Reactive Aldehydes Research Articles

Novel silkworm (Bombyx mori) sulfotransferase swSULT ST3 is involved in metabolism of polyphenols from mulberry leaves.

Polyphenols in plants are important for defense responses against microorganisms, insect herbivory, and control of feeding. Owing to their antioxidant, anti-cancer, and anti-inflammatory activities, their importance in human nutrition has been acknowledged. However, metabolism of polyphenols derived from mulberry leaves in silkworms (Bombyx mori) remains unclear. Sulfotransferases (SULT) are involved in the metabolism of xenobiotics and endogenous compounds. The purpose of this study is to investigate the metabolic mechanism of polyphenols mediated by B. mori SULT. Here, we identified a novel SULT in silkworms (herein, swSULT ST3). Recombinant swSULT ST3 overexpressed in Escherichia coli effectively sulfated polyphenols present in mulberry leaves. swSULT ST3 showed high specific activity toward genistein among the polyphenols. Genistein-7-sulfate was produced by the activity of swSULT ST3. Higher expression of swSULT ST3 mRNA was observed in the midgut and fat body than in the hemocytes, testis, ovary, and silk gland. Polyphenols inhibited the aldo-keto reductase detoxification of reactive aldehydes from mulberry leaves, and the most noticeable inhibition was observed with genistein. Our results suggest that swSULT ST3 plays a role in the detoxification of polyphenols, including genistein, and contributes to the effects of aldo-keto reductase in the midgut of silkworms. This study provides new insight into the functions of SULTs and the molecular mechanism responsible for host plant selection in lepidopteran insects.

Spatial localization of β-unsaturated aldehyde markers in murine diabetic kidney tissue by mass spectrometry imaging

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease. Limitations in current diagnosis and screening methods have sparked a search for more specific and conclusive biomarkers. Hyperglycemic conditions generate a plethora of harmful molecules in circulation and within tissues. Oxidative stress generates reactive α-dicarbonyls and β-unsaturated hydroxyhexenals, which react with proteins to form advanced glycation end products. Mass spectrometry imaging (MSI) enables the detection and spatial localization of molecules in biological tissue sections. Here, for the first time, the localization and semiquantitative analysis of “reactive aldehydes” (RAs) 4-hydroxyhexenal (4-HHE), 4-hydroxynonenal (4-HNE), and 4-oxo-2-nonenal (4-ONE) in the kidney tissues of a diabetic mouse model is presented. Ionization efficiency was enhanced through on-tissue chemical derivatization (OTCD) using Girard’s reagent T (GT), forming positively charged hydrazone derivatives. MSI analysis was performed using matrix-assisted laser desorption ionization (MALDI) coupled with Fourier-transform ion cyclotron resonance mass spectrometry (FT-ICR). RA levels were elevated in diabetic kidney tissues compared to lean controls and localized throughout the kidney sections at a spatial resolution of 100 µm. This was confirmed by liquid extraction surface analysis–MSI (LESA-MSI) and liquid chromatography–mass spectrometry (LC–MS). This method identified β-unsaturated aldehydes as “potential” biomarkers of DN and demonstrated the capability of OTCD-MSI for detection and localization of poorly ionizable molecules by adapting existing chemical derivatization methods. Untargeted exploratory distribution analysis of some precursor lipids was also assessed using MALDI-FT-ICR-MSI.Graphical abstract

Integrated Multilayer Omics Reveals the Genomic, Proteomic, and Metabolic Influences of Histidyl Dipeptides on theHeart.

BackgroundHistidyl dipeptides such as carnosine are present in a micromolar to millimolar range in mammalian hearts. These dipeptides facilitate glycolysis by proton buffering. They form conjugates with reactive aldehydes, such as acrolein, and attenuate myocardial ischemia–reperfusion injury. Although these dipeptides exhibit multifunctional properties, a composite understanding of their role in the myocardium is lacking.Methods and ResultsTo identify histidyl dipeptide–mediated responses in the heart, we used an integrated triomics approach, which involved genome‐wide RNA sequencing, global proteomics, and unbiased metabolomics to identify the effects of cardiospecific transgenic overexpression of the carnosine synthesizing enzyme, carnosine synthase (Carns), in mice. Our result showed that higher myocardial levels of histidyl dipeptides were associated with extensive changes in the levels of several microRNAs, which target the expression of contractile proteins, β‐fatty acid oxidation, and citric acid cycle (TCA) enzymes. Global proteomic analysis showed enrichment in the expression of contractile proteins, enzymes of β‐fatty acid oxidation, and the TCA in the Carns transgenic heart. Under aerobic conditions, the Carns transgenic hearts had lower levels of short‐ and long‐chain fatty acids as well as the TCA intermediate—succinic acid; whereas, under ischemic conditions, the accumulation of fatty acids and TCA intermediates was significantly attenuated. Integration of multiple data sets suggested that β‐fatty acid oxidation and TCA pathways exhibit correlative changes in the Carns transgenic hearts at all 3 levels.ConclusionsTaken together, these findings reveal a central role of histidyl dipeptides in coordinated regulation of myocardial structure, function, and energetics.

Aldehyde Dehydrogenase 2 (ALDH2) Elicits Protection against Pulmonary Hypertension via Inhibition of ERK1/2-Mediated Autophagy.

Pulmonary hypertension (PH) is caused by chronic hypoxia that induces the migration and proliferation of pulmonary arterial smooth muscle cells (PASMCs), eventually resulting in right heart failure. PH has been related to aberrant autophagy; however, the hidden mechanisms are still unclear. Approximately 40% East Asians, equivalent to 8% of the universal population, carry a mutation in Aldehyde dehydrogenase 2 (ALDH2), which leads to the aggregation of noxious reactive aldehydes and increases the propensity of several diseases. Therefore, we explored the potential aspect of ALDH2 in autophagy associated with PH. In vitro mechanistic studies were conducted in human PASMCs (HPASMCs) after lentiviral ALDH2 knockdown and treatment with platelet-derived growth factor-BB (PDGF-BB). PH was induced in wild-type (WT) and ALDH2-knockout (ALDH2−/−) mice using vascular endothelial growth factor receptor inhibitor SU5416 under hypoxic conditions (HySU). Right ventricular function was assessed using echocardiography and invasive hemodynamic monitoring. Histological and immunohistochemical analyses were performed to evaluate pulmonary vascular remodeling. EdU, transwell, and wound healing assays were used to evaluate HPASMC migration and proliferation, and electron microscopy and immunohistochemical and immunoblot assays were performed to assess autophagy. The findings demonstrated that ALDH2 deficiency exacerbated right ventricular pressure, hypertrophy, fibrosis, and right heart failure resulting from HySU-induced PH. ALDH2−/− mice exhibited increased pulmonary artery muscularization and 4-hydroxynonenal (4-HNE) levels in lung tissues. ALDH2 knockdown increased PDGF-BB-induced PASMC migration and proliferation and 4-HNE accumulation in vitro. Additionally, ALDH2 deficiency increased the number of autophagosomes and autophagic lysosomes together with autophagic flux and ERK1/2-Beclin-1 activity in lung tissues and PASMCs, indicating enhanced autophagy. In conclusion, the study shows that ALDH2 has a protective role against the migration and proliferation of PASMCs and PH, possibly by regulating autophagy through the ERK1/2-Beclin-1 pathway.

Mechanisms and Regulation of DNA-Protein Crosslink Repair During DNA Replication by SPRTN Protease.

DNA-protein crosslinks (DPCs) are deleterious DNA lesions that occur when proteins are covalently crosslinked to the DNA by the action of variety of agents like reactive oxygen species, aldehydes and metabolites, radiation, and chemotherapeutic drugs. Unrepaired DPCs are blockades to all DNA metabolic processes. Specifically, during DNA replication, replication forks stall at DPCs and are vulnerable to fork collapse, causing DNA breakage leading to genome instability and cancer. Replication-coupled DPC repair involves DPC degradation by proteases such as SPRTN or the proteasome and the subsequent removal of DNA-peptide adducts by nucleases and canonical DNA repair pathways. SPRTN is a DNA-dependent metalloprotease that cleaves DPC substrates in a sequence-independent manner and is also required for translesion DNA synthesis following DPC degradation. Biallelic mutations in SPRTN cause Ruijs-Aalfs (RJALS) syndrome, characterized by hepatocellular carcinoma and segmental progeria, indicating the critical role for SPRTN and DPC repair pathway in genome maintenance. In this review, we will discuss the mechanism of replication-coupled DPC repair, regulation of SPRTN function and its implications in human disease and cancer.

Constructing ultra-stable photothermal plastics assisted by carbon dots with photocaged reactivity

Constructing ultra-stable photothermal plastics assisted by carbon dots with photocaged reactivity

ALDH1A1 overexpression in melanoma cells promotes tumor angiogenesis by activating the IL‑8/Notch signaling cascade.

ALDH1A1 is a cytosolic enzyme upregulated in tumor cells, involved in detoxifying cells from reactive aldehydes and in acquiring resistance to chemotherapeutic drugs. Its expression correlates with poor clinical outcomes in a number of cancers, including melanoma. The present study hypothesized that the increased ALDH1A1 expression and activity upregulated the release of proangiogenic factors from melanoma cells, which regulate angiogenic features in endothelial cells (ECs) through a rearrangement of the Notch pathway. In vivo, when subcutaneously implanted in immunodeficient mice, ALDH1A1 overexpressing melanoma cells displayed a higher microvessel density. In a 3D multicellular system, obtained co-culturing melanoma cancer cells with stromal cells, including ECs, melanoma ALDH1A1 overexpression induced the recruitment of ECs into the core of the tumorspheres. By using a genes array, overexpression of ALDH1A1 in tumor cells also promoted modulation of Notch cascade gene expression in ECs, suggesting an interaction between tumor cells and ECs mediated by enrichment of angiogenic factors in the tumor microenvironment. To confirm this hypothesis, inactivation of ALDH1A1 by the pharmacological inhibitor CM037 significantly affected the release of angiogenic factors, including IL-8, from melanoma cells. High levels of ALDH1A1, through the retinoic acid pathway, regulated the activation of NF-κB-p65 and IL-8. Further, in a 2D co-culture system, the addition of an IL-8 neutralizing antibody to ECs co-cultured with melanoma cells forced to express ALDH1A1 dampened endothelial angiogenic features, both at the molecular (in terms of gene and protein expression of mediators of the Notch pathway) and at the functional level (proliferation, scratch assay, tube formation and permeability). In conclusion, these findings demonstrated the existence of a link between melanoma ALDH1A1 expression and EC Notch signaling modification that results in a pro-angiogenic phenotype. Based on the crucial role of ALDH1A1 in melanoma control of the tumor microenvironment, the enzyme seems a promising target for the development of novel drugs able to interrupt the cross-talk between cancer (stem) cells and endothelial cells.

Lipid Peroxidation Induced ApoE Receptor-Ligand Disruption as a Unifying Hypothesis Underlying Sporadic Alzheimer's Disease in Humans.

Sporadic Alzheimer's disease (sAD) lacks a unifying hypothesis that can account for the lipid peroxidation observed early in the disease, enrichment of ApoE in the core of neuritic plaques, hallmark plaques and tangles, and selective vulnerability of entorhinal-hippocampal structures. We hypothesized that 1) high expression of ApoER2 (receptor for ApoE and Reelin) helps explain this anatomical vulnerability; 2) lipid peroxidation of ApoE and ApoER2 contributes to sAD pathogenesis, by disrupting neuronal ApoE delivery and Reelin-ApoER2-Dab1 signaling cascades. In vitro biochemical experiments; Single-marker and multiplex fluorescence-immunohistochemistry (IHC) in postmortem specimens from 26 individuals who died cognitively normal, with mild cognitive impairment or with sAD. ApoE and ApoER2 peptides and proteins were susceptible to attack by reactive lipid aldehydes, generating lipid-protein adducts and crosslinked ApoE-ApoER2 complexes. Using insitu hybridization alongside IHC, we observed that: 1) ApoER2 is strongly expressed in terminal zones of the entorhinal-hippocampal 'perforant path' projections that underlie memory; 2) ApoE, lipid aldehyde-modified ApoE, Reelin, ApoER2, and the downstream Reelin-ApoER2 cascade components Dab1 and Thr19-phosphorylated PSD95 accumulated in the vicinity of neuritic plaques in perforant path terminal zones in sAD cases; 3) several ApoE/Reelin-ApoER2-Dab1 pathway markers were higher in sAD cases and positively correlated with histological progression and cognitive deficits. Results demonstrate derangements in multiple ApoE/Reelin-ApoER2-Dab1 axis components in perforant path terminal zones in sAD and provide proof-of-concept that ApoE and ApoER2 are vulnerable to aldehyde-induced adduction and crosslinking. Findings provide the foundation for a unifying hypothesis implicating lipid peroxidation of ApoE and ApoE receptors in sAD.

Molecular and Physiological Responses of Citrus sinensis Leaves to Long-Term Low pH Revealed by RNA-Seq Integrated with Targeted Metabolomics.

Low pH-induced alterations in gene expression profiles and organic acids (OA) and free amino acid (FAA) abundances were investigated in sweet orange [Citrus sinensis (L.) Osbeck cv. Xuegan] leaves. We identified 503 downregulated and 349 upregulated genes in low pH-treated leaves. Further analysis indicated that low pH impaired light reaction and carbon fixation in photosynthetic organisms, thereby lowering photosynthesis in leaves. Low pH reduced carbon and carbohydrate metabolisms, OA biosynthesis and ATP production in leaves. Low pH downregulated the biosynthesis of nitrogen compounds, proteins, and FAAs in leaves, which might be conducive to maintaining energy homeostasis during ATP deprivation. Low pH-treated leaves displayed some adaptive responses to phosphate starvation, including phosphate recycling, lipid remodeling, and phosphate transport, thus enhancing leaf acid-tolerance. Low pH upregulated the expression of some reactive oxygen species (ROS) and aldehyde detoxifying enzyme (peroxidase and superoxidase) genes and the concentrations of some antioxidants (L-tryptophan, L-proline, nicotinic acid, pantothenic acid, and pyroglutamic acid), but it impaired the pentose phosphate pathway and VE and secondary metabolite biosynthesis and downregulated the expression of some ROS and aldehyde detoxifying enzyme (ascorbate peroxidase, aldo-keto reductase, and 2-alkenal reductase) genes and the concentrations of some antioxidants (pyridoxine and γ-aminobutyric acid), thus disturbing the balance between production and detoxification of ROS and aldehydes and causing oxidative damage to leaves.

Reproxalap Activity and Estimation of Clinically Relevant Thresholds for Ocular Itching and Redness in a Randomized Allergic Conjunctivitis Field Trial.

IntroductionThis clinical trial assessed the activity of reproxalap, a novel reactive aldehyde species modulator, and estimated clinically relevant thresholds for changes in ocular itching and redness in an allergic conjunctivitis field trial.MethodsThis was a randomized, double-masked, vehicle-controlled phase 2 trial. Patients with ragweed-associated allergic conjunctivitis were assessed over 28 days in an environmental setting with approximately four doses per day of either 0.25% reproxalap, 0.5% reproxalap, or vehicle. Patients recorded ocular itching, redness, tearing, and eyelid swelling scores (each with a 0–4 scale, except for a 0–3 scale for swelling), and completed the Allergic Conjunctivitis Quality of Life Questionnaire at the beginning and end of the trial.ResultsMixed model of repeated measures analysis demonstrated statistically lower itching and tearing scores (pooled P = 0.026 and P < 0.001, respectively) and numerically lower redness and eyelid swelling scores than vehicle on days when pollen exceeded the 95th percentile value. Using three anchor-based and three distribution-based approaches, the meaningful within-patient change and the between-group meaningful difference for patient-reported ocular itching and redness was estimated to be approximately 0.5. The most common treatment-emergent adverse event associated with reproxalap was transient irritation upon instillation.ConclusionIn a field clinical trial, reproxalap was well tolerated and superior to vehicle in reducing ocular itching on high-pollen days. The clinical meaningfulness threshold estimates of 0.5 units are among the first such calculations generated for the standard ocular itching and redness scores, providing important context for the clinical interpretation of clinical trials in allergic conjunctivitis.

Odor perception and symptoms during acrolein exposure in individuals with and without building-related symptoms

Building-related symptoms (BRS) is a significant work-related and public health problem, characterized by non-specific symptoms occurring in a particular building. The cause of BRS is unknown, but certain reactive compounds are suggested risk factors. The aim of this controlled exposure study was to investigate whether BRS cases report more odor annoyance and symptoms and show altered autonomous nervous system (ANS) response during exposure to the reactive aldehyde, acrolein in comparison with referents. Individuals with BRS (n = 18) and referents (n = 14) took part in two exposure sessions (80 min). One session contained heptane alone, and the other heptane and acrolein. Perceived odor annoyance; eye, nose, and throat symptoms; and ANS response were measured continuously. BRS cases did not experience more odor annoyance; eye, nose, and throat symptoms; or altered ANS response in comparison with referents during the exposures. Supplementary analyses revealed that BRS cases that also reported chemical intolerance perceived more symptoms than referents during acrolein exposure. Acrolein exposure at a concentration below previously reported sensory irritation detection thresholds is perceived as more irritating by a subgroup of BRS individuals compared with referents. The results of this study indicate that a subset of individuals with building related symptoms (BRS) has a lowered sensory irritation threshold towards acrolein exposure. Future guidelines on chemical exposures to acrolein should take time and individual sensitivity into account.

Maternal heme-enriched diet promotes a gut pro-oxidative status associated with microbiota alteration, gut leakiness and glucose intolerance in mice offspring

Maternal environment, including nutrition and microbiota, plays a critical role in determining offspring's risk of chronic diseases such as diabetes later in life. Heme iron requirement is amplified during pregnancy and lactation, while excessive dietary heme iron intake, compared to non-heme iron, has shown to trigger acute oxidative stress in the gut resulting from reactive aldehyde formation in conjunction with microbiota reshape. Given the immaturity of the antioxidant defense system in early life, we investigated the extent to which a maternal diet enriched with heme iron may have a lasting impact on gut homeostasis and glucose metabolism in 60-day-old C3H/HeN mice offspring.As hypothesized, the form of iron added to the maternal diet differentially governed the offspring's microbiota establishment despite identical fecal iron status in the offspring. Importantly, despite female offspring was unaffected, oxidative stress markers were however higher in the gut of male offspring from heme enriched-fed mothers, and were accompanied by increases in fecal lipocalin-2, intestinal para-cellular permeability and TNF-α expression. In addition, male mice displayed blood glucose intolerance resulting from impaired insulin secretion following oral glucose challenge. Using an integrated approach including an aldehydomic analysis, this male-specific phenotype was further characterized and revealed close covariations between unidentified putative reactive aldehydes and bacterial communities belonging to Bacteroidales and Lachnospirales orders.Our work highlights how the form of dietary iron in the maternal diet can dictate the oxidative status in gut offspring in a sex-dependent manner, and how a gut microbiota-driven oxidative challenge in early life can be associated with gut barrier defects and glucose metabolism disorders that may be predictive of diabetes development.

Differential Regulation of Retinoic Acid Signaling in Fanconi Anemia

Fanconi anemia (FA) is a rare genetic disease characterized by heterogeneous congenital defects, and increased risk for early‐onset bone marrow failure and cancer. Biallelic mutations in any one of 23 genes leads to FA. In vitro experiments have established a coordinated role for the FA gene network in the repair of DNA interstrand crosslinks (ICLs). However, the endogenous source(s) of DNA damage and chromosome instability in FA patients remain largely unknown. Recent studies have suggested that the FA proteins may play an important role in the repair of DNA damage caused by genotoxic reactive aldehydes produced during cellular metabolism, e.g., acetaldehyde and formaldehyde.To discover novel metabolic pathways linked to FA, we recently performed RNA‐seq analysis on telomerase‐immortalized mutant and functionally complemented FA‐D2 (FANCD2‐/‐) patient cells. Gene ontology enrichment analysis uncovered dysregulation of retinoid metabolism and retinoic acid signaling in mutant FA‐D2 (FANCD2‐/‐) cells. For example, we observed increased expression of the retinoid metabolism genes RDH10, ALDH1A1, and CYP26B1, in the absence of FANCD2. RDH10 converts retinol to retinaldehyde; ALDH1A1 converts retinaldehyde to retinoic acid; CYP26B1 degrades excess retinoic acid. In addition, we observed altered expression of multiple retinoic acid regulated genes including RARA, EGR1, and TGM2, and several members of the HOX, PAX, and SOX gene families. Using immunoblotting and qPCR, we have validated differential expression of many of these genes. We have also observed altered retinoid metabolism in Fancd2‐/‐ mouse cells. Furthermore, in preliminary flow cytometry experiments, we have determined that FA‐D2 (FANCD2‐/‐) patient cells exhibit increased aldehyde dehydrogenase activity.These findings are potentially highly significant and suggest that dysregulated retinoid metabolism and retinoic acid signaling ‐ as well as retinaldehyde‐associated genotoxicity ‐ might be key molecular features of FA. Further characterization of this newly discovered link could pave the way for the discovery of new therapeutic targets for FA patients.

Formation of the Major Circulating Metabolite of Cannabidiol by Non‐P450, Cytosolic Enzymes

Cannabidiol (CBD), a natural product derived from cannabis, was recently FDA‐approved to treat epilepsy in children. CBD is extensively metabolized by hepatic cytochrome P450 (P450) enzymes to form the pharmacologically active metabolite 7‐hydroxy‐cannabidiol (7‐OH‐CBD). This metabolite is further converted to the major circulating metabolite, 7‐carboxy‐cannabidiol (7‐COOH‐CBD), prior to hepatobiliary excretion. CBD is mainly eliminated in the form of 7‐COOH‐CBD and related hydroxylated derivatives, and the plasma area under the curve of 7‐COOH‐CBD is up to 40 times higher than that of the parent compound. While prior work has shown that 7‐OH‐CBD is mainly formed by CYP2C9 and CYP2C19, the enzymes involved in 7‐COOH‐CBD formation have not been clearly established. Preliminary data from in vitro experiments with hepatocytes and hepatic subcellular fractions suggests that cytosolic enzymes may contribute to formation of 7‐COOH‐CBD. The objective of this study was to define the roles of P450 versus non‐P450 enzymes in 7‐COOH‐CBD generation. We hypothesized that 7‐OH‐CBD may be metabolized through a multi‐step reaction involving an aldehyde intermediate prior to conversion to 7‐COOH‐CBD. Reaction phenotyping experiments were performed with 7‐OH‐CBD and human liver microsomes, cytosol, and S9 fraction in the presence of selective enzyme inhibitors and cofactors to determine their effects on 7‐COOH‐CBD formation. Results show that 7‐COOH‐CBD formation is largely NAD+‐dependent, and the cytosolic enzyme aldehyde dehydrogenase can generate 7‐COOH‐CBD. In addition, reactions performed in the presence of the trapping agent methoxylamine show decreased 7‐COOH‐CBD formation in human liver S9 fraction compared to those lacking this agent, suggesting that a reactive aldehyde intermediate may be formed from 7‐OH‐CBD. These data fill a critical research gap in our understanding of cannabinoid metabolism and help identify potential safety risks and drug‐drug interactions for patients and consumers taking CBD.

Rotenone-Induced 4-HNE Aggresome Formation and Degradation in HL-1 Cardiomyocytes: Role of Autophagy Flux.

Reactive oxygen species (ROS) cause oxidative stress by generating reactive aldehydes known as 4-hydroxynonenal (4-HNE). 4-HNE modifies protein via covalent adduction; however, little is known about the degradation mechanism of 4-HNE-adducted proteins. Autophagy is a dynamic process that maintains cellular homeostasis by removing damaged organelles and proteins. In this study, we determined the role of a superoxide dismutase (SOD) mimetic MnTnBuOE-2-PyP5+ (MnP, BMX-001) on rotenone-induced 4-HNE aggresome degradation in HL-1 cardiomyocytes. A rotenone treatment (500 nM) given for 24 h demonstrated both increased ROS and 4-HNE aggresome accumulation in HL-1 cardiomyocytes. In addition, cardiomyocytes treated with rotenone displayed an increase in the autophagy marker LC3-II, as shown by immunoblotting and immunofluorescence. A pre-treatment with MnP (20 µM) for 24 h attenuated rotenone-induced ROS formation. An MnP pre-treatment showed decreased 4-HNE aggresomes and LC3-II formation. A rotenone-induced increase in autophagosomes was attenuated by a pre-treatment with MnP, as shown by fluorescent-tagged LC3 (tfLC3). Rotenone increased tubulin hyperacetylation through the ROS-mediated pathway, which was attenuated by MnP. The disruption of autophagy caused HL-1 cell death because a 3-methyladenine inhibitor of autophagosomes caused reduced cell death. Yet, rapamycin, an inducer of autophagy, increased cell death. These results indicated that a pre-treatment with MnP decreased rotenone-induced 4-HNE aggresomes by enhancing the degradation process.

The Potential Role of Mitochondrial Acetaldehyde Dehydrogenase 2 in Urological Cancers From the Perspective of Ferroptosis and Cellular Senescence.

Overproduction of reactive oxygen species (ROS) and superlative lipid peroxidation promote tumorigenesis, and mitochondrial aldehyde dehydrogenase 2 (ALDH2) is associated with the detoxification of ROS-mediated lipid peroxidation-generated reactive aldehydes such as 4-hydroxy-2-nonenal (4-HNE), malondialdehyde, and acrolein due to tobacco smoking. ALDH2 has been demonstrated to be highly associated with the prognosis and chemoradiotherapy sensitivity of many types of cancer, including leukemia, lung cancer, head and neck cancer, esophageal cancer, hepatocellular cancer, pancreatic cancer, and ovarian cancer. In this study, we explored the possible relationship between ALDH2 and urological cancers from the aspects of ferroptosis, epigenetic alterations, proteostasis, mitochondrial dysfunction, and cellular senescence.

The aldehyde hypothesis: metabolic intermediates as antimicrobial effectors.

There are many reactive intermediates found in metabolic pathways. Could these potentially toxic molecules be exploited for an organism's benefit? We propose that during certain microbial infections, the production of inherently reactive aldehydes by an infected host is a previously unappreciated innate immune defence mechanism. While there has been a significant focus on the effects of aldehydes on mammalian physiology, the idea that they might be exploited or purposefully induced to kill pathogens is new. Given that aldehydes are made as parts of metabolic programmes that accompany immune cell activation by the cytokine interferon-gamma (IFN-γ) during infections, we hypothesize that aldehydes are among the arsenal of IFN-γ-inducible effectors needed for pathogen control.

Effect of Dialdehyde Carboxymethyl Cellulose Cross-Linking on the Porous Structure of the Collagen Matrix.

Porous structures are essential for some collagen-based biomaterials and can be regulated by crosslinkers. Herein, dialdehyde carboxymethyl cellulose (DCMC) crosslinkers with similar size but different aldehyde group contents were prepared through periodate oxidation of sodium carboxymethyl cellulose with varying degrees of substitution (DS). They can penetrate into the hierarchy of fibril and form inter-molecular and intra-fibril cross-linking within the collagen matrix due to their nanoscale sizes and reactive aldehyde groups. The collagen matrices possessed higher porosity, significantly greater proportion of large pores (Φ > 10 μm), and shorter D-periodicity after cross-linking, showing greater potential for biomedical applications. In addition, the crosslinked collagen matrices showed satisfactory biocompatibility and biodegradation. The decreased DS of carboxymethyl cellulose, which led to the increased aldehyde content of corresponding DCMC, brought about an enhanced cross-linking degree, porosity, and proportion of large pores of the crosslinked collagen matrix. DCMC dosage of 6% was sufficient for cross-linking and pore formation. Excess DCMC would physically deposit in the matrix and decrease the porosity instead. Therefore, the desired pore properties of the collagen matrix could be obtained by regulating the structure of DCMC and thereby achieving the required functions of the biomaterial.

Molecular mechanisms for pH-mediated amelioration of aluminum-toxicity revealed by conjoint analysis of transcriptome and metabolome in Citrus sinensis roots

Little is known about the effects of pH-aluminum (Al) interactions on gene expression and/or metabolite profiles in plants. Eleven-week-old seedlings of Citrus sinensis were fertilized with nutrient solution at an Al level of 0 or 1 mM and a pH of 3.0 or 4.0 for 18 weeks. Increased pH mitigated Al-toxicity-induced accumulation of callose, an Al-sensitive marker. In this study, we identified more differentially expressed genes and differentially abundant metabolites in pH 4.0 + 1 mM Al-treated roots (P4AR) vs pH 4.0 + 0 mM Al-treated roots (P4R) than in pH 3.0 + 1 mM Al-treated roots (P3AR) vs pH 3.0 + 0 mM Al-treated roots (P3R), suggesting that increased pH enhanced root metabolic adaptations to Al-toxicity. Further analysis indicated that increased pH-mediated mitigation of root Al-toxicity might be related to several factors, including: enhanced capacity to maintain the homeostasis of phosphate and energy and the balance between generation and scavenging of reactive oxygen species and aldehydes; and elevated accumulation of secondary metabolites such as polyphenol, proanthocyanidins and phenolamides and adaptations of cell wall and plasma membrane to Al-toxicity.

Cigarette Smoke Containing Acrolein Contributes to Cisplatin Resistance in Human Bladder Cancers through the Regulation of HER2 Pathway or FGFR3 Pathway.

Cisplatin-based chemotherapy is the first-line therapy for bladder cancer. However, cisplatin resistance has been associated with the recurrence of bladder cancer. Previous studies have shown that activation of FGFR and HER2 signaling are involved in bladder cancer cell proliferation and drug resistance. Smoking is the most common etiologic risk factor for bladder cancer, and there is emerging evidence that smoking is associated with cisplatin resistance. However, the underlying mechanism remains elusive. Acrolein, a highly reactive aldehyde, is abundant in tobacco smoke, cooking fumes, and automobile exhaust fumes. Our previous studies have shown that acrolein contributes to bladder carcinogenesis through the induction of DNA damage and inhibition of DNA repair. In this study, we found that acrolein induced cisplatin resistance and tumor progression in both non-muscle invasive bladder cancer (NMIBC) and muscle invasive bladder cancer (MIBC) cell lines RT4 and T24, respectively. Activation of HER2 and FGFR3 signaling contributes to acrolein-induced cisplatin resistance in RT4 and T24 cells, respectively. Furthermore, trastuzumab, an anti-HER2 antibody, and PD173074, an FGFR inhibitor, reversed cisplatin resistance in RT4 and T24 cells, respectively. Using a xenograft mouse model with acrolein-induced cisplatin-resistant T24 clones, we found that cisplatin combined with PD173074 significantly reduced tumor size compared with cisplatin alone. These results indicate that differential molecular alterations behind cisplatin resistance in NMIBC and MIBC significantly alter the effectiveness of targeted therapy combined with chemotherapy. This study provides valuable insights into therapeutic strategies for cisplatin-resistant bladder cancer.