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.

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.

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.

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.

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.

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.

The protective effect of nigeglanine on dextran sulfate sodium-induced experimental colitis in mice and Caco-2 cells.

Ulcerative colitis (UC) was a nonspecific inflammatory disease. The treatment of UC is imperative. The present study aimed to investigate the effect of nigeglanine on dextran sulfate sodium-induced UC in experimental mice and Caco-2 cells and define the underlying mechanism. The nigeglanine was shown a significant protective effect on the colon, significantly reduced the weight and colon length loss and inhibited intestinal epithelial cell damage. Nigeglanine also reduced proinflammatory factors and increased anti-inflammatory factor production. The results indicate that nigeglanine suppresses the nuclear factor kappa B and mitogen-activated protein kinases pathways in addition to NLRP3 inflammasome action, inhibiting colon epithelial cell pyroptosis. Surprisingly, ZO-1 and occludin protein levels increased with nigeglanine treatment, suggesting that nigeglanine plays a protective role in barrier integrity, reducing colitis progression. The present study suggests that dietary therapy with nigeglanine may be a useful treatment for prophylaxis and palliative UC.

Selenium deficiency induced an inflammatory response by the HSP60 - TLR2-MAPKs signalling pathway in the liver of carp.

Selenium (Se) is one of the essential trace elements for immune regulation and antioxidant systems in fish growth. The dietary Se plays an important role in immune regulation and inflammation by regulating HSPs and TLRs in liver of many animals. The liver is an important digestive organ in carp. Liver damage can seriously affect the growth and survival of carp. This study was conducted to determine whether Se regulated liver inflammation by affecting HSPs-TLR2 signalling and the potential mechanisms of action in common carp. The gene was analysed by qPCR. The proteins of inflammatory factors were detected by ELISA. The others proteins were analysed by Western blot. The results indicated the Se concentrations in blood and liver tissues were significantly influenced by dietary Se. The Se deficiency increased the expression of HSP60 and TLR2 and the secretion of the proinflammatory factor TNF-α, IL-1ß and IL-6, induced a low secretion of the anti-inflammatory TGF-ß, but the Se supplements could transform these events. Further research showed that with the dose-dependently decrease of Se, the HSP60 expressions were increased, and the MAPKs pathway were significantly activated by the phosphorylation of p38, JNK and ERK in liver tissue and cell. The results provide evidence that Se deficiency induced and exacerbated inflammatory injury to the liver through the HSP60 and TLR2-MAPKs signalling pathways in carp.

Selenium deficiency inhibits micRNA-146a to promote ROS-induced inflammation via regulation of the MAPK pathway in the head kidney of carp.

Selenium (Se) is a necessity in multiple species of fish. Se plays an important role in immunoregulation, inflammation, and antioxidant systems in fish and other animals. The head kidney is the major immune organ in adult carp, and it produces white blood cells and destroys old red blood cells. The present study aimed to explore the effects and regulatory molecular mechanisms of Se on ROS and micRNA-146a as part of the inflammatory response in fancy carp. Adult fancy carp were fed different concentrations of Se in their diets. The Se content of the head kidney changed in a pattern consistent with the dietary content of Se. Se deficiency induced a significant increase in ROS, restrained the activities of GPx, SOD and CAT and increased MDA content. qPCR analysis showed a reduction in micRNA-146a with Se deficiency. The Se content, miRNA-146a expression and ROS levels were correlated. H2O2 cell stimulation assays found that ROS could activate the MAPK pathway, and ELISA results showed p38, JNK and ERK phosphorylation significantly increased with H2O2 stimulation. TNF-α, IL-1ß, and IL-6 were appreciably increased. At same time, miRNA-146a, which should have increased to regulate the inflammatory response, was reduced with Se deficiency. Therefore, with Se deficiency, the head kidney was inflamed. All these results indicated that Se deficiency inhibits micRNA-146a to promote ROS-induced inflammation via regulating the MAPK pathway in the head kidney of carp. The present study revealed that supplementing the diet of carp with selenium is beneficial for growth and disease prevention.

Fecal Microbiota Transplantation in Experimental Ulcerative Colitis Reveals Associated Gut Microbial and Host Metabolic Reprogramming.

Fecal microbiota transplantation (FMT) is gaining attention for the treatment of ulcerative colitis (UC). Data from individual case studies have suggested that FMT may be beneficial for UC, but the detailed microbial and molecular basis remains unknown. Here, we employ 16S rRNA gene sequencing and metabolomics to investigate the influence of FMT on gut microbial community composition and host metabolism in the dextran sulfate sodium-induced UC rat model. The findings from this pilot study suggest that FMT from normal donors to UC recipients could alleviate UC symptoms without close resemblance of donor's gut microbial and metabolic pattern. Meanwhile, FMT from UC donors to normal recipient rats triggered UC symptoms, UC-prone microbial shift, and host metabolic adaption. Gut microbiota under normal conditions could maintain stable species richness and diversity upon FMT intervention, but the disturbed gut microbiota under UC conditions could not maintain such homeostasis. Significant correlations between altered bacterial composition and host metabolism could be assigned to the pathological effects of UC (accounting for 8.0 to 16.2% of total variance) and/or the FMT intervention effects (3.9 to 7.0% of total variance). Overall, our study reveals diverse gut microbial shifts in UC related FMT and their association with host metabolic reprogramming.IMPORTANCE This study combined clinical symptoms measurement, 16S rRNA gene microbial profiling and metabolomics to comprehensively investigate the gut bacterial and host metabolic association and reprogramming in FMT-treated experimental UC. These data can advance our understanding of the effect of FMT on UC and the involvement of gut microbial dysbiosis in the development of UC.

Bacterial Outer Membrane Vesicles from Dextran Sulfate Sodium-Induced Colitis Differentially Regulate Intestinal UDP-Glucuronosyltransferase 1A1 Partially Through Toll-Like Receptor 4/Mitogen-Activated Protein Kinase/Phosphatidylinositol 3-Kinase Pathway.

UDP-glucuronosyltransferase 1A1 (UGT1A1) constitutes an important part of intestinal epithelial barrier and catalyzes glucuronidation of many endogenous compounds and drugs. Downregulation of UGT1A1 in inflammation has been reported, whereas the association with gut dysbiosis is poorly defined. This study verified the involvement of gut microbiota in intestinal UGT1A1 regulation using dextran sulfate sodium (DSS)-induced rat colitis model plus fecal microbiota transplantation (FMT). Generally, both DSS induction and colitis-to-normal FMT suppressed mRNA and protein expressions of UGT1A1 and nuclear xenobiotic receptors (NRs) in colon, but enhanced mRNA and decreased protein of rat UGT1A1/rat NRs in small intestine. Normal-to-colitis FMT alleviated DSS-induced changes. Bacterial outer membrane vesicles (OMVs) from colitis rats and rats receiving colitis feces reduced both mRNA and protein of human UGT1A1 (hUGT1A1)/human NRs (hNRs) in Caco-2 cells. Interestingly, using deoxycholate to reduce lipopolysaccharide, normal OMVs upregulated hUGT1A1/hNRs, whereas colitis OMVs decreased, indicating the involvement of other OMVs components in UGT1A1 regulation. The 10- to 50-kDa fractions from both normal and colitis OMVs downregulated hUGT1A1, human PXR, and human PPAR-γ, whereas >50-kDa fractions from normal rats upregulated hUGT1A1 and human CAR. Additionally, the conditioned medium from OMVs-stimulated rat primary macrophages also reduced hUGT1A1/hNRs expression. Both Toll-like receptor (TLR)2 and TLR4 were activated by DSS, colitis-to-normal FMT, and the opposite, whereas only TLR4 was increased in OMVs-treated cells. TLR4 small interfering RNA blocked hUGT1A1/hNRs downregulation and phosphatidylinositol 3-kinase/Akt, extracellular signal-regulated kinase, and nuclear factor κB phosphorylation evoked by bacterial OMVs. Taken together, this study demonstrated that gut microbiota regulate intestinal UGT1A1 partially through secreting OMVs, which interact with intestinal epithelial cells directly or via activating macrophage.

Isolation and Crystallographic Characterization of Lu3 N@C2n (2n=80-88): Cage Selection by Cluster Size.

The small Sc3 N cluster has only been found in such small cages as C2n (2n=68, 78, 80, 82), whereas the large M3 N (M=Y, Gd, Tb, Tm) clusters choose those larger cages C2n (2n=82-88). Herein, concrete experimental evidence is presented to establish the size effect of the internal metallic cluster on selecting the outer cage of endohedral metallofullerenes (EMFs) by using a medium-sized metal, lutetium, which possesses an ionic radius between Sc and Gd. A series of lutetium-containing EMFs have been obtained and their structures are unambiguously determined as Lu3 N@Ih (7)-C80 , Lu3 N@D5h (6)-C80 , Lu3 N@C2v (9)-C82 , Lu3 N@Cs (51365)-C84 , Lu3 N@D3 (17)-C86 , and Lu3 N@D2 (35)-C88 by single-crystal X-ray diffraction crystallography. It was confirmed that the encaged Lu3 N cluster always adopts a planar geometry in Lu3 N@C80-88 isomers to ensure substantial metal-cage/metal-nitrogen interactions. As a result, the Lu3 N cluster selects the C2v (9)-C82 cage, which also encapsulates Sc3 N, instead of the Cs (39663)-C82 cage which is more suitable for M3 N (M=Y, Gd, Tb, Tm). However, different from Sc3 N, Lu3 N can also template the C84-88 cages which are absent for Sc3 N-containing EMFs, confirming clearly the size effect of the internal cluster on selecting the outer cage.

[Regulatory mechanisms of gut microbiota on intestinal CYP3A and P-glycoprotein in rats with dextran sulfate sodium-induced colitis].

As important constituents of the first-line of host defense barrier, intestinal cytochrome P450 3A (CYP3A) and P-glycoprotein (P-gp) play important roles in disease pathogenesis as well as drug absorption and exposure. Clinical reports and experimental data revealed diminished intestinal CYP3 A and P-gp expression accompanying with gut dysbiosis in inflammatory bowel disease. Yet whether gut dysbiosis is associated with the down-regulation of CYP3A and P-gp and the underlying mechanisms are unclear. In this study, daily administration of fresh feces from normal rats and rats with ulcerative colitis (UC) induced by dextran sulfate sodium to normal rats resulted in alterations of gut bacterial compositions. Intestinal CYP3A2 and P-gp were significantly down-regulated in rats receiving UC feces. Outer-membrane vesicles (OMVs) are nano-scale special buds of the outer membrane which are produced by Gram-negative bacteria and mediate diverse functions including interactions within bacterial communities and communications with host. Expressions of CYP3A4 and P-gp m RNA were diminished in human epithelial colorectal adenocarcinoma cells (Caco-2) treated by OMVs from all different groups with OMVs from UC rats or rats receiving UC feces showing more significant effects. Moreover, the OMVs fractions within 30 000­50 000 Daltons from both normal and UC rats elicited more effects than fractions of other molecular weights. Treatment of Caco-2 cells with toll like receptor 4 (TLR4) inhibitor resatorvid (TAK-242) or TLR4 silence RNA (siRNA) blocked CYP3A4 and P-gp down-regulation induced by bacterial OMVs. Taken together, we proved in this study that gut microbiota can down-regulate intestinal CYP3A and P-gp partially through producing OMVs to activate the TLR4 signaling pathway.

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.

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.

Green tea polyphenols alleviate TBBPA-induced gastric inflammation and apoptosis by modulating the ROS-PERK/IRE-1/ATF6 pathway in mouse models.

Green tea polyphenols (GTP), an important phytochemical in the daily human diet, bind to various cellular receptors and exert anti-inflammatory and antioxidant benefits. The environmental contaminant tetrabromobisphenol A (TBBPA) enters the digestive system through multiple pathways, resulting in oxidative stress (OS), gastroenteritis, and mucosal injury. The aim of this study was to explore the molecular mechanisms of TBBPA-induced gastritis in mice treated with GTP in vivo and in an in vitro model. The results showed that exposure to TBBPA increased reactive oxygen species (ROS) levels, activated oxidative stress (OS) induced endoplasmic reticulum stress (ERS), and the expression of endoplasmic reticulum stress-related factors (e.g., GRP78, PERK, IRE-1, ATF-6, etc.) increased. The inflammatory pathway NF-κB was activated, and the pro-inflammatory factors TNF-α, IL-1ß, and IL-6 increased, while triggering a cascade reaction mediated by caspase-3. However, the addition of GTP could inhibit OS, restore the balance of endoplasmic reticulum homeostasis, and improve the inflammatory infiltration and apoptosis of gastric mucosal epithelial cells. Therefore, GTP alleviated ERS, reduced inflammation and apoptosis, and restored the gastric mucosal barrier by alleviating TBBPA-induced OS in mouse gastric tissues and GES-1 cells. This provides basic information for exploring the antioxidant mechanism of GTP and further investigating the toxic effects of TBBPA on mouse gastric mucosa.

Zinc supplementation alleviates oxidative stress to inhibit chronic gastritis via the ROS/NF-κB pathway in a mouse model.

Zinc (Zn) is an important trace element; it is involved in the regulation and maintenance of many physiological functions in organisms and has anti-inflammatory and antioxidant properties. Chronic gastritis is closely associated with damage to the gastric mucosa, which is detrimental to the health of humans and animals. There are few studies on the effects of zinc on, for example, gastric mucosal damage, oxidative stress, inflammation and cell death in mice. Therefore, we established in vivo and in vitro models of inflammatory injury and investigated the effects of zinc supplementation in C57BL/6 mice and Ges-1 cells and examined the expression of factors associated with oxidative stress, inflammation and cell death. In this study, the results of in vivo and in vitro experiments showed that reactive oxygen species (ROS) levels increased after sodium salicylate exposure. Malondialdehyde levels increased, the activity of the antioxidant enzymes catalase and superoxide dismutase decreased, and the activity of glutathione decreased. The NF-κB signaling pathway was activated, the levels of proinflammatory factors (TNF-α, IL-1ß, and IL-6) increased, and the expression of cell death-related factors (Bax, Bcl-2, Caspase3, Caspase7, Caspase9, RIP1, RIP3, and MLKL) increased. Zinc supplementation attenuated the level of oxidative stress and reduced the level of inflammation and cell death. Our study indicated that sodium salicylate induced the production of large amounts of reactive oxygen species and activated the NF-κB pathway, leading to inflammatory damage and cell death in the mouse stomach. Zinc supplementation modulated the ROS/NF-κB pathway, reduced the level of oxidative stress, and attenuated inflammation and cell death in the mouse stomach and Ges-1 cells.

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.

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.