Neoantigen-specific cytotoxic Tr1 CD4 T cells suppress cancer immunotherapy.

CD4+ T cells can either enhance or inhibit tumour immunity. Although regulatory T cells have long been known to impede antitumour responses1-5, other CD4+ T cells have recently been implicated in inhibiting this response6,7. Yet, the nature and function of the latter remain unclear. Here, using vaccines containing MHC class I (MHC-I) neoantigens (neoAgs) and different doses of tumour-derived MHC-II neoAgs, we discovered that whereas the inclusion of vaccines with low doses of MHC-II-restricted peptides (LDVax) promoted tumour rejection, vaccines containing high doses of the same MHC-II neoAgs (HDVax) inhibited rejection. Characterization of the inhibitory cells induced by HDVax identified them as type 1 regulatory T (Tr1) cells expressing IL-10, granzyme B, perforin, CCL5 and LILRB4. Tumour-specific Tr1 cells suppressed tumour rejection induced by anti-PD1, LDVax or adoptively transferred tumour-specific effector T cells. Mechanistically, HDVax-induced Tr1 cells selectively killed MHC-II tumour antigen-presenting type 1 conventional dendritic cells (cDC1s), leading to low numbers of cDC1s in tumours. We then documented modalities to overcome this inhibition, specifically via anti-LILRB4 blockade, using a CD8-directed IL-2 mutein, or targeted loss of cDC2/monocytes. Collectively, these data show that cytotoxic Tr1 cells, which maintain peripheral tolerance, also inhibit antitumour responses and thereby function to impede immune control of cancer.

The use of faecal microbiota transplant as treatment for recurrent or refractory Clostridioides difficile infection and other potential indications: second edition of joint British Society of Gastroenterology (BSG) and Healthcare Infection Society (HIS) guidelines.

The first British Society of Gastroenterology (BSG) and Healthcare Infection Society (HIS)-endorsed faecal microbiota transplant (FMT) guidelines were published in 2018. Over the past 5 years, there has been considerable growth in the evidence base (including publication of outcomes from large national FMT registries), necessitating an updated critical review of the literature and a second edition of the BSG/HIS FMT guidelines. These have been produced in accordance with National Institute for Health and Care Excellence-accredited methodology, thus have particular relevance for UK-based clinicians, but are intended to be of pertinence internationally. This second edition of the guidelines have been divided into recommendations, good practice points and recommendations against certain practices. With respect to FMT for Clostridioides difficile infection (CDI), key focus areas centred around timing of administration, increasing clinical experience of encapsulated FMT preparations and optimising donor screening. The latter topic is of particular relevance given the COVID-19 pandemic, and cases of patient morbidity and mortality resulting from FMT-related pathogen transmission. The guidelines also considered emergent literature on the use of FMT in non-CDI settings (including both gastrointestinal and non-gastrointestinal indications), reviewing relevant randomised controlled trials. Recommendations are provided regarding special areas (including compassionate FMT use), and considerations regarding the evolving landscape of FMT and microbiome therapeutics.

Arabidopsis stromal carbonic anhydrases exhibit non-overlapping roles in photosynthetic efficiency and development.

Carbonic anhydrases (CAs) are ubiquitous enzymes that accelerate the reversible conversion of CO2 to HCO3 - . The Arabidopsis genome encodes members of the α-, ß- and γ-CA families, and it has been hypothesized that ßCA activity has a role in photosynthesis. In this work, we tested this hypothesis by characterizing the two plastidial ßCAs, ßCA1 and ßCA5, in physiological conditions of growth. We conclusively established that both proteins are localized in the chloroplast stroma and that the loss of ßCA5 induced the expression of ßCA1, supporting the existence of regulatory mechanisms to control the expression of stromal ßCAs. We also established that ßCA1 and ßCA5 have markedly different enzymatic kinetics and physiological relevance. Specifically, we found that ßCA5 had a first-order rate constant ~10-fold lower than ßCA1, and that the loss of ßCA5 is detrimental to growth and could be rescued by high CO2 . Furthermore, we established that, while a ßCA1 mutation showed near wild-type growth and no significant impact on photosynthetic efficiency, the loss of ßCA5 markedly disrupted photosynthetic efficiency and light-harvesting capacity at ambient CO2 . Therefore, we conclude that in physiological autotrophic growth, the loss of the more highly expressed ßCA1 does not compensate for the loss of a less active ßCA5, which in turn is involved in growth and photosynthesis at ambient CO2 levels. These results lend support to the hypothesis that, in Arabidopsis,ßCAs have non-overlapping roles in photosynthesis and identify a critical activity of stromal ßCA5 and a dispensable role for ßCA1.

Effects of transcutaneous electrical nerve stimulation on recovery of gastrointestinal motility after laparotomy: A randomized controlled trial.

INTRODUCTION: Postoperative Ileus (POI) negatively impacts patient outcomes and increases healthcare costs. Transcutaneous electrical nerve stimulation (TENS) has been found to improve gastrointestinal (GI) motility following abdominal surgery. However, its effectiveness in this context is not well-established. This study was designed to evaluate the role of TENS on the recovery of GI motility after exploratory laparotomy. METHODS: Patients undergoing exploratory laparotomy were randomized in a 1:1 ratio into control (standard treatment alone) and experimental (standard treatment + TENS) arms. TENS was terminated after 6 days or after the passage of stool or stoma movement. The primary outcome was time for the first passage of stool/functioning stoma. Non-passage of stool or nonfunctioning stoma beyond 6 days was labeled as prolonged POI. Patients were monitored until discharge. RESULTS: Median (interquartile range) time to first passage of stool/functioning stoma was 82.6 (49-115) hours in the standard treatment group and 50 (22-70.6) hours in the TENS group [p < 0.001]. Prolonged POI was noted in 11 patients in the standard treatment group (35.5%) and one in the TENS group (3.2%) [p = 0.003]. Postoperative hospital stay was similar in the two groups. CONCLUSION: TENS resulted in early recovery of GI motility by shortening the duration of POI without any improvement in postoperative hospital stay. TRIAL REGISTRATION NUMBER: CTRI/2021/10/037054.

Apple (Malus × domestica Borkh.) production and quality in response to anti-hail nets.

Anti-hail nets are the best way to mitigate the effects of hailstorms in the orchards. Apple trees covered with nets may exhibit a variety of vegetative and reproductive responses, inclusive of changes in tree vigour, cropping, sugar contents, and fruit colour. The present study was conducted to assess the effect of timing of installation and colour of anti-hail net on cropping and fruit quality in high-density apple orchard for two consecutive seasons (2021 and 2022). White and blue colour nets of size (9 m × 30 m) 80 GSM (square mesh with non-sliding threaded, leno weave, and < 30% shading factor) were installed at three different time intervals (15 days before estimated full bloom, at full bloom, and 15 days after full bloom) on apple cultivar 'Jeromine'. The installation at different time and colour of anti-hail nets significantly exhibit variability in cropping, fruit quality, and bio-chemical metrics. The significant highest cropping (fruit yield, productivity, and yield efficiency) and fruit biochemical parameters (total soluble solids) were recorded in T3C2 (15 days after full bloom + white colour anti-hail net) followed by T2C2 (installed at full bloom + white colour anti-hail net). Hence, white colour anti-hail nets installed 15 days after full bloom increased fruit production and improved quality in comparison to blue colour anti-hail net in apple under high-density plantations.

Gallbladder perforation: Diagnostic accuracy of new CT difficulty score in predicting complicated laparoscopic cholecystectomy.

PURPOSE: To formulate and evaluate the diagnostic performance and utility of a new CT difficulty score in predicting difficult laparoscopic surgery in cases of gallbladder (GB) perforation. METHODS: This prospective single centre study included a total of 48 diagnosed cases of GB perforation on CT between December 2021 and June 2023, out of which 24 patients were operated. A new 6-point CT difficulty scoring system was devised to predict difficult laparoscopic approach, based on patterns of inflammation around the perforated GB that were found to be surgically relevant. The pre-operative imaging findings on CT were studied in detail and correlation coefficients of various imaging findings were calculated to predict difficult surgery. RESULTS: On CECT, the type of perforation, according to the revised Niemeier's classification could be exactly delineated in all 48 patients. A CT difficulty score of ≥ 3 was found to a good predictor difficult laparoscopic approach, with statistical significance (p = 0.001), sensitivity of 94.44%, specificity of 83.33%, PPV of 94.44% and NPV of 83.33%. Inflammatory changes around duodenum showed maximum correlation coefficient of 0.744 (p = 0.0001), around colon showed a correlation coefficient of 0.657 (p = 0.0005), and in the omentum had a correlation coefficient of 0.5 (p = 0.013)). Inter-observer agreement was also calculated for various findings and it was found to have moderate to strong agreement (κ value 0.5-1.0). CONCLUSION: The CT difficulty scoring system can be an effective tool in predicting difficult laparoscopic surgery in cases of GB perforation in an emergency setting which can help in decision making and improved patient outcome.

Ginsenoside Re attenuates 8-OH-DPAT-induced serotonergic behaviors in mice via interactive modulation between PKCδ gene and Nrf2.

It has been recognized that serotonergic blocker showed serious side effects, and that ginsenoside modulated serotonergic system with the safety. However, the effects of ginsenoside on serotonergic impairments remain to be clarified. Thus, we investigated ginsenoside Re (GRe), a major bioactive component in the mountain-cultivated ginseng on (±)-8-hydroxy-dipropylaminotetralin (8-OH-DPAT), a 5-HT1A receptor agonist. In the present study, we observed that the treatment with GRe resulted in significant inhibition of protein kinase C δ (PKCδ) phosphorylation induced by the 5-HT1A receptor agonist (±)-8-hydroxy-dipropylaminotetralin (8-OH-DPAT) in the hypothalamus of the wild-type (WT) mice. The inhibition of GRe was comparable with that of the PKCδ inhibitor rottlerin or the 5-HT1A receptor antagonist WAY100635 (WAY). 8-OH-DPAT-induced significant reduction in nuclear factor erythroid-2-related factor 2 (Nrf2)-related system (i.e., Nrf2 DNA binding activity, γ-glutamylcysteine ligase modifier (GCLm) and γ-glutamylcysteine ligase catalytic (GCLc) mRNA expression, and glutathione (GSH)/oxidized glutathione (GSSG) ratio) was significantly attenuated by GRe, rottlerin, or WAY in WT mice. However, PKCδ gene knockout significantly protected the Nrf2-dependent system from 8-OH-DPAT insult in mice. Increases in 5-hydroxytryptophan (5-HT) turnover rate, overall serotonergic behavioral score, and hypothermia induced by 8-OH-DPAT were significantly attenuated by GRe, rottlerin, or WAY in WT mice. Consistently, PKCδ gene knockout significantly attenuated these parameters in mice. However, GRe or WAY did not provide any additional positive effects on the serotonergic protective potential mediated by PKCδ gene knockout in mice. Therefore, our results suggest that PKCδ is an important mediator for GRe-mediated protective activity against serotonergic impairments/oxidative burden caused by the 5-HT1A receptor.

Draft genome sequence of Indian mulberry (Morus indica) provides a resource for functional and translational genomics.

Mulberry is an important crop plant for the sericulture industry. Here, we report high-quality genome sequence of a cultivated Indian mulberry (Morus indica cv K2) obtained by combining data from four different technologies, including Illumina, single-molecule real-time sequencing, chromosome conformation capture and optical mapping, with a gene completeness of 96.5%. Based on the genome sequence, we identified 49.2% of repetitive DNA and 27,435 high-confidence protein-coding genes with >90% of them supported by transcript evidence. A comparative analysis with other plant genomes identified 4.8% of species-specific genes in the M. indica genome. Transcriptome profiling revealed tissue-specific and differential expression across multiple accessions of ~4.7% and 2-5% of protein-coding genes, respectively, implicated in diverse biological processes. Whole genome resequencing of 21 accessions/species revealed ~2.5 million single nucleotide polymorphisms and ~ 0.2 million insertions/deletions. These data and results provide a comprehensive resource to accelerate the genomics research in mulberry for its improvement.

Insight into Structure Activity Relationship of DPP-4 Inhibitors for Development of Antidiabetic Agents.

This article sheds light on the various scaffolds that can be used in the designing and development of novel synthetic compounds to create DPP-4 inhibitors for the treatment of type 2 diabetes mellitus (T2DM). This review highlights a variety of scaffolds with high DPP-4 inhibition activity, such as pyrazolopyrimidine, tetrahydro pyridopyrimidine, uracil-based benzoic acid and esters, triazole-based, fluorophenyl-based, glycinamide, glycolamide, ß-carbonyl 1,2,4-triazole, and quinazoline motifs. The article further explains that the potential of the compounds can be increased by substituting atoms such as fluorine, chlorine, and bromine. Docking of existing drugs like sitagliptin, saxagliptin, and vildagliptin was done using Maestro 12.5, and the interaction with specific residues was studied to gain a better understanding of the active sites of DPP-4. The structural activities of the various scaffolds against DPP-4 were further illustrated by their inhibitory concentration (IC50) values. Additionally, various synthesis schemes were developed to make several commercially available DPP4 inhibitors such as vildagliptin, sitagliptin and omarigliptin. In conclusion, the use of halogenated scaffolds for the development of DPP-4 inhibitors is likely to be an area of increasing interest in the future.

Exploring genetic diversity and ascertaining genetic loci associated with important fruit quality traits in apple (Malus × domestica Borkh.).

Genetic diversity is the primary source of variability in any crop improvement program, and the diverse germplasm of any crop species represents an important genetic resource for gene or allele mining to meet future needs. Huge genetic and phenotypic diversity is present in the apple gene pool, even though, breeding programs have been mainly focused on a few traits of interests, which have resulted in the reduction of the diversity in the cultivated lines of apple. Therefore, the present study was carried out on 70 diverse apple genotypes with the objective of analyzing the genetic diversity and to identify the genetic loci associated with important fruit quality traits. A total of 140 SSR primers were used to characterize the 70 genotypes of apples, out of which only 88 SSRs were found to be polymorphic. The PIC values varied from 0.03 to 0.75. The value of MI, EMR, and RP varied from 0.03 to 3.5, 0.5 to 5.0, and 1.89 to 6.74, respectively. The dendrogram and structure analysis divided all the genotypes into two main groups. In addition to this, large phenotypic variability was observed for the fruit quality traits under study indicated the suitability of the genotypes for association studies. Altogether 71 novel MTAs were identified for 10 fruit quality traits, of which 15 for fruit length, 15 for fruit diameter, 12 for fruit weight, 2 for total sugar, 2 for TSS, 4 for reducing sugar, 5 for non-reducing sugar, 5 for fruit firmness, 5 for fruit acidity and 6 for anthocyanin, respectively. Consistent with the physicochemical evaluation of traits, there was a significant correlation coefficient among different fruit quality characters, and many common markers were found to be associated with these traits (fruit diameter, length, TSS, total sugar, acidity and anthocyanin, respectively) by using the different modeling techniques (GLM, MLM). The inferred genetic structure, diversity pattern and the identified MTAs will be serving as resourceful grounds for better predictions and understanding of apple genome towards efficient conservation and utilization of apple germplasm for facilitating genetic improvement of fruit quality traits. Furthermore, these findings also suggested that association mapping could be a viable alternative to the conventional QTL mapping approach in apple. Supplementary Information: The online version contains supplementary material available at 10.1007/s12298-023-01382-w.

TLR1/2 ligand enhances antitumor efficacy of CTLA-4 blockade by increasing intratumoral Treg depletion.

Immune checkpoint inhibitors such as anti-CTLA-4 antibody are widely accepted therapeutic options for many cancers, but there is still a considerable gap in achieving their full potential. We explored the potential of activating the innate and adaptive immune pathways together to improve tumor reduction and survival outcomes. We treated a mouse model of melanoma with intratumoral injections of Toll-like receptor 1/2 (TLR1/2) ligand Pam3CSK4 plus i.p. injections of anti-CTLA-4 antibody. This combination treatment enhanced antitumor immune responses both qualitatively and quantitatively over anti-CTLA-4 alone, and its efficacy depended on CD4 T cells, CD8 T cells, Fcγ receptor IV, and macrophages. Interestingly, our results suggest a unique mechanism by which TLR1/2 ligand increased Fcγ receptor IV expression on macrophages, leading to antibody-dependent macrophage-mediated depletion of regulatory T cells in the tumor microenvironment and increasing efficacy of anti-CTLA-4 antibody in the combination treatment. This mechanism could be harnessed to modulate the clinical outcome of anti-CTLA-4 antibodies and possibly other antibody-based immunotherapies.

Laparoscopic transhiatal oesophageal diverticulectomy: An experience of large epiphrenic oesophageal diverticulum and review literature.

Epiphrenic diverticulum is a rare abnormality of the distal oesophagus. Both thoracic and abdominal approaches are suitable for this diverticulum. A 46-year-old male presented with complaints of regurgitation and chest pain for 2 years. Contrast-enhanced computed tomography of the neck, thorax, abdomen and oesophageal endoscopy revealed 12 cm × 10 cm size large intrathoracic oesophageal diverticulum. He underwent an elective laparoscopic transabdominal oesophageal diverticulectomy. Gastrograffin study on the first post-operative day did not reveal any leak. In this case report, we are sharing our experience in the management of large epiphrenic oesophageal diverticulum through a laparoscopic approach. The benefits of the laparoscopic approach include decreased morbidity because we can avoid large thoracotomy or laparotomy incision.

Decoding the wheat awn transcriptome and overexpressing TaRca1ß in rice for heat stress tolerance.

KEY MESSAGE: Role of Rubisco Activase in imparting thermotolerance to the photosynthetic apparatus under high temperature. Thus, to improve the grain filling, we need to fine tune these crucial enzymes and their regulation, which directly or indirectly affect spike photosynthesis. CO2 fixation in cereals crops like bread wheat (Triticum aestivum L.) is also contributed by ear photosynthesis beside the other organs like leaves or the flag leaf. 1000-grain weight of three Indian wheat cultivars (cvs.) PBW343, K7903, and HD2329 were calculated under three treatments until maturity stage (i.e. removal of flag leaf, removal of awns and shaded spikes). We observed that awn removal showed a significant decrease in 1000-grain weight in all cultivars. To delve deeper into the biological and molecular pathways taking place underlying the awn physiology, we conducted the awn transcriptome analysis of thermosusceptible Indian wheat cv. PBW343 under heat stress (HS) at 42 °C for 2 h using RNA-sequencing (RNA-seq). Differential expression analysis revealed, 160 transcripts, out of these, 143 transcripts were significantly upregulated and 17 transcripts were repressed under HS conditions. Of these Rca1ß was selected for characterization and overexpression studies. Ectopic expression of TaRca1ß in rice transgenics indicate a direct correlation with tolerance under HS conditions. TaRca1ß provides a better photosynthate energy partitioning under HS with a significant reduction in the non-photochemical fluorescence quenching of the photosynthetic machinery.

Outcomes of Renal Trauma in Indian Urban Tertiary Healthcare Centres: A Multicentre Cohort Study.

BACKGROUND: Renal trauma is present in 0.5-5% of patients admitted for trauma. Advancements in radiologic imaging and minimal-invasive techniques have led to decreased need for surgical intervention. We used a large trauma cohort to characterise renal trauma patients, their management and outcomes. METHODS: We analysed "Towards Improved Trauma Care Outcomes in India" cohort from four urban tertiary public hospitals in India between 1st September 2013 and 31st December 2015. The data of patients with renal trauma were extracted using International Classification of Diseases 10 codes and analysed for demographic and clinical details. RESULTS: A total of 16,047 trauma patients were included in this cohort. Abdominal trauma comprised 1119 (7%) cases, of which 144 (13%) had renal trauma. Renal trauma was present in 1% of all the patients admitted for trauma. The mean age was 28 years (SD-14.7). A total of 119 (83%) patients were male. Majority (93%) were due to blunt injuries. Road traffic injuries were the most common mechanism (53%) followed by falls (29%). Most renal injuries (89%) were associated with other organ injuries. Seven of the 144 (5%) patients required nephrectomy. Three patients had grade V trauma; all underwent nephrectomy. The 30-day in-hospital mortality, in patients with renal trauma, was 17% (24/144). CONCLUSION: Most renal trauma patients were managed nonoperatively. 89% of patients with renal trauma had concomitant injuries. The renal trauma profile from this large cohort may be generalisable to urban contexts in India and other low- and middle-income countries.

An Analysis of 30-Day in-Hospital Trauma Mortality in Four Urban University Hospitals Using the Australia India Trauma Registry.

BACKGROUND: India has one-sixth (16%) of the world's population but more than one-fifth (21%) of the world's injury mortality. A trauma registry established by the Australia India Trauma Systems Collaboration (AITSC) Project was utilized to study 30-day in-hospital trauma mortality at high-volume Indian hospitals. METHODS: The AITSC Project collected data prospectively between April 2016 and March 2018 at four Indian university hospitals in New Delhi, Mumbai, and Ahmedabad. Patients admitted with an injury mechanism of road or rail-related injury, fall, assault, or burns were included. The associations between demographic, physiological on-admission vitals, and process-of-care parameters with early (0-24 h), delayed (1-7 days), and late (8-30 days) in-hospital trauma mortality were analyzed. RESULTS: Of 9354 patients in the AITSC registry, 8606 were subjected to analysis. The 30-day mortality was 12.4% among all trauma victims. Early (24-h) mortality was 1.9%, delayed (1-7 days) mortality was 7.3%, and late (8-30 days) mortality was 3.2%. Abnormal physiological parameters such as a low SBP, SpO2, and GCS and high HR and RR were observed among non-survivors. Early initiation of trauma assessment and monitoring on arrival was an important process of care indicator for predicting 30-day survival. CONCLUSIONS: One in ten admitted trauma patients (12.4%) died in urban trauma centers in India. More than half of the trauma deaths were delayed, beyond 24 h but within one week following injury. On-admission physiological vital signs remain a valid predictor of early 24-h trauma mortality.

Ginsenoside Re Protects against Serotonergic Behaviors Evoked by 2,5-Dimethoxy-4-iodo-amphetamine in Mice via Inhibition of PKCδ-Mediated Mitochondrial Dysfunction.

It has been recognized that serotonin 2A receptor (5-HT2A) agonist 2,5-dimethoxy-4-iodo-amphetamine (DOI) impairs serotonergic homeostasis. However, the mechanism of DOI-induced serotonergic behaviors remains to be explored. Moreover, little is known about therapeutic interventions against serotonin syndrome, although evidence suggests that ginseng might possess modulating effects on the serotonin system. As ginsenoside Re (GRe) is well-known as a novel antioxidant in the nervous system, we investigated whether GRe modulates 5-HT2A receptor agonist DOI-induced serotonin impairments. We proposed that protein kinase Cδ (PKCδ) mediates serotonergic impairments. Treatment with GRe or 5-HT2A receptor antagonist MDL11939 significantly attenuated DOI-induced serotonergic behaviors (i.e., overall serotonergic syndrome behaviors, head twitch response, hyperthermia) by inhibiting mitochondrial translocation of PKCδ, reducing mitochondrial glutathione peroxidase activity, mitochondrial dysfunction, and mitochondrial oxidative stress in wild-type mice. These attenuations were in line with those observed upon PKCδ inhibition (i.e., pharmacologic inhibitor rottlerin or PKCδ knockout mice). Furthermore, GRe was not further implicated in attenuation mediated by PKCδ knockout in mice. Our results suggest that PKCδ is a therapeutic target for GRe against serotonergic behaviors induced by DOI.

Glutathione Peroxidase-1 Knockout Facilitates Memory Impairment Induced by ß-Amyloid (1-42) in Mice via Inhibition of PKC ßII-Mediated ERK Signaling; Application with Glutathione Peroxidase-1 Gene-Encoded Adenovirus Vector.

A growing body evidence suggests that selenium (Se) deficiency is associated with an increased risk of developing Alzheimer's disease (AD). Se-dependent glutathione peroxidase-1 (GPx-1) of a major antioxidant enzyme, and the most abundant isoform of GPx in the brain. In the present study, we investigated whether GPx-1 is protective against memory impairments induced by beta-amyloid (Aß) (1-42) in mice. As the alteration of protein kinase C (PKC)-mediated ERK activation was recognized in the early stage of AD, we examined whether the GPx-1 gene modulates Aß (1-42)-induced changes in PKC and ERK levels. We observed that Aß (1-42) treatment (400 pmol, i.c.v.) significantly decreased PKC ßII expression in the hippocampus of mice. Aß (1-42)-induced neurotoxic changes [i.e., oxidative stress (i.e., reactive oxygen species, 4-hydroxy-2-noneal, and protein carbonyl), reduced PKC ßII and phospho-ERK expressions, and memory impairment under Y-maze and passive avoidance test] were more pronounced in GPx-1 knockout than in wild type mice. Importantly, exposure to a GPx-1 gene-encoded adenovirus vector (Adv-GPx-1) significantly increased GPx-1 mRNA and GPx activity in the hippocampus of GPx-1 knockout mice. Adv-GPx-1 exposure also significantly blocked the neurotoxic changes induced by Aß (1-42) in GPx-1 knockout mice. Treatment with ERK inhibitor U0126 did not significantly change Adv-GPx-1-mediated attenuation in PKC ßII expression. In contrast, treatment with PKC inhibitor chelerythrine (CHE) reversed Adv-GPx-1-mediated attenuation in ERK phosphorylation, suggesting that PKC ßII-mediated ERK signaling is important for Adv-GPx-1-mediated potentials against Aß (1-42) insult. Our results suggest that treatment with the antioxidant gene GPx-1 rescues Aß (1-42)-induced memory impairment via activating PKC ßII-mediated ERK signaling.

Lithium attenuates d-amphetamine-induced hyperlocomotor activity in mice via inhibition of interaction between cyclooxygenase-2 and indoleamine-2,3-dioxygenase.

In the present study, we investigated whether mood stabilizer lithium (Li) protects against d-amphetamine (AMP)-induced mania-like behaviours via modulating the novel proinflammatory potential. Repeated treatment with AMP resulted in significant increases in proinflammatory cyclooxygenase-2 (COX-2) and indolemaine-2,3-dioxygenase-1 (IDO)-1 expression in the prefrontal cortex (PFC) of mice. However, AMP treatment did not significantly change IDO-2 and 5-lipoxygenase (5-LOX) expression, suggesting that proinflammatory parameters such as COX-2 and IDO-1 are specific for AMP-induced behaviours. AMP-induced initial expression of COX-2 (15 minutes post-AMP) was earlier than that of IDO-1 (1 hour post-AMP). Mood stabilizer Li and COX-2 inhibitor meloxicam significantly attenuated COX-2 expression 15 minutes post-AMP, whereas IDO-1 inhibitor 1-methyl-DL-tryptophan (1-MT) did not affect COX-2 expression. However, AMP-induced IDO-1 expression was significantly attenuated by Li, meloxicam or 1-MT, suggesting that COX-2 is an upstream molecule for the induction of IDO-1 caused by AMP. Consistently, co-immunoprecipitation between COX-2 and IDO-1 was observed at 30 minutes, 1, 3, and 6 hours after the final AMP treatment. This interaction was also significantly inhibited by Li, meloxicam or 1-MT. Furthermore, AMP-induced hyperlocomotion was significantly attenuated by Li, meloxicam or 1-MT. We report, for the first time, that mood stabilizer Li attenuates AMP-induced mania-like behaviour via attenuation of interaction between COX-2 and IDO-1, and that the interaction of COX-2 and IDO-1 may be critical for the therapeutic intervention mediated by mood stabilizer.