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1.
Development of small-molecule inhibitors that target PI3Kβ.
Yu, Y, Gu, D, Cai, L, Yang, H, Sheng, R
Drug discovery today. 2024;(1):103854
Abstract
Phosphatidylinositol-3 kinase (PI3K) β, a subtype of class I PI3Ks, has an essential role in PTEN-deficient tumors and links to thrombosis, male fertility, and Fragile X syndrome. PI3Kβ-specific targeting therapy could be an efficacious treatment for diseases highly dependent on PI3Kβ, while mitigating the severe toxicity of pan-PI3K inhibitors. Achieving selectivity can be accomplished through three primary strategies, namely, binding to the induced lipophilic pocket, targeting the unique amino acid residue of PI3Kβ, or using atropisomerism to lock conformation. In this review, we focus on advances in the development of these β-isoform-selective PI3K inhibitors, providing potential guidance for the further development of novel clinical candidates.
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2.
Ketogenic therapy towards precision medicine for brain diseases.
Liu, Y, Fan, L, Yang, H, Wang, D, Liu, R, Shan, T, Xia, X
Frontiers in nutrition. 2024;:1266690
Abstract
Precision nutrition and nutrigenomics are emerging in the development of therapies for multiple diseases. The ketogenic diet (KD) is the most widely used clinical diet, providing high fat, low carbohydrate, and adequate protein. KD produces ketones and alters the metabolism of patients. Growing evidence suggests that KD has therapeutic effects in a wide range of neuronal diseases including epilepsy, neurodegeneration, cancer, and metabolic disorders. Although KD is considered to be a low-side-effect diet treatment, its therapeutic mechanism has not yet been fully elucidated. Also, its induced keto-response among different populations has not been elucidated. Understanding the ketone metabolism in health and disease is critical for the development of KD-associated therapeutics and synergistic therapy under any physiological background. Here, we review the current advances and known heterogeneity of the KD response and discuss the prospects for KD therapy from a precision nutrition perspective.
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3.
The masking phenomenon of microplastics additives on oxidative stress responses in freshwater food chains.
Li, X, Pu, Q, Xu, Y, Yang, H, Wu, Y, Wang, W, Li, Y
The Science of the total environment. 2024;:172156
Abstract
The variability and intrinsic mechanisms of oxidative stress induced by microplastics at different trophic levels in freshwater food chains are not well understood. To comprehensively assess the oxidative stress induced by polystyrene microplastics (PS-MPs) in freshwater food chains, the present study first quantified the oxidative stress induced by PS-MPs in organisms at different trophic levels using factorial experimental design and molecular dynamics methods. Then focuses on analyzing the variability of these responses across different trophic levels using mathematical statistical analysis. Notably, higher trophic level organisms exhibit diminished responses under PS-MPs exposure. Furthermore, the coexistence of multiple additives was found to mask these responses, with antioxidant plastic additives significantly influencing oxidative stress responses. Mechanism analysis using computational chemistry simulation determines that protein structure and amino acid characteristics are key factors driving PS-MPs induced oxidative stress variation in freshwater organisms at different nutrient levels. Increased hydrophobic additives induce protein helicalization and amino acid residue aggregation. This study systematically reveals the variability of biological oxidative stress response under different nutrient levels, emphasizing the pivotal role of chemical additives. Overall, this study offers crucial insights into PS-MPs' impact on oxidative stress responses in freshwater ecosystems, informing future environmental risk assessment.
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4.
First-in-Human Phase 1 Study Evaluating the Safety, Pharmacokinetics, and Pharmacodynamics of DISC-0974, an Anti-Hemojuvelin Antibody, in Healthy Participants.
Novikov, N, Buch, A, Yang, H, Andruk, M, Liu, G, Wu, M, Howell, H, MacDonald, B, Savage, W
Journal of clinical pharmacology. 2024
Abstract
Pathologic elevations in hepcidin, a key regulator of iron homeostasis, contribute to anemia of inflammation in chronic disease. DISC-0974 is a monoclonal antibody that binds to hemojuvelin and blocks bone morphogenetic protein signaling, thereby suppressing hepcidin production. Reduction of systemic hepcidin levels is predicted to increase iron absorption and mobilize stored iron into circulation, where it may be utilized by red blood cell (RBC) precursors in the bone marrow to improve hemoglobin levels and to potentially alleviate anemia of inflammation. We conducted a first-in-human, double-blind, placebo-controlled, single-ascending dose study to evaluate safety, pharmacokinetics, and pharmacodynamics of DISC-0974 in healthy participants. Overall, 42 participants were enrolled and received a single dose of placebo or DISC-0974 at escalating dose levels (7-56 mg), administered intravenously (IV) or subcutaneously (SC). DISC-0974 was well tolerated, with a safety profile comparable to that of placebo. Pharmacokinetic data was dose and route related, with a terminal half-life of approximately 7 days. The bioavailability of SC dosing was ∼50%. Pharmacodynamic data showed dose-dependent decreases in serum hepcidin, with reductions of nearly 75% relative to baseline at the highest dose level tested, and corresponding increases in serum iron in response to DISC-0974 administration. Dose-dependent changes in serum ferritin and hematology parameters were also observed, indicating mobilization of iron stores and downstream effects of enhanced hemoglobinization and production of RBCs. Altogether, these data are consistent with the mechanism of action of DISC-0974 and support the selection of a biologically active dose range for evaluation in clinical trials for individuals with anemia of inflammation.
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5.
Early enteral nutrition versus early supplemental parenteral nutrition in patients undergoing major abdominal surgery: a secondary analysis of 2 randomized clinical trials.
Gao, X, Zhang, Y, Qi, X, Xiao, Y, Gao, T, Jin, G, Wang, K, Zhou, Y, Chi, Q, Yang, H, et al
The American journal of clinical nutrition. 2024;(4):1036-1043
Abstract
BACKGROUND The effect of early isoenergetic feeding routes [early enteral nutrition (E-EN) or early supplemental parenteral nutrition (E-SPN)] on the outcome of patients undergoing major abdominal surgery is controversial. OBJECTIVES The aim of this study was to investigate the impact of early isoenergetic EN compared with early isoenergetic SPN on nosocomial infections in patients undergoing major abdominal surgery. METHODS This study is a secondary, post hoc analysis of data from 2 open-label randomized clinical trials. Participants were recruited from the general surgery department of 11 academic hospitals in China undergoing major abdominal surgery and with Nutritional Risk Screening 2002 score ≥3. All eligible patients were categorized into 2 groups based on their achievement of the 100% energy target on postoperative day (POD) 3: the E-EN group (n = 199) and the E-SPN group (n = 115). The primary outcome was the incidence of nosocomial infections between POD 3 and hospital discharge. RESULTS In total, 314 patients [mean (SD) age, 59.2 (11.4) y; 113 (36.0%) females] were included. Patients in the E-EN group showed no significant difference in nosocomial infections compared with those in the E-SPN group {17/199 [8.5%] compared with 10/115 [8.7%], risk difference, 0.2% [95% confidence interval (CI): -6.3, 6.6]}. The hematological nutritional status of the E-EN group showed a significant improvement at discharge compared with the E-SPN group (albumin: 38.0 ± 6.0 g/L compared with 35.5 ± 7.6 g/L; mean difference, -2.5 g/L; 95% CI: -4.0, -1.0 g/L; prealbumin: 200.0 ± 8.0 mg/L compared with 158.4 ± 38.1 mg/L; mean difference, -41.6 mg/L; 95% CI: -41.7, -36.1 mg/L). Other indicators were comparable between groups. CONCLUSION E-EN compared with isoenergetic SPN may not be associated with a reduced rate of nosocomial infection in patients undergoing major abdominal surgery, but may be associated with improved hematological nutritional status. TRIAL REGISTRATION NUMBER This trial was registered at clinicaltrials.gov as NCT03115957 (https://clinicaltrials.gov/ct2/show/NCT03115957) and NCT03117348 (https://clinicaltrials.gov/ct2/show/NCT03117348).
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6.
International clinical practice guideline on the use of traditional Chinese medicine for ulcerative colitis by Board of Specialty Committee of Digestive System Disease of World Federation of Chinese Medicine Societies (2023).
Zhang, S, Zhao, L, Shen, H, Tang, Z, Qin, D, Li, J, Zhang, B, Yang, G, Chen, M, Wu, K, et al
Phytotherapy research : PTR. 2024;(2):970-999
Abstract
Ulcerative colitis (UC), a chronic and nonspecific inflammatory disease of the intestine, has become a prevalent global health concern. This guideline aims to equip clinicians and caregivers with effective strategies for the treatment and management of adult UC patients using traditional Chinese medicine (TCM). The guideline systematically evaluated contemporary evidence through the Grading of Recommendations Assessment, Development, and Evaluation framework. Additionally, it incorporated insights from ancient Chinese medical sources, employing the evidence grading method found in traditional TCM literature. The development process involved collaboration with multidisciplinary experts and included input from patients with UC. The guideline, based on a comprehensive review of available evidence, present 40 recommendations. They offer a condensed overview of TCM's role in understanding the pathogenesis, diagnosis, and treatment of UC, along with an assessment of the efficacy of various TCM-based treatments. TCM exhibits promising outcomes in the treatment of UC. However, to establish its efficacy conclusively, further high-quality clinical studies on TCM for UC are essential.
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7.
Weed biology and management in the multi-omics era: Progress and perspectives.
Chen, K, Yang, H, Wu, D, Peng, Y, Lian, L, Bai, L, Wang, L
Plant communications. 2024;(4):100816
Abstract
Weeds pose a significant threat to crop production, resulting in substantial yield reduction. In addition, they possess robust weedy traits that enable them to survive in extreme environments and evade human control. In recent years, the application of multi-omics biotechnologies has helped to reveal the molecular mechanisms underlying these weedy traits. In this review, we systematically describe diverse applications of multi-omics platforms for characterizing key aspects of weed biology, including the origins of weed species, weed classification, and the underlying genetic and molecular bases of important weedy traits such as crop-weed interactions, adaptability to different environments, photoperiodic flowering responses, and herbicide resistance. In addition, we discuss limitations to the application of multi-omics techniques in weed science, particularly compared with their extensive use in model plants and crops. In this regard, we provide a forward-looking perspective on the future application of multi-omics technologies to weed science research. These powerful tools hold great promise for comprehensively and efficiently unraveling the intricate molecular genetic mechanisms that underlie weedy traits. The resulting advances will facilitate the development of sustainable and highly effective weed management strategies, promoting greener practices in agriculture.
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8.
Simulated gastrointestinal digestion of walnut protein yields anti-inflammatory peptides.
Xia, W, Gao, Y, Fang, X, Jin, L, Liu, R, Wang, LS, Deng, Y, Gao, J, Yang, H, Wu, W, et al
Food chemistry. 2024;:138646
Abstract
The impact of the simulated gastrointestinal digestion process on walnut protein and the potential anti-inflammatory properties of its metabolites was studied. Structural changes induced by digestion, notably in α-Helix, β-Turn, and Random Coil configurations, were unveiled. Proteins over 10,000 Da significantly decreased by 35.6 %. Antioxidant activity in these metabolites paralleled increased amino acid content. Molecular docking identified three walnut polypeptides-IPAGTPVYLINR, FQGQLPR, and VVYVLR-with potent anti-inflammatory properties. RMSD and RMSF analysis demonstrated the stable and flexible interaction of these polypeptides with their target proteins. In lipopolysaccharide (LPS)-induced inflammation in normal human colon mucosal epithelial NCM460 cells, these peptides decreased 5-hydroxytryptamine (5-HT), tumor necrosis factor-alpha (TNF-α), and vascular endothelial growth factor (VEGF) expression, while mitigating cell apoptosis and inflammation. Our study offers valuable insights into walnut protein physiology, shedding light on its potential health benefits.
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9.
Bioavailability and mechanisms of dietary polyphenols affected by non-thermal processing technology in fruits and vegetables.
Liu, Y, Deng, J, Zhao, T, Yang, X, Zhang, J, Yang, H
Current research in food science. 2024;:100715
Abstract
Plant polyphenols play an essential role in human health. The bioactivity of polyphenols depends not only on their content but also on their bioavailability in food. The processing techniques, especially non-thermal processing, improve the retention and bioavailability of polyphenolic substances. However, there are limited studies summarizing the relationship between non-thermal processing, the bioavailability of polyphenols, and potential mechanisms. This review aims to summarize the effects of non-thermal processing techniques on the content and bioavailability of polyphenols in fruits and vegetables. Importantly, the disruption of cell walls and membranes, the inhibition of enzyme activities, free radical reactions, plant stress responses, and interactions of polyphenols with the food matrix caused by non-thermal processing are described. This study aims to enhance understanding of the significance of non-thermal processing technology in preserving the nutritional properties of dietary polyphenols in plant-based foods. It also offers theoretical support for the contribution of non-thermal processing technology in improving food nutrition.
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10.
Revealing the clinical effect and biological mechanism of acupuncture in COPD: A review.
Shi, F, Cao, J, Zhou, D, Wang, X, Yang, H, Liu, T, Chen, Z, Zeng, J, Du, S, Yang, L, et al
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2024;:115926
Abstract
BACKGROUND To provide new ideas for the clinical and mechanism research of acupuncture in the treatment of chronic obstructive pulmonary disease (COPD), this study systematically reviews clinical research and the progress of basic research of acupuncture in the treatment of COPD. METHODS PubMed and Web of Science databases were searched using acupuncture and COPD as keywords in the last 10 years, and the included literature was determined according to exclusion criteria. FINDINGS Acupuncture can relieve clinical symptoms, improve exercise tolerance, anxiety, and nutritional status, as well as hemorheological changes (blood viscosity), reduce the inflammatory response, and reduce the duration and frequency of COPD in patients with COPD. Mechanistically, acupuncture inhibits M1 macrophage activity, reduces neutrophil infiltration, reduces inflammatory factor production in alveolar type II epithelial cells, inhibits mucus hypersecretion of airway epithelial cells, inhibits the development of chronic inflammation in COPD, and slows tissue structure destruction. Acupuncture may control pulmonary COPD inflammation through the vagal-cholinergic anti-inflammatory, vagal-adrenomedullary-dopamine, vagal-dual-sensory nerve fiber-pulmonary, and CNS-hypothalamus-orexin pathways. Furthermore, acupuncture can increase endogenous cortisol levels by inhibiting the HPA axis, thus improving airway antioxidant capacity and reducing airway inflammation in COPD. In conclusion, the inhibition of the chronic inflammatory response is the key mechanism of acupuncture treatment for COPD.