Social Experience During Development and Female Offspring Aggression in Peromyscus Mice

Cross‐fostering between the highly aggressive, biparental California mouse (Peromyscus californicus) and the less aggressive, less parental white‐footed mouse (P. leucopus) influences female offspring attack latency in California mice, but not in white‐footed mice. Adult female California mice raised by white‐footed mice expressed longer attack latencies in a neutral‐arena test but not in a resident‐intruder test. One social cue that may be used by offspring to develop environmentally appropriate levels of aggression is the type of parental care during development. In California mice, a composite score of maternal behavior was positively associated with neutral‐arena aggression as indicated by decreased attack latency. In both species, paternal nest‐building was positively associated with neutral‐arena aggression and higher maternal retrieval behavior predicted higher offspring resident‐intruder aggression as indicated by decreased attack latency. Together, these results indicate that parental behavior has the potential to shape the development of attack latency in female offspring.     

Different susceptibility of prefrontal cortex and hippocampus to oxidative stress following chronic social isolation stress

Chronic oxidative stress plays an important role in depression. The aim of present study was to examine the stress-induced changes in serum corticosterone (CORT) levels, cytosolic protein carbonyl groups, malondialdehyde (MDA), reduced glutathione (GSH), nitric oxide (NO) and total superoxide dismutase (SOD) activity in the prefrontal cortex versus hippocampus of male Wistar rats exposed to acute (2 h of immobilization or cold), chronic (21d of social isolation) stress, and their combination (chronic + acute stress). The subcellular distribution of nuclear factor-κB (NF-κB) and cytosolic cyclooxygenase 2 (COX-2) protein expressions were also examined. Depressive- and anxiety-like behaviors were assessed via the forced swim, sucrose preference, and marble burying tests in chronically isolated rats. Although both acute stressors resulted in elevated CORT, increased MDA in the prefrontal cortex and NF-κB activation accompanied by increased NO in the hippocampus were detected only following acute cold stress. Chronic isolation resulted in no change in CORT levels, but disabled appropriate response to novel acute stress and led to depressive- and anxiety-like behaviors. Increased oxidative/nitrosative stress markers, likely by NF-κB nuclear translocation and concomitant COX-2 upregulation, associated with decreased SOD activity and GSH levels, suggested the existence of oxidative stress in the prefrontal cortex. In contrast, hippocampus was less susceptible to oxidative damage showing only increase in protein carbonyl groups and depleted GSH. Taken together, the prefrontal cortex seems to be more sensitive to oxidative stress than the hippocampus following chronic isolation stress, which may be relevant for further research related to stress-induced depressive-like behavior.     

Downregulation of matrix metalloproteinase-9 by melatonin during prevention of alcohol-induced liver injury in mice

Matrix metalloproteinases (MMPs) have been implicated in inflammatory and degradative processes in several diseases. The study aims to explore the mechanism of MMP-9 regulation in alcohol-induced acute liver injury and its protection by melatonin in mice. Alcohol-induced acute liver injury was induced in female Balb/C mice by ethanol administration and protection studies were carried out with a well-known antioxidant molecule, melatonin. Degree of liver injury was monitored by histological and biochemical analysis of liver tissues. Oral administration of ethanol in mouse caused significant increase in alanine amino transferase (ALT) activity in serum. Depletion of glutathione and enhancement of lipid peroxidation as well as protein oxidation was observed in liver tissues following ethanol treatment. However, melatonin exhibited potent hepatoprotective activity by inhibiting ALT activity and oxidative stress. Additionally, MMP-9 expression was increased by ethanol in a dose and time dependent manner in liver tissue and serum. Increased secretion of proMMP-9 was strongly correlated with the expression of proinflammatory cytokines e.g., tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL6. Melatonin showed hepatoprotective role by downregulation of MMP-9 and upregulation of tissue inhibitor of metalloproteases (TIMP-1) expression in liver tissue. Nuclear factor (NF)-κB, plays an important role in inducing inflammatory genes during oxidative stress, thus the role of NF-κB in ethanol-induced liver injury was investigated. Ethanol induced nuclear translocation of NF-κB and increased degradation of inhibitor of NF-κB (IκBα) in liver tissues. Moreover, ethanol-induced NF-κB translocation into nucleus was inhibited significantly by melatonin. This is the first study to elucidate the induction of MMP-9 expression by NF-κB-dependent pathway in ethanol-induced acute liver injury in mice. This study also identifies the novel role of melatonin in hepatoprotection via MMP-9 down regulation.     

SENP1 modulates microglia-mediated neuroinflammation toward intermittent hypoxia-induced cognitive decline through the de-SUMOylation of NEMO

Intermittent hypoxia (IH)-induced cognition decline is related to the neuroinflammation in microglia. SUMOylation is associated with multiple human diseases, which can be reversed by sentrin/SUMO-specific proteases 1 (SENP1). Herein, we investigated the role of SENP1 in IH-induced inflammation and cognition decline. BV-2 microglial cells and mice were used for inflammatory response and cognition function evaluation following IH treatment. Biochemical analysis and Morris water maze methods were used to elaborate the mechanism of SENP1 in IH impairment. Molecular results revealed that IH induced the inflammatory response, as evidenced by the up-regulation of NF-κB activation, IL-1β and TNF-α in vitro and in vivo. Moreover, IH decreased the expression of SENP1, and increased the SUMOylation of NEMO, not NF-κB P65. Moreover, SENP1 overexpression inhibited IH-induced inflammatory response and SUMOylation of NEMO. However, the inhibitions were abolished by siRNA-NEMO. In contrast, SENP1 depletion enhanced IH-induced inflammatory response and SUMOylation of NEMO, accompanying with increased latency and reduced dwell time in mice. Overall, the results demonstrated that SENP1 regulated IH-induced neuroinflammation by modulating the SUMOylation of NEMO, thus activating the NF-κB pathway, revealing that targeting SENP1 in microglia may represent a novel therapeutic strategy for IH-induced cognitive decline.     

Reduced hypothermic and hypnotic responses to ethanol in PACAP-deficient mice

Using pituitary adenylate cyclase-activating polypeptide (PACAP)-deficient mice, we investigated whether PACAP is involved in the intoxicating effects of ethanol. The structure of PACAP is highly conserved during evolution, and in Drosophila, loss-of-function mutations in a PACAP-like neuropeptide gene, amnesiac, result in impairment of memory retention and increased sensitivity to ethanol. In mice, PACAP deficiency is associated with impaired memory performance and hippocampal long-term potentiation (LTP), however, sensitivity to ethanol has not been well investigated. Here, we addressed this issue in our recently developed PACAP-deficient mice. Sleep time (duration of the loss of righting reflex) was markedly shortened in PACAP-deficient mice compared with wild-type, although latency to the loss of righting reflex was not different between the two groups. Ethanol-induced hypothermia in wild-type control mice was significantly reduced in PACAP-deficient mice. Blood ethanol levels were not different between the two groups, excluding the possibility of increased ethanol metabolism. Thus, in contrast to that in Drosophila, PACAP deficiency in mammals caused a reduced sensitivity to ethanol. However, in both cases, PACAP or amnesiac products are likely to play significant roles in modifying the intoxicating effects of ethanol.     

The GAD65 knock out mouse – a model for GABAergic processes in fear‐ and stress‐induced psychopathology

The γ‐amino butyric acid (GABA) synthetic enzyme glutamic acid decarboxylase (GAD)65 is critically involved in the activity‐dependent regulation of GABAergic inhibition in the central nervous system. It is also required for the maturation of the GABAergic system during adolescence, a phase that is critical for the development of several neuropsychiatric diseases. Mice bearing a null mutation of the GAD65 gene develop hyperexcitability of the amygdala and hippocampus, and a phenotype of increased anxiety and pathological fear memory reminiscent of posttraumatic stress disorder. Although genetic association of GAD65 in human has not yet been reported, these findings are in line with observations of reduced GABAergic function in these brain regions of anxiety disorder patients. The particular value of GAD65(?/?) mice thus lies in modeling the effects of reduced GABAergic function in the mature nervous system. The expression of GAD65 and a second GAD isozyme, GAD67, are differentially regulated in response to stress in limbic brain areas suggesting that by controlling GABAergic inhibition these enzymes determine the vulnerability for the development of pathological anxiety and other stress‐induced phenotypes. In fact, we could recently show that GAD65 haplodeficiency, which results in delayed postnatal increase of GABA levels, provides resilience to juvenile‐stress‐induced anxiety to GAD65(+/?) mice thus foiling the increased fear and anxiety in homozygous GAD65(?/?) mice.     

Gestational diabetes mellitus affects odontoblastic differentiation of dental papilla cells via Toll-like receptor 4 signaling in offspring

Gestational diabetes mellitus (GDM) is an important factor involved in the pathogenesis of organ development in the offspring. Here, we analyzed the effects of GDM on odontoblastic differentiation of dental papilla cells (DPCs) and dentin formation in offspring and investigated their underlying mechanisms. A GDM rat model was induced by intraperitoneal injection of streptozotocin and offspring were collected. The results showed that GDM significantly affected odontoblast differentiation and dentin formation in offspring tooth. GDM activated the toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-ĸB) signaling pathway and inhibited SMAD1/5/9 signaling to modulate the odontoblastic differentiation of DPCs in offspring. Inhibition of TLR4 signaling by treated with TAK-242 significantly reverses the suppression of odonto-differentiation of DPCs in diabetic offspring. Taken together, these data indicate GDM activated the offspring DPCs TLR4/NF-ĸB signaling, which suppressed the SMAD1/5/9 phosphorylation and then inhibited odontoblasts differentiation and dentin formation.     

Attenuation of NF-κβ mediated apoptotic signaling by tocotrienol ameliorates cognitive deficits in rats postnatally exposed to ethanol

Ethanol-induced damage in the developing brain may result in cognitive impairment including deficits on neuropsychological tests of learning, memory and executive function, yet the underlying mechanisms remain elusive. In the present study we investigated the protective effect of tocotrienol against cognitive deficit, neuroinflammation and neuronal apoptosis in rat pups postnatally exposed to ethanol. Pups were administered ethanol (5g/kg, 12% v/v) by intragastric intubation on postnatal days 7, 8 and 9. Ethanol-exposed pups showed significant memory impairment in Morris water maze task as evident from increase in escape latency and total distance travelled to reach the hidden platform. Time spent in target quadrant, % total distance traversed in target quadrant and frequency of appearance in target quadrant was also significantly decreased in ethanol exposed pups in probe trial. Poor memory retention was exhibited by ethanol-exposed pups in elevated plus maze test also. Impaired cognition was associated with significantly enhanced acetylcholinesterase activity, increased neuroinflammation (oxidative-nitrosative stress, TNF-α, IL-1β and TGF-β1) and neuronal apoptosis (NF-κβ and Caspase-3) in different brain regions of ethanol-exposed pups. Co-administration with tocotrienol significantly ameliorated all the behavioral, biochemical and molecular alterations in the different brain regions of ethanol exposed pups. The current study thus demonstrates the possible involvement of NF-κβ mediated apoptotic signaling in cognitive deficits associated with postnatal ethanol exposure in rats and points to the potential of tocotrienol in the prevention of cognitive deficits in children with fetal alcohol spectrum disorders (FASDs).     

Effects of melatonin on oxidative stress and spatial memory impairment induced by acute ethanol treatment in rats

Melatonin has recently been suggested as an antioxidant that may protect neurons from oxidative stress. Acute ethanol administration produces both lipid peroxidation as an indicator of oxidative stress in the brain and impairs water-maze performance in spatial learning and memory tasks. The present study investigated the effect of melatonin against ethanol-induced oxidative stress and spatial memory impairment. The Morris water maze was used to evaluate the cognitive functions of rats. Thiobarbituric acid reactive substances (TBARS), which are the indicators of lipid peroxidation, and the activities of antioxidative enzymes (glutathione peroxidase and superoxide dismutase) were measured in the rat hippocampus and prefrontal cortex which form interconnected neural circuits for spatial memory. Acute administration of ethanol significantly increased TBARS levels in the hippocampus. Combined melatonin-ethanol treatment caused a significant increase in glutathione peroxidase activities and a significant decrease of TBARS in the rat hippocampus. In the prefrontal cortex, there was only a significant decrease of TBARS levels in the combined melatonin-ethanol receiving group as compared to the ethanol-treated group. Melatonin did not affect the impairment of spatial memory due to acute ethanol exposure, but melatonin alone had a positive effect on water maze performances. Our study demonstrated that melatonin decreased ethanol-induced lipid peroxidation and increased glutathione peroxidase activity in the rat hippocampus.     

Chronic social isolation induces NF-κB activation and upregulation of iNOS protein expression in rat prefrontal cortex

Exposure of an organism to stress, results in oxidative stress and increased nitric oxide (NO) production in the brain. The role of the processes caused by chronic stress in the prefrontal cortex has not been fully investigated. Considering that chronic stress increases NO production by the enzyme nitric oxide synthase (NOS), we examined the cytosolic neuronal (nNOS) or inducible (iNOS) protein levels in the prefrontal cortex of rats exposed to 21 d of chronic social isolation stress, an animal model of depression, alone or in combination with 2 h of acute immobilization or cold (4 °C) stress (combined stress). Antioxidative status via cytosolic CuZnSOD and mitochondrial MnSOD activity, cytosolic redox status via reduced glutathione (GSH) concentration were determined. Furthermore, cytosolic inducible heat shock protein 70 (Hsp70i), cytosolic/nuclear distributions of NF-κB and serum corticosterone (CORT) were also investigated to elucidate the possible mechanism involved in the cellular NOS pathway. Our results showed that both acute stressors led to increases of CORT and nNOS protein while iNOS protein expression was unaffected. In contrast to the acute stress, chronic social isolation compromised hypothalamic–pituitary-adrenal axis functioning such that the normal stress response was impaired following subsequent acute stressors. Downregulated redox GSH status as well as decreased activity of CuZnSOD and MnSOD suggests the existence of oxidative stress which remained as such following combined stressors. Changes in redox-status associated with decreased Hsp70i protein expression enabled NF-κB translocation into the nucleus, causing increased cytosolic nNOS and iNOS protein expression. Results suggest that NOS signaling pathway plays a differential role between acute and chronic stress whereby state of oxidative/nitrosative stress after chronic social isolation is caused, at least in part, by NF-κB activation and increased iNOS protein expression.     

Effects of Dexmedetomidine and Oxycodone on Neurocognitive and Inflammatory Response After Tourniquet-Induced Ischemia–Reperfusion Injury

To evaluate the effects of dexmedetomidine (Dex) and oxycodone (Oxy) on neurocognitive and inflammatory response after tourniquet-induced ischemia–reperfusion (I/R) injury. C57/BL6 mice were used to construct the mouse model of tourniquet-induced I/R injury. Mice (n?=?48) were randomly divided into sham, I/R, Dex or Oxy group. Morris water maze test was performed to assess the spatial learning and memory function. The expression of NF-κB, TLR4, NR2B, M1 (CD68 and TNF-α) and M2 (CD206 and IL-10) polarization markers in mice hippocampus were detected by western blot or immunofluorescent staining. Spontaneous excitatory post-synaptic currents (sEPSCs) were recorded by electrophysiology. Dex treatment alleviated I/R-induced declines in learning and memory (p < 0.05), while Oxy had no significant effect on it. Compared with I/R group, Dex and Oxy treatment down-regulated the expression of NF-κB, TLR4, TNF-α and CD68 (all p < 0.05), while no significantly different was found in CD206 and IL-10. In addition, Dex treatment down-regulated the expression of NR2B and reduced the frequency and amplitude of sEPSCs in I/R model mice (all p < 0.05), while Oxy had no significant effect on them. Tourniquet-induced I/R could impair the neurocognitive function of mice. Dex treatment could alleviate I/R-induced neurocognitive disorder by inhibiting abnormal synaptic transmission in hippocampal neurons. Both Dex and Oxy could alleviate the inflammatory response likely by inhibiting the polarization of microglia toward M1 phenotype via TLR4/NF-κB pathway. Future studies are needed to further examine the effects of Dex on neurocognitive disorder after tourniquet-induced I/R injury and investigate the exact mechanism.

     

Glutamic acid decarboxylase 67 haplodeficiency impairs social behavior in mice

Reduced glutamic acid decarboxylase (GAD)67 expression may be causally involved in the development of social withdrawal in neuropsychiatric states such as autism, schizophrenia and bipolar disorder. In this study, we report disturbance of social behavior in male GAD67 haplodeficient mice. GAD67^+/? mice, compared to GAD67^+/+ littermates, show reduced sociability and decreased intermale aggression, but normal nest building and urine marking behavior, as well as unchanged locomotor activity and anxiety‐like behavior. Moreover, the mutants display a reduced sensitivity to both social and non‐social odors, indicating a disturbance in the detection and/or processing of socially relevant olfactory stimuli. Indeed, we observed reduced activation of the lateral septum, medial preoptic area, bed nucleus of the stria terminalis, medial and cortical amygdala upon exposure of GAD67^+/? mice to social interaction paradigm, as indicated by c‐Fos immunohistochemistry. These data suggest a disturbance of stimulus processing in the brain circuitry controlling social behavior in GAD67^+/? mice, which may provide a useful model for studying the impact of a reduced GAD67 expression on alterations of social behavior related to neuropsychiatric disorders .     

Gastrointestinal phenotype of GAD67lacZ transgenic mice with early postnatal lethality

It has been proposed that gamma-aminobutyric acid (GABA) in the gut may function as a neurotransmitter, hormone and/or paracrine agent. Our aim was to examine transgenic mice of the GAD67-lacZ line with impaired postnatal growth and early postnatal lethality for gastrointestinal abnormalities. The gastrointestinal tract was dissected and processed for histology, immunohistochemistry, electron microscopy, western blotting and measurement of GAD activity. Homozygous mice of both sexes displayed an intestinal phenotype characterized by a fragile and haemorrhagic intestinal wall, a reduced number of villi, epithelial lesions and the occasional appearance of pseudostratified epithelium. The number of GABA-immunoreactive enteroendocrine cells and mucin-secreting goblet cells increased significantly relative to wild-type epithelium. The appearance of GABA-immunopositive neuronal perikarya and the lack of GABA-immunoreactive varicose fibres were observed in the enteric plexuses of transgenic mice. Tissue homogenates of transgenic mice showed higher levels of expression of GAD67 and GAD65 as compared with wild-type mice. Our results suggest that the possible reason underlying the growth impairment and postnatal lethality observed in GAD67 transgenic mice is a functional impairment of GABAergic enteric neurons and disintegration of intestinal epithelium.     

A quantitative trait locus on chromosome 1 modulates intermale aggression in mice

Aggression between male conspecifics is a complex social behavior that is likely modulated by multiple gene variants. In this study, the BXD recombinant inbred mouse strains (RIS) were used to map quantitative trait loci (QTLs) underlying behaviors associated with intermale aggression. Four hundred and fifty‐seven males from 55 strains (including the parentals) were observed at an age of 13 ± 1 week in a resident‐intruder test following 10 days of isolation. Attack latency was measured directly within a 10‐minute time period and the test was repeated 24 hours later. The variables we analyzed were the proportion of attacking males in a given strain as well as the attack latency (on days 1 and 2, and both days combined). On day 1, 29% of males attacked, and this increased to 37% on day 2. Large strain differences were obtained for all measures of aggression, indicating substantial heritability (intraclass correlations 0.10‐0.18). We identified a significant QTL on chromosome (Chr) 1 and suggestive QTLs on mouse Chrs 1 and 12 for both attack and latency variables. The significant Chr 1 locus maps to a gene‐sparse region between 82 and 88.5 Mb with the C57BL/6J allele increasing aggression and explaining about 18% of the variance. The most likely candidate gene modulating this trait is Htr2b which encodes the serotonin 2B receptor and has been implicated in aggressive and impulsive behavior in mice, humans and other species.     

Transglutaminase 2 gene ablation protects against renal ischemic injury by blocking constant NF-κB activation

Transglutaminase 2 knockout (TGase2(-/-)) mice show significantly reduced inflammation with decreased myofibroblasts in a unilateral ureteral obstruction (UUO) model, but the mechanism remains to be clarified. Nuclear factor-κB (NF-κB) activation plays a major role in the progression of inflammation in an obstructive nephropathy model. However, the key factors extending the duration of NF-κB activation in UUO are not known. In several inflammatory diseases, we and others recently found that TGase 2 plays a key role in extending NF-κB activation, which contributes to the pathogenesis of disease. In the current study, we found that NF-κB activity in mouse embryogenic fibroblasts (MEFs) from TGase2(-/-) mice remained at the control level while the NF-κB activity of wild-type (WT) MEFs was highly increased under hypoxic stress. Using the obstructive nephropathy model, we found that NF-κB activity remained at the control level in TGase2(-/-) mouse kidney tissues, as measured by COX-2 expression, but was highly increased in WT tissues. We conclude that TGase 2 gene ablation reduces the duration of NF-κB activation in ischemic injury.     

Amplification of proinflammatory phenotype, damage, and weakness by oxidative stress in the diaphragm muscle of mdx mice

Duchenne muscular dystrophy (DMD) is a common and devastating type of childhood-onset muscular dystrophy, attributed to an X-linked defect in the gene that encodes dystrophin. Myopathy with DMD is most pronounced in the diaphragm muscle and fast-twitch limb muscles and is dependent upon susceptibility to damage, inflammatory cell infiltration, and proinflammatory signaling (nuclear factor-κB; NF-κB). Although recent papers have reawakened the notion that oxidative stress links inflammatory signaling with pathology in DMD in limb muscle, the importance of redox mechanisms had been clouded by inconsistent results from indirect scavenger approaches, including in the diaphragm muscle. Therefore, we used a novel catalytic mimetic of superoxide dismutase and catalase (EUK-134) as a direct scavenger of oxidative stress in myopathy in the diaphragm of the mdx mouse model. EUK-134 reduced 4-hydroxynonenal and total hydroperoxides, markers of oxidative stress in the mdx diaphragm. EUK-134 also attenuated positive staining of macrophages and T-cells as well as activation of NF-κB and p65 protein abundance. Moreover, EUK-134 ameliorated markers of muscle damage including internalized nuclei, variability of cross-sectional area, and type IIc fibers. Finally, impairment of contractile force was partially rescued by EUK-134 in the diaphragm of mdx mice. We conclude that oxidative stress amplifies DMD pathology in the diaphragm muscle.     

Impaired GAD1 expression in schizophrenia‐related WISKET rat model with sex‐dependent aggressive behavior and motivational deficit

After peri‐adolescence isolation rearing (IS) and subchronic ketamine (KET) treatment, adult, selectively bred Wistar rats (named WISKET) mimic abnormal behaviors reminiscent of human schizophrenia, including reduced prepulse‐inhibition of startle reflex, disturbances in cognition, locomotor activity and thermoregulation, decreased pain sensitivity and electrophysiological alterations. To further validate our WISKET rat line, regarding its translational utility in schizophrenia research, we examined their social behavior and introduced a short and simple holeboard (HB)‐like test to investigate their motivational deficit that predicts the cognitive disturbance. Sex‐dependent alterations in schizophrenia may yield important insights into its etiology; thus, male and female WISKET rats were also investigated and compared with their naive Wistar counterparts. Considering the contribution of the hippocampal and cortical GABAergic inhibitory circuitry in these behavioral alterations, molecular‐biology studies were also performed regarding the GAD1 gene products. Impaired social activity with increased aggression, stress‐related behavior, active social withdrawal, motivation deficit and decreased exploration were observed, especially in male WISKET rats, compared with Wistar ones and their corresponding females. These alterations were accompanied by sex‐dependent alterations regarding GAD67 mRNA and protein expression in the prefrontal cortex and hippocampus. In conclusion, the WISKET animals are valuable tools for animal‐based preclinical drug discovery studies for predictive screening of novel compounds improving negative symptoms with potential antipsychotic efficacy.     

Epigallocatechin-3-gallate prevents lupus nephritis development in mice via enhancing the Nrf2 antioxidant pathway and inhibiting NLRP3 inflammasome activation

Patients with lupus nephritis show an impaired oxidative status and increased levels of interleukin (IL)-1β and IL-18, which are closely linked to inflammation and correlated with disease activity. Although epigallocatechin-3-gallate (EGCG), the major bioactive polyphenol present in green tea with antioxidant and free radical scavenging activities, has been reported to have anti-inflammatory effects by inhibiting nuclear factor-kappa B (NF-κB)-mediated inflammatory responses in vivo, its effectiveness for the treatment of lupus nephritis is still unknown. In the present study, 12-week-old New Zealand black/white (NZB/W) F1 lupus-prone mice were treated daily with EGCG by gavage until sacrificed at 34 weeks old for clinical, pathological, and mechanistic evaluation. We found that the administration (1) prevented proteinuria, renal function impairment, and severe renal lesions; (2) increased renal nuclear factor E2-related factor 2 (Nrf2) and glutathione peroxidase activity; (3) reduced renal oxidative stress, NF-κB activation, and NLRP3 mRNA/protein expression and protein levels of mature caspase-1, IL-1β, and IL-18; and (4) enhanced splenic regulatory T (Treg) cell activity. Our data clearly demonstrate that EGCG has prophylactic effects on lupus nephritis in these mice that are highly associated with its effects of enhancing the Nrf2 antioxidant signaling pathway, decreasing renal NLRP3 inflammasome activation, and increasing systemic Treg cell activity.