The c-Fos/AP-1 inhibitor inhibits sulfur mustard-induced chondrogenesis impairment in zebrafish larvae.

Sulfur mustard (SM, dichlorodiethyl sulfide) is a potent erosive chemical poison that can cause pulmonary lung, skin and eye disease complications in humans. Currently, there is no designated remedy for SM, and its operation's toxicological process remains unidentified. This work employed zebrafish as a model organism to investigate the toxic manifestations and mechanisms of exposure to SM, aiming to offer novel insights for preventing and treating this condition. The results showed that SM caused a decrease in the survival rate of the zebrafish larvae (LC50 = 2.47 mg/L), a reduction in the hatching rate, an increase in the pericardial area, and small head syndrome. However, T-5224 (a selective inhibitor of c-Fos/activator protein) attenuated the reduction in mortality (LC50 = 2.79 mg/L), the reduction in hatching rate, and the worsening of morphological changes. We discovered that SM causes cartilage developmental disorders in zebrafish larvae. The reverse transcription-quantitative polymerase chain reaction found that SM increased the expression of inflammation-related genes (IL-1ß, IL-6, and TNF-α) and significantly increased cartilage development-related gene expression (fosab, mmp9, and atf3). However, the expression of sox9a, sox9b, and Col2a1a was reduced. The protein level detection also found an increase in c-fos protein expression and a significant decrease in COL2A1 expression. However, T-5224,also and mitigated the changes in gene expression, and protein levels caused by SM exposure. The results of this study indicate that SM-induced cartilage development disorders are closely related to the c-Fos/AP-1 pathway in zebrafish.

Cardiotoxicity of (-)-borneol, (+)-borneol, and isoborneol in zebrafish embryos is associated with Na+ /K+ -ATPase and Ca2+ -ATPase inhibition.

Borneol is an example of traditional Chinese medicine widely used in Asia. There are different isomers of chiral borneol in the market, but its toxicity and effects need further study. In this study, we used zebrafish embryos to examine the effects of exposure to three isomers of borneol [(-)-borneol, (+)-borneol, and isoborneol] on heart development and the association with Na+ /K+ -ATPase from 4 h post-fertilization (4 hpf). The results showed that the three isomers of borneol increased mortality and decreased hatching rate when the zebrafish embryo developed to 72 hpf. All three isomers of borneol (0.01-1.0 mM) significantly reduced heart rate from 48 to 120 hpf and reduced the expression of genes related to Ca2+ -ATPase (cacna1ab and cacna1da) and Na+ /K+ -ATPase (atp1b2b, atp1a3b, and atp1a2). At the same time, the three isomers of borneol significantly reduced the activities of Ca2+ -ATPase and Na+ /K+ -ATPase at 0.1 to 1.0 mM. (+)-Borneol caused the most significant reduction (p < 0.05), followed by isoborneol and (-)-borneol. Na+ /K+ -ATPase was mainly expressed in otic vesicles and protonephridium. All three isomers of borneol reduced Na+ /K+ -ATPase mRNA expression, but isoborneol was the most significant (p < 0.01). Our results indicated that (+)-borneol was the least toxic of the three isomers while the isoborneol showed the most substantial toxic effect, closely related to effects on Na+ /K+ -ATPase.

Tissue-specific regulatory mechanism of LncRNAs and methylation in sheep adipose and muscle induced by Allium mongolicum Regel extracts.

Allium mongolicum Regel (A. mongolicum) is a perennial and xerophytic Liliaceous allium plant in high altitude desert steppe and desert areas. Feeding A. mongolicum greatly reduced unpleasant mutton flavor and improves meat quality of sheep. We analyzed epigenetic regulatory mechanisms of water extracts of A. mongolicum (WEA) on sheep muscle and adipose using RNA-Seq and whole-genome Bisulfite sequencing. Feeding WEA reduced differentially expressed genes and long non-coding RNAs (lncRNAs) between two tissues but increased differentially methylation regions (DMRs). LncRNA and DMR targets were both involved in ATP binding, ubiquitin, protein kinase binding, regulation of cell proliferation, and related signaling pathways, but not unsaturated fatty acids metabolism. Besides, tissue specific targets were involved in distinct functional annotations, e.g., Golgi membrane and endoplasmic reticulum for muscle lncRNA, oxidative phosphorylation metabolism for adipose lncRNA, dsRNA binding for muscle DMRs. Epigenetic regulatory networks were also discovered to discovered essential co-regulated modules, e.g., co-regulated insulin secretion module (PDPK1, ATP1A2, CACNA1S and CAMK2D) in adipose. The results indicated that WEA induced distinct epigenetic regulation on muscle and adipose to diminish transcriptome differences between tissues, which highlights biological functions of A. mongolicum, tissue similarity and specificity, as well as regulatory mechanism of mutton odor.

Sulforaphane attenuates hexavalent chromium-induced cardiotoxicity via the activation of the Sesn2/AMPK/Nrf2 signaling pathway.

Hexavalent chromium (Cr(vi)), the most toxic valence state of chromium, is widely present in industrial effluents and wastes. Sulforaphane (SFN), rich in Brassica genus plants, bears multiple biological activity. Wistar rats were used to explore the protective role of SFN against the cardiotoxicity of chronic potassium dichromate (K2Cr2O7) exposure and reveal the potential molecular mechanism. The data showed that SFN alleviated hematological variations, oxidative stress, heart dysfunction and structure disorder, and cardiomyocyte apoptosis induced by K2Cr2O7. Moreover, SFN reduced p53, cleaved caspase-3, Bcl2-associated X protein, nuclear factor kappa-B, and interleukin-1ß levels, and increased Sesn2, nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1, NAD(P)H quinone oxidoreductase-1, and phosphorylated adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) levels. This study demonstrates that SFN ameliorates Cr(vi)-induced cardiotoxicity via activation of the Sesn2/AMPK/Nrf2 signaling pathway. SFN may be a protector against Cr(vi)-induced heart injury and a novel therapy for chronic Cr(vi) exposure.

Hexavalent chromium induces mitochondrial dynamics disorder in rat liver by inhibiting AMPK/PGC-1α signaling pathway.

Occupational exposure to hexavalent chromium (Cr(VI)) can cause cytotoxicity and carcinogenicity. In this study, we established a liver injury model in rats via intraperitoneal injection of potassium dichromate (0, 2, 4, and 6 mg/kg body weight) for 35 d to investigate the mechanism of Cr(VI)-induced liver injury. We found that Cr(VI) induced hepatic histopathological lesions, oxidative stress, and apoptosis and reduced the expression of mitochondrial-related regulatory factors such as adenosine 5'-monophosphate-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) in a dose-dependent manner. Furthermore, Cr(VI) promoted mitochondrial division and inhibited fusion, leading to increased expression of caspase-3 and production of mitochondrial reactive oxygen species. Our study demonstrates that long-term exposure to Cr(VI) induces mitochondrial dynamics disorder by inhibiting AMPK/PGC-1α signaling pathway in rat liver.

Imidacloprid-induced liver fibrosis in quails via activation of the TGF-ß1/Smad pathway.

Imidacloprid (IMI) is one of the most frequently used neonicotinoid insecticide, and its potential toxicity and environmental hazards have gradually attracted people's attention. Liver fibrosis caused by long-term inflammation or oxidative stress can lead to cirrhosis and liver failure, even death. However, the mechanism of liver fibrosis induced by neonicotinoid insecticide remains unclear. This study investigates whether IMI could induce liver fibrosis in quails and a potential mechanism. Our study used a quail 90-day IMI-induced liver fibrosis model. The results showed that IMI induced histopathological lesions, oxidative stress, inflammation, fibrosis, and changes in nuclear factor-kappa B (NF-κB), nuclear factor-E2-related factor-2 (Nrf2), and transforming growth factor (TGF-ß1) levels. Furthermore, IMI enhanced the expression of liver fibrosis marker proteins, including collagen I, α-smooth muscle actin (α-SMA), and fibronectin 1 (FN-1), by activating the TGF-ß1/Smad signaling pathway. In conclusion, our study demonstrated that IMI exposure induces liver fibrosis via activation of the TGF-ß1/Smad signaling pathway in quails.

Vaccination of plasmid DNA encoding ORF81 gene of CJ strains of KHV provides protection to immunized carp.

In order to construct the recombinant plasmid of pIRES-ORF81, the nucleic acid isolated from Koi herpes virus-CJ (KHV-CJ) strains was used as a template to insert the ORF81 gene fragments amplified by PCR into the pIRES-neo, a kind of eukaryotic expression vector. Using Western blotting analysis, it was verified that ORF81 gene protein can be expressed correctly by pIRES-ORF81, after MFC cells were transfected. The recombinant plasmid pIRES-ORF81 was set into three immunization dose gradients: 1, 10, and 50 µg/carp. Empty plasmid group, PBS group, and blank control group were set simultaneously. Giving intramuscular injections to healthy carps with an average body mass of 246 ± 20 g, indirect ELISA was used to regularly determine antibody levels after three times immunization injection. Neutralizing antibodies were detected by neutralization assay. The results of inoculation tests showed that the pIRES-ORF81 recombinant plasmid can induce the production of carp-specific antibodies. The differences of immune effect between the three different doses of immune gradients were not significant (P > 0.05), but they can induce the production of neutralizing antibodies. After 25 d of inoculation, carp mortality of pIRES-neo empty vector treatment groups was 85%, while the carp mortality of eukaryotic expression recombinant plasmid pIRES-ORF81 injected with three different doses of immune gradients was 20, 17.5, and 12.5%, respectively. Differences in comparison to the control group were highly significant (P < 0.01). However, histopathological section of immunohistochemistry organization revealed no significant changes. It demonstrated that the DNA vaccine pIRES-ORF81 constructed in the experiment displayed a good protective effect against KHV, which had the potential to industrial applications.

Resveratrol ameliorates the oxidative damage induced by arsenic trioxide in the feline lung.

The objective of this study was to evaluate the possible protection of resveratrol against lung injury induced by arsenic trioxide (As2O3). Twenty-four healthy Chinese Dragon Li cats of either sex were randomly divided into four groups: control (1 ml/kg physiological saline), As2O3 (1 mg/kg), resveratrol (3 mg/kg) and resveratrol (3 mg/kg) + As2O3 (1 mg/kg). The resveratrol + As2O3- treated group was given resveratrol 1 hr before As2O3 (1 mg/kg) administration. We found that pretreatment with resveratrol in a clinically comparable dose regimen can reversed the changes in morphological and biochemical parameters induced by As2O3 in the lung. Resveratrol treatment also upregulated the activities of antioxidant enzymes and attenuated As2O3-induced increases in reactive oxygen species, 8-hydroxydeoxyguanosine and malondialdehyde production in the lung. In addition, resveratrol attenuated the As2O3-induced reduction in the ratio of reduced glutathione to oxidized glutathione, the content of total glutathione and lung arsenic burden. These findings indicated that resveratrol can provide significant protection against As2O3-induced oxidative damage.

Attenuation of arsenic retention by resveratrol in lung of arsenic trioxide-exposed rats.

Arsenic trioxide (As2O3) is an important environmental toxin. In this study, the effect of resveratrol on As2O3-induced lung injury in rats is evaluated. The results showed that pre-treatment with resveratrol protected As2O3-induced lung injury by the maintenance of glutathione redox system and decrease in arsenic retention. These suggest supplement with resveratrol may alleviate lung injury in the individuals with chronic exposure to arsenic.

Resveratrol protects against arsenic trioxide-induced nephrotoxicity by facilitating arsenic metabolism and decreasing oxidative stress.

Arsenic trioxide (As(2)O(3)) is an environmental toxicant and a potent antineoplastic agent. Exposure to arsenic causes renal cancer. Resveratrol is a well-known polyphenolic compound that is reported to reduce As(2)O(3)-induced cardiotoxicity. The present study aimed to investigate the effect of resveratrol on As(2)O(3)-induced nephrotoxicity and arsenic metabolism. Chinese Dragon-Li cats were injected with 1 mg/kg As(2)O(3) on alternate days; resveratrol (3 mg/kg) was administered via the forearm vein 1 h before the As(2)O(3) treatment. On the sixth day, the cats were killed to determine the histological renal damage, renal function, the accumulation of arsenic, and antioxidant activities in the kidney. Urine samples were taken for arsenic speciation. In the resveratrol + As(2)O(3)-treated group, activities of glutathione peroxidase, catalase, and superoxide dismutase, the ratio of reduced glutathione to oxidized glutathione, the total arsenic concentrations, and the percentage of methylated arsenic in urine were significantly increased. The concentrations of renal malondialdehyde, reactive oxygen species, 8-hydroxydeoxyguanosine, serum creatinine, blood urea nitrogen, and renal arsenic accumulation were significantly decreased and reduced renal morphologic injury was observed compared with the As(2)O(3)-treated group. These results demonstrate that resveratrol could significantly scavenge reactive oxygen species, inhibit As(2)O(3)-induced oxidative damage, and significantly attenuate the accumulation of arsenic in renal tissues by facilitating As(2)O(3) metabolism. These data suggest that use of resveratrol as postremission therapy for acute promyelocytic leukemia as well as adjunctive therapy in patients with exposure to arsenic may decrease arsenic nephrotoxicity.

Anti-inflammatory effects of linalool in RAW 264.7 macrophages and lipopolysaccharide-induced lung injury model.

BACKGROUND: Inflammation, characterized by redness, swelling, pain and a sensation of heat, is one of the body's self-defense systems. Although the inflammation response has an important role in host survival, it also leads to chronic inflammatory diseases. Linalool is a natural compound of the essential oils in several aromatic plants species. It possesses anti-inflammatory, antinociceptive, and other bioactive properties. In the present study, we investigated the protective effects of linalool on inflammation in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells and an LPS-induced in vivo lung injury model. METHODS: We evaluated the effects of linalool on LPS-induced production of inflammatory mediators in Raw 264.7 murine macrophages by enzyme-linked immunosorbent assay and Western blot. To confirm the anti-inflammatory activity of linalool in vivo, we induced an acute lung injury in an LPS-induced mouse model. RESULTS: Linalool attenuated the production of LPS-induced tumor necrosis-α and interleukin-6 both in vitro and in vivo. Furthermore, phosphorylation of IκBα protein, p38, c-Jun terminal kinase, and extracellular signal-regulated kinase in LPS-stimulated RAW 264.7 cells was blocked by linalool. Our in vivo study also found that linalool attenuated lung histopathologic changes in mouse models. CONCLUSIONS: The results suggest that linalool inhibits inflammation both in vitro and in vivo, and may be a potential therapeutic candidate for the treatment of inflammatory diseases.

Resveratrol attenuates hepatotoxicity of rats exposed to arsenic trioxide.

Arsenic trioxide (As(2)O(3)) is an environmental pollutant and potent toxicant to humans. However, it also shows substantial anti-cancer activity in individuals with acute promyelocytic leukemia (APL). Unfortunately, As(2)O(3)-treated leukemia patients suffer hepatotoxicity. Resveratrol has been demonstrated to have efficient antioxidant and antineoplastic activities. The study that how As(2)O(3) in combination with resveratrol affects hepatotoxicity and arsenic accumulation in the liver is lacking, and the present study tackles this question. Wistar rats were injected with 3mg/kg As(2)O(3) on alternate days; resveratrol (8mg/kg) was administered 1h before As(2)O(3). Rats were killed on the 8th day to determine histological liver damage, the antioxidant enzymes in serum, the ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG), and arsenic accumulation in the liver. In the resveratrol+As(2)O(3) group, activities of superoxide dismutase, catalase in serum and GSH/GSSG were significantly increased, histopathological effects were reduced, and arsenic accumulation markedly decreased in the liver, compared with the As(2)O(3)-treated group. Thus, resveratrol attenuated As(2)O(3)-induced hepatotoxicity by decreasing oxidative stress and arsenic accumulation in the liver. These data suggest that use of resveratrol as post-remission therapy of APL and adjunctive therapy in patients with chronic exposure to arsenic may decrease arsenic hepatotoxicity.