Glufosinate-ammonium causes liver injury in zebrafish by blocking the Nrf2 pathway.

Glufosinate-ammonium (GLA) is a widely used herbicide, but less research has been done on its harmful effects on non-target organisms, especially aquatic organisms. In this study, 600 adult zebrafish were exposed to different concentration of GLA (0, 1.25, 2.5, 5, 10, and 20 mg/L) for 7 days, and the livers were dissected on the eighth day to examine the changes in liver structure, function, oxidative stress, inflammation, apoptosis, and Nrf2 pathway, and finally to clarify the mechanism of GLA induced liver injury in zebrafish. The levels of alanine aminotransferase, aspartate aminotransferase, reactive oxygen species, malondialdehyde, inflammatory factors (IL-6 and TNF-α), and caspase-3 gradually increased, while the levels of superoxide dismutase, catalase, glutathione, and glutathione peroxidase gradually decreased with the increase of GLA concentration. The Nrf2 pathway was activated at low concentrations (1.25-5 mg/L) and significantly inhibited at high concentrations (10 and 20 mg/L). These results suggested that GLA could cause oxidative stress, inflammation, and apoptosis in zebrafish liver. Therefore, GLA can cause liver injury in zebrafish, and at high concentrations, the inhibition of Nrf2 pathway is one of the important causes of liver injury.

Paeoniflorin ameliorates lipopolysaccharide-induced acute liver injury by inhibiting oxidative stress and inflammation via SIRT1/FOXO1a/SOD2 signaling in rats.

Acute liver injury (ALI) is a poor prognosis and high mortality complication of sepsis. Paeoniflorin (PF) has remarkable anti-inflammatory effects in different disease models. Here, we explored the protective effect and underlying molecular mechanisms of PF against lipopolysaccharide (LPS)-induced ALI. Sprague-Dawley rats received intraperitoneal (i.p.) injection of PF for 7 days, 1 h after the last administration, and rats were injected i.p. 10 mg/kg LPS. PF improved liver structure and function, reduced hepatic reactive oxygen species (ROS) and methane dicarboxylic aldehyde (MDA) levels, and increased superoxide dismutase (SOD) activity. Western blot analysis suggested that PF significantly inhibited expression of inflammatory cytokines (TNF-α, IL-1ß, and IL-18) and inhibited activation of the NLRP3 inflammasome. PF or mitochondrial ROS scavenger (mito-TEMPO) significantly improved liver mitochondrial function by scavenging mitochondrial ROS (mROS), restoring mitochondrial membrane potential loss and increasing level of ATP and enzyme activity of complex I and III. In addition, PF increased expression of sirtuin-1 (SIRT1), forkhead box O1 (FOXO1a) and manganese superoxide dismutase (SOD2), and increased FOXO1a nuclear retention. However, the inhibitor of SIRT1 (EX527) abolished the protective effect of PF. Taken together, PF promotes mROS clearance to inhibit mitochondrial damage and activation of the NLRP3 inflammasome via SIRT1/FOXO1a/SOD2 signaling.

Autophagy Plays a Protective Role in Sodium Hydrosulfide-Induced Acute Lung Injury by Attenuating Oxidative Stress and Inflammation in Rats.

Sodium hydrosulfide (NaHS), as an exogenous hydrogen sulfide (H2S) donor, has been used in various pathological models. NaHS is usually considered to be primarily protective, however, the toxic effect of NaHS has not been well elucidated. The aim of this study was to investigate whether NaHS (1 mg/kg) can induce acute lung injury (ALI is a disease process characterized by diffuse inflammation of the lung parenchyma) and define the mechanism by which NaHS-induced ALI involves autophagy, oxidative stress, and inflammatory response. Wistar rats were randomly divided into three groups (control group, NaHS group, and 3-MA + NaHS group), and samples from each group were collected from 2, 6, 12, and 24 h. We found that intraperitoneal injection of NaHS (1 mg/kg) increased the pulmonary levels of H2S and oxidative stress-related indicators (reactive oxygen species, myeloperoxidase, and malondialdehyde) in a time-dependent manner. Intraperitoneal injection of NaHS (1 mg/kg) induced histopathological changes of ALI and inhibition of autophagy exacerbated the lung injury. This study demonstrates that administration of NaHS (1 mg/kg) induces ALI in rats and autophagy in response to ROS is protective in NaHS-induced ALI by attenuating oxidative stress and inflammation.

Toxic effects of hydrogen sulfide donor NaHS induced liver apoptosis is regulated by complex IV subunits and reactive oxygen species generation in rats.

In recent years, the protective effect of hydrogensulfide donor sodium hydrosulfide(NaHS) on multiple organs has been widely reported. The study aimed to explorethe effect of commonly used concentration of NaHS on theliver and its potential damage mechanism. Rats divided into 4 groups: control, NaHS I (1 mg/kg), II (3 mg/kg) and III(5 mg/kg) groups, and each group is divided into four-timepoints (2, 6, 12, and 24 hours). Results showed that H2S concentration increased, mitochondrial complex IV activity inhibited, the COX I and IV subunits and mitochondrial apoptosis pathway-related proteins expression increased in atime- and dose-dependent manner. We confirmed that 1 mg/kg NaHS had no injuryeffect on the liver, 3 and 5 mg/kg NaHS inhibitsthe activity of mitochondrial complex IV by promoting COX I and IV subunits expression, leading to the increase in ROS and ultimately inducing apoptosis and liver injury.

Dexmedetomidine improves acute stress-induced liver injury in rats by regulating MKP-1, inhibiting NF-κB pathway and cell apoptosis.

Acute stress is a frequent and unpredictable disease for many animals. Stress is widely considered to affect liver function. However, the underlying mechanism by which dexmedetomidine (DEX) attenuates acute stress-induced liver injury in rats remains unclear. In this study, we used forced swimming for 15 min and acute 3-hr restraint stress model. Behavioral tests and changes in norepinephrine levels confirmed the successful establishment of the acute stress model. Acute stress-induced liver injury, evidenced by hematoxylin and eosin-stained pathological sections and increased serum aminotransferase and aspartate aminotransferase levels, was reduced in DEX-treated livers. Reactive oxygen species and oxidative stress levels were dramatically decreased with DEX treatment compared with acute stress-induced liver injury. DEX significantly reduced acute stress-induced liver inflammation and apoptosis, as assessed by terminal deoxynucleotidyl transferase dUTP nick-end labeling staining and inflammation and apoptosis-related protein levels. DEX treatment also effectively inhibited acute stress-induced c-Jun N-terminal kinase (JNK), P38, and BAD signaling pathway activation, and significantly induced MKP-1 activation. Thus, DEX has a protective effect on acute-stress-induced liver injury by reducing inflammation and apoptosis, which suggests a potential clinical application for DEX in stress syndrome.

Dexmedetomidine ameliorates lipopolysaccharide-induced acute kidney injury in rats by inhibiting inflammation and oxidative stress via the GSK-3ß/Nrf2 signaling pathway.

Acute kidney injury (AKI) is a frequent and serious complication of sepsis; however, there are currently no effective therapies. Inflammation and oxidative stress are the major mechanisms implicated in lipopolysaccharide (LPS)-induced AKI. Dexmedetomidine (DEX) has been reported to have remarkable anti-inflammatory and antioxidant effects. Here, we examined the renoprotective effects of DEX and potential underlying mechanisms in rats with LPS-induced AKI. We analyzed renal function and structure; serum inflammatory cytokine; renal oxidant and antioxidant levels; and renal expression of glycogen synthase kinase-3ß (GSK-3ß)/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway-related proteins in rats 4 hr after administration of LPS. Pretreatment with DEX improved renal function and significantly reduced the levels of inflammatory cytokines and oxidative stress markers. Treatment with DEX and the GSK-3ß inhibitor SB216367 promoted phosphorylation of GSK-3ß, induced Nrf2 nuclear translocation, and increased transcription of the Nrf2 target genes heme oxygenase-1 and NAD(P)H quinone oxidoreductase-1, primarily in renal tubules. Alpha-2-adrenergic receptor (α2-AR) antagonist atipamezole and imidazoline I 2 receptor (I 2 R) antagonist idazoxan reversed the effects of DEX. These results suggest that the renoprotective effects of DEX are mediated via α2-AR and I 2 R-dependent pathways that reduce inflammation and oxidative stress through GSK-3ß/Nrf2 signaling.

Dexmedetomidine alleviates lipopolysaccharide-induced acute kidney injury by inhibiting the NLRP3 inflammasome activation via regulating the TLR4/NOX4/NF-κB pathway.

Dexmedetomidine (DEX) prevents kidney damage caused by sepsis, but the mechanism of this effect remains unclear. In this study, the protective molecular mechanism of DEX in lipopolysaccharide (LPS)-induced acute kidney injury was investigated and its potential pharmacological targets from the perspective of inhibiting oxidative stress damage and the nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome activation. Intraperitoneal injection of DEX (30 µg/kg) significantly improved LPS (10 mg/kg) induced renal pathological damage and renal dysfunction. DEX also ameliorated oxidative stress damage by reducing the contents of reactive oxygen species, malondialdehyde and hydrogen peroxide, and increasing the level of glutathione, as well as the activity of superoxide dismutase and catalase. In addition, DEX prevented nuclear factor-kappa B (NF-κB) activation and I-kappa B (IκB) phosphorylation, as well as the expressions of NLRP3 inflammasome-associated protein and downstream IL-18 and IL-1ß. The messengerRNA (mRNA) and protein expressions of toll-like receptor 4 (TLR4), NADPH oxidase-4 (NOX4), NF-κB, and NLRP3 were also significantly reduced by DEX. Their expressions were further evaluated by immunohistochemistry, yielding results were consistent with the results of mRNA and protein detection. Interestingly, the protective effects of DEX were reversed by atipamezole-an alpha 2 adrenal receptor (α2 AR) inhibitor, whereas idazoxan-an imidazoline receptor (IR) inhibitor failed to reverse this change. In conclusion, DEX attenuated LPS-induced AKI by inhibiting oxidative stress damage and NLRP3 inflammasome activation via regulating the TLR4/NOX4/NF-κB pathway, mainly acting on the α2 AR rather than IR.

Dexmedetomidine attenuates lipopolysaccharide-induced liver oxidative stress and cell apoptosis in rats by increasing GSK-3ß/MKP-1/Nrf2 pathway activity via the α2 adrenergic receptor.

Dexmedetomidine (DEX) protects against liver damage caused by sepsis. The purpose of this study was to confirm the regulatory effects of DEX on glycogen synthase kinase 3 beta (GSK-3ß) via the α2 adrenergic receptor (α2AR) and evaluate the role of GSK-3ß in lipopolysaccharide (LPS)-induced liver injury. Sprague-Dawley (SD) rats were administered an intraperitoneal injection of DEX (30 µg/kg) 30 min before an intraperitoneal injection of LPS (10 mg/kg). HE staining and serum biochemical test results indicated that DEX significantly improved liver histopathological damage and liver function indices. Furthermore, DEX increased super oxide dismutase (SOD) activity and L-glutathione (GSH) levels, and inhibited malondialdehyde (MDA) production. Western blot (WB) analysis demonstrated that treatment with the GSK-3ß inhibitor SB216763 increased antioxidant-related protein mitogen-activated protein kinase phosphatase 1 (MKP-1) and nuclear factor erythroid 2-related factor 2 (Nrf2) expression. In addition, anti-apoptosis-related proteins were up-regulated and pro-apoptosis-related proteins were down-regulated by SB21676 administration. WB analysis also showed that DEX increased anti-apoptosis-related protein levels and decreased pro-apoptotic protein levels in LPS-induced liver injury. Nrf2, p53, and activated caspase-3 levels were further evaluated using immunohistochemistry (IHC), producing results consistent with WB results. The α2AR antagonist atipamezole (AT) significantly reversed the protective effects of DEX, as shown by WB analysis. Our data suggested that α2AR plays an important role in reversing the effects of liver oxidative stress and apoptosis via DEX, and that DEX exerts antioxidant and anti-apoptosis effects through regulation of the GSK-3ß/MKP-1/Nrf2 pathway.

Dexmedetomidine protects against lipopolysaccharide-induced early acute kidney injury by inhibiting the iNOS/NO signaling pathway in rats.

Increasing evidence has demonstrated that dexmedetomidine (DEX) possesses multiple pharmacological actions. Herein, we explored the protective effect and potential molecular mechanism of DEX on lipopolysaccharide (LPS)-induced early acute kidney injury (AKI) from the perspective of antioxidant stress. We found that DEX (30 µg/kg, i.p.) ameliorated the renal dysfunction and histopathological damage (tubular necrosis, vacuolar degeneration, infiltration of inflammatory cells and cast formation) induced by LPS (10 mg/kg). DEX also attenuated renal oxidative stress remarkably in LPS-induced early AKI, as evidenced by reduction in production of reactive nitrogen species, decreasing malondialdehyde levels, as well as increasing superoxide dismutase activity and glutathione content. DEX prevented activator protein-1 translocation, inhibited phosphorylation of I-kappa B (IκB) and activation of nuclear factor kappa B (NF-κB) in LPS-induced early AKI, as assessed by real-time quantitative polymerase chain reaction and protein levels of c-Jun, c-Fos, IκB and NF-κB. Notably, DEX pretreatment had the same effect as intraperitoneal injection of an inhibitor of inducible nitric oxide synthase inhibitor (1400W; 15 mg/kg), and inhibited the activity of renal inducible nitric oxide synthase (iNOS) and decreased the expression of iNOS mRNA and NO production. However, the protective effect of DEX on LPS-induced early AKI was reversed by the alpha 2 adrenal receptor (α2-AR) inhibitor atipamezole, whereas the imidazoline receptor inhibitor idazoxan did not. Taken together, DEX protects against LPS-induced early AKI in rats by inhibiting the iNOS/NO signaling pathway, mainly by acting on α2-ARs instead of IRs.

Hydrogen sulfide attenuates isoflurane-induced neuroapoptosis and cognitive impairment in the developing rat brain.

BACKGROUND: Isoflurane-induced neuroapoptosis and cognitive impairment has been previously reported. Hydrogen sulfide (H2S) has been shown to be a neuromodulator that is thought to have anti-apoptotic, anti-inflammatory, and anti-oxidative benefits. However, it is not known if H2S is protective against anesthesia-induced apoptosis and cognitive defects. METHODS: In this study, postnatal day 7 (P7) Sprague-Dawley rats were randomly divided into four groups: control group (normal saline), H2S group (NaHS 28 µM/kg), isoflurane group (normal saline +0.75% isoflurane) and H2S preconditioning group (NaHS 28 µM/kg + 0.75% isoflurane). After exposure to isoflurane for 6 h, half the numbers of rats in each group were euthanized, and the hippocampus and cerebral cortex were dissected and examined for apoptosis by the terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) technique and western blot. After 6 weeks, the remaining rats were subjected to a Morris water maze (MWM) test for behavioral assessment. RESULTS: The TUNEL assay and western blot showed that when rats were preconditioned with NaHS, neuroapoptosis decreased significantly both in hippocampus and cerebral cortex compering with the isofulrane group. The MWM showed that P7 rats administration of NaHS improved cognitive impairments induced by isoflurane. CONCLUSIONS: The current study demonstrates that H2S attenuates isoflurane-induced neuroapoptosis and improves cognitive impairments in the developing rat brain.

Behavioral and cardiopulmonary effects of dexmedetomidine-midazolam and dexmedetomidine-midazolam-butorphanol in the silver fox (Vulpes vulpes).

OBJECTIVE: To evaluate the behavior and some cardiopulmonary variables of dexmedetomidine-midazolam or dexmedetomidine-midazolam-butor-phanol in the silver fox (Vulpes vulpes). STUDY DESIGN: Blinded, randomized design. ANIMALS: Sixteen adult silver foxes, aged 7-9 months, weighting 6.0-9.2 kg. METHODS: Animals were randomly assigned to dexmedetomidine (50 µg kg-1) and midazolam (0.45 mg kg-1) (group DM) or to dexmedetomidine (30 µg kg-1), midazolam (0.45 mg kg-1) and butorphanol (0.25 mg kg-1) (group DMB), administered intramuscularly. Pulse rate (PR), respiratory rate (fR), noninvasive arterial pressures, oxygen saturation (SpO2), rectal temperature (T) and behavioral scores (posture, sedation, antinociception, jaw relaxation and auditory response) were measured at 5, 10, 20, 30, 40, 50 and 60 minutes after injection. Time from drug injection to recumbency with no response to stimuli (IT) and time from administration of atipamezole (0.2 mg kg-1) to standing with coordination (RT) were recorded. The occurrences of adverse events were recorded. Data were analyzed by two-tailed unpaired t-tests and Bonferroni post hoc tests. Significant differences were accepted at p<0.05. RESULTS: There were no statistically significant differences between the groups for IT or RT. Arterial pressures were higher in DMB at each time point except at 5 minutes. PR was lower in DM at each time point except at 10 and 60 minutes. No significant difference was found between the groups for fR, SpO2 and T. The behavioral scores were significantly lower (lower quality immobilization) in DMB at 5,10 and 60 minutes. CONCLUSIONS AND CLINICAL RELEVANCE: IT and RT were not different between the groups. Both protocols provided immobilization for 30-40 minutes with excellent muscle relaxation and analgesia adequate for clinical examinations and some simple surgical procedures.

Comparison of the effects of propofol and emulsified isoflurane alone or combined with dexmedetomidine on induction of anesthesia in dogs.

OBJECTIVE: To compare the respective effects of propofol and emulsified isoflurane administered alone and in combination with dexmedetomidine on the quality of induction of anesthesia, physiological variables and recovery in dogs. STUDY DESIGN: Prospective, randomized, experimental trial. ANIMALS: Thirty-six adult mixed-breed dogs. METHODS: Animals were randomly assigned to one of four induction protocols: propofol alone (group P); emulsified isoflurane alone (group EI); both propofol and dexmedetomidine (group PD), or both emulsified isoflurane and dexmedetomidine (group EID). Pulse rate (PR), respiratory rate (fR ), non-invasive arterial blood pressure and arterial blood gases were measured at baseline, before induction, immediately after intubation (time 0), and at 5 minute intervals until the dog began to swallow and the trachea was extubated. The quality of induction and recovery, and degree of ataxia were scored by a single investigator unaware of group assignment. The durations of anesthesia and recovery, and the incidence of adverse events were recorded. RESULTS: There were no clinically significant differences among the groups in induction quality. Systolic arterial pressure was lower in EID compared with P at 5 minutes. PR and fR were lower in PD and EID compared with P after induction. The PaCO2 at 5 minutes was higher than at baseline in group P. Ataxia score was lower in EID than in P. Time from induction to extubation and time from extubation to sternal recumbency were lower in EID compared with PD. CONCLUSIONS AND CLINICAL RELEVANCE: There were no clinically significant differences among the groups in induction quality. In PD and EID, but not in P, PR and fR were decreased after induction. The EID combination resulted in smooth and rapid induction and recovery and thus may be useful clinically for induction of anesthesia.

Swine Colibacillosis: Analysis of the Gut Bacterial Microbiome.

This study aimed to evaluate the disruption of the swine gut microbiota and histopathological changes caused by infection with enterotoxigenic E. coli. Fecal samples were collected from piglets suffering from diarrhea post-recovery and healthy animals. Intestinal tissues were collected for histopathological changes. The results revealed histopathological changes mainly in the ileum of the infected animals compared to those in the ileum of the control and recovered animals. The operational taxonomic units (OTUs) revealed that the E. coli diarrheal group exhibited the highest bacterial richness. Principal coordinate analysis (PCoA) corroborated the presence of dysbiosis in the gut microbiota following E. coli-induced diarrhea. While the normal control and infected groups displayed slight clustering, the recovery group formed a distinct cluster with a distinct flora. Bacteroidetes, Firmicutes, and Fusobacteria were the dominant phyla in both the healthy and recovered piglets and in the diarrheal group. LEfSe and the associated LDA score analysis revealed that the recovered group exhibited dominance of the phyla Euryarchaeota and Bacteroidota, while groups N and I showed dominance of the phyla Firmicutes and Fusobacteriota, respectively. The LDA scores highlighted a significant expression of the Muribaculacea family in group R. The obtained findings will help in understanding the microbiome during swine colibacillosis, which will support control of the outbreaks.

Dexmedetomidine Alleviates Acute Stress-Induced Acute Kidney Injury by Attenuating Inflammation and Oxidative Stress via Inhibiting the P2X7R/NF-κB/NLRP3 Pathway in Rats.

This study aimed to investigate the potential protective effects of Dexmedetomidine (DEX) against acute kidney injury (AKI) induced by acute stress (AS). Wistar rats were divided into five groups: Control, DEX, AS, AS + DEX, and AS + A438079. The results showed that AS led to AKI by increasing inflammatory biomarkers and oxidative stress-related indicators. The acute stress model in rats was successfully established. Renal function, histopathology, oxidative stress, and inflammation were assessed. Localization of P2X7 receptor (P2X7R) was determined by immunofluorescence. Additionally, the key inflammatory proteins of the P2X7R/NF-κB/NLRP3 signaling pathway were measured by Western blotting. DEX significantly improved kidney function, alleviated kidney injury, and reduced oxidative stress and inflammation. DEX inhibited the activation of the P2X7R, decreased the expression of NF-κB, NLRP3 inflammasome, and Caspase-1, and inhibited the expression of interleukin-1ß (IL-1ß) and tumor necrosis factor α (TNFα). Furthermore, DEX also alleviated AS-induced AKI by inhibiting the excessive production of reactive oxygen species (ROS) and reducing oxidative stress. In conclusion, DEX attenuates AS-induced AKI by mitigating inflammation and oxidative stress through the inhibition of the P2X7R/NF-κB/NLRP3 pathway in rats.

PFOS Exposure Promotes Hepatotoxicity in Quails by Exacerbating Oxidative Stress and Inflammation-Induced Apoptosis through Activating TLR4/MyD88/NF-κb Signaling.

PFOS is a ubiquitous pollutant garnering considerable attention due to its deleterious effects on both human and animal health. Given the poultry industry's intimate link with human health, investigating PFOS's impact on quails is crucial. PFOS readily accumulates in the liver, causing hepatotoxicity, yet its molecular mechanisms remain elusive. In our study, we fed quail diets contaminated with varying PFOS concentrations (12.5, 25, and 50 mg/kg) and observed dose-dependent liver damage in quails. The results show that PFOS damages mitochondrial structure, increases ROS levels, and downregulates antioxidants to promote oxidative stress damage in hepatocytes. PFOS also upregulated pro-inflammatory molecules (TNF-α, IL-1ß, and IL-6) while downregulating the anti-inflammatory factor IL-10, activating the TLR4//MyD88/NF-κB signaling pathway, thereby potentiating liver inflammation. Then, oxidative stress and inflammation by PFOS induce apoptosis in quail hepatocytes through the mitochondrial pathway, with severity closely related to hepatotoxicity. In conclusion, PFOS induces mitochondrial apoptosis by exacerbating oxidative stress and inflammation by activating the TLR4/MyD88/NF-κB signaling pathway, ultimately leading to hepatotoxicity in quails.

Network pharmacology and in vivo studies reveal the pharmacological effects and molecular mechanisms of Celastrol against acute hepatic injury induced by LPS.

Sepsis is currently the main factor of death in the ICU, and the liver, as an important organ of immunity and stable metabolism, can be acutely damaged during sepsis, and the mortality rate of patients with sepsis complicated by acute liver injury is greatly increased. Celastrol (CEL) is derived from the root bark of Tripterygium wilfordii Hook.f.. As a traditional Chinese medicine, CEL has anti-inflammatory, anti-cancer, anti-oxidant, and other biological activities. Obtain CEL and AHI intersection targets via database and construct protein-protein interaction (PPI) network by STRING. GO functional enrichment and KEGG pathway analyses were performed by R studio. Targets were finally selected to perform molecular docking simulations with CEL. In vivo experiments based on the model of AHI were established by intraperitoneal injection of Lipopolysaccharide (LPS) 4 h, and pre-treated with CEL (0.5 mg/kg, 1 mg/kg, 1.5 mg/kg). The results are as follows: 273 genes with the intersection of CEL and AHI were obtained, and GO and KEGG enrichment analysis were used to design the mechanism of inflammation, apoptosis, and oxidative stress-related injury. By constructing the PPI network selected top 10 targets are: STAT3, RELA, MAPK1, MAPK3, TP53, AKT1, HSP90AA1, JUN, TNF, MAPK14, predicted CEL protection AHI design related pathways of MAPK and PI3K/AKT-related signal pathways. In vivo experiments, CEL inhibited the activation of MAPK and PI3K/AKT related pathways, reduced inflammatory response, apoptosis, and oxidative stress, and significantly improved LPS-induced AHI. In summary, this study predicted the mechanisms involved in the protective effect of CEL on AHI through network pharmacology. In vivo, CEL inhibited MAPK and PI3K/AKT-related signaling pathways, and reduced inflammatory response, apoptosis, and oxidative stress to protect LPS-induced AHI.

Chlorogenic Acid Alleviates Chronic Stress-Induced Intestinal Damage by Inhibiting the P38MAPK/NF-κB Pathway.

Chronic stress can cause intestinal barrier damage. MAPK and NF-κB are closely related to it. Chlorogenic acid (CGA), a dietary polyphenol, has been shown to have intestinal protective effects, but whether by regulating MAPK and NF-κB is not known. Therefore, in this experiment, 24 Wistar rats were randomly divided into 4 groups (C group, CS group, CS + SB203580, and CS + CGA group). Rats in the CS group were restrained stress for 6 h per day for 21 days. Rats in the CS + SB203580 group were given SB203582 (0.5 mg/kg, intraperitoneal injection) 1 h before restraint stress every other day. Rats in the CS + CGA group were given CGA (100 mg/kg, gavage) 1 h before restraint stress. In chronic stress, intestinal barrier damage was evident, while being restored after CGA treatment. After chronic stress, the levels of p-P38 were increased (P < 0.01), while the levels of p-JNK and p-ERK were not changed. The levels of p-p38 were elevated after CGA treatment (P < 0.01). These results suggested that p38MAPK played an important role in chronic stress-induced intestinal injury, and CGA could inhibit p38MAPK activity. Therefore, we chose SB203582 (P38MAPK inhibitor) to elucidate the role of p38. After chronic stress, intestinal tight junction key proteins Occludin, ZO-1, and Claudin3 protein and gene expression were reduced (P < 0.01), while being elevated after CGA or SB203582 intervention (P < 0.05). After CGA treatment, the levels of p-IκB, p-p65, p-p38, and TNF-α were reduced (P < 0.01). SB203582 intervention reduced p-p65 and TNF-α levels significantly (P < 0.01). These results suggested that CGA could inhibit the NF-κB pathway by suppressing p38MAPK, thereby alleviating chronic stress-induced intestinal damage.

The analysis of spatial-temporal effects of relevant factors on carbon intensity in China.

The increasing carbon emissions have been a major concern for most countries around the world. And as a result, every country is concerned about developing appropriate strategies to curtail it. As a major economy and the largest carbon emitter in the world, China has pledged to reduce the carbon intensity by 60-65% by 2030, compared with 2005 levels, and achieve carbon neutrality before 2060. Therefore, the analysis of the impact of China's carbon intensity is becoming an increasing important topic. Due to the spatial heterogeneity of carbon intensity, various spatial econometric models have been applied in this field. However, the existing literatures failed to consider the cross-products of relevant factors. This paper constructs our dynamic general nesting spatial panel model (GNS) with common factors to deal with the dilemma, and examines the direct and spatial-temporal spillover effects of industrial structure, GDP per capita, investment in anti-pollution projects as percentage of GDP and energy price on carbon intensity in China over the period 2003-2017. Our analysis shows that: (1) China's carbon intensity showed the spatial agglomeration and temporal "inertia" from 2003 to 2017. (2) From the time dimension, the long-term effect of industrial structure first increased and then gradually decreased. (3) From the spatial dimension, industrial structure and investment in anti-pollution projects as percentage of GDP accounted for the main spatial heterogeneity. Furthermore, this paper attempts to provide policy implications to help reduce carbon intensity and achieve carbon neutrality in China.

Melatonin attenuates chronic stress-induced hippocampal inflammatory response and apoptosis by inhibiting ADAM17/TNF-α axis.

Melatonin, as a dietary supplement, has a potent neuroprotective effect and exerts a certain antidepressant effect. This study explored the molecular mechanisms and targets of melatonin on chronic stress-induced hippocampal damage from the perspective of inhibiting inflammatory cytokines release. Our results indicated that melatonin alleviated chronic restraint stress (CRS)-induced inflammatory response and apoptosis, thus improving hippocampal structural damage and subsequent depression-like behaviors in rats. The radar map displayed that the change of TNF-α content was the most significant. Meanwhile, correlation analysis showed that TNF-α content was highly positively correlated with apoptosis. Molecular autodocking studies suggested that TNF-α converting enzyme ADAM17 as a potential target has a priority in docking with melatonin. Molecular mechanism studies indicated that melatonin inhibited CRS-induced activation of the ADAM17/TNF-α axis and its downstream proteins p38 and p53 phosphorylation in the hippocampus. Analogously, Both ADAM17 inhibitor TMI-1 and TNF-α inhibitor thalidomide relieved the effects of CRS on ADAM17/TNF-α axis and its downstream proteins phosphorylation, hippocampal apoptosis, hippocampal inflammatory response, and depression-like behaviors in rats. Altogether, these findings reveal that melatonin relieves CRS-induced inflammatory response and apoptosis, and subsequent depression-like behaviors by inhibiting ADAM17/TNF-α axis.

Lycopene Alleviates Chronic Stress-Induced Spleen Apoptosis and Immunosuppression via Inhibiting the Notch Signaling Pathway in Rats.

Chronic stress induction in immunosuppression and splenocyte apoptosis is commonly associated with increased susceptibility to various diseases. Lycopene (LYC) is a member of the carotenoid family with immune restoration and anti-apoptotic function. However, little is known about the mechanisms underlying the protective roles of LYC against spleen injury induced by chronic stress. Herein, male Wistar rats were undergoing chronic restraint stress and/or administered LYC (10 mg/kg) for 21 days. The effective model establishment was validated by open-field tests and levels of corticosterone in serum. Histopathological staining observation displayed that LYC could reduce chronic stress-induced spleen structure damage. Furthermore, LYC treatment significantly reduced the number of apoptotic-positive splenocytes caused by chronic stress via the death receptor apoptotic pathway. We detected the interleukin 4 and interferon γ levels in serum and spleen to determine the ratio of Th1 and Th2 and found that LYC can alleviate the immunosuppression induced by chronic stress. Notably, western blot and real-time polymerase chain reaction indicated that LYC can reduce the expression of the Notch-pathway-related proteins and mRNA in rats exposed to chronic stress. Further study of the potential mechanisms by adding the Notch pathway inhibitor DAPT revealed that LYC alleviates the structure damage, apoptosis, and immunosuppression caused by chronic stress via the suppression of the Notch pathway. Overall, this study presents a strong rationale to target LYC as a treatment strategy to relieve chronic stress-induced spleen injury.