Aromatic-fused γ-pyrones are structural features of many bioactive natural products and valid scaffolds for medicinal chemistry. However, the enzymology of their formation has not been completely established. Now it is demonstrated that TxnO9, a CalC-like protein belonging to a START family, functions as an unexpected anthraquinone-γ-pyrone synthase involved in the biosynthesis of antitumor antibiotic trioxacarcin A (TXN-A). Structural analysis by NMR identified a likely substrate/product-binding mode and putative key active sites of TxnO9, which allowed an enzymatic mechanism to be proposed. Moreover, a subset of uncharacterized homologous proteins bearing an unexamined Lys-Thr dyad exhibit the same function. Therefore, the functional assignment and mechanistic investigation of this γ-pyrone synthase elucidated an undescribed step in TXN-A biosynthesis, and the discovery of this new branch of polyketide heterocyclases expands the functions of the START superfamily.

Context: Heart failure is one of the most serious diseases worldwide. Astragaloside IV (ASI) is widely used in the treatment of cardiovascular diseases.

Objective: To elucidate the antioxidative mechanism of ASI in a rat model of left coronary artery ligation.

Materials and methods: Left coronary artery of Sprague-Dawley rats was ligated to establish the model of heart failure, and then vehicle (saline) or ASI (1 mg/kg/day) was orally administered to the rats (n = 15) for 6 weeks. Echocardiography was used to evaluate the cardiac function. Myocardial infarct size was measured by triphenyltetrazolium chloride staining. Oxidative stress in the ventricular myocardium was determined. Molecular mechanisms were investigated by Western blot and chromatin immunoprecipitation.

Results: ASI improved the cardiac function, especially ejection fraction (75.27 ± 5.75% vs. 36.26 ± 4.14%) and fractional shortening (45.39 ± 3.66% vs. 17.88 ± 1.32%), and reduced the infarct size of left ventricle (20.69 ± 2.98% vs. 39.11 ± 3.97%). ASI maintained the levels of glutathione, catalase and superoxide dismutase and prevented the leakage of creatine kinase. In addition, ASI induced the protein expression of Nrf2 (1.97-fold) and HO-1 (2.79-fold), while reduced that of Keap-1 (0.77-fold) in the ventricular myocardium. In H9c2 cells, a rat cardiomyocyte cell line, ASI induced the translocation of Nrf2 from cytoplasm to nucleus, followed by transcriptional activation of NQO-1 (8.27-fold), SOD-2 (3.27-fold) and Txn-1 (9.83-fold) genes.

Discussion and conclusions: ASI prevented heart failure by counteracting oxidative stress through the Nrf2/HO-1 pathway. Application in clinical practice warrants further investigation.

Keywords: HO-1; Keap-1; Oxidative stress; transcriptional activation.

This paper aims to assess changes in the extreme climate indices of the Lower Songkhram River Basin of Thailand under Representative Concentration Pathways (RCPs) scenarios. A linear scaling method was used to correct climate data bias in three Regional Climate Models (RCMs) under RCP 4.5 and RCP 8.5 scenarios. Thereafter, extreme climate indices related to temperature and rainfall were analysed for the wet and dry seasons in upstream and downstream areas of the basin. A total of 14 climate indices were analysed for three time periods: the 2030s (2020-2044), 2055s (2045-2069), and 2080s (2070-2094) and compared with the baseline climate from 1980‒2004. The results show that considerable variability is expected in the extreme climate of the basin in future. The average annual and monthly maximum and minimum temperature is projected to increase, with a lesser increase in the near future and higher in the far future. Heat events (TXx, TXn) are projected to increase while the cold events (TNx, TNn) are projected to decrease in both dry and wet seasons upstream and downstream of the basin. The future average annual rainfall in the basin is projected to decrease under RCP 4.5 and RCP 8.5 scenarios for all three periods. However, the variability in average monthly rainfall is expected to increase in the dry season (Jan-May) and decrease in the wet (Aug-Dec). The most intense rainfall in one day (RX1Day) and five consecutive days (RX5Day) in the wet season is observed to increase in future, with a higher increase in the near future and a lower increase in the far future. The very heavy rainfall days (R20) (the number of days receiving more than 20 mm/day in the basin) are observed to decrease in both wet and dry seasons under RCP 4.5 and RCP 8.5 scenarios in both locations. The results of this study will be helpful for the planning and management of natural resources as well as disaster risk reduction in the Lower Songkhram River Basin.

Keywords: Climate change; Extreme events; Rainfall; Temperature; Thailand.

S-1 is a newly developed dihydropyrimidine dehydrogenase inhibitory fluoropyrimidine that exhibits high clinical efficacy against non-small cell lung cancers. To identify genes that may be associated with chemosensitivity to the antitumor drug S-1, we used a low density array representing 93 genes to analyze expression profiles in 4 orthotopically implanted lung cancers derived from human lung cancer cell lines (Lu99, Lu130, LC6 and A549). The tumor growth inhibition (TGI) rates of S-1 in orthotopically implanted tumors of the Lu99, Lu130, LC6 and A549 cell lines were 34.6, 37.5, 32.1 and 3.6%, respectively. The expression of the PRSS3, ABCC4, TXN, SHMT1 and CMPK genes was significantly promoted in the orthotopically implanted SCID mouse model of the 4 lung cancer cell lines by the administration of S-1, while the expression of the LMO7 and FOLH1 genes was significantly suppressed. The expression of the ABCC1, 2 and TST genes was negatively correlated with TGI. The expression of the TK1 and ERCC2 genes was positively correlated with TGI. The results of the present study suggest that the expression of the ABCC1, 2, TST, TK1 and ERCC2 genes is related to resistance to the antitumor drug S-1.

Glandular epithelial cells (GE) in the endometrium are thought to support the elongation and survival of ruminant embryos by secreting histotrophs. In the present study, the gene expression of bovine endometrial epithelial cells cultured in matrigel was analyzed and examined whether it could be an in vitro model of GE. Bovine endometrial epithelial cells (BEE) and stromal cells (BES) were isolated from the slaughterhouse uteri and cultured in DMEM/F12 + 10% FBS. BEE showed the gland-like structure morphological changes when cultured in 15% matrigel but could not be identified in higher concentrations of the matrigel (30% or 60%). The expression of typical genes expressed in GE, SERPINA14 and GRP, was substantially high in matrigel-cultured BEE than in monolayer (P < 0.05). P4 and INFα have no significant effect on the SERPINA14 expression of BEE cultured in matrigel without co-culture with BES. On the other hand, when BEE were co-cultured with BES in matrigel culture, the expression of FGF13 was increased by the P4 treatment (P < 0.05). Furthermore, SERPINA14 and TXN expressions were increased by P4 + IFNα treatment (P < 0.05). These results demonstrate the appropriate conditions for BEE to form glandular structures in matrigel and the effect of co-culture with BES. The present study highlighted the possible use of matrigel for the culture of BEE to investigate the expression of cell-specific glandular epithelial genes as well as P4 and type-I IFN as factors controlling endometrial function during the implantation period.

Keywords: Bovine; Endometrium; Epithelial cells; Gene expression; Matrigel.

Tryparedoxins (TXN) are thioredoxin-related proteins which, as trypanothione:peroxiredoxin oxidoreductases, constitute the trypanothione-dependent antioxidant defense and may also serve as substrates for ribonucleotide reductase in trypanosomatids. The active site motif of TXNTXNTXNs, although belonging to the thioredoxin superfamily, represent a group of enzymes distinct from thioredoxins and glutaredoxins in terms of specificity, and appear attractive as molecular targets for the design of trypanocidal compounds.

Introduction: Skin, as the outermost organ, is exposed to a wide range of environmental risk factors including ultraviolet (UV) and all kinds of pollutants. Excessive UV exposure contributes to many disorders, such as photoaging, skin inflammation, and carcinogenesis.

Methods: To determine the effects of bamboo extract (BEX) from our local plant, Acidosasa longiligula, on UV-irritated human skin, we conducted a variety of studies, including Western blot, apoptosis assays, reactive oxygen species (ROS) detection, and thioredoxin (TXN) and thioredoxin reductase (TXNRD) activity assays in primary skin keratinocytes.

<strong class="sub-title"> Results: </strong> We first determined that BEX protects human skin keratinocytes against UV radiation-induced apoptosis and ROS production. UV radiation can robustly impair <em>TXN</em> and <em>TXN</em>RD activity which can, in turn, be significantly rescued by BEX treatment. Moreover, BEX regulates <em>TXN</em>1 levels in primary skin keratinocytes and <em>TXN</em>1 is proved to be required for the protective function of BEX. Last, we found that the NF-κB/p65 pathway mediates the protective function of BEX against UV.

Discussion: Collectively, our work delineates the beneficial role of BEX in UV-induced skin cell damage and provides a novel therapeutic reagent to prevent or alleviate the progress of photoaging and other UV-provoked skin diseases.

Keywords: Acidosasa longiligula; BEX; NF-κB pathway; TXN; UV radiation; bamboo extract; thioredoxin; ultraviolet radiation.

During implantation in rodents, attachment and invasion of embryonic trophoblast is accompanied by decidualization of the adjacent endometrial stroma. Decidualization can be initiated only when the endometrium is receptive, and this occurs for a short period in pregnancy. The molecular mechanisms underlying this phenomenon remain unclear. In the current study, using differential display and northern blot analysis, we found that steady-state levels of mRNA for vitamin D3 upregulated protein 1 (Vdup1) were significantly higher in 'refractory' and 'delayed' endometrium compared with 'receptive' endometrium or endometrium undergoing artificially induced decidualization. Conversely, thioredoxin (Txn), a ubiquitously expressed cellular redox regulator known to promote growth and proliferation, was found to have elevated transcript levels within the decidualizing endometrium. VDUP1 has previously been shown to bind TXN and inhibit its action. In an inverse, but cooperative, relationship, these molecules have been implicated in regulating cell growth and proliferation in a number of tissues and during transformation to cancer. The Vdup1 mRNA is localized to the uterine stroma in the nonreceptive endometrium, the site of increased Txn mRNA levels during decidualization. In addition, Vdup1 mRNA levels are inversely regulated by progesterone and estrogen; prolonged progesterone exposure stimulates an increase in Vdup1 mRNA levels whereas estrogen decreases Vdup1 transcript levels. Together, these results suggest a novel mechanism by which suppression of the decidual response in the nonreceptive endometrium may occur.

The aim of the present study was to evaluate the effect of troxerutin (TXN) on Nickel (Ni) toxicity by using rats and in-vitro model. Ni toxicity induced in male albino wistar rats (20 mg/kg body weight (b.w) was administered orally for 20 days). TXN was administered orally (100 mg/kg (b.w) for 20 days with administration of Ni. The toxic effect of Ni and the action of TXN was measure by determining the lipid peroxidation markers and antioxidant levels in plasma and various in-vitro antioxidant systems. TXN exhibited a significant (p < 0.05) antioxidant activity in Ni induced toxicity by reversing the changes observed in TBARS, HP, Vitamin C, E and GSH. The free radical scavenging properties of TXN at different concentrations (10-50ug/mL) were investigated with various in-vitro methods such as 2, 2'-diphenyl-1- picrylhydrazyl radical (DPPH), 2, 2'-azinobis (3-ethylbenzothiazoline-6-sulfonic acid) radical (ABTS•+), hydroxyl radical, superoxide anion scavenging activity and reducing power. Among the different concentrations, 50 μg/mL of TXN was more effective compared to other concentrations in all in-vitro assays. The above study conclude that TXN possesses potent in-vivo and in-vitro antioxidant activity with effective free radical scavenger for potential therapeutic value.

Keywords: Antioxidants; Free radical; Hydroxyl radical; Nickel; Reducing power; Troxerutin.

Triple negative breast carcinoma (TNBC) is an aggressive form of cancer, with high rates of morbidity, mortality, poor prognosis and limited therapeutic options. The objective of the present study was to elaborate the anticancer activity of Troxerutin (TXN) in TNBC/MDA-MB-231 cells. Herein, we demonstrated the inhibitory effects of TXN on the breast cancer cell growth via induction of apoptosis. Mitochondrial membrane potential (∆Ψm), DNA damage and apoptotic nuclear changes were analyzed by flowcytometry, AO/EtBr and Hoechst staining, respectively. Furthermore, apoptotic protein and gene expressions were analyzed by western blot and reverse transcription polymerase chain reaction (RT-PCR), respectively. Our results indicated that TXN induces apoptosis as evidenced by inhibit the cell proliferation, enhanced apoptotic activation, altered mitochondrial membrane potential and elevated level of DNA damage in TNBC cells. Furthermore, the TXN inhibit anti-apoptotic protein expression with the subsequent upregulation of Cytochrome c, Caspase-9 and Caspase-3. Thus, TXN induces apoptosis in TNBC cells through inducing nuclear damage and altered apoptotic marker expressions. Therefore, TXN might be used as a potential therapeutic agent for the treatment of triple negative breast cancer.

Keywords: MDA-MB-231 cells; RT-PCR; anti-cancer; triple negative breast cancer; troxerutin.

Septic encephalopathy (SE) is a devastating consequence of sepsis, a hyper-triggered host response against infectious challenge, which ultimately leads to brain damage. The present study examined whether sevoflurane (SVF), a volatile anaesthetic, can counteract the perturbation of homeostasis in a caecal ligation and puncture (CLP)-induced mouse model of SE. SVF enhances neurocognition in terms of spatial memory improvement via counter-regulation of activated oxidative-inflammatory stress and pyroptotic processes in SE. Further, the beneficial effects of SVF against SE are mediated by activation of silent information regulator 1 (SIRT1)-mediated reduction of reactive oxygen species (ROS) level, regulation of thioredoxin (TXN) and thioredoxin interacting protein (TIP) levels, reduction of inflammatory-pyroptotic signalling (NLRP3, caspase 1/11, GSDMD, TLR4 and TRIF) proteins, as well as a reduction of inflammatory cytokine (IL-1β and IL-18) levels. These findings suggest that SVF may have therapeutic potential for the treatment of SE and associated cognitive malfunction.

Keywords: Caecal ligation and puncture; SIRT1; septic encephalopathy; sevoflurane; thioredoxin.

The toxoflavin (Txn), broad host range phytotoxin produced by a variety of bacteria, including Burkholderia glumae, is a key pathogenicity factor of B. glumae in rice and field crops. Two bacteria exhibiting Txn-degrading activity were isolated from healthy rice seeds and identified as Sphingomonas adhaesiva and Agrobacterium sp. respectively. The genes stdR and stdA, encoding proteins responsible for Txn degradation of both bacterial isolates, were identical, indicating that horizontal gene transfer occurred between microbial communities in the same ecosystem. We identified a novel Txn-quenching regulation of bacteria, demonstrating that the LysR-type transcriptional regulator (LTTR) StdR induces the expression of the stdA, which encodes a Txn-degrading enzyme, in the presence of Txn as a coinducer. Here we show that the bacterial StdR^Txn -quenching regulatory system mimics the ToxR^Txn -mediated biosynthetic regulation of B. glumae. Substrate specificity investigations revealed that Txn is the only coinducer of StdR and that StdA has a high degree of specificity for Txn. Rice plants expressing StdA showed Txn resistance. Collectively, bacteria mimic the mechanism of Txn biosynthesis regulation, employ it in the development of a Txn-quenching regulatory system and share it with neighbouring bacteria for survival in rice environments full of Txn.

The association between selenium and peptide in gastric cancer is an important research topic. The present study reported the facile synthesis of anticancer bioactive peptide (ACBP)‑functionalized selenium (ACBP‑S‑Se) particles with enhanced anticancer activities and a detailed mechanistic evaluation of their ability to regulate oxidative stress in vitro. Structural and chemical characterizations were revealed by ultraviolet absorption, Fourier transform infrared, X‑ray photoelectron, nuclear magnetic resonance carbon and hydrogen, energy dispersive X‑ray spectroscopy and inductively coupled plasma mass spectrometry, as well as scanning electron microscopy. Sulfhydrylation modifications of ACBP were achieved with S‑acetylmercaptosuccinic anhydride via chemical absorption. After the polypeptide was modified by sulfhydrylation, the ACBP chain was linked to sulfhydryl groups by amide bonds to form the ACBP‑chelated selenium complex. Two gastric cancer cell lines (MKN‑45 and MKN‑74 cells) demonstrated high susceptibility to ACBP‑S‑Se particles and displayed significantly decreased proliferation ability following treatment. The results suggested that the bioactive peptide‑chelated selenium particles effectively inhibited the proliferation of MKN‑45 and MKN‑74 cells in vitro. The genes encoding CDK inhibitor 1A (CDKN1A), cyclin B1, thioredoxin (TXN) and mitogen‑activated protein kinase kinase kinase 5 are associated with regulation of oxidative stress, while CDKN1A and TXN protect cells by decreasing oxidative stress and promoting cell growth arrest. Therefore, ACBP‑S‑Se may be an ideal chemotherapeutic candidate for human cancer, especially gastric cancer.

Keywords: anticancer bioactive peptide; antitumor agent; gastric cancer; selenium element.

It has shown that schizophrenia (SCZ) is associated with a higher chance of myocardial infarction (MI) and increased mortality. However, the underlying mechanism is largely unknown. Here, we first constructed a literature-based genetic pathway linking SCZ and MI, and then we tested the expression levels of the genes involved in the pathway by a meta-analysis using nine gene expression datasets of MI. In addition, a literature-based data mining process was conducted to explore the connection between SCZ at different levels: small molecules, complex molecules, and functional classes. The genetic pathway revealed nine genes connecting SCZ and MI. Specifically, SCZ activates two promoters of MI (IL6 and CRP) and deactivates seven inhibitors of MI (ADIPOQ, SOD2, TXN, NGF, ADORA1, NOS1, and CTNNB1), suggesting that no protective role of SCZ in MI was detected. Meta-analysis showed that one promoter of MI (CRP) presented no significant increase, and six out of seven genetic inhibitors of MI demonstrated minor to moderately increased expression. Therefore, the elevation of CRP and inhibition of the six inhibitors of MI by SCZ could be critical pathways to promote MI. Nine other regulators of MI were influenced by SCZ, including two gene families (inflammatory cytokine and IL1 family), five small molecules (lipid peroxide, superoxide, ATP, ascorbic acid, melatonin, arachidonic acid), and two complexes (CaM kinase 2 and IL23). Our results suggested that SCZ promotes the development and progression of MI at different levels, including genes, small molecules, complex molecules, and functional classes.

Keywords: genetic pathway; meta-analysis; myocardial infarction; regression analysis; schizophrenia.

We previously reported xanthohumol (XN), and its synthetic derivative tetrahydro-XN (TXN), attenuates high-fat diet (HFD)-induced obesity and metabolic syndrome in C57Bl/6J mice. The objective of the current study was to determine the effect of XN and TXN on lipid accumulation in the liver. Non-supplemented mice were unable to adapt their caloric intake to 60% HFD, resulting in obesity and hepatic steatosis; however, TXN reduced weight gain and decreased hepatic steatosis. Liver transcriptomics indicated that TXN might antagonize lipogenic PPARγ actions in vivo. XN and TXN inhibited rosiglitazone-induced 3T3-L1 cell differentiation concomitant with decreased expression of lipogenesis-related genes. A peroxisome proliferator activated receptor gamma (PPARγ) competitive binding assay showed that XN and TXN bind to PPARγ with an IC₅₀ similar to pioglitazone and 8-10 times stronger than oleate. Molecular docking simulations demonstrated that XN and TXN bind in the PPARγ ligand-binding domain pocket. Our findings are consistent with XN and TXN acting as antagonists of PPARγ.

Keywords: antagonist; cell biology; hepatosteatosis; medicine; metabolic syndrome; mouse; obesity; ppar gamma; xanthohumol.

Cerebral ischemic reperfusion (I/R) infarction is mostly associated with serious brain injury, cognitive damage, and neurological deficits. The oxidative stress mechanisms in the neurological region lead to higher reactive oxygen species production followed by oxidative stress, inflammation of neurons, and death of brain cells. The current work aims to evaluate the effect of troxerutin (TXN) on cerebral injury stimulated by I/R-induced ischemic stroke and examines the mechanistic effect of TXN on neuroinflammation in the Sprague Dawley model. The experimental rats were randomized in to four groups: (i) sham control, (ii) I/R + vehicle, (iii) I/R + 10 mg/kg bw TXN, and (iv) I/R + 20 mg/kg bw TXN. In the TXN administration and control, groups were injected intraperitoneally 15 min before reperfusion and every day for 7 days, except the sham group. Orally administered TXN (10 and 20 mg/kg/bw) modulated the water content, lowered the infarct volume, and abrogated score defects of neuron and changes in the brain tissue sample. In our study, the TXN-stimulated cerebral injury exhibited leakage of thiobarbituric acid reactive substances (TBARS), lipid hydroperoxides (LOOH) of the neuronal sample of tissues and showed higher antioxidant enzymes superoxide dismutase, catalase, the oxidized form of glutathione peroxidase, and the reduced form of glutathione levels. This biochemical result was additionally proved by histopathological assessment. Changes were made in antioxidant and inflammatory markers expressions interleukin-6 (IL-6), IL-4, IL-10, vascular endothelial growth factor, and cerebral induced rats. The overall findings showed that TXN protected the brain tissues from neuroinflammatory oxidative stress by reducing cerebral injury in Sprague Dawley rats. Further, the messenger RNA expression of cerebral I/R-induced animal tissues down-regulated NLRP3, caspase-1, tumor necrosis factor-α, ASC, IL-1β, and Toll-like receptor 3 (TLR3). Therefore, the TXN action on TLR3 induced brain stroke is an excellent therapeutic approach for brain damage.

Evidence from both in vivo and in vitro studies suggests that gene expression changes from long-term exposure to arsenite evolve markedly over time, including reversals in the direction of expression change in key regulatory genes. In this study, human uroepithelial cells from the ureter segments of 4 kidney-donors were continuously treated in culture with arsenite at concentrations of 0.1 or 1 µM for 60 days. Gene expression at 10, 20, 30, 40, and 60 days was determined using Affymetrix human genome microarrays and signal pathway analysis was performed using GeneGo Metacore. Arsenic treated cells continued to proliferate for the full 60-day period, whereas untreated cells ceased proliferating after approximately 30 days. A peak in the number of gene changes in the treated cells compared to untreated controls was observed between 30 and 40 days of exposure, with substantially fewer changes at 10 and 60 days, suggesting remodeling of the cells over time. Consistent with this possibility, the direction of expression change for a number of key genes was reversed between 20 and 30 days, including CFOS and MDM2. While the progression of gene changes was different for each subject, a common pattern was observed in arsenic treated cells over time, with early upregulation of oxidative stress responses (HMOX1, NQ01, TXN, TXNRD1) and down-regulation of immune/inflammatory responses (IKKα). At around 30 days, there was a transition to increased inflammatory and proliferative signaling (AKT, CFOS), evidence of epithelial-to-mesenchymal transition (EMT), and alterations in DNA damage responses (MDM2, ATM). A common element in the changing response of cells to arsenite over time appears to involve up-regulation of MDM2 by inflammatory signaling (through AP-1 and NF-κB), leading to inhibition of P53 function.

Keywords: Arsenic; Carcinogenicity; Genomics; In vitro; Mode of action.

The aim of this study was to generate and analyze the atlas of the loggerhead turtle blood transcriptome by RNA-seq, as well as identify and characterize thioredoxin (Tnxs) and peroxiredoxin (Prdxs) antioxidant enzymes of the greatest interest in the control of peroxide levels and other biological functions. The transcriptome of loggerhead turtle was sequenced using the Illumina Hiseq 2000 platform and de novo assembly was performed using the Trinity pipeline. The assembly comprised 515,597 contigs with an N50 of 2,631 bp. Contigs were analyzed with CD-Hit obtaining 374,545 unigenes, of which 165,676 had ORFs encoding putative proteins longer than 100 amino acids. A total of 52,147 (31.5%) of these transcripts had significant homology matches in at least one of the five databases used. From the enrichment of GO terms, 180 proteins with antioxidant activity were identified, among these 28 Prdxs and 50 putative Tnxs. The putative proteins of loggerhead turtles encoded by the genes Prdx1, Prdx3, Prdx5, Prdx6, Txn and Txnip were predicted and characterized in silico. When comparing Prdxs and Txns of loggerhead turtle with homologous human proteins, they showed 18 (9%), 52 (18%) 94 (43%), 36 (16%), 35 (33%) and 74 (19%) amino acid mutations respectively. However, they showed high conservation in active sites and structural motifs (98%), with few specific modifications. Of these, Prdx1, Prdx3, Prdx5, Prdx6, Txn and Txnip presented 0, 25, 18, three, six and two deleterious changes. This study provides a high quality blood transcriptome and functional annotation of loggerhead sea turtles.

Keywords: 3D modelling; Blood; Caretta caretta; KEGG pathway; Peroxiredoxin; RNA-seq; Thioredoxin; Transcriptome.

Background/aim: The thioredoxin-1 (Trx-1) inhibitor, PX-12, is active against several cancer types. This study aimed to evaluate its effects on local osteosarcoma (OS) progression and to describe PX-12-related signal transduction pathways.

Materials and methods: Publicly available expression cohort data were analyzed to determine the relationship between the expression levels of TXN, which codes for the Trx protein, and survival in patients with OS. Murine LM8 OS cells were stimulated with PX-12. Apoptosis-related protein levels, cell viability, caspase activity, and wound healing were evaluated. PX-12 efficacy in suppressing tumor progression was evaluated in C3H mice injected with LM8 cells.

Results: High TXN expression was a negative prognostic factor for metastasis and overall survival in OS patients. PX-12 induced apoptosis in OS cells via the oxidative stress-MAPK-caspase 3 pathway and suppressed OS cell migration. PX-12 suppressed local OS progression.

Conclusion: PX-12 is a potential therapeutic agent for use in suppressing local OS progression.

Keywords: Osteosarcoma; PX-12; oxidative stress; thioredoxin.

Background: Inflammatory bowel disease may arise with inadequate immune response to intestinal bacteria. NOD2 is an established gene in Crohn's disease pathogenesis, with deleterious variation associated with reduced NFKB signaling. We hypothesized that deleterious variation across the NOD2 signaling pathway impacts on transcription.

Methods: Treatment-naïve pediatric inflammatory bowel disease patients had ileal biopsies for targeted autoimmune RNA-sequencing and blood for whole exome sequencing collected at diagnostic endoscopy. Utilizing GenePy, a per-individual, per-gene score, genes within the NOD signaling pathway were assigned a quantitative score representing total variant burden. Where multiple genes formed complexes, GenePy scores were summed to create a "complex" score. Normalized transcript expression of 95 genes within this pathway was retrieved. Regression analysis was performed to determine the impact of genomic variation on gene transcription.

Results: Thirty-nine patients were included. Limited clustering of patients based on NOD signaling transcripts was related to underlying genomic variation. Patients harboring deleterious variation in NOD2 had reduced NOD2 (β = -0.702, P = 4.3 × 10-5) and increased NFKBIA (β = 0.486, P = .001), reflecting reduced NFKB signal activation. Deleterious variation in the NOD2-RIPK2 complex was associated with increased NLRP3 (β = 0.8, P = 3.1475 × 10-8) and TXN (β = -0.417, P = 8.4 × 10-5) transcription, components of the NLRP3 inflammasome. Deleterious variation in the TAK1-TAB complex resulted in reduced MAPK14 transcription (β = -0.677, P = 1.7 × 10-5), a key signal transduction protein in the NOD2 signaling cascade and increased IFNA1 (β = 0.479, P = .001), indicating reduced transcription of NFKB activators and alternative interferon transcription in these patients.

Conclusions: Data integration identified perturbation of NOD2 signaling transcription correlated with genomic variation. A hypoimmune NFKB signaling transcription response was observed. Alternative inflammatory pathways were activated and may represent therapeutic targets in specific patients.

Keywords: Crohn’s disease; IBD; NOD2; WES; transcriptome.

Thioredoxin-interacting protein (TXNIP) is involved in multiple disease-associated functions related to oxidative stress, especially by inhibiting the anti-oxidant- and thiol-reducing activity of thioredoxin (TXN). Shiga-Y5 (SY5), a fluorine-19 magnetic resonance probe for detecting amyloid-β deposition in the brain, previously showed therapeutic effects in a mouse model of Alzheimer's disease; however, the mechanism of action of SY5 remains unclear. SY5 passes the blood-brain barrier and then undergoes hydrolysis to produce a derivative, Shiga-Y6 (SY6), which is a TXNIP-negative regulator. Therefore, this study investigates the therapeutic role of SY5 as the prodrug of SY6 in the thioredoxin system in the brain of a mouse model of Alzheimer's disease. The intraperitoneal injection of SY5 significantly inhibited TXNIP mRNA (p = 0.0072) and protein expression (p = 0.0143) induced in the brain of APP/PS1 mice. In contrast, the levels of TXN mRNA (p = 0.0285) and protein (p = 0.0039) in the brain of APP/PS1 mice were increased after the injection of SY5. The ratio of TXN to TXNIP, which was decreased (p = 0.0131) in the brain of APP/PS1 mice, was significantly increased (p = 0.0072) after the injection of SY5. These results suggest that SY5 acts as a prodrug of SY6 in targeting the thioredoxin system and could be a potential therapeutic compound in oxidative stress-related diseases in the brain.

Keywords: Alzheimer’s disease; TXNIP; curcumin; oxidative stress; thioredoxin.

A representative polycyclic aromatic hydrocarbon, benzo[a]pyrene (B[a]P), has been widely detected in environmental compartments and is highly carcinogenic to humans. Oral ingestion of B[a]P is the dominant exposure pathway. The esophagus acts as the first contact point when B[a]P enters the human body. However, its role in the development of human esophageal cancer is rarely discussed. Herein, we employed untargeted metabolomics in combination with proteomics to explore B[a]P-related intracellular responses in human esophageal cell lines. Our results demonstrated that B[a]P exposure induced significant metabolic disorders, further leading to overproduction of reactive oxygen species (ROS) and disturbance of the cellular viability process and migration ability of esophageal cells. In response, glutathione (GSH) was consumed to meet the demand for cellular detoxification, and thioredoxin (TXN) was upregulated to balance the cellular redox. These alterations caused the reregulation of some specific protein families, including S100A proteins, ribosomal proteins, and histone H1 proteins. Such changes impeded the viability and migration of esophageal cells, which could adversely affect wound healing of the epithelium. These cellular responses indicate that B[a]P will cause serious cellular damage to esophageal cells and increase the carcinogenic risk even as a result of short-term exposure. SYNOPSIS: Our omics study demonstrated how benzo[a]pyrene hampered the migration of esophageal cells and proposed a plausible mechanism underlying its carcinogenicity, which may contribute to our understanding of environmental pollutants.

Keywords: Benzo[a]pyrene; Esophageal cancer; Metabolomics; Polycyclic aromatic hydrocarbon; Proteomics.

Climate extremes are becoming more prevalent and hazardous as global climate change increases. The purpose of this study was to find out how often severe rainfall and temperature events occur, as well as the study area's spatial vulnerability indexes to extremes of both indices. Thirty years of daily rainfall and temperature data from 10 national meteorological stations were used. Four rainfall and eight temperature extremes were extracted using Climpact2 software tools. These variables were calculated for standardized anomaly and vulnerability indices and mapped using ArcMap. The results showed that the spatial variation of climatic extremes in the study area was significantly varied. Avery high rainfall (R95P) and extremely high rainfall (R99P) were widely experienced in the study area's west-south, but in the southeast, similar trends were rare. R95P had a statistically significant growing trend, but R99P did not. The warmest night temperature (TNx) event was widely observed in the east, southeast, and northwest, but the coldest night temperature (TNn) was only found in the eastern part. Extremely cold daytime temperatures (TXn) were more prevalent in the south and southeast of the study area, whereas extremely warm daytime temperatures (TXx) were more prevalent in the north. The number of dry spells (CDD), R95P, R99P, cold spells at night (TN10P), warm spells at night (TN90P), cold spells during the day (TX10P), and warm spells during the day (TX10P) frequency bell curves were skewed to the left side of the histogram. This suggests that the distribution of the variables was not symmetrical due to the fact that the negative anomaly frequencies of the variables were higher than the positive ones. The results of the spatial vulnerability study show that all provinces were vulnerable to the combined effects of climatic extremes, with scores ranging from 0.20 to 0.8, with none of them vulnerable and extremely vulnerable areas. Omo-Nada and Chora-Botor were particularly sensitive to climate change with an average score of 0.61. Only 12 of the 27 severe climate indexes were taken into account in this study, and the remaining 15 extreme indices will have to be investigated further.

Keywords: Anomaly indices; Bell curve; Climapact2; Climate extremes indices; Spatial distribution; Vulnerability.

Several kinds of solvents have been applied to Nepenthes extractions exhibiting antioxidant and anticancer effects. However, they were rarely investigated for Nepenthes ethyl acetate extract (EANT), especially leukemia cells. The purpose of the present study was to evaluate the antioxidant properties and explore the antiproliferation impact and mechanism of EANT in leukemia cells. Five standard assays demonstrated that EANT exhibits antioxidant capability. In the cell line model, EANT dose-responsively inhibited cell viabilities of three leukemia cell lines (HL-60, K-562, and MOLT-4) based on 24 h MTS assays, which were reverted by pretreating oxidative stress and apoptosis inhibitors (N-acetylcysteine and Z-VAD-FMK). Due to similar sensitivities among the three cell lines, leukemia HL-60 cells were chosen for exploring antiproliferation mechanisms. EANT caused subG1 and G1 cumulations, triggered annexin V-detected apoptosis, activated apoptotic caspase 3/7 activity, and induced poly ADP-ribose polymerase expression. Moreover, reactive oxygen species, mitochondrial superoxide, and mitochondrial membrane depolarization were generated by EANT, which was reverted by N-acetylcysteine. The antioxidant response to oxidative stress showed that EANT upregulated mRNA expressions for nuclear factor erythroid 2-like 2 (NFE2L2), catalase (CAT), thioredoxin (TXN), heme oxygenase 1 (HMOX1), and NAD(P)H quinone dehydrogenase 1 (NQO1) genes. Moreover, these oxidative stresses led to DNA damage (γH2AX and 8-hydroxy-2-deoxyguanosine) and were alleviated by N-acetylcysteine. Taken together, EANT demonstrated oxidative stress-dependent anti-leukemia ability to HL-60 cells associated with apoptosis and DNA damage.

Keywords: DNA damage; Nepenthes; antioxidant; apoptosis; leukemia cells; oxidative stress.