Surfactants are amphiphilic molecules that are capable of mixing water and oil. Biosurfactants are eco-friendly, low-toxicity, and stable to a variety of environmental factors. Optimizing conditions for microorganisms to produce biosurfactants can lead to improved production suitable for scaling up. In this study, we compared heterologous expression levels of the luminescence system luxCDABE operon controlled by regulatable promoters araC-PBAD and its strong version araC-PBAD-SD in Escherichia coli K12, Pseudomonas aeruginosa PAO1, and P. putida KT2440. Real-time monitoring of luminescence levels in the three strains indicated that luxCDABE controlled by araC-PBAD-SD promoter with 0.2% arabinose supplementation in P. putida produced the highest level of luminescence. By using the araC-PBAD-SD promoter-controlled rhlAB expression in P. putida, we were able to produce mono-rhamnolipid at a level of 1.5 g L-1 when 0.02% arabinose was supplemented. With the same system to express olsB, lyso-ornithine lipid was produced at a level of 10 mg L-1 when 0.2% arabinose was supplemented. To our knowledge, this is the first report about optimizing conditions for lyso-ornithine lipid production at a level up to 10 mg L-1. Taken together, our results demonstrate that regulatable araC-PBAD-SD promoter in P. putida KT2440 is a useful system for heterologous production of biosurfactants.

UNASSIGNED: The Hand, Foot and Mouth Disease (HFMD), caused by enterovirus 71 infection, is a global public health emergency. Severe HFMD poses a significant threat to the life and well-being of children. Numerous studies have indicated that the occurrence of severe HFMD is associated with cytokine storm. However, the precise molecular mechanism underlying cytokine storm development remains elusive, and there are currently no safe and effective treatments available for severe HFMD in children.
UNASSIGNED: In this study, we established a mouse model of severe HFMD to investigate the molecular mechanisms driving cytokine storm. We specifically analyzed metabolic disturbances, focusing on arginine/ornithine metabolism, and assessed the potential therapeutic effects of spermine, an ornithine metabolite.
UNASSIGNED: Our results identified disturbances in arginine/ornithine metabolism as a pivotal factor driving cytokine storm onset in severe HFMD cases. Additionally, we discovered that spermine effectively mitigated the inflammatory injury phenotype observed in mice with severe HFMD.
UNASSIGNED: In conclusion, our findings provide novel insights into the molecular mechanisms underlying severe HFMD from a metabolic perspective while offering a promising new strategy for its safe and effective treatment.

UNASSIGNED: Proliferative diabetic retinopathy (PDR) is a common diabetes complication, significantly impacting vision and quality of life. Previous studies have suggested a potential link between arginine pathway metabolites and diabetic retinopathy (DR). Connective tissue growth factor (CTGF) plays a role in the occurrence and development of fibrovascular proliferation (FVP) in PDR patients. However, the relationship between arginine pathway metabolites and FVP in PDR remains undefined. This study aimed to explore the correlation between four arginine pathway metabolites (arginine, asymmetric dimethylarginine[ADMA], ornithine, and citrulline) and the severity of FVP in PDR patients.
UNASSIGNED: In this study, plasma and aqueous humor samples were respectively collected from 30 patients with age-related cataracts without diabetes mellitus (DM) and from 85 PDR patients. The PDR patients were categorized as mild-to-moderate or severe based on the severity of fundal FVP. The study used Kruskal-Wallis test to compare arginine, ADMA, ornithine, and citrulline levels across three groups. Binary logistic regression identified risk factors for severe PDR. Spearman correlation analysis assessed associations between plasma and aqueous humor metabolite levels, and between ADMA and CTGF levels in aqueous humor among PDR patients.
UNASSIGNED: ADMA levels in the aqueous humor were significantly greater in patients with severe PDR than in those with mild-to-moderate PDR(P=0.0004). However, the plasma and aqueous humor levels of arginine, ornithine, and citrulline did not significantly differ between mild-to-moderate PDR patients and severe PDR patients (P>0.05). Binary logistic regression analysis indicated that the plasma (P=0.01) and aqueous humor (P=0.006) ADMA levels in PDR patients were risk factors for severe PDR. Furthermore, significant correlations were found between plasma and aqueous humor ADMA levels (r=0.263, P=0.015) and between aqueous humor ADMA and CTGF levels (r=0.837, P<0.001).
UNASSIGNED: Elevated ADMA levels in plasma and aqueous humor positively correlate with the severity of FVP in PDR, indicating ADMA as a risk factor for severe PDR.

Hairgrass (Deschampsia caespitosa), a widely distributed grass species considered promising in the ecological restoration of degraded grassland in the Qinghai-Xizang Plateau, is likely to be subjected to frequent drought and waterlogging stress due to ongoing climate change, further aggravating the degradation of grassland in this region. However, whether it would acclimate to water stresses resulting from extreme climates remains unknown. Proline accumulation is a crucial metabolic response of plants to challenging environmental conditions. This study aims to investigate the changes in proline accumulation and key enzymes in hairgrass shoot and root tissues in response to distinct climate extremes including moderate drought, moderate waterlogging, and dry-wet variations over 28 days using a completely randomized block design. The proline accumulation, contribution of the glutamate and ornithine pathways, and key enzyme activities related to proline metabolism in shoot and root tissues were examined. The results showed that water stress led to proline accumulation in both shoot and root tissues of hairgrass, highlighting the importance of this osmoprotectant in mitigating the effects of environmental challenges. The differential accumulation of proline in shoots compared to roots suggests a strategic allocation of resources by the plant to cope with osmotic stress. Enzymatic activities related to proline metabolism, such as Δ1-pyrroline-5-carboxylate synthetase, ornithine aminotransferase, Δ1-pyrroline-5-carboxylate reductase, Δ1-pyrroline-5-carboxylate dehydrogenase, and proline dehydrogenase, further emphasize the dynamic regulation of proline levels in hairgrass under water stress conditions. These findings support the potential for enhancing the stress resistance of hairgrass through the genetic manipulation of proline biosynthesis and catabolism pathways.

Activating Nrf2 by small molecules is a promising strategy to treat postmenopausal osteoporosis. However, there is currently no Nrf2 activator approved for treating chronic diseases, and the downstream mechanism underlying the regulation of Nrf2 on osteoclast differentiation remains unclear. Here, we found that bitopertin, a clinical-stage glycine uptake inhibitor, suppresses osteoclast differentiation and ameliorates ovariectomy-induced bone loss by activating Nrf2. Mechanistically, bitopertin interacts with the Keap1 Kelch domain and decreases Keap1-Nrf2 binding, leading to reduced Nrf2 ubiquitination and degradation. Bitopertin is associated with less adverse events than clinically approved Nrf2 activators in both mice and human subjects. Furthermore, Nrf2 transcriptionally activates ferroportin-coding gene Slc40a1 to reduce intracellular iron levels in osteoclasts. Loss of Nrf2 or iron supplementation upregulates ornithine-metabolizing enzyme Odc1, which decreases ornithine levels and thereby promotes osteoclast differentiation. Collectively, our findings identify a novel clinical-stage Nrf2 activator and propose a novel Nrf2-iron-ornithine metabolic axis in osteoclasts.

Antibiotic-induced dysbiosis is a major risk factor for Clostridioides difficile infection (CDI), and fecal microbiota transplantation (FMT) is recommended for treating CDI. However, the underlying mechanisms remain unclear. Here, we show that Tritrichomonas musculis (T.mu), an integral member of the mouse gut commensal microbiota, reduces CDI-induced intestinal damage by inhibiting neutrophil recruitment and IL-1β secretion, while promoting Th1 cell differentiation and IFN-γ secretion, which in turn enhances goblet cell production and mucin secretion to protect the intestinal mucosa. T.mu can actively metabolize arginine, not only influencing the host\'s arginine-ornithine metabolic pathway, but also shaping the metabolic environment for the microbial community in the host\'s intestinal lumen. This leads to a relatively low ornithine state in the intestinal lumen in C. difficile-infected mice. These changes modulate C. difficile\'s virulence and the host intestinal immune response, and thus collectively alleviating CDI. These findings strongly suggest interactions between an intestinal commensal eukaryote, a pathogenic bacterium, and the host immune system via inter-related arginine-ornithine metabolism in the regulation of pathogenesis and provide further insights for treating CDI.

The blood vessels of the placenta are crucial for fetal growth. Here, lower vessel density and ornithine (Orn) content were observed in placentae for low-birth-weight fetuses versus normal-birth-weight fetuses at day 75 of gestation. Furthermore, the Orn content in placentae decreased from day 75 to 110 of gestation. To investigate the role of Orn in placental angiogenesis, 48 gilts (Bama pig) were allocated into four groups. The gilts in the control group were fed a basal diet (CON group), while those in the experimental groups were fed a basal diet supplemented with 0.05% Orn (0.05% Orn group), 0.10% Orn (0.10% Orn group), and 0.15% Orn (0.15% Orn group), respectively. The results showed that 0.15% Orn and 0.10% Orn groups exhibited increased birth weight of piglets compared with the CON group. Moreover, the 0.15% Orn group was higher than the CON group in the blood vessel densities of placenta. Mechanistically, Orn facilitated placental angiogenesis by regulating vascular endothelial growth factor-A (VEGF-A). Furthermore, maternal supplementation with 0.15% Orn during gestation increased the jejunal and ileal villi height and the concentrations of colonic propionate and butyrate in suckling piglets. Collectively, these results showed that maternal supplementation with Orn promotes placental angiogenesis and improves intestinal development of suckling piglets.

OBJECTIVE: To explore the genetic basis for a Chinese pedigree affected with co-morbid Ornithine carbamoyl transferase deficiency (OTCD) and MECP2 duplication syndrome.
METHODS: A proband who was admitted to the Neonatal Intensive Care Unit of Gansu Provincial Maternal and Child Health Care Hospital on December 19, 2017 was selected as the study subject. High-throughput sequencing and multiplex ligation-dependent probe amplification (MLPA) were carried out for her pedigree, and short tandem repeat-based linkage analysis and chromosome copy number variation sequencing (CNV-seq) were used for the prenatal diagnosis.
RESULTS: The proband, a 3-day-old female, was found to harbor heterozygous deletion of exons 7-9 of the OTC gene. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was classified as likely pathogenic (PVS1+PM2_Supporting+PP4). The proband was diagnosed with OTCD , which was in keeping with her acute encephalopathy and metabolic abnormalities (manifesting as hyperammonemia, decreased blood citrulline, and increased urine orotic acid). Prenatal diagnosis was carried out for the subsequent pregnancy. The fetus did not harbor the exons 7-9 deletion of the OTC gene, but was found to carry a duplication in Xq28 region (which encompassed the whole region of MECP2 duplication syndrome) and was positive for the SRY sequence. The same duplication was also found in the proband and her mother. Considering the possible existence of X-chromosome inactivation, the proband was diagnosed with two X-linked recessive disorders including OTCD and MECP2 duplication syndrome, and the fetus was determined as a male affected with the MECP2 duplication syndrome.
CONCLUSIONS: Discoveries of the pathogenic variants underlying the OTCD and MECP2 duplication syndrome have enabled clinical intervention, treatment, genetic counseling and prenatal diagnosis for this pedigree.

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BACKGROUND: Intrinsic capacity is the combination of individual physical and mental abilities, reflecting the aging degree of the older adults. However, the mechanisms and metabolic characteristics of the decline in intrinsic capacity are still unclear.
OBJECTIVE: To identify metabolic signatures and associated pathways of decline in intrinsic capacity based on the metabolite features.
METHODS: We recruited 70 participants aged 77.19 ± 8.31 years. The five domains of intrinsic capacity were assessed by Short Physical Performance Battery (for mobility), Montreal cognition assessment (for cognition), 30-Item Geriatric Depression Scale (for psychology), self-reported hearing/visual impairment (for sensory) and Nutritional risk screening (for vitality), respectively. The serum samples of participants were analyzed by liquid chromatography-mass spectrometry-based metabolomics, followed by metabolite set enrichment analysis and metabolic pathway analysis.
RESULTS: There were 50 participants with a decline in intrinsic capacity in at least one of the domains. A total of 349 metabolites were identified from their serum samples. Overall, 24 differential metabolites, 5 metabolite sets and 13 pathways were associated with the decline in intrinsic capacity.
CONCLUSIONS: Our results indicated that decline in intrinsic capacity had unique metabolomic profiles.
CONCLUSIONS: The specific change of acyl carnitines was observed to be a feature of decline in intrinsic capacity. Dysregulation of the pentose phosphate pathway and of arginine and ornithine metabolism was strongly associated with the decline in intrinsic capacity.