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Non-communicable diseases (NCDs), including cardiovascular diseases, cancer, metabolic diseases, and skeletal diseases, pose significant challenges to public health worldwide. The complex pathogenesis of these diseases is closely linked to oxidative stress and inflammatory damage. Nuclear factor erythroid 2-related factor 2 (Nrf2), a critical transcription factor, plays an important role in regulating antioxidant and anti-inflammatory responses to protect the cells from oxidative damage and inflammation-mediated injury. Therefore, Nrf2-targeting therapies hold promise for preventing and treating NCDs. Quercetin (Que) is a widely available flavonoid that has significant antioxidant and anti-inflammatory properties. It modulates the Nrf2 signaling pathway to ameliorate oxidative stress and inflammation. Que modulates mitochondrial function, apoptosis, autophagy, and cell damage biomarkers to regulate oxidative stress and inflammation, highlighting its efficacy as a therapeutic agent against NCDs. Here, we discussed, for the first time, the close association between NCD pathogenesis and the Nrf2 signaling pathway, involved in neurodegenerative diseases (NDDs), cardiovascular disease, cancers, organ damage, and bone damage. Furthermore, we reviewed the availability, pharmacokinetics, pharmaceutics, and therapeutic applications of Que in treating NCDs. In addition, we focused on the challenges and prospects for its clinical use. Que represents a promising candidate for the treatment of NCDs due to its Nrf2-targeting properties.
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Sepsis and septic shock are critical medical conditions characterized by a systemic inflammatory response to infection, significantly contributing to global mortality rates. The progression to multiple organ dysfunction syndrome (MODS) represents the most severe complication of sepsis and markedly increases clinical mortality. Central to the pathophysiology of sepsis, endothelial cells play a crucial role in regulating microcirculation and maintaining barrier integrity across various organs and tissues. Recent studies have underscored the pivotal role of endothelial function in the development of sepsis-induced MODS. This review aims to provide a comprehensive overview of the pathophysiology of sepsis-induced MODS, with a specific focus on endothelial dysfunction. It also compiles compelling evidence regarding potential small molecules that could attenuate sepsis and subsequent multi-organ damage by modulating endothelial function. Thus, this review serves as an essential resource for clinical practitioners involved in the diagnosing, managing, and providing intensive care for sepsis and associated multi-organ injuries, emphasizing the importance of targeting endothelial cells to enhance outcomes of the patients.
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BACKGROUND: Septic shock, an extremely dangerous condition that causes impairment of organ function, always largely contributes to mortality in intensive care units. The impact of septic shock-induced organ damage on morbidity and mortality is substantially influenced by myocardial dysfunction. However, it remains unclear whether and in what manner anisodamine (654-1/654-2) ameliorates myocardial dysfunction caused by septic shock. PURPOSE: This study is the pioneering investigation and validation about the protective efficacy of anisodamine (654-1/654-2) against LPS-induced myocardial dysfunction in septic shock rats. It also aims to explore the differences in the underlying molecular mechanisms of both drugs. METHODS: A septic shock model was established in SD rats by after tail vein administration of LPS. 64 rats were distributed into eight groups, such as LPS group, control group, LPS+654-1 group (1.25, 2.5, and 5 mg/kg), and LPS+654-2 group (1.25, 2.5, and 5 mg/kg). The hemodynamics, echocardiography, immunohistochemical analysis, TEM, TUNEL assay, and H&E staining were utilized to assess the septic shock model and myocardial function. Lactic acid, inflammatory markers (IL-1ß, IL-6, and TNF-α), endothelial injure markers (SDC-1, HS and TM) and myocardial injury markers (CK, c-TNT and NT-pro BNP) were assessed using ELISA or biochemical kits. Additionally, the mechanisms of 654-1/654-2 were analyzed using RNA-seq and bioinformatics, and validated using western blotting and RT-PCR. RESULTS: Administration of 654-1/654-2 significantly restored hemodynamics and improved myocardial and endothelial glycocalyx injury in septic shock rats. Furthermore, 654-1/654-2 dose-dependently reduced plasma levels of lactic acid, inflammatory cytokines, and markers of endothelial and myocardial injury. Analyses using RNA-seq, WB and RT-PCR techniques indicated that 654-1/654-2 could mitigate myocardial and endothelial injury by inhibiting the NF-κB and NLRP-3 pathways, and activating the PI3K-AKT pathway. CONCLUSIONS: These findings demonstrated that 654-1/654-2 could alleviate myocardial damage in septic shock rats. Specifically, 654-1 inhibited the NF-κB/NLRP-3 pathway, whereas 654-2 promoted the PI3K-AKT pathway and inhibited the NF-κB pathway, effectively mitigating the inflammatory response and cell apoptosis.
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Cardiomiopatias , Choque Séptico , Alcaloides de Solanáceas , Ratos , Animais , NF-kappa B/metabolismo , Choque Séptico/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais , Lipopolissacarídeos/farmacologia , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/metabolismo , Ácido Láctico/farmacologiaRESUMO
Cardiometabolic multimorbidity (CMM) is an increasingly significant global public health concern. It encompasses the coexistence of multiple cardiometabolic diseases, including hypertension, stroke, heart disease, atherosclerosis, and T2DM. A crucial component to the development of CMM is the disruption of endothelial homeostasis. Therefore, therapies targeting endothelial cells through multi-targeted and multi-pathway approaches hold promise for preventing and treatment of CMM. Curcumin, a widely used dietary supplement derived from the golden spice Carcuma longa, has demonstrated remarkable potential in treatment of CMM through its interaction with endothelial cells. Numerous studies have identified various molecular targets of curcumin (such as NF-κB/PI3K/AKT, MAPK/NF-κB/IL-1ß, HO-1, NOs, VEGF, ICAM-1 and ROS). These findings highlight the efficacy of curcumin as a therapeutic agent against CMM through the regulation of endothelial function. It is worth noting that there is a close relationship between the progression of CMM and endothelial damage, characterized by oxidative stress, inflammation, abnormal NO bioavailability and cell adhesion. This paper provides a comprehensive review of curcumin, including its availability, pharmacokinetics, pharmaceutics, and therapeutic application in treatment of CMM, as well as the challenges and future prospects for its clinical translation. In summary, curcumin shows promise as a potential treatment option for CMM, particularly due to its ability to target endothelial cells. It represents a novel and natural lead compound that may offer significant therapeutic benefits in the management of CMM.
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Aterosclerose , Curcumina , Humanos , Células Endoteliais , Curcumina/farmacologia , Curcumina/uso terapêutico , Multimorbidade , NF-kappa B , Fosfatidilinositol 3-Quinases , EspeciariasRESUMO
This study was aimed to investigate the therapeutic effect and mechanism of AKHO on 5-fluorouracil (5-FU)-induced intestinal mucositis in mice. Mouse body weight, diarrhea score, and H&E staining were applied to judge the therapeutic effect of AKHO. 16S rDNA and nontargeted metabolomics have been used to study the mechanism. WB, ELISA, and immunohistochemistry were adopted to validate possible mechanisms. The results demonstrated that AKHO significantly reduced diarrhea scores and intestinal damage induced by 5-FU in mice. AKHO lowered the serum levels of LD and DAO, and upregulated the expressions of ZO-1 and occludin in the ileum. Also, AKHO upregulated the abundance of Lactobacillus in the gut and suppressed KEGG pathways such as cortisol synthesis and secretion and arachidonic acid metabolism. Further validation studies indicated that AKHO downregulated the expressions of prostaglandin E2 (PGE2), microsomal prostaglandin E synthase-1 (mPGES-1), and PGE2 receptor EP4, as well as upregulated the expression of glucocorticoid (GC) receptor (GR), leading to improved intestinal epithelial barrier function. Taken together, AKHO elicited protective effects against 5-FU-induced mucositis by regulating the expressions of tight junction proteins via modulation of GC/GR and mPGES-1/PGE2/EP4 pathway, providing novel insights into the utilization and development of this pharmaceutical/food resource.
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Alpinia , Microbioma Gastrointestinal , Mucosite , Óleos Voláteis , Camundongos , Animais , Mucosite/induzido quimicamente , Mucosite/tratamento farmacológico , Dinoprostona , Prostaglandina-E Sintases/genética , Prostaglandina-E Sintases/metabolismo , Óleos Voláteis/farmacologia , Fluoruracila/efeitos adversos , DiarreiaRESUMO
Although multivalent glycosidase inhibitors have shown enhanced glycosidase inhibition activities, further applications and research directions need to be developed in the future. In this paper, two positional isomeric perylene bisimide derivatives (PBI-4DNJ-1 and PBI-4DNJ-2) with 1-deoxynojirimycin conjugated were synthesized. Furthermore, PBI-4DNJ-1 and PBI-4DNJ-2 showed positional isomeric effects on the optical properties, self-assembly behaviors, glycosidase inhibition activities, and hypoglycemic effects. Importantly, PBI-4DNJ-1 exhibited potent hypoglycemic effects in mice with 41.33 ± 2.84 and 37.45 ± 3.94% decreases in blood glucose at 15 and 30 min, respectively. The molecular docking results showed that the active fragment of PBI-4DNJ-1 has the highest binding energy (9.649 kcal/mol) and the highest total hydrogen bond energy (62.83 kJ/mol), which were related to the positional isomeric effect on the hypoglycemic effect in mice. This work introduced a new means to develop antihyperglycemic agents in the field of multivalent glycomimetics.
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Glucosamina/análogos & derivados , Glicosídeo Hidrolases/metabolismo , Hipoglicemiantes/química , Imidas/química , Perileno/análogos & derivados , Administração Oral , Animais , Sítios de Ligação , Glicemia/análise , Glucosamina/química , Glicosídeo Hidrolases/antagonistas & inibidores , Ligação de Hidrogênio , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/metabolismo , Isomerismo , Cinética , Camundongos , Conformação Molecular , Simulação de Acoplamento Molecular , Perileno/química , Ligação Proteica , TermodinâmicaRESUMO
OBJECTIVE: To investigate the impact of hip fracture on coagulation function in elderly patients. METHODS: In our study, 127 elderly patients with hip fracture were diagnosed and admitted to Peking University People's Hospital from January 2011 to March 2012. Specimens of their venous blood were obtained before and after the surgery, and measured for fibrinogen (FIB) and D-dimer. Also, we analyzed their age, type of fracture, fracture time, and concomitant diseases. RESULTS: The FIB level of the patients (127 cases) before surgery was (3.91 ± 1.06) g/L, and 42.52% (54/127) patients' FIB was higher than normal. After the surgery, 28 patients underwent FIB test [(4.21 ± 1.24) g/L], which was higher than the FIB value before surgery, but was not statistically significant. Before surgery, 15 patients underwent D-dimer test [(2 059.5 ± 1 948.0) µg/L]. After the surgery, 26 patients underwent D-dimer test [(2 574.9 ± 1 702.4) µg/L].The two values were significantly higher than normal (P<0.05). The elevated value of FIB had no relationship with age, diabetes, cardiovascular or cerebrovascular diseases. Before surgery, 45.83% (22/48) of the intertrochanteric fracture patients had abnormal FIB, and 40.50% (32/79) of the patients with femoral neck fracture had abnormal FIB, but they were not statistically significant. Grouped according to the fracture time, when fracture time was longer than 96 h, the ratio of abnormal FIB was 26.7%, lower than those of other groups, and the difference was statistically significant (P<0.05). CONCLUSION: The hip fracture in elderly patients has a direct impact on coagulation system, and FIB and D-dimer have significantly changed. According to the variation of FIB after fracture,we speculate that fracture surgery after 96 h may affect the coagulation system at the lowest level.