Acute hypobaric hypoxic brain damage is a potentially fatal high-altitude sickness. Autophagy plays a critical role in ischemic brain injury, but its role in hypobaric hypoxia (HH) remains unknown. Here we used an HH chamber to demonstrate that acute HH exposure impairs autophagic activity in both the early and late stages of the mouse brain, and is partially responsible for HH-induced oxidative stress, neuronal loss, and brain damage. The autophagic agonist rapamycin only promotes the initiation of autophagy. By proteome analysis, a screen showed that protein dynamin2 (DNM2) potentially regulates autophagic flux. Overexpression of DNM2 significantly increased the formation of autolysosomes, thus maintaining autophagic flux in combination with rapamycin. Furthermore, the enhancement of autophagic activity attenuated oxidative stress and neurological deficits after HH exposure. These results contribute to evidence supporting the conclusion that DNM2-mediated autophagic flux represents a new therapeutic target in HH-induced brain damage.
Mice ; Animals ; Hypoxia ; Oxidative Stress ; Autophagy ; Cognition ; Sirolimus/therapeutic use*

OBJECTIVE

The aim of this study was to investigate the protective effects of Lactobacillus brevis BIOTECH 1766 against oxidative damage in the brain, liver, and kidneys induced by aluminum (Al) poisoning in ICR mice.

Twenty mice were divided into four groups (n = 5): (I) control, (II) Al, (III) citric acid (CA), and (IV) L. brevis BIOTECH 1766 group. A 14-day treatment period was implemented, wherein groups I and II received sterile water, while groups III and IV received 10 mg/kg bw of CA and 1 x 109 cfu/kg bw of L. brevis BIOTECH 1766, respectively. On day 15, all except the control group received a single oral dose of 1438 mg/kg bw of AlCl3. 6H2O. After 24 h, mice were euthanized to collect the brain, liver, and kidneys for the oxidative stress marker analyses and histopathological examination.

Acute intoxication of Al led to a significant increase in tissue malondialdehyde (MDA) and a significant decrease in the tissue's reduced glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD). Mice pretreated with CA or L. brevis BIOTECH 1766 have markedly reduced CAT activity in the liver, and SOD in all three organs. Extensive organ injuries were also prevented by CA and L. brevis BIOTECH 1766 pretreatment, with the latter providing better protection against liver damage.

The findings showed that L. brevis BIOTECH 1766 provides a protective effect against acute Al poisoning in mice by ameliorating oxidative damage in the brain, liver, and kidneys.

OBJECTIVE: To explore the mechanism underlying the inhibitory effect of quercetin against testicular oxidative damage induced by a mixture of 3 commonly used phthalates (MPEs) in rats. METHODS: Forty male Sprague-Dawley rats were randomly divided into control group, MPEs exposure group, and MPEs with low-, median- and high-dose quercetin treatment groups. For MPEs exposure, the rats were subjected to intragastric administration of MPEs at the daily dose of 900 mg/kg for 30 consecutive days; Quercetin treatments were administered in the same manner at the daily dose of 10, 30, and 90 mg/kg. After the treatments, serum levels of testosterone, luteinizing hormone (LH), follicle stimulating hormone (FSH), and testicular malondialdeyhde (MDA), catalase (CAT) and superoxide dismutase (SOD) were detected, and testicular pathologies of the rats were observed with HE staining. The expressions of nuclear factor-E2-related factor 2 (Nrf2), Kelch-like ECH2 associated protein 1 (Keap1) and heme oxygenase 1 (HO-1) in the testis were detected using immunofluorescence assay and Western blotting. RESULTS: Compared with the control group, the rats with MPEs exposure showed significant reductions of the anogenital distance, weight of the testis and epididymis, and the coefficients of the testis and epididymis with lowered serum testosterone, LH and FSH levels (P < 0.05). Testicular histological examination revealed atrophy of the seminiferous tubules, spermatogenic arrest, and hyperplasia of the Leydig cells in MPEs-exposed rats. MPEs exposure also caused significant increments of testicular Nrf2, MDA, SOD, CAT and HO-1 expressions and lowered testicular Keap1 expression (P < 0.05). Treatment with quercetin at the median and high doses significantly ameliorated the pathological changes induced by MPEs exposure (P < 0.05). CONCLUSION Quercetin treatment inhibits MPEs-induced oxidative testicular damage in rats possibly by direct scavenging of free radicals to lower testicular oxidative stress and restore the regulation of the Nrf2 signaling pathway.
Rats ; Male ; Animals ; Testis ; Quercetin/pharmacology* ; Rats, Sprague-Dawley ; NF-E2-Related Factor 2/metabolism* ; Kelch-Like ECH-Associated Protein 1/metabolism* ; Oxidative Stress ; Testosterone/pharmacology* ; Superoxide Dismutase/metabolism* ; Follicle Stimulating Hormone ; Luteinizing Hormone

OBJECTIVE: This study investigated the effects of bis (2-butoxyethyl) phthalate (BBOP) on the onset of male puberty by affecting Leydig cell development in rats. METHODS: Thirty 35-day-old male Sprague-Dawley rats were randomly allocated to five groups mg/kg bw per day that were gavaged for 21 days with BBOP at 0, 10, 100, 250, or 500 mg/kg bw per day. The hormone profiles; Leydig cell morphological metrics; mRNA and protein levels; oxidative stress; and AKT, mTOR, ERK1/2, and GSK3β pathways were assessed. RESULTS: BBOP at 250 and/or 500 mg/kg bw per day decreased serum testosterone, luteinizing hormone, and follicle-stimulating hormone levels mg/kg bw per day (P < 0.05). BBOP at 500 mg/kg bw per day decreased Leydig cell number mg/kg bw per day and downregulated Cyp11a1, Insl3, Hsd11b1, and Dhh in the testes, and Lhb and Fshb mRNAs in the pituitary gland (P < 0.05). The malondialdehyde content in the testis significantly increased, while Sod1 and Sod2 mRNAs were markedly down-regulated, by BBOP treatment at 250-500 mg/kg bw per day (P < 0.05). Furthermore, BBOP at 500 mg/kg bw per day decreased AKT1/AKT2, mTOR, and ERK1/2 phosphorylation, and GSK3β and SIRT1 levels mg/kg bw per day (P < 0.05). Finally, BBOP at 100 or 500 μmol/L induced ROS and apoptosis in Leydig cells after 24 h of treatment in vitro (P < 0.05). CONCLUSION: BBOP delays puberty onset by increasing oxidative stress and apoptosis in Leydig cells in rats. UNLABELLED The graphical abstract is available on the website www.besjournal.com.
Rats ; Male ; Animals ; Leydig Cells/metabolism* ; Testosterone ; Glycogen Synthase Kinase 3 beta/pharmacology* ; Rats, Sprague-Dawley ; Sexual Maturation ; Testis ; Oxidative Stress ; TOR Serine-Threonine Kinases/metabolism* ; Apoptosis

Protein aggregation is a critical issue in the production of biopharmaceuticals. During protein production, transport and storage, various factors can lead to protein aggregation. With the in-depth study, different ways of protein aggregation and various influencing factors were identified. This includes physical and chemical factors, translation modifications and protein structure. Since protein aggregation exerts major impact on the activity and homogeneity of proteins, it is of great importance to study the ways of protein aggregation and how to control it to obtain high-quality proteins. The review focuses on three ways of protein aggregation, namely 3D domain swapping, salt bridge formation, and oxidative stress, as well as methods to control protein aggregation during protein production, transport and storage. This may facilitate reducing the loss caused by the formation of protein aggregation and improving the purity and homogeneity of protein in research and commercial production.
Protein Aggregates ; Proteins/chemistry* ; Oxidative Stress

Bisphenol A (BPA) is widely used to produce epoxy resin and polycarbonate plastic products. In severe cases, these plastics may release BPA, which then infiltrates into the environment. Various concentrations of BPA have been found in most biological fluid. Its presence has been well shown to be closely related to many chronic diseases, including chronic kidney disease (CKD). However, little is known regarding the adverse effects of BPA exposure and its succedent cellular events on CKD. Hence, in the current in vivo study, we aimed to assess the effects of chronic exposure to BPA on animal nephrotoxicity through investigating oxidative stress and apoptosis. Upon exposure to BPA at 0.01, 0.1, and 1 mg/L via drinking water for four weeks, the mated and pregnant females were continuously exposed to BPA until weaning. Subsequently, three weeks old F1-male neonates were also orally challenged with the same three doses of BPA for ten weeks. The results showed that the kidneys of 0.1 and 1 mg/L BPA-treated mice were seriously damaged; the contents of serum renal function indexes and lipid peroxidation products were significantly increased, including urea nitrogen, creatinine, uric acid, and thiobarbituric acid reactive substances; the morphological structure of mouse kidneys was impaired; the expressions of antioxidant-related genes at mRNA and protein levels from mouse kidneys were markedly diminished, including glutathione-S-transferase, superoxide dismutase, and catalase; the expressions of genes and proteins related to apoptosis index (ratio of Bax/Bcl-1 and Caspase-3) were significantly enhanced. The data manifested that cumulative oxidative stress and apoptosis might play an essential role in the animal nephrotoxicity induced by chronic exposure to BPA.
Female ; Male ; Mice ; Animals ; Oxidative Stress ; Antioxidants ; Apoptosis ; Renal Insufficiency, Chronic

Salvianolic acid B(Sal B) is the main water-soluble component of Salvia miltiorrhiza Bunge. Studies have found that Sal B has a good protective effect on blood vessels. Sal B can protect endothelial cells by anti-oxidative stress, inducing autophagy, inhibiting endoplasmic reticulum stress(ERS), inhibiting endothelial inflammation and adhesion molecule expression, inhibiting endothelial cell permeability, anti-thrombosis, and other ways. In addition, Sal B can alleviate endothelial cell damage caused by high glucose(HG). For vascular smooth muscle cell(VSMC), Sal B can reduce the synthesis and secretion of inflammatory factors by inhibiting cyclooxygenase. It can also play a vasodilatory role by inhibiting Ca~(2+) influx. In addition, Sal B can inhibit VSMC proliferation and migration, thereby alleviating vascular stenosis. Sal B also inhibits lipid deposition in the subendothelium, inhibits macrophage conversion to foam cells, and reduces macrophage apoptosis, thereby reducing the volume of subendothelial lipid plaques. For some atherosclerosis(AS) complications, such as peripheral artery disease(PAD), Sal B can promote angiogenesis, thereby improving ischemia. It should be pointed out that the conclusions obtained from different experiments are not completely consistent, which needs further research. In addition, previous pharmacokinetics showed that Sal B was poorly absorbed by oral administration, and it was unstable in the stomach, with a large first-pass effect in the liver. Sal B had fast distribution and metabolism in vivo and short drug action time. These affect the bioavailability and biological effects of Sal B, and the development of clinically valuable Sal B non-injectable delivery systems remains a great challenge.
Endothelial Cells ; Oxidative Stress ; Benzofurans/pharmacology* ; Lipids

To elucidate the chemical material basis of Rhododendron nivale, this study comprehensively used various chromatographic techniques to isolate and obtain five new meroterpenoid enantiomers(1a/1b-5a/5b) from the ethyl acetate extract of R. nivale. A variety of spectral analytical methods, such as high-resolution mass spectrometry(HRMS), nuclear magnetic resonance spectroscopy(NMR), and infrared(IR) spectrum, were used to evaluate the structure, combined with the measurement and calculation of electronic circular dichroism(ECD). The new compounds 1a/1b-4a/4b were named as(±)-nivalones A-B(1a/1b-2a/2b) and(±)-nivalnoids C-D(3a/3b-4a/4b), along with one known enantiomer(±)-anthoponoid G(5a/5b). Human neuroblastoma cells(SH-SY5Y cells) induced by hydrogen peroxide(H_2O_2) were used as oxidative stress models to evaluate the protective activity of the isolated compounds against oxidative damage to nerve cells. It was found that compounds 2a and 3a had a certain protective effect on nerve cells against H_2O_2-induced oxidative damage at concentrations of 50 μmol·L~(-1), which increased the cell survival rate from 44.02%±2.30% to 67.82%±1.12% and 62.20%±1.87%, respectively. Other compounds did not show a significant ability to protect cells from oxidative damage. These findings enrich the chemical constituents of R. nivale and provide valuable information for identifying the structure of its meroterpenoids.
Humans ; Rhododendron/chemistry* ; Neuroblastoma ; Oxidative Stress ; Magnetic Resonance Spectroscopy ; Stereoisomerism ; Molecular Structure

Objective: To investigate the effect of oxidative stress caused by heat exposure on the blood pressure increase of treadmill rats and the intervention of antioxidants. Methods: In June 2021, Twenty-four healthy SD male rats were randomly divided into four groups: normal temperature feeding, normal temperature treadmill, high temperature treadmill and high temperature treadmill supplementation with vitamin C groups, 6 rats in each group. The rats run on the platform in normal temperature or heat exposure environment for 30 min in the morning and in the afternoon daily, 6 days per week. The daily vitamin C supplement dose of high temperature treadmill supplementation with vitamin C group was 10 mg/kg. BP recordings were done at the end of the week. The rat vascular lipofuscin (LF) was detected by ELISA, the rat serum nitric oxide (NO) was detected by nitrate reductase method, the serum malondialdehyde (MDA) was detected by thibabituric acid method, the serum glutathione peroxidase (GPx) and superoxide dismutase (SOD) were detected by chemiluminescence method, and the serum catalase (CAT) was detected by ammonium molybdate method. The total antioxidant capacity (T-AOC) of serum was measured by iron reduction/antioxidant capacity method, and the content of nuclear erythroid 2-related factor 2 (Nrf2) in vascular tissue was measured by Western blot. The intra-group mean was compared by repeated measurement analysis of variance, and the inter-group mean was compared by single-factor analysis of variance and post-event LSD-t test. Results: Compared with the previous time point, the systolic BP and diastolic BP of the high temperature treadmill group were significantly increased at 7, 14 and 21 d, and decreased at 28 d which were higher than the initial level (P<0.05), and the systolic BP and diastolic BP values at each experimental time point were significantly higher than those of normal temperature treadmill group (P<0.001). The changes of thickening of the artery wall, no smoothing of the endodermis and irregular arrangement of muscle cells in high temperature treadmill group were observed. Compared with the normal temperature treadmill group, the content of MDA in serum, and LF in vascular tissue were significantly increased, the activities of SOD, CAT, T-AOC, the content of NO in serum, and the expression of Nrf2 in vascular tissue were significantly decreased in high temperature treadmill group (P<0.05). Compared with the high temperature treadmill group, the systolic BP and diastolic BP values at 7, 14, 21 and 28 d, the content of serum MDA and LF in vascular tissue were significantly decreased, the activities of CAT and T-AOC, and the expression of Nrf2 in vascular tissue significantly increased (P<0.05), the histopathological changes of the artery wall improved in high temperature treadmill supplementation with vitamin C group. Conclusion: Heat exposure has effect on oxidative stress, which may be related to the increase of BP. Vitamin C as an anti-oxidative enhancer can prevent those negative effects, which could alleviate the pathological changes of vessel intima in heat-exposed rats. And the Nrf2 may be a regulated factor to vascular protection.
Male ; Animals ; Rats ; Ascorbic Acid ; Antioxidants/pharmacology* ; Blood Pressure ; Hot Temperature ; NF-E2-Related Factor 2 ; Oxidative Stress ; Fever

Objective: To investigate the role of Keap1/Nrf2/HO-1 signaling pathway in liver injury induced by neodymium oxide (Nd(2)O(3)) in mice. Methods: In March 2021, forty-eight SPF grade healthy male C57BL/6J mice were randomly divided into control group (0.9% NaCl), low dose group (62.5 mg/ml Nd(2)O(3)), medium dose group (125.0 mg/ml Nd(2)O(3)), and high dose group (250.0 mg/ml Nd(2)O(3)), each group consisted of 12 animals. The infected groups were treated with Nd(2)O(3) suspension by non-exposed tracheal drip and were killed 35 days after dust exposure. The liver weight of each group was weighed and the organ coefficient was calculated. The content of Nd(3+) in liver tissue was detected by inductively coupled plasma mass spectrometry (ICP-MS). HE staining and immunofluorescence was used to observe the changes of inflammation and nuclear entry. The mRNA expression levels of Keap1, Nrf2 and HO-1 in mice liver tissue were detected by qRT-PCR. Western blotting was used to detect the protein expression levels of Keap1 and HO-1. The contents of catalase (CAT), glutathione peroxidase (GSH-Px) and total superoxide dismutase (T-SOD) were detected by colorimetric method. The contents of interleukin 1β (IL-1β), interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) were determined by ELISA. The data was expressed in Mean±SD. Two-independent sample t-test was used for inter-group comparison, and one-way analysis of variance was used for multi-group comparison. Results: Compared with the control group, the liver organ coefficient of mice in medium and high dose groups were increased, and the Nd(3+) accumulation in liver of mice in all dose groups were significantly increased (P<0.05). Pathology showed that the structure of liver lobules in the high dose group was slightly disordered, the liver cells showed balloon-like lesions, the arrangement of liver cell cords was disordered, and the inflammatory exudation was obvious. Compared with the control group, the levels of IL-1β and IL-6 in liver tissue of mice in all dose groups were increased, and the levels of TNF-α in liver tissue of mice in high dose group were increased (P<0.05). Compared with the control group, the mRNA and protein expression levels of Keap1 in high dose group were significantly decreased, while the mRNA expression level of Nrf2, the mRNA and protein expression levels of HO-1 were significantly increased (P<0.05), and Nrf2 was successfully activated into the nucleus. Compared with the control group, the activities of CAT, GSH-Px and T-SOD in high dose group were significantly decreased (P<0.05) . Conclusion: A large amount of Nd(2)O(3) accumulates in the liver of male mice, which may lead to oxidative stress and inflammatory response through activation of Keap1/Nrf2/HO-1 signal pathway. It is suggested that Keap1/Nrf2/HO-1 signal pathway may be one of the mechanisms of Nd(2)O(3) expose-induced liver injury in mice.
Mice ; Male ; Animals ; NF-E2-Related Factor 2/metabolism* ; Tumor Necrosis Factor-alpha/metabolism* ; Kelch-Like ECH-Associated Protein 1/metabolism* ; Interleukin-6/metabolism* ; Mice, Inbred C57BL ; Oxidative Stress ; Liver/metabolism* ; Metals, Rare Earth ; Signal Transduction ; Superoxide Dismutase/metabolism* ; RNA, Messenger/metabolism*