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Isoliensinine (ISO), a natural compound, is a bibenzyl isoquinoline alkaloid monomer in lotus seed, which has strong antioxidant and free radical scavenging activities. The oxidative toxicity caused by glutamic acid overdose is one of the important mechanisms of nerve cell injury, and the oxidative toxicity caused by glutamic acid is related to ferroptosis. This study aims to establish a glutamate-induced injury model of mouse hippocampal neurons HT-22 cells, and investigate the protective effect of ISO on the neurotoxicity of glutamate-induced HT-22 cells. The results showed that ISO inhibited glutamate-induced ferroptosis of neuronal cells through nuclear factor E2-related factor 2/glutathione peroxidase 4 (Nrf2/GPX4) signaling pathway. Pretreatment of HT-22 cells with ISO significantly reduced glutamate-induced cell death. Ferroptosis inhibitors have the same effect. ISO inhibited the decrease of mitochondrial membrane potential detection and the increase of iron content induced by glutamate, the increase of malondialdehyde and reactive oxygen species in cytoplasm and lipid, and protected the activities of GPx and superoxide dismutase enzymes. In addition, WB showed that glutamic acid could induce the upregulated expression of long-chain esteryl coA synthase 4 (ACSL4) protein and the downregulated expression of SLC7A11 and GPX4 protein in HT-22 cells, while ISO could prevent the abnormal expression of these proteins induced by glutamic acid. The nuclear translocation of Nrf2 in HT-22 cells was increased, and the expression of downstream heme oxygenase-1 protein was upregulated. In summary, ISO protects HT-22 cells from glutamate-induced ferroptosis through a novel mechanism of the Nrf2/GPX4 signaling pathway.
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Ferroptose , Ácido Glutâmico , Fator 2 Relacionado a NF-E2 , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Transdução de Sinais , Animais , Ferroptose/efeitos dos fármacos , Camundongos , Ácido Glutâmico/toxicidade , Ácido Glutâmico/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Linhagem Celular , Isoquinolinas/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismoRESUMO
Cell death is a fundamental biological process with different modes including apoptosis and necrosis. In contrast to programmed apoptosis, necrosis was previously considered disordered and passive, but it is now being realized to be under regulation by certain biological pathways. However, the intracellular dynamics that coordinates with cellular structure changes during necrosis remains unknown, limiting our understanding of the principles of necrosis. Here, we characterized the spatiotemporal intracellular diffusion dynamics in cells undergoing necrosis, using three-dimensional single-particle tracking of quantum dots. We found temporally increased diffusion rates in necrotic cells and spatially enhanced diffusion heterogeneity in the cell periphery, which could be attributed to the reduced molecular crowding resulting from cell swelling and peripheral blebbing, respectively. Moreover, the three-dimensional intracellular diffusion transits from strong anisotropy to nearly isotropy, suggesting a remodeling of the cytoarchitecture that relieves the axial constraint on intracellular diffusion during necrosis. Our results reveal the remarkable alterations of intracellular diffusion dynamics and biophysical properties in necrosis, providing insight into the well-organized nonequilibrium necrotic cell death from a biophysical perspective.
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Necrose , Pontos Quânticos , Pontos Quânticos/química , Humanos , Difusão , Células HeLaRESUMO
OBJECTIVES: Dihydroisotanshinone I (DT) is a kind of diterpenoid compound extracted from the dried roots of Salvia miltiorrhiza Bunge, and exhibits multiple biological activities including anti-tumor activity. Cisplatin is one of the first-line drugs for the treatment of lung adenocarcinoma (LAUD), but the drug resistance and toxicity limit its efficacy. DT is known to induce apoptosis and ferroptosis, but it is unclear whether DT can inhibit the cisplatin-resistant LAUD cells and reverse the drug resistance in LAUD. Therefore, our study intends to establish the cisplatin-resistant human LAUD cells (A549/DDP), and figure out the influence and related mechanisms of DT reversing cisplatin resistance in A549/DDP cells, so as to provide a theoretical basis for the DT as a new natural candidate for the treatment of LAUD. METHODS: The establishment of A549/DDP was the continuous stimulation by exposing A549 to gradient concentrations of Cisplatin. The cell viability of A549 and A549/DDP was detected by CCK-8 kit, and the IC50 value was calculated. The morphological changes of A549 and A549/DDP cells were observed by an inverted microscope. The contents of malondialdehyde (MDA) and glutathione (GSH) in A549/DDP cells after drug treatment were detected by related kits. The levels of Fe2+, cytosolic reactive oxygen species (ROS), and lipid reactive oxygen species (lipid ROS) were detected by a fluorescence microplate reader or fluorescence cell imager according to the related fluorescent probe kit instructions. Western blot was used to detect the expressions of PI3K, phospho-PI3K, AKT, phospho-AKT, MDM2, p53, GPX4, and SLC7A11 in A549/DDP after different drug treatments. KEY FINDINGS: Our study demonstrated that the inhibitory effect of DT on A549 and A549/DDP cells was time-dependent and concentration-dependent, and DT and DDP had a synergistic effect on inhibiting the proliferation of A549/DDP cells. Furthermore, DT mainly induced ferroptosis in A549/DDP cells and synergized with cisplatin to promote ferroptosis in A549/DDP cells. The result of KEGG pathway analysis, molecular docking and western blot showed that DT could enhance the cisplatin sensitivity of A549/DDP by inhibiting PI3K/MDM2/P53 signaling pathway. CONCLUSIONS: Consequently, we concluded that DT promotes ferroptosis in cisplatin-resistant LAUD A549/DDP cells. Additionally, DT reverses cisplatin resistance by promoting ferroptosis via PI3K/MDM2/P53 pathway in A549/DDP cells.
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The mitochondrion, which is an intracellular organelle responsible for most of the energy-producing pathways, can have its genome targeted for climate-driven selection. However, climate-driven mitochondrial selection remains a sparsely studied area in reptiles. Here, we reported the complete mitochondrial genome sequence of a lacertid lizard (Takydromus intermedius) and used mitogenomes from 54 species of lacertid lizards to study their phylogenetic relationships and to identify the mitochondrial genes under positive selection by climate. The length of the complete mitochondrial genome sequence of T. intermedius was 17,713 bp, which was within the range of lengths (17,224-18,943) ever reported for Takydromus species. The arrangement of mitochondrial genes in T. intermedius was the same as in other congeneric species. The 54 lacertid species could be divided into three geographically and climatically different clades. We identified three mitochondrial genes (ATP6, ATP8, and ND3) under positive selection by climate, and found that isothermality, temperature seasonality, precipitation of wettest month, and precipitation seasonality were the most important climatic variables contributing to the gene selection.
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BACKGROUND: Potassium bismuth citrate is a gastric mucosal protector and a key drug for treating peptic ulcers. OBJECTIVE: To evaluate the pharmacokinetic characteristics and safety of 120-mg bismuth potassium citrate formulations administered orally under fasting conditions in healthy Chinese subjects. METHOD: A single-center open two-cycle trial was conducted on 12 healthy subjects who received a single oral dose of 120 mg of bismuth potassium citrate. The plasma concentration of bismuth was determined using a validated inductively coupled plasma mass spectrometry (ICPâMS) method. The pharmacokinetic parameters, including maximum serum concentration (Cmax) and area under the curve concentration-time curve (AUC0-t and AUC0-∞), and safety were evaluated via noncompartment analysis. RESULTS: The ratios of the least square geometric mean ratio between the test (T) and reference (R) formulations for Cmax, AUC0-t, and AUC0-∞ were 44.8%, 55.5%, and 64.4%, respectively; the bilateral 95% confidence intervals (Cis) for these parameters were 20.2-99.6%, 24.1-127.5%, and 23.7-175.0%, respectively, and the non-inferior limits for these parameters were 169.4%, 198.8%, and 200.5%, respectively. The upper limits of the one-sided 97.5% confidence interval for the least squares geometric mean ratio (T/R) were lower than the non-inferior limits. No serious adverse reactions or adverse reactions leading to detachment were observed among the subjects. CONCLUSION: The concentration of bismuth in the blood of healthy subjects in the T formulation was not greater than that in the R formulation. Similarly, the safety of oral administration of 120 mg of bismuth potassium citrate formulations to healthy subjects was good. The trial registration number (TRN) was [2018] 013, 6 December 2018.
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Objective: To investigate the correlations of cognitive function with glycated albumin (GA), the ratio of GA to glycated hemoglobin (GA/HbA1c), and the concentrations of interleukin-6 (IL-6) and superoxide dismutase (SOD) in elderly patients with type 2 diabetes mellitus (T2DM). Methods: A total of 44 elderly T2DM patients were evaluated for cognitive function using the mini-mental state examination (MMSE) and the Montreal cognitive assessment (MoCA). Patients were then divided into two groups based on the MMSE and MoCA scores: a cognitive dysfunction group and a normal cognitive function group. The correlations of the MMSE and MoCA scores with GA/HbA1c, GA, IL-6, and SOD were analyzed. Logistic regression analysis was used to identify independent influential factors for cognitive dysfunction. The predictive value of GA and GA/HbA1c for cognitive dysfunction in elderly T2DM patients was evaluated by receiver operating characteristic (ROC) curve analysis. Results: Among these patients, 28 had cognitive impairment. They had significantly higher GA/HbA1c, increased GA and IL-6 levels, and lower SOD concentrations than the normal cognitive function group (all P < 0.05). GA/HbA1c was negatively correlated with the MMSE (r = -0.430, P = 0.007) and MoCA (r = -0.432, P = 0.007) scores. SOD was positively correlated with the MMSE (r = 0.585, P=0.014) and MoCA (r = 0.635, P=0.006) scores. IL-6 was negatively correlated with the MoCA score (r = -0.421, P=0.015). Age and GA/HbA1c were independent factors contributing to cognitive dysfunction. The areas under the ROC curves of GA and GA/HbA1c for the diagnosis of cognitive dysfunction were 0.712 and 0.720, respectively. Conclusions: GA and GA/HbA1c are related to cognitive dysfunction in elderly patients with T2DM.
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BACKGROUND: Wilson disease (WD) is the most common genetic metabolic liver disease. Some studies have shown that comorbidities may have important effects on WD. Data on hepatitis B virus (HBV) infection in patients with WD are limited. AIM: To investigate the prevalence and clinical impact of HBV infection in patients with WD. METHODS: The clinical data of patients with WD were analyzed retrospectively, and the data of patients with concurrent WD and HBV infection were compared with those of patients with isolated WD. RESULTS: Among a total of 915 WD patients recruited, the total prevalence of current and previous HBV infection was 2.1% [95% confidence interval (CI): 1.2%-3.0%] and 9.2% (95%CI: 7.3%-11.1%), respectively. The main finding of this study was the identification of 19 patients with concurrent WD and chronic hepatitis B (CHB) infection. The diagnosis of WD was missed in all but two patients with CHB infection. The mean delay in the diagnosis of WD in patients with concurrent WD and CHB infection was 32.5 mo, which was significantly longer than that in patients with isolated WD (10.5 mo). The rates of severe liver disease and mortality in patients with concurrent WD and CHB infection were significantly higher than those in patients with isolated WD (63.1% vs 19.3%, P = 0.000 and 36.8% vs 4.1%, P < 0.001, respectively). Binary logistic regression analysis revealed a significantly higher risk of severe liver disease at the diagnosis of WD in patients with current HBV infection [odds ratio (OR) = 7.748; 95%CI: 2.890-20.774; P = 0.000)] or previous HBV infection (OR = 5.525; 95%CI: 3.159-8.739; P = 0.000) than in patients with isolated WD. CONCLUSION: The total prevalence of current HBV infection in patients with WD was 2.1%. The diagnosis of WD in CHB patients is usually missed. HBV infection is an independent risk factor for severe liver disease in WD patients. The diagnosis of WD should be ruled out in some patients with CHB infection.
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Hepatite B , Degeneração Hepatolenticular , Humanos , Vírus da Hepatite B , Degeneração Hepatolenticular/diagnóstico , Degeneração Hepatolenticular/epidemiologia , Estudos Retrospectivos , Hepatite B/diagnóstico , Hepatite B/epidemiologiaRESUMO
Cell migration plays important roles in many biological processes, but how migrating cells orchestrate intracellular molecules and subcellular structures to regulate their speed and direction is still not clear. Here, by characterizing the intracellular diffusion and the three-dimensional lamellipodium structures of fish keratocyte cells, we observe a strong positive correlation between the intracellular diffusion and cell migration speed and, more importantly, discover a switching of cell migration modes with reversible intracellular diffusion variation and lamellipodium structure deformation. Distinct from the normal fast mode, cells migrating in the newly-found slow mode have a deformed lamellipodium with swollen-up front and thinned-down rear, reduced intracellular diffusion and compartmentalized macromolecule distribution in the lamellipodium. Furthermore, in turning cells, both lamellipodium structure and intracellular diffusion dynamics are also changed, with left-right symmetry breaking. We propose a mechanism involving the front-localized actin polymerization and increased molecular crowding in the lamellipodium to explain how cells spatiotemporally coordinate the intracellular diffusion dynamics and the lamellipodium structure in regulating their migrations.
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Eritrócitos Anormais , Pseudópodes , Animais , Movimento Celular , DifusãoRESUMO
BACKGROUND: Intracranial and extracranial artery stenosis is associated with cerebral infarction. Vascular calcification and atherosclerosis are the main causes of stenosis and major risk factors for cardiovascular and cerebrovascular events in patients with type 2 diabetes mellitus (T2DM). Bone turnover biomarkers (BTMs) are associated with vascular calcification, atherosclerosis, glucose, and lipid metabolism. AIM: To investigate the association of circulating BTM levels with severe intracranial and extracranial artery stenosis in patients with T2DM. METHODS: For this cross-sectional study including 257 T2DM patients, levels of the BTMs serum osteocalcin (OC), C-terminal cross-linked telopeptide of type I collagen (CTX), and procollagen type I N-peptide were measured by electrical chemiluminescent immunoassay, and artery stenosis was assessed by color Doppler and transcranial Doppler. Patients were grouped according to the existence and location (intracranial vs. extracranial) of artery stenosis. Correlations between BTM levels, previous stroke, stenosis location, and glucose and lipid metabolism were analyzed. RESULTS: T2DM patients with severe artery stenosis had a higher frequency of previous stroke and levels of all three tested BTMs (all P < 0.05) than patients without. Some differences in OC and CTX levels were observed according to the location of artery stenosis. Significant associations were also observed between BTM levels and some glucose and lipid homeostasis parameters. On multivariate logistic regression analysis, all BTMs were significant predictors of artery stenosis in T2DM patients with and without adjustment for confounding factors (all P < 0.001), and receiver operating characteristic curve analysis demonstrated the ability of BTM levels to predict artery stenosis in T2DM patients. CONCLUSION: BTM levels were found to be independent risk factors for severe intracranial and extracranial artery stenosis and were differentially associated with glucose and lipid metabolism in patients with T2DM. Therefore, BTMs may be promising biomarkers and potential therapeutic targets for artery stenosis.
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OBJECTIVE: Sacubitril/valsartan is a commonly used medicine for treating heart failure (HF) patients, but the treatment effects significantly vary. Neprilysin (NEP) and carboxylesterase 1 (CES1) play an important role in the efficacy of sacubitril/valsartan. The purpose of this study was to explore the relationship between NEP and CES1 gene polymorphisms and the efficacy and safety of sacubitril/valsartan treatment in HF patients. METHODS: Genotyping of 10 single nucleotide polymorphisms (SNPs) of the NEP and CES1 genes in 116 HF patients was performed by the Sequenom MassARRAY method, and logistic regression and haplotype analysis were used to evaluate the associations between SNPs and the clinical efficacy and safety of sacubitril/valsartan in HF patients. RESULTS: A total of 116 Chinese patients with HF completed the whole trial, and T variations in rs701109 in NEP gene were an independent risk factor (P = 0.013, OR = 3.292, 95% CI:1.287-8.422) for the clinical efficacy of sacubitril/valsartan. Furthermore, haplotype analysis of 6 NEP SNPs (including rs701109) was performed and showed that the CGTACC and TGTACC haplotypes were significantly associated with clinical efficacy (OR = 0.095, 95%CI: 0.012-0.723, P = 0.003; OR = 5.586, 95% CI: 1.621-19.248, P = 0.005). Moreover, no association was found between SNPs of other selected genes in terms of efficacy in HF patients, and no association was observed between SNPs and symptomatic hypotension. CONCLUSION: Our results suggest an association between rs701109 and sacubitril/valsartan response in HF patients. Symptomatic hypotension is not associated with the presence of NEP polymorphisms.
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Insuficiência Cardíaca , Hipotensão , Neprilisina , Humanos , Aminobutiratos/uso terapêutico , Antagonistas de Receptores de Angiotensina/uso terapêutico , Compostos de Bifenilo/uso terapêutico , Combinação de Medicamentos , População do Leste Asiático , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/genética , Hipotensão/induzido quimicamente , Hipotensão/genética , Neprilisina/genética , Polimorfismo Genético , Volume Sistólico , Tetrazóis/uso terapêutico , Resultado do Tratamento , Valsartana/uso terapêuticoRESUMO
The purpose of this trial was to evaluate the pharmacokinetics (PK), bioequivalence (BE), and safety of 2 preparations of hydroxychloroquine (200-mg tablet) under fasting and fed conditions. A total of 180 subjects (fasting condition: n = 80; fed condition: n = 100) were randomly enrolled in this randomized, open, single-dose, single-cycle parallel phase â clinical study. Under the 2 conditions, the subjects were randomly administered the test (T) or reference (R) tablet, both at a dose of 200 mg (1 tablet). Liquid chromatography-tandem mass spectrometry was used to determine the concentration of hydroxychloroquine in healthy subjects after oral administration of the T or R preparation to evaluate the PK characteristics. In this trial, the T and R preparations of hydroxychloroquine were bioequivalent under both conditions within the range of 80%-125%. No serious adverse events (SAEs) were found in the safety assessments for either condition, and all adverse events (AEs) were mild, except for 2 moderate AEs in the fed condition, indicating good safety.
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Hidroxicloroquina , Equivalência Terapêutica , Humanos , Área Sob a Curva , População do Leste Asiático , Jejum , Voluntários Saudáveis , Hidroxicloroquina/farmacocinética , ComprimidosRESUMO
OBJECTIVE: To evaluate the pharmacokinetics (PK), safety, and bioequivalence of two formulations of apixaban in healthy Chinese subjects under fasting and fed conditions. MATERIALS AND METHODS: A single-center, randomized, open, single-dose, two-period crossover PK study was carried out under fasting and fed conditions in 64 healthy subjects enrolled in either the fasting (36 subjects) or the fed (28 subjects) arms of the study. Subjects received a single oral dose of 2.5 mg apixaban tablets as test (T) or reference (R) formulation. The primary PK parameters determined were the area under the plasma concentration-time curve from zero to t and ∞ (AUC0-t and AUC0-∞) and the maximal plasma concentration (Cmax). Safety was assessed mainly from the occurrence of adverse events (AEs). RESULTS: A single drop-out in the fed arm of the trial was excluded from the statistical evaluation. The 90% confidence intervals (CIs) for the geometric mean ratio (GMR) for T/R using AUC0-t were 95.4 - 100.9% and 97.8 - 103.8%, and for AUC0-∞ were 95.3 - 100.6% and 98.3 - 104.3% under fasting (36 subjects) and fed (27 subjects) conditions, respectively. Similarly, the 90% CIs for Cmax were 94.6 - 103.1% and 88.8 - 102.0% under fasting (36 subjects) and the fed (27 subjects) conditions, respectively. Therefore, the 90% CIs for the T/R AUC and Cmax ratios were within the standard range for bioequivalence (80.0 - 125.0%). There were no serious adverse events (SAEs). CONCLUSION: The test and reference 2.5 mg apixaban tablets were bioequivalent and both showed good tolerability and safety.
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População do Leste Asiático , Pirazóis , Piridonas , Equivalência Terapêutica , Humanos , Área Sob a Curva , Estudos Cross-Over , Jejum , Voluntários Saudáveis , Comprimidos , Pirazóis/farmacocinética , Piridonas/farmacocinéticaRESUMO
Malignant tumor is a major killer that seriously endangers human health. At present, the methods of treating tumors include surgical resection, chemotherapy, radiotherapy and immunotherapy. However, the survival rate of patients is still very low due to the complicated mechanism of tumor occurrence and development and high recurrence rate. Individualized treatment will be the main direction of tumor treatment in the future. Because only by understanding the molecular mechanism of tumor development and differentially expressed genes can we carry out accurate treatment and improve the therapeutic effect. MicroRNA (miRNA) is a kind of small non coding RNA, which regulates gene expression at mRNA level and plays a key role in tumor regulation. Ferroptosis is a kind of programmed death caused by iron dependent lipid peroxidation, which is different from apoptosis, necrosis and other cell death modes. Now it has been found that ferroptosis plays an important role in the occurrence and development of tumors and drug resistance. More and more studies have found that miRNAs can regulate tumor development and drug resistance through ferroptosis. Therefore, in this review, the mechanism of ferroptosis is briefly outlined, and the relationship between miRNAs and ferroptosis in tumors is reviewed.
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BACKGROUND: Cloperastine is a pivotal antibechic widely prescribed to treat cough caused by respiratory diseases. The present trial evaluated the pharmacokinetics (PK), bioequivalence (BE) and safety effects of the generic test (T) tablet of cloperastine after single-dose administration of cloperastine, compared with the original reference (R) tablet of cloperastine. OBJECTIVE: The purpose of this trial was to compare the PK, BE and safety of a test 10 mg versus the reference 10 mg formulation of cloperastine under fasting and postprandial conditions in healthy Chinese volunteers. METHODS: A single-centre, randomised, open, double-cycle, self-crossover, single oral administration Phase I trial was performed in healthy Chinese volunteers. A total of 60 subjects were enrolled in either the fasting (28 subjects) or the postprandial condition (32 subjects). Subjects randomly received a single dose of the T or R preparation (10 mg dose). Plasma concentrations of cloperastine were analysed by a validated LC-MS/MS method. The primary endpoints of the PK parameters were the area under the plasma concentration-time curve from zero to 72 h (AUC0-72h), under the plasma concentration-time curve from zero to infinity (AUC0-∞) and the maximal plasma concentration (Cmax). The equivalence standard range (80.0-125.0%) was used to evaluate the BE of the two preparations. The safety parameter as secondary endpoint was mainly evaluated by the occurrence of adverse events (AEs). RESULTS: A total of 25 and 30 subjects in the fasting and postprandial conditions completed this clinical trial, respectively. The geometric mean ratio (GMR) of the T/R for the Cmax, AUC0-72h and AUC0-∞ were 102.1%, 103.8% and 104.0% in the fasting condition, respectively. In the postprandial condition, the GMR of the T/R for the Cmax, AUC0-72h and AUC0-∞ were 94.2%, 98.8% and 99.0%, respectively. All the values fell within the range (80.0-125.0%). The Cmax and AUC0-72h values of the T and R preparations in fasting and postprandial conditions were not statistically significant (P > 0.05). Furthermore, no serious adverse events (SAEs) occurred during the whole trial. CONCLUSIONS: The T and R preparations were bioequivalent under both conditions. Food has no significant effect on the absorption of cloperastine. Moreover, T and R preparations were well tolerated. The trial registration number (TRN) and date of registrations were CTR20212515, 13 October 2021.
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Jejum , Espectrometria de Massas em Tandem , Humanos , Equivalência Terapêutica , Cromatografia Líquida , Voluntários Saudáveis , Comprimidos , ChinaRESUMO
The activation of ferroptosis is a new effective way to treat drug-resistant solid tumors. Ferroptosis is an iron-mediated form of cell death caused by the accumulation of lipid peroxides. The intracellular imbalance between oxidant and antioxidant due to the abnormal expression of multiple redox active enzymes will promote the produce of reactive oxygen species (ROS). So far, a few pathways and regulators have been discovered to regulate ferroptosis. In particular, the cystine/glutamate antiporter (System Xc -), glutathione peroxidase 4 (GPX4) and glutathione (GSH) (System Xc -/GSH/GPX4 axis) plays a key role in preventing lipid peroxidation-mediated ferroptosis, because of which could be inhibited by blocking System Xc -/GSH/GPX4 axis. This review aims to present the current understanding of the mechanism of ferroptosis based on the System Xc -/GSH/GPX4 axis in the treatment of drug-resistant solid tumors.
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To prepare peptides with high angiotensin-converting enzyme (ACE) inhibitory (ACEi) activity, Alcalase was screened from five proteases and employed to prepare protein hydrolysate (TMH) of skipjack tuna (Katsuwonus pelamis) milts. Subsequently, 10 novel ACEi peptides were isolated from the high-ACEi activity TMH and identified as Tyr-Asp-Asp (YDD), Thr-Arg-Glu (TRE), Arg-Asp-Tyr (RDY), Thr-Glu-Arg-Met (TERM), Asp-Arg-Arg-Tyr-Gly (DRRYG), Ile-Cys-Tyr (ICY), Leu-Ser-Phe-Arg (LSFR), Gly-Val-Arg-Phe (GVRF), Lys-Leu-Tyr-Ala-Leu-Phe (KLYALF), and Ile-Tyr-Ser-Pro (IYSP) with molecular weights of 411.35, 404.41, 452.45, 535.60, 665.69, 397.48, 521.61, 477.55, 753.91, and 478.53 Da, respectively. Among them, the IC50 values of ICY, LSFR, and IYSP on ACE were 0.48, 0.59, and 0.76 mg/mL, respectively. The significant ACEi activity of ICY, LSFR, and IYSP with affinities of -7.0, -8.5, and -8.3 kcal/mol mainly attributed to effectively combining with the ACEi active sites through hydrogen bonding, electrostatic force, and hydrophobic interaction. Moreover, ICY, LSFR, and IYSP could positively influence the production of nitric oxide (NO) and endothelin-1 (ET-1) secretion in human umbilical vein endothelial cells (HUVECs) and weaken the adverse impact of norepinephrine (NE) on the production of NO and ET-1. In addition, ICY, LSFR, and IYSP could provide significant protection to HUVECs against H2O2 damage by increasing antioxidase levels to decrease the contents of reactive oxide species and malondialdehyde. Therefore, the ACEi peptides of ICY, LSFR, and IYSP are beneficial functional molecules for healthy foods against hypertension and cardiovascular diseases.
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Alzheimer's disease (AD), the most common type of senile dementia, includes the complex pathogenesis of abnormal deposition of amyloid beta-protein (Aß), phosphorylated tau (p-tau) and neuroimmune inflammatory. The neurodegenerative process of AD triggers microglial activation, and the overactivation of microglia produces a large number of neuroimmune inflammatory factors. Microglia dysfunction can lead to disturbances in iron metabolism and enhance iron-induced neuronal degeneration in AD, while elevated iron levels in brain areas affect microglia phenotype and function. In this manuscript, we firstly discuss the role of microglia in AD and then introduce the role of microglia in the immune-inflammatory pathology of AD. Their role in AD iron homeostasis is emphasized. Recent studies on microglia and ferroptosis in AD are also reviewed. It will help readers better understand the role of microglia in iron metabolism in AD, and provides a basis for better regulation of iron metabolism disorders in AD and the discovery of new potential therapeutic targets for AD.
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Inflammation is a protective response of the body to an irritant. When an inflammatory response occurs, immune cells are recruited to the injury, eliminating the irritation. The excessive inflammatory response can cause harm to the organism. Inflammation has been found to contribute to cervical cancer if there is a problem with the regulation of inflammatory response. Cervical cancer is one of the most common malignant tumors globally, and the incidence tends to be younger. The harm of cervical cancer cannot be ignored. The standard treatments for cervical cancer include surgery, radiotherapy and chemotherapy. However, the prognosis for this treatment is poor, so it is urgent to find a safer and more effective treatment. Natural products are considered excellent candidates for the treatment of cervical cancer. In this review, we first describe the mechanisms by which inflammation induces cervical cancer. Subsequently, we highlight natural products that can treat cervical cancer through inflammatory pathways. We also introduce natural products for the treatment of cervical cancer in clinical trials. Finally, methods to improve the anticancer properties of natural products were added, and the development status of natural products was discussed.
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OBJECTIVE: To investigate the effects of Tongmai Yangxin Pill (TMYXP) combined with metoprolol tartrate or metoprolol alone for the treatment of premature ventricular complex (PVC) in patients with symptomatic frequent PVC. METHODS: A total of 584 patients with symptomatic frequent PVC were randomly assigned (in a 1:1 ratio) into two groups: study group [n = 292, TMYXP (40 pills twice/day, orally) combined with metoprolol tartrate (25 mg twice/day, orally)] and control group [n = 292, metoprolol tartrate (25 mg twice/day, orally) plus placebo pill (40 pills twice/day, orally)]. The total treatment period was eight weeks. RESULTS: After eight weeks of treatment, the total effective rate of reduction of PVC in the study group and the control group were 76.4% and 51.4%, respectively (P < 0.001). TMYXP combined with metoprolol tartrate demonstrated a signiï¬cantly greater reduction of the frequency of PVCs compared with the metoprolol tartrate alone (-4537 times/24 h vs. -3013 times/24 h, P < 0.001). The study group also showed a better result compared with the control group with respect to PVC related symptoms. In terms of New York Heart Association classification improvement, the total effective rates were 21.9% in the study group and 12.4% in the control group ( P < 0.05). Both the study group and the control group exhibited improvements in echocardiographic indexes. Left ventricular ejection fraction was significantly improved in the study group compared with the control group ( P < 0.05). There was no significant difference in the incidence of adverse events between the two groups. CONCLUSIONS: Compared with metoprolol tartrate alone, TMYXP combined with metoprolol tartrate could more effectively reduce the frequency of PVC and alleviated PVC related symptoms, and improve cardiac function in patients with symptomatic PVC.
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Alzheimer's disease (AD), an age-related neurodegenerative disease, is a striking global health problem. Ferroptosis is a newly discovered form of cell death characterized by iron-dependent lipid peroxidation products and the accumulation of lethal reactive oxygen species. Strict regulation of iron metabolism is essential to ensure neuronal homeostasis. Excess and deficiency of iron are both associated with neurodegeneration. Studies have shown that oxidative stress caused by cerebral iron metabolism disorders in the body is involved in the process of AD, ferroptosis may play an important role in the pathogenesis of AD, and regulating ferroptosis is expected to be a new direction for the treatment of AD. Various organelles are closely related to ferroptosis: mitochondria, endoplasmic reticulum, Golgi apparatus, and lysosome are involved in the regulation of ferroptosis from the aspects of iron metabolism and redox imbalance. In this review, the relationship between AD and the dysfunction of organelles (including mitochondria, endoplasmic reticulum, lysosome, and Golgi apparatus) and the role of organelles in ferroptosis of AD were reviewed to provide insights for understanding the relationship between organelles and ferroptosis in AD and the treatment of AD.