OBJECTIVE: Treponema denticola has been strongly implicated in the pathogenesis of chronic periodontitis. Previously, we reported that the potential transcriptional regulator TDE_0259 (oxtR1) is upregulated in the bacteriocin ABC transporter gene-deficient mutant. OxtR1 may regulate genes to adapt to environmental conditions during colonization; however, the exact role of the gene in T. denticola has not been reported. Therefore, we investigated its function using an oxtR1-deficient mutant.
METHODS: The growth rates of the wild-type and oxtR1 mutant were monitored under anaerobic conditions; their antibacterial agent susceptibility and gene expression were assessed using a liquid dilution assay and DNA microarray, respectively. An electrophoretic mobility shift assay was performed to investigate the binding of OxtR1 to promoter regions.
RESULTS: The growth rate of the bacterium was accelerated by the inactivation of oxtR1, and the mutant exhibited an increased minimum inhibitory concentration against ofloxacin. We observed a relative increase in the expression of genes associated with potential ferrodoxin (TDE_0260), flavodoxin, ABC transporters, heat-shock proteins, DNA helicase, iron compounds, and lipoproteins in the mutant. OxtR1 expression increased upon oxygen exposure, and oxtR1 complementation suppressed the expression of potential ferrodoxin. Our findings also suggested that OxtR1 binds to a potential promoter region of the TDE_0259-260 operon. Moreover, the mutant showed a marginal yet significantly faster growth rate than the wild-type strain under H2O2 exposure.
CONCLUSIONS: The oxygen-sensing regulator OxtR1 plays a role in regulating the expression of a potential ferrodoxin, which may contribute to the response of T. denticola to oxygen-induced stress.

Glaucoma is a neurodegenerative disease that affects the retinal ganglion cells (RGCs). The main risk factor is elevated intraocular pressure (IOP), but the actual cause of the disease remains unknown. Emerging evidence indicates that metabolic dysfunction plays a central role. The aim of the current study was to determine and compare the effect of universal hypoxia on the metabolomic signature in plasma samples from healthy controls (n = 10), patients with normal-tension glaucoma (NTG, n = 10), and ocular hypertension (OHT, n = 10). By subjecting humans to universal hypoxia, we aim to mimic a state in which the mitochondria in the body are universally stressed. Participants were exposed to normobaric hypoxia for two hours, followed by a 30 min recovery period in normobaric normoxia. Blood samples were collected at baseline, during hypoxia, and in recovery. Plasma samples were analyzed using a non-targeted metabolomics approach based on liquid chromatography coupled with high-resolution mass spectrometry (LC-HRMS). Multivariate analyses were conducted using principal component analysis (PCA) and orthogonal partial least squares-discriminant analysis (OPLS-DA), and univariate analysis using the Wilcoxon signed-rank test and false discovery rate (FDR) correction. Unique metabolites involved in fatty acid biosynthesis and ketone body metabolism were upregulated, while metabolites of the kynurenine pathway were downregulated in OHT patients exposed to universal hypoxia. Differential affection of metabolic pathways may explain why patients with OHT initially do not suffer or are more resilient from optic nerve degeneration. The metabolomes of NTG and OHT patients are regulated differently from control subjects and show dysregulation of metabolites important for energy production. These dysregulated processes may potentially contribute to the elevation of IOP and, ultimately, cell death of the RGCs.

Ferroptosis is a distinctive form of iron-dependent necrotic cell death, characterized by excessive lipid peroxidation on cellular membranes and compromised cellular antioxidant defenses. Multiple metabolic pathways, including iron and lipid metabolism, as well as antioxidant systems, contribute to the execution of ferroptosis. The gut microbiota exerts regulatory effects on ferroptosis through its microbial composition, biological functions, and metabolites. Notably, most pathogenic bacteria tend to promote ferroptosis, thereby inducing or exacerbating diseases, while most probiotics have been shown to protect against cell death. Given microbiota colonization in the gut, an intimate association is found between intestinal diseases and microbiota. This review consolidates the essential aspects of ferroptotic processes, emphasizing key molecules and delineating the intricate interplay between gut microbiota and ferroptosis. Moreover, this review underscores the potential utility of gut microbiota modulation in regulating ferroptosis for the treatment of intestinal diseases.

Ischemia-reperfusion injury (IRI) involves a positive amplification feedback loop that stimulates innate immune-driven tissue damage associated with organ procurement from deceased donors and during transplantation surgery. As our appreciation of its basic immune mechanisms has improved in recent years, translating putative biomarkers into therapeutic interventions in clinical transplantation remains challenging.
This review presents advances in translational/clinical studies targeting immune responses to reactive oxygen species in IRI-stressed solid organ transplants, especially livers. Here we focus on novel concepts to rejuvenate suboptimal donor organs and improve transplant function using pharmacologic and machine perfusion (MP) strategies. Cellular damage induced by cold ischemia/warm reperfusion and the latest mechanistic insights into the microenvironment\'s role that leads to reperfusion-induced sterile inflammation is critically discussed.
Efforts to improve clinical outcomes and increase the donor organ pool will depend on improving donor management and our better appreciation of the complex mechanisms encompassing organ IRI that govern the innate-adaptive immune interface triggered in the peritransplant period and subsequent allo-Ag challenge. Computational techniques and deep machine learning incorporating the vast cellular and molecular mechanisms will predict which peri-transplant signals and immune interactions are essential for improving access to the long-term function of life-saving transplants.

IL-32 is a pro-inflammatory cytokine expressed by several types of cancer cells and immune cells. Currently, no treatment targeting IL-32 is available, and its intracellular and exosomal localization make IL-32 less accessible to drugs. We previously showed that hypoxia promotes IL-32 expression through HIF1α in multiple myeloma cells. Here, we demonstrate that high-speed translation and ubiquitin-dependent proteasomal degradation lead to a rapid IL-32 protein turnover. We find that IL-32 protein half-life is regulated by the oxygen-sensing cysteine-dioxygenase ADO and that deubiquitinases actively remove ubiquitin from IL-32 and promote protein stability. Deubiquitinase inhibitors promoted the degradation of IL-32 and may represent a strategy for reducing IL-32 levels in multiple myeloma. The fast turnover and enzymatic deubiquitination of IL-32 are conserved in primary human T cells; thus, deubiquitinase inhibitors may also affect T-cell responses in various diseases.

The effect of chronic oxygen exposure on growth and development of insects is an active field of research. It seeks to unravel the triggers and limitations to molting and growth across many insect groups, although even now there are gaps in our knowledge and inconsistencies that need to be addressed. The oxygen dependent induction of molting (ODIM) hypothesis states that the impetus for molting is triggered by the development of hypoxic tissue due to the rapid increase in mass coupled with the fixed nature of tracheal systems between molts. In this study, we raised Manduca sexta in three chronic oxygen treatments (10, 21, & 30% O2). We measured the mass of these insects throughout their larval development and as adults. We found that both hyperoxia and hypoxia had marked effects on size and developmental times. Hyperoxia exposure resulted in increased mass throughout development and into adulthood while increasing developmental times. Hypoxia also increased developmental time and decreased mass of adult moths. We show that pupation is a critical window for exposure to altered oxygen levels. This suggests that oxygen may play a role in affecting the timing of eclosion at the end of pupation.

Chemotherapy is used for childhood cancer but may lead to infertility in patients. Spermatogonia stem cells are present in the testes of prepubertal boys, although they do not produce sperm at this age. Herein, we evaluated the toxicity of cisplatin, a known medicine for cancer treatment, in neonatal mouse testes using in vitro organ culture. Mouse testicular fragments (MTFs) derived from 5.5-d postpartum mouse testes were exposed to 1-10 μg/mL cisplatin. The results showed that cisplatin significantly downregulated the expression of germ cell marker genes, including differentiated and undifferentiated, in a dose-dependent manner. In particular, a high dose of cisplatin (10 μg/mL) led to germ cell depletion. In addition, the expression levels of the Sertoli cell marker gene, the number of SOX9+ Sertoli cells, and the levels of SOX9 protein were markedly decreased in cisplatin-treated MTFs compared to controls. The mRNA expression of steroidogenic enzyme-related genes significantly increased in cisplatin-treated MTFs, except for estrogen receptor 1 (Esr1). Consistently, 3β-hydroxysteroid dehydrogenase protein was also observed in the interstitial regions of cisplatin-treated MTFs. Altogether, our findings showed a significant impairment in germ cell development, Sertoli cell survival, and steroidogenesis in the MTFs of cisplatin-treated mice.

Micro-aeration can facilitate anaerobic digestion (AD) by regulating microbial communities and promoting the growth of facultative taxa, thereby increasing methane yield and stabilizing the AD process. Additionally, micro-aeration contributes to hydrogen sulfide stripping by oxidization to produce molecular sulfur or sulfuric acid. Although micro-aeration can positively affect AD, it must be strictly regulated to maintain an overall anaerobic environment that permits anaerobic microorganisms to thrive. Even so, obligate anaerobes, especially methanogens, could suffer from oxidative stress during micro-aeration. This review describes the applications of micro-aeration in AD and examines the cutting-edge advances in how methanogens survive under oxygen stress. Moreover, barriers and corresponding solutions are proposed to move micro-aeration technology closer to application at scale.

Organohalide pollutants are prevalent in the environment, causing harms to wildlife and human. Organohalide-respiring bacteria (OHRB) could detoxify these pollutants in anaerobic environments, but the most competent OHRB (i.e., Dehalococcoides) is susceptible to oxygen. This study reports exceptional resistance and resilience of sewage sludge microbial communities to oxygen stress for attenuation of structurally distinct organohalide pollutants, including tetrachloroethene, tetrabromobisphenol A, and polybrominated diphenyl ethers. The dehalogenation rate constant of these organohalide pollutants in oxygen-exposed sludge microcosms was maintained as 74-120% as that in the control without oxygen exposure. Subsequent top-down experiments clarified that sludge flocs and non-OHRB contributed to alleviating oxygen stress on OHRB. In the dehalogenating microcosms, multiple OHRB (Dehahlococcoides, Dehalogenimonas, and Sulfurospirillum) harboring distinct reductive dehalogenase genes (pceA, pteA, tceA, vcrA, and bdeA) collaborated to detoxify organohalide pollutants but responded differentially to oxygen stress. Comprehensive microbial community analyses (taxonomy, diversity, and structure) demonstrated certain resilience of the sludge-derived dehalogenating microbial communities to oxygen stress. Additionally, microbial co-occurrence networks were intensified by oxygen stress in most microcosms, as a possible stress mitigation strategy. Altogether the mechanistic and ecological findings in this study contribute to remediation of organohalide-contaminated sites encountering oxygen disturbance.

Microbial electrosynthesis (MES) from CO2 provides chemicals and fuels by driving the metabolism of microorganisms with electrons from cathodes in bioelectrochemical systems. These microorganisms are usually strictly anaerobic. At the same time, the anode reaction of bioelectrochemical systems is almost exclusively water splitting through the oxygen evolution reaction (OER). This creates a dilemma for MES development and engineering. Oxygen penetration to the cathode has to be excluded to avoid toxicity and efficiency losses while assuring low resistance. We show that this dilemma derives a strong need to identify novel reactor designs when using the OER as an anode reaction or to fully replace OER with alternative oxidation reactions.