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Background: The cross-protective nature of Bacillus Calmette-Guerin (BCG) vaccine against SARS-CoV-2 virus was previously suggested, however its effect in COVID-19 patients with type 2 diabetes (T2D) and the underlying metabolic pathways has not been addressed. This study aims to investigate the difference in the metabolomic patterns of type 2 diabetic patients with BCG vaccination showing different severity levels of COVID-19 infection. Methods: Sixty-seven COVID-19 patients were categorized into diabetic and non-diabetic individuals who had been previously vaccinated or not with BCG vaccination. Targeted metabolomics were performed from serum samples from all patients using tandem mass spectrometry. Statistical analysis included multivariate and univariate models. Results: Data suggested that while BCG vaccination may provide protection for individuals who do not have diabetes, it appears to be linked to more severe COVID-19 symptoms in T2D patients (p = 0.02). Comparing the metabolic signature of BCG vaccinated T2D individuals to non-vaccinated counterparts revealed that amino acid (sarcosine), cholesterol esters (CE 20:0, 20:1, 22:2), carboxylic acid (Aconitic acid) were enriched in BCG vaccinated T2D patients, whereas spermidine, glycosylceramides (Hex3Cer(d18:1_22:0), Hex2Cer(d18:1/22:0), HexCer(d18:1/26:1), Hex2Cer(d18:1/24:0), HexCer(d18:1/22:0) were higher in BCG vaccinated non- T2D patients. Furthermore, data indicated a decrease in sarcosine synthesis from glycine and choline and increase in spermidine synthesis in the BCG vaccinated cohort in T2D and non-T2D groups, respectively. Conclusion: This pilot study suggests increased severity of COVID-19 in BCG vaccinated T2D patients, which was marked by decreased sarcosine synthesis, perhaps via lower sarcosine-mediated removal of viral antigens. [ABSTRACT FROM AUTHOR]

Background: Pathogens of otitis media (OM) induce inflammatory responses in the middle ear (ME), characterized by mucosal hyperplasia, leukocyte infiltration, and inflammatory mediators, including arachidonic acid metabolites. We studied the role of the eicosanoid leukotriene B4 (LTB4) in OM. Methods: Expression of LTB4-related genes was evaluated by gene array and single-cell RNA-Seq in MEs infected with nontypeable Haemophilus influenzae (NTHi). An inhibitor of LTB4 receptor 1 (i.e. U75302) was also used to block LTB4 responses. Results: ME expression of LTB4-related genes was observed by gene arrays and scRNA-Seq. However, not all genes involved in LTB4 generation occurred in any one specific cell type. Moreover, LTB4 receptor inhibition significantly reduced mucosal hyperplasia and virtually eliminated leukocyte infiltration. Conclusions: ME expression of LTB4-related genes suggest a functional role in OM disease. The fact that LTB4-generation is spread across different cell types is consistent with a transcellular pathway of eicosanoid biosynthesis involving cell-to-cell signaling as well as transfer of biosynthetic intermediates between cells. The dramatic reduction in ME leukocyte infiltration caused by U75302 indicates that LTB4 plays a major role in ME inflammatory cell recruitment, acting via the LTB4R1 receptor. Given that there are many other chemotactic factors that occur in the ME during OM, the ability of LTB4 to activate leukocytes and stimulate their extravasation may explain the effects of inhibition. Reduction in mucosal hyperplasia due to U75302 administration may be secondary to the reduction in leukocytes since LTB4R1 is not expressed by mucosal epithelial or stromal cells. The results suggest that LTB4 receptor antagonists could be useful in treating OM. [ABSTRACT FROM AUTHOR]

BackgroundPathogens of otitis media (OM) induce inflammatory responses in the middle ear (ME), characterized by mucosal hyperplasia, leukocyte infiltration, and inflammatory mediators, including arachidonic acid metabolites. We studied the role of the eicosanoid leukotriene B4 (LTB4) in OM.MethodsExpression of LTB4-related genes was evaluated by gene array and single-cell RNA-Seq in MEs infected with nontypeable Haemophilus influenzae (NTHi). An inhibitor of LTB4 receptor 1 (i.e. U75302) was also used to block LTB4 responses.ResultsME expression of LTB4-related genes was observed by gene arrays and scRNA-Seq. However, not all genes involved in LTB4 generation occurred in any one specific cell type. Moreover, LTB4 receptor inhibition significantly reduced mucosal hyperplasia and virtually eliminated leukocyte infiltration.ConclusionsME expression of LTB4-related genes suggest a functional role in OM disease. The fact that LTB4-generation is spread across different cell types is consistent with a transcellular pathway of eicosanoid biosynthesis involving cell-to-cell signaling as well as transfer of biosynthetic intermediates between cells. The dramatic reduction in ME leukocyte infiltration caused by U75302 indicates that LTB4 plays a major role in ME inflammatory cell recruitment, acting via the LTB4R1 receptor. Given that there are many other chemotactic factors that occur in the ME during OM, the ability of LTB4 to activate leukocytes and stimulate their extravasation may explain the effects of inhibition. Reduction in mucosal hyperplasia due to U75302 administration may be secondary to the reduction in leukocytes since LTB4R1 is not expressed by mucosal epithelial or stromal cells. The results suggest that LTB4 receptor antagonists could be useful in treating OM.

Polyunsaturated fatty acids serve multiple functions in neurodevelopment and neurocognitive function. Intravenous lipid emulsions are administered to children that are dependent on parenteral nutrition to provide the essential fatty acids needed to sustain growth and development. One of these emulsions, derived from fish-oil, is particularly poor in the traditional essential fatty acids, linoleic and alpha-linolenic acids. However, it does contain adequate amounts of its main derivatives, arachidonic acid (ARA) and docosahexaenoic acid (DHA), respectively. This skewed composition has raised concern about the sole use of fish-oil based lipid emulsions in children and how its administration can be detrimental to their neurodevelopment. Using a custom-made diet that contains ARA and DHA as a sole source of polyunsaturated fatty acids, we bred and fed mice for multiple generations. Compared to adult, chow-fed mice, animals maintained on this special diet showed similar outcomes in a battery of neurocognitive tests performed under controlled conditions. Chow-fed mice did perform better in the rotarod test for ataxia and balance, although both experimental groups showed a conserved motor learning capacity. Conversely, mice fed the custom diet rich in DHA and ARA showed less neophobia than the chow-fed animals. Results from these experiments suggest that providing a diet where ARA and DHA are the sole source of polyunsaturated fatty acids is sufficient to support gross visual, cognitive, motor, and social development in mice.

Polyunsaturated fatty acids serve multiple functions in neurodevelopment and neurocognitive function. Intravenous lipid emulsions are administered to children that are dependent on parenteral nutrition to provide the essential fatty acids needed to sustain growth and development. One of these emulsions, derived from fish-oil, is particularly poor in the traditional essential fatty acids, linoleic and alpha-linolenic acids. However, it does contain adequate amounts of its main derivatives, arachidonic acid (ARA) and docosahexaenoic acid (DHA), respectively. This skewed composition has raised concern about the sole use of fish-oil based lipid emulsions in children and how its administration can be detrimental to their neurodevelopment. Using a custom-made diet that contains ARA and DHA as a sole source of polyunsaturated fatty acids, we bred and fed mice for multiple generations. Compared to adult, chow-fed mice, animals maintained on this special diet showed similar outcomes in a battery of neurocognitive tests performed under controlled conditions. Chow-fed mice did perform better in the rotarod test for ataxia and balance, although both experimental groups showed a conserved motor learning capacity. Conversely, mice fed the custom diet rich in DHA and ARA showed less neophobia than the chow-fed animals. Results from these experiments suggest that providing a diet where ARA and DHA are the sole source of polyunsaturated fatty acids is sufficient to support gross visual, cognitive, motor, and social development in mice. [ABSTRACT FROM AUTHOR]

Cell-non-autonomous signals dictate the functional state of cellular quality control systems, remodeling the ability of cells to cope with stress and maintain protein homeostasis (proteostasis). One highly regulated cell-non-autonomous switch controls proteostatic capacity in Caenorhabditis elegans adulthood. Signals from the reproductive system down-regulate cyto-protective pathways, unless countered by signals reporting on germline proliferation disruption. Here, we utilized dihomo-γ-linolenic acid (DGLA) that depletes the C. elegans germline to ask when cell-non-autonomous signals from the reproductive system determine somatic proteostasis and whether such regulation is reversible. We found that diet supplementation of DGLA resulted in the maintenance of somatic proteostasis after the onset of reproduction. DGLA-dependent proteostasis remodeling was only effective if animals were exposed to DGLA during larval development. A short exposure of 16 h during the second to fourth larval stages was sufficient and required to maintain somatic proteostasis in adulthood but not to extend lifespan. The reproductive system was required for DGLA-dependent remodeling of proteostasis in adulthood, likely via DGLA-dependent disruption of germline stem cells. However, arachidonic acid (AA), a somatic regulator of this pathway that does not require the reproductive system, presented similar regulatory timing. Finally, we showed that DGLA- and AA-supplementation led to activation of the gonadal longevity pathway but presented differential regulatory timing. Proteostasis and stress response regulators, including hsf-1 and daf-16, were only activated if exposed to DGLA and AA during development, while other gonadal longevity factors did not show this regulatory timing. We propose that C. elegans determines its proteostatic fate during development and is committed to either reproduction, and thus present restricted proteostasis, or survival, and thus present robust proteostasis. Given the critical role of proteostatic networks in the onset and progression of many aging-related diseases, such a choice could impact susceptibility to protein misfolding diseases later in life.

Caenorhabditis elegans somatic protein homeostasis (proteostasis) is actively remodeled at the onset of reproduction. This proteostatic collapse is regulated cell-nonautonomously by signals from the reproductive system that transmit the commitment to reproduction to somatic cells. Here, we asked whether the link between the reproductive system and somatic proteostasis could be uncoupled by activating downstream effectors in the gonadal longevity cascade. Specifically, we examined whether over-expression of lipl-4 (lipl-4(oe)), a target gene of the gonadal longevity pathway, or increase in arachidonic acid (AA) levels, associated with lipl-4(oe), modulated proteostasis and reproduction. We found that lipl-4(oe) rescued somatic proteostasis and postponed the onset of aggregation and toxicity in C. elegans models of polyglutamine (polyQ) diseases. However, lipl-4(oe) also disrupted fatty acid transport into developing oocytes and reduced reproductive success. In contrast, diet supplementation of AA recapitulated lipl-4(oe)-mediated proteostasis enhancement in wild type animals but did not affect the reproductive system. Thus, the gonadal longevity pathway mediates a trade-off between somatic maintenance and reproduction, in part by regulating the expression of genes, such as lipl-4, with inverse effects on somatic maintenance and reproduction. We propose that AA could uncouple such germline to soma crosstalk, with beneficial implications protein misfolding diseases.

Cell-non-autonomous signals dictate the functional state of cellular quality control systems, remodeling the ability of cells to cope with stress and maintain protein homeostasis (proteostasis). One highly regulated cell-non-autonomous switch controls proteostatic capacity in Caenorhabditis elegans adulthood. Signals from the reproductive system down-regulate cyto-protective pathways, unless countered by signals reporting on germline proliferation disruption. Here, we utilized dihomo-γ-linolenic acid (DGLA) that depletes the C. elegans germline to ask when cell-non-autonomous signals from the reproductive system determine somatic proteostasis and whether such regulation is reversible. We found that diet supplementation of DGLA resulted in the maintenance of somatic proteostasis after the onset of reproduction. DGLA-dependent proteostasis remodeling was only effective if animals were exposed to DGLA during larval development. A short exposure of 16 h during the second to fourth larval stages was sufficient and required to maintain somatic proteostasis in adulthood but not to extend lifespan. The reproductive system was required for DGLA-dependent remodeling of proteostasis in adulthood, likely via DGLA-dependent disruption of germline stem cells. However, arachidonic acid (AA), a somatic regulator of this pathway that does not require the reproductive system, presented similar regulatory timing. Finally, we showed that DGLA- and AA-supplementation led to activation of the gonadal longevity pathway but presented differential regulatory timing. Proteostasis and stress response regulators, including hsf-1 and daf-16, were only activated if exposed to DGLA and AA during development, while other gonadal longevity factors did not show this regulatory timing. We propose that C. elegans determines its proteostatic fate during development and is committed to either reproduction, and thus present restricted proteostasis, or survival, and thus present robust proteostasis. Given the critical role of proteostatic networks in the onset and progression of many aging-related diseases, such a choice could impact susceptibility to protein misfolding diseases later in life. [ABSTRACT FROM AUTHOR]

Caenorhabditis elegans somatic protein homeostasis (proteostasis) is actively remodeled at the onset of reproduction. This proteostatic collapse is regulated cell-nonautonomously by signals from the reproductive system that transmit the commitment to reproduction to somatic cells. Here, we asked whether the link between the reproductive system and somatic proteostasis could be uncoupled by activating downstream effectors in the gonadal longevity cascade. Specifically, we examined whether over-expression of lipl-4 (lipl-4(oe)), a target gene of the gonadal longevity pathway, or increase in arachidonic acid (AA) levels, associated with lipl-4(oe), modulated proteostasis and reproduction. We found that lipl-4(oe) rescued somatic proteostasis and postponed the onset of aggregation and toxicity in C. elegans models of polyglutamine (polyQ) diseases. However, lipl-4(oe) also disrupted fatty acid transport into developing oocytes and reduced reproductive success. In contrast, diet supplementation of AA recapitulated lipl-4(oe)-mediated proteostasis enhancement in wild type animals but did not affect the reproductive system. Thus, the gonadal longevity pathway mediates a trade-off between somatic maintenance and reproduction, in part by regulating the expression of genes, such as lipl-4, with inverse effects on somatic maintenance and reproduction. We propose that AA could uncouple such germline to soma crosstalk, with beneficial implications protein misfolding diseases. [ABSTRACT FROM AUTHOR]