Green tea polyphenols inhibit TBBPA-induced lung injury via enhancing antioxidant capacity and modulating the NF-κB pathway in mice.

Tetrabromobisphenol A (TBBPA) is a global pollutant. When TBBPA is absorbed by the body through various routes, it can have a wide range of harmful effects on the body. Green tea polyphenols (GTPs) can act as antioxidants, resisting the toxic effects of TBBPA on animals. The effects and mechanisms of GTP and TBBPA on oxidative stress, inflammation and apoptosis in the mouse lung are unknown. Therefore, we established in vivo and in vitro models of TBBPA exposure and GTP antagonism using C57 mice and A549 cells and examined the expression of factors related to oxidative stress, autophagy, inflammation and apoptosis. The results of the study showed that the increase in reactive oxygen species (ROS) levels after TBBPA exposure decreased the expression of autophagy-related factors Beclin1, LC3-II, ATG3, ATG5, ATG7 and ATG12 and increased the expression of p62; oxidative stress inhibits autophagy levels. The increased expression of the pro-inflammatory factors IL-1ß, IL-6 and TNF-α decreased the expression of the anti-inflammatory factor IL-10 and activation of the NF-κB p65/TNF-α pathway. The increased expression of Bax, caspase-3, caspase-7 and caspase-9 and the decreased expression of Bcl-2 activate apoptosis-related pathways. The addition of GTP attenuated oxidative stress levels, restored autophagy inhibition and reduced the inflammation and apoptosis levels. Our results suggest that GTP can attenuate the toxic effects of TBBPA by modulating ROS, reducing oxidative stress levels, increasing autophagy and attenuating inflammation and apoptosis in mouse lung and A549 cells. These results provide fundamental information for exploring the antioxidant mechanism of GTP and further for studying the toxic effects of TBBPA.

8-shogaol derived from dietary ginger alleviated acute and inflammatory pain by targeting TRPV1.

Ginger, a well-known spice plant, has been used widely in medicinal preparations for pain relief. However, little is known about its analgesic components and the underlying mechanism. Here, we ascertained, the efficacy of ginger ingredient 8-Shogaol (8S), on inflammatory pain and tolerance induced by morphine, and probed the role of TRPV1 in its analgesic action using genetic and electrophysiology approaches. Results showed that 8S effectively reduced nociceptive behaviors of mice elicited by chemical stimuli, noxious heat as well as inflammation, and antagonized morphine analgesic tolerance independent on opioid receptor function. Genetic deletion of TRPV1 significantly abolished 8S' analgesia action. Further calcium imaging and patch-clamp recording showed that 8S could specifically activate TRPV1 in TRPV1-expressing HEK293T cells and dorsal root ganglion (DRG) neurons. The increase of [Ca2+]i in DRG was primarily mediated through TRPV1. Mutational and computation studies revealed the key binding sites for the interactions between 8S and TRPV1 included Leu515, Leu670, Ile573, Phe587, Tyr511, and Phe591. Further studies showed that TRPV1 activation evoked by 8S resulted in channel desensitization both in vitro and in vivo, as may be attributed to TRPV1 degradation or TRPV1 withdrawal from the cell surface. Collectively, this work provides the first evidence for the attractive analgesia of 8S in inflammatory pain and morphine analgesic tolerance mediated by targeting pain-sensing TRPV1 channel. 8S from dietary ginger has potential as a candidate drug for the treatment of inflammatory pain.

The mechanism of selenium regulating the permeability of vascular endothelial cells through selenoprotein O.

Vascular diseases, a leading cause of death in human, are strongly associated with pathological damage to blood vessels. The selenoprotein (Sel) have been reported to play important roles in vascular disease. However, the role of SelO in vascular disease has not been conclusively investigated. The present experiment was to investigate the regulatory mechanism of the effect of SelO on the permeability of vascular endothelial. The H.E staining, FITC-Dextran staining, Dil-AC-LDL staining and FITC-WGA staining showed that vascular structure was damaged, and intercellular junctions were disrupted with selenium (Se)-deficient. Immunohistochemistry, qPCR and Western blot revealed decreased expression of the adhesion plaque proteins vinculin, talin and paxillin, decreased expression of the vascular connectivity effector molecules connexin, claudin-1 and E-cadherin and increased expression of JAM-A and N-cadherin, as well as decreased expression of the ZO-1 signaling pathways ZO-1, Rock, rhoGEF, cingulin and MLC-2. In a screening of 24 Sel present in mice, SelO showed the most pronounced changes in vascular tissues, and a possible association between SelO and vascular intercellular junction effectors was determined using IBM SPSS Statistics 25. Silencing of SelO, vascular endothelial intercellular junction adverse effects present. The regulatory relationship between SelO and vascular endothelial intercellular junctions was determined. The results showed that Se deficiency lead to increased vascular endothelial permeability and vascular tissue damage by decreasing SelO expression, suggesting a possible role for SelO in regulating vascular endothelial permeability.

Polyethylene microplastics induced inflammation via the miR-21/IRAK4/NF-κB axis resulting to endoplasmic reticulum stress and apoptosis in muscle of carp.

As a widespread environmental pollutant, microplastics pose a great threat to the tissues and organs of aquatic animals. The carp's muscles are necessary for movement and survival. However, the mechanism of injury of polyethylene microplastics (PE-MPs) to carp muscle remains unclear. Therefore, in this study, PE-MPs with the diameter of 8 µm and the concentration of 1000 ng/L were used to feed carp for 21 days, and polyethylene microplastic treatment groups was established. The results showed that PE-MPs could cause structural abnormalities and disarrangement of muscle fibers, and aggravate oxidative stress in muscles. Exposure to PE-MPs reduced microRNA (miR-21) in muscle tissue, negatively regulated Interleukin-1 Receptor Associated Kinase 4 (IRAK4), activated Nuclear Factor Kappa-B (NF-κB) pathway, induced inflammation, and led to endoplasmic reticulum stress and apoptosis. The present study provides different targets for the prevention of muscle injury induced by polyethylene microplastics.

Selenium Deficiency Causes Iron Death and Inflammatory Injury Through Oxidative Stress in the Mice Gastric Mucosa.

Selenium (Se) is a trace element essential for the maintenance of normal physiological functions in living organisms. Oxidative stress is a state in which there is an imbalance between oxidative and antioxidant effects in the body. A deficiency of Se can make the body more inclined to oxidation, which can induce related diseases. The aim of this experimental study was to investigate the mechanisms by which Se deficiency affects the digestive system through oxidation. The results showed that Se deficiency treatment led to a decrease in the levels of GPX4 and antioxidant enzymes and an increase in the levels of ROS, MDA, and lipid peroxide (LPO) in the gastric mucosa. Oxidative stress was activated. Triple stimulation of ROS, Fe2+, and LPO induced iron death. The TLR4/NF-κB signaling pathway was activated, inducing an inflammatory response. The expression of the BCL family and caspase family genes was increased, leading to apoptotic cell death. Meanwhile, the RIP3/MLKL signaling pathway was activated, leading to cell necrosis. Taken together, Se deficiency can induce iron death through oxidative stress. Meanwhile, the production of large amounts of ROS activated the TLR4/NF-κB signaling pathway, leading to apoptosis and necrosis of the gastric mucosa.

Trimethyltin chloride exposure induces apoptosis and necrosis and impairs islet function through autophagic interference.

Trimethyltin chloride (TMT) is a highly toxic organotin compound often used in plastic heat stabilizers, chemical pesticides, and wood preservatives. TMT accumulates mainly through the environment and food chain. Exposure to organotin compounds is associated with disorders of glucolipid metabolism and obesity. The mechanism by which TMT damages pancreatic tissue is unclear. For this purpose, a subacute exposure model of TMT was designed for this experiment to study the mechanism of damage by TMT on islet. The fasting blood glucose and blood lipid content of mice exposed to TMT were significantly increased. Histopathological and ultrastructural observation and analysis showed that the TMT-exposed group had inflammatory cell infiltration and necrosis. Then, mouse pancreatic islet tumour cells (MIN-6) were treated with TMT. Autophagy levels were detected by fluorescence microscopy. Real-time quantitative polymerase chain reaction and Western blotting were used for verification. A large amount of autophagy occurred at a low concentration of TMT but stagnated at a high concentration. Excessive autophagy activates apoptosis when exposed to low levels of TMT. With the increase in TMT concentration, the expression of necrosis-related genes increased. Taken together, different concentrations of TMT induced apoptosis and necrosis through autophagy disturbance. TMT impairs pancreatic (islet ß cell) function.

TBBPA causes inflammation and cell death via the ROS/NF-κB pathway in the gastric mucosa.

Tetrabromobisphenol A (TBBPA) is a common brominated flame retardant that has a wide range of toxic effects on organisms. However, the mechanism of the toxic effects of TBBPA on the digestive system has rarely been studied. The purpose of this study was to investigate the mechanism of TBBPA toxicity on the gastric mucosa. In this study, TBBPA (mixed with corn oil) was administered by gavage at doses of 0 mg/kg (CG), 10 mg/kg and 20 mg/kg. The results showed that the levels of ROS, MDA and LPO were increased, and the activities of antioxidant enzymes were decreased. Large amounts of ROS activated the NF-κB pathway, leading to the development of an inflammatory response. The expression of BCL family and Caspase (Cas) family genes was increased, inducing apoptosis. The RIP3/MLKL pathway was activated, leading to cell necrosis. In summary, TBBPA can cause damage to the gastric mucosa through oxidative stress, leading to increased ROS activation of the NF-κB pathway. Treatment with the antioxidant NAC alleviated the damage to the gastric mucosa caused by TBBPA.

Rosmarinic acid alleviates intestinal inflammatory damage and inhibits endoplasmic reticulum stress and smooth muscle contraction abnormalities in intestinal tissues by regulating gut microbiota.

The host-bacterial interactions play the key role in inflammatory bowel disease (IBD). Dysbiosis of the intestinal flora can lead to pathological changes in the intestine. Rosmarinic acid (RA) is a natural phenolic acid compound with antioxidant, anti-cancer, anti-inflammatory, anti-apoptotic, anti-fibrotic, and anti-bacterial activities that has a palliative effect on acute IBD. We have established an in vivo model for mice. Histological staining was performed to directly observe RA alterations in the intestinal tract. The alteration of RA on mouse intestinal flora was observed by 16S rRNA high-throughput sequencing, and the effect of RA on intestinal mechanism of action was detected by qPCR and western blot. The results showed that RA had a significant protective effect on the intestine. RA upregulated the abundance of Lactobacillus johnsonii and Candidatus Arthromitus sp SFB-mouse-NL and downregulated the abundance of Bifidobacterium pseudolongum, Escherichia coli, and Romboutsia ilealis. RA downregulated the expressions of ROCK, RhoA, CaM, MLC, MLCK, ZEB1, ZO-1, ZO-2, occludin, E-cadherin, IL-1ß, IL-6, TNF-α, GRP78, PERK, IRE1, ATF6, CHOP, Caspase12, Caspase9, Caspase3, Bax, Cytc, RIPK1, RIPK3, MLKL, and upregulated the expression of IL-10 and Bcl-2. These results displayed that RA inhibited the inflammation, which is caused by tight junction damage, by repairing intestinal flora dysbiosis, relieved endoplasmic reticulum stress, inhibited cell death, and corrected smooth muscle contractile dysregulation. The results of this study revealed RA could have a protective effect on the small intestine of mice by regulating intestinal flora. IMPORTANCE Inflammatory bowel disease (IBD) is a chronic, relapsing, remitting disorder of the gastrointestinal system. In this study, we investigated the protective effects of rosmarinic acid on the intestinal tract. The results showed that RA was effective in reducing inflammatory damage, endoplasmic reticulum stress, smooth muscle contraction abnormalities, and regulating intestinal flora disorders.

TBBPA induced ROS overproduction promotes apoptosis and inflammation by inhibiting autophagy in mice lung.

Tetrabromobisphenol A (TBBPA), a non-degradable environmental pollutant, was discharge into the air during the manufacture, use and recycling of plastic products. Respiratory exposure is the main way to inhalation of TBBPA. However, the research on the damage of TBBPA to the respiratory system is still extremely few. The aim of this experiment was to explore the mechanism of TBBPA toxicity to the lungs. Forty C57BL/6 J mice randomly divided into 4 groups, and the experimental groups with TBBPA at 10 n M/kg, 20 n M/kg and 40 n M/kg for 14 consecutive days. Histopathological and ultrastructural analysis showed that the inflammatory cells infiltrated and tissue structure damaged in the lung of mice with exposing to TBBPA. The ROS and MDA levels increase and the T-AOC, GSH-Px, CAT, SOD activities inhibition was found in lung tissue with TBBPA exposure. The expression of autophagy-related factors Beclin-1, P62, LC3-II, ATG5, and ATG7 decreased. The activation of NF-κB/TNF-α pathway indicates the occurrence of inflammation. The expression of Bax, caspase3, caspase7, caspase 9 increase, the expression of Bcl-2 decreased, and the apoptosis pathway activated. The autophagy inducer rapamycin can reverse the adverse effects of inflammation and apoptosis. Taken together, TBBPA inhibits autophagy-induced pneumonia and apoptosis by overproduction ROS.

Selenium Deficiency Promotes the Expression of LncRNA-MORC3, Activating NLRP3-Caspase-1/IL-1ß Signaling to Induce Inflammatory Damage and Disrupt Tight Junctions in Piglets.

Selenium (Se), as a trace element, is widely found in animals in the form of selenomethionine, which can provide nutrition to the body and has anti-inflammatory effects to prevent inflammatory damage in animals. In the past decade, there have been many studies on piglet diseases caused by selenium deficiency; however, under Se deficiency, the relationship between LncRNA-MORC3, inflammatory injury, and tight junctions in piglets has not yet been studied. We established piglet selenium deficiency models divided into three groups and obtained small intestinal tissues after 35 days of feeding. Small intestinal epithelial IPEC-J2 cells were divided into three groups, and samples were collected after 24 h of culture for qPCR and Western blot experiments. First, we found that Se deficiency led to an increase in LncRNA-MORC3 expression in piglets in vivo and in vitro. We found that the binding site of NLRP3 on LncRNA-MORC3 and the expression trends of both were the same: Se deficiency increased the secretion of NLRP3 and the expression levels of the inflammatory factors Caspase-1, ASC, IL-1ß, IL-17, IL-6, IL-10, and TNF-α, which are related to the NLRP3-Caspase-1/IL-1ß signaling pathway. At the same time, Se deficiency decreased the expression levels of the tight junction factors ZO-1, Z0-2, Occludin, E-cadherin, and ZEB-1. This result showed that the tight junctions were disrupted. Herein, we demonstrated that Se deficiency promotes the expression of both LncRNA-MORC3 and inflammatory factors in piglets to activate the NLRP3-Caspase-1/IL-1ß signaling pathway and disrupt tight junctions. Ultimately, these factors lead to inflammatory damage in piglet small intestinal tissues.

Zinc Deficiency Induces Inflammation and Apoptosis via Oxidative Stress in the Kidneys of Mice.

Zinc (Zn) is an essential element that regulates not only cellular immunity but also antioxidant and anti-inflammatory agents. The present study investigated the effect of Zn deficiency on renal cell apoptosis and its mechanism. A Zn-deficient kidney model in mice was created by a Zn-deficient diet. Mice were fed diets with different Zn levels for 41 days as follows: normal-Zn group (NG, 34 mg Zn/kg), low-Zn group (LG, 2 mg Zn/kg), and high-Zn group (HG, 100 mg Zn/kg). H&E staining showed that inflammatory cells and many erythrocytes exuded in the renal tissue space of the low-Zn group, and TUNEL staining indicated massive death of kidney cells in the low-Zn group. In the low-Zn group, the levels of oxygen free radicals (ROS) were significantly increased, the antioxidants were significantly decreased, and the total antioxidant capacity was decreased. Moreover, RT-qPCR and ELISA results showed that inflammatory factors (TNF-α, IL-1ß, and IL-6) were significantly increased in the low-Zn group. In addition, the levels of p-IκBα, p-NF-κB p65, p-ERK, p-JNK, and p-p38 were significantly increased in the low-Zn group, indicating that zinc deficiency activates NF-κB and MAPK signalling as well as increases its expression. RT-qPCR analysis of apoptosis-related genes, including Bcl-2 Bax, Caspa8, Caspa6, and Caspa3, demonstrated that the expression levels of proapoptotic genes in mouse kidneys were significantly increased. Importantly, the in vitro results were consistent with the in vivo results. Together, these data suggested that zinc deficiency induces renal oxidative stress to activate NF-κB and MAPK signalling, thereby inducing renal cell apoptosis.

Berberine Depresses Inflammation and Adjusts Smooth Muscle to Ameliorate Ulcerative Colitis of Cats by Regulating Gut Microbiota.

Intestinal microbiota dysbiosis is a well established characteristic of ulcerative colitis (UC). Regulating the gut microbiota is an effective UC treatment strategy. Berberine (BBR), an alkaloid extracted from several Chinese herbs, is a common traditional Chinese medicine. To establish the efficacy and mechanism of action of BBR, we constructed a UC model using healthy adult shorthair cats to conduct a systematic study of colonic tissue pathology, inflammatory factor expression, and gut microbiota structure. We investigated the therapeutic capacity of BBR for regulating the gut microbiota and thus work against UC in cats using 16S rRNA genes amplicon sequencing technology. Our results revealed that dextran sulfate sodium (DSS)-induced cat models of UC showed weight loss, diarrhea accompanied by mucous and blood, histological abnormalities, and shortening of the colon, all of which were significantly alleviated by supplementation with BBR. A 16S rRNA gene-based microbiota analysis demonstrated that BBR could significantly benefit gut microbiota. Western blot, quantitative PCR, and enzyme-linked immunosorbent assays (ELISAs) showed that in DSS-induced cat models, the expression of the inflammatory factors was increased, activating the JAK2/STAT3 signaling pathway, and treatment with BBR reversed this effect. The myosin light chain (MLC) phosphorylation in the smooth muscle of the intestines is associated with motility of inflammation-related diarrhea in cats. This study used gut flora analyses to demonstrate the anti-UC effects of BBR and its potential therapeutic mechanisms and offers novel insights into the prevention of inflammatory diseases using natural products. IMPORTANCE Ulcerative colitis (UC) is common in clinics. Intestinal microbiota disorder is correlated with ulcerative colitis. Although there are many studies on ulcerative colitis in rats, there are few studies on colitis in cats. Therefore, this study explored the possibility of the use of BBR as a safe and efficient treatment for colitis in cats. The results demonstrated the therapeutic effects of BBR on UC based on the state of the intestinal flora. The study found BBR supplementation to be effective against dextran sulfate sodium (DSS)-induced colitis, smooth muscle damage, and gut microbiota dysbiosis.

Lithium intoxication induced pyroptosis via ROS/NF-κB/NLRP3 inflammasome regulatory networks in kidney of mice.

Humans and animals may be exposed to increasing contaminant lithium (Li) concentrations in the environment with the use and disposal of Li-containing products. Meanwhile, Li plays a key role in the treatment of human mental disorders, while the excessive accumulation of Li salts in the body can cause renal damage and nephrotic syndrome. In this study, the mechanism of renal inflammatory reaction induced by Li excessive intake was studied by establishing mice models in vitro and in vivo. The results of histopathology staining and TdT-mediated dUTP nick-end labeling assay showed that high Li condition (Lithium carbonate, 20 mg/kg/twice a day, i.e., for 30 consecutive days) caused inflammatory damage and apoptosis in kidney tissue cells. Western blot, qPCR, and immunohistochemical analysis were used to further study. In the vivo experiments, we found that Li reduced antioxidant enzyme capacity (glutathione peroxidase, total superoxide dismutase, total antioxidant capacity, and catalase) and induced the production of reactive oxygen species (ROS). Moreover, excessive Li activated nuclear factor kappa-B (NF-κB) signaling pathway and nucleotide-binding oligomerization domain-like receptors domains-containing protein 3 (NLRP3) inflammasome, resulting in activation of inflammatory factors tumor necrosis factor-α and IL-1ß in the kidney of mice. In the vitro study, ROS as an upstream signal phosphorylated IκBα and NF-κB, up-regulated the NLRP3 inflammasome, increased caspase3, 6, 7, and 9 to exaggerate inflammation response, finally inducing pyroptosis in renal cells.

Selenium Deficiency Promotes Oxidative Stress-Induced Mastitis via Activating the NF-κB and MAPK Pathways in Dairy Cow.

Selenium (Se) is an antioxidant and immunomodulator that can participate in the control of specific endocrine pathways. Disturbance of redox homeostasis is closely related to the pathogenesis of many diseases. Se is also an important nutrient element for dairy cows. First, oxidative stress (OS) induced by Se deficiency was investigated along with a possible mechanism of its induction of mammary gland inflammation. This investigation used in vivo and in vitro experiments for verification. Once the OS response was triggered, the activity of antioxidant enzymes was reduced by regulation of the concentration of Se, which led to the accumulation of ROS. TNF-α, IL-1ß, and IL-6 secretion was promoted to activate the NF-κB/MAPK signaling pathway. This process further promoted the accumulation of cytokines that aggravated the inflammatory response. Herein, it was verified that Se deficiency induces OS, which leads to ROS accumulation and the secretion of inflammatory factors to activate the NF-κB/MAPK signaling pathway and promote the occurrence of mastitis.

Dextran sulfate sodium-induced colitis and ginseng intervention altered oral pharmacokinetics of cyclosporine A in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Application of cyclosporine A (CsA) as a rescue treatment in acute severe ulcerative colitis (UC) is limited by its narrow therapeutic window and great interpatient variability. As a substrate of cytochrome P450 3A enzyme (CYP3A) and P-glycoprotein (P-gp), the oral pharmacokinetics of CsA is susceptible to disease status and concomitant medications. Combined treatment with ginseng, a famous medicinal herb frequently prescribed for ameliorating abnormal immune response in many diseases including UC, showed immunologic safety in CsA-based immunosuppression. AIM OF THE STUDY: Since the therapeutic levels of CsA can be achieved within 24 h, this study first assessed the impact of acute colitis and ginseng intervention on the single oral dose pharmacokinetics of CsA and explored the underlying mechanisms in dextran sulfate sodium (DSS)-induced colitis rats and Caco-2 cells. MATERIALS AND METHODS: Rats received drinking water (normal group), 5% DSS (UC group), or 5% DSS plus daily oral ginseng extract (GS+UC group). On day 7, GS+UC group only received an oral dose of CsA (5 mg/kg), while animals of normal or UC group received an oral, intravenous (1.25 mg/kg), or intraperitoneal dose of CsA (1.25 mg/kg), respectively. Blood, liver/intestine tissues and fecal samples were collected for determining CsA and main hydroxylated metabolite HO-CsA or measuring hepatic/intestinal CYP3A activity. Caco-2 cells were incubated with gut microbial culture supernatant (CS) of different groups or ginseng (decoction or polysaccharides), and then CYP3A, P-gp and tight junction (TJ) proteins were determined. RESULTS: Oral CsA exhibited enhanced absorption, systemic exposure and tissue accumulation, and lower fecal excretion, while intravenous or intraperitoneal CsA showed lower systemic exposure and enhanced distribution, in colitis rats. Diminished intestinal and hepatic P-gp expression well explained the changes with DSS-induced colitis. Moreover, blood exposures of HO-CsA in both normal and colitis after oral dosing were significantly higher than intravenous/intraperitoneal dosing, supporting the dominant role of intestinal first-pass metabolism. Interestingly, colitis reduced CYP3A expression in intestine and liver but only potentiated intestinal CYP3A activity, causing higher oral systemic exposure of HO-CsA. Oral ginseng mitigated colitis-induced down-regulation of CYP3A and P-gp expression, facilitated HO-CsA production, biliary excretion and colonic sequestration of CsA, while not affected CsA oral systemic exposure. In Caco-2 cells, gut microbial CS from both colitis and GS+UC group diminished P-gp function, while ginseng polysaccharides directly affected ZO-1 distribution and suppressed TJ proteins expression, explaining unaltered oral CsA systemic exposure. CONCLUSIONS: DSS-induced colitis significantly altered oral CsA disposition through regulating intestinal and hepatic P-gp and CYP3A. One-week ginseng treatment enhanced colonic accumulation while not altered the systemic exposure of CsA after single oral dosing, indicating pharmacokinetic compatibility between the two medications.

Pb exposure triggers MAPK-dependent inflammation by activating oxidative stress and miRNA-155 expression in carp head kidney.

Lead (Pb) is a toxic heavy metal and an aquatic pollutant. Various amounts of heavy metals are released into the environment through industrial discharge, causing excessive contamination of aquatic ecosystems. The head kidney is a unique immune organ of the bony fish and plays an important role in the metabolism of heavy metals. Studies of toxic Pb exposure that have investigated the head kidney of carp are limited. This study was carried out to explore the potential immunotoxicity effects of Pb and the specific related mechanisms in the carp head kidney. Pb poisoning was shown to induce the production of reactive oxygen species (ROS) and increase the expression levels of phosphorylated proteins related to the MAPK pathway, including p38, extracellular signal-regulated protein kinase (ERK), and c-Jun N-terminal kinase (JNK). We also found that microRNA-155 played a key role in regulating the production of inflammatory factors TNF-α, IL-1ß, and IL-6, and the pre-miRNA-155 inhibitor reversed the Pb-induced inflammation. In conclusion, these in vitro and in vivo findings suggest that oxidative stress and the MAPKs are involved in the Pb-induced inflammasome response, and the production of microRNA-155 aggravated the occurrence of inflammation in carp head kidney.

Effects of agomelatine and mirtazapine on sleep disturbances in major depressive disorder: evidence from polysomnographic and resting-state functional connectivity analyses.

To investigate effects of agomelatine and mirtazapine on sleep disturbances in patients with major depressive disorder. A total of 30 depressed patients with sleep disturbances, 27 of which completed the study, took agomelatine or mirtazapine for 8 weeks. Subjective scales were administered, and polysomnography was performed at baseline and at the end of week 1 and 8. Functional magnetic resonance imaging was performed at baseline and at the end of week 8. Compared with baseline, scores on the Hamilton Depression Scale, Hamilton Anxiety Scale, Pittsburgh Sleep Quality Index, Sleep Dysfunction Rating Scale, and Insomnia Severity Index after 8 weeks of treatment significantly decreased in both groups, with no significant differences between groups, accompanied by significant increases in total sleep time, sleep efficiency, and rapid eye movement (REM) sleep and significant decrease in wake after sleep onset. Mirtazapine treatment increased N3 sleep at week 1 compared with agomelatine treatment, but this difference disappeared at week 8. The increases in the percentage and duration of N3 sleep were positively correlated with increases in connectivity between right dorsal lateral prefrontal cortex (dlPFC) and right precuneus and between left posterior cingulate cortex and right precuneus in both groups, respectively. Functional connectivity (FC) between right dlPFC and left precuneus in mirtazapine group was higher compared with agomelatine group after 8 weeks of treatment. These findings indicated that both agomelatine and mirtazapine improved sleep in depressed patients, and the effect of mirtazapine was greater than agomelatine with regard to rapidly increasing N3 sleep and gradually improving FC in the brain.

Environmental contaminant ammonia triggers epithelial-to-mesenchymal transition-mediated jejunal fibrosis with the disassembly of epithelial cell-cell contacts in chicken.

Ammonia (NH3) is an environmental contaminant that is causing increasing problems with human and animal health due to the development of poultry industry. There are limited studies on the effect of NH3 inhalation toxicity on the intestinal tract of animals, and underlying molecular mechanisms remain unclear. In the present study, we established a chicken model of NH3 aspiration-induced injury for 42 days and observed histopathological changes of the jejunum. Tandem mass tag-based quantitative proteomic analysis was applied to investigate changes in the protein profile in the jejunum tissue of chickens that were exposed to NH3. Overall, 48 significantly differentially expressed proteins (DEPs) were identified. GO and KEGG analyses revealed that most DEPs were closely related to epithelial-to-mesenchymal transition (EMT), cell-cell junctions, and fibrosis-related factors. Regarding fibrosis, type I collagen and fibronectin were significantly increased. With respect to EMT, epithelial marker proteins (such as E-cadherin and keratin) were repressed, while mesenchymal marker proteins (such as vimentin) were activated. Loss of epithelial cell-cell junctions (such as tight junctions, adherens junctions and desmosomes) were observed. Additionally, overexpression of transforming growth factor-beta (TGF-ß) may play a key role in the EMT process and fibrosis. Taken together, these findings suggested that NH3 triggered the EMT and disassembly of epithelial cell-cell contacts, resulting in jejunal fibrosis that was mediated by TGF-ß in chickens. The results of our study will contribute to provide a technical reference regarding the research methods of intestinal toxicity of NH3 and have largely regulatory implications for ecological risk assessment of human health.

Author Correction: AMPK signaling in the nucleus accumbens core mediates cue-induced reinstatement of cocaine seeking.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.