta-analysis, an inverse association was found between each additional daily 100 g of fruits [RR: 0.89, 95%CI = (0.83, 0.97)], 100 g of vegetables [RR: 0.92, 95%CI = (0.85, 0.99)], 12 g of alcohol [RR: 0.91, 95%CI = (0.88, 0.94)] and 1 cup of coffee [RR: 0.95, 95%CI = (0.83, 0.97)] intake and the risk of renal cell carcinoma. Conversely, each additional daily 100 g of red meat intake was positively associated with renal cell carcinoma [RR: 1.41, 95%CI = (1.03, 2.10)]. Inverse associations were observed between each additional daily 50 g of egg [RR: 0.73, 95%CI = (0.62, 0.87)] and each additional daily 1 cup of tea consumption and bladder cancer risk [RR: 0.97, 95%CI = (0.94, 0.99)]. There were no significant associations for nonlinear dose-response relationships between 12 food groups and urological cancers. Conclusion: Our meta-analysis strengthens the evidence that appropriate intake of specific food groups, such as fruits, vegetables, alcohol, tea, and coffee, is associated with the risk of renal cell carcinoma or bladder cancer. More studies are required to fill the knowledge gap on the links between various food groups and urologic cancers because the evidence was less credible in this meta-analysis. Systematic Review Registration: This study was registered on PROSPERO (CRD42022340336).

Regulatory roles of copper metabolism and cuproptosis in human cancers.

Copper is an essential micronutrient for human body and plays a vital role in various biological processes including cellular respiration and free radical detoxification. Generally, copper metabolism in the body is in a stable state, and there are specific mechanisms to regulate copper metabolism and maintain copper homeostasis. Dysregulation of copper metabolism may have a great connection with various types of diseases, such as Wilson disease causing copper overload and Menkes disease causing copper deficiency. Cancer presents high mortality rates in the world due to the unlimited proliferation potential, apoptosis escape and immune escape properties to induce organ failure. Copper is thought to have a great connection with cancer, such as elevated levels in cancer tissue and serum. Copper also affects tumor progression by affecting angiogenesis, metastasis and other processes. Notably, cuproptosis is a novel form of cell death that may provide novel targeting strategies for developing cancer therapy. Copper chelators and copper ionophores are two copper coordinating compounds for the treatment of cancer. This review will explore the relationship between copper metabolism and cancers, and clarify copper metabolism and cuproptosis for cancer targeted therapy.

Effects of TCFA on stent neointimal coverage at 9 months after EXCEL drug-eluting stent implantation assessed by OCT.

BACKGROUND: The aim of this study was to investigate the effects of thin-cap fibroatheromas (TCFAs) on stent neointimal coverage at the 9­month follow-up after EXCEL stent implantation assessed by optical coherence tomography (OCT). METHODS: A total of 93 patients with non-ST elevation acute coronary syndrome (NSTEACS) who underwent EXCEL stent implantation were prospectively enrolled in the study and divided into a TCFA group (n = 47) and a non-TCFA group (n = 46) according to whether EXCEL stents covered the TCFAs. A TCFA was defined as a plaque with lipid content in more than one quadrant and fibrous cap thickness measuring less than 65 µm. The effect of TCFAs on stent neointimal coverage at the 9­month follow-up after stent implantation was evaluated by OCT. The primary study endpoints were the incidence of neointimal uncoverage and stent malapposition. RESULTS: At the 9­month follow-up, the minimal lumen diameter of the TCFA group tended to be smaller (2.8 ± 0.8 vs. 2.1 ± 0.8, p = 0.08) and the diameter of stenosis in the TCFA group tended to be larger (15.1 ± 10.3% vs. 26.3 ± 15.1%, p = 0.08) than those in the non-TCFA group. The mean intimal thickness of the TCFA group was significantly lower than that of the non-TCFA group (67.2 ± 35.5 vs. 145.1 ± 48.7, p < 0.001). The uncovered struts (10.1 ± 9.7 vs. 4.8 ± 4.3, p = 0.05) and malapposed struts (2.1 ± 4.7 vs. 0.3 ± 0.5, p = 0.003) in the TCFA group were more significant than those in the non-TCFA group. Multivariate analysis showed that TCFAs and lesion types were independent predictors of incomplete neointimal coverage (p < 0.05), and lesion types were independent predictors of stent malapposition (p < 0.05). CONCLUSION: In patients with NSTEACS, TCFAs delayed endothelium coverage at 9 months after stent implantation, and TCFAs were independent predictors of incomplete neointimal coverage of the stent.

Fucoidan Protects against Doxorubicin-Induced Cardiotoxicity by Reducing Oxidative Stress and Preventing Mitochondrial Function Injury.

Doxorubicin (DOXO) is a potent chemotherapeutic drug widely used to treat various cancers. However, its clinical application is limited due to serious adverse effects on dose-dependent cardiotoxicity. Although the underlying mechanism has not been fully clarified, DOXO-induced cardiotoxicity has been mainly attributed to the accumulation of reactive oxygen species (ROS) in cardiomyocytes. Fucoidan, as a kind of sulphated polysaccharide existing in numerous brown seaweed, has potent anti-oxidant, immune-regulatory, anti-tumor, anti-coagulate and anti-viral activities. Here, we explore the potential protective role and mechanism of fucoidan in DOXO-induced cardiotoxicity in mice. Our results show that oral fucoidan supplement exerts potent protective effects against DOXO-induced cardiotoxicity by reducing oxidative stress and preventing mitochondrial function injury. The improved effect of fucoidan on DOXO-induced cardiotoxicity was evaluated by echocardiography, cardiac myocytes size and cardiac fibrosis analysis, and the expression of genes related to cardiac dysfunction and remodeling. Fucoidan reduced the ROS content and the MDA levels but enhanced the activity of antioxidant enzymes GSH-PX and SOD in the mouse serum in a DOXO-induced cardiotoxicity model. In addition, fucoidan also increased the ATP production capacity and restored the levels of a mitochondrial respiratory chain complex in heart tissue. Collectively, this study highlights fucoidan as a potential polysaccharide for protecting against DOXO-induced cardiovascular diseases.

Natural Polysaccharide ß-Glucan Protects against Doxorubicin-Induced Cardiotoxicity by Suppressing Oxidative Stress.

Doxorubicin (DOXO) can be used to treat a variety of human tumors, but its clinical application is limited due to severe cardiotoxic side effect. Here, we explore the role of ß-glucan in DOXO-induced cardiotoxicity in mice and study its underlying mechanism. When co-administered with DOXO, ß-glucan was observed to prevent left ventricular dilation and fibrosis. In fact, DOXO reduces the activity of mitochondrial respiratory chain complex and enhances oxidative stress, which in turn impairs heart function. DOXO decreases the ATP production capacity of the heart and increases the ROS content, while ß-glucan can restore the heart capacity and reduce oxidative stress. ß-glucan also increases the activity of antioxidant enzymes GSH-PX and SOD, and reduces the level of MDA in the serum. In addition, the mRNAs of cardiac dysfunction marker genes ANP, BNP and Myh7 were significantly increased after DOXO induction, however, they did not increase when combined with ß-glucan administration. In conclusion, our results indicate that ß-glucan can improve the antioxidant capacity of the heart, thereby serving as a potential therapeutic strategy to prevent DOXO-induced cardiotoxicity.