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The notion that Nrf2 may serve as an hormetic mediator not only provides a regulatory-based evolutionary understanding of temporal acquired resilience and adaptive homeostasis but also causally integrates toxicological and pharmacological detoxification processes that are central to ecological and human risk assessments as well as to the development of drugs and therapeutics. selleck products These findings can also account for considerable inter-individual variation in susceptibility to toxic substances, the differential effectiveness of numerous therapeutic agents, and the variation in onset and severity of numerous age-related illnesses, such as type II diabetes.The invasion and metastasis of tumor cells are the hallmarks of malignant diseases and the greatest obstacle to overcome. Heparanase-mediated degradation of heparan sulfate (HS) is the critical process for tumor angiogenesis and metastasis, therefore, heparanase become an attractive target for cancer research. Herein, we reported a native fucosylated glycosaminoglycan (nHG) extracted from sea cucumber Holothuria fuscopunctata and a depolymerized nHG (dHG) and its contained oligosaccharides (hs17, hs14, hs11, hs8 and hs5), acting as heparanase inhibitors. nHG and its derivatives have the ability to bind with heparanase directly, leading to significant inhibition of heparanase activity. Moreover, their apparent binding affinity to heparanase was comparable to their inhibitory effect, which was elevated along with the increase of chain length, similar to the effect of heparins. In addition, oligosaccharides inhibited the migration and invasion of 4T1 mammary carcinoma cells and human umbilical vein endothelial cells (HUVECs) and also suppressed tube formation in Matrigel matrix and angiogenesis in the chick chorioallantoic membrane (CAM) assay. In the metastatic mouse model, oligosaccharides exhibited practical antimetastatic effects on 4T1 mammary carcinoma cells. According to the reported anticoagulant activity and the low bleeding tendency of dHG and its oligosaccharides, the use of the oligosaccharides may lead to better effects on tumor patients with thrombosis tendency.Heat shock protein 90 (HSP90) is a chaperone protein that has been shown to regulate cancer progression. As a result, HSP90 has emerged as an attractive target for cancer therapy. Tubocapsenolide A (TA) is an anti-tumor component isolated from Tubocapsicum anomalum. Although the anti-tumor activity of TA was considered to be related to HSP90, the binding site and deep anti-tumor mechanisms still need to be elucidated. In this study, we found that TA is a covalent inhibitor of HSP90, which inhibits HSP90 ATPase activity without blocking ATP binding. Further studies indicated that TA targets the C-terminal Cys521 site, which led to HSP90 partial oligomerization and hindered its anti-aggregation and refolding activity. The damage of the chaperone activity disrupted the interaction between HSP90 and its cochaperone CDC37 as well as its client proteins, thereby inducing cell cycle arrest and apoptosis. Moreover, TA was found to have therapeutic effects on the xenograft tumor model by inducing the degradation of HSP90 client proteins. Together, our results identified HSP90 as the direct target of TA for mediating the anti-tumor activity. TA could serve as a lead compound for developing novel HSP90 C-terminal covalent inhibitors with binding site different from the ATP-binding domain.Excessive daytime sleepiness is considered as the prominent symptom in narcolepsy and Obstructive Sleep Apnea (OSA). Pitolisant is a novel selective histamine H3 receptor antagonist approved for improving excessive daytime sleepiness. The meta-analysis is conducted to assess the efficacy and safety of pitolisant versus placebo for excessive daytime sleepiness in narcolepsy and OSA. PubMed, Embase and Cochrane Library databases were searched from earliest date to November 2020 for randomized controlled trials (RCTs). The primary outcomes were mean changes in Epworth Sleepiness Scale (ESS), mean sleep latency, European quality-of-life questionnaire (EQ-5D), and risk ratio of treatment-emergent adverse events (TEAEs). We pooled 678 patients from four RCTs and found pitolisant significantly decreased ESS by mean difference (MD) of - 2.86 points (95% CI -3.75 to -1.96), increased mean sleep latency by MD of 3.14 min (95% CI 2.18-4.11), and increased EQ-5D by MD of 3.32 points (95% CI 0.26-6.39) compared with placebo. The risk ratio of TEAE was 1.37 (95% CI 1.08-1.74). Insomnia was the only TEAE significantly associated with pitolisant treatment. In conclusion, pitolisant showed great efficacy and controllable security versus placebo for excessive daytime sleepiness in narcolepsy and OSA. Compared with narcolepsy, patients with OSA were deemed to benefit more from pitolisant especially in terms of improving mobility and quality of life of patients without continuous positive airway pressure therapy.Natural biflavonoids, such as amentoflavone, bilobetin, ginkgetin, isoginkgetin, taiwaniaflavone, morelloflavone, delicaflavone, hinokiflavone, and other derivatives (~ 40 biflavonoids), are isolated from Selaginella sp., Ginkgo biloba, Garcinia sp., and several other species of plants. They are able to exert therapeutic benefits by regulating several proteins/enzymes (PPAR-γ, CCAAT/enhancer-binding protein α [C/EBPα], STAT5, pancreatic lipase, PTP1B, fatty acid synthase, α-glucosidase [AG]) and insulin signaling pathways (via PI3K-AKT), which are linked to metabolism, cell growth, and cell survival mechanisms. Deregulated insulin signaling can cause complications of obesity and diabetes, which can lead to cognitive disorders such as Alzheimer's, Parkinson's, and dementia; therefore, the therapeutic benefits of these biflavones in these areas are highlighted. Since biflavonoids have shown potential to regulate metabolism, growth- and survival-related protein/enzymes, their relation to tumor growth and metastasis of cancer associated with angiogenesis are highlighted. The translational role of biflavones in cancer with respect to the inhibition of metabolism-related processes/pathways, enzymes, or proteins, such as STAT3/SHP-1/PTEN, kinesins, tissue kallikreins, aromatase, estrogen, protein modifiers, antioxidant, autophagy, and apoptosis induction mechanisms, are discussed. Finally, considering their observed bioactivity potential, oral bioavailability studies of biflavones and related clinical trials are outlined.selleck products